RU2155754C2 - Quinoline derivatives as techychinin nk3 receptor antagonists - Google Patents

Abstract

FIELD: medicine. SUBSTANCE: described is quinoline derivative of formula I:

or solvate or salt thereof wherein A is phenyl optionally substituted by halogen, OH or C_1-6: benzyl, thienyl, pyridyl, C_5-7 cycloalkadienyl group; R is C_1-8 alkyl, C_3-7 is cycloalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, di-C_1-6 alkylaminoalkyl, C_1-6 alkoxyalkyl, C_1-6 alkylcarbonyl, carboxy, C_1-6 alkoxycarbonyl, C_1-6 alkoxycarbonylalkyl, alkylaminocarbonyl, halogen-C_1-6 alkyl; R₁ and R₂ are the same of different and are hydrogen or C_1-6 alkyl (for other definitions of radicals see claim 1). Said derivative is non-peptide NK₃ antagonist and is potentially therapeutical useful in treating convulsion disorders, kidney disorders, inflammatory pains, and enuresis. EFFECT: improved properties of the title compounds. 14 cl, 113 ex, 6 tbl

Description

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

Mammal Peptide Neurokinin B (NKB) belongs to the Tachykinin (TK) peptide family, which also includes Substance P (SP) and Neurokinin A (NKA). Pharmacological and molecular biological evidence has shown the existence of three subtypes of the TK receptor (NK ₁ , NK ₂ and NK ₃ ), and NKB binds preferentially to the NK ₃ receptor, although it also recognizes the other two receptors with lower affinity (Maggi et al, 1993 , J. Auton. Pharmacol., 13, 23 - 93).

Known selective peptide antagonists of the NK ₃ receptor (Drapeau, 1990 Regul. Pept., 31, 125 - 135) and findings or discoveries associated with peptide antagonists of the NK ₃ receptor suggest that NKB by activating the NK ₃ receptor plays a key role in modulating neural entry into the upper respiratory tract, skin, spinal cord and nigrostriatal tract (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 known antagonists makes them likely to be too labile from a metabolic point of view to serve as practical therapeutic agents.

The inventors have now discovered a new class of selective non-peptide NK ₃ antagonists, which are much more metabolic stable than the known peptide antagonists of the NK ₃ receptor, and represent potential therapeutic utility or applicability in the treatment of pulmonary disorders (asthma, chronic obstructive pulmonary diseases - COPD-, airway hyperresponsiveness, coughing), skin disorders and itching or scabies (e.g., atopic dermatitis and skin blisters and red dermogr aphism), neurogenic inflammation and disorders of the central nervous system (Parkinson's disease, impaired motor ability, anxiety or fear and psychosis). These disorders or disorders are hereinafter referred to as primary disorders or disorders.

The new NK ₃ antagonists _{of the} present invention are also of potential therapeutic benefit in the treatment of convulsive disorders (e.g., epilepsy), kidney disorders, urinary incontinence, eye inflammation, inflammatory pain, eating disorders (food inhibition), allergic rhinitis, neurodegenerative disorders (e.g. Alzheimer's disease), psoriasis, Huntington’s disease and depression (hereinafter referred to as secondary disorders).

в которой Ar представляет необязательно замещенную фенильную, нафтильную или C_5-7циклоалкдиенильную группу или необязательно замещенную одинарную или сконденсированную кольцевую гетероциклическую группу, имеющую ароматический характер, содержащую от 5 до 12 кольцевых атомов и включающую до четырех гетеро-атомов в кольце или в каждом кольце, выбранных из S, О, N;
R представляет линейный или разветвленный C_1-8алкил, C_3-7циклоалкил, C_4-7циклоалкилалкил, необязательно замещенный фенил или фенил C_1-6алкил, необязательно замещенное пятичленное гетероароматическое кольцо, включающее до четырех гетероатомов, выбранных из О и N, гидрокси C_1-6алкил, амино C_1-6алкил, C_1-6алкиламиноалкил, ди-C_1-6алкиламиноалкил, C_1-6ациламиноалкил, C_1-6алкоксиалкил, C_1-6алкилкарбонил, карбокси, C_1-6алкоксикарбонил, C_1-6алкоксикарбонил-C_1-6алкил, аминокарбонил, C_1-6алкиламинокарбонил, ди-C_1-6алкиламинокарбонил, галоид C_1-6алкил; или представляет группу -(CH₂)_p-, когда он циклизован с Ar, где p представляет 2 или 3.According to the present invention, there are provided compounds, or solvates thereof, or salts of formula (I):

in which Ar represents an optionally substituted phenyl, naphthyl or C _5-7 cycloalkdienyl group or an optionally substituted single or fused ring heterocyclic group having an aromatic character containing 5 to 12 ring atoms and including up to four hetero atoms in the ring or in each ring selected from S, O, N;
R represents a linear or branched C _1-8 alkyl, C _3-7 cycloalkyl, C _4-7 cycloalkylalkyl, optionally substituted phenyl or phenyl C _1-6 alkyl, optionally substituted five-membered heteroaromatic ring, including up to four heteroatoms selected from O and N , hydroxy C _1-6 alkyl, amino C _1-6 alkyl, C _1-6 alkylaminoalkyl, di-C _1-6 alkylaminoalkyl, C _1-6 acylaminoalkyl, C _1-6 alkoxyalkyl, C _1-6 alkylcarbonyl, carboxy, C _1-6 alkoxycarbonyl, C _1-6 alkoxycarbonyl-C _1-6 alkyl, aminocarbonyl, C _1-6 alkylaminocarbonyl, di-C _1-6 alkylaminocarbonyl, halogen C _1-6 alkyl; or represents a group - (CH ₂ ) _p - when it is cyclized with Ar, where p represents 2 or 3.

R ₁ and R ₂ , which may be the same or different, independently represent hydrogen or C _1-6 linear or branched alkyl, or together form a group - (CH ₂ ) _n - in which n represents 3, 4 or 5; or R ₁ together with R forms a group - (CH ₂ ) _q -, in which q represents 2, 3, 4 or 5.

в которой V и V₁ представляют независимо водород или кислород, и u представляет 0, 1 или 2; -O(CH₂)_s-OW₂, в которой s представляет 2, 3 или 4, и W представляет водород или C_1-6алкил; гидроксиалкил, аминоалкил, моно- или диалкиламиноалкил, ациламино, алкилсульфониламино, аминоациламино, моно- или диалкиламиноациламино; причем в хинолиновом ядре присутствует до четырех R₃ заместителей; или R₄ представляет группу -(CH₂)_t, когда он циклизован с R₅ в виде арила, в которой t представляет 1, 2 или 3;
R₅ представляет линейный или разветвленный C_1-6алкил, C_3-7циклоалкил, C_4-7циклоалкилалкил, необязательно замещенный арил или необязательно замещенную одинарную или сконденсированную кольцевую гетероциклическую группу, имеющую ароматический характер, содержащую от 5 до 12 кольцевых атомов и включающую до четырех гетеро-атомов в кольце или в каждом кольце, выбранных из S, О, N;
X представляет О, S или N-C≡N.
Примерами Ar являются фенил, необязательно замещенный гидрокси, галогеном, C_1-6алкокси или C_1-6алкилом. Примерами галогена являются хлор и фтор, примером C_1-6алкокси является метокси, и примером C_1-6алкила - метил.R ₃ and R ₄ , which may be the same or different, are independently hydrogen, C _1-6 linear or branched alkyl, C _1-6 alkenyl, aryl, C _1-6 alkoxy, hydroxy, halogen, nitro, cyano, carboxy, carboxamido, sulfonamido, C _1-6 alkoxycarbonyl, trifluoromethyl, acyloxy, phthalimido, amino, mono or di-C _1-6 alkylamino, —O (CH ₂ ) _r —NT ₂ , in which r represents 2, 3 or 4, and T represents hydrogen or C _1-6 alkyl, or it forms a group with adjacent nitrogen

in which V and V ₁ independently represent hydrogen or oxygen, and u represents 0, 1 or 2; —O (CH ₂ ) _s —OW ₂ , in which s is 2, 3 or 4, and W is hydrogen or C _1-6 alkyl; hydroxyalkyl, aminoalkyl, mono- or dialkylaminoalkyl, acylamino, alkylsulfonylamino, aminoacylamino, mono- or dialkylaminoacylamino; moreover, up to four R ₃ substituents are present in the quinoline core; or R ₄ represents a group - (CH ₂ ) _t when it is cyclized with R ₅ in the form of aryl, in which t represents 1, 2 or 3;
R ₅ represents a linear or branched C _1-6 alkyl, C _3-7 cycloalkyl, C _4-7 cycloalkylalkyl, optionally substituted aryl or optionally substituted single or fused ring heterocyclic group having an aromatic character containing from 5 to 12 ring atoms and including up to four hetero atoms in the ring or in each ring selected from S, O, N;
X represents O, S or NC≡N.
Examples of Ar are phenyl optionally substituted with hydroxy, halogen, C _1-6 alkoxy or C _1-6 alkyl. Examples of halogen are chlorine and fluorine, an example of C _1-6 alkoxy is methoxy, and an example of C _1-6 alkyl is methyl.

 Examples of Ar as a heterocyclic group are thienyl and pyridyl.

Examples of Ar as a C _5-7 cycloalkenyl group are cyclohexadienyl.

Примером R₁ и R₂ в виде C_1-6 алкила является метил; примером R₁ вместе с R, образующими группу -(CH₂)_q-, является спироциклопентан.Examples of R are the following:
C _1-8 alkyl: methyl, ethyl, n-propyl, iso-propyl, n-butyl, heptyl;
phenyl C _1-6 alkyl: benzyl;
hydroxy C _1-6 alkyl: -CH ₂ OH, -CH ₂ CH ₂ OH, CH (Me) OH;
amino C _1-6 alkyl: - CH ₂ NH ₂ ;
di-C _1-6 alkylaminoalkyl: —CH ₂ NMe ₂ ;
C _1-6 alkoxyalkyl: - CH ₂ OMe;
C _1-6 alkylcarbonyl: COMe;
C _1-6 alkoxycarbonyl: COOMe;
C _1-6 alkoxycarbonyl C _1-6 alkyl: CH ₂ COOMe;
C _1-6 alkylaminocarbonyl: CONHMe;
di-C _1-6 alkylaminocarbonyl: CONMe ₂ , CO (1-pyrrolidinyl); halogen C _1-6 alkyl: trifluoromethyl;
- (CH ₂ ) _p - when cyclized with Ar:

Examples of R ₁ and R ₂ as C _1-6 alkyl are methyl; an example of R ₁ together with R forming the group - (CH ₂ ) _q - is spirocyclopentane.

Examples of R ₃ and R ₄ are methyl, ethyl, n-propyl, n-butyl, methoxy, hydroxy, amino, chlorine, fluorine, bromine, acetyloxy, 2- (dimethylamino) ethoxy, 2- (1-phthaloyl) ethoxy, aminoethoxy , 2- (1-pyrrolidinyl) ethoxy, phthaloyl, dimethylaminopropoxy, dimethylaminoacetylamino, acetylamino, dimethylaminomethyl and phenyl.

Examples of R ₅ are cyclohexyl, phenyl optionally substituted as defined above for Ar; examples of R ₅ in the form of a heterocyclic group are furyl, thienyl, pyrryl, thiazolyl, benzofuryl and pyridyl.

A preferred group of compounds of formula (I) are compounds in which:
Ar is phenyl optionally substituted with C _1-6 alkyl or halogen; thienyl or C _5-7 cycloalkenyl group;
R represents C _1-6 alkyl, C _1-6 alkoxycarbonyl, C _1-6 alkylcarbonyl, hydroxy C _1-6 alkyl;
R ₁ and R ₂ represent each hydrogen or C _1-6 alkyl;
R _{3 is} hydrogen, hydroxy, halogen, C _1-6 alkoxy, C _1-6 alkyl;
R ₄ represents hydrogen, C _1-6 alkyl, C _1-6 alkoxy, hydroxy, amino, halogen, aminoalkoxy, mono- or dialkylaminoalkoxy, mono- or dialkylaminoalkyl, phthaloalkoxy, mono- or dialkylaminoacylamino and acylamino;
R ₅ represents phenyl, thienyl, furyl, pyrryl and thiazolyl.

An additional preferred group of compounds of formula (I) are compounds in which:
Ar represents phenyl, 2-chlorophenyl, 2-thienyl or cyclohexadienyl;
R represents methyl, ethyl, n-propyl, —COOMe, —COMe;
R ₁ and R ₂ each represents hydrogen or methyl;
R ₃ represents hydrogen, methoxy or hydroxy;
R ₄ represents hydrogen, methyl, ethyl, methoxy, hydroxy, amino, chloro, bromo, dimethylaminoethoxy, 2- (1-phthaloyl) ethoxy, aminoethoxy, 2- (1-pyrrolidinyl) ethoxy, dimethylaminopropoxy, dimethylaminoacetylamino, acetylamino and dimethylaminomethyl;
R ₅ represents phenyl, 2-thienyl, 2-furyl, 2-pyrryl, 2-thiazolyl and 3-thienyl; and
X represents oxygen.

в которой R, R₂, R₃ и R₄ имеют значения, определенные для формулы (I), и Y и Z, которые могут быть одинаковыми или различными, каждый представляет Ar, как он определен для формулы (I).A preferred subgroup of compounds within the scope of formula (I) above are compounds of formula (Ia):

in which R, R ₂ , R ₃ and R ₄ have the meanings defined for formula (I), and Y and Z, which may be the same or different, each represents Ar as defined for formula (I).

 A particularly preferred group of compounds of formula (Ia) are compounds of formula (Ib) in which the group R is oriented downward and H is upward.

Соединения формулы (I) или их соли или сольваты представлены предпочтительно в фармацевтически приемлемой или по существу чистой форме. Под фармацевтически приемлемой формой соединений имеются в виду, наряду с другими, соединения фармацевтически приемлемого уровня чистоты, исключая обычные фармацевтические добавки, такие как разбавители и носители, и не включающие вещества, считающиеся токсичными при обычных дозировочных уровнях. По существу чистая форма обычно содержит, по крайней мере, 50% (исключая обычные фармацевтические добавки), предпочтительно 75%, более предпочтительно 90% и еще более предпочтительно 95% соединения формулы (I) или его соли или сольвата. Одну из предпочтительных фармацевтически приемлемых форм составляет кристаллическая форма, включая такую форму в фармацевтической композиции. В случае солей и сольватов дополнительные части - ионная и растворителя также должны быть нетоксичными.

The compounds of formula (I) or their salts or solvates are preferably presented in pharmaceutically acceptable or essentially pure form. By pharmaceutically acceptable form of the compounds are meant, among others, compounds of a pharmaceutically acceptable level of purity, excluding conventional pharmaceutical additives, such as diluents and carriers, and not including substances that are considered toxic at conventional dosage levels. The substantially pure form typically contains at least 50% (excluding conventional pharmaceutical additives), preferably 75%, more preferably 90% and even more preferably 95% of the compound of formula (I) or a salt or solvate thereof. One of the preferred pharmaceutically acceptable forms is a crystalline form, including such a form in a pharmaceutical composition. In the case of salts and solvates, the additional parts — ionic and solvent — must also be non-toxic.

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

 Examples of pharmaceutically acceptable solvates of the compounds of formula (I) include hydrates.

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

в которой R', R'₁, R'₂ и Ar' представляют R, R₁, R₂ и Ar, как они определены для формулы (I), или группу или атом, способные превращаться в R, R₁, R₂, и Ar, с соединением формулы (II)

или его активным производным, в которой R'₃, R'₄, R'₅ и X' представляют R₃, R₄, R₅ и X, как они определены для формулы (I), или группу, способную превращаться в R₃, R₄, R₅ и X, с получением соединения формулы (Ic)

и необязательное выполнение после этого одной или более из следующих стадий:
(а) когда R', R'₁ - R'₅, Ar' и X' являются иными, чем R, R₁-R₅, Ar и X, превращение любого одного из R', R'₁ - R'₅, Ar' и X' в R, R₁ - R₅, Ar и X с получением соединения формулы (I),
(b) когда R', R'₁ - R'₅, Ar' и X' представляют R, R₁ - R₅, Ar и X, превращение любого одного из R, R₁ - R₅, Ar и X в иной R, R₁ - R₅, Ar и X с получением соединения формулы (I),
(с) образование соли и/или сольвата полученного соединения формулы (Ic).The invention also provides a process for preparing compounds of formula (I), which comprises reacting a compound of formula (III)

in which R ', R' ₁ , R ' ₂ and Ar' represent R, R ₁ , R ₂ and Ar, as defined for formula (I), or a group or atom capable of converting to R, R ₁ , R ₂ , and Ar, with a compound of formula (II)

or its active derivative, in which R ' ₃ , R' ₄ , R ' ₅ and X' represent R ₃ , R ₄ , R ₅ and X, as defined for formula (I), or a group capable of converting to R ₃ , R ₄ , R ₅ and X, to obtain a compound of formula (Ic)

and optionally performing thereafter one or more of the following steps:
(a) when R ', R' ₁ - R ' ₅ , Ar' and X 'are other than R, R ₁ -R ₅ , Ar and X, the conversion of any one of R', R ' ₁ - R' ₅ , Ar 'and X' in R, R ₁ is R ₅ , Ar and X to give a compound of formula (I),
(b) when R ', R' ₁ - R ' ₅ , Ar' and X 'represent R, R ₁ - R ₅ , Ar and X, the conversion of any one of R, R ₁ - R ₅ , Ar and X to another R, R ₁ - R ₅ , Ar and X to obtain the compounds of formula (I),
(c) formation of a salt and / or solvate of the obtained compound of formula (Ic).

