ITMI950495A1 - Quinoline derivatives. - Google Patents

Abstract

This invention describes new quinoline derivatives, the methods for their preparation and their use in medicine in the treatment of lung and skin disorders, itching, neurogenic inflammations and CNS (central nervous system) disorders.

Description

"QUINOLINE DERIVATIVES"

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

Neurokinin B (NKB), a mammalian peptide, belongs to the Tachikin (TK) family of peptides, which also includes Substance P (SP) and Neurokinin A (NKA). Pharmacological and molecular biology tests have demonstrated the existence of three subtypes of the TK receptor (NK ^, NK2 and NK3); NKB binds preferably to the NK3 receptor, although it also recognizes the other two receptors, with less affinity (Maggi et al., 1993, J. Auton. Pharmacol., 13, 23-93).

Selective peptide antagonists of the NK3 receptor are known (Drapeau, 1990 Regul. Pept., 31, 125-135), and the evidence on peptide agonists of the NK3 receptor suggests that NKB, by activating the NK3 receptor, plays a fundamental role in modulation of neuronal input at the level of the respiratory tract, skin, spine and nigro-striatal 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 labile, from the metabolic point of view, to serve as therapeutic agents in practice.

We have now found a new class of selective nonpeptide NK3 receptor antagonists, far more metabolically stable than the known NK3 receptor peptide antagonists, of potential therapeutic utility in the treatment of pulmonary disorders (asthma, chronic obstructive pulmonary diseases - COPD-, respiratory tract hyper-reactivity, cough), skin disorders and itching (e.g. atopic dermatitis and skin burns and burns), neurogenic inflammation and CNS disorders (Parkinson's disease, motor disorders,

anxiety). These disorders are hereinafter referred to as Primary Disorders.

The novel NK3 antagonists of the present invention are also of potential therapeutic utility in the treatment of seizure disorders,

epilepsy, kidney disorders, urinary incontinence, inflammation

eye, inflammatory pains, eating disorders (inhibition

food intake), allergic rhinitis, neuro-degenerative disorders

(e.g. Alzheimer's disease), psoriasis, Huntington's disease, e

depression (hereafter referred to as Secondary Disorders).

According to the present invention, a compound, or one thereof, is provided

solvate or salt, of formula (I)

r

(THE)

in which

Ar is a phenyl, naphthyl or -cycloalkadienyl group, optionally substituted, or a heterocyclic group with single or fused ring, optionally substituted, having an aromatic character, containing from 5 to 12 ring atoms and comprising up to 4 heteroatoms in the ring or in each ring, selected from S, 0, N;

R is linear or branched alkyl, cycloalkyl

cycloalkylalkyl, phenyl, or optionally substituted phenyl alkyl, optionally substituted five-membered heteroaromatic ring, comprising up to four heteroatoms selected from 0 or N, hydroxy -alkyl, amino alkyl, -alkylaminoalkyl, di-alkylaminoalkyl, acylaminoalkyl, alkoxyalkyl, - carboxy, alkoxycarbonyl, alkoxycarbonyl- -alkyl, aminocarbonyl, alkylamino-carbonyl, di- -alkylamino carbonyl, halogen alkyl; or it is a group - when it is cyclized on Ar, where p is 2 or 3;

R1 and R2, which may be the same or different, independently represent hydrogen or linear or branched alkyl, or together form an i * 1 group of which n represents 3, 4 or 5; or Ri together with R form a group where q is 2, 3, 4 or 5;

R3 and R4, which may be the same or different, independently represent hydrogen, linear or branched alkyl, alkenyl, aryl, alkoxy, hydroxy, halogen, nitro, cyano, carboxy, carboxamido, sulfonamido, alkoxycarbonyl, trifluoromethyl, acyloxy, phthalimido, animino, -0 where r is 2, 3 or 4 and T is hydrogen or C ^ lkyl, -0 where s is 2, 3 or 4 and W is hydrogen or C ^ lkyl; hydroxyalkyl, aminoalkyl, mono or dialkylaminoalkyl, acylamino, alkylsulfonylamino, aminoacylaminino, mono- or dialkylaminoacylamino; up to four substituents R3 being present in the quinolinic nucleus; or R4 is a -1 group as long as it is cyclized on R5 as aryl, where t is i, 2 or 3;

R5 is branched or linear C alkyl, Cicloalkyl, C

cycloalkylalkyl, optionally substituted aryl, or is a. heterocyclic group with single or fused ring, optionally substituted, having an aromatic character, containing from 5 to 12 ring atoms and comprising up to 4 heteroatoms in the ring or in each ring, selected from S, 0, N;

X is 0, S, or N

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

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

Examples of Ar as a cycloalkadienyl group are cyclopentadienyl and cyclohexadienyl.

Examples of R are as follows:

alkyl: methyl, ethyl, n-propyl, iso-propyl;

cycloalkyl: cyclopropyl;

hydroxy, amino, chlorine, fluorine, bromine, methoxycarbonyl and phenyl.

