MXPA00002695A - Method for the synthesis of quinoline derivatives - Google Patents

Abstract

This invention relates to novel intermediates and processes for preparing pharmaceutically active quinoline compounds, including (-)-(S)-N-(&agr;- ethylbenzyl)- 3-hydroxy-2- phenylquinoline- 4-carboxamide.

Description

METHOD FOR THE SYNTHESIS OF QUINOLINE DERIVATIVES FIELD OF THE INVENTION This invention relates to novel intermediates and methods for preparing pharmaceutically active quinoline compounds, including (-) - (S) -N- (α-ethylbenzyl) -3-hydroxy-2-phenylquinoline-4-carbo-xamide.

BACKGROUND OF THE INVENTION Compounds of the structural formula (I) Formula (I) or a pharmaceutically acceptable salt thereof, wherein: Ar an optionally substituted phenyl group, or a naphthyl or a C5-C cycloalkadienyl group, or an optionally substituted fused single ring heterocyclic group, having an aromatic character, containing 5 to 12 ring atoms and comprises up to four heteroatoms in the ring, or in each, selected from S, O, N; R is straight or branched Ci-Cs alkyl, C5-C7 cycloalkyl, (C4-C7 cycloalkyl) alkyl, an optionally substituted phenyl group or a phenyl (Ci-Cß alkyl) group, a five-membered heteroaromatic ring optionally substituted which comprises up to four heteroatoms selected from O and N, hydroxy (Ci-Cß alkyl), and di (Cr C 1 -aminoalkyl), (C 1 -C 9 -aminoalkyl acyl, (C 6 -C 6 alkoxy) alkyl, (Ci-CßJ- alkyl) carbonyl, carboxy, (CrC6) alkoxycarbonyl, (CrC6 alkoxy) carbonyl (Ci-Cß alkyl), aminocarbonyl, (Ci-Ce alkyl) -aminocarbonyl, di (Ci-C-aminocarbonyl) alkyl, or is a group - (CH2) P- when cyclized to Ar, where p is 2 or 3, R1 and R2, which may be equal or different, are independently hydrogen or straight or branched alkyl of Ci-Cß, or together form a group - (CH2) n- in which n represent 3, 4 or 5, or Rt together with R form a group - (CH2) q- in which q is 2, 3, 4 or 5; R3 and R4, which can be the same or different, are independently hydrogen, linear or branched alkyl of Ci-Cß, alkenyl of CrC6, aryl, C6-C6 alkoxy, hydroxy, halogen, nitro, cyano, carboxy, carboxamido, sulfonamido, trifluoromethyl, amino, mono - and di (Ci-Cß alkyl) amino, - (CH2) r-NT2, wherein r is 2, 3 or 4 and T is CrC6 alkyl or forms a heterocyclic group wherein V and Vi are hydrogen and u is 0, 1 or 2; -O (CH2) s-OW2 wherein s is 2, 3 or 4 and W is Cr6 alkyl; hydroxyalkyl, mono- or dialkylaminoalkyl, acylamino, alkylsulfonylamino, aminoacylamino, mono- or dialkylaminoacylamino; up to four substituents R3 being present in the quinoline nucleus; or Hi is a group - (CH2) t- when cyclizing to R5 as aryl, in which t is 1, 2 or 3; and R 5 is branched or linear C 1-6 alkyl, C 3 - cycloalkyl, C 4 - (cycloalkyl) alkyl, optionally substituted aryl, wherein the optional substituent is one of hydroxy, halogen, C 6 alkoxy or C alkyl? -6, or an optionally substituted fused single ring heterocyclic group, having an aromatic character, containing from 5 to 12 ring atoms and comprising up to four heteroatoms in the ring or in each, selected from S, O, N; they are antagonists of NK-3 and are useful in the treatment of pulmonary disorders (asthma, chronic obstructive pulmonary diseases (OPDC), hyper-responsiveness of the airways), skin disorders and itching (for example, atopic dermatitis and skin rashes and flushing) ), and neurogenic formation, CNS disorders (Parkinson's disease, movement disorders, anxiety), seizure disorders (for example epilepsy), kidney disorders, urinary incontinence, eye inflammation, inflammatory pain, eating disorders (inhibition of absorption of elements), allergic rhinitis, neurogenerative disorders (for example Alzheimer's disease), psoriasis, Huntington's disease and depression. A particularly useful NK-3 receptor antagonist which falls within the genus of formula (I) is (-) - (S) -N- (α-ethylbenzyl) -3-hydroxy-2-phenylquinoline-4- carboxamide. Such compounds and methods for preparing the compounds are set forth in PCT / EP95 / 02000, published December 7, 1995, as WO 95/32948, whose citations are mentioned herein by reference. Antagonists of the NK-3 receptor are useful in the treatment of OPDC symptoms and urinary incontinence in mammals. An example of such a compound is the potent (-) - (S) -N- (α-ethylbenzyl) -3-hydroxy-2-phenylquinoline-4-carboxamide antagonist. While the route published in PCT / EP95 / 02000, published on December 7, 1995, as WO 95/32948, requires only three steps, the synthesis is riddled with costly starting materials (eg, 2-scheme 1). , α-methoxyacetophenone) and chromatography in the low-yield final step. As illustrated in scheme 1, the coupling of DCC-mediated dicyclohexylcarbodiimide of 4-scheme 1, 3-hydroxy-2-phenylquinoline-4-carboxylic acid, with (S) -1-phenyl-propylamine led to a 30-50% yield isolated from (-) - (S) -N- (a-ethylbenzyl) -3-hydroxy-2-phenylquinoline-4-carboxamide together with 10-20% of compound 6-scheme 1, ( S) -2-phenyl-4 - [[1-phenylpropyl) -amino] carbonyl] -3-quinolinyl-3-hydroxy-2-phenyl-4-quinoline-carboxylate, requiring chromatography for removal . Without being bound by any particular theory, (S) -2-phenyl-4 - [[(1-phenylpropyl) amino] carbonyl] -3-quinolinyl-3-hydroxy-2-phenyl-4-quinoline-carboxylate appears to form a byproduct of a phenolic oxygen attack of (-) - (S) -N- (a-ethylbenzyl) -3-hydroxy-2-phenylquinoline-4-carboxamide to the acid activated by DCC of 3-hydroxy-2 acid phenylquinoline-4-carboxylic acid.

SCHEME 1 Given the known synthesis for the quinoline NK-3 receptor antagonists of the formula (I), there was a need for an environmentally friendly, commercially feasible, more economical and more efficient process, with increased yields, for coupling an orthodox acid. hydroxy with an amine to provide (-) - (S) -N- (a-ethylbenzyl) -3-hydroxy-2-phenylquinoline-4-carboxamide and related compounds. The present invention provides novel synthetic methods for the synthesis of (-) - (S) -N- (α-ethylbenzyl) -3-hydroxy-2-phenylquinoline-4-carboxamide and related compounds, which eliminate the need for the use of -schema 1, -methoxyacetophenone, the need for the use of a chromatography step to remove 6-scheme 1, (S) -2-phenyl-4 - [[(1-phenylpropyl) -amino] carbonyl] -3-quinolin L-3-hydroxy-2-phenyl-4-quinolinecarboxylate, and which increases the yield of desired product from 30 to 50% to more than 70%. In addition, the hydrochloride salt of the free base of (-) - (S) -N- (α-ethylbenzyl) -3-hydroxy-2-phenylquinoline-4-carboxamide and related compounds is optionally prepared in accordance with this invention. , in a reaction vessel, without the need to isolate and purify the free base. Cragoe et al., J. Org. Chem, 1953, 19 pp., 561-569, disclose the reaction of 7-carboxy-substituted satins with substituted phenacyl acetates to provide 3-hydroxycinconinic acid derivatives. Phenacyl acetates are known and / or can be prepared according to Normant et al., Synthesis, 1975, pgs. 805-807, which disclose the reaction of potassium acetate with alkyl bromides catalyzed by diamines in acetonitrile to provide such acetates. An optimized method for preparing anhydro-O-carboxy-alicyclic acid and anhydro-O-carboxyglycolic acid is disclosed in Davies, W.H., J. Chem, Soc, 1951, p. 1357-1359. A preparation for five-membered ring sulfites from the reaction of thionyl chloride and α-hydroxycarboxylic acids is discussed in Blackbourn et al., J. Chem. Soc. (C), 1971, pp. 257- None of the documents cited above describes the methods of the present invention for the synthesis of the quinoline NK-3 receptor antagonists of formula (I) or formula (1a) or the compounds of the invention which are useful as intermediates for the synthesis of such antagonists of the NK-3 receptor of quinoline.

