WO1997024331A1 - Naphthalene quinolines having leukotriene-antagonistic action - Google Patents

Abstract

The present invention relates to novel naphthalene quinolines of formula (I), wherein the substituent containing A is bound to the 6- or 7-position of the 2-naphthol system; -R?1, R2, R6¿ are independently hydrogen, fluorine, chlorine, bromine, -OCH¿3? or (C1-C4)-alkyl; R?3¿ is hydrogen or methyl; R4, R5 are independently hydrogen, -OH, -NH¿2?, (C1-C4)-alkyl, (C1-C4)-alkoxy, (C1-C4)-alkylamino, (C1-C4)-alkoxycarbonyl, (C1-C4)-alkylcarbonylamino, (C1-C4)-alkoxycarbonylalkyl, carbamoyl, carbamoylalkyl, N,N-dialkylcarbamoylalkyl; -A- is a diradical -O-, -S-, -SO2-, -SO-, -SO2NR?7¿- or -NR7SO2- wherein R7 is hydrogen or (C¿1?-C4)-alkyl; B is a sulfur or oxygen atom or a -SO2- or -SO- group or a single bond; D is a 5-tetrazolyl or -COOR?8¿ group, wherein R8 is hydrogen, a (C¿1?-C4)-alkyl; or a phenylalkyl group of less than 10 carbon atoms; m is an integer from 0 to 4; n and p are integers from 0 to 6, with the proviso that n + p is less or equal to 6. Said compounds show a leukotriene-antagonistic activity, and they are valuable as anti-inflammatory and antiallergic medicaments or in the treatment of cardiovascular diseases.

Description

NAPHTHALENE QUINOLINES HAVING LKTIKOTRIENE-ANTAGONISTIC SUΩH

The present invention relates to novel naphthalene quinolines, the pharmaceutically acceptable salts and solvates 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 naphthalene quinolines, as well as to the therapeutic use thereof. TECHNOLOGICAL BACKGROUND

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., ~2. , 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., 8J2, 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, having an inhibitory action on enzyme 5-lipoxygenase, and a leukotriene antagonistic activity. Mauleόn D. et al. (Spanish Patent Application ES 9401696/8) disclosed a series of naphthalene amides as leukotriene antagonists. All of the compounds disclosed in the cited patent application have an amide group as the most characteristic functional group in their structure, the compounds disclosed in the present invention being not included within their general formula.

On the other hand, Huang F. C. et al. (US 4920131, EP 315399, US 4920131, and EP 348155) disclosed quinoline ethers, thioethers, sulfoxides, solfones, amides, ketones and amines with an inhibitory action on 5-lipoxygenase and a leukotriene antagonistic activity. Said compounds generally have in their general formulae only phenyl quinolines, the naphthalene quinolines of the present invention being therefore definitely excluded.

The obtention of compounds with high leukotriene antagonistic activity and good oral bioavailability 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 provides novel naphthalene quinolines of general formula I,

wherein: the substituent containing A is bound to the 6- or 7- position of the 2-naphthol system; -R¹, R², R⁶ are independently hydrogen, fluorine, chlorine, bromine, -OCH₃ or (C₁-C₄)-alkyl;

-R³ is hydrogen or methyl;

-R⁴, R⁵ are independently hydrogen, -OH, -NH₂, (C₁-C₄)- alkyl, (C₁-C₄)-alkoxy, (C₁-C₄)-alkylamino, (C₁-C₄)- alkoxycarbonyl, (C₁-C₄)-alkylcarbonylamino, (C₁-C₄)- alkoxycarbonylalkyl, carbamoyl, carbamoylalkyl, N,N- dialkylcarbamoylalkyl;

-A- is a diradical -0-, -S-, -SO, n-—,, -—S0O_l-—,, -^—SϋUOo-.N'R⁷- or

-NR⁷S0₂- wherein R⁷ is hydrogen or (^-C^-alkyl; -B is a sulfur or oxygen atom or a -S0₂- or -SO- group or a single bond;

-D is a 5-tetrazolyl or -COOR⁸ group, wherein R⁸ is hydrogen, a (C₁-C₄)-alkyl or a phenylalkyl group of less than 10 carbon atoms; m is an integer from 0 to 4; n and p are integers from 0 to 6, with the proviso that n + p is less or equal to 6.

The present invention also relates to a process for the preparation of the novel naphthalene quinolines, as well as the therapeutical use thereof.

The present invention also relates to the solvates and the pharmaceutically acceptable salts of the quinolines of formula I and particularly the salts represented by formula Ia,

Ia 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 stereoisomers as well as the mixtures thereof. Preferred compounds are those wherein R² is hydrogen and D is a 5-tetrazolyl or COOR⁸ group, wherein R⁸ is hydrogen, methyl, ethyl or benzyl.

Also preferred are the compounds of formula I wherein R is hydrogen or chlorine and -A- is -0- or -S-.

Also preferred are the compounds of formula I wherein R¹ is hydrogen or chlorine and -A- is -S0₂NR⁷- or -NR⁷S0₂-, wherein R⁷ is hydrogen or methyl.

Particularly preferred are the compounds of formula

I wherein the substituent containing A is bound to the 7- position of the 2-naphthol ring, R¹ is hydrogen and

-A- is -0- or -S-, n and p being integers from 0 to 4.

Particularly preferred are the compounds of formula

I wherein the substituent containing A is bound to the

7- position of the 2-naphthol ring, m is 0 and -A- is -S0₂NR⁷- or -NR S0₂~, wherein R⁷ is hydrogen or methyl, n and p being integers from 0 to 4.

Particularly preferred compounds of the present invention are the following ones:

4-[3-[7-(2-quinolinylmethyloxy)-2-naphthyloxy]propyl]- benzoic acid;

5-[4-[3-[7-(2-quinolinγlmethyloxy)-2-naphthyloxy]pro- pyl]phenyl]-lH-tetrazole;

4-[3-[7-(2-quinolinylmethyloxy)-2-naphthyloxy]butyl]- benzoic acid; 4-[2-[7-(2-quinolinylmethyloxy)-2-naphthyloxy]ethoxy]- benzoic acid;

4-[2-[7-(2-quinolinylmethyloxy)-2-naphthylmethyloxy]- ethyl.benzoic acid;

4-E7-(2-quinolinylmethyloxy)-2-naphthylmethyloxymethyl]- benzoic acid;

4-[2-[[7-(2-quinolinylmethyloxy)-2-naphthyl]sulfonyl- amino]ethyl]benzoic acid;

N-methyl-4-[2-[[7-(2-quinolinyl-methyloxγ)-2-naphthyl]- sulfonylamino]ethyl]benzoic acid; 4-[2-[[7-(2-quinolinylmethyloxy)-2-naphthyl]sulfonyl- amino]methyl]benzoic acid; 4-[2-hydroxy-3-[7-(2-quinolinylmethyloxy)-2-naphthyl- oxy]propyloxy]benzoic acid;

5-[4-[2-[7-(2-quinolinylmethyloxy)-2-naphthylmethyloxy]- ethyl]phenyl]-1 f-tetrazole; 3-fluoro-4-[2-17-(2-quinolinylmethyloxy)-2-naphthylme- thyloxy]ethyl]benzoic acid;

2-fluoro-4-[2-[7-(2-quinolinylmethyloxy)-2-naphthyl- methyloxy]ethyl]benzoic acid;

3-methoxy-4-[2-[7-(2-quinolinylmethyloxy)-2-naphthyl- methyloxγ]ethyl]benzoic acid;

3-[2-[7-(2-quinolinylmethyloxy)-2-naρhthylmethyloxy]- ethyl]benzoic acid;

4-[2-[7-(2-quinolinylmethyloxy)-2-naphthylmethylthio]- ethyl.benzoic acid; 3-fluoro-4-[2-[[7-(2-quinolinylmethyloxy)-2-naphthyl3- sulfonylamino]ethyl]benzoic acid;

4-[l-methyl-2-[7-(2-quinolinylmethyloxy)-2-naphthylsul- fonylamino]ethyl]benzoic acid;

4-[1,l-dimethyl-2-[7-(2-quinolinylmethyloxy)-2-naphthyl- sulfonylamino]ethyl]benzoic acid;

4-[2-[[7-(2-quinolinylmethyloxy)-2-naphthyl]sulfonylami- no]propyl]benzoic acid;

5-[4-[2-[[7-(2-quinolinylmethyloxy)-2-naphthyl]sulfonyl¬ amino]propyl]phenyl] -lH-tetrazole; 3-fluoro-4-[2-[[7-(2-quinolinylmethyloxy)-2-naphthyl]- sulfonylamino]propyl]benzoic acid;

3-methoxy-4-[2-[[7-(2-quinolinylmethyloxy)-2-naphthγl]- sulfonylamino]propyl]benzoic acid;

4-[2-[[7-(2-quinolinylmethyloxy)-2-naphthyl]sulfonylami- no]ethyl]phenylacetic acid;

4-[2-[[7-(2-quinolinylmethyloxy)-2-naphthyl]sulfonylami- no]propyl]phenylacetic acid;

4-[l-[[7-(2-quinolinylmethyloxy)-2-naphthyl]sulfonylami- no]ethyl]phenylacetic acid;

2-[1-[[7—(2-quinolinyl ethyloxy)-2-naphthγl]sulfonyla i- no]ethyl]phenγlacetic acid.

According to the present invention the compounds of general formula I wherein A is -0- or -S- are obtained by a process in which a starting compound of general formula II,

H

II wherein R¹, R², R³ and m have the above defined meanings and A is oxygen or sulfur, is reacted with a compound

III,

III wherein R⁴, R⁵, R⁶, B, n and p have the above defined meanings, X is a chlorine or bromine atom or an alkyl- or arylsulfonate group and E can be equivalent to the group D in I or, when D in formula I is COOH or a 5- tetrazolyl group, then E is CN, or alternatively, when D in formula I is COOH, then E can contain a suitable carboxy-protecting group, for example a methyl, ethyl or benzyl ester. The reaction between II and III is carried out previously preparing a salt of the alcohol or of the thiol II, by treatment with a suitable base, such as a metal hydride when A is oxygen and m = 1 or a metal hydroxide, alkoxide or carbonate in the other cases, and subsequently reacting the salt of II with compound III in a suitable solvent such as N,N-dimethylformamide, benzene or tetrahydrofuran, at a temperature ranging from 0^βC to the solvent reflux, for a time between 3 and 24 hours. A compound of formula IV,

IV is thereby obtained, which coincides with I or is transformed into I either removing any COOH-protecting groups present in E or hydrolysing the nitrile group present in E to carboxylic acid or converting said nitrile group to a 5-tetrazolyl group by reaction with sodium azide. Therefore, when E 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 methanol, ethanol or tetrahydrofuran, at a temperature from 20^βC to the solvent reflux, for a time between 1 and 48 hours. When E is a nitrile group, it can be hydrolyzed to carboxylic acid with 35% NaOH in a suitable organic solvent such as ethanol or dioxane, at the solvent reflux, for a time between 1 and 18 hours. When E is a nitrile group it can be transformed into a 5-tetrazolγl group either by treatment with sodium azide or in the presence of a mild acid such as ammonium chloride or piperidinium chloride, or in the presence of tributyltin chloride, in a suitable organic solvent such as N,N-dimethγlformamide, at a temperature from 70* to 150"C, for a time between 5 and 72 hours.

Alternatively, a compound of general formula IV wherein A is oxygen or sulfur can be obtained following the same process as above, starting from the compounds V and VI,

VI

wherein R¹, R², R³, R⁴, R⁵, R⁶, B, X, n, m and p have the above defined meanings, A is oxygen or sulfur and E represents the groups defined above with the exception of the 5-tetrazolyl group.

A compound of general formula I wherein A is -S0₂- NR⁷- is obtained by a process in which a starting compound of general formula VII,

VII wherein R¹, R², R ³ and m have the above defined meanings, is reacted with a compound VIII,

H

VIII wherein R⁴, R^, R⁶, R⁷, B, E, n and p have the above defined meanings. The reaction between VII and VIII is carried out previously preparing the acid chloride of the compound VII by treatment, for example, with phosphorous pentachloride, phosphorous trichloride or thionyl chloride in an inert solvent at a temperature from 25" to 80^βC for a time between 1 and 24 hours, and subsequently reacting it with the compound VIII in the presence of a base such as triethylamine, pyridine or 4- dimethylaminopyridine, in a suitable aprotic solvent such as chloroform, ethylene chloride or N,N- dimethylformamide, at a temperature from 0^* to 80^*C for a time between 1 and 24 hours, thereby obtaining a compound of formula IXa,

IXa which coincides with I or is converted into I, either removing any COOH-protecting groups present in E, or hydrolysing the nitrile group present in E to carboxylic acid, or converting said nitrile group to a 5-tetrazolyl group by reaction with sodium azide, as described above.

Alternatively, a compound of general formula IXa wherein R⁷ is (C₁-C₄)-alkγl can be obtained starting from a compound of formula IXa wherein R⁷ is hydrogen by alkylation with a (C^-C₄)-alkγl bromide or chloride in the presence of a base such as a metal hydride or alkoxide, in a suitable solvent such as N,N- dimethylformamide, tetrahydrofuran or benzene, at a temperature from 25^* to 120^*C, for a time between 4 and 24 hours.

A compound of general formula I wherein A is -NR⁷- S0₂- is obtained following the same process as above, starting from the compounds X and XI,

XI wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, E, m, n, and p have the above defined meanings, thereby obtaining a compound of formula IXb,

IXb which coincides with I or is converted into I, either removing any COOH-protecting groups present in E, or by hydrolysis to carboxylic acid of the nitrile group present in E or converting said nitrile group to a 5- tetrazolyl group by reaction with sodium azide, as described above.

Alternatively, a compound of general formula IXb where R⁷ is (C^-C₄)-alkyl can be obtained starting from a compound of formula IXb where R⁷ is hydrogen, following the process described for the preparation of IXa where R⁷ is (C₁-C₄)-alkyl, starting from IXa where R⁷ is hydrogen.

A compound of general formula I wherein A is -S0₂- or -SO- is obtained starting from a compound IV by reaction with a suitable oxidizing reagent, according to conventional processes described in literature.

A starting product of formula Ila, i.e. of general formula II wherein A is oxygen and m = 0, can be obtained, for example, following the synthetic sequence shown in scheme 1.

Scheme 1

XII

XIV

11 a

In this sequence, a compound XIV can be obtained, for example, subjecting a compound XII, commercial or easily available by similar chemical processes, to the action of a base such as sodium methoxide or sodium hydride, and subsequently reacting it with a compound XIII, wherein R and X have the above defined meanings, in a suitable organic solvent such as benzene, N,N- dimethylformamide or tetrahydrofuran, at a temperature from 0' to 25^*C for a time between 3 and 24 hours (step 1).

A compound Ila can be obtained starting from XIV by treatment with boron tribromide in a suitable organic solvent, such as chloroform or dichloromethane, at a temperature from -70^*C to 25^*C for a time between 2 and

24 hours (step 2) .

Analogously, a starting compound of formula lib,

lib i.e. of general formula II wherein A is oxygen, m=l and with no substituents at the methylene bound to the hydroxyl, can be obtained, for example, starting from a compound XV,

XV wherein R¹, R², R³ and m have the above defined meanings, by reduction of the carboxylic acid group with a metal hydride, such as lithium aluminum hydride or borane, in a suitable aprotic solvent such as ethyl ether or tetrahydrofuran at a temperature from -10^βC to the solvent reflux for a time between 2 and 24 hours.

Similarly, a starting compound of formula lie, i.e. of general formula II wherein A is oxygen, m=l and where R³ is methyl bound to the hydroxyl-substituted carbon can be obtained, for example, following the synthetic sequence shown in the scheme 2.

Scheme 2

XVI

lie

In such a sequence, a compound XVI can be obtained by reaction of a compound XV with methyl lithium in the presence of trimethylsilyl chloride in a suitable aprotic solvent such as ethyl ether or tetrahydrofuran at a temperature from -10* to 25 ^*C for a time between 2 and 24 hours.

A compound lie can be obtained, for example, by reduction of a compound XVI by the action of a metal hydride such as sodium borohydride or lithium aluminum hydride in a suitable solvent such as tetrahydrofuran or ethyl ether, at a temperature from 0^*C to the solvent reflux and for a time between 2 and 24 hours.

A compound of general formula V where X is an alkyl- or arylsulfonic group can be obtained starting from a compound II by reaction with an alkyl- or arylsulfonyl chloride such as mesyl or tosyl chloride, in the presence of a base such as triethylamine or pyridine, in a suitable solvent such as methylene chloride or chloroform, at a temperature from -30" to

25"C, for a time between 2 and 24 hours.

A starting compound of general formula II wherein A is sulfur can be obtained starting from a compound II wherein A is oxygen, following chemical processes similar to those described in literature.

A starting compound of formula Vila,

i.e. of general formula VII with = 0, can be obtained by reaction of a compound XVII,

H

XVII commercial or easily available by similar chemical processes, wherein R² represents the groups defined above, with a compound XIII, following the process described for the preparation of XIV starting from XII. A starting compound of formula VII where m = 1 can be obtained, for example, by reaction of a compound V with a metal sulfite such as sodium sulfite in water or mixtures of water with a miscible organic solvent such as ethanol, methanol or tetrahydrofuran, at the solvent reflux and for a time between 2 and 24 hours.

The starting compounds of formulae X and XV can be obtained following the synthetic processes described in literature (application n ES 9401696/8).