Examples of R5 are isopropyl, cyclopentyl, cyclohexyl, cyclopentylmethyl, cyclohexylmethyl, optionally substituted phenyl as defined above for Ar, and heterocyclic groups as defined above for Ar.

A preferred group of compounds of formula (I) are those in which:

Ar is phenyl, 2-thienyl or cyclohexadienyl;

R is methyl, ethyl, n-propyl,

R ^ and R2 are each hydrogen or methyl;

R3 is hydrogen, methoxy or hydroxy;

R4 is hydrogen, methyl, ethyl, methoxy, hydroxy, amino, chlorine, bromine, dimethylaminoethoxy;

R5 is phenyl, 2-thienyl, 2-furyl, 2-pyrryl and 3-thienyl;

and X is oxygen.

A preferred subgroup of compounds in the scope of formula (I) is that of formula (la)

in which:

R, R2, R3 and R4 are 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:

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 a pharmaceutically acceptable level of purity, with the exclusion of normal pharmaceutical additives, such as diluents and carriers, 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 the addition salts with conventional pharmaceutical acids, for example maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, mandelic, tartaric, succinic acids. , benzoic, ascorbic and methanesulfonic.

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

The compounds of formula (I) can have at least one center of asymmetry and therefore can exist in more than one stereoisomeric form. The invention extends to all these forms and mixtures thereof, including racemes.

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)

(ffl)

where they are as defined for the

formula (I), or a group or atom convertible to with a

compound of formula (II)

(Π)

or an active derivative of it, in which they are like

defined for formula (I) or a group convertible to

so as to form a compound of formula (le)

(the)

and possibly the subsequent performance of one or more of the following

stages:

a) when they are different from

the transformation of any one of

so as to obtain a compound of formula (I),

b) when they are the

conversion of any one of into another R, R ^ - Rg, Ar and X so as to obtain a compound of formula (I),

c) the formation of a salt and / or 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 alkylchloroformiate; another suitable derivative is the activated ester, such as cyanomethyl ester, thiophenyl ester, pnitrophenyl ester, p-nitrothiophenyl ester, 2,4,6-trichlorophenyl ester, pentachlorophenyl ester, pentafluorophenyl ester, N-hydroxy-phthalimido ester, N-hydroxypiperidino ester, N-hydroxy imido ester, N-hydroxybenzotriazolester; or the carboxy group can be activated using a carbodiimide or N, N'-carbonyldiimidazole.

For example, in standard methods well known to those 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 dimethylformamide (DMF) at a temperature in the range of -70 to 50 * C (preferably in the range of -10 to 20 * C),

(b) with acid in the presence of a suitable condensing agent, such as Ν, Ν-carbonyldiimidazole (CDI) or a carbodiimide such as dicyclohexylcarbodiimide (DCC) or N-dimethylaminopropyl-N'-ethylcarbodiimide and N-hydroxybenzotriazole (Η0ΒΤ) 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, to a temperature in the range from -70 to 50 * C (preferably in a range from -10 to 25 * C) (see Scheme 1).

Scheme 1

(c) with a mixed anhydride generated in situ from the acid and an alkyl1 (e.g. isopropyl) 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 inter-conversion of suitable substituents. Therefore, certain compounds of formula (I) and (I) are useful intermediates in the formation of other compounds of the present invention.

For example R'2 can be hydrogen and converted into P®r alkyl bond, for example methyl, by conventional amide alkylation procedures (Zabicky, The 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 thioamides, such as P2S5 (Chem. Rev., 61, 45, 1961 or Angew. Chem., 78, 517, 1966) or the reagent by Lawesson (Tetrahedron, 41, 5061, 1985). When Ar 'or R'5 is a methoxy-substituted phenyl, it can be converted to another Ar' or R'5 hydroxy-substituted phenyl by standard Lewis acid demethylation procedures, such as boron tribromide (Synthesis, 249 , 1983) or with mineral acids, such as hydrobromic or hydrogen iodide. When R is an alkoxycarbonyl 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; aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl by transammidation with ammonia, a primary aimiine or a secondary amine in methanol as a solvent at a temperature in the range of 10 to 120 * 0, possibly in the presence of a catalytic amount of NaCN (J. Org. Chem., 52, 2033, 1987) or using trimethylaluminium (Μβ3Αΐ) (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 MeOH (Bull. Chem. Soc. Japan, 57, 1948, 1984 or Synth . Commun., 12, 463, 1982); alkyl carbonyl by formation of an acyl chloride and subsequent reaction with alkylmagnesium halides in THF as solvent, 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 or LiCl (J.Org.Chem., 47, 2590, 1982). Another group into which R 'as methoxycarbonyl can be converted is a substituted heteroaromatic 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

are as described in formula (I), in a

other compound of formula (I).