 Suitable active derivatives of the compounds of formula (II) are acid halides (preferably acid chlorides), acid azides or acid anhydrides. Another suitable derivative is mixed anhydride formed between an acid and an alkyl chloroformate; another suitable derivative is an activated ester such as cyanomethyl, thiophenyl, n-nitrophenyl, n-nitrothiophenyl ethers, 2,4,6-trichlorophenyl ether, pentachlorophenyl, pentafluorophenyl ethers, N-hydroxy-phthalimido ether, N-hydroxypyri N-hydroxysuccinimide ether; N-hydroxy-benzotriazole ether; or a carboxy group can be activated using carbodiimide or N, N'-carbonyldiimidazole.

For example, according to standard methods well known to those skilled in the art, compounds of formula (III) may be combined:
(a) with an acid chloride in the presence of an inorganic or organic base in a suitable aprotic solvent such as dimethylformamide (DMF or DMF), at a temperature in the range of -70 to 50 ^° C (preferably in the range of -10 to 20 ^° C),
(b) with an acid in the presence of a suitable condensing agent, such as, for example, N, N'-carbonyldiimidazole (GDI) or carbodiimide, such as dicyclohexylcarbodiimide (DCC) or N-dimethylaminopropyl-N'-ethylcarbodiimide and N-hydroxybenzotriazole (HOBT) , in order to achieve maximum yields and in order to avoid racemization processes (Synthesis, 453, 1972) in an aprotic solvent such as a mixture of acetonitrile (MeCN) and tetrahydrofuran (TGF or THF) in a ratio of 1: 9 to 7: 3, respectively at a temperature in the range from -70 to 50 ^o C (preferably in the range from -10 to 25 ^o C) (see scheme 1),
(c) with a mixed anhydride obtained in situ (in situ) from an acid and an alkyl (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 the range of - 20 to 20 ^o C). Obviously, it is understood that a compound of formula (Ic) can be converted to a compound of formula (I), or one compound of formula (I) can be converted to another compound of formula (I) by interconversion of suitable substituents. Thus, some compounds of formula (I) and (Ic) are useful intermediates in the formation of other compounds of the present invention.

For example, R ′ ₂ can be hydrogen and converted to an R ₂ alkyl group, for example methyl, using 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 using standard thioamide formation reagents such as P ₂ S ₅ (Chem. Rev. 61, 45, 1961 or Angew.Chem. 78, 517, 1966) or Lawesson (Tetrahedron, 41, 5061, 1985). When Ar ′ or R ′ ₅ is methoxy substituted phenyl, it can be converted to another Ar ′ or R ′ ₅ hydroxy-substituted phenyl using standard demethylation techniques using Lewis acids such as boron tribromide (Synthesis, 249, 1983), or mineral acids, such as hydrobromic or hydroiodic acid. When R represents an alkoxycarbonyl group, for example methoxycarbonyl, it can be converted to another R, such as ethoxycarbonyl by complex transesterification with an appropriate alcohol at a temperature in the range of 0 to 120 ^° C., carboxy by hydrolysis in an acidic or basic medium, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl via transamidation with ammonia, a primary amine or a secondary amine in methanol as solvent at a temperature ranging from 10 to 120 ^o C, optionally in the presence of kata iticheskogo amount of NaCN (J. Org. Chem., 52 2033, 1987) or by using trimethylaluminium (Me ₃ Al) (Tetrahedron Letters, 48, 4171, 1977), hydroxymethyl by a selective metal hydride reduction, such as recovery borohydride lithium (Tetrahedron, 35, 567, 1979) or reduction with sodium borohydride in a mixture of THF + MeOH (Bull Chem. Soc. Japan, 57, 1948, 1984 or Syntn. Commun., 12, 463, 1982), alkylcarbonyl by formation acyl chloride and subsequent reaction with alkyl magnesium halides in THF as a solvent at a temperature in the range from -78 to 30 ^o C (Tetrahedron Letters, 4303, 1979) or with alkyl lcadmium halides or dialkyl cadmium in the presence of MgCl ₂ or lithium chloride (J. Org. Chem., 47: 2590, 1982). Another R ′ group like methoxycarbonyl can be converted to a substituted heterocyclic ring, such as oxadiazole (J. Med. Chem., 34: 2726, 1991), a heteroaromatic ring, such as oxadiazole (J. Med. Chem., 34, 2726, 1991).

Scheme 2 summarizes some of the methods described above for converting a compound of formula (Ic) or (I) in which X 'is oxygen, R' is COOMe, Ar 'and R' ₁ -R ' ₅ have the meanings described for formula (I) , to another compound of formula (I) (Scheme 2, see end of description).

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

 Solvates of the compounds of formula (I) may be formed by crystallization or recrystallization from an appropriate solvent. For example, hydrates can be obtained by crystallization or recrystallization from aqueous solutions, or solutions in organic solvents containing water.

 Salts or solvates of compounds of formula (I) that are not pharmaceutically acceptable may also be useful as intermediates in the preparation of pharmaceutically acceptable salts and solvates. Accordingly, such salts and solvates also form part of this invention.

подвергаются реакции с соединениями формулы (II) с получением соединений формулы (I'd) или (I'e).As mentioned above, the compounds of formula (I) can exist in more than one stereoisomeric form, and the process of the present invention can produce racemates as well as enantiomerically pure forms. To obtain pure enantiomers, the corresponding enantiomerically pure primary or secondary amines of the formula (IIId) or (IIIe)

are reacted with compounds of formula (II) to give compounds of formula (I'd) or (I'e).

Соединения формулы (I'd) или (I'e) могут впоследствии превращаться в соединения формулы (Id) или (Ie) с помощью методов превращения, упомянутых выше.

Compounds of formula (I'd) or (I'e) can subsequently be converted to compounds of formula (Id) or (Ie) using the conversion methods mentioned above.

Соединения формулы (II) являются известными или могут получаться из известных соединений с помощью известных способов.

The compounds of formula (II) are known or can be obtained from known compounds using known methods.

For example, a compound of formula (II) in which X ′ is oxygen, R ′ ₃ , R ′ ₄ and R ′ ₅ are hydrogen is described in Pfitzinger, J. Prakt. Chem. 38, 582, 1882 and in the work of Pfitzinger, J. Prakt. Chem., 56, 293, 1897; a compound of formula (II) in which X 'is oxygen, R' ₃ and R ' ₄ are hydrogen and R' ₅ is 2-pyridyl, described in Risaliti, Ric. Scient. , 28, 561, 1958; 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; a compound of formula (II) in which X ′ is oxygen, R ′ ₃ and R ′ ₄ are hydrogen, and R ′ ₅ is p-methoxyphenyl, described in Ciusa and Luzzatto, Gazz. Chim. Ital., 44, 64, 1914; a compound of formula (II) in which X ′ is oxygen, R ′ ₃ and R ′ ₄ are hydrogen, and R ′ ₅ is m-trifluoromethylphenyl, described by Shargier and Lalezari, J. Chem. Eng. Data, 8, 276, 1963; a compound of formula (II) in which X ′ is oxygen, R ′ ₃ and R ′ ₄ are hydrogen, and R ′ ₅ is p-fluorophenyl, described by Bu Hoi et al., Rec Trav. Chim. 68, 781, 1949; a compound of formula (II) in which X ′ is oxygen, R ′ ₃ and R ′ ₄ are hydrogen, and R ′ ₅ is p-methylphenyl, described in Prevost et al., Compt. Rend. Acad Sci., 258, 954, 1964; a compound of formula (II) in which X ′ is oxygen, R ′ ₃ and R ′ ₄ are hydrogen, and R ′ ₅ is p-bromophenyl, described in Nicolai et al. , Eur. J. Med. Chem., 27, 977, 1992; a compound of formula (II) in which X ′ is oxygen, R ′ ₄ and R ′ ₅ are hydrogen, and R ′ ₃ is 6-methyl, described by Buchmann and Howton, J. Am. Chem. Soc. 68, 2718, 1946; a compound of formula (II) in which X ′ is oxygen, R ′ ₄ and R ′ ₅ are hydrogen, and R ′ ₃ is 8-nitro, described by Buchmann et al, J. Am. Chem. Soc., 69, 380, 1947; a compound of formula (II) in which X ′ is oxygen, R ′ ₄ is hydrogen, R ′ ₃ is 6-chloro, R ′ ₅ is p-chlorophenyl, described in Lutz et al., J. Am. Chem. Soc., 68, 1813, 1946; a compound of formula (II) in which X ′ is oxygen, R ′ ₃ and R ′ ₄ are hydrogen, and R ′ ₅ is 2-thiazolyl, as described in European patent application EP 112776; the compounds of formula (II) in which X 'represents oxygen, R' ₃ represents 8-trifluoromethyl, R ' ₄ represents hydrogen and R' ₅ represents phenyl, o- and p-fluorophenyl, 3,4-dichlorophenyl, p-methoxyphenyl, are described in Nicolai et al. , Eur. J. Med. Chem., 27, 977, 1992; a compound of formula (II), wherein X'predstavlyaet oxygen, R _'3 is 6-bromo, R' ₄ is hydrogen and R _'5 represents 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 German patent application DE 3721222 and in European patent application EP 384313.

The compounds of formulas (III), (IIId) and (IIIe) are commercially available compounds or can be obtained from known compounds using known methods (for example, compounds of formula (III) in which R ′ is alkoxy carbonyl, R ′ ₁ and R ' ₂ represents hydrogen and Ar' has the meanings defined for the compounds of formula (I) described in Liebigs Ann. Der Chemie, 523, 199, 1936).

The activity of the compounds of formula (I) as antagonists of the NK ₃ receptor in standard trials indicates that they have potential therapeutic usefulness in the treatment of both primary and secondary disorders, which were previously referred to. The discovery that NK ₃ receptor antagonists are of potential therapeutic benefit in the treatment of secondary disorders is new, and in accordance with a further aspect of the present invention, the use of NK ₃ receptor antagonists in the treatment of secondary disorders is provided. The use of NK ₃ receptor antagonists in the manufacture of drugs for the treatment of any of the secondary disorders is also provided.

 The present invention also provides compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof for use as active therapeutic substances.

 The present invention further provides pharmaceutical compositions comprising 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 compounds of formula (I) or their pharmaceutically acceptable salts or solvates in the manufacture of medicines for the treatment of primary and secondary disorders.

 Such medicaments and compositions of the present invention can be obtained by mixing a compound of the invention with an appropriate carrier. They may contain conventional diluents, binders, fillers, disintegrating agents, flavoring or aromatic agents, coloring agents, lubricating or preserving agents.

 These conventional excipients are those that can be used, for example, in the preparation of compositions with known agents for the treatment of these conditions.

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

 The range of suitable doses for the compounds of the invention depends on the compound used and on the condition of the patient. It also depends on the relationship of activity or strength of action and ability to absorb and the frequency and method of administration for taking the drug.

 The compound or composition of the invention can be formulated for administration in any way, and preferably in the form of a unit dose or in a form that a person can take as a dose in a single dose. The composition may advantageously be in a form suitable for oral, rectal, topical or local, parenteral, intravenous or intramuscular administration. Preparations can be made in such a way as to provide a slow release of the active ingredient.

 The compositions may be, for example, in the form of tablets, capsules, sachets, vials or tubes, powders, granules, lozenges, reconstituted or reconstituted powders or liquid preparations, for example solutions or suspensions, or in the form of medical suppositories or suppositories.

 Compositions, for example, those suitable for oral administration, may contain conventional excipients, such as binding agents, for example syrup, acacia gum, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone; fillers, for example lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine; tablet lubricants, for example magnesium stearate; disintegrating agents, for example starch, polyvinyl pyrrolidone, sodium starch glycolate or microcrystalline cellulose; or pharmaceutically acceptable solidification agents, such as sodium lauryl sulfate.

 Solid compositions may be prepared using conventional methods of mixing, filling, tabletting or the like. Repeated mixing operations can be used to distribute or distribute the active agent in compositions that employ large quantities of excipients. When the composition is in the form of a tablet, powder, or lozenge, any carrier suitable for the formation of solid pharmaceutical compositions may be used, examples being magnesium stearate, starch, glucose, lactose, sucrose, rice flour and chalk. Tablets may be coated according to methods well known in ordinary pharmaceutical practice, in particular with an enteric coating. The composition may also be in the form of a swallowable capsule, for example, from a gelatin-containing compound, if desired with a carrier or other excipients.

 Compositions for oral administration in the form of liquids may be in the form of, for example, emulsions, syrups or elixirs, or they may be presented as a dry product intended for reconstitution with water or another suitable vehicle before use. Such liquid compositions may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel, hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate or acacia gum; aqueous or non-aqueous vehicles that include edible oils, such as almond oil, fractionated coconut oil, oily esters, for example glycerol or propylene glycol esters or ethyl alcohol, glycerin, water or a normal physiological or saline solution; preservatives, for example methyl or propyl p-hydroxybenzoate or ascorbic acid; and, if desired, conventional flavoring or coloring agents.

 The compositions of this invention may also be administered for oral administration. In accordance with conventional pharmaceutical procedures, the compositions may be formulated for rectal administration in the form of medical suppositories. They can also be formulated or formulated to be presented in an injectable form in an aqueous or non-aqueous solution, suspension or emulsion in a pharmaceutically acceptable liquid, for example sterile, pyrogen-free water or in a parenterally acceptable oil or mixture of liquids. The liquid may contain antibacterial agents, antioxidants, or other preservatives, buffers, or dissolved substances to render the solution isotonic with blood, thickening agents, suspending agents, or other pharmaceutically acceptable additives. Such forms are presented in the form of a single dose, such as ampoules or single injectable products, or in the form of many doses, such as a bottle or bottle, from which an appropriate dose can be taken, or a solid form or concentrate that can be used to prepare injectable preparations forms.

 The compounds of this invention may also be administered by inhalation through the nose or mouth. Such drug administration can be carried out using a spray form, comprising a compound of the invention and a suitable carrier, optionally suspended, for example, in a hydrocarbon reactive fuel substance.

 Preferred spray formulations include the finest (micronized) particles of the compound in combination with a surface-active agent, solvent, or dispersant to prevent sedimentation of the suspended particles. The particle size of the compound is preferably from about 2 to 10 microns.

 An additional method for administering the compounds of the invention includes transdermal delivery using a formulation in the form of a skin patch. A preferred formulation is a compound of the invention dispersed in a pressure sensitive adhesive that adheres to the skin, thereby allowing the compound to diffuse from the adhesive through the skin for delivery to the patient. For a constant degree or rate of absorption through the skin, pressure sensitive adhesives known in the art, such as natural rubber or silicone, can be used.

 As mentioned above, the effective dose of a compound depends on the particular compound employed, the condition of the patient, and the frequency and route of administration. A unit dose usually contains from 20 to 1000 mg, and preferably from 30 to 500 mg, in particular 50, 100, 150, 200, 250, 300, 350, 400, 450 or 500 mg. The composition may be prescribed to be taken one or more times a day, for example, 2, 3 or 4 times a day, and the total daily dose for an adult weighing 70 kg is usually in the range from 100 to 3000 mg. Alternatively, a single dose contains from 2 to 20 mg of the active ingredient and is taken multiple times, if necessary, to give the indicated daily dose.

 In the case of the compounds of the invention, when they are taken in accordance with the invention, no unacceptable toxicological effects are expected.

 The present invention also provides a method of treating and / or preventing primary and secondary disorders in mammals, in particular humans, which comprises administering to a mammal in need of such treatment and / or prevention an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.

The invention further provides a method of treating and / or preventing secondary disorders in mammals, especially humans, which comprises administering to a mammal in need of such treatment and / or prevention an effective amount of an NK ₃ receptor antagonist.