BRIEF DESCRIPTION OF THE INVENTION The objects of this invention are to provide novel intermediates and methods for preparing these intermediates that are useful in the preparation of pharmaceutically active compounds. According to the above, in one aspect, this invention is a method for preparing a compound of formula (I): Formula (I) or a pharmaceutically acceptable salt thereof, wherein: Ar an optionally substituted phenyl group, or a naphthyl or a C5-C7 cycloalkadienyl group, or an optionally substituted fused single ring heterocyclic group, having aromatic character , which contains from 5 to 12 ring atoms and comprises up to four heteroatoms in the ring, or in each, selected from S, O, N; R is straight or branched CrC8 alkyl, C5-C cycloalkyl, (C4-C-cycloalkyl) alkyl, an optionally substituted phenyl group or a phenyl group (Ci-Cß alkyl), an optionally substituted five-membered heteroaromatic ring comprising up to four heteroatoms selected from O and N, hydroxy (C-alkyl) -? - C6), and di (d-C-alkyl) alkyl, (d-C-J-aminoalkyl acyl, (Ci-C-Jakalkyl-alkoxy, (CrCS-carbonyl, carboxy, (Ci-C-) alkoxycarbonyl, (C-C6-alkoxy ) carbonyl (Ci-Cß alkyl), aminocarbonyl, (CI-CT alkyl) -aminocarbonyl, di (Ci-C 1 J-carinocarbonyl alkyl, or is a group - (CH 2) P- when cyclized to Ar, where p is 2 or 3, i and R2, which may be the same or different, are independently hydrogen or linear or branched alkyl of C -? - C6, or together they form a group - (CH2) n- in which n represent 3, 4 or 5; or R1 together with R form a group - (CH2) q- in which q is 2, 3, 4 or 5; R3 and R4, which may be the same or different, are independently hydrogen, linear or branched alkyl of Ci-Cβ, alkenyl of Ci-Cd, aryl, Ci-Cβ alkoxy, hydroxy, halogen, nitro, cyano, carboxy, carboxamido, sulfonamido, trifluoromethyl, amino, mono- and di (CrC6 alkyl) amino, - (CH2) r-NT2, wherein r is 2, 3 or 4 and T is Ci-Cß alkyl or forms a heterocyclic group in which V and Vi are hydrogen and u is 0, 1 or 2; -O (CH2) s-OW2 wherein s is 2, 3 or 4 and W is C6 alkyl; hydroxyalkyl, mono- or dialkylaminoalkyl, acylamino, alkylsulfonylamino, aminoacylamino, mono- or dialkylaminoacylamino; up to four substituents R3 being present in the quinoline nucleus; or R4 is a group - (CH2) t- when cyclizing to R5 as aryl, in which t is 1, 2 or 3; and Rs is branched or linear C alkyl, C3-7 cycloalkyl, (C4-7 cycloalkyl) alkyl, optionally substituted aryl, wherein the optional substituent is one of hydroxy, halogen, C alkoxy or C alquilo alkyl. β, or an optionally substituted fused single ring heterocyclic group, having an aromatic character, containing from 5 to 12 ring atoms and comprising up to four heteroatoms in the ring or in each, selected from S, O, N; which comprises: 1) adding a compound of the formula (III): Formula (III) to the base in a suitable solvent, to form a first reaction mixture, by adding to the first reaction mixture a compound of the formula (II): Formula (II) for forming a second reaction mixture and heating the second reaction mixture to form a compound of the formula (IV): Formula (IV) 2) isolating the compound of the formula (IV) and then reacting the compound of the formula (IV), in a suitable solvent, with a base to form a third reaction mixture, cooling the third reaction mixture and adding an agent carbonyl activator to form a fourth reaction mixture; 3) add a compound of the formula (V): Formula (V) to the fourth reaction mixture to form a fifth reaction mixture; 4) heating the fifth reaction mixture; and 5) optionally converting the compound of the formula (I) to a pharmaceutically acceptable salt, wherein Ar, R, Ri, R 2, R 3, 4 and R 5 as used in a compound in the formulas (II) to (VI) they are as defined for a compound of the formula (I). In another aspect, this invention is a method for preparing (-) - (S) -N- (α-ethylbenzyl) -3-hydroxy-2-phenylquinoline-4-carboxamide comprising: 1) adding satin to the base in a suitable solvent, to form a first reaction mixture, add to the first reaction mixture an α-acetoxyketone to form a second reaction mixture and heat the second reaction mixture to form an α-hydroxy acid; 2) isolate the α-hydroxy acid and then react it, in a suitable solvent, with a base to form a third reaction mixture, cool the third reaction mixture and add a carbonyl activating agent to form a fourth reaction mixture; 4) adding a primary or secondary amine, for example, (S) -1-phenylpropylamine, to the fourth reaction mixture to form a fifth reaction mixture; 5) heat the fifth reaction mixture. In still another aspect, this invention is a method for preparing (-) - (S) -N- (-ethylbenzyl) -3-hydroxy-2-phenylquinoline-3-carbonamide, which comprises: 1) reacting acid to- hydroxy, in a suitable solvent, with a base to form a first reaction mixture, cooling the first reaction mixture and adding a carbonyl activating agent to form a second reaction mixture; 2) adding a primary or secondary amine to the second reaction mixture to form a third reaction mixture; 3) heating the third reaction mixture; and 4) optionally converting (-) - (S) -N- (α-ethylbenzyl) -3-hydroxy-2-phenylquinoline-4-carboxamide to a pharmaceutically acceptable salt. In still another aspect, this invention is in a novel intermediate compound of the formula (VII): wherein Ar and R3 are as defined above for formula (I), and wherein R'4 is OH or -O-C (O) -Ra, wherein Ra is a Cr6 alkyl, aryl, preferably methyl. In additional aspect, this invention is in a novel intermediate compound of the formula (VIII): Formula (VIII) wherein: Ar and R3 are as defined for a compound of the formula (I) as claimed in claim 1; and n is 1 or 3.

