PL188872B1 - Quinoline derivatives as tachykinin nk3 receptor antagonists - Google Patents

Abstract

Quinoline derivatives of formula (I), solvates or salts thereof in which formula: Ar is phenyl, 2-chlorophenyl, 2-thienyl or cyclohexadienyl; R is methyl, ethyl, n-propyl, -COOMe or -COMe; R1 and R2 are each hydrogen or methyl; R3 is hydrogen, methoxy or hydroxy; R4 is hydrogen, methyl, ethyl, methoxy, hydroxy, amino, chlorine, bromine, dimethylaminoethoxy, 2-(1-phthaloyl)ethoxy, aminoethoxy, 2-(1-pyrrolidinyl)ethoxy, dimethylaminopropoxy, dimethylaminoacetylamino, acetylam inov a, or dimethylaminomethyl; R5 is phenyl, 2-thienyl, 2-furyl, 2-pyridyl, 2-thiazolyl or 3-thienyl; and hydrogen atom and R is -COOMe. PL PL PL

Description

The subject of the invention is new quinoline derivatives represented by formula (I).

The mammalian 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 demonstrated the existence of three subtypes of TK receptors (NK1, NK2 and NK3), and NKB binds preferentially to the NK3 receptor, although it also recognizes both other receptors with lower affinity (Maggi et al., 1993, J. Auton. Pharmaeol. ., 13, 23-93).

Selective peptide NK3 receptor antagonists are known (Drapeau, 1990 Reg. Pept., 31, 125-135), and the findings of NK3 receptor peptide agonists suggest that NKB, by activating the NK3 receptor, plays a key role in the modulation of nerve inputs in the airways, skin, spinal cord and nigro-striatal 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 the known antagonists makes them not very stable from a metabolic point of view to serve as practical therapeutic agents.

We have now discovered a new class of selective, non-peptide NK3 antagonists much more stable from a metabolic point of view than known peptide NK3 receptor antagonists with potential therapeutic utility in the treatment of pulmonary disorders (asthma, chronic obstructive pulmonary diseases - COPD, hypersensitivity, cough), skin disorders and itching ( e.g., non-local dermatitis and skin blisters and redness), neurogenic inflammation, and disorders of the central nervous system (Parkinson's disease, movement disorders, medications, and psychosis). These disorders are hereinafter referred to as primary disorders.

The novel NK3 antagonists of the invention also have potential therapeutic utility in the treatment of convulsive disorders (e.g., epilepsy), renal disorders, urinary incontinence, inflammation of the eyes, inflammatory pain, eating disorders (inhibition of food intake).

Allergic rhinitis, neurodegenerative disorders (e.g., Alzheimer's disease), psoriasis, Huntigton's disease and depression (hereinafter referred to as secondary disorders).

The subject matter is compounds, solvates or salts of formula I,

wherein:

Ar is phenyl, 2-chlorophenyl, 2-thienyl, or cyclohexadienyl; R is methyl, ethyl, n-propyl, -COOMe, or -COMe; each R) and R2 are hydrogen or methyl; R3 is hydrogen, methoxy or hydroxy; R4 is hydrogen, methyl, ethyl, methoxy, hydroxyl, amino group, chlorine, bromine, dimethylaminoethoxy, 2- (1-phthaloyl) ethoxy, aminoethoxy, 2- (1-pyrrolidinyl) -ethoxy, dimethylaminopropoxy, dimethylaminoacetylamino group, acetylamino group, or dimethylaminomethyl; R5 is phenyl, 2-thienyl, 2-furyl, 2-pyrryl, 2-thiazolyl, or 3-thienyl; and X is oxygen, with the exception that the compound of formula (T) is not N- (α-ethylbenzyl) -3-hydroxy-2-phenylchmoline-4-carboxamide, and compounds where R4 is hydrogen and R is -COOMe.

The subject compound or a salt or solvate thereof is preferably in a pharmaceutically acceptable or substantially pure form. By pharmaceutically acceptable form is meant a form which is pharmaceutically acceptable in purity without the usual pharmaceutical additives such as diluents and carriers and free from substances considered toxic at normal dosages. The substantially pure form will normally contain at least 50% (apart from conventional pharmaceutical additives), preferably 75%, more preferably 90% and even more preferably 95% of the compound or a salt or solvate thereof. One of the preferred pharmaceutically acceptable forms is the crystalline form, including the form in a pharmaceutical composition. In the case of salts and solvates, the additional ionic and solvent components must also be non-toxic.

Examples of pharmaceutically acceptable salts of the compound include an acid addition salt with conventional pharmaceutical acids, e.g., maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, almond, tartaric, succinic, benzoic, shellic and methanesulfonic acids.

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

The compound contains an asymmetric center and can therefore exist in stereoisomeric form. The invention therefore includes stereoisomers and mixtures thereof, including racemates.

The compound of the invention can be obtained by reacting a compound of formula (III),

N — C — Ar 'r;

(III) · wherein R ', R'i, R'2 and Ar' are R, R), R2 and Ar as defined for formula (I) or a group or atom convertible to R, Ri, R2 and Ar, with a compound of formula (II)

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or an active derivative thereof, in which R'3, R'4, R'5 and X 'are _R3, R4, _R5 and X as defined for formula (I) or a group convertible to R3, R4, R5 and X to give a compound of formula (Ic)

and possibly then carrying out one or more of the following steps:

(a) when R ', R'i to R'5, Ar' and X 'are not R, R1 to R5, Ar and X, transform each R', R '! to R'5, Ar 'and X' of R, Ri to R5, Ar and X to form a compound of formula (I), (b) when R ', R'i to R'5, Ar' and X 'are R, Ri to R5, Ar and X, transform each R, Ri to R5, Ar and X to another R, Ri to R5, Ar and X to form a compound of formula (I), (c) salt formation and / or a solvate of the obtained compound of formula (Ic).

Suitable active derivatives of compounds of formula (II) are acid halides (preferably chlorides), acid azides or acid anhydrides. Another convenient derivative is the mixed anhydride formed between the acid and the alkyl chloroformate; another suitable derivative is an activated ester such as cyanomethyl, thiophenyl, p-nitrophenyl, p-nitrothiophenyl, 2,4,6-trichlorophenyl, pentachlorophenyl, pentafluorophenyl, N-hydroxyphthalimide, N-hydroxypiperidine, N-hydroxyburinyl -hydroxybenzotriazole; or the carboxyl group can be activated using carbodiimide or N, N'-carbonyldiimidazole.

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

(a) with an acid chloride in the presence of an inorganic or organic base in a suitable aprotic solvent such as dimethylformamide (DMF) at a temperature from -70 to 50 ° C (preferably from -10 to 20 ° C), (b) with acid in the presence of a suitable condensing agent such as e.g. N, N'-carbonyldiimidazole (CDI) or a carbodiimide such as dicyclohexylcarbodiimide (DCC) or N-dimethylaminopropyl-N'-ethylcarbodiimide and N-hydroxybenzotriazole (HOBT i) to increase the yield avoiding racemization processes (Synthesis, 453, 1972) in an aprotic solvent such as a mixture of acetonitrile (MeCN) and tetrahydrofuran (THF) in a ratio of 1: 9 to 7: 3, respectively, at a temperature of -70 to 50 ° C (preferably from -10 to 25 ° C) (see diagram 1),

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Scheme 1

Rh COOMe N — C — Ar '

DCC, HOBT "

MeCN / THF 3: 7 0-20'C (III) '

(c) with a mixed anhydride formed in situ from an acid and an alkyl (e.g. isopropyl) chloroformate with a suitable bpTOtonyrospusscableil, such as dichloromethane, at -70 to 50 ° C (preferably from -20 to 2 ° C).

It is understood that a compound of formula (Ic) 'may be converted to a compound of formula (I), or that one compound of formula (I) may be converted to another compound of formula (I) by conversion of suitable substituents. Thus, certain compounds of formula (I) and (Ic) are useful intermediates in the preparation of other compounds of the invention.

For example, R'2 may be hydrogen and converted to alkyl R2, e.g. methyl, by conventional amide alkylation (Zabicky, The chemistry of amides; Interscience, London, 1970, p. 749). When X 'is oxygen, it can be converted to sulfur X by standard thioamide-forming reagents such as P2S5 (Chem. Rev., 61, 45, 1961 or Angew. Chem. 78, 517, 1966) or Lawesson's reagent (Terrahedron, 41 , 5061, 1985). When Ar 'or R'5 is methoxide substituted with phenyl, it can be converted to another Ar' or R'5 hydroxy-substituted phenyl by standard devetification with Lewis acids such as boron tribromide (Synthesis, 249, 1983) or with mineral acids such as hydrohydroxy hydrobromides. When R is bVxycarbynyl group, e.g. vetoxkbrbynzl, it can be converted to other Rs such as etoVscarbynzl by transesterification with an appropriate alcohol at 20 to 120 ° C, carboxyl by acid or basic hydrolysis, aminocbrbynyr, clVirokmycarbbynzl or dibribonzl transavidilation with ammonia, primary amine or secondary amine in methanol as a solvent at a temperature of 10 to 120 ° C, optionally in the presence of a catalytic amount of NaCN (J. Org. Chem., 52, 2033, 1987) or using trimethylgHn (Me ^ Al) ( Tetrahedron Letters, 48, 4171, 1977), a method of selective reduction with a metal hydride such as lithium borohydride (Tetrahedron, 35, 567, 1979) or sodium borohydride in THF + MeOH (Bull. Chem. Soc. Japan. 57, 1948, 1984 or Synth. Commun., 12, 463, 1982), alkylcbrboezl by acyl chloride formation followed by reaction with brvagnesium halides in THF as solvent at -78 to 30 ° C ( Tetrahedron Letters, 4303, 1979) or with arWilyWadmium halides or diblkirocadmium in the presence of MgCh or LiCl (J. Org. Chem., 47, 2590, 1982). Another group that can be converted to R 'as vetoxoVbrbonzl is a substituted heteroarovctic ring such as oWsadikzylyzl (J. Med. Chem., 34, 2726, 1991).

Scheme 2 summarizes some of the above-described procedures for transforming a compound of formula (Ic) or (I) wherein X 'is oxygen. R 'is COOMe, Ar' and R'i to R'5 are as described for formula (I), in another compound of formula (I).

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Scheme 2

A compound of formula (I) can be converted into pharmaceutically acceptable acid addition salts by reaction with appropriate organic or mineral acids.

Solvates of a compound of formula (I) can be prepared by crystallization or recrystallization from an appropriate solvent. For example, hydrates can be prepared by crystallization or recrystallization from aqueous solutions, or solutions in organic solvents containing water.

Also, non-pharmaceutically acceptable salts or solvates of the compounds of formula (I) may be useful as intermediates in the preparation of pharmaceutically acceptable salts or solvates. Thus, salts or solvates also form part of the invention.

As mentioned above, the compounds of formula (I) may exist in more than one stereoisomeric form and the method of their preparation may lead to the formation of racemates and enantiomerically pure forms. To prepare pure enantiomers, appropriate enantiomerically pure primary or secondary amines of formula (IIId) or (IIIe) $ * 2 $ '2 R. ¹

And? AND

N — C — Ar 'N — C — Ar' ^z ► ^z 's ^H R ¹ ! ^H R ¹ !

(IIId) (IIIe)

The 188,872 is reacted with compounds of formula (II) to give compounds of formula (I'd) or (I'e).