The activity of the compounds of the present invention as NK ₃ ligands is determined by their ability to inhibit the binding of radioactively labeled NK ₃ , [ ¹²⁵ I] - [Me-Phe ⁷ ] -NKB or [ ³ H] -Senctide ligands, to NK ₃ guinea pig and human 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 assays used make it possible to determine the concentration of an individual compound required to reduce by 50% the specific binding of [ ¹²⁵ I] - [Me-Phe ⁷ ] -NKB and [ ³ H] -Senctide to the NK ₃ receptor under equilibrium (IC ₅₀ ). Binding assays give, for each compound tested, an average IC ₅₀ of 2-5 separate experiments performed in duplicate or triplicate. The most active compounds of the present invention show IC ₅₀ values in the range of 1 to 1000 nM; in particular, in the experiment with the cerebral cortex of the guinea pigs with the replacement (displacement) of [ ³ H] -Senctide, the compounds of Examples 22, 47, 48 and 85 show KiS (nM) of 5.6, 8.8, 12.0 and 4.8, respectively (n = 3). The NK ₃ antagonistic activity of the compounds of the present invention is determined by their ability to inhibit senctid-induced guinea pig ileum contraction (Maggi et al, 1990, Br. J, Pharmacol. 101, 996-1000) and isolated rabbit iris sphincter muscle (Hall et al., 1991, Eur. J. Pharmacol., 199, 9-14) and NK ₃ Ca ⁺⁺ receptor-mediated mobilization (Mochizuki et al., 1994, J. Biol. Chem., 269. 9651-9658). Functional in vitro analyzes on guinea pigs and rabbits give for each test compound the average value of K _B from 3-8 separate experiments, where K _B represents the concentration of an individual compound necessary to obtain a 2-fold shift to the right on the senctid concentration-response curve. Functional analysis with human receptors allows you to determine the concentration of an individual compound necessary to reduce by 50% (IC ₅₀ value) Ca ⁺⁺ mobilization induced by an NKB antagonist. In this assay, the compounds of the present invention behave as antagonists.

 The therapeutic potential of the compounds of the present invention in the treatment of these conditions can be assessed using rodent disease models.

 The following descriptions illustrate the preparation of intermediates, while the examples illustrate the preparation of compounds of the present invention. The compounds of the examples are presented in tables 1 to 6.

DESCRIPTION 1
2-phenylquinoline-4-carboxylic acid chloride
11.7 ml (136.3 mmol) of oxalyl chloride was dissolved in 150 ml of methylene chloride. The solution was cooled at -10 ^° C, and 20 g (80.2 mmol) of commercially available 2-phenylquinoline-4-carboxylic acid were added portionwise. The reaction mixture was left overnight at room temperature and then evaporated to dryness, giving 22 g of the title compound, used without further purification.

C ₁₆ H ₁₀ ClNO
M.V. = 267.76
DESCRIPTION 2
7-methoxy-2-phenylquinoline-4-carboxylic 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 were dissolved in 22.9 ml of absolute ethanol, and the suspension was heated at 80 ^o C within 42 hours. After cooling the reaction mixture, 50 ml of water was added, and the solution was extracted with 50 ml of diethyl ether. The ice-cooled aqueous phase was acidified to pH 1 with 37% HCl, and the precipitate was collected by filtration and washed with water. The resulting solid was dried in vacuo at 40 ^° C. to give 7.0 g of the title compound.

C ₁₇ H ₁₃ NO ₃
T. pl. = 226- 228 ^o C
M.V. = 279.30
Elemental analysis: Calculated C 73.11; H 4.69; N 5.01
Found C, 72.07; H 4.59; N, 4.90.

IR (KBr): 3420, 1630 cm ^-1
DESCRIPTION 3
7-Methoxy-2-phenylquinoline-4-carboxylic acid chloride
2.8 ml (32.3 mmol) of oxalyl chloride was dissolved in 60 ml of methylene chloride. The solution was cooled at -10 ^° C, and 6 g (19.0 mmol) of 7-methoxy-2-phenylquinoline-4-carboxylic acid were added portionwise. The reaction mixture was left overnight at room temperature and then evaporated to dryness, giving 7 g of the title compound, used without further purification.

C ₁₇ H ₁₂ ClNO ₂
M.V. = 297.74
DESCRIPTION 4
7-hydroxy-2-phenylquinoline-4-carboxylic acid hydroiodide
1.5 g (5.4 mmol) of 7-methoxy-2-phenylquinoline-4-carboxylic acid was added portionwise to 50 ml of 57% aqueous HI. The reaction mixture was refluxed and vigorously stirred for 5 hours; then it was evaporated to dryness in vacuo to give 2.1 g of the title compound.

C ₁₆ H ₁₁ NO ₃ • HI
M.V. = 393.17
IR (KBr): 3120; 1650; 1620 cm ^-1 .

DESCRIPTION 5
2- (2-thienyl) quinoline-4-carboxylic 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 were dissolved
in 40 ml of absolute ethanol, and the suspension was heated at 80 ^o C for 16 hours. After cooling the reaction mixture, 50 ml of water was added, and the solution was extracted with 50 ml of diethyl ether. The ice-cooled aqueous phase was acidified to pH 1 with 37% HCl, and the precipitate was collected by filtration and washed with water. The resulting crude product was dried in vacuo at 40 ^° C. and triturated with ethyl acetate to give 4.8 g of the title compound.

C ₁₄ H ₉ NO ₂ S
Mp = 181 - 183 ^o C
M.V. = 255.29
IR (KBr): 1620 cm ^-1
300 MHz ¹ H-NMR (DMSO-d ₆ ): δ 8.60 (d, 1H); 8.45 (s, 1H); 8.10 (m, 2H); 7.78 (m, 2H); 7.68 (t, 1H); 7.22 (m, 1H).

DESCRIPTION 6
2- (2-furyl) quinoline-4-carboxylic 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 were dissolved in 40.9 ml of absolute ethanol, and the suspension was heated at 80 ^o C within 12 hours. After cooling the reaction mixture, 50 ml of water was added, and the solution was extracted with 50 ml of diethyl ether. The ice-cooled aqueous phase was acidified to pH 1 with 37% HCl, and the precipitate was collected by filtration and washed with water. The resulting crude product was dried in vacuo at 40 ^° C. to give 8.5 g of the title compound.

C ₁₄ H ₉ NO ₃
MB = 239.23
DESCRIPTION 7
2- (2-furyl) quinoline-4-carboxylic acid chloride 5.2 ml (60.4 mmol) of oxalyl chloride was dissolved in 70 ml of methylene chloride. The solution was cooled at -10 ^° C and 8.5 g (35.5 mmol) of 2- (2-furyl) quinoline-4-carboxylic acid were added portionwise. The reaction mixture was left overnight at room temperature and then evaporated to dryness, giving 9.2 g of the title compound, used without further purification.

C ₁₄ H ₈ ClNO ₂
M.V. = 257.78
DESCRIPTION 8
2- (4-Pyridyl) quinoline-4-carboxylic acid chloride
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 were dissolved in 40 ml of absolute ethanol, and the suspension was heated at 80 ^° C within 12 hours. After cooling the reaction mixture, 50 ml of water was added, and the solution was extracted with 50 ml of diethyl ether. The ice-cooled aqueous phase was acidified to pH 1 with 37% HCl, and the precipitate was collected by filtration and washed with water.

 The aqueous solution was evaporated to dryness in vacuo, the residue was triturated with ethanol and filtered. Evaporation of the solvent afforded 6.0 g of the crude title compound. This product was combined with the previously obtained precipitate and recrystallized from toluene containing traces of methanol to give 4.5 g of the title compound.

C ₁₅ H ₁₀ N ₂ O ₂ • HCl
Mp = 297 - 301 ^o C
M.V. = 286.72
IR (KBr): 1705, 1635, 1610 cm ^-1 .

300 MHz ¹ H-NMR (DMSO-d ₆ ): δ 8.90 (d, 2H), 8.70 (m, 2H), 8.50 (s, 2H), 8.28 (d. , 1H); 7.89 (dt, 2H).

DESCRIPTION 9
2- (4-Pyridyl) quinoline-4-carboxylic acid hydrochloride
1.3 ml (10.4 mmol) of oxalyl chloride was dissolved in 60 ml of methylene chloride. The solution was cooled at −10 ^° C. and 3.0 g (14.4 mmol) of 2- (4-pyridyl) quinoline-4-carboxylic acid hydrochloride was added portionwise. The reaction mixture was left at room temperature for 72 hours and then evaporated to dryness to give 4.0 g of the title compound, used without further purification.

C ₁₅ H ₉ ClN ₂ O • HCl
M.V. = 305.22
Example 1
(R, S) -N- (α-methylbenzyl) -2-phenylquinoline-4-carboxamide 1.2 ml (9.4 mmol) (R, S) (α-methylbenzylamine and 1.6 ml (11.7 mmol ) triethylamine (TEA) was dissolved in a nitrogen atmosphere in a 50 ml 1: 1 mixture of dry methylene chloride and CH ₃ CN. To an ice-cooled amine solution was added dropwise 2.0 g (7.8 mmol) of 2-phenylquinoline-4-carbonyl chloride, dissolved in a 50 ml 1: 4 mixture of dry methylene chloride and DMF, and the reaction mixture was stored at 0-5 ^° C for 1 hour and left overnight at room temperature.The reaction mixture was evaporated to dryness in vacuo, the residue was dissolved in ethyl acetate These were washed twice with saturated sodium bicarbonate solution. The organic layer was separated, dried over sodium sulfate, filtered and evaporated to dryness in vacuo. The residual oil crystallized from ethyl acetate to give 1.1 g of the target compound as a white solid.

C ₂₄ H ₂₀ N ₂ O
Mp = 156 - 157 ^o C
M.V. = 352.43
Elemental analysis: Calculated C 81.79; H 5.72; N 7.95
Found C, 81.99; H 5.69; N 7.89
IR (KBr): 3240, 1645 cm ^-1 .

300 MHz ¹ H-NMR (DMSO-d ₆ ): δ 9.29 (d, 1H), 8.32 (d, 2H), 8.13 (d, 1H), 8.13 (s. , 1H), 8.06 (d, 1H), 7.81 (ddd, 1H), 7.68-7.52 (m, 4H), 7.47 (d, 2H), 7, 39 (dd, 2H), 7.27 (dd, 1H), 5.30 (dq, 1H), 1.52 (d, 3H).

MC (EI; source 200 ^° C, 70 V, 200 mA): 352 (M +.), 337, 232, 204, 77.

Example 2
S - (+) - N- (α-methylbenzyl) -2-phenylquinoline-4-carboxamide
It was obtained, as in example 1, from 1.2 ml (9.4 mmol) of S - (-) - α-methylbenzylamine, 1.6 ml (11.7 mmol) of TEA, 2.0 g (7.8 mmol) 2-phenylquinoline-4-carbonyl chloride in 100 ml of a mixture of methylene chloride, CH ₃ CN and DMF. Processing of the reaction mixture was carried out in the same manner as described in example 1. The residual oil crystallized from ethyl acetate, giving 1.1 g of the target compound.

C ₂₄ H ₂₀ N ₂ O
Mp = 161 - 162 ^o C
M.V. = 352.43
[α] $\genfrac{}{}{0ex}{}{\text{20}}{\text{D}}$ = +25 (C = 0.5 DMF) IR (KBr): 3240, 1645 cm ^-1
300 MHz ¹ H-NMR (DMSO-d ₆ ): δ 9.29 (d, 1H), 8.32 (d, 2H), 8.13 (d, 1H), 8.13 (s. , 1H), 8.06 (d, 1H), 7.81 (ddd, 1H), 7.68-7.52 (m, 4H), 7.47 (d, 2H), 7, 39 (dd, 1H), 7.27 (dd, 1H), 5.30 (dq, 1H), 1.52 (d, 3H).

 MS spectrum was identical to the spectrum of example 1.

Example 3
R - (-) - N- (α-methylbenzyl) -2-phenylquinoline-4-carboxamide
It was obtained, as in example 1, from 1.2 ml (9.4 mmol) of R - (+) - α-methylbenzylamine, 1.6 ml (11.7 mmol) of TEA, 2.0 g (7.8 mmol) 2-phenylquinoline-4-carbonyl chloride in 100 ml of a mixture of methylene chloride, CH ₃ CN and DMF. Processing of the reaction mixture was carried out in the same manner as described in example 1. The residual oil crystallized from ethyl acetate, giving 1.1 g of the target compound.

C ₂₄ H ₂₀ N ₂ O
Mp = 158 - 160 ^o C
MB = 352.43
[α] $\genfrac{}{}{0ex}{}{\text{20}}{\text{D}}$ = -25 (C = 0.5 DMF) IR (KBr): 3240, 1645 cm ^-1
1 H-NMR and MS spectra were identical to the spectra of examples 1 and 2.

Example 4
(R, S) -N- [α- (methoxycarbonyl) benzyl] -2-phenylquinoline-4-carboxamide
2.0 g (8.0 mmol) of 2-phenylquinoline-4-carboxylic acid was dissolved in a nitrogen atmosphere in 130 ml of dry THF and 100 ml of CH ₃ CN. 2.0 g (9.9 mmol) of methylphenyl glycyanate hydrochloride (D, L) and 1.5 ml (10.7 mmol) of TEA were added, and the reaction mixture was cooled at 5 ^° C. 2.5 g was added dropwise (12, 1 mmol) of dicyclohexylcarbodiimide (DCC) dissolved in 10 ml of dry methylene chloride, and the solution was allowed to reach room temperature, the solution was stirred for 5 hours and left overnight. The precipitated dicyclohexylurea was filtered off and the solution was evaporated to dryness in vacuo. The residue was dissolved in methylene chloride and then washed with water. The organic layer was separated, dried over sodium sulfate and evaporated to dryness in vacuo to give 6.0 g of a crude product, which was dissolved in 20 ml of methylene chloride and left overnight. A further amount of dicyclohexylurea precipitated and was filtered off.

 The solution was evaporated to dryness in vacuo, and the residue was flash chromatographed on 230-400 mesh silica gel, eluting with a hexane / ethyl acetate 3/2 mixture containing 0.5% ammonium hydroxide. The resulting crude or crude solid was triturated with warm diisopropyl ether, filtered off, washed and dried to give 1.1 g of the target compound.

C ₂₅ H ₂₀ N ₂ O ₃
Mp = 170 - 172 ^o C
M.V. = 396.45
Elemental analysis: Calculated C 75.74; H 5.09; N 7.07
Found C, 75.88; H 5.12; N 7.06
IR (nujol): 3240, 1750, 1670 cm ^-1 .

300 MHz ¹ H-NMR (DMSO-d ₆ ): δ 9.72 (d, 1H), 8.28 (dd, 2H), 8.20 (dd, 1H), 8.13 (dd. , 1H), 8.11 (s, 1H), 7.83 (ddd, 1H), 7.66 (ddd, 1H), 7.60-7.50 (m, 5H), 7, 47-7.37 (m, 3H), 5.78 (d, 1H), 3.72 (s, 3H).

MS (EI; source 200 ^° C, 70 V, 200 mA): 396 (M +.), 337, 232, 204.

Example. 5
(+) - (S) -N- [α- (methoxycarbonyl) benzyl] -2- phenylquinoline-4-carboxamide
2.0 g (8.0 mmol) of 2-phenylquinoline-4-carboxylic acid was dissolved in a nitrogen atmosphere in 70 ml of dry THF and 30 ml of CH ₃ CN. 1.7 g (8.4 mmol) of methyl phenyl glycinate hydrochloride, 1.1 ml (9.9 mmol) of N-methylmorpholine and 2.1 ml (15.5 mmol) of N-hydroxybenzotriazole (HOBT) were added, and the reaction the mixture was cooled at 0 ^° C. 1.85 g (9.0 mmol) of DCC dissolved in 10 ml of methylene chloride was added dropwise, and the solution was stored at 0-5 ^° C for 1 hour and then at room temperature for 2 hours. The precipitated dicyclohexylurea was filtered off and the solution was evaporated to dryness in vacuo. The residue was dissolved in methylene chloride and washed with water, saturated sodium bicarbonate solution, 5% citric acid, saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic layer was separated, dried over sodium sulfate and evaporated in vacuo to dryness, the residue was dissolved in 20 ml of methylene chloride and left overnight. A further amount of dicyclohexylurea precipitated and was filtered off. The solution was evaporated to dryness in vacuo, and 2.6 g of crude product was obtained, which was triturated with petroleum ether, dissolved, washed with diisopropyl ether, and then recrystallized from 70 ml of isopropanol, giving 1.7 g of the target compound.

C ₂₅ H ₂₀ N ₂ O ₃
Mp = 180 - 181 ^o C
M.V. = 396.45
IR (nujol): 3300, 1750, 1640 cm ^-1
[α] $\genfrac{}{}{0ex}{}{\text{20}}{\text{D}}$ = +42 (C = 0.5 methanol).

¹ H-NMR and MS spectra were identical to the spectra of example 4.

Example 6
(-) - (R) -N- [α- (methoxycarbonyl) benzyl] -2-phenylquinoline-4-carboxamide
It was obtained, as in example 5, from 2.0 g (8.0 mmol) of 2-phenylquinoline-4-carboxylic acid, 1.7 g (8.4 mmol) of (D) methylphenyl glycinate hydrochloride, 1.1 ml (9, 9 mmol) N-methylmorpholine, 2.1 g (15.5 mmol) of HOBT and 1.85 g (9.0 mmol) of DCC in 70 ml of dry THF and 30 ml of CH ₃ CN. Processing of the reaction mixture was carried out in the same manner as described in Example 5. The resulting crude product (3.5 g) was triturated twice with warm diisopropyl ether, filtered, washed, and then recrystallized from 80 ml of isopropanol to give 2.3 g of the target compound.

C ₂₅ H ₂₀ N ₂ O ₃
Mp = 180 - 181 ^o C
M.V. = 396.45
IR (nujol): 3300, 1750, 1640 cm ^-1 .

