WO1996004246A1

WO1996004246A1 - Phenylacetamides having leukotriene-antagonistic action

Info

Publication number: WO1996004246A1
Application number: PCT/EP1995/002958
Authority: WO
Inventors: David Mauleon Casellas; Germano Carganico; Maria Luisa Garcia Perez; Mª de los Desamparados FOS TORRO
Original assignee: Laboratorios Menarini S.A.
Priority date: 1994-08-01
Filing date: 1995-07-26
Publication date: 1996-02-15
Also published as: AU3221995A; ES2103180A1; ES2103180B1

Abstract

Phenylacetamides of formula (I) wherein the substituent containing a -CONR3- is bound to the 3- or 4- position of the phenol system; the substituent containing B is bound to the benzene ring at any free position; R1 is hydrogen, fluorine, chlorine or -OCH¿3; R?2 is hydrogen, fluorine, chlorine or bromine; R3 is hydrogen or methyl; B is a 5-tetrazolyl group or -COOR4, wherein R4 is hydrogen, a (C¿1?-C4)-alkyl or a phenylalkyl group of less than 10 carbon atoms; m and n are integers from 0 to 6, with the proviso that m + n is less or equal to 6; have leukotriene antagonistic action.

Description

PHKNYLACKTAMIDBS HAVING LBUKOTRIEHE-A AGONISTIC ACTION

The present invention relates to novel phenylacetamides, the solvates and pharmaceutically acceptable salts thereof, and pharmaceutical compositions containing them, having a leukotriene- antagonistic activity. The present invention also relates to a process for the preparation of the novel phenylacetamides, as well as to the therapeutical use thereof.

State of the art It is well known that most eicosanoids, prostaglandins, leukotrienes and related compounds derive from a fatty acid having 20 carbons and 4 unsaturations, called arachidonic acid (AA), which fundamentally esterifies the hydroxyl at the 2- position of the glycerol of the phospholipids contained in the cell membranes. AA is released from the phospholipid containing it by the action of a lipase, phospholipase A₂ (PLA2) ("CRC Handbook of Eicosanoids and Related Lipids", vol. II, Ed. A.L.Willis, CRS Press Inc., Florida (1989)). After being released AA is metabolized in mammals mainly by two different pathways or enzyme systems. Through cyclooxygenase it produces prostaglandins and thromboxanes, the most significant being PGE₂ and TxA₂, which are directly involved in inflammation (Higgs et al. Annals of Clinical Research, 16, 287 (1984)). Through lipoxygenase it produces leukotrienes, the most important being LTB₄, and the peptide-leukotrienes LTC₄, LTD₄ and LTE₄. All of them are also involved in inflammatory reactions, exhibiting chemotactic activities, stimulating the secretion of lysosomic enzymes and playing an important role in immediate hypersensitivity reactions (Bailey and Casey, Ann. Rep. Med. Chem., 12, 203 (1982)). Leukotriene LTB₄ is a strong chemotactic agent which promotes the infiltration of leukocytes and their subsequent degranulation. (Salmon et al., Prog. Drug Res., 21, 9 (1991)). It has been widely shown that LTC₄ and LTD₄ have strong constrictive action on human bronchi (Dahlen et al., Nature, 288, 484 (1980)), causing the obstruction of airways by inflammation and mucus production (Marom et al., Am. Rev. Resp. Dis., 126. 449 (1982)), being thus involved in the pathogenesis of bronchial asthma, chronic bronchitis, allergic rhinitis, etc. Peptide-leukotrienes also bring about a blood extravasation caused by the increase of vascular permeability (Camp et al.,Br.J. Pharmacol..80.497 (1883)) and are involved in some inflammatory diseases such as atopic eczema and psoriasis. On the other hand, several effects of peptide-leukotrienes on human cardiovascular system have been observed; they are mainly involved in the pathogenesis of the ischaemic cardiopathy. This relationship has been confirmed by the fact that coronary arteries can produce these mediators (Piomelli et al., J. Clin. Res., 33, 521A (1985)). These effects, together with the strong contractions observed in heart tissue caused by LTC₄ and LTD₄, suggest that these mediators might contribute to other cardiovascular disorders, such as coronary spasm, heart anaphylaxis, cerebral oedema and endotoxic shock.

From what said above it follows that the control of the biological activity of leukotrienes through compounds which inhibit their release or antagonize their effects, represents a new rational approach to the prevention, elimination or improvement of different allergic, anaphylactic, inflammatory and thrombotic conditions, in which such mediators are involved.

In literature some compounds have been described that can be considered as structurally related to the compounds of the present invention since they contain an amide function and a terminal carboxylic or 5-tetrazolyl group and furthermore exhibit an inhibiting action on enzyme 5-lypooxygenase. On one hand, Stevenson D. et al. (US 4,579,866) described compounds containing the amide function and a terminal carboxylic group, but differing from the compounds of the present invention in that the amide function has been formed with the amino group of the amino acids glycine or phenylalanine. On the other hand, Mohrs K. et al. (EP 344,519) disclosed compounds resulting from the formation of an amide function with the amino group of the amino acid glycine, but also differing from the compounds of the present invention in that the acetamide 2- position is substituted by a norbornyl or cycloalkyl group. More recently, Raddatz S. et al. (EP 530,639) described 5-lipooxygenase inhibitors containing an a ido function and a 5-tetrazolyl group, but differing from the compounds of the present invention in that the 5-tetrazolyl group is bound directly to the amido function without any spacer between them, and also in that they are 2- cycloalkylacetamides.

The obtaining of compounds with high leukotriene antagonistic activity is still a problem in the therapy. The present invention provides a number of novel compounds that exhibit the above mentioned antagonistic action and that are useful in therapy.

