MXPA00012155A - Tetrahydroquinoline derivatives as glycine antagonists - Google Patents

Abstract

Compounds of formula (I), or a salt or a non toxic metabolically labile esters thereof, wherein Y represents a carbon atom;Z is the group CH which is linked to the group Y via a double bond and X is CH or Z is methylene or NR11 and X is a carbon atom linked to the group Y via a double bond;A represents a C1-2alkylene chain and which chain may be substituted by one or two groups selected from C1-6alkyl optionally substituted by hydroxy, amino, C1-4alkyl amino or C1-4dialkyl amino or which chain may be substituted by the group=0;R represents a halogen atom or C1-4alkyl group;R1 represents a hydrogen, a halogen atom or C1-4alkyl group;R2 represents optionally substituted phenyl, a 5 membered heteroaryl group containing 1 to 3 heteroatoms selected from oxygen, sulphur and nitrogen or 6 membered heteroaryl group containing 1 to 3 nitrogen atoms, processes for their preparation and their use as glycine antagonists.

Description

DERIVATIVES OF TETRAHYDROQUINOLINE AS ANTAGONISTS OF GLYCINE This invention relates to 1, 2, 3, 4 tetrahydroquinoline derivatives, to processes for their preparation, to pharmaceutical compositions containing them and to their use in medicine. In particular, it refers to 1, 2, 3, 4 tetrahydroquinoline derivatives which are potent and specific excitatory amino acid antagonists. Caring et al., Bioorganic and Medicinal Chemistry Letters, Vol. 13 pp. 65-70, 1993 teaches 2-carboxy tetrahydroquinolines 4-subsitutes that have good affinity in vitro towards the glycine modulator site of the NMDA receptor complex but in the best case it is only weak in its activity in vivo. More particularly, it teaches that such derivatives substituted at the 4-position by the group CH2C02H or CH2CONHPh have little or no activity in vivo when administered systemically (ip). 'WO 97/12870 and WO 98/07704 describe 2-carboxy-tetrahydroquinoline derivatives 4-substituted ones which not only have a good in vitro affinity towards the binding site of REF..125689 strychnine-insensitive glycine, associated with the NMDA receptor complex but also have good in vitro activity when administered intravenously (iv ). A new group of 4-substituted 2-carboxy tetrahydroquinolines has now been discovered, which has a particularly useful profile of activity as selective antagonists towards the strychnine-insensitive glycine binding site with the NMDA receptor complex. Accordingly, the present invention provides a compound of the formula (I) 0) or a labile or stable metabolically non-toxic salt or esters thereof, wherein Y represents a carbon atom; Z is the CH group which is attached to the group Y by means of a double bond and X is CH or Z is methylene or NRn and X is a carbon atom attached to the group Y by means of a double bond; A represents an alkylene chain with 1 to 2 carbon atoms and which may be substituted by one or two groups selected from alkyl having 1 to 6 carbon atoms optionally substituted by hydroxy, amino, C? -alkylamino or C-1 -4-dialkyl amino or such a chain may be substituted by the group = 0; R represents a halogen atom or an alkyl group with 1 to 4 carbon atoms; Ri represents a hydrogen, a halogen atom or an alkyl group with 1 to 4 carbon atoms; R2 represents phenyl which can be substituted with up to 3 groups selected from halogen, hydrogen, or (CH2) nR3 wherein R3 is C0R4, NR6R5, NHCOR7, NHC0R9R8 or the group NH S02 R10 or R2 is a heteroaryl group of 5 elements which contains 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen; or a 6-membered heteroaryl group containing 1 to 3 nitrogen atoms R4 represents an amino, a hydroxyl or an alkoxy group with C1-4 or Rj, and Re each independently represents hydrogen or an alkyl group with C? -4 or Rs and RT together with the nitrogen atom to which they are attached represents a saturated 5-7 element heterocyclic group, optionally containing an additional heteroatom selected from oxygen, sulfur or nitrogen R7 represents a hydrogen atom or alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, or phenyl; R8 represents hydrogen or an alkyl group with 1 to 4 carbon atoms; R9 represents hydrogen, optionally substituted alkyl with 1 to 4 carbon atoms (optionally substituted by one or more hydroxy carboxyl and amino groups), phenyl; Rn represents hydrogen or an alkyl group with 1 to 4 carbon atoms; Rio represents hydrogen, alkyl having 1 to 4 carbon atoms or a nitrogen protecting group, n is zero or an integer from 1 to 2; A further embodiment of the invention provides the compounds of the formula (I) or a salt or the metabolically non-toxic labile or stable esters thereof, wherein Y represents a carbon atom; Z is the CH group which is linked to the group by means of a double bond and X is CH or Z is methylene or NR and X is a carbon atom attached to the group Y by means of a double bond; A represents an alkylene chain having 1 to 2 carbon atoms and such a chain can be substituted by one or two groups selected from alkyl having 1 to 6 carbon atoms optionally substituted by hydroxy, amino, C? -alkylamino or C-? _4 dialkyl amino or such a chain may be substituted by the group = 0; R represents a halogen atom; Ri represents a hydrogen, or a halogen atom; R2 represents phenyl which may be substituted with up to 3 groups selected from halogen, hydrogen, or (CH2) nR3 wherein R3 is C0R4, NR6Rs, NHCOR7, NHCORgRs or the NH group S02 R10 or R2 is a heteroaryl group of 5 elements which contains 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen; or a heteroaryl group of 6 elements containing 1 to 3 nitrogen atoms R 4 represents an amino, or a hydroxyl; R5 and Re each independently represents hydrogen or an alkyl group with 1 to 4 carbon atoms or R5 and Re together with the nitrogen atom to which they are attached represents a saturated 5-7 element heterocyclic group, optionally containing a additional heteroatom selected from oxygen, sulfur or nitrogen R7 represents a hydrogen atom or alkyl having 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, or phenyl; R8 represents hydrogen or an alkyl group with 1 to 4 carbon atoms; Rg represents hydrogen, alkyl having 1 to 4 carbon atoms optionally substituted (optionally substituted by one or more hydroxy carboxyl and amino groups), phenyl; Rn represents hydrogen or an alkyl group with 1 to 4 carbon atoms; Rio represents hydrogen, alkyl having 1 to 4 carbon atoms or a nitrogen protecting group, n is zero or an integer from 1 to 2 with the proviso that when X is a carbon atom attached to the group Y by means of a double bond, then Rx is hydrogen; For use in medicine, the salts of the compounds of the formula (I) will be pharmaceutically acceptable thereof. Other salts, however, may be useful in the preparation of the compounds of the formula (I) or the physiologically acceptable salts thereof. Therefore, unless stated otherwise, references to salts include both physiologically acceptable salts and physiologically unacceptable salts of the compounds of formula (I). Suitable physiologically acceptable salts of the compounds of the invention include the basic addition salts and, where appropriate, the acid addition salts. Suitable physiologically acceptable basic addition salts of the compounds of the formula (I) include alkali metal salts or alkali metal salts such as the potassium, calcium, magnesium and ammonium salts formed with the amino acids (eg lysine and arginine) and organic bases (for example procaine, phenylbenzylamine, ethanolamine, diethanolamine and N-methyl glucosamine). The compounds of the formula (I) and / or the salts thereof can form solvates (for example hydrates) and the invention includes such solvates. The term "halogen" refers to a fluorine, chlorine, bromine or iodine atom. The term alkyl having 1 to 4 carbon atoms when used herein, as a group or a part of a group, refers to a straight or branched chain alkyl group containing from 1 to 4 carbon atoms, examples of such Groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, secondary butyl or tertiary butyl. When R2 is a 5- or 6-membered heteroaryl group, it may be for example furanyl, thiophenyl, imidazolyl, thiazolyl, oxazolyl, pyridyl or pyrimidinyl. When R5 and Re together with the nitrogen atom to which they are attached form a saturated 5-7 element heterocyclic group, optionally containing an additional heteroatom selected from oxygen, sulfur or nitrogen, this may be morpholino, 2.6 dimethylmorpholino, thio orfolino, piperidino, pyrrolidino, piperazino or N-methylpiperazino.

When R is a substituted phenyl group it is conveniently a substituted phenyl group. The substituent is conveniently in the meta position or more conveniently in the para position. When X-Y represents a double bond, the compounds of the formula (I) possess at least one asymmetric carbon atom (especially the carbon atom occupying position 2 of the ring system of 1)., 2, 3, 4 tetrahydroquinoline) and other asymmetric carbon atoms are possible in the R2 group. It is to be understood that all enantiomers and diastereomers and mixtures thereof are encompassed within the scope of the present invention. When XY represents a single bond, the compounds of the formula (I) possess at least two asymmetric carbon atoms (especially the carbon atom occupying positions 2 and 4 of the 1, 2, 3, 4 tetrahydroquinoline ring system) and these can be represented by the formulas (la, Ib, le and Id). The bond with a solid wedge shape indicates that the bond is above the plane of the paper and is referred to as the ß configuration. The interrupted line indicates that the link is below the plane of the paper and is referred to as the configuration a. In addition other asymmetric carbon atoms are possible in the R2 groups. It is to be understood that all enantiomers and diastereomers and mixtures thereof are encompassed within the scope of the present invention. The metabolically non-toxic labile esters of the formula (I) are the esters of the compounds of the formula (I) which are hydrolyzed in vivo to give the compound of the formula I and a physiologically acceptable alcohol. The metabolically non-toxic esters of the compound of the formula (I) can be formed by esterification, for example of any of the carboxylic acid groups in the original compound of the general formula (I) with, where appropriate, pre-protection from any other reactive groups present in the molecule, followed by deprotection if required. Examples of such metabolically labile esters include alkyl esters with 1 to 4 carbon atoms, for example methyl or ethyl esters, substituted or unsubstituted aminoalkyl esters (for example aminoethyl, 2- (N, N-diethylamino) ethyl), or esters of '2-4-morpholino) ethyl or acyloxyalkyl esters such as acyloxymethyl or 1-acyloxyethyl for example pivaloyloxymethyl, 1-pivaloyloxyethyl, acetoxymethyl, 1-acetoxyethyl, 1- (1-methoxy-1-methyl) ) ethylcarbonyloxyethyl, 1-benzoyloxyethyl, isopropoxycarbonyloxymethyl, 1-isopropoxycarbonyloxyethyl, cyclohexylcarbonyloxymethyl, 1-cyclohexylcarbonyloxyethyl ester, cyclohexyloxycarbonyloxymethyl, 1-cyclohexyloxycarbonyloxyethyl, 1- (4-tetrahydropyranyloxy) carbonyloxyethyl or 1- (4-tetrahydropyranyl) carbonyloxyethyl. The group R is conveniently chlorine. The group Ri is conveniently a hydrogen atom or a chlorine atom. A preferred class of the compounds of the formula (I) is that wherein R is chlorine and Ri is a hydrogen or a chlorine atom. A further preferred class of the compounds of the formula (I) is that wherein R is chlorine and Ri is a hydrogen atom. When XY is a single bond, a preferred class of the compounds of the formula (I) is that in which the carbon atom in the 4-position is the β-configuration and the carbon atom in the 2-position is in the configuration a (la) and that in which the carbon atom in position 4 is the configuration a and the carbon atom in position 2 is in the configuration ß (le). When A is an optionally substituted 1 to 2 carbon substituted alkylene chain, it may be, for example, methylene, ethylene or C = 0. A preferred class of the compounds of the formula (I) includes those wherein A is a chain selected from - (CH2-, - (CH2) 2-, C = 0. When Z is a group NRn this is conveniently the NH group A preferred class of the compounds of the formula (I) includes those wherein Z is CH which is attached to the group Y by means of a double bond, a methylene or an NH group When R2 is an optionally substituted phenyl group, this is conveniently phenyl substituted by a single substituent selected from (CH2) nNR6R5 in which R5 is hydrogen and R6 is hydrogen, alkyl with 1 to 4 carbon atoms (for example methyl, ethyl) or NR6R5 represents a saturated 6-element ring containing oxygen, for example morpholino; (CH) nNHCOR7 wherein R7 is hydrogen, alkyl for example methyl, isopropyl, isobutyl, phenyl; (CH2) nNHCONHR9 wherein R9 is hydrogen; (CH2) nNH S02 Rio in which Rio is alkyl for example methyl, n is zero or an integer from 1 to 2; Examples of such R2 groups include phenyl (optionally substituted by amino, t-butoxycarbonylamino, acetylamino or methanesulphonylamino). When R2 is substituted phenyl, the substituents are conveniently in the meta position or more preferably in the para position. When R2 is a 5- or 6-membered heteroaryl group as defined above, it is conveniently pyridyl for example 3-pyridyl. A preferred class of the compounds of the formula (I) is that wherein R2 represents phenyl (optionally substituted by acetylamino, ethanesulfonylamino) or 3-pyridyl. Particularly preferred within this class are those in which R2 is phenyl. A further preferred class of the compounds of the formula (I) is that wherein X is a carbon atom attached to the group Y by means of a double bond.

A preferred group of the compounds of the formula (I) is that wherein A is a chain selected from -CH2- or - (CH2) 2-, Z is a CH group which is attached to the group Y by means of a double bond or a methylene group, or A is the chain CO and Z is an NH group, R is chlorine, Ri is chlorine or hydrogen and R2 is phenyl (optionally substituted by acetylamino or methanesul fonilamino) or 3-pyridyl. Preferred specific compounds of the invention include: Acid. { +) 7-chloro-4- (2-oxo-l-phenyl-3-pyrrolidinylidene) -1,2,3,4-tetrahydro-2-quinoline carboxylic acid, (+ _) 7-chloro-4- (l) -phenyl-? 3-pyrrolin-2-one-3-yl) -1,2,3,4-tetrahydro-2-quinoline carboxylic acid and the physiologically acceptable salts (for example the sodium salt the metabolically non-toxic labile esters or the enantiomers thereof. [+ _) 7-chloro-4- (2-oxo-l-phenyl-3-pyrrolidinylidene) -1,2,4,4-tetrahydro-2-quinoline carboxylate of (-) - sodium (L) 7-Chloro-4- (1-phenyl-3-pyrrolin-2-one-3-yl) -1,2,3,4-tetrahydroquinoline carboxylic acid (-) -sodium. (+) 7-Chloro-4- (1-phenyl-3-pyrrolin-2-one-3-yl) -1,2,3,4-tetrahydroquinoline-2-carboxylate of (+) sodium.