DETAILED DESCRIPTION OF THE INVENTION In the development of the present inventive methods, particularly when, for the compound of the formula (IV), R4 is hydroxy, it was desirable to activate the carboxyl group of the 4-acid portion towards the addition while at the same time and in a single operation, to protect the phenol oxygen of R4. According to known methods (see, for example, Davis, WH, J. Chem. Soc. 1951, pp. 1357-1359), the coupling of an amine with an activated α-hydroxy acid provides a compound in which the addition of the amine occurs in an undesired position, thus teaching from the production of the desired a-hydroxy amide. In addition, this procedure requires the use of phosgene (COCI2) as a reagent, a very toxic compound, requiring specialized equipment for industrial application. furtherIt is known that by using thionyl chloride, one can couple acids with amines to provide amines. However, using that method to provide amides of a α-hydroxy acid starting material, one skilled in the art would expect a result lower yields and unwanted by-products (see Gnaim, JM et al., J. Org. Chem. ., 1991, 56, p 4525), particularly due to the α-hydroxy moiety. Without being limited to any particular mechanistic theory for the present inventive process, it is believed that in contrast to those exhibited in the art, the coupling step between the compound of formula (IV) and an amine of formula (V) appears to proceed, among others, by means of novel intermediates of the formula (VII) and of the formula (VIII), both of which are converted to the desired product, thus increasing the yield doubly. The use of the present method thus avoids the formation of unwanted by-products that must be removed by some form of purification, for example chromatography. In fact, while these novel intermediates, as well as the compound of the formula (VI), are still produced in situ by the methods of the invention, they are all easily converted to the desired product, thus explaining a more efficient process (more of the 70% yields with this procedure), as well as avoiding the need for a chromatography step. Thus, the present invention provides a process for preparing a compound of the formula: Formula (I) or a pharmaceutically acceptable salt thereof, wherein: Ar an optionally substituted phenyl group, or a naphthyl or a C5-C7 cycloalkadienyl group, or an optionally substituted fused single ring heterocyclic group, having an aromatic character , which contains from 5 to 12 ring atoms and comprises up to four heteroatoms in the ring, or in each, selected from S, O, N; R is straight or branched C?-C8 alkyl, C-C7 cycloalkyl, (C4-C) cycloalkyl, an optionally substituted phenyl group or a phenyl (Ci-Cß alkyl) group, a five-membered heteroaromatic ring optionally substituted comprising up to four heteroatoms selected from O and N, hydroxy (C-? -C6 alkyl), and di (d-C6 alkyl) aminoalkyl, (CrC6 acyl) aminoalkyl, (Ci-C-Jakalkyl alkoxy, ( CrC6 alkyl) -carbonyl, carboxy, (Ci-C, carbonyl alkoxy, (C, C6 alkoxy) carbonyl (Ci-C, alkyl), aminocarbonyl, (C, -C, alkyl) aminocarbonyl, di (CrC6 alkyl) aminocarbonyl, or is a group - (CH2) P- when cyclized to Ar, where p is 2 or 3; R i and R 2, which may be identical or different, are independently hydrogen or linear or branched C 1 β alkyl, or together form a group - (CH 2) n - in which n represents 3, 4 or 5; or R1 together with R form a group - (CH2) q- in which q is 2, 3, 4 or 5; R3 and R4) which may be the same or different, are independently hydrogen, linear or branched alkyl of Ci-Cß, alkenyl of CI-CT, aryl, C6-C6 alkoxy, hydroxy, halogen, nitro, cyano, carboxy, carboxamido , sulfonamido, trifluoromethyl, amino, mono- and di (d-Cß alkyl) amino, - (CH2) r-NT2, wherein r is 2, 3 or 4 and T is CrC6 alkyl or forms a heterocyclic group wherein V and Vi are hydrogen and u is 0, 1 or 2; -O (CH2) s-OW2 wherein s is 2, 3 or 4 and W is C6 alkyl; hydroxyalkyl, mono- or dialkylaminoalkyl, acylamino, alkylsulfonylamino, aminoacylamino, mono- or dialkylaminoacylamino; up to four substituents R3 being present in the quinoline nucleus; or R4 is a group - (CH) t- when cyclized to R as aryl, wherein t is 1, 2 or 3; and R5 is branched or linear d-β alkyl, C3-7 cycloalkyl, (C4-7 cycloalkyl) alkyl, optionally substituted aryl, wherein the optional substituent is one of hydroxy, halogen, d-β alkoxy or alkyl of C ß, or an optionally substituted fused single ring heterocyclic group, having aromatic character, containing from 5 to 12 ring atoms and comprising up to four heteroatoms in the ring or in each, selected from S, O, N; which comprises: 1) adding a compound of the formula (III): Formula (III) to the base in a suitable solvent, to form a first reaction mixture, by adding to the first reaction mixture a compound of the formula (II): to form a second reaction mixture and heat the second reaction mixture to form a compound of the formula (IV): Formula (IV) 2) isolating the compound of the formula (IV) and then reacting the compound of the formula (IV), in a suitable solvent, with a base to form a third reaction mixture, cooling the third reaction mixture and adding an agent carbonyl activator to form a fourth reaction mixture; 3) add a compound of the formula (V): Formula (V) to the fourth reaction mixture to form a fifth reaction mixture; 4) heating the fifth reaction mixture; and 5) optionally converting the compound of the formula (I) to a pharmaceutically acceptable salt, wherein Ar, R, Ri, R 2, R 3, R 4 and R 5 as used in a compound in the formulas (II) to (VI) they are as defined for a compound of the formula (I). It will be understood that when R 4 is defined in the compound of the formula (IV) as hydroxy, then R 4 in the compound of the formula (II) should be a protected alcohol, protected for example by an acetate group, which is ultimately deprotected. It will also be understood that the fifth reaction mixture comprises the compound of the formula (I) and the compound of the formula (VI): Formula (VI) Upon heating the fifth reaction mixture, the compound of the formula (VI) is converted to the desired product of the formula (I). An example of Ar, such as phenyl, is phenyl optionally substituted by hydroxy, halogen, C alkoxy and C 1-6 alkyl. When Ar is substituted, the substituents are preferably independently one or more of halogen or C 1-6 alkyl. Examples of Ar as a heterocyclic group are thienyl, pyridyl and the like. Examples of Ar as a cycloalkadienyl group of C5- is cyclohexadienyl. A preferred group of compounds is when Ar is phenyl, optionally substituted by d-β alkyl or halogen; thienyl, furyl, pyrryl, thiazolyl or cycloalkalienyl group of C5-7. A still more preferred group is when Ar is phenyl, optionally substituted by C 6 alkyl or halogen; thienyl or a cycloalkenyl group of Cs-. A particularly preferred group of compounds is when Ar is phenyl, 2-chlorophenyl, 2-thienyl or cyclohexadienyl.