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

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

For example, a compound of formula (II) wherein X 'is oxygen, R'3, R'4 and R'5 are hydrogen, is described by Pfitzinger, J. Prakt. Chem. 38, 582, 1882 and Pfitzinger, J. Prakt. Chem., 56, 293, 1897; a compound of formula (II) wherein X 'is oxygen, R'3 and R'4 are hydrogen and R'5 is 2-pyridyl is described by Risaliti, Rie. Scient., 28, 561, 1958; a compound of formula (II) in which X 'is oxygen, R'3 and R'4 are hydrogen and R'5 is 0-, m- and p-chlorophenyl, o-chlorophenyl and 3,4-dichlorophenyl are described by Brown and in., J. Am. Chem. Soc., 68, 2705, 1946; a compound of formula (II) wherein X 'is oxygen, R'3 and R'4 are hydrogen and R'5 is p-methoxyphenyl describes Ciusa and Luzzatto. Gazz. Chim. Ital. 44, 64, 1914; a compound of formula (II) wherein X 'is oxygen, R' 3 and R'4 are hydrogen and R '5 is m-trichloromethylphenyl is described by Shargier and Lalezari, J. Chem. Eng. Data, 8, 276, 1963; a compound of formula (II) wherein X 'is oxygen, R'3 and R'4 are hydrogen and R'5 is p-chlorophenyl is described by Buo Hoi et al., Rec Trav. Chim. 68, 781, 1949; a compound of formula (II) wherein X 'is oxygen, R' 3 and R '4 are hydrogen and R' 5 is p-methylphenyl is described by Prevost et al., Compt. Rend. Acad. Sci., 258,954,1964; a compound of formula (II) wherein X 'is oxygen, R'3 and R'4 are hydrogen and R'5 is p-bromophenyl is described by Nicolai et al., Eur. J. Med. Chem., 27, 977, 1992; a compound of formula (II) wherein X 'is oxygen, R' 4 and R '5 are hydrogen and R' 3 is 6-methyl is described by Buchmann and Howton, J. Am. Chem. Soc., 68, 2718, 1946; a compound of formula (II) wherein X 'is oxygen, R'4 and R'5 are hydrogen and R'3 is an 8-nitro group is described by Buchmann et al., J. Am. Chem. Soc., 69, 380, 1947; a compound of formula (II) where X 'is oxygen, R' 4 is hydrogen, R'3 is 6-chlorine, R'5 is p-chlorophenyl is described by Lutz et al., 1. 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, described in European Patent Application No. EP 112 776; compounds of formula (II) in which X 'is oxygen, R' 3 is 8-trichloromethyl, R'4 is hydrogen and R'5 is phenyl, o- and p-chlorophenyl, 3,4-dichlorophenyl, p-methoxyphenyl describes Nicolai et al., Eur. J. Med. Chem., 21, 977, 1992; compounds of formula (II) in which X 'is oxygen, R' 3 is 6-bromo, R'4 is hydrogen and R'5 is phenyl or p-chlorophenyl are described by Nicolai et al., Eur. J. Med.

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Chem., 27, 977, 1992; other compounds of formula (II) are described in German Patent No. DE 3721222 and European Patent Application No. EP 384313.

Compounds of formula (III), (Ilid) and (Ille) are commercially available or can be prepared from known compounds by known methods (e.g., compounds of formula (III) where R 'is alkoxycarbonyl, R'i and RS are hydrogen and Ar 'is as defined for compounds of formula (I) described by Liebigs Ann. der Chemie, 523, 199, 1936).

The activity of the compounds of formula (I) as antagonists of NK3 receptors in standard tests indicates that they have potential therapeutic utility in the treatment of the primary and secondary disorders discussed previously.

Accordingly, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, find use as active drug substances. As NK3 receptor antagonists, they find use in the manufacture of a medicament for the treatment of any secondary disorder.

A compound of the invention finds use in the preparation of a pharmaceutical composition comprising the subject compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

The carrier may include a diluent, binder, filler, disintegrant, flavor, colorant, lubricant, or preservative in a conventional manner.

These conventional excipients can be used, for example, such as in the preparation of compositions of known agents for the treatment of disease states.

The pharmaceutical composition containing a compound of formula (I) according to the invention is preferably in unit dosage form for use in human or veterinary medicine. For example, such preparations may be packaged with written instructions for use of the agent to treat a disease state.

Convenient dosage ranges for the compounds of the invention depend on the compound and the condition of the patient. They will also depend on, inter alia, absorption capacity and the frequency and frequency of administration.

The compound of the invention is suitable for administration by any route, preferably in unit dose form or in a form which a human can take as a single dose. A composition containing a compound of the invention can be administered orally, rectally, topically, parenterally, intravenously or intramuscularly. The compositions can be designed as slow release compositions of the active ingredient.

The compositions can take the form of, for example, tablets, capsules, sachets, vials, powders, granules, lozenges, wettable powders, or liquid preparations, e.g., solutions or suspensions, or suppositories.

Compositions, e.g. suitable for oral administration, may contain conventional excipients such as binding agents, e.g. syrup, acacia, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone; fillers, e.g., lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine; tablet lubricants, e.g., magnesium stearate; disintegrants, e.g. starch, polyvinylpyrrolidone, sodium starch glycolate or microcrystalline cellulose; or a pharmaceutically acceptable shear such as sodium lauryl sulfate.

Solid compositions can be obtained by conventional mixing, filling, tabletting or the like methods. Successive mixing operations can be used to distribute the active agent throughout the composition with a large amount of fillers. When the composition is in the form of a tablet, powder or lozenge, any carrier suitable for formulating solid pharmaceutical compositions may be used, examples include magnesium stearate, starch, glucose, lactose, sucrose, rice flour and chalk. The tablets may be coated by methods well known in normal pharmaceutical practice, in particular an enteric coating. The composition may also be in the form of an digestible capsule, e.g. of gelatin, containing the compound, with a carrier or other diluents if desired.

Compositions for oral administration as liquids may take the form of, for example, emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or other convenient vehicle before use. Such liquid compositions may contain conventional additives such as suspending agents, e.g. sorbitol, syrup, methyl cellulose, gelatin,

Hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel, hydrogenated edible fats; emulsifiers, e.g. lecithin, sorbitan monooleate, or acacia; aqueous or non-aqueous vehicles, including edible oils, e.g. almond oil, fractionated coconut oil, oil esters, e.g. glycerin or propylene glycol esters, or ethyl alcohol, glycerin, water or normal saline; preservatives, for example, methyl or propyl p-hydroxybenzoate or sorbic acid; and, if desired, conventional flavoring or coloring agents.

The compounds of the invention may also be administered non-orally. In accordance with the usual pharmaceutical practice, the compositions may be formulated, e.g., for rectal administration as a suppository. They may also be formulated for injection in an aqueous or non-aqueous solution, suspension or emulsion in a pharmaceutically acceptable liquid, e.g. sterile pyrogen-free water, or parenterally in an acceptable oil or liquid mixture. The liquid may contain bacteriostatic agents, antioxidants or other preservatives, buffers or substances that are soluble to make the solution isotonic with blood, thickening agents, suspending agents, or other pharmaceutically acceptable additives. Such forms will be in unit doses such as ampoules or disposable injection devices, or in multi-dose forms such as bottles from which the correct dose can be withdrawn, or as solid concentrate forms for preparing injectable compositions.

The compounds of the invention may also be administered by inhalation, intranasal or oral routes. Such modes of administration may be accomplished by an aerosol composition containing a compound of the invention and a suitable carrier, optionally suspended in, e.g., a hydrocarbon propellant.

Preferred aerosol compositions contain micronized compound particles in combination with a surfactant, solvent, or dispersant to prevent sedimentation of suspended particles. Preferably, the compound particles are from about 2 to 10 µm.

Further modes of administration of the compounds of the invention include transdermal administration using skin patches. A preferred composition comprises a compound of the invention dispersed in a pressure-sensitive adhesive which adheres to the skin allowing the compound to diffuse out of the adhesive through the patient's skin. Known pressure sensitive adhesives such as natural rubber or silicone can be used to obtain a constant rate of skin absorption.

As mentioned above, the effective dose of the compound depends on the nature of the particular compound, the condition of the patient, and the frequency and route of administration. The unit size will usually be 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 administered once or several times daily, e.g. 2, 3 or 4 times daily, and the total daily dose for a 70 kg adult will usually be in the range of 100 to 3000 mg. Alternatively, a unit dose will contain from 2 to 20 mg of active ingredient and will be administered repeatedly as necessary to make up the appropriate daily dose.

No unacceptable toxicological effects are expected when the compounds are administered according to the method of the invention.

The compounds of the invention are useful for the treatment and / or prophylaxis of primary and secondary conditions in mammals, particularly humans.

The activity of the compounds of the invention as NK3 ligands is determined by their ability to inhibit the binding of radiolabeled NK 3 ligands, [ ¹²⁵ I] - [Me-Phe ⁷ ] -NKB or [ ³ H] -Senktide, to human and guinea pig NK3 receptors ( Renzetti et al., 1991, Neuropeptide, 18, 104-114; Buell et al., 1992, FEBS, 299 (1), 90-95; Chung et al., 1994, Biochem. Biophys. Res. Commun., 198 (3), 967-972). The binding assays used determine the concentration of the individual compound required to reduce by 50% the specific binding of [ ^I25 I] - [Me-Phe7] -NKB or [3H] -Senktide to NK3 receptors under equilibrium conditions (IC50). The binding assays provide, for each test compound, the mean IC50 value from 2-5 separate experiments performed in duplicate or in triplicate. The most potent compounds of the invention show IC50 values in the range of 1-1000 nM; in particular, in guinea pig bark membranes

With the [H] -Senktide displacement, the compounds of Examples 9, 27 and 28 exhibit a KjS (nM) of 5.6, 8.8, 12.0 and 4.8 respectively (n = 3). The NK3 antagonist activity of the compounds of the invention is determined by their ability to inhibit Senktide-induced contraction of guinea pig ileum (Maggi et al., 1990, Br. J. Pharmaeol., 101, 996-1000) and isolated rabbit iris sphincter muscle (Hall et al. , 1991, Eur. J. Pharmaeol., 199, 9-14) and human NIK3-mediated Ca2 mobilization (Mochizuki et al., 1994, J. Biol. Chem., 269, 9651-9658). The guinea pig and rabbit functional tests yield for each test compound an average K _B value from 3-8 separate experiments, where Kb is the concentration of the individual compound necessary to produce a double shift to the right of the concentration-response curve for Senktide. The human receptor functional assay allows the determination of the concentration of the individual compound necessary to reduce by 50% (IC50 values) Ca + mobilization and the NKB agonist induced. In this assay, the compounds of the invention behave as antagonists. The therapeutic potential of the compounds of the invention in the treatment of conditions can be tested using a rodent disease model.

The following descriptions illustrate the preparation of the intermediates and the examples illustrate the preparation of the compounds of the invention. The compounds of the examples are summarized in Tables 1 to 5.

Description 1

2-phenyhinoline-4-kaoboxγlrwy chloride

11.7 ml (136.3 mmol) of oxalyl chloride dissolved in 150 ml CH 2 Cl _2. The solution was cooled to -10 ° C and 20 g (80.2 mmol) of commercially available 2-lenylquinoline-4-carboxylic acid were added portionwise. The reaction mixture was allowed to stand overnight at room temperature and then evaporated to dryness to give 22 g of the title compound, used without further purification.

C16H and ₀ C1NO

Molecular Weight = 267.76

Description 2

7-megoxy-2-phenic acid), Chmoline-4-carboxylic acid, 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 EtOH and the suspension was heated at 80 ° C for 42 hours. After cooling the reaction mixture, 50 ml of water was added and the solution was extracted with 50 ml of Et2O. The ice-cooled aqueous phase was acidified to pH 1 with 37% HCl, and the precipitate was filtered off and washed with water.

