WO1997005114A1

WO1997005114A1 - Quinolone sulfonimides having leukotriene-antagonistic action

Info

Publication number: WO1997005114A1
Application number: PCT/EP1996/003168
Authority: WO
Inventors: Mercedes Alvarez Domingo; David MAULEÓN CASELLAS; Maria Luisa GARCÍA PÉREZ; Maria de Los Desamparados FOS TORRÓ; Rosa GRIERA FARRÉS
Original assignee: Laboratorios Menarini S.A.
Priority date: 1995-07-31
Filing date: 1996-07-18
Publication date: 1997-02-13
Also published as: ES2108641B1; ES2108641A1; AU6657696A

Abstract

The present invention relates to novel quinolone sulfonimides of formula (I), wherein the substituent containing A is bound at the 5-, 6- or 7-position; the substituent containing COHNSO2 is bound at the 1- or 2-position of the 4-quinolone ring; R1 is bound at the 1- or 2-position of the 4-quinolone ring and is hydrogen, alkyl, -OH, -OCH¿3?, -CH2X, X is -OH, -OCH3 or -COOR?8, R8¿ being hydrogen or alkyl; R2 is hydrogen, fluorine, chlorine, alkyl or -OCH¿3; R?3 is hydrogen, fluorine, chlorine, alkyl or -OCH¿3; R?4 is hydrogen, fluorine, chlorine, or -OCH¿3; R?5 is hydrogen or methyl; R6 is alkyl, cycloalkyl or phenylalkyl; R7 is hydrogen, alkyl, -OCH¿3? or -CH2X; A is oxygen, methylene or -NR?9-; R9¿ is hydrogen or methyl. Said compounds having a leukotriene-antagonistic activity and they can be used as antiinflammatory and antiallergic agents or in the treatment of cardiovascular diseases.

Description

_{pcτ/Ep96/o3i68}

QUINOLONE SULFONIMIDES HAVING LEUKOTRIBNB-ANTAGONISTIC A J-IOJS

The present invention relates to novel quinolone sulfonimideε, the pharmaceutically acceptable salts and solvates thereof, and the pharmaceutical compositions containing them, having a leukotriene-antagonistic action. The present invention also relates to a process for the preparation of the novel quinolone sulfoni ides, as well as to the therapeutic use thereof. TECHNOLOGICA, BACKGRQVflP

It is well known that most eicosanoids, prosta- glandins, leukotrienes and related compounds derive from a fatty acid having 20 carbons and 4 unsaturations, cal¬ led 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 iε metabolized in mammals mainly by two different pathways or enzyme systems. Through cyclooxygenase it produces prosta- glandins and thromboxanes, the most significant being PGE2 and TxA₂, which are directly involved in inflam¬ mation (Higgs et al. Annals of Clinical Research, 16, 287 (1984)). Through lipo-oxygenase it produces leuko¬ trienes, 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., H, 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., 32, 9 (1991)). It has been widely shown that LTC₄ and LTD₄ have strong constricting 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 perme¬ ability (Camp et al., Br. J. Pharmacol., 80_/ 497 (1883)) and are involved in some inflammatory diseases such as atopic eczema and psoriasis. On the other hand, several effects of peptide-leukotrienes on human cardiovascular system have been observed; they are mainly involved in the pathogenesis of the ischaemic cardiopathy. This relationship has been confirmed by the fact that coronary arteries can produce these mediators (Piomelli et al., J. Clin. Res., 33, 521A (1985)). These effects, together with the strong contractions observed in heart tissue caused by LTC₄ and LTD₄, suggest that these mediators might contribute to other cardiovascular disorders, such as coronary spasm, heart anaphylaxis, cerebral oedema and endotoxic shock.

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

Matassa et al. (J. Med. Chem., 3, 1781 (1990), J.

Med. Chem., 13, 2621 (1990) and EP 199,543) disclose a series of heterocyclic compoundε having leukotriene- antagonistic activity. These compounds differ from those of the present invention in the nature of the heterocycle.

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

DISCLOSURE OF THE INVENTION

The present invention relates to novel quinolone sulfonimides of general formula I,

wherein: the substituent containing A is attached at the 5-, 6- or 7- position of the 4-quinolone ring; the substituent containing CONHS0₂ is bound at the 1- or 2- position of the 4-quinolone ring; the group R¹ is bound at the 1- or 2- position of the 4- quinolone ring, depending on the poεition of the substituent containing CONHS0₂; the group R⁴ is bound at any one of the 5-, 6-, 7- or 8- free positions of the 4-quinolone ring;

R¹ is hydrogen, straight or branched C₁-C₄-alkyl, -OH,

-OCH3, -CH₂X, wherein X is -OH, -OCH3 or -COOR⁸, wherein

R⁸ is hydrogen or straight or branched C₁-C₄-alkyl;

R² is hydrogen, fluorine, chlorine, straight or branched (C₁-C₄)-alkyl or -OCH3, and is bound at the benzene ring at any one of its free positions;

R³ is hydrogen, fluorine, chlorine, straight or branched

(C₁-C₄)-alkyl or -OCH₃, and is bound at the benzene ring at any one of its free positions; R⁴ is hydrogen, fluorine, chlorine,or -OCH₃;

R⁵ is hydrogen or methyl;

R⁶ iε straight or branched (C^-Cg)-alkyl, cycloalkyl or a phenylalkyl group of less than 10 carbon atoms;

R⁷ is hydrogen, straight or branched (C₁-C₄)-alkyl, -OCH3, -CH₂X, wherein X is -OH, -OCH3 or -COOR⁸, wherein

R⁸ is hydrogen or straight or branched C₁-C₄-alkγl;

A is an oxygen atom, a methylene group or a group -NR⁹-, wherein R⁹ is hydrogen or methyl.

The present invention also relates to a process for the preparation of the novel quinolone sulfonimides, as well as to the therapeutical uεe thereof.

The preεent invention also relates to the solvates and the pharmaceutically acceptable salts of the amides of formula I and particularly the saltε represented by formula Ia,

la wherein M⁺ is a 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 a 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 A is an oxygen atom or a methylene group, R² is -OCH3, R³ is straight (C^-C₄)-alkyl and R^ is hydrogen.

Particularly preferred the compounds of formula I wherein R² is bound at the 3- position of the benzene ring, R³ is methyl and iε bound at the 2- position of the benzene ring and R⁶ is cyclopentyl.

When the substituent containing CONHS0₂ is bound at the 1- position of the 4-quinolone ring, particularly preferred are the compounds of formula I wherein R*- and R⁷ are hydrogen.

When the substituent containing CONHS0₂ is bound at the 2- position of the 4-quinolone ring, particularly preferred are the compounds of formula I wherein R¹ is methyl and R⁷ is hydrogen.

Particularly preferred compounds of the preεent invention are the following oneε:

N- [ 4- (5-cyclopentylacetamido-l,4-dihγdro-4-oxo-quinolin- 1-yImethyl)-3-methoxybenzoyl]-2-methylbenzenesulfonami¬ de; JV-[4-(6-cyclopentylacetamido-l,4-dihydro-4-oxo-quinolin- 1-ylmethyl)-3-methoxybenzoyl]-2-methylbenzeneεulfonami¬ de;

JV-[4-(7-cyclopentylacetamido-l,4-dihydro-4-oxo-quinolin- l-ylmethyl)-3-methoxybenzoyl]-2-methylbenzeneεulfonami- de;

JV-C4-(5-cyclopentyloxycarbonylamino-l-methyl-l,4-dihy- dro-4-oxo-quinolin-2-ylmethyl)-3-methoxybenzoyl]-2-me- thylbenzeneεulfonamide;

JV-[4-(6-cyclopentyloxycarbonylamino-l-methyl-l,4-dihy- dro-4-oxo-quinolin-2-ylmethyl)-3-methoxybenzoyl]-2-me- thylbenzenesulfonamide;

JV-[4-(7-cyclopentyloxycarbonylamino-l-methyl-l,4-dihy- dro-4-oxo-quinolin-2-yImethy1)-3-methoxybenzoyl]-2-me- thylbenzenesulfonamide. According to the present invention, the compounds of general formula I are prepared by a process in which a starting acid of general formula II

zz wherein R¹, R², R⁴, R⁵, R⁶ and R⁷ repreεent the groupε defined above, reacted with the benzeneεulfonamide III

(either commercial or obtained by conventional procedures), wherein R³ represents the groupε defined above.

xzx

The condensation between II and III is carried out in the presence of an activating reagent such as l-[3- (dimethylamino)propyl]-3-ethylcarbodiimide and a base such as triethylamine or 4-dimethylaminopyridine, in a suitable aprotic solvent such as methylene chloride, tetrahydrofuran or JV,JV-dimethyIformamide, at room temperature for a time between 5 and 24 hours, thereby obtaining the compound of general formula I.

