ITMI941099A1 - KINOLINIC DERIVATIVES - Google Patents

Abstract

new quinolinic derivatives, the procedures for their preparation and their use in medicine in the treatment of lung disorders, skin disorders and itching, neurogenic inflammation and CNS disorders are described.

Description

Description of the industrial invention entitled:

"CHIHOLINE DERIVATIVES"

in the name: SmithKline Beecham Farmaceutici S.p.A. NflG, 1984! '

The present invention relates to new quinolinic derivatives, the processes for their preparation and their use in medicine.

Neurokinin B (NKB), a marble peptide, belongs to the family of Tachikinin (TK) peptides, which also includes Substance P (SP) and Neurokinin A (NKA). Pharmacological and molecular biology tests have shown the existence of three TK receptor subtypes (NK ^ fNK2 and NK3): NKB binds preferably to the NKg receptor, although it also recognizes the other two receptors, albeit with a lower affinity (Maggi et al, 1993, J.Autcn.Pharmaool., 13, 23-93).

Selective peptic NK ^ receptor antagonists are known (Drapeau, 1990, Regul. Pept., 31, 125-135) and the evidence on peptic NK ^ receptor agonists suggests that NKB, by activating the NK3 receptor, plays a fundamental role in modulation of the neuronal input at the level of the respiratory tract, skin, spine and nigrostriatal tracts (Myers and Undem, 1993, J.Phisiol., 470, 665-679; Counture et al., 1993, Regul. Peptides, 46, 426- 429; Mccarson and Krause, 1994, J. Neurosci., 14 (2), 712-720; Arenas et al ,. 1991, J.Neurosci., 11, 2332-8).

However, the peptide-like nature of the known antagonists probably makes them too metabolically labile to serve as therapeutic agents in practice.

We have now found a new class of selective nonpeptide NK receptor antagonists, far more metabolically stable than peptide NK receptor antagonists, and of potential therapeutic utility in the treatment of pulmonary disorders (asthma, chronic obstructive pulmonary disease -COPD-, hyper reactivity of the respiratory tract, cough), skin disorders and itching (for example atopic dermatitis, blisters, burns and skin burns), neurogenic inflammation and CNS disorders (Parkinson's no., Motor disorders, anxiety) .

According to the present invention, a compound, or a salt or solvate thereof, of general formula (I) is provided:

(THE)

in which

Ar is an optionally substituted phenyl or naphthyl or a heterocyclic group with a single or fused ring, optionally substituted, of aromatic character, containing from 5 to 12 ring atoms and comprising up to four heteroatoms in the ring or in each ring, selected from among S, 0, N; with the proviso that Ar we is p-isobutylphenyl; R is linear or branched alkyl, C3-? cycloalkyl, C4-7 cycloalkylalkyl, phenyl optionally substituted, heteroaromatic rings optionally substituted with 5-elements, ccrp yielding up to four heteroatoms selected from 0 or N, hydroxy C ^ _g alkyl, arnino C ^ _g alkyl, C ^ _g alkylamyricalkyl, di C ^ _g alkyliminoalkyl, C ^ _g acylanminocarbonyl, C ^ _g alkoxyalkyl, C ^ _g alkylcarbonyl, carboxy, C ^ _g alkoxycarbonyl, aminocarbylene, C ^ _g alkylanminocarbonyl, C ^ _g alkyl alkyl alkyl;

R1 and R2, which may be the same or different, are independently hydrogen or linear or branched Cj_g alkyl, or together they form a - (CH2) n_ group in which n represents 3, 4 or 5;

R3 and R ^, which may be the same or different, are independently hydrogen, C ^ _g linear or branched alkyl, C ^ _g alkenyl, aryl, c ^ _g alkoxy, hydroxy, halogen, nitro, cyano, carboxy, carboxamnide, sulfonanide, C 1 -g alkoxycarbonyl or trifluoromethyl, with up to four substituents in the quinoline nucleus;

R3⁄4 is Cj_g linear or branched alkyl, Cg_7 cycloalkyl, C4JZ7 cycloalkylalkyl, optionally substituted aryl, or a single or fused ring heterocyclic group, optionally substituted, of aromatic character, containing from 5 to 12 ring atoms and comprising up to four heteroatcms in the ring or in each ring, chosen from S, 0, N; XèO, So N-C = N.

Preferably, Ar is phenyl optionally substituted by hydroxy, halogen, C ^ g alkoxy or trifluorcmethyl. Examples of halogen are chlorine and fluorine, and an example of C ^ g alkoxy is methoxy.

Ar elements as a heterocyclic group are furyl, thienyl, pyridyl, pyrryl, thiazolyl, indolyl, benzofuryl or benzothienyl.

Examples of healthy R are the following:

Cj_g alkyl: methyl, ethyl, n-propyl, isopropyl;

C3 7 cycloalkyl: cyclopyl;

C4-? cycloalkylalkyl: ci cloprcpi lmet the e;

heteroaromatic rings: oxadiazoles, methyloxadiazoles;

hydroxy Gualkyl: -CH2OH, -CH2CH2OH / CH (Me) OH, CH2CH (Me) OH;

amino C1-g alkyl: -CH2NH2;

C - ^ _ g alkylaninoalkyl: -CH2NHMe, -CH2NHEt;

of C ^ _g alkylaninoalkyl: -CH2NHMe2, -CH2NHEt2;

^ 1-6 acylaninoalkyl: -CH2NHOOMe;

C - ^ _ g alkoxylalkyl: CH2OMe;

C ^ _g alkylcarbonyl: COMe;

c ^ _g alkoxycarbonyl: CCOMe; COOEt; -COOi-Pr;

C-j_g alkylanminocarbonyl: -CCNHMe, -CONHEt;

of C ^ _g alkylanminocarbonyl: CONMe2, OONEt2, -CONMeEt;

halogen C ^ _g alkyl: trifluoromethyl.

Examples of and R2 are methyl, ethyl and n-propyl.

Examples of R ^ and R4 are methyl, ethyl, n-propyl, methoxy, ethoxy, chloro, fluorine, bromine and methoxycarbyl.

Examples of Rg are isopropyl, cyclopentyl, cyclohexyl, cyclopentylmethyl, cyclohexylmethyl, possibly substituted filyl as defined above for Ar, and the heterocyclic groups as defined above for Ar.