[α] $\genfrac{}{}{0ex}{}{\text{20}}{\text{D}}$ = -42.0 (C = 0.5 methanol).

¹ H-NMR and MS spectra were identical to the spectra of examples 4 and 5.

Example 7
(R, S) -N- [α- (methoxycarbonyl) benzyl] -7-methoxy-2-phenylquinoline-4-carboxamide
1.0 g (5.0 mmol) of methylphenyl glycinate hydrochloride (D, L) was dissolved in a nitrogen atmosphere in 30 ml of dry DMF. 2.5 g (18.1 mmol) of anhydrous potassium carbonate was added, and the solution was cooled to 0 ^° C. 0.7 g (2.3 mmol) of the compound of description 3 dissolved in 25 ml of dry DMF was added dropwise, and the solution was stored at 0 - 5 ^o C for 1 hour and at room temperature overnight. The reaction mixture was evaporated to dryness in vacuo, and the residue was dissolved in ethyl acetate and washed twice with water. The organic layer was separated, dried over sodium sulfate, filtered and evaporated to dryness in vacuo. The residual oil was flash chromatographed on 230-400 mesh silica gel, eluting with a 3: 2 mixture of hexane and ethyl acetate containing 0.5% ammonium hydroxide to give 0.1 g of crude product, which was triturated with diisopropyl ether to give 0.08 g of the target compound.

C ₂₆ H ₂₂ N ₂ O ₄
Mp = 187 - 190 ^o C
M.V. = 426.48
IR (KBr): 3220, 1750, 1660, 1620 cm ^-1 .

300 MHz ¹ H-NMR (CDCl ₃ ): δ 8.13-8.08 (m, 3H), 7.80 (s, 1H), 7.55 -7.38 (m, 9H), 7.21 (dd, 1H), 7.02 (d. Broad, H), 5.88 (d., 1H), 3.97 (s, 3H), 3.80 (s, 3H) .

MS (EI; source 200 ^° C, 70 V, 200 mA): 426 (M +.), 367, 262, 234, 191, 77.

Example 8
(R, S) -N- [α- (methoxycarbonyl) benzyl] -7-hydroxy-2-phenylquinoline-4-carboxamide
It was obtained, as in example 5, from 2.1 g (5.3 mmol) of the compound of description 4, 1.08 g (5.3 mmol) of methylphenyl glycinate hydrochloride (D, L), 1.5 ml (10.7 mmol) TEA, 1.7 g (12.5 mmol) of HOBT and 1.2 g (5.8 mmol) of DCC in 70 ml of dry THF and 30 ml of CH ₃ CN. Processing of the reaction mixture was carried out in the same manner as described in Example 5. The resulting crude product was triturated with diisopropyl ether and then recrystallized twice from isopropanol to give 0.06 g of the target compound.

C ₂₅ H ₂₀ N ₂ O ₄
Mp = 256 - 257 ^o C
M.V. = 412.45
IR (KBr): 3270, 1750, 1650, 1620 cm ^-1
300 MHz ¹ H-NMR (DMSO-d ₆ ): δ 10.30 (s broad, 1H), 9.64 (d, 1H), 8.22 (d, 2H), 8.04 (d ., 1H), 7.85 (s, 1H), 7.60-7.34 (m, 9H), 7.21 (dd., 1H), 5.74 (d, 1H), 3 71 (s, 3H).

MS (EI; source 200 ^° C, 70 V, 200 mA): 412 (M +.), 353, 248, 220, 77.

Example 9
(R, S) -N- [α- (carboxy) benzyl] -7-methoxy-2-phenylquinoline-4-carboxamide hydrochloride
0.18 g (0.4 mmol) of the product of example 7 was dissolved in 10 ml of 10% HCl and 5 ml of dioxane. The reaction mixture was refluxed and stirred for 3 hours, and then evaporated to dryness in vacuo. The crude product was triturated with warm ethyl acetate (containing a few drops of ethanol) to give 0.16 g of the target compound.

C ₂₅ H ₂₀ N ₂ O ₄ • HCl
Mp = 228-230 ^o C
M.V. = 448.91
IR (KBr): 3180, 1735, 1655, 1630 cm ^-1 .

300 MHz ¹ H-NMR (DMSO-d ₆ ): δ 9.6 (d, 1H), 8.26 (dd, 2H), 8.14 (d, 1H), 7.98 (s. , 1H), 7.63-7.52 (m, 6H), 7.46-7.36 (m, 3H), 7.33 (dd, 1H), 5.66 (d, 1H) ), 3.98 (s, 3H).

MS (EI; source 200 ^° C, 70 V, 200 mA): 412 (M +.), 368, 262, 234, 191, 77.

Example 10
(R, S) -N- [α- (methylaminocarbonyl) benzyl] -2- phenylquinoline-4-carboxamide
0.45 g (1.1 mmol) of the product of example 4 was dissolved in 40 ml of a mixture of 33% MeNH ₂ / EtOH, a catalytic amount of NaCN was added, and the reaction mixture was heated at 70 ^° C for 1 hour in a Parr apparatus. Internal pressure rose to 40 lb / ⁱⁿ² (2,812 kg / cm ^2). The solution was evaporated to dryness in vacuo, and the residue was triturated with water, filtered and recrystallized from a mixture of isopropanol (50 ml) and ethanol (30 ml), giving 0.2 g of the target compound.

C ₂₅ H ₂₁ N ₃ O ₂
Mp = 261 - 263 ^o C
M.V. = 395.47
Elemental analysis: Calculated C 75.93; H 5.35; N 10.63
Found C 75.65; H 5.34; N 10.55
IR (KBr): 3300, 3270, 1660, 1635 cm ^-1
300 MHz ¹ H-NMR (DMSO-d ₆ ): δ 9.48 (d, 1H), 8.33-8.25 (M., 3H), 8.18-8.10 (m, 3H ), 7.80 (ddd, 1H), 7.68-7.50 (m, 6H), 7.40-7.28 (m, 3H), 5.75 (d, 1H), 2.63 (d, 3H).

MS (EI; source 200 ^° C, 70 V, 200 mA): 395 (M +.), 337, 232, 204, 77.

Example 11
(R, S) -N- [α- (methoxycarbonyl) benzyl] -2- (2-thienyl) quinoline-4-carboxamide
It was obtained, as in example 5, from 2.0 g (7.3 mmol) of 2- (2-thienyl) quinoline-4-carboxylic acid, 1.7 g (8.4 mmol) of (D, L) methylphenyl glycinate hydrochloride, 1.1 ml (10 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 dry THF, 30 ml of methyl cyanide and 10 ml of methylene chloride. Processing of the reaction mixture was carried out in the same manner as described in example 5. The resulting crude product crystallized from ethyl acetate and then recrystallized from absolute ethanol, giving 0.9 g of the target compound.

C ₂₃ H ₁₈ N ₂ O ₃ S
Mp = 178 - 180 ^o C
M.V. = 402.47
Elemental analysis: Calculated C 68.64; H 4.51; N 6.96
Found C, 67.50; H 4.99; N, 7.43
IR (KBr): 3300, 1745, 1645 cm ^-1 .

300 MHz ¹ H-NMR (DMSO-d ₆ ): δ 9.70 (d, 1H), 8.12 (d, 1H), 8.08 (s, 1H), 8.04 (d. , 1H), 8.02 (d, 1H), 7.19 (t, 1H), 7.76 (d, 1H), 7.62 (t, 1H), 7.53 (d. , 2H), 7.46-7.37 (m, 3H), 7.3 (dd, 1H), 5.68 (d, 1H), 3.68 (s, 3H).

MC (EI; source 200 ^° C, 70 V, 200 mA): 402 (M +.), 343, 238, 210, 77.

Example 12
(R, S) -N- [α- (methoxycarbonyl) benzyl] -2- (2-furyl) quinoline-4-carboxamide
It was obtained, as in Example 1, from 7.2 g (35.5 mmol) of methyl phenyl glycinate hydrochloride (D, L), 12.4 ml (88.8 mmol) of TEA and 9.1 g (35.5 mmol) of crude 2 - (2-furyl) quinoline-4-carbonyl chloride in 350 ml of a mixture of methylene chloride, methyl cyanide and DMF. Processing of the reaction mixture was carried out in the same manner as described in example 1. The resulting crude product was triturated with methanol to give 3.3 g of the target compound.

C ₂₃ H ₁₈ N ₂ O ₄
Mp = 178-180 ^o C
M.V. = 386,405
Elemental analysis: Calculated C 71.49; H 4.70; N 7.25
Found C, 71.67; H 4.74; N, 7.17.

IR (KBr): 3300, 1750, 1650 cm ^-1 .

300 MHz ¹ H-NMR (DMSO-d ₆ ): δ 9.72 (d, 1H), 8.12 (d, 1H), 8.06 (d, 1H), 7.96 (dd. , 1H), 7.92 (s, 1H), 7.80 (ddd, 1H), 7.62 (ddd, 1H), 7.52 (dd, 2H), 7.45-7, 35 (m, 4H), 6.73 (dd, 1H), 5.77 (d, 1H), 3.74 (s, 3H).

MS (EI; source 200 ^° C, 70 V, 200 mA): 386 (M +.), 327, 222, 194, 77.

Example 13
(R, S) -N- [α- (methoxycarbonyl) benzyl] -2- (4-pyridyl) quinoline-4-carboxamide
It was obtained, as in Example 1, from 3.4 g (16.7 mmol) of methyl phenyl glycinate hydrochloride (D, L), 3.9 ml (27.8 mmol) of TEA and 3.0 g (11.1 mmol) of 2- (4-pyridyl) quinoline-4-carbonyl chloride in 100 ml of a mixture of methylene chloride, methyl cyanide and DMF. Processing of the reaction mixture was carried out in the same manner as described in example 1. The resulting crude product was recrystallized three times from ethyl acetate, giving 1.9 g of the target compound.

C ₂₄ H ₁₉ N ₃ O ₃
Mp = 172 - 174 ^o C,
M.V. = 397.43
Elemental analysis: C, 72.53; H 4.82; N 10.57
Found C, 71.87; H 4.87; N 10.44
IR (KBr): 3240, 1750, 1670 cm ^-1 .

300 MHz ¹ H-NMR (DMSO-d ₆ ): δ 9.74 (d, 1H), 8.79 (dd, 2H), 8.27-8.17 (m, 5H), 7, 89 (ddd, 1H), 7.74 (ddd, 1H), 7.54 (dd, 2H), 7.47-7.38 (m, 3H), 5.8 (d, 1H) ), 3.75 (s, 3H).

MS (EI; source 200 ^° C, 70 V, 200 mA): 397 (M +.), 338, 233, 205, 77.

Example 14
(R, S) -N- [α- (methoxycarbonyl) -2-thienylmethyl] -2- phenylquinoline-4-carboxamide
It was obtained, as in example 1, from 1.94 g (9.4 mmol) of methylphenyl glycinate hydrochloride (D, L), 2.7 ml (19.5 mmol) of TEA and 2.0 g (7.8 mmol) of 2- phenylquinoline-4-carbonyl chloride in 100 ml of a mixture of methylene chloride, methyl cyanide and DMF. Processing of the reaction mixture was carried out in the same manner as described in example 1. The resulting crude product was recrystallized three times from ethyl acetate, giving 0.66 g of the target compound.

C ₂₃ H ₁₈ N ₂ O ₃ S
Mp = 144 - 145 ^o C
M.V. = 402.47
Elemental analysis: Calculated C 68.64; H 4.51; N 6.96
Found C, 68.81; H 4.46; N, 6.96.

IR (KBr): 3295, 1745, 1640 cm ^-1 .

300 MHz ¹ H-NMR (DMSO-d ₆ ): δ 8.25 (dd, 1H), 8.22 (dd, 1H), 8.17 (dd, 2H), 7.95 (s. , 1H), 7.78 (ddd, 1H), 7.60 (ddd, 1H), 7.56-7.45 (m, 3H), 7.35 (dd, 1H), 7.20 (d, 1H), 7.05 (dd, 1H), 7.05 (s. broad, 1H), 6.22 (d, 1H), 3.9 (s, 3H).

MS (EI; source 200 ^° C, 70 V, 200 mA): 402 (M +.), 343, 232, 204.

Example 15
(R, S) -N- [α- (methoxycarbonylmethyl) benzyl] -2- phenylquinoline-4-carboxamide
It was obtained, as in example 5, from 1.39 g (5.60 mmol) of 2-phenylquinoline-4-carboxylic acid, 1.2 g (5.60 mmol) of (R, S) methyl-3-amino-3 hydrochloride -phenylpropionate, 0.78 ml (5.60 mmol) of TEA, 1.51 g (11.2 mmol) of HOBT and 2.31 g (11.2 mmol) of DCC in 10 ml of THF, 4 ml of CH ₃ CN and 7 ml of methylene chloride. Processing of the reaction mixture was carried out in the same manner as described in Example 5. The resulting crude product was dissolved in methylene chloride and left overnight at 0 ^° C. Some more dicyclohexylurea precipitated and was filtered off. The solution was evaporated to dryness in vacuo to give 1.4 g of a crude product, which was triturated with a mixture of diisopropyl ether and acetone 99: 1, to give 1.2 g of the target compound as a white solid.

C ₂₆ H ₂₂ N ₂ O ₃
Mp = 156 - 158 ^o C
M.V. = 410.47
Elemental analysis: Calculated C 76.07; H 5.40; N 6.82
Found C 75.77; H 5.38; N, 6.94.

IR (KBr): 3295, 1755, 1645, 1590, 1530 cm ^-1 .

300 MHz ¹ H-NMR (DMSO-d ₆ ): δ 9.40 (d, 1H), 8.29 (dd, 2H), 8.14 (d, 1H), 8.07 (d. , 1H), 8.04 (s, 1H), 7.83 (ddd, 1H), 7.66-7.52 (m, 4H), 7.50 (d, 2H), 7.40 (dd, 2H), 7.31 (ddd., 1H), 5.60 (dt, 1H), 3.65 (s, 3H), 3.40-2.89 (m, 2H).

MS (EI; source 200 ^° C, 70 V, 200 mA): 410 (M +.), 337, 233, 205.

 The compounds of examples 16-49 of the general formula (I) (see table 2) were synthesized based on the corresponding acyl chlorides of compounds (II) and amines (III) shown in the table and following the synthesis procedure described in example 1. Acyl chlorides were synthesized based on from the corresponding acid of formula (II) and following the description 1. The yields from the reaction are calculated on purified, but not recrystallized material. Analytical and spectroscopic data of the compounds of examples 16-49 are shown in table 5.

 The compounds of examples 50-88 of the general formula (I) (see table 3) were synthesized based on the corresponding reagents (II) and (III) shown in the table and following the synthesis procedure described in example 5. The reaction yields were calculated for purified but non-recrystallized substance. Analytical and spectroscopic data of the compounds of examples 50-88 are shown in table 5.

 The compounds of examples 89-92 of general formula (I) (see table 4) were synthesized starting from other compounds of formula (I) (i.e., compounds of formula Ic) and following the synthesis procedure described in example 10 (for compounds of examples 89, 90 and 91) and in Example 9 (for the compound of Example 92). The reaction yields are calculated on purified but non-recrystallized material. Analytical and spectroscopic data of the compounds of examples 89-92 are shown in table 5.

The conventions in Table 5 have the following meanings:
IR = IR (infrared)
cm = cm
MHz = MHz
¹ H NMR = NMR
DMSO = DMSO
Calcd. = calculated
Found = found
d = d. (doublet or double)
dd = dd (double doublet)
s = s. (singlet)
br = wide
m = m. (multiplet)
q = sq. (quartet)
t = t. (triplet)
Example 93
(R, S) -N- [α- (methoxycarbonyl) benzyl] -2- (p-chlorophenyl) quinoline-4-carboxamide
2 g (7.0 mmol) of 2- (p-chlorophenyl) quinoline-4-carboxylic acid and 1.7 ml (15.4 mmol) of N-methylmorpholine were dissolved in a nitrogen atmosphere in 50 ml of dry THF. The solution was cooled to -20 ^° C, and 0.91 ml (7.0 mmol) of isobutyl chloroformate was added. After 20 minutes, 2.12 g (10.5 mmol) of methyl (R, S) phenyl glycinate hydrochloride and 1.3 ml (11.9 mmol) of N-methylmorpholine dissolved in 30 ml of dry THF were added and the reaction mixture was stirred at room temperature temperature during the night. Then 5 ml of H ₂ O was added and the reaction mixture was evaporated to dryness in vacuo. The residue was dissolved in Et ₂ O, washed with saturated NaHCO ₃ solution, separated, dried over sodium sulfate and evaporated to dryness in vacuo. The residual oil was flash chromatographed on a 230-400 mesh silica gel column, eluting with a 7: 3 hexane / isopropyl ether mixture to give 0.9 g of a crude product, which was recrystallized three times with iso-PrO ₂ / toluene, giving 0.5 g target compound.

