SI9300202A - Hydroxyquinolone derivates - Google Patents

Abstract

A group of 4-hydroxy-2- (1H) -quinolone derivatives, substituted at the 3-position by an optionally substituted aryl substituents are selectively non-competitive N-methyl-D-aspartate receptor antagonists and / or antagonists of 2-amino-3-hydroxy-5-methyl-4-isoxazole receptors propionic acids and are therefore useful for treating conditions such as neurodegenerative diseases, spasms or schizophrenia requiring the administration of an antagonist of the N-methyl-D-aspartate receptor and / or 2-amino-3-hydroxy-5-methyl-4-isoxazolpropionic acid

Description

HYDROXYCINOLONE DERIVATIVES

The present invention relates to a group of 4-hydroxy-2 (1H) -quinolones substituted at position 3 with an optionally substituted aryl substituent. These compounds are selective non-competitive N-methyl-D-aspartate receptor (NMDA) antagonists. More specifically, the group of compounds provided by the present invention are ligands for the glycine modulatory position of NMDA receptor, which is non-strychnine, and therefore useful for the treatment and / or prevention of neurodegenerative disorders resulting from such pathological conditions as stroke, hypoglycemia, cerebral palsy, transient cerebral ischemic attack, cerebral ischemia during cardiac or pulmonary surgery or cardiac arrest, perinatal damping, epilepsy, Huntington's chorea, Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, olive-atrophycaine, olivopharynx due to drowning, spinal and head damage, and poisoning by exogenous and endogenous NMDA receptor agonists and neurotoxins, including surrounding neurotoxins.

The compounds of the present invention, by virtue of their NMDA receptor antagonist properties, are also useful as anti-seizure and vomiting agents, as well as in preventing or reducing dependence on addictive agents such as narcotics.

NMDA receptor antagonists have recently been shown to exert a mitigating effect (see, for example, Dickenson and Aydar, Neuroscience Lett., 1991, 121, 263; Murray et al., Pain, 1991, 44, 179; and Moolf and Thompson, Pain. , 1991, 44, 293) against depression (see, e.g., Trullas and Skolnick, Eur. J. Pharmacol., 1990, 185, 1) and anxiety (see, for example, Kehne et al., Eur. J. Pharmacol ., 1991, 193, 283) and therefore the compounds of the present invention may be useful in the management of pain, depression and anxiety.

The association of NMDA receptor antagonists with the regulation of the nigrostriatic dopaminergic system has recently been reported (see, e.g., Warling et al., J. Pharmacol. Exp. Ther. 1990, 255, 40; Graham et al., Nature (London)). 1991, 349, 414). This indicates the ability of the compounds of the present invention to assist in the prevention and / or treatment of disorders of the dopaminergic system such as schizophrenia and Parkinson's disease.

They also recently reported (see Lauritzen et al., Journal of Cerebral Blood Flow and Metabolism, 1991, vol. 11, suppl. 2, Abstract XV-4) that NMDA receptor antagonists block cortical spread (CSD). which may therefore be clinically relevant, as CSD is a possible mechanism of migraine. The group of substituted 2-amino-4-phosphonomethylalk-3-ene carboxylic acids and esters described in EP-A-0420806, which are said to be selective NMDA antagonists, are thus believed to be potentially useful for the treatment of inter alia migrene.

Irritable amino acid receptor antagonists, including inter alia NMDA receptor antagonists, are stated in EP-A-0432994 to be useful for stopping vomiting.

Recent reports in the literature have also suggested a link between the neurotoxicity of some viruses and the deleterious effects of these viruses on organisms caused by enhancement of neurotransmission via irritable amino acid receptors. The compounds of the present invention may therefore be effective, based on their activity as NMDA receptor antagonists, in controlling the manifestation of neuroviral diseases such as measles, rabies, tetanus (cf. Bagetta et al., Br. J. Pharmacol., Neuroscience Abstracts, 1990, 16, 128.11).

Furthermore, NMDA antagonists have been shown to show effects on the neuroendocrine system (see, for example, van de Pol et al., Science, 1990, 250, 1276; and Urbanski, Endocinology, 1990, 127, 2223), and are therefore compounds of this of the invention can be effective in controlling seasonal cultivation in mammals.

In addition, certain compounds of the invention are 2-amino-3-hydroxy-5-methyl-4-isoxazolpropionic acid (AMPA) receptor antagonists, also known as quisqualate receptors. It is well known that due to irritation of the premolar membrane, amino acids are secreted and directed to the nucleus accumbens (a special part of the forebrain that houses dopamine-sensitive neurons) (see, for example, J.Neurochem., 1985, 45, 477) . It is also well known that glutamate modulates dopaminergic transmission in the striatum (see, for example, Neurochem. Int. 1983, 5, 479), as well as excessive activity combined with presynaptic stimulation of the dopamine system by AMPA in nucleus accumbens (cf. Life Sci., 1981, 28, 1597). Compounds that are antagonists of AMPA receptors are therefore useful as neuroleptic agents.

A group of 4-hydroxy-3-phenyl-2 (1H) -quinolones derivatives substituted at the 7-position by an unsubstituted straight or branched alkoxy group containing 2 to 10 carbon atoms or a straight or branched alkoxy group containing 1 to 6 carbon atoms having at least one substituent selected from hydroxy, carboxy and carbamoyl are described in JP-A-63-295561. It is claimed here that these compounds exhibit potent inhibitory action on bone resorption and a stimulating effect on ossification and are therefore useful as therapeutic agents for the prevention and treatment of osteoporosis.

EP-A-0293146 and JP-A-1-242585 describe a series of 4-hydroxy-3-phenyl-2 (1H) quinolones substituted at different positions by hydroxy or lower alkoxy substituents as intermediates in the preparation of different benzofuro derivatives [ 3,2 -clquinoline. The latter compounds are also said to be useful agents for the prevention and treatment of osteoporosis.

A specific derivative of methoxylated 4-hydroxy-3-phenyl-2 (1H) -quinolone, namely 3- (2,4-dimethoxyphenyl) -4-hydroxy-7-methoxy-2 (1H) -quinolone, is disclosed in d. Heterocycl. Chem., 1984, 21, 737.

Yakugaku Zasshi, 1970, 90, 818 describes a series of 4-hydroxy-3-phenyl-2 (1H) quinolones optionally substituted at the 6-, 7- or 8-position with different functional groups. In some of these compounds, the 3-phenyl substituent is itself substituted at the ortho or para position by a methyl group.

Various 4-hydroxy-3-phenyl 1-2 (1H) -quinoline one derivatives, optionally mono- or disubstituted on the benzo moiety of the tetrahydroquinoline ring system, and optionally monosubstituted on the ortho or para position of the 3-phenyl substituent with different groups, are disclosed in EP-A-OO93521; Monatsh. Chem., 1967, 98, 100; Buli. Chem. Soc. Jpn., 1980 53, 1057; J. Heterocycl. Chem., 1989, 26,281; J. Heterocycl. Chem., 1988, 25, 857; J. Heterocycl. Chem., 1975, 12, 351; Z. Naturforsch., 19882, 37b, 1196; and Helv. Chim. Acta, 1951, 34, 1050.

Other than JP-A-63-295561, as mentioned above, none of the foregoing publications discloses any therapeutic benefit of the various 4-hydroxy-3-phenyl-2 (1H) -quinolone derivatives described therein. In addition, there is no suggestion in any prior art document that the compounds described therein will assist in solving the problem of preparing effective agents for the treatment and / or prevention of conditions requiring administration of an NMDA antagonist and / or AMPA receptor.

The present invention therefore allows the use of a compound of formula I or a pharmaceutically acceptable salt or prodrug thereof:

(D in which

R 1 and R ² independently represent hydrogen, hydrocarbon, heterocyclic group, halogen, cyano, trifluoromethyl, nitro, -O R ^a , -SR ^a , -SOR ^a , -SO ^{2 a} , -SO ² NR ^a R ^b , -NR ^a R ^b , - NR ^a COR ^b , -NR ^a CO2R ^b , -COR ^a , -CO ² R ^a or -CONR ^a R ^b ; or R ² and R ² together represent the residue of a carbocyclic or heterocyclic ring;

R ³ , r \ r 5 and r 6 independently represent hydrogen, hydrocarbon, heterocyclic group, halogen, cyano, trifluoromethyl, nitro, -O R ^a ,

-SR ^a , -SOR ^a , -SO2R ^a , -SO2NR ^a R ^b , -NR ^a R ^b , -NR ^a COR ^b , -NR ^a CO ₂ R ^b , -COR ^a ,

CO ₂ R ^a or -CONR ^a R ^b ; and

R ^a and R 4 independently represent a hydrogen, hydrocarbon or heterocyclic group;

for the manufacture of a medicament for the treatment and / or prevention of conditions, in particular neurodegenerative disorders, which require the administration of a selective non-competitive NMDA receptor antagonist.

The present invention further provides the use of a compound of formula I as defined above, or pharmaceutically acceptable salts or prodrugs thereof, for the manufacture of a medicament for the treatment and / or prevention of conditions, such as schizophrenia, requiring administration of an AMPA receptor antagonist.

The compound of formula I will generally exist in equilibrium with its other tautomeric forms, including those of formulas A to D:

(A) (B)

(c) (D) in which R ^ to R® are determined by reference to Formula I above.

Of course, in the foregoing references to the prior art, the compounds disclosed therein are variously designated by reference to one or the other of these tautomeric forms. It is to be understood that all tautomeric forms of the compounds of formula I, as well as all possible mixtures thereof, are included within the scope of the present invention.

The term hydrocarbon as used herein includes unbranched, branched and cyclic groups containing up to 18 carbon atoms, up to 15 carbon atoms and up to 12 carbon atoms, respectively. Suitable hydrocarbon groups include C | .G alkyl, _C2 _6 alkenyl, _C2 _6 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkyl (Cj_g) alkyl, aryl, aryl (C |. ₆₎ alkyl, aryl (C ₂ _g ) alkenyl1 and aryl (¢ 2-5) al which is not 1.

The term heterocyclic group as used herein includes cyclic groups containing up to 18 carbon atoms and at least one heteroatom, preferably selected from oxygen, nitrogen and sulfur. The heterocyclic group appropriately contains up to 15 carbon atoms and up to 12 carbon atoms and is preferably carbon bonded. Examples of suitable heterocyclic groups include C3-7 heterocycloalkyl, C3-7 heterocycloalkyl (C1-8) alkyl, heteroaryl, and heteroaryl (C1-6) alkyl groups.

Suitable alkyl groups include straight and branched alkyl groups containing from 1 to 6 carbon atoms. Typical examples include the methyl and ethyl groups and the unbranched or branched propyl and butyl groups. Special alkyl groups are methyl, ethyl and t-butyl.

Suitable alkenyl groups include straight and branched alkenyl groups containing from 2 to 6 carbon atoms. Typical examples include vinyl and allyl groups.

Suitable alkynyl groups include straight and branched alkynyl groups containing from 2 to 6 carbon atoms. Typical examples include the ethynyl and propyl groups.

Suitable cycloalkyl groups include groups containing from 3 to carbon atoms. Special cycloalkyl groups are cyclopropyl and cyclohexyl.

Suitable aryl groups include phenyl and naphthyl groups.

The particular aryl (C1-8) alky 1 per group is benzyl.

Particular aryl (C ₂ _g) alkenyl group is phenylethenyl.

The particular aryl (C2_g) alky ni1 per group is phenylethynyl.

Suitable heterocycloalkyl groups include the piperidyl, piperazinyl and morpholinyl groups.

The particular heterocycloalkyl (C1-8) alkyl group is morpholinylethyl.

Suitable heteroaryl groups include a pyridyl, quinolyl, isoquinolyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, indolyl, pyranyl, furyl, benzofuryl, thienyl, benztienyl, imidazolyl, oxadiazolyl and thiadiazolyl groups. Special heteroaryl groups are pyridyl, pyrrolyl, indolyl, furyl, benzofuryl, thienyl, benzthienyl and oxadiazolyl.

Specific heteroaryl (C 1-10) alkyl groups 1 include pyridylmethyl, pyrrolylmethyl, indolylmethyl, furylmethyl and thienylmethyl.

Where R ¹ and R together represent a residue of a carbocyclic or heterocyclic ring, the ring may be saturated or unsaturated. The ring may be an appropriate 4- to 9-member ring, but preferably a 5- or 6-member ring. Wherein R ^ and R ² together represent a radical of the heterocyclic ring, this ring may contain up to four heteroatoms selected from oxygen, nitrogen and sulfur. Suitable carbocyclic rings of which R and R ² n together represent the residue include cyclohexane, cikloheksenov, cikloheksadienov and the benzene ring. Suitable heterocyclic rings, of which R and R together represent a residue, include dioxylane, dioxane, pyridine, furan, thiophene, pyrrole, thiazole and thiadiazole ring.

The hydrocarbon and heterocyclic groups, as well as the carbocyclic or heterocyclic ring supplemented with and R ² , may in turn be substituted by one or more groups selected from C 1-6 alkyl, adamantyl, phenyl, halogen, C 1-8 haloalkyl, morpholinyl (C 3-8 glufluoromethyl) , hydroxy, Cj.g alkoxy, Cj_g alkoxy (Cj_θ) which al 1 a, Cj_g alkoxy (Cj_ ₆₎ alkoxy, aryloxy, keto, Cj_ ₃ alkilensdioksi, nitro, cyano, carboxy, C £ _g alkoxycarbonyl, C £ _6 alkoxycarbonyl ( C 1-8 alkyl, C 1-6 alkylcarbonyloxy, arylcarbonyloxy, C 2-8 alkylcarbonyl, aryl carbonyl, C 1-8 alkylthio, C 1-8 alkynylsulfinyl, C 1-8 alkylsulfonyl, amino, mono- or di (C 1-6) alkylamino, C 2-5 alkylcarbonyl ~ g alkoxycarbonyl amino.

The term halogen as used herein includes fluorine, chlorine, bromine and iodine, in particular chlorine.

The corresponding meaning of the substituents R and R ² are: Cj.g alkyl, aryl, aryl (Cj_g) alkyl, aryl (C ₂ _6) alkenyl 1, aryl (C ₂ _6) alkynyl, heteroaryl (CPG) alkyl, Cj_g alkoxy, C2-5 alkenyloxy, aryloxy, aryl (C1-8) alkoxy, heteroaryloxy, arylthio, arylsulfonyl, arylamino, aryl (C1-8) alkylamino, di (C1-8) alkylamino, ary Icarbonylamino, arylcarbonyl or heteroaryl carbonyl, wherein each of these groups may be optionally substituted; and hydrogen, halogen, trifluoromethyl or nitro. Examples of any substituents on the groups R 1 and / or R ² include C 1-8 alkyl, morpholinyl (C 1-6) alkyl, hydroxy, C 1-8 alkoxy, C 1-8 alkoxy (C 1-8) alkyl, C 1-8 alkoxy (C 1-8) alkoxy, C 1-8 alkylthio and di (C1-8) alkylamino.

Particularly important for the substituents R ^ and R ² are hydrogen, methyl, phenyl, benzyl, methoxymethyl-benzyl, morpholinylethyl-benzyl, hydroxybenzyl, methoxybenzyl, methoxymethoxy-benzyl, methylthio-benzyl, phenylethenyl, phenylethynyl, thienylmethyl, pyrrolylmethyl, indolylmethyl chloro, bromo, iodo, trifluoromethyl, nitro, methoxy, ethoxy, allyloxy, methyl-allyloxy, phenoxy, methyl-phenoxy, methoxy-phenoxy, dimethylamino-phenoxy, benzyloxy, furyloxy, thienyloxy, pyridyloxy, benzyloxy, phenylethyl, phenylethyl, phenylethyl , dimethylamino, phenylcarbonylamino, phenylcarbonyl, furylcarbonyl and thienylcarbonyl.

It corresponds to one of R ^ and R ² being hydrogen. Preferably, at least one of R ^ and R ^ is different from hydrogen.

Where R1 and R4 together represent a carbocyclic or heterocyclic ring, it may in particular be a dioxolane or an optionally substituted benzene ring.

The benzo moiety of the 4-hydroxy-2 (1H) -quinolone ring system exemplified by formula I above may be substituted or unsubstituted. Specific substituents include hydrogen, cyano, trifluoromethyl, nitro, hydroxy, amino, carboxy, Cj_g alkyl, C ₂ _g alkenyl, Cj.g alkoxy, Cj.g alkoxy and C £ _y al alkoxy carbonyl 1. Corresponding to the R & is hydrogen, and R ^, R ^ and R $ independently are hydrogen, halogen, cyano, trifluoromethyl, nitro, Cj.g alkyl or C £ _g alkenyl, it is desirable that at least one of R, R and R ^J is other than hydrogen. Preferably R4 and R4 each represent hydrogen and R4 and R8 independently represent hydrogen, cyano, trifluoromethyl, nitro, methyl, ethyl, vinyl or halogen, in particular chlorine or iodine. In a particular embodiment, R1

O cyano, trifluoromethyl, nitro or halogen, in particular chlorine; and R is hydrogen or ethyl.

A further aspect of the invention is a pharmaceutical composition comprising a compound of Formula IA or a pharmaceutically acceptable salt or prodrug thereof:

(IA) in which rH and rl 2 independently represent hydrogen, hydrocarbon, heterocyclic group, halogen, cyano, trifluoromethyl, nitro, -O R ^a , -SR ^a , -SOR ^a , -SO ² R ^a , -SO ² NR ^a R ^b , - NR ^a R ^b , -NR ^a COR ^b , -NR ^a CO2R ^b , -COR ^a , -CO ² R ^a or -CONR ^a R ^b ; or R ^ and R ^ together represent the residue of a carbocyclic or heterocyclic ring;

_rH> pl5 _and pl6 _neo lifting $ no represent hydrogen, hydrocarbon, heterocyclic group, halogen, cyano, trifluoromethyl, nitro, -OR ^a, -SR ^a, -SOR ^a, -SO2R ^a, -SO2NR ^a R ^b, -NR ^a R ^b, -NR ^a COR ^b, -NR ^a CO 2 R ^b, -COR ^a, -CO2R ^a, or -CONR ^a R ^b; and

R ^a and R ^b independently represent a hydrogen, hydrocarbon or heterocyclic group;

provided that when R ^, R ^, R ^, R ^ and R ^ each represent hydrogen, then R ^ does not mean an unsubstituted unbranched or branched alkoxy group containing 2 to 10 carbon atoms, or unbranched or branched alkoxy group, containing from 1 to 6 carbon atoms with at least one substituent selected from hydroxy, carboxy and carbamoyl;

together with one or more pharmaceutically acceptable carriers and / or excipients.

The invention also provides a compound of formula IA as defined above, or a pharmaceutically acceptable salt or prodrug thereof for use in therapy.

The substituents R ^ to R ^ in the compounds of formula IA, subject to the abovementioned condition, each coincide with the substituents R ^ to R ⁶ , as determined by reference to the compounds of formula I.

Individual pharmaceutical compositions of the invention contain, as an active ingredient, at least one of the following compounds:

4-hydroxy-3-phenyl-2 (1H) -quinolone;

- kioro-4-h and drox i-3-pheny 1-2 (1H) - quinol;

- chloro-4-hydroxy-3- (2-methylphenyl) -2 (1H) -quinoline; 7-chloro-4-hydroxy-3- (4-methylphenyl) -2 (1H) -quinolone;

4-hydroxy-3-phenyl-7-trifluoromethyl-2 (1H) -quinolone; 6,7-dichloro-4-hydroxy-3-phenyl-2 (1H) -quinolone;

and their pharmaceutically acceptable salts and prodrugs.

Some of the compounds that fall within the above definition of formula I are novel. Thus, a further aspect of the present invention provides a compound of formula IB or a salt or prodrug thereof:

in which and R ^{22 a} group, ^} 2

R ²¹ heterocyclic -SR ^a , -SOR ^a ,

-SO.- ³ independently represent hydrogen, hydrocarbon, and halogen, cyano, trifluoromethyl, nitro, -OR -SO ₂ NR ^a R ^b , -NR ^a R ^b , -NR ^a COR ^b , -NR ^a CO ₂ R ^b , -COR ^a ,

-CO ₂ R ^a or -CONR ^a R ^b ; or R ² and R ²² together represent the residue of a carbocyclic or heterocyclic ring;

R ²³ , R ² , R ² and R ² independently represent hydrogen, hydrocarbon, heterocyclic group, halogen, cyano, trifluoromethyl, nitro, -O R ^a , -SR ^a , -SOR ^a , -SO ^{2 a} , -SO ² NR ^a R ^b , -NR ^a R ^b , -NR ^a COR ^b ,

-NR ^a CO2R ^b , -C0R ^a , -CO2R ^a, or -CONR ^a R ^b ; and

R ^a and R ^b independently represent a hydrogen, hydrocarbon or heterocyclic group;

provided that when R ² ^ and R ²² each represent hydrogen, then:

(i) R ²⁴ does not represent hydrogen, methyl, chloro, hydroxy, methoxy or pnpr acetoxy when R, R and R each each represent hydrogen; and (ii) R ² does not mean methyl, chloro, trifluoromethyl, hydroxy, benzoyloxy or unsubstituted unbranched or branched alkoxy group containing 1 to 10 carbon atoms or unbranched or branched alkoxy group containing 1 to 6 carbon atoms with at least one substituents selected from hydroxy, carbos and carbamoyl when R ²³ , R ²⁴ and R ^{2 are} each hydrogen; and (iii) R ^{2 is} not methyl, phenyl, chloro or methoxy when R ²³ , R ² and R ^{2 are} each hydrogen; and (iv) R ^{2 is} not chloro when R ²³ and R ^{2 are} each hydrogen and R ^{26 is} methoxy or when R ²³ and R ^{2 are} each hydrogen and R ^{2 is} chloro;

(v) R ² ^ does not chloro when R ²³ j _n p25 _{all (<p Omen} j is hydrogen and R ²⁴ is chloro, or when R ²⁴ and R ^ ² each represents hydrogen, and R ²³ is chloro;

also provided that when one of R ² and R ²² represents hydroxy or lower alkoxy and the other represents hydrogen, hydroxy or alkoxy, and R ²³ , R ²⁴ and R ² each represent hydrogen, then R ²³ does not represent hydrogen or and lower alkoxy;

also provided that when R ^{2 is} 2'-methyl and R ^{22 is} hydrogen, then:

(i) R ²⁴ does not represent hydrogen, chloro or methoxy when R ²³ , R ^{2 '} and R each represent hydrogen; and (ii) r25 is not chloro or methoxy when R ²³ , R ²⁴ and R ^{2 are} each hydrogen; and

(iii) R ²⁶ does not mean chloro when R ²³ , R ²⁴ and R ²³ each means hydrogen; right so provided that, when R ² ^ and R ₂₃ each means hydrogen, one of the of substituents R ²⁴ , R ² $ and R ²⁶ means chloro and yes the others

are hydrogen, then R ^{22 is} not 4'-methyl;

also provided that when R is ² ^ 2'-methoxy and R ²² , R ²³ ,

R ²³ j _n p26 _all | _{<P Omen} j is hydrogen, then R ²⁴ does not represent hydrogen, fluoro, chloro or bromo;

further provided that when R ² , R ²³ , R ²⁴ , R ² , and R ^{2 are} each hydrogen, then R is not 2'-fluoro, 2'-nitro, 2'-amino, 4'chloro, 4'-hydroxy or 4'-methoxy.