The obtained solid was dried under reduced pressure at 40 ° C to give 7.0 g of the title compound.

C17H13NO3

Melting point = 226-228 ° C

Molecular Weight = 279.30

Elemental analysis:

Calculated C, 73.11; H, 4.69; N, 5.01;

Found: C, 72.07; H, 4.59; N, 4.90.

L.R. (KBr): 3420; 1630 cm'1 Description 3

7-methoxy-2-phenylchmohno-4-carboxyl chloride

2.8 ml (32.3 ram 1) of oxalyl chloride was dissolved in 6 µm 1 CH ₂ Cl ₂ . The solution was cooled at -10 ° C and 6 g (19.0 mmol) of 7-methoxy-2-phenylquinoline-4-cocboxylic acid were added portionwise. The reaction mixture was allowed to stand overnight at room temperature and then evaporated to dryness to yield 7 g of the title compound, used without further purification.

C17H12C1N O 2

Molecular Weight = 291.74

Description 4

7-Hydroxy-2-phenylquinoline-4-carboxylic acid, hydroiodide

1.5 g (5.4 mmo 1) of kwa) in Y-maloxy-2-Senγloquinohno-4-carboxyhora in portions to 50 ml of 57% aqueous solution of Yrno HJ. The reaction mixture was heated to reflux

And vigorously stirred for 5 hours; then evaporated under reduced pressure to dryness to give 2.1 g of the title compound.

C, 6 HnNO _v HJ

Molecular Weight = 393.17

IR (KBr): 3120; 1650; 1620 cm ⁴ .

Description 5

2- (2-thienyl) cbinolin-4 -Carbosylic acid g (34.0 mmol) isatin, 4.4 ml (40.8 mmol) 2-acetylthiophene and 6.3 g (112.2 mmol) potassium hydroxide are dissolved in 40 mL of absolute EtOH and the suspension was heated at 80 ° C for 16 hours. After cooling the reaction mixture, 50 ml of water was added and the solution was extracted with 50 ml of EttO. The ice-cooled aqueous phase was acidified to pH 1 with 37% HCl, and the precipitate was filtered off and washed with water.

The crude product obtained was dried under vacuum at 40 ° C and triturated with EtOAc to give 4.8 g of the title compound.

C14H9N O 2S

Melting point = 181-183 ° C

Molecular Weight = 255.29

IR (KBr): 1620 cm.

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 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 EtOH and the suspension was heated at 80 ° C for 12 hours. After cooling the reaction mixture, 50 ml of water was added and the solution was extracted with 50 ml of EtiO. The ice-cooled aqueous phase was acidified to pH 1 with 37% HCl, and the precipitate was filtered off and washed with water. The crude product obtained was dried under reduced pressure at 40 ° C to give 8.5 g of the title compound.

C14H9NO3

Molecular Weight = 239.23

Description 7

2- (2-Furyl) quinoline-4-SarboSyl chloride

5.2 mL (60.4 mmol) of oxalyl chloride was dissolved in 70 mL of CH2Cl2. The solution was cooled at -10 ° C and 8.5 g (35.5 mmol) of Swosu 2- (2-furyl) quinoline-4-carboxylic acid were added portionwise. The reaction mixture was allowed to stand overnight at room temperature and then evaporated to dryness to give 9.2 g of the title compound, used without further purification.

C ₁₄ H ₈ C1N O2

Molecular margin = 257.78

Description 8

2- (4-Pyridyl) quinoline-4-carboxylic acid hydrochloride g (34.0 mmol) isatin, 4.5 ml (40.8 mmol) 4-acetylpyridine and 6.3 g (112.2 mmol) potassium hydroxide were dissolved in 40 mL of absolute EtOH and the suspension was heated at 80 ° C for 12 hours. After cooling the reaction mixture, 50 ml of water was added and the solution was extracted with 50 ml of EttO. The ice-cooled aqueous phase was acidified to pH 1 with 37% HCl, and the precipitate was filtered off and washed with water.

The aqueous solution was evaporated in vacuo to a drizzle, the residue was triturated with EtOH and filtered. Evaporation of the solvent gave 6.0 g of the tubular title compound. The product was combined with the previously obtained precipitate and recrystallized from toluene containing traces of MeOH to give 4.5 g of the title compound.

C 15 H, oNtO 2 HCl 'Melting point = 297-301 ° C

Molecular margin = 286.72

I.R. (KBr): 1705; 1635; 1610 cm '.

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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 CH2Cl2. The solution was cooled at -10 ° C and 3.0 g (14.4 mmol) of 2- (4-pyridyl) quinoline-4-carboxylic acid hydrochloride were added portionwise. The reaction mixture was left for 72 hours at room temperature and then evaporated to dryness to yield 4.0 g of the title compound, used without further purification.

C15H9CIN2 O • HCl

Molecular Weight = 305.22

Example 1 (R, S) -N- (α-methylbenzyl) -2-phenylquinoline-4-carboxamide

1.2 ml (9.4 mmol) of (R, S) -α-methylbenzylamine and 1.6 ml (11.7 mmol) of triethylamine (TEA) were dissolved under nitrogen in 50 ml of a 1: 1 mixture of dry CH2Cl2 and CH3CN.

2.0 g (7.8 mmol) of 2-ienylquinoline-4-carbonyl chloride dissolved in 50 ml of a 1: 4 mixture of dry CH2Cl2 and DMF were added dropwise to an ice-cooled amine solution and kept at 0 ° -5 ° C for 1 hour and left at room temperature overnight.

The mixture was evaporated in vacuo to dryness, the residue was dissolved in EtOAc and washed twice with saturated NaHCO3 solution. The organic layer was separated, dried over Na2SO4, filtered and evaporated in vacuo to dryness. The residual oil was crystallized from EtOAc to give 1.1 g of the title compound as a white solid.

C24H20N 2O

Melting point = 156-157 ° C

Molecular Weight = 352.43

Elemental analysis:

Calcd C, 81.79; FI, 5J2; N, 7.95;

Found: C, 81.99; Η,; N,

IR (KBr): 3240; 1645 cm ' ¹ .

300 MHz'H-NMR (DMSO-d6): 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).

MS (FI; source 200 ° C; 70V; 200mA): 352 (M +.); 337; 232; 204; 77.

Example 2

S - (+) - N- (α-methylbenzyl) -2-phenylquinoline-4-carboxamide

Prepared as in Example 1 from 1.2 ml (9.4 mmol) of S - (-) - ct-methylbenzylamine, 1.6 ml (11.7 mmol) of TEA, 2.0 g (7.8 mmol) of chloride 2 -ienylquinoline-4-carbonyl in 100 ml of a mixture of CH 2 Cl 2, CH 3 CN and DMF.

Work-up of the reaction mixture was carried out in the same manner as described in Example 1. The residual oil was crystallized from EtOAc to give 1.1 g of the title compound.

C24H20N2O

Melting point = 161-162 ° C

Molecular Weight = 352.43

[(] d20 = + 25 (C = 0.5, DMF)

IR (KBr): 3240; 1645 cm ' ¹ .

300 MFIz 1 H-NMR (DMSO-d ₆ ):? 9.29 (d, 1H); 8.32 (d. 2H); 8.13 (d. 1H); 8.13 (s. 1H); 8.06 (d. 1H); 1.81 (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).

The MS spectrum was identical to example 1.

Example 3

R - (-) - N- (α-methylbenzyl) -2-phenylquinoline-4-carboxamide

Prepared as in Example 1 from 1.2 ml (9.4 mmol) of R - (+) - α-methylbenzylamine, 1.6 ml (11.7 mmol) of TEA and 2.0 g (7.8 mmol) of chloride 2 -phenylquinol-4-carbcinyl in 100 ml of the mixture

188 872

CH2G2, CH3CN and DMF. The processing of the reaction mixture was the same. the method as described in Example 1. The residual oil was crystallized from EtOAc to give 1.1 g of the title compound.

C24H2ON2O

Melting point = 158-160 ° C

Molecular Weight = 352.43

[α] _η 2 ^θ = -25 (C = 0.5, DMF)

IR (KBr): 3240; 1645 cm- ¹ .

Ή-NMR and MS spectra were identical to Examples 1 and 2.

Example 4 (+) - (S) -N- [α- (methoxycarbonyl) benzyl] -2-phenylquinoline-4-carboxamide

2.0 g (8.0 mmol) of 2-phenylquinoline-4-carboxylic acid were dissolved in 70 ml of dry THF and 30 ml of CH3CN under a nitrogen atmosphere. 1.7 g (8.4 mmol) of methyl (L) -phenylcglycinate hydrochloride, 1.1 ml (9.9 mmol) of N-methylmorpholine and 2.1 g (15.5 mmol) of N-hydroxybenzotriazole (HOBT) were added and the reaction mixture was cooled to 0 ° C.

1.85 g (9.0 mmol) of DCC, dissolved in 10 ml of CH 2 Cl 2, was added dropwise and the solution was kept at 0 ° -5 ° C for 1 hour and then at room temperature for 2 hours. The precipitated dicyclichexylcrystalline was filtered off and the solution was evaporated under reduced pressure to dryness. The residue was dissolved in CH2Cl2 and washed with H2O, saturated NaHCO3, 5% citric acid, saturated NaHCO3, and saturated NaCl.

The organic layer was separated, dried over Na2SO4 and evaporated in vacuo to dryness; the residue was dissolved in 20 ml of CH2 CE and left overnight. The dicyclohexylurea that had precipitated was filtered off.

The solution was evaporated to dryness under reduced pressure to give 2.6 g of crude product which was triturated with petroleum ether, filtered, washed with i-Pr2O and then recrystallized with 70 ml of i-PrOH to give 1.7 g of the title compound.

C25H20N2O3

Melting point = 181-181 ° C

Molecular Weight = 396.45

I.R. (nujol): 3300; 1750; 1640 cm '!

[ajo = +42.0 (C = 0.5, MeOH).

Table 1 ΐ ² Z

Ex. Ar R Ri r ₂ R3 R4 R5 * Pattern temp. top ° C [α] ₀ ² θ c = 0.5, MeOH 1 Ph Me H. H. H. H. Ph (R, s) C24H20N2O 156-157 2 Ph Me H. H. H. H. Ph (S) C24H20N2O 161-162 + 25 ° a 3 Ph Me H. H. H. H. Ph (R) C24H20N2O 158-160 -25 ° ^a 4 Ph COOMe H. H. H. H. Ph (S) C25H20N2O3 180-181 + 42 °

188 872

The compounds of Examples 5-29 of general formula (I) (grouped in Table 2 below) were synthesized from the corresponding acyl chlorides of formula (II) and amines of formula (III) shown in the table and according to the synthesis procedure described in Example 1. Chlorides acyl was synthesized from the corresponding acid of formula (II) as described in description 1. The yields of the reaction were calculated relative to purified but non-crystallized material. The analytical and spectroscopic data of the compounds of Examples 5-29 are grouped in Table 4.