A starting compound III where X is an alkyl- or arylsulfonate group can be obtained by reaction of a compound VI with an alkyl- or arylsulfonyl chloride in the conditions described for the preparation of V starting from II.

Analogously, a compound III where X is a chlorine or bromine atom and B is an oxygen or sulfur atom can be obtained by reaction of a compound XVIII,

XVIII commercial or easily available by similar chemical processes, wherein R^ and p have the above defined meanings, E represents the groups defined above with the exception of the 5-tetrazolyl group and B is an oxygen or sulfur atom, with a compound XIX,

R⁴ I

XIX wherein R⁴, R⁵, X and n have the above defined meanings, following the process described above for the preparation of IV starting from II and III.

A starting compound of formula XX, i.e. of general formula VI where B is a single bond and A is an oxygen atom, can be prepared, when not commercially available, according to the synthetic sequence represented in scheme 3

Scheme 3

XXI XXIII

A compound XXIII can be prepared starting from the compounds XXI and XXII, commercial or easily available following simple chemical processes, wherein R⁴ and R^ have the above defined meanings, E represents the groups defined above with the exception of nitrile, r and s are integers from 0 to 4 so that r+s+2 = n and R⁹ is a suitable hydroxy-protecting group, easily removable by catalytic hydrogenation, such as the benzyl group. The reaction between XXI and XXII (step 5) is carried out in the conditions usually described for the Wittig reaction, in the presence of a suitable base such as lithium bis(trimethylsilyl)amide in a suitable solvent such as ethyl ether or tetrahydrofuran, at a temperature from 25^*C to the solvent reflux, for a time between 45 minutes and 18 hours. Starting from a compound XXIII, a compound XX can be obtained by catalytic hydrogenation under room pressure and temperature, in the presence of palladium hydroxide, in a etanol:water mixture and for a time between 8 and 24 hours (step 6).

Alternatively, a starting compound of formula XXIV, i.e. of general formula VI where n = 3, p - 0, A is oxygen, B is a single bond and E is a nitrile group, can be obtained according to the synthetic sequence shown in scheme 4.

Scheme 4

In such a sequence, starting from a compound XXV, commercial or easily available by similar chemical processes, wherein R⁴ and R⁵ have the above defined meanings and Y is a chlorine or bromine atom, a compound

XXVI can be prepared by reduction with a metal hydride, such as lithium aluminum hydride, in a suitable solvent such as ethyl ether or tetrahydrofuran, at a temperature between 25"C and the solvent reflux, for a time between the 3 and 8 hours (step 7). A compound XXIV can be obtained by reaction of a compound XXVI with CuCN in a high boiling solvent such as N-methylpyrrolidone at a temperature from 180° to 220^*C for a time between 1 and

4 hours (step 8) . A starting compound of formula VI wherein A is a sulfur atom can be obtained starting from a compound VI wherein A is oxygen, following similar chemical processes described in literature. A starting compound VIII where R⁴ and R⁵ are hydrogen, can be obtained following similar chemical processes described in literature (see Spanish

Application 9401696/8 from the same applicants).

A starting compound XI can be prepared starting from a compound VI following the process described above for the preparation of VII starting from V.

The compounds of the present invention show a remarkable 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 endotoxyc 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 of the compounds of the present invention.

Example 1; 4-r3-r7-fOuinolinvlmethvloxv )-2-naphthvloxvl- propvllbenzoic acid

IA 2-f7-MethQχy-2-nflPhthYlσχγmethyl)quincline

A 25% sodium methoxide solution in methanol (2.48 ml, 43.4 mmol) was added to a solution of 7-methoxy-2- naphthol (7.55 g, 43.4 mmol) in DMF (200 ml) stirring at room temperature for 15 min. After that 2- chloro ethylquinoline (7.70 g, 43.4 mmol) was added stirring at room temperature for 18 h. Subsequently the solution was evaporated to dryness, the residue was dissolved in ethyl acetate (250 ml), washed with 5% NaHC0₃ (3x25 ml), dried and the solvent was evaporated off, to obtain a crude which was purified by chromatography through a silica gel column eluting with petroleum ether:ethyl acetate mixtures of increasing polarity. 9.55 g of the title product were thereby obtained (70% yield).

-E N.M.R. (300 MHz, CDCI3) 5 ppm: 3.87 (s, 3H); 5.50 (s, 2H); 7.00 ( , 2H); 7.17 (m, 2H); 7.55 (t, 1H); 7.63-7.79 (sc, 4H); 7.82 (d, 1H); 8.13 (d, 1H); 8.19 (d, 1H) . IB 7-f2-Quinolinvlmethvloxv)-2-naphthol A solution of 1M boron tribromide in dichloromethane (57 ml) was added at -30^*C to a solution of 2-(7-methoxy-2-naphthyloxymethyl)-quinoline (9.55 g,

30.3 mmol) in dichloromethane (100 ml). The mixture was left to cool, stirring for 5 hours at room temperature.

Subsequently, methanol (70 ml) was added, stirring for 1 h. After that the mixture was evaporated to dryness, the residue was dissolved in ethyl acetate (250 ml), washed with 2% NaHC0₃ (1x30 ml), dried and the solvent was evaporated off, to obtain a crude which was purified by crystallization in methanol, thereby obtaining 4.14 g of the title compound as a yellow solid (45% yield).

¹H N.M.R. (300 MHz, CDC1₃/CD₃0D mixtures) δ ppm: 5.45 (s, 2H); 6.91 (dd, 1H); 7.00 (d, 1H); 7.09 (dd, 1H); 7.12 (d, 1H); 7.61-7.85 (sc, 5H); 7.95 (d, 1H); 8.09 (d, 1H); 8.37 (d, 1H). IC 3-U-Bromophenvnpropan-l-ol

To a suspension of lithium aluminum hydride (2.49 g, 66 mmol) in dry ethyl ether (130 ml) was added under inert atmosphere a solution of 4-bromocinnamic acid (5.0 g, 22 mmol) in 20 ml of dry ethyl ether, stirring at room temperature for 2 hours. Subsequently, a NaCl aqueous saturated solution (80 ml) was slowly added, the two phases were separated and the aqueous one was extracted with ethyl acetate (3x50 ml). The organic extracts were dried and the solvent was evaporated off to obtain 3.60 g of the title compound as a yellowish oil (76 % yield) .

¹H N.M.R. (300 MHz, CDC1₃) δ ppm: 1.85 ( , 2H); 2.66 (t, 2H); 3.65 (t, 2H); 7.06 (d, 2H); 7.39 (d, 2H). ID 4-f3-Hvdroxvpropvl benzonitrile A mixture of 3-(4-bromophenyl)propan-l-ol (2.0 g, 9.3 mmol), copper (I) cyanide (1.49 g, 16.7 mmol) and N- methylpyrrolidinone (13 ml) was left under stirring at

200^*C for 2.5 hours. Subsequently the reaction mixture was cooled to room temperature, poured onto a solution of diethylamine (30 g) and water (80 ml) and extracted with ethyl acetate (3x40 ml). The combined organic phases were dried and the volatiles were evaporated off, to obtain an oil from which N-methylpyrrolidinone was removed by distillation under high vacuum (0.5 torr,

85^*C), thereby obtaining 0.78 g of the title compound (52 % yield) .

¹H N.M.R. (300 MHz, CDC1₃) 5 ppm: 1.85 ( , 2H); 2.42 (s broad, 1H); 2.76 (t, 2H); 3.64 (t, 2H); 7.29 (d, 2H); 7.53 (d, 2H). IE 3-(4-Cvanophenvl IPΓOPVI methanesulfonate Triethylamine (0.54 ml, 4.03 mmol) and methanesulfonyl chloride (0.30 ml, 4.03 mmol) were added to a solution of 4-(3-hydroxypropyl)benzonitrile (0.50 g, 3.10 mmol) in dry methylene chloride (15 ml), cooled at 0^βC and under inert atmosphere. The mixture was left under stirring at 0^*C for 2 hours. After that it was diluted with methylene chloride (50 ml), washed successively with 0.05M HCl, with a NaCl saturated solution, dried and the solvent was evaporated off, thereby obtaining 0.675 g of the title compound as a semi-solid oil (94 % yield).

¹H N.M.R. (300 MHz, CDC1₃) δ ppm: 1.89 (m, 2H); 2.63 (t,

2H); 2.85 (s, 3H) ; 4.05 (t, 2H); 7.14 (d, 2H) ; 7.38 (d,

2H).

IF 4-T3-r7- (Ouinolinvl ethvloxv )-2-naphthvloxv1 ropyl1- benzonitrile

Following the process described in point A, starting from 7-(2-quinolinylmethyloxy)-2-naphthol and

3-( 4-cyanophenyl)propyl methanesulfonate, the title compound was prepared and purified by chromatography through, a silica gel column eluting with petroleum ether:chloroform, 1:1, (40% yield).

-U N.M.R. (300 MHz, CDC1₃) δ ppm: 1.99 (m, 2H); 2.76 (t,

2H); 3.88 (t, 2H) ; 5.38 (s, 2H) ; 6.83 (d, 1H); 6.87 (dd,

1H); 7.01 (d, 1H); 7.05 (dd, 1H); 7.17 (d, 2H) ; 7.43 (m,

3H); 7.53-7.59 ( , 3H) ; 7.63 (dt, 1H) ; 7.69 (d, 1H); 8.00 (d, 1H); 8.04 (d, 1H) .

1__ 4-r3-r7-fOuinolinvlmethvloxv^-2-naphthvloxv1-propvn- benzoic acid

A solution of 35% NaOH (22 ml) was added to a solution of 4-[3-[7-(quinolinylmethγloxy)-2-naphthyl- oxy]propyl]-benzonitrile (635 mg, 1.43 mmol) in ethanol (50 ml) refluxing for 8 h. After that the mixture was acidified with 1M HCl to pH of about 5 and the precipitated solid was recovered by filtration, thereby obtaining 391 mg of the title compound as a yellow solid with melting point 197^*-198^βC. (59% yield).

¹H N.M.R. (300 MHz, DMSO) 5 ppm: 2.09 (m, 2H) ; 2.85 (t, 2H); 4.05 (t, 2H); 5.47 (s, 2H) ; 7.00 (dd, 1H); 7.16 (d, 2H); 7.34 (dd, 1H) ; 7.37 (d, 2H); 7.63 (dt, 1H) ; 7.70- 7.79 (m, 3H); 7.80 (dt, 1H); 7.87 (d, 2H); 8.01 (d, 1H); 8.05 (d, 1H); 8.43 (d, 1H) .

Example 2 5- -r3-T7-( 2-Ouinoι invlmethvloxvl^- naphthvloxvlpropvnphenv:! 1-lff-tetrazole

Tributyltin chloride (0.74 ml, 2.74 mmol) was added under inert atmosphere to a suspension of sodium azide (178 mg, 2.74 mmol) in dry toluene (20 ml), stirring at room temperature for 30 min. Subsequently a solution of 4-[3-[7-(quinolinylmethyloxy)-2-naphthyloxy]propyl]ben- zonitrile (338 mg, 0.76 mmol) in DMF (4 ml) was added, stirring for 73 hours at 100'C. After this time, the mixture was left to cool at room temperature and a mixture of methanol (9 ml) and 1M HCl (1 ml) was added.

After lh stirring at room temperature, the mixture was diluted with ethyl acetate, washed with a NaCl saturated solution, dried and the solvent was evaporated off. The resulting residue was purified by chromatography through a silica gel column eluting with chloroform:methanol, 9:1, followed by digestion in methanol, thereby obtaining 59 mg of the title compound as a yellowish solid with melting point 192.3°-193.5'C. ¹H N.M.R. (300 MHz, DMSO) δ ppm: 2.12 ( , 2H); 2.87 (t, 2H); 4.07 (t, 2H); 5.47 (s, 2H); 7.00 (dd, IH); 7.14 (dd, IH); 7.17 (d, IH); 7.34 (d, IH); 7.48 (d, 2H); 7.62 (dt, IH); 7.70-7.82 (m, 4H); 7.96 (d, 2H); 8.00 (d, IH); 8.05 (d, IH); 8.43 (d, IH). Example 3: 4-T3-T7-ιOuinolinvlmethvloxv)-2-naphthvloxvl- butvllbenzoic acid

3A Methvl 4-f4-benzvloxv-l-butenvl benzoate

Lithium bis(trimethylsilyl)amide (3.35 ml, 3.35 mmol) was added to a solution of (3-benzyloxy- propyl)triphenylphosphonium bromide (1.5 g, 3.05 mmol) in dry tetrahydrofuran (20 ml), stirring at room temperature for 15 min. Subsequently a solution of methyl 4-formylbenzoate (0.40 g, 2.44 mmol) in tetrahydrofuran (minimum amount for the solution) stirring for 30 min. at room temperature. After that the mixture was diluted with tetrahydrofuran (20 ml), washed successively with 0.1M HCl and water, dried and the solvent was evaporated off, to obtain a residue which was purified by chromatography through a silica gel column eluting with petroleum ether:ethyl ether, 8:2, thereby, obtaining 0.60 g of the title compound as a colourless oil (67% yield).

¹H N.M.R. (300 MHz, CDC1₃) δ ppm: 2.69 (m, 2H); 3.59 (t,

2H); 3.90 (s, 3H); 4.53 (s, IH); 5.87 (m, IH); 6.50 (m,

IH); 7.30-7.40 (sc, 7H); 8.04 (d, 2H).

3B Methvl 4-f4-hvdroxvbutvlIbenzoate

10% Pd(OH)₂ on carbon was added to a solution of methyl 4-(4-benzyloxy-l-butenyl)benzoate (519 mg, 1.80 mmol) in a methanol:water, 9:1 mixture (30 ml), stirring at room temperature for 18 h, under hydrogen atmosphere.

Subsequently the catalyst was filtered off and the filtrate was evaporated to dryness, to obtain 209 mg of the title compound as a colourless oil (58% yield). ^^■H N.M.R. (300 MHz, CDC1₃) 6 ppm: 1.72 (m, 2H); 1.83 (m, 2H); 2.80 (t, 2H); 3.77 (t, 2H); 4.03 (s, 3H); 7.37 (d, 2H); 8.08 (d, 2H) . 3C Methvl 4-T4-(Methvlsulfonvloxvϊbutvlϊbenzoate

Triethylamine (0.16 ml, 1.24 mmol) and methanesulfonyl chloride (0.112 ml, 1.24 mmol) were added to a solution of methyl 4-(4-hydroxybutyl)benzoate (200 mg, 0.96 mmol) in dry methylene chloride (15 ml), cooled at 0"C and under inert atmosphere. The mixture was stirred at 0^*C for 2 hours, then diluted with methylene chloride (50 ml), washed successively with 0.05M HCl and with a NaCl saturated solution, dried and the solvent was evaporated off, to obtain a residue which was purified by chromatography through a silica gel column eluting with petroleum ether:chloroform, 7:3, thereby obtaining 190 mg of the title compound as a colourless oil (70 % yield).

^XH N.M.R. (300 MHz, CDC1₃) δ ppm: 1.76 (m, 4H); 2.70 (t,

2H); 2.97 (s, 3H); 3.89 (s, 3H); 4.22 (t, 2H); 7.23 (d, 2H); 7.94 (d, 2H).

-LD Methvl 4-r3-r7-(Ouinolinvlmethvloxv)-2-naphthvloxv1- butvll-benzoate

Following the process described in example 1 (point

B), starting from 7-( 2-quinolinylmethyloxy)-2-naphthol and methyl 4-[4-(methylsulfonyloxy)butyl]benzoate, the title compound was prepared (50% yield).

^XH N.M.R. (300 MHz, CDC1-) 6 ppm: 1.82 (m, 4H) ; 2.74 (t, 2H); 3.87 (s, 3H); 4.02 (t, 2H); 5.47 (s, 2H); 6.94 (d, IH); 6.95 (dd, IH); 7.10 (d, IH); 7.12 (dd, IH); 7.25 (d, 2H); 7.53 (t, IH); 7.60-7.76 (sc, 4H); 7.81 (d, IH); 7.93 (d, 2H); 8.09 (d, IH); 8.16 (d, IH).

-IE 4-r3-r7-fOuinolinvlmethvloxvϊ-2-naphthvloxv1-butvl1- benzoic acid

A IM solution of potassium hydroxide (1.52 ml) was added to a solution of methyl 4-[3-[7- (quinolinylmethyloxy)-2-naρhthyloxy]butyl]-benzoate (0.150 mg, 0.31 mmol) in ethanol (7 ml). The mixture was stirred under reflux for 2 h, after that was neutralized with IM HCl and ethanol was removed. The resulting crude was suspended in water (30 ml) and extracted with ethyl acetate (4x30 ml). The organic phase was dried and the solvent was evaporated off, to obtain 102 mg of the title compound as a yellowish solid with melting point 197.9^β-199.9'C (69% yield). - N.M.R. (300 MHz, DMSO) δ ppm: 1.77 (m, 4H); 2.73 (t broad, 2H); 4.07 (t broad, 2H); 5.48 (s, 2H); 6.99 (dd, IH); 7.14 (dd, IH); 7.18 (d, IH); 7.28 (d, 2H); 7.33 (d,

IH); 7.63 (dt, IH); 7.70-7.80 (m, 4H ) ; 7.87 (d, 2H);

8.01 (d, IH); 8.05 (d, IH); 8.43 (d, IH).