The substituents R ² to R ² ® in the compounds of formula IB, subject to the aforementioned condition, each coincide with the substituents R ¹ to R ² as defined by reference to the compounds of formula I.

For use in medicine, salts of compounds of formula IB will be non-toxic pharmaceutically acceptable salts. However, other salts may be useful in the preparation of the compounds of the invention or their non-toxic pharmaceutically acceptable salts i.

Suitable pharmaceutically acceptable salts of the compounds of Formulas I, IA and IB, which have been illustrated above, include alkali metal salts, e.g.

lithium, sodium or potassium salts; alkaline earth metal salts, e.g. calcium or magnesium salts; and salts formed with the corresponding organic ligands, e.g. quaternary ammonium salts. Where appropriate, acid addition salts can be prepared by mixing a solution of a compound of the invention with a solution of a pharmaceutically acceptable non-toxic acid such as hydrochloric acid, formic acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, phosphoric acid or phosphoric acid .

The present invention includes within its scope the prodrugs of the compounds of formulas I, IA and IB above. Typically, such prodrugs will be functional derivatives of compounds of formulas I, IA and IB, which can be easily in vivo metabolised to the required compound. The usual procedures for selecting and preparing the corresponding prodrug derivatives are described, for example, in Design of Prodrugs, ed. H. Bungaard, Elsevier, 1985.

If the compounds of the invention have at least one asymmetric center, they will therefore exist as enantiomers. If the compounds of the invention have two or more asymmetric centers, they may additionally exist as diastereoisomers. It is to be understood that the scope of the present invention includes all such isomers and mixtures thereof.

One subset of the compounds of the invention are compounds of formula IIA and their salts and prodrugs:

H (ΠΑ) in which R 31 _and R 32 independently represent ^ Cj_g alkyl, C ₂ _g alkenyl, C ₂ .G alkynyl, aryl, aryl (Cj_g) alkyl, aryl (C2_g) alkenyl, aryl ^ .glalkinil, heteroaryl (Cj_g) alkyl , C1-6 alkoxy, C1-6 alkenyloxy, aryloxy, aryl (C1-8) alkoxy, heteroaryloxy, C1-8 alkylthio, arylthio, arylsulfonyl, arylamino, aryl (C1-8) alkylamino, di (C1-8) alkylamino, arylcarbonylcarbonylamino, arylcarbonylcarbonylamino, arylcarbonylcarbonylamino, arylcarbonylcarbonylamino, arylcarbonylcarbonylamino C 1-7 alkoxycarbonyl, each of these groups being optionally substituted; or hydrogen, halogen, cyano, trifluoromethyl, nitro, hydroxy, amino or carboxy; or p31 _and p32 _s | < _U p _a j represent the residue of a carbocyclic or heterocyclic ring;

or

R and R independently represent halogen, cyano, trifluoromethyl, nitro, hydroxy, amino, carboxy, C1-8 alkyl, C1-8 alkenyl, C1-6 alkoxy, C1-6 alkylthio or C2-7 alkoxycarbonyl; and

R ³ represents hydrogen or halogen.

Examples of any substituents on the groups R ³ and / or R ³² include C 1-8 alkyl, morpholinyl (C 1-8) alkyl, hydroxy, C 1-8 alkoxy, C 1-8 alkoxy (C 1-8) alkyl, C 1-8 alkoxy (C 1-8) aloxo, C 1-8 alkylthio and di (C1-8) alkylamino.

Particularly important of R ³ and / or R ³² , with respect to formula IIA, are hydrogen, methyl, phenyl, benzyl, methoxymethyl-benzyl, morpholinylethyl-benzyl, hydroxybenzyl, methoxybenzyl, methoxymethoxy-benzyl, methylthio-benzyl, phenylethenyl, phenylethynyl , thienylmethyl, pyrrolylmethyl, indolylmethyl, fluoro, chloro, bromo, iodo, trifluoromethyl, nitro, methoxy, ethoxy, allyloxy, methyl-allyloxy, phenoxy, methyl-phenoxy, methoxy-phenoxy, dimethylamino-phenoxy, benzyloxy, benzyloxy, benzyloxy, benzyloxy, benzyloxy, benzyloxy, benzyloxy, benzyloxy , phenylthio, phenylsulfones 1, phenylamino, benzylamino, dimethylamino, phenylcarbonylamino, phenylcarbonyl, furylcarbonyl and thienylcarbonyl.

O 1 OO

Correspondingly, one of R ¹ and R represents hydrogen. Preferably at least one of

R ³¹ _and p32 d _rU hydrogenated. In one particular embodiment, one of R ^{3 is} ^ and 00

R is hydrogen and the other is hydrogen or phenoxy.

0

Suitably R is nitro, methyl, ethyl, vinyl or halogen, in particular chlorine or iodine. Preferably R ^{33 is} ethyl or iodine.

Corresponds to that R ³ represents hydrogen or chlorine, preferably hydrogen.

Suitably, R ³⁵ is cyano, trifluoromethyl, nitro, methyl or halogen, preferably chlorine.

Another subgroup of compounds of the invention for their salts and prodrugs: represent compounds of formula IIB and R * ³ OH .R ⁴² x _R 41 * I l H (1 IB) in which means C1-8 alkyl, ^C 2-4 alkenyl, C ₂ _5 alkynyl, aryl, aryl-

(Cj.g) alkyl, aryl (C2.g) alkenyl, aryl (C ₂ _g) alkynyl, heteroaryl ((^ .θ) alkyl, C | _g alkoxy, C2_g alkenyloxy, aryloxy, aryl (Cj. ^) Alkoxy, heteroaryloxy, C1-6 alkylthio, arylthio, arylsulfonyl, arylamino, aryl (C1-8) alkylamino, di (C1-6) alky 1amino, arylcarbonylamino, arylcarbonyl, heteroarylcarbonyl or C2-7 alkoxycarbonyl, each of these groups may be cyano, or halogen, or halogen, halogen, or halogen; , hydroxy, amino or carboxy;

R 4 represents C _1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, aryl, aryl (C 1-8) alkyl, arylC 1-6 alkenyl, aryl C 1-6 alkynyl, heteroarylC 1-6 alkyl, C _1-6 alkoxy, C 2-6 alkenyloxy, aryloxy , aryl (Cj_ ₆₎ alkoxy, heteroaryloxy, Cj_ ₆ alkylthio, arylthio, arylsulphonyl, arylamino, aryl (C j_θ) alkyl 1amino, di (Cj_ ₆₎ alkylamino, arylcarbonylamino, each of these groups may be optionally substituted; or hydrogen, halogen, cyano, trifluoromethyl, nitro, hydroxy, amino or carboxy; or and R4 together represent the residue of a carbocyclic or heterocyclic ring;

R ³ and R ^ independently represent hydrogen, halogen, cyano, trifluo16 Romet, nitro, hydroxy, amino, carboxy, Cj.g alkyl, C ₂ .G alkenyl, Cj_ θ alkoxy Cj_g alkylthio or C ₂ _ ₇ alkoxycarbonyl; and R45 is hydrogen, halogen, cyano, trifluoromethyl, nitro, hydroxy, amino, carboxy, Cj_g alkyl, C ₂ _g alkenyl, C | _g alkoxy, or C ₂ _y alkoxycarbonyl.

Examples of any substituents on the groups R ⁴¹ and / or R ⁴² include C 1-8 alkyl, morpholines 1 (C 1-8) alky 1, hydroxy, C 1-8 alkoxy, C 1-8 alkoxy (C 1-8) alk 1, C 1-8 alkoxy (C 1-8) alkyl coke, C 1-8 alkylthio and di (Cj_ g) alki 1ami no.

Particularly important of R ⁴ and / or R ⁴² with respect to formula IIA are methyl, phenyl, benzyl, methoxymethyl-benzyl, morpholinylethyl-benzyl, hydroxybenzyl, methoxybenzyl, methoxymethoxy-benzyl, methylthio-benzyl, phenylethenyl, phenylethynyl, thienylmethyl , pyrrolylmethyl, indolylmethyl, fluoro, chloro, bromo, iodo, trifluoromethyl, nitro, methoxy, ethoxy, allyloxy, methylallyloxy, phenoxy, methyl-phenoxy, methoxy-phenoxy, dimethylamino-phenoxy, benzyloxy, furyloxy, phenyloxy, sulfonyloxy, sulfonyloxy, furryloxy, sulfonyloxy , phenylamino, benzylamino, dimethylamino, phenylcarbonylamino, phenylcarbonyl, furylcarbonyl and thienylcarbonyl. R ⁴² may additionally mean hydrogen. In addition, R ⁴ and R ^{42 may} together, respectively, together represent the residue of a dioxolane or an optionally substituted benzene ring.

Corresponds to that R ⁴² is hydrogen or methoxy, preferably hydrogen.

It is appropriate that R ⁴³ and R ⁴⁴ independently represent hydrogen, nitro, methyl, ethyl, vinyl or halogen, in particular chlorine or iodine. Preferably R ^{43 is} hydrogen, ethyl or iodine. Preferably R ^{44 is} hydrogen.

Corresponds to that R ⁴³ is hydrogen, cyano, trifluoromethyl, nitro or halogen, preferably chlorine.

A special subset of the compounds of Formula IIB above is represented by the compounds of Formula IIC and their salts and prodrugs:

Η (ι ic) wherein R ⁴³ , R ⁴⁴ and R ^{48 are} as defined above with reference to formula IIB;

X represents a portion of the formula -CH ₂ ~, -CH = CH-, -C ^ C-, -O-, -OCH ₂ -, -S-, -S0-, -NH-, -NHCH ₂ -, -NHCO- , or -CO-; and

Y represents a group of formula (i), (ii), (iii) or) IV):

in which Z is oxygen, sulfur or NH; and r47 j _n p48 independently represent hydrogen, C 1-6 alkyl, morpholinyl (C _1-6 ) alkyl, hydroxy, C 1-8 alkoxy, C 1-8 alkoxy (C 1-6 alkyl, C 1-8 alkylthio or di (C 1-6) alkyl 1amino; or R ⁴⁷ and R ⁴ ® together they represent the residue of a benzene ring.

Particularly important of R ⁴ ? and / or R ⁴ ® are hydrogen, methyl, morpholinylethyl, hydroxy, methoxy, methoxymethyl, methoxymethoxy, methylthio and dimethylamino. Corresponds to at least one of R ⁴⁷ and R ^{48 being} hydrogen.

Specific compounds within the scope of the present invention are:

7-chloro-4-hydroxy-3- (4-nitrophenyl) -2 (1H) -quinolone;

7-chloro-4-hydroxy-3- (4-methoxyphenyl) -2 (1H) -quinolone;

- Chloro-4-hydroxy-3- (2-n and trophin-1) -2 (1H) -quino! he;

7-chloro-4-hydroxy-3- (4-trifluoromethylphenyl) -2 (1H) -quinolone

7-chloro-4-h and throx i-3- (3-methylphenyl) -2 (1H) -quinolone;

3- (4-benzyloxyphenyl) -7-chloro-4-hydroxy-2 (1H) -quinolone;

7-chloro-3- (4-chlorophenyl) -4-hydroxy-2 (1H) -quinolone;

7-chloro-3- (4-fluorophenyl) -4-hydroxy-2 (1H) -quinoline;

7-chloro-4-hydroxy-3- (3-methoxyphenyl) -2 (1H) -quinolone;

7-chloro-4-hydroxy-3- (3-iodophenyl) -2 (1H) -quinolone;

3- (4-bromophenyl) -7-chloro-4-chloroxyl-2 (1H) -quinoline;

7-chloro-4-hydroxy-3- (3-nitrophenyl) -2 (1H) -quinolone;

4- h and drox 1-7 - n and tro-3-phenyl 1 - 2 (1H) - nolone;

7-chloro-3- (2,5, -dimethoxyphenyl) -4-hydroxy-2 (1H) -quinolone;

3- (2-bromophenyl) -7-chloro-4-hydroxy-2 (1H) -quinolone;

3- (3-bromophenyl) -7-chloro-4-hydroxy-2 (1H) -quinolone;

7-chloro-3- (2-fluorophenyl) -4-hydroxy-2 (1H) -quinolone;

7-chloro-3- (3-fluorophenyl) -4-h and droxy-2 (1H) -quinolone;

3- (4'-biphenyl) -7-chloro-4-hydroxy-2 (1H) -quinolone;

7-oro-3- (4-dimethylaminophenyl) -4-hydroxy-2 (1H) -quinolone;

7-chloro-3- (2-chlorophenyl) -4-hydroxy-2 (1H) -quinolone),

7-chloro-4-hydroxy-3- (2-methoxyphenyl) -2 (1H) -quinolone;

7-chloro-4-hydroxy-3- (2-phenoxyphenyl) -2 (1H) -quinolone;

7-chloro-4-hydroxy-3- (2-naphthyl) -2 (1H) -quinoline;

7-chloro-4-hydroxy-3- (1-naphthyl) -2 (1H) -quinoline;

3- (3-benzyloxyphenyl) -7-chloro-4-hydroxy-2 (1H) -quinolone;

7-chloro-3- (3-chlorophenyl) -4-h-idroxyl-2 (H) - nolone;

7-chloro-4-hydroxy-3- (3-phenoxyphenyl) -2 (1H) -quinolone;

7-chloro-4-hydroxy-3- (4-phenoxyphenyl) -2 (1H) -quinolone;

7-chloro-5-ethyl-4-hydroxy-3-phenyl-2 (1H) -quinolone;

7-chloro-4-hydroxy-3- [3- (2-phenylethynyl) phenyl] -2 (1H) -quinol

7-chloro-4-hydroxy-5-iodo-3-phenyl1-2 (1H) -nylone;

7-chloro-4-hydroxy-3- (3,4-methylenedioxyphenyl) -2 (1H) -quinol

7-chloro-4-hydroxy-3-phenyl -5-vinyl-2 (1H) -quinoline;

7-chloro-4-hydroxy-3- (4-iodophenyl) -2 (1H) -quinoline;

7-chloro-3- (3,5-dimethylphenyl) -4-hydroxy-2 (1H) -quinolone;

7-chloro-5-ethyl-4-hydroxy-3- (3-phenoxyphenyl) -2 (1H) -quinolone;

4-hydroxy-7-methyl-3- (3-phenoxyphenyl) -2 (1H) -quinolone;

7-chloro-4-hydroxy-3- (3-phenylcarbonylphenyl) -2 (1H) -quinolone;

7-chloro-4-hydroxy-3-1 3- (3-1 and one and 1 carbonyl) phenyl) -2 (1H) -quinolone;

7-chloro-3-and 3- (3-fluoro and 1-carbon and 1) phenyl and 11-4-h and drox and -2 (1H) -quinoline;

7-chloro-4-hydroxy-3-1 3- (1-pyrrole and Have 1) phenyl J-2 (1H) -quinolone;

7-chloro-4-hydroxy-3- (3- (1-indole and Have 1) phenyl] -2 (1H) -quinolone;

7-Chloro-4-chloroxy -3-1 3- (3-D One having 1) phenyl -1 2 (1H) -quinolone;

7-chloro-4-hydroxy-3-3- (4-methoxymethyl 1 benzyl) phenyl 1-2 (1H) -quinolone;

- (3-benzylphenyl) -7-chloro-4-hydroxy-2 (1H) -quinoline;

7-chloro-4-hydroxy -3-13- (4-methylbenzyl) phenyl 1-2 (1H) -quinol;

7-chloro-4-hydroxy-3-1 3- (4-methoxymethoxybenzyl) phenyl 1-2 (1H) -quinolone;

7-chloro-4-hydroxy-3-1 3- (4-hydroxybenzyl) phenyl] -2 (1H) -quinolone;

7-chloro-4-hydroxy-3-13-14- (2-morpholin-1-ylethyl) benzylphenyl) -2 (1H) quinolone;

7-chloro-4-hydroxy-3-1 4- (2-phenyl-cis-ethenyl) phenyl 1-2 (1H) -quinolone;

7-chloro-4-hydroxy-3- (3- (2-phenyl 1-trans-ethenyl) phenyl 1-2 (1H) -quinolone;

7-chloro-4-hydroxy-3-t 3- (2-phenyl-cis-ethenyl) phenyl 1-2 (1H) -quinolone;

7-chloro-4-hydroxy-3- [3- (3-indolylmethyl) phenyl 11 -2 (1H) -quinolone;

7-bromo-4-hydroxy-3-phenyl 1-2 (1H) -quinolone;

- which oro-4-hydroxy-3- [3- (2-pyridyl oxy) phenyl] -2 (1H) -quinolone;

7-chloro-4-hydroxy-3- [3- (3-thienyloxy) phenyl] -2 (1H) -quinolone;

7-chloro-3-1,3- (3-fluoro and 1-oxo) phenyl] -4-hydroxy-2 (1H) -quinoline;

7-chloro-4-hydroxy-3- (3-phenylaminophenyl) -2 (1H) -quinolone;

7-chloro-3- [3- (2-dimethylaminophenoxy) phenyl 1-4-h and droxyl-2 (1H) -quinolone;

7-chloro-4-hydroxy-3- [3- (4-methoxybenzyl) phenyl] -2 (1H) -quinolone;

7-chloro-4-hydroxy-3- [3- (3-methoxyphenoxy) phenyl 1-2 (1H) -quinolone;

- chloro-4-hydroxy i-3- [3- (2-methoxyphenoxy) phenyl) -2 (1H) -quinolone;

7-chloro-4-hydroxy-3- {3- (2-methylphenoxy) phenyl 11-2 (1H) -quinolone;

3- (3'-biphenyl) -7-chloro-4-hydroxy-2 (1H) -quinolone;

7-chloro-4-hydroxy-3- (3-phenylthiophenyl) -2 (1H) -quinoline;

7-chloro-4-hydroxy-3- (3-phenylsulfonylphenyl) -2 (1H) -quinone;

7-chloro-4-hydroxy-3- (3-phenylcarbonylaminophenyl) -2 (1H) -quinolone;

3- (3-benzylaminophenyl) -7-chloro-4-hydroxy-2 (1H) -quinolone;

7-chloro-4-hydroxy-3- [3- (2-propenyloxy) phenyl 11-2 (1H) -quinone;

7-chloro-4-hydroxy i-3- (3- (2-methyl-2-propenyloxy) phenyl-2 (1H) -quinolone;

- chloro-3- (2,5-dimethoxyphenyl) -4-hydroxy-2 (1H) nolone;

7-chloro-3- (4-ethoxyphenyl) -4-hydroxy-2 (1H) -quinoline;

7-chloro-4-hydroxy-3- (3- (4-methoxyphenoxy) phenyl] -2 (1H) -quinolone;

7-chloro-4-hydroxy-3-1 3- (4-methylphenoxy) phenyl1-2 (1H) -quinoline;

and their salts and prodrugs.

The pharmaceutical compositions of the present invention are preferably in the form of dosage units, such as tablets, pills, capsules, powders, granules, sterile solutions or suspensions, or suppositories, for oral, intravenous, parenteral or rectal administration. For the preparation of solid compositions such as tablets, the main active ingredient is mixed with a pharmaceutical carrier, e.g. common ingredients of tablets such as cornstarch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gum, and other pharmaceutical diluents, e.g. water to form a solid preformulated composition comprising a homogeneous mixture of a compound of the present invention or a non-toxic salt thereof. When referring to these pre-formulated compositions as homogeneous, this means that the active ingredient is uniformly dispersed throughout the composition so that the composition can be divided into equally effective dosage unit forms, such as tablets, pills and capsules. This solid pre-formulated composition is then administered in the form of dosage units described below containing from 0.1 to about 500 mg of the active ingredient of the present invention. The tablets or pills of the new composition may be coated or otherwise coated to provide dosage forms which have the advantage of prolonged action. For example, a tablet or pill may contain an inner and outer dosage component, the latter being in the form of an envelope above the first. These two components can be separated by an enteric layer that serves to prevent disintegration in the stomach and allows the inner component to pass intact into the duodenum or to be restrained. Various substances may be used for such enteric layers or coatings, and such substances may include various polymeric acids and mixtures of polymeric acids with such substances as shellac, cetyl alcohol and cellulose acetate.

Liquid forms in which new compositions of the present invention can be incorporated, for oral administration or injection, include aqueous solutions, appropriately flavored syrups, aqueous or oily suspensions, suitably flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil oil or peanut oil, as well as elixirs and similar pharmaceutical carriers. Suitable dispersing or suspending agents in aqueous suspensions are synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone or gelatin.

For the treatment of neurodegeneration, a dose level of about 0.01 to 250 mg / kg per day, preferably about 0.05 to 100 mg / kg per day, in particular about 0.05 to 5 mg / kg per day, is appropriate. The compounds may be administered once to four times daily. In a particular embodiment, the compounds may be suitably administered by intravenous infusion.

Compounds of formula (I) above, including new compounds of the invention, can be prepared by a process comprising the cyclization of a compound of formula (III):

(HI) wherein R ⁴ , R ⁴ , R ³ , R ⁴ , R ³ and R 1 are as defined above; and (p represents a reactive carboxylate group.

The reaction is usually carried out in the presence of a base, then mildly acidified as described, for example, in J. Heterocycl. Chem., 1975, 12, 351. Suitable bases for use in the reaction are sodium hydride and potassium hexamethyldisilazide.

As the reactive carboxylate moiety (p are, for example, alkyl esters;

acidic anhydrides, for example mixed anhydrides with alkanoic acids; acid halides, for example acid chlorides; orthoesters; and primary, secu24 nary and tertiary amides.

Preferably, the group represents methoxycarbonyl or ethoxycarbonyl

The intermediates of the above Formula III can be suitably prepared by reaction of a compound of Formula IV with a compound of Formula V:

wherein R ^, R ^, r \ r \ are as defined above and r5, r6 and as defined above; and represents a reactive carboxylate group.

The reaction is suitably carried out by mixing the reagents in an inert solvent such as dichloromethane or 1,2-dichloroethane and heating the reaction mixture at elevated temperature, for example the reflux temperature of the solvent used.

For the reactive carboxylate group, the one defined above is for (J ^1. Preferably the group is an acidic halide group, in particular an acidic chloride group. A compound of formula V in which Q is an acid chloride group can be suitably prepared from the corresponding compound of formula V, in which the carboxy group represents -CO ₂ H, by treatment with oxalyl chloride or thionyl chloride, under standard conditions well known in the art.

In an alternative process, compounds of the above Formula I, including new compounds of the invention, can be prepared by cyclization of a compound of Formula VI:

(VI) wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ^{6 are} as defined above; and Q ³ represents a reactive carboxylate group.

The reaction is suitably carried out in the presence of a base such as potassium hexamethyl disilazide.

For the reactive carboxylate group Q ³ corresponds to that specified above for (p. Preferably, the group Q ^{3 is a C} 1-4 alkyl ester group such as methoxycarbonyl or ethoxycarbonyl.

In case p ³ represents a C 1-4 alkyl ester group, the intermediates of formula VI can be suitably prepared by Claisen condensation of an ester of a compound of formula IV with a compound of formula IV with a compound of formula V, where (p and Q ² both represent C _1-4 alkyl ester This includes heating the reactants together, in the presence of a strong base such as potassium hexamethyldisilazide, Under suitable conditions, the reactants can be in situ directly converted into the desired cyclic product of formula I without the necessity of isolating the intermediate of formula VI.