Alternatively, compound I in which the subεtituent containing CONHS0₂ is bound at the 2- position of the 4- quinolone ring and R¹ is hydrogen can be prepared by treatment of a compound I, wherein R¹ is CH₂X being X the group -OCH₃, with an acid such as hydrochloric acid or boron trifluoride etherate.

A starting compound of general formula lla, characterized by having the benzyl subεtituent at the 1- poεition of the 4-quinolone heterocyclic ring, can be obtained, for example, following the εynthetic εequence shown in scheme 1.

In such sequence, a compound lla can be obtained by alkali hydrolysis of IX with an alkali base εuch as lithium hydroxide in an organic solvent such as methanol, at room temperature, for a time between 12 and 24 hours (step 4) .

A compound IX, wherein A is an oxygen atom or a methylene group, can be obtained, for example, by condensation of the amino derivative VII with a compound

Villa, wherein A is an oxygen atom or a methylene group and X is a hydroxy group or chlorine, (step 3) in similar conditions to those described for the preparation of the compound of general formula I. Similarly, a compound IX wherein A is a group -NR⁹-, being R⁹ hydrogen, can be obtained by reaction of VII with an isocyanate Vlllb in a suitable εolvent εuch as methylene chloride or chloroform at a temperature between 0^*C and the solvent reflux for a time between 4 and 24 hours.

A compound Villa, wherein R^ represents the groupε defined above, A iε an oxygen atom or a methylene group and X is a hydroxy group or chlorine, can be obtained through the following procedures: a) when A is an oxygen atom, either it can be a commercial product in the form of the corresponding chloroformate or it can be prepared by reaction of the alcohol R⁶OH with phosgene or an equivalent synthetic analogue (triphosgene) following the usual procedures for the preparation of such compounds and b) when A is a methylene group, it can be prepared starting from the corresponding commercial carboxylic acids R⁶CH₂COOH by reaction with thionyl chloride or oxalyl chloride, following the usual procedures for the preparation of acid chlorides. A compound Vlllb, wherein R⁶ represents the groups defined above, can be obtained starting from the corresponding commercial amines by reaction with phosgene or triphosgene, following the usual procedures in the synthesis of isocyanates.

A compound VII wherein R is hydrogen can be obtained by reduction of the nitroderivative VI, operating in standard conditions for the reduction of nitro groups, for example either by catalytic hydrogena¬ tion using palladiu -on-charcoal as the catalyst in an organic solvent such as methanol, or with ammonium formate with palladium-on-charcoal in methanol, keeping the reaction mixture under reflux for a time between 2 and 5 hours (step 2). Similarly, a compound VII wherein R5 is methyl can be obtained, for example, starting from a compound VII wherein R-*' is hydrogen by methylaton of the amine, following for example a process involving first the formylation of the amino group, with mixtures of acetic anhydride and formaldehyde in a suitable solvent such as tetrahydrofuran or ethyl ether at a temperature between 0^β and 25^*C for 3-24 hours, followed by reduction of the formyl group with the BH3- tetrahydrofuran complex in a suitable solvent such as tetrahydrofuran at a temperature between -78^βC and 0^βC for 6-24 hours.

A compound VI can be obtained by reaction between nitroquinolone IV and benzyl halide V in a basic medium, using sodium hydride as the base in tetrahydrofuran, keeping the reaction mixture at the reflux temperature for 4 hours (step 1). The nitroquinolones IV can be prepared following procedures similar to those described by C. Cidda, G. Sleiter, Gazz. Chim. Ital., 110. 155

(1980) for 5- and 7-nitroquinolones and by R. Cassis, R.

Tapia, J. A. Valderrama, Synth. Commun., 15., 125 (1985) for 6-nitroquinolone.

A compound V wherein R² is -OCH₃ bound at the 3- position of the benzene ring, can be prepared starting from commercial 4-methyl-3-methoxybenzoic acid through a two-step process consisting in the esterification with saturated hydrogen chloride methanol, followed by benzyl halogenation with JV-bromosuccinimide, uεing azaisobu- tironitrile as the radical initiator in carbon tetrachloride. Analogously, the other compounds of formula V can be prepared starting from the acid with the suitable R² substituent.

A starting compound of general formula lib, wherein the benzyl substituent of the 4-quinolone heterocyclic ring iε at the 2- position, R², R⁴, R⁵, R⁶ and R⁷ represent the groups defined above and R¹⁰ represents a group equivalent to R¹, with the proviso that it cannot be hydrogen, can be obtained, for example, following the synthetic sequence shown in scheme 2.

2-Lithium quinolones X can be prepared starting from the corresponding quinolones, following procedures similar to thoεe deεcribed for the preparation of 2- lithium-1-methylquinolone (M. Alvarez, M. Salaε, Ll. Rigat, A. of Veciana, J. A. Joule, J. Chem. Soc. Perkin

Trans 1, 351 (1992) and G. J. Atwell, B. F. Cain, J.

Med. Chem., 16, 673 (1973)).

A compound XII can be prepared by condensation between the 2-lithiumquinolone X and an aldehyde XI in usual reactivity conditions of lithium derivatives, i.e. in an aprotic solvent such as tetrahydrofuran or dioxane at a temperature between -75^ΦC and room temperature and with a reaction time from 2 to 18 h (step 5).

An aldehyde XI can be prepared starting from a bromide V by transformation of the bromide into alcohol by reaction with amberiite A carbonate in benzene at reflux temperature for a time from 1 to 3 h. The oxidation of such alcohol with manganese dioxide in methylene chloride at the reflux temperature for 10-18 h provides the corresponding aldehyde.

The transformation of the hydroxy group of XII into a good leaving group can be carried out for example by formation of the mesyl derivative of general structure XIII. Thus, a compound XIII can be prepared by reaction of compound XII with mesyl chloride in an organic solvent such as methylene chloride and in the presence of a base such as triethylamine or pyridine in methylene chloride and at O'C for 1-2 h (step 6).

A compound XIV can be prepared for example by treatment of a compound XIII with sodium borohydride in a solution of a non-nucleophilic alcohol, εuch as isopropanol, at a temperature between O'C and the room temperature for a time of 2-4 h (step 7).

Starting from XIV, lib can be prepared following a process analogous to that described in scheme 1 for the preparation of lla (steps 8-10).

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

Said compounds can be therefore used in human the¬ rapy, for the prevention and treatment of allergic rhi¬ nitis, bronchial asthma, hyperεenεitivity reactionε εuch as allergic conjunctivitis, various inflammatory condi- tions such as rheumatoid arthritis, osteoarthritiε, ten¬ dinitis, bursitis, psoriasis and related inflammations.

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

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

The following examples illustrate the preparation and the pharmacological activity of the compounds of the present invention.

EXAMPLE 1/ N-C4- (6-Cvclopentylacetamido-l.4-dihydro-4- oxo-quinolin-l-ylmethyl)-3-metho^χybenzoyl1-2-mβthylben- zenβSUlfr a-ai ήtn

IA/ l-r2-Methoχy-4-(methoχycarbonyl)benzvπ-6-nitro-l.4- dihydro-4-oxo-quinoline.

To a suspension of sodium hydride (832 mg, 20.8 mmol) in tetrahydrofuran (10 ml) cooled at O'C under nitrogen atmosphere, a suεpenεion of 6-nitro-l,4- dihydro-4-quinoline (2.0 g, 10.4 mmol) in tetrahydrofuran (150 ml) is added. The resulting mixture is stirred for 30 minutes at the same temperature. After that, a solution of methyl 4-bromomethyl-3- methoxybenzoate (8.1 g, 31.2 mmol) in tetrahydrofuran (50 ml) is added, keeping under stirring at the reflux temperature for 4 hours. After this time, an ammonium chloride aqueous saturated εolution iε added, the organic solvent is evaporated off under reduced pressure and the residue is extracted with methylene chloride. The combined organic phases are dried and the solvent is evaporated off, to obtain a crude which is purified by silica gel chromatography. Eluting with methylene chloride: methanol 99:1, 3.16 g of the title product are obtained as a solid with melting point 210-212'C (82% yield) .