Ar is most preferably phenyl. Examples of R are as follows: C Al alkyl: methyl, ethyl, n-propyl, ε-propyl, n-butyl, heptyl and the like. Phenyl (d-β alkyl): benzyl and the like. Hydroxy (C 6 alkyl): -CH 2 OH, -CH 2 CH 2 OH, -CH (Me) OH; di (C6-alkyl) aminoalkyl: -CH2NMe2; (d-6 alkoxy) alkyl: CH2OMe; (d-6-alkyl) carbonyl: -COMe; (C6-C6 alkoxy) carbonyl: -COOMe; (d-6) alkoxycarbonyl (Cr6 alkyl): - CH COOMe; (d-β-aminocarbonyl alkyl: -CONHMe; di (Cr-aminocarbonyl-alkyl: -CONMß2 or -CO (1-pyrrolidinyl); When cyclized to Ar as follows: - (CH2) p- A preferred group of compounds is when R is Ci-6 alkyl, (d-6 alkoxy) alkyl, (C6-alkyl) carbonyl or hydroxy (C6-alkyl). A preferred group of compounds is when R is Ci-β alkyl. Most preferably, R is ethyl. An example of Ri and R2 as C alkyl is methyl, ethyl, n-propyl, iso-propyl, n-butyl and the like; an example of Ri together with R forming a group - (CH2) q- is spirocyclopentane. Preferably Ri and R2 are hydrogen or d-6- alkyl. Most preferably, Ri and R2 are each hydrogen. Example of R3 and R4 are independently hydrogen, methyl, ethyl, n-propyl, n-butyl, methoxy, hydroxy, chloro, fluoro, bromo, 2- (diemthylamino) ethoxy, dimethylaminopropoxy, dimethylaminoacetylamino, dimethylaminomethyl and phenyl. Preferably, R3 is hydrogen, hydroxy, halogen, d-β alkoxy, C? -6 alkyl. Preferably, R4 is hydrogen, C6-6alkyl, C6-6alkoxy, hydroxy, amino, halogen, aminoalkoxy, mono- or dialkylaminoalkoxy, mono- or dialkylaminoalkyl, phthaloylalkoxy, mono- or dialkylaminoacylamino and acylamino. Most preferably, R3 is hydrogen. Most preferably, R 4 is d-6 alkoxy or hydroxy. Particularly preferable is when R4 is hydroxy. Examples R5 are cyclohexyl, optionally substituted phenyl as defined for Ar before; Examples of R 5 as a heterocyclic group are furyl, quinyl, pyrryl, thiazolyl, benzofuryl and pyridyl. Preferably, R5 is phenyl, thienyl, furyl, pyrryl and thiazolyl. Most preferably, R5 is phenyl. Preferred compounds of formula (I) made by the process of the invention are those in which Ar is phenyl, optionally substituted by d-β alkyl or halogen; phenyl a C5-7 cycloalkenyl group; R is d-β alkyl, (C 6 -alkoxy) carbonyl, d-β -carbonyl alkyl, hydroxy (d-β alkyl), each of R 1 and R 2 is hydrogen or d-6 alkyl; is hydrogen, hydroxy, halogen, d-6 alkoxy, d-β alkyl, R 4 is hydrogen, d-6 alkyl, d-6 alkoxy, hydroxy, amino, halogen, phthaloylalkyloxy, mono- or dialkylaminoacylamino and acylamino; and R 5 is phenyl, thienyl, furyl, pyrryl and triazolyl A more preferred compound made by the process of this invention is that in which Ar is phenyl, R is ethyl, each of R 1 and R 2 is hydrogen, R 3 is hydrogen, R 4 is hydroxy, and R5 is phenyl The term "alkyl" as used herein in all occurrences means both straight and branched chain radicals of 1 to carbon atoms, unless otherwise limited to the object of the chain, including, but not limited to, methyl ethyl, n-propyl, / so-propyl, n-butyl, sec-butyl, / so-butyl, tert-butyl, and the like. The term "alkoxy" is used herein in all occurrences to mean a straight or branched chain radical of 1 to 8 carbon atoms, unless the chain length is limited thereto, linked to a carbon atom. oxygen, including, but not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and the like. The term "halogen" is used herein in all occurrences to mean chlorine, fluorine, iodine and bromine. The term "cycloalkyl" is used herein in all occurrences to mean cyclic radicals, preferably 3 to 7 carbons, including, but not limited to, cyclopropyl, cyclopentyl, cyclohexyl, and the like. The terms "aryl" or "heteroaryl" are used herein in all occurrences to signify rings or unsubstituted aromatic ring systems which may include bi- or tricyclic systems and heteroaryl functions, which may include, but are not limited to, the same. , heteroatoms selected from O, N or S. Representative examples include, but are not limited to, phenyl, benzyl, naphthyl, pyridyl, qinolinyl, thiazinyl and furanyl. The term "optionally substituted" is used herein in all occurrences to mean that the portion may or may not be substituted, and if substituted, one or more hydrogens on each portion are replaced with one or more substituents, each substituent being independently selected between hydroxy, halogen, C 1-6 alkoxy or d-6 alkyl, as defined above. A particularly preferred compound of the formula (I) is (-) - (S) -N- (α-ethylbenzyl) -3-hydroxy-2-phenylquinoline-4-carboxamide. A preferred pharmaceutically active salt of the formula (I) is (-) - (S) -N- (α-ethylbenzyl) -3-hydroxy-2-phenylquinoline-4-carboxamide hydrochloride. The compounds described herein may have asymmetric centers. Unless indicated otherwise, all chiral, diastereomeric and racemic forms are included in the present invention. As is often the case, the optimal therapeutic activity is provided only with a configuration of the two chiral centers. It is therefore desirable to produce this material in a form that is highly enriched only in an absolute configuration of chiral centers. It is well known in the art how to prepare the optically active compound, for example by resolution of the racemic mixture or by synthesis of the optically active starting materials. The satin and the substituted satins of the formula (III) are commercially available or are made by methods known in the art, such as Marvel, et al., Org. Synt. Collect. Vol. I, 1941, p. 327. Compounds of the formula (II) and the related formula (II ') are also commercially available, or can be made by known methods. See, for example, Normant et al., Synthesis, 1975, p. 805-807. A particularly useful compound of formula (II) is a-acetoxyacetophenone, sold by Lancaster Synthesis Company. Compounds of the formula (IV) and the related formula (IV) are known or are made by known methods including those set forth in Marshall et al., Cinchoninic Acid Derivatives, Vol. 95, 1949, p. 185-190; patent of E.U.A. Nos. 2,749,347, issued June 5, 1956; and 2,776,290, issued January 1, 1957. The procedure described by Marshall was modified herein, using LiOH as a preferable base over NaOH. The reactions of the synthetic methods set forth herein are carried out in a suitable solvent, which is a substantially non-reactive solvent (except if reagents are also required), with the reactants, intermediates or products at the temperatures at which the reactions are carried out. Suitable solvents for coupling a compound of the formula (III) with a compound of the formula (II) are water, C? -4 alco alcohols, dimethyl sulfoxide ("DMSO") and dimethylformamide ("DMF"). Water is preferred. Suitable aqueous bases used in this coupling step are lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide. The hydroxide in lithium is preferred. Suitably, the base is present in an amount between 2 and 6 equivalents, preferably 3 to 5 equivalents and most preferably 4 equivalents of base are used. The compound of the formula (III) is added to the aqueous base which has been heated to a temperature between about 40 and 70 ° C, preferably between about 50 and 60 ° C. The ring of the compound of the formula (III) is opened with the reaction with the aqueous base. The compound of the formula (II) is then added, with an exotherm of about 15 ° C. After the addition of the compound of the formula (II) is complete, the temperature of the resulting reaction mixture is raised to a temperature between about 40 ° C and about 110 ° C, preferably up to about 80 ° C, during a appropriate time (up to about 3 hours) until the coupling term provides a compound of the formula (IV). The compound of the formula (IV) is isolated before carrying out the next step in the process. It is important that the next step be conducted under anhydrous conditions since the carbonyl activating agent eg SOCI2, oxalyl chloride, DCC, POCI3, COCI2, etc., is hydrolytically unstable and would be destroyed with water. A preferable carbonyl activating agent for use in the methods herein is thionyl chloride. Suitable solvents for use in this step are aprotic solvents, including, but not limited to, miscellaneous, polar aprotic organic solvents. More specifically, solvents useful herein include, but are not limited thereto, ethyl acetate, toluene, tetrahydrofuran or acetonitrile. A preferred solvent for use herein is ethyl acetate. Suitable bases useful in this process step include amine bases, particularly tertiary amine bases. Preferred amine bases are triethylamine and disopropylethylamine. Triethylamine is very preferred. Suitably, at least 3 equivalents of the amine base are used in the present reaction process. After the addition of the base to the compound of the formula (IV), the reaction mixture is cooled to a temperature below 5 ° C. preferably, the temperature varies between about -2 and 2 ° C. The carbonyl activating agent (for example thionyl chloride, COCI and POCI3) is added and the reaction mixture is then slowly allowed to warm up (approximately 1 hour) at room temperature (approximately 25 ° C), at which point a compound of the formula (V) to the formula (Va), which is shown below. The compounds of the formula (V) are commercially available from BASF, Celgene, Inc., and Zeeland Chemical Co., or can be made using methods known in the art, for example Itsuno, S. et al. J Chem. Soc, Perkin Trans. I, 1985, p. 2039; Burk, M.J. et al., J. Am. Chem. Soc, 1996, 118, p. 5142; and Beak, P. et al., J. Am. Chem. Soc, 1996, 118, p. 3757. A particular preferred compound of the formulas (V) to (Va) for use of the method herein is (S) -l-phenylpropylamine. Again, without being bound by any particular theory, an investigation of the reaction sequences to determine the species of actual clustering revealed, by thin layer chromatography, three major components in the reaction mixture formed before the addition of the compound in the formula (V) When they had been isolated, the three components were consistent with (1) a compound of the formula (VII); (2) a compound of the formula (VIII), wherein n is 1; and (3) a compound of the formula (VIII), wherein n is 3. The reaction of each of the three components with a component of the formula (V) under the conditions defined herein, each provided the desired compound of the formula (I). The trimer of the compound of the formula (VIII) was also isolated, however, even under forced conditions, this compound did not provide the desired compound of the formula (I). While there is no spectral evidence of formation during the coupling of compound (IV) and compound (V) in the following intermediate: speculation leads one to predict that the tertiary amine base catalyses a rapid conversion of the putative intermediate to the coupling species of the formula (VIII). After the addition of the compound of the formula (V) at room temperature, the compound of the formula (VIII), wherein n is 1, reacts to produce an additional intermediate of the formula (VI), which, upon heating to temperatures between 50 and 60 ° C, reacts with another molecule of the compound of the formula (V) to finally produce two molecules of the desired compound of the formula (I). By promoting the intermediates to react with the compound of the formula (V), the yield of the desired product increases. In addition, converting the by-product of formula (VI) to product, increases the yield and eliminates the need for chromatographic removal of this by-product. A preferred subgroup of compounds within the scope of formula (I) are the compounds of formula (la): where: Ar is an optionally substituted phenyl group, or a naphthyl or a C 5-7 cycloalkadienyl group, or an optionally substituted single or fused heterocyclic group having the aromatic character, containing from 5 to 12 ring atoms and comprising up to 4 heteroatoms in the ring, or in each, selected from S, O, N; R is linear or branched d-β alkyl, C3-7 cycloalkyl, (C4-cycloalkyl) alkyl, an optionally substituted phenyl group or a phenyl (d-β) alkyl group, an optionally substituted five-membered heteroaromatic ring comprising up to four heteroatoms selected from O and N, hydroxy (d-β alkyl), di (d-6 alkyl) -aminoalkyl, (C?-6 acyl) aminoalkyl, (C?-6 alkyl) carbonyl, carboxy, (C?-6) alkoxycarbonyl, (C?-6) alkoxycarbonyl (d-βalkyl), aminocarbonyl, (C? .6alkyl) aminocarbonyl, di (alkyl) d-6) -aminocarbonyl; or is a group - (CH2) P- when cyclized to Ar, where p is 2 or 3; R2 is hydrogen or straight or branched alkyl of d-β; and R3 and R4, which may be the same or different, are independently hydrogen, straight or branched alkyl of d-6, alkenyl of C-? 6, aryl, d-β alkoxy, hydroxy, halogen, nitro, cyano, carboxy , carboxamido, sulfonamido, trifluoromethyl amino, mono- and di (alkyl of d-6) amino, -O (CH2) r NT2, in which r is 2, 3 or 4 and T is alkyl of d-6 or forms a heterocyclic group wherein V and Vi are hydrogen and u is 0, 1 or 2; -O (CH2) s-OW2 wherein s is 2, 3 or 4 and W is d6 alkyl; hydroxyalkyl, mono- or dialkylaminoalkyl, acylamino, alkylsulfonylamino, aminoacylamino, mono- or dialkylaminoacylamino; up to four substituents R3 being present in the quinoline nucleus; which can be prepared by a method comprising: 1) adding a compound of the formula (III): Formula (III) to the base in a suitable solvent, to form a first reaction mixture, add the first reaction mixture a compound in the formula (lia): Formula (Ha) to form a second reaction mixture and heat the second reaction mixture to form a compound of the formula (IVa): Formula (IVa) 2) isolate the compound of the formula (IVa) and then react the compound of the formula (IVa), in a suitable solvent, with a base to form a third reaction mixture, cooling the third reaction mixture and adding a carbonyl activating agent to form a fourth reaction mixture; 3) Add a compound of the formula (Va): to the fourth reaction mixture to form a fifth reaction mixture; 4) Heat the fifth reaction mixture; and 5) Optionally converting the compound of the formula (la) to a pharmaceutically acceptable salt thereof, wherein Ar, R, R1 f R2, R3, R4 and R5 as used in a compound of the formulas (Na) e ( IVa) to (Via) are as defined for a compound of the formula (la).