In a further process, compounds of the above Formula I, including new compounds of the invention, can be prepared by cyclization of a compound of Formula VII:

in which fČ, R ² , r \ r \ R ^ and R® are as defined above.

The cyclization is suitably carried out by heating or treating a compound of formula VII with phosphorus pentoxide in methanesulfonic acid, as described, for example, in J. Hetercycl. Chem., 1988, 25, 857.

The intermediates of formula VII above can be suitably prepared by reacting a compound of formula VIII with a malonate derivative of formula IX:

wherein R ² , R ² , R ⁴ , R ⁴ , R ⁸ and R 5 are as defined above; and R is alkyl.

The reaction is suitably carried out by co-heating the mixture of reagents for 15 to 20 hours, as described, for example, in J. Hetercyc1. Chem., 1988, 25, 857.

Aromatic intermediates of the above formulas IV, V, VIII and IX, including precursors of formula V in which Q ² is -CO ₂ H, which are not commercially available, can be prepared by the methods described in the attached examples or by analogous methods , which will also be immediately apparent to those skilled in the art.

It will be appreciated that any compound of formula I, IA or IB, originally obtained by any of the above methods, may, where appropriate, be subsequently transformed into a further desired compound of formula I, IA or IB, using techniques known in the art.

In the case of obtaining the mixture of stereoisomers by the methods of preparation of the compounds of the invention described above, these isomers can be separated by conventional techniques such as preparative chromatography. The compounds may be prepared in racemic form, or individual enantiomers may be prepared, either by enantiospecific synthesis or by resolution. Compounds, for example, can be separated into enantiomers that form them by standard methods such as the formation of diastereoisomeric pairs by the formation of salts with optically active acid, such as (-) - di-p-tolui1-d-tartaric acid and / or (-i -) - di-p-toluyl-1-tartaric acid, followed by fractional crystallization and free base regeneration. The compounds can also be separated by the formation of diastereomeric esters or amides and then by chromatographic separation and removal of chiral auxiliaries.

It may be necessary and during or during any of the aforementioned consecutive synthesis reactions to protect and / or protect sensitive or reactive groups on any of the molecules involved in the process. This can be achieved by conventional protecting groups such as those described in Protective Groups and Organic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, 1981. Protective groups can be removed at a convenient next stage, by methods known in the art.

The following examples illustrate the preparation of the compounds of the invention.

I

Compounds useful in the present invention potently and selectively block NMDA and / or AMPA responses in the rat cerebellar lobes and inhibit agonist and antagonist binding to a strychnine non-sensitive site located at the NMDA receptor and / or membrane AMPA binding the front brain of rats.

Test for lobes of the cerebral membrane

The effect of the compounds of the invention on the response to NMDA and AMPA was evaluated in the rat cerebellar lobes as described by Wong et al. Hatl. Acad. Sci, USA, 1986, 83, 7104. The equilibrium constant (Kfc>) was calculated from the shift to the right of the response curve of the NMDA al1 AMPA concentration induced by the compound being tested. We have shown that for all the compounds of the accompanying examples tested in response to NMDA, Κβ values are below 150 μm. The compound of Example 12 was tested and found that the Kjj value, in response to AMPA, was below 150 μM.

Binding test

The ability of test compounds to replace ^ HL-689,560 (trans-2-carboxy5,7-dichloro-4-phenyl-aminocarbonylamino-1,2,3,4-tetrahydroquinoline) bound to a strychnine-insensitive position present at the NMDA receptor rat anterior membrane membranes were determined by the method of Grimwood et al., Proceedings of the Britlsh Pharmacological Society, July 1991, Abstract C78. The concentration of the compounds of the accompanying examples required to replace 50% specific bound substance (ICgg) is below 50 µm in each case.

Unless otherwise stated, NMR spectra were obtained at 360MHz. We did not correct the melting point.

EXAMPLE 1

7-Chloro-4-hydroxy-3- (3-inethoxyphenyl) -2 (1H) -quinolone

3-Meloxyphenylacetyl chloride (1.1 lg, 6mmol) was added methyl 2-amino-chlorobenzoate (0.93g, 5mmol) in dichloromethane (30ml) and the solution was stirred at reflux for 18 hours. The residual oil residue, after evaporation of the solvent, was triturated with diethyl ether to give methyl 4-chloro-2- (3-methoxyphenyl) -acetane indobenzoate as a colorless solid (1.51 g). 144-146 ° C.

To a solution of the aforementioned amide (0.50g, 1.5mmol) in tetrahydrofuran (20ml) was added a solution of potassium hexamethyldisilazide in toluene (0.5M, 8ml, 4mmol) and the resulting mixture was stirred under nitrogen for 1.5 hours. Methanol (3ml) was then added and the solution evaporated. The remaining residue was partitioned between diethyl ether (10 ml) and aqueous sodium hydroxide solution (0.5M, 20ml) and the aqueous layer was acidified with hydrochloric acid (5M). The precipitated solid was collected, washed with water and recrystallized from dimethylformamide to give the title compound as a colorless solid; m.p. &Gt; 320 ° C (dec.) (Found: C, 63.44; H, 3.89; N, 4.54. Ci ₆ H ₁₂ C1NO ₃ requires C, 63.69; H, 4.01; N. 4.64%); δ _Η (DMSO-d ₆ ) 3.76 (3H, s, OCIT ₃ ), 6.88-6.94 (311, m, ArH), 7.20 (1H, dd, J 8.7 and 2; 1 Hz, 6-H), 7.28-7.32 (2H, m, Aryl), 7.91 (1H, d, J 8.7Hz, 5-H), 10.24 (1H, br s. OH) and 11.48 (1H, s, NH); m / z 301 (M +).

Unless otherwise stated, the following examples were prepared in an analogous manner from suitable arylacetyl chlorides. Acid chlorides can be prepared from acids by treatment with excess oxalyl chloride and catalytic DMF in dichloromethane at room temperature for 1 hour and then by evaporation.

EXAMPLE 2

7-Chloro-4-hydroxy-3- (3-iodophenyl) -2 (1H) -quinoline

Tal. > 350 ° C (from DMF) (Found: C, 45.56; H, 1.99; N, 3.39. CJ5IT9CIINO2 requires C, 45.31; H, 2.28; N, 3.52%) ; δ _Η (DMSO-d ₆ ) 7.19-7.24 (2H, m, ArH and 6-II), 7.32 (1H, d, J 1.9Hz, 8-H), 7.39 (1H , d, J 7.8Hz, ArH), 7.69-7.71 (2H, m 2 'and ArH), 7.94 (1H, d, J 9.4Hz, 5-H), 10.50 ( 1H, br s, OH) and 11.57 (1H, s, NH); m / z 397 (M +).

EXAMPLE 3

7-Chloro-4-hydroxy-3- (4-th (lofenil) -2 (1H) -quinolone

Tal. &Gt; 350 [deg.] C. (from DMF / water) (Found: C, 5.51; H, 2.10; N, 3.45. C19H18ClN4 requires C, 45.31; H, 2.28; N. 3.52%); δ _Η (DMSO-d ₆ ) 7.18-7.23 (3H, m, Aryl),

7.31 (1H, s, J1, 9IIz, 8-H), 7.75 (2H, d, J 8.3Hz, Ar'H), 7.93 (1H, d, J 8.7Hz, 5 -H), 10.42 (1H, brs, OH) and 11.53 (1H, s, NH); m / z 397 (M +).

EXAMPLE 4

7-Chloro-4-hydroxy-3- (2-phenoxyphenyl) -2 (1H) -quinone

Tal. 284-288 ° C (from DMF / water) (Found: C, 68.77; H, 4.04; N, 3.94. C2iH ₁₄ ClNO ₃ .0,125H2O requires C, 68.91; H, 3, 92; N, 3.88%); δ _Η (DMSO-d ₆ ) 6.87 (1H, d, J 7.7Hz, ArH), 6.96-7.03 (3H, m, ArH), 7.16-7.20 (211, m , ArH), 7,267.37 (5H, m, ArH), 7.87 (1H, d, J 8.7hz, 5-H), 10.29 (1H, br s, OH) and 11.41 (1H, , s, NH); m / z 363 (M +).

7-Chloro-4-hydroxy-3- (3-phenoxyphenyl) -2 (1H) -quinolone

EXAMPLE 5

Tal. 303-306 ° C (from DMF / water) (Found: C, 69.09; H, 3.96; N, 3.82. C21H14CINO3 requires C, 69.33; H, 3.88; N, 3. 85%); δ _Η (DMSO-d ₆ ) 6.96 (1H, dd, J 7.4, 1.8HZ, 4'-H), 7.01 (1H, s, 2'-H), 7.08-7.14 (4H, m, ArH), 7.20 (1H, dd, J 8.8, 2.0Hz, 6-H),

7.31 (1H, d, J 2.0 Hz, 8H), 7.36-7.43 (3H, m, ArH). 7.92 (1H, d, J 8.8Hz, 5-H), 10.40 (1H, br s, OH) and 11.53 (1H, s, NH); m / z 363 (M +).

EXAMPLE 6

7-Chloro-4-hydroxy-3- (4-phenoxyphenyl) -2 (1H) -quinone

Tal. 274-276 ° C (from DMF / water) (Found: C, 68.83; H, 3.93; N, 3.75. C21H14CINO3.O.I25H2O requires C, 68.91; H, 3.92; N, 3.83%); δ _Η (DMSO-d ₆ ) 7.01-7.08 (4H, m, ArH), 7.15 (1H, t, J 7.5Hz, 4-H), 7.21 (lil, dd, J 8.7 and 2.1Hz, 6-H),

7.32 (1H, d, J 2, 1H, 8-H), 7.37-7.44 (4H, m, ArH), 7.93 (III, d, J 8.7Hz, 5-II) , 10.29 (1H, br s, OH) and 11.55 (1H, s, NH); m / z 363 (M +).

EXAMPLE 7

7-Chloro-4-hydroxy-3- (3-phenylethynylphenyl) -2 (1H) -quinone

To a solution of methyl 2- (3-iodophenylacetamido) -4-chlorobenzoate (m.p. 100-101 ° C; prepared according to the general procedure described above; 860mg, 2mmol) in triethylamine (20ml) and tetrahydrofuran (5ml) was added copper (I) iodide (5mg), bis (triphenylosine) palladium (II) dichloride (20mg) and phenylacetylene (0.33ml, 306mg, 3mmol) and the mixture was stirred overnight at room temperature and then refluxed for 5 hours. The solvents were removed, the residue partitioned between ethyl acetate (30ml) and aqueous citric acid (10%, 25ml) and the organic layer was washed with water (25ml) and brine (25ml). After drying (MgSO4), the solution was evaporated and the residue was chromatographed on silica gel (4: 1 pellrol-ethyl acetate as eluent) to give methyl 4-chloro-2- (3-phennethynylphenyl) acetamidobenzoate as colorless gum (824mg); δ _Η (CDC1 ₃ ) 3.75 (2H, s, -CH ₂ -), 3.87 (3H, s, CO ₂ Me), 7.03 (1H, dd, J 9.4 and 2.1 Hz) ,

5-H), 7.33-7.38 (5Η, ra, ArH), 7.48-7.55 (4H, ra, ArH), 7.91 (1H, d, J 9.4Hz, 6- H), 8.82 (1H, d, J 2.1Hz, 3-H) and 11.14 (1H, br s, -NHCO-).

A portion of this amide was cyclized as before to give the title compound from the ground. 297-300θΟ (from DMF / water) (Found: C, 74.30; H, 3.80; N, 3.77%); _H (DMSO-dg) 7.23 (1H, dd, J 8.6 and 2.0Hz, 6-H), 7.33 (1H, d, J 2.0Hz, 8-H), 7.41- 7.51 (9H, m, ArH), 7.95 (1H, d, J 8.6Hz, 5-H), 10.50 (1H, brs, OH) and 11.58 (1H, s, NH) ; m / z 371 (M +).

EXAMPLE 8

7-Chloro-4-hydroxy-3- (2-nitrophenyl) -2 (1H) -quinolone

Tal. 298-300 ° C (from DMF / water) (Found: C, 56.74; H, 2.86; N, 8.85; C ₁₅ H9C1N ₂ O4 requires C, 56.89; H, 2.86; N, 8.85%); δ _Η (DMSO-d ₆ ) 7.26 (1H, dd, J 8.6 and 2.1 Hz, 6H), 7.33 (1H, d, J = 2.1Hz, 8H), 7.52 (1H, d, J 6.4 Hz, 6'-H), 7.60 (III, t, J 7.6 Hz, 5'-H), 7.75 (1H, t, J 7.6 Hz, 4 ' - H), 7.96 (1H, d, J 8.7Hz, 5-H), 8.06 (1H, d, J 7.1 Hz, 3'-H) and 11.63 (1H, with NH) ); m / z 316 (M +).

EXAMPLE 9

7-Chloro-4-hydroxy-3 ~ (4-methoxyphenyl) -2 (1H) -quinoline;

Tal. > 350 ° C (from DMF / water); δ _Η (250 MHz; DMSO-d ₆ ) 3.81 (3H, s, OCH ₃ ); 6.96 (2H, d, J 7.2Hz, 2'-H, 6'-H), 7.21 (1H, dd, J, 8.6 and 2.1Hz, 6-H), 7.29 (2H, d, J = 7.2Hz, 3-H, 5'-H), 7.33 (1H, d, J = 2.1Hz, 8-H), 7.96 (1H, d, j 8, 7Hz, 5-H) and 11.49 (1H, with NH); m / z 301 (M +) (found: m / z 301.0478; Ο ^ Η ^ ΟΝΟβ requires m / z 301.0507).

EXAMPLE 10

3- (4-Bromophenyl) -7-chloro-4-hi (lroxy-2 (] H) -quinolone

Tal. > 350 ° C (from DMF / water) (found: C, 51.10; H, 2.55; N, 3.92; C15H9B1CINO2 requires C, 51.38; H, 2.58; N, 3.99 %); δ _Η (250MHz; DMSO-d ₆ ) 7.23 (1H, dd, J 8.6 and 2Hz, 6-H), 7.32-7.40 (3H, m, 2'-H, 6'- H, 8-H), 7.58 (2H, d, J 10.8Hz, 3'-H, 5'-H), 7.90 (1H, d, J 8.6Hz, 5-H) and 11 , 48 (1H, s, NH); m / z 351 (M +).

EXAMPLE

7-Chloro-4-hydroxy-3- (3-nitrophenyl) -2 (1H) -quinolone

Tal. 329-332 ° C (from DMF / water) (found: C, 56.63; H, 2.58; N, 8.66; Ο ₁₅ Ηι ₅ ΟΙΝ ₂ θ4 requires C, 56.89; H, 2. 86; N, 8.85%); δ _Η (DMSO-d ₆ ) 7.26 1H, dd, J 8.6 and 2Hz, 6H), 7.35 (1H, s, 8-H), 7.69 (1H, t, J 8Hz, 5 '- H), 7.88 (1H, d, J 7.7Hz, 5-H), 7.99 (1H, d, J 8.7Hz, 6'-H), 8.17 (1H, d. J 9.6Hz, 4'-H), 8.26 (1H, s, 2'-H) and 11.67 (1H, s, NH); m / z 316 (M +).

EXAMPLE 12

4-Hydroxy-7-nitro-3-phenyl-2 ((H) -quinolone

Tal. > 330 ° C (from DMF / water) (found: C, 62.98; H, 3.47; N, 9.82; C15H10N2O4, 0.2H ₂ O requires C, 63.02; H, 3.67 N, 9.80%; δπ (DMSO-d ₆ ) 7.32-7.45 (5H, m, ArH), 7.97 (1H, dd, J 8.8 and 2.3Hz, 6-H), 8.13-8, 16 (2H, m, 5-H, 8-H), 10.57 (1H, br s, OH) and 11.88 (1H, s, NH); m / z 2.82 (M +).

EXAMPLE 13

7-Chloro-4-hydroxy-3- (2,5-dimethoxyphenyl-2 (1H) -quinolone

Tal. 280-282 ° C (from DMF / water) (Found: C, 61.35; H, 4.14; N, 4.29; Cj ₇ H ₁₄ CINO4.0, 1H ₂ O requires C, 61.21; H, 4.29; N, 4.29%; δ _Η (DMSO-d ₆ ) 3.71 (3H, s, OCH3), 6.70 (1H, d, J 3Hz, 6'-H), 6.88 (2H, m, 3 ', 4'- H), 7.19 (1H, dd, J 8.6 and 2.1Hz, 6-H), 7.30 (1H, s, 8-H), 7.86 (1H, d, J 8.6Hz) , 5-H), 9.95 (1H, br s, OH) and 11.42 (1H, s, NH); m / z 331 (M +).

EXAMPLE 14

3- (3-Benzyloxyphenyl) -7-chloro-4-hi (lroxy-2 (1H) -quinoline

Tal. 293-295 ° C (from DMF / water) (Found: C, 69.23; H, 4.39; N, 3.73; C22 ^h 16C1NO3.0.25H ₂ O requires C, 69.11; H. 4.35; N, 3.66%; δ _Η (DMSO- d ₆ ) 5.10 (2H, with CH ₂ Ph), 6.93-7.08 (3H, m, ArH), 7.21 (1H, d, J 8.6 and 2, 0Hz, 6-H), 7,197.47 (7H, m, ArH), 7.92 (1H, dd, J 8.6Hz, 5-H), 10.26 (1H, br s, OH) and 11, 52 (1H, s, NH); m / z 377 (M +).

EXAMPLE 15

7-Chloro-v-4-hydroxy-3- (naphthyl 1) -2 (1H) -quinolone

Tal. > 350 ° C (from DMF / water) (Found: C, 70.83; H, 4.05; N, 4.34; C _I9 11 | ₂ C1NO ₂ requires C, 70.92; H, 3.67 N, 4.35%; δ _Η (DMSO-d ₆ ) 7.23 (1H, dd, J 8.6 and 2.0Hz,

6-H), 7.36-7.58 (6H, m, ArH), 7.92-7.97 (3H, m, ArH), 10.17 (1H, br s, OH) and 11.58 (1H, s, NH); m / z 321 (M +).

EXAMPLE 16

7-Chloro-4-h (lroxy-3- (2-naphthyl) -2 (1H) -quinone

Tal. &Gt; 350 ° C (from DMF / water) (found: C, 70.62; H, 4.14; N, 4.37; Ci ₉ H ₁₂ CINO ₂ requires C, 70.92; H, 3.76; N, 4.35%); δ _Η (DMSO-d ₆ ) 7.23 (1H, dd, J 8.6 and 2.0Hz,

6-H), 7.34 (1H, d, J 1.7 Hz, 8-H), 7.48-7.52 (3H, m, Aryl), 7.90-7.96 (5H, m. ArH) and 11.58 (1H, s, NH); m / z 321 (M +).

EXAMPLE 17

7-Chloro-4-hydroxy-3- (3,4-methylenedioxyphenyl) -2 (1H) -quinolone

Tal. > 350 ° C (from DMF / water) (found: C, 60.61; H, 3.00; N, 4.47; C16H10CINO4 requires C, 60.87; H, 3.19; N, 4.34 %); δ _Η (DMSO-d ₆ ) 6.02 (2H, s, -OC11 ₂ O-) 6.81 (1H, dd, J 8.0 and 1.7Hz, 6'-H), 6.87 (1H , d, J 1.7Hz, 2'-H), 6.93 (1H, d, J 8.0Hz, 5'-H), 7.19 (1H, dd, J 8.6 and 2.0Hz, 6-H), 7.30 (1H, d, J 2.0Hz, 8-H), 7.90 (1H, d, J 8.6Hz, 5H), 10.16 (1H, br s, OH) and 11.49 (1H, s, NH); m / z 315 (M +).

EXAMPLE 18

3- (4-Benzyloxyphenyl) -7-chloro-4-hydroxy-2 (1H) -quinolone

Tal. > 350 ° C (from DMF) (Found: C, 69.69; H, 4.03; N, 3.60; C ₂₂ Hi ₆ C1N () ₃ requires C, 69.94; H, 4.27; N, 3.71%; 8 _H (DMSO-d ₆ ) 5.15 (2H, s, CH ₂ Ph), 7.03 (211, m, ArH), 7.20 (1H, dd, J 8.6 and 2.0FIz, 6 -H), 7.28-7.49 (8H, m, ArH), 7.91 (1H, d, J 8.6Hz, 5-H), 10.13 (1H, br s, OH) and 11 , 49 (1H, s, NH); m / z 377 (M +).

EXAMPLE 19

7-Chloro-4-hydroxy-3- (3-methylphenyl) -2 (1H) -quinolone

Tal. > 350 ° C (from DMF / water) (Found: C, 67.15; H, 4.11; N, 4.82; Ci ₆ H ₁₂ C1NO2 requires C, 67.26; H, 4.23; N , 4.90%); 5 _H (DMSO-d ₆ ) 2.35 (311, s, PhCI 1 ₃ ), 7.117.17 (4H, m, ArH), 7.26-7.31 (2H, m, ArH), 7.91 (1H, d, J 8.6Hz, 5-H) and 11.49 (1H, s, NH); m / z 285 (M +).

EXAMPLE 20

7-Chloro-4-hydroxy-3- (4-trifluoromethylphenyl) -2 (1H) -quinolone

Tal. 325-327 ° C (dec.) (From DMF / water) (Found: C, 56.43; H, 2.58; N, 4.03; C16H9CIF3NO2 requires C, 56.57; H, 2.67; N, 4.12%); δ _Η (DMSO-d ₆ ) 7.23 (1H, dd, J 8.6 and 2.0Hz, 6-H), 7.34 (1H, d, J 2.0Hz, 8- H), 7. 61 (2H, d, J 8.0Hz, 2'-H, 6'-H), 7.74 (2H, d J 8.0Hz, 3'-H, 5'-H), 7.98 (1H , d, J 8.6Hz, 5-H) and 11.64 (1H, s, NH); m / z 339 (M +).

EXAMPLE 21

7-Chloro-4-hydroxy-3- (4-nitiophenyl) -2 (1H) -quinolone

Tal. > 350 ° C (from DMF / water) (Found: C, 56.08; H, 2.76; N, 8.63; C15I and i9ClN ₂ O4.0.25H2O requires C, 56.09; H, 2 , 98; N, 8.72%); δ _Η (DMSO-d ₆ ) 7.24 (1H, dd, J 8.6 and 2.0Hz, 6-H), 7.34 (1H, d, J 1.8Hz, 8- H), 7. 72 (2H, d, j 8.8Hz, ΤΗ, 6'-H), 8.00 (1H, d, J 8.6Hz, 5-H), 8.24 (12H, d, J 8.8Hz, 3'-H, 5'-H) and 11.65 (1H, s, NH); m / z 316 (M ⁺ ).

EXAMPLE 22

7-Chloro-3- (4-chloro-phenyl) -4-hi (1-oxy-2 (1H) -quinolone

Tal. > 300 ° C (from DMF / water) (Found: C, 58.62; H, 2.94; N, 4.33; C15II9CI2NO2 requires C, 58.85; H, 2.96; N, 4.58 %); δ _Η (DMSO-d ₆ ) 7.22 (1H, dd, J 8.6, 2.0Hz,

6-H), 7.31 (1H, s, 8-H), 7.32-7.46 (4H, m, 2'-H, 3'-H, 5'-I 1, 6'-H ), 7.93-7.95 (1H, d, J 8.6Hz, 5-H), 10.43 (1H, br s, OH) and 11.57 (1H, s, NH); m / z 305 (M +).