Disclosure of the invention

The present invention relates to novel phenylacetamides of formula I,

wherein: the substituent containing a -CONR³- is bound to the 3- or 4- position of the phenol system; the substituent containing B is bound to the benzene ring at any free position;

- R¹ is hydrogen, fluorine, chlorine or -OCH₃; - R² is hydrogen, fluorine, chlorine or bromine;

- R3 is hydrogen or methyl;

- B is a 5-tetrazolyl group or -COOR⁴, wherein R⁴ is hydrogen, a (C₁-C₄)-alkyl or a phenylalkyl group of less than 10 carbon atoms; and n are integers from 0 to 6, with the proviso that m + n is less or equal to 6.

The present invention also relates to a process for the preparation of the novel phenylacetamides, as well as the therapeutical use thereof. The present invention also relates to the solvates and the pharmaceutically acceptable salts of the amides of formula I and particularly the salts represented by formula Ia,

la

wherein M⁺ is an alkali metal cation (e.g. Na⁺, K⁺) or represents a half amount of an alkaline-earth metal cation (e.g. 1/2 Ca²⁺, 1/2 Mg²⁺), or a cation deriving from an amine or quaternary ammonium salt (such as triethanolammonium, tris(hydroxymethyl)methylammonium) . The compounds of formula I can have one or more asymmetric carbons in their structure. The present invention comprises all the possible stereoiso ers as well as the mixtures thereof.

Preferred compounds are those wherein R¹ is hydrogen, R² is hydrogen or chlorine and B is a 5- tetrazolyl or -COOR⁴ group, wherein R⁴ is hydrogen, methyl, ethyl or benzyl.

Particularly preferred are the compounds of formula

I wherein R³ is hydrogen, m and n being integers ranging between 0 and 3. Particularly preferred compounds of the present invention are the following ones:

4-[4-[4-(2-quinolinylmethoxy)phenylacetamido]phenyl]buta noic acid;

4-14-[3-(2-quinolinyl ethoxy)phenylacetamido]pheny1]buta noic acid;

N-[4-(lf-5-tetrazolyl)phenylmethyl]-4-(2-quinolinyl- methoxy)phenylacetamide;

N-(4-(ltf-5-tetrazolyl)methylphenyl)-4-(2-quinolinylmetho xyJphenylacetamide;

N-(2-(lff-5-tetrazolyl)methylphenyl)-4-(2-quinolinyl- methoxy)phenylacetamide;

4-[4-[4-[(7-chloro-2-quinoliny1)methoxy]pheny1- acetamido]phenyl]butanoic acid;

N-[4-[3-(1ff-5-tetrazolyl)propγl]phenyl]-4-(2-quinolinylm ethoxy)phenylacetamide; N-methyl-4-[4-[4-(2-quinolinylmethoxy)phenylacetamido]ph enyljbutanoic acid; as well as the carboxylic acid esters described in the examples.

According to the present invention, the compounds of general formula I are obtained by a process in which, starting from a compound of general formula II,

II

wherein R and R² have the above defined meanings, is reacted with a compound III,

III wherein R³, m and n have the above defined meanings and D can be equivalent to the group B in I or, when B in formula I is COOH, then D contains a suitable carboxy- protecting group, for example as the methyl, ethyl or benzyl ester. The reaction between II and III is carried out in the presence of a carboxy-activating agent such as dicyclohexylcarbodiimide or l-[3-(dimethγlamino)propyl]-3-ethylcarbodiimide and a base such as triethylamine or 4-dimethylaminopyridine, in a suitable aprotic solvent such as chloroform, methylene chloride or N,N-dimethylformamide, at a temperature ranging between 0^* and 40*C for a time between 3 and 24 hours. In this way, a compound of formula IV

IV

is obtained, which coincides with I or is converted into I by removing any COOH-protecting group present in D, then, when D is for example a methyl, ethyl or benzyl ester, it can be removed by treatment with a suitable base such as lithium or sodium hydroxide in aqueous solution, in a suitable organic solvent such as ethanol, ethanol or tetrahydrofuran, at a temperature ranging between 20^*C and the solvent reflux, for a time from 1 to 48 hours.

When a given salt of general formula Ia is desired, a compound I can be treated with a suitable base or ion- exchanger, according to the conventional chemical techniques. Thus, for example, I can be treated with sodium hydroxide or tris(hydroxymethyl)methylamine in a suitable solvent such as water-methanol or ethanol mixtures, for a time from 15 min to 2 hours, at a temperature ranging between 25^*C and the solvent reflux.

A starting product of formula II can be obtained, for example, following the synthesis sequence shown in scheme 1.

Scheme 1

VI I

I I

In this sequence, a compound VII can be obtained, for example, subjecting a compound V (commercial or easily available by means of simple chemical processes) to the action of a base such as sodium methoxide or sodium hydride and, after that, reacting it with a compound VI, wherein R² represents the groups defined above and X is a bromine or chlorine atom, in a suitable organic solvent such as benzene, N,N-dimethylformamide or tetrahydrofuran, at a temperature ranging between 0^* and 25^*C for a time from 3 to 24 hours (step (1)).

A compound II can be obtained starting from VII (step (2)) by basic hydrolysis as described for the preparation of I with B=C00H starting from IV.

A starting compound III can be prepared following the synthesis sequence shown in scheme 2.

Scheme 2

VIII (3)

IX

II Ic ( III with R³=CH₃ and D=COOR⁴ )

X

Ilia (III with R³=H and D=COOR⁴ )

- (continued) - Scheme 2 - (continued) -

(X)

QHN-(CH₂

XIII

Illb (III with R³=H and D=5-tetrazolyl)

Hid (III with R³=CH₃ and D=5 tetrazolyl)

Starting from a compound VIII, commercial or easily available following simple chemical processes, wherein m and n have the above defined meanings, R⁴ represents the groups described above except hydrogen and X is a halogen atom, a compound IX can be prepared by treatment with NaCN in a suitable solvent such as dimethylsulfoxide, water or ethanol, at a temperature ranging between 25^*C and the solvent reflux for 1-8 hours (step (3)). A compound Ilia, which is equivalent to a compound of general formula III with R³=H and D=COOR⁴, can be obtained, for example, by catalytic hydrogenation of IX, with a suitable catalyst, such as Pd-C or Pd(OH)₂-C in a suitable solvent such as ethanol or methanol in the presence of an acid such as acetic acid or hydrochloric acid, under hydrogen pressures ranging between atmosphere pressure and 2 Kg/cm², at a temperature from 25^* to 50^*C, for a time between 3 and 24 hours (step (4) ) .