C ₂₅ H ₁₉ ClN ₂ O ₃
Mp = 170-172 ^o C
M.V. = 430.90
Elemental analysis: Calculated C 69.72; H 4.45; N 6.50
Found C, 69.82; H 4.47; N, 6.48
I.K. (KBr): 3280; 1740; 1670; 1635; 1590; 1530 cm ^-1 .

300 MHz ¹ H-NMR (DMSO-d ₆ ): δ 9.71 (d, 1H); 8.32 (d, 2H); 8.21 (d, 1H); 8.13 (d, 1H); 8.13 (s, 1H); 7.85 (dd, 1H); 7.67 (dd, 1H); 7.63 (d, 2H); 7.53 (dd, 2H); 7.46-7.38 (m, 3H); 5.79 (d, 1H); 3.74 (s, 3H).

MS (EI; source 200 ^° C; 70 eV; 200 μA): 430 (M +.); 371; 266; 238; 203.

Example 94
(R) -N- [α- (methoxycarbonyl) -4-methoxybenzyl] -2-phenylquinoline-4-carboxamide
0.62 g (1.5 mmol) of (R) -N [α- (methoxycarbonyl) -4-hydroxybenzyl] -2-phenylquinoline-4-carboxamide (compound of Example 83) was dissolved in 30 ml of dry acetone and 2 ml of dry DMF then 0.14 g (0.75 mmol) of K ₂ CO _{3 was} added and the reaction mixture was stirred for 30 minutes. At room temperature, 0.093 ml (1.5 mmol) of methyl iodide was added and the reaction mixture was heated at 40 ^° C. for 4 hours. Then, 0.104 g (0.75 mmol) of K ₂ CO ₃ and 0.093 ml (1.5 mmol) of methyl iodide were added again, and the mixture was heated under reflux for an additional 6 hours. The mixture was evaporated to dryness in vacuo, dissolved in EtOAc and washed with water. The organic layer was dried over sodium sulfate and evaporated to dryness in vacuo. The residue was recrystallized from Et ₂ O, giving 0.45 g of the target compound.

C ₂₆ H ₂₂ N ₂ O ₄
Mp = 160-162 ^o C
M.V. = 426.48
Elemental analysis: Calculated C 73.22; H 5.20; N 6.57
Found C, 73.01; H 5.20; N, 6.48
I.K. (KBr): 3210; 1750; 1635; 1625; 1590; 1530; 1515 cm ^-1
300 MHz ¹ H-NMR (DMSO-d ₆ ): δ 9.65 (d, 1H); 8.28 (d, 2H); 8.21 (d, 1H); 8.14 (d, 1H); 8.10 (s, 1H); 7.84 (dd, 1H); 7.67 (dd, 1H); 7.61-7.49 (m, 3H); 7.44 (d, 2H); 6.98 (d, 2H); 4.70 (d, 1H); 3.79 (s, 3H); 3.76 (s, 3H).

MS (EI; source 200 ^° C; 70 eV; 200 μA): 426 (M +.); 367; 232; 204.

Example 95
(R, S) -N- [α- (methoxycarbonyl) - α- (methyl) benzyl] -N-methyl-2-phenylquinoline-4-carboxamide hydrochloride
0.50 g (1.3 mmol) of (R, S) -N- [α- (methoxycarbonyl) benzyl] -2-phenylquinoline-4-carboxamide (compound of Example 4) was dissolved in 10 ml of dry DMF in a nitrogen atmosphere. The solution was cooled to 0 ^° C. and 0.052 g (1.3 mmol) of NaH (60%) was added; after 20 minutes at 0 ^° C., the temperature rose to room temperature and 0.09 ml (1.4 mmol) of MeI was added. The reaction mixture was stirred at room temperature overnight, then the procedure was repeated with the addition of an additional 0.052 g (1.3 mmol) of NaH (60%) and 0.1 ml (1.6 mmol) of MeI. After 6 hours at room temperature, 10 ml of a saturated solution of NH ₄ Cl was added and the reaction mixture was evaporated to dryness in vacuo. The residue was dissolved in CH ₂ Cl ₂ and washed with water; the organic layer was separated, dried over sodium sulfate and evaporated to dryness in vacuo. The residual oil was flash chromatographed on a 230-400 mesh silica gel column, eluting with a 3: 2 hexane / ethyl acetate mixture containing 0.5% conc. NH ₄ OH, giving 0.18 g of a crude product, which was dissolved in Et ₂ O and treated with a mixture of HCl / Et ₂ O, giving 0.15 g of the target compound.

C ₂₇ H ₂₄ N ₂ O ₃ • HCl
M.V. = 460.96
I.K. (KBr): 1745; 1640; 1610 cm ^-1 .

MS (EI; source 200 ^° C; 70 eV; 200 μA): 424 (M +.); 365; 232; 204.

Example 96
(R, S) -N- [α- (methylcarbonyl) benzyl] -2-phenylquinoline-4-carboxamide
0.27 ml (3.1 mmol) of oxalyl chloride was dissolved in 2.3 ml of dry CH ₂ Cl ₂ in a nitrogen atmosphere. The solution was cooled to -55 ^° C, and 0.22 ml (3.1 mmol) was added dropwise. DMSO dissolved in 0.7 ml of dry CH ₂ Cl ₂ while maintaining the temperature below -50 ^o C. The reaction mixture was stirred at -55 ^o C for 7 minutes, then 0.97 g (2.5 mmol) was added (R , S) -N- [α- (1-hydroxyethyl) benzyl] -2-phenylquinoline-4-carboxamide (compound of Example 17) dissolved in 25 ml of dry CH ₂ Cl ₂ while maintaining the temperature between -50 and -55 ^o C After 30 minutes at -55 ^° C, 1.9 ml (13.6 mmol) of TEA was added without exceeding -40 ^° C, then the reaction mixture was allowed to reach room temperature and it was stirred for an additional 15 minutes. The reaction was quenched with 5 ml of water and extracted with CH ₂ Cl ₂ ; the organic layer was washed with water, 20% citric acid, saturated NaHCO ₃ solution and brine; the organic layer was separated, dried over sodium sulfate and evaporated to dryness in vacuo. The residual oil was flash chromatographed on a 230-400 mesh silica gel column, eluting with a 70:30 hexane / ethyl acetate mixture containing 0.5% conc. NH ₄ OH, giving 0.64 g of a crude product, which was triturated with a warm mixture of iso-Pr ₂ O / iso-PrOH 2: 1, was filtered and dried, giving 0.5 g of the target compound.

C ₂₅ H ₂₀ N ₂ O ₂
Mp = 160-161 ^o C
M.V. = 380.45
Elemental analysis: C, 78.93; H 5.30; N, 7.36
Found C, 79.01; H 5.31; N 7.27
I.K. (KBr): 3400; 3265; 1725; 1660; 1640; 1592 cm ^-1 .

300 MHz ¹ H-NMR (DMSO-d ₆ ): δ 9.60 (d, 1H); 8.29 (d, 2H); 8.17 (d, 1H); 8.14 (d, 1H); 8.12 (s, 1H); 7.82 (dd, 1H); 7.65 (dd, 1H); 7.61-7.51 (m, 5H); 7.48-7.36 (m, 3H); 2.19 (s, 3H).

MS (EI; source 200 ^° C; 70 eV; 200 μA): 380 (M +.); 337; 232; 204.

Example 97
(R, S) -N- [α- (2-hydroxyethyl) benzyl] -2-phenylquinoline-4-carboxamide
0.7 g (1.7 mmol) of (R, S) -N- [α- (methoxycarbonylmethyl) benzyl] -2-phenylquinoline-4-carboxamide (compound of Example 15) was dissolved in 50 ml of tert-BuOH and 2 ml of MeOH in an atmosphere of nitrogen. 60 mg (1.6 mmol) of NaBH _{4 was} added to the boiling solution over 15 minutes. The reaction mixture was refluxed for 6 hours, quenched with 5 ml of a saturated solution of NH ₄ Cl and then evaporated to dryness in vacuo. The residue was dissolved in CH ₂ Cl ₂ and washed with brine; the organic layer was separated, dried over sodium sulfate and evaporated to dryness in vacuo. The crude product was flash chromatographed on a 230-400 mesh silica gel column, eluting with Et ₂ O containing 0.5% conc. NH ₄ OH, and then crystallized from iso-PrOH, giving 0.19 g of the target compound.

C ₂₅ H ₂₂ N ₂ O ₂
Mp = 167-169 ^o C
M.V. = 382.47
Elemental analysis: Calculated C 78.52; H 5.80; N, 7.32
Found C, 78.49; H 5.79; N 7.29
I.K. (KBr): 3360; 1650; 1592 cm ^-1 .

300 MHz ¹ H-NMR (DMSO-d ₆ ): δ 9.30 (d, 1H); 8.31 (d, 2H); 8.13 (d, 1H); 8.10 (s, 1H); 8.03 (d, 1H); 7.81 (dd, 1H); 7.64-7.51 (m, 4H); 7.46 (d, 2H); 7.39 (dd, 2H); 7.29 (dd, 1H); 5.30 (dt, 1H); 4.61 (t, 1H); 3.61-3.41 (m, 2H); 2.11-1.86 (m, 2H).

MS (EI; source 200 ^° C; 70 eV; 200 μA): 382 (M +.); 337; 232; 204.

Example 98
Hydrochloride (S) -N- ( ethylbenzyl) -3- (2-dimethylaminoethoxy) -2-phenylquinoline-4-carboxamide
0.62 g (1.6 mmol) of (S) -N- (α-ethylbenzyl) -3-hydroxy-2-phenylquinoline-4-carboxamide (compound of Example 85) was dissolved in 30 ml of dry DMF. Then, 0.58 g (4.0 mmol) of dimethylaminoethyl chloride hydrochloride and 0.56 g (4.0 mmol) of K ₂ CO ₃ were added, and the reaction mixture was heated under reflux for 20 hours. K ₂ CO _{3 was} filtered off and the mixture was evaporated to dryness in vacuo, dissolved in AcOEt and washed with water and 20% citric acid. The aqueous layer was basified with 2 norms. NaOH and extracted with EtOAc; the organic layer was washed with brine, separated, dried over sodium sulfate and evaporated to dryness in vacuo. The residue was subjected to flash chromatography on a silica gel column with 230-400 holes, eluting with a mixture of CH ₂ Cl ₂ / MeOH 98: 2 containing 0.4% conc. NH ₄ OH, and then with a mixture of CH ₂ Cl ₂ / MeOH 86: 10 containing 0.6% conc. NH ₄ OH, giving 85 mg of a crude product, which was dissolved in EtOAc and treated with a mixture of HCl / Et ₂ O to obtain 75 mg of the target compound.

C ₂₉ H ₃₁ N ₃ O ₂ • HCl
Mp = 70 ^o C decom.

M.V. = 490.05
I.K. (nujol): 3600; 3100; 1650: 1550 cm ^-1 .

300 MHz ¹ H-NMR (DMSO-d ₆ ): δ 10.28 (br s, 1H); 9.50 (d, 1H); 8.10 (d, 1H); 7.96 (dd, 2H); 7.78 (m, 1H); 7.67-7.61 (m, 2H); 7.61-7.51 (m, 3H); 7.49-7.39 (m, 4H); 7.33 (dd, 1H); 5.08 (dt, 1H); 3.90 (t, 2H); 2.96 (dt, 2H); 2.49 (s, 6H); 1.85 (m, 2H); 0.97 (t, 3H).

MS (FAB POS., Thioglycerol matrix, Xe gas, 8 KeV, source 50 ^° C): 454 (MH +).

Example 99
(S) -N- (α-ethylbenzyl) -3-acetylamino-2-phenylquinoline-4-carboxamide
0.40 g (1.05 mmol) of (S) -N- (α-ethylbenzyl) -3-amino-2-phenylquinoline-4-carboxamide (compound of Example 69) was heated in 25 ml of acetic anhydride at 70 ^° C. for 1 hour and then at 100 ^o C for an additional 3 hours. The reaction mixture was then evaporated to dryness in vacuo, and the residue was dissolved in EtOAc; the solution was washed with water, saturated NaHCO ₃ solution, brine, dried over sodium sulfate and evaporated to dryness in vacuo. The crude product (0.39 g) was purified by flash chromatography on a silica gel column, eluting with hexane / EtOAc / conc. NH ₄ OH 70: 30: 0.5, respectively, giving 0.2 g of pure compound, which was recrystallized from acetone, giving 0.14 g of the target compound.

C ₂₇ H ₂₅ N ₃ O ₂
Mp = 268-269 ^o C
M.V. = 423.52
Elemental analysis: C, 76.57; H 5.95; N 9.92
Found C, 76.38; H 5.98; N, 9.90.

I.K. (KBr): 3230, 1670, 1640, 1555, 1525 cm ^-1
300 MHz ¹ H-NMR (DMSO-d ₆ ): δ 9.65 (s, 1H), 9.05 (d, 1H), 8.10 (d, 1H), 7.80 (t. , 1H), 7.70-7.50 (m, 4H), 7.45-7.20 (m, 8H), 5.08 (dt, 1H), 1.85 (m, 2H) ), 1.60 (s, 3H), 0.97 (t, 3H).

MS (EI; source 200 ^° C, 70 eV, 200 μA): 423 (M +.), 381, 334, 289, 261, 247, 218.

Example 100
(-) - (S) -N- (α-ethylbenzyl) -3- (3-dimethylaminopropoxy) -2-phenylquinoline-4-carboxamide hydrochloride
1.2 g (3.1 mmol) (-) - (S) -N- (α-ethylbenzyl) -3-hydroxy-2-phenylquinoline-4-carboxamide (compound of Example 85) was dissolved in 15 ml of dry THF. 1.0 g (8.2 mmol) of 3-dimethylaminopropyl chloride dissolved in 10 ml of Et ₂ O, 1.3 g (9.4 mmol) of K ₂ CO ₃ and 0.16 g of KI were added, and the reaction mixture was stirred at room temperature for 30 minutes and then refluxed for 2 hours. Then, every 12 hours, 0.77 g (6.3 mmol), 1.0 g (8.2 mmol), 0.6 g (4.9 mmol) and an additional 0.6 g (4.9 mmol) were added 3 -dimethylaminopropyl chloride, each time dissolved in 10 ml of Et ₂ O, and a little KI, and the reaction mixture was heated under reflux. K ₂ CO _{3 was} filtered off and the mixture was evaporated to dryness in vacuo, dissolved in EtOAc and washed with water and 20% citric acid. The aqueous layer was basified with 2 norms. NaOH and extracted with EtOAc; the organic layer was washed with brine, separated, dried over sodium sulfate and evaporated to dryness in vacuo. The residue was flash chromatographed on a 230-400 mesh silica gel column, eluting with a CH ₂ Cl ₂ / MeOH 95: 5 mixture containing 0.5% conc. NH ₄ OH, giving 0.9 g of a crude product, which was dissolved in EtOAc and treated with a mixture of HCl / Et ₂ O, giving 0.62 g of the target compound.

C ₃₀ H ₃₃ N ₃ O ₂ • HCl,
Mp = 108 ^o C decomp.

M.V. = 504.08
[α] $\genfrac{}{}{0ex}{}{\text{20}}{\text{D}}$ = - 16.0 (s = 0.5, MeOH)
I.K. (KBr): 3400, 3080, 1655, 1545 cm ^-1 .

300 MHz ¹ H-NMR (DMSO-d ₆ ): δ 10.55 (br s, 1H), 9.35 (d, 1H), 8.09 (d, 1H), 7.92 ( dd., 2H), 7.76 (ddd., 1H), 7.65-7.51 (m, 5H), 7.48-7.40 (m, 4H), 7.31 (dd. , 1H), 5.10 (dt, 1H), 3.72-3.62 (m, 2H), 2.75-2.60 (m, 2H), 2.58 (d, 3H) ), 2.56 (d, 3H), 1.90-1.67 (m, 4H), 1.00 (t, 3H).

MS (EI; source 180 ^° C, 70 V, 200 mA): 467 (M +.), 466, 395, 58.

Example 101
(-) - (S) -N- (α-ethylbenzyl) -3- [2- (1-phthaloyl) ethoxy] -2-phenylquinoline-4-carboxamide hydrochloride
1.9 g (5.0 mmol) of (-) - (S) -N- (α-ethylbenzyl) -3-hydroxy-2-phenylquinoline-4-carboxamide (compound of Example 85) was dissolved in 20 ml of dry THF. 3.8 g (14.9 mmol) of 2-phthalimidoethyl bromide dissolved in 15 ml of THF, 2.0 g (14.5 mmol) of K ₂ CO ₃ and 0.25 g of KI were added and the reaction
the mixture was stirred at room temperature for 2.5 hours and then heated under reflux for 2 hours. Then 1.9 g (7.4 mmol) of 2-phthalimidoethyl bromide and a little KI were added, and the reaction mixture was heated under reflux for an additional 3.5 hours. Again, 0.5 g (2.0 mmol) of 2-phthalimidoethyl bromide and a little KI were added, and the mixture was refluxed for 5 hours. K ₂ CO _{3 was} filtered off and the mixture was evaporated to dryness in vacuo, dissolved in CH ₂ Cl ₂ and washed with water. The organic layer was dried over sodium sulfate and evaporated to dryness in vacuo. The residue was flash chromatographed on a 230-400 mesh silica gel column, eluting with a hexane / EtOAc 80:20 mixture containing 0.5% conc. NH ₄ OH and then with a mixture of hexane / EtOAc 60:40 containing 0.5% conc. NH ₄ OH, giving 2.6 g of a purified product, which was triturated with iso-Pr ₂ O, giving 2.5 g of the target compound.