IR (KBr): 1721, 1645, 1486, 1336 cm^-1.

^•Ϊ-H-NMR (CDC1₃, 300 MHz): 3.88 (s, 3 H); 3.96 (ε, 3 H); 5.34 (ε, 2 H); 6.40 (d, J = 8.0 Hz, 2 H); 6.85 (d, J = 8.0 Hz, 1 H); 7.37 (d, J = 9.5 Hz, 1 H); 7.53 (dd, J = 8.0 and 1.5 Hz, 1 H); 7.60 (d, J = 1.5 Hz, 1 H); 7.68 ( d , J = 8 . 0 Hz , 1 H ) ; 8 . 31 ( dd , J = 9 . 5 and 2 . 5 Hz , 1

H ) ; 9 . 27 ( d , J = 2 . 5 Hz , 1 H ) .

Elemental analysis calculated for

^C' 61.95;

H, 4.37; N, 7.60. Found, 62.03; H, 4.43; N, 7.20 IB/ 6-Amino-l-r2-methoχy-4-(methoχycarbonyl)benzyll-1.4- dihydro-4-oxo-σuinoline.

To a solution of l-[2-methoxy-4-(methoxycar- bonyl)benzyl]-6-nitro-l,4-dihydro-4-oxo-quinoline (972 mg, 2.6 mmol) in anhydrous methanol (65 ml), 210 mg 10% Pd/C and ammonium formate (1.33 g, 21.1 mmol) are added and the resulting mixture iε εtirred at the reflux temperature for 2 hours 30 minutes, under nitrogen atmosphere. After this time, the reaction mixture is left to cool at room temperature, the catalyεt is filtered through Celite and the resulting solution is evaporated. To the residue, a sodium hydrogen carbonate saturated aqueous solution iε added and the mixture iε extracted with methylene chloride. The dry organic phases are evaporated to give 871 mg of the title product as a solid with melting point 217-219'C (97% yield) .

IR (KBr): 3426, 3330, 1720, 1604 cm^-1. iH-NMR (CDC1₃, 200 MHz): 3.92 (s, 3 H); 4.00 (ε, 3 H);

5.30 (ε, 2 H); 6.28 (d, J = 7.7 Hz, 1 H); 6.77 (d, J = 8.0 Hz, 1 H); 6.94 (dd, J = 8.9, 2.5 Hz, 1 H); 7.08 (d,

J = 8.9 Hz, 1 H); 7.45-7.61 (m, 3 H, H-2); 7.71 (d, J =

2.5 Hz, 1 H).

Elemental analysis calculated for C^gH^gN₂0 : C, 67.44;

H, 5.36; N, 8.28. Found, C, 67.10; H, 5.42; N, 8.04. IC/ 6-Cyclopentylacetami<?Q-1-T2-methoχy-4-(methoxycarbo- nyl)-benzyl]-1.4-dihydro-4-oxo-σuinoline. A mixture of 6-amino-l-[2-methoxy-4-(methoxycarbo- nyl)benzyl]-l,4-dihydro-4-oxo-quinoline (762 mg, 2.3 mmol), cyclopentylacetic acid (2.94 mg, 2.5 mmol), 4-

(dimethylamino)pyridine (280 mg, 2.5 mmol) and l-[3- (dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride

(441 mg, 2.5 mmol) is disεolved in anhydrous methylene chloride (35 ml) and is stirred at room temperature for

24 hours under nitrogen atmosphere. After thiε time, the reaction mixture is added to a IN hydrochloric acid aqueous solution and is extracted with methylene chloride. The dry organic phaεeε are evaporated to give a reεidue which is purified by flash chromatography through a silica gel column with methylene chloride as the eluent. 762 mg of the title product are recovered aε a εolid with melting point 231-234'C (75% yield). IR (KBr): 3286, 1725, 1681, 1630 cm^-1.

^••••H-NMR (CDC1₃, 200 MHz): 1.20-2.00 (m, 8 H); 2.30-2.50 (m, 1 H); 2.52 (d, J = 7.3 Hz, 2H); 3.90 (ε, 3 H); 3.99 (ε, 3 H); 5.35 (s, 2 H); 6.29 (d, J = 7.7 Hz, 1 H); 6.80 (d, J = 7.8 Hz, 1 H); 7.28 (d, J = 9.3 Hz, 1 H); 7.51 (dd, J = 7.9 and 1.5 Hz, 1 H); 7.61 (d, J = 1.5 Hz, 1 H); 7.65 (d, J = 7.6 Hz, 1 H); 8.48 (d, J = 2.6 Hz, 1 H); 8.63 (dd, J = 9.3 and 2.6 Hz, 1 H); 9.43 (bs, 1 H). Elemental analysis calculated for C₂₆H₂₈N₂0₅: C, 69.62; H, 6.29; N, 6.24. Found, C, 69.62; H, 6.70; N, 5.25.

ID/ 4-(6-CvclopentylacetaπHd -^*i ,4-dihydro-4-oxo-cruino- lin-1-ylmethyl)-3-methoχybenzoic acid.

A solution of lithium hydroxide (280 mg, 6.7 mmol) in water (4 ml) is added to a solution of cyclo- pentγlacetamido-1-[2-methoxy-4-methoxycarbonylbenzγl]- l,4-dihydro-4-oxo-quinoline (579 mg, 1.3 mmol) in methanol (10 ml) and tetrahydrofuran (8 ml), with stirring and under nitrogen atmosphere. The reaction mixture is stirred for 24 hours at room temperature.

After this time, it is concentrated under reduced pressure and is acidified with 1 N hydrochloric acid.

The resulting precipitate is filtered off and washed with water. The dry residue yields 489 mg of the title product as a solid with melting point 231-234'C (85% yield) . IR (KBr): 3446, 1698, 1649, 1561 cm^-1. iH-NMR (CD3OD, 300 MHz): 1.30-1.41 (m, 2 H); 1.62-1.82 (m, 4 H); 1.90-2.10 (m, 2 H); 2.35-2.80 (m, 1 H); 2.50 (d, J = 7.3 Hz, 2H); 4.06 (s, 3H); 5.84 (ε, 2H); 6.80 (d, J = 7.3 Hz, 1 H); 7.14 (d, J = 7.9 Hz, 1 H); 7.67 (dd, J = 7.9 and 1.4 Hz, 1 H); 7.77 (d, J = 1.3 Hz, 1 H); 7.91 (d, J = 9.4 Hz, 1 H); 8.15 (dd, J = 9.4 and 2.5 Hz, 1 H); 8.57 (d, J = 7.3 Hz, 1 H); 8.72 (d, J = 2.5 Hz, 1 H). Elemental analyεiε calculated for C₂₅H_2gN₂0₅.H₂0: C, 66.35; H, 6.23; N, 6.19. Found, C, 66.36; H, 5.96; N, 5.95.

IB/ N- T 4- 16-Cvclopentylacetamido-l .4-dihydro-4-oxo-q-αi- nolin-1-yl-methyl ) 3-methoxybenzovn-2-methylbenzenesul- fnnami de . A mixture of 4- ( cyclopentylacetamido-l , 4-dihydro-4- oxo-quinolin-l-ylmethyl )-3-methoxγbenzoic acid ( 389 mg , 0.9 mmol ) , o-toluenesulf onamide ( 156 mg , 1.05 mmol ) , 4- ( dimethylamino ) pyridine ( 111 mg , 1.05 mmol ) and l- [ 3- ( dimethylamino ) propyl ]-3-ethylcarbodi imide hydrochloride ( 175 mg , 1.05 mmol ) in dry methylene chloride ( 50 ml ) iε stirred at room temperature and under nitrogen atmosphere for 24 hourε. After thiε time, the reaction mixture is poured onto a solution of 1 N hydrochloric acid and the aqueous phase is extracted with methylene chloride. The organic phases are washed with a sodium chloride saturated aqueous solution, then with water, and they are dried and evaporated under reduced presεure. The reεulting reεidue iε purified by flaεh chromatography through silica gel. Eluting with 96:4 methylene chloride: methanol, 206 mg of the title compound are recovered as a solid with melting point 261-263'C (40% yield). IR (KBr): 3300, 1612, 1592, 1538 cm^-1.