Additional preferred specific compounds of the invention include: (+) - 7-Chloro-4- (1- (3-pyridin) -? 3-pyrrolin-2-one-3-yl) -1,2,3, 4- tetrahydroquinoline-2-carboxylic acid, (+ _) -7-chloro-4- (l-phenyl-3-5,6-dihydro-pyridin-2-one-3-yl) -1,2,3,4-tetrahydroquinoline- 2-carboxylic, Acid (+ _) -5,7-dichloro-4- (l-phenyl-? 3-pyrrolin-2-one-3-yl) -1,2,4,4-tetrahydroquinoline-2-carboxylic acid (+ / -) - 7-chloro-4- (l- (4-acetylamino) -1-phenyl-? 3-pyrrolin-2-one-3-yl) -1,2,3,4-tetrahydroquinoline-2-carboxylic acid (+ / -) 7-Chloro-4- (1- (4-methanesulfonylamino) -1-phenyl-3-pyrrolin-2-one-3-yl) -1,2,3,4-tetrahydroquinoline-2-carboxylic acid , Acid (+/-) -7-chloro-4- (2-oxo-l-phenyl-3-piperidinylidene) -1, 2, 3, 4-tetrahydro-2-quinolinecarboxylic acid, Acid (+ _) -7- chloro-4- (2, 5-dioxo-l-phenyl-imidazolidin-4-ylidene)) -1,2,3,4-tetrahydro-2-quinolinecarboxylic acid. (+) - 7-chloro-4- (2-oxo-l- (pyridin-3-yl) -pyrrolidin-3-ylidene) -1,2,3,4-tetrahydro-2-quinolinecarboxylate. (+ _) -7-Chloro-4- (2-oxo-l- (4-acetylamino) phenyl-pyrrolidin-3-ylidene) -1,2,3,4-tetrahydro-2-quinolinecarboxylic acid.

Acid A) 7-chloro-4- (2-oxo-l- ((4-methanesulfonyl amino) phenyl-pyrrolidin-3-ylidene) -1,2,3,4-tetrahydro-2-quinolinecarboxylic acid 5.7 -dichloro-4- (2-oxo-l- (phenyl) -pyrrolidin-3-ylidene) -1, 2, 3, 4-tetrahydro-2-quinoline carboxylic acid (enantiomer A); 5,7-dichloro-4 acid - (2-oxo-l- (phenyl) -? 3-pyrrolin-2-one-3-yl) -1,2,4,4-tetrahydro-2-quinoline-2-carboxylic acid (enantiomer A); and the physiologically acceptable salts (for example sodium salts), metabolically non-toxic labile esters or enantiomers thereof. The compounds of the formula (I) and / or the physiologically acceptable salts thereof are antagonists of excitatory amino acids. More particularly they are potent antagonists at the strychnine-insensitive glycine binding site associated with the NMDA receptor complex. As such they are potent antagonists of the NMDA receptor complex. These compounds are therefore useful in the treatment or prevention of neurotoxic damage or neurodegenerative diseases. Accordingly, the compounds are useful for the treatment of neurotoxic lesions which follow the shock or cerebral attack, trojaboembolic attack, hemorrhagic attack, cerebral ischemia, cerebral vasospasm, hypoglycemia, amnesia, hypoxia, anoxia, cardiac arrest by perinatal asphyxia. The compounds are useful in the treatment of chronic neurodegenerative diseases such as: Huntingdon's disease, senile dementia of Alzheimer's, amyotrophic lateral sclerosis, types of glutaric acidemia, dementia by multi-infarcts, status epilepticus, contusive lesions (for example, spinal injuries) vertebral and head injuries), neurodegeneration induced by viral infection (eg AIDS, encephalopathies), Down syndrome, ocular neurodegeneration (eg glaucoma), epilepsy, schizophrenia, depression, migraine, headaches, including severe headaches and / or head pain due to tension, anxiety, pain (for example, inflammatory pain and neuropathic pain), neurogenic bladder, vomiting, irritable bladder disorders, drug dependence, including withdrawal symptoms of alcohol, cocaine, substances of opium, nicotine (for example quit smoking) benzodiazepines, inhibition of induced tolerance by opioids (ie morphine).The potent and selective action of the compound of the invention at the strychnine-insensitive glycine binding site present on the NMDA receptor complex can be easily determined using conventional test methods. Therefore the binding capacity at the strychnine-insensitive glycine binding site was determined using the procedure of Kishimoto H et al., J Neuroche. 1981, 37, 1015-1024. The selectivity of the action of the compounds of the invention for the strychnine-insensitive glycine site was confirmed in studies in other known ionotropic excitatory amino acid receptors. Accordingly, the compounds of the invention are found to exhibit a small affinity or no affinity for the alanic acid receptor (kainate), the a-amino-3-hydroxy-5-methyl-4-isoxazole-proprionic acid (AMPA) receptor. ) or at the NMDA binding site. The compounds of the invention can be found to inhibit NMDA-induced seizures in mice using the method of Chia ulera C et al., Psychopharmacology (1990), 102, 551-552.

The neuroprotective activity of the compounds of the invention can be demonstrated in the preparation of the occlusion of the intermediate cerebral artery in mice, using the procedure described by Chiamulera C. et al., European Journal of Pharmacology, 216 (1992) p. 335-336. The ability of the compounds of the invention to alleviate nicotine withdrawal symptoms following cessation of smoking can be demonstrated in conventional tests for nicotine-induced relapse using the procedure described in C. Chiamulera et al., Arch. Pharmacol., 358, 1998. The invention therefore provides the use of a compound of the formula (I) and / or the physiologically acceptable salts or the metabolically labile, non-toxic esters thereof for use in the Therapy and in particular the use as a medicine to antagonize the effects of the excitatory amino acids on the NMDA receptor complex. The ability of the compounds of the invention to inhibit pain can be demonstrated in conventional analgesic screening or analysis such as those described by Dibuisson and Dennis, Pain, 1977, 4: 161-174, J.j. Bennett and J.K Xue, Pain, 1988, 41, 87-107. The invention also provides the use of a compound of the formula (I) and / or the physiologically acceptable salt or the metabolically non-toxic labile esters thereof, for the manufacture of a medicament for antagonizing the effects of the excitatory amino acids on the complex of the NMDA receptor. According to a further aspect, the invention also provides a method for antagonizing the effects of excitatory amino acids on the NMDA receptor complex, which comprises administering to a patient in need thereof, an antagonist amount of a compound of the invention. formula (I) and / or a pharmaceutically acceptable salt thereof. It will be appreciated by those skilled in the art that the reference herein to treatment extends to prophylaxis as well as treatment of established diseases or symptoms. It will further be appreciated that the amount of a compound of the invention required for use in the treatment will vary with the nature of the condition being treated, the route of administration and the age and condition of the patient and will ultimately be at the discretion of the physician. that provides the attention.

However, in general the doses employed for the treatment of an adult human will typically be in the range of 2 to 800 mg per day, depending on the route of administration. Accordingly for parenteral administration a daily dose will typically be in the range of 20-100 mg, preferably 60-80 mg per day. For oral administration, a daily dose will typically be within the range of 200-800 mg, for example 400-600 mg per day. The desired dose can be conveniently presented in a single dose or as divided doses administered at appropriate intervals, for example as two, three, four or more sub-doses per day. Although it is possible that, for use in therapy, a compound of the invention can be administered as the raw material, it is preferable to present the active ingredient as a pharmaceutical formulation. The invention thus further provides a pharmaceutical formulation comprising a compound of the formula (I) or a pharmaceutically acceptable salt or metabolically labile, non-toxic esters thereof, together with one or more pharmaceutically acceptable carriers thereof and optionally , other therapeutic and / or prophylactic ingredients. The vehicle (s) must be "acceptable" in the sense that they are compatible with the other ingredients of the formulation and not harmful to the recipient thereof. The compositions of the invention include those in a form especially formulated for oral, buccal, parenteral, inhlation or insufflation, implant or rectal administration. Tablets and capsules for oral administration may contain conventional excipients such as binding agents, for example, syrup, acacia, gelatin, sorbitol, tragacanth, starch mucilage or polyvinylpyrrolidone, fillers, for example, lactose, sugar, microcrystalline cellulose, starch. corn, calcium phosphate or sorbitol; lubricants, for example, magnesium stearate, stearic acid, talc, polyethylene glycol or silica; disintegrants, for example, potato starch or sodium starch glycolate, or wetting agents such as sodium lauryl sulfate. The tablets can be coated according to methods well known in the art. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example, sorbitol syrup, methyl cellulose, sugar syrup / glucose, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminum stearate gel or hydrogenated edible fats, emulsifying agents, example, lecithin, sorbitan or acacia mono-oleate, non-aqueous vehicles (which may include edible oils), for example, almond oil, fractionated coconut oil, oily esters, propylene glycol or ethyl alcohol; solubilizers such as surfactants for example polysorbates or other agents such as cyclodextrins; and preservatives, for example, methyl b-propyl p-hydroxybenzoates or ascorbic acid. The compositions can also be formulated as suppositories, for example containing conventional suppository bases such as cocoa butter or other glycerides. For buccal administration, the composition can take the form of tablets or lozenges formulated in a conventional manner. The composition according to the invention can be formulated for parenteral administration by continuous injection or infusion. Formulations for injection may be presented in the unit dosage form in ampoules, or in multiple dose containers with an added condom. The composition may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents. Alternatively, the ingredient may be in the form of powder for constitution with a suitable vehicle, eg, pyrogen-free, sterile water, before use. For administration by inhalation the compounds according to the invention are conveniently supplied in the form of a presentation of aerosol spray solution from pressurized containers, with the use of a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichloro-tetrafluoroethane, carbon dioxide or other suitable propellants, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gases, or from a nebulizer. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to supply a metered amount. Alternatively, for administration by inhalation or insufflation, the compounds according to the invention may take the form of a dry powder composition, for example a powder mixture of the compound and a suitable carrier such as lactose or starch. The powder composition can be presented in the unit dosage form in, for example, capsules or cartridges for example of gelatin, or packets of vesicles from which the powder can be administered with the aid of an inhaler or insufflator. The composition according to the invention can also be formulated as a tank preparation. Such long-term formulations can be administered by implant (for example subcutaneously or intramuscularly) or by intramuscular injection. Accordingly, for example, the compounds of the invention can be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins., or as sparingly soluble derivatives, for example, as a sparingly soluble salt. The compositions according to the invention may contain between 0.1-99% of the active ingredient, conveniently from '30-95% for tablets and capsules and 3-50% for liquid preparations. The compounds of the general formula (I), the enantiomers and the salts thereof, can be prepared by the general methods described hereinafter. In the following description, the groups R, Ri, R2, A, Z, X and Y are as defined for the compounds of the formula (I) unless stated otherwise. The compounds of the formula (I) and the enantiomers thereof can be prepared by the cyclization of a compound of the formula (II) in which R 2 is a carboxylic protecting group, R 3 represents a bromine atom or of iodine, Ri4 represents hydrogen a protective group of the removal of one or more protective groups. In one embodiment of this process, the reaction can be carried out using a catalytic amount of a Palladium (O) complex such as tetrakis (triphenylphosphine) palladium and a suitable organic base such as trialkylamine, for example triethylamine or an inorganic base, for example potassium carbonate. The reaction is conveniently carried out in an aprotic polar solvent such as acetonitrile, dimethylformamide, or in an apolar aprotic solvent such as a hydrocarbon (ie toluene, xylene, hexane) at a temperature in the range of 60 ° C to 150 °. C followed, where necessary or desirable, by the subsequent removal of the carboxyl protecting group Ri2 and any protecting group R14. In a further embodiment of the process, the reaction is carried out using a catalytic amount of a Pd (II) salt such as palladium acetate or palladium dichloride in the presence of a suitable organic base such as trialkyl amine e.g. triethylamine and of a triarylphosphine such as triphenylphosphine. The reaction is carried out in an aprotic solvent such as acetonitrile or dimethylformamide and preferably with heating followed, where necessary or desirable, by the subsequent removal of the carboxyl protecting group Ri2 and any nitrogen protecting group R? 4. The compounds of the formula (I) wherein XY is a double bond can be prepared regioselectively by carrying out the cyclization reaction in an apolar aprotic solvent such as toluene in the presence of a catalytic amount of a Palladium (O) complex as tetrakis (triphenylphosphine) palladium and a suitable organic base such as a trialkylamine for example triethylamine or an inorganic base, for example potassium carbonate. Compounds of the formula (I) wherein XY is a single bond can be prepared by carrying out the cyclization reaction in a polar aprotic solvent (such as acetonitrile, dimethylformamide) in the presence of a catalytic amount of a Pd salt ( II) such as: palladium acetate or palladium dichloride in the presence of a suitable organic base such as a trialkyl amine for example triethylamine and a triarylphosphine such as triphenylphosphine. Suitable carboxyl protecting groups R 2 for use in this reaction include alkyl, such as ethyl, trichloroalkyl, trialkylsilylalkyl, or arylmethyl groups such as benzyl, nitrobenzyl or trifly. Suitable additional carboxyl protecting groups are those which have a chiral group derived from chiral alcohols such as (+) -S-indanol, (+) -S-methyl mandelate, (C? -) chiral alkyl lactate: ie (+) - R- or (-) -S-methyl lactate, (+) - Rt-butyl lactate, (+) - R- or (-) - S-ethyl lactate, (-) lactate ) -S-isopropyl, (-) -S-butyl lactate, (+) - R-isobutyl lactate or chiral aralkyl lactate (ie benzyl lactate), (-) -S-phenyl alcohol, propionate (-) -methyl- (R) -3-hydroxy-2-methyl, (-) - (R) -2-butanol, (-) - (S) -2-methyl-1-butanol. Ri2 is preferably an ethyl, a benzyl group or a group derived from an alkyl lactate alcohol with chiral (C? 4) for example (+) - (R) -t-butyl lactate, (-) - lactate S-butyl, lactate alcohol of (+) - R-isobutyl). When Ri4 is nitrogen, examples of protection of suitable groups include alkoxycarbonyl for example t-butoxycarbonyl, arylsul fonyl for example phenylsulfonyl or 2-trimethylsilyl ethoxymethyl. The compounds of the formula (II) can be prepared from the compound of the formula (III) in which R12 is a carboxyl protecting group and R14 is hydrogen or a nitrogen protecting group as defined in the formula (II) and R13 represents a bromine or iodine atom. ttll} by reaction with an appropriate phosphorus reagent capable of converting the CHO group to the group followed, where necessary or desired, by the removal of the carboxyl protecting group Ri2 and the nitrogen protecting group R13. In one embodiment of this process the reaction can be carried out using a phosphide ylide of the formula (IV) (IV) wherein R15 is an alkyl or phenyl group. The reaction is carried out in an aprotic solvent such as acetonitrile or dimethylformamide at a temperature ranging from -20 ° C to the reflux temperature of the solvent. The compounds of formula (III) and (IV) are either known compounds or can be prepared by methods analogous to those used for known compounds. A convenient method for the preparation of the compounds of the formula (III) is to react the compound of the formula (V) in which R12 is a carboxyl protecting group and Ri4 is hydrogen or a nitrogen protecting group as defined in Formula (II) and R13 represents a bromine or iodine atom with an alkyltin trihalide (VI) followed by the ozonation reaction (Vi) The reaction is conveniently carried out in a solvent such as a hydrocarbon, for example toluene or a halogenated hydrocarbon (for example dichloromethane at a temperature ranging from -78 ° C to room temperature). The ozonation can be carried out by passing a stream of ozone to a solution in the presence of dimethyl sulfide or triphenylphosphine in a suitable solvent such as a halohydrocarbon (for example dichloromethane) at a low temperature for example -78 ° C. The alternative compounds (III) can be prepared by the aldol reaction of the imino compound (V), with the enol ether (VII), wherein Ri6 is an alkyl group with C? _4.