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

The solvates of the composites of formula (I) can be formed by crystallization or recrystallization from the appropriate solvent. For example, hydrates can be formed by crystallization or recrystallization 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) can exist in more than one stereoisomer form and the process of the invention produces racemates as well as enantiomerically pure forms. To obtain the pure enantiomers, appropriate enantiomerically pure primary or secondary amines of formula (Illd) or (Ille)

are made to react with the compounds of formula (II), to obtain the compounds of formula (I * d) or (I’e).

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

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 X1 is oxygen, R13, R'4 and R'5 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 '^ 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! 5 is o-, m- and p-chlorophenyl, o-fluorophenyl and 3,4-dichlorophenyl are described in Brown et al., J. Am. Chem. Soc., 68, 2705, 1946; the compound of formula (II), in which X 'is oxygen, R'3 and R * 4 are hydrogen and R's 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-R15 is m-trifluoromethylphenyl is described in Shargier and Lalezari, J. Chem.Eng. Date, 8, 276.1963; the compound of formula (II), in which X is oxygen, R'3 and R'4 are hydrogen and R'5 is pfluorophenyl is described in Bu Hoi et al., Ree. Trav. Chim., 68, 781, 1949; the compound of formula (II), in which X1 is oxygen, R'3 and R'4 are hydrogen and R'5 is p-methylphenyl is described in Prevost et al., Conpt. Rend.Acad.Sci., 258, 954, 1964; the compound of formula (II), in which X 'is oxygen, R13 and R'4 are hydrogen and R'5 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's are hydrogen and R'3 is phimethyl is described in Buchmann and Howton, J. Am.Chem. Soc., 68,2718, 1946; the compound of formula (II), in which X1 is oxygen, R'4 and R'3⁄4 are hydrogen and H'3 is 8-nitro is described in Buchmann et al., J. Am. Chem. Soc., 69, 380, 1947; the compound of formula (II), in which X1 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 X 'is oxygen, R'3 and R'4 are hydrogen and R'j is 2-thia2olyl 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'4 is hydrogen and R'5 is phenyl, o- and p-fluorophenyl, 3,4-dichlorophenyl, p- methoxyphenyl are described in Nicolai et ad., Eur. J. Med. Chem., 27, 977, 1992; the compounds of formula (II), in which X 'is oxygen, R'3 is fibrous, 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), (Illd) and (Ille) are commercially available compounds or they can be prepared from known compounds by known methods (for example, the compounds of formula (III) in which R 'is alkoxycarbonyl, R' ^ and R'2 are hydrogen and Ar '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 NK3 receptor in the standard tests indicates that they are of potential therapeutic utility in the treatment of both Primary and Secondary Disorders mentioned above. The finding that NK3 receptor antagonists have potential therapeutic utility in the treatment of Secondary Disorders is new, and a further aspect of the present invention provides the use of an NK3 receptor antagonist for the treatment of Secondary Disorders. Also provided is the use of an NK3 receptor antagonist in the manufacture of a medicament useful for the treatment of any of the Secondary Disorders.

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 comprises 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 the Primary and Secondary Disorders previously identified.

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

These conventional excipients can 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 each 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 route of administration.

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-administer it 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, reconstitutable powders, or liquid preparations, for example solutions or suspensions, or suppositories.

The compositions, for example those suitable for oral administration, may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, corn starch, calcium phosphate, sorbitol or glyein; compression lubricants, for example magnesium stearate; disintegrants, for example starch, polyvinylpyrrolidone, sodium starch glycolate 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 tablet, powder or lozenge, any vehicle suitable for formulating 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, for example of 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 gum; aqueous or non-aqueous carriers, which include edible oils, for example, almond oil, fractionated coconut oil, oily esters, for example, glycerin esters, or propylene glycol, or ethyl alcohol, glycerin, water or saline; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid; and, if desired, conventional flavoring or coloring agents.

The compounds of this invention can also be administered via 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, buffers 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 comprising a compound and a suitable carrier, optionally suspended for example 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 about 2 to 10 μ.

A further mode of administration of the compounds of the invention comprises transdermal delivery using a skin patch formulation. A preferred formulation comprises 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 yielded to the patient. For a constant rate of percutaneous absorption, pressure sensitive adhesives known in the art, such as natural rubber 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 given once or more times a day, for example 2, 3 or 4 times a day, and the total daily dose for an adult of 70 kg 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 toxicological effects are expected.

The present invention also provides a method for the treatment and / or prophylaxis of Primary and Secondary Conditions in mammals, particularly in humans, which includes administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.

The invention also provides a method for the treatment and / or prophylaxis of Secondary Conditions in mammals, particularly in humans, which includes administering to the mammal requiring such treatment, and / or prophylaxis of an effective amount of the antagonist of the NK3 receptor.

The activity of the compounds of the present invention, as ligands of the NK3 receptor, is determined by their ability to inhibit the binding of the radiolabeled ligands of the receptor.