For a compound of the formula (la) the preferred embodiments are as follows. Suitably, Ar is phenyl, optionally substituted by d-6 alkyl or halogen; thienyl, furyl, pyrryl, thiazolyl, or a C5- cycloacdynyl group. Preferably, Ar is phenyl. Suitably, R is d-βalkyl, d-ylcarbonyl alkoxy, d-ylcarbonyl alkyl or hydroxy (d-βalkyl), Preferably, R is C6-6alkyl, most preferably ethyl. R2 is hydrogen or C? -6 alkyl, Preferably, R2 is hydrogen, R3 is hydrogen, hydroxy, halogen, C-? 6 alkoxy or d-b alkyl, preferably R3 is hydrogen, suitably R4 is hydrogen, C 1-6 alkyl, d-6 alkoxy, hydroxy, amino, halogen, aminoalkoxy, mono- or dialkylaminoalkoxy, mono- or dialkylaminoalkyl, phthaloylalkoxy, mono- or dialkylaminoacylamino and acylamino. Preferably, R 4 is C 1-6 alkoxy or hydroxy, most preferably hydroxy A preferred group of compounds of formula (Ia) made by a process of this invention is that in which Ar is phenyl, optionally substituted by d-β alkyl or halogen, thianyl, furyl, pyrryl , thiazolyl or cycloalkadienyl group of C5-; R is C1-6alkyl, (C? -6alkoxy) ca rbonyl, (d-β -carbonyl alkyl or hydroxy (d-β alkyl); R2 is hydrogen or C-? -6 alkyl; R3 is hydrogen, hydroxy, halogen, C6-6 alkoxy, C1-6 alkyl; and R 4 is hydrogen, d-6 alkyl, C 1 -6 alkoxy, hydroxy, amino, halogen, aminoalkoxy, mono- or dialkylaminoalkoxy, mono- or dialkylaminoalkyl, phthaloylakoxy, mono- or dialkylaminoacylamino and acylamino. A most preferred group of compounds of formula (Ia) made by the process of this invention is that in which Ar is phenyl; R is C 1 -β alkyl; R2 is hydrogen; R3 is hydrogen; and R 4 is d-β or hydroxy alkoxy. A most preferred compound of the formula (la) is that in which Ar is phenyl; R is ethyl; R2 is hydrogen; R3 is hydrogen; and R4 is hydroxy. The optically pure compounds of the formula (Va) are commercially available from BASF, Celgene, Inc., and Zeeland Chemical Co., or may be made by methods known in the art, for example Itsuno, S. et al., J. Chem. Soc, Perkin Trans. I, 1985, p. 2039; Burk, M.J. et al., J.Am. Chem. Soc, 1996, 118, p. 5142; and Beak, P. et al., J. Am. Chem.

Soc, 1996, 118, p. 3757. If the racemic mixture of the formula (V) is used, then the racemate of the final product of the formula (I) is made. Separation of the optically active enantiomers is carried out by known methods, for example CLAR. Suitable solvents for coupling a compound of the formula (III) with a compound of the formula (lia) are water, C-alcohols, dimethyl sulfoxide ("DMSO") and dimethylformamide ("DMF"). Water is preferred. Suitable aqueous bases used in this coupling step are lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide and barium hydroxide. The lithium hydroxide is preferred. Suitably, the base is present in an amount of between 2 and 6 equivalents, preferably between 3 and 5 equivalents and most preferably 4 equivalents of base are used. The compound of formula (III) is added to the aqueous base which has been heated to a temperature between about 40 and 70 ° C, preferably between about 50 and 60 ° C. The ring of the compound of the formula (III) is opened with the reaction with the aqueous base. The compound of the formula (lia) is then added, with an exotherm of about 15 ° C. After the addition of the compound of the formula (lia) is complete, the temperature of the resulting reaction mixture is raised to a temperature between about 40 ° C and about 110 ° C, preferably up to about 80 ° C, for a time appropriate (up to about 3 hours) or until the coupling term provides a compound of formula (IVa). The compound of the formula (IVa) is isolated before carrying out the next step in the process. It is important that the next step is conducted under anhydrous conditions since the carbonyl activating agent, eg, SOCI2, oxalyl chloride, DCC, POCI3, COCI2, etc., is hydrolytically unstable and is destroyed with water. The preferred carbonyl activating agent for use in the methods herein is thionyl chloride. Suitable solvents for use in this step are aprotic solvents, including but not limited to the same polar aprotic organic solvents. More specifically, solvents useful herein include, but are not limited thereto, ethyl acetate, toluene, tetrahydrofuran or acetonitrile. A preferred solvent for use herein is ethyl acetate. Suitable bases useful in this process step include amine bases, particularly tertiary amine bases. Preferred tertiary amine bases are triethylamine and diisopropylethylamine. Triethylamine is very preferred. Suitably, at least 3 equivalents of the amine base are used in the present reaction process. After the addition of the base to the compound of the formula (IVa), the reaction mixture is cooled to a temperature below 5 ° C. Preferably the temperature varies between approximately -2 and 2 ° C. The carbonyl activating agent is added and the reaction mixture is then allowed to warm slowly (about 1 hour) at room temperature (about 25 ° C), at which point the compound of the formula (Va), shown later. A particularly preferred compound of the formula (Va) for use in the method herein is (S) -1-phenylpropylamine. It will be understood that the fifth reaction mixture comprises the compound of the formula (I) and a compound of the formula (Via): Formula (VI) By heating the fifth reaction mixture, the compound of the formula (VI) is converted to the desired product. This invention also provides a method for preparing (-) - (S) -N- (α-ethylbenzyl) -3-hydroxy-2-phenylquinoline-4-carboxamide which comprises: 1) adding satin to the base in a solvent suitable for forming a first reaction mixture, adding an a-acetoxyketone to the first reaction mixture to form a second reaction mixture and heating the second reaction mixture to form an α-hydroxy acid; 2) reacting the α-hydroxy acid, in a suitable solvent, with a tertiary amine base to form a third reaction mixture, cooling the third reaction mixture and adding a carbonyl activating agent to form a fourth reaction mixture; 3) adding a primary or secondary amine to the fourth reaction mixture to form a fifth reaction mixture; 4) heating the fifth reaction mixture; and 5) optionally converting (-) - (S) -N- (α-ethylbenzyl) -3-hydroxy-2-phenylquinoline-4-carboxamide to a pharmaceutically acceptable salt. Suitably, for step (1) the base is an aqueous base, preferably LiOH. Preferably, the α-acetoxyketone is α-acetoxyacetophenone. Preferably, the α-hydroxy acid formed in step (1) is 3-hydroxy-2-phenylquinoline-4-carboxylic acid. Preferably, the tertiary amine base of step (2) is triethylamine. Preferably, the carbonyl activating agent of step (2) is thionyl chloride. Preferably, the amine of step (3) is (S) -l-phenylpropylamine. The fifth reaction mixture suitably comprises (-) - (S) -N- (α-ethylbenzyl) -3-hydroxy-2-phenylquinoline-4-carboxamide and (S) -2-phenyl-4 - [[( 1-phenylepropyl) amino] carbonyl] -3-quinolinyl-3-hydroxy-2-phenyl-4-quinoline-carboxylate. A particularly preferred pharmaceutically acceptable salt is the novel hydrochloride of (-) - (S) -N- (α-ethylbenzyl) -3-hydroxy-2-phenylquinoline-4-carboxamide. The hydrochloride salt is prepared according to the examples described below. The product of the reaction defined above can be transformed to other intermediates which can be active compounds of the formula (I) or the formula (a) or which can be useful in the production of compounds of the formula (I) and the formula (la) by well-known methods.