^-N R (CDC1₃+CD₃0D, 200 MHz): 1.20-2.00 (m, 8H); 2.20- 2.50 (m, 3 H); 2.69 (s, 3H); 3.89 (s, 3H); 5.36 (ε, 2H); 6.36 (d, J = 7.4 Hz, 1 H); 6.71 (d, J = 7.7 Hz, 1 H); 7.26- 7.56 (m, 6H); 7.76 (d, J = 7.4 Hz, 1 H); 7.92 (d, J = 2.3 Hz, 1 H); 8.16 (d, J = 7.7 Hz, 1 H); 8.46 (dd, J = 9.3 and 2.4 Hz, 1 H) . Elemental analysis calculated for C₃ H N θ S, CH₂C1₂: C, 58.91; H, 5.23; N, 6.25. Found, C, 58.89; H, 5.33; N, 5.99.

EXAMPLE 2/ HF-T4-(5-cvclopentylacetam-jdn-1. -dihydro-4- oxo-cminolin-l-ylmethyl)-3-methoxybenzoyl1-2-methylbep- zenesulfnnam-ilie. 2A/ l-r2-Methoχy-4-(methoχycarbonyl)benzyl^"l-5-nitro-l.4- dihydro-4-oxo-σuinolipe and l-r2-methoχy-4-(methoχycar- bonyl)benzyl]-7-nitro-l.4-dihydro-4-oxo-αuinoline.

Following the procesε described in example 1 (step

A), starting from a mixture of 5-nitro- and 6-nitro-4- quinolone, the title compoundε were prepared, which could be εeparated by εilica gel chromatography. Elution with methylene chloride yieldε a εolid with melting point 189-191'C, which waε identified aε l-[2-methoxy-4-

(methoxycarbony1)benzyl3-5-nitro-l,4-dihydro-4-oxo-qui- noline (47% yield). IR (KBr): 1720, 1635, 1607, 1292 cm^-1.

^•^-H-NMR (CDC1₃, 200 MHz): 3.91 (ε, 3 H); 3.98 (ε, 3 H);

5.36 (ε, 2 H); 6.28 (d, J = 7.9 Hz, 1 H); 6.85 (d, J =

7,9 Hz, 1 H); 7.23 (dd, J = 7.9 and 1.0 Hz, 1 H); 7.41

(dd, J = 7.8 and 1.0 Hz, 1 H); 7.52- 7.61 (m, 3H); 7.66 (d, J = 7.9 Hz, 1 H).

Elemental analysis calculated for ^cι Hι N₂0 1/2H₂0 : C,

61.21; H, 4.46; N, 7.51. Found, C, 61.17; H, 4.60; N,

6.94.

On elution with 99:1 methylene chloride: methanol, l-[2- methoxy-4-(methoxycarbonyl)benzyl]-7-nitro-l,4-dihydro-

4-oxo-quinoline waε recovered aε a εolid with melting point 138-140"C (50% yield).

IR (KBr): 1721, 1638, 1599 cm^_1

^••■-H-NMR (CDCI3, 200 MHz): 3.90 (ε, 3 H); 4.05 (ε, 3 H); 5.40 (s, 2 H); 6.42 (d, J= 7.8 Hz, 1 H); 7.05 (d, J= 7.9

Hz, 1 H); 7.58 (dd, J= 7.9 and 1.5 Hz, 1 H); 7.60 (d, J=

1.5 Hz, 1 H); 7.82 (d, J= 7.8 Hz, 1 H); 8.10 (dd, J= 8.8 and 1.9 Hz, 1 H); 8.39 (d, J= 1.9 Hz, 1 H); 8.58 (d, J=

8.8 Hz, 1 H). Elemental analysis calculated for ^cιg^Hi6^N2°6 ^1H2^{0: C}'

59.06; H, 4.69; N, 7.25. Found, C, 59.39; H, 4.54; N,

7.01.

2B/ 5-Amino-l-r2-methoχy-4-( ethoxycarbony1)benzyl1-1.4- dihydro-4-oxo-cπιinoline. Following the process described in example 1 (step

B), starting from l-[2-methoxy-4-(methoxycarbonyl)ben- zyl]-5-nitro-l,4-dihydro-4-oxo-quinoline (200 mg, 0.54 mmol), the title compound was prepared as a solid with melting point 151-154'C (98% yield).

IR (KBr): 3450, 1717, 1631 cm^"1. iH- MR (CDC1₃, 200 MHz): 3.90 (ε, 3 H); 3.96 (s, 3 H);

5.16 (s, 2 H); 6.14 (d, J = 7.6 Hz, 1 H); 6.24 (d, J =

8.2 Hz, 1 H); 6.34 (d, J = 8.2 Hz, 1 H); 6.80 (d, J =

7.8 Hz, 1 H); 7.14 (t, J= 8.2 Hz, IH); 7.24 (d, J = 7.6

Hz, IH); 7.51 (dd, J= 7.8 and 1.4 Hz, IH); 7.56 (d, J= 1.4 Hz, IH).

Elemental analyεis calculated for C^ H^gN 0₄: C, 67.44; H, 5.36; N, 8.28. Found, C, 67.41; H, 5.67; N, 8.67. 2C/ 5-Cyclopentylacetamido-1-r2-methoχy-4-(methoχycarbo- nil)-benzyl!-1.4-dihydro-4-oxo-*uinoline. Following the procesε deεcribed in example 1 (εtep C), εtarting from 5-amino-l-[2-methoxy-4-(methoxycarbo- nyl)benzyl]-l,4-dihydro-4-oxo-quinoline (490 mg, 1.44 mmol), the title compound was prepared as a solid with melting point 188-191'C (71% yield). IR (KBr): 3500, 1721, 1636, 1605 cm^-1. -H-NMR (CDCI3, 200 MHz): 1.20-2.00 (m, 8 H); 2.30-2.50 (m, 1 H); 2.52 (d, J= 6.5 Hz, 2 H); 3.92 (s, 3 H); 3.99 (s, 3 H); 5.32 (s, 2 H); 6.32 (d, J = 7.6 Hz, 1 H); 6.79 (d, J = 7.8 Hz, 1 H); 6.87 (d, J = 8.4 Hz, 1 H); 7.43- 7.64 (m, 4 H); 8.68 (d, J = 8.0 Hz, 1 H); 13.91 (bε, 1 H).

2D/ 4-(5-Cyclopentylaπetamido-1.4-dihydro-4-oxo-σuino- lin-1-ylmethyl)-3-methoχybenzoic acid.

Following the process described in example 1 (step D), starting from 5-cyclopentylacetamido-l-[2-methoxy-4- (methoxycarbonyl)benzyl]-l,4-dihydro-4-oxo-quinoline (300 mg, 0.67 mmol), the title compound was prepared as a solid with melting point 129-134'C (70% yield).

IR (KBr): 3450, 2949, 1780, 1630, 1522 cm^-1. iH-NMR (CDC1₃, 200 MHz): 1.40-2.10 (m, 8 H); 2.10-2.51 (m, 3 H); 4.00 (s, 3H); 5.35 (s, 2 H); 6.40 (d, J= 7.6

Hz, 1 H); 6.80 (d, J= 8.0 Hz, 1 H); 6.88 (d, J= 8.5 Hz,

1 H); 7.49 (dd, J= 8.5 and 8.1 Hz, 1 H); 7.58 (d, J= 1.4

Hz, 1 H); 7.60-7.70 (m, 2H); 8.68 (d, J= 8.1 Hz, IH);

13.90 (bs, 1 H). Elemental analysiε calculated for C₂₅H₂₆N₂0₅. 3/4 MeOH: C, 67.45; H, 6.37; N, 6.11. Found: C, 67.53; H, 6.47; N, 6.14.

2E/ JV-T4-(5-cyclopenty1acet.amido-1.4-dihydro-4-oxo-crui- nolin-l-ylmethyl)-3-methoχybepzoyl^'1-2-methylbepzenesul- fonamifla.