Example 4: 4-T2-r7-(2-Ouinolinylmethvloxv)-2-naphthvl- oxvlethoxvlbenzoic acid

4A Methyl 4-hvdroxvbenzoate

Concentrated sulfuric acid (56 ml) was added to a solution of 4-hydroxybenzoic acid (10 g, 72.4 mmol) in methanol (420 ml), stirring under reflux for 2 h. After that, the volatiles were evaporated off under reduced pressure and the resulting residue was neutralized with a sodium bicarbonate saturated solution and extracted with ethyl ether (4x100 ml). The mixture was dried and solvent evaporated off under reduced pressure, to obtain 10.79 g of the title compound as a white solid (98% yield) . N.M.R. (300 MHz, CDC1₃) δ ppm: 3.57 (s, 3H); 6.56 (d, 2H); 7.60 (d, 2H). 4B Methvl 4-f2-bromoethvloxv)benzoate A solution of KOH (3.69 g, 32.9 mmol) in dimethylsulfoxide (10 ml) was added to a solution of methyl 4-hydroxybenzoate (5.0 g, 32.9 mmol) in dimethylsulfoxide (10 ml), stirring at room temperature for 15 min. Subsequently 1,2-dibromoethane (5.67 ml, 32.9 mmol) was added, stirring at room temperature for 18 h. After that the mixture was diluted with water (50 ml) and extracted with ethyl ether. The mixture was dried and the solvent was evaporated off to obtain a residue which was purified by chromatography through a silica gel column eluting with mixtures of n-hexane:chloroform of increasing polarity, thereby obtaining 1.99 g of the title compound (23% yield).

¹H N.M.R. (300 MHz, CDC1₃) δ ppm: 3.67 (t, 2H) ; 3.90 (s,

3H); 4.35 (t, 2H) ; 6.93 (d, 2H) ; 8.01 (d, 2H) .

AC Methvl 4-r2-r7-(2-αuinolinvlmethvloxv)-2-naphthvl- QxylethoxYl-benzoate

Following the process described in point B, starting from 7-(2-quinolinylmethyloxy)-2-naphthol and methyl 4-(2-bromoethyloxγ)benzoate, the title compound was prepared, which was purified by crystallization in methanol (66% yield).

-K N.M.R. (300 MHz, DMSO) δ ppm: 3.82 (s, 3H) ; 4.45 ( , 4H); 5.48 (ε, 2H); 7.04 (dd, IH); 7.12 (d, 2H); 7.18 (dd, IH); 7.26 (d, IH) ; 7.35 (d, IH); 7.63 (t, IH); 7.71-7.82 ( , 4H); 7.93 (d, 2H); 8.02 (d, IH) ; 8.06 (d, IH); 8.44 (d, IH) .

__E 4-r2-r7-(2-QuinQlinYl et_.ylPχy)-2-naP-.thYlQ?.γ1-etho-

XYlbenzpic acid

Following the process described in example 3 (point

E), starting from methyl 4-[2-[7-(2-quinolinγl- methγloxγ)-2-naphthyloxy]ethoxy]benzoate, the title compound was prepared as a white solid with melting point 231^β-233^*C, and purified by digestion in methanol.

¹H N.M.R. (300 MHz, DMSO) δ ppm: 4.43 (s broad, 4H);

5.49 (s, 2H); 7.03 (dd, IH); 7.08 (d, 2H); 7.16 (dd, IH); 7.26 (d, IH); 7.35 (d, IH); 7.62 (t, IH); 7.71-7.82

(m, 4H); 7.92 (d, 2H); 8.00 (d, IH); 8.06 (d, IH); 8.42 d, IH).

Example 5: 4-r2-Hvdroxv-3-r7-.2-σuinolinvlmethvloxv)-2- naphthvloxvlpropvloxvlbenzoic acid 5A Methvl 4-(2.3-epoxvpropvloxv.benzoate

Potassium carbonate (4.69 g, 17 mmol) was added to a solution of methyl 4-hydroxybenzoate (2.61 g, 17 mmol) in N,N-dimethylformamide (75 ml) stirring at room temperature for 10 minutes. After that, 1,3-dibromo-2- propanol (3.74 g, 17 mmol) was added and the mixture was left under stirring at 60'C for 5 h. Subsequently water

(50 ml) was added and the mixture was extracted with ethyl ether (3x75 ml). The solution was dried and the solvents were evaporated off to obtain 2.50 g of the title compound (70% yield). ^ N.M.R. (300 MHz, CDC1-) δ ppm: 2.76 (dd, IH); 2.91 (dd, IH); 3.35 (m, IH); 3.86 (ε, 3H); 3.96 (dd, IH) ; 4.28 (dd, IH), 6.92 (d, 2H); 7.96 (d, 2H) .

__B ____tJ___l 4-r2-hYdroχγ-3-r7-(2-guinQlinγlmethγlQ γ)-2- naphthvloxylpropyloxvlbenzoate A dispersion of sodium hydride (62 mg, 1.56 mmol) in 60% mineral oil was washed by decantation with anhydrous hexane, then it was resuspended dry N,N- di ethylformamide (25 ml). The resulting suspension was added at 0^*C and under inert atmosfere to a solution 7- (2-quinolinylmethyloxy)-2-naphthol (469 mg, 1.56 mmol) in N,N-dimethylformamide (10 ml) stirring at room temperature for 30 min. After that methyl 4-(2,3- epoxyproργloxγ)benzoate (250 mg, 1.20 mmol). The mixture was stirred at room temperature for 24 h. Subsequently water was added (50 ml) and the mixture was extracted with ethyl acetate (4x50 ml). The organic phase was dried and the solvent was removed under reduced pressure, to obtain a crude which was purified by chromatography through a silica gel column eluting with mixtures of n-hexane:chloroform of increasing polarity. 190 mg of the title compound were thereby obtained (31% yield) .

¹H N.M.R. (300 MHz, CDC1₃) δ ppm: 3.82 (s, 3H); 4.15 (m,

4H); 4.41 ( , IH); 5.42 (s, 2H); 6.87 (d, 2H); 6.90-7.12

(sc, 4H); 7.45-7.80 (εc, 5H); 7.91 ( , 3H); 8.00 (d, IH); 8.04 (d, IH) .

__C 4-r2-Hγdro..γ-3-r7-(2-quinQlinγlπιet__YlQXY)-2-nap-_thYl- pxYlprppYloxylbenzpJc acid

Following the process described in example 3 (point E), starting from methyl 4-[2-hydroxy-3-[7-(2-quino- linylmethyloxy)-2-naphthyloxy]propyloxy]benzoate, the title compound was prepared as a white solid with mel¬ ting point 212-214*C.

¹H N.M.R. (300 MHz, DMSO) δppm: 4.05-4.21 (m, 5H); 5.43 (s, 3H); 7.00 (m, 3H); 7.11 (dd, IH); 7.18 (s, IH); 7.31 (s, IH); 7.58 (t, IH); 7.72 (m, 4H); 7.84 (d, 2H); 7.96 (d, IH); 8.01 (d, IH) , 8.38 (d, IH).

Example 6: 4-r2-T7-(2-0uinolinvlmethvloxv)-2-naphthvl- methvloxvlethvllbenzoic acid 6A 7-Methoxy-2-trifluoromethvlsulfonvloxvnaphthalene Pyridine (6.87 ml) and trifluoromethanesulfonic anhydride (10 ml, 59.0 mmol) were added to a solution of 7-methoxy-2-naphthol (8.5 g, 46.7 mmol) in methylene chloride (150 ml), cooled at O'C and under inert atmosphere. The mixture was left under stirring at this temperature for 1 h, then was diluted with ethyl ether (100 ml), washed in succession with 0.01M HCl, a NaHC0₃ saturated solution and NaCl saturated solution, dried and the solvent was removed, to obtain 15.1 g of the title compound as an orange oil (97 % yield). - N.M.R. (300 MHz, CDC1₃) δ ppm: 3.83 (s, 3H); 7.03 (d, IH); 7.14 (dd, 2H); 7.58 (d, IH); 7.66 (d, IH); 7.71 (d, IH ) .

6B Methvl 7-mfithoxv-2-naphtalenecarboxvlate

A solution of 7-methoxy-2-trifluoro- ethylsulfonyl- oxynaphthalene (15.0 g, 47.5 mmol) in absolute methanol (95 ml) was added with triethylamine (28 ml), dimethyl- sulfoxide (140 ml), Pd(OAc)₂ (0.319 g, 1.43 mmol) and l,3-bis(diphenylphosphine)propane (0.580 g, 1.43 mmol).

A carbon monoxide stream was bubbled for 4 min, heating at 75"C for 3 h under carbon monoxide atmosphere. Then the mixture was cooled at room temperature, filtered through celite and methanol was evaporated off. The re¬ sulting solution was diluted with ethyl ether and was washed in seccsion with water, 5% HCl, a 5% NaHCO-. solu¬ tion and a NaCl saturated solution, dried and the sol- vent was evaporated off, to obtain a crude which was purified by flash chromatography through a silica gel column. Eluting with petroleum ether.-ethyl ether, 75:25, 6.46 g of the title compound were obtained (64% yield). -U N.M.R. (300 MHz, CDC1₃) δ ppm: 3.92 (s, 3H); 3.97 (s, 3H); 7.22 (d, IH); 7.24 (dd, IH); 7.76 (d, IH); 7.79 (d, IH); 7.92 (dd, IH); 8.50 (s, IH). 6C Methvl 7-hvdroxv-2-naphtalenecarboxvlate

Following the process described in example 1 (point B), starting from methyl 7-methoxy-2-naphtalenecarboxy- late, the title compound was prepared (90% yield).

¹H N.M.R. (300 MHz, CD₃0D) 8 ppm: 3.99 (s, 3H); 7.24

(dd, IH); 7.26 (s, IH); 7.82 ( , 3H); 8.41 (s, IH) .

6D Methvl 7-f2-σuinol invlmethvloxv -2-naphtalenecarboxv-

_______ Following the process described in example 1 (point A), starting from methyl 7-hydroxy-2-naphtalenecarboxy- late, the title compound was prepared (97 % yield).

-E N.M.R. (300 MHz, CDC1₃) δ ppm: 3.98 (s, 3H); 5.55 (ε,

2H); 7.36 (d, IH); 7.43 (dd, IH); 7.59 (dt, IH) ; 7.81

(m, 5H); 7.95 (dd, IH); 8.16 (d, IH); 8.23 (d, IH); 8.47 (s, IH).

6E 7-(2-Ouinolinvlmethvloxv)-2-naphtalenecarboxvlic acid

Following the process described in example 3 (point

E), starting from methyl 7-(2-quinolinylmethyloxy)-2- naphtalenecarboxylate, the title compound was prepared (95% yield) . N.M.R. (300 MHz, CD₃0D) δ ppm: 5.52 (s, 2H); 7.41 (s, IH); 7.43 (dd, IH); 7.62 (dt, IH); 7.77-7.95 (sc, 6H); 8.11 (d, IH); 8.32 (d, IH); 8.49 (s, IH). 6F 7-(2-Ouinolinvlmethvloxv^-2-naphthvlmethanol A solution of IM borane in tetrahydrofuran (6.56 ml, 6.56 mmol) was added to a solution of 7-(2-quino- linyl ethyloxy)-2-naphtalenecarboxylic acid (1.0 g, 3.04 mmol) in tetrahydrofuran (15 ml), stirring at room tem¬ perature for 18 h. Subsequently, a NaCl saturated solu- tion was added, the phases were separated and the orga¬ nic phase was dried and the solvent was. evaporated off, to obtain a residue which was purified by chromatography through a silica gel column eluting with chloro- form:methanol, 98:2 (59% yield). -E N.M.R. (300 MHz, CD₃0D) δ ppm: 4.69 (s, 2H); 5.39 (s, 2H); 7.24 (dd, IH); 7.28 (d, IH); 7.31 (dd, IH); 7.57 (dt, IH); 7.65-7.79 (sc, 5H); 7.88 (d, IH); 8.04 (d, IH); 8.30 (d, IH). 6G 7-(2-Quinolinvlmethvloxv)-2-naphthvlmethvl methane- sulfonate

Following the process described in example 1 (point E), starting from 7-(2-quinolinylmethyloxy)-2-naphthyl- methanol, the title compound was prepared (55% yield).

¹H N.M.R. (300 MHz, CDC1₃) δ ppm: 2.90 (s, 3H) ; 5.35 (s,

2H); 5.56 (ε, 2H); 7.25 (s, IH); 7.28 (dd, IH) ; 7.31 (dd, IH); 7.60 (dt, IH); 7.70-7.90 (sc, 6H); 8.20 (d,

IH); 8.28 (d, IH).

6H 4-f2-Hvdroxveth.vl1banzon.trila

A mixture of 2-(4-bromophenyl)ethyl alcohol (1 g,

4.96 mmol), copper (I) cyanide (0.797 g, 8.89 mmol) and N-methylpyrrolydinone (6 ml) was refluxed for 3 h. After that, the reaction crude was poured onto a 8% ethylene- diamine aqueous solution (15 ml), extracted with ethyl ether (3x20 ml), the volatiles were evaporated off and N-methylpyrrolydinone was distilled under reduced pres- sure (0.1 torr), thereby obtaining 0.722 g of the title compound (99% yield).

¹H N.M.R. (300 MHz, CDC1₃) 8 ppm: 2.89 (t, 2H); 3.84 (t, 2H); 7.35 (d, 2H); 7.56 (d, 2H). ≤J 4-r2-r7-(2-0uinolinvlmethvloxvl-2-naphthvlmethvloxv1- ethvllbenzonitrile

A dispersion of potassium hydride (0.608 g, 5.36 mmol) in 35% mineral oil was washed by decantation with anhydrous hexane and, subsequently, resuspended in anhy¬ drous benzene (25 ml). The resulting suspension was ad- ded at 0^βC and under inert atmosphere to a solution of 4-(2-hydroxyethyl)benzonitrile (0.722 mg, 5.34 mmol) in benzene (10 ml), stirring at room temperature for 15 min. After that, 7-(2-quinolinylmethyloxy)-2-naphthyl- ethyl methanesulfonate (1.66 g, 4.46 mmol) was added the mixture was left under stirring at room temperature for 18 h, the water (50 ml) was added and the mixture was extracted with ethyl acetate (4x50 ml). The organic phase was dried and the solvent was evaporated off, to obtain a crude which was purified by chromatography through. a silica gel column, eluting with mixtures of petroleum ether:chloroform of increasing polarity, the¬ reby obtaining 0.654 g of the title compound as a yel¬ lowish oil (33% yield). H N.M.R. (300 MHz, CDC1₃) 5 ppm: 2.89 (t, 2H); 3.64 (t, 2H); 4.54 (ε, 2H); 5.45 (s, 2H); 7.14 (s, IH); 7.16 (dd, IH); 7.21-7.26 (m, 3H); 7.47-7.52 (m, 4H); 7.63-7.71 (m, 4H); 7.76 (d, IH); 8.06 (d, IH); 8.12 (d, IH) .

£_Σ 4-r 2- T 7- t 2-0uinolinvlmethvloxv1-2-naphthvlmethvloxv1- ethvllbenzoic acid

Following the process described in example 1 (point G), starting from 4-[2-[7-(2-quinolinylmethyloxy)-2- naρhthylmethyloxγ]ethyl]benzonitrile, the title compound was prepared as a white solid with melting point 243.2^*- 245.2^βC, which was purified by crystallization in metha¬ nol (64% yield) . ^-H N.M.R. (300 MHz, DMSO) δ ppm: 2.89 (t, 2H) ; 3.68 (t, 2H); 4.61 (s, 2H); 5.50 (s, 2H); 7.19 (d, 2H); 7.27 (d, IH), 7.30 (d, IH); 7.43 (s, IH); 7.63 (t, IH); 7.66 (s, IH); 7.73-7.86 (sc, 6H); 8.01 (d, IH), 8.06 (d, IH); 8.43 (d, IH). Example 7: 4-fT7-f2-Ouinolinvlmethvloxv1-2-naphthvl- methvloxvlmethvllbenzoic acid 7A Methvl 4-(methvlsulfonvloxvmethvl Ibenzoate

Following the process described in example 1 (point E), starting from methyl 4-(hydroxymethyl)benzoate, the title compound was prepared (85% yield).

!H N.M.R. (300 MHz, CDC1₃) δ ppm: 3.04 (s, 3H); 3.98 (s, 3H ) ; 5 . 34 ( s , 2H ) ; 7 . 54 ( d , 2H ) ; 8 . 13 ( d , 2H ) .

7B Methyl 4-H-f2-σuinolinylrnethvloxv)-2-naphthvlmethv- loxymethyllbenzoate

Following the proceεε deεcribed in example 6 (point I), starting from 7-(2-quinolinylmethyloxy)-2-naphthyl- methanol and methyl 4-(methylsulfonyloxymethyl)benzoate, the title compound was prepared and purified by chroma¬ tography through a εilica gel column, eluting with mix¬ tures of petroleum ether:chlorofor of increasing pola- rity (56% yield) .

^ N.M.R. (300 MHz, CDC1₃) 8 ppm: 3.90 (s, 3H); 4.59 (s, 2H); 4.69 (s, 2H); 4.50 (s, 2H) ; 7.21-7.36 ( , 4H) ; 7.41 (d, IH); 7.54 (t, IH); 7.69-7.83 (sc, 8H); 8.09 (d, IH); 8.18 (d, IH). 2£ 4-rr7-(2-QuinplinγlmethγlPXY)-2-napht__γlmethγlQxγ1- ethvllbenzoic

Following the process described in example 3 (point

E), starting from methyl 4-[[7-(2-quinolinylmethyloxy)-

2-naphthylmethyloxy]methγl]benzoate, the title compound was prepared as a white solid with melting point 249^*-

252^βC which was purified by crystallization in methanol

(70% yield) .