EXAMPLE 23

7-Chloro-3- (4-fluorophenyl) -4-hi (lroxy-2 (1H) -quinoline

Tal. > 335-337 ° C (from DMF / water) (Found: C, 62.09; H, 3.03; F, 6.25; N, 4.67. C45H9CIFNO2 requires C, 62.19; H, 3 , 13; F, 6.56; N, 4.84%); δ _Η (DMSO-d ₆ ), 7.13-7.18 (3H, m, 6-H, 3'-H, 5'-H), 7.32 (1H, s, 8-H), 7 , 38-7.42 (2H, m, 3'-H, 5'-H), 7.92-7.94 (1H, d, J 8.6Hz, 5-H), 10.19 (1H, br s, OH) and 11.54 (1H, s, NH); m / z 289 (M +).

EXAMPLE 24

3- (4-Biphenyl) -7-chloro-4-yl (hydroxy-2 (1H) -quinolone

Tal. > 300 ° C (from DMF) (Found: C, 72.15; H, 4.01; N, 4.11; C21H14CINO2 requires C, 72.50; H, 4.05; N, 4.03%) ; δ _Η (DMSO-dg) 7.20-7.24 (1H, dd, J 8.6Hz, 6-H), 7.32 (1H, s, 8-H), 7.32-7.40 ( 1H, m, Ar-FI), 7.49-7.51 (4H, m, Ar-H), 7.68-7.72 (4H, m Ar-H), 7.94-7.98 ( 1H, d, J 8.6Hz, 5-H), 10.37 (1H, br s, OH) and 11.56 (1H, s, NH); m / z 347 (M +).

EXAMPLE 25

7-Chloro-4-hydroxy-3- (2-inethoxyphenyl) -2 (1H) -quinolone

Tal. > 300 ° C (from DMF) (Found: C, 63.26; H, 4.15; N, 4.52; C ₁₆ H _{] 2} CINO ₃ requires C, 63.69; H, 4.01; N , 4.64%); δ _Η (DMSO-d ₆ ) 3.69 (3H, s, OCH3), 6.94-6.99 (1H, m, Ar-H), 7.03 (1H, d, J 8.1Hz, Ar-H), 7.10 (1H, dd, J 7.4, 1.7Hz, Ar-H), 7.18 (111, dd, J 8.6, 2.0Hz, 6H), 7 , 30-7.36 (2H, m, Ar-H, 8-H), 7.86 (1H, d, J 8.6Hz, 5-H), 9.92 (1H, br s, OH) and 11.42 (1H, s, NH); m / z 301 (M +).

EXAMPLE 26

7-Chloro-3- (4-dunethylaminophenyl) -4-hydroxy-2 (1H) -quinolone

Tal. > 300 ° C (from DMF) (Found: C, 64.42; H, 5.02; N, 8.79; C ₇ H ₁₅ C1N ₂ O2 requires C, 64.87; H, 4.80; N , 8.90%) _H (DMSO-d ₆ ) 2.93 (6H, s, 2 x CH ₃ ), 6.76 (2H, d, J 8.7, 2'-H, 6'-H) , 7.17-7.29 (4H, m, 3'-H, 5'-H, 6-H, 8-H), 7.89 (1H, d, J 8.6Hz, 5-H), 8.94 (1H, br s, OH) and 11.44 (1H, s, NH); m / z 314 (M +).

EXAMPLE 27

7-Chloro-3- (2-chlorophenyl) -4-) and (hyoxy-2 (] H) -quinolone

Tal. > 300 ° C (from DMF) (Found: C, 58.36; H, 3.19; N, 4.54. C15H9CI2NO2 requires C, 58.86; H, 2.96; N, 4.58%) 0 _H (DMSO-d ₆ ) 7.21-7.53 (6H, m, ArH), 7.93 (1H, d, J 8.6 Hz, 5-H), 10.48 (1H, br s. OH) and 11.56 (1H, s, NH); m / z 306 (M +).

EXAMPLE 28

7-Chloro-3- (3-chlorophenyl) -4-hydroxy-2 (1H) -quinolone

Tal. > 300 ° C (from DMF) (Found: C, 58.64; H, 3.06; N, 4.60. C15H9CI2NO2 requires C, 58.84; H, 2.96; N, 4.57%) ; δ _Η (DMSO-d ₆ ) 7.22 (III, dd, J 8.6, 2.0Hz, 6-H), 7.32-7.45 (5H, m, 8-H, 3'-H , 4'-H, 5'-H, 6'-H), 7.94 (1H, d, J 8.6Hz, 5-H), 10.54 (1H, br s, OH) and 11.60 (1H, s, NH); m / z 306 (M +).

EXAMPLE 29

3- (2-Bromophenyl) -7-chloro-4-hydroxy-2 (1H) -quinolone

Tal. 357-358 ° C (from DMF) (Found: C, 51.58; H, 2.47; N, 3.86%); C15H9B1CINO2 requires C, 51.39; H, 2.59; N, 4.00; δ _Η (DMSO-d ₆ ) 7.41 (6H, m, ArH, 6-H, 8-H), 7.91 (1H, d, J 8.6Hz, 5-H) and 11.54 (1H , s, NH); m / z 351 (M +).

EXAMPLE 30

3- (3-Bromophenyl) -7-chloro-4-hydroxy-2 (1H) -quinolone

Tal. 358 ° C (from DMF) (Found: C, 49.38; H, 2.54; N, 3.76; C ₁₅ H ₉ BrClNO2.0.7H2O requires C, 49.60; H, 2.89; N, 3.86%; δ _Η (DMSO-d ₆ ) 7.23 (1H, dd, J 8.5, 2.0Hz, 6-H), 7.38 (3H, m, ArH), 7.51 (1H, m, ArH ), 7.54 (111, d, J 2.0Hz, 8-H), 7.95 (1H, d, J 8.5Hz, 5-H) and 11.60 (1H, s, NH); m / z 351 (M +).

EXAMPLE 31

7-Chloro-3- (2-fluorophenyl) -4-hi (hydroxy-2 (1H) -quinolone

Tal. > 350 ° C (from DMF) (Found: C, 60.87; H, 3.10; N, 4.65; C15H9CIFNO2 requires C, 60.68; H, 3.33; N, 4.72); δ _Η (DMSO-d ₆ ) 7.32 (6H, m, ArH, 6-H, 8-H), 7.94 (1H, d, J 8.6Hz, 5-H) and 11.59 (1H , s, NH); m / z 290 (M +).

EXAMPLE 32

7-Chloro-3- (3- / chlorophenyl) -4-hydroxy-2 (1H) -quinolone

Tal. > 350 ° C (from DMF) (Found: C, 61.66; H, 3.14; N, 4.77; C15H9CIFNO2 requires C, 61.43; H, 3.23; N, 4.78); δ _Η (DMSO-d ₆ ) 7.22 (4H, m, ArH, 6-H), 7.33 (111, d, J 2.2Hz, 8-H), 7.44 (1H, m, ArH ), 7.95 (1H, d, J = 8.6Hz, 5-H) and 11.60 (1H, s, NH); m / z 290 (M +).

7-Chloro-3- (3,5-dimethylphenyl) -4-hydroxy-2 (1H) -quinolone

EXAMPLE 33

Tal. 369 ° C (from DMF) (Found: C, 67.91; H, 4.66; N, 4.61; C ₁₇ Hi ₄ C1NO ₂ requires C, 68.12; H, 4.71; N, 4 , 67); δ _Η (DMSO-d ₆ ) 2.29 (6H, s, 2 x CH ₃ ), 6.94 (3H, m, ArH), 7.20 (1H, dd, J 8.6 and 1.9Hz, 6-H), 7.35 (1H, d J 1.9 Hz, 8-H), 7.90 (1 H, d, J 8.6 Hz, 5-H) and 11.50 (1 H, s, NH); m / z (M +).

EXAMPLE 34

7-Chloro-4-chloroyloxy-5-iodo-3-phenyl-2 (1H) -quinone

A solution of 3-chloro-5-iodoaniline (63.41g) in water (150ml), concentrated hydrochloric acid (22.1ml) and 1,4-dioxane (60ml) was added to a mixture of chloral hydrate (90.24g) and sodium sulfate (650g) in water (600ml) which was heated to 50 ° C. Hydroxylamine hydrochloride (110.56g) and water (250ml) were then added and the reaction mixture was heated at reflux for 45 minutes before being allowed to cool to room temperature, and the resulting yellow precipitate of 3AIoro-5-iodophenylisomtrozoacetanilide was filtered off, washed with water and dried under vacuum. over silica gel.

The pre-heated concentrated sulfuric acid (175ml, 50 ° C) was partially added to the sample of isonitrosoacetanilide (45g) while maintaining the internal temperature with an ice bath between 50 ° C and 70 ° C. After complete addition, the reaction mixture was heated at 80 ° C for 10 minutes before being allowed to cool to room temperature and then poured into ten times the reaction volume of ice. The resulting paste was stirred vigorously and then left to stand for one hour before the resulting precipitate of brown color was filtered off, washed with water and dried in vacuo over phosphorus pentoxide. Thus a mixture of 6-chloro-4-iodine and

4-Chloro-6-iodo isalines. δρ-j (DMSO-dg) 6.98 (1H, d, J 1.6Hz, H-5 or H-7), 7.25 (1H, d, J 1.01-Iz, H-5 'or H-7 '), 7.50 (1H, d, J 1.0 Hz, H-5' or H-7 '), 7.55 (1H, d, J 1.6 Hz, 115 or H-7), 11.18 (1H, s, NH) and 11.26 (1H, s, ΝΉ).

To a solution of a mixture of the aforementioned isalines (53.68g) in 1 M sodium hydroxide solution (525ml) at room temperature, 30% hydrogen peroxide (35.7ml) was added in portions. When boiling stopped, the reaction mixture was carefully neutralized with 2M hydrochloric acid and filtered to remove insoluble matter before acidification to pH 2-3. The resulting sandy yellow precipitate was filtered off and washed with water before drying in vacuo over phosphorus pentoxide to give a mixture of 2-amino-4-chloro-iodine and 2-amino-6-chloro-4-iodo benzoic acid (10 , 56g). The mixture of isomers (8g) was dissolved in boiling acetone and the volume was reduced until the solid began to crystallize, resulting in the formation of a Schiff base (10: 1 enriched with the more dominant 4chloro-6-iodo isomer). Hydrolysis of this imine with 2M hydrochloric acid gave the amino benzoic acid. Repeating this process gave 2-amino-4-chloro-6-iodo-benzoic acid (3.75g) with a purity> 95%. (DMSO-d6) 6.79 (1H, d, J 1.9Hz, H-3 or H-5), 7.05 (1H, d, J 1.9Hz, H-3 or H-5).

Treatment of the ethereal acid solution (2.68g) with diazomethane and concentration in vacuo gave the desired methyl 2-amino-4-chloro-6-iodobenzoate (2.8g). 5j j (DMSOd ₆ ) 3.61 (3H, s, CH ₃ ), 5.89 (2H, s, NH ₂ ), 6.78 (1H, d, J 1.9 Hz, H-3 or H-5) ), 7.04 (1H, d, J 1.9Hz, H-3 or H-5), which was used as described above, for the preparation of methyl 4-chloro-6-iodo-2-phenylacetamidobenzoate, with its eclization, as described above, was obtained with the title compound 'sublimated at 256 ° C (from DMF / water); (Found: C, 45.77; H, 2.24; N, 3.41. C15H9CIINO2.0.08 DMF requires C, 45.37; H, 2.39; N, 3.75%); h (DMSO-d ₆ ) 7.30-7.42 (6Η, m, ArH and 6-H or 8-H), 7.82 (1H, d, J 2.0Hz, 6-H or 8-H) ), 10.28 (1H, br s, OH) and 11.62 (1H, s, NH); m / z 397 (M +).

EXAMPLE 35

7-Chloro-4-hydroxy-3-phenyl-5-vinyl-2 (] H) -quinolone

Bis (triphenylphosphine) palladium (II) chloride (0, 1g) was added to a solution of methyl 2-amino-4-chloro-iodo benzoate (0.52g), dry lithium chloride (0.25g) and vinyl ibutyltin (0.6 ml) in dry DMF (10 mL) under N ₂ . The mixture was heated at 60 ° C for 45 min, allowed to cool to room temperature and diluted with ethyl acetate. The organic layer was washed with water and brine and then dried over magnesium sulfate. The solvent was removed in vacuo to give a brown oil which was purified by chromatography on silica gel eluting with 10% ethyl acetate in hexane to give 0.26g of the desired methyl 2-amino-4-chloro-6-vinyl benzoate. δ _Η (250MHz; DMSO-d ₆ ) 3.80 (3H, s, CH3), 5.26 (1H, d, J 11.07Hz, CH _A H _B , H _a trans with respect to Ar), 5, 62 (1H, d, J 17.5Hz, CH _A H _B , 1I _B cis with respect to Ar), 6.02 (2H, s, NH ₂ ), 6.74 (1H, d, J 2.5Hz, H-3 or H-5), 6.76 (1H, d, J

2.5Hz, H-3 or H-5), 6.84 (1H, dd, J 17.5 and 11.0Hz, CH). This was used to prepare methyl 4-chloro-2-phenylacetamido-6-vinylbenzoate as described above. j (250MHz, DMSO-dg) 3.65 (2H, s, CH ₂ -Ph), 3.66 (3H, s, CO ₂ CH ₃ ), 5.41 (1H, d, J 11Hz, CH _A Hg , Ha trans with respect to Ar), 5.88 (1H, d, J 17.5Hz, CH _A Hg, Hg cis with respect to Ar), 6.76 (1H, dd, J 17.5Hz and 11Hz, CH ), 7.24-7.38 (5H, m, ArH), 7.57 (2H, m, H-3 and H-5), 9.93 (1H, s, NH).

Cyclization of this amide gave the title compound from the ground. 240-244 ° C (from DMF / water); (Found: C, 68.61; H, 4.14; N, 4.79. C ₁₇ H ₁₂ C1NO ₂ requires C, 68.58; H, 4.06; N, 4.70%); δ _Η (DMSO-dg) 5.27 (1H, dd, J 11.0 and 1.3Hz, CH _A Hg, Hg trans with respect to Ar), 5.56 (1H, dd, J 17.3 and 1 , 3Hz, CH _A Hg, H _A cis with respect to Ar), 7.16 (1H, d, J 2.1Hz, H-6 or H-8), 7.29-7.43 (6H, m, ArH and H-6 or H-8), 7.71 (1H, dd, J 17.3 and 11.0Hz, CH), 9.99 (1H, br s, OH), and 11.55 (1H, s, NH); m / z 297 (M +).

EXAMPLE 36

7-Chloro-5-ethyl-4-hydroxy-3-phenyl-2 (1H) -quinolone

To a solution of methyl 2-a> nino-4-chloro-6-vinylbenzoate (0.362g) in ethyl acetate, a platinum paste on sulfide carbon was added under nitrogen. This mixture was hydrogenated at 30 psi for 2 hours. The catalyst was filtered off and the solvent removed in vacuo to give the desired methyl 2-amino-4-chloro-6-ethylbenzoate as a yellow oil (0.34g). δρ-j (250MHz, DMSOd ₆ ) 1.08 (3H, t, J 7.5 Hz, CH ₂ CH ₃ ), 2.60 (2H, q, J 7.5 Hz, CH ₂ CH ₃ ), 3.81 (3H, s, CO ₂ CH ₃ ), 5.85 (2H, s, NH ₂ ), 6.46 (1H, d, J 2.5 Hz, H-3 or H-5), 6.65 (1H , d, J 2.51 Iz, H-3 or H-5).

Methyl 4-chloro-6-ethyl-2-phenylacetamido-benzoate was prepared in an analogous manner to that described above. (DMSO-dg) 1.12 (3H, 1, J 7.5 Hz, CH ₂ Ch ₃ ), 2.62 (2I I, q, J 7.5 Hz, CH ₂ -CH ₃ ), 3.64 (5H , s, CO ₂ CH ₃ and Cll ₂ -Ph), 7.22-7.34 (6H, m, Ari I and 3-h or 5-11), 7.48 (1H, d, J 2.5Hz , 3-H or 5-H) 9.86 (1H, s, NH); m / z 332 ((M + 1) &lt; + &gt;).

From this compound, the title compound was obtained by cyclization from the ground. 284-288 ⁽ 'C (from DMF / water); (Found: C, 67.88; H, 4.62; N, 4.60. C ₁₇ Hi ₄ C1NO ₂ requires V, 68.12; H, 4 , 71; N, 4.67%; δ _Η (DMSO-d ₆ ) 1.20 (3H, t, J 7.3Hz, CH ₂ CH ₃ ), 3.12 (2FI, q, J 7.3Hz ,

CH ₂ -CH ₃ ), 6.99 (1H, d, J 2.1Hz, H-6 or H-8), 7.20 (1H, d, J 2.1Hz, H-6 or H-8) , 7.30-7.43 (5H, m, ArH), 9.83 (1H, br s, OH) and 11.49 (1H, s, NH); m / z 299 (M +).

EXAMPLE 37

7-Chloro-5-ethyl-4-hydroxy-3- (3-phenoxyphenyl) -2 (1H) -quinolone

Large brown-yellow cubic crystals from the ground. 222-224 ° C from ethyl acetate / hexane (found: C, 70.30; H, 4.44, 3.30. C ₂₃ Hi ₈ CNO ₃ requires C, 70.50; H, 4.63; N. 3.57%); δ _Η (360MHz, DMSO-d ₆ ) 1.21 (3H, t, J 7.4Hz, CH ₃ ), 3.14 (2H, q, J 7.4Hz, C1I ₂ ), 6.976.99 (3H. m, Ar-H), 7.08-7.13 (4H, m, Ar-H), 7.22 8IH, d, J 2.2Hz, Ar-H), 7.36-7.44 (3H , m, Ar-H), 9.75-10.0 (1H, in brs, OH), 1.35 (1H, brs, NH); m / z (E1 +) 391 (M +).

EXAMPLE 38

5-Hydroxy-2-phenyl-7-trifluoroinethyl-2 (1H) -quinolone

Tal. 310 C (slow decomposition, from MeOH / H ₂ O) (found: C, 62.59; H, 3.04; N, 4.38; Ci 6 ^H 10 ^F 3 ^NO 2 ^with ^ ^h t ^eva - C, 62.96; H, 3.30; N, 4.59%); δ _Η (DMSO-d ₆ ) 7.29-7.62 (7H, m, 6H, 8H and 5 x ArH), 8.16 (1H, d, J 8.6Hz, 5-H), 11.71 (1H, s, NH); m / z 305 (M +).

EXAMPLE 39

7-Chloro-4-hydroxy-3- (3-benzoylbenzyl) -2 (1H) -quinoline-m-tolylacetic acid (50g) and N-bromosuccimide (60g) were refluxed in carbon tetrachloride (400ml) for 3 hours. The mixture was filtered, evaporated in vacuo and the solid recrystallized from toluene and hexane to give 3-bromomethyl phenylacetic acid (28.6g) as white needles. δ _Η (250MHz, DMSO-d ₆ ) 3.63 (2H, s, CH ₂ CO), 4.28 (2H, s, CH ₂ Br), 7.1-7.7 (4H, m, ArH) . A solution of only acid (25g) in methanol (500ml) was bubbled with hydrogen chloride for 5 minutes, then the solution was left at room temperature for 1 hour, then evaporated in vacuo, then (300ml) was added and the solution was washed with saturated sodium bicarbonate. water and brine, dried and then evaporated in vacuo to give methyl 3-bromoctylphenyl acetate (25g) as an oil; (360MHz, CDCl3) 3.58 (2H, s, CH ₂ CO), 3.68 (3H, s, Me), 4.47 (2H, s, CH ₂ Br), 7.27.4 (4H. m, ArH). The ester (2.5g) was added to sodium hydrogen carbonate (5g) in dimethylsulfoxide (35ml) at 120 ° C. After 20 minutes, the mixture was cooled in an ice bath, diluted with water and extracted with ether (x 3). The ether extracts were washed with water and brine, dried, evaporated in vacuo and purified by flash chromatography eluting with hchsan: ethyl acetate (4: 1 v / v) to give methyl 3-formylphenylacetate (2.02g) as an oil ; δ _Η (360MHz, CDCI3) 3.71 (5H, s, CH ₂ and Me), 7.25-7.4 (2H, m, ArH), 7.8-7.85 (211, m, ArH) , 10.0 (1H, s, CHO); m / z (EI +) 178 (M ⁺ ). Phenyl magnesium bromide (1.9ml, 3M in ether) was added to a solution of aldehyde (1.02g) in ether (20ml) at -78 ° C. The mixture was warmed to room temperature, cooled to -78 ° C and phenylmagnesium bromide (1.9ml, 3M) was added, then warmed to room temperature. The mixture was washed with saturated ammonium chloride solution, water and brine, dried and evaporated in vacuo to give an oil. To this oil in dichloromethane (20ml) was added pyridinium chlorochromate (1g) and the mixture was stirred for 1 hour. Ether (50ml) was added and the mixture filtered through silica gel and evaporated to give an oil (0.63g). This oil was dissolved in THF (15ml) and lithium hydroxide (6ml, 0.5M in water) was added. After one hour, ether and water were added, the mixture separated and the aqueous layer was acidified with IM HCl, then extracted with ethyl acetate (x 3). Ethyl acetate was washed with water and brine, dried and evaporated in vacuo to give 3-benzoylphenylacetic acid (310mg) as white tiles from the ground. 101-103 C; δΗ (250MHz, CDCl3) 3.76 (2H, s, CH2), 7.4-7.9 (9H, m, ArH); m / z (EI ⁺ ) 240 (M ⁺ ). The acid was digested in the usual way to give the title compound as a light yellow tile from the floor. 294-295 ° C (from dimethylformamide / water); (Found: C, 68.94; H, 3.91; N, 3.60. C22Hi4NO ₃ Cl + 0.4 H ₂ O requires C, 68.98; H, 3.89; N, 3.65% ); δ _Η (360MHz, DMSO-d ₆ ) 7.31 (111, dd, J 8.7 and 2.0Hz, H-6), 7.32 (1H, d, J 2.0Hz, H-8), 7.5-7.9 (9H, m, ArH), 7.96 (1H, d, J 8.7Hz, H-5), 10.6 (1H, s, OH), 11.6 (1H, s, NH); m / z (EI +) 375 (M ⁺ ).

EXAMPLE 40

7-Chloro-4-hydroxy-3-1,3- (3-thiophenecarbonyl) phenyl] -2 (1H) -quinolone

White amorphous solid, m.p. 287-290 ° C (from dimethylformamide / accton / water) (Found:

C, 63.02; H, 2.94; N, 3.59%. C ₂ oH ₁₂ NO ₃ SC1 requires C, 62.91; H, 3.17; N, 3.67%); δ _Η (360 MHz, DMSO-dg) 7.24 (1H, dd, J 2.0 and 8.6 Hz, H-6), 7.35 (1H, d, J 2.0 Hz, H-8) ),

7.55-7.65 (2Η, m), 7.65-7.8 (3H, m), 7.84 (1H, d, J 1 Hz, H-2 '), 7.96 (1H, d, J 8.6 Hz, H-5), 8.30 (1H, dd, J 1 and 2 Hz, thiophene H-2), 10.6 (1H, br s), 11.82 (1H, s ); m / z (E1 +) 381 (M +).