Starting from a compound Ilia, a compound Illb, i.e. of general formula III with R³=H and D=5-tetrazolyl, can be obtained by a process which comprises the steps (6)-(10). First, the amino group in Ilia is protected with a benzyloxycarbonyl or t-butoxycarbonyl group, following processes widely described in literature, to yield compound X, wherein Q represents one of the amino-protecting groups mentioned above. The basic hydrolysis of X leads to the preparation of XI, starting from which a compound XII can be prepared by means, for example, of a reaction with thionyl chloride or with ethyl chloroformate in the presence of a base such as triethylamine or pyridine, in a solvent such as tetrahydrofuran or ethyl ether and subsequent treatment with gas ammonia or an ammonium hydroxide aqueous solution at a temperature between 0* and 25^*C for a time from 30 in to 3 hours. The dehydration of a compound XII, for example with phosphorous oxychloride in a solvent such as N,N-dimethylformamide at a temperature ranging between 0^* and 50^*C for 3-24 hours, leads to the preparation of a compound XIII. The treatment of a compound XIII with sodium azide in a suitable solvent such as N,N-dimethylformamide at a temperature ranging between 25*C and the solvent's reflux and the subsequent elimination of the protective group present on the amino group, according conventional techniques, yields a compound Illb. Alternatively, when a compound XIV is commercial or easily available by simple synthetic methods, a compound Illb can be obtained starting from XIV by reaction with sodium azide (step (12)) and subsequent reduction of the azide (step (13)), by catalytic hydrogenation with a catalyst such as Pd-C or in a solvent such as ethanol, methanol or ethyl acetate, under hydrogen pressures ranging between atmosphere pressure and 2 Kg/cm², at a temperature between 0* and 50^*C, for a time from 6 to 24 hours. Starting from a compound of formula Ilia or of formula Illb, a compound IIIc or Hid can be obtained respectively by ethylation of the a ine following, for example, a process comprising first the formylation of the amino group, with acetic anhydride and formaldehyde mixtures in a suitable solvent, such as tetrahydrofuran or ethyl ether, at a temperature between 0' and 25*C for 3-24 h, followed by reduction of the formyl group with the BH3~tetrahydrofuran complex in a solvent such as tetrahydrofuran or ethyl ether at a temperature ranging between -78^* and 0^*C, for 6-24 hours.

A compound Hie (III with m=0) can be prepared following the process shown in scheme 3.

Scheme 3

XVI⁾ (X_VII)

(XVIII) _(XIX)

Starting from a compound XVI, commercial or easily available following similar chemical processes, a compound XIX can be prepared (steps (14)-(16)), according to a process similar to the one shown in scheme 2 for the preparation of Illb. Finally, the reduction of XIX, for example by catalytic hydrogenation with a catalyst such as Pd-C in a suitable solvent, such as ethanol or methanol, in the presence of an acid such as hydrochloric acid, under hydrogen pressures ranging from atmosphere pressure to 2 Kg/cm², at a temperature between 25* and 50^*C, for a time from 3 to 24 hours (step (17) ), leads to the desired compound Hie.

The compounds of the present invention show a marked antagonistic activity of leukotrienes effects and they have therefore anti-inflammatory and anti-allergic properties which make them useful in the treatment of diseases wherein those mediators are involved.

Said compounds can be therefore used in human therapy, for the prevention and treatment of allergic rhinitis, bronchial asthma, hypersensitivity reactions such as allergic conjunctivitis, various inflammatory conditions such as rheumatoid arthritis, osteoarthritis, tendinitis, bursitis, psoriasis and related inflammations.

The compound of the present invention may also be used in the treatment of diseases of the cardiovascular system, such as cardiac ischemia, yocardic infarct, coronary spasm, cardiac anaphylaxis, cerebral oedema and endotoxic schock.

For the intended therapeutic uses, the compounds of the invention are formulated in suitable pharmaceutical compositions, using conventional techniques and methods, as disclosed in Remington's Pharmaceutical Science Handbook, Mack Pub. Co., N.Y. U.S.A. Examples of said formulations include capsules, tablets, syrups and the like, containing from 1 to 1000 mg of active principle per unit dose. EXAMPLES The following examples illustrate the preparation and the pharmacological activity of the compounds of the present invention.

Example 1: Methvl 4-T4-F4-(2-σuinolinvlmethoxv)- phenvlacetamidolphenvllbutanoate

IA Methyl 4-(2-σuinolinvlmethoxv)phenvlacetate Sodium methoxide (0.58 ml, 3.01 mmol) was added to a solution of methyl 4-hydroxyphenylacetate (0.500 g, 3.01 mmol) in DMF (10 ml) and stirred at room temperature for 5 in. After that to the reaction mixture was added 2-chloromethylquinoline (0.550 g, 3.01 mmol), stirred at room temperature for 18 h, then evaporated to dryness, the residue was dissolved in ethyl acetate (25 ml), washed with 5% NaHC03 (3x5 ml), dried and the solvent was evaporated off, to obtain a crude which was purified by crystallization in methanol, thereby obtaining 0.700 g of the title compound (76% yield. ) . *H N.M.R. (300 MHz, CDCL3) 6 ppm: 3.56 (s, 2H) , 3.67 (s, 3H); 5.37 (s, 2H); 6.98 (d, 2H); 7.19 (d, 2H); 7.54 (t, 1H); 7.66 (d, 1H); 7.73 (t, 1H); 7.82 (d, 1H); 8.08 (d, 1H); 8.18 (d, 1H).

IB 4-(2-Ouinolinylmethoxy)phenvlacetic acid 1M lithium hydroxide (7.8 ml) was added to a solution of methyl 4-(2-quinolinylmethoxy)phenylacetate (0.476 g, 1.55 mmol) in THF (8 ml) and stirred at room temperature for 3 h. After that THF was evaporated off, pH was adjusted to 4-5 with 1M HC1 and the mixture was extracted with ethyl acetate, to obtain 0.461 g of the title compound as a white solid of melting point 156- 158*C (90% yield. ).