The reaction can be carried out in a solvent such as methylene chloride or acetonitrile in the presence of a Lewis acid such as ytterbium triflate. In any of the above reactions, the carboxyl protecting group can be removed by conventional known methods to remove such groups. Accordingly the compounds wherein Ri2 is a benzyl, ethyl or lactate group of (+) - (R) - or (-) -St-butyl can be removed by hydrolysis using an alkali metal hydroxide, for example lithium hydroxide or sodium hydroxide in a suitable solvent such as ethanol or isopropanol, water or mixtures thereof, followed, where desirable or necessary, by some addition of a suitable acid for example hydrochloric acid to give the corresponding free carboxylic acid. In any of the above reactions the nitrogen protecting group can be removed by known conventional methods to remove such groups, for example by acid or basic hydrolysis. Accordingly, when Ri 4 is alkoxycarbonyl for example t-butoxycarbonyl or phenylsulfonyl, it can be removed by alkaline hydrolysis using for example lithium hydroxide in a suitable solvent such as tetrahydrofuran or an alkanol for example isopropanol. Alternatively, the alkoxycarbonyl group can be removed by acid hydrolysis.

The physiologically acceptable salts of the compounds of the formula (I) can be prepared by treating the corresponding acid with an appropriate base in a suitable solvent. For example, the sodium or potassium salt can be prepared by treating a solution of the corresponding acid of a compound of the formula (I) with a sodium or potassium 2-ethylhexanoate with an alkali or alkali metal hydroxide, or the corresponding carbonate or bicarbonate. of the same. Alternatively, the alkali or alkali metal salts can be prepared by the direct hydrolysis of the protected carboxyl derivatives of the compounds of the formula (I) with the appropriate alkali metal or alkali metal hydroxide. The metabolically labile esters of the compounds of the formula I can be prepared by esterification of the carboxylic acid group or a salt thereof or by transesterification using conventional methods. Accordingly, for example, the axyloxyalkyl esters can be prepared by reacting the free carboxylic acid or a salt thereof with the appropriate acyloxyalkyl halide in a suitable solvent such as dimethylformamide. For the esterification of the free carboxyl group, this reaction is preferably carried out in the presence of a quaternary ammonium halide such as tetrabutylammonium chloride or benzyltriethylammonium chloride. Specific enantiomers of the compounds of the formula (I) can also be obtained from the corresponding racemic compounds of the formula (I) using the chiral HPLC method. Alternatively, the enantiomers can be prepared by esterification of the corresponding racemic compounds of the formula (I) with a suitable chiral alcohol, separating the resulting diastereomeric esters by conventional means, for example by chromatography or crystallization followed by hydrolysis of the diastereomeric esters. Suitable chiral alcohols for use in the process include (+) -S-indanol, (+) -S-methyl mandelate, chiral (C? _4) alkyl lactate: ie (+) - R- lactate or (-) -S-methyl, (+) - Rt-butyl lactate, (+) - R- or (-) - S-ethyl lactate, (-) -S-isopropyl lactate, (-) lactate -S-butyl, (+) - R-isobutyl lactate or chiral aralkyl lactate (ie benzyl lactate), (-) - S-perilyl alcohol, (-) - methyl- (R) -3- propionate hydroxy-2-methyl, (-) - (R) -2-butanol, (-) - (S) -2-methyl-1-butanol. The diastereomeric esters of the compounds of the formula (I) can be prepared by conventional means such as the reaction of the chiral alcohol with an activated derivative of a compound of the formula (I) in an aprotic solvent such as ether for example tetrahydrofuran. The activated derivative of a compound of the formula (I) can be prepared from the compounds (I) using conventional means for preparing the activated derivatives of one of the carboxylic acid groups such as those conveniently used in the synthesis of the peptides. A particularly convenient method for preparing the diastereomeric esters of the compounds (I) is to prepare the activated derivative of the compounds (I) in the presence of the chiral alcohol. Accordingly, for example the racemic mixture of the compounds (I) can be treated with the combination of Mitsunobu reagents, ie a dialkyl azo-dicarboxylate such as diethyl azodicarboxylate and a triarylphosphine for example triphenylphosphine or trialkylphosphine (i.e. tributylphosphine) in the presence of chiral alcohol. The reaction is conveniently carried out in the presence of a suitable solvent such as an ether (for example diethyl ether or tetrahydrofuran), a halohydrocarbon (for example dichloromethane) or a nitrile (for example acetonitrile) or a mixture thereof to a temperature that varies from 0-30 ° C. The required single diastereomeric ester of the compounds (I) can be obtained from the mixture thereof by conventional means, for example by the use of conventional chromatographic methods such as preparative HPLC or by fractional crystallization. Alternatively, the required single diastereomeric ester of the compound of the formula (I) can be obtained using a suitable chiral protecting group Ri2 as defined in the formula (II). The specific enantiomers of the compounds of the formula (I) can be prepared from the corresponding single diastereomeric ester of the compounds (I) by hydrolysis, for example alkaline hydrolysis. Accordingly, for example, the hydrolysis can be carried out using an alkali metal hydroxide for example sodium hydroxide or lithium hydroxide in a solvent such as an ether for example tetrahydrofuran and water. Alternatively, specific enantiomers of the compounds of the formula (I) can be prepared by the stereoselective enzymatic hydrolysis of the compounds of the formula wherein R17 is a carboxyl protecting group. Suitable carboxyl protecting groups Ri for use in this reaction include alkyl with C?-Such as methyl, ethyl, propyl, butyl, or arylmethyl groups such as benzyl, nitrobenzyl or trifly. Enzymes suitable for use in this reaction are lipase enzymes such as ILIpase-DS from Aspergillus niger (AP-12) (Aspergillus ny ger, Amano), lipase from Candi da rugosa (Amano), lipase from Candida cylindracea (Amano), lipase from Alcaligenes sp. rhi zopus arrhi zus lipase (Biotal), wheat germ lipase (Sigma), Rhiz opus nius us (Amano) lipase, Promod 215-P protease (Biocatalyst), lipase E-7 (Themogen), lipase E-17 (Thermogen). Additional suitable enzymes which can be used in this reaction are pancreatic pig lipase, alpha-chymotrypsin or trypsin. A particularly preferred enzyme for use in this reaction is Aspergillus niger (AP-12). The remaining cells of the following organisms can also be used in this reaction, Aspergillus ochraceus, Aspergillus niger, Aspergillus chevalieri and Aspergillus cervinus. The reaction is conveniently carried out in an aprotic solvent such as DMSO, tetrahydrofuran in the presence of a suitable aqueous buffer (i.e., phosphate buffer or CaC12). If a solubilizing agent such as Tween-80 is required it can be added to the reaction mixture. In a further process the enzyme can be immobilized and the reaction is carried out in organic solvents saturated with essentially "pure" water such as methyl tert-butyl ether or tert-amyl alcohol. For the invention to be understood more fully, the following examples are given by way of illustration only. In the Intermediate Compounds and the Examples unless otherwise stated: The melting points (m.p.) were determined on a Gallenkamp apparatus and are uncorrected. All temperatures refer to ° C. The infrared spectra were measured on an FT-IR instrument. The Proton Magnetic Resonance (1H NMR) spectra were recorded at 400 MHz, the chemical shifts are reported in ppm downfield (d) from Me4Si, used as the internal standard, and assigned as singlets- (s), doublets (d), doublets of doublets (dd), triplets, (t), quartets (q) or multiplets (m). Column chromatography was carried out on silica gel (Merck AG Darmsstaadt, Germany). The following abbreviations are used in the text: EA = ethyl acetate, CH = cyclohexane, DCM = dichloromethane, THF = tetrahydrofuran, TFAA = trifluoroacetic acid, TEA = triethylamine, DMF = dimethylformamide, Ac20 = acetic anhydride, PPA = polyphosphoric acid, DBU = 1, 8-diazobicyclo [5, 4, 0] undec-7-ene, DMSO = dimethyl sulfoxide, IMS = mixture of Ethanol with 5% methanol, LHDMS = lithium bis (trimethylsilyl) amide, DIPEA = diisopropylethylamine , Tic refers to thin layer chromatography on the silica plates, and drying refers to a solution dried over anhydrous sodium sulfate; r.t. (RT) refers to the ambient temperature. The A-enantiomer or the diastereomer A refer to a single enantiomer or a single diastereomer, respectively, whose absolute stereochemistry was not characterized.

Intermediate Compound 1 2- (5-Chloro-2-iodoanilino) -4-pentenoate of (±) -Ethyl To a solution of the 2-iodo-4-chloroaniline (9.1 g) in dry toluene (150 ml) are added ethyl glyoxylate (50% solution in toluene, 14.6 ml) and MgSO4 (2 g) and the resulting suspension is subjected to I reflux all night. It is filtered and concentrated to dryness under high vacuum at 50 ° C for 1.5 h. The resulting brown oil is dissolved in dichloromethane (150 ml), cooled to -78 ° C and TiCl 4 (99.995% purity, 4 ml) is added via syringe. The suspension is stirred 15 minutes at -78 ° C, then it is allowed to warm to rt for 15 minutes before being cooled again to -78 ° C. Then add allytributyltin (17 ml) and the reaction is allowed to proceed for 1 h. The black solution is poured into 200 ml of ethyl acetate and washed first with a saturated solution of NH 4 Cl (2 x 150 ml), then with water and brine. The organic phase is dried and concentrated to give the crude product, which is purified by column chromatography (cyclohexane, then cyclohexane / ethyl acetate 98/2) to give the title compound (10.4 g) as a colorless oil. NMR (CDCl 3) d (ppm) 7.57 (d, 1H), 6.49 (dd, 1H), 6.45 (dd, 1H), 5.79 (m, 1H), 5.25 (dd, 1H), 5.24 (dd, 1H), 4.83 (d, 1H), 4.25 (q, 2H), 4.13 (, 1H), 2.66 (m, 2H), 1.30 (t, 3H) Intermediate Compound 2 2- (5-Chloro-2-iodoanilino) -4-oxobutanoate of (±) -ethyl A solution of intermediate 1 (5.2 g) in dichloromethane (150 ml) is cooled to -78 ° C and ozone is bubbled through it until the clear solution becomes brick red. At this point the ozone flow is interrupted and the solution is purged with nitrogen for a few minutes. Triphenylphosphine (7.1 g) is added and stirring is continued for 1.5 h, without temperature control. The resulting solution is poured into 200 ml of ethyl acetate and washed first with a saturated solution of NH C1 (2 x 150 ml), then with water and brine. The organic phase is dried and concentrated to give the crude product, which is purified by column chromatography (cyclohexane / ethyl acetate 80/20) to give the title compound (2.4 g) as a colorless oil. NMR (DMSO) d (ppm) 9.80 (t, 1H), 7.57 (d, 1H), 6.55 (d, 1H), 6.51 (dd, 1H), 4.99 (d, 1H), 4.46 (m, 1H), 4.24 (q, 2H), 3.08 (m, 2H), 1.28 (t, 3H) Intermediate Compound 2a 2- (3, 5-Dichloro-2-iodoanilino) -4-oxobutanoate (+) ethyl A solution of ethyl glyoxylate (50% solution in toluene (1 ml) and MgSO4 (7 g) in toluene (30 ml) is refluxed in a Dean-Stark apparatus for 0.5 hours, then the 3 is added, 5-chloro-2-iodoaniline, and the mixture is refluxed for 1 h, then the mixture is cooled, filtered through celite to remove MgSO 4, and concentrated The resulting brown oil is dissolved in dichloromethane (15 g). ml) is cooled to -78 ° C and Yb (OTf) 3xH20 (0.186 g) is added The suspension is stirred for 5 minutes at -78 ° C, then the vinyloxytrimethylsilane (0.29 g) is added and the temperature is raised to 20 ° C. After 1 h at this temperature, add a saturated solution of NH 4 Cl (20 ml) followed by ethyl acetate (30 ml) The organic phase is washed with brine (20 ml) and dried over sodium sulfate. Sodium and concentrated to give the crude product, which is purified by column chromatography (cyclohexane, then cyclohexane / ethyl acetate 85/15) to give the Tit of the title (0.562 g) as a colorless oil. NMR (CDC13) d (ppm) 9.65 (s, 1H), 7.00 (d, 1H), 6.70 (d, 1H), 5.60 (d, 1H), 4.80 (m, 1H), 4.10 (q, 2H), 3.10 (m, 2H), 1.15 (t, 3H).

Intermediate Compound 3 Tributyl (2-oxo-l-phenylpyrrolidin-1-yl) phosphonium bromide N, N, N1N1-tetramethylene-ethylene diamine (23.3 ml) is added to a solution of N-methylpyrrolidinone (5 g) in dichloromethane (50 ml). The solution is cooled to 0-5 ° and trimethylsilyl triflate (8.4 ml) is added for almost 20 minutes maintaining the temperature in the range of 0-5 ° C. The resulting solution is stirred for 10 minutes and a solution of pyridinium bromide perbromide is added (13 g) in acetonitrile (20 ml) for ca 20 minutes, maintaining the temperature in the range of 0-10 ° C. The resulting suspension is stirred at 0-5 ° C for almost 60 minutes. The aqueous sodium bicarbonate solution (50 ml) is added carefully. The mixture is stirred for almost 5 minutes and the layers are separated. The aqueous phase is diluted with water (20 ml) and again extracted with dichloromethane (20 ml). The combined organic phases are washed with additional sodium bicarbonate solution (50 ml), 2 M hydrochloric acid (2 × 50 ml) and water (50 ml), extracting each wash again with dichloromethane (10 ml). The organic solution is dried (MgSO4) and concentrated in a rotoevaporator. The brown / red solid is stirred with ethyl acetate (50 ml) and heated to a solution which is then cooled and tributylphosphine (8.5 ml) is added. The solution is heated to reflux and refluxed for 2.5 hours. The solution is allowed to cool to room temperature and then cooled to 0-5 ° C. The resulting suspension is aged at 0-5 ° C for almost 60 minutes. The product is isolated by vacuum filtration and then washed with ethyl acetate: t-butylmethyl ether (1: 1, 40 ml) and dried in a vacuum oven at 45 ° C to give the title compound as a solid. crystalline white (10.12 g), mp 127-128 ° C.

Intermediate Compound 4 2- (5-Chloro-2-iodoanilino) -4- (2-oxo-l-phenyl-3-pyrrolidinylidene) butanoate of (+) E-ethyl (4a); 2- (5-chloro-2-iodoanilino) -4- (2-oxo-l-phenyl-3-pyrrolidinylidene) butanoate of (±) -Z-ethyl (4b) To a solution of intermediate 2 (2.4 g) in acetonitrile (100 ml) at t.a., intermediate 3 (3.7 g) and DBU (13 ml) are added and stirring is continued overnight at -20 ° C. The crude solution is poured into 200 ml of ethyl acetate and washed with a saturated solution of NH 4 Cl (2 x 150 ml), then with water and brine. The organic phase is dried and concentrated to give the crude product as a 4/1 mixture of the compounds 4a / 4b. Purification by column chromatography (cyclohexane / ethyl acetate 80/20) gave the title compound 4a (2.16 g) and the title compound 4b (0.5 g) as colorless oils.