Following the process described in example 1 (εtep E), starting from 4-(5-cyclopentylacetamido-l,4-dihydro- 4-oxo-quinolin-l-ylmethyl)-3-methoxybenzoic acid (170 mg, 0.34 mmol), the title compound was prepared as a solid with melting point 268-270'C (yield 60%). IR (KBr): 3400, 1700, 1625, 1520 cm^-1. iH-NMR (CDCI3-CD3OD, 200 MHz): 1.20-2.00 (m, 8 H); 2.13- 2.45 (m, 3 H); 2.69 (s, 3 H); 3.92 (ε, 3 H); 5.29 (ε, 2 H); 6.28 (d, J = 7.5 Hz, 1 H); 6.62 (d, J= 8.0 Hz, 1 H); 6.78 (d, J= 8.7 Hz, 1 H); 7.25-7.50 (m, 6 H); 7.60 (d, J= 7.5 Hz, 1 H); 8.26 (d, J= 8.0 Hz, 1 H); 8.60 (d, J= 8.0 Hz, 1 H); 13.74 (ε, 1 H).

Elemental analysis calculated for

.3H 0: C, 59.89; H, 6.01; N, 6.55; S, 4.99. Found: C, 60.04; H, 5.34; N, 6.25; S, 4.80.

EXAMPLE 3/ JV- r4- ( 7-cγclopentylacetamido-l .4-dihydro-4- oxo-cminolin-l-ylmethyl -3-methoχybenzoyl1-2-ιnethylben- zenesulfonamide.

3A/ 7-Amino-l-r2-methoχy-4-(methoχycarbonyl)benzyl!-1.4- dihydro-4-oxo-σuinoline. Following the process described in example 1 (step B), starting from l-[2-methoxy-4-(methoxycarbonyl)ben¬ zyl]-7-nitro-l,4-dihγdro-4-oxo-quinoline (360 mg, 0.97 mmol), the title compound was prepared as a solid with melting point 216-220'C (92% yield). IR (KBr): 1722, 1614 cm^-1. iH-NMR (CDC1₃, 200 MHz): 3.90 (s, 3 H); 3.97 (ε, 3 H); 5.17 (ε, 2 H); 6.19 (d J= 7.7 Hz, 1 H); 6.26 (d, J= 1.9 Hz, 1 H); 6.65 (dd, J= 8.7 and 1.9 Hz, 1 H); 6.77 (d, J= 7.8 Hz, 1 H); 7.43 (d, J= 7.7 Hz, 1 H); 7.51(dd, J= 7.8 and 1.4 Hz, 1 H); 7.58 (d, J= 1.4 Hz, 1 H); 8.22 (d, J= 8.7 Hz, 1 H).

Elemental analysis calculated for C₁₉H₁₈N₂0₄ .3MeOH: C, 60.82; H, 6.90; N, 6.45. Found: C, 60.99; H, 6.84; N, 6.08. 3B/ 7-Cyclopentylacetamido-l-T2-methoχy-4-(methoxycarbo- nil)-benzyl1-1.4-dihydro-4-oxo-αuinoline.

Following the procesε deεcribed in example 1 (step C), starting from 7-amino-l-[2-methoxy-4-(methoxycarbo- nyl)benzyl]-l,4-dihydro-4-oxo-quinoline (473 mg, 1.4 mmol), the title compound was prepared which waε purified by flash chromatography through silica gel with ether: acetone: diethylamine (70:30:5). A sample recrystallized from methylene chloride/methanol had melting point of 216-218'C. 64% Yield. IR (KBr): 1719, 1612, 1561 cm^-1. iH-NMR (CDCI3, 200 MHz): 1.20-2.00 (m, 8 H); 2.20-2.40 (m, 3 H); 3.90 (s, 3 H); 3.96 (s, 3 H); 5.31 (s, 2 H);

6.28 (d, J= 7.8 Hz, 1 H); 7.02 (dd, J= 9.5 and 1.1 Hz, 1

H); 7.09 (d, J= 8.2 Hz, 1 H); 7.50-7.60 (m, 2H); 7.64

(d, J= 7.8 Hz, 1 H); 7.70 (bs, 1 H); 8.33 (d, J= 8.7 Hz, 1 H); 8.36 (bs, 1 H).

EM (IE): 448 (M⁺, 1); 179 (10); 111 (10); 97 (22); 57

(100).

Elemental analysis calculated for C H₂gN₂0g .H₂0: C,

66.93; H, 6.48; N, 6.00. Found: C, 67.04; H, 6.33; N, 5.49.

3C/ 4-f7-Cyclopentylacetamido-l.4-dihydro-4-oxo-σuino- lin-l-ylmethyl)-3-methoχybenzoic.

Following the process described in example 1 (step

D), starting from 7-cyclopentylacetamido-l-[2-methoxγ-4- methoxycarbonyl-benzyl]-l,4-dihydro-4-oxo-quinoline (120 mg, 0.27 mmol), the title product was recovered as a solid with melting point 235-240'C (yield 85%).

IR (KBr): 3400, 3100, 1662, 1625, 1613 cm^-1. iH-NMR (DMSO-dg, 300 MHz): 1.52-1.88 (m, 8 H); 2.05-2.20 (m, 1 H); 2.28 (d J= 7.0 Hz, 2 H); 3.95 (s, 3 H); 5.36

(s, 2 H); 6.05 (d, J= 7.8 Hz, 1 H); 6.82 (d, J= 7.8 Hz,

1 H); 7.43 (d, J= 8.2 Hz, 1 H); 7.54 (s, 1 H); 7.89 (ε,

1 H); 8.07 (d, J= 8.2 Hz, 2 H); 10.20 (ε, 2 H); 12.50

(bε, 1 H). Elemental analyεis calculated for C₂₅H_2gN₂0₅.3/4 MeOH:

C, 67.45; H, 6.37; N, 6.11. Found: C, 67.69; H, 6.04; N,

6.72.

3D/ JV-r4-(7-cyclopentylacetamido-l .4-dihydro-4-oxo-σui- nolin-l-γlmethyl)-3-methoχybenzoyl^~l-2-methylbenzenesul- fonamide.

Following the procesε described in example 1 (step E), starting from 4-(7-cyclopentylacetamido-l,4-dihydro-

4-oxo-quinolin-l-ylmethyl)-3-methoxybenzoic acid (70 mg,

0.16 mmol), the title compound was prepared as a solid with melting point 258-260'C (yield 32%). IR (KBr): 3400, 1614, 1563, 1519 cm^-1. iH-NMR (CDC1₃, 200 MHz): 1.12-1.95 (m, 8 H); 2.20-2.50

(m, 3 H); 2.70 (ε, 3 H); 3.92 (ε, 3 H); 5.35 (ε, 2 H);

6.34 (d, J= 7.7 Hz, 1 H); 7.07-7.52 ( , 8 H); 7.82 (d,

J= 7.7 Hz, 1 H); 8.21 (bε, 1 H); 8.26 (d, J= 8.8 Hz, 1 H); 8.39 (d, J=l.7 Hz, IH).

Elemental analysis calculated for C3₂H33N θ S .3H₂0: C,

59.89; H, 6.01; N, 6.55; S, 4.99. Found: C, 59.85; H,

5.47; N, 6.38; S, 4.27.

EXAMPLE 4/ JV-T4—⁽7-c^yclo^pent^ylo^χycarhopγ|^*amino-l-^*Bethyl- 1.4-dihydro-4-oxo-σuinolin-2-y methy1)-3-methoχybenzo- yπ-2-methylbenzenesιιifonam-i At> .

4A/ Methyl 4-bromomethyl-3-methoχybenzoate.

A εolution of methyl 4-methyl-3-methoxybenzoate (3 g, 17.1 mmol), N-bromosuccinimide (3.26 g, 18.5 mmol) and a catalytic amount of biεazaiεobutironitrile in 132 ml of carbon tetrachloride waε heated at the reflux temperature for 4 hours. After thiε time, the reaction mixture was filtered and the filtrate was washed with a sodium chloride saturated aqueous solution. The dry organic phaseε were evaporated to yield the title compound aε a solid with melting point 73-75'C (97% yield) .

IR (KBr): 1717, 758 cm^-1.

^•J-H-NMR (CDCI3, 200 MHz): 3.92 (ε, 3H); 3.96 (ε, 3H); 4.55 (s, 2H); 7.39 (d, J = 7.8 Hz, IH); 7.54 (d, J = 1.6

Hz, 2 H); 7.61 (dd, J = 7.8 and 1.6 Hz, IH). Elemental analysis calculated for: C₁₀H₁₁0₃Br: C, 43.74;

H, 4.48. Found: C, 43.47; H, 4.11.