The present invention also provides a method for preparing (-) - (S) -N- (α-ethylbenzyl) -3-hydroxy-2-phenylquinoline-4-carboxamide, which comprises: 1) reacting 3- hydroxy-2-phenylquinoline-4-carboxylic acid, in a suitable solvent, with triethylamine to form a first reaction mixture, cool the first reaction mixture and add thionyl chloride to form a second reaction mixture comprising 6.14, 22,30-tetraphenyl- [1, 5,9,13] tetraoxahexadecino [2,3-c: 6,7-c ': 10, 11 -c ": 14, 15-c'"] tetraquinoline-8,16 , 24,32-tetrone and ethyl 3-acetoxy-2-phenylquinoline-4-carboxylate; 2) add (S) -l-phenylpropylamine to the second reaction mixture to form a third reaction mixture comprising (-) - (S) -N- (α-ethylbenzyl) -3-hydroxy-2-phenylquinoline-4 -carboxamide and (S) -2-phenyl-4 - [[(1-phenyl-propyl) amino] carbonyl] -3-quinolinyl-3-hydroxy-2-phenyl-4-quinoline-carboxylate; 3) heating the third reaction mixture; and 4) optionally converting (-) - (S) -N- (α-ethylbenzyl) -3-hydroxy-2-phenylquinoline-4-carboxamide to a pharmaceutically acceptable salt. It will be understood that the reaction of 3-hydroxy-2-phenylquinoline-4-carboxylic acid can be made by the processes described above for formula (IV) and formula (IVa). The present invention also provides novel compounds of the formula (VII): wherein: Ar is an optionally substituted phenyl group, or a naphthyl or a cycloalkadienyl group of Cs-, or an optionally substituted single or fused heterocyclic group, having an aromatic character, containing from 5 to 12 ring atoms and comprising up to 4 heteroatoms in the ring, or in each ring one, selected from S, O, N; and R3 is hydrogen, straight or branched alkyl of d-6, alkenyl of d-6, aryl, d-β alkoxy, hydroxy, halogen, nitro, cyano, carboxy, carboxamido, sulfonamido, trifluoromethyl, amino, mono- and di- (C? -6) amino amino, -O (CH2) r- NT2, wherein r is 2, 3 or 4 and T is C? -6 alkyl or forms a heterocyclic group wherein V and Vi are hydrogen and u is 0, 1 or 2; -O (CH2) s-OW2 wherein s is 2, 3 or 4 and W is C1-6 alkyl; hydroxyalkyl, mono- or dialkylaminoalkyl, acylamino, alkylsufonylamino, aminoacylamino, mono- or dialkylaminoacylamino; up to 4 substituents R3 being present in the quinoline nucleus; and R'4 is OH or OAc; which are useful as intermediates for the synthesis of pharmaceutically active quinoline compounds in the formula (I) or pharmaceutically acceptable salts thereof, particularly of (-) - (S) -N- (a-ethylbenzyl) -3-hydroxy- 2-phenylquinoline-4-carboxamide and its hydrochloride salt. For a compound of the formula (VII), preferred embodiments are as follows: Suitably, Ar is phenyl, optionally substituted by hydroxy, halogen, d-β alkoxy or d-β alkyl; thienyl or a C5-7 cycloalkenyl group. Preferably, when Ar is substituted phenyl, the substituents are d-6 alkyl or halogen. Examples of Ar as a heterocyclic group are thienyl and pyridyl. Examples of Ar as a C5-7 cycloalkenyl group is cyclohexadienyl. Most preferably, Ar is phenyl. Examples of R3 are methyl, ethyl, n-propyl, n-butyl, methoxy, hydroxy, amino, chloro, fluoro, bromo, 2- (dimethylamini) ethoxy, dimethylaminopropoxy, dimethylaminoacetylamino, acetylamino, dimethylaminomethyl and phenyl. Suitably, R3 is hydrogen, hydroxy, halogen, d-6 alkoxy or C-? -6 alkyl. Preferably R3 is hydrogen. Suitably, R'4 is acetoxy or hydroxy. An especially preferred compound is ethyl 3-acetoxy-2-phenylquinoline-4-carboxylate, that is, a compound of the formula (VII), wherein Ar is phenyl, R3 is hydrogen and R'4 is OAc. The novel intermediates of the formula (VII) were prepared using a preferred subgroup of compound within the scope of the formula (I), of the formula (II) and of the formula (IV), that is, the compounds of the formulas (II ') and (IV). The method for making intermediates of the formula (VII) comprises: 1) adding a compound of the formula (III): Formula (III) of at least 2 and up to 6 equivalents, most preferably 4 equivalents, of aqueous base, preferably lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide and barium hydroxide, most preferably lithium hydroxide in a suitable solvent, for example, water, alcohols of C-DMSO and DMF, preferably water, to form a first reaction mixture, by adding to the first reaction mixture a compound of the formula (II '): Ar ^^ R'4 Formula for forming a second reaction mixture and heating the second reaction mixture to form a compound of the formula (IV): Formula (IV) 2) isolating the compound of the formula (IV) and then reacting the compound of the formula (IV), in a suitable solvent, for example ethyl acetate, with a base, suitably at least 3 equivalents of an amine base, for example triethylamine or disopropylethylamine, to form a third reaction mixture, cooling the third reaction mixture below about 5 ° C, preferably between -2 and 2 ° C, and adding carbonyl activating agent, for example thionyl carbide to form a fourth reaction mixture comprising a compound of the formula (VII) wherein R3, R '4 and Ar are as defined above for the formula (VII). The present invention also provides novel compounds of the formula (VIII): Formula (VIII) wherein: Ar and R3 are as defined for a compound of the formula (I) as claimed in claim 1; and n is 1 or 3. The intermediary of formula (VIII) is prepared for the process described above to prepare the intermediate of formula (VII) except that, as would be expected by one skilled in the art, the mechanism for producing the two intermediates is not It is probably the same. A preferable intermediate of the formula (VIII) is that in which n is 1, ie 6,14-diphenyl- [1,5] dioxochino [2,3-c: 6,7-c '] diquinyl- n- 8, 16-diona. Another intermediate of the formula (VIII) is that in which n is 3, that is, 6,14,22,30-tetraphenyl- [1, 5,9,13] tetraoxahexadecino [2,3-c: 6,7 -c ': 10,11-c ": 14,15-c'"] tetraquinoli-8,16,24,32-tetrone. The following examples are not intended in any way to limit the scope of this invention. The nomenclature and common abbreviations in the chemical technique are used in the examples. The melting points are uncorrected. Liquid chromatography is placed on a Zorbax SB C18 3.5 micron column (0.46 X 7.5 cm) with a flow rate of 1.0 ml per minute detection at 360 nm. The solvents were 40:60:01 acetonitrile: water: trifluoroacetic acid. The chiral purity was determined in the products by chiral HPLC conducted on a Chiralpak AD 10 micron (0.46X25 cm) column, with a flow rate of 1.0 ml per minute and detection at 360 nm. The solvents were 85:15 of n-hexane: ethanol. All 13C NMR (carbon magnetic resonance) and 1H NMR (proton magnetic resonance) spectra were obtained using a Bruker instrument in dimethyl sulfoxide-d6. The 13 C spectra were conducted using the GASPE pulse sequence (Gated-Spin Echo-synchronized spin echo).