Senktide, to guinea pig and human NK3 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. Commun., 198 (3), 967-972). The binding tests used allow the determination of the concentration of each single compound necessary to reduce the specific binding of Senktide to the NK3 receptor by 50% in equilibrium conditions.The binding tests provide for each compound tested the averages of the IC5Q values of 2 -5 separate experiments performed in triplicate or in quadruplicate. The more potent compounds of the present invention show IC5Q values in the range of 1-1000 nM; in particular, in the cortical membranes of guinea pigs, by displacement of [3⁄4] -Senktide, the compounds of Examples 22, 47,48 and 85 show values of (nM) respectively of 5,6, 8,8,12,0 and 4.8 (n = 3).

The NK3 ~ antagonist activity of the compounds of the present invention is determined by their ability to inhibit Senktide-induced contraction of guinea pig ileum (Maggi et al., 1990, Br. J. Ph axmacol., IDI, 996-1000) and the mobilization of Ca ++ mediated by human NK3 receptors (Mochizuki et al., 1994, J. Biol. Chem., 269, 9651-9658). The functional test on the guinea pig provides averages of the KB values of 3-8 separate experiments for each compound tested, where KB 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 contents of the Examples are summarized in Tables 1-5.

DESCRIPTION 1

2-phenyl-4-quinolincarbonyl chloride

11.7 ml (136.3 mmol) of oxalyl chloride is dissolved in 150 ml of. The solution is cooled to -10 ° C and 20 g (80.2 mmoles) of commercially available 2-phenyl-4-quinolincarboxylic acid are added in several portions. 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-methoxy-4-quinolincarboxylic acid

5 g (28.2 mmol) of 6-methoxyisatin, 4 ml (33.8 mmol) of acetophenone and 5.2 g (92.6 mmol) of potassium hydroxide are dissolved in 22.9 ml of absolute EtOH and 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 Et2. The aqueous phase, cooled with ice, is acidified to pH 1 with HCl at 37% 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-quinolincarbonyl chloride

2.8 ml (32.3 mmol) of oxalyl chloride is dissolved in 60 ml of

The solution is cooled to -10 “C and added, in

plus portions, 6 g (19.0 mmol) of 7-methoxy-2-phenyl-4-quinolynolincarboxylic acid. The reaction mixture is left alone, at room temperature, overnight and then evaporated to dryness under empty. 7.0 g of the desired product are obtained, used without further purifications.

DESCRIPTION 4

2-phenyl-7-hydroxy-4-quinolincarboxyl acid or iodide

1.5 g (5.4 mmoles) of 7-methoxy-2-phenyl-4-quinolincarboxylic acid are added, in more 1 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-quinolincarboxyl acid

5 g (34.0 mmol) of isatin, 4.4 ml (40.8 mmol) of 2-acetylthiophene and 6.3 g (112.2 mmol) of potassium hydroxide are dissolved in 40 ml of absolute EtOH and the suspension is heated at 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 pH 1 with 37% HC1 and the precipitate is collected by filtration, washed with water, dried under vacuum at 40 ° C 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 mmol) of isatin, 4 ml (40.8 mmol) of 2-acetylfuran and 6.3 g (112.2 mmol) of potassium hydroxide are dissolved in 40.9 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 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 mmol) of oxalyl chloride is dissolved in 70 ml of

The solution is cooled to -10 “c and added, in

plus portions, 8.5 g (35.5 mmol) of 2- (2-furyl) -4-quinolincarboxylic acid. The reaction mixture is left alone, at room temperature, for the whole night and then evaporated to dryness under vacuum. 9.2 g of the desired product are obtained, used without further purifications.

DESCRIPTION 8

2- {4-pyridyl) -4 ~ quinolincarboxylic acid hydrochloride

5 g (34.0 mmol) of isatin, 4.5 ml (40.8 mmol) of 4-acetylpyridine and 6.3 g (112.2 mmol) 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 Et20. The aqueous phase, cooled with ice, is acidified to ρΗ 1 with HC1 at 37% 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. The evaporation of the solvent gives 6.0 g of crude which, combined to the precipitate obtained previously, it is recrystallized from toluene containing traces of MeOH, giving 4.5 g of the desired product.

DESCRIPTION 9

2- (4-pyridyl) -4-quinolincarbonii chloride hydrochloride

1.3 ml (10.4 mmoles) of oxalyl chloride are dissolved in 60 ml of CH2 Cl2- solution is cooled to -10 ° C and 3.0 g (14.4 mmoles) of acid are added in several portions. 2- (4-pyridyl) -4-quinolincarboxylic hydrochloride. The reaction mixture is left alone, 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 purif ications.