A preferred subgroup of compounds under formula (I) is that of formula (la): - - - - -

(there)

in which:

R, R2, R3 and R4 30110 as defined in formula (I) and Y and Z, which may be the same or different, are each Ar as defined in formula (I).

A particularly preferred group of compounds of formula (la) are those of formula (Ib), in which the group R is oriented downwards and H upwards, with respect to the N-C-Z plane.

(Ib)

The compounds of formula (I) or their salts or solvates are preferably in pharmaceutically acceptable or substantially pure form. By pharmaceutically acceptable form is meant, inter alia, of a pharmaceutically acceptable level of purity, with the exclusion of normal pharmaceutical excipients such as diluents and vehicles, and not including material considered toxic at normal dosage levels.

A substantially pure form will generally contain at least 50% (excluding normal pharmaceutical additives), preferably 75%, more preferably 90% and even more preferably 95% of the compound of formula (I) or its salt or solvate.

A preferred pharmaceutically acceptable form is the crystalline form, including that form in a pharmaceutical composition. In the case of salts and solvates, the ionic portions and additional solvents must also be non-toxic.

Examples of pharmaceutically acceptable salts of a compound of formula (I) include acid addition salts with conventional pharmaceutical acids, for example maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, mandelioo, tartaric, suocinic acids. , benzoic, ascorbic and methanesulfonic.

Examples of pharmaceutically acceptable solvates of a compound of formula (I) include hydrates.

The compounds of formula (I) have at least one asymmetric center and therefore exist in more than one stereoisomeric form. The invention extends to all such forms and their mixtures, including racemates.

The invention also provides a process for the preparation of a compound of formula (I), which comprises the reaction of a compound of formula (III)

(ITI)

where R1, R '^, R * 2 and Ar * are R, R ^, R2 and Ar as defined for the *

formula (I), or a group or atom convertible into R, R ^, R2 and Ar, with a body of formula (II)

Gì)

or an active derivative thereof, in which R'3, R'p R'5 and X 'saio R ^, R4, R ^ and X, care defined by the formula (I), or a group convertible into R ^, R ^, R5 and X, to form a compound of formula (le)

Oc)

and possibly subsequently realization of one or more of the following stages:

(a) where R ', from R'x to R'5, Ar'e X' are different from R, from R1 to R5, Ar and X, conversion of any one of R ', from R' ^ to R ' ^, Ar 'and X' in R, from R ^ to R5, Ar and X, to obtain a compound of formula (I),

(b) where R ', from R ^ to R'5, Ar' and X 'are R, from Rj to R5 # Ar and X, conversion of any one of R, from R ^ to R ^ f Ar and X into another R, from R ^ to R5, Ar and X, to obtain a compound of formula (I),

(c) formation of a salt and / or a solvate of the compound of formula (I) obtained.

Suitable active derivatives of the compounds of formula (II) are the acyl halides (preferably the chlorides), the azides of acids or the anhydrides of acids. Another suitable derivative is the mixed anhydride formed between the acid and an alkyl chloroformate; another suitable derivative is the activated ester, such as cyanamethyl ester, thiophenyl ester, p-nitrophenyl ester, p-nitrothiophenyl ester, 2,4,6-trichlorophenyl ester, pentachlorophenyl ester, pentafluorophenyl ester, N-hydroxy-phthalyrmido ester, N -hydroxypiperidino ester, N-hydroxysuccinyrmido ester, N-hydroxybenzotriazol ester; or the carboxy group can be activated using a carbodiiirmide or N, N'-carbonyldiimidazole.

For example, in standard methods well known to the skilled in the art, the compounds of formula (III) can be coupled:

(a) with an acyl chloride in the presence of an inorganic or organic base, in a suitable aprotic solvent such as dielectric mass (DMF) at a temperature in the range of -70 to 50 ° C (preferably in a range -10 to 20 ° C),

(b) with acid in the presence of a suitable condensing agent, such as, Ν-carbonyldiimidazole (CDI) or a cartoodiimnide such as dicyclohexylcarbodiinmide (DOC) or N-dimethylanminopropyl-N'-ethylcarbodiimide and N-hydroxybenzotriazole (HOBT) to maximize yields and avoid racemization processes (Synthesis, 453, 1972) in an aprotic solvent such as a mixture of acetonitrile (MeCN) and tetrahydrofuran (THF) in a ratio of 1: 9 to 7: 3, respectively, at a temperature in the range from -70 to 50 ° C (preferably in the range from -10 to 25 ° C) (see Scheme 1).

Scheme 1

(c) with a mixed anhydride generated in situ from acid and an alkyl (e.g. isoprcpil) chloroformate in a suitable aprotic solvent such as dichloromethane, at a temperature in the range of -70 to 50 ° C (preferably in a range -20 to 20 ° C).

It will be noted that a compound of formula (I) can be converted into a compound of formula (I), or that a compound of formula (I) can be converted into another compound of formula (I), by interversion of suitable substituents. Therefore, certain compounds of form (I) and (le) are useful intermediates in the formation of other compounds of the present invention.

For example, R'j can be hydrogen and caiverted into a 1 * 2 alkyl group for example methyl, by conventional amrdde alkylation procedures (Zabicky, Ibe chemistry of amides; InterScience, London, 1970, p. 749). When X 'is oxygen, it can be converted to X sulfur with standard reagents for the formation of thioaimddi, such as P2s5 (Chem. Rev., 61, 45, 1961 or Angew. Chem., 78, 517, 1966) or the reagent by Lawesscn (Tetrahedron, 41, 5061, 1985). When Ar 'or R' ^ is a methoxy-substituted phenyl, it can be converted to another Ar 'or R'g hydroxy-substituted phenyl by standard Lewis acid demethylation procedures, such as song tribromide {Synthesis, 249 , 1983) and yet with mineral acids, such as hydrobromic or hydrogen iodide. When R is a haloxycarbonyl group, for example methoxycarbonyl, it can be converted to another R, such as ethoxycarbonyl, by transesterification with an appropriate alcohol at a temperature in the range of 20 to 120 ° C; carboxy by hydrolysis in an acid or basic medium; artninocarbonyl, alkylaminocarbonyl or dialkylanminocarbonyl by ammonia transarmidation, a primary antine or a secondary annum in methanol as a solvent at a temperature in the range of 10 to 120eC, possibly in the presence of a catalytic amount of NaCN (J. Org. Chem. , 52, 2033, 1987) or using trimethylaluminium (Me ^ Al) (Tetrahedron Letters, 48, 4171, 1977); hydroxymethyl by selective reduction with a metal hydride, such as reduction with lithium borohydride, (Tetrahedron, 35, 567, 1979) or reduction with sodium borohydride in THF MeCH (Bull. Chem. Soc. Japan, 57, 1948, 1984 or Synth . Comnun., 12, 463, 1982); alkyl carbonyl by the formation of an acyl chloride and subsequent reaction with alkylmagnesium halides in solvent THF, at a temperature in the range from -78 to 30 ° C (Tetrahedron Letters, 4303, 1979), or with alkylcadmium or dialkylcadmium halides in the presence of MgCl2 ° LiCl (J. Org.Chem., 47, 2590, 1982). Another group into which R'as methoxycarbonyl can be converted is a substituted heteroarcmatic ring, such as an oxadiazole (J. Med.Chem., 34, 2726, 1991).