EXAMPLE 41

7-Chloro-4-hydroxy-3-1,3- (3-furanylcarbonyl) phenyl] -2 (1 H) -quinolone

A brownish amorphous solid, m.p. 284-286 ° C (Found: C, 64.98; H, 3.29; N, 3.69. C20H12NO4CI + 0.2 H ₂ O requires C, 65.03; H, 3.38; N, 3 , 79%); δ _Η (360 MHz, DMSO-dg) 6.94 (1H, d, J 1.5 Hz, furan H-4), 7.24 (1H, dd, J 1.3 and 6.7 Hz, H-6) , 7.34 (1H, d, J 1.3 Hz, H-8), 7.59 (1H, t, J 8 Hz, H-5 '), 7.74 (1H, d with a second fine coupling, J 8 Hz, H-4 'or H-6'), 7.77 (1H, d, with other fine coupling, J 8 Hz, H-6 'or H-4'), 7.90-7.9 ( 2H, m, H-2 'and furan H-5), 7.99 (1H, d, J 6.7 Hz, H-5), 8.41 (1H, s, furan H-2), 10. 6 (1H, brs), 11.62 (1H, s); m / z (C1 + NH3) 366 (M + + H).

EXAMPLE 42

7-Chloro-4-hydroxy-3-1,3- (1-pyrrolinethyl) phenyl] -2 (JH) -quinolone

Oxalyl chloride (15.2 ml) was added at room temperature to a solution of 3-bromomethylphenyl acetic acid (20 g) and dimethylformamide (4 drops) in dichloromethane (350 ml). After 1 hour, the solution was evaporated in vacuo, then methyl 4-chloroantranilate (10.6 g) was added and the dichloroethane (300 ml) ler mixture was refluxed for 35 minutes, then cooled, the mixture was washed with sodium hydrogen carbonate solution and brine, dried , evaporated in vacuo and recrystallized from ethyl acetate / hexane to give methyl 2- (3-bromonictylphenylacetaniido) -4-chlorobenzoate as a white solid; δρ {(360 MHz, CDCI3) 3.75 (2H, s, CH ₂ CO), 3.86 (3H, s, Me), 4.50 (2H, s, CH ₂ Br), 7.03 (1H , dd, J 8.7 and 1.90 Hz, H-5), 7.2-7.4 (4H, m, ArH), 7.91 (1H, d, J 8.7 Hz, H-6) ), 8.80 (1H, d, J 1.9 Hz, H-3), 11.15 (1H, s, 1H); m / z (EI ⁺ ) 397 (M ⁺ ). Potassium hexamethyldisilyl azide (22 ml, 0.5 M in toluene) was added to a solution of pyrrole (0.74 g) in THF (20 ml) at -78 ° C, warmed to room temperature and then cooled again to -30 ° C. The above amide (2 g) in THF (20 ml) was added, maintaining the solution temperature at -30 ° C for 1 hour, then saturated ammonium chloride was added. The mixture was diluted with ethyl acetate, separated and the organic layer was washed with water and brine, dried, evaporated in vacuo and purified by flash chromatography eluting with hexane: ethyl acetate (5: 1 v / v) to give methyl 2- [3- (1-Pyrrolmethyl) phenylacetamido] -4-chlorobenzoate; δρρ (360 MHz, CDCI3) 3.65 (2H, s, CH ₂ CO), 3.86 (3H, s, Me), 5.08 (2H, s, CH ₂ N), 6.16 (2H. t, J 2 Hz, pyrrole H-3), 6.69 (2H, t, J 2 Hz, pyrrole H-2), 7.0-7.3 (5H, m, ArH), 7.91 (1H , d, J 8.4 Hz, CHCCO), 8.8 (1H, s, CHCN), 11.1 (1H, s, NH). This compound was cyclized in the usual way to give the title compound as a white solid, m.p. > 300 ° C (dimethylformamide / water); (Found: C, 68.35; H, 4.03; N, 8.23. C20H15N2O2CI requires C, 68.48; H, 4.31; N, 7.99%); δ _Η (250 MHz, DMSO-dg) 5.11 (2H, s, CH ₂ ), 6.01 (2H, t, J 2 Hz, pyrrole H-3), 6.86 (2H, t, J 2) Hz, pyrrole H-2), 7.1-7.4 (6H, m, ArH), 7.96 (1H, d, J 9 Hz, H-5), 10.3 (1H, s, OH) , 11.52 (1H, s, NH).

EXAMPLE 43

7-Chloro-4-hydroxy-3-1,3- (1-indolmethyl) phenyl] -2 (1H) -quinolone

White granular solid, m.p. 285-287 ° C (from dimethylformamide / water) (Found: C, 72.08; H, 4.23; N, 7.11. C ₂ 4H ₁₇ N ₂ O ₂ C1 requires C, 71.91; H. 4.28; N, 6.99%; δ _Η (360 MHz, DMSO-d ₆ ) 5.43 (2H, s, CH ₂ ), 6.47 (1H, d, J 4.2 Hz, indole H-3), 7.00 (1H, t , J 7.1 Hz), 7.08-7.12 (2H, m), 7.21 (1H, dd, J 2.1 and 8.6 Hz, H-6), 7.24-7.31 ( 3H, m), 7.34-7.55 (4H, m), 7.91 (1H, d, J 8.6 Hz, H-5), 10.3 (III, br s, OH), 11 , 51 (1H, s, NH); m / z (El) 400 (M ⁺ ).

EXAMPLE 44

7-Chloro-4-hydroxy-3- [3d3-thiophenylethyl) phenyl-2 (JH) -quinolone n-Bulillithium (92 ml, 1.6 M in hexane, 147 mmol) was added to a solution of 3bromothiophene (24 g, 147 mmol) in ether (200 ml) at -78 ° C for 10 minutes. After 30 minutes, the mixture was transferred by cannula to a solution of methyl 3-formylphenylacetate (20 g, 113 mmol) in ether (200 ml) at -78 ° C and then the mixture was warmed to room temperature. The mixture was washed with water and brine, dried, evaporated in vacuo and purified by flash chromatography eluting with hexane: ethyl acetate (5: 2 v / v) to give methyl 3- (3-thiophenhydroxymethylphenyl acetate (17.4 g ) col oil; (360 MHz, CDCI3) 3.50 (2H, s,

CH ₂ ), 3.66 (3H, s, Me), 5.87 (1H, s, CHO), 6.9-7.3 (7H, m, ArH). The oil was dissolved in dichloromethane (200 ml) with triethylsilane (20.8 ml), cooled to 0 ° C and trifluoroacetic acid (10 ml) added. After 45 minutes, the solution was washed with saturated sodium bicarbonate solution, water and brine, dried and evaporated in vacuo and purified by flash chromatography eluting with hexane: ethyl acetate (8: 1 v / v) to give methyl 3 - (3-thiophenylmethyl) phenylacetate (9.4 g) as an oil; (360 MHz, CDCI3) 3.54 (2H, s, CH ₂ CO), 3.68 (3H, s, Me), 3.88 (2H, s, ArCH ₂ Ar), 6.8-7.3 (7H, m, ArH). This compound was metabolised in the usual way to give the title compound (4.10 g) in a very light yellow needle; m.p. 320-322 ° C (from dimethylformamide); (Found: C, 64.96; H, 3.82; N, 4.17. C ₂₀ Hi ₄ C1NO ₂ S requires C, 65.30; H, 3.83; N, 3.81%); δ _Η (360 MHz, DMSO-d ₆ ) 3.96 (2H, s, CH ₂ ), 6.99 (1H, d, J 8.5 Hz, lyophen H-4), 7.1-7.3 (7H, m, ArH), 7.43 (1H, dd, J 3.0 and 8.5 Hz, thiophene H-5), 7.91 (1H, d, J 8.6 Hz, H-5) , 10.2 (1H, s, OH), 11.49 (1H, s, NIT); m / z (E1 +) 367 (M +).

EXAMPLE 45

7-Chloro-4-hydroxy-3-1,3- (4-> nonoxymethylbenzyl) phenyl] -2 (7H) -quinoline

4-Bromobenzyl alcohol (5.0 g, 26.7 mmol) was dissolved in THF (130 ml) and methyl iodide (6.7 ml, 107.0 mmol) was added. Sodium hydride (1.20 g 80% dispersion in oil, 40.1 mmol) was added in two portions while stirring at room temperature under nitrogen. After stirring for 2 hours, the solvents were removed in vacuo and the residue was partitioned between water and ether. The water was re-extracted with ether and the combined organic fractions before drying (Na ₂ SO ₄ ) and evaporated in vacuo with water and brine to give 4bromobenzylmethyl ether as an orange liquid (5.3 g, 26.4 mmol). δ _[4 (250 MHz, CDCl3) 3.39 (3H, s, CH3), 4.40 (2H, s, CH _2), 7.21 (211, d, J 7.5 Hz, Ar-H) , 7.48 (2H, d, J 7.5 Hz, Ar-H).

Bromobenzylcyl ether (2.28 g, 11.35 mmol) was dissolved in anhydrous ether (40 ml) and cooled to -78 ° C while stirring under nitrogen. Te / r-butyllithium (13.4 ml of a 1.7 M solution in pentane, 22.7 mmol) was added dropwise over 5 minutes and stirred for 45 min. This mixture was transferred by cannula while stirring under nitrogen to a suspension of pentinyl copper (1.48 g, 11.35 mmol) in anhydrous ether (40 ml) at -78 ° C and allowed to warm to -40 ° C. . The mixture was protected from light by aluminum foil. After 15 minutes, a solution of methyl 2- (3-bromomethylmethylcyclamido) -4-chlorobenzoal (1.5 g, 3.78 mmol) in anhydrous THF (10 ml) was added. The mixture was manually mixed as needed. After stirring at -40 ° C for 1.5 hours, the reaction mixture was allowed to warm to room temperature and was then stirred for another 1 hour. Saturated ammonium chloride solution was added and the mixture filtered through celite to remove copper residues. The organic layer was separated and washed with water and brine before drying (Na ₂ SO ₄ ) ' ⁿ evaporation to give a yellow oil. The oil was purified by flash chromatography eluting with 15% ethyl acetate in hexane to give methyl 2- [3- (4myloxymethylbenzylphenyl acetamido) -4-chlorobenzoate as a clear colorless oil (0.81 g, 1.85 mmol); δ _Η (360 MHz, CDCI3) 3.36 (3H, s, CH ₂ OCH ₃ ), 3.71 (2H, s, NHCOCH ₂ ), 3.84 (3H, s, COCH3), 3.99 (2H , s, ArCH ₂ Ar), 4.41 (2H, s, ArCH ₂ O), 7.03 (1H, dd, J

8.6 and 2.1 Hz, 5-H), 7.10 (1H, d, J 7.5 Hz, Ar-H), 7.16-7.30 (7H, m, Ar-H), 7.91 (1H, d, J 8.6 Hz, 6-H), 8.81 (1H, d, J 2.1 Hz, 3-H), 11.06 (1H, brs, NH); m / z (EI +) 437 (M +).

The acctamide ester was cyclized in the usual way to give the title compound as a white amorphous solid from the ground. 276-278 ° C (DMF / acetone / water) (Found: C, 71.35; H, 4.87; N, 3.37. C ₂₄ H ₂₀ ClNO3 Claim C, 71.20 H, 4.73N. 3.46%; δ _Η (360 MHz, DMSOd ₆ ) 3.25 (3H, s, CH ₃ ), 3.96 (2H, s, ArCH ₂ Ar), 4.35 (2H, s, ArCH ₂ O) ), 7.14-7.33 (10H, m, 8 x Ar-H, 6-H and 8-H), 7.92 (1H, d, J 8.6 Hz, 5-H), 10, 0-10.4 (1H, in br s, OH), 11.50 (1H, brs, NH); m / z (EI +) 450 (M +).

EXAMPLE 46

7-Chloro-4-hydroxy-3- (3-benzylphenyl) - (1H) -quinoline

White amorphous solid, m.p. 304-306 ° C (from dimethylformamide / water) (Found: C, 71.43; H, 4.42; N, 3.46. C ₂₂ H ₁₆ NO ₂ C1 + 0.5 H ₂ O requires C, 71 , 26; H, 4.62; N, 3.77%); δ _Η (360 MHz, DMSO-d ₆ ) 3.96 (2H, s, CH ₂ ), 7.1-7.4 (1H, m, ArH), 7.92 (1H, d, J 8, 6 Hz, H-5), 10.2 (1H, s, OH), 11.50 (1H, s, NH); m / z (C1 +, NH3) 362 (M + + H).

EXAMPLE 47

7-Chloro-4-hydroxy-3- [3- (4-methylthiobenzyl) phenyl] -2 (11) -quinolone

White amorphous solid, m.p. 296-297 ° C (from dimethylformamide / water) (Found: C, 67.85; H, 4.42; N, 3.44. C ₂₃ H ₁₈ NO ₂ SC1 requires C, 67.72; H, 4.45; N, 3.43%; δ _Η (360 MHz, DMSO-dg) 2.43 (3H, s, Me), 3.92 (2H, s, CH ₂ ), 7.1-7.3 (10H, m, ArH), 7. 92 (1H, d, J 8.7 Hz, H-5), 10.1 (1H, brs, OH), 11.51 (1H, s, NH); m / z (EI +) 407 (M +).

EXAMPLE 48

7-Chloro-4-hydroxy-3-1,3- (4-methoxyinethoxybenzyl) phenyl] -2 (1H) -quinoline

White amorphous solid, m.p. 261-264 ° C (from dimethyllormamide / aecton / water) (Found: C, 68.72; H, 4.88; N, 3.33. C24H20CINO4 requires C, 68.33; H, 4.78; N. 3.32%); δ _Η (360 MHz, DMSO-d ₆ ) 3.35 (3H, s, CH ₃ ), 3.90 (2H, s, ArCH ₂ Ar), 5.13 (2H, s, OCH ₂ O), 6.93 (2H, d, J 8.6 Hz, 3-H), 7.13-7.22 (6H, m, 6 x ArH), 7.28-7.32 (2H, m, 2 x Ar-H) ), 7.92 (1H, d, J 8.6 Hz, 5-H), 10.0-10.3 (1H, in br s, OH), 11.51 (1H, br s, NH); m / z (El +) 421 (M +).

EXAMPLE 49

7-Chloro-4-hydroxy-3- [3- (4-hydroxybenzyl) phenyl] -2 (1H) -quinolone

A brownish amorphous solid, m.p. 288-292 ° C (from dimethylformamide / aeetone / water) (Found: C, 68.76; H, 4.37; N, 3.69. C 22 H 16 ^NO 3 ^cl + ° - ^{3 H} 2 ° requires C, 68; 95; H, 4.37; N, 3.66%); δ _Η (360 MHz, DMSO-d ₆ ) 3.84 (2H, s, CH ₂ ), 6.66 (2H, d, J 8.4 Hz, H3), 7.04 (2H, d, J 8) , 4 Hz, H-2), 7.11 (1H, d, J 7 Hz), 7.17 (1H, d, J 7 Hz), 7.18 (III, s, H-2 '), 7 , 20 (1H, dd, J 8.6 and 1.8 Hz, H-6), 7.29 (lil, t, J 7 Hz, H-5 '), 7.31 (III, d, J 1 , 8 Hz, H-8), 7.91 (1H, d, J 8.6 Hz, H-5), 9.14 (1H, s, OH), 10.21 (1H, br s, NH) , 11.50 (1H, s, OH); m / z (C1 +, NH ₃ ) 378 (M + + H).

EXAMPLE 50

7-Chloro-4-h (Jroxy-3-1,3- (4- (H-inorpholin-2-ethyl) benzyl) phenyl] -2 (JH) -quinolone

1-Pcniynyl copper (6.61 g, 50.6 mmol) was used for coupling with TBDMS protected

Of 4-bromophenyl alcohol (15.89 g, 50.4 mmol) and methyl 4-chloro-2- (3-bromomethylphenylacetamidobenzoate (6.68 g, 16.9 mmol) as described above Flash flash chromatography (5% ethyl) acetate / hexane) gave methyl 4-chloro-2- [3- (4 (1 H -butyldimethylsilyloxy-2-ethyl) -benzyl) phenylacetamido] benzoate as a yellow oil (8.02 g); δ _Η (250 MHz, CDCl ₃ ) 0.02 (6H, s, OS ₁ CH ₃ CH ₃ ), 0.88 (9H, s, ¹ Bu), 2.80 (2H, t, J 7.0 Hz, ArCH ₂ CH ₃ ), 3. 74 (2H, s, ArCH ₃ CONH), 3.80 (2H, 1, J 7.0 Hz, CH ₂ () Si), 3.87 (3H, s, CO ₂ Me), 3.99 (2H, s , ArCH ₂ Ar), 7.02-7.32 (9H, m, ArCH ₂ Ar and 5-H), 7.92 (1H, d, J 8.4 Hz, 6-H), 8.85 ( 1H, J 2.8 Hz, 3-H), 11.07 (1H, br s, NH); m / z (E1 +) 552 (M +).

The resulting amide (8.02 g, 14.54 mmol) was dissolved in a mixture of dry methanol (60 ml) and dry dichloromethane (10 ml). Dowex 50 W x 8 acidic ion exchanger (which was previously washed with methanol and dried at a pump, 16 g) was then added to the solution and the mixture was stirred for 16 hours at room temperature under nitrogen. Dowex was filtered off and the filtrate concentrated in vacuo. The product was isolated by flash chromatography (2% mclanol / dichloromethane) to give 4-chloro-2- [3- (4- (2-hydroxyethyl) -benzyl) -phenylethylamido] benzoate as a viscous yellow oil (5.38 g); (250 MHz, CDCI3) 2.83 (211, d, J 6.5)

Hz, ArCH ₂ CH ₂ ), 3.71 (2H, s, ArCH ₂ CONH), 3.84 (211, t, J 6.5 Ilz, ArCl ₁ CH ₂ OI 1), 3.84 (3H, s , CO ₂ Me), 3.97 (2H, s, ArCH ₂ Ar), 7.03 (1H, dd, J 8.6 and 2.1 Hz, 5-H), 7.107.32 (8H, m. ArCH ₂ Ar), 7.91 (1H, d, 8.6 Hz, 6-H), 8.82 (1H, d, J 2.1 Hz, 3-H), 11.06 (1H, br s , NH); m / z (EI +) 438 (M +).

This alcohol was mesylated by the addition of mclansulfonyl chloride (0.186 ml, 2.40 mmol) to a solution of alcohol (1.017 g, 2.32 mmol) and trictylamine (0.48 ml, 3.44 mmol) in a mixture of dry diclily ether (10 ml) and dry tetrahydrofuran (4 ml) under nitrogen at 0 ° C. The reaction mixture was allowed to warm to room temperature and then stirred for 30 minutes before filtering off the white precipitate of triethylamine hydrochloride and concentrating the filtrate in vacuo to give the mesylated intermediate as a colorless oil.

The resulting oil was dissolved in a mixture of dry methanol (5 ml) and dry dichloromethane (2 ml). Morpholine (4 ml, 45.87 mmol) in nitrogen was added to the solution at room temperature and stirred for 24 hours before concentrating the reaction in vacuo. The residue was taken up in ethyl acetate, washed with saturated sodium hydrogen carbonate solution, water and brine, and then dried (MgSO3). The organic phase was concentrated in vacuo to leave a yellow oil which was purified by flash chromatography (2% methanol / dichloromelane) to give methyl 4-chloro-2- [3- (4- (N-morpholin-2-yl) benzyl) ) phenylacetamidobenzoate as a colorless oil (0.417 g); 6jj (250 MHz, CDCl ₃ ) 2.53-2.61 (6H, m, NCH2CH2O and ΝΟΗ ₂ ΟΗ ₂ Αγ), 2.74-2.80 (2H, m, NCH ₂ CH ₂ Ar), 3. 71 (2H, s, ArCH ₂ CONH), 3.75 (4H, t, J 4.7 Hz, OCH ₂ CH ₂ N), 3.84 (3H, s, CO2Me), 3.96 (2H, s, ArCH ₂ Ar), 7.03 (1H, dd, 8.7 and 2.1 Hz, 5-H), 7.07-7.31 (8H, m, ArCH ₂ Ar), 7.91 (1H, d , J 8.7 Hz, 6-H), 8.82 (1H, d, J 2.1 Hz, 3-H), 11.06 (1H, br s, NH); m / z 507 (E1 +) (M +) ·

The above amide was cyclized under standard conditions. The reaction was quenched with methanol and the mixture was concentrated in vacuo to give a yellow gummy residue. This was partitioned between ethyl acetate and 2N sodium hydroxide solution. The aqueous fraction was acidified with 2N hydrochloric acid to pH 1 and the resulting emulsion concentrated (but not dry) in vacuo. The resulting suspension was filtered and the solid was washed with water before drying it at the pump to give a white solid. This solid was recrystallized from methanol to give the title compound as white plates; m.p. 275-276 ° C (from methanol); (Found: C, 65.86; H, 5.54; N, 5.38. C28H27CIN2O3 · HCl requires C, 65.76; H, 5.52; N, 5.48%); δ _Η (360 MHz, DMSO-d ₆ ) 2.94-3.10 (6H, m, NCH ₂ CH ₂ O and ΝΟΗ ₂ ΟΗ ₂ Αγ), 3.10-3.30 (211, m, NCH ₂ CH ₂ Ar),), 3.84-3.94 (4H, m, NCH ₂ CH ₂ O)), 3.97 (2H, s, Ar CH ₂ Ar), 7.14-7.33 (9H , m, ArCH ₂ Ar and 6-H), 7.38 (1H, d, J 2.0 Hz, 8-H), 7.95 (1H, d, J 8.6 Hz, 5-H), 11.52 (1H, s, Nile); m / z (M ++ H) 475 (C1 +).

EXAMPLE 51

6,7-Dichloro-4-hi (livxy-3-phenyl-2 (1H) -quinox> ii

White needles; m.p. 347-349 ° C (from DMSO); (Found: C, 58.29; H, 2.81; N, 4.35. C15H9CI2NO2 · 0.1 H ₂ O requires C, 58.50; H, 3.01; N, 4.55%); 6h (360 Mi Iz, DMSOd ₆ ) 7.29-7.42 (5H, m, Ph), 7.48 (1H, s, 5-H or 8-H), 8.11 (1H, s, 5) -H or 8-H), 11.62 (1H, s, NH); m / z (EI ⁺ ) 305 (M +).