EXAMPLE 1

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

1.2 ml (9.4 mmol) of (R, S) α-methylbenzylamine and 1.6 ml (11.7 mmol) of triethylamine (TEA) are dissolved, under nitrogen, in 50 ml of a 1: 1 mixture of anhydrous and 2.0 g (7.8 mmol) of 2-phenyl-4-quinolincarbonium chloride, dissolved in 50 ml of a 1: 4 mixture of

anhydrous and DMF, are dropped into the amine solution,

cooled in an ice bath. The reaction is maintained for 1 hour between 0 "and 5 * C and then at room temperature for the whole night. The reaction mixture is evaporated to dryness under vacuum and the residue is dissolved in AcOEt and washed twice with a saturated solution of

The organic phase is separated, dried over filtered and

evaporated to dryness under vacuum.

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

Elementary analysis:

EXAMPLE 2

S - (+) - N- (a-methylhenzyl) -2-phenylquinoline-4-carboxyimiid

Prepared as described in Example 1 starting from 1.2 ml (9.4 mmol) of S - (-) - a-methylbenzylamine, 1.6 ml (11.7 mmol) of TEA, 2.0 g (7, 8 mmoles) 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 from AcOEt to yield 1.1 g of the desired product.

The mass spectrum is identical to that of Example 1.

EXAMPLE 3

R- (-) -K- <α-methylbenzyl) -2- f enylquinol ina-4-car bossamraide

Prepared as described in Example 1 starting from 1.2 ml (9.4 mmol) of R - (+) - a-methylbenzylamine 1.6 ml (11.7 mmol) of TEA, 2.0 g (7.8 mmoles) of 2-phenyl-4-quinolincarbonyl chloride in 100 ml of a mixture of

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.

^ H-NMR and mass spectrum are identical to those of Examples 1 and 2. EXAMPLE 4

(R, S) -N- Ca- (methoxycarbonyl) benzyl 3 -2-ph enylquinoline-4-carboxaranide 2.0 g (8.0 mmol) of 2-phenyl-4-quinolynolincarboxylic acid are dissolved, under nitrogen, in 130 ml of anhydrous THF and 100 ml of CH3CN. 2.0 g (9.9 mmol) of (D, L) phenylglycine methyl ester hydrochloride and 1.5 ml (10.7 mmol) of TEA are added and the reaction mixture is cooled to 5'C,

2.5 g (12.1 mmoles) of dicyclohexylcarbodiimide (DCC) are added dropwise, dissolved in 10 ml of anhydrous, and the reaction is left to soak at room temperature and per se overnight.

The precipitating dicyclohexylurea is filtered off and the solution evaporated to dryness in vacuo. The residue is dissolved in and washed with water. The separated organic phase is dried up and evaporated to dryness under vacuum to obtain 6.0 g of crude product which is dissolved in 20 ml of and left to stand overnight. The other dicyclohexylurea precipitates and is filtered off.

The solution is evaporated to dryness under vacuum and the flash chromatographed residue on silica gel (230-400 mesh) using as eluent a mixture of hexane / AcOEt 3: 2 containing 0.5% of (at 28%). The product obtained is hot triturated with filtrate, washed and dried to give 1.1 g of the desired product.

EXAMPLE 5

(+) - (S) -N- [a (methoxycarbonyl) benzyl] -2-phenylquinoline-4-carboxanmide 2.0 g (8.0 mmol) of 2-phenyl-4-quinolincarboxylic acid are dissolved, under nitrogen, in 70 ml of anhydrous THF and 30 ml of.

1.7 g (8.4 mmol) of (L) phenylglycine methyl ester hydrochloride, 1.1 ml (9.9 mmol) of N-methylmorpholine and 2.1 g (15.5 mmol) of N-hydroxybenzotriazole (HOBT) and the reaction mixture is cooled to 0 ° C. 1.85 g (9.0 mmoles) of DCC are dropped, dissolved in 10 ml of anhydrous, and the reaction is then kept between 0 ° and 5 "C for 1 hour and at room temperature for 2 hours. The dicyclohexylurea which precipitates is filtered off and the solution is evaporated to dryness under vacuum. The residue is dissolved in and washed with water, Na-HCO3 sol.sat., citric acid 5%, sol.sat. and NaCl sol.sat.

The separated organic phase is dried up and evaporated to dryness under vacuum; the residue is dissolved in 20 ml of 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-Pr20 and recrystallized with 70 ml of i-PrOH to obtain 1.7 g of the desired product. .

^ H-NMR and mass spectrum are identical to those of Example 4. EXAMPLE 6

(-) - (R) -N- [a- (methoxycarbonyl) benzyll] -2-phenylquinoline-4-carboxanmide Prepared as described in Example 5 from 2.0 g (8.0 mmol) of acid 2- phenyl-4-quinolincarboxylic, 1.7 g (8.4 mmol) of (D) phenylglycine methyl ester hydrochloride, 1.1 ml (9.9 mmol) of N-methylmorpholine, 2.1 g (15, 5 mmol) of HOBT and 1.85 g (9.0 mmol) of DCC in 70 ml of anhydrous THF and 30 ml of CH3CN.