Scheme 2 summarizes some procedures described above to convert a compound of formula (le) or (I), where X is oxygen, R 'is COOMe, Ar' and from R '^ to R' ^ are described in the formula (I), in another compound of formula (I).

Scheme 2

The caipositas of formula (I) can be converted into their addition salts with pharmaceutically acceptable acids by reaction with the appropriate organic or mineral acids.

The solvents of the compounds of formula (I) can be formed by crystallization or recrystallization from the appropriate solvent. For example, the hydrates can be formed by crystallization or re

crystallization from aqueous solutions or from solutions in organic solvents containing water.

Even salts or solvates of the compounds of formula (I) which are not pharmaceutically acceptable, can be useful as intermediates in the production of pharmaceutically acceptable salts or solvates. Consequently, such salts or solvates also form part of this invention.

As mentioned above, the compounds of formula (I) exist in more than one stereo form and the process of the invention produces racemates as well as enantiomerically pure forms. To obtain the pure enantiomers, enantiomerically pure appropriate primary or secondary airminas of formula (Illd) or (IIle)

they are reacted with the compounds of formula (II), to obtain the compounds of formula (l 'd) or (I' e).

The compounds of formula (l'd) or (I'e) can subsequently be converted into the compounds of formula (Id) or (le) with the conversion methods mentioned above.

(Id) de) The compounds of formula (II) are known compounds or can be prepared from known compounds by known methods.

For example, the compound of formula (II) in which X 'is oxygen, R13, R'4 and R' ^ are hydrogen, is described in Pfitzinger, J. Prakt. Chem., 38, 582, 1882 and in Pfitzinger, J. Prakt. Chem., 56, 293, 1897; the compound of formula (II) in which X is oxygen, R'3 and R'4 are hydrogen and R'5 is 2-pyridyl is described in Risaliti, Rie. Scient., 28, 561, 1958; the compounds of formula (II) in which X * is oxygen, R'3 and R'4 are hydrogen and R '^ is o-, m- and p-chlorophenyl, o-fluorophenyl and 3,4-dichlorophenyl are described in Brcwn et al., J. Am. Chem. Soc., 68, 2705, 1946; the compound of formula (II), in which X1 is oxygen, R '^ and R'4 are hydrogen and R'3 is p-methoxyphenyl is described in Ciusa and Luzzatto, Gazz. Chim. Ital., 44, 64, 1914; the compound of formula (II), in which X 'is oxygen, R'3 and R'4 are hydrogen and R'5 is m-trifluorcmethylphenyl is described in Shargier and Lalezari, J. Chem. Eng. Data, 8, 276, 1963; the compound of formula (II), in which X 'is oxygen, R'3 and R'4 are hydrogen and R' ^ is pfluorophenyl is described in Bu Hoi et al., Ree. Trav. Chim., 68, 781, 1949; the compound of formula (II), in which X 'is oxygen, R'3 and R'4 are hydrogen and R' ^ is p-methylphenyl is described in Prevost et al., Caipt. Rend.Acad. Sci., 258, 954, 1964; the compound of formula (II), in which X1 is oxygen, R '^ and R' ^ j are hydrogen and R'j is p-bromophenyl is described in Nicolai et al., Eur. J. Med. Chem., 27 , 977, 1992; the compound of formula (II), in which X 'is oxygen, R'4 and R · ,. are hydrogen and R'3 is 6-methyl is described in Buchmann and Hcwtcn, J. Am. Chem. Soc., 68, 2718, 1946; the compound of formula (II), in which X 'is oxygen, R'4 and R' ^ are hydrogen and R'3 is 8-nitro is described in Buchmann et al., J. Am. Chem. Soc., 69, 380, 1947; the compound of formula (II), in which X 'is oxygen, R'4 is hydrogen, R'3 is 6-chloro, R'5 is p-chlorophenyl is described in Lutz et al., J. Am. Chem. Soc., 68, 1813, 1946; the compound of formula (II), in which X1 is oxygen, R'3 and R '^ are hydrogen and R'g is 2-thiazolyl is described in European patent application EP 112,776; the compounds of formula (II), in which X 'is oxygen, R'3 is 8-trifluoromethyl, R' ^ is hydrogen and R '^ is phenyl, o- and p-fluorophenyl, 3,4-dichlorophenyl, p- sine methoxyphenyl described in Nicolai et al., Eur. J. Med. Chem., 27, 977, 1992; the compounds of formula (II), in which X1 is oxygen, R1 ^ is 6-bream, R'4 is hydrogen and R'5 is phenyl or p-fluorophenyl are described in Nicolai et al., Eur. J. Med. Chem., 27, 977, 1992; other compounds of formula (II) are described in Ger. Offen. DE 3,721,222 and in European patent application EP 384,313.

The compounds of formula (III), (IHd) and (Ille) are commercially available compounds or they can be prepared from known compounds with known methods (for example, the compounds of formula (III) in which R 'is alkoxycarbonyl, R' ^ and R ^ are hydrogen and to 'is as defined for the compounds of formula (I), are described in Liebigs Ann. der Chemie, 523, 199, 1936.

The activity of the compounds of formula (I) as antagonists of the NK receptor in standard tests indicates that they are of potential therapeutic utility in the treatment of pulmonary disorders (asthma, OOPD, respiratory tract hyperreactivity, cough), skin disorders and pruritus (atcpic dermatitis, blisters, burns and skin burns), neurogenic inflammation and CNS disorders (Parkinson's disease, motor disorders, anxiety) (hereinafter referred to as "Conditions").