!H N.M.R. (300 MHz, CD30D) 6 ppm: 3.53 (s, 2H); 5.33 (s, 2H); 7.00 (d, 2H); 7.21 (d, 2H); 7.60 (t, 1H); 7.70 (d, 1H); 7.78 (t, 1H); 7.93 (d, 1H); 8.04 (d, 1H); 8.35 (d, 1H). 1C Methvl 4-(4-aminophenvl)bu anoate 8.4 ml of concentrated H₂S0₄ were added to a solution of 4-(4-aminophenyl)butanoic acid (2.0 g, 11.6 mmol) in methanol (84 ml) and refluxed for 2 h. After that the reaction mixture was cooled at room temperature, Na₂C0₃ to basic pH and extracted with ethyl acetate. The organic phase was dried and the solvent was evaporated off, to obtain 1.7 g of the title compound (82% yield. ). *H N.M.R. (300 MHz, CD30D) δ ppm: 1.83 (q, 2H); 2.28 (t, 2H); 2.49 (t, 2H) ; 3.62 (s, 3H); 6.66 (d, 2H); 6.92 (d, 2H) .

ID Methvl 4-r4-T4-(2-σuinolinvlmethoχy)phenyl- acetamidolphenvllbutanoate Methyl 4-(4-aminophenyl)butanoate (0.270 g, 1.40 mmol), N,N-dimethylaminopyridine (0.171 g, 1.40 mmol) and 1-[3(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.268 g, 1.40 mmol) were added to a solution of 4-(2-quinolinylmethoxy)phenylacetic acid (0.392 g, 1.33 mmol) in dry methylene chloride (10 ml). The reaction mixture was stirred at room temperature for 24 h, then poured onto water (30 ml), pH was adjusted to 5 with 1M HC1, the phases were separated and the organic one was extracted with ethyl acetate (4x50 ml). The combined organic extracts were dried and the solvent was removed, to obtain a crude which was purified by crystallization in methanol, thereby obtaining 0.427 g of the title compound (69% yield.).

^XH N.M.R. (300 MHz, CDC13) δ ppm: 1.90 ( , 2H) 2.29 (t, 2H); 2.58 (t, 2H); 3.65 (s, 5H); 5.39 (s, 1H) 7.04 (d, 2H); 7.07 (d, 2H); 7.24 (d, 2H); 7.32 (d, 2H) 7.56 (t, IH); 7.68 (d, IH); 7.75 (t, IH); 7.84 (d, IH); 8.09 (d, IH); 8.20 (d, IH).

Example 2: 4-T4-r4-(2-αuinolinylmethoχy)phenyl- acetamidolphenyllbutanoic acid Following the process described in example 1 (point B), starting from methyl 4-[4-[4-(2- quinolinylmethoxy)phenylacetamido]phenyl]butanoate, the title compound was prepared (99% yield.). !H N.M.R. (300 MHz, DMSO) δ ppm: 1.75 ( , 2H); 2.18 (t, 2H); 2.51 (t, 2H); 3.54 (s, 2H); 5.35 (s, 2H); 7.02 (d, 2H); 7.09 (d, 2H); 7.25 (d, 2H); 7.49 (d, 2H); 7.61 (t, IH); 7.66 (d, IH); 7.78 (t, IH); 8.01 (t, 2H); 8.40 (d, IH).

Example 3_j methvl 4-r4-r3-(2-σuinolinvlmethoxv - phenylacetamidolphenyllbutanoate

3A Methyl 3-(2-quinolinylmethoxy)phenylacetate Following the process described in example 1 (point A), starting from methyl 3-hydroxyphenylacetate, the title compound was prepared as a white solid with melting point 186.1-188.3^*C (87% yield.).

^XH N.M.R. (300 MHz CDC13) 6 ppm: 3.50 (s, 2H); 3.56 (s, 3H); 5.29 (s, 2H); 6.82 (m, 2H); 6.90 (s, IH); 7.14 (t, IH); 7.45 (t, IH); 7.58 (d, IH); 7.64 (t, IH); 7.73 (d, IH); 8.01 (d, IH); 8.09 (d, IH). 3B 3-(2-Quinolinylmethoxy)phenylacetic acid

Following the process described in example 1 (point B), starting from methyl 3-(2- quinolinylmethoxy)phenylacetate, the title compound was prepared (95% yield.). !H N.M.R. (300 MHz, DMSO) δ ppm: 3.56 (s, 2H); 5.36 (s, 2H); 6.87 (d, IH); 6.95 (d, IH); 7.02 (s, IH); 7.24 (t, IH); 7.62 (t, IH); 7.68 (d, IH); 7.79 (t, IH); 8.00 (d,

IH); 8.04 (d, IH); 8.42 (d, IH) .

3C Methyl 4-r4-r3-(2-quinolinylmethoχy)phenyl- acetamidol heny11butanoate Following the process described in example 1 (point

D), starting from 3-(2-quinolinylmethoxy)phenylacetic acid, the title compound was prepared (75% yield. ).

*H N.M.R. (300 MHz, CDC13) δ ppm: 1.89 (m, 2H) ; 2.28 (t,

2H); 2.57 (t, 2H) ; 3.64 (ε, 5H); 5.36 (s, 2H) ; 6.94 (t, 2H); 7.01 (s, IH); 7.04 (d, 2H) ; 7.26-7.31 ( , 3H) ; 7.54

(t, IH); 7.65 (d, IH); 7.72 (t, IH); 7.81 (d, IH); 8.07

(d, IH); 8.17 (d, IH).