EXAMPLE 52 cis-7-Chloro-4-chloroxy-3- (4-phenylethenylphenyl) -2 (1H) quinolone

4-Bromoethylphenylacetic acid (20 g, 8.7 mmol) was suspended in toluene (300 ml). Triphenylphosphine (45 g, 170 mmol) was added and the mixture was refluxed for 16 hours to give a thick white precipitate. This solid was filtered off, washed three times with ether and dried under high vacuum to give 4-triphenylphosphinylphenylacetyl bromide (42 g, 86 mmol); δ _Η (250 MHz, DMSO-d ₆ ) 3.52 (2H, s, CH ₂ COOH), 5.12 (2H, d, J 15 Hz, CH ₂ P), 6.92 (2H, dd, J 8 and 2 Hz, PCH ₂ CCH), 7.12 (2H, d, J 8 Hz, HOOCCH ₂ CCH), 7.61-7.79 (12H, m, Ph-H), 7.90 (3H. dt, J 7 and 2 Hz, PPh (4) H). Foslonium salt (40 g,

81.5 mmol) was suspended in anhydrous THF (300 ml) and diisopropylamine (35.4 ml, 187 mmol) was added. The mixture was cooled to -78 ° C and n -bulyl lithium (70 ml of a 2.5 M solution in hexanes, 175 mmol) was slowly added while maintaining the temperature of the mixture at <-60 ° C. A change in color from yellow and orange to brown was observed. The reaction vessel was heated to 0 ° C and stirred for 30 minutes. After being cooled again to -78 ° C, fresh przdesylated benzene aldehyde (10.4 g, 97.8 mmol) was added and the color faded to orange. The reaction mixture was stirred for 30 minutes before being allowed to warm to room temperature for a further 30 minutes and changed to yellow. The mixture was evaporated in vacuo to a volume of 100 ml and then diluted with ethyl acetate and then washed with water and brine, dried (Na ₂ SO ₂ ) and evaporated to give a white solid. This was extracted with loluene and hot ether. The combined organic extracts were evaporated in vacuo. The residue (20.5 g) was dissolved in methanol (250 ml) and cooled to 0 ° C. The solution was bubbled with hydrogen chloride gas for 5 minutes, then the mixture was stirred for 16 hours under nitrogen at room temperature. The resulting solid was removed by filtration. The filtrate was evaporated, overflowed with ether, filtered again and evaporated in vacuo. The residue was purified by flash flash chromatography, eluted with 0% -8% ethyl acetate in hexane to give a mixture of cis and trans methyl 4-stilben acetates (3.9 g). This mixture was separated by flash chromatography, eluting with 6% ethyl acetate / hexane to give slurry isomers A (1.45 g) and slurry isomers B (1.25 g). Isomer A (1.0 g, 4.0 mmol) was dissolved in THF (15 ml) and water (10 ml). Lithium hydroxide (9.52 ml of 0.5 M solution, 4.8 mmol) was added and the mixture was stirred at room temperature for 45 minutes. THF was removed in vacuo and the aqueous residue was partitioned between ether and sodium hydroxide solution. The aqueous phase was maintained and acidified to pH 1 (hydrochloric acid) to give a white precipitate, which was extracted twice with ethyl acetate. The combined organic fractions were washed with water and brine before drying (Na ₂ SO4) and evaporating in vacuo to give cis 4-stilben acetic acid as a clear colorless oil (0.95 g, 4.0 mmol). (360 MHz, DMSO-dg) 3.52 (2H, s, CII ₂ ), 6.59 (1H, d, 12.4 Hz, ArCH: CHAr), 6.64 (1H, d, J 12.4) Hz, ArClkCHAr), 7.11-7.30 (9H, m, Ar-H); m / z (EI ⁺ ) 238 (M ⁺ ). [Isomer B was treated with lithium hydroxide as described for isomer A to give trans 4-stilben acetic acid. (250 MHz, DMSO-df,) 7.14 (1H, d, J 15.5 Hz, ArCHtCHAr)]. Isomer A was converted to the title compound to give a yellow-brown amorphous solid; m.p. 284-286 ° C (from dimethylformamide / acelone / water) (Found: C, 73.80; H, 3.97; N, 3.69. 023Η] βΟΝ () 2 requires C, 73.90; H, 4 , 31; N, 3.75%); δ _Η (360 MHz, DMSO-d ₆ ) 6.64 (2H, s, ArCH: CHAr), 7.20-7.35 (1H, m, Ar-H, 6-H and 8-H), 7.93 (1H, d, J 8.7 Hz, 5-H), 10, ΙΙΟ, 5 (1H, in br s, OH), 11.53 (1H, br s, NH); m / z (EI +) 273 (M +).

EXAMPLE 53 trans-7-Chloro-4-hydroxy-3- (3-phenylethenylphenyl) - (R) -quinolone

White needles, m.p. 320-324 ° C (from dimethylformamide / water) (Found: C, 73.66; H, 4.35; N, 3.68. C ₂ 3H ₁₆ NO ₂ CI requires C, 73.90; H, 4. 31; N, 3.75%); δ _Η (360 MHz, DMSO-d ₆ ) 7.2-7.7 (13H, m, ArH and CH = CH), 7.94 (1H, d, J 8.7 Hz, H-5), 10 , 33 (1H, s, OH), 11.6 (1H, s, NH); m / z (C1 +, NH3) 374 (M + + H).

EXAMPLE 54 cis-7-Chloro-4-hydroxy-3- (phenylethenylphenyl) - (1H) -quinoline

A brownish amorphous solid, m.p. 247-249 ° C (from methanol) (Found: C, 72.98; II, 4.30; N, 3.71. Ο ₂₃ Η ₁₆ ΝΟ ₂ α + 0.2 H ₂ O requires C, 73.19 II, 4.38; N, 3.71%; δ _Η (360 MHz, DMSO-d ₆ ) 6.60 (1H, d, J 12.6 Hz, CH _A = CH _B ), 6.64 (III, d, J 12.6 Hz, CH _A = CH _B ), 7.1-7.5 (UH, m, ArH), 7.92 (1H, d, J 8.7 Hz, H-5), 10.3 (1H, s, OH), 11. 5 (1H, s, NH); m / z (C1 +, NII3) 374 (M + + H).

EXAMPLE 55

7-Chloro-4-hydroxy-3-3- (3-indolmethyl) phenyl] -2 (1H) -quinolone

Indole (2.53 g, 21.6 mmol) was dissolved in anhydrous THF (100 ml) and ethyl magnesium bromide (7.2 ml of 3 M ether solution, 21.6 mmol) was carefully added while stirring at room temperature under nitrogen. . After stirring for 30 minutes, the mixture was heated at reflux for two hours. After cooling, 3-bromomecylphenyl acetate (3.33 ml, 20.6 mmol) was added and the reaction mixture was stirred at room temperature under nitrogen for 72 hours. The solvent was removed on a rotavapor and the residue was redissolved in ethyl acetate and washed with citric acid (0.5 M), saturated sodium bicarbonate solution and brine before drying (Na ₂ SO4) and evaporation. The product was partially purified by flash chromatography eluting with 15% ethyl acetate in hexane to give an orange oil (750 mg). This oil (740 mg) was dissolved in THF (12 ml) and water (6 ml), a 0.5 M solution of lithium hydroxide (6.37 ml, 3.18 mmol) was added and the reaction mixture was stirred for 2 hours at room temperature. THF was removed in vacuo and the aqueous residue was partitioned between ether and sodium hydroxide solution. The organic layer was re-extracted with the base and the combined aqueous fractions acidified (pH 1, hydrochloric acid). The precipitate was extracted twice into ethyl acetate. The organic fractions were washed with hydrogen with brine before drying (Na ₂ SO4) and removing the solvent in vacuo to give 3-indole methyl phenylacetic acid col (571 mg, 2.15 mmol); (250 MHz, DMSO-dg) 3.49 (2H, s, ArCH ₂ COOH), 4.01 (2H, s, ArCH ₂ Ar), 6.91 (1H, t, J 7.5 Hz, Ar- H), 7.01-7.22 (6Η, m, Ar-H), 7.33 (1H, d, J 8.0 Hz, Ar-H), 7.42 (1H, d, J 7, 5 Hz, Ar-H); m / z (E1 +) 265 (M +). This compound was converted by the usual route to the final compound, an amorphous orange solid; m.p. 293-295 ° C (from melanol / water) (Found: C, 68.95; H, 4.33; N, 6.35. C ₂ 4 H ₁₇ C1N ₂ O2-H2O requires C, 68.82; H, 4.57; N, 6.69%; δ _Η (360 MHz, DMSO-d ₆ ) 4.06 (211, s, CH ₂ ), 6.93 (1H, d, J 7.2 Hz, indole 6-H or indole 7-H), 7, 04 (1H, i, J 7.5 Hz, indole 6-H or indole 7-H), 7.13-7.34 (8H, m, Ar-H), 7.51 (1H, d, J 7 , 8 Hz, Ar-H), 7.91 (1H, d, J 8.7 Hz. 5-H), 10.15-10.3 (1H, br s, OH), 10.81 (1H, brs, 1H, NH); 11.50 (111, br s, 1H, NH); m / z (EI +) 400 (M +).

EXAMPLE 56

7-Bromo-4-hydroxy-3-phenyl-2 (1H) -quinolone

White needles; m.p. 343-345 ° C (from DMF); (Found: C, 56.71; H, 3.21; N, 4.40. C ₁₅ Hi ₀ BrNO ₂ requires C, 56.99; H, 3.19; N, 4.43%); δ _Η (360 MHz, DMSO-d ₆ ) 7,297.42 (6H, m, Ph and 6-H), 7.47 (1H, d, J 1.8 Hz, 8-H), 7.86 (1H , d, J 8.6 Hz, 5-H), 10.29 (1H, brs.OH), 11.52 (111, s, 1H, NH); m / z (EI +) 315 (M +).

EXAMPLE 57

7-Chloro-4-liidioxy-3-1,3- (2-pyridyl) oxy) phenyl] -2 (1H) -quinol

A catalytic amount of concentrated sulfuric acid (1.0 ml) was added to a solution (3hydroxy) of phenylacetic acid (17.38 g, 0.114 mol) in methanol (100 ml). The reaction mixture was stirred for three hours at room temperature and then concentrated in vacuo. The residue was partitioned between ether (200 ml) and saturated aqueous sodium hydrogen carbonate solution (200 ml). The ether phase was separated and washed with unsaturated sodium hydrogen carbonate solution (200 ml) and saturated brine (100 ml). The ether extract was dried with magnesium sulfate. The solvent was evaporated and the residue was dried to give methyl 3 hydroxyrenyl acetate as a yellow oil (18.61 g, 98%); (360 MHz, CDCI3) 3.58 (2H, s,

CH ₂ ), 3.70, 3H, s, COOCH 3), 5.54 (1H, br s, OH), 6.74 (2H, m, ArH), 6.81 (1H, d, J = 8 Hz). ArH), 7.17 (1H, d, J = 8 Hz, ArH).

2-Bromopyridine (1.1 mi, 11.5 mmol) and potassium carbonate (2.76, 20.0 mmol) were added to a solution of methyl 3-hydroxylenylacetate (1.66 g, 9.99 mmol) in anhydrous pyridine ( 12 ml). The reaction mixture was warmed to 90 ° C with vigorous stirring under nitrogen, and then copper (II) oxide (1.99 g, 25.0 mmol) was added under nitrogen pressure. The reaction mixture was refluxed for 16 hours, cooled and diluted with dichloromethane. The mixture was filtered through hyflo and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with 1: 3 ethyl acelal / pellroller (60-80 °) followed by 1: 2 ethyl acetate / pctroleter (60-80 °) to give methyl [3- (2 -pyridyloxy) phenyl] acetate as a pale yellow oil (1.85 g, 78%); δ _Η (360 MHz, CDCI3) 3.63 (2H, s, CH ₂ ), 3.69 (3H, s, COOCH3), 6.90 (1H, d, J 8 Hz, ArH), 6.99 ( 1H, m, ArH), 7.06 (2H, m, ArH),

7.11 (1H, d, J 8 Hz, ArH), 7.34 (1H, t, J 8 Hz, 5'-H), 7.67 (111, m, ArH), 8.19 (III. m,

6-H), m / z 243 (M +).

Potassium bis (trimethylsilyl) amide in toluene (0.5 M, 10.8 ml, 5.4 mmol) was added dropwise to a solution of methyl [3- (2-pyridyloxy) phenyl] acetate (0.52 g, 2, 14 mmol) and methyl 2 amino-4-chlorobenzoate (0.43 g, 2.32 mmol) in dry THF (30 ml). The reaction mixture was stirred at room temperature for 3 hours, then methanol (10 ml) was added. The solution was concentrated in vacuo, the residue was dissolved in 0.5 M sodium hydroxide (25 ml) and washed with ether (2 x 25 ml). The aqueous phase was acidified with 5 M hydrochloric acid. The resulting precipitate was isolated and recrystallized from dimethylformamide / water to give the title compound as a pale drape solid (0.463, 59%). Further recrystallization from propan-2-ol gave an analytically pure compound; m.p. 269-271 ° C (from propan-2-ol) (Found: C, 65.92; H, 3.71; N, 7.59. C20H13CIN2O3 requires C, 65.85; H, 3.71; N. 7.68%); δ _Η (360 MHz, DMSO-d ₆ ) 7.03-7.14 (4H, m, ArH), 7.23 (1H, dt, J 2, 8.5 Hz, ArH), 7.32 (1H , d, J 2 Hz, ArH), 7.43 (1H, t, J 8 Hz, 5'-H), 7.85 (1H, m, ArH), 7.94 (1H, d, J 8, 7 Hz, 5-H), 8.18 (1H, dd, J 5, 2 Hz, 6-H), 10.46 (1H, br s, OH), 11.55 (1H, br s, NH) , m / z 364 (M +).

The following compounds were prepared in an analogous manner using appropriate heteroaryl bromide for the Ullman condensation reaction.

EXAMPLE 58

7-Chloro-44ii (hydroxy-3-1,3- (3-thienyl () xy) phenyl] -2 (1H) -quinoline

Tal. > 315 ° C (decomposition) (from dimethylformamide / water) (Found; C, 61.57; H, 2, x8; N, 3.74. Ci ₉ H _J2 C1NO3S requires C, 61.71; H, 3. 27; N, 3.79%); δ _Η (360 MHz, DMSO-d ₆ ) 6.93 (3H, m, ArH), 7.05 (1H, brs, ArH), 7.14 (1H, brd, J 8 Hz, ArH), 7. 21 (1H, dd, J 8.6, 2 Hz, 6-H), 7.31 (1H, d, J 2 Hz, 8-H), 7.37 (1H, t, J 8 Hz, 5 ' -H), 7.56 (1H, dd, J 5, 3 Hz, ArH), 7.93 (1H, d, J 8.6 Hz, 5-H), 10.37 (1H, br s, OH ), and 1.52 (1H, br s, NH); m / z 369 (M +).

EXAMPLE 59

7-Chloro-3- [3- (3-furyloxy) phenyl] -4-hydroxy-2 ((H) -quinolone)

Mp> 260 ° C (decomposition) (lyophilized); δ _Η (360 MHz, DMSO-d ₆ ) 6.50 (1H, m, 4-H), 6.99 (1H, dd, J 8Hz, 4-H), 7.08 (1H, br s, 2 -H), 7.20 (1H, dd, J 8.6, 2 Hz, 6-H), 7.30 (1H, d, J 2 Hz, 8-H), 7.36 (1H, t. J 8 Hz, 5'-H), 7.63 (1H, t, J 1.8 Hz, 5-H), 7.70 (1H, d, J 8.6 Hz, 5-H), 10. 36 (1H, br s, OH), 11.45 (1H, br s, NH); m / z 353 (M +), (Found: M +, 353.0446. C ₁ 9H ₁₂ C1NO4 requires M, 353.0455.

EXAMPLE 60

7-Chloro-4-yl (1r () xy-3- (3-phenylainino) phenyl-2 (1H) -quinolone

To a solution of sodium methoxide (251 mg, 4.65 mmol) in dry methanol (20 ml) was added a solution of methyl 3-hydroxyphenyl acetate (716 mg, 4.65 mmol) in methanol (5 ml). Then benzaniline hydrochloride (1 g, 4.65 mmol) was added rapidly to ether / methanol (10 ml: 2 ml). The reaction mixture was stirred at room temperature overnight. The solvent was evaporated and the residue partitioned between water (20 ml) and dichloromethane (20 ml). The aqueous phase was further extracted with dichloromellane (2 x 40 ml) and the combined organic extracts were dried and evaporated. The residue was chromatographed on silica gel eluting with 25% ethyl acetal / 60-80 ⁰ petroleum ether to give N-phenylbenzimmo-3- (carboxyloxymethyl) phenyl ether as an oil (1 g); δ _Η (CDC1 ₃ ) 3.55 (2H, s, CH ₂ CO ₂ Me), 3.66 (3H, s, CO ₂ Mc), 6.946,98 (511, m, ArH), 7.15-7 , 19 (5H, m, ArH), 7.35-7.41 (4H, m, ArH).

The above imidate (1 g, 3.1 mmol) in diphenyl ether (20 ml) was heated at 240 ^{0 for} 72 hours. The reaction mixture was cooled, diluted with acetonitrile (100 ml) and extracted with 60-80 ⁰ pclroller (5 x 100 ml). The acetonitrile phase was evaporated and the residue was chromatographed on silica gel, eluting with 25% ethyl acetal / 60-80 ⁰ petroleum ether to give 3 (N-benzoylanilino) phenylacetate (800 mg); Bj-j (CDCI3) 3.54 (2IT, s, CH ₂ C () ₂ Mc).

3.64 (3H, s, CO ₂ Mc), 7.04-7.29 (12H, m, ArH), 7.42 (2H, d, J 7.2 Hz, ArH).

The ester (600 mg, 1.9 mmol) in 4 N sodium hydroxide (20 ml) and methanol (20 ml) were stirred at room temperature overnight. The solvent was evaporated and the residue was dissolved in water (10 ml) and acidified with 5 N hydrochloric acid. The acidic solution was extracted with dichloromethane (3 × 50 mL) and the combined extracts were dried and evaporated to give 3- (Nbenzoylanilino) phenylacetic acid as an oil (550 mg); (CDCI3) 3.59 (2H, s, CH ₂ CO ₂ H), 6.83-7.29 (10H, m, ArH), 7.42-7.48 (3H, m, ArH), 8.09 ( 2H, d, J 7.2 Hz, ArH).

The title compound was prepared from precursor acetic acid; m.p. 259-262 ° C (from DMF / H ₂ O) (Found: C, 68.51; H, 3.50; N, 7.21. C _{2 and} H ₅ C ₁ N ₂ O ₂ requires C, 69.52; H , 4.16; N, 7.75%); δ _Η (DMSO-d ₆ ) 6.77-6.82 (1H, m, ArH), 7.03 (1H, d, J 7.2 Hz, ArH), 7.08-7.11 (2H, m. ArH), 7.19-7.21 (5H, m, ArH), 7.91 (1H, d, J 8.7 Hz, 5-11), 8.15 (1H, s, ArH), 10. 21 (1H, br s, OH), 11,52 (1H, br s, NH); m / z 362 (M ⁺ ).

EXAMPLE 61

7-Chloro-4-hydroxy-3-3- (2-dimethylaminophenoxy)] phenyl-2 (1H) -quinoline) ii

2-Fluoronylrobenzene (4.2 ml, 40 mmol), methyl 3-hydroxyphenylacetal (5 g, 32.5 mmol) and potassium carbonate (6.9 g, 50 mmol) in DMF (100 ml) were heated together at 100 ° C 36 hours. After evaporation of the solvent, the residue was partitioned between water (100 ml) and dichloromethane (100 ml) and the aqueous phase was further extracted with dichloromethane (2 x 100 ml). The combined organic extracts were dried and evaporated and the residue was chromatographed on silica gel, eluting with 25% ethyl acetate / 60-80 ⁰ petroleum ether to give methyl 3- (2nitrophenyloxy) phenylacetate (4 g); (CDCl 3) 3.62 (2H, s, CH ₂ CO ₂ Me), 3.69 (3H. S CO ₂ Mc), 6.94 (1H, d, J 7.2 Hz, ArH). 7.00-7.04 (2H, m, ArH), 7.09 (1H, d, J 8.3 Hz, ArH), 7.19 (1H, t, J 8.3 Hz, ArH), 7 , 32 (1H, t, J 7.9 Hz, ArH), 7.50 (1H, t, J 7.2 Hz, ArH). 7.94 (1H, d, J 8.2 Hz, ArH).

A solution of ester (1g) in ethanol (20 ml) containing formaldehyde (37%) in water, 5 ml) was hydrogenated with 10% Pd / C (150 mg) at 50 psi for 5 hours. After removal of the catalyst and evaporation of the solvent, the residue was chromatographed on silica gel eluting with 25% ethyl acetate / 60-80 ⁰ petroleum ether to give methyl 3- (2-dimethylaminophenoxy) phenyl acetate as an oil (800 mg); δ _Η (CDC1 ₃ ) 2.60 (6H, s, NMe ₂ ), 3.58 (2H, s, CH ₂ CO ₂ Me), 3.66 (311, s, CO ₂ Me), 6.62- 6.90 (4H, m, ArH), 6.95-7.00 (1H, m, ArH), 7.04-7.11 (1H, m, Aryl), 7.23 (1H, t, J 7.8 Hz, ArH); m / z 285 (M +).

The ester (1 g) in a mixture of methanol (20 ml) and 4N sodium hydroxide (20 ml) was stirred for 3 hours. The solvent was evaporated, water (10 ml) was added to the residue, and the mixture was acidified with 5N hydrochloric acid. The acidic solution was extracted with dichloromethane (3 x 50 ml) and the combined organic extracts were dried and evaporated to give 3- (2-dimethylaminophenoxy) phenylacetic acid (650 mg); 8j-j (CDCI3) 2.99 (611, s, NMC2), 3.62 (2H, s, CH ₂ CO ₂ NH), 6.87-6.95 (4H, m, ArH), 7.03 -7.13 (3H, m, ArH), 7.25-7.31 (1H, m, ArH).

The title compound of the above acetic acid; m.p. 269-271 ^(J C (from DMF / water) (Found: C, 67.98; H, 4.83; N, 6.96. C23H19CIN2O3 requires C, 67.90; H, 4.71; N, 6 , 88%); δ _Η (DMSO-d ₆ ) 2.75 (6H, s, NMe ₂ ), 6.78 (1H, dd, J 7.7 and 1.9 Hz, ArH), 6.87- 6.94 (3H, m, ArH), 7.00-7.10 (3H, m, ArH), 7.19 (1H, dd, J 8.6 and 2.0 Hz, ArH), 7.29 -7.35 (2H, m, ArH), 7.92 (1H, d, J 8.4 Hz, 5-H), 11.48 (1H, br s, NH); m / z 406 (M +) .

EXAMPLE 62

7-KI () io-4-hi (hydroxy-3- [3- (4-nithoxybenzyl) phenyl] -2 (1H) -quinolone

White amorphous thorny substance, m.p. 282-284 ° C (from dimethylformamide); (Found: C, 70.65; H, 4.28; N, 3.70. Ο ₂ 3Η ₁₈ ΝΟ ₃ α requires C, 70.50; H, 4.63; N, 3.57%); δ _Η (360 MHz, DMSO-d ^) 3.71 (3H, s, OMe), 3.90 (2H, s, CH ₂ ), 6.83 (2H, d, J 7Hz, ArH; Ho at OMe) ), 7.1-7.3 (8H, m, ArH), 7.91 (1H, d, J 8.6 Hz, H-5), 10.23 (1H, br s, OH), 11. 50 (1H, s, NH); m / z (EI +) 391 (M +).