Intermediate 4a NMR (CDCl 3) d (ppm) 7.72 (d, 2H), 7.56 (d, 1H), 7.38 (t, 2H), 7.16 (t, 1H), 6.6 (m, 1H), 6.50 (dd, 1H), 6.49 (d, 1H), 4.88 (d, 1H), 4.26 (m, 3H), 3.87 (t, 2H), 2.79 (m, 4H), 1.30 (t, 3H) Intermediate 4b NMR (CDCl 3) d (ppm) 7.69 (d, 2H), 7.52 (d, 1H), 7.38 (t, 2H), 7.17 (t, 1H), 6.47 (d, 1H), 6.44 (dd, 1 HOUR) , . 98 (m, 1H), 5.00 (d, 1H), 4.22 (m, 2H), 4.13 (, 1H), 3.84 (t, 2H), 3.2-3.6 (m, 2H), 2.85 (m, 2H), 1.26 (t, 3H) Compound Intermediate 5 i 2- (5-Chloro-2-iodoanilino) -4-pentenoate of (IR) -2- (tert-butoxy) -l-methyl-2-oxoethyl (5a) and 2- (5-chloro-2-iodoanilino) ) -4-pentenoate of (IR) -2- (tert-butoxy) -1-methyl-2-oxoethyl (5b) A solution of intermediate 1-! 1-tert-butyl- (R) -2 (oxoacetoxy) -2-methyl acetate (4.1 g) in toluene (200 ml) is refluxed in a Dean-Stark apparatus for 2 hours. After cooling to room temperature, the 5-, 1-chloro-2-iodoaniline (4.3 g) is added, and the solution is refluxed in the presence of MgSO4 for 3 hours. The clear solution is cooled, filtered through cotton to remove MgSO4, concentrated to dryness and redissolved in dichloromethane (150 ml).

The solution is cooled to -78 ° C, and TiCl 4 (1.9 ml) is slowly added from a syringe. After 15 minutes, allyl tributyltin (7.9 ml) is added, and the resulting black suspension is stirred, for 1 hour. It is then poured onto ethyl acetate (300 ml), and saturated NH4C1 (150 ml) is added. The organic phase is separated, washed with water and brine, dried and concentrated. Final purification by column chromatography (cyclohexane / ethyl acetate 95/5) afforded the title compound (4.1 g) (65/35 mixture of the diastereomers) as a colorless oil (7.01 g). NMR (CDC13) d (ppm) 7.54 (1H), 6.46 (dd, 1H), 5.86 (m, 1H), 5.3-5.2 (m, 2H), 5.03 (m, 1H), 4.77 (bd, 1H), 4.16 (m.1H), 2.8-2.68 (m, 2H), 1.50 (d, 3H), 1. 45 (s, 9H) Intermediate Compound 5a 2- (5-Chloro-2-iodoanilino) -4-pentenoate of (lR) -2- (tert-butoxy) -l-methyl-2-oxoethyl To a solution of allyltributyl tin (3.3 g) in dry DCM (100 ml) is added an IM solution in DCM of SnC14 (10 ml) at -78 ° C. The mixture is stirred for 20 minutes, then the intermediate compound of the 2- [2- (5-chloro-2-iodo-phenylimino) -acetoxy] -l- (R) -methyl-acetic acid terbutyl ester is added. (2.39 g) in dry DCM (50 ml). The reaction mixture is allowed to react at -78 ° C for 20 minutes, then a saturated solution of NH 4 Cl and the resulting mixture is extracted with ethyl acetate (2 × 200 ml). The organic layer is washed with a 10% KF solution in water, then diethyl ether is added and the resulting solid is filtered. The solution is dried and evaporated under vacuum. The final purification by flash chromatography (CH / EA 95: 5) gave the title compound as a pure diastereomer as a colorless oil (1.3 g). NMR (CDC13): 7.55 (d, 1H); 6.47 (d, 1H); 6.43 (d, 1H); 5.88 (, 1H); 5.27 (m, 2H); 5.05 (q, 1H); 4.78 (d, 1H); 4.18 (m, 1H0; 2.74 (m, 2H); 1.52 (d, 3H); 1. 67 (s, 9H). IR (DCD13): 3379, 1740 Intermediate Compound 6 (IR) -2- (tert-butoxy) -? -methyl-2-oxoeti 1-2 - (5-chlor? '-2-iodoani flax) -4-oxobutanoate (6a) and (1R) -2- (tert-butoxy) -1-methyl-2- oxoethyl -2-- (5-chloro-2-iodoani flax) -4-oxobutanoate (6b) A solution of intermediate 5 (7.1 g) in dichloromethane (200 ml) is cooled to -78 ° C and the ozone is bubbled through it until the solution turned red. Then triphenylphosphine (8 g) is added, and the reaction is allowed to stir for 2 hours, without temperature control. The crude mixture is evaporated to dryness and purified repeatedly by column chromatography ((cyclohexane / ethyl acetate 85/15) to give the title compound 6a (2.75 g) and 6b (0.87 g) as colorless oils.

Compound 6a: NMR (CDC1) d (ppm) 9.85 (t, 1H), 7.57 (d, 1H), 6.58 (d, 1H), 6.51 (dd, 1H), 5.04 (q, 1H), 4.96 (d, 1H), 4.62 (m, 1H), 3.13 (dd, 2H), 1.55-1.42 (m, 12 H) IR (CDC13) (cm "1) 1740 Compound 6b: NMR (CDCl 3) d (ppm) 9.81 (t, 1H), 7.57 (d, 1H), 6.60 (d, 1H), 6.52 (dd, 1H), 5.02 (q, 1H), 4.95 (d, 1H), 4.55 (m, 1H), 3.11 (m, 2H), 1.55-1.43 (m, 12H). IR (CDC13) (cm "1740.

Intermediate Compound 6a (IR) -2- (tert-butoxy) -l-methyl-2-oxoethyl-2- (5-chloro-2-iodoanilino) -4-oxobutanoate The title compound was obtained starting from intermediate 5a following the same procedure described for intermediate 6.

Intermediate Compound 7 2- (5-Chloro-2-iodoanilino) -4- (2-oxo-l-phenyl-3-pyrrolidinylidene) butanoate of (E) - (IR) -2- (tert-butoxy) -l-methyl-2 -oxoethyl (diastereoisomer A) To a solution of intermediate compound 6a (2.7 g) in acetonitrile (60 ml) are added 2b (3 g) and DBU (1 ml) and the mixture is reacted at 20 ° C overnight. It is then taken up in ethyl acetate (300 ml) and washed with IN HCl, water and brine, dried and concentrated. Final purification by column chromatography (cyclohexane / ethyl acetate 85/15) afforded the title compound (2.1 g) as a white solid, m.p. 36-39 °, [a] D 22 ° (c = 0.160% w / v in DMSO) NMR (CDC1) d (ppm) 7.72 (d, 2H), 7.55 (d, 1H), 7.38 (t, 2H) , 7.15 (t, 1H), 6.66 (m, 1H), 6.49 (dd, 1H), 6.48 (d, 1H), 5.05 (m, 1H), 4.81 (d, 1H), 4.30 (m, 1H), 3.87 (t, 2H), 3.0 (m, 2H), 2.75 (m, 2H), 1.51 (d, 3H), 1.45 (s, 9H) Intermediate Compound 8 7-Chloro-4- (1-phenyl-3-pyrrolin-2-one-3-yl) -1,2,3,4-tetrahydroquinoline-2-carboxylate of (-) (1R) -2-tert-butoxy) -l-methyl-2-oxoethyl (8a) [1- (R) - (1-tert-butoxycarbonyl) -3-ethyl ester of (-) 7-chloro-4- (2-oxo-l-phenyl-3-) pyrrolidinylidene) -1,2,3,4-tetrahydro-2-quinoline-2-carboxylic acid (8b) To a solution of intermediate 7 (2.1 g) in DMF (40 ml) are added Pd (PPh3) 4 (0.393 g) and triethylamine (0.95 ml) and the mixture is heated at 150 ° C for 1 hour. The crude solution is taken up in ethyl acetate and washed with IN HCl, water and brine, dried and evaporated. Final purification by column chromatography (exano cycle / dichloromethane / ethyl acetate 50/40/10) afforded the title compound 8a (0.7 g) as a white solid m.p. = 69-73 ° C [a] D -70.1 ° (c = 0.190% w / v in DMSO) NMR (DMSO) d (ppm) 7.80 (m, 2H), 7.12 (m, 1H), 6.82 (d, 1H), 6.77 (d, 1H), 6.70 (m, 1H), 6.49 (dd, 1H), 6.46 (bs, 1H), 4.93 (q, 1H), 4.49 (m, 2H), 4.02 (m, 1H) ), 3.87 (m, 1H), 2.44 (m, 1H), 2.00 (m, 1H), 1.39 (s, 9H), 1.38 (d, 3H). IR (Nujol) (crn-1) 3380, 1741, 1681, 1601 and the title compound 8b (0.8 g) as a yellow solid. m.p. 59-64 ° C, [a] D -76.2 ° (c = 0.510 p / v in DMSO) NMR (DMSO) d (ppm) 7.73 (m, 2H), 7.36 (m, 2H), 7.21 (d, 1H ), 7.11 (m, 1H), 6.98 (day, 1H), 6.75 (d, 1H), 6.57 (dd, 1H), 4.70 (q, 1H), 4.24 (m, 2H), 3.84 (m, 1H) , 3.75 (m, 1H), 3.18 (m, 1H), 3.05 (m, 1H), 2.94 (m, 1H), 1.25 (s, 9H), 1.23 (d, 3H) Intermediate Compound 9 2- (5-Chloro-2-iodoanilino) -4- (2-oxo-l-phenylpiperidinylidene) butanoate of (±) -E-ethyl To a solution of tributyl-3- (1-phenyl-2-piperidinone bromide ) phosphonium (0.83 g) in acetonitrile (20 ml) is added DBU (0.27 ml) and after 15 minutes a solution of intermediate 2 (0.35 g) in acetonitrile (20 ml). The reaction mixture is stirred for 30 minutes, then it is diluted with ethyl acetate and washed with an IN solution of HCl and brine. The organic phase is dried and concentrated to give the crude product which is purified by flash column chromatography to obtain the title compound (0.29 g) as a faint yellow foam. NMR (CDC13) d (ppm) 7.56 (dd, 1H), 7.38 (dd, 2H), 7.27 (dd, 2H), 7.24 (t, 1H), 6.93 (t, 1H), 6.50-6.47 (m, 2H) ), 4.85 (d, 1H), 4.25 (q, 2H), 4.22 (m, 1H), 3.71 (m, 2H), 2.76 (m, 2H), 2.59 (, 2H), 2.01 (m, 2H), 1.29 (t, 3H) Intermediate Compound 10 2- (5-Chloro-2-iodoanilino) -4- (2-oxo-l- (pyridin-3-yl) phenylpyrrolidin-3-ylidene) butanoate of (±) -E-ethyl To a solution of (1- (pyridin-3-yl) -2-oxo-pyrrolidin-3-yl) tributylphosphonium bromide (0.93 g) in acetonitrile (10 ml) is added DBU (0.22 ml) and after 10 minutes a solution of intermediate 2 (0.46 g) in acetonitrile (10 ml). The reaction mixture is stirred for 3 hours, then diluted with ethyl acetate and washed with a saturated solution of NH 4 Cl and brine. The organic phase is dried and concentrated to give the crude product which is purified by flash column chromatography to obtain the title compound (0.047 g) as a mixture of the E / Z isomer (80/20). MS (m / z) 526 Intermediate Compound 11 2- (3, 5-Dichloro-2-iodoanilino) -4- (2-oxo-l-phenyl-pyrrolidinylidene) butanoate of (±) -E-ethyl (lia); 2- (3, 5-dichloro-2-iodoanilino) -4- (2-oxo-l-phenyl-pyrrolidinylidene) butanoate of (±) -Z-ethyl (11b) To a solution of intermediate 2a in acetonitrile (10 ml) at r.t. 2b (0.726 g) and DBU (0.33 ml) are added and stirring is continued overnight at -20 ° C. The crude solution is poured into 20 ml of ethyl acetate and washed first with a saturated solution of NH 4 Cl (2 x 15 ml), then with water and brine. The organic phase is dried and concentrated to give the crude product as a 4/1 mixture of the Z / E isomers. Purification by column chromatography (cyclohexane / ethyl acetate 85/15) gave the title compound lia (0.498 g) and the title compound 11b (0.122 g) as colorless oils.

Intermediate Compound NMR (CDC13) d (ppm) 7.78 (d, 2H), 7.39 (t, 2H), 7.16 (t, 1H), 6.90 (d, 1H), 6.58 (m, 1H), 6.36 (d, 1H), 5.22 (d, 1H), 4.26 (m, 3H), 3.87 (t, 2H), 2.79 (m, 4H), 1.30 (t, 3H) IR (CDC13) (cm "1) 3370, 1738, 1697, 1671 MS (m / z) 559.

Intermediate 11b NMR (CDCl 3) d (ppm) 7.69 (d, 2H), 7.38 (t, 2H), 7.17 (t, 1H), 6.84 (d, 1H), 6.34 (d, 1H), 5.96 (m, 1H), 5.34 (d, 1H), 4.22 (m, 2H), 4.12 (m, 1H), 3.84 (t, 2H), 3.63-3.27 (m, 2H), 2.85 (t, 2H), 1.26 (t , 3H) IR (CDC13) (citf1) 1733, 1685 MS (m / z) 559.

Intermediate Compound 12 2- (5-Chloro-2-iodoanilino) -4- (2-oxo-l-phenyl-3-pyrrolidinylidene) butanoate of - (IR) -2- (tert-butoxy) -1-methy1-2-oxoethyl ( diastereomer B) To a solution of intermediate compound 6b (0.87 g) in acetonitrile (20 ml) are added tributyl-3- (N-phenyl-1-pyrrolidonyl) phosphonium bromide (1.6 g) and DBU (0.33 ml) and the mixture is reacted at -20 ° C all the night. It is then taken up in ethyl acetate (100 ml) and washed with 1N HCl, water and brine, dried and concentrated. The final purification. by column chromatography (cyclohexane / ethyl acetate 85/15) afforded the title compound (0.47 g) as a white solid oil. m.p. = 38-42 ° C NMR (CDC13) d (ppm) 7.72 (d, 2H), 7.55 (d, 1H), 7.38 (t, 2H), 7.16 (t, 1H), 6.60 (m, 1H), 6.56 (d, 1H), 6.49 (dd, 1H), 5.03 (q, 1H), 4.80 (d, 1H), 4.33 (m, 1H), 3.88 (t, 2H), 2.9 (m, 2H), 2.75 ( m, 2H), 1.48 (d, 3H), 1.44 (s, 9H) IR (CDC13) (cm-1) 3375, 1738, 1693, 1665 Intermediate Compound 13 7-Chloro-4- (1-phenyl-3-pyrrolin-2-one-3-yl) -1,2,3,4-tetrahydroquinoline-2-carboxylate of - (IR) -2- (tert-butoxy) - l-methyl-2-oxoethyl (diastereomer B) To a solution of intermediate 12 (0.46 g) in DMF (8 ml) are added (Pd (PPh3) 4 (0.043 g) and triethylamine (0.21 ml) and the mixture is heated at 150 ° C for 1 h. The crude product is taken up in ethyl acetate and washed with 1N HCl, water and brine, dried and evaporated, the final purification by column chromatography. (cyclohexane / dichloromethane / ethyl acetate 50/40/10) afforded the title compound (0.114 g) as a white solid, m.p. = 62.67 ° C NMR (DMSO) d (ppm) 7.79 (m, 2H), 7.38 (m, 2H), 7.11 (t, 1H), 6.81 (d, 1H), 6.77 (d, 1H), 6.70 (d , 1H), 6.55 (bs, 1H), 6.48 (dd, 1H), 4.90 (q, 1H), 4.5 (m, 2H), 3.99 (m, 1H), 3.84 (t, 1H), 2.35 (m, 1H), 2.02 (m, 1H), 1.39 (s, 12H) Intermediate Compound 14 2,4-dibromo-N- (4-tert-butoxycarbonylamino) phenyl) -butyramide To the 2,4-dibromobutyryl bromide derivative (3.1 g) in dry dichloromethane (60 ml) is added pyridine (3.2 ml), the mixture is kept at 0 ° C under an atmosphere of argon for 10 minutes and then added by dripping Nt-butoxy carbonyl-1, 4-phenylene diamine (2.08 g). After 1 hour the mixture is poured into a saturated solution of NH4C1 (200 ml), extracted with EA (3x150 ml) and the organic phase is washed with brine (200 ml), dried and concentrated in vacuo, the crude product purify by flash chromatography (eluting with CH / EA 80:20) to give the title compound as a yellow foam (3.5 g). T.l.c. CH / EA 8: 2, Rf = 0.53. 1H-HMR: 7.89 (s); 7.44 (d); 6.46 (sa); 4.66 (dd); 3.60 (m); 2.76 (m); 2.55 (m); 1.51 (s).