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

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

(R, S) -N- [a- {methoxycarbonyl) benzyl] -2-phenyl-7-methoxyquinoline-4-carboxansnide

1/0 g (5.0 mmoles) of (D, L) phenylglycine methyl ester hydrochloride are dissolved, under nitrogen, in 30 ml of anhydrous DMF. 2.5 g (18.1 mmoles) of anhydrous potassium carbonate are added and the solution is cooled to 0 ° C. 0.7 g (2.3 mmoles) of the product of Description 3 are dropped, dissolved in 25 ml of anhydrous DMF, and the reaction is kept 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 AcOEt and washed twice with water. The separated organic phase is dried over filtered and evaporated to dryness under vacuum.

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

EXAMPLE 8

(R, S) -N- [a- (methoxycarbonyl) benzyl] -2-phenyl-7-hydroxyquinoline-4-carboxamnide

Prepared as described in Example 5 from 2.1 g (5.3 mmol) of the product of Description 4, 1.08 g (5.3 mmol) of (D, L) phenylglycine methyl ester hydrochloride, 1, 5 ml (10.7 mmol) of TEA, 1.7 g (12.5 mmol) of HOBT and 1.2 g (5.8 mmol) of DCC in 70 ml of anhydrous THF and 30 ml of CH3CN.

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- [a- (carboxy) benzyl] -2-phenyl-7-methoxyquinoline-4-carboxant [iide hydrochloride

0.18 g (0.4 mmoles) 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 EtOH) to yield 0.16 g of the desired product.

EXAMPLE 10

(R, S) -N- [a- (methylairminocarbonyl) benzyl] 2-phenylquinoline-4-carboxannd. And 0.45 g (1.1 mmol) of the product of Example 4 are dissolved in 40 ml of; after the addition of a catalytic quantity of NaCN the reaction mixture is heated to 70 ° C for 1 hour in a Parr apparatus. The 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 EtOH (30 ml) to obtain 0.2 g of the desired product.

EXAMPLE 11

(R, S) -N- [a (methoxycarbonyl) benzyl] -2- {2-thienyl) quinoline-4-carboxanroid Prepared as described in Example 5 from 2.0 g (7.3 mmol) of acid 2 - (2-thienyl) -4-quinolincarboxylic, 1.7 g (8.4 mmol) of (D, L) phenylglycine methyl ester hydrochloride, 1.1 ml (10 mmol) of N-methyl morpholine, 2, 1 g (15.5 mmol) of HOBT and 1.85 g (9.0 mmol) of DCC in 70 ml of anhydrous THF and 30 ml of CH3CN.

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

Elementary analysis:

EXAMPLE 12

(R, S) -N- [a- (methoxycarbonyl) benzyl3-2- (2-furyl) quinoline-4-carboxanBnide Prepared as described in Example 1 from 7.2 g (35.5 mmol) of hydrochloride methyl ester of (D, L) phenylglycine, 12.4 ml (88.8 mmol) of TEA and 9.1 g (35.5 mmol) of 2- (2-furyl) -4-quinolincarbonyl chloride in 350 ml of a mixture of CH2CI2, CH3CN and IMF. 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.

Elementary analysis:

EXAMPLE 13

(R, S) -Ν- [α- (methoxycarbonyl) benzyl] -2- (4-pyridyl) quinoline-4-carboxamide

Prepared as described in Example 1 from 3.4 g (16.7 mmol) of (D, L) phenylglycine methyl ester hydrochloride, 3.9 ml (27.8 mmol) of TEA and 3.0 g ( 11.1 mmoles) of 2- (4-pyridyl) -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 crude product is recrystallized three times by AcOEt to yield 1.9 g of the desired product.

Elementary analysis:

EXAMPLE 14

(R, S) -N- [a- (methoxy carbonyl) -2-thienylroethyl] -2-f emlquinoline-4-carboxamide

Prepared as described in Example 1 from 1.94 g (9.4 mmol) of (D, L) thienylglycine methyl ester hydrochloride, 2.7 ml (19.5 mmol) of TEA and 2.0 g ( 7.8 mmol) of 2-phenyl-4-quinolincarbonyl chloride in 100 ml of a mixture of The reaction mixture is processed as described in Example 1. The crude product is recrystallized three times by AcOEt to yield 0.66 g of the desired product.

Elementary analysis:

EXAMPLE 15

(R, S) -N- [a- (methoxycarbonylmethyl) benzyl] -2-phenylquinoline-4-carboxamnide

Prepared as described in Example 5 from 1.39 g (5.6 mmol) of 2-phenyl-4-quinolincarboxylic acid, 1.2 g (5.6 mmol) of (R, S) 3-amino hydrochloride Methyl-3-phenylproprionate, 0.78 ml (5.6 mrroles) of TEA, 1.51 g (11.2 mmol) of HOBT and 2.31 g (11.2 mmol) of DCC ir. 10 ml of Anhydrous THF, 4 ml and 7 ml of The reaction mixture is processed as described in Example 5. The crude product is dissolved in 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-Pr20 / acetone 99: 1. 1.2 g of the desired product are obtained.