¹H N.M.R. (300 MHz, DMSO) δ ppm: 4.52 (s, 2H) ; 4.61 (s,

2H); 5.45 (s, 2H); 7.22-7.31 (m, 4H); 7.44 (d, IH); 7.58 (t, IH); 7.69-7.83 (sc, 7H); 7.96 (d, IH) ; 8.01 (d, IH) ;

8.39 (d, IH).

Example 8: 5-T4-r2-T 7- (2-Ouinolinvlmethvloxv ) -2- naphthvlmethvloxvlethvllphenvn-l ff-tetrazole

Following the process described in example 2, star- ting from 4-[2-[7-(2-quinolinylmethyloxy)-2-naphthyl- methyloxy]ethyl]benzonitrile, the title compound was prepared as a yellowish solid with melting point 181-

183°C.

^^■H N.M.R. (300 MHz, DMSO) δ ppm: 2.97 (t, 2H); 3.74 (t,

2H); 4.62 (s, 2H); 5.48 (s, 2H); 7.26 (dd, IH); 7.30 (dd, IH), 7.41 (s, IH); 7.49 (d, 2H); 7.63 (t, IH) ; 7.66

(s, IH); 7.73 (d, IH); 7.74-7.94 (sc, 5H); 8.00 (d, IH),

8.05 (d, IH); 8.43 (d, IH).

Example 9: 3-Fluoro-4-r2-T7-(2-σuino nvlmet.hvloxv)-?- naphthvlmethyloxylethyllbenzoic acid 9A 4-Rromo-2-fluorohanzv. brPmide

N-Bromosuccinimide (5.3 g, 29.1 mmol) and some cry¬ stals of dibenzoyl peroxide were added to a solution of 4-bromo-2-fluorotoluene (5 g, 26.5 mmol) in dry carbon tetrachloride (100 ml). The mixture was refluxed for 4 h, then cooled at room temperature, the formed precipi¬ tate was filtered off and the filtrate was washed in succession with a 5% sodium thiosulfate solution (1x20ml) and a NaCl εaturated solution (2x20 ml), dried and the solvent was evaporated off, thereby obtaining 7.07 g of the title compound as an orange oil (quantitative yield).

^XE N.M.R. (300 MHz, CDC1₃) δ ppm: 4.41 (s, 2H); 7.20- 7.40 (sc, 3H). 9B 4-Bromo-2-fluorophenvlacetonitrile 4-Bromo-2-fluorobenzyl bromide (7.07 g, 26.5 mmol) dissolved in ethanol (12 ml) was added to a solution of sodium cyanide (4.0 g, 81.6 mmol) in water (5 ml), stir¬ ring at 100'C for 3 h. After that, the mixture was coo¬ led at room temperature, added with ethyl ether (30 ml) and washed with a NaCl saturated solution (20 ml). The two phases were separated and the aqueous phase was ex- tracted with ethyl ether (3x25 ml). The ether extracts were dried and the solvent was evaporated off under re¬ duced pressure, to obtain a crude which was purified by flash chromatography through a silica gel column. Elu- ting with petroleum ether:ethyl ether, 98:2, 4.30 g of the title compound were obtained as an orange oil (76 % yield) .

¹H N.M.R. (300 MHz, CDC1₃) δ ppm: 3.61 (s, 2H) ; 7.09-

7.18 (sc, 3H). 9C 4-Bromo-2-fluorophenvlacetic acid

Following the process described in example 1 (point

G), starting from 4-bromo-2-fluorophenylacetonitrile, the title compound was prepared (95% yield).

¹H N.M.R. (300 MHz, CDC1₃) δ ppm: 3.61 (ε, 2H); 7.12- 7.24 (sc, 3H).

9D Methvl 4-bromo-2-fluorophenvlacetate

Following the process described in example 4 (point

A), starting from 4-bromo-2-fluorophenylacetic acid, the title compound was prepared (90% yield). -E N.M.R. (300 MHz, CDC1₃) δ ppm: 3.61 (s, 2H); 3.71 (s,

3H); 7.14 (t, IH); 7.24 (m, 2H).

9E 2-(4-Bromo-2-fluorophenyDethanol

Following the process described in example 1 (point

C), starting from methyl 4-bromo-2-fluorophenylacetate, the title compound was prepared (60% yield).

¹H N.M.R. (300 MHz, CDC1-) δ ppm: 2.75 (t, 2H); 3.68 (t,

2H); 4.12 (s broad, IH); 7.03 (t, IH); 7.13 (m, 2H) .

9F 3-FTuoro-4-(2-hvdroxvethvl)benzonitrile

Following the process described in example 6 (point H), starting from 2-(4-bromo-2-fluorophenyDethanol, the title compound was prepared which was purified by chro- matography through a silica gel column eluting with di- cloro ethane (50% yield).

¹H N.M.R. (300 MHz, CDC1₃) δ ppm: 2.27 (t broad, IH);

2.95 (t_Λ 2H); 3.87 (dt, 2H); 7.30 (d, IH); 7.39 (m, 2H). 2G 3-Fluoro-4-r2-r7-f2-σuino nvlmethvloxv)-2-naphthvl- methvloxvlethvllbenzonitrile

Following the process described in example 6 (point

I), starting from 7-(2-quinolinylmethyloxγ)-2-naphthyl- methyl methanesulfonate and 3-fluoro-4-(2-hy- droxyethyl)benzonitrile, the title compound was prepared

(35% yield) .

-E N.M.R. (300 MHz, CDClg) δ ppm: 2.97 (t, 2H); 3.69 (t,

2H); 4.58 (s, 2H); 5.48 (ε, 2H); 7.18 (s, IH); 7.19 (dd,

IH); 7.26 (t, IH); 7.31 (m, 3H); 7.52 (m, 2H); 7.63-7.71 (m, 4H); 7.80 (d, IH); 8.12 (d, IH); 8.15 (d, IH) .

9H 3-Fluoro-4-r2-r7-(2-σuinolinvlmethvloxv)-2-naphthvl- methvloxvlethv lbenzoic acid

Following the process described in example 1 (point

G), starting from 3-fluoro-4-[2-[7-(2-quinolinylmethyl- oxy)-2-naphthylmethyloxy]ethyl]benzonitrile, the title compound was prepared as a yellow solid with melting point 161-162^βC which was purified by crystallization in methanol (75% yield).

¹H N.M.R. (300 MHz, DMSO) δ ppm: 2.93 (t, 2H); 3.71 (t, 2H); 4.61 (s, 2H); 5.49 (s, 2H); 7.23 (d, IH); 7.30 (dd,

IH), 7.39 (d, IH); 7.49 (t, IH); 7.60-7.65 (m, 3H);

7.71-7.86 (sc, 5H); 8.01 (d, IH) , 8.06 (d, IH); 8.43 (d,

IH). Example 10: 3-Methoxy-4-r2-r7-(2-σuinolinvlmethvloxv1-2- naphthvlmethvloxvlethvllbenzoic acid

10A 5-Chloro-2-methylphenol

A suspension of 5-chloro-2-methylaniline (5 g, 35.3 mmol) in water (18 ml) was added in succession at 0°C with concentrated sulfuric acid (6.3 ml), ice (16 g) and sodium nitrite (2.84 g, 41.5 mmol) dissolved in water (8 ml), stirring at 0^βC for 5 min. After that, the resulting solution was slowly poured onto a hot mixture of sodium sulfate (13.2 g), concentrated sulfuric acid (9.5 ml) and water (10 ml). The resulting mixture was left under stirring at 135*C for 3 h., then cooled at room temperature and extracted with ethyl ether (3x50 ml); the organic phase was washed with a 5% sodium thio- sulfate solution, dried and the solvent was removed un¬ der reduced pressure. The resulting residue was purified by column chromatography eluting with mixtures of petro¬ leum ether:ethyl ether of increasing polarity, thereby obtaining 2.63 g of the title compound (52% yield). N.M.R. (300 MHz, CDC1₃) δ ppm: 2.17 (s, 3H); 6.75 (d, IH); 6.81 (dd, IH); 6.97 (d, IH); 12.55 (s, IH). 10B 5-Chloro-2-methvl-l-methoxvbenzene

5.23 M sodium methoxide in methanol (2.80 ml, 14.5 mmol) was added to a solution of 5-chloro-2-methylphenol (1.73 g, 12.1 mmol) in methanol (40 ml), stirring at room temperature for 5 min. After that, methyl iodide (2.3 ml, 36.4 mmol) was added, stirring at the solvent reflux for 1 h. Subsequently, the reaction mixture was distilled under normal pressure and the distillate was partitioned on a mixture of water:petroleum ether, 1:1 (100 ml total). The aqueous phase was extracted with pe- troleu ether (3x50 ml), the combined organic phases were dried and the solvent was cold evaporated under re¬ duced pressure, thereby obtaining 1.70 g of the title compound as a colourless oil (90% yield). ¹H N.M.R. (300 MHz, CDC1₃) δ ppm: 2.17 (s, 3H) ; 3.81 (ε,

3H); 6.79-6.85 (m, 2H); 7.03 (d, IH).

10C 4-Chloro-2-methoxvbenzvl bromide

Following the process described in example 9 (point

A), εtarting from 5-chloro-2-methyl-l-methoxybenzene, the title compound waε prepared which was purified by flash chromatography through a silica gel column eluting with petroleum ether (60% yield).

¹H N.M.R. (300 MHz, CDCl-) δ ppm: 3.82 (s, 3H); 4.46 (s,

2H); 6.81-6.87 (m, 2H); 7.19 (d, IH). 10D 4-Chloro-2-methoxvphenvlacetonitrile

Following the process described in example 9 (point

B), starting from 4-chloro-2-methoxybenzyl bromide, the title compound was prepared (89% yield).

IH N.M.R. (300 MHz, CDC1₃) 5 ppm: 3.53 (s, 2H); 3.75 (s, 3H); 6.78 (d, IH); 6.84 (dd, IH); 7.15 (d, IH).

10E Methvl 4-chloro-2-methoxvacetate

Following successively the processs described in example 9 (points C and D), starting from 4-chloro-2- ethoxyphenylacetonitrile, the title compound was prepa- red (90% total yield).

¹H N.M.R. (300 MHz, CDC1₃) δ ppm: 3.55 (s, 2H); 3.64 (s,

3H); 3.74 (s, 3H); 6.83 (d, IH); 6.85 (dd, IH); 7.06 (d,

IH) .

10F 2-U-Chιoro-2-methoxvphenvlMethanol Following the process described in example 1 (point

C), starting from methyl 4-chloro-2-methoxyphenylace- tate, the title compound was prepared which was purified by chromatography through a silica gel column eluting with dicloromethane (71% yield).

^^■H N.M.R. (300 MHz, CDC1₃) δ ppm: 2.79 (t, 2H) ; 3.70 (t, 2H); 3.73 (s, 3H); 6.79 (s, IH); 6.81 (dd, IH); 7.03 (d,

IH) .

10g 4-(2-Hγ.rpχyethγl)-3-meth,pχγbenzpnitrile

Following the process described in example 6 (point

H), εtarting from 2-(4-chloro-2-methoxyphenyl)ethanol, the title compound was prepared which was purified by chromatography through a silica gel column eluting with dicloromethane (45% yield).

¹H N.M.R. (300 MHz, CDC1-.) δ ppm: 2.93 (t, 2H); 3.84 (t,

2H); 3.86 (s, 3H); 7.07 (d, IH); 7.21 (dd, IH); 7.27 (d, IH).

1__H 3-Methoxv-4-r2-r7-(2-αuinolinvlmethvloxv)-2- naphthylmethyloxylethvllbenzonitrile

Following the process described in example 6 (point

I), starting from 7-(2-quinolinylmethyloxy)-2-naphthyl- methyl methanesulfonate and 4-(2-hydroxyethyl)-3- ethoxybenzonitrile, the title compound was prepared

(41% yield) .

-E N.M.R. (300 MHz, CDC1₃) δ ppm: 2.97 (t, 2H) ; 3.67 (t,

2H); 3.74 (s, 3H); 4.61 (s, 2H); 5.52 (s, 2H); 7.00 (ε, IH); 7.16-7.31 (sc, 5H); 7.54-7.58 (m, 2H); 7.70-7.77

(m, 4H); 7.80 (d, IH); 8.13 (d, IH) ; 8.20 (d, IH).

____H 3-MethPXY-4-r -r7-(2-quin^plinγlmet.iYlPXY⁾-2- naphthvlmethvloxvlethvllbenzoic acid

Following the process described in example 1 (point G), starting from 3-methoxy-4-[2-[7-(2-quinolinylmethy- loxy)-2-naphthylmethyloxy]ethyl]benzonitrile, the title compound was prepared as a white solid with melting point 180-181^βC, which was purified by crystallization from dicloromethane and methanol mixtures and recrystal- lized in methanol (75% yield). ¹H N.M.R. (300 MHz, DMSO) 6 ppm: 2.93 (t, 2H); 3.66 (t,

2H); 3.80 (s, 3H); 4.61 (ε, 2H); 5.50 (s, 2H); 7.26 (dd,

IH); 7.30-7.34 (m, 2H); 7.44 (d, IH); 7.46 (s, IH); 7.50

(dd, IH); 7.61-7.67 (m, 2H); 7.75 (d, IH); 7.79-7.86

(sc, 3H); 8.01 (d, IH), 8.06 (d, IH); 8.44 (d, IH). Example ; 3-r2-r7-(2-Ouinolinvlmathvloxv)-2-napht.hvl- m_thγlpχγ]ethyl1benzpic acid

11A 3-(2-Hydrpχγethγl)benzpnitrile

Following the process described in example 6 (point H), starting from 2-(3-bromophenyl)ethanol, the title compound was prepared which was purified by chromato¬ graphy through a silica gel column eluting with dicloro¬ methane (74% yield).

^XH N.M.R. (300 MHz, CDC1₃) δ ppm: 2.54 (s broad, IH); 2.87 (t, 2H); 3.84 (t, 2H); 7.38-7.53 (εc, 4H) . 11B 3-r2-r7-f2-Ouinolinvlmethvloxv')-2-naphthvlmethvl- oxvlethvllbenzonitrile

Following the process described in example 6 (point I), starting from ethanesulfonate of 7-(2-quinolinyl- methyloxy)-2-naphthγlmethyl and of the 3-(2-hy- droxyethyl)benzonitrile, the title compound was prepared (43% yield).

^^■H N.M.R. (300 MHz, CDC1₃) 8 ppm: 2.88 (t, 2H); 3.64 (t, 2H); 4.57 (s, 2H); 5.48 (s, 2H); 7.19 (s, IH); 7.21 (dd, IH); 7.29 (t, 2H); 7.38-7.51 (sc, 5H); 7.66-7.79 (sc, 5H), 8.10 (d, IH); 8.12 (d, IH). li 3-r2-r7-(2-Ouinolinvlmethvloxv)-2-naPhthvlmethvl- oxilethyllbenzoic acid

Following the procesε described in example 1 (point G), starting from 3-[2-[7-(2-quinolinylmethyloxy)-2- naphthylmethyloxy]ethyl]benzonitrile, the title compound was prepared as a yellow solid with melting point 59- 60"C, which was purified by crystallization in dichloro¬ methane and methanol mixtures and recrystallized in methanol (58% yield). ¹H N.M.R. (300 MHz, DMSO) δ ppm: 2.90 (t, 2H); 3.65 (t, 2H); 4.56 (s, 2H); 5.45 (ε, 2H); 7.20 (dd, IH); 7.25 (dd, IH), 7.33 (s, IH); 7.36 (d, IH); 7.47 (d, IH); 7.56 (s, IH); 7.58 (t, IH); 7.69 (d, IH); 7.71-7.83 (sc, 5H); 7.96 (d, IH), 8.02 (d, IH); 8.39 (d, IH). Example 12 4-r2-T7-(2-Ouinolinvlmethvloxv)-2-naphthyl- methvlthiolethvl Ibenzoic acid

12A S-2-,4-Cvanophenvl)ethvl thioacetate

Diethyl azodicarboxylate (1.07 ml, 6.8 mmol) was added at 0^*C to a solution of triphenylphosphin (1.82 g, 6.8 mmol) in anhydrous tetrahydrofuran (20 ml), stirring at 0"C for 30 min. A solution of 4-(2-hy- droxyethγl)benzonitrile (0.5 g, 3.4 mmol) and thioacetic acid (0.506 ml, 6.8 mmol) dissolved in tetrahydrofuran (5 ml) was added to the resulting suspension, stirring at room temperature for 24 h. Subsequently, the solvents were evaporated off under reduced pressure and the re¬ sulting residue was purified by chromatography through a silica gel column, eluting with petroleum ether:dicloromethane, 6:4, thereby obtaining 0.626 g of the title compound (90% yield). N.M.R. (300 MHz, CDC1₃) δ ppm: 2.25 (s, 3H); 2.86 (t, 2H ) ; 3 . 05 ( t , 2H ) ; 7 . 27 ( d , 2H ) ; 7 . 52 ( d , 2H ) .

12B 4-( 2-MercaptoethvlIbenzonitrile

Following the process described in example 4 (point

A), starting from S-2-(4-cyanophenyl)ethyl thioacetate, the title compound was prepared (73% yield).

-E N.M.R. (300 MHz, CDC1₃) δ ppm: 2.79 (t, 2H) ; 2.96 (t,

2H); 7.29 (d, 2H); 7.56 (d, 2H).