Intermediate Compound 15 3-Bromo-l- (4- (tert-butoxycarbonylamino) phenyl-2-oxo-pyrrolidine To a solution of intermediate 14 (3.5 g) in dry THF (50 ml) cooled (0 ° C), a solution of LHMDS (9.6 ml of a solution) is added. 1M in tetrahydrofuran) by drip. The mixture is stirred under nitrogen until the temperature reached r.t. for 2 hours. It was quenched in a saturated NH4C1 solution (200 ml) and extracted with EA (3x150 ml) and the organic extracts were washed with brine. (200 ml), dry and concentrate in vacuum. The mixture is purified by flash chromatography (eluting with CH / EA 8: 2) to give the title compound (2.6 g). T.l.c. CH / EA 8: 2, Rf = 0.31. ^ -NMR: 7.57 (d); 7.39. (d); 6.49 (sa); 4.59 (m); 4.03 (m); 3.81 (m); 2.73 (m); 2.46 (m); 1.53 (s).

Intermediate Compound 16 2- (5-chloro-2-iodoanilino) -4- (2-oxo-l- (4-tert-butoxycarbonilamino) phenyl-pyrrolidin-3-ylidene) butanoate of (+/-) -Z-Ethyl A solution of intermediate 15 (2.6 g) in dry DMF (100 ml) and tributylphosphine is refluxed at 110 ° C under nitrogen atmosphere for 4 h, until the reaction complements (TLC). The mixture is concentrated in vacuo to give the crude 1- (4-tert-butoxycarbonylamino) phenyl-2-oxo-pyrrolidin-3-yl-tributylphosphonium bromide (1.75 g) which is dissolved in dry CH3CN 100 ml), cool to -30 ° C and stir under a nitrogen atmosphere, then add DBU (0.44 ml) and intermediate 2 (1.0 g). The mixture is stirred for 1 h then it is poured into a saturated solution of NH C1 (200 ml) and extracted with EA (3x150 ml) and the organic extracts are washed with brine (200 ml), dried and concentrated in vacuo. give a yellow oil which is purified by flash chromatography (eluting with CH / EA 80:20) to give the title compound (0.085 g) as a white solid. T.l.c. CH / EA (7: 3), Rf = 0.23 IR: 1727 and 1695 (C = 0) cm -i H-NMR: 7.64 (d); 7.53 (d); 7.38 (d); 6.48 (d) 6. 47 (sa); 6.45 (dd); 5.97 (m); 5.02 (d); 4.23 (m); 4.14 (m); 3.8 (t); 3.6 (m); 3.3 (m); 2.85 (m); 1.53 (s); 1.27 (t).

Intermediate Compound 17 2- (5-chloro-2-iodoanilino) -4- (2, 5-dioxo-l-phenyl-imidazolidin-4-ylidene) butanoate of (+/-) -Z-Benzyl To a solution of the ester derivative N - (phenylaminocarbonyl) α-phosphonoglycine-trimethyl (0.1 g) in acetonitrile (10 ml) is added DBU (0.1 ml) and after 10 minutes a solution of the benzyl ester of (+/-) -2- (5-chloro- 2-iodo-phenylamino) -4-oxo-butyric acid (0.1 g) in acetonitrile (2 ml). The reaction mixture is stirred for 1 1/2 hours, then diluted with ethyl acetate and washed with a 1N HCl solution and brine. The organic phase is dried and concentrated to give the crude product which is purified by flash column chromatography to obtain the title compound (0.065 g). NMR (.DMSO) d (ppm) 10.80 (s, 1H), 7.65 (d, 1H), 7.7-7.3 (m, 10H), 6.75 (d, 1H), 6.55 (dd, 1H), 5.70 (t, 1H), 5.20 (s, 2H), 5.07 (d, 1H), 4.72 (m, 1H), 2.86 (t, 2H) IR (Nujol) (cm "1) 3339, 3160, 1768, 1721, 1691 Intermediate Compound l: 7-Chloro-4- (2, 5-dioxo-l-phenyl-imidazolidin-4-ylidene) - 1, 2, 3, 4-tetrahydro-2-quinolinecarboxylate of (±) - Benzyl To a solution of intermediate 17 (0.065 g) in DMF (5 ml) are added Pd (PPh3) 4 (16 mg) and TEA (0.05) ml) and the resulting solution is heated at 110 ° C for 1 h. The crude solution is poured into ethyl acetate and washed with an IN solution of HCl and brine. The organic phase is dried and concentrated to give the crude product which is purified by flash column chromatography to obtain the title compound (0.015 g) as a yellow powder. m.p. >; 220 ° C NMR (DMSO) d (ppm) 10.5 (s, 1H), 7.5-7.2 (, 11H), 7.16 (bd, 1H), 6.75 (d, 1H), 6.58 (dd, 1H), 5.2- 5.01 (dd, 2H), 4.40 (m, 1H), 4.25 (dd, 1H), 2.83 (dd, 1H). IR Nujol (cm "1) 3378, 1752, 1728, 1704 Intermediate Compound 19 Isobutyl 2- [2- (5-Chloro-2-iodo-phenylimino) -acetoxy] -1- (R) -methyl-acetic acid isobutyl ester To a solution of the 1-isobutoxycarbonyl-1- (R) -methylmethyl ester of acrylic acid (3.7 g) in THF / H20 is added Os004 4% in H20 (4 ml). The black suspension is then treated with NaI04 (10.5 g) in portions. After 5 hours, the solution is taken up in ethyl acetate (2 x 50 ml) and washed with water (2x50 ml). The organic phase is evaporated under vacuum and the crude mixture is purified by flash chromatography (CH / EA 1: 1) to give 2- (2-oxo-acetoxy) -1- (R) -methyl-acetic acid isobutyl ester. as a colorless oil (3 g). 24.8 g of the 2- (2-oxo-acetoxy) -1- (R) -methyl-acetic acid isobutyl ester in toluene (1000 ml) and refluxed in a Dean-Stark apparatus for 2 hours. After cooling to room temperature, 5-chloro-2-iodoaniline (22 g) is added, and the solution is refluxed in the presence of MgSO 4 for 3 hours. The clear solution is cooled, filtered through cotton to remove MgSO4, concentrated to dryness to obtain the title compound (38 g) as a yellow oil. NMR (CDC13) d (ppm) 7.83 (1H, d), 7.79 (s, 1H), 7.02 (dd, 1H), 6.96 (d, 1H), 5.373 (q, 1H), 4.00 (m, 2H), 2.00 (m, 1H), 1.67 (d, 3H), 0.96 (2d, 6H) IR (CDC13): 1749, 1730 Intermediate Compound 20 2- (5-Chloro-2-iodo-phenylamino) -4-oxo-butyric acid (1-isobutoxycarbonyl-1 (R) -methylmethyl ester (20a and 20b) A solution of intermediate 19 (38 g) in toluene (1 ml) is cooled to -20 ° C and Yb (OTf) 3 (16.5 g) is added and, after a few minutes, vinyloxytrimethylsilane (12.5 g) is added dropwise. g) dissolved in toluene (50 ml). The bath is removed and the reaction mixture is allowed to stir for 2 hours. The crude mixture is taken up in ethyl acetate (500 ml) and the organic phase is washed with a saturated solution of ammonium chloride (300 ml) and evaporated. Then, the mixture is purified by column chromatography (cyclohexane / ethyl acetate 85/15) to give the title compounds 20 (a) (14 g) and 20b (4 g) as colorless oils.

Intermediate 20a NMR (CDC13) d (ppm) 9.85 (s, 1H), 7.57 (d, 1H), 6.58 (d, 1H), 6.51 (dd, 1H), 5.19 (m, 1H), 4.97 (d, 1H), 4.63 (m, 1H), 3.93 (m, 2H), 3.24-3.04 (, 2H), 1.94 (m, 1H), 1.53 (d, 3H), 0.93 (dt, 3H); 0.91 (d, 3H). IR (CDC13) (Cl "1) 1742, 1740 Intermediate 20b NMR (CDC13) d (ppm) 9.81 (s, 1H), 7.57 (d, 1H), 6.60 (d, 1H), 6.52 (dd, 1H), 5.17 (m, 1H), 4.95 (d, 1H), 4.57 (m, 1H), 3.92 (m, 2H), 3.11 (m, 2H); 1.92 (m, 1H); 1.50 (d, 3H); 0.90 (d, 6H). IR (CDC13) (crn-1) 3375, 1734 Intermediate Compound 21 Ester 1-isobutoxycarbonyl-l- (R) methyl-methyl-ethyl (E) -2- (% -chloro-2-iodo-phenylamino) -4- (2-oxo-l-phenyl-pyrrole idin-3) iliden) -butyric To a solution of intermediate 3 (14.45 g) in acetonitrile (200 ml) is added DBU (4.43 ml) at room temperature and the mixture is stirred for 10 minutes. Then the mixture is cooled to -25 ° C and intermediate 31a (12.98 g) in 60 ml of CH 3 CN are added dropwise over 15 minutes. Then the reaction is stirred at this temperature for 2 h. The mixture is then taken up in ethyl acetate (100 ml) and the organic phase is washed with a saturated solution of NH 4 Cl (150 ml), and 2% HCl (200 ml) and brine (2 × 200 ml). The solution is then dried and concentrated. Final purification by column chromatography (cyclohexane / ethyl acetate / CH2C12 7 / 0.5 / 2.5) afforded the title compound (11.04 g) as a white foam NMR (CDC13) d (ppm) 7.73 (m, 2H), 7.56 (d, 1H), 7.38 (t, 2H), 7.16 (m, 1H), 6.67 (m, 1H), 6.50 (dd, 1H), 6.49 (s, 1H), 5.20 (q, 1H), 4.81 ( d, 1H), 4.33 (m, 1H), 3.94 (d, 2H), 3.88 (t, 2H), 3.0-2.74 (m, 4H), 1.94 (m, 1H), 1.57 (d, 3H); 0.91 (d, 6H). IR (CDC13); 1696, 1670 cm-1 Intermediate Compound 22 [1- (R) -methyl-1-isobutoxycarbonyl] -methyl acid of 7-chloro-4- (2-oxo-l-phenyl-pyrrolidin-3-ylidene) -1, 2, 3, 4-tetrahydro- quinoline-2-carboxylic (diastereoisomer A) To a solution of intermediate 21 (9.55 g) in toluene (130 ml), Pd (PPh3) 4 (3.52 g) and triethylamine (5.1 ml) are added in portions and the mixture is heated at 110 ° C for 3.5 hours. The crude solution is taken up in ethyl acetate (600 ml) and washed with NH 4 Cl and brine, dried and evaporated. Purification by column chromatography (cyclohexane / dichloromethane / ethyl acetate 6.5 / 3 / 0.5) afforded the title compound (6.08 g) as a yellow foam. NMR (DMSO) d (ppm) 7.71 (d, 2H), 7.35 (t, 2H), 7.20 (d, 1H), 7.11 (t, 1H), 7.00 (s, 1H), 6.74 (d, 1H), 6.57 (dd, 1H), 4.89 (q, 1H), 4.24 (m, 2H), 3.84-3.60 (m, 4H), 3.2-2.8 (m, 3H), 1.70 (m, 1H), 1.24 (d, 3H); 0.73 (d, 6H). IR (nujol): 3377, 1746, 1670 Intermediate Compound 23 [1- (R) -methyl-1-isobutoxycarbonyl] -methyl acid of 7-chloro-4- (2-oxo-l-phenyl-2,5-dihydro-lH-pyrrol-3-yl) -1, 2, 3, 4 -tetrahydro-quinoline-2-carboxylic acid To a solution of intermediate compound 22 (3.67 g) in DMF (50 ml) are added Pd (PPh3) 4 (0.340 g) and triethylamine (2 ml) and the mixture is heated to 110 ° C for 2 hours. The crude solution is taken up in ethyl acetate (2 × 200 ml) and washed with NH 4 Cl and brine, dried and evaporated. The final purification by column chromatography (cyclohexane / dichloromethane / ethyl acetate 6.5 / 3 / 0.5) afforded the title compound (1289 g) as a yellow foam. NMR (DMSO) d (ppm) 7.79 (d, 2H), 7.38 (t, 2H), 7.11 (t, 1H), 6.79 (d, 1H), 6.57 (d, 1H), 6.74 (d, 1H); 6.47 (dd, 1H); 5.10 (q, 1H); 4.49 (m, 2H); 4.06 (m, 1H); 3.92-3.82 (m, 3H); 2.45 (m, 1H); 2.019 (m, 1H); 1.84 (m, 1H); 1.42 (d, 3H); 0.84 (d, 6H). IR (nujol): 3375, 1749, 1683.

Intermediate Compound 24 r 2- (3,5-Dichloro-2-iodo-phenylamino) -4-oxo-butyric acid (1-n-butoxycarbonyl-l (S) -methyl-methyl ester (24a and 24b) To a solution of the intermediate 1-n-butoxycarbonyl-1- (S) -methyl-1-methyl ester of acrylic acid (4.9 g) in THF / H20 (100 ml, 2/1) is added Os04 4% in H20 (2.8 g). The black suspension is then treated with NaI04 (13 g) in portions. After 5 hours, the solution is taken up in ethyl acetate (2 × 50 ml) and washed with water (2 × 50 ml). The organic phase is evaporated under vacuum and the crude mixture is purified by flash chromatography (CH / EA 1: 1) to give the 2- (2-oxo-acetoxy) -1- (S) -methyl n-butyl ester. -acetic as a colorless oil (4.85 g), (2.5 g) of which are dissolved in toluene (200 ml) and refluxed in a Dean-Stark apparatus for 2 hours. After cooling to room temperature, 3, 5-dichloro-2-iodoaniline (2.46 g) is added, and the solution is refluxed in the presence of MgSO4 for 3 hours. The clear solution is cooled, filtered through cotton to remove MgSO, concentrated to dryness to obtain the (2- [2- (5-chloro-2-iodo-phenylimino) acetoxy] n-butyl ester] - 1- (S) -methyl-acetic acid (4 g) as a yellow oil.A solution of such yellow oil in CH3CN (70 ml) is cooled to -30 ° C and added Yb (OTf) 3 (2.1 g) and, after a few minutes, the vinyloxy trimethylsilane (1.1 g) dissolved in CH 3 CN is added dropwise. The reaction is stirred for 10 minutes. The crude mixture is taken up in ethyl acetate (500 ml) and the organic phase is washed with a saturated solution of ammonium chloride (2 × 50 ml) and evaporated. Then, the mixture is purified by column chromatography (cyclohexane / ethyl acetate 90/10) to give the title compounds 24a (1.4 g) and 24b (0.7 g) as a colorless oil.