EXAMPLE 63

7-Chloro () - 4-hi (hydroxy-3-l3- (3-inethoxyfluoxy) phenyl-2 (III quinolone)

To a solution of the sodium salt of 3-hydroxybenzyl alcohol (8.1 g, 50 mmol) in N-melyl pyrrolidinone (20 ml) was added 3-bromoanisole (11.22 g, 60 mmol), copper (I) chloride (0.1 g, 1 mmol) and p-hydroxyquinoline (0.1 g, 1 mmol) and the reaction mixture was heated at 170 ° C for 50 hours. The reaction mixture was cooled to room temperature, diluted with water (150 ml) and extracted with ether (5 x 50 ml). The combined extracts were dried (MgStLj) and evaporated. The residue was purified by flash chromatography (eluent 10% ethyl acetal / 60-80 ° petroleum ether) to give 3- (3-methoxyphenoxy) benzyl alcohol col. 6.0 g (52%); δ _Η (CDC1 ₃ ) 3.80 (3H, s, OCH ₃ ), 4.64 (2H, s, CH ₂ OH), 6.54-6.70 (3H, m, ArH), 6.88- 7.10 (3H, m, ArH), 7.18-7.36 (2H, m, ArH).

The resulting alcohol (5.31 g, 23 mmol) was dissolved in dichloromethane (40 ml) and digested with thionyl chloride (2.6 ml, 35 mmol) and dimethylformamide (5 drops as catalyst). The reaction mixture was stirred overnight, then evaporated in vacuo and then azeotroped (= azeotropically distilled) with toluene (2 x 10 ml) to give 3- (3-methoxyphenoxy) benzyl chloride as a light brown oil (5 , 57 g, 97%). The resulting chloride (5.30 g, 21.3 mmol) was dissolved in dimethyl sulfoxide (20 ml) and potassium cyanide (1.45 g, 22.4 mmol) was added and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with water (100 ml) and extracted with ether. The combined extracts were dried (MgSOri * ^{n was} evaporated to give 3- (3-methoxyphenoxy) phenyl acelonyl or yl as a brown oil (4.04 g, 79%).

The resulting nilrile (4.0 g, 16.7 mmol) was dissolved in ethanol (20 ml), aqueous sodium hydroxide (5 M, 7 ml) was added and the mixture was heated at reflux for two hours, then cooled to room temperature and concentrated in a vacuum. The residue was diluted with aqueous sodium hydroxide (1N, 40 ml) and washed with ether (40 ml, 2 x 20 ml). The aqueous layer was acidified (5N, HCl) and the resulting rubber mass was extracted into dichloromellane (3 x 25 ml). The combined organic phases were dried (MgSO 2) and evaporated to give 3- (3meloxyphenoxy) phenylacetic acid as a liquid brown oil (2.36 g, 55%). δρ | (CDCl3) 3.61 (2H, s. CH ₂ CO ₂ H), 3.77 (3Η, s, OCH3), 6.55-6.70 (3H, m. ArH), 6.88-7.02 (3H. M. ArH), 7.14-7.29 (2H, m, ArH); m / z 285 (M +).

The title compound was prepared by procedures analogous to those described above.

m.p. 268-270 ° C (from DMF / _H-20). (Found: C, 66.81; H, 3.59; N, 3.67. C ₂₂ H 16 ^CINO 4 requires C, 67.10; H, 4.10; N, 3.65%). δ _Η (DMSO-d ₆ ) 3.37 (3H, s, OCH3), 6.63 (211, m, ArH), 6.69 (1H, dd, J 7.9 and 2.1 Hz, ArH) , 6.94 (111, dd, J 8.0 and 2.0 Hz, 6-11), 7.0 (1H, s, ArH), 7.17-7.41 (5H, m, ArH), 7.92 (1H, d, J 8.6 Hz, 5-H), 11.37 (1H, s, NH); m / z 392 (M +).

EXAMPLE 64

7-Chloro-4-hydroxy-3-1,3- (2-methoxyphenoxy) phenyl] -2 (1H) -quinoline

This compound was prepared in an analogous manner from 2-bromoanisole.

Tal. 258-260 ° C (from DMF / H ₂ O) (Found: C, 67.05; H, 3.73; N, 3.29. C ₂₂ HI6CINO4 requires C, 67.10; H, 4.10; N, 3.65%). δ _Η (DMSO-d ₆ ) 3.78 (3H, s, OCH3), 6.75 (1H, dd, J 10.2 and 2.09 Hz, ArH), 6.89 (1H, s, ArH) , 6.96 (1H, m, ArH), 7.05 (2H, d, J 7.2 Hz, ArH), 7.17 (3H, m, ArH), 7.30 (2H, m, ArH). , 7.92 (1H, d, J 8.7 Hz, 5-H), 11.48 (1H, br s, NH); m / z 392 (C1 +, NH ₃ ) 394 (M + + H).

EXAMPLE 65

7-Chloro-4-hydroxy-3-3- (2-methylphenoxy) phenyl] -2 (1H) -quinolone

This compound was prepared in an analogous manner from 2-bromotoluene.

Tal. 288-290 ° C (from DMF / II ₂ O) (Found: C, 69.21; H, 3.92; N, 3.99. C ₂₂ Hi ₆ ClNO ₃ 0.15 (H ₂₀ ) requires C. 69.44; H, 4.32; N, 3.68%. δ _Η (DMSO-d ₆ ) 2.22 (3H, s, CH ₃ ), 6.84 (1H, dd, J 8.0 and 1.7 Hz, ArH), 6.89 (1H, s, ArH) ), 6.96 (1H, d, J 8.0 Hz, ArH), 7.05-7.10 (2H, m, ArH), 7.18-7.22 (2H. M. ArH), 7 , 30-7.36 (3H. M, ArH). 7.92 (1H, d, J 8.6 Hz, 5-H), 11.49 (1H, s, NH); m / z 377 (M + + H).

EXAMPLE 66

7-Chloro-4-hydroxy-3- (3'-biphenyl) -2 (1H) -quinolone

Tal. > 345 ° C (decomposition) (from DMF / H ₂ O) (Found: C, 71.58; H, 4.17; N 4.10. C21H14CINO2 -0.25 (H ₂₀ ) requires C, 71.59 H, 4.15; N, 3.98%. δ _Η (DMS () - d _fi ) 7.22 (1H, dd, J 8.6 and 1.9 Hz, 6-H), 7.34-7.38 (3H, m, ArH), 7. 45-7.52 (3H, m, ArH), 7,607.68 (4H, m, ArH), 7.96 (1H, d, J 8.6 Hz, 5-H), 10.39 (1H, br. s, OH), 11.57 (1H, s, NH); m / z 347 (M +).

EXAMPLE 67

7-Chloro-4-hydroxy-3- (3-phenylthio) phenyl) -2 (1H) -cyliolone

To a solution of 3-bromobenzaldehyde (14.22 g, 77 mmol) in toluene (100 ml) was added paratoluenesulfonic acid (760 mg, 4 mmol) and ethylene glycol (9.5 g, 154 mmol). The mixture was heated at reflux under Dean-Slark conditions for sixteen hours. The reaction mixture was cooled to room temperature and washed with sodium carbonate (2 x 40 ml) and water (2 x 40 ml). The organic phase was dried (MgSO 2) and evaporated in vacuo to give 3-bromobenzaldehyde ethylene glycol acetal as a pale yellow oil (17.5 g, 100%). A solution of the previous bromide (5.5 g, 24 mmol) in tetrahydrofuran (80 mi) was cooled to -78 ° C (dry ice / acctone) and digested with tert. butyllithium (48 mmol in pentane) followed by phenyldisulfide (5 g, 25 mmol) in THF (40 ml). After the addition was complete, the reaction mixture was stirred at -78 ° C for one hour, then allowed to warm to room temperature. After one hour at room temperature, the reaction was quenched by the addition of guides (150 ml). The mixture was concentrated in vacuo and the residue was extracted into ether (5 x 25 ml). The combined extracts were dried (MgSO2p was evaporated in vacuo. The mixture was purified by flash chromatography (eluted with 10% ethyl acetal / 60-80 o pellrolelea) to give (3-phenylthio) benzaldehyde ethylene glycol acetal col oil (5.40 g. Hydrochloric acid (5 M, 8 ml) was added to a solution of the previous thioether (5.3 g, 20.5 mmol) in tetrahydrofuran, and the mixture was stirred for fifteen hours, a further portion of acid (4 ml) was added and continued. The mixture was concentrated in vacuo, diluted with water (25 ml) and extracted with dichloromethane (5 x 25 ml). The combined extracts were washed with sodium carbonate (50 ml), dried (MgSO 2) and evaporated in vacuo. to give 3-phenylthio benzaldehyde as a yellow oil (4.21 g, 89%). 5pj (CDCl 3) 7.25-7.58 (7H. m, ArH), 7.66-7.80 (2H, m, ArH), 9.92 (1H, s, CHO).

The previous aldehyde (4.21 g, 18.3 mmol) was dissolved in tetrahydrofuran (40 ml), Triton B (2 ml 40% solution in methanol) and methyl methyl liomethylsulfoxide (4.2 ml, 40.3 mmol) were added. ) and heated at reflux for sixty-five hours. The mixture was cooled to room temperature and concentrated in vacuo. The residue was diluted with dichloromethane (40 ml), washed with water (15 ml), sodium bisulfite (2 x 15 ml) and water (15 ml) before drying (MgSO4) and evaporated in vacuo. The mixture was purified by flash chromatography (eluted with 25% ethyl acetate / petroleum ether 60-80 °) to give 1-methylsulfonyl-1-methyllio-2 (3-phenyllio) phenylethylene as a pale oil (4.97 g, 85%) . To a solution of the preceding ethylene (4.9 g, 15.3 mmol) in 1,2-dimethoxy-ethane (40 ml) was added concentrated hydrochloric acid (10 ml) and the mixture was heated at reflux for two hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was dissolved in aqueous sodium hydroxide (1N, 50 ml) and washed with ether (3x15 ml). The aqueous layer was acidified (5N HCl) and the resulting precipitate was extracted into dichloroctane (4 x 15 ml). The combined organic phases were dried (MgSO ₄ ) and evaporated in vacuo to give 3-phenylthio phenylacetic acid as a pale oil which crystallized from the state (2.29 g, 61%). δ { ₄ (CDCI ₃ ) 3.59 (2H, s, CH2CO ₂ H), 7.14-7.43 (9H, m, ArH).

The title compound was prepared using procedures analogous to the above.

Tal. 291-293 ° C (decomposition) (from DMF / water) (Found: C, 66.62; H, 3.75; N, 3.96. C21H14NCIO2S requires C, 66.40; H, 3.72; N , 3.69%). δ _Η (DMSO-d ₆ ) 7.21 (1H, dd;

8.6 and 2.0 Hz, 6-H), 7.35 (9H, m, ArH), 7.93 (111, d, J 8.6 Hz, 5-H), 10.45 (1H, br s, OH), 11.55 (1H, s, NH); m / z 379 (M +).

EXAMPLE 68

7-Kioiv-4-hi (hvk $ i-3- (3-phenylsilylphenylphenyl) -2 (1H) -quinolt> n

To a solution of methyl-4-chloro-2 - [(3-phenylthio) phenylacetamido] benzoal (513 mg, 1.25 mmol) (intermediate from the example above) in dichloromethane (20 mi) was added methochloroperoxybenzoic acid (616 mg 70% solid) substances, 2.5 mmol) and the mixture was stirred for 3 hours at room temperature. The reaction mixture was washed with sodium carbonate (25 ml) and the aqueous layer extracted with dichloromethane (3x15 ml). The combined organic phases were dried (MgSO ₄ ) and evaporated in vacuo. The mixture was purified by flash chromatography on silica gel (eluted with 10% ethyl acetate / 60-80o pellrolecl) to give methyl 4-chloro-2 - ((3phenylsulfonyl) phenylacetamido] benzoate as a white solid (532 mg, 96%,) .δ] j (CDCl 3) 3.73 (2H, s, CH ₂ Ph), 3.76 (3H, s, CO ₂ Me), 7.03 (1H, dd, J 8.4 and 2.1 Hz). , 5-H), 7,197.37 (9H, m, ArH), 7.90 (1H, d, J 8.6 Hz, 6-H), 8.79 (1H, d, J 2.1 Hz, 3-H).

The amide was cyclized to give the title compound with a melting point of 260 ° C (slow decay) (from DMF / water) (Found: C, 61.54; H, 3.53; N, 3.80. C ₂ | Hj ₄ NC10 ₄ S requires C, 61.24; H, 3.43; N, 3.40%. δρι (DMSO-d ₆ ) 7.24 (1H, dd, J 8.6 and 2.0 Hz, 6-H), 7.34 (1H, d, J 2.0 Hz, 8-H), 7 , 60-7.72 (5H, m, ArH), 7.88 (1H, m, ArH), 7.96-7.99 (4H, m, ArH), 10.74 (1H, in brs, OH ), 11.63 (1H, s, NH); m / z 411 (M +).

3- (3-Benzoylamino) phenyl-7-cloiv-4-yl (h (> xy-2 (1H) -quinolone)

EXAMPLE 69

A suspension of platinum oxide (0.35 g) in ethyl acetate (100 ml) containing methyl 4-chloro 2- (3-nitrophenyl) acelamidobenzoate (9.96 g, 28.6 mmol) was shaken under a hydrogen atmosphere at a pressure of 40 psi until did not stop hydrogen consumption. The suspension was filtered and the filtrate was evaporated to give the remaining methyl 2- (3-aminophenyl) acetainido-4-chlorobenzoate as a pale green solid (9.22 g); δ _Η (CDC1 ₃ ) 3.65 (2H, s, CH ₂ ), 3.66 (3H, s, OCH ₃ ), 6.61 (1H, dd, J 7.9 and 2.1 Hz, ArH) , 6.70 (1H, s, ArH), 6.74 (1H, d, J 7.6 Hz, ArH), 7.01 (lil, dd, J 8.6 and 2.0 Hz, 5-H ), 7.14 (1H, d, J 7.7 Hz, ArH), 7.89 (1H, d, J 8.6 Hz, 6-H), 8.81 (1H, d, J 2.0). Hz, 3-H), and 11.03 (1H, br s, CONH).

A sample of the aforementioned amine (90 mg, 2.8 mmol) was stirred for 5h with benzoyl chloride (4.23 mg, 3 mmol) and dichloromethane (20 ml) containing pyridine (1 ml). The mixture was washed with HCl (IM, 15 ml), dried (MgSO ₄ ), filtered and the filtrate evaporated to give a solid which was recrystallized from methanol to give methyl 2- (3benzoylamino) acetamido-4-chloro-benzoate ( 901 mg) as a colorless solid; m.p. Mp 156-157 ° C.

By cyclization as above, the title compound was obtained as a yellow-brown solid; m.p. 310-312 ° C (from DMF / water) (Found: C, 67.88; H, 3.62; N, 7.08. C ₂₂ H ₁₅ C1N ₂ O ₃ requires C, 67.61; H, 3 , 87; N, 7.17%). δ _Η (DMSO-dg) 7.09 (1H, d, J 7.7 Hz, 6'-H), 7.21 (1H, dd, J 9.0 and 2.0 Hz, 4'-H) , 7.32 (1H, d, J 2.0 Hz, 2'-H), 7.37 (1H, t, J 7.8 Hz, 5'-H) 7.50-7.61 (3H, m, ArH), 7.78-7.81 (2H, m, ArH), 7.93-7.78 (3H, m, ArH), 10.26 (1H, br s, NHCOPh), and 11, 53 (1H, br s, NHCO); m / z 391 (M +).

EXAMPLE 70

3 (3-N-Benzylainine ()) phenyl-7-chloro-4-yl (hydroxy-2 (1H) -quinone

A solution of methyl 2- (3-aminophenylaclamido) -4-chloro-benzoate (1.80 g, 5.6 mmol) and benzaldehyde (0.62 g, 5.8 mmol) in toluene (60 ml) containing a trace of p-toluenesulfone The acids were stirred for 50 minutes at reflux in a Dean-Slark paste. After cooling, the solvent was evaporated, the residue was dissolved in THF (15 ml) and a solution of potassium hexamctyldisilazide in toluene (0.5 M, 25 ml) was added. After stirring for 1.5 hours, enough methanol was added to the suspension to dissolve the precipitate and evaporate the resulting solution to give the remaining yellow solid. This was redissolved in methanol (50 ml) and an excess of acetic acid was added. After a 0.5-hour state, the precipitated solid was filtered off, washed with methanol and dried to give the appropriate act as a yellow-brown powder (1.81 g) ·

The sample (300 mg, 0.8 mmol) was dissolved in a mixture of acetic acid (10 ml) and DMF (5 ml) and sodium cyanoborohydride (150 mg, 2.4 mmol) was added. After stirring for 1.5 hours, the solution was evaporated and the residue was dissolved in dilute aqueous sodium hydroxide containing some methanol. Addition of 10% aqueous citric acid gave a precipitate which was filtered off and crystallized to give the title compound as a yellow-brown tile; m.p. 259-260 ° C (from DMF / water) (Found: C, 70.20; H, 4.35; N, 7.22. C22H17CIN2O2 requires C, 70.12; H, 4.55; N, 7. 43%). δ _Η (DMSO-d ₆ ) 4.27 (211, d, J 4.5 Hz, NHCH ₂ Ph), 6.16 (1H, t, J 5.9 Hz, NHCH ₂ Ph), 6.50 ( 2H, dd, J 7.7 and 1.7 Hz, Ar-H), 6.62 (1H, s, 2'-H), 7.06 (1H, t, J 7.7 Hz, ArH), 7.17-7.24 (2H, m, ArH), 7.287.39 (5H, m, ArH), 7.88 (1H, d, J 8.7 Hz, ArH), 10.00 (1H, br s, OH), and 11.44 (1H, br s, NH); m / z 377 (M +).

EXAMPLE 71

3- (3'-Allyl () xiphenyl) -7-chloro-4-hyloxy-2 (1H) -quinolone

Tal. > 300 ° C (from DMF / water) (Found: C, 65.63; H, 4.32; N, 4.08. C _1S H ₁₄ C1N () 3 requires C, 65.96; H, 4. 31; N, 4.27%). δ _Η (DMSO-d ₆ ) 4.56 (2H, d, J 5.2 Hz, OCH ₂ CH: Cn ₂ ), 5.26 (1H, dd, J 10.5 and 2.1 Hz, OCH ₂ CH: CH ₂ ), 5.42 (1H, dd, J 17.3 and 2.1 Hz, OCH ₂ CH: CH ₂ ), 6.06 (1H, m, OCH ₂ CH: CH ₂ ), 6, 90-6.94 (3H, m, ArH), 7.20 (1H, dd, J 8.6 and 2.0 Hz, 6-H), 7.28-7.31 (2H, m, Aryl and 8-H), 7.92 (1H, d, J 8.6 Hz, 5H), 10.22 (1H, brs, OH) and 11.51 (1H, brs, NH).

EXAMPLE 72

7-Chloro-4-hydroxy-3- (3- (2-methylprop-2-enyloxy)) phenyl-2 (1H) -quinolone

Tal. 297-299 ° C (from DMF / water) (Found: C, 66.58; Fl, 4.88; N, 4.15. C _iy II j ₆ C1NO ₃ requires C, 66.77; H, 4. 72; N, 4.10%). δ _Η (DMSO-d ₀ ) 1.23 (311, s, CH3), 4.40 (211, s, OCH ₂ ), 4.96 (1H, s, C: CH ₂ ), 5.08 (1H , s, C: CH ₂ ), 6.70-6.94 (3H, m ArH), 7.20 (III, dd, J 8.6 and 1.9 Hz, 6-H), 7.27- 7.31 (2H, m, ArH and 8-H), 7.92 (1H, d, J 8.6 Hz, 5-11), and 11.50 (1H, brs, NH); m / z 342 (M +).

EXAMPLE 73

4-Hydroxy-7-methyl-3- (3-phenoxyphenyl) - (1H) -quinolone

Tal. 299.3-300.5 ° C (from DMF / H ₂ O) (Found: C, 76.66; H, 4.79; N, 4.01. C ₂₂ H ₁₇ NO ₃ requires C, 76.95 H, 4.99; N, 4.08%. δ _Η (DMSO-d ₆ ) 2.37 (3H, s, CH3), 6.94-7.42 (1H, m, 6H, 8H and 9 x ArH), 7.83 (1H, d, J) 8.6 Hz, 5-H), 10.10 (1H, bs, OH), 11.36 (111, s, NH); m / z 344 (M + 1).

EXAMPLE 74

7-Chloro-4-hydroxy-3- (3,4-dimethoxyphenyl) -2 (1H) -quinolone

Tal. 312-314 ° C (from DMF / H ₂ O); δ _Η (360 MHz, DMSO-d ₆ ) 3.74 (3FI, s, OCH3), 3.79 (3H, s, OCH3), 6.87-7.00 (3H, m, ArH), 7. 19 (1H, d, J 8.6 Hz, 6-H), 7.31 (1H, s, 8-H), 7.90 (1H, d, J 8.6 Hz, 5-11), 11 , 48 (1H, br s, NH); m / z 331 (M +) (Found m / z 331.0613; C ₁₇ H ₁₄ C1NO4 requires 331.0611).

EXAMPLE 75

7-Chloro-3- (4-ethoxyphenyl) -4-hydroxy-2 (II) -quinolone

Tal. > 320 ° C (from DMF / H ₂ O) (Found: C, 64.60; H, 4.35; N, 4.32. C ₇ H ₁₆ ClNO ₃ requires C, 64.67; H, 4. 47; N, 4.44%). δ _Η (360 MHz, DMSO-d ₆ ) 1, 35 (3H, t, 6.9 Hz,

CH ₂ CH ₃ ), 4.05 (2H, q, J 6.9 Hz, CH ₂ CH ₃ ), 6.92 (2H, d, J 8.7 Hz, 2'-H, 6'-H) , 7.17 (lil, dd, J 8.6 Hz and 2.0 Hz, 6-H), 7.28 (1H, s, 8-H), 7.30 (1H, dd, J 8.6 Hz and 2.0 Hz, 3'-H, 5'-H), 7.90 (1H, d, J 8.7 Hz, 5-H), 11.39 (1H, br s, NH); m / z 315 (M +).

EXAMPLE 76

7-Chloro-4-hydroxy-3- (4-methoxyphenyl) phenyl-2 (1H-quinalane)

Tal. 291-293 ° C (from DMF / H ₂ O) (Found: C, 66.04; H, 4.43; N, 3.45, Cl, 9.17%; C ₂₂ H ₆ ClNO4-0.25 H ₂ O requires C, 66.33; H, 4.17; N, 3.52; Cl, 8.90%; δ _Η (DMSOd ₆ ) 3.74 (3H, s, OCH ₃ ), 6.86 -6.98 (7H, m, ArH), 7.03-7.08 (3H, m, ArH, 6-H), 7.20 (1H, dd, J 8.6 Hz and 2.0 Hz, ArH), 7.30 (1H, br s, 8-H), 7.36 (1H, i, J 7.89 Hz, ArH), 7.92 (1H, d, J 8.6 Hz, 5- H), 11.52 (1H, br s, NH); m / z 393 (M +).

EXAMPLE 77

7-Chloro-4-hydroxy-3- (4-methylphenoxy) phenyl-2 (1H) -quinone

Tal. 296-298 ° C (from DMF / H ₂ O) (Found: C, 69.37; H, 4.45; N, 3.52%; C ₂₂ H ₁₆ C1NO0 ₃ -0.15 H ₂ O requires C , 69.44; H, 4.32; N, 3.68%; δ _Η (DMSO-d ₆ ) 2.28 (3H, s, CH3), 6.90-6.99 (4H, m, ArH ), 7.11 (1H, d, J 6.6 Hz, 6-H), 7.17-7.22 (3H, m, ArH), 7.31 (1H, s, 8-H), 7 , 38 (1H, t, J 7.9 Hz, ArH), 7.92 (1H, d, J 8.6 Hz, 5-H), 11.53 (1H, brs, NH); m / z 376 (M +).