C ₃₅ H ₂₉ N ₃ O ₄
Mp = 172 - 175 ^o C
M.V. = 555.64
[α] $\genfrac{}{}{0ex}{}{\text{20}}{\text{D}}$ = -16.3 (s = 0.5 MeOH)
I.K. (KBr): 3280, 3060, 2960, 1780, 1715, 1660, 1530 cm ^-1 .

300 MHz ¹ H-NMR (DMSO-d ₆ ): δ 9.27 (d, 1H), 8.03 (d, 1H), 7.92-7.84 (m, 4H), 7, 78-7.69 (m, 3H), 7.60-7.53 (m, 2H), 7.46-7.38 (m, 4H), 7.27 (dd, 1H), 7.13-7.04 (m, 3H), 4.96 (dt, 1H), 3.92-3.78 (m, 2H), 3.72-3.55 (m, 2H) ), 1.78 (q. Q., 2H), 0.93 (t, 3H).

MS (EI; source 180 ^o C, 70 V, 200 mA): 555 (M +.), 526, 421, 174.

Example 102
(-) - (S) -N- (α-ethylbenzyl) -3- (2-aminoethoxy) -2-phenylquinoline-4-carboxamide hydrochloride
2.2 g (3.9 mmol) of (-) - (S) -N- [α-ethylbenzyl) -3- [2- (1-phthaloyl) ethoxy] -2-phenylquinoline-4-carboxamide hydrochloride (compound of Example 101) was dissolved in 150 ml of 96% EtOH, and 0.38 ml (7.8 mmol) of hydrazine hydrate was added to the boiling solution, and the solution was heated under reflux for 4 hours. Then, every 12 hours, 0.4 ml (8.2 mmol), 0.2 ml (4.1 mmol), 0.2 ml (4.1 mmol), 0.4 ml (8.2 mmol) were added and 0.4 ml (8.2 mmol) of hydrazine hydrate and the reaction mixture was maintained under reflux. The reaction mixture was then evaporated to dryness in vacuo, dissolved in 20 ml of water, cooled and acidified with 10 ml of conc. HC1. The mixture was boiled for 1 hour and cooled, the phthalhydrazide was filtered off. The aqueous layer was washed with EtOAc and then basified with 2 norms. NaOH and extracted with EtOAc, the organic layer was washed with brine, separated, dried over sodium sulfate and evaporated to dryness in vacuo. The residue was chromatographed on a 230-400 mesh silica gel column, eluting with EtOAc / MeOH 96: 4 containing 1.2% conc. NH ₄ OH, giving a purified product that was dissolved in EtOAc and treated with a mixture of HCl / Et ₂ O, giving 1.2 g of the target compound.

C ₂₇ H ₂₇ N ₃ O ₂ • HCl
Mp = 119 ^o C decomp.

M.V. = 462.00
[α] $\genfrac{}{}{0ex}{}{\text{20}}{\text{D}}$ = -19.4 (c = 0.5 MeOH)
I.K. (KBr): 3400, 3080, 1640, 1545 cm ^-1
300 MHz ¹ H-NMR (DMSO-d ₆ ): δ 9.45 (d, 1H), 8.09 (d, 1H), 8.00 (dd, 1H), 7.94 (br. s., 3H), 7.76 (ddd., 1H), 7.65-7.51 (m, 4H), 7.48-7.40 (m, 3H), 7.31 (dd. , 1H), 5.09 (dt, 1H), 3.83 (t, 2H), 2.72 (m, 2H), 1.93-1.80 (m, 2H), 0, 99 (t, 3H).

MS (FAB POS, thioglycerol matrix, Xe gas, 8 keV, source 50 ^° C.): 426 (MH +).

Example 103
(+) - (S) -N- (α-ethylbenzyl) -3- [2- (1-pyrrolidinyl) ethoxy] -2-phenylquinoline-4-carboxamide hydrochloride
2.0 g (5.2 mmol) of (-) - (S) -N- (α-ethylbenzyl) -3-hydroxy-2-phenylquinoline-4-carboxamide (compound of Example 85) was dissolved in 25 ml of dry THF. 1.0 g (7.5 mmol) of 2-pyrrolidinoethyl chloride and 2.2 g (15.9 mmol) of K ₂ CO _{3 were} added and the reaction mixture was stirred at room temperature for 30 minutes and then refluxed to boiling 1.1 g (8.2 mmol) of 2-pyrrolidinoethyl chloride was added to the solution, and the solution was heated under reflux overnight. K ₂ CO _{3 was} filtered off and the mixture was evaporated to dryness in vacuo, dissolved in EtOAc and washed with water and 20% citric acid. The aqueous layer was basified with 2 norms. NaOH and extracted with EtOAc, the organic layer was washed with brine, separated, dried over sodium sulfate and evaporated to dryness in vacuo. The residue was flash chromatographed on 230-400 mesh silica gel, eluting with CH ₂ Cl ₂ / MeOH 97: 3 containing 0.5% conc. NH ₄ OH, giving 1.8 g of a purified product, which was dissolved in EtOAc and treated with a mixture of HCl / Et ₂ O, giving 2.0 g of the target compound.

C ₃₁ H ₃₃ N ₃ O ₂ • HCl
Mp = 110 - 115 ^o C (decomp.)
M.V. = 516.08
[α] $\genfrac{}{}{0ex}{}{\text{20}}{\text{D}}$ = +4.5 (c = 0.5 MeOH)
I.K. (KBr): 3400, 3080, 1655, 1545 cm ^-1 .

300 MHz ¹ H-NMR (DMSO-d ₆ ): δ 10.50 (br s, 1H), 9.50 (d, 1H), 8.10 (d, 1H), 7.96 ( dd., 2H), 7.78 (ddd., 1H), 7.68-7.30 (m, 10H), 5.10 (dt, 1H), 3.90 (m, 2H), 3.20 (m, 2H), 3.00 (m, 2H), 2.65 (m, 2H), 1.95-1.65 (m, 6H), 1.94 (t. , 3H).

MS (EI; source 180 ^° C, 70 V, 200 mA): 479 (M +.), 478, 383, 97.84.

Example 104
(-) - (S) -N- (α-ethylbenzyl) -3- (dimethylaminoacetylamino) -2- phenylquinoline-4-carboxamide
1.1 g (2.8 mmol) (-) - (S) -N- (α-ethylbenzyl) -3-amino-2-phenylquinoline-4-carboxamide (compound of Example 69) was dissolved in 10 ml of warm toluene in the atmosphere nitrogen. 0.96 g (5.6 mmol) of chloroacetic anhydride dissolved in 5 ml of toluene was added dropwise to the solution, and the solution was heated under reflux for 1 hour. The reaction mixture was evaporated to dryness in vacuo, suspended in 10 ml of CH ₂ Cl ₂ and poured dropwise into 5 ml of ice-cold 28% Me ₂ NH / EtOH mixture. The solution was stirred at room temperature overnight, then 15 ml of a mixture of 28% Me ₂ NH / EtOH was added, and the reaction mixture was heated at 60 ^° C. in a Parr apparatus. The mixture was evaporated to dryness in vacuo, dissolved in 20% citric acid and washed with EtOAc. The aqueous layer was basified with 2 norms. NaOH and extracted with EtOAc, the organic layer was washed with brine, separated, dried over sodium sulfate and evaporated to dryness in vacuo to give 1.4 g of a crude product. This product was triturated with warm iso-Pr ₂ O, giving 0.86 g of the target compound.

C ₂₉ H ₃₀ N ₄ O ₂
Mp = 189 - 191 ^o C
M.V. = 466.59
[α] $\genfrac{}{}{0ex}{}{\text{20}}{\text{D}}$ = -63.1 (c = 0.5 MeOH)
I.K. (KBr): 3230, 3180, 1670, 1630, 1540 cm ^-1 .

300 MHz ¹ H-NMR (DMSO-d ₆ ): δ 9.41 (s, 1H), 8.97 (d, 1H), 8.08 (d, 1H), 7.81 (dd. , 1H), 7.70-7.59 (m, 4H), 7.49-7.26 (m, 8H), 5.00 (dt, 1H), 2.55 (s, 2H) ), 1.97 (s, 3H), 1.90-1.65 (m, 2H), 0.93 (t, 3H).

MS (EI; source 180 ^° C, 70V, 200 mA): 466 (M +.), 331, 58.

Example 105
N- (α, α-dimethylbenzyl) -3-hydroxy-2-phenylquinoline-4-carboxamide
2.0 g (7.5 mmol) of 3-hydroxy-2-phenylquinoline-4-carboxylic acid in a nitrogen atmosphere was dissolved in 70 ml of dry THF and 30 ml of CH ₃ CN. Then, 1.02 g (7.5 mmol) of cumylamine and 1.12 g (8.3 mmol) of N-hydroxybenzotriazole (HOBT) were added, and the reaction mixture was cooled at -10 ^° C. 1.71 g (8) was added dropwise. , 3 mmol) of DCC dissolved in 20 ml of CH ₂ Cl ₂ and the solution was kept at -5 ^° C for 2 hours and then at room temperature overnight. The precipitated dicyclohexylurea was filtered off and the solution was evaporated to dryness in vacuo. The residue was dissolved in CH ₂ Cl ₂ and washed with water, saturated NaHCO ₃ solution, 5% citric acid, saturated NaHCO ₃ solution and brine. The organic layer was separated, dried over sodium sulfate and evaporated to dryness in vacuo, the residue was dissolved in 20 ml of CH ₂ Cl ₂ and left overnight. A further amount of dicyclohexylurea precipitated and was filtered off. The solution was evaporated to dryness in vacuo to give 1.4 g of a crude product which was flash chromatographed on silica gel 230-400 mesh, eluting first with a 9: 1 hexane / EtOAc mixture and then with an 8: 2 hexane / EtOAc mixture, giving 0.4 g purified product, which recrystallized twice from iso-PrOH, giving 0.15 g of the target compound.

C ₂₅ H ₂₂ N ₂ O ₂
Mp = 166 - 169 ^o C (decomp.)
M.V. = 382.47
I.K. (nujol): 3200, 1650, 1580, 1535 cm ^-1 .

300 MHz ¹ H-NMR (DMSO-d ₆ ): δ 9.56 (s, 1H), 8.92 (br.s, 1H), 8.00-7.94 (m, 3H), 7.76 (brd, 1H), 7.63-7.45 (m, 7H), 7.36 (dd, 2H), 7.24 (dd, 1H), 1.72 ( s., 6H).

MS (EI; source 180 ^° C, 70 V, 200 mA): 382 (M +.), 264, 247, 219, 119.

Example 106
N- (α, α-dimethylbenzyl) -3-amino-2-phenylquinoline-4-carboxamide
2.0 g (7.6 mmol) of 3-amino-2-phenylquinoline-4-carboxylic acid in a nitrogen atmosphere was dissolved in 70 ml of dry THF and 30 ml of CH ₃ CN. Then, 1.02 g (7.6 mmol) of cumylamine and 1.12 g (8.3 mmol) of N-hydroxybenzotriazole (HOBT) were added, and the reaction mixture was cooled at -10 ^° C. 1.72 g (8) was added dropwise. , 3 mmol) of DCC dissolved in 20 ml of CH ₂ Cl ₂ , and the solution was kept at - 5 ^° C for 2 hours and then at room temperature overnight. The precipitated dicyclohexylurea was filtered off and the solution was evaporated to dryness in vacuo. The residue was dissolved in CH ₂ Cl ₂ and washed with water, saturated NaHCO ₃ solution, 5% citric acid, saturated NaHCO ₃ solution and brine. The organic layer was separated, dried over sodium sulfate and evaporated to dryness in vacuo, the residue was dissolved in 20 ml of CH ₂ Cl ₂ and left overnight. A further amount of dicyclohexylurea precipitated and was filtered off. The solution was evaporated to dryness in vacuo to give 2.0 g of a crude product, which was flash chromatographed on 230-400 mesh silica gel, eluting with hexane / EtOAc 6: 4 containing 1% conc. NH ₄ OH, giving 0.9 g of a purified product, which was recrystallized from a 1: 1 hexane / EtOAc mixture and then from iso-PrOH, giving 0.45 g of the target compound.

C ₂₅ H ₂₃ N ₃ O
Mp = 166--168 ^o C
M.V. = 381.48
I.K. (nujol): 3460, 3360, 3220, 1667, 1605, 1527 cm ^-1 .

300 MHz ¹ H-NMR (DMSO-d ₆ ): δ 9.05 (s, 1H), 7.87 (dd, 1H), 7.74-7.68 (m, 3H), 7, 60-7.42 (m, 7H), 7.37 (dd, 2H), 7.24 (dd, 1H), 4.74 (s, 2H), 1.71 (s, 6H) )

MS (EI; source 180 ^° C, 70 V, 200 mA): 381 (M +.), 263, 218, 119.

Example 107
(-) - (S) -N- (α-ethylbenzyl) -5-methyl-2-phenylquinoline-4-carboxamide
0.8 g (3.04 mmol) of 5-methyl-2-phenylquinoline-4-carboxylic acid in a nitrogen atmosphere was dissolved in 30 ml of dry THF and 12 ml of CH ₃ CN. 0.43 g (3.20 mmol) of (S) - (-) - α-ethylbenzylamine and 0.78 g (5.78 mmol) of N-hydroxybenzotriazole (HOBT) were added, and the reaction mixture was cooled at -10 ^° C. 0.69 g (3.34 mmol) of DCC dissolved in 5 ml of CH ₂ Cl _{2 was} added dropwise, and the solution was kept at -5 ^° C for 2 hours and then at room temperature overnight. The precipitated dicyclohexylurea was filtered off and the solution was evaporated to dryness in vacuo. The residue was dissolved in CH ₂ Cl ₂ and washed with water, saturated NaHCO ₃ solution, 5% citric acid, saturated NaHCO ₃ solution and brine. The organic layer was separated, dried over sodium sulfate and evaporated to dryness in vacuo, the residue was dissolved in 10 ml of CH ₂ Cl ₂ and left overnight. A further amount of dicyclohexylurea precipitated and was filtered off. The solution was evaporated to dryness in vacuo to give 1.15 g of a crude product, which was flash chromatographed on 230-400 mesh silica gel, eluting with hexane / EtOAc 6: 2 containing 0.5% conc. NH ₄ OH, giving 0.47 g of a purified product, which was recrystallized from iso-Pr ₂ O containing a few drops of EtOAc, giving 0.36 g of the target compound as a white powder.

C ₂₆ H ₂₄ N ₂ O
Mp = 189 - 192 ^o C
M.V. = 380.49
[α] $\genfrac{}{}{0ex}{}{\text{20}}{\text{D}}$ = -3.8 (s = 0.5 MeOH)
I.K. (KBr): 3280, 3070, 3020, 1635, 1545 cm ^-1 .

300 MHz ¹ H-NMR (DMSO-d ₆ ): δ 9.20 (d, 1H), 8.23 (d, 2H), 7.93 (d, 1H), 7.78 (s. , 1H), 7.20-7.70 (m, 10H), 5.00 (dt, 1H), 2.38 (br s, 3H), 1.70-1.90 (m. , 2H); 0.95 (t, 3H).

MS (EI; source 180 ^° C, 70 V, 200 mA): 380 (M +.), 246, 218.

Example 108
(R, S) -N- [α- (1-hydroxyethyl) benzyl] - 3-methyl-2-phenylquinoline-4-carboxamide
Obtained as described in example 1, starting from 11.08 g (39.33 mmol) of crude 3-methyl-2-phenylquinoline-4-carbonyl chloride, 4.87 g (32.20 mmol) of 1-phenyl-2-hydroxypropylamine and 10.33 ml (74.14 mmol) of TEA in 150 ml of a 1: 1 mixture of dry CH ₂ Cl ₂ and CH ₃ CN. The precipitated TEA hydrochloride was filtered off and the filtrate was concentrated in vacuo to dryness, the residue was dissolved in CH ₂ Cl ₂ (100 ml) and washed with saturated NaHCO ₃ solution, 20% citric acid and brine. The organic layer was dried over sodium sulfate and evaporated to dryness in vacuo to give 13.23 g of an oil that crystallized from iso-PrО ₂ (100 ml) containing 6 ml of iso-PrOH, giving 9.14 g of the target compound as an off-white solid matter.