Intermediate Compound 24a :. NMR (CDC13) (ppm) 9.84 (t, 1H), 6.92 (d, 1H); 6.45 (d, 1H); 5.33 (day, 1H); 5.17 (q, 1H); 4.60 (m, 1H); 4.14 (m, 2H); 3.34-3.06 (, 2H); 1.6 (, 2H); 1.52 (d, 3H); 1.37 (m, 2H); 0.93 (t, 3H).

Intermediate 24b: NMR (CDCl 3) d (ppm) 9.80 (s, 1H), 6.92 (d, 1H); 6.47 (d, 1H); 5.3 (day, 1H); 5.15 (q, 1H); 4.55 (m, 1H); 4.14. (m, 2H); 3.13 (, 2H); 1.57 (m, 2H); 1.49 (d, 3H); 1.34 (m, 2H); 0.91 (t, 3H). IR (CDC13) (crn-1) 3370, 1744.

Intermediate Compound 25 1-n-Butoxycarbonyl-1- (S) methyl-methyl ester of (E) -2- (3,5-dichloro-2-iodo-phenylamino) -4- (2-oxo-1-phenyl-pyrrolidin- 3-ylidene) -butyric (diastereoisomer A) to a solution of intermediate 2a (0.893) in acetonitrile (20 ml) is added DBU (0.25 ml) at room temperature and the mixture is stirred for 10 minutes. The mixture is then cooled to -25 ° C and intermediate compound 6b is added dropwise. (0.8 g) in 10 ml of CH3CN for 15 minutes. The reaction is then stirred at this temperature for 30 minutes. The mixture is then taken up in ethyl acetate (50 ml) and the organic phase is washed with a saturated solution of NH 4 Cl (50 ml), and 2% HCl (10 ml) and brine (2 × 20 ml). The solution is dried and then concentrated. Final purification by column chromatography (cyclohexane / ethyl acetate 8/2) afforded the title product (0.734 g) as a white foam. NMR (CDC13) d (ppm) 7.72 (d, 2H), 7.39 (t, 2H), 7.17 (t, 1H); 6.92 (d, 1H); 6.60 (m, 1H); 6.43 (d, 1H); 5.16 (q, 1H); 5.14 (d, 1H); 4.34 (d, 1H); 4.15 (m, 2H); 3.89 (t, 2H); 2.75-2.4 (m, 4H); 1.60 (m, '2H); 1.53 (d, 3H); 1.34 (m, 2H); 0.91 (t, 3H). IR (CDC13); 3377, 1744, 1697, 1672 cm "1 Intermediate Compound 26 Ester [5- (S) -methyl-1-n-butoxycarbonyl] -methyl of 5,7-dichloro-4- (2-oxo-l-phenyl-2,5-dihydro-lH-pyrrol-3-yl) ) -1, 2, 3, 4-tetrahydro-quinoline-2-carboxylic acid (26a), 5-7-dichloro-4- (1- (S) -methyl-1-n-butoxycarbonyl] -methyl ester of 5,7-dichloro-4- ( 2-oxo-l-phenyl-pyrrolidin-3-ylidene) -1,2,3,4-tetrahydro-quinoline-2-carboxylic acid (26b) To a solution of intermediate 25 (0.734 g) in DMF (20 ml) are added Pd (OAc) 2 (0.110 g) and triethylamine (0.37 ml), in portions, and the mixture is heated at 120 ° C for 3 hours . The crude solution is taken up in ethyl acetate (1000 ml) and washed with NH 4 Cl and brine, dried and evaporated. Final purification by column chromatography (cyclohexane / dichloromethane / ethyl acetate 7 / 2.5 / 0.59 afforded the title compound 26 (0.35 g) and 26b (0.06 g) as a yellow foam Intermediate 26a NMR (DMSO) d ( ppm) 7.80 (d, 2H), 7.38 (t, 2H), 7.11 (t, 1H), 6.89 (d, 1H), 6.83 (s, 1H), 6.68 (d, 1H), 6.47 (d, 1H); 5.07 (q, 1H); 4.48 (m, 2H); 4.11 (m, 1H); 4.06 (t, 2H); 3.8 (dd, 1H); 2.3-1.8 (m, 2H); 1. 52 (m, 2H); 1.40 (d, 3H); 1.54 (m, 2H); 1.3 (m, 2H); 0.84 (t, 3-3). IR (nujol): 3374, 1740, 1683 cm "1 Intermediate 26b NMR (DMSO) d (ppm) 7.69 (d, 2H); 7.39 (t, 2H); 7.33 (d, 1H); 7.15 (t, 1H); 6.71 (d, 1H); 6.62 (d, 1H); 4. 72 (d, 1H); 4.40 (q, 1H); 4.40 (m, 1H); 3.94 (t, 2H); 3.60 (q, 1H); 3.12 (m, 1H); 2.35 (m, 1H); 2.21 (dd, 1H); 1.42 (m.2H); 1.21 (m, 2H); 0.97 (d, 3H); 0.82 (t, 3H) ..

Example 1 7-Chloro-4- (l-phenyl-? 3-pyrrolin-2-one-3-yl) -1, 2, 3, 4-tetrahydroquinoline-2-carboxylate of (±) -Sodium To a solution of example 31a (540 mg) in IMS (5% methanol in absolute ethanol, 7 ml) is added NaOH (IN, 1.4 ml) and stirring is continued 2 hours. The resulting solution is dried on a rotary evaporator and the resulting solid is triturated with diethyl ether. After filtration and drying the title compound (440 mg) was obtained as a discolored white solid. m.p. > 200 ° C NMR (DMSO) d (ppm) 7.80 (, 2H), 7.39 (m, 2H), 7.11 (m, 1H); 6.80 (d, 1H), 6.72 (d, 1H), 6.36 (d, 1H), 6.34 (dd, 1H), 5.71 (s, 1H), 4.42 (m 2H), 3.77 (m, 1H), 3.3 ( m, 1H), 2.29 (m, 1H), 1.44 (, 1H). IR (Nujol) (crn-1) 1672, 1600.

Example 2 7-Chloro-4- (1-phenyl-β-pyrrolin-2-one-3-yl) -1,2,3,4-tetrahydroquinoline-2-carboxylate of (-) -Sodium To a solution of intermediate 8a (690 mg) in THF / H20 (1/1) (14 ml) is added LiOH (65 mg) and stirring is continued for 1 h. The resulting solution is concentrated to dryness, taken up in ethyl acetate and IN HCl is added. After vigorous stirring, the organic phase is separated, washed with water and brine and concentrated. The resulting residue is dissolved in THF (15 ml) and treated with sodium ethylhexanoate (232 mg) for 30 minutes. After drying, the resulting solid is triturated with hot diethyl ether and filtered, to give the title compound (160 mg) as a white solid. e.e. = 99% [a] D = -102.3 ° (c = 0.09% w / v in DMSO) m.p. > 200 ° C NMR (DMSO) d (ppm) 7.80 (m, 2H), 7.39 (m, 2H), 7.11 (m, 1H), 6.80 (d, 1H), 6.72 (d, 1H), 6.36 (d, 1H), 6.34 (dd, 1H), 5.71 (s, 1H), 4.42 (m, 2H), 3.77 ( m, 1H), 3.13 (m, 1H), 2.29 (m, 1H), 1.44 (m, 1H). IR / Nujol) (cm "1) 1672, 1600.

Example 3 7-Chloro-4- (l-phenyl-? 3-5,6-dihydro-pyridin-2-one-3-yl) -1,2,4,4-tetrahydroquinoline-2-carboxylate of (±) -Ethyl (3a) 7-Chloro-4- (2-oxo-l-phenyl-3-piperidinylidene) -1,2,4,4-tetrahydro-2-quinolinecarboxylate of (+) -Ethyl.

To a solution of intermediate 9 (0.2 g) in DMF (5 ml) are added Pd (PPh3) 4 (41 mg) and TEA (0.1 ml) and the resulting solution is heated at 110 ° C for 2 hours. The crude solution is poured into ethyl acetate and washed with an IN solution of HCl and brine. The organic phase is dried and concentrated to give the crude product which is purified by flash column chromatography to obtain the title compound 3a (0.085 g) as a white powder. m.p. = 131-133 ° C NMR (DMSO) d (ppm) 7.4-7.3 (m, 4H), 7.20 (t, 1H), 6. 78 (d, 1H), 6.75 (d, 1H), 6.48 (dd, 2H), 6.34 (bs, 1H), 5.99 (t, 1H), 4.13 (, 2H), 3.97 (t, 1H), 3.93 (dd, 1H), 3.77 (m, 2H), 2.45 (m, 2H), 2.15 (m, 1H), 1. 85 (m, 1H), 1.19 (t, 3H). IR (Nujol) (cm "1) 3392, 1723, 1659 and the title compound 3b (0.055 g) as a faint yellow powder mp = 99-101 ° C NMR (DMSO) d (ppm) 7.4-7.2 (m , 5H), 7.01 (d, -1H), 6. 93 (d, 1H), 6.68 (d, 1H), 6.52 (dd, 1H), 4.20 (m, 1H), 4.16-3.96 (m, 2H), 3.74-3.60, 3.40 (m, 2H), 2.9-2.5 (m, 3H), 2.0-1.6 (m, 2H), 1.14 (t, 3H).

Example 4 7-Chloro-4- (l-pyridin-3-pyrrolin-2-one-3-yl) -1,2,4,4-tetrahydroquinoline-2-carboxylate of (+) - Ethyl (4a) 7-Chloro-4 - (2-oxo-l- (pyridin-3-yl) -pyrrolidin-3-ylidene) -1, 2, 3, 4-tetrahydro-2-quinolinecarboxylate of (±) -Ethyl (4b) To a solution of Example 3 (0.47 g) in DMF (20 ml) are added Pd (PPh3) 4) (100 mg) and TEA (0.38 ml) and the resulting solution is heated at 110 ° C for 1 1/2 h . The crude solution is poured into ethyl acetate and washed with a saturated solution of NH 4 Cl and brine. The organic phase is dried and concentrated to give the crude mixture which is dissolved in ethyl acetate (2 ml) and treated with petroleum (2 ml), the solid is filtered to give the title compound 4a (0.08 g) like a white powder. m.p. = 132-134 ° C NMR, (DMSO) d (ppm) 8.99 (d, 1H), 8.32 (dd, 1H), 8.21 (, 1H), 7.41 (dd, 1H), 6.80 (d, 1H), 6.77 (m, 1H), 6.75 (d, 1H), 6.47 (dd, 1H), 6.45 (m, 1H), 4.56 (m, 1H), 4.50 (m, 1H), 4.2-4.02 (m, 2H), 3.99 (m, 1H), 3.81 (t, 1H), 2.31 (m, 1H), 1.97 (m, 1H), 1.18 (t, 3H). IR (Nujol) (cpf1) 3391, 1728, 1679 The mother liquor is purified by flash chromatography to obtain a product which is triturated in cyclohexane to obtain the title compound 4b (0.067 g, yellow powder). NMR (DMSO) d (ppm) 8.94 (d, 1H), 8.34 (dd, 1H), 8.14 (, 1H), 7.41 (d, 1H), 7.19 (d, 1H), 7.00 (d, 1H), 6.73 (d, 1H), 6.56 (dd, 1H), 4.27 (m, 1H), 4.20 (m, 1H), 4.00 (m, 1H), 3.89 (m, 1H), 3.85 (m, 1H), 3.72 ( m, 1H), 3.21 (m, 1H), 2.93 (m, 1H), 2.84 (m, 1H), 0.90 (t, 3H). IR (Nujol) (cm "1) 3366, 1734, 1676.

Example 5 , 7-Dichloro-4- (1-phenyl-? 3-pyrrole-2-one-3-yl) -1, 2, 3, 4-tetrahydroquinoline-2-carboxylate of (+) - Ethyl To a solution of intermediate ly (0.430 g) in DMF 10 ml) are added Pd (OAc) 2 (11.6 mg) and TEA (0.12 ml) and the resulting solution is heated at 130 ° C for 2 h. The crude solution is poured into 20 ml of ethyl acetate and washed first with a saturated solution of NH 4 Cl (2 x 15 ml), then with water and brine. The organic phase is dried with Na 2 SO 4 and concentrated to give the crude product. Purification by column chromatography (cyclohexane / dichloromethane / ethyl acetate 60/30/10) gave the title compound (0.087 g) as a discolored white solid. NMR (DMSO) d (ppm) 7.81 (m, 2H), 7.40 (m, 2H), 7.13 (m, 1H), 6.91 (d, 1H), 6.75 (Sa, 1H), 6.68 (d, 1H), 6.45 (m, 1H), 4.46 (m, 2H), 4.17-4.10 (m, 3H), 3.79 (dd, 1H), 2.31 (m, 1H), 1.84 (m, 1H), 1.20 (t, 3H) IR (Nujol) (crn-1) 3390, 1724, 1678.

Example 6 7-Chloro-4- (1- (4-tert-butoxycarbonylamino) -phenyl-3-pyrrolin-2-one-3-yl) -1,2,3,4-tetrahydroquinoline-2-carboxylate (+/-) -Ethyl A solution of intermediate 16 (0.085 g) in dry DMF (5 ml) is stirred in the presence of TEA (0.018 ml) and Pd (OAc) 2 (0.0015 g) under a nitrogen atmosphere at 110 ° C for 1 hour. The mixture is diluted with a saturated aqueous ammonium chloride solution (100 ml) and EA (100 ml); the organic layer is washed with brine (100 ml), dried and concentrated in vacuo. The crude mixture is purified by flash chromatography (eluting with CH / EA 8: 2) to give the title compound as a yellow solid (0.050 g). T.l.c. CH-EA (8: 2) Rf = 0.30. ^ -NMR: 9.30 (sa); 7.64 (d); 7.43 (d); 6.80 (d); 6.75 (d); 6.63 (m); 6.46 (dd); 6.42 (sa); 4.40 (m); 4.13 (m); 3.92 (m); 3.78 (m); 2.31 (m); 1.94 (m); 1.45 (s); 1.18 (t) .- Example 7 7-Chloro-4- (1- (4-amino) -phenyl-? 3-pyrrolin-2-one-3-yl) -1,2,4,4-tetrahydroquinoline-2-carboxylate of (+/-) Ethyl To a solution of Example 6 (0.070 g) in ethyl acetate (35 mL) conc. HCl is added. (2.0 ml). The mixture is stirred at r.t. under nitrogen atmosphere for 1 hour. The mixture is poured into a saturated aqueous solution of NaHCO 3 (100 ml) and extracted with EA (200 ml); the organic layer is dried and concentrated in vacuum. The crude mixture is purified by flash chromatography (eluting with CH / EA 1: 1) to give the title compound - as a yellow solid (0.043 g). T.l.c. EA Rf = 0.289. IR: 3388 (NH), 3161 (NH2), 1718 and 1670 (C = 0) c "1 XH-NMR: 7.36 (d); 6.80 (d); 6.75 (d); 6.56 (m); 6.47 (dd); 6.41 (sa); 4.97 (); 4.32 (m); 4.14 (m); 3.91 (m); 3.77 (m); 2.31 (m); 1.94 (m); 1.19 (t).