12__ 4-r2-r7- (2-Ouinolinvlmethvloxv )-2-naphthvlmethvl- thiolethv Ibenzonitrile Cesium carbonate (1.658 g, 5.0 mmol) was added to a solution of 4-(2-mercaptoethyl)benzonitrile (0.441 g, 2.48 mmol) in tetrahydrofuran (30 ml), stirring at room temperature for 15 min. After that, 7-(2- quinolinyl ethyloxy)-2-naphthylmethyl methanesulfonate (1.0 g, 2.48 mmol) dissolved in the minimum amount of tetrahydrofuran was added, stirring at room temperature for 24 h. Subsequently the reaction mixture was filtered and the filtrate was evaporated to dryness. The resulting residue was purified by chromatography through a silica gel column eluting with dicloromethane, thereby obtaining 0.741 g of the title compound (65% yield). ¹H N.M.R. (300 MHz, CDC1₃) δ ppm: 2.56 (t, 2H) ; 2.77 (t, 2H); 3.74 (s, 2H); 5.46 (s, 2H); 7.04 (d, 2H) ; 7.16 (s, IH); 7.22-7.26 (m, 2H); 7.47-7.28 (m, 2H) ; 7.40 (d, IH); 7.49 (m, 2H) ; 7.63-7.74 (sc, 4H) ; 8.10 (d, 2H) .

1212 4-r?r7-( 2-Ouinolinvlmethvloxv1-2-naphthvlmethvl- thip1ethyl Ibenzpic acid

Following the process described in example 1 (point G), starting from 4-[2-[7-(2-quinolinylmethyloxy)-2- naphthylmethylthio]ethyl]benzonitrile, the title com¬ pound was prepared as a white solid with melting point 158-160*C which was purified by crystallization in methanol (60% yield).

¹H N.M.R. (300 MHz, DMSO) δ ppm: 2.64 (t, 2H); 2.87 (t,

2H); 3.89 (s, 2H); 5.50 (s, 2H); 7.29 (d, 2H); 7.30 (d, IH), 7.34 (d, IH); 4.41 (d, IH); 7.63 (t, IH) ; 7.68 (s,

IH); 7.74 (d, IH); 7.78-7.83 (εc, 3H) ; 7.84 (d, 2H);

8.00 (d, IH), 8.06 (d, IH); 8.43 (d, IH).

Example 13: 4-T2-fr - (2-Ouinolinvlmethvloxv1-2- naphthvllsulfonvlaminolethvl Ibenzoic acid 13A Methyl 4-cγanpmethγlbenzpate

Methyl 4-chloromethylbenzoate (8 g, 43.3 mmol) diε- solved in ethanol (6 ml) was added to a solution of so¬ dium cyanide (2.5 g, 51.0 mmol) in water (3 ml) leaving at 100"C for 3 h. The the mixture was cooled at room temperature, and ethyl ether (30 ml) and NaCl saturated solution (10 ml) were added thereto. The two phases were separated and the aqueous one was extracted with ethyl ether (3x25 ml). The ether extracts were dried and the solvent was evaporated off, to obtain a crude which was purified by flash chromatography through a silica gel column, eluting with petroleum ether:ethyl acetate, 3:2, thereby obtaining 6.1 g of the title compound as a yel¬ lowish oil (80 % yield). ¹H N.M.R. (300 MHz, CDC1₃) δ ppm: 3.85 (s, 2H); 3.95 (s, 2H); 7.44 (d, 2H); 8.07 (d, 2H).

13B Methvl 4- (2-aminoethvlIbenzoate

2.27 g of 10% palladium on carbon were added to a solution of methyl 4-cyanomethylbenzoate (6.10 g, 34.9 mmol) in methanol (400 ml) and HCl concentrated (20 ml), stirring 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 crystal¬ lizing 6.78 g of the title compound hydrochloride as a yellowish solid with melting point >360"C (90 % yield). -E N.M.R. (300 MHz, CD₃OD) 5 ppm: 3.07 (t, 2H); 3.32 (t, 2H); 3.92 (s, 3H); 7.44 (d, 2H) ; 8.03 (d, 2H) . 13C Sodium 7-(2-σuinolinvlmethvloxv1-2-naphthvlsulfonata Following the proceεs described in example 1 (point A), starting from sodium 7-hydroxynaphthyl-2-sulfonate and 2-chloromethylquinoline, the title compound was pre¬ pared (75% yield) .

¹H N.M.R. (300 MHz, DMSO) δ ppm: 5.50 (s, 2H); 7.34 (dd, IH); 7.56-7.66 ( , 3H); 7.76-7.83 ( , 3H); 7.88 (d, IH); 8.01 (d, IH); 8.06 (d, IH) ; 8.07 (s, IH); 8.44 (d, IH). 13D Methyl 4-T2-rT7-(2-σuinolinylmethyloxy -2-naphthvn- sulfonvlaminolethvllbenzoate

A mixture of phosphorous pentachloride (1.59 g, 7.64 mmol) and carbon tetrachloride (30 ml) was added to a solution of sodium 7-(2-quinolinylmethyloxy)-2- naphthylsulfonate (1.42 g, 3.82 mmol), εtirring under reflux for 4 h. Subsequently the solvent was evaporated off and the residue was washed repeatedly with water. The washed solid was dried under reduced pressure over phosphorous pentoxide for 18 h. After that, a mixture consiεting of the solid obtained above, methyl 4-(2-ami- noethyl)benzoate hydrochloride (0.906 g, 4.20 mmol) and chloroform (100 ml) was added with triethylamine (2.13 ml, 15.3 mmol), stirring at reflux for 18 h. Subsequen¬ tly the mixture was evaporated to dryness and the resul- ting residue was chromatographed through a silica gel column eluting with mixtures of n-hexane:chloroform of increasing polarity, thereby obtaining 1.363 g of the title compound (67% yield).

*H N.M.R. (300 MHz, CDC1₃/CD₃0D mixtures) δ ppm: 2.80

(t, 2H); 3.22 (t, 2H); 3.86 (s, 3H); 5.47 (s, 2H); 7.11 (d, 2H); 7.34 (s, IH) ; 7.43 (dd, IH); 7.56 (dt, IH);

7.63 (dd, IH); 7.70 (d, IH); 7.75 (dt, IH); 7.80-7.85

(m, 5H), 8.09 (d, IH); 8.22 (d, IH); 8.23 (d, IH).

13E 4-r2-rr7-(2-Ouinolinvlmethvloxv1-2-naphthvllsulfo- nylaminolathvllbenzoic acid Following the procesε deεcribed in example 3 (point E), εtarting from methyl 4-[2-[[7-(2-quinolinylmethy- loxy)-2-naphthyl]εulfonylamino]ethyl]benzoate, the title compound was prepared as a white solid with melting point 213.4^β-214.8^*C (87% yield). iH N.M.R. (300 MHz, mixtures CDC1₃/CD₃0D) δ ppm: 2.73 (t, 2H); 3.09 (t, 2H); 5.45 (s, 2H); 7.06 (d, 2H) ; 7.40 (dd, IH); 7.44 (d, IH); 7.57 (dt, IH); 7.68 (dd, IH); 7.72 (d, IH); 7.76 (dt, IH); 7.80-7.90 (m, 5H), 8.05 (d, IH); 8.26 (d, IH); 8.31 (d, IH) . Example 14: N-Methyl-4-T2-TT7-(2-σuinolinylmethyloχy)-2- naphthvllsulfonvlaminolethvl Ibenzoic acid

14A Methvl N-methvl-4-f2-T f7-f2-σuinolinvlmethvloxv)-2- naphthvϋsπlfonvlaminolathyl Ibenzoate

A dispersion of sodium hydride (19 mg, 0.47 mmol) in 60% mineral was washed by decantation with anhydrous hexane and, subsequently, resuspended in dry N,N-di- ethylformamide (10 ml). The resulting suspension was added at 0*C and under inert atmosphere with a solution of methyl 4-[2-[[7-(2-quinolinylmethyloxy)-2-naphthyl]- sulfonylamino]ethyl]benzoate (0.250 mg, 0.47 mmol) in benzene (10 ml), stirring at room temperature for 4 h. After that, methyl iodide (0.15 ml, 0.47 mmol) was added, stirring at room temperature for 18 h. After this time, water (50 ml) waε added and the mixture waε extracted with ethyl acetate (4x50 ml). The organic phaεe was dried and the solvent was evaporated off, to obtain a crude which was purified by chromatography through a silica gel column, eluting with mixtures of petroleum ether:chlorofor of increasing polarity, the¬ reby obtaining 50 mg of the title compound (20% yield). 1H N.M.R. (300 MHz, CDC1₃) 8 ppm: 2.69 (s, 2H); 2.81 (t, 2H); 3.24 (t, 2H); 3.81 (ε, 3H); 5.42 (ε, 2H); 7.15 (d, 2H); 7.24 (d, IH); 7.36 (d , IH); 7.47 (dt, IH); 7.49 (d, IH); 7.59 (d, IH); 7.67 ( t, IH); 7.72-7.78 (m, 3H), 7.834 (d, 2H); 8.03 (d, IH); 8.22 (s broad, IH); 8.12 (d, IH).

14E N-Methvl-4-r2-rr7-(2-σuinolinvlmethvloxv_i-2- naphthγπsul pnγlaminp]et γπbenzpic acid

Following the process described in example 3 (point

E), starting from methyl N-methyl-4-[2-[[7-(2-quino- linyl ethyloxy)-2-naphthyl]sulfonylamino]ethyl]benzoate, the title compound was obtained as a white solid with melting point 213.6^β-215.0^βC (87% yield).

¹H N.M.R. (300 MHz, DMSO) δ ppm: 2.74 (s, 3H); 2.88 (t,

2H); 3.29 (t, 2H); 5.53 (s, 2H); 7.36 (d, 2H) ; 7.53 (dd, IH); 7.58-7.68 (m, 2H) ; 7.72-7.84 (m, 3H); 7.86 (d, 2H);

8.00-8.10 ( , 4H); 8.32 (s, IH); 8.45 (d, IH).

Example ____ 4-r2-TT7-(2-Oυinplιnylmet.ιylPχγ)-2- naphthvllsulfonvlaminolmethvllbenzoic acid 15A Methvl 4-cvanobenzoate Following the process described in example 4 (point A), starting from 4-cyanobenzoic acid, the title com- pound waε prepared as an yellowish oil (93% yield).

¹H N.M.R. (300 MHz, CDC1₃) δ ppm: 4.11 (s, 3H); 7.89 (d, 2H); 8.28 (d, 2H). 15B Methyl 4-aminomethvlbenzoate Following the process described in example 13 (point B), starting from methyl 4-cyanobenzoate and re¬ acting for 4 h, the title compound was prepared as semi- solid oil (87% yield). -E N.M.R. (300 MHz, CD-OD) δ ppm: 3.91 (s, 3H); 4.21 (s, 2H); 7.59 (d, 2H); 8.07 (d, 2H) .

15C Methvl 4-T2-rT7-(2-αuinolinvlmethvloxv1-2-naphthvl1- sulfonvlaminolmethvllbenzoate

Following the process described in example 13 (point D), starting from sodium 7-(2-quinolinylmethy- loxy)-2-naphthylsulfonate and methyl 4-aminomethylbenzo- ate, the title compound was prepared which was purified by digestion with methanol (29% yield).

-E N.M.R. (300 MHz, mixtures CDC1₃/CD₃0D) δ ppm: 3.86 (s, 3H); 4.18 (s, 2H); 5.49 (s, 2H); 7.11 (d, 2H); 7.34 (s, IH); 7.44 (dd, IH); 7.56 (dt, IH); 7.63 (dd, IH); 7.70 (d, IH); 7.75 (dt, IH); 7.80-7.85 (m, 5H), 8.11 (d, IH); 8.21 (d, IH); 8.22 (d, IH). -L__Q 4-r2-rr7-f2-Quinolinvlmethv1oxv1-2-naphthvnsulfo- nylaminplmethYllbenzpic acid Following the process described in example 3 (point E), starting from methyl 4-[2-[[7-(2-quinolinylmethy- loxy)-2-naphthyl]εulfonylamino]methyl]benzoate, the ti¬ tle compound was prepared as a white solid with melting point 223.1"-224.9^*C (98% yield). ~H N.M.R. (300 MHz, mixtures DMSO) δ ppm: 4.08 (d, 2H); 5.55 (s, 2H); 7.36 (d, 2H); 7.51 (dd, IH); 7.62-7.70 (m, 3H); 7.77-7.85 (m, 4H); 7.99-8.10 (m, 4H ) ; 8.28 (s broad, IH); 8.40 (t, IH); 8.48 (d, IH).

Example 16: 3-Fluoro-4- ϊ2-r .7-(2-αuinolinvlmethvloxvl -7- naphthYllsulfpnylaminplethylIbenzpic acid 16A Methvl 4-(bromomethvl1-3- luorobenzoate

Following the process described in example 9 (point A), starting from methyl 3-fluoro-4-methγlbenzoate, the title compound was prepared which was purified by chro¬ matography through a silica gel column eluting with pe- troleum ether:ethyl ether, 95:5 (65% yield).

¹H N.M.R. (300 MHz, CDC1₃) δ ppm: 3.90 (s, 3H); 4.50 (s, 2H); 7.42 (t, IH); 7.68 (d, IH); 7.78 (d, IH). 16B Methvl 4-(cvanomethvl ι-3-fluorobenzoate

Following the process described in example 9 (point B) , starting from methyl 4-(bromomethyl)-3-fluorobenzo¬ ate, the title compound was prepared (93% yield). IH N.M.R. (300 MHz, CDC1₃) δ ppm: 3.82 (s, 2H); 3.92 (s, 3H); 7.53 (t, IH); 7.71 (dd, IH); 7.84 (dd, IH). 16C Methyl 4-f2-aminoethvl1-3-fluorobenzoate 0.266 g of 10% palladium on carbon was added to a solution of methyl 4-(cyanomethyl)-3-fluorobenzoate (0.515 g, 2.67 mmol) in methanol (50 ml) and concentrated HCl (1.6 ml), stirring at room temperature for 24 h, under hydrogen atmosphere. After that, the mixture was filtered and the filtrate was evaporated to dryness to obtain 0.607 g of the title compound as the hydrochloride (97% yield).

*H N.M.R. (300 MHz, CDC1₃) 6 ppm: 3.10 (t, 2H); 3.21 (t, 2H); 3.91 (s, 3H); 7.47 (t, IH); 7.72 (d, IH); 7.83 (d, IH). fiD Methvl 3-fluoro-4-r2-rr7-f2-σuinolinvlmethvloχy)-2- naphthvllsulfonvlaminolethvllbenzoate

Following the process described in example 13 (point _.D), starting from sodium 7-(2-quinolinylmethy- loxy)-2-naphthylsulfonate and methyl 4-(2-aminoethyl)-3- fluorobenzoate, the title compound waε obtained which was purified by chromatography through a silica gel co¬ lumn, eluting with petroleum ether: chloroform 25:75 (70% yield) . -E N.M.R. (300 MHz, CDC1₃) δ ppm: 2.83 (t, 2H) ; 3.28 (q, 2H); 3.87 (s, 3H) ; 5.01 (m broad, IH); 5.48 (s, 2H) ; 7.11 (t, IH); 7.26 (s, IH); 7.28 (d, IH); 7.42 (dd, IH); 7.49 (d, IH); 7.56 (t, IH); 7.57-7.62 (m, 2H); 7.68 (d, IH); 7.75 (t, IH); 7.78-7.84 (m, 2H), 8.10 (d, IH); 8.18 (s, IH); 8.19 (d, IH). lfLE 3-Fluoro-4-r2-fT7-(2-σuinolinvlmethvloxv)-2- naphthvllsulfonylaminolethvllbenzoic acid

Following the process described in example 3 (point E), starting from methyl 3-fluoro-4-[2-[ [7-(2-quino- linylmethyloxy)-2-naphthyl]sulfonylamino]ethyl]benzoate, the title compound was prepared as a white solid with melting point 196-198"C which was purified by chromato¬ graphy through a silica gel column, eluting with chloro¬ form:methanol, 98:2 (87% yield). -E N.M.R. (300 MHz, DMSO) δ ppm: 2.78 (t, 2H) ; 3.04 (q, 2H); 5.53 (s, 2H) ; 7.35 (t, IH); 7.51 (sc, 2H) ; 7.63 (m, 3H); 7.71 (s, IH); 7.74-7.83 (m, 2H) ; 7.86 (t, IH); 7.98-8.07 (m, 4H), 8.27 (s, IH); 8.44 (d, IH). Example 17: 4-ri-Methvl-2-^r7-f2-αuinolinvlmethvloxv>-2- naphthvlsuT onvlaminolethvllbenzoic acid

17A Methvl A- (cyanomethvlϊbenzoate

Following the process described in example 9 (point B), starting from methyl 4-(bromomethyl)benzoate, the title compound was prepared (86% yield).

¹H N.M.R. (300 MHz, CDC1₃) δ ppm: 3.82 (s, 2H); 3.90 (s,

3H); 7.40 (d, 2H); 8.00 (d, 2H).