Table 2

Acyl chloride (II) + (III) -> (I)

Ex Chloride acyl (11) (111) (AND) Stereo- chemistry Pattern Mass part. Ed (%) Temp, m.p. ° C (Reg. krys) [α] ο ²⁰ (c = 1, MeOH) 1 2 3 4 5 6 7 8 9 10 5 e $ ,. ϊ, γθ COOMe (R) C 25H22N2O3 398.47 16 120-122 (iPiCj) -18.9 (c = 0.5) 6 ° ^ z ^C ΜγΟ -Ό) Η (R, s) single diast. C25H22N2O2 382.47 44 204-205 (iPrO ₂ / iPrt0 ₂ ) 7 Et (R, s) C26H22N2O2 396.49 48 163-165 (iPrOH / iPrO2) 8 y ox VyO El (R, s) C29H30N2O 422.58 thirty 120-122 (hexane) 9 Et ax (S) C26H24N2O 380.49 58 153-155 (iPrOz) -36.0 10 γ ¹ ca; Et Y (R) C26H24N2O 388.49 78 155-156 (1PrO 2) +35.9 11 «,’ ΓΌ COOMe (R, s) C26H22N2O4 426.48 55 124-125 (toluene) 12 • yO COOH (R, s) C25HI9FN2O3 414.44 75 146-147 (toluene) 13 Λ «.« YCC Et (R, s) C25H20O2N2O 435.36 44 193-194 (toluene) 14 OyCl ca. «, ΝγΟ El (R, s) C25H22N ₂ O 366.47 80 141-143 (toluene)

188 872 table 2 continued

1 2 3 4 5 6 7 8 9 10 15 ° <sx ^cl αχ ’,» Γθ COOK c $ f (R, s) C26H22N2O3 410.48 60 180-181 (toluene/- iPrO2) 16 ox «.ΓΟ Et cfc (R, s) C26H24N2O 380.49 55 156-158 (toluene/- hexane) 17 VyC COOMe Y »UO Jcir (R, s) C25H, 9ClN2O3 430.90 48 141-143 (toluene) 18 Oy £ l Πλ " VyO COOMe Y »<0 X $ C (R, s) C26H22N2O3 410.48 48 179-181 (toluene) 19 O ^ Cl Okay ko ^ ¹ c5 ^ (R, s) C25H22N2O2 382.47 42 144-145 (toluene) twenty », Γθ COOMe YV® ^cl sz ^ As U ** · © X (R, s) C25 ^ 1) C1N2O3 430.90 46 197-199 (toluene) 21 '' '' rSh Κ, »γθ COOMe Ύ'γΟ C&F (R, s) C27H24N2O3 424.50 52 156-157 (toluene/- hexane) 22 O ^ Ct H, y-0 nPr o $ y ° (R, s) C26H24N2O 380.49 50 149-150 (toluene) 23 about £ νΟ Et cS ^ (R, s) C27H26N2O 394.52 53 158-159 (Et2O / IPrO2) 24 ff ^ j ^ Y ^znPr «, ^Ν γΟ Et (R, s) C28H28N2O 408.55 71 149-151 (toluene/- hexane) 25 -¾ VvO Et (S) C ₂ 6H22Bi2N2O 538.30 24 230-231 (Et ₂ O / iPrO2) -49.8 (c = 0.2) 26 AND =, ’Χχθ Et (S) C 26 H ₂ 2BrN2O 459.40 39 179-180 (hexane / - iPrOH) -60.5

188 872 table 2 continued

1 2 3 4 5 6 7 8 9 10 27 ^l ' ^s ^ ^,, Sr''Ph Μ-νΌ Et (S) C26H24N2O2 396.49 58 132-134 (Me3CO) -45 (c = 0.5) 28 OyCI Et (S) C27H20N2O 394.52 53 118-120 (hexane) -42 (c = 0.5) 29 okay Et (R, s) C25H2, ClN2O 400.91 40 177-178 (toluene)

The compounds of Examples 30-41 of general formula (I) (grouped in table 3 below) were synthesized from the corresponding reagents of formula (II) and (III) shown in the table and according to the synthesis procedure described in Example 5. The yields of the reactions were calculated relative to the purified but non-crystallized material. The analytical and spectroscopic data of the compounds of Examples 30-41 are grouped in Table 4.

Table 3 (II) + (III) -> (1)

Ex (H) (110 (AND) Stereo- chemistry Pattern Mass part. Ed. (%) Temp top ° C (Reg. krys) Md20 (c = 1, MeOH) 1 2 3 4 5 6 7 8 9 10 thirty Ρ-γΌ COOWe γν® ^cw ** w? (R, s) C23H19N3O3 385.42 44 209-211 (iPrOH) 31 COOH , »Γθ CCOUo ^{£ ΟβΜ} · (R, s) C22H17N3O3 403.45 50 209-211 (iPrOH) 32 COOH cek, Κ · Μ · * " C25H22N2O 366.47 75 173-174 (iPrOH) 33 COOH σλ. , _ιν σ "Et (R, s) C26H24N2O 380.49 90 160-162 (iPrOH) 34 «,« Νθ Et v ~ ^> OX (S) C25H23N3O 381.48 78 153-155 (iPrOH / - iPrOp) -68.8 (c = 0.5) 35 COOH »? YO El (S) CjH2iClN2O 400.91 58 137-139 (toluene/- hexane) -40.5 (c = 0.5)

188 872 Table 3 continued

1 vol 3 4 5 6 7 8 9 10 36 COOH 0¾ Et (S) CtsHtiBrNtO 445.37 twenty 119-122 (toluene/- hexane) -41.4 (c = 0.5) 37 COOH , Ν-γ-Ο Et γνΟ (S) C25H22N2O 366.46 77 140-141 (iPrOH) -26.7 38 COOH ^t; , ^N yO Et σχ (R) C25H22N2O 366.46 51 151-152 (iPrOH) +26.6 39 COOH YyO Et (S) C25H22N2O2 382.47 66 122-125 (iPr2O) -28.4 (c = 0.5) 40 COOH αΧ Et ΟΧ ’ (R) C25H22N2O2 382.47 66 122-125 (hexane / - EtOAc) +27.2 (c = 0.5) 41 COOH c &: COOlfe c $ r (R) C25H20N2O4 412.45 70 125-127 (iPr2O) -50 (c = 0.5)

Table 4

Analytical and spectroscopic data of the compounds of examples 5-42

Ex Elemental analysis IR (KBr); cm ⁴ MS (EI, source 200 &lt; 0 &gt;C; 70 eV, 200 μΑ) 300 MHz. 1 H NMR (DMSO), 303 K AND 2 3 4 5 5 3240; 1750, 1640; 1595 1545 398 (M +); 232; 204 9.40 (d, 1H); 8.30 (d, 2H); 8.18 (d. 1H); 8.13 (d. 1H); 8.10 (s. 1H); 7.83 (dd. 1H); 7.66 (dd. 1H); 7.63-7.51 (m, 3H); 5.87 (s br, 1H), 5.70 (m, 2H); 5.12 (d, 1H) 3.80 (s, 3H); 2.92-2.60 (m, 4H). 6 Ob. C, 78.51, H, 5.80, N, 7.32 Zamak. C, 78.27, H, 5.83, N, 7.24 3400, 3200, 1640; 1595 1532 337 (M-C2H4OH) +, 232, 204 9.20 (d. 1H); 8.31 (d. 2H); 8.14 (d. 1H); 8.08 (s. 1H); 8.04 (d. 1H); 7.82 (dd. 1H); 7.64-7.51 (m, 4H); 7.47 (d, 2H); 7.37 (dd. 2H); 7.27 (dd. 1H); 5.10 (dd. 1H); 4.81 (d. 1H); 4.13 (dq. 1H); 1.18 (d, 3H) 7 Ob. C, 78.76; H, 6.10; N, 7.07 Found C, 78.60, H, 6.08; N, 7.00 3260; 3220, 1632, 1550 * 396 (M +); 367; 262; 219 9.24 (d. 1H); 8.07 (d. 1H); 7.97 (dd. 2H); 7.76-7.70 (m, 1H); 7.62-7.51 (m, 5H); 7.46 (d, 2H); 7.39 (dd. 2H); 7.29 (dd, 1H), 5.10 (d, 1H), 3.52 (s, 3H), 1.82 (dq, 2H); 1.00 (t, 3H) 8 Ob. C.82.43; H, 7.16, N, 6.63 Zamal C, 82.31; H, 7.20, N, 6.58 3240, 1630; 1540 423 (MH +) ' (353 K) · 8.89 (d Br, 1H), 8.00 (d, 1H); 7.70 (dd, 1H), 7.60-7.42 (m, 9H); 7.36 (dd, 2H), 7.28 (dd, 1H), 5.13 (dt, 1H); 2.66 (m, 2H); 1.90 (ddq, 2H), 1.30 (m, 2H); 1.00 (t, 3H), 0.95 (m, 2H), 0.57 (t Br, 3H)

188 872 table 4 continued

1 2 3 4 5 9 Obi Ci 82.07; H, 6.36; N, 7.36 3260, 380 (M +), 351; 246, (353 K) - 8.90 (d br, 1H); 8.01 (d. 1H); 7.72 (ddJH); Found Ci81.95, H, 6.33, N, 7.30 1630, 218 7.65 (d br, 1H); 7.60-7.49 (m, 6H); 7.46 (d. 2H); 7.38 1535 (dd. 2H); 7.24 (dd. 1H); 5.12 (dt. 1H); 2.30 (s, 3H); 1.98-1.78 (m, 2H); 0.99 (t, 3H). (353 K): 8.90 (d br, 1H), 8.01 (d, 1H), 7.72 (dd, 1H); Obi C, 82.07, H, 6.36, N, 7.36 380 (M +); 351.246, 7.65 (d br, 1H); 7.60-7.49 (m, 6H); 7.46 (d, 2H); 7.38 Zamal 0.81.80, H, 6.37, N, 7.30 218 (dd. 2H), 7.24 (dd. 1H), 5.12 (dt. 1H); 2.30 (s, 3H), 1 5.3 5 1.98-1.78 (m, 2H); 0.99 (t, 3H) 11 Obli C, 73.22; H, 5.20, N, 6.57 3282, 426 (M +); 367, 277 9.65 (d, 1H), 8.18 (d, 1H), 8.11 (d, 1H), 7.96 (s, 1H); He knew. 0.72.88, H, 5.25, N, 6.44 1750; 7.83 (dd. 1H); 7.81 (dd. 1H); 7.66 (dd, 1H), 7.54-7.46 1640; (m, 3H), 7.44-7.33 (m, 3H); 7.22 (d. 1H); 7.13 (dd. 1H); 1530 5.80 (d, 1H), 3.87 (s, 1H); 3.71 (s, 3H). 12 Obli C, 72.45; H, 4.62; N, 6.76 3320, 414 (M +); 355; 250, 9.70 (d, 1H); 8.21 (d. 1H); 8.16 (d. 1H); 8.07 (dd. 1H); Zamal 0.72.19; H, 4.66, N, 6.69 1745, 222 7.90 (d, 1H), 7.86 (dd, 1H); 7.72 (dd, 1H), 7.64-7.55 1650; (m, 1H), 7.51 (dd, 1H), 7.45-7.34 (m, 4H); 5.80 (d, 1H); 1595 3.75 (s, 3H). 13 Obli 0.69.03; H, 4.62, N, 6.44 3250; 434 (M +); 405,232; 9.50 (d, 1H), 8.31 (d, 2H); 8.15 (d, 1H), 8.10 (s, 1H), Zamak 0.68.97; H, 4.63, N, 6.43 1650, 204 8.00 (d. 1H); 7.81 (dd. 1H); 7.72 (d, 1H); 7.66 (d. 1H). 1585 7.64-7.52 (m, 4H); 7.46 (dd, 1H), 4.11 (dt, 1H), 1.83 1550 (dq, 2H); 0.98 (t, 3H) 14 Obli C, 81.93; H, 6.05, N, 7.64 3260, 366 (M + i), 337; 232, 9.24 (d. 1H); 8.30 (d, 2H); 8.14 (d. 1H); 8.09 (s, 1H), Found C, 81.79; H, 6.06, N, 7.62 1650, 204 8.02 (d. 1H); 7.82 (dd. 1H); 7.63-7.51 (m, 4H); 7.46 1595 (d. 2H); 7.38 (dd. 2H); 7.24 (dd. 1H); 5.14 (dt. 1H); 1550 1.95-1.78 (m, 2H); 0.98 (t, 3H) 15 Cald, 0.76.08, H, 5.40, N, 6.83 3260, 410 (M +), 351.261, 9.70 (d, 1H), 8.02 (d, 1H); 7.76 (dd. 1H); 7.70-7.47 Found C, 75.88, H, 5.37; N, 7.08 1755; 246,217 (m, 9H), 7.47-7.34 (m, 3H), 6.82 (d, 1H); 3.75 (s, 3H); 1735i 2.32 (s, br, 3H) 1640, 1580, 1530 16 Obli C.82.08; H, 6.36, N, 7.36 3220, 380 (M +); 351; 246, (353 K) 9.00 (d, 1H), 8.01 (d, 1H); 7.37 (dd, 1H), They knew C, 81.82, H, 6.34, N, 7.33 1630; 217 7.60-7.48 (ml, 7H); 7.45 (d. 2H); 7.38 (dd. 2H); 7.28 1550 (dd. 1H); 5.10 (dt, 1H); 2.28 (s. 3H); 2.00-1.80 (m, 2H); 1.00 (t, 3H) 17 Obli C, 69.69, H, 4.45, N, 6.50 3270, 430 (M +); 371.266, 9.78 (d, 1H), 8.29 (d, 2H), 8.24 (d, 1H), 8.19 (d, 1H); They knew C, 69.58, H, 4.49, N, 6.49 1750, 238; 203 8.16 (s, 1H), 7.73 (dd, 1H), 7.61-7.49 (m, 5H); 7.47-7.36 1670, (m, 3H); 5.80 (d, 1H); 3.79 (s, 3H). 1595 1520 18 Obli C, 76.49, H, 5.40; N, 6.82 3240, 410 (M +), 351, 246, 9.70 (d, 1H); 8.26 (d, 2H); 8.08 (s, 1H); 8.03 (d. 1H); Found C, 76.74, H, 5.40, N, 6.88 1750, 218 7.96 (s, 1H); 7.68 (dd, 1H); 7.60-7.50 (m, 5H), 7.48-7.36 1665, (m, 3H), 5.80 (d, 1H); 3.79 (s, 3H); 2.50 (s, 3H) 1590, 1510, 1500