4B/ Methyl 4-hydroχymethyl-3-methoχybenzoate.

A mixture of methyl 4-bromomethyl-3-methoxybenzoate (904 mg, 3.5 mmol) and Amberiite A 26 carbonate (5.5 g,

12.8 meq) in 12 ml of benzene was stirred at the reflux temperature for 45 minutes. After this time the reaction mixture was filtered and the solid was washed with methanol. The combined organic phases were evaporated to dryness. The resulting residue was purified by flash chromatography through silica gel eluting with methylene chloride, to obtain the title compound as a solid with melting point 84-86^*C (50% yield).

IR (KBr): 3321, 1713, 1294, 1265 cm^-1. iH-NMR (CDC1₃, 200 MHz): 3.87 (s, 3H); 3.90 (ε, 3H);

4.70 (ε, 2H); 7.37 (d, J = 7.8 Hz, IH); 7.48 (ε, IH);

7.60 (d, J = 6.6 Hz, IH).

Elemental analyεis calculated for Cιo^H12°4^: ' ⁶¹-¹' ^H'

6.2. Found: C, 60.6; H, 6.3. 4C/ Methyl 4-formyl-3-methoχybenzoate.

A suspension of methyl 4-hγdroxymethγl-3-methoxy- benzoate (1.8 g, 9.2 mmol) and manganese dioxide (6.9 g,

79.4 mmol) in methylene chloride (287 ml) was stirred at the reflux temperature for 15 hourε. After that, it waε filtered through Celite and the solvent was evaporated off, to yield the title compound (1.4 g, yield 78%). A sample recrystallized from diisopropyl ether had melting point 78-81'C.

IR (KBr): 1726, 1685, 1295 cm^-1. iH-NMR (CDCI3, 200 MHz): 3.85 (s, 3H); 3.89 (s, 3H);

7.30-7.60 (m, 3H); 7.74 (d, J = 8.3 Hz, IH); 10.39 (s, 1 H ) .

Elemental analysis calculated for C₁₀H₁₀O₄.l/8 H₂0: C,

61.14: H, 5.26. Found: C, 61.21, H, 5.31.

4D/ 2-( l-Hydroχy-2-methoχy-4-methoχycarbonylbenzyl )-l- methyl-7-nitro-l .4-dihydro-4-oxo-cπιinoline .

A solution of l-methyl-7-nitro-l , 4-dihydro-4-oxo- quinoline (400 mg, 1.96 mmol) in tetrahydrofuran (40 ml) was slowly added to a solution of LDA (5.9 mmol) in tetrahydrofuran (20 ml) externally cooled at -78'C stirring the system under a nitrogen stream. When the addition was completed, the mixture was stirred for 30 minutes at the same temperature. After that, a solution of methyl 4-formyl-3-methoxybenzoate (4 mmol) in tetrahydrofuran (15 ml) was added, after 30 minutes the outer bath was removed, leaving under stirring for 2 hours at room temperature. When the reaction was completed, an ammonium chloride aqueous solution waε added, tetrahydrofuran was evaporated off and the residue was extracted with methylene chloride and purified by flash chromatography through silica gel. Eluting with 90:10 ethyl acetate: methanol, title compound was recovered in a 30% yield. IR (KBr): 3120, 1730, 1593, 1503 cm^-1. ^•••-H-NMR (CDC1₃, 200 MHz): 3.86 (ε, 3H); 3.92 (ε, 3H); 3.96 (s, 3H); 6.30 (s, IH); 6.57 (ε, IH); 7.49 (d, J = 7.9 Hz, IH); 7.62 (s, IH); 7.72 (d, J = 7.9 Hz, 2 H); 8.17 (dd, J = 8.8 and 1.6 Hz, IH); 8.49 (d, J = 1.6Hz, IH); 8.56 (d, J = 8.8 Hz, IH). Elemental analysis calculated for C₂₀H₁₈N₂O₇: C, 60.29, H, 4.55, N, 7.03. Found: C, 59.95, H, 5.09, N, 7.16.

4E/ 2-(1-Mesyloχy-2-methoχy-4-methoχycarbonylbenzyl)-1- methyl-7-nitro-l.4-dihydro-4-oxo-σuinoline.

To a solution of 2-[l-hydroxy-l-(2-methoxy-4-metho- xycarbonylbenzyl)]-l-methyl-7-nitro-l,4-dihydro-4-oxo- quinoline (200 mg, 0.5 mmol) in dry methylene chloride (10 ml), mesyl chloride (0.06 mg, 0.75 mmol) and triethylamine (0.12 ml, 0.9 mmol) were added. The resulting mixture was stirred at O'C under nitrogen atmosphere for an hour. After this time the solution was washed with a sodium hydrogen carbonate saturated aqueous solution. The dry organic phases were evaporated to give the title product in a 96% yield. IR (NaCI): 1721; 1640; 1351; 1177 cm^-1. iH-NMR (CDC1₃, 300 MHz): 3.07 (s, 3H); 3.78 (s, 3H); 3.94 (s, 3H); 4.01 (ε, 3H); 6.63 (ε, IH); 7.22 (ε, IH); 7.42 (d, J= 8.0 Hz, IH); 7.68-7.71 (m, 2H); 8.17 (d, J= 8.8 Hz, IH); 8.44 (d, J= 1.8 Hz, IH); 8.57 (d, J= 8.52 Hz, IH).

4F/ l-Metb.yl-2-(2-methoxy-4-methoχycarbonylbenzyl)-7-ni- tro-1.4-dihγdro-4-oxo-quinoline. To a solution of 2-[l-mesyloxy-l-(2-methoxy-4-me- thoxycarbonylbenzyl)]-l-methyl-7-nitro-l,4-dihydro-4- oxo-quinoline (140 mg, 0.29 mmol) in isopropanol (10 ml), sodium borohydride (66 mg, 1.74 mmol) was added, stirring at room temperature for 3 hours. After this time the solvent was evaporated off under reduced pressure, the residue was dissolved in water and extracted with methylene chloride. The organic solution was dried and evaporated to drynesε. The residue was purified by flash chromatography through silica gel to recover the title compound in a 63% yield.

IR (NaCI): 1720, 1632, 1600, 1463, 1291 cm"¹. iH-NMR (CDCI3, 200 MHz): 3.71 (s, 3H); 3.93 (s, 3H);

3.95 (ε, 3H); 4.15 (ε, 2H); 6.31 (s, IH); 7.06 (d, J =

8.2 Hz, IH); 7.57-7.61 (m, 2H); 8.17 (dd, J = 8.8 and

1.8 Hz, IH); 8.43 (d, J = 1.8 Hz, IH); 8.61 (d, J = 8.8 Hz, IH).

4G/ 7-Amino-l-methyl-2-(2-methoxy-4-methoxycarbonylben- zyl)-1.4-dihydro-4-oxo-σuinoline.

A solution of l-methyl-2-(2-methoxy-4-methoxycarbo- nylbenzyl)-7-nitro-l,4-dihydro-4-oxo-quinoline (100 mg, 0.26 mmol) and 10% Pd/C in methanol (10 ml)/ trifluoroacetic acid (0.5 ml) was stirred under hydrogen atmosphere for 20 hours. When the reaction was complete, the catalyεt waε filtered off through celite and the solvent was evaporated at reduced presεure. The residue was disεolved in a εodium hydrogen carbonate saturated aqueous solution and extracted with methylene chloride, the organic solution was dried, evaporated and purified by silica gel chromatography. The fractions eluted with ethyl acetate give the title compound in a 71% yield. IR (NaCI): 3343, 1718, 1605 cm^-1.

^•'-H-NMR (CDCI3, 200 MHz): 3.41 (s, 3H); 3.91 (s, 3H); 3.92 (s, 3H); 4.01 (ε, 2H); 6.10 (s, IH); 6.52 (s, IH); 6.67 (d, J = 8.4 Hz, IH); 6.96 (d, J = 7.8, IH); 7.48- 7.54 (m, 2H); 8.16 (d, J = 8.4 Hz, IH). 4H/ 7-Cyclopentyloxycarbonylamino-l-methyl-2-T2-methoxy- 4-methoχycarbonylbenzvn-l.4-dihydro-4-oxo-cruinoline.