Accordingly, the present invention also provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use as a therapeutically active substance.

The present invention further provides a pharmaceutical composition which includes a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

The present invention also provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of conditions.

Such medicament, and a composition of the invention, can be prepared by mixing a compound with a suitable carrier, which may contain a diluent, binder, filler, disintegrant, flavoring agent, coloring agent, lubricant or preservative in a conventional manner.

These conventional excipients may be used, for example, in the preparation of compositions of known agents, for the treatment of conditions.

Preferably, a pharmaceutical composition of the invention is in unit dosage form and in a form suitable for use in the medical or veterinary field. For example, such preparations may be in packaged form accompanied by written or printed instructions for use as an agent in the treatment of any of the conditions.

The suitable dosage range for the compounds of the invention depends on the compound to be employed and the condition of the patient. It will also depend, among other things, on the relationship between potency and absorbability, on the frequency and on the path of somnainis traction.

The compound or composition of the invention can be formulated for any route of administration and is preferably in unit dosage form or in a form such that a human patient can self-manage in a single dosage. Advantageously, the composition is suitable for oral, rectal, topical, parenteral, intravenous or intramuscular administration. The preparations can be formulated to give a slow release of the active ingredient.

The compositions can be, for example, in the form of tablets, capsules, sachets, ampoules, powders, granules, tablets, re-replaceable powders, or liquid preparations, for example solutions or suspensions, or suppositories.

The compositions, for example those suitable for oral treatment, may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, e.g. lactose, sugar, corn starch, calcium phosphate, sorbitol or glyein; pressing lubricants, for example magnesium stearate; disintegrants, for example starch, polyvinylpyrrolidone, juggled sodium starch or microcrystalline cellulose; or pharmaceutically acceptable curing agents such as sodium lauryl sulfate.

The solid compositions can be obtained by conventional methods of mixing, filling, pressing or the like. Repeated mixing operations can be used to distribute the active ingredient in those compositions which employ large amounts of fillers. When the composition is in the form of a coupress, powder or tablet, any vehicle suitable for the formulation of solid pharmaceutical compositions can be used, for example magnesium stearate, starch, glucose, lactose, sucrose, rice flour and gypsum.

The tablets can be coated according to methods known in normal pharmaceutical practice, in particular with gastro-resistant coatings. The composition may also be in the form of a capsule to be swallowed, e.g. gelatin containing the compound, if desired with a vehicle or other excipients.

The liquid compositions for oral administration can be in the form, for example, of emulsions, syrups or elixirs, or they can be presented as a dry product to be reconstituted with water or other suitable vehicle before use. Such liquid compositions can contain conventional additives such as suspending agents, for example sorbitol, syrup, methylcellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia skirt; aqueous or non-aqueous vehicles, which include digestible oils, for example, almond oil, fractionated coconut oil, oily esters, for example, glycerin esters, or glycerin glycol, or ethyl alcohol, glycerin, water or saline; preservatives, for example methyl or prpyl p-hydroxybenzoate or sorbic acid; and, if desired, conventional flavoring or coloring agents.

The compounds of this invention can also be judged through a non-oral route. According to the usual pharmaceutical procedure, the compositions can be formulated, for example for rectal administration as a suppository. They may also be formulated, for presentation in injectable form, in an aqueous or non-aqueous solution, suspension or emulsion, in a pharmaceutically acceptable liquid, e.g. sterile pyrogenic water or acceptable oil for parenteral administration or a mixture of liquids. The liquid may contain bacteriostatic agents, antioxidants or other preservatives, tans or solutes to make the solution isotonic with blood, thickening agents, suspending agents or other pharmaceutically acceptable additives. Such forms will be presented in unit dosage form such as ampoules or disposable injection devices or in multi-dose forms such as bottles, from which the appropriate dose can be taken, or a solid or concentrated form that can be used to prepare an injectable formulation.

The compounds of this invention can also be administered by inhalation, through the nasal or oral route. This administration can be carried out with a spray formulation learning a suitable compound and carrier, optionally suspended in a hydrocarbon propellant.

Preferred spray formulations include micronized compound particles in combination with a surfactant, solvent or dispersing agent to prevent sedimentation of the suspended particles. Preferably, the particle size of the compound is from about 2 to 10 µ.

A further modality of administration of the compounds of the invention comprises transdermal delivery using a skin patch formulation. A preferred formulation includes a compound dispersed in a pressure sensitive adhesive which adheres to the skin, thereby allowing the compound to diffuse from the adhesive through the skin to be delivered to the patient. For a constant rate of pereutaneous absorption, pressure sensitive adhesives known in the art, such as natural gum or silicone, can be used.

As mentioned above, the effective dose of compound depends on the particular compound employed, the patient's condition and the frequency and route of administration. A unit dose will generally contain from 20 to 1000 mg and preferably will contain from 30 to 500 mg, in particular 50, 100, 150, 200, 250, 300, 350, 400, 450 or 500 mg. The composition can be administered one or more times a day, for example 2, 3 or 4 times a day, and the total daily dose for a 70 kg adult will normally be in the range of 100 to 3000 mg. Alternatively, the unit dose will contain from 2 to 20 mg of active ingredient and will be administered in multiple doses, if desired, to give the above daily dose.

If the compounds are administered according to the invention, no unacceptable toxic-logical effects are expected.

The present invention also provides a method for the treatment and / or prophylaxis of the Conditions in mammals, in particular in humans, which comprises the administration to the marble that requires such treatment and / or prophylaxis of an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.

The activity of the compounds of the present invention, as ligands of the NK ^ receptor, is determined by their ability to inhibit the binding of the root-marked ligands of the NK ^ receptor, [^ I] - [Me-Phe ^] - NKB or [1⁄ 2] -Senktide, to guinea pig and human NK ^ receptors (Renzetti et al-, 1991, Neuropeptide, 18, 104-114; Buell et al., 1992, FEBS, 299 (1), 90-95; Chung et al. , 1994, Biochem. Biophys. Res. Conmun., 198 (3), 967-972). The binding tests used allow the determination of the concentration of each single compound necessary to reduce by 50% the specific binding of f ^^^ I] - [Me-Phe ^ J-NKB and [1⁄2] -Senktide to the NK receptor ^ in conditions of equilibrium. The binding tests provide for each compound tested the averages of the IC ^ Q values of 2-5 separate experiments performed in triplicate or quadruplicate. The more potent compounds of the present invention show IC ^ Q values in the range of 1-1000 nM; for example, the compound of Eserrpio 12 shows an IC5Q of 66 nM (n = 3) in the cortical membranes of guinea pigs, by displacement of (3⁄4] -Senktide.