188 872 table 4 continued

1 2 3 4 5 19 Obl. C, 78.51, H, 5.79, N, 7.32 3220, 382 (M +), 337; 232; 9.35 (d. 1H); 8.32 (d. 2H); 8.14 (d. 1H); 8.11 (d. 1H); He knew. C, 78.78; H, 5.78; N, 7.23 1740, 204 8.10 (s, 1H), 7.84 (dd, 1H); 7.64 (dd. 1H); 7.61-7.54 1695; (m, 3H); 7.50 (d, 2H); 7.40 (dd. 2H); 7.30 (dd. 1H); 1535 5.41 (dt, 1H); 3.73-3.60 (m, 2H); 3.36 (s, 3H). twenty Obl. C, 69.69, H, 4.45, N, 6.50 3240, 430 (M +), 371; 266; 9.80 (d, 1H), 8.29 (d, 2H); 8.27 (d. 1H); 8.21 (s, 1H), Zamak C, 70.27; H, 4.46, N, 6.45 1750; 238, 203 8.16 (d. 1H); 7.86 (dd. 1H); 7.61-7.51 (m, 5H); 7.48-7.38 1670, (m, 3H); 5.80 (d, 1H); 3.75 (s, 3H). 1590; 1550; 1500 21 Obl. C, 76.40, H, 5.70, N, 6.60 3240; 425 (MH +) ' (353 K). 9.52 (d. 1H); 8.01 (d. 1H); 7.89 (s br, 1H); 7.74 He knew. C, 76.44, H, 5.72, N, 6.62 1760; (dd. 1H); 7.60 (dd. 1H); 7.54-7.48 (m, 7H), 7.44-7.33 1640; (m, 3H); 4.88 (d, 1H); 3.78 (s, 3H), 2.91-2.68 (m, 2H); 1540 0.91 (t, 3H). 22 Obl. C, 82.08, H, 6.36; N, 7.36 3300; 380 (M +), 337; 232; 9.28 (d. 1H); 8.14 (d, 1H), 8.07 (s, 1H); 8.01 (d. 1H); He knew. C, 82.21, H, 6.39, N, 7.34 1635, 204 7.82 (dd, 1H), 7.64-7.51 (m, 4H); 7.46 (d, 2H), 7.39 1590, (dd, 2H), 7.28 (dd, 1H), 5.15 (dt, 1H); 1.94-1.69 (m, 2H), 1545 1.54-1.29 (m, 2H); 0.95 (t, 3H) 23 Obl C, 82.20; H, 6.64, N, 7.10 3240, 395 (MH +); CI. (353 K) 8.91 (d, 1H), 8.00 (d, 1H); 7.71 (dd. 1H); Found C, 82.34; H, 6.64, N, 7.07 1640; Reagent gas methane; 7.68-7.48 (m, 7H), 7.45 (d, 2H), 7.39 (dd, 2H); 7.29 1550 P 5000 mTr; (dd. 1H); 5.11 (dt. 1H); 2.78-2. 62 (m, 2H); 2.00-1.80 source 150 ° Cr (m, 2H), 1.00 (t, 3H); 0.90 (t Dr, 3H). 24 Obl. C, 82.32; H, 6.91; N, 6.86 3250; 408 (M +.); 379,289; (373 K): 8.72 (d, 1H); 8.00 (d. 1H); 7.70 (dd, 1H), Found C, 82.02; H, 6.95, N, 6.90 1635, 274; 246 7.55-7.42 (m, 9H); 7.38 (dd, 2H); 7.28 (dd. 1H); 5.15 1550 (dt, 1H), 2.66 (dd, 2H), 1.94 (ddq, 2H); 1.33 (m, 2H); 1.01 (t, 3H), 0.56 (t, 3H) 25 Ob. C, 58.02, H, 4.12, N, 5.20, 3250; 537/539/541 (MH +) ' (353 K). 8.95 (d. 1H); 7.96 (d. 1H); 7.83 (dd. 1H), 7.76 Br, 29.69 1650, (d, 1H); 7.71 (d. 2H); 7.55 (d. 2H); 7.45 (dd. 2H); 7.39 He knew. C, 58.14; H, 4.18; N, 5.22; 1540 (dd. 2H), 7.30 (dd. 1H); 5.10 (dt, 1H), 2.92 (s, 3H); Br, 29.44 2.30 (s, 3H); 1.88 (ddq, 2H), 1.01 (t, 3H). 26 Ob. C, 67.98, H, 5.04; N, 6.10; 3260, 459/461 (MH +) * (353 K) 8.94 (d br, 1H); 7.96 (d. 1H); 7.81 (dd. 1H); Br, 17.39 1640, 7.76 (d, 1H), 7.60-7.49 (m, 4H), 7.45 (d, 2H); 7.40 Zamak C, 68.04; H, 5.02, N, 6.05; 1540 (dd. 2H), 7.30 (dd. 1H); 5.10 (dt, 1H); 2.30 (s, 3H); Br, 17.26 1.89 (ddq, 2H); 1.01 (t, 3H). 27 Ob. C, 78.74, H, 6.10; N, 7.06 3250, 396 (M +.), 367, 262, 9.24 (d, 1H), 8.07 (d, 1H); 7.97 (dd, 2H), 7.76-7.70 Zamak C, 78.72, H, 6.10; N, 7.01 1635; 219 (m, 1H), 7.62-7.51 (m, 5H); 7.46 (d. 2H); 7.39 (dd. 2H); 1550, 7.29 (dd. 1H); 5.10 (dt, 1H); 3.52 (s, 3H); 1.82 (dq, 2H), 1500 1.00 (t, 3H). 28 Ob. C, 82.18, H, 6.64, N, 7.10 3250, 394 (M +.); 365, 275; (353 K) '8.90 (d br, 1H), 8.00 (d, 1H), 7.70 (dd, 1H), Zamak C, 81.93, H, 6.64, N, 7.05 1630, 260 7.56-7.42 (m, 9H); 7.38 (dd. 2H); 7.29 (dd. 1H); 5.13 1540, (dt. 1H); 2.72 (m, 2H), 1.90 (ddq, 2H); 1.00 (t, 3H); 1500 0.90 (t br, 3H).