Elementary analysis:

Table below.

EXAMPLE 93

(R, S) -H- [a- (Methoxycarbonyl) benzyl] -2- {p-chlorophenyl) quinoline-4-carboxamide

2 g (7.0 mmoles) of 2- (p-chlorophenyl) quinolin-4-carboxylic acid and 1.7 ml (15.4 mmoles) of N-methylmorpholine are dissolved, under nitrogen, in 50 ml of anhydrous THF.

The solution is cooled to -20 ° C and 0.91 ml (7.0 mmol) of isobutyl chloroformate are added. After 20 minutes, 2.12 g (10.5 mmol) of (R, S) methyl phenylglycinate hydrochloride and 1.3 ml (11.9 mmol) of N-methylmorpholine are added, dissolved in 30 ml of THF anhydrous; the reaction mixture is then stirred at room temperature overnight.

5 ml of is added and the reaction mixture is evaporated in vacuo to dryness. The residue is dissolved in washed with a saturated solution of NaHC (> 3 and the organic phase, dried on, is evaporated under vacuum to dryness.

The oily residue is purified by flash chromatography on silica gel 230-400 mesh, eluting with a mixture of hexane / isopropyl ether 7: 3, to give 0.9 g of the crude product, which is recrystallized three times to give 0, 5 g of the desired product.

EXAMPLE 94

(R) -N- [a- (Hetoxycarbonyl) -4-methoxybenzyl] -2-phenylquinoline-4-carboxanmide

0.62 g (1.5 mmol) of (R) -N- [a- (methoxycarbonyl) -4-hydroxybenzyl] -2-phenylquinoline-4-carboxamide (compound of Ex. 83) are dissolved in 30 ml of anhydrous acetone and 2 ml of anhydrous DMF; 0.14 g (0.75 mmoles) of K2CO3 are added and the reaction mixture is left under stirring for 30 minutes.

0.093 ml (1.5 mmoles) of methyl iodide are then added at room temperature and the reaction mixture is heated at 40 ° C for 4 hours. Again 0.104 g (0.75 mmoles) of K2CO3 and 0.093 ml (1.5 mmoles) of methyl iodide are added and the mixture heated under reflux for a further 6 hours.

The reaction is then evaporated to dryness under vacuum and the residue dissolved in AcOEt and washed with Η20. The organic phase, dried up

it is evaporated again under vacuum to dryness. The residue

it is crystallized from Et20 to give 0.45 g of the desired product.

EXAMPLE 95

(R, S) -N- [α- (Methoxycarbonyl) -a- (methyl) benzyl] -N-methyl-2-phenylquinoline-4-carboxanmide hydrochloride

0.50 g (1.3 mmoles) of (R, S) -N- [a- (methoxycarbonyl) benzylJ-2-phenylquinoline-4-carboxamide (compound of Example 4) are dissolved, under nitrogen, in 10 ml of anhydrous DMF.

The solution is cooled to 0 ° C and 0.052 g (1.3 mmoles) of 60% NaH are added; after 20 minutes at 0 ° C, the reaction is brought to room temperature and 0.09 ml (1.4 mmoles) of Mei are added. The reaction mixture is then stirred at room temperature overnight and, thereafter, the procedure is repeated by adding another 0.052 g (1.3 mmol) of 60% NaH and 0.1 ml (1.6 mmol) of Mei. .

After 6 hours at room temperature, 10 ml of saturated solution are added and then the reaction mixture is evaporated to dryness. The residue is dissolved in and washed with water; the organic phase is then separated, dried up and evaporated to dryness.

The oily residue is purified by flash chromatography on silica gel 230-400 mesh, eluting with a mixture of hexane / ethyl acetate 3: 2, containing 0.5% of concentrated NH4OH to give 0.18 g of the crude product. , which is dissolved in Et20 and treated with HCl / Et20 to yield 0.15 g of the desired product.

EXAMPLE 96

(R, S) —N— [a- (Methylcarbeffyl) benzyl] -2-phenylquinoline-4 ~ carboxaninide 0.27 ml (3.1 mmoles) of oxalyl chloride are dissolved, under nitrogen, in 2.3 ml of anhydrous.

The solution is cooled to -55 ° C and 0.22 ml (3.1 mmoles) of DMSO are dropped, dissolved in 0.7 ml of anhydrous, keeping the temperature below -50 ° C. The reaction is stirred at -55 ° C for 7 minutes and subsequently 0.97 g (2.5 mmoles) of (R, S) -N- [a- (1-hydroxyethyl) benzyl] -2-phenylquinoline- are added 4-carboxamide (compound of Ex. 17), dissolved in 25 ml of anhydrous, maintaining the temperature between -50 and -55 ° C.

After 30 minutes at -55 ° C, 1.9 ml (13.6 mmoles) of TEA are added without exceeding -40 ° C; the reaction is then slowly brought to room temperature and stirred for another 15 minutes.