To a solution of 7-amino-l-methyl-2-(2-methoxy-4- methoxycarbonylbenzy1)-1,4-dihydro-4-oxo-quinoline (40 mg, 0.1 mmol) and JV-methylmorpholine (60 mg, 0.2 mmol) in dry methylene chloride (2 ml), cyclopentyl chloroformate (29 mg, 2 mmol) was added under nitrogen atmosphere. The reaction mixture was stirred under nitrogen atmosphere for 2 hourε. After thiε time, the reaction mixture was poured onto 1 N hydrochloric acid and extracted with methylene chloride. The organic solution was dried, evaporated and purified by flash chromatography. On elution with methylene chloride:methanol (99:1), the title compound was recovered as a solid with melting point 233-235"C in a

70% yield. IR (NaCI): 2960, 1748, 1727, 1628, 1607 cm"¹. l-H-NMR (CDC1₃, 200 MHz): 1.60-1.90 (m, 8H); 3.80 (ε, 3H); 3.90 (s, 3H); 3.96 (ε, 3H); 4.30 (ε, 2H); 5.10 (m, IH); 6.10 (s, IH); 6.92 (d, J = 7.5 Hz, IH); 7.20-7.28 ( , 2H); 7.55 (d, J = 7.5 Hz, IH); 7.62 (s, IH); 8.35 (d, J = 7.5 Hz, IH); 8.43 (bs, IH).

41/ 4-(7-Cyclopentyloχycarboτιγlamino-l-methyl-1.4-dihv- dro-4-oxo-cruinolin-2-ylmethyl)-3-methoχybenzoic acid.

Following the procesε deεcribed in example 1 (εtep D), starting from 7-cyclopentyloxycarbonylamino-l- methyl-2-[2-methoxy-4-methoxycarbonylbenzyl]-l,4-dihy- dro-4-oxo-quinoline (40 mg, 0.086 mmoles), the title compound was prepared as a solid with melting point 226- 229'C (85% yield). IR (KBr): 3432, 1710, 1627, 1620 cm^"1. iH-NMR (CD3OD, 300 MHz): 1.80-2.10 (m, 8H); 3.99 (s, 3H); 4.30 (s, 3H; 4.67 (s, 2H); 6.73 (s, IH); 7.41 (d, J = 8.0 Hz, IH); 7.75-7.81 (m, 3H); 8.42 (d, J = 9.1 Hz, IH); 8.70 (d, J = 1.4, IH); 10.32 (ε, IH). 4J/ Jf-T4-(7-cγclopentyloxycarbonγlamino-l-methyl-1.4-di- hydro-4-oxo-cruinolin-2-ylmethyl )-3-metb.oχybenzoyl1-2-me- thylbenzenesulfnnamide. Following the process described in example 1 (step

E), starting from 4-(7-cyclopentyloxycarbonylamino-l- methyl-1,4-dihydro-4-oxo-quinolin-2-ylmethyl)-3-methoxy- benzoic acid (35 mg, 0.07 mmol), a residue was recovered which was purified by flash chromatography through silica gel. On elution with ether: acetone: diethylamine

(70:30:5), the title compound was prepared as a solid with melting point 138-140'C (60% yield).

IR (KBr): 1700, 1627, 1603, 1459, 1453 cm"¹. ^-NMR (CD₃OD, 300 MHz): 1.70-2.05 (m, 8H); 2.78 (s, 3H); 3.97 (s, 3H); 4.24 (s, 3H); 4.63 (ε, 2H); 5.35 (m, IH); 6.67 (ε, IH); 7.40 (d, J = 7.7 Hz, IH); 7.48 (d, J = 7.8 Hz); 7.53 (d, J = 7.4 Hz, IH); 7.59-7.66 (m, 3H); 7.74 (dd, J = 9.1 and 1.7 Hz, IH); 8.25 (dd, J = 7.9 and 1.2 Hz, 1 H); 8.40 (d, J = 9.1 Hz, 1 H); 8.66 (d, J = 1.7 Hz, IH).

EXAMPLE 5/ JV-T -(6-Cyclopentyloχycarho γlamino-i-nethyl- 4-oxo-cnιinolin-2-yl ethy1)-3-methoχybenzoyl1-2-metb.yl- benzene«ιιT-fr>*n ιnirift 5 A/ 2-(l-Hydroχy-2-methoχy-4-methoχycarbopylbenzyl)-1- methyl-6-nitro-l.4-dihydro-4-oxo-σuinoline.

Following the procesε deεcribed in example 4 (εtep D), starting from l-methyl-6-nitro-l,4-dihydro-4-oxo- quinoline (180 mg, 0.88 mmol), the title compound was prepared which was purified by flash chromatography through silica gel. On elution with ethyl acetate: methanol (90:10), the title compound was recovered in a 30% yield. IR (KBr): 3266, 1731, 1635, 1492 cm^"1. iH-NMR (CDCI3 + CD3OD, 300 MHz): 3.81 (ε, 3H); 3.89 (s, 3H); 3.94 (s, 3H); 6.26 (ε, IH); 6.48 (ε, IH); 7.48 (d, J = 7.9 Hz, 1 H); 7.59 (d, J = 1.5 Hz, IH); 7.64 (d, J =

9.5 Hz, 1 H); 7.69 (dd, J = 7.9 and 1.5 Hz, IH); 8.41

(dd, J = 9.5 and 2.8 Hz, IH); 9.12 (d, J = 2.8 Hz, IH).

5B/ 2-(l-Mesyloχy-2-metho^χy-4-methoxycarbonylbenzγl)-l- methyl-6-nitro-l.4-dihydro-4-oxo-σuinoline.

Starting from 2-(l-hydroxy-2-methoxy-4-methoxycar- bonyl-benzyl)-l-methyl-6-nitro-l,4-dihydro-4-oxo- quinoline (42 mg, 0.1 mmol), following the process described in example 4 (step E), the title compound was recovered in a 90% yield.

IR (NaCI): 1722; 1338; 1177 cm^"1.

^••■-H-NMR (CDC1₃, 200 MHz): 3.10 (s, 3H); 3.77 (s, 3H);

3.96 (s, 3H); 4.04 (ε, 3H); 6.63 (s, IH); 7.31 (s, IH);

7.45 (d, J = 7.7 Hz, 1 H); 7.64-7.74 (m, 3H): 8.46 (dd, J = 9.5 and 2.8 Hz, IH); 9.21 (d, J = 2.8 Hz, IH).

5C/ l-Methyl-2-(2-methoχy-4-methoχycarbonylbenzyl)-β-ni- tro-1.4-dihvdro-4-oxo-σuinoliπe.

Starting from 2-(l-mesyloxy-2-methoxy-4-methoxycar- bonylbenzyl)-l-methyl-6-nitro-l,4-dihydro-4-oxo- quinoline (476 mg, 1 mmol), following the process described in example 4 (step F), the title compound was recovered as a solid with melting point 230-232"C (31% yield) .

IR (KBr): 1634, 1609, 1488, 1337, 1291 cm^"1. ^-H-NMR (CDCI3, 300 MHz): 3.67 (s, 3H); 3.92 (ε, 3H);

3.95 (ε, 3H); 4.13 (ε, 2H); 6.20 (ε, IH); 7.07 (d, J =

8.2 Hz, IH); 7.56-7.62 (m, 3H); 8.40 (dd, J = 9.4 and

2.8 Hz, IH); 9.20 (d, J = 2.8, IH).

Elemental analyεiε calculated for C₂₀H₁gN₂Og.l/2 H₂0 C, 61.38; H, 4.89; N, 7.16. Found C, 61.26; H, 5.00; N,

6.91. 5D/ 6-Amino-l-methyl-2-(2-methoχy-4-methoχycarbonylben- zyl)-l. -dihvdro-4-oxo-σuinoline.

Following the process described in example 4 (step

G), starting from l-methγl-2-(2-methoxy-4-methoxycarbo- nylbenzyl)-6-nitro-l,4-dihydro-4-oxo-quinoline (120 mg,

0.31 mmol), the title compound was prepared in a 91% yield.

IR (film): 3385, 1701, 1594 cm"¹.

^•-H-NMR (CDC1₃, 300 MHz): 3.52 (s, 3H); 3.90 (ε, 3H); 3.93 (s, 3H); 4.05 (s, 2H); 6.15 (s, IH); 7.00 (d, J=

8.0 Hz, 1 H); 7.05 (dd, J= 8.5 and 2.6 Hz, IH); 7.30 (d, J= 8.6 Hz, 1 H); 7.50-7.60 (m, 2H); 7.67 (d, J= 2.2Hz, IH).

5B/ 6-Cyclopentyloχycarbonylamino-l-methyl-2- 12-methoχy- 4-methoχycarbonylbenzy11-1.4-dihydro-4-oxo-αuinoline.