188 872 table 4 continued

1 2 3 4 5 29 Obi C, 74.90, H, 5.28, N, 6.99 3270, 400 (M +), 371; 232, 9.20 (d, 1H), 8.32 (d, 2H); 8.08 (dd. 2H); 8.06 (s, 1H), Found C, 74.67; H, 5.33. N, 7.03 1645 204 7.82 (t, 1H), 7.65-7.40 (m, 8H), 5.00 (dt, 1H), 1.93-1.73 1590, (m, 2H), 0.98 (t, 3H) 1550; 1495; 770 thirty Ob. C, 71.68; H, 4.97, N, 10.90 3410, 385 (M +), 221; 193 11.68 (s br, 1H), 9.71 (d, 1H); 8.17 (d, 1H), 7.99 He knew. C, 7I, 39, H, 4.99; N, 10.81 3250, (d, 1H); 7.86 (s. 1H); 7.66 (dd, 1H), 7.58-7.35 (m, 6H), 1740, 7.00 (s br, 2H); 6.22 (s br, 1H); 5.75 (d. 1H); 3.73 (s, 3H). 1678, 1600 * 31 Obl. C, 65.50, H, 4.25; N, 10.42 3300, 344 (M-COOCH ₃ ) +, 9.82 (d. 1H); 8.28 (s. 1H); 8.19 (d. 1H); 8.14 (d, 1H) He knew. C, 65.48; H, 4.22; N, 10.38 1755; 239.21 1 8.10 (d. 1H); 8.00 (d. 1H); 7.88 (dd, 1H), 7.73 (dd, 1H), 1645; 7.53 (d. 2H); 7.47-7.36 (m, 3H); 5.80 (d, 1H); 3.78 (s, 3H) 1585 1530 OM C, 81.94, H, 6.05, N, 7.64 220, 366 (M +), 351; 248, 9.01 (s br, 1H), 8.34 (dd, 2H), 8.15 (s, 1H); 8.13 1640, 32 Found C, 82.02, H, 6.07, N, 7.60 590; 232.204 (d, 1H); 8.01 (d, 1H), 7.81 (dd, 1H); 7.66-7.52 (m, 6H), 1545 7.39 (dd. 2H); 7.25 (dd, 1H) 33 OM C, 82.07, H 6.36, N, 7.36 320, 380 (M +), 351.232, 9.20 (d. 1H); 8.29 (dd. 2H); 8.14 (d, 1H), 8.06 (s, 1H); He knew. C, 82.15; H, 6.36, N, 7.41 1640; 204 8.03 (d, 1H), 7.81 (dd, 1H); 7.64-7.50 (m, 4H), 7.34 590, (d, 2H), 7.19 (d, 2H), 5.00 (dt, 1H), 2.30 (s, 3H), 1530 1.93-1.73 (m, 2H), 0.98 (t, 3H). 34 Obl. C, 78.71, H, 6.08; N, 11.01 3490, 381 (M +.), 352; 247; 9.20 (d, 1H), 7.87 (m, 1H); 7.70 (d, 2H); 7.59-7.26 He found C.78.45; H, 6.10, N, 10.96 3380, 219.218 (m, 11H); 5.08 (dt, 1H); 4.80 (s br, 1H); 2.81 (dq. 2H); 3260, 0.95 (0.3H) 1630, 1600 35 Otl. C / 74.90, H, 5.28, N, 6.99; 3230; 400 (M +); 371; 266, 9.37 (d, 1H); 8.10 (d, 1H); 7.85 (dd. 1H); 7.75-7.35 Cl, 8.84 1640, 238, 203 (m, 12H); 5.07 (dt, 1H), 1.80 (dq, 2H), 0.98 (t, 3H). Zamak C.74.88, H, 5.25, N, 6.98, Cl, 8.92 1550 36 Ob! C, 67.42, H, 4.75; N, 6.29; 3240, 444/446 (M-h), 9.35 (d, 1H); 8.10 (d, 1H); 7.85 (dd br, 1H), 7.70-7.30 Br, 17.94 1640, 415/417; 310/312, (m, 12H) 5.05 (dt, 1H); 1.81 (dq. 2H); 0.99 (t, 3H) He knew. C, 67.57; H, 4.80, N, 6.31; Br, 18.00 1545 203 37 Obl. C, 81.94, H, 6.05; N, 7.64 3320; 366 (M +); 337; 232, 9.24 (d, UI), 8.30 (d, 2H), 8.14 (d, 1H); 8.09 (s, 1H), Zamak C, 79.33, H, 5.82, N, 7.34 1635, 204 8.02 (d. 1H); 7.82 (dd, 1H), 7.63-7.51 (m, 4H); 7.46 1590, (d, 2H), 7.38 (dd, 2H), 7.24 (dd, 1H), 5.14 (dt, 1H), 1535 1.95-1.78 (m, 2H), 0.98 (t, 3H) 38 Ob. C, 81.94, H, 6.05. N, 7.64 3280, 366 (M +), 337, 232, 9.24 (d, 1H); 8.30 (d, 2H); 8.14 (d. 1H); 8.09 (s. 1H); He knew. C, 82.08, H, 6.09, N 7.59 1637, 204 8.02 (d, 1H), 7.82 (dd, 1H), 7.63-7.51 (m, 4H); 7.46 1590, (d.2H); 7.38 (dd. 2H); 7.24 (dd. 1H); 5.14 (dt, 1H), 1540 1.95-1.78 (m, 2H), 0.98 (t, 3H)

188 872 table 4 continued

1 2 3 4 5 39 Obl. C, 78.51; H, 5.80; N, 7.33 3370; 382 (M +.), 264; 247; 9.80 (s. 1H); 9.11 (d, 1H), 8.00-7.94 (m, 3H), 7.61-7.42 Found C, 78.49; H, 5.84, N 7.26 1625, 1525 219 (m, 8H), 7.38 (dd, 2H); 7.28 (dd. 1H); 5.06 (dt, 1H); 1.82 (ddq, 2H), 0.97 (t, 3H) 40 Obl. C, 78.51; H, 5.80; N, 7.33 3270, 382 (M +.); 264, 247; 9.80 (s. 1H); 9.11 (d, 1H), 8.00-7.94 (m, 3H); 7.61-7.42 He found C.78.55; H, 5.84; N, 7.30 1650, 1630, 1570, 1535 219 (m, 8H); 7.38 (dd. 2H); 7.28 (dd. 1H); 5.06 (dt, 1H), 1.82 (ddq, 2H), 0.97 (t, 3H). 41 Obl C, 72.80; H, 4.89; N, 6.79 3360, 412 (M +); 353; 248; 9.85 (s. 1H); 9.63 (d br, 1H); 7.97 (m, 3H); 7.89 (d br, 1H) He knew. C.72.12, H, 4.88, N, 6.63 1735; 1625; 1530 219 7.62-7.34 (m, 10H); 5.75 (d, 1H); 3.76 (s, 3H)

* oil tablet; • FAB POS, thioglycerin matrix, Xe gas, 8 KeV, 50 ° C source

Example 42 (R, S) -N- [α- (methylcarbonyb) ben / yl] -2-phenylchmoline-4-carbonoxyamide

0.27 ml (3.1 mmol) of oxalyl chloride was dissolved in 2.3 ml of dry CH2Cl2 under a nitrogen atmosphere.

The solution was cooled to -55 ° C and 0.22 ml (3.1 mmol) of DMSO dissolved in 0.7 ml of dry CH 2 O 2 was added dropwise maintaining the temperature below -50 ° C. The reaction was stirred at -55 ° C for 7 minutes, then 0.97 g (2.5 mmol) of (R, S) -N- [α- (1-hydroxyethic)) benzyl | -2-phenylicicliin-4- carboxamide (compound of Example 6), dissolved in 25 ml of dry CH2G2, keeping the temperature between -50 and -55 ° C.

After 30 minutes at -55 ° C, 1.9 mL (13.6 mmol) of TEA was added not exceeding -40 ° C, then the reaction mixture was allowed to warm to room temperature and stirred for an additional 15 minutes.

The reaction was quenched with 5 mL of H 2 O and extracted with CH 2 Cl 2, the organic layer was washed with H 2 O, 20% citric acid, saturated NaHCO 3, and brine; the organic layer was separated, dried over Na2SO4 and evaporated in vacuo to dryness.

The residual oil was flash chromatographed on 0.06-0.37 mm (230-400 mesh) silica gel, eluting with a 70:30 hexane / ethyl acetate mixture containing 0.5% concentrated NH4OH to give 0.64 g of the crude product which was triturated. with warm i-Pr ₂ O / i-PrOH 2: 1, filtered, washed and dried to give 0.5 g of the title compound.

C25H20N 2 O2

Melting point = 160-161 ° C

Molecular Weight = 380.45

Elemental analysis:

Calculated C, 78.93; H, 5.30; N, 7.36;

Found: C, 79.01; H, 5.31, N, 7.27.

IR (KBr): 3400; 3265; 1725; 1660; 1640; 1592 cm ' ¹ .

300 MHz 1 H-NMR (DMSO-d 6): 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); 7.48-1.36 (m, 3H); 2.19 (s, 3H).

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

188 872

Example 43

(S) -N- (α-ethylrbenzyl) -3- (2-O-methylaminretoxy) -2-phenyhinrlin-4-carboxamide hydrochloride

0.62 g (1.6 mmol) of (S) -N- (α.-ethylbenzyl) -3-hydroxy-2-phenylquinoline-O-corboxomide (compound of Example 39) was dissolved in 30 ml of dry DMF. 0.58 g (4.0 mmol) of dimethylaminoethyl chloride hydrochloride and 0.56 g (4.0 mmol) of K2 CO3 are added and the reaction mixture is heated to reflux for 20 hours. K2CO3 was filtered off and the mixture was evaporated in vacuo to dryness, dissolved in AcOEt and washed with H2O and 20% citric acid. The aqueous layer was solSalizomo6o with 2N NaOH and extracted with EtOAc; the organic layer was washed with brine, separated. dried over No2SO4 and evaporated in vacuo to dryness.

The residue was flash chromatographed on 0.06-0.37 mm (230-400 mesh) silica gel, eluting with CH2Cl2 / MeOH 98: 2 containing 0.4% concentrated NH4OH and then CH2O2 / MeOH 86:10 containing 0, 6% concentrated NH4OH to give 85mg of crude product which was dissolved in EtOAc and treated with HCl / Et2O to give 75mg of the title compound.

C29H31N3O2-HCl

Melting point = 70 ° C with decomposition

Molecular Weight = 490.05

1R. (nujol): 3600; 3100; 1650; 1550 cm'1

300 MHz. 1-NMR (DMSO-6 g): 10.28 (s br, 1H); 9.50 (d. 1H); 8.10 (d. 1H); 1.96 (dd. 2H); 7.78 (m, 1H); 7.67-7.61 (m, 2H); 1.61-7.51 (m, 3H); 7.49-7.39 (m, 4H); 7.33 (OOIH); 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, thiogliceoy 6 ohm matrix, Xe gas, 8 KeV, 50 ° C source): 454 (MH +).

Example 44 (S) -N- (α-ethylbenzyl) -3-acetyl-4-phenylquinoline-4-carboxomide

0.40 g (1.05 mmol) of (S) -N- (α-ethylrbenzyl) -0-ami6o-2-phenylquinimoo4-carboxylO (compound of Example 34) was heated in 25 ml acetic anhydride at 70 ° C for 1 one hour and then at 100 ° C for an additional 3 hours.

The reaction mixture was then evaporated in vacuo to dryness and the residue was dissolved in EtOAc; the solution was washed with water, saturated NoHCO3, brine, dried over Na ₂ SO 4 and evaporated under reduced pressure to dryness. The crude product (0.39 g) was purified by column chromatography on silica gel. eluting with a mixture of hexane / Et 2 OA 4 / Concentrated NH 4 OH 70: 30: 0.5, respectively, to give 0.2 g of pure compound which was recrystallized from acetone to give 0.14 g of the title compound.

C27H 25N 3O2

Melting point = 268-269 ^° C

Molecular Weight = 423.52

Elemental analysis:

Calculated C, 16.57; PI, 5.95; N, 9.92;

Found C, 76.38; H, 5.98; N, 9.90.

LR. (KBr): 3230; 1670; 1640; 1555; 1525 cm'1

300 MHz'H-NMR (DMSOO6): 9.65 (s, 1H); 9.05 (d. 1H); 8.10 (d. 1H); 1.80 (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 &lt; 0 &gt;C; 70 eV; 200 Al. 1: 43 3 (M +. 13 311; 344; 289; 211; 447; 118.

Example 45

(-) - (S) -N- (α.-ethylrbeI6ζyl) -3- (O-dimethylaminopropoxy) -2-phenylchmino-4-korboxamino hydrochloride

1.2 g (3.1 mmol) of (-) - (S) -N- (α.-ethylrbenzyl) -3-hydroxy-2-phenylquinoline-O-carboxamide (compound of example 39) was dissolved in 15 ml of dry THF . 1.0 g mmol) O-chloro-O-methylamino-propyl was added. dissolved in 10 mL of ΙΉΟ, 1.3 g mmol) K2CO3 and 0.16 g KJ and the mixture was stirred at room temperature for 30 minutes and then heated under reflux for 2 hours. Further 0.77 g mmol), 1.0 g (8.2 mmol), 0.6 g (4.9 mmol) and 0.6 g (4.9 mmol) of O-methylaminopropyl chloride were added every 12 hours.

Was dissolved in 10 mL of Et2O each time, and some KJ was added every 12 hours and the reaction was heated to reflux.

K2CO3 was filtered off and the mixture was evaporated in vacuo to dry mash, dissolved in EtOAc and washed with IbO and 20% citric acid. The aqueous layer was basified with 2N NaOH and extracted with EtOAc; the organic layer was washed with brine, separated, dried over Na 2 SO 4, and evaporated under reduced pressure to a loose mass.

The residue was flash chromatographed on silica gel, 0.06-0.37mm, (230-400 mesh), eluting with CHtClt / MeOH 95: 5 containing 0.5% concentrated NH4OH to give 0.9 g of crude product which was dissolved in EtOAc and treated with HCl / Et2D to give 0.62 g of the title compound.