Example 4j 4-T4-T3-( 2-αuinolinvlmethoχy)phenyl- acetamidolphenvllbutanoic acid Following the process described in example 1 (point

B), starting from methyl 4-[4-[3-(2- quinolinylmethoxy)phenylacetamido]phenyl]butanoate, the title compound was prepared as a white solid with melting point 140.5-141.6'C (86% yield. ). ¹H N.M.R. (300 MHz, DMSO) δ ppm: 1.76 ( , 2H); 2.19 (t,

2H); 2.51 (t, 2H) 3.59 (s, 2H); 5.36 (s, 2H); 6.95 (m, 2H); 7.08 (m, 3H) 7.25 (t, IH); 7.48 (d, 2H); 7.62 (t, IH); 7.67 (d, IH) 7.78 (t, IH); 8.01 (t, 2H); 8.40 (d,

IH). Example 5: N-r4-(lH-5-tetrazolyl)phenylmethyll-4-

(2-αuinolinylmethoxy)phenylacetamide

5A 4-(lH-5-Tetrazolyl )azidomethylbenzene

Sodium azide (15 g, 230 mmol) and ammonium chloride

(12.3 g, 230 mmol) were added to a solution of 4-bromomethylbenzonitrile (5 g, 25.5 mmol) in DMF (75 ml). The reaction mixture was stirred at 110^*C for 16 h, then poured onto 200 ml of IM HCl and extracted with ethyl acetate (4x75 ml). The organic phase was dried and volatiles were removed, to obtain a oil which was diluted with ethyl ether and petroleum ether, to give a precipitate which was filtered and washed with petroleum ether, thereby obtaining 5 g of the title compound (97% yield. ) .

^XH N.M.R. (300 MHz, CD30D) 6 ppm: 4.52 (s, 2H); 7.59 (d, 2H); 8.07 (d, 2H). 5B 4-(lH-5-Tetrazolvl)benzvlamine hvdrochloride

1.4 g of 10% palladium on charcoal was added to a solution of 4-(lH-5-tetrazolyl)-azidomethylbenzene (4.3 g, 21.5 mmol) in methanol (400 ml) and concentrated HCl (14 ml) and stirred at room temperature for 4 days, under hydrogen atmosphere. After that the mixture was filtered and the filtrate was evaporated to dryness to obtain a crude which was redissolved in hot methanol, thereby crystallizing 3.7 g of the title compound as a yellowish solid with melting point >360'C (80% yield). *H N.M.R. (300 MHz, DMSO) δ ppm: 4.16 (d, 2H); 7.75 (d, 2H); 8.18 (d, 2H); 8.56 (s, 3H).

5C N-r4-(lH-5-Tetrazolyl)phenylmethvn-4-(2- uino- linylmethoxi)phenylacetamide

Following the process described in example 1 (point D), starting from 3-(2-quinolinyl-methoxy)phenylacetic acid and 4-(lH-5tetrazolyl)benzylamine hydrochloride, the title compound was prepared as a white solid with melting point 217.2-217.5'C (80% yield.). !H N.M.R. IH (300 MHz, DMSO) δ ppm: 3.42 (s, 2H); 4.34 (d, 2H); 5.35 (s, 2H); 7.00 (d, 2H); 7.21 (d, 2H); 7.43 (d, 2H); 7.61 (dt, IH); 7.67 (d, IH); 7.78 (dt, IH); 8.00 (m, 4H); 8.42 (d, IH); 8.59 (t, IH).

Example 6_; N-(2-(lH-5-tetrazolylImethyl- phenyl)-4-(2-quinolinylmethoχy)phenylacetamide 6A 5-(2-Nitrophenvlmethvl)-lH-tetrazol Following the process described in example 5 (point A), starting from 2-nitrophenylacetonitrile, the title compound was prepared (76% yield.). l-H N.M.R. (300 MHz, DMSO) δ ppm: 4.67 (s, 2H) ; 7.64 (m, 2H); 7.76 ( , 2H) ; 8.16 (dd, IH). 6B 5-(2-Aminophenvlmethvl)-lH-tetrazol

Following the process described in example 5 (point B), starting from 5-(2-nitrophenyl-methyl)-lH-tetrazol, the title compound was prepared as a white solid with melting point 161.5-163.7^*C (95% yield). ^XH N.M.R. (300 MHz, DMSO) δ ppm: 4.54 (s, 2H) ; 7.15 (d, IH); 7.38 (m, 2H); 7.53 (d, IH).

6C N-(2-(IH-5-Tetrazolyl )methyl-phenyl)-4-(2-σui- nolinyl ethoxyIphenylacetamide

Following the process described in example 1 (point D), starting from 4-(2-quinolinyl-methoxy)phenylacetic acid and 5-(2-aminophenyl-methyl)-lH-tetrazol, the title compound was prepared as a white solid with melting point 140^*C (76% yield.). ill N.M.R. (300 MHz, DMSO) δ ppm: 3.72 (s, IH) ; 4.00 (s, IH); 5.39 (s, IH); 7.09 (m, 3H) ; 7.16 (dt, IH) ; 7.26 (d, IH); 7.40 (d, 2H); 7.68 ( , 2H) ; 7.82 (dt, IH) ; 8.05 (m, 2H); 8.44 (d, IH); 11.49 (s, IH) .

Example 7 N-(4-(lH-5-tetrazolyl)methyl- phenyl)-4- (2-αuinolinvlmethoxv)phenvlacetamide Following the process described in example 5 (point A), starting from (2-quinolinylmethoxy)-phenylacetic acid and 5-(4-aminophenyl-methyl)-lH-tetrazol, the title compound was prepared as a white solid with melting point 220.4-221.0^*C (80% yield.).

^XH N.M.R. (300 MHz, DMSO) δ ppm: 3.57 (s, 2H); 4.24 (s, 2H); 5.38 (s, 2H); 7.09 (d, 2H); 7.21 (d, 2H); 7.28 (d, 2H); 7.60 (m, 4H); 7.82 (dt, IH); 8.09 (t, 2H); 8.44 (d, IH); 10.15 (s, IH).