EXAMPLES EXAMPLE 1 Synthesis of 3-hydroxy-2-phenylquinoline-4-carboxylic acid A 1 liter round bottom flask was charged with 360 ml of water and L 2 OH "H 2 O (34.3 g, 800 mmol) and stirred at 50-60 ° C. Isatin (30 g, 200 mmol) was added and stirred in the reaction for 30 minutes at 50-60 ° C. The α-acetoxyacetophenone (40.95 g, 230 mmol, 1.15 equiv.) Was added as a solid in one portion and the solution was heated at 80-85 ° C until < 5% PAR of isatin remains as shown by CLAR (typically 3 hours). The reaction was cooled to room temperature, diluted with water (90 ml) and tert-butyl methyl ether ("TBME") (210 ml) and transferred to a separatory funnel. Stir the mixture and drain the aqueous layer to an Erlenmeyer flask. An aqueous layer was acidified to the equal pH 3.0-3.5 using concentrated HCl (-61 ml) and monitored with a pH meter. The suspension of yellow solid was heated to 60-70 ° C and maintained at that temperature for 5-10 minutes and filtered through the Buchner funnel. The flask was rinsed with 90 ml of water at 60-70 ° C and the filter cake was washed with this rinse. The solid was dried by suction for 10 minutes and reloaded into the 1 liter flask. The flask was charged with 600 ml of water, the suspension was heated to 60-70 ° C, kept there for 10 minutes and filtered through a Buchner funnel. The flask was rinsed with 150 ml of water at 60-70 ° C and the filter tower was rinsed with this rinse. The filter cake was dried in a vacuum oven at 80-90 ° C and < 1 mm Hg. After drying to constant weight, the product 3-hydroxy-2-phenylquinoline-4-carboxylic acid (82%) was obtained as a bright yellow solid: m.p. 206 ° C; IR (c? T? 1) 3430.2600, 1634; 1 H NMR (300 MHz, DMSOd 6) d 8.75 (1, d, j = 8.2 Hz), 8.01 (3H, m), 7.59 (5H, m); 13 C NMR (75 MHz, DMSO-d 6) d 171.03, 153.98, 151.38, 139.68, 135.62, 129.60, 129.38, 128.27, 127.83, 126.27, 125.22, 124.54, 115.26.

EXAMPLE 2 Synthesis of (-) - (S) -N- (a-ethylbenzyl) -3-hydroxy-2-phenylquinoline-4-carboxamide hydrochloride An appropriate reaction vessel was charged with 265 g (1 mol) of 3-hydroxy-2-phenylquinoline-4-carboxylic acid and ethyl acetate (25 volumes, . 98 kg, 6.63). The yellow suspension was heated to 30-40 ° C and the ethyl acetate was distilled off under high vacuum until 15 volumes of solvent remained in the still. After vacuum distillation, the yellow suspension was cooled to 20-25 ° C. Triethylamine (3.0 mol, 0.31 kg, 0.42 I) was added to provide a dark orange solution. The solution was cooled to -2 ° C and thionyl chloride (1.05 mol, 0.13 kg, 0.080 I) was added slowly, for about 30 minutes, keeping the temperature of the solution at less than 2 ° C. After complete addition, the suspension was stirred at 25 ° C for 1 hour. It was added and heated to 65-70 ° C for about 3 hours. After 3 hours at 65-60 ° C, the reaction was cooled to 20-25 ° C. The reactor was charged with ethyl acetate (10 volumes, 2.39 kg, 2.65 I) and stirred for 5-10 minutes. Deionized water (15 volumes, 3.98 kg, 3. 98 I). The contents of the reactor were stirred at room temperature for 5 minutes and then the phases were separated. The organic layer was washed with 0.5 M in aqueous citric acid (2 x 10 volumes, 2 x 2.8 kg, 2 x 2.6 I) followed by deionized water (5 volumes, 1.3 kg, 1.3 I). At this point, a sample of the organic phase can be removed and analyzed by HPLC to determine the presence and content of the free base form of the desired product, (note: the yields of the typical solution vary between 80 to 84% and one can proceed assuming 80% of the solution's performance). Toluene (15 volumes, 3.44 kg, 3.98 I) was added and the solution was concentrated by vacuum distillation until a final volume in the 2.2 I reactor was obtained (this represents 7 volumes of solvent left based on the available free base). ). The reactor was charged with IPA (isopropylamine) (3 volumes based on the free base available, 0.72 kg, 0.92 I) and the reactor content was heated to 70 ° C to provide a clear solution. To the solution was added by bubbling 58.4 g (2 equiv.) Of HCl (g) slowly to precipitate the desired product. The precipitate was cooled to 0 ° C and maintained for about 1 hour. The product was collected by filtering by suction. The reaction flask was rinsed with TBME (4 volumes, 0.90 kg, 1.22 I) and the TBME was used as a rinse to wash the filter cake. This wash was repeated with an additional portion of TBME (4 volumes, 0.90 kg, 1.22 I). The product was dried at a constant weight in a vacuum oven at 70 ° C / <; 1.0 mm Hg. The yield of the desired product was 301 g, providing a 72% yield of a light beige product: P.f. = 179-180 ° C, IR (cm'1) 2450, 1627, 1322; 1 H NMR (300 MHz, DMSO-d 6) d 9.20 (1 H, d J = 8.0 Hz), 8.19 (1 H, d, J = 8.4 Hz), 7.96 (2 H, m), 7.71 (1 H, m) , 7.60 (5H, m), 7.44 (2H, m), 7.37 (2H, m), 7.27 (1 H, m), 5.02 (1 H, q, J = 7.5 Hz), 1.81 (2H, m), 0.94 (3H, t, J = 7.2 Hz). 13C NMR (100.625 Mhz) d 169.8, 151.7, 144.8, 143.3, 139.7, 134.9, 131.3, 129.9, 129.8, 128.2, 128.0, 126.8, 126.7, 126.5, 125.7, 123.9, 55.0, 29.3, 11.1. All publications are hereby incorporated by reference, including, but not limited to, the same, patents and patent applications cited in this specification, as if specifically and individually indicating that each individual publication is incorporated by reference herein, as if it were exposed completely. The foregoing description fully discloses the invention including preferred embodiments thereof. Modifications and improvements of the modalities specifically set forth herein are within the scope of the following claims. Without further detail, it is believed that one skilled in the art, given the description given, can use the present invention to its fullest extent. Therefore, any examples should be construed as merely illustrative and not in any way as limiting the scope of the present invention. The methods of the invention are defined in which a property or exclusive privilege can be claimed, as follows.

Claims (10)

NOVELTY OF THE INVENTION CLAIMS

1. - a method for preparing a compound of formula (I): Formula (I) or a pharmaceutically acceptable salt thereof, wherein: Ar an optionally substituted phenyl group, or a naphthyl or a C5-C7 cycloalkadienyl group, or an optionally substituted fused single ring heterocyclic group, having an aromatic character, containing 5 to 12 ring atoms and comprises up to four heteroatoms in the ring, or in each, selected from S, O, N; R is straight or branched Ci-Cs alkyl, C5-C7 cycloalkyl, (d-d-kekyl cycloalkyl, an optionally substituted phenyl group or a phenyl group (C? -C6 alkyl), an optionally substituted five-membered heteroaromatic ring comprising up to four heteroatoms selected from O and N, hydroxy (C? -C6 alkyl), and di (CrC? Jaminoalkyl alkyl, (C? -C6 acyl) aminoalkyl, (d-C6 alkoxy) alkyl It, (d-C 1 J -carbonyl, carboxy, (CrC 6 alkoxy) carbonyl, (C 6 alkoxy) carbonyl (d-Cß alkyl), aminocarbonyl, (d-C 6) alkyl-aminocarbonyl, di ( d-C6 alkyl) aminocarbonyl, or is a group - (CH2) P- when cyclized to Ar, where p is 2 or 3; Ri and R2, which may be equal or different, are independently hydrogen or linear alkyl or branched dC ?, or together form a group - (CH2) n- in which n represent 3, 4 or 5; Ri together with R form a group - (CH2) q- in which q is 2, 3, 4 or 5; R3 and R4, which may be identical or different, are independently hydrogen, linear or branched alkyl of d-C6, alkenyl of d-Cß, aryl, d-Cß alkoxy, hydroxy, halogen, nitro, cyano, carboxy, carboxamido , sulfonamido, trifluoromethyl, amino, mono- and di (CrCßJamino alkyl, - (CH2) r-NT2, wherein r is 2, 3 or 4 and T is d-Cß alkyl or forms a heterocyclic group wherein V and Vi are hydrogen and u is 0, 1 or 2; -O (CH2) s-OW2 wherein s is 2, 3 or 4 and W is C1-6 alkyl; hydroxyalkyl, mono- or dialkylaminoalkyl, acylamino, alkylsulfonylamino, aminoacylamino, mono- or dialkylaminoacylamino; up to four substituents R3 being present in the quinoline nucleus; or R4 is a group - (CH2) t- when cyclizing to R5 as aryl, in which t is 1, 2 or 3; and R5 is branched or linear C1-6 alkyl, C3-7 cycloalkyl, (C4-7 cycloalkyl) alkyl, optionally substituted aryl, wherein the optional substituents is one of hydroxy, halogen, C1-6 alkoxy or alkyl of C1-6, or an optionally substituted fused single ring heterocyclic group, having an aromatic character, containing from 5 to 12 ring atoms and comprising up to four ring heteroatoms or each, selected from S, O, N; which comprises: 1) adding a compound of the formula (III): Formula (III) to the base in a suitable solvent, to form a first reaction mixture, by adding to the first reaction mixture a compound of the formula (II): Formula (II) for forming a second reaction mixture and heating the second reaction mixture to form a compound of the formula (IV): Formula (IV)