The NK - ^ - antagenic activity of the compounds of the present invention is determined by their ability to inhibit the contraction of the guinea pig ileum induced by Senktide (Maggi et al., 1990, Br. J. Pharmacol., 101, 996-1000 ) and the mobilization of Ca ++ mediated by human NK ^ receptors (Mochizuki et al., 1994, J. Biol. Chem., 269, 9651-9658). The functional test on the guinea pig provides for each compound tested inedited kg values from 3-8 separate experiments, where kg is the concentration of the individual compound required to produce a two-fold rightward shift in the Senktide dose-response curve.

The functional tests on human receptors allow the determination of the concentration of each single compound necessary to reduce by 50% (IC50 values) the mobilization of Ca ++ induced by the NKB agonist. In this test the compounds of the present invention behave as antagonists.

The therapeutic potential of the compounds of the present invention in the treatment of the Conditions can be determined using disease models with rodents.

The following Descriptions illustrate the preparation of the intermediates, while the Examples illustrate the preparation of the compounds of the present invention. The compounds of the Examples are summarized in Table.

DESCRIPTION 1

2-phenyl-4-quinolincarbonyl chloride

11.7 ml (136.3 nmoles) of oxalyl chloride are dissolved in 150 ml of CHjC ^ The solution is cooled to -10 ° C and 20 g (80.2 nmoles) of 2- acid are added in several portions. phenyl-4-quinolincarboxyl, commercially available. The reaction mixture is left alone, at room temperature, for the whole night and then evaporated to dryness under vacuum. 22 g of the desired product are obtained, used without further purification.

DESCRIPTION 2

2-phenyl-7-raethoxy-4-quinolincarboxylic acid

5 g (28.2 mmol) of 6-methoxyisatin, 4 ml (33.8 limol) of acetophenone and 5.2 g (92.6 mmol) of potassium hydroxide are dissolved in 22.9 ml of absolute EtOH and the suspension is heated to 80 ° C for 42 hours. The reaction mixture is cooled, 50 ml of water are added and the solution is extracted with 50 ml of. The aqueous phase, cooled with ice, is acidified to pH 1 with 37% HCl and the precipitate is collected by filtration, washed with water and dried under vacuum at 40 ° C. 7.0 g of the desired product are obtained.

DESCRIPTION 3

2-phenyl-7-methoxy-4 -quinoline arbonyl chloride

2.8 ml (32.3 limols) of oxalyl chloride are dissolved in 60 ml of CH2C12 * solution is cooled to -10 ° C and 6 g (19.0 ml) of 7- acid are added in several portions. methoxy-2-phenyl-4-quinolincarboxylic. The reaction mixture is left alone, at room temperature, for the whole night and then evaporated to dryness under vacuum. 7.0 g of the desired product are obtained, used without further purifications.

C17H12aN02

P.M. - 297.74

DESCRIPTION 4

2-phenyl-7-hydroxy-4-quinolincarboxylic acid iodide

1.5 g (5.4 percent) of 7-methoxy-2-phenyl-4-quinolincarboxylic acid are added, in several portions, to 50 ml of 57% HI. The reaction mixture is refluxed under vigorous magnetic stirring for 5 hours and then evaporated to dryness under vacuum to yield 2.1 g of the desired product.

DESCRIPTION 5

2- (2-thienyl) -4-quinolincarboxylic acid

5 g (34.0 nmoles) of isatin, 4.4 ml (40.8 limols) of 2-acetylthiophene and 6.3 g (112.2 nmoles) of potassium hydroxide are dissolved in 40 ml of absolute Et OH and the suspension is heated to 80 ° C for 16 hours. The reaction mixture is cooled, 50 ml of water are added and the solution is extracted with 50 ml of Et20. The aqueous phase, cooled with ice, is acidified to ρΗ 1 with 37% HC1 and the precipitate is collected by filtration, washed with water, dried under vacuum at 40eC and triturated with AcOEt. 4.8 g of the desired product are obtained.

DESCRIPTION 6

2- (2-furyl) -4-quinolincarboxylic acid

5 g (34.0 limol) of isatin, 4 ml (40.8 itmol) of 2-acetofuran and 6.3 g (112.2 limol) of potassium hydroxide are dissolved in 40.9 ml of absolute EtCH and the suspension is heated to 80 ° C for 12 hours. The reaction mixture is cooled, 50 ml of water are added and the solution is extracted with 50 ml of Et20. The aqueous phase, cooled with ice, is acidified to pH 1 with 37% HCl and the precipitate is collected by filtration, washed with water and dried under vacuum at 40 ° C. 8.5 g of the desired product are obtained.

DESCRIPTION 7

2- (2-furyl) -4-quinolincarbonyl chloride

5.2 ml (60.4 µmoles) of oxalyl chloride are dissolved in 70 ml of CH 2 Cl 2. The solution is cooled to -10 ° C and 8.5 g (35.5 mmoles) of 2- (2-furyl) -4-quinolincartooxylic acid are added in several portions. The reaction mixture is left to settle, at an aft temperature, for the whole night and then evaporated to dryness under vacuum. 9.2 g of the desired product are obtained, used without further purif reactions.

DESCRIPTION 8

2- (4-pyridyl) -4-quinolincarboxylic acid hydrochloride

5 g (34.0 limols) of isatin, 4.5 ml (40.8 ranoles) of 4-acetylpyridine and 6.3 g (112.2 nmoles) of potassium hydroxide are dissolved in 40 ml of absolute EtOH and the suspension is heated to 80 ° C for 12 hours. The reaction mixture is cooled, 50 ml of water are added and the solution is extracted with 50 ml of Et2o. The aqueous phase, cooled with ice, is acidified to pH 1 with 37% HC1 and the precipitate is collected by filtration and washed with water. The aqueous solution is evaporated to dryness under vacuum, the residue is triturated with EtOH and filtered off. Evaporation of the solvent gives 6.0 g of crude which, combined with the precipitate obtained above, is recrystallized from toluene containing traces of MeCH. 4.5 g of the desired product are obtained.