Example § methvl 4-r4-r4-r(7-chloro-

2-σuinolinvl)methoxv1phenvlacetamido1phenvl1butanoate 8A 2-Bromomethvl-7-chloroquinoline

N-bromosuccinimide (3.3 g, 18.5 mmol) and some crystals of 2,2'-azobis(2-methylpropionitrile) (AIBN) were added to a solution of 7-chloro-2-methylquinoline (3 g, 16.9 mmol) in dry carbon tetrachloride (100 ml). The reaction mixture was refluxed for 4 h, then cooled at room temperature, the precipitate was filtered off, the filtrate was washed with a NaCl saturated solution (3x20 ml) and dried, the solvent was evaporated off to obtain a crude which was purified by flash chromatography through a silica gel column. Eluting with petroleum ether:chloroform, 3:2, 2.3 g of the title compound was prepared as a white solid with melting point 110-111'C (52% yield.). ^XH N.M.R. (300 MHz, CDC13) δ ppm: 4.65 (s, 2H); 7.47 (dd, IH); 7.53 (d, IH); 7.71 (d, IH); 8.03 (d, IH); 8.11 (d, IH).

8B Methyl 4-r(7-chloro-2-σuinolinvl)-methoxv1- phenylacetate

Following the process described in example 1 (point A), starting from methyl 4-hydroxyphenylacetate and 2-bromomethyl-7-chloroquinoline, the title compound was prepared (88% yield). ill N.M.R. (300 MHz, CDC13) 6 ppm: 3.51 (s, 2H); 3.63 (s, 3H); 5.30 (s, 2H); 6.92 (d, 2H); 7.15 (d, 2H); 7.40 (dd, IH); 7.62 (d, IH); 7.72 (d, IH); 8.03 (s, IH); 8.11 (d, IH).

8C 4-r(7-Chloro-2-quinolinvl)methoxv1phenylacetic

___l

Following the process described in example 1 (point

3), starting from methyl 4-[(7-chloro-2- quinolinyl)methoxy]phenylacetate, the title compound was prepared as a white solid with melting point 265^*C (92% yield) .

^XH N.M.R. (300 MHz, CD30D) 6 ppm: 3.41 (s, 2H); 5.32 (s, 2H); 6.94 (d, 2H); 7.22 (d, 2H); 7.57 (dd, IH); 7.71 (d, IH); 7.93 (d, IH); 8;03 (d, IH); 8.35 (d, IH).

£E &Xh∑l 4-r4-r4-π7-chloro-2-αuinolinyl.- methoxvlphenvlacetamidolphenvllbutanoate

Following the process described in example 1 (point

D), starting from 4-[(7-chloro-2-quinolinyl)- methoxy]phenylacetic acid and methyl 4-(4- aminophenyl)butanoate, the title compound was prepared

(76% yield. ).

*H N.M.R. (300 MHz, CDC13) δ ppm: 1.91 ( , 2H); 2.28 (t, 2H); 2.58 (t, 2H); 3.66 (s, 3H); 5.38 (s, 2H); 7.02-7.10 (m, 5H); 7.24-7.34 (m, 3H); 7.52 (dd, IH); 7.68 (d, IH); 7.78 (d, IH); 8.09 (s, IH); 8.19 (d, IH) .

Example 9: 4-T4-T4-r(7-chloro-2-αuinolinvl)- methoxyIphenylacetamidolphenyllbutanoic acid

Following the process described in example 1 (point B), starting from methyl 4-[4-[4-[(7- chloro-2-quinoliny1)methoxy] henylacetamido]pheny1]butan oate, the title compound was prepared as a white solid with melting point 247-250'C (69% yield.). ^XH N.M.R. (300 MHz, DMSO) δ ppm: 1.89 (m, 2H); 2.28 (t, 2H); 2.62 (t, 2H); 3.60 (s, 2H); 5.36 (s, 2H); 7.01 (d, 2H); 7.12 (d, 2H); 7.29 (d, 2H); 7.44 (d, 2H); 7.58 (dd, IH); 7.74 (d, IH); 7.92 (d, IH); 8.05 (d, IH); 8.36 (d, IH).

Example 10 N-r4-r3-(lH-5-tetrazolyl)propyl1- phenvl1-4-(2-quinolinvlmethoχy)phenylacetamide 10A 4-(4-Nitrophenyl)butanamide

Thionyl chloride (6.9 ml) was added drop by drop to a solution of 4-(4-nitrophenyl)butanoic acid (3.00 g, 14.34 mmol) in carbon tetrachloride (7 ml). The reaction mixture was stirred at 80*C for 1.5 h, then evaporated to dryness to obtain a colourless oil which was added to a 30% NH₄0H solution (6.3 ml), stirred at room temperature for 15 min, then evaporated to dryness to obtain a residue which was redissolved in water (20 ml), extracted with ethyl acetate (4x25 ml) and dried; the solvent was evaporated off to obtain the title compound (58% yield. ).

¹H N.M.R. (300 MHz, CDC13/CD30D) 6 ppm: 2.02 (m, 2H); 2.29 (t, 2H); 2.79 (t, 2H); 7.40 (d, 2H); 8.15 (d, 2H) . 10B 4-(3-Cvanopropvl)nitrobenzene A solution of 4-(4-nitrophenyl)butanamide (2.69 g, 14.16 mmol) in 10 ml of DMF was added to a solution of phosphorous oxychloride (6.9 ml, 14.70 mmol) in anhydrous DMF (78 ml), kept at -10"C under inert atmosphere for 30 min. The reaction mixture was stirred at room temperature for 24 h, then poured onto water (15 ml), extracted with ethyl acetate (4x30 ml), dried and the solvent was evaporated off, to obtain 2.36 g of the title compound (88% yield.). l-H N.M.R. (300 MHz, CDC13) 6 ppm: 2.04 (m, 2H) ; 2.41 (t,

2H); 2.92 (t, 2H); 7.40 (d, 2H); 8.18 (d, 2H) . 10C 4-(3-(lH-5-Tetrazolvl)propvlnitrobenzene

Following the process described in example 5 (point

A), starting from 4-(3-cyanopropyl)nitrobenzene, the title compound was prepared as a white solid with melting point 150-151'C (76% yield) *H N.M.R. (300 MHz, CD₃0D/CDC1₃) δ ppm: 2.19 (m, 2H);