2) isolating the compound of the formula (IV) and then reacting the compound of the formula (IV), in a suitable solvent, with a base to form a third reaction mixture, cooling the third reaction mixture and adding an agent carbonyl activator to form a fourth reaction mixture; 3) add a compound of the formula (V): to the fourth reaction mixture to form a fifth reaction mixture; 4) heating the fifth reaction mixture; and 5) optionally converting the compound of the formula (I) to a pharmaceutically acceptable salt, wherein Ar, R, Ri, R2, R3. R4 and R5 as used in a compound in the formulas (II) to (VI) are as defined for a compound of the formula (I). 2. The method according to claim 1, further characterized in that for the compound of the formula (I): Ar is phenyl, optionally substituted by C6 alkyl or halogen; thienyl or a C5-7 cycloalkadienyl group; R is C alkyl. (C6-C6-alkoxy) carbonyl, (Cr6-alkyl) carbonyl, hydroxy (Ci-β-alkyl); each of R1 and R2 is hydrogen or d-C6 alkyl; R3 is hydrogen, hydroxy, halogen, C1-6 alkoxy, C1-6 alkyl; R is hydrogen, C 6 alkyl > C 1-6 alkoxy, hydroxy, amino, halogen, aminoalkoxy, mono- or dialkylaminoalkoxy, mono- or dialkylaminoalkyl, phthaloylalkoxy, mono- or dialkylaminoacylamino and acylamino; and R5 is phenyl, thienyl, furyl, pyryl and thiazolyl.

3. - The method according to claim 2, further characterized in that for the compound of the formula (I): Ar is phenyl; R is ethyl; each of Ri and R is hydrogen; R3 is hydrogen; R4 is hydroxy; and R5 is phenyl.

4. A method for preparing (-) - (S) -N- (a-ethylbenzyl) -3-hydroxy-2-phenylquinoline-4-carboxamide, which comprises: 1) reacting 3-hydroxy-2- acid phenylquinoline-4-carboxylic acid, in a suitable solvent, with triethylamine to form a first reaction mixture, cool the first reaction mixture and add thionyl chloride to form a second reaction mixture comprising 6,14,22, 30-tetraphenyl - [1, 5,9,13] tetraoxahexa-decino [2.3-c: 6,7-c ': 10,11-c ": 14,15-c",] tetraquinoline-8,16,24,32- tetrana and ethyl 3-acetoxy-2-phenylquinoline-4-carboxylate; 2) add (S) -l-phenylpropylamine to the second reaction mixture to form a third reaction mixture comprising (-) - (S) -N- (α-ethylbenzyl) -3-hydroxy-2-phenylquinoline-4 -carboxamide and (S) -2-phenyl-4 - [[(1-phenylpropyl) amino] carbonyl] 3-quinolinyl, 3-hydroxy-2-phenyl-4-quinoline-carboxylate; 3) heating the third reaction mixture; 4) optionally converting (-) - (S) -N- (α-ethylbenzyl) -3-hydroxy-2-phenylquinoline-4-carboxamide to a pharmaceutically acceptable salt.

5. A compound of the formula (VII): Formula (VII) wherein: Ar is an optionally substituted phenyl group, or a naphthyl or a C5-7 cycloalkadienyl group, or an optionally substituted single or fused heterocyclic group, having an aromatic character, containing from 5 to 12 ring atoms and comprising up to 4 heteroatoms in the ring, or in each, selected from S, O, N; and R3 is hydrogen, straight or branched C1-6 alkyl, C6-6 alkenyl, aryl, d-6 alkoxy, hydroxy, halogen, nitro, cyano, carboxy, carboxamido, sulfonamido, trifluoromethyl, amino, mono- and di (C? -6) amino amino, -O (CH2) r-NT2, wherein r is 2, 3 or 4 and T is d6 alkyl or forms a heterocyclic group wherein V and Vi are hydrogen and u is 0, 1 or 2; -O (CH2) s-OW2 in which s is 2, 3 or 4 and W is d-β alkyl; hydroxyalkyl, mono- or dialkylaminoalkyl, acylamino, alkylsufonylamino, aminoacylamino, mono- or dialkylaminoacylamino; up to 4 substituents R3 being present in the quinoline nucleus; and R'4 is OH or OAc.

6. The compound of the formula (VII) according to claim 5, which is

7. - A compound of the formula (VIII): Formula (VIII) wherein: Ar and R3 are as defined for a compound of the formula (I) according to claim 1; and n is 1 or 3

8. The method according to claim 1, further characterized in that the compound of the formula (I) is (-) - (S) -N- (a-ethylbenzyl) -3-hydroxy-2 phenylquinoline-4-carboxamide.

9. A compound that is hydrochloride salt of (-) - (S) -N- (α-ethylbenzyl) -3-hydroxy-2-phenylquinoline-4-carboxamide.

10. A method for repairing a compound of the formula (1a): wherein: Ar is an optionally substituted phenyl group, or a naphthyl or a C5-7 cycloalcienyl group, or an optionally substituted single or fused heterocyclic group, having an aromatic character, containing from 5 to 12 ring atoms and comprises up to 4 heteroatoms in the ring, or in each, selected from S, O, N; R is straight or branched C? -8 alkyl, C3-7 cycloalkyl, (d-alkyl) cycloalkyl, an optionally substituted phenyl group or a phenyl (d-b) alkyl group, an optionally substituted 5-membered heteroaromatic ring comprises up to 4 heteroatoms selected from O and N, hydroxy, (CI-T alkyl), di (dd alkyl) -aminoalkyl, (Cristamine alkyl acyl, (d-6 alkyl) carbonyl, carboxy, (C 1 alkoxy; -6) carbonyl, (d-β) alkoxycarbonyl (d-β alkyl), aminocarbonyl, (C?-6) aminocarbonyl alkyl, di- (C 6 alkyl) -aminocarbonyl, or is a group - ( CH2) P when cyclized to Ar, where p is 2 or 3, R2 is hydrogen or straight or branched alkyl of -β, and R3 and R4, which may be the same or different, are independently hydrogen, linear or branched alkyl of d-β, Cr6 alkenyl, aryl, Cr6 alkoxy, hydroxy, halogen, nitro, cyano, carboxy, carboxamido, sulfonamido, trifluoromethyl, amino, mono- or di (Cristamine alkyl, -O (CH2) r-NT2 , in which r is 2, 3 or 4 and T is d-β alkyl or forms a heterocyclic group wherein V and Vison hydrogen and u is 0, 1 or 2; -O (CH 2) s-OW 2 wherein s is 2, 3 or 4, and W is d-β-hydroxyalkyl, mono- or dialkylaminoalkyl, acylamino, alkylsulfonylamino, aminoacylamino, mono- or dialkylaminoacylamino; up to 4 substituents R3 being present in the quinoline nucleus; which comprises: 1) adding a compound of the formula (III): Formula (III) to the base in a suitable solvent, to form a first reaction mixture, add to the first reaction mixture a compound of the formula (lia): to form a second reaction mixture, and heating the second reaction mixture to form a compound of the formula (IVa): Formula (IVa) 2) isolating the compound of the formula (IVa) and then reacting the compound of the formula (IVa), in a suitable solvent, with a base to form a third reaction mixture, cooling the third reaction mixture and adding an agent carbonyl activator to form a fourth reaction mixture; 3) add a compound of the formula (Va): Formula (Va) to the fourth reaction mixture to form a fifth reaction mixture; 4) heating the fifth reaction mixture; and 5) optionally converting the compound of the formula (I) to a pharmaceutically acceptable salt thereof, wherein Ar, R, Ri, R 2, R 3, R 4 and R 5 as used in a compound of the formulas (Na), and (IVa) to (Via) are as defined for a compound of the formula (1a).