17B Methvl 4-(1-cvanoethvl)benzoate A solution of 1.6M n-butyl lithium in hexane (3.14 ml, 5.03 mmol) was added to a solution of diisopropyla- mine (0.774 ml, 5.48 mmol) in anhydrous tetrahydrofuran (20 ml), under inert atmosphere and at -78^*C, stirring at -78^*C for 30 min. After that, methyl 4- (cyanomethyl)benzoate (0.80 g, 4.57 mmol) was added slowly at -78'C, stirring at this temperature for 30 min. Subsequently, hexamethylphosphoramide (HMPA) (0.784 ml, 4.48 mmol) and methyl iodide (0.285 ml, 4.57 mmol) were added in succession, keeping at -78^*C with stirring under inert atmosphere for 4 h. After this time, the mixture was left to cool and water (10 ml) and IM HCl (10 ml) were added immediately. The mixture was extracted with ethyl ether (4x50 ml), dried and the sol¬ vent was evaporated off, the residue was purified by flash chromatography through a silica gel column, elu¬ ting with mixtures of petroleum ether:ethyl ether of in¬ creasing polarity, thereby obtaining 0.434 g of the ti¬ tle compound (50% yield). -K N.M.R. (300 MHz, CDCI3) δ ppm: 1.68 (d, 3H); 3.92 (s, 3H); 4.00 (q, IH); 7.47 (d, 2H); 8.07 (d, 2H). 17C Methyl 4- t 2-aπti.no-l-methvlethvl ι benzoate

Following the process described in example 16

(point C), starting from methyl 4-(l-cyano- ethyl)benzoate, the title compound was prepared as the hydrochloride (83% yield).

-E N.M.R. (300 MHz, CD-_jOD) δ ppm: 1.38 (d, 3H); 3.19 (m,

3H); 3.90 (s, 3H); 7.46 (d, 2H); 8.01 (d, 2H).

17D Methyl 4-Tl-methvl-2-T7-f2-σuinolinvlmethvloxv)-2- naphthylsulfonylaminolethvllbenzoate Following the process described in example 13 (point D), starting from sodium 7-( 2-quinolinylmethy- loxy)-2-naphthylsulfonate and methyl 4-(2-amino-l-methy- lethyl)benzoate, the title compound was obtained which was purified by digestion in methanol (60% yield). ¹H N.M.R. (300 MHz, CDC1₃) δ ppm: 1.21 (d, 3H) ; 2.95 (m, IH); 3.08 (m, IH); 3.25 ( , IH) ; 3.89 (s, 3H); 4.75 (m broad, IH); 5.54 (s, 2H); 7.10 (d, 2H) ; 7.32 (s, IH); 7.48 (dd, IH); 7.59 (t, 2H) ; 7.72 (d, IH); 7.84 (m, 6H); 8.18 (d, IH); 8.19 (s, IH); 8.24 (d, IH). 17E 4- r i -Met.hvl-2- r 7- t 2-αuinol invlmethvloxv 1 -2-naphthvl- εulfonvlaminolethvnbenzoic acid

Following the process described in example 3 (point E), starting from methyl 4-[l-methyl-2-[7-(2-quinolinyl- methyloxy)-2-naphthylsulfonylamino]ethyl]benzoate, the title compound was prepared as a white solid with mel¬ ting point 186.5-187.3^*C, which was purified by dige¬ stion in tetrahydrofuran and methanol (80% yield). -E N.M.R. (300 MHz, DMSO) 5 ppm: 1.14 (d, 3H) ; 2.90 (m, 3H); 5.51 (ε, 2H) ; 7.25 (d, 2H); 7.50 (dd, IH); 7.62 (t, 2H); 7.70 (d, IH); 7.32-7.81 (m, 4H) ; 7.96-8.02 ( , 3H); 8.04 (d, IH); 8.23 (s, IH); 8.43 (d, IH) . Example 18: 4-fl .l-Dimethvl-2-r7-(2-αuinolinvlmethv- loxv i-2-naphthvlsulfonvlaminolethvllbenzoic 18A: Methyl 4-f1-cvano-l-methylethyl)benzoate

Following the process described in example 14 (point A), starting from methyl 4-(cyanomethyl)benzoate, sodium hydride, methyl iodide (2 equivalents) and tetra¬ hydrofuran, the title compound was prepared (88% yield). 3-H N.M.R. (300 MHz, CDC1₃) 8 ppm: 1.79 (s, 6H); 3.94 (s, 3H); 7.57 (d, 2H); 8.08 (d, 2H). 18B Methvl 4- (2-amino-l .1-dimethvlethvl)benzoate

Following the proceεε described in example 16 (point C), starting from methyl 4-(1-cyano-l-methy- lethyl)benzoate, the title compound was prepared as the hydrochloride (quantitative yield). *H N.M.R. (300 MHz, CDC1₃) δ ppm: 1.51 (s, 6H) ; 3.14 (s broad, 3H); 3.90 (s, 3H); 7.49 (d, 2H); 8.02 (d, 2H). 18C Methvl 4-Tl .l-dimethvl-2-r7-f2-αuinolinvlmethvloχγ)- 2-naphthylsulfonylaminolethyllbenzoate

Following the process described in example 13 (point D), starting from sodium 7-(2-quinolinylmethy- loxy)-2-naphthylsulfonate and methyl 4-(2-amino-l,l-di- methylethyl)benzoate, the title compound was prepared which was purified by chromatography through a silica gel column eluting with chloroform (55% yield). ¹H N.M.R. (300 MHz, CDC1-) δ ppm: 1.30 (s, 6H); 3.11 (d, 2H); 3.85 (ε, 3H) ; 4.75 (m broad, IH) ; 5.47 (s, 2H) ; 7.21-7.27 ( , 3H); 7.45 (dd, IH); 7.54 (t, 2H); 7.66 (d, IH); 7.75 (t, IH); 7.80 (m, 5H); 8.11 (d, IH); 8.15 (s, IH); 8.20 (d, IH). 18D 4-ri .l-Dimethyl-2-r7-f2-σuinolinvlmethvloxvl-2- naphthvlsulfonvlaminolethvllbenzoic

Following the process described in example 3 (point

E), starting from methyl 4-[1,l-dimethyl-2-[7-(2-quino- linyImethyloxy)-2-naphthylεulfonylamino]ethyl]benzoate, the title compound was prepared as a white solid with melting point 219-220^*C which was purified by digestion methanol (50% yield).

¹H N.M.R. (300 MHz, DMSO) δ ppm: 1.23 (s, 6H); 2.90 (d, 2H); 5.52 (ε, 2H); 7.40 (d, 2H); 7.48 (dd, IH); 7.57-

7.64 (m, 2H); 7.68 (s, IH) ; 7.72-7.82 ( , 4H); 7.96-8.05

(m, 4H); 8.23 (s, IH); 8.43 (d, IH).

Example 12Δ 4-T2-r n- (2-Ouinolinvlmethvloχy)-2- naphthvllsulfonylaminoIpropvllbenzoic acid 19A Methvl 4-formylbenzoate

Following the process described in example 4 (point

A), starting from 4-formylbenzoic, the title compound was prepared (quantitative yield).

¹H N.M.R. (300 MHz, CDC1₃) δ ppm: 3.94 (s, 3H); 7.94 (d, 2H); 8.18 (d, 2H); 10.08 (s, IH).

19B Methvl 4-f2-nitro-l-propenvlϊbenzoate

A mixture of methyl 4-formylbenzoate (4.82 g, 29.4 mmol), ammonium acetate (2.26 g, 29.4 mmol) and nitro- ethane (87 ml) was stirred at 110^*C for 2.5 h. After this time, the solvent waε evaporated off under reduced pressure and the resulting residue was partitioned in a mixture of dicloromethane:water, 1:1 (100 ml). The aqueous phase was extracted with dicloromethane (3x50 ml) and the combined organic extracts were dried and evaporated to drynesε under reduced pressure. The reεulting residue was purified by chromatography through a silica gel column, eluting with hexane:chloroform,

1:1, thereby obtaining 5.39 g of the title compound (83% yield) .

¹H N.M.R. (300 MHz, CDC1₃) δ ppm: 2.42 (s, 3H) ; 3.92 (ε, 3H); 7.48 (d, 2H); 8.08 (s, IH); 8.10 (d, 2H) .

19C Methvl 4- (2-oxopropvlϊbenzoate

Glacial acetic acid (50 ml) was added to a mixture of methyl 4-(2-nitro-l-propenyl)benzoate (3.4 g, 15.4 mmol), powder iron (8.34 g, 0.149 mol), methanol (50 ml) and water (6.2 ml), stirring at reflux for 3 h. After that, the mixture was cooled and filtered over, washing with methanol. The filtrate was concentrated by evapora¬ tion under reduced pressure and extracted with dicloro¬ methane (4x50 ml). The organic phase was dried and the solvent was evaporated off under reduced pressure, the¬ reby obtaining 2.833 g of the title compound (95% yield) .

¹H N.M.R. (300 MHz, CDC1₃) δ ppm: 2.15 (s, 3H) ; 3.71 (s, 2H); 3.88 (s, 3H); 7.23 (d. 2H); 7.97 (d, 2H). 19D Methyl 4-(2-aminopropvIIbenzoate

Sodium borohydride (0.684 g, 10.9 mmol) was added to a solution of methyl 4-(2-oxopropyl)benzoate (2.10 g, 10.9 mmol) and ammonium acetate (8.40 g, 10.9 mmol) in methanol (45 ml), stirring at room temperature for 18 h. After that the solvent was evaporated off and the resi¬ due was partitioned in a mixture of dicloro¬ methane:water, 1:1 (100 ml). The aqueous phase was alka- linized with IN NaOH and extracted with dicloromethane (3x50 ml), then dried and the solvent was evaporated off under reduced pressure to obtain a residue which was pu¬ rified by chromatography through a silica gel column eluting with chloroform:methanol, 97:3, thereby obtai¬ ning 1,36 g of the title compound (64% yield). ¹H N.M.R. (300 MHz, CDC1₃) δ ppm: 1.02 (d, 3H); 1.91 (s broad, 2H); 2.52 (dd, IH); 2.68 (dd, IH); 3.80 (s, 3H); 7.16 (d, 2H); 7.87 (d, 2H).

19E Methyl 4-T2-f T7-(2-αuinolinylmethvloxv -2-naphthvll- sulfonila inolpropvllbenzoate

Following the process described in example 13 (point D), starting from sodium 7-(2-quinolinylmethyl- oxy)-2-naphthylsulfonate and methyl 4-(2-amino- propyl)benzoate, the title compound was prepared which was purified by chromatography through a silica gel co¬ lumn eluting with petroleum ether:chlorofor , 2:8 (75% yield) . -E N.M.R. (300 MHz, CDC1₃) δ ppm: 1.12 (d, 3H); 2.68 (d, 2H); 3.60 (m, IH) ; 3.84 (s, 3H); 5.14 (d, IH); 5.47 (s, 2H); 6.99 (d, 2H); 7.24 (s, IH); 7.41 (dd, IH); 7.50 (dd, IH); 7.53 (t, IH); 7.64 (d, IH); 7.67-7.81 (sc, 6H); 8.11 (s, IH); 8.12 (d, IH); 8.18 (d, IH). 121 4-r2-rr7-(2-Ouinolinylmethyloxy)-2-naphthyl1sulfo- nvlaminolpropvllbenzoic _______

Following the process described in example 3 (point E), starting from methyl 4-[2-[[7-(2-quinolinylmethyl- oxy)2-naphthyl]εulfonylamino]propyl]benzoate, the title compound was prepared as a white solid with melting point 221-224"C which was purified by digestion in ethyl ether (85% yield)

-E N.M.R. (300 MHz, DMSO) δ ppm: 0.91 (d, 3H); 2.68 (d, 2H); 3.48 (m, IH); 5.54 (s, 2H); 7.17 (d, 2H); 7.48 (dd, IH); 7.56 (dd, IH); 7.63 (t, IH); 7.69 (ε, IH); 7.71 (d, 2H); 7.78 (d, IH); 7.79-7.84 (m, 2H); 7.94 (d, IH); 7.96 (d, IH); 8.02 (d, IH); 8.08 (d, IH); 8.23 (s, IH); 8.46

(d, IH).

Example 2J_ 5-r4-f2-T T7-(Ouinolinvlmethvloxvl-2- naphthvllsulfonylamino Ipropvllphenvn-l t-tetrazole 2QA 4-(2-Nitrp-l-prppenγl)benzpnitrile

Following the proceεs described in example 19 (point B), starting from 4-formylbenzonitrile, the title compound was prepared (85% yield).

¹H N.M.R. (300 MHz, CDC1₃) δ ppm: 2.44 (ε, 3H); 7.54 (d, 2H); 7.76 (d, 2H); 8.05 (s, IH).

2QB 4-(2-Qχpprppγl)benzpnitrile

Following the process described in example 19 (point C), starting from 4-(2-nitro-l-pro- penyl)benzonitrile, the title compound was prepared (87% yield).

-E N.M.R. (300 MHz, CDC1₃) δ ppm: 2.22 (s, 3H); 3.80 (s, 2H); 7.31 (d, 2H); 7.63 (d, 2H) .

2QC 4-(2-Aminpprppγl)benzpnit;τile

Following the process described in example 19 (point D), starting from 4-(2-oxopropyl)benzonitrile, the title compound was prepared (67% yield). ¹H N.M.R. (300 MHz, CD₃OD) δ ppm: 1.09 (d, 3H); 2.73 (dd, 2H); 3.17 (m, IH); 7.39 (d, 2H); 7.64 (d, 2H). 20D 4-T2-rr I- I2-Ouinolinvlmethvloxv )-2-naphthvl1sulfo- nvlaminolprπpvllbenzonitrile

Following the process described in example 13 (Point D), starting from sodium 7-(2-quinolinylmethyl- oxy)-2-naphthylsulfonate and 4-(2-aminopropyl)- benzonitrile, the title compound was prepared which was purified by chromatography through a silica gel column eluting with chloroform (72% yield). ¹H N.M.R. (300 MHz, CDC1₃) 8 ppm: 1.12 (d, 3H); 2.71 (t,

2H); 3.59 ( , IH); 4.70 (d, IH); 5.52 (ε, 2H); 7.03 (d,

2H); 7.26 (t, 3H); 7.47 (m, 2H); 7.57 (t, IH); 7.70-7.87

(sc, 5H); 8.13 (s, IH); 8.13 (d, IH); 8.22 (d, IH) . 20E 5-r4-T2-T Γ I- (Ouinolinvlmethvloxv)-2-naphthvl1sulfo- nγlaminplprppγllphenγll-1/.-tetrazple

Follov/ing the process described in example 2, star¬ ting from 4-[2-[[7-(2-quinolinylmethγloxy)-2-naphthyl]- sulfonylamino]propyl]benzonitrile, the title compound was prepared as a white solid with melting point 128- 130"c which was purified by chromatography through a silica gel column eluting with chloroform:methanol, 96:4 (83% yield) . ^XE N.M.R. (300 MHz, DMSO) 5 ppm: 0.97 (d, 3H); 2.66 ( , 2H); 3.49 (m, IH); 4.70 (d, IH); 5.48 (s, 2H); 7.24 (d, 2H); 7.33 (dd, IH); 7.50 (d, IH); 7.60 (s, IH); 7.63 (t, IH); 7.69 (d, 2H); 7.69-7.87 (sc, 5H); 8.02 (d, IH); 8.06 (d, IH); 8.12 (s, IH); 8.46 (d, IH) . Example 21; 3-Fluprp-4-T -rr7-(2-quinplinγlmethγlpχy)-2- naohthvl Isulfonvlaminolpropvllbenzoic acid

21A Methvl 3-fluoro-4-formvlbenzoate

Following the process described in example 4 (point

A), starting from 3-fluoro-4-formylbenzoic acid, the title compound was prepared (quantitative yield). ¹H N.M.R. (300 MHz, CDC1₃) δ ppm: 3.97 (s, 3H) ; 7.79 (d,

IH); 7.89 (m, 2H); 10.39 (s, IH).

21B Methyl 3-f1UPΓP-4-( -nitrp-l-prppenγl)benzpate

Following the proceεε described in example 19 (point B), starting from methyl 3-fluoro-4-formylbenzo- ate, the title compound was prepared (65% yield).

¹H N.M.R. (300 MHz, CDC1₃) 8 ppm: 2.40 (ε, 3H); 3.96 (s, 3H); 7.47 (t, IH); 7.80 (dd, IH); 7.91 (dd, IH); 8.07

(s, IH).

21C Methvl 3-fluoro-4-f2-oxopropylϊbenzoate

Following the process described in example 19 (point C), starting from methyl 3-fluoro-4-(2-nitro-l- propenyl)benzoate, the title compound was prepared (90% yield) .

^XH N.M.R. (300 MHz, CDC1₃) δ ppm: 2.21 (s, 3H); 3.81 (ε,

2H); 3.89 (s, 3H); 7.24 (t, IH); 7.68 (d, IH); 7.76 (d, IH).

21D Methvl 4-f2-aminopropvli-3-fluorobenzoate

Following the procesε described in example 19 (point D), starting from methyl 3-fluoro-4-(2-oxo- propyl)benzoate, the title compound was prepared (76% yield) .

¹H N.M.R. (300 MHz, CDC1-) δ ppm: 1.13 (d, 3H); 1.87 (s broad, 2H); 2.68 (dd, IH); 2.77 (dd, IH); 3.23 (m, IH); 7.28 (t, IH); 7.69 (d, IH) ; 7.77 (d, IH) . 21E Methyl 3- luoro-4-r -\ \l-i2-σuinolinvlmethvloxv)-2- naphthvl Isulfonylaminolpropvllbenzoate

Following the process described in example 13 (point D), starting from sodium 7-(2-quinolinylmethyl- oxy)-2-naphthylsulfonate and methyl 4-(2-aminopropγl)-3- fluorobenzoate, the title compound was prepared which waε purified by chromatography through a silica gel co¬ lumn eluting with petroleum ether:chloroform, 1:4 (65% yield) .