C30H33N3O2 · HCl

Melting point = 108 ° C with decomposition

Molecular Weight = 504.08

[a] _d 20 = -16.0 (c = 0.5, MeOH)

IR (KBr): 3400; 3080; 1655; 1545 cm ⁴ .

300 MHz. 1 H-NMR (DMSO-d ₆ ): δ 10.55 (r br, 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; 70V; 200mA): 467 (M +.); 466; 395; 58.

Example 46

Hydrochloride (-) - (S) -N- (a-ethylbei ^^; ^lo) - ^: ^ - [: ^^ (1-ftai ^ olo) ethokry) -2-phenylquinoline-4-carboxamide

1.9 g (5.0 mmol) of (-) - (S) 4 ^ '- (α-ethylben / yl) -3-by-oxy-2-phenylquinobno-4-carboxamip (compound of example 39) was dissolved in 20 ml dry THF.

3.8 g (14.9 mmol) of O-2-SalimidoethldI bromide was dissolved in Hm and Timi was added 2.0 g (14.5 mmol) of K 2 O 3 and 0.25 g of KJ and the reaction mixture was stirred at room temperature for 2.5 hours and then heated to reflux for 2 hours. 1.9 g (7.4 mmol) of 2-phthalimioethyl bromide and some KJ were added and the reaction was heated to reflux for an additional 3.5 hours.

0.5 g (2.0 mmol) of 2-phthalimioethyl bromide and some KJ were again added and the mixture was heated to reflux for 5 hours.

K 2 CO 3 was filtered off and the mixture was evaporated in vacuo to dryness, taken up in CH 3 h and washed with HA). The organic layer was dried over Na2SO4 and evaporated in vacuo to dryness.

The residue was flash chromatographed on 0.06-0.37 mm silica gel (230-400 mesh), eluting with 80:20 hexane / EtOAc containing 0.5% concentrated NH4OH followed by hexane / EtOAc 60:40 containing 0 -5% concentrated NH4OH to give 2.6 g of purified product which was triturated with i-Pr2O to give 2.5 g of the title compound.

C35H29N 3O4

Melting point = 172-175 ° C

Molecular Weight = 555.64

[a] _D 20 = -16.3 (c - 0.5, MeOH)

IR (KBr): 3280; 3060; 2960; 1780; 1715; 1660; 1530 cm ⁴ .

300 MHz'H-NMR (DMSO-d6): 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 (dq. 2H); 0.93 (t, 3H).

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

Example 47

(-) - (S) -N- (a.-ethylbenzyl) -3- (2-aminoethoxyl) -2-phenylquinoline-4-carboxamide

2.2 g (3.9 π (πιο1) chk) hydrocarbon L -) - (S) -N ((α-ethyl (obenzole) -3- [0) -3- [taloyl) eloOsyt-2-phenylquinohno- 4-SarboSsamiOp (compound of Example 46) was dissolved in 150 ml of 96% EtOH and 0.38 ml (7.8 mmol) of hydrazine hydrate was added to the boiling solution which was then heated under reflux for 4 hours.

188 872

Additional 0.4 ml (8.2 mmol), 0.2 ml (4.1 mmol), 0.2 ml (4.1 mmol), 0.4 ml (8.2 mmol) and 0 , 4 wl (8.2 vol) hydrazine hydrate and the reaction mixture was heated to reflux.

The reaction mixture was then evaporated to dryness under reduced pressure, dissolved in 20 ml of H 2 O, cooled and acidified with 10 ml of concentrated HCl.

The mixture was boiled for 1 hour and cooled; the phthalyl hydrazide was filtered off. The aqueous layer was washed with EtOAc and then recalculated with 2NNaOH and extracted with EtOAc; the organic layer was washed with brine, separated, dried over Na2SO4 and evaporated in vacuo to dryness.

The residue was flash chromatographed on 0.06-0.37 mmw (230-400 mesh) silica gel, eluting with EtOAc / MeOH 96: 4 containing 1.2% concentrated NH4OH to give a purified product which was dissolved in EtOAc and treated with HCl / Ethyl to give 1.2 g of the title compound.

C27H27N3O2 · HCl

Melting point = 119 DEG C. with decomposition

Molecular Weight = 462.00

[α] d ²⁰ = -19.4 (c = 0.5, MeOH)

I.R. (KBr): 3400; 3080; 1640; 1545 cm '

300 MHz 1 H-NMR (DMSO-d 6): δ 9.4 5 (d, 1H); 8.99 (d, 1H); 8.00 (dd. 1H); 1.44 (s br. 3H);

7.76 (ddd. 1H); 7.65-7.51 (w, 4H); 7.48-7.40 (w, 3H); 7.31 (dd. 1H); 5.09 (dt, 1H); 3.83 (t, 2H); 2.72 (d, 2H); 1.93-1.80 (m, 2H); 0.99 (t, 3H).

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

Example 48

(+) - (S) -N- (α-etzlybelezyl) -3- [2- (1-pyrrolid; zeyl) ethoxy] -2-phenylquinolmy-4-Nebbyoxhavid hydrochloride

2.0 g (5.2 mmol) of (-) - (S) -N- (α-etzlybeezzry) -3-hzdroksz-2-phenylquininyriey-4-carbyksh-amide (compound of example 39) was dissolved in 25 l of dry THF.

1.0 g (7.5 mmol) of 2-pibylidyethyl chloride and 2.2 g (15.9 vol) of K2CO3 were added and the reaction mixture was stirred at room temperature for 30 minutes and then heated to reflux; 1.1 g (8.2 mmol) of 2-pyrrolidine ether chloride were added to the boiling solution, which was heated to reflux overnight.

K 2 CO 3 was filtered off and the mixture was evaporated in vacuo to dryness, dissolved in EtOAc and washed with H 2 O and 20% citric acid. The aqueous layer was quenched with 2 N NaOH and extracted with EtOAc; the organic layer was washed with brine, separated, dried over Na2SO4 and evaporated in vacuo to dryness.

The residue was flash chromatographed on 0.06-0.37 mmw (230-400 mesh) silica gel, eluting with CFhCh / MeOH 97: 3 containing 0.5% concentrated NH4OH to give 1.8 g of purified product which was dissolved in EtOAc and treated with HCl / Et2O to give 2.0 g of the title compound.

C31H33N3O2 HC 1

Melting point = 110-115 ° C with decomposition

Molecular Weight = 516.08

[<x] d20 = + 4.5 (c = 0.5, MeOH)

IR (KBr): 3400; 3080; 1655; 1545 cm ' ¹ .

300 MHz 1 H-NMR (DMSO-d 6): δ 10.50 (s br, 1H); 9.50 (d. 1H); 8.10 (d. 1H); 7.96 (dd. 2H); 7.78 (ddd, 1H); 7.68-7.30 (w, 10H); 5.10 (dt, 1H); 3.90 (w, 2H); 3.20 (m, 2H); 3.00 (w, 2H); 2.65 (m, 2H); 1.95-1.65 (w, 6H); 1.94 (t, 3H). '

MS (EI; source 180 ° C; 70V; 200mA): 479 (M +.); 478; 383; 97; 84.

Example 49 (-) - (S) -N- (σ.-etzlybcesyl ') - ^ 3 · ^ (diimctzlyamieykcetzlyamiey) -2-fcezlychinyriey-4-WkbbyWsz-amide

1.1 g (2.8 mmol) of (-) - (S) -N- (α-ethylbenzyl) -3-amino-2-penzyquinilin-4-Wbrby. Shamide (compound of example 34) was dissolved in 10 ml under nitrogen. warm toluene. 0.96 g (5.6 mmol) of chloroacetic anhydride, dissolved in 5 ml of toluene, was added dropwise, and the solution was heated to reflux for 1 hour.

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The reaction mixture was evaporated to dryness under reduced pressure, suspended in 10 ml of CH2Cl2 and added dropwise to 5 ml of ice-cooled 28% Me2NH / EtOH.

The solution was stirred at room temperature overnight, then 15 mL of 28% Me2NH / EtOH was added and the reaction mixture was heated to 60 ° C on a Parr apparatus.

The mixture was evaporated in vacuo to dryness, dissolved in 20% citric acid and washed with EtOAc. The aqueous layer was basified with 2N NaOH and extracted with EtOAc; the organic layer was washed with brine, separated, dried over Na2SO4 and evaporated in vacuo to dryness to yield 1.4 g of crude product. The product was triturated with warm i-Pr2O to give 0.86 g of the title compound.

C29H 30N 4O2

Melting point = 189-191 ° C

Molecular Weight = 466.59

[a] o ² 0 = - 63.1 (c = 0.5, MeOH)

I.R. (KBr): 3230; 3180; 1670; 1630; 1540 cm '.

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; 200mA): 466 (M +.); 331; 58.

Example 50

N- (α, α-dimethylbenzyl) -3-hydroxy-2-phenylquinoline-4-carboxamide

2.0 g (7.5 mmol) of 3-hydroxy-2-phenylquinoline-4-carboxylic acid were dissolved under nitrogen in 70 ml of dry THF and 30 ml of CH3CN.

1.02 g (7.5 mmol) of cumylamine and 1.12 g (8.3 mmol) of N-hydroxybenzotriazole (HOBT) were added and cooled to -10 ° C.

1.71 g (8.3 mmol) of DCC, dissolved in 20 ml of CH 2 Cl 2, was added dropwise and the solution was kept at -5 ° -0 ° C for 2 hours and at room temperature overnight. The precipitated dihydrohexylurea was filtered off and the solution was evaporated under reduced pressure to dryness. The residue was dissolved in CH 2 CE and washed with H 2 O, saturated NaHCO 3, 5% citric acid, saturated NaHCO 3, and brine.

The organic layer was separated, dried over Na2SO4 and evaporated in vacuo to dryness; the residue was dissolved in 20 ml of CH2 CE and left overnight. Some more dicyclohexylurea precipitated out and was filtered off. The solution was evaporated in vacuo to dryness to yield 1.4 g of crude product which was flash chromatographed on 0.06-0.37 mm silica gel (230-400 mesh), eluting initially with hexane / EtOAc 9/1 and then hexane / EtOAc 8/2 to give 0.4 g of purified product which was recrystallized twice with i-PrOH to give 0.15 g of the title compound.

C25H22N 2O2

Melting point = 166-169 ° C with decomposition

Molecular Weight = 382.47

I.R. (nujol): 3200; 1650; 1580; 1535 cm'1

300 MHz. 1H-NMR (DMSO-d6): δ 9.56 (s, 1H); 8.92 (s br, 1H); 8.00-7.94 (m, 3H); 7.76 (d br, 1H); 7.63-7.45 (m, 7H); 7.36 (dd. 2H); 7.24 (dd. 1H); 1.72 (s, 6H).

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

Example 51

N- (α, α-dimethylcbenzyl) -3-ammo-2-phenylquinoline-4-carboxamide

2.0 g (7.6 mmol) of 3-amino-2-phenylquinoline-4-carboxylic acid were dissolved under nitrogen in 70 ml of dry THF and 30 ml of CH 3 CN.

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 to -10 ° C.

1.72 g (8.3 mmol) of DCC, dissolved in 20 ml of CH2 CE, were added dropwise and the solution was kept at -5 ° -0 ° C for 2 hours and then at room temperature overnight. The precipitated dicyclohexyltartrate was filtered off and the solution was evaporated under reduced pressure to dryness. The residue was dissolved in CH2Cl2 and washed with H2O,

Saturated NaHCO ₃ solution, 5% citric acid, saturated NaHCO ₃ solution and brine.