C ₂₆ H ₂₄ N ₂ O ₂
Mp = 163-165 ^o C
M.V. = 396.49
I.K. (nujol): 3400, 3260, 1635, 1580 cm ^-1
Example 109
(R, S) -N- [α- (1-methylcarbonyl) benzyl] -3-methyl-2-phenylquinoline-4-carboxamide
It was obtained as described in example 96, starting from 3.25 g (25.60 mmol) of oxalyl chloride, 3.88 g (49.66 mmol) of DMSO, 8.2 g (20.68 mmol) of (R, S) - N- [α- (1-hydroxyethyl) benzyl] - 3-methyl-2-phenylquinoline-4-carboxamide (compound of Example 108) and 15.72 ml (112.76 mmol) of TEA in 230 ml of dry CH ₂ Cl ₂ . The reaction mixture was quenched with 40 ml of water, and the organic layer was separated and washed with 20% citric acid, saturated NaHCO ₃ solution and brine. The organic layer was dried over sodium sulfate and evaporated to dryness in vacuo to give 9.4 g of the crude title compound as an oil. This residual oil was flash chromatographed on 230-400 mesh silica gel, eluting with 70:30 hexane / ethyl acetate containing 1% conc. NH ₄ OH, giving 7.7 g of a purified product, which crystallized from EtOAc / hexane 1: 3, respectively, giving 6.0 g of pure target compound.

C ₂₆ H ₂₂ N ₂ O ₂
Mp = 156-158 ^o C
M.V. = 394.48
I.K. (nujol): 3270, 3180, 1735, 1725, 1660, 1630, 1527, 1460 cm ^-1 .

300 MHz ¹ H-NMR (DMSO-d ₆ ): δ 9.53 (d, 1H), 8.01 (d, 1H), 7.73 (dd, 1H), 7.62-7, 35 (m, 12H), 5.97 (d, 1H), 2.30 (br s, 3H), 2.18 (s, 3H).

MS (EI; source 180 ^° C, 70 V, 200 mA): 394 (M +.), 352, 351, 246, 218, 217.

Example 110
(R, S) -N- [α- (ethyl) -4-pyridylmethyl] -2-phenylquinoline-4-carboxamide
4.12 g (16.52 mmol) of 2-phenylquinoline-4-carboxylic acid was dissolved in a nitrogen atmosphere in 40 ml of dry CH ₂ Cl ₂ and 30 ml of THF. 1.50 g (11.01 mmol) of 1- (4-pyridyl) -n-propylamine and 2.23 g (16.52 mmol) of N-hydroxybenzotriazole (HOBT) were added and the reaction mixture was cooled at 0 ^° C. 3.41 g (16.52 mmol) of DCC dissolved in 26 ml of dry CH ₂ Cl _{2 was} added dropwise, and the solution was kept at 0 ^° C for 2 hours and then stirred at room temperature for 36 hours. The precipitated dicyclohexylurea was filtered off and the solution was evaporated to dryness in vacuo. The residue was dissolved in 100 ml of CH ₂ Cl ₂ and washed with water, 10% K ₂ CO ₃ , 5% citric acid and brine. The organic layer was separated, dried over sodium sulfate and evaporated to dryness in vacuo, the residue was dissolved in 30 ml of CH ₂ Cl ₂ and left overnight. A further amount of dicyclohexylurea precipitated and was filtered off. The solution was evaporated to dryness in vacuo to give 3.5 g of a crude product, which was recrystallized three times from iso-PrOH, to give 0.91 g of the target compound.

C ₂₄ H ₂₁ N ₃ O
Mp = 218 - 219 ^o C
M.V. = 367.45
I.K. (KBr): 3260, 3060, 1648, 1595, 1545, 1350 cm ^-1 .

300 MHz ¹ H-NMR (DMSO-d ₆ ): δ 9.33 (d, 1H), 8.53 (d, 2H), 8.33 (dd, 2H), 8.15 (d. , 1H), 8.14 (s, 1H), 8.03 (d, 1H), 7.82 (dd, 1H), 7.66-7.52 (m, 4H), 7, 47 (d, 2H), 5.05 (dt, 1H), 1.85 (dq, 2H), 1.00 (t, 3H).

MS (EI; source 180 ^o C, 70 V, 200 mA): 367 (M +.), 338, 232, 204.

Example 111
(R, S) -N- [α-ethyl) -2-thienylmethyl] -2-phenylquinoline-4-carboxamide
1.40 g (8.00 mmol) of 1- (2-thienyl) -n-propylamine hydrochloride and 2.45 ml (17.60 mmol) of TEA were dissolved in a nitrogen atmosphere in 50 ml of dry CH ₂ Cl ₂ and 30 ml of CH ₃ CN. 2.0 g (8.00 mmol) of 2-phenylquinoline-4-carboxylic acid and 1.30 g (9.60 mmol) of N-hydroxybenzotriazole (HOBT) were added. 2.48 g (12.0 mmol) of DCC dissolved in 30 ml of dry CH ₂ Cl _{2 was} added dropwise, and the solution was stirred at room temperature for 36 hours. Then 50 ml of 10% HCl was added and the solution was further stirred for 2 hours. The precipitated dicyclohexylurea was filtered off and the organic layer was washed with 10% citric acid and 10% K ₂ CO ₃ . The organic layer was separated, dried over sodium sulfate and evaporated to dryness in vacuo. The crude product was flash chromatographed on 230-400 mesh silica gel, eluting with a hexane / EtOAc / CH ₂ Cl ₂ mixture of 80: 15: 0.5 to give 2.0 g of a yellow oil which crystallized from toluene / hexane to give 0.9 g of pure target compound in the form of white crystals.

C ₂₃ H ₂₀ N ₂ OS
Mp = 134 - 137 ^o C
M.V. = 372.49
I.K. (KBr): 3230, 3060, 1630, 1590, 1545 cm ^-1 .

300 MHz ¹ H-NMR (DMSO-d ₆ ): δ 9.33 (d, 1H), 8.30 (dd, 2H), 8.15 (d, 1H), 8.13 (d. , 1H), 8.08 (s, 1H), 7.84 (ddd, 1H), 7.68-7.51 (m, 4H), 7.44 (dd, 1H), 7, 11 (d, 1H), 7.02 (dd, 1H), 5.33 (dt, 1H), 2.10-1.88 (m, 2H), 1.05 (t, 3H) )

MS (EI; source 180 ^° C, 70 V, 200 mA): 372 (M +.), 343, 232, 204.

Example 112 (+) - (S) -N- (α-ethylbenzyl) -3-dimethylaminomethyl-2-phenylquinoline-4-carboxamide hydrochloride
5.60 g (21.27 mmol) of 3-methyl-2-phenylquinoline-4-carboxylic acid was dissolved in 100 ml of dichloroethane. 7.60 g (42.50 mmol) of N-bromosuccinimide and 0.52 g (2.00 mmol) of dibenzoyl peroxide were added, and the solution was heated under reflux for 24 hours. The reaction mixture was evaporated to dryness in vacuo, suspended in 100 ml of a mixture of 33% Me ₂ NH / EtOH and stirred overnight at room temperature. The solution was evaporated to dryness in vacuo, dissolved in 50 ml of 20% K ₂ CO ₃ and again evaporated to dryness in vacuo. 50 ml of water was added to the residue, and the solution acidified with 37% HCl was evaporated to dryness in vacuo. The crude residue and 10.8 ml (77.20 mmol) of TEA were dissolved in 50 ml of CH ₂ Cl ₂ , 50 ml of THF and 100 ml of CH ₃ CN. 3.00 g (22.20 mmol) of (S) - (-) - α-ethylbenzylamine, 0.78 g (5.78 mmol) of N-hydroxybenzotriazole (HOBT) and 11.9 g (57.90 mmol) were added. DCC, and the solution was stirred at room temperature overnight. The precipitated dicyclohexylurea was filtered off and the organic layer was evaporated to dryness in vacuo. The brown oily residue was dissolved in 100 ml of CH ₂ Cl ₂ , and the precipitate was filtered off. The filtrate was extracted three times with 40% citric acid. The aqueous layer, basified with solid K ₂ CO ₃ , was extracted with CH ₂ Cl ₂ , the organic layer was dried over sodium sulfate and evaporated to dryness in vacuo, giving 10 g of a brown oil. The crude product was flash chromatographed on 230-400 mesh silica gel, eluting with iso-Pr ₂ O / CH ₂ Cl ₂ 9: 1 to give 2.5 g of a white solid, which was dissolved in toluene and left overnight. The precipitated DCU was filtered off and the solution treated with ethanol HCl was evaporated to dryness in vacuo. The crude product was recrystallized from toluene / EtOH to give 0.7 g of the pure target compound as colorless crystals.

C ₂₈ H ₂₉ N ₃ O • HCl
Mp = 164 - 167 ^o C
M.V. = 460.02
[α] $\genfrac{}{}{0ex}{}{\text{20}}{\text{D}}$ = +25.3 (c = 1, MeOH)
I.K. (KBr): 3440, 3150, 3020, 2560, 2460, 1650, 1540 cm ^-1 .

300 MHz ¹ H-NMR (DMSO-d ₆ , 353 K): δ 9.70 (br s, 1H), 8.10 (d, 1H), 7.85 (dd, 1H), 7 80 (br s, 1H), 7.70-7.10 (m, 12H), 5.15 (dt, 1H), 4.38-4.20 (m, 2H), 2 30 (s, 3H), 2.22 (s, 6H), 2.10-1.82 (m, 2H), 1.00 (t, 3H).

MS (EI; source 180 ^° C, 70 V, 200 mA): 423 (M +.), 380, 288.

Example 113
(S) -N- (α-ethylbenzyl) -3-methyl-7-methoxy-2-phenylquinoline-4-carboxamide
It was obtained as described in example 1, starting from 1.27 g (4.09 mmol) of crude 3-methyl-7-methoxy-2-phenylquinoline-4-carbonyl chloride, 0.55 g (4.09 mmol) (S) - (-) - α-ethylbenzylamine and 1.71 ml (12.27 mmol) of TEA in 24 ml of dry CH ₂ Cl ₂ and 1 ml of DMF to promote solubility. The reaction mixture was stirred at room temperature for 12 hours. After concentration in vacuo to dryness, the residue was dissolved in CH ₂ Cl ₂ (30 ml) and washed with 10% NaHCO ₃ , 5% citric acid and brine. The organic layer was dried over sodium sulfate and evaporated to dryness in vacuo to give 1.87 g of a crude product, which was flash chromatographed on 230-400 mesh silica gel, eluting with 70:30 hexane / EtOAc to give 0.35 g of a yellow oil.

C ₂₇ H ₂₆ N ₂ O ₂
M.V. = 410.51
I.K. (KBr): 3240, 2965. 2930. 1635. 1535, 1220 cm ^-1
Example 114
(S) -N- (α-ethylbenzyl) -3-amino-5-methyl-2-phenylquinoline-4-carboxamide
0.75 g (2.64 mmol) of 3-amino-5-methyl-2-phenylquinoline-4-carboxylic acid in a nitrogen atmosphere was dissolved in 30 ml of dry THF and 10 ml of CH ₃ CN. 0.38 g (2.83 mmol) of (S) - (-) - α-ethylbenzylamine and 0.69 g (5.18 mmol) of N-hydroxybenzotriazole (HOBT) were added and the reaction mixture was cooled at -10 ^° C. 0.61 g (2.97 mmol) of DCC dissolved in 5 ml of CH ₂ Cl _{2 was} added dropwise, and the solution was kept at -5 - 0 ^° C for 2 hours, heated at 50 ^° C for 4 hours and then kept at room temperature overnight. The precipitated dicyclohexylurea was filtered off and the solution was evaporated to dryness in vacuo. The residue was dissolved in CH ₂ Cl ₂ and washed with water, saturated NaHCO ₃ solution, 5% citric acid, saturated NaHCO ₃ solution and brine. The organic layer was separated, dried over sodium sulfate and evaporated to dryness in vacuo; the residue was dissolved in 10 ml of CH ₂ Cl ₂ and left overnight. A further amount of dicyclohexylurea precipitated and was filtered off. The solution was evaporated to dryness in vacuo to give 0.86 g of a crude product, which was flash chromatographed on 230-400 mesh silica gel, eluting with CH ₂ Cl ₂ / MeOH / conc. NH ₄ OH 90: 10: 0.5, respectively, giving 0.41 g of the target compound as an oil.

C ₂₆ H ₂₅ N ₃ O
M.V. = 395.50
I.K. (KBr): 3480; 3390; 3230; 3020; 1635; 1615; 1545 cm ^-1 .

Example 115
(S) -N- (α-ethylbenzyl) -3-methoxy-5-methyl-2-phenylquinoline-4-carboxamide
1.29 g (4.40 mmol) of 3-methoxy-5-methyl-2-phenylquinoline-4-carboxylic acid in a nitrogen atmosphere was dissolved in 40 ml of dry THF and 20 ml of CH ₃ CN. 0.63 g (4.62 mmol) of (S) - (-) - (α-ethylbenzylamine and 1.13 g (8.36 mmol) of N-hydroxybenzotriazole (HOBT) was added and the reaction mixture was cooled at -10 ^° C 1.0 g (4.84 mmol) of DCC dissolved in 5 ml of CH ₂ Cl _{2 was} added dropwise and the solution was kept at -5 ^° C to 0 ^° C for 2 hours, heated at 50 ^° C for 4 hours and then It was allowed to stand overnight at room temperature. The precipitated dicyclohexylurea was filtered off and the solution evaporated to dryness in vacuo. The residue was dissolved in CH ₂ Cl ₂ and washed with water, saturated NaHCO _3, 5% citric acid, saturated sodium NaHCO ₃ and brine. The organic layer was separated, dried over sodium sulfate and evaporated in vacuo to dryness, the residue dissolved in 20 ml of CH ₂ Cl ₂ and left overnight. Sedimented some more dicyclohexylurea and was filtered off. The solution was evaporated to dryness in vacuo, giving 2 45 g of a crude product which was flash chromatographed on 230-400 mesh silica gel was eluted with a hexane / EtOAc 7: 2 mixture containing 0.5% conc. NH ₄ OH, giving 0.28 g of the target compound as an oil.

C ₂₇ H ₂₆ N ₂ O ₂
M.V. = 410.52
I.K. (KBr): 3270; 3020; 1635; 1535 cm ^-1 .

Claims (13)

1. A quinoline derivative of formula I, a solvate or salt thereof

where Ar is phenyl optionally substituted with halogen, OH or C _1-6 alkyl; benzyl, thienyl, pyridyl, C _5-7 cycloalkadienyl group;
R represents C _1-8 alkyl, C _3-7 cycloalkyl, hydroxy-C _1-6 alkyl, aminoalkyl, alkylaminoalkyl, di-C _1-6 alkylaminoalkyl, C _1-6 alkoxyalkyl, C _1-6 alkylcarbonyl, carboxy, C _{1 -6} alkoxycarbonyl, C _1-6 alkoxycarbonyl-C _1-6 alkyl, C _1-6 alkylaminocarbonyl, halogen-C _1-6 alkyl;
R ₁ and R ₂ , which may be the same or different, are independently hydrogen or C _1-6 linear or branched alkyl;
R ₃ and R ₄ , which may be the same or different, are independently hydrogen or C _1-6 linear or branched alkyl, phenyl, C _1-6 alkoxy, hydroxy, halogen, carboximido, acyloxy, phthalimido, amino, mono or di -C _1-6 alkylamino, -O (CH ₂ ) _r -NT ₂ , in which r = 2, 3 or 4, and T is C _1-6 alkyl;
R ₅ represents C _5-7 cycloalkyl, phenyl optionally substituted with 1 to 2 halogen atoms, or a single or benzo-fused heterocyclic group having an aromatic character containing 5 to 9 ring atoms and including 1 to 2 hetero atoms in the ring selected from N, O and S;
X represents 0. 2. The compound according to claim 1, wherein Ar is phenyl optionally substituted with C _1-6 alkyl or halogen; thienyl, or a C _5-7 cycloalkadienyl group. 3. The compound of claim 1 or 2, wherein R is C _1-6 alkyl, C _1-6 alkoxycarbonyl, C _1-6 alkylcarbonyl or hydroxy-C _1-6 alkyl. 4. The compound according to any one of claims 1 to 3, in which R ₃ represents hydrogen, hydroxy, halogen, C _1-6 alkoxy or R _1-6 alkyl. 5. The compound according to any one of claims 1 to 4, in which R ₄ represents hydrogen, C _1-6 alkyl, C _1-6 alkoxy, hydroxy, halogen, dialkylaminoalkoxy, dialkylaminoalkyl. 6. The compound according to any one of claims 1 to 5, in which R ₅ represents phenyl, thienyl, furyl, pyrryl or thiazolyl. 7. The compound according to claim 1 of formula I or a salt or solvate thereof, in which Ar is phenyl, 2-chlorophenyl, 2-thienyl or cyclohexadienyl; R represents methyl, ethyl, n-propyl, —COOMe or —COMe; R ₁ and R ₂ represent each hydrogen or methyl; R ₃ represents hydrogen, methoxy or hydroxy; R ₄ represents hydrogen, methyl, ethyl, methoxy, hydroxy, chloro, bromo, dimethylaminoethoxy, 2- (1-phthaloyl) ethoxy, 2- (1-pyrrolidinyl) ethoxy, dimethylaminopropoxy; R ₅ represents phenyl, 2-thienyl, 2-furyl, 2-pyrryl, 2-thiazolyl or 3-thienyl; and X represents oxygen. 8. The compound according to any one of claims 1 to 6, or its salt or MES of formula Ia