Example 7-Chloro-4- (1- (4-acetylamino) -phenyl-? 3-pyrrolin-2-one-3-yl) -1,2,3,4-tetrahydroquinoline-2-carboxylate of (+/-) - Ethyl To a solution of example 7 (0.030 g) in dry pyridine (1 ml), * Ac20 (0.012 ml) is added. The mixture is stirred at t.a. under nitrogen atmosphere for 30 minutes. The mixture is poured into a saturated aqueous solution of NH4C1 (50 ml) and extracted with EA (50 ml), the organic layer is dried and concentrated in vacuo. The crude mixture is triturated with EA to give the title compound as a white solid (0.025 g).

T.l.c. CH / EA (1: 1) Rf = 0.33. IR: 3401 (NH), 1730, 1675, 1651 (C = 0) cm "1. d 1H-N R: 9.9 (s); 7.69 (d); 7.56 (d); 6.80 (d); 6.75 (d); 665 (m); 6.47 (dd); 6.43 (sa); 4.5-4.37 (m); 4. 13 (m); 3.93 (m); 3.79 (m); 2.3-1.94 (m); 2.03 (s); 1. 19 (t).

Example 9 7-Chloro-4- (1- (4-methanesulfonylamino) -phenyl-? 3-pyrrolin-2-one-3-yl) -1,2,3,4-tetrahydroquinoline-2-carboxylate of (+/-) -Ethyl To a solution of Example 7 (0.040 g) - in dry CH2C12 (10 ml) is added DIPEA (0.021 ml) and CH S02C1 (0.008 ml). The mixture is stirred at t.a. under nitrogen atmosphere for 1 h. The mixture is poured onto a saturated aqueous solution of NH C1 (50 ml) and extracted with EA (50 ml), the organic layer is dried and concentrated in vacuo. The crude mixture is purified by flash chromatography (eluting with CH / EA (1: 1) to give the title compound as a yellow solid (0.027 g).

T.l.c. CH / EA (1: 1) Rf = 0.63. IR: 3394 (NH, 1726, 1680, 1635 (C = 0), (C = C) cm "1. ^ -NM: 7-89 (d), 7.52 (d), 6.81 (d), 6.76 (d) ), 6.76 (s), 6.47 (dd), 6.45 (s), 4.52 (), 4.13 (m), 3.94 (m), 3.81 (m), 3.51 (s), 2.3-1.97 (m), 1.19 ( t) Example 10 7-Chloro-4- (2-oxo-l- ((4-tert-butoxycarbonylamino) phenyl-pyrrolidin-3-ylidene) -1,2,3,4-tetrahydro-2-quinoxy-carboxylate of (±) - Ethyl A solution of intermediate 16 (1.02 g) in dry DMF (100 ml) is stirred in the presence of TEA (0.018 ml) and Pd (PPh3) (0.184 g) under a nitrogen atmosphere at 110 ° C for 2 h until which complements the reaction (TLC). The mixture is diluted with a saturated aqueous ammonium chloride solution (100 ml) and EA (200 ml); the organic layer is washed with brine (200 ml), dried and concentrated in vacuo. The crude mixture is purified by flash chromatography (eluting with CH / DCM / EA 5: 4: 1) to give the title compound (280 mg). IR: 3350 (NH), 1718 and 1670 (C = 0) cm "1. H-NMR: 9.32 (s); 759 (d); 7.43 (d); 7.17 (d); 6.94 (d); 6.72 (d); m), 6.55 (dd), 4.26 (dd), 4.19 (m), 4.04-3.88 (m), 3.8-3.6 (m), 3.18 (m), 2.94-2.86 (m), 1.46 (s), 0.92. (t).

Example 11 7-Chloro-4- (2-oxo-l- (4-amino) phenyl-pyrrolidin-3-ylidene) -1, 2, 3, 4- tetrahydro-2-quinolinecarboxylate of (±) -Ethyl To a solution of Example 10 (0.280 g) in ethyl acetate (100 mL) is added concentrated HCl (9.5 mL). The mixture is stirred at t.a. under nitrogen atmosphere for 1 h until the reaction complements (Tic). The mixture is poured into a saturated aqueous solution of NaHCO3 (100 mL) and extracted with EA (200 mL); the organic layer is dried and concentrated in vacuo. The crude mixture is triturated with CH / EA 1: 1 to give the title compound as a yellow solid (0.191 g). T.l.c. EA Rf = 0.33. IR: 3464-3406 (NH), 3364 (NH2), 1730, 1658 and 1633 (C = 0) c "1. XH-NMR: 7.31 (d), 7.16 (d), 6.91 (day), 6.71 (d) ); 655 (d); 6.54 (dd); 5.01 (s); 4.26 (dd): 4.17 (m); 4.04-3.9 (m); 3.74-3.54 (m); 3.14 (m); 2.87 (m);; 0.96 (t).

Example 12 7-Chloro-4- (2-oxo-l- (4-acetylamino) phenyl-pyrrolidin-3-ylidene) -1, 2, 3, 4-tetrahydro-2-quinolinecarboxylate of (±) -Ethyl To a solution of intermediate 19 is added dry pyridine (1 ml) Ac20 (0.010 ml). The mixture is stirred at r.t. under nitrogen atmosphere for 30 minutes. The mixture is poured onto a saturated aqueous solution of NH C1 (50 ml) and extracted with EA (50 ml), the organic layer is dried and concentrated in vacuo. The crude mixture is triturated * with EA to give the title compound as a yellow solid (0.027 g). T.l.c. CH / EA (1: 1) Rf = 0.63. IR: 3396-3325 (NH), 1724-1685 (C = 0) cm "1 H-NMR: 9.92 (s); 7.62 (d), 7.55 (d); 7.16 (d); 6.95 (da); 6.71 (d); 655 (dd); 5.01 (s); 4.25 (dd); 4.18 (m); 4.1-3.85 (m); 3.77 (m); 3.64 (m); 3.18 (m); 2.88 (m); ); 2.01 (s); 0.91 (t).

Example 13 7-Chloro-4- (2-oxo-l- ((4-methanesulfonyl-amino) phenyl-pyrrolidin-3-ylidene) -1,2,3,4-tetrahydro-2-quinoline-carboxylate of (+) - Ethyl To a solution of Example 12 (0.040 g) in dry CH2C12 (10 mL) are added DIPEA (0.021 mL) and CH3S02C1 (0.008 mL). The mixture is stirred at r.t. under nitrogen atmosphere for 1 h (Tic). The mixture is poured onto a saturated aqueous solution of NH 4 Cl (50 ml) and extracted with EA (50 ml), the organic layer is dried and concentrated in vacuum. The crude mixture is crystallized with CH / EA (1: 1) to give the title compound as a yellow solid (0.023 g). T.l.c. CH / EA (1: 1) Rf = 0.63. IR: 3384 (NH), 1734, 1683 (C = 0), 1600 (C = C) cm "1. XH-NMR: 7.83 (d), 7.53 (d), 7.21 (d), 7.00 (d); 6.75 (d), 6.57 (dd), 4.2-4.3 (m), 4.01 (m), 3.93 (m), 3.87 (m), 3.73 (m), 3.52 (s), 3.22 (m), 3.0-2.9 (); 0.95 (t).

Example 14 7-Chloro-4- (1-3-pyridin) -? 3-pyrrolin-2-one-3-yl) -1,2,4,4-tetrahydroquinoline-2-carboxylate of (±) -Sodium To a solution of example 4a (70 mg) in IMS (5% methanol in ethanol) 10 ml) is added an IN NaOH solution (0.18 ml) and the reaction mixture is stirred for 1 1/2 hours. The solvent is evaporated and the crude product is triturated first in methanol / ethyl acetate 05ml / 2ml then in isopropyl alcohol (3ml) to give the title compound (40mg) as a faint yellow solid. m.p. > 220 ° C NMR (CDC13) d (ppm) 8.98 (d, 1H), 8.31 (dd, 1H), 8.21 (m, 1H), 7.421 (m, 1H), 6.79 (d, 1H), 6.72 (d, 1H), 6.42 (d, 1H), 6.33 (dd, 1H), 5.71 (s, 1H), 4.50 (m, 1H), 4.44 (m, 1H), 3.76 (m, 1H), 3.11 (m, 1H), 2.27 (m, 1H), 1.43 (m, 1H). IR (Nujol) (cm "1) 3300, 1684.

Example 15 7-Chloro-4- (l-phenyl-? 3-5, 6-dihydro-pyridin-2-one-3-yl) -1, 2, 3, 4-tetrahydroquinoline-2-carboxylate of (+) -Sodium A solution of example 3a (80 mg) in IMS (5% methanol in ethanol) (6 ml) is added a 0. IN NaOH solution (2.9 ml) and the reaction mixture is stirred for 1 hour. The solution is poured into ethyl acetate and washed with an IN solution of HCl and brine. The organic phase is dried with Na 2 SO and concentrated to give the crude acid compound. The latter is suspended in ethyl acetate (2 ml) and sodium 2-ethylhexanoate (35 mg) is added obtaining a solution. Diethyl ether (4 ml) and petroleum ether (3 ml) are added to precipitate the title compound (42 mg) as a white solid. m.p. > 163-166 ° C NMR (DMSO) d (ppm) 7.4-7-34 (m, 4H), 7.19 (, 1H), 6.72 (d, 1H), 6.67 (d, 1H), 6.32 (d, 1H) , 6.32 (dd, 1H), 5.71 (t, 1H), 5.64 (s, 1H), 3.96 (m, 1H), 3.8-3.65 (m, 2H), 3.17 (dd, 1H), 2.4 (m, 2H ), 2.08 (1H), 1.3 (m, 1H) IR (Nujol) (cm "1) 3373, 1658, 1653 Example 16 ,7-Dichloro-4- (l-phenyl-? 3-pyrrolin-2-one-3-yl) -1,2,4,4-tetrahydroquinoline-2-carboxylate of (±) -Sodium To a solution of example 5 (87 mg) in IMS (5% methanol in absolute ethanol, 5 ml) is added NaOH (1N, 0.22 ml) and stirring is continued for 3 hours. The resulting solution is dried on a rotary evaporator and the resulting solid is triturated with diethyl ether. After filtration and drying, the title compound (78 mg) is obtained as a colorless white solid. NMR (DMSO) d (ppm) 7.80 (m, 2H), 7.38 (t, 2H), 7.10 (t, 1H), 6.82 (d, 1H), 6.46 (d, 1H), 6.37 (s, 1H), 6.11 (s, 1H), 4.42 (s, 2H), 3.98 (d, 1H), 3.05 (dd, 1H), 2.24 (dd, 1H), 1.34 (m, 1H) IR (Nujol) (cm "1) 3385, 1663, 1591, 1555 Example 17 7-Chloro-4- (1-phenyl-3-pyrrolin-2-one-3-yl) -1,2,3,4-tetrahydroquinoline-2-carboxylate of (+) -Sodium Method AA a solution of intermediate 13 (110 mg) in THF / H20 (1/1) (3 ml) is added LiOH (11 mg) and stirring is continued for 1 hour. The resulting solution is concentrated to dryness, taken up in ethyl acetate and IN HCl is added.

After vigorous stirring, the organic phase is separated, washed with water, and brine and concentrated.

The resulting solid is dissolved in THF (15 ml) and treated with sodium ethylhexanoate (39 mg) for 30 minutes. After drying, the resulting solid is triturated with warm diethyl ether and filtered, to give the title compound (69 mg) as a white solid. e.r. = 98% [a] D = 92.5 ° (c = 0.420% w / v in DMSO) m.p. > 200 ° C NMR (DMSO) 5 (ppm) 7.80 (m, 2H), 7.39 (m, 2H), 7.11 (m, 1H), 6.80 (d, 1H), 6.72 (d, 1H), 6.36 (d, 1H), 6.34 (d, 1H),, 5.71 (s, 1H), 4.42 (m, 2H), 3.77 (m, 1H), 3.13 (, 1H), 2.29 (m, 1H), 1.44 (m, 1H). IR (Nujol) (cm "1) 1672, 1600.

Method B Starting from Example 28 using the procedure described for Example 21 (Method B).

Example 1' Acid (+/-) -7-Chloro-4- (1- (4-acetylamino) -phenyl-3-pyrrolin-2-one-3-yl) -1,2,3,4-tetrahydroquinoline-2-carboxylic acid To a solution of Example 8 (0.023 g) in IMS (5 mL) is added NaOH (0.150 mL) and the mixture is stirred at r.t. for 1 h. The mixture is poured into a 6N HCl solution (50 ml) and extracted with EA (50 ml), the organic layer is washed with brine (30 ml), dried and concentrated in vacuum. The crude mixture is triturated with Et20 to give the title compound as a yellow solid (0.019 g). T.l.c.

EA Rf = 0.2. IR: 3401 (NH, OH), 1734, 1651 (C = 0) cm "1 ^ -NMR: 1284 (bs), 9.9 (s), 7.69 (d), 7.56 (d), 6.80 (d), 6.76 (d), 6.6 (d), 6.45 (dd), 6.33 (sa), 4.42 (m), 3.84-3.78 (m), 3.70 (m), 2.3 (m), 2.017 (s), 1.9 (m), .

Example 19 Acid (+/-) 7-Chloro-4- (1- (-metanesulfonylamino) -phenyl-? 3-pyrrolin-2-one-3-yl) -1,2,3,4-tetrahydroquinoline-2-carboxylic acid To a solution of Example 9 (0.027 g) in IMS (5 ml) is added NaOH (0.142 ml). The mixture is stirred at r.t. for 2 h. The mixture is poured into a 6N HCl solution (50 ml) and extracted with EA (50 ml), the organic layer is washed with brine (30 ml), dried and concentrated in vacuo. The crude mixture is crystallized with CH / EA (1: 1) to give the title compound as a yellow solid (0.015 g). T.l.c. EA Rf = 0.2. IR: 3346 (NH,), 1732- (C = 0), 1337-1154 (S02) cm "1. XH-NMR: 13-12 (broad); 9.61 (s); 7.75 (d); 7.21 (d) ), 6.80 (d), 6.76 (d), 6.63 (dd), 6.46 (dd), 6.34 (dd), 4.43 (m), 3.85-3.78 (m), 2.93 (s), 2.3 (m), 1.92 (m).