DESCRIPTION 9

2- (4-pyridyl) ^ - quinolincarbonyl chloride hydrochloride

1.3 ml (10.4 µmoles) of oxalyl chloride are dissolved in 60 ml of CH2Cl2 The solution is cooled to -10 ° C and 3.0 g (14.4 nmoles) of 2- (4-pyridyl) -4-chi no linear -boxylic acid hydrochloride. The reaction mixture is left at se1, at room temperature, for 72 hours and then evaporated to dryness under vacuum. 4.0 g of the desired product are obtained, used without further purifications.

EXAMPLE 1

(R, S) -N- (0 (-methylbenzyl) -2-phenylquinoline-4-carboxamide

1.2 ml (9.4 nmoles) of (R, S) O2 -methylbenzylamine and 1.6 ml (11.7 limols) of triethylanine (TEA) are dissolved, under nitrogen, in 50 ml of a mixture 1: 1 of anhydrous CH2ci2 and CH ^CN. 2.0 g (7.8 ml) of 2-phenyl-4-quinolincarbonyl chloride, dissolved in 50 ml of a 1: 4 mixture of anhydrous CH2ci2 and DMF, are dropped into the anine solution, cooled in a gravel bath . The reaction is maintained for 1 hour between 0 ° and 5eC and then at terrier atura anfoiente for the whole night. The reaction mixture is evaporated to dryness under vacuum and the residue is dissolved in AcCEt and washed twice with a saturated solution of NaHCO2. The organic phase is separated, dried over Na2SO4, filtered and evaporated to dryness under vacuum.

The residual oil is crystallized by AcOEt to yield 1.1 g of the desired product.

EXAMPLE 2

S— (+) -N- (or ^ -methylbenzyl) -2-phenylquinoline-4-carboxaninide

Prepared as described in Example 1 starting from 1.2 ml (9.4 nmol) of S - (-) - 0 ^ netylbenzylairmine, 1.6 ml (11.7 mmol) of TEA, 2.0 g (7, 8 nmoles) of 2-phenyl-4-quinolincarbonyl chloride in 100 ml of a mixture of CH2ci2, CH3CN and IMF. The reaction mixture is processed as described in Example 1. The residual oil is crystallized from AcOEt to yield 1.1 g of the desired product.

The mass spectrum is identical to that of Example 1.

EXAMPLE 3

R- (-) -N- Cfr-methylbenzyl) -2-f enylquinoline-4-carboxamnide

Dog preparation described in Example 1 starting from 1.2 ml (9.4 limols) of R- () -0 ^ -nethylbenzylanine 1.6 ml (11.7 nmoles) of TEA, 2.0 g (7.8 limols) of 2-phenyl-4-quinolincarbonyl chloride in 100 ml of a mixture of CH2ci2, CH3CN and DMF.

The reaction mixture is processed as described in Example 1. The residual oil is crystallized by AcCEt to yield 1.1 g of the desired product.

1⁄2-MMR and sine mass spectrum identical to those of Examples 1 and 2.

EXAMPLE 4

(R # S) -N- [or (- (methoxycarbonylJbenzyl] -2-phenylquinoline-4-carbossamnd.de

2.0 g (8.0 mmoles) of 2-phenyl-4-quinolincarboxylic acid are dissolved, under nitrogen, in 130 ml of anhydrous THF and 100 ml of CH2 CN. 2.0 g (9.9 mmoles) of (D, L) phenylglycine methyl ester hydrochloride and 1.5 ml (10.7 mmoles) of TEA are added and the reaction mixture is cooled to 5 ° C.

2.5 g (12.1 limol) of dicyclohexylcarbodiimnide (DOC) are added dropwise, dissolved in 10 ml of anhydrous CH2ci2, and the reaction is allowed to rise overnight at room temperature and at se1.

The precipitating dieyclohexylurea is filtered off and the solution evaporated to dryness in vacuo. The residue is dissolved in CH 2 Cl 2 and washed with water. The separated organic phase is dried over Na2SC> 4 and evaporated to dryness under vacuum to obtain 6.0 g of crude product which is dissolved in 20 ml of CH2ci2 and left to stand overnight. The other dicyclohexilunea falls and is filtered away.

The solution is evaporated to dryness under vacuum and the flash chromatographed residue on silica gel (230-400 mesh) using an eluent mixture of hexane / AcQEt 3: 2 containing 0.5% NH ^ OH (28%) . The product obtained is hot triturated with i-Pr2o, filtered, washed and dried to give 1.1 g of the desired product.

Elementary analysis:

EXAMPLE 5

() - (S) -N- [o ^ methoxycartxxiì 1) benzyl] -2-f enylquinoline-4-carboxamirip

2.0 g (8.0 limols) of 2-phenyl-4-quinolincarboxylic acid are dissolved, under nitrogen, in 70 ml of anhydrous THF and 30 ml of CH2 CN.

1.7 g (8.4 nrnoles) of hydrochloride of the (L) phenylglycine methyl ester, 1.1 ml (9.9 limols) of N-methylmorpholine and 2.1 g (15.5 limols) of N-hydroxybenzotriazole (HDBT) and the reaction mixture is cooled to 0eC. 1.85 g (9.0 limols) of DOC, dissolved in 10 ml of anhydrous CHjC ^, are added dropwise, and the reaction is then kept between 0 ° and 5 ° C for 1 hour and at room temperature for 2 hours. The precipitating dicyclohexylurea is filtered off and the solution evaporated to dryness in vacuo. The residue is dissolved in CHjC ^ and washed with water, Na-HCOg sol. sat. , 5% citric acid / NaHCO ^ sol. sat. and NaCl sol. sat. .

The separated organic phase is dried over 280% and evaporated to dryness under vacuum; the residue is dissolved in 20 ml of CH2Cl2 and left to stand overnight. The other dicyclohexylurea precipitates and is filtered off.

The solution is evaporated to dryness under vacuum to obtain 2.6 g of crude product which is triturated with petroleum ether, filtered, washed with i-Pr2o and recrystallized with 70 ml of i-PrOH to obtain 1.7 g of the desired product. .

1⁄2-NMR and mass spectrum are identical to those of Example 4.