2.85 (t, 2H); 3.01 (t, 2H); 7.41 (d, 2H); 8.16 (d, 2H) . 10P 4-(3-(lH-5-Tetra^PlYl)propyl)ani r,e Following the process described in example 5 (point

B), starting from 4-(3-(lH-5- tetrazolyl)propylJnitrobenzene, the title compound was prepared as a white solid with melting point

195.0-196.5'C (83% yield) H N.M.R. (300 MHz, CD30D) δ ppm: 2.13 (m, 2H); 2.76 (t,

2H); 2.98 (t, 2H); 7.36 (d, 2H); 7.40 (d, 2H). 1Q_ N-r4-r3-(lH-5-Tetrazolyl)propγl1- phenyl1-4-(2-quinolinvlmethoxv)phenvlacetamide

Following the process described in example 1 (point

D), starting from 4-(2-quinolinyl-methoxyJphenylacetic acid and 4-(3-(lH-5-tetrazolyl)propyl)aniline, the title compound was prepared as a white solid with melting point 189.0-189.8'C (67% yield.).

^XH N.M.R. (300 MHz, CD30D/CDC13) δ ppm: 2.07 (m, 2H)

2.63 (t, 2H); 2.89 (t, 2H); 3.61 (s, 2H); 5.34 (s, 2H)

7.00 (d, 2H); 7.08 (d, 2H); 7.28 (d, 2H); 7.43 (d, 2H) 7.58 (t, IH); 7.69 (d, IH); 7.76 (t, IH); 7.87 (d, IH)

8.06 (d, IH); 8.26 (d, IH). Exa ple U- N-r4-r3-(lH-5-tetrazolvD- propvnphenyl1-4-(2-quinolinvlmethoχy)phenvlacetamide (sodium salt).

IM sodium hydroxide (0.104 ml) was added to a solution of N-[4-[3-(lH-5-tetrazolyl)- propy1]pheny1]-4-(2-quinolinylmethoxy)phenylacetamide (0.050 g, 0.104 mmol) in methanol (1 ml) and stirred at room temperature for 30 min. After that the mixture was evaporated to dryness and the residue was recrystallized from ethanol-ethyl ether, to obtain 0.040 g of the title compound as a white solid with melting point 235.7-236.9"C (88% yield.).

¹H N.M.R. (300 MHz, CD₃OD) 6 ppm: 1.83 (m, 2H); 2.56 ( , 4H); 3.53 (s, 2H); 5.34 (s, 2H); 7.01 (d, 2H); 7.10 (d, 2H); 7.25 (d, 2H); 7.47 (d, 2H); 7.61 (t, IH); 7.66 (d, IH); 7.78 (t, IH); 8.00 (t, 2H); 8.40 (d, IH) .

Example _2 methy N-methvl-4-r4-r4-(2-σuino- linvlmethoxvlphenvlacetamidolphenvllbutanoate

12A Methvl 4-T4-(formvlamino)phenvl1butanoate Acetic formic anhydride (0.60 g, 6.88 mmol) was added drop by drop, under inert atmosphere to a solution of methyl 4-(4-aminophenyl)butanoate (0.56 g, 2.55 mmol) in anhydrous THF (15 ml). The reaction mixture was stirred at room temperature for 24 h, then added a 50% NaHC0₃ solution (5 ml). The two phases were separated and the aqueous one was extracted with ethyl acetate (3x10 ml). The combined organic extracts were dried and the solvent was evaporated off, to obtain 0.50 g of the title compound as a white solid with melting point 92.7-94.2'C (93% yield.).

^XH N.M.R. (300 MHz, CDC13) δ ppm: 1.92 (q, 2H); 2.31 (s, 3H); 2.66 (t, 2H); 7.10-7.56 (m, 4H); 8.26 (s, IH) . 12B Methvl 4-r4-(methylamino,phenyl1butanoate The complex IM BH₃.THF (1.96 ml) was added drop by drop to a solution of methyl 4-[4-(formylamino)- phenyl]butanoate (0.217 g, 0.98 mmol) in anhydrous THF (10 ml), cooled at -20^*C and under inert atmosphere. The reaction mixture was stirred at room temperature for 18h, then evaporated to dryness, to obtain a crude which was purified by flash chromatography through a silica gel column. Eluting with petroleum ether:ethyl ether, 2:1, 0.157 g of the title compound was prepared as a white solid with melting point 158-160'C. (77% yield.). ^•T-H N.M.R. (300 MHz, CDC13) δ ppm: 2.98 (q, 2H); 2.41 (t, 2H); 2.62 (t, 2H); 2.89 (s, 3H); 3.74 (s, 3H); 6.61 (d, 2H); 7.09 (d, 2H) .

12C Methyl N-methyl-4-r4-r4-(2-αuinolinyl- methoxy)phenylacetamidol heny11butanoate

Following the process described in example 1 (point D), starting from 4-(2-quinolinyl-methoxy)phenylacetic acid and methyl 4-[4(methylamino)phenyl]butanoate, the title compound was prepared (62% yield.). !H N.M.R. (300 MHz, CDC13) δ ppm: 2.15 (m, 2H); 2.54 (t, 2H); 2.85 (t, 2H); 3.42 (s, 3H); 3.57 (d, 2H); 3.87 (s, 3H); 5.54 (d, 2H); 7.02-7.21 ( , 6H) ; 7.36 (d, 2H); 7.73 (t, IH); 7.84 (d, IH); 7.92 (d , IH); 8.01 (d, IH); 8.27 (d, IH); 8.36 (d, IH) .