The reaction is quenched with 5 ml of and extracted with the organic phase, it is washed with citric acid at 20%, saturated solution of NaHC03 and again saturated with salt; the organic phase is then separated, dried up and evaporated to dryness.

The oily residue is purified by flash chromatography on silica gel 230-400 mesh, eluting with a 70: 30 hexane / ethyl acetate mixture, containing 0.5% concentrated NH4OH, to give 0.64 g of product crude, which is triturated with a mixture of hot i-Pr20 / i-PrOH in the ratio of 2: 1; the precipitate is filtered, washed and dried to give 0.5 g of the desired product.

EXAMPLE 97

(R, S) -N- [a- (2-Hydroxyethyl) benzyl] -2-phenylquinoliia-4-carboxan «nide 0.7 g (1.7 iranols) of (R, S) -N- [a- (methoxycarbonyl methyl) benzyl] -2-phenylquinoline-4-carboxamide (compound of Ex. 15) are dissolved, under nitrogen, in 50 ml of t-BuOH and 2 ml of MeOH and the reaction is heated under reflux.

60 mg (1.6 mmoles) of solution are added in 15 minutes to the boiling solution. The reaction mixture is heated under reflux for 6 hours, quenched with 5 ml of saturated solution and then evaporated to dryness under vacuum. The residue is dissolved in and washed with water saturated with salt; the organic phase is then separated, dried on

and evaporated under vacuum again to dryness.

The crude product is purified by flash chromatography on silica gel 230-400 mesh, eluting with a mixture of Et20, containing 0.5% concentrate and then recrystallized from i-PrOH to give 0.19 g of the desired product.

EXAMPLE 98

(S) -N- (α-Ethylbenzyl) -3- (2-dimethylanDminoethoxy) -2-phenylquinoline-4-carboxamide hydrochloride

0.62 g (1.6 iranols) of (S) -N- (α-ethylbenzyl) -3-hydroxy-2-phenylchiroline-4-carboxyimide hydrochloride (compound of Ex. 85) are dissolved in 30 ml of DMF anhydrous.

0.58 g (4.0 mmol) of dimethylaminoethyl chloride hydrochloride and 0.56 g (4.0 mmol) of are added and the reaction mixture is refluxed for 20 hours.

The is subsequently filtered off and the solution evaporated to dryness under vacuum; the residue, dissolved in, is washed with and 20% citric acid. The aqueous phase is made alkaline with 2 N NaOH and extracted with AcOEt; it is then washed with water saturated with salt, separated, dried on and evaporated to dryness.

The residue is purified by flash chromatography on 230-400 mesh silica gel, eluting with a mixture of

containing 0.4% concentrate and subsequently with

, containing 0.6% concentrate to give 85

mg of the crude product, which is dissolved in AcOEt and treated with to yield 75 mg of the desired product.

And-

EXAMPLE 99

{S) -N- (a-Ethylbenzyl) -3-acetylamine-2-phenylquinoline-4-carboxanmi of 0.40 g (1.05 mmol) of (S) -N- (α-ethylbenzyl) -3 -amino-2-phenylquinoline-4-carboxamide (compound of Example 69) are heated in 25 ml of acetic anhydride at 70eC for 1 hour and then at 100 ° C for a further 3 hours.

The reaction mixture is evaporated in vacuo to dryness and the

residue dissolved in the organic phase is washed with water,

saturated solution of water saturated with salt, dried up and evaporated under vacuum again to dryness.

The crude product (0.39 g) is purified by flash chromatography on silica gel 230-400 mesh, eluting with a mixture of hexane / concentrate, 70: 30: 0.5 respectively, to give 0.2 g of a product chromatographically pure which is crystallized from f-acetone to yield 0.14 g of the desired product.

Claims (1)

CLAIM Compounds of formula (I) (D m 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 S, 0, N; with the proviso that Ar is not p-isobutylphenyl; R is 3⁄4 linear or branched alkyl, cycloalkyl, cycloalkylalkyl, optionally substituted phenyl, optionally substituted 5-element heteroaromatic rings, comprising up to four heteroatoms selected from 0 or N, hydroxy alkyl, armino alkyl, alkylaminoalkyl, alkylaminoalkyl, acylaminoalkyl, -alkoxyalkyl, -alkylcarbonyl, carboxy, alkoxycarbo- nyl, aminocarbonyl, alkylamino carbonyl, di alkylaminocarbonyl, halogen -alkyl; which can be the same or different, they are independently hydrogen or linear or branched alkyl, or together form a group where n represents 3, 4 or 5; which can be the same or different, are independently hydrogen, linear or branched alkyl, alkenyl, aryl, -alkoxy, hydroxy, halogen, nitro, cyano, carboxy, carboxamido, sulfonanmido, alkoxycarbonyl or trifluoromethyl, with up to four R3 substituents in the quinoline nucleus; r5 ^ linear or branched alkyl, cycloalkyl, 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.