EXAMPLE 6

{-) - (R) -N- [or (- (methoxycarbonyl) benzyl] -2-phenylquinoline-4-carboxamide

Prepared as described in Example 5 of 2.0 g (8.0 µmnoles) of 2-phenyl-4-quinolincarboxylic acid, 1.7 g (8.4 µmol) of (D) phenylglycine methyl ester hydrochloride, 1.1 ml (9.9 noles) of N-methylmorpholine, 2.1 g (15.5 limols) of HOBT and 1.85 g (9.0 nols) of DGC in 70 ml of anhydrous THF and 30 ml of CH ^ CN.

The reaction mixture is processed as described in Example 5. The crude product obtained (3.5 g) is hot triturated twice with i-PrjO, filtered, washed and recrystallized with 80 ml of i-PrCH to obtain 2, 3 g of the desired product.

1⁄2-NMR and sine mass spectrum identical to those of Examples 4 and 5. ES34PI0 7

(R, S) -N- (methoxycarbonyl-benzyl] -2-phenyl-7-3⁄4-methoxyquinoline — 4-cartx3ssannd.de

1.0 g (5.0 nmoles) of (D, L) phenylglycine methyl ester hydrochloride are dissolved, under nitrogen, in 30 ml of anhydrous DMF. 2.5 g (18.1 nmoles) of anhydrous potassium carbonate are added and the solution is cooled to 0eC. 0.7 g (2.3 limols) of the product of Description 3 are dropped, dissolved in 25 ml of anhydrous DMF, and the reaction is maintained between 0 ° and 5 ° C for 1 hour and at room temperature overnight.

The reaction mixture is evaporated to dryness under vacuum and the residue is dissolved in AcQEt and washed twice with water. The separated organic phase is dried over Na2SO4, filtered and evaporated to dryness under vacuum.

The residual oil is flash chromatographed on silica gel (230-400 mesh) using a mixture of hexane / AcCEt 3: 2 containing 0.5% NH ^ QH (at 28%), to obtain 0.1 g of crude product which is triturated with i-P ^ o. 0.08 g of the desired product are obtained.

Esracio 8

(R, S) -W- (methoxycarbonyl) benzyl] -2-f enyl-7- hydroxyquinoline-4-carbossaBnKri.de

Prepared as described in Example 5 from 2.1 g (5.3 limols) of the product of Description 4, 1.08 g (5.3 hymn) of hydrochloride of the methyl ester of (D, L) phenylglidna, 1 , 5 ml (10.7 nmoles) of TEA, 1.7 g (12.5 ichthyols) of HDBT and 1.2 g (5.8 ichthyols) of DCC in 70 ml of anhydrous THF and 30 ml of CH ^ CN .

The reaction mixture is processed as described in Example 5. The crude product obtained is triturated with i-P2 O and recrystallized twice from i-PrOH to obtain 0.06 g of the desired product.

EXAMPLE 9

(R, S) -N- (carboxy) benzyl] -2-phenyl-7-roethoxyquinoline-4-carboxanmide hydrochloride

0.18 g (0.4 nmoles) of the product of Example 7 are dissolved in 10 ml of 10% HCl and 5 ml of dioxane. The reaction mixture is heated under reflux under magnetic stirring for 3 hours and then evaporated to dryness under vacuum.

The crude product is hot triturated with AcOEt (containing a few drops of Et OH) to provide 0.16 g of the desired product.

EXAMPLE 10

(R, S) -N- (netylanminocarbonyl) benzyl] 2-phenylquinoline-4-carfooxanad.de

0.45 g (1.1 limol) of the product of Example 4 are dissolved in 40 ml of MeN2 / EtOH at 33%; after the addition of a catalytic quantity of NaCN, the reaction mixture is heated to 70 ° C for 1 hour in a Parr apparatus. Internal pressure rises to 40 psi.

The solution is then evaporated to dryness under vacuum and the residue is triturated with water, filtered, dried and recrystallized with a mixture of i-PrOH (50 ml) and EtCH (30 ml) to obtain 0.2 g of the desired product.

Esatio il

(R, S) -N- [(^ (methoxycarbonyl) benzyl] -2- (2-thienyl) quinoline-4-carbossannd.de

Prepared as described in Example 5 from 2.0 g (7.3 moles) of 2- (2-thienyl) -4-chi non linear silicone acid, 1.7 g (8.4 moles) of hydrochloride of methyl ester of (D, L) phenylglycine, 1.1 ml (10 moles) of N-methylmorpholine, 2.1 g (15.5 limols) of HOBT and 1.85 g (9.0 limols) of DOC in 70 ml of anhydrous THF and 30 ml of CH2 CN.

The reaction mixture is processed as described in Example 5. The crude product obtained is crystallized from AcOEt and then recrystallized from absolute Et OH to obtain 0.9 g of the desired product.

EXAMPLE 12

(R, S) -N- | Q ^ - (methoxycarbonyl) benzyl] -2- (2-furyl) quinoline-4-carboxamnide

Prepared as described in Example 1 of 7.2 g (35.5 limol) of (D, L) phenylglycine methyl ester hydrochloride, 12.4 ml (88.8 limol) of ΊΕΑ and 9.1 g ( 35.5 ml) of 2- (2-furyl) -4-quinolincarbene chloride in 350 ml of a mixture of CH2Cl2, CH2CN and DMF. The reaction mixture is processed as described in Example 1. The crude product is triturated with MeOH to yield 3.3 g of the desired product.

EXAMPLE 13

(R, S) -N- [jD ^ - (methoxycarbonyl) benzyl] -2- (4-pyridyl) quinoline-4-carfaossannd.de

Dog preparation described in Example 1 of 3.4 g (16.7 irmel) of (D, L) phenylglycine methyl ester hydrochloride, 3.9 ml (27.8 limol) of TEA and 3.0 g ( 11, 1 limol) of 2- (4-pyridyl) -4-quinolincarbene chloride in 100 ml of a mixture of CH ^C ^, CH ^CN and DMF. The reaction mixture is processed as described in Example 1. The crude product is recrystallized three times by AcOEt to yield 1.9 g of the desired product.