Example 13 N-methyl-4-r4-r4-(2-quinolinyl- methoxy) henylace amidolpheny11butanoic acid

Following the process described in example 1 (point B), starting from methyl N-methyl-4-[4-

[4-(2-quinolinylmethoxy)phenylacetamido]pheny1]butanoate , the title compound was prepared (69% yield.). !H N.M.R. (300 MHz, DMSO) δ ppm: 2.08 (m, 2H); 2.42 (t, 2H); 2.72 (t, 2H); 3.27 (s, 3H); 3.43 (s, 2H); 5.40 (s, 2H); 6.89-6.97 (m, 4H); 7.02 (d, 2H); 7.19 (d, 2H); 7.59 (t, IH); 7.71 (d, IH); 7.77 (dt, IH); 7.86 (d, IH); 8.17 (d, IH); 8.23 (d, IH).

αuinea-piσ lung membranes

The antagonistic activity on LTD₄ of the compounds of the present invention is determined by means of an inhibition test of the [³H]-LTD₄ receptor binding in guinea-pig lung membranes, and a test of inhibition of LTD₄-induced contractions in the mienteric plexus of guinea-pig isolated ileum. Guinea pig lung membranes, containing the LTD₄ receptors, are purified following the method described by Mong et. al. (Mong et al., Prostaglandins, 2_ , 805 (1984)). These purified membranes (150 μg/ml) are added to an incubation mixture containing 10 mM of PIPES buffer (piperazin-N,N'-bis(2-ethanesulfonic acid) (pH 7.4), 10 mM of CaCl₂, 10 mM of 5 MgCl₂, 2 rnM of cysteine, 2 mM of glycine, 0.5 nM of [³H]-LTD₄ (4700-6400 GBq/mmol) and different concentrations of the product under test in a final volume of 310 μl. The reaction mixture is incubated for 30 minutes at 25^*C.

The radioligand bound to the membranes is separated from the free one by dilution with 4 ml washing buffer (10 mM Tris-HCl (pH 7.4) and 100 mM NaCl) at 0^*C and filtration with Whatman GF/B filters, by means of a Brandel Cell Harvester. The filters are washed 4 times with a total volume of 16 ml of washing buffer at 0^*C. The radioactivity present in the filters is determined by liquid scintillation.

The specific binding is defined as the difference between the total binding of [³H]-LTD₄ and the non- specific binding determined in the presence of 1 μM LTD₄. The data obtained in the competition tests are analyzed by a computational program, which determines the inhibition constant of each compound (K_j) by means of the Cheng-Prusoff equation (Cheng et al., Biochem. Pharmacol., __ , 3094 (1973)). ^κi = ^IC50 / ^{(1 + [L]} ! ^κd> wherein IC₅₀ is the concentration of compound which desplaces a 50% of the bound radioligand, [L] is the concentration of [³H]LTD₄ free in the test and K_d is the dissociation constant of the LTD₄ obtained in an independent way by means of Scatchard analysis.

Table 1 shows some of the activity values found for the compounds of the present invention.

Table 1

Compound Inhibition of the [³H]-LTD₄ Example N' receptor binding K^ (nM)

2 7.3±3.6

4 40±4

5 250±90

6 609±194

7 108±43

9 4.84±0.01

10 88±7

11 104125

13 297179

Claims

1. A compound of formula I,

wherein: the substituent containing a -CONR³- is bound to the 3- or 4- position of the phenol system; the substituent containing B is bound to the benzene ring at any free position; - R¹ is hydrogen, fluorine, chlorine or -OCH ;

- R² is hydrogen, fluorine, chlorine or bromine;

- R³ is hydrogen or methyl;

- B is a 5-tetrazolyl group or -C00R⁴, wherein R⁴ is hydrogen, a (C₁~C₄)-alkyl or a phenylalkyl group of less than 10 carbon atoms; and n are integers from 0 to 6, with the proviso that m + n is less or equal to 6; and the solvates and the pharmaceutically acceptable salts.

2. A compound according to claim 1, wherein R¹ is hydrogen, R² is hydrogen or chlorine, R³ is a 5- tetrazolyl or -COOR⁴ group and R⁴ is hydrogen, methyl, ethyl or benzyl.

3. A compound according to claim 2, wherein R³ is hydrogen.

4. A compound according to claim 3, wherein m and n are integers ranging between 0 and 3.

5. A compound according to claim 1 selected from the following ones:

4-[4-14-(2-quinolinyl ethoxy)phenylace amido]pheny1]buta noic acid;

4-[4-[3-(2-quinolinylmethoxy)phenylacetamido]pheny1]buta noic acid;

N-[4-(lH-5-tetrazolyl)phenylmethyl]-4-(2-quinolinyl- methoxy)phenylacetamide; N-(4-(lH-5-tetrazolyl)methylphenyl)-4-(2-quinolinylmetho xy)phenylacetamide;

N-(2-(lH-5-tetrazolyl)methylphenyl)-4-(2-quinolinylmetho xy)phenylacetamide;

4-[4-[4-[ (7-chloro-2-quinolinyl)methoxy]phenylaceta- mido]phenyl]butanoic acid;

N-[4-[3-(lH-5-tetrazolyl)propyl]-phenyl]-4-(2-quinoli- nyl-methoxy)phenylacetamide;

N-methy1-4-[4-[4-(2-quinolinylmethoxy)phenylacetamido]ph enyl]butanoic acid.

6. A process for the preparation of the compounds of general formula I of claim 1, and the pharmaceutically acceptable salts thereof, in which process: a) a compound of general formula II,

II

wherein R¹ and R² are the groups defined above, is reacted with a compound HI, HN r-—(CH₂) -Q. (CH₂)_n-D ,3

III

wherein R³, m and n have the above defined meanings and D can be equivalent to group B in I or, when B in formula I is COOH, then D contains a suitable carboxy- protecting group; in the presence of a carboxy-activating agent and a base, to obtain a compound of formula IV,

which coincides with I, or is converted into I by removing the COOH-protectmg group; b) if necessary, the compound of general formula I is salified by treatment with a suitable base or ion- exchanger, according to conventional techniques.

7. The use of a compound of any one of claims 1 to 5 for the preparation of a medicament for the therapeutical treatment of leukotriene-mediated diseases.

8. The use according to claim 7, wherein the leukotriene-mediated diseases are inflammatory, allergic or cardiovascular diseases.