The organic layer was separated, dried over Na2SO4 and evaporated in vacuo to dryness; the residue was dissolved in 20 ml of CH2 Cl2 and left overnight. Further dicyclohexylurea precipitated and filtered off. The solution was evaporated to dryness in vacuo to give 2.0 g of a crude product which was flash chromatographed on silica gel 0.06-0.37 mm (230-400 mesh) eluting with a hexane / EtOAc 6/4 mixture containing 1% concentrated NH4OH to give 0.9 g of purified product which was recrystallized from hexane / EtOAc 1/1 and then from i-PrOH to give 0.45 g of the title compound.

C25H23N3O

Melting point = 166-168 ° C

Molecular Weight = 381.48

IR (nujol): 3460; 3360; 3220; 1667; 1605; 1527 cm ' ¹ .

300 MHz. 1-NMR (DMSO-d 6): 89.05 (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; 70V; 200mA): 381 (M +.); 263; 218; 119.

Example 52 (-) - (S) - \ ^ α-ethylbem / qjo) -5-inethyl-2-imylquinolinc! -4-carboxamide

0.80 g (3.04 mmol) of 5-methylc-2-phenylquinoline-4-carboxylic acid was dissolved under nitrogen in 30 ml of dry THF and 12 ml of CH3CN.

0.43 g (3.20 mmol) of (S) - (-) - α - 4-ethylbenziline and 0.78 g (5.78 mmol) of N-hydroxybenzctriazole (HOBT) were added and the reaction mixture was cooled to temperature -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 ° -0 ° C for 2 hours and then at room temperature overnight. The precipitated dicyclohexyl chloride was filtered off and the solution was evaporated in vacuo to dryness. The residue was dissolved in CH2Cl2 and washed with H2O, saturated NaHCO3, 5% citric acid, saturated NaHCO3, and brine.

The organic layer was separated, dried over Na2SO4 and evaporated in vacuo to dryness; the residue was dissolved in 10 ml of CH2 Cl2 and left overnight.

Further dicyclohexylm3c / nic precipitated and was filtered off. The solution was evaporated to dryness in vacuo to yield 1.15 g of crude product which was flash chromatographed on 0.06-0.37 mm silica gel (230-400 mesh) eluting with a hexane / EtOAc 6/2 mixture containing 0, 5% concentrated NH4OH to give 0.47 g of purified product which was recrystallized from i-Pr20 containing a few drops of EtOAc to give 0.36 g of the title compound as a white powder.

C26H24N 2O

Melting point = 189-192 ° C

Molecular Weight = 380.49

[a] o20 = - 3.8 (c = 0.5, MeOH)

1.R. (KBr): 3280; 3070; 3020; 1635; 1545 cm '.

300 MHz H-NMR (DMSO-d _C): 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 (s br. 3H); 1.70-1.90 (m, 2H); 0.95 (t, 3H).

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

Example 53 (R, S) -N- [α- (1-Yydroxyethyl) benzyl] 33-methyl-2-eenylquinoline-4-carboxamide

Prepared as described in Example 1, starting with 11.08 g (39.33 mmol) of crude 3-methylol-2-phenylquinoline-4kα4 'bonyl chloride, 4.87 g (32.20 mmol) of Ι-- © ^ - © ^ -! '^!'! - xypropylamine and 10.33 ml (74.14 mmcl) TEA in 150 ml of a 1: 1 mixture of dry CH2 C 'and CH3CN.

The precipitated TEA hydrochloride was filtered off and the filtrate was concentrated under reduced pressure to dryness; the residue was dissolved in CH 2 Cl (100 ml) and washed with saturated NaHCO 3 solution, 20% citric acid and brine. The organic solution was dried over Na2SO4 and evaporated in vacuo to dryness to yield 13.23 g

An oil that was crystallized from i-PrO ₂ (100 ml) containing 6 ml of i-PrOH to give 9.14 g of the title compound as an off-white solid.

C26H24N 2O2

Melting point = 163-165 ° C

Molecular Weight = 396.49

IR (nujol): 3400; 3260; 1635; 1580 cm ' ¹ .

Example 54 (R.S) -N - [(x- (methylcarbony / o) benz, yl] -3-methyl-2-ienylquinol-4-carboxamide

Prepared as described in Example 42, 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) (R, S) - N- [α- (1-hydroxy-ethyl-benzyl] -G-methyl-phenylquinoline-A-carboxamide (compound of example 108) and 15.72 ml (112.76 mmol) TEA in 230 ml dry CH2Cl2.

The reaction was quenched with 40 mL of H 2 O and the organic layer was separated and washed with 20% citric acid, saturated NaHCO 3, and brine. The organic solution was dried over Na2SO4 and evaporated in vacuo to dryness to yield 9.4 g of the crude title compound as an oil. The residual oil was flash chromatographed on 0.06-0.37 mm (230-400 mesh) silica gel, eluting with 70:30 hexane / ethyl acetate containing ¹⁰ % concentrated NH4OH to give 7.7 g of purified product which was crystallized from 1: 3 EtOAc / hexane mixtures, respectively, to give 6.0 g of pure title compound.

C26H22N2O2

Melting point = 156-158 ° C

Molecular Weight = 394.48

IR (nujol): 3270: 3180; 1735; 1725; 1660; 1630; 1527; 1460 cm ' ¹ .

300 MHz'H-NMR (DMSO-d6): 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 (s br. 3H); 2.18 (s, 3H).

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

Example 55 (R, S) -N - [α- (ethyl) -2-thiene methyl] -2-phenylquinoline-4-hydroxyamide

1.40 g (8.00 mmol) of 1- (2-thienyl) -n-propγylaminγ hydrochloride and 2.45 ml (17.60 mmol) of TEA were dissolved under nitrogen in 50 ml of dry CH2Cl2 and 30 ml of CH3CN.

2.0 g (8.00 mmol) of 2-phenic) -cicnoline-4-carboxylic acid and 1.30 g (9.60 mmol) of N-hydroxybenzotriazole (HOBt) were added.

2.48 g (12.00 mmol) of DCC, dissolved in 30 ml of dry CH2Cl2, were added dropwise and the solution was stirred at room temperature for 36 hours. 50 mL of 10% HCl was added and the solution was stirred for an additional 2 hours. The precipitated dicyclohexylurea was filtered off and the organic layer was washed with 10% citric acid and 10% K2CO3.

The organic layer was separated, dried over Na2SO4 and evaporated in vacuo to dryness. The crude product was flash chromatographed on silica gel, 0.06-0.37mm, (230-400 mesh) eluting with hexane / EtOAc / CH2Cl2 80: 15: 0.5 to give 2.0 g of a yellow oil which crystallized from a mixture of toluene / hexane to give 0.9 g of pure title compound as white crystals.

C23H20N2O5

Melting point = 134-137 ° C

Molecular Weight = 372.49

IR (KBr): 3230; 3060; 1630; 1590; 1545 cm ' ¹

300 MHz. 1 H-NMR (DMSO-d ₆ ):? 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; 70V; 200mA): 372 (M +.); 343; 232; 204.

Example 56

(+) - (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 were dissolved in 100 ml of dichloroethane.

188 872

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 refluxed for 24 hours. The reaction mixture was evaporated under reduced pressure to dryness, suspended in 100 ml of 33% Me2NH / EtOH and stirred overnight at room temperature. The solution was evaporated to dryness under reduced pressure, washed with 50 ml of 20% K 2 CO 3 and evaporated again in vacuo to dryness. 50 ml of water was added to the residue and the solution, acidified with 37% HCl, was evaporated under reduced pressure to dryness.

The crude residue and 10.8 ml (77.20 mmol) of TEA were dissolved in 50 ml of CH2Cl2, 50 ml of THF and 100 ml of CH3CN.

3.00 g (22.20 mmol) of (S) and (-) iα-ethylbene / ylαmmy, 0.78 g (5.78 mmol) of N-hydroxybenzotriazole (HOBT) and 11.9 g (57, 90 mmol) of DCC and the solution was stirred at room temperature overnight.

The precipitated dicyclohexyl acetate was filtered off and the organic layer was evaporated under reduced pressure to dryness.

The brown oily residue was dissolved in 100 ml of CH2Cl2 and the precipitate was filtered off. The filtrate was extracted three times with 40% citric acid. The aqueous layer, basified with solid K2 CO3, was extracted with CH2Cl2; the organic solution, dried over Na2SO4 and evaporated in vacuo to dryness to give 10 g of a brown oil. The crude product was flash chromatographed on 0.06-0.37 mm silica gel (230-400 mesh), eluting with a mixture of i-Pr2O / CH2Cl2 9: 1 to give 2.5 g of a white solid which was dissolved in toluene and left to stand. for night.

The precipitated DCU was filtered and the solution, treated with ethanolic HCl, was evaporated under reduced pressure to dryness. The crude product was recrystallized from toluene / EtOH to give 0.7 g of pure title compound as colorless crystals.

C28H29N3O · HCl

Melting point = 164-167 ° C

Molecular Weight = 460.02

[a] o20 = + 25.3 (c = 1, MeOH)

I.R. (KBr): 3440; 3150; 3020; 2560; 2460; 1650; 1540 cm1

300 MHz 1 H-NMR (DMSO-d6, 353 K): δ 9.70 (s br, 1H); 8.10 (d. 1H); 7.85 (dd. 1H); 7.80 (s br, 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; 70V; 200mA): 423 (M +.), 380, 288.

Example 57 (S) -N- (α, iethylbenzyl) -3-methyl-7-methoxy-2-phenylquinolmo-4-kίnboxamide

Prepared as in Example 1, starting from 1.27 g (4.09 mmol) of crude 3-methyl-Oi7-mytoxy-2-phenylquinolmo-4-carbonyl chloride, 0.55 g (4.09 mmol) of (S) - (- ) -α-ethylbenzylamine and 1.71 ml (12.27 mmol) TEA in 24 ml dry CH2Cl2 and 1 ml DMF to increase solubility. The reaction mixture was stirred for 12 hours at room temperature.

After concentration under reduced pressure to dryness, the residue was dissolved in CH2Cl2 (30 ml) and washed with 10% NaHCO3, 5% citric acid and brine. The organic solution was dried over Na 2 SO 4 and evaporated in vacuo to dryness to give 1.87 g of crude product which was flash chromatographed on silica gel 0.06-0.37 mm, (230-400 mesh) eluting with a mixture of hexane / EtOAc 70:30 to give 0.350 g of a yellow oil. -

Claims (1)

Claims Quinoline derivatives of formula (I), solvates or salts thereof in which formula: Ar is phenyl, 2-chlorophenyl, 2-thienyl, or cyclohexadienyl; R is methyl, ethyl, n-propyl, -COOMe, or -COMe; each R 1 and R ₂ are hydrogen or methyl; R3 is hydrogen, methoxy or hydroxy; R4 is hydrogen, methyl, ethyl, methoxy, hydroxy, amino, chlorine, bromine, dimethylaminoethoxy, 2- (1-phthaloyl) ethoxy, aminoethoxy, 2- (1-pyrrolidin; yl) -ethoxy, dimethylaminopropoxy, a dimethylaminoacetylamino group, an acetylamino group, or a dimethylaminomethyl group; R5 is phenyl, 2-thienyl, 2-furyl, 2-pyridyl, 2-thiazolyl, or 3-thienyl; and X is oxygen, with the exception that the compound of formula (I) is not N- (α-ethylbenzyl) -3-hydroxy-2-phenylquinoline-4-carboxamide, and compounds where R4 is hydrogen and R is -COOMe.