where R, R ₂ , R ₃ and R ₄ have the meanings defined for formula I in any one of claims 1 to 6;
Y represents phenyl optionally substituted with 1 to 2 halogen atoms;
Z represents Ar, as defined in claim 1. 9. The compound of claim 8 of formula Ib

where R, R ₂ , R ₃ and R ₄ , Y and Z have the meanings defined in clause 8. 10. The compound according to claim 1, selected from the group consisting of
(R, S) -N- (alpha-methylbenzyl) -2-phenylquinoline-4-carboxamide,
(+) - (S) -N- (alpha-methylbenzyl) -2-phenylquinoline-4-carboxamide,
(-) - (R) -N- (alpha-methylbenzyl) -2-phenylquinoline-4-carboxamide,
(R, S) -N- [alpha- (methoxycarbonyl) benzyl] -2-phenylquinoline-4-carboxamide,
(+) - (S) -N- [alpha- (methoxycarbonyl) benzyl] -2-phenylquinoline-4-carboxamide,
(-) - (R) -N- [alpha-methoxycarbonyl) benzyl] -2-phenylquinoline-4-carboxamide,
(R, S) -N- [alpha- (methoxycarbonyl) benzyl] -7-methoxy-2-phenylquinoline-4-carboxamide,
(R, S) -N- [alpha- (methoxycarbonyl) benzyl] -7-hydroxy-2-phenylquinoline-4-carboxamide,
(R, S) -N- [alpha- (carboxy) benzyl] -7-methoxy-2-phenylquinoline-4-carboxamide hydrochloride,
(R, S) -N- [alpha- (methylaminocarbonyl) benzyl] -2-phenylquinoline-4-carboxamide,
(R, S) -N- [alpha- (methoxycarbonyl) benzyl] -2- (2-thienyl) quinoline-4-carboxamide,
(R, S) -N- [alpha- (methoxycarbonyl) benzyl] -2- (2-furyl) quinoline-4-carboxamide,
(R, S) -N- [alpha- (methoxycarbonyl) benzyl] -2- (2-pyridyl) quinoline-4-carboxamide,
(R, S) -N- [alpha- (methoxycarbonyl) -2-thienylmethyl] -2-phenylquinoline-4-carboxamide,
(R, S) -N- [alpha- (methoxycarbonylmethyl) benzyl] -2-phenylquinoline-4-carboxamide,
(-) - (R) -N- [alpha- (methoxycarbonyl) -1,4-cycloheptadienylmethyl] -2-phenylquinoline-4-carboxamide,
unity. diast. (R, S) -N- [alpha- (1-hydroxyethyl) benzyl] -2-phenylquinoline-4-carboxamide,
(R, S) -N- (alpha-ethylbenzyl) -3-methoxy-2-phenylquinoline-4-carboxamide,
(R, S) -N- (alpha-ethylbenzyl) -3-n-butyl-2-phenylquinoline-4-carboxamide,
(R, S) -N- [alpha- (methoxycarbonyl) benzyl] benzo-1,3-cyclopentadieno [1,2-b] quinoline-8-carboxamide,
(R, S) -N- (alpha-ethylbenzyl) -3-hexyl-2-phenylquinoline-4-carboxamide,
(-) - (S) -N- (alpha-ethylbenzyl) -3-methyl-2-phenylquinoline-4-carboxamide,
(+) - (R) -N- (alpha-ethylbenzyl) -3-methyl-2-phenylquinoline-4-carboxamide,
(R, S) -N- [alpha- (methoxycarbonyl) benzyl] -2- (2-methoxyphenyl) quinoline-4-carboxamide,
(R, S) -N- (alpha-ethylbenzyl) -3-phenyl-2-phenylquinoline-4-carboxamide,
(R, S) -N- [alpha- (methoxycarbonyl) benzyl] -2- (2-fluorophenyl) quinoline-4-carboxamide,
(R, S) -N- [alpha- (ethyl) -3,4-dichlorobenzyl] -2-phenylquinoline-4-carboxamide,
(R, S) -N- [alpha- (hydroxymethyl) benzyl] -2-phenylquinoline-4-carboxamide,
(R, S) -N- (alpha-ethylbenzyl) -2-phenylquinoline-4-carboxamide,
(R, S) -N- [alpha- (methoxycarbonyl) benzyl] -3-methyl-2-phenylquinoline-4-carboxamide,
(R, S) -N- (alpha-ethylbenzyl) -3-methyl-2-phenylquinoline-4-carboxamide,
(R, S) -N- [alpha- (methoxycarbonyl) benzyl] -7-chloro-2-phenylquinoline-4-carboxamide,
(R, S) -N- [alpha- (methoxycarbonyl) benzyl] -6-methyl-2-phenylquinoline-4-carboxamide,
(R, S) -N- [alpha- (methoxymethyl) benzyl] -2-phenylquinoline-4-carboxamide,
(R, S) -N- [alpha- (methoxycarbonyl) benzyl] -6-chloro-2-phenylquinoline-4-carboxamide,
(R, S) -N- [alpha- (methoxycarbonyl) benzyl] -3-ethyl-2-phenylquinoline-4-carboxamide,
(R, S) -N- (alpha-n-propylbenzyl) -2-phenylquinoline-4-carboxamide,
(R, S) -N- (alpha-ethylbenzyl) -3-ethyl-2-phenylquinoline-4-carboxamide,
(R, S) -N- (alpha-ethylbenzyl) -3-phthalimido-2-phenylquinoline-4-carboxamide,
(R, S) -N- (alpha-ethylbenzyl) -3-n-propyl-2-phenylquinoline-4-carboxamide,
(-) - (S) -N- (alpha-ethylbenzyl) -6-bromo-3-methyl-2- (4-bromophenyl) quinoline-4-carboxamide,
(-) - (S) -N- (alpha-ethylbenzyl) -6-bromo-3-methyl-2-phenylquinoline-4-carboxamide,
(R, S) -N- [alpha- (methoxycarbonyl) benzyl] -6-methoxy-2-phenylquinoline-4-carboxamide,
(R, S) -N- [alpha- (methoxycarbonyl) benzyl] -2- (2-benzofuryl) quinoline-4-carboxamide,
(R, S) -N - [(1,2-diphenyl) ethyl] -2-phenylquinoline-4-carboxamide,
(R, S) -N- (alpha-trifluoromethylbenzyl) -2-phenylquinoline-4-carboxamide,
(-) - (S) -N- (alpha-ethylbenzyl) -3-methoxy-2-phenylquinoline-4-carboxamide,
(-) - (S) -N- (alpha-ethylbenzyl) -3-ethyl-2-phenylquinoline-4-carboxamide,
(R, S) -N- [alpha- (ethyl) -4-chlorobenzyl] -2-phenylquinoline-4-carboxamide,
(R, S) -N- [alpha- (methoxycarbonyl) benzyl] -N-methyl-2-phenylquinoline-4-carboxamide,
(R, S) -N- [alpha- (methoxycarbonyl) benzyl] -2- (3-thienyl) quinoline-4-carboxamide,
(R, S) -N- [alpha- (methoxycarbonyl) benzyl] -5,6-dihydrobenzo [a] acridine-7-carboxamide,
(R, S) -N- [alpha- (methoxycarbonyl) benzyl] -2- (2-pyrryl) quinoline-4-carboxamide,
(R, S) -N- [alpha- (methoxycarbonyl) benzyl] -2- (2-thiazolyl) quinoline-4-carboxamide,
(R, S) -N- [1-indanyl] -2-phenylquinoline-4-carboxamide,
(R, S) -N- (alpha-n-butylbenzyl) -2-phenylquinoline-4-carboxamide,
(R, S) -N- [alpha- (methoxycarbonyl) benzyl] -2- (4-methylphenyl) quinoline-4-carboxamide,
(R, S) -N- (alpha-heptylbenzyl) -2-phenylquinoline-4-carboxamide,
(R, S) -N- [alpha- (methoxycarbonyl) benzyl] -2- (2-methylphenyl) quinoline-4-carboxamide,
(R, S) -N- [alpha- (methoxycarbonyl) benzyl] -2- (4-methoxyphenyl) quinoline-4-carboxamide,
N- (1-phenylcyclopentyl) -2-phenylquinoline-4-carboxamide,
(R, S) -N- [alpha- (methoxycarbonyl) benzyl] -2- (4-hydroxyphenyl) quinoline-4-carboxamide,
(R, S) -N- [alpha- (methoxycarbonyl) benzyl] -2- (3,4-methylenedioxyphenyl) quinoline-4-carboxamide,
N- (alpha, alpha-dimethylbenzyl) -2-phenylquinoline-4-carboxamide,
(R, S) -N- [alpha- (ethyl) -4-methylbenzyl] -2-phenylquinoline-4-carboxamide,
(R, S) -N- [alpha- (methoxycarbonyl) benzyl] -2- (3-pyrryl) quinoline-4-carboxamide,
(R, S) -N- [alpha- (methoxycarbonyl) benzyl] -2- (3,4-dichlorophenyl) quinoline-4-carboxamide,
(-) - (R) -N- [alpha- (aminomethyl) benzyl] -2-phenylquinoline-4-carboxamide,
(-) - (S) -N- [alpha-ethylbenzyl) -3-amino-2-phenylquinoline-4-carboxamide,
(-) - (S) -N- [alpha-ethylbenzyl) -3-chloro-2-phenylquinoline-4-carboxamide,
(-) - (S) -N- [alpha-ethylbenzyl) -3-bromo-2-phenylquinoline-4-carboxamide,
(R, S) -N- (alpha-iso-propylbenzyl) -2-phenylquinoline-4-carboxamide,
(-) - (S) -N- (alpha-ethylbenzyl) -2-phenylquinoline-4-carboxamide,
(+) - (R) -N- (alpha-ethylbenzyl) -2-phenylquinoline-4-carboxamide,
(R, S) -N- [alpha- (methoxycarbonyl) benzyl] -6-fluoro-2-phenylquinoline-4-carboxamide,
(R, S) -N- [alpha- (methoxycarbonyl) benzyl] -2-cyclohexylquinoline-4-carboxamide,
(R, S) -N- [alpha- (methoxycarbonyl) benzyl] -2- (3-chlorophenyl) quinoline-4-carboxamide,
(R, S) -N- [alpha- (methoxycarbonyl) benzyl] -2- (2-chlorophenyl) quinoline-4-carboxamide,
(R, S) -N- (alpha-ethylbenzyl) -3-hydroxy-2-phenylquinoline-4-carboxamide,
(R, S) -N- [alpha- (methoxycarbonyl) benzyl] -8-acetyloxy-2-phenylquinoline-4-carboxamide,
(R, S) -N- [alpha- (methoxycarbonyl) benzyl] -8-hydroxy-2-phenylquinoline-4-carboxamide,
(R, S) -N- [alpha- (methoxycarbonyl) benzyl] -2- (2,4-dichlorophenyl) quinoline-4-carboxamide,
(-) - (R) -N- [alpha- (methoxycarbonyl) -4-hydroxybenzyl] -2-phenylquinoline-4-carboxamide hydrochloride,
N-diphenylmethyl-2-phenylquinoline-4-carboxamide,
(-) - (S) -N- (alpha-ethylbenzyl) -3-hydroxy-2-phenylquinoline-4-carboxamide,
(+) - (R) -N- (alpha-ethylbenzyl) -3-hydroxy-2-phenylquinoline-4-carboxamide,
(-) - (R) -N- [alpha- (methoxycarbonyl) benzyl] -3-hydroxy-2-phenylquinoline-4-carboxamide,
(-) - (R) -N- [alpha- (dimethylaminomethyl) benzyl] -2-phenylquinoline-4-carboxamide,
(R, S) -N- [alpha- (dimethylaminomethyl) benzyl] -2-phenylquinoline-4-carboxamide,
(R, S) -N- [alpha- (aminocarbonyl) benzyl] -2-phenylquinoline-4-carboxamide,
(R, S) -N- [alpha- (1-pyrrolidinylcarbonyl) benzyl] -2-phenylquinoline-4-carboxamide,
(-) - (R) -N- [alpha- (carboxy) benzyl] -2-phenylquinoline-4-carboxamide hydrochloride,
(R, S) -N- [alpha- (methoxycarbonyl) benzyl] -2- (4-chlorophenyl) quinoline-4-carboxamide,
(R, S) -N- [alpha- (methoxycarbonyl) -4-methoxybenzyl] -2-phenylquinoline-4-carboxamide,
hydrochloride of (R, S) -N- [alpha- (methoxycarbonyl) -alpha- (methyl) benzyl] -N-methyl-2-phenylquinoline-4-carboxamide,
(R, S) -N- [alpha- (methylcarbonyl) benzyl] -2-phenylquinoline-4-carboxamide,
(R, S) -N- [alpha- (2-hydroxyethyl) benzyl] -2-phenylquinoline-4-carboxamide,
(-) - (S) -N- (alpha-ethylbenzyl) -3- (2-dimethylaminoethoxy) -2-phenylquinoline-4-carboxamide hydrochloride,
(-) - (S) -N- (alpha-ethylbenzyl) -3-acetylamino-2-phenylquinoline-4-carboxamide,
(-) - (S) -N- (alpha-ethylbenzyl) -3- (3-dimethylaminopropoxy) -2-phenylquinoline-4-carboxamide hydrochloride,
(-) - (S) -N- (alpha-ethylbenzyl) -3- [2- (1-phthaloyl) ethoxy] -2-phenylquinoline-4-carboxamide hydrochloride,
(-) - (S) -N- (alpha-ethylbenzyl) -3- (2-aminoethoxy) -2-phenylquinoline-4-carboxamide hydrochloride,
(+) - (S) -N- (alpha-ethylbenzyl) -3- [2- (1-pyrrolidinyl) ethoxy] -2-phenylquinoline-4-carboxamide hydrochloride,
(-) - (S) -N- (alpha-ethylbenzyl) -3- (dimethylaminoacetylamino) -2-phenylquinoline-4-carboxamide,
N- (alpha, alpha-dimethylbenzyl) -3-hydroxy-2-phenylquinoline-4-carboxamide,
N- (alpha, alpha-dimethylbenzyl) -3-amino-2-phenylquinoline-4-carboxamide,
(-) - (S) -N- (alpha-ethylbenzyl) -5-methyl-2-phenylquinoline-4-carboxamide,
(R, S) -N- [alpha- (1-hydroxyethyl) benzyl] -3-methyl-2-phenylquinoline-4-carboxamide,
(R, S) -N- [alpha- (methylcarbonyl) benzyl] -3-methyl-2-phenylquinoline-4-carboxamide,
(R, S) -N- [alpha- (ethyl) -4-pyridylmethyl] -2-phenylquinoline-4-carboxamide,
(R, S) -N- [alpha- (ethyl) -2-thienylmethyl] -2-phenylquinoline-4-carboxamide,
(+) - (S) -N- (alpha-ethylbenzyl) -3-dimethylaminomethyl-2-phenylquinoline-4-carboxamide hydrochloride,
(S) -N- (alpha-ethylbenzyl) -3-methyl-7-methoxy-2-phenylquinoline-4-carboxamide,
(S) -N- (alpha-ethylbenzyl) -3-amino-5-methyl-2-phenylquinoline-4-carboxamide,
(S) -N- (alpha-ethylbenzyl) -3-methoxy-5-methyl-2-phenylquinoline-4-carboxamide. 11. The method of obtaining the compounds of formula I, characterized in any one of claims 1 to 10, or its solvate or salt, which includes the reaction of the compounds of formula III

where R ', R' ₁ , R ' ₂ and Ar' have the meanings R, R ₁ , R ₂ and Ar, defined for formula I, or a group or atom capable of converting to R, R ₁ , R ₂ and Ar, with the compound of formula II

where R ' ₃ , R' ₄ , R ' ₅ and X' have the meanings of R ₃ , R ₄ , R ₅ and X, as defined for formula I, or a group or atom capable of converting to R ₃ , R ₄ , R ₅ and X, or an active derivative thereof, to form a compound of formula Ic

and then optionally carrying out one or more of the following steps:
(a) when R ', R' ₁ - R ' ₅ , Ar' and X 'have values other than R, R ₁ - R ₅ , Ar and X, the transformation of any one of the groups R', R ' ₁ - R' ₅ , Ar 'and X' to the group R, R ₁ - R ₅ , Ar and X to obtain a compound of formula I,
(b) when R ', R' ₁ - R ' ₅ , Ar' and X 'have the meanings R, R ₁ - R ₅ , Ar and X, the conversion of any one of the groups R, R ₁ - R ₅ , Ar and X in another group R, R ₁ - R ₅ , Ar and X to obtain a compound of formula I,
(c) formation of a salt and / or solvate of the obtained compound of formula I.  12. The method according to claim 11, in which the active derivative of the compounds of formula II is an acid halide. 13. A pharmaceutical composition exhibiting the properties of an NK ₃ receptor antagonist and containing an effective amount of a compound of formula I according to any one of claims 1 to 10, or a salt or solvate thereof, and a pharmaceutically acceptable carrier.

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