¹H N.M.R. (300 MHz, CDC1₃) δ ppm: 1.21 (d, 3H); 2.70 (d, 2H); 3.66 (m, IH); 3.84 (s, 3H); 4.79 (d, IH); 5.50 (s, 2H); 6.99 (t, IH) ; 7.23 (s, IH); 7.25 (dd, IH); 7.39 (d, 2H); 7.49 (dd, IH); 7.56 (t, IH); 7.67 (d, IH); 7.72- 7.78 (sc, 3H); 7.83 (d, IH); 8.05 (s, IH ) ; 8.13 (d,

IH); 8.21 (d, IH).

21F 3-Fluoro-4-r2-fT7-(2-αuinolinγlmethyloχy)-2- naphthyllsulfonylaminoloropvllbenzoic acid Following the procesε described in example 3 (point

E), starting from methyl 3-fluoro-4-[2-[[7-(2-quinoli- nylmethyloxy)-2-naphthyl]εulfonyla ino]propyl]benzoate, the title compound waε prepared as a white solid with melting point 228-230^βC which was purified by digeεtion in ethyl ether (77% yield). E N.M.R. (300 MHz, DMSO) 5 ppm: 0.94 (d, 3H); 2.68 (d, 2H); 3.48 (m, IH); 5.54 (s, 2H); 7.28 (t, IH); 7.35 (d, IH); 7.46-7.54 (m, 3H); 7.67 ( , 2H); 7.77-7.95 (sc, 5H); 8.02 (d, IH); 8.07 (d, IH); 8.18 (s, IH); 8.46 (d, IH).

Example 22: 3-Methoxv-4-r2-fT7-f2-σuinolinvlmethvloxvϊ- 2-naphthvllsulfonylaminolpropvllbenzoic acid 22A Methvl 4-methvl-3-methoxvbenzoate

Potasεium carbonate (4.54 g, 32.9 mmol) and methyl iodide (3.07 ml, 49.3 mmol) were added in succesεion to a solution of 3-hydroxy-4-methylbenzoic acid (2.5 g, 16.4 mmol) in acetone (30 ml), stirring at reflux for 18 h. After that, the solution was filtered and the fil¬ trate was washed with water (20 ml). The organic phase was dried and the solvent was evaporated off under redu¬ ced presεure, thereby obtaining 3.18 g of the title com¬ pound (quantitative yield).

¹H N.M.R. (300 MHz, CDC1₃) δ ppm: 2.25 (s, 3H); 3.85 (s, 3H); 3.88 (s, 3H); 7.15 (d, IH); 7.48 (s, IH); 7.55 (d, IH). 22B Methvl 4-fdibromomethyl)-3-met.hoxvbenzoate

Following the procesε described in example 9 (point

A), starting from methyl 4-methyl-3-methoxybenzoate and

2 equivalents of N-bromosuccinimide, the title compound was prepared (quantitative yield).

*H N.M.R. (300 MHz, CDC1₃) δ ppm: 3.91 (s, 3H); 3.92 (s,

3H); 7.11 (s, IH); 7.48 (d, IH); 7.67 ( d, IH); 7.89 (d,

IH).

22C Methvl 4- ormvl-3-methoxybenzoate Water (3 ml) was added to a mixture of methyl 4- (dibromo ethyl)-3-methoxybenzoate (1.80 g, 4.81 mmol) and calcium carbonate (1.64 g, 16.3 mmol), stirring at reflux for 2 h. After that, water (10 ml) and a 0.2N HCl solution (10 ml) were poured onto the cooled mixture which was extracted with ethyl ether (4x25 ml). The ether phase was dried and the solvent was evaporated un¬ der reduced pressure to obtain 0.86 g of the title com¬ pound (91% yield) . ¹H N.M.R. (300 MHz, CDC1₃) δ ppm: 3.94 (s, 3H); 3.98 (s, 3H); 7.61 (s, IH); 7.62 (d, IH); 7.81 (dd, IH) ; 10.47 (s, IH). 22D Methvl 3-methoxv-4-(2-nitro-l-propenvl)benzoate

Following the proceεs described in example 19 (point B), starting from methyl 4-formyl-3-methoxγbenzo- ate, the title compound was prepared (quantitative yield) .

^XH N.M.R. (300 MHz, CDC1₃) δ ppm: 2.37 (s, 3H); 3.93 (s, 3H); 3.94 (ε, 3H); 7.34 (d, IH); 7.60 (ε, IH); 7.68 (d, IH); 8.20 (s, IH). 22E Methvl 3-methoxv-4-(2-oxopropvl)benzoate

Following the process described in example 19 (point C), starting from methyl 3-methoxy-4-(2-nitro-l- propenyl)benzoate, the title compound was prepared (65% yield) .

-E N.M.R. (300 MHz, CDC1-) δ ppm: 2.15 (s, 3H); 3.72 (s, 2H); 3.86 (s, 3H); 3.90 (s, 3H); 7.18 (d, IH); 7.54 (d,

IH); 7.62 (dd, IH).

22F Methyl 4-f2-aminopropyl -3-methoxybenzoate

Following the process described in example 19

(point D), starting from methyl 3-methoxy-4-(2-oxo- propyl)benzoate, the title compound was prepared which was purified by chromatography through a silica gel co¬ lumn eluting with chloroform:methanol, 99:1 (85% yield). ¹H N.M.R. (300 MHz, CDC1₃) 5 ppm: 1.11 (s, 3H); 1.92 (s broad, 2H); 2.63 (dd, IH); 2.76 (dd, IH); 3.22 (m, IH); 3.86 (ε, 3H); 3.90 (ε, 3H); 7.19 (d, IH); 7.51 (d, IH); 7.58 (dd, IH).

225. 3-Methoxv-4- Ϊ 2- T Ϊ 1- 12-αuinolinvlmethvloxv )-2- naohthvl1sulfonvlaminoloropvlIbenzoic acid

Following the procesε described in example 13 (point D), starting from sodium 7-(2-quinolinylmethyl- oxy)-2-naphthylεulfonate and methyl 4-(2-aminopropyl)-3- ethoxybenzoate, the title compound waε prepared which was purified by chromatography through a silica gel co¬ lumn eluting with chloroform (64% yield). -E N.M.R. (300 MHz, CDC1₃) δ ppm: 1.22 (d, 3H); 2.54 (m, 2H); 3.41 (s, 3H); 3.60 ( , IH); 3.78 (s, 3H); 5.38 (d, IH); 5.42 (s, 2H); 6.79 (d, IH); 6.87 (s, IH); 7.12 (s, IH); 7.13 (dd, IH); 7.29-7.35 (m, 3H); 7.62-7.74 (sc, 5H); 7.94 (s, IH); 8.07 (d, IH); 8.11 (d, IH). _-2_- 3-MethPχγ-4-r2-r ϊ7-(2-guinplinγlmethγlPXY)-2- naphthγllsυlfpnγlaminplprppγl1benzcic acid

Following the process described in example 3 (point

E), starting from methyl 3-methoxy-4-[2-[[7-(2-quinoli- nylmethyloxy)-2-naphthyl]sulfonylamino]propyl]benzoate, the title compound was prepared as a white solid with melting point 186-187"C (94% yield).

-E N.M.R. (300 MHz, DMSO) δ ppm: 0.95 (d, 3H); 2.57 (m,

2H); 3.48 (s, 3H); 3.51 (m, IH) ; 5.56 (s, 2H); 7.10 (s, IH); 7.12 (d, IH); 7.36 (d, IH); 7.50 (m, 2H); 7.64 (t,

IH); 7.69 (s, IH); 7.77-7.84 (m, 3H); 7.85 (d, IH); 7.94

(d, IH); 8.02 (d, IH); 8.07 (d, IH); 8.20 (s, IH); 8.46

(d, IH).

Example 23: 4-f2-rT7-f2-Ouinolinvlmethvloxv)-2- naohthvllsulfonylaminolethvllphenvlacetic

23A 4-fCvanomethvl^Phenvlacetic acid

Following the process described in example 9 (point

B), starting from 4-(bromomethyl)phenγlacetic acid, the title compound was prepared (92% yield). -E N.M.R. (300 MHz, CD₃OD) δ ppm: 3.65 (s, 2H); 3.70 (s,

3H); 7.30 (s, 4H) .

23B Methyl 4-(cvanomethylϊphenvlacetate

Following the process described in example 4 (point

A), starting from 4-(cyanomethyl)phenylacetic acid, the title compound was prepared (60% yield).

¹H N.M.R. (300 MHz, CDCI3) δ ppm: 3.60 (s, 2H) ; 3.66 (s,

3H); 3.68 (s, 2H); 7.26 (ε, 4H).

23C Methvl 4-f2-aminoethvl )phenvlacetate

Following the process described in example 16 (point C), starting from methyl 4-(cyano- methyl)phenylacetate, the title compound was prepared as the hydrochloride (85% yield).

¹H N.M.R. (300 MHz, CD₃OD) 6 ppm: 3.00 (t, 2H) ; 3.21 (t,

2H); 3.69 (s, 2H) ; 3.71 (s, 3H); 7.30 (s, 4H) .

23D Methyl 4-T2~r f7-f2-αuinolinvlmethvloxv)-2-naphthvl1- sulfonylaminolethvllphenylacetate

Following the proceεε deεcribed in example 13

(point D), starting from sodium 7-(2-quinolinylmethyl- oxy)-2-naphthylεulfonate and methyl 4-( 2-aminoethyl )- phenylacetate, the title compound was prepared which was purified by chromatography through a εilica gel column eluting with petroleum ether :chloroform 3:7 (55% yield). ¹H N.M.R. (300 MHz, CDC1₃) δ ppm: 2.85 (t, 2H); 3.35 (q, 2H); 3.67 (s, 2H); 3.80 (s, 3H); 5.32 (t broad, IH); 5.61 (s. 2H); 7.13 (d, 2H); 7.24 (d, 2H) ; 7.45 (s, IH); 7.56 (dd, IH) ; 7.68 (t, IH) ; 7.77 (dd, IH) ; 7.81 (d, IH); 7.87 (dt, IH); 7.92-7.97 (m, 3H); 8.25 (d, IH); 8.32 (d, IH); 8.39 (s, IH).

23E 4-r2-rr7-f2-Ouinolinylmethyloxy)-2-naphthyllsulfo- nvlaminolethvllphenvlacetic acid Following the process described in example 3 (point E), starting from methyl 4-[2-[ [7-( 2-quinolinylmethyl- oxy)-2-naphthyl]sulfonylamino]ethyl]phenylacetate, the title compound was prepared as a white solid with mel¬ ting point 217-219'C (92% yield). ¹H N.M.R. (300 MHz, DMSO) δ ppm: 2.68 (t, 2H) ; 2.99 (q, 2H); 3.19 (s, 2H); 5.54 (ε, 2H); 7.07 (d, 2H); 7.12 (d, 2H); 7.53 (dd, IH) ; 7.65 (t, IH); 7.68 (ε, IH); 7.74- 7.85 (m, 4H); 8.00-8.08 (m, 4H), 8.30 (s, IH); 8.46 (d, IH) . Example 2_ϋ 4-T2-r T7-(2-Qu.inplinγlmet_-γloχγ)-2- naphthvllsulfonylaminolpropylIphenvlacetic acid 24A 4-FormylPhenylacetic acid

A mixture of 4-(bromomethyl)phenγlacetic acid (4.14 g, 18.2 mmol), hexamethylenetetramine (3.06 g, 21.9 mmol), water (8 ml) and glacial acetic acid (8 ml) was refluxed with stirring for 2.5 h. After this time, 0.2 ml of concentrated HCl were added, stirring at the tem¬ perature of reflux for a further 15 minutes. Subsequen- tly the mixture was left to cool, extracted with ethyl ether (4x25 ml) and dried, and the solvent was evapora¬ ted off to obtain 1.93 g of the title compound (88% yield) . ¹H N.M.R. (300 MHz, CDC1₃) δ ppm: 3.78 (s, 2H); 7.45 (d, 2H); 7.86 (d, 2H); 9.99 (s, IH) . 24B Methvl 4-formvlphenvlacetate

Following the process described in example 4 (point A), starting from 4-formylphenylacetic acid, the title compound was prepared (96% yield). ^-H N.M.R. (300 MHz, CDC1₃) δ ppm: 3.66 (s, 2H); 3.70 (s, 3H); 7.43 (d, 2H); 7.79 (d, 2H); 9.94 (s, IH). 24C Methvl 4-f2-nitro-l-propenvl)phenvlacetate

Following the process described in example 19 (point B), starting from methyl 4-formylphenylacetate, the title compound was prepared (65% yield).

¹H N.M.R. (300 MHz, CDC1₃) δ ppm: 2.44 (s, 3H); 3.69 (s, 2H); 3.70 (s, 3H); 7.38 (s, 4H); 8.05 (s, IH). 24D Methyl 4-foxoproovl)phenvlacetate

Following the process described in example 19 (point C), starting from methyl 4-(2-nitro-l-pro- penyl)phenylacetate, the title compound waε prepared (88% yield) .

¹H N.M.R. (300 MHz, CDC1₃) δ ppm: 2.12 (s, 3H); 3.59 (s,

2H); 3.64 (s, 7H); 7.14 (d, 2H) ; 7.22 (d, 2H) .

Following the process described in example 19

(point D), starting from methyl 4-(2-oxo- propyl Jphenylacetate, the title compound was prepared

(62% yield) .

¹H N.M.R. (300 MHz, CDC1₃) δ ppm: 1.09 (d, 3H); 1.99 (s broad, 2H); 2.50 (dd, IH) ; 2.68 (dd, IH); 3.12 (m, IH); 3.58 (s, 2H); 3.65 (s, 3H); 7.13 (d, 2H); 7.19 (d, 2H). 24F Methvl 4-f2-T T7-(2-αuinolinvlmethvloxv)-2-naphthvl1- sulfonvla inolpropvllphenylacetate

Following the process described in example 13 (Point D), starting from sodium 7-(2-quinolinylmethyl- oxy)-2-naphthylεulfonate and methyl 4-(2-amino- propyl)phenylacetate, the title compound was prepared which was purified by chromatography through a silica gel column eluting with petroleum ether:chloroform, 4:6 (55% yield) .

¹H N.M.R. (300 MHz, CDC1₃) δ ppm: 1.05 (d, 3H) ; 2.61 (d, 2H); 3.45 (s, 2H); 3.52 (m, IH); 3.64 (s, 3H) ; 5.65 (d, IH); 5.49 (s, 2H) ; 6.88 (d, 2H); 6.97 (d_. 2H) ; 7.29 (d, IH); 7.41 (dd, IH); 7.48 (dd, IH); 7.54 (t, IH) ; 7.67 (d, IH); 7.73-7.80 (sc, 4H) ; 8.10 (d, IH) ; 8.17 (s, IH); 8.18 (d, IH).

2AS. 4-r2-rr7-f2-Ouinolinvlmethvloxv^-2-naphthvllsul¬ fonylaminoIpropvllphenvlacetic acid

Following the process described in example 3 (point E), starting from methyl 4-[2-[[7-(2-quinolinylmethyl- oxy)-2-naphthyl]sulfonylamino]propyl]phenylacetate, the title compound waε prepared as a white solid with melting point 212-213'C (85% yield).

¹H N.M.R. (300 MHz, DMSO) δ ppm: 0.83 (d, 3H); 2.47 (dd,

IH); 2.58 (dd, IH); 3.38 (m, IH); 3.39 (s, 2H); 5.51 (s, 2H); 6.93 (d, 2H) ; 6.98 (d, 2H) ; 7.47 (dd, IH); 7.52

(dd, IH); 7.61 (dt, IH); 7.69-7.81 (sc, 4H); 7.93-8.00

(sc, 3H); 8.03 (d, IH); 8.24 (s, IH); 8.43 (d, IH) .

Example 25: 4- ϊ1-f f7-f2-Ouinolinylmethyloxyϊ-2- naphthvl Isulfonvlaminolethvπphenvlacetic acid 25A Methvl 4-acetYlPhenYlacetate and methvl 2-acetvl- henvlacetate

Aluminium trichloride (19.58 g, 0.145 mol) was ad¬ ded to a mixture of methyl phenylacetate (10.0 g, 0.066 mol) and acetyl chloride (9.42 ml, 0.132 mol). The mixture was kept under stirring at 90°C for 4 h, then it waε left to cool, added slowly with water (30 ml) and extracted with ethyl ether (4x30 ml). The combined ether extracts were dried and the solvent was evaporated off under reduced pressure. The resulting oily residue was distilled under high vacuum (0.1 torr) to obtain 10.1 g of a distilled oil which was a mixture 1:1 of the two title iso ers (84% total yield).

¹H N.M.R. (300 MHz, CDC1₃) of the isomer para δ ppm: 2.62 (ε, 3H); 3.72 (ε, 5H); 7.41 (d, 2H); 7.95 (d, 2H) . ¹H N.M.R. (300 MHz, CDC1₃) of the isomer ortho δ ppm: 2.62 (s, 3H); 3.72 (s, 5H); 7.46 (t, IH); 7.52 (t, IH); 7.90 (m, 2H).

Following the process described in example 19 (point D), starting from the isomer mixture obtained in point A of example 25, a 1:1 mixture of the title isomers waε obtained (67% total yield).

¹H N.M.R. (300 MHz, CDC1₃) of the iεomer para δ ppm:

1.33 (d, 3H); 1.57 (ε broad, 2H); 3.58 (ε, 2H); 3.64 (ε, 3H); 4.05 (q, IH); 7.22 (ε, 4H).