Following the process described in example 4 (step

H), starting from 6-amino-l-methyl-2-(2-methoxy-4- methoxycarbonylbenzy1)-1,4-dihydro-4-oxo-quinoline (120 mg, 0.22 mmolε), the title compound was prepared in a 65% yield.

IR (KBr) 3460, 1721, 1604 cm^"1.

^•J-H-NMR (CDCI3, 300 MHz): 1. 50-1.80 (m, 7H); 3.73 (s,

3H); 3.93 (ε, 3H); 3.94 (ε, 3H); 3.96 (ε, 2H); 5.94 (s,

IH); 5.96 (ε, IH); 7.01 (d, J= 7.9 Hz, IH); 7.46 (d, J= 7.9 Hz, 1 H); 7.50-7.72 (m, 2 H); 8.15 (dd, J= 3.8 and

1.1 Hz, IH); 8.65 (d, J= 5.5 Hz, IH); 8.98 (d, J= 1.7 Hz, IH).

5F/ 4-(6-Cvclopentyloχycarbnnylamino-l-metb.yl-4-oxo-crui- nolin-2-yImethy1)-3-methoχybenzoic acid. Following the procesε described in example 1 (step D), εtarting from 6-cyclopentyloxycarbonylamino-l- methyl-2-[2-methoxy-4-methoxycarbonylbenzyl]-1,4-dihy- dro-4-oxo-quinoline (100 mg, 0.21 mmol), the title compound was prepared (37% yield).

IR (KBr): 3480, 1703, 1641, 1573 cm^"1. ^-HNMR (DMSO, 300 MHz): 3.97 (s, 3H); 4.04 (ε, 3H); 4.22

(s, 2H); 6.36 (s, IH); 6.63 (bs, IH); 7.05 (dd, J= 6.0 and 3.0 Hz, 1 H); 7.34 (d, J= 7.4 Hz, IH); 7.43 (d, J=

7.7 Hz, IH); 8.00-8.21 ( , 2H); 8.57 (s, IH).

5G/ JV-T4-(6-cyclopentyloχycarbonylamino-l-methyl-4-oxo- cnιinolin-2-ylmethyl)-3-methoxybenzoyl1-2-methylbenzene- sulfonamide.

Following the process described in example 1 (step E), starting from 4-(6-cyclopentyloxycarbonylamino-l-me- thyl-1,4-dihydro-4-oxo-quinolin-2-ylmethγl)-3-methoxy- benzoic acid, a residue was recovered which was purified by silica gel flaεh chromatography. On elution with ether: acetone: diethylamine (70:30:5) the title compound was obtained (30% yield). IR (film) 1720, 1604, 1434 cm^"1. ¹H-NMR (CDC1₃, 300 MHz): 1.59-1.89 (m, 8H); 2.72 (s, 3H); 3.61 (s, 3H); 3.83 (ε, 3H); 4.01 (s, 2H); 5.18 (s, IH); 6.09 (s, IH); 6.89 (d, J = 7.0 Hz, IH); 7.16-7.29 (m, 2H); 7.39-7.50 (m, 4H); 8.10 (ε, IH); 8.27-8.31 (m, 2H).

Claims

CJΔIMS

A compound of formula I,

X wherein: the subεtituent containing A iε bound at the 5-, 6- or

7- position of the 4-quinolone ring; the substituent containing CONHS0₂ is bound at the 1- or

2- position of the 4-quinolone ring; the group R¹ iε bound at the 1- or 2- poεition of the 4- quinolone ring, depending on the poεition of the substituent containing CONHS0₂; the group R⁴ iε bound at any one of the 5-, 6-, 7- or 8- free poεitionε of the 4-quinolone ring; R¹ iε hydrogen, straight or branched C₁-C₄-alkγl, -OH,

-OCH₃, -CH X, wherein X is -OH, -OCH₃ or -COOR⁸, wherein

R⁸ is hydrogen or straight or branched C₁-C₄-alkyl;

R² iε hydrogen, fluorine, chlorine, straight or branched

(C₁-C₄)-alkyl or -OCH3, and is bound at the benzene ring at any one of its free positions;

R³ is hydrogen, fluorine, chlorine, straight or branched

(C₁-C₄)-alkyl or -OCH3, and iε bound at the benzene ring at any one of itε free positions;

R⁴ is hydrogen, fluorine, chlorine,or -OCH₃; R⁵ is hydrogen or methyl;

R⁶ is straight or branched (C₁-Cg)-alkyl, cycloalkyl or a phenylalkyl group of leεs than 10 carbon atoms;

R⁷ is hydrogen, εtraight or branched (C«-C )-alkyl,

-OCH3, -CH₂X, wherein X is -OH, -OCH3 or -COOR⁸, wherein

R⁸ is hydrogen or straight or branched C^-C ~alkyl; A is an oxygen atom, a methylene group or a group -NR⁹-, wherein R⁹ is hydrogen or methyl; and the pharmaceutically acceptable saltε thereof.

2. A compound according to claim 1, wherein A iε an oxygen atom or a methylene group, R² is -OCH3, R³ is straight (C₁~C₄)-alkyl and R⁵ is hydrogen.

3. A compound according to claim 1, wherein R² is bound at the 3- position of the benzene ring and R³ is methyl bound at the 2- poεition of the benzene ring.

4. A compound according to any one of claimε 1 to 3, wherein R⁶ is cyclopentyl.

5. A compound according to any one of claimε 1 to 4, wherein the substituent containing CONHS0₂ is bound at the 1- position of the 4-quinolone ring.

6. A compound according to claim 5, wherein R¹ and R⁷ are hydrogen.

7. A compound according to any one of claims 1 to 4, wherein the substituent containing CONHS0₂ is bound at the 2- position of the 4-quinolone ring.

8. A compound according to claim 7, wherein R¹ iε methyl and R⁷ iε hydrogen.

9. A compound according to claim 1 εelected from the following oneε:

JV-[4-(5-cyclopentylacetamido-l,4-dihydro-4-oxo-quinolin- l-ylmethyl)-3-methoxybenzoyl]-2-methylbenzenesulfonami- de;

JV-[4-(6-cyclopentylacetamido-l,4-dihydro-4-oxo-quinolin- 1-ylmethyl)-3-methoxybenzoyl]-2-methylbenzenesulfonami¬ de;

JV-[4-(7-cyclopentylacetamido-l,4-dihydro-4-oxo-quinolin- 1-ylmethyl)-3-methoxybenzoyl]-2-methylbenzenesulfonami- de;

JV-[4-(5-cyclopentyloxycarbonylamino-l-methyl-l,4-dihy- dro-4-oxo-quinolin-2-ylmethyl)-3-methoxybenzoyl]-2-me- thylbenzenesulfonamide;

JV-[4-(7-cyclopentyloxycarbonylamino-l-methyl-l,4-dihy- dro-4-oxo-quinolin-2-ylmethyl)-3-methoxybenzoyl]-2-me- thylbenzenesulfonamide.

10. A process for the preparation of the compounds of general formula I of claim 1, and of the pharmaceuti¬ cally acceptable salts thereof, wherein: a) a compound of general formula II,

XI

wherein R¹, R², R⁴, R⁵, R^ and R⁷ represent the groups defined above, iε reacted with a compound III,

XXX wherein R³ represents the groups defined above; the reaction between II and III being carried out in the presence of a carboxy-activating agent and a base, to obtain compound of formula I; b) alternatively, a compound of general formula I, wherein the substituent containing CONHS0₂ is bound at the 2- position of the 4-quinolone ring, R¹ is -CH₂X, wherein X is -OCH₃ and R², R³, R⁴, R⁵, R⁶ and R⁷ represent the groups defined above, is reacted with an acid, to obtain a compound of formula I wherein R¹ is hydrogen; c) and, if necessary, the compound of general formula I is converted into the desired salt, by treatment with a baεe or a suitable ion-exchanger, according to conventional methods.

11. The use of a compound of any one of claims 1 to 9 in the preparation of a medicament for the therapeutical treatment of leukotriene-mediated diεeaεes.

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