EXBOTO 15

(R f s) -N- (methoxycarbonylmethyl) benzyl] -2-phenylquinoline-4-cartx> ssanmide

Dog preparation described in Example 5 from 1.39 g (5.6 irmel) of 2-phenyl-4-quinolincarboxylic acid, 1.2 g (5.6 mmol) of (R, S) 3-amino hydrochloride Methyl-3-phenylprionate, 0.78ml (5.6 ranoles) of TEA, 1.51g (11.2mmol) of HOBT and 2.31g (11.2mmol) of DCC in 10ml of THF anhydrous, 4 ml of CH ^ CN and 7 ml of CHjC ^. The reaction mixture is processed as described in Example 5. The crude product is dissolved in CH2CI2 and left at 0 ° C overnight. The precipitating dicyclohexylurea is filtered off. The solution is evaporated to dryness under vacuum to obtain 1.4 g of crude product which is triturated with a mixture of i-Pr2o / acetone 99: 1. 1.2 g of the desired product are obtained.

E92MPIO 14

(R, S) -N- (methoxycarbonyl) -2-thienylmethyl] -2-f enylquinoline-4-carboxanmide

Dog preparation described in Example 1 of 1.94 g (9.4 irmel) of hydrochloride of the methyl ester of (D, L) thienylglycine, 2.7 ml (19.5 nraols) of TEA and 2.0 g ( 7,8 mmel) of 2-phenyl-4-quinolincarbcryl chloride in 100 ml of a mixture of ΟΗ2οΐ2 ”CH ^CN and DMF. The reaction mixture is processed as described in Eseirpio 1. The crude product is recrystallized three times by AcOEt to yield 0.66 g of the desired product.

The characteristics of the Eseirpi sine compounds reported in the following Table.

Following the procedure described in the previous examples, the complements were prepared which appeared in the following list.

1) N- EX - (methoxycarbonyl Jbenzyl] -2-cyclohexylquinolin-4-carboxantnide; 2) N- [3⁄4- {methoxycarbonyl) benzyl] -2- (o-chlorophenyl) quinolin-4-carbossamnd.de;

3) N- [3⁄4- (meth ss icarbcn il) benz il] -2 - (m-c lorofen il) chi noli n-4-carbos sanvmide;

4) {methoxycarbonyl) benzyl] -2- (p-chlorophenyl) quino lin-4-carboxamide;

5) (R) -N- [& (- (methoxycarbonyl) -4-hydroxybenzyl] -2-phenylquinolin-4-carbossaimu.de;

6) N-f) (- (hydroxymethyl Jbenzyl J-2-phenylquinolin-4-carbossannri.de;

7) N- [(χ- (airminocarbene il) benz il] -2-phenolquinolin-4-carbos sannu.de;

8) N- [or (- (dimethylanininocarbonyl) benzyl J-2-phenylquinolin-4-carbossannd.de; 9) N- [3⁄4 (- (methoxycarbonyl) benzyl] -N-methyl-2-phenolquinolin -4-carbosamide;

10) N- [D (- (methoxycarbonyl Jbenzyl J-3-methyl-2-phenylquinolin-4-carboxamide;

11) N- [EX- (methoxycarbonyl Jbenzyl] - 6— fluor-2-phenylquinolin-4-carboxamide;

12) N-ttx- (methoxycarbonyl Jbenzyl] -6-methoxy-2-phenylquinolin-4-carboxamide;

13) N- [3⁄4 (- (methoxycarbonyl) benzyl] -6-methyl-2-phenylquinolin-4-carboxamide;

14) N- [3⁄4- (ethyl) benzyl] -2-phenylquinolin-4-carbossairnu.de;

15) N- [3⁄4- (raethoxycarbonyl) -c (- (methyl) benzyl] -N-methyl-2-phenylquinolin-4-carboxamtide;

16) N- [3⁄4- (methoxycarbonyl) benzyl] -2- (3-thienyl) quinolin-4-carboxamide; 17) N- (methoxycarbonyl) benzyl] -2- (2-pyrryl) quinolin-4-carboxalimidej 18) N- [i> (- (methoxycarboxyl) benzyl] -2- (2-thiazolyl) quinolin-4-carboxaramide;

19) N- [o (- (methoxycarbonyl) benzyl] -6-c their-2-phenylinolin-4-carbosanimi de;

20) N- [or (- (methoxycarbonyl) benzyl] -7-chloro-2-phenylquinolin-4-carboxamide;%

21) N- [0 <- (inethylcarbonyl) benzyl} -2-phenylquinolin-4-carboxaimide;

22) N- [Q (- (anminomethyl) benzyl] -2-phenylquinolin-4-carboxarmdde;

23) Ν - [. Χ- (trifluoramethyl) benzyl] -2-phenylquinolin-4-carboxamide.

Claims (1)

REVIEW Compounds of formula (I) where: (I) Ar is an optionally substituted phenyl or naphthyl or a heterocyclic group with a single or fused ring, optionally substituted, of aromatic character, containing from 5 to 12 ring atoms and comprising up to four heteroatoms in the ring or in each ring, selected from S, 0, N; with the proviso that Ar is not p-isobutylphenyl; R is C- ^ g linear or branched alkyl, C ^ _- j cycloalkyl, C4-7 cycloalkylalkyl, optionally substituted phenyl, and eventually substituted 5-element heroaromatic rings, comprising up to four heteroatoms selected from 0 or N, hydroxy C ^ _g alkyl, armino Cj_g alkyl, C ^ _g alkylairminoalkyl, of C ^ _g alkylaminoalkyl, Cj_g acylaminoalkyl, C ^ _g alkoxyalkyl, C ^ _g alkylcarbonyl, carboxy, Cj_g alkylaminoalkyl, alkylaminoalkyl ^ , C1_g alkyl halogen; R1 and R 2, which may be the same or different, are independently hydrogen or linear or branched C3 alkyl, or together they form a group - (CHj) - in which n represents 3, 4 or 5; Rg and R4, which may be the same or different, are independently hydrogen, linear or branched C ^ _g, Ci-6 alkenyl, aryl, Cl-6 alkoxy, hydroxy, halogen, nitro, cyano, cartooxy, carboxalimido, sulfonannide, alkoxycarbonyl or trifluoranethyl, with up to four substituents in the quinoline nucleus; R5 is C ^ _g linear or branched alkyl, C3_7 cycloalkyl, C4S7 cycloalkylalkyl, optionally substituted aryl, or a heterocyclic group with single or fused ring, optionally substituted, of aromatic character, containing from 5 to 12 atoms in the ring and comprising up to four heteroatoms in the ring or in each ring, selected from S, 0, N; X is 0, S or N-C≡N.