Example 20 7-Chloro-4- (2-oxo-2-phenyl-3-pyrro1idinylidene) -1,2,3,4-tetrahydro-2-quinolinecarboxylate of (+) -Sodium To a solution of example 31b (540 mg) in IMS (5% methanol in absolute ethanol, 7 ml) is added NaOH (IN, 1.4 ml) and stirring is continued for 2 hours. The resulting suspension is filtered and the solid is washed with small portions of diethyl ether. After drying, the title compound (450 mg) was obtained as a yellow solid. m.p. > 200 ° C NMR (DMSO) d (ppm) 7.74 (d, 2H), 7.37 (t, 2H), 7.11 (t, 1H), 7.12 (d, 1H), 6.77 (d, 1H), 6.38 (dd, 1H), 6.13 (bs, 1H), 4.48 (dd, 1H), 3.78 (m, 2H), 3.2-3.4 (m, 2H), 2.90 (m, 1H), 1.98 (m, 1H) E pg 21 7-Chloro-4- (2-oxo-l-phenyl-3-pyrrolidinylidene) -1,2,3,4-tetrahydro-2-quinolinecarboxylate of (-) -Sodium Method A To a solution of intermediate 8b (790 mg) in THF / H20 (1/1) (16 ml) is added LiOH (73 mg) and stirring is continued for 1 hour. The resulting solution is concentrated to dryness, taken up in ethyl acetate and 1 N HCl is added. After vigorous stirring, the organic phase is separated, washed with water and brine and concentrated. The resulting solid is dissolved in THF (15 ml) and treated with sodium ethylhexanoate (265 mg) for 30 minutes. After drying, the resulting solid is triturated with hot ethyl acetate and filtered to give the title compound (400 mg) as a yellow solid. ee = 88.8% [CL. D -603.7 ° (c = 0.316% w / v in DMSO) m.p. > 200 ° C NMR (DMSO) d (ppm) 7.74 (d, 2H), 7.37 (t, 2H), 7.11 (t, 1H), 7.12 (d, 1H), 6.77 (d, 1H), 6.38 (dd, 1H), 6.13 (bs, 1H), 4.48 (dd, 1H), 3.78 (m, 2H), 3.2-3.4 (m, 2H), 2.90 (m, 1H), 1.98 (m, 1H) IR (Nujol) (cm "1) 3425, 1666, 1592 Method B To a solution of example 27 (3.18 g) in IMS (5% methanol in ethanol) (100 ml) is added a solution 1 of NaOH (8.64 ml): the sodium solution precipitates after 5 minutes. To the resulting solution is added diethyl ether (50 ml) and the solid is filtered. The solution is evaporated and the solid obtained is mixed with the previous one and triturated with diethyl ether to give the title sodium salt (3.2 g) as a yellow solid. m.p. > 220 ° C NMR (DMSO) d (ppm) 7.74 (d, 2H), 7.37 (t, 2H), 7.11 (t, 1H); 7.11 (d, 1H); 6.76 (d, 1H); 6.38 (dd, 1H), 6.11 (s, 1H); 4.48 (dd, 1H); 3.78 (m, 2H); 3.4-3.2 (m, 2H); 2.9 (m, 1H); 1.95 (m, 1H). IR (Nujol) (c "1) 3392, 1669. [a] D -603.7 ° (c = 0.316% w / v in DMSO) e.e.: 96% Method C 125 g of Aspergillus niger lipase (Amano AP12) is suspended in 650 ml of lOOmM calcium chloride solution in a stirred reactor.

The suspension is cooled to 15 ° C. 50 g of Example 31b were then dissolved in dimethyl sulfoxide (350 ml) and this solution is added to the reactor. The reactor is then heated to 37 ° C and the mixture is stirred for 24 hours. The temperature of the reactor is allowed to reduce to 20 ° C and 1 liter of 0.2M hydrochloric acid is slowly added to the reactor. The reactor is then emptied and 50 g of the filtration aid (Dicalite) are added to the reaction mixture. Then the mixture is filtered and the filter cake is washed with water, before being dried. A 20 g sample of the dried filter cake is dispersed in 390 ml of methyl t-butyl ether and 10 ml of 2M hydrochloric acid are added. This is stirred for 3 hours and filtered, the filter cake is washed with 100 ml of methyl t-butyl ether. The product was again extracted from the methyl t-butyl ether in 500 ml of 0.05M sodium hydroxide solution. The aqueous layer is then separated, acidified with 6 ml of 5M hydrochloric acid and the product is extracted into 500 ml of ethyl acetate. The ethyl acetate is removed by evaporation and the residue is dissolved in IMS (80 ml). The title compound is identified in this solution by the HPLC assay as follows: 0.5 ml of the reaction mixture is diluted in 2 ml of DMSO and mixed to dissolve. 5 ml of this solution are further diluted in 1 ml of the mobile phase (70% acetonitrile in 20mM ammonium acetate pH 3.0), Column: Spherisorb C6 50x4.6mm, Flow rate. 1 ml / min., Detection of UV adsorption at 254 nm, Injection Vol. 10 ul, Retention time: 0.8 min. The solution is diluted to 96 ml with IMS and stirred while 10 ml of 1M sodium hydroxide are added dropwise over 15 minutes. 40 ml of diethyl ether are added for 10 minutes and stirring is continued for 1 hour. The mixture is then placed in the refrigerator for 1 hour and the product is filtered, washed with 50 ml of cold diethyl ether before being dried overnight under vacuum to obtain the title compound (3.3 g). HPLC analysis: the title compound was dissolved in DMSO at 1 mg / ml. 10 ul of this are diluted in 990ul of the mobile phase.

Column: Phenomenex Luna Phenyl hexyl 150x4.6 mm, Injection volume: 50 ul, Retention time: 3.4 min.

Example 22 7-Chloro-4- (2-oxo-l- (pyridin-3-yl) -pyrrolidin-3-ylidene) -1, 2,3,4-tetrahydro-2-quinolinecarboxylate (±) -Sodium To a solution of example 4b (55 mg) in IMS (5% methanol in ethanol) (10 ml) is added an IN NaOH solution (0.145 ml) and the reaction mixture is stirred for 1 1/2 hours. The solvent is evaporated and the crude product is triturated in ethyl acetate (2 ml) to give the title compound (38 mg) as a yellow solid. m.p. > 220 ° C NMR (DMSO) d (ppm) 8.96 (d, 1H), 8.32 (dd, 1H), 8.18 (m, 1H), 7.40 (m, 1H), 7.12 (d, 1H), 6.78 (d, 1H), 6.38 (dd, 1H), 6.15 (s, 1H), 4.46 (m, 1H), 3.83 (m, 2H), 3.3-3.2 (m, 2H), 2.92 (m, 1H), 1.97 (m , 1 HOUR) . IR (Nujol) (cm "1) 3361, 1669.

Example 23 Acid (±) -7-Chloro-4- (2-oxo-l-phenyl-3-piperidinylidene) -1,2,3,4-tetrahydro-2-quinolinecarboxylic acid To a solution of example 3b (48 mg) in IMS (5% methanol in ethanol) (2 ml) is added a 0. IN NaOH solution (1.2 ml) and the reaction mixture is stirred for 2 1/2. hours. The solution is poured into ethyl acetate and washed with an IN solution of HCl and brine. The organic phase is dried and concentrated to give the crude product which is triturated in ethyl acetate / petroleum 2 ml / 5 ml, to give the title compound (14 mg) as a yellow solid. m.p. > 130-133 ° C NMR (DMSO) d (ppm) 12.64 (s, 1H), 7.38 (t, 2H), 7.30 (d, 2H), 7.22 (t, 1H), 6.99 (d, 1H), 6.87 ( bd, 1H), 6.67 (d, 1H), 6.50 (dd, 1H), 4.08 (m, 1H), 3.54 (m, 2H), 3.43 (m, 1H), 2.83 (m, 1H), 2.72 (m , 1H), 2.58 (1H), 1.93-1.8 (m, 2H). IR (Nujol) (cm "1) 3348, 1732, 1717 MS (m / z) 383 Example 24 (+) -7-Chloro-4- (2,5-dioxo-l-phenyl-imidazolidin-4-ylidene) -1,2,3,4-tetrahydro-2-quinolinecarboxylic acid To a solution of intermediate 18 (10 mg) in CH2C12 (5 ml) is added an BCl3 in hexane (0.1 ml) at -78 ° C and the reaction mixture is stirred for 1 1/2 hours keeping the temperature at -20 to -10 ° C. The solution is poured into ethyl acetate and washed with a 3N HCl solution and brine. The organic phase is dried with Na 2 SO 4 and concentrated to give the crude product which. triturate in diethyl ether / petroleum (1 ml / 3ml), to give the title compound (6 mg) as a yellow solid. m.p. > 190 degrees C NMR (DMSO) d (ppm) 12.75 (bs, 1H), 10.50 (bs, 1H), 7.50-7.39 (m, 6H), 6.99 (bs, 1H), 6.76 (d, 1H), 6.57 (dd, 1H), 4.15 (m, 1H), 3.77 (m, 1H), 3.17 (dd, 1H). IR (Nujol) (cm "1) 3400, 2800, 1746, 1701 Example 25 Acid (+/-) -7-Chloro-4- (2-oxo-l- (4-acetylamino) phenyl-pyrrolidin-3-ylidene) -1,2,3,4-tetrahydro-2-quinoline-carboxylic acid To a solution of Example 12 (0.027 g) in THF H20 (3: 1) (10 mL) is added LiOH (0.010 g). The mixture is stirred at r.t. for 1 h. The mixture is poured onto a saturated aqueous solution of NH 4 Cl (50 ml) and extracted with EA (50 ml), the organic layer is washed with brine (30 ml), dried and concentrated in vacuo. The crude mixture is triturated with EA to give the title compound as a yellow solid (0.020 g). T.l.c. CH / EA (1: 1) Rf = 0.2. IR: 3400-2700 (NH, OH), 1660 (C = 0) c "1. ^ -NMR: 12.63 (sa), 9.94 (sa), 7.65 (d), 7.58 (d), 7.20 (d), 6.83 (sa), 6.74 (d), 654 (dd), 4.03 (m), 3.78 (m), 3.70 (m), 3.2-2.6 (m), 2.03 (s).

Example 26 Acid (+/-) 7-Chloro-4- (2-oxo-l- ((4-methanesulfonyl amino) phenyl-pyrrolidin-3-ylidene) -1,2,3,4-tetrahydro-2-quinolinecarboxylic acid To a solution of Example 13 (0.023 g) in IMS (5 mL) is added NaOH (0.120 mL). The mixture is stirred at r.t. for 2 hours. The mixture is poured into a 6N HCl solution (50 ml) and extracted with EA (50 ml), the organic layer is washed with brine (30 ml), dried and concentrated in vacuo. The crude mixture is chromatographed with Et20 to give the title compound as a yellow solid (0.007 g). T.l.c. CH / EA (1: 1) Rf = 0.2 IR: 3411 (NH,), 1692, 1651-1583 (C = 0), (C = C), 1306-1154 (S02) cm "1. 1H-NMR: 9.65 (s); 7.69 (d); 7.22 (d); 7.20 (d); 6.73 (d); 655 (dd); 4.03 (m); 3.8-3.5 (m); 3.3-2.9 (m); 2.9 (s) Example 27 7-Chloro-4- (2-oxo-l-phenyl-3-pyrrolidinylidene) -1,2,3,4,4-tetrahydro-2-quinolinecarboxylic acid (enantiomer A_ To a solution of intermediate 22 (6.2 g) in THF / H20 (100 ml), (3/1) at room temperature LiOH (1 g) is added and stirring is continued for 1 hour. The THF is evaporated and H20 (100 ml) is added. The resulting solution is washed with diethyl ether (2 × 50 ml). The aqueous phase is acidified to pH = 4 with 10% HCl and the product is extracted with ethyl acetate (2x100 ml). The organic phase is washed with water and brine, dried and evaporated to give the title compound (4.2 g) as a yellow solid. m.p. > 200 ° C NMR (DMSO) d (ppm) 12.62 (bs, 1H), 7.72 (d, 2H), 7.38 (t, 2H), 7.20 (d, 1H), 7.13 (t, 1H), 6.86 (d, 1H), 6.74 (d, 1H), 6.54 (dd, 1H), 4.06 (m, 1H), 3.86-3.68 (m, 3H), 3.3 (m, 1H), 3.18-2.88 (m, 2H). IR (nujol): 3356, 1724 Example 28 7-Chloro-4- (2-oxo-l- phenyl-? 3-pyrrolin-2-one-3-yl) -l, 2,3, 4-tetra idroquinol in-2-carboxylic acid; (enantiomer A) To a solution of intermediate 10 (1289 g) in THF / H20 (30 ml, 3/1) at room temperature is added 1 OH (0.24 g) and stirring is continued for one hour. The THF is evaporated and H20 (80 ml) is added. The resulting solution is washed with diethyl ether (2 × 50 ml). The aqueous phase is acidified to pH = 4 with 10% HCl and the product is filtered and washed with water (10 ml). The product is dried under vacuum at 60 ° C for 12 hours to obtain 0.734 g as a white solid, m.p. : 190 ° C e.e. 100% NMR (DMSO) d (ppm) 12.86 (bs, 1H); 7.79 (d, 2H), 7.38 (t, 2H), 7.11 (d, 1H), 6.81 (d, 1H), 6.77 (d, 1H), 6.64 (s, 1H), 6.46 (dd, 1H); 6.34 (s, 1H); 4.46 (m, 1H), 3.82-3.79 (m, 2H), 2.34 (m, 1H); 1.92 (m, 1H). IR (nujol): 3356, 1724 Example 29 Sodium, 5,7-dichloro-4- (2-oxo-l-phenyl-3-pyrrolin-2-one-3-yl) -1,2,4,4-tetrahydroquinoline-2-carboxylic acid (enantiomer TO) To a solution of intermediate 26a (0.35 g) in THF / H20 (10 ml, 371) at room temperature is added LiOH (0.06 g) and stirring is continued for 30 minutes. The THF is evaporated and H20 (5 ml) is added. The resulting solution is washed with diethyl ether (2 × 50 ml). The aqueous phase is acidified to pH = 4 with 10% HCl and the product is filtered and dried under vacuum at 60 ° C for 12 hours to give the title compound (0.134 g) as a white solid. The solid is dissolved in IMS (5% methanol in ethanol) (10 ml) and a ln NaOH solution (0.33 ml) is added. To the resulting suspension is added diethyl ether (10 ml) and the solid is filtered, washed with diethyl ether (10 ml) and dried under vacuum for 12 hours to give the title compound (0.082 g) as a white solid. m.p. > 220 ° C NMR (D20) d (ppm) 7.49 (d, 2H); 7.40 (t, 2H); 7.23 (t, 1H); 6.74 (d, 1H); 6.70 (d, 1H); 6.51 (m, 1H); 4. 40-4.35 (m, 2H), 4.11 (m, 1H); 3.53 (dd, 1H); 2.18 (m, 1H); 1.74 (td, 1H) HPLC column: Cyclobond I, R, S-hydroxypropyl ether 25 cm × 4.6 mm; Mobile phase: methanol = 50 20 mM Ammonium Acetate buffer solution pH 5 = 50% by volume; flow rate: 1 ml / minute; Retention time: 12 minutes.

Example 30 Sodium 5,7-Dichloro-4- (2-oxo-l- (phenyl) -pyrrolidin-3-ylidene) -1,2,3,4-tetrahydro-2-quinolinecarboxylate (enantiomer A) To a solution of intermediate 26b (0.