EXAMPLE 78

Preparation of tablets

Tablets containing 1.0, 2.0, 25.0, 26.0, 50.0 and 100.0 mg of the following compounds are prepared as illustrated below:

7-Chloro-4-bidroxy-3- (3-phenoxyphenyl) -2 (1H) -quinolone

7-Chloro-4-hydroxy-3- [3- (4-methoxymethoxybenzyl) phenyl] -2 (1H) -quinolone

7-Chloro-4-hydroxy-3- [3- (4-methoxybenzyl) phenyl] -2 (1H) -quinolone

7-Chloro-4-hydroxy-3- [3- (2-propynyloxy) phenyl] -2 (1H) -quinolone

DOSAGE TABLE CONTAINING 1-25 MG ACTIVE COMPOUNDS

Amount - mg

The active compound 1.0 2.0 25.0 M crystals zero on cellulose 49.25 48.75 37.25 Modified dietary corn starch 49.25 48.75 37.25 Magnesium stearate 0.50 0.50 0.50

DOSAGE TABLE CONTAINING 26-100 MG OF ACTIVE COMPOUNDS

Amount - mg

The active compound 26.0 50.0 100.0 Microcrystalline cellulose 52.0 100.0 200.0 Modified dietary corn starch 2.21 4.25 8.5 Magnesium stearate 0.39 0.75 1.5

All active compounds, cellulose and part of cornstarch are mixed and granulated in a 10% cornstarch paste. The resulting granulation is sieved, dried and sown with cornstarch residue and magnesium stearate. The resulting granulate is compressed into tablets containing 1.0 mg, 2.0 mg, 25.0 mg, 26.0 mg, 50.0 mg and 100 mg of active ingredient per tablet.

Claims (11)

PATENT APPLICATIONS 1. The use of a compound of formula I or a pharmaceutically acceptable salt or prodrug thereof: (I) where they mean hydrogen, hydrocarbon, -SR ^a, -SOR ^a, -SO2R ^a, -SO2NR R ^d CO ₂ R ^a or -CONR ^a R ^b; and and R ^d is independently a heterocyclic group, halogen, cyano, trifluoromethyl, nitro, -0R ^a, -SR ^a, -SOR ^a, S02 ^a, -SO2NR ^a R ^b, -NR ^a R ^b, -NR ^a COR ^b, -NR ^a CO2R ^b , -COR ^a , -CO2R ^a, or -CONR ^a R ^b ; or R ² and R ² together represent the residue of a carbocyclic or heterocyclic ring; R ³ , R ⁴ , r 5 and r 6 independently represent hydrogen, hydrocarbon, heterocyclic group, halogen, cyano, trifluoromethyl, nitro, -O R ^a , -NR ^a R ^b , -NR ^a COR ^b , -NR ^a CO ₂ R ^b , -COR ^a , means hydrogen, hydrocarbon or a _D b R ^a and R ^{d are} independently heterocyclic; for the manufacture of a medicament for the treatment and / or prevention of conditions requiring the administration of a selective non-competitive N-methyl-Daspartate receptor antagonist. Use of a compound of formula I as defined in the claim 1, or a pharmaceutically acceptable salt or prodrug thereof, for the manufacture of a medicament for the treatment and / or prevention of conditions requiring the administration of a 2-amino-3-hydroxy-5-methyl4-isoxazolpropionic acid receptor antagonist. 3. with the formula IA pre-treats lo: A pharmaceutical or composition thereof comprising a compound of a pharmaceutically acceptable salt or (IA) thereof in which R ¹¹ and R ^{12 are} heterocyclic groups independently of hydrogen, hydrocarbon, halogen, cyano, trifluoromethyl, nitro, -O R ^a , -SR ^a , -SOR ^a , -SO ² R ^a , -SO ² NR ^a R ^b , -NR ^a R ^b , -NR ^a COR ^b , -NR ^a CO2R ^b , -COR ^a , -CO2R ^a or -CONR ^a R ^b ; or R ^ and R ^ ² together represent the residue of a carbocyclic or heterocyclic ring; R ¹³ , R ⁴ , R ¹⁵ and R 16 independently represent hydrogen, hydrocarbon, heterocyclic group, halogen, cyano, trifluoromethyl, nitro, -OR ^a , -SR ^a , -SOR ^a , -SO ^{2 a} , -SO ² NR ^a R ^b , -NR ^a R ^b , -NR ^a COR ^b , -NR ^a CO2R ^b , -COR ^a , -CO ² R ^a or -CONR ^a R ^b ; and R ^a and R ^b independently represent a hydrogen, hydrocarbon or heterocyclic group; provided that when R ^, R ^ ² , R ^ ³ , R ^ ⁴ and R ^ each represent hydrogen, then R ^ does not mean an unsubstituted unbranched or branched alkoxy group containing 2 to 10 carbon atoms or unbranched or branched alkoxy a group containing 1 to 6 carbon atoms with at least one substituent selected from hydroxy, carboxy and carbamoyl; together with one or more pharmaceutically acceptable carriers and / or excipients. A compound of formula IA as defined in claim 3, or a pharmaceutically acceptable salt or prodrug thereof, for use in therapy. Composition as claimed in claim 3, characterized in that the active ingredient is selected from: 4-hydroxy-3-phenyl-2 (1H) -quinolone; 7-chloro-4-hydroxy-3-phenyl-2 (1H) -quinolone; 7-chloro-4-hydroxy-3- (2-methylphenyl) -2 (1H) -quinolone; 7-chloro-4-h and drox i-3- (4-methylphenyl) -2 (1H) -nolone; 4-hydroxy-3-phenyl-7-trifluoromethyl-2 (1H) -quinolone; 6,7-dichloro-4-hydroxy-3-phenyl-2 (1H) -quinolone; and their pharmaceutically acceptable salts and prodrugs thereof a. 6. A compound of formula IB, or a salt or prodrug thereof: (IB) in which o i 2? R and R independently represent hydrogen, hydrocarbon, heterocyclic group, halogen, cyano, trifluoromethyl, nitro, -O R ^a , -SR ^a , -SOR ^a , -SO ^{2 a} , -SO ² NR ^a R ^b , -NR ^a R ^b , -NR ^a COR ^b , -NR ^a CO2R ^b , -COR ^a , -CO ² R ^a or -CONR ^a R ^b ; or R ² and R ²² together represent the residue of a carbocyclic or heterocyclic ring; R ² , R ² , R ²⁵ , R ²⁵ , R 26 independently represent hydrogen, hydrocarbon, heterocyclic group, halogen, cyano, trifluoromethyl, nitro, -O R ^a , -SR ^a , -SOR ^a , -SO ^{2 a} , -SO ² NR ^a R ^b , - NR ^a R ^b , -NR ^a COR ^b , + -NR ^a CO2R ^b , -COR ^a , -CO2R ^a, or -CONR ^a R ^b ; and R ^a and R ^b independently represent a hydrogen, hydrocarbon or heterocyclic group; o i oo provided that when R and R each represent hydrogen, then: (i) R ²⁴ does not mean hydrogen, methyl, chloro, hydroxy, methoxy or acetoxy when R ²³ , R ² and R ² each represent hydrogen; and (ii) R ² does not mean methyl, chloro, trifluoromethyl, hydroxy, benzoyloxy or unsubstituted straight or branched alkoxy group containing 1 to 10 carbon atoms or unbranched or branched alkoxy group containing 1 to 6 carbon atoms with at least one substituents selected from hydroxy, carbos and carbamoyl when R ²³ , R ²⁴ and R ^2b each represent hydrogen; and (iii) R ^{2 is} not methyl, phenyl, chloro or methoxy when R, R and R ^{6 are} each hydrogen; and (iv) R ^{2 is} not chloro when R ²³ and R ^{24 are} each hydrogen? 4 and R is methoxy or when R and R are each hydrogen and R is chloro; and (v) R ^{2 is} not chloro when R ²³ and R ^{2 are} each hydrogen and R ^{24 is} chloro or when R ²⁴ and R ^{25 are} each hydrogen and R ^{22 is} chloro; also provided that when one of R ^C1 and R is hydroxy or lower alkoxy and the other represents hydrogen, hydroxy or lower alkoxy and R ²³ , R ²⁴ and R ²⁶ each represent hydrogen, then R ²⁵ does not represent hydrogen or lower alkoxy; also provided that when R ^{21 is} 2'-methyl and R ^{22 is} hydrogen, then: (i) R ^{24 is} not hydrogen, chloro or methoxy when R ²³ , R ² and R ^{2 are} each hydrogen; and (ii) R ^{25 is} not chloro or methoxy when R ²³ , R ^{24 or} R ^{26 are} each hydrogen; and (iii) R ^{2 is} not chloro when R ²³ , R ²⁴ and R ^{2 are} each hydrogen; also, provided that when R ^{21 and R} 23 are each hydrogen, one of the substituents R ²⁴ , R ² and R ² is chloro and the others are hydrogen, then R is not 4'-methyl; also provided that when R is ² ^ 2'-methoxy and R ²² , R ²³ , R ² and R ^{2 are} each hydrogen, then R ^{24 is} not hydrogen, fluoro, chloro or bromo; further provided that when R ^, R ^ ³ , R ^^, R ^ and R ^ each represent hydrogen, then it does not mean 2'-fluoro, 2'-nitro, 2'-amino, 4'chloro, 4 '-hydroxy or 4'-methoxy. A compound as claimed in claim 6, characterized in that it is represented by formula IIA and its salts and prodrugs: H (IIA) in which r31 _xn r32 _neoc | _in j _sno denote Cj_g alkyl, C2-5 alkenyl, C2_g alkynyl, aryl, aryl-1 (C _θ) which al 1, aryl (C 2-5) alkeni1, aryl (C2_g) al kinil, heteroaryl (C | _g) alkyl, alkoxy Cj_g , C2-6 alkenyloxy, aryloxy, aryl 1 (C1-6) alkoxy, heteroaryloxy, C1-6 alkylthio, arylthio, arylsulfonyl, arylamino, aryl (C1-6) alky 1amino, di (cj_θ) alky 1amino, arylcarbonylamino, arylcarbonylcarbonylcarbonylcarbonylcarbonylcarbonylcarbonylcarbonylcarbonyl to which each of these groups is optionally substituted; or hydrogen, halogen, cyano, trifluoromethyl, nitro, hydroxy, amino or carboxy; or r31 and r32 together represent the residue of a carbocyclic or heterocyclic ring; r33 _xn r35 _neoc | _in i _SN are halogen, cyano, trifluoromethyl, nitro, hydroxy, amino, carboxy, Cj_ ₆₎ alkyl, C ₂ _5 alkenyl, Cj_g alkoxy, C θ alkylthio or C ₂ _7 alkoxycarbonyl; and R ³⁴ represents hydrogen or halogen. A compound as claimed in claim 6, represented by formula IIB, and salts and prodrugs thereof: (110) in which means Cj_g alkyl, C ₂ _4 alkenyl, C ₂ _g alkynyl, aryl, aryl (Cj- ₆₎ alkyl, aryl (C _{2nd 6)} alkenyl, aryl (C ₂ _g) alkynyl, heteroaryl (Cj_g) alkyl, Cj.g alkoxy, C ₂ _g alkenyloxy, aryloxy, aryl (Cj_θ) alkoxy, heteroaryloxy, Cj.g alkylthio, arylthio, arylsulphonyl, arylamino, aryl (Cj_g) alkyl 1amino, di (Cj_θ) alkyl a 1-amino, arylcarbonylamino, arylcarbonyl, heteroarylcarbonyl or C ₂ _7 alkoxycarbonyl, each of these groups may be optionally substituted; or halogen, cyano, trifluoromethyl, nitro, hydroxy, amino or carboxy; and R ⁴² is C | .G alkyl, C ₂ _g alkenyl, C ₂ .G alkynyl, aryl, aryl (Cj.g) alkyl, aryl (C ₂ _g) alkenyl, aryl (C ₂ _g) al which is not 1, heteroariHpg ) alkyl, C | _ ₆ alkoxy, C ₂ _galkeni1oksi, aryloxy, aryl (Cj.g) alkoxy, heteroaryloxy, C | _g alkylthio, arylthio, arylsulphonyl, arylamino, aryl (C | .G) alkylamino, di (Cj.g ) alkylamino, arylcarbonylamino, any of these groups may be optionally substituted; or hydrogen, halogen, cyano, trifluoromethyl, nitro, hydroxy, amino or carboxy; or R 41 and R ⁴² together represent a residue of a carbocyclic or heterocyclic ring; R ⁴³ and R ⁴⁴ independently represent hydrogen, halogen, cyano, trifluoromethyl, nitro, hydroxy, amino, carboxy, Cj_g alkyl, C ₂ _g alkenyl, Cj_ ₆ alkoxy, Cj_ ₆ alkylthio or C ₂ _y alkoxycarbonyl; and R ⁴⁵ represents hydrogen, halčogen, cyano, trifluoromethyl, nitro, hydroxy, amino, carboxy, Cj_g alkyl, C ₂ _ ₅ alkenyl, alkylthio or C ₂ _7 alkoxycarbonyl. A compound as claimed in claim 8, characterized in that it is represented by formula IIC, and salts and prodrugs thereof: H (IIC): wherein R ^3, R44 and R45 | <pp j _e defined in claim 8; X represents a portion of the formula -CH ₂ ~, -CH = CH-, -CzC-, -O-, -OCH ₂ -, -S-, -S0-, -NH-, -NHCH ₂ -, -NHCO- or -CO-; and Y represents a group of formula (i), (ii), (iii) or (IV): in which Z is oxygen, sulfur or NH; and R ^ and R ^ independently represent hydrogen, C1-6 alkyl, morpholinyl (C1-8) alkyl, hydroxy, C1-6 alkoxy, C1-8 alkoxy (C3-8) alkyl, alkoxy (C1-8) alkoxy, C1-6 alkyl. g alkylthio or di (C1-8) alkylamino; or R47j _n r48 _s k _U p _a j denote the residue of a benzene ring. A compound as claimed in claim 6, selected from: 7-chloro-4-hydroxy-3- (4-nitrophenyl) -2 (1H) -quinolone; 7-chloro-4-hydroxy-3- (4-methoxyphenyl) -2 (1H) -quinolone; 7-chloro-4-hydroxy-3- (2-nitrophenyl) -2 (1H) -quinolone; 7-chloro-4-hydroxy-3- (4-trifluoromethylphenyl) -2 (1H) -quinolone; 7-chloro-4-hydroxy-3- (3-methylphenyl) -2 (1H) -quinolone; 3- (4-benzyloxyphenyl) -7-chloro-4-hydroxy-2 (1H) -quinolone; 7-chloro-3- (4-chlorophenyl) -4-hydroxy-2 (1H) -quinolone; 7-chloro-3- (4-fluorophenyl) -4-hydroxyl-2 (1H) -nolone; 7-chloro-4-hydroxy-3- (3-methoxyphenyl) -2 (1H) -quinolone; 7-chloro-4-h and throx i-3- (3-iodophenyl) -2 (1H) -quinolone; 3- (4-bromophenyl) -7-chloro-4-h and droxy-2 (1H) -quinone; 7 - chloro-4-hirox i-3 - (3-n and trophin 1) -2 (1H) -nolone; 4-hydroxy-7-nitro-3-phenyl-2 (1H) -quinolone; 7-chloro-3- (2,5, -dimethoxyphenyl) -4-hydroxy-2 (1H) -quinolone; 3- (2-bromophenyl) -7-chloro-4-hydroxy-2 (1H) -quinoline; 3- (3-bromophenyl) -7-chloro-4-hydroxy-2 (1H) -quinolone; 7-chloro-3- (2-fluorophenyl) -4-chloroxyl-2 (1H) -quinolone; 7-chloro-3- (3-fluorophenyl) -4-hydroxy-2 (1H) -quinolone; 3- (4'-biphenyl) -7-chloro-4-hydroxy-2 (1H) -quinone; 7-chloro-3- (4-dimethylaminophenyl) -4-hydroxy-2 (1H) -quinolone; 7-chloro-3- (2-chlorophenyl) -4-hydroxy-2 (1H) -quinolone), 7-chloro-4-hydroxy-3- (2-methoxyphenyl) -2 (1H) -quinolone; 7-chloro-4-hydroxy-3- (2-phenoxyphenyl) -2 (1H) -quinolone; 7 - chloro-4-h and drox i-3- (2-naphthyl) -2 (1H) -quinoline; 7 - chloro-4-h and drox i-3- (1-naphthyl and 1) -2 (1H) -quinoline; 3- (3-benzyloxyphenyl) -7-chloro-4-hydroxy-2 (1H) -quinolone; 7-chloro-3- (3-chlorophenyl) -4-hydroxy-2 (H) -quinolone; 7 - chloro-4-hydroxy-3- (3-phenoxyphenyl) -2 (1H) -quinolone; 7-chloro-4-hydroxy-3- (4-phenoxyphenyl) -2 (1H) -quinolone; 7-chloro-5-ethyl-4-hydroxy-3-phenyl-2 (1H) -quinolone; 7-chloro-4-hydroxy-3-t3- (2-phenylethynyl) phenyl 1-2 (1H) -quinol 7-chloro-4-hydroxy-5-iodo-3-phenyl-2 (1H) -quinol he; 7-chloro-4-hydroxy-3- (3,4-methylenedi ox and phenyl) -2 (1H) -quinoline 7-chloro-4-hydroxy-3-phenyl-5-vinyl-2 (1H ) -quinol on; 7-chloro-4-hydroxy-3- (4-iodophenyl) -2 (1H) -quinolone; 7-chloro-3- (3,5-dimethylphenyl) -4-hydroxy-2 (1H) -quinolone; 7-chloro-5-ethyl-4-hydroxy-3- (3-phenoxyphenyl) -2 (1H) -quinolone; 4-hydroxy-7-methyl-3- (3-phenoxyphenyl) -2 (1H) -quinolone; 7-chloro-4-hydroxy-3- (3-phenylcarbonylphenyl) -2 (1H) -quinone; 7-chloro-4-hydroxy-3- [3- (3-thienylcarbonyl) phenyl 11-2 (1H) -quinoline; 7-chloro-3- [3- (3-fluoro 1 carbonyl) phenyl 1-4-hydroxy-2 (1H) -quinolone; 7-chloro-4-hydroxy-3-1 3- (1-pyrrolylmethyl) phenyl 1 1-2 (1H) -quinolone; 7-chloro-4-hydroxy-3-13- (1-indolimethyl) phenyl 1-2 (1H) -quinolone; 7-chloro-4-hydroxy-3- [3- (3-membered 1) phenyl 11-2 (1H) -quinone; 7-chloro-4-hydroxy-3- [3- (4-methoxymethylbenzyl) phenyl] -2 (1H) -quinolone; 3- (3-benzylphenyl) -1-chloro-4-hydroxy-2 (1H) -quinolone; 7-chloro-4-hydroxy -3- (3- (4-methyl-thiobenzyl) phenyl] -2 (1H) -quinoline; 7-chloro-4-hydroxy-3- [3- (4-methoxymethoxybenzyl) phenyl 1-2 (1H) -quinolone; 7-chloro-4-hydroxy-3- [3- (4-hydroxybenzyl) phenyl] -2 (1H) -quinone; 7-chloro-4-hydroxy-3- (3- [4- (2-morpholin-1-ylethyl) benzyl]] phenyl 11-2 (1H) quinolone; 7-chloro-4-hydroxy-3- [4- (2-phenyl-cis-ethenyl) phenyl} -2 (1H) -quinolone; 7-chloro-4-hydroxy-3- (3- (2-phenyl-trans-ethenyl) phenyl 1-2 (1H) -quinolone; 7-chloro-4-hydroxy-3- [3- (2-phenyl- cis-ethenyl) phenyl] -2 (1H) -quinol one; 7-chloro-4-hydroxy-3- [3- (3-indolinomethyl) phenyl] -2 (1H) -quinolone; 7-bromo-4-hydroxy-3-phenyl-2 (1H) -quinolone; 7- chloro-4-hydroxy-3 -1 3- (2-pyridoxy) phenyl 1 -2-(1H) -quinone; 7-chloro-4-hydroxy-3- [3- (3-thienyloxy) phenyl] -2 (1H) -quinolone; 7-chloro-3- [3- (3-fluoroxy) phenyl 1-4-hydroxy-2 (1H) -quinolone; 7-chloro-4-hydroxy-3- (3-phenylaminophenyl) -2 (1H) -quinolone; 7-chloro-3- (3- (2-dimethylaminophenoxy) phenyl] -4-hydroxy-2 (1H) -quinolone; 7-chloro-4-hydroxy-3- [3- (4-methoxybenzyl) phenyl] -2 (1H) -quinolone; 7-chloro-4-hydroxy-3- [3- (3-methoxyphenoxy) phenyl-2 (1H) -quinolone; 7-chloro-4-hydroxy-3- [3- (2-methoxyphenoxy) phenyl-2 (1H) -quinolone; 7-chloro-4-hydroxy-3- [3- (2-methylphenoxy) phenyl] -2 (1H) -quinolone; 3- (3'-biphenyl) -7-chloro-4-hydroxy-2 (1H) -quinolone; 7-chloro-4-hydroxy-3- (3-phenylthiophenyl) -2 (1H) -quinolone; 7-chloro-4-hydroxy-3- (3-phenylsulfonylphenyl) -2 (1H) -quinolone; 7-chloro-4-hydroxy i-3- (3-phenylcarbonylaminophenyl) -2 (1H) -quinoline; 3- (3-benzylaminophenyl) -7-chloro-4-chloro-ix-2 (1H) -quinolone; 7-chloro-4-hydroxy-3- [3- (2-propenyloxy) phenyl] -2 (1H) -quinolone; 7-chloro-4-h-hydroxy-3- [3- (2-methyl-2-propenyloxy) phenyl] -2 (1H) -quinolone 7-chloro-3- (2,5-dimethoxyphenyl) -4-h-hydroxy-2 (1H) -quinoline; 7-chloro-3- (4-ethoxyphenyl) -4-hydroxy-2 (1H) -quinolone; 7-chloro-4-hydroxy-3-13- (4-methoxyphenoxy) phenyl1-2 (1H) -quinolone; 7-chloro-4-hydroxy-3-13- (4-methylphenoxy) phenyl 11-2 (1H) -quinoline; as specified in and their salts and prodrugs. A process for the preparation of a compound of formula I, claim 1, comprising: (A) cyclization of a compound of formula III: (HI) in which R ^, R ^, R ^, R ^, R $ and R ^ as defined represents a reactive carboxylate group; or (B) cyclization of a compound of formula VI: claim 1; and (p (VI) wherein R ^, R ^, R ^, R ^, R ^ and R® are as defined by claim 1; and Q represents a reactive carboxylate group; or (C) cyclization of a compound of formula VII: in which R ^, R ² , R ³ , R ⁴ , r 5 and R ⁴ as defined in claim 1; and (D) where appropriate, the conversion of a compound of formula I obtained initially to a further compound of formula I, using methods known per se.