¹H N.M.R. (300 MHz, CDC1₃) of the isomer orto δ ppm:

1.32 (d, 3H); 1.57 (s broad, 2H); 3.56 (s, 2H) ; 3.63 (s,

3H); 4.05 (q, IH); 7.10-7.24 (m, 4H).

25C Methyl 4-fl-rT7-f2-αuinolinylmethyloxy)-2-naphthyll- sulfonyla-minolethyllphenylacetate and methvl 2~ \ l- l l l~ f2-Ouinolinylmethyloxy)-2-naphthvl1sulfonylaminolethvll- henvlacetate

Following the process described in example 13 (point D), starting from sodium 7-(2-quinolinylmethyl- oxy)-2-naphthylsulfonate and the isomer mixture obtained in point B of example 25, a mixture of the title isomers was prepared. The isomer methyl 4-[l-[[7-(2-quino- linylmethyloxy)-2-naphthyl]sulfonylamino]ethyl]phenyl¬ acetate was separated from the mixture by crystallization with petroleum ether:chloroform mixtures (30% yield), whereas the isomer methyl 2-[l-[[7-(2-qui- nolinylmethyloxy)-2-naphthyl]sulfonylamino]ethyl]phenyl¬ acetate waε recovered from crystallization mother liquors once separated the isomer para (36% yield). -E N.M.R. (300 MHz, CDC1₃) of the isomer para 8 ppm: 1.41 (d, 3H); 3.41 (s, 2H); 3.66 (s, 3H); 4.50 (m, IH); 5.29 (d, IH); 5.53 (ε, 2H); 6.98 (d, 2H); 7.05 (d, 2H); 7.27 (d, IH); 7.44 (dd, IH); 7.58 (dd, IH); 7.60 (t, IH); 7.72 (d, IH); 7.76-7.88 (sc, 4H); 8.13 (s, IH); 8.18 (d, IH); 8.24 (d, IH).

^-H N.M.R. (300 MHz, CDC1₃) of the isomer ortho 8 ppm: 1.38 (d, 3H); 3.25 (s, 2H ) ; 3.60 (s, 3H ) ; 4.50 (m, IH);

5.48 (s, 2H); 5.79 (d, IH ) ; 6.85-7.05 (sc, 4H ) ; 7.20 (d,

IH); 7.38 (dd, IH); 7.53 (t, IH ) ; 7.58 ( dd , IH); 7.74

(d, IH); 7.78-7.85 ( sc , 4H ) ; 8.05 (s, IH ) ; 8.13 (d, IH); 8.18 (d, IH).

2__J_ 4-ri-rr7-(2-QuinplinylmethγlPxv)-2-naPhthγl1su,lfp- nvlaminolethvllphenvlacetic acid

Following the process described in example 3 (point

E), starting from methyl 4-[l-[[7-(2-quinolinylmethyl- oxy)-2-naphthyl]sulfonylamino]ethyl]phenylacetate, the title compound was prepared as a white solid with melting point 204-206'C which was purified by crystallization in methanol (92% yield).

^XE N.M.R. (300 MHz, DMSO) δ ppm: 1.16 (d, 3H); 3.17 (d, 2H); 4.36 ( , IH); 5.53 (s, 2H); 6.98 (d, 2H) ; 7.11 (d,

2H); 7.48 (dd, IH); 7.59 (dt, IH) ; 7.61-7.66 (εc, 2H);

7.75-7.83 (εc, 2H) ; 7.94-8.08 (εc, 4H); 8.15 (s, IH) ;

8.22 (d, IH); 8.46 (d, IH).

Example 26: 2-Tl-r ϊ7-( 2-Ouinolinylmethyloxy )-2- naphthyllsulfonylaminolethyllphenylacetic acid

Following the process described in .example 3 (point

E), starting from methyl 2-[l-[ [7-( 2-quinolinylmethyl- oxy)-2-naphthyl]sulfonylamino]ethyl]phenylacetate, the title compound was prepared as a white solid with mel- ting point 185-186^*C which was purified by crystallization in methanol (92% yield).

^^■H N.M.R. (300 MHz, DMSO) δ ppm: 1.17 (d, 3H); 3.17 (d,

2H); 4.38 (m, IH) ; 5.52 (s, 2H); 6.90-7.15 (sc, 4H) ;

7.48 (dd, IH); 7.59 (dt, IH); 7.61-7.66 (sc, 2H); 7.75- 7.83 (sc, 2H); 7.94-8.08 (sc, 4H); 8.12 (ε, IH); 8.25

(d, IH); 8.46 (d, IH). Biological activity tests

The antagonistic activity on LTD₄ of the compoundε of the present invention is determined by means of an inhibition test of the [^H]-LTD₄ receptor binding in guinea-pig lung membranes, and a test of inhibition of

LTD^-induced contractions in the myenteric plexus of guinea-pig isolated ileum.

lung membranes 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 M of CaCl_2/ 10 mM of 5 MgCl₂, 2 M 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 M Tris-HCl (pH 7.4) and 100 mM NaCl) at 0^βC 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^βC. 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^) by means of the Cheng-Prusoff equation (Cheng et al., Biochem. Pharmacol., 22, 3094 (1973)).

K_i = IC₅₀ / (1 + [L] / K_d) wherein IC_5Q is the concentration of compound which displaces a 50% of the bound radioligand, [ ] is the concentration of [³H]LTD₄ free in the test and K_d is the dissociation constant of the TD₄ obtained in an independent way by means of Scatchard analysis.

The selected compounds of general formula I show in the described test, inhibition of the receptor binding Ki ranging between 1000 and 0.1 nM. Inhibition test of the contractions induced bv TD^ in the mventeric plexus of αuinea-pjg isolated ileum.

The antagonistic activity of the compounds of the present invention in the isolated organ was evaluated as its ability to inhibit the contraction caused by LTD₄ in the myenteric plexus of the ileum of Dunkin Hartley male albino guinea-pig, weighing 300-350 g (Cristol J.P. and Sirois P. Res. Commun. Chem. Pathol., !___., 423 (1988)).

The smooth muscle of guinea-pig ileum exhibits εenεitivity to leukotrieneε and eεpecially to LTD₄, which actε aε primary mediator in the inflammatory and allergic response (Carnathan G.W. et al. Agents Actions, __£), 124 (1987)).

The myenteric plexus is extracted from a 2-3 cm segment of the terminal portion of the guinea-pig ileum, previously sacrificed by cervical dislocation. The plexus is put, at a tension of 0.5 g, in a 5 ml organ bath, containing a solution of Tyrode (137 M NaCl, 2.7 M KCI, 1.4 mM CaCl₂, 0.4 mM NaH-P0₄, 11.9 mM NaHC0₃,

0.8 mM MgS0₄, 5.5 mM glucose), saturated with carbogen gas (95% 0₂-5% C0₂) at 37^βC. The solution also contains indomethacin (3.3 μM) and atropine (0.4 μM) to remove the action of the intrinsic prostaglandins and the cholinergic responses.

After a 45 minute stabilization period a maximum isotonic response is obtained (100% contractile response) adding to the bath chamber the LTD₄ agonist (3 nM). This process is repeated until the same contraction response is obtained twice. The isometric measures are made in an isotonic transducer.

After stabilization is restored, the product under test is incubated at different concentrations (disεolved in 0.1% final concentration DMSO) for 2.5 minutes, and after that the contraction with LTD₄ is induced again. The antagonistic activity is expresεed aε IC_5Q, the concentration of compound which reduceε by 50% the maximum contraction.

The εelected compoundε of general formula I εhow in the deεcribed test inhibition of the contractions in the myenteric plexus of ileum IC^ ranging between 100 and 0.1 nM.

Claims

__LΔI2___

A compound of formula I,

wherein: the εubεtituent containing A iε bound to the 6- or 7- position of the 2-naphthol system;

-R¹, R², R⁶ are independently hydrogen, fluorine, chlorine, bromine, -OCH₃ or (C^-C₄)-alkyl; -R³ is hydrogen or methyl;

-R⁴, R⁵ are independently hydrogen, -OH, -NH₂, (C₁-C₄)- alkyl, (C₁-C₄)-alkoxy, (C₁-C₄)-alkylamino, (C₁-C₄)- alkoxycarbonyl, (C₁-C₄)-alkylcarbonylamino, (C₁-C₄)- alkoxycarbonylalkyl, carbamoyl, carbamoylalkyl, N,N- dialkylcarbamoylalkyl;

-A- is a diradical -0-, -S-, -S0₂-, -SO-, -S0₂NR⁷- or

-NR⁷S0₂- wherein R⁷ is hydrogen or methyl;

-B is a sulfur or oxygen atom or a -S0₂- or -SO- group or a εingle bond; -D iε a 5-tetrazolyl or -C00R⁸ group, wherein R⁸ iε hydrogen, a

)-alkyl or a phenylalkyl group of less than 10 carbon atoms; m is an integer from 0 to 4; n and p are integers from 0 to 6, with the proviso that n + p is less or equal to 6.

2. A compound according to claim 1 wherein R² is hydrogen, D is a 5-tetrazolyl or COOR⁸ group, and R⁸ is hydrogen, methyl, ethyl or benzyl.

3. A compound according to any one of claims 1 or 2 wherein R^- is hydrogen or chlorine, and -A- iε -0-, -S-, -S0₂NR⁷- or -NR⁷S0₂~, wherein R⁷ iε hydrogen or methyl.

4. A compound according to any one of claimε 1 a 3 wherein the substituent containing A is bound to the 7- poεition of the 2-naphthol ring.

5. A compound according to claim 4 wherein m iε 0 and -A- is -O- or -S-.

6. A compound according to claim 4 wherein m is 1 and -A- is -0- or -S-.

7. A compound according to claim 4 wherein m is 0 and -A- is -S0 NR⁷-, wherein R⁷ is hydrogen or methyl.

8. A compound according to claim 4 wherein n and p are integers from 0 to 4.

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

4-[3-[7-(2-quinolinylmethyloxy)-2-naphthyloxy]propyl]- benzoic acid;

5-[4-[3-[7-(2-quinolinylmethyloxy)-2-naphthyloxy]pro¬ pyl]-phenyl]-lH-tetrazole;

4-[3-[7-(2-quinolinylmethyloxy)-2-naphthyloxy]butyl]- benzoic acid; 4-[2-[7-(2-quinolinylmethyloxy)-2-naphthyloxγ]ethoxγ]- benzoic acid;

4-[2-[7-(2-quinolinylmethyloxy)-2-naphthylmethyloxy]- ethyl]benzoic acid;

4-[7-(2-quinolinylmethyloxy)-2-naphthγlmethyloxymethyl]- benzoic acid;

4-[2-[[7-(2-quinolinylmethyloxy)-2-naphthyl]sulfonylami- no]ethyl]benzoic acid;

N-methyl-4-[2-[[7-(2-quinolinyl-methyloxy)-2-naphthγl]- εulfonylamino]ethyl]benzoic acid;

4-[2-[[7-(2-quinolinylmethγloxγ)-2-naphthyl]sulfony1- amino]methyl]benzoic acid;

4-[2-hydroxy-3-[7-(2-quinolinylmethyloxγ)-2-naphthyl- oxy]propyloxγ]benzoic acid;

5-[4-[2-[7-(2-quinolinylmethyloxy)-2-naphthylmethyloxy]- ethy1]phenyl]-lH-tetrazole; 3-fluoro-4-[2-[7-(2-quinolinylmethyloxy)-2-naphthylme- thyloxy]ethyl]benzoic acid;

2-fluoro-4-[2-[7-{2-quinolinylmethyloxy)-2-naphthγl- methγloxy]ethyl]benzoic acid;

3-methoxy-4-[2-[7-(2-quinolinylmethyloxy)-2-naphthyl- methγloxy]ethγl]benzoic acid;

3-_2-[7-(2-quinolinγlmethyloxy)-2-naphthylmethyloxγ]- ethyl]benzoic acid;

4-[2-[7-(2-quinolinγlmethyloxγ)-2-naphthylmethylthio]- ethyl]benzoic acid; 3-fluoro-4-[2-[[7-(2-quinolinylmethyloxy)-2-naphthyl]- sulfonylamino]ethyl]benzoic acid;

4-[l-methyl-2-[7-(2-quinolinylmethyloxy)-2-naphthylsul- fonylamino]ethyl]benzoic acid;

4-[1,1-dimethy1-2-[7-(2-quinolinylmethyloxy)-2-naphthyl- sulfonylamino]ethyl]benzoic acid;

4-[2-1[7-(2-quinolinylmethyloxγ)-2-naphthyl]sulfonylami- no]propyl]benzoic acid;

5-[4-[2-[[7-(2-quinolinylmethyloxy)-2-naphthy1]sulfonyl¬ amino]propyl]phenyl]-l.ϊ-tetrazole; 3-fluoro-4-[2-[[7-(2-quinolinylmethyloxy)-2-naphthy1]- sulfonylamino]propyl]benzoic acid; 3-methoxy-4-[2-[[7-(2-quinolinylmethyloxy)-2-naphthyl]- sulfonylamino]propyl]benzoic acid;

4-C2-C[7-(2-quinolinylmethyloxy)-2-naphthyl]sulfonylami- no]ethyl]phenylacetic acid;

4-[2-[[7-(2-quinolinylmethyloxy)-2-naphthyl]sulfonylami- no]propyl]phenylacetic acid;

4-[l-[[7-(2-quinolinylmethyloxy)-2-naphthyl]εulfonylami- no]ethyl]phenylacetic acid;

2-[l-[[7-(2-quinolinylmethyloxy)-2-naphthyl]sulfonylami- no]ethyl]phenylacetic acid.

10. A proceεε for the preparation of the compound of general formula I of claim 1, and the pharmaceutically acceptable εaltε thereof, in which process: a) when in formula I -A- is -0- or -S-, then a compound of general formula II,

II wherein R^-, R², R³ and have the above defined meanings and A is oxygen or sulfur, is reacted with a compound III,

III wherein R⁴, R5, R⁶, B, n and p have the above defined meaningε, X iε a chlorine or bromine atom or an alkyl- or arylεulfonate group and E can be equivalent to the group D in I or, when D in formula I is COOH or a 5- tetrazolyl group, then E is CN, or alternatively, when D in formula I is COOH, then E can contain a suitable carboxy-protecting group; the reaction being carried out previously preparing a salt of the alcohol or thiol II, subjecting it to the action of a suitable base, then reacting it with the compound III, to obtain a compound of formula IV,

IV which coincides with I or iε converted into I either removing any COOH-protecting groups present in E or hydrolysing the nitrile group present in E to carboxylic acid or converting said nitrile group to a 5-tetrazolγl group by reaction with sodium azide; b) alternatively, when in formula I -A- iε -0- or -S-, then a compound of formula IV iε obtained following the same process as above, starting from compounds V and VI,

VI wherein R¹, R², R³, R⁴, R⁵, R⁶, B, X, n, m and p have the above defined meanings, A is oxygen or sulfur and E represents the groups defined above with the exception of the 5-tetrazolyl group; c) when in formula I -A- is -S0₂NR⁷-, then a compound of general formula VII,

VII wherein R , R², R³ and m have the above defined meanings, is reacted with a compound VIII,

VIII wherein R' R B, E, n and p have the above defined meanings; the reaction being carried out previously preparing the acid chloride of the compound VII, then reacting it with compound VIII in the presence of a base, to obtain a compound of formula IXa,

IXa which coincides with I or is converted into I either removing any COOH-protecting groups present in E or hydrolysing the nitrile group present in E to carboxylic acid or converting said nitrile group to a 5-tetrazolyl group by reaction with sodium azide; d) when in formula I -A- is -NR⁷S0₂-, then a compound of general formula X,

wherein R¹, R², R³, R⁷ and m have the above defined meanings, is reacted with a compound XI,

XI wherein R⁴, R⁵, R⁶, R⁷, B, E, n and p have the above defined meanings; the reaction being carried out previously preparing the acid chloride of compound XI, then reacting it with compound X in the presence of a base, to obtain a compound of formula IXb,

IXb which coincides with I or is converted into I either removing any COOH-protecting groups present in E or hydrolysing the nitrile group present in E to carboxylic acid or converting said nitrile group to a 5-tetrazolyl group by reaction with sodium azide; e) alternatively, when in formula I -A- is -S0₂NR⁷- or -NR⁷S0₂-, then a compound of general formula IXa or IXb, wherein R¹, R², R³, R⁴, R⁵, R⁶, B, E, n, p and m have the above defined meanings and R⁷ iε a (C₁-C )-alkyl, can be obtained εtarting from a compound IXa or IXb where R⁷ is hydrogen, by reaction with a (C^-C₄)-alkyl chloride or bromide in the presence of a suitable base; f) when compound I in the form of a salt is desired, it can be prepared starting from I, by treatment with a base or a suitable ion-exchanger, according to conventional methods.

11. The use of a compound of any one of claims 1 to 11 in the preparation of a medicament for the therapeutical treatment of leukotriene-mediated diseases.

12. The use according to claim 11, wherein the leukotriene-mediated diseases are of inflammatory or allergic type.

13. The use according to claim 12, wherein the inflammatory or allergic diseaεeε are: bronchial asthma, allergic rhinitis, allergic conjunctivitis, rheumatoid arthritis, osteoarthritis, tendinitis, bursitiε or psoriasis.

14. The use according to claim 11, wherein the leukotriene-mediated diseaεeε are of cardiovascular type.

15. The use according to claim 14, wherein the diseases of cardiovascular type are: cardiac ischemia, cardiac infarction, coronary spasm, cardiac anaphylaxis, cerebral oedema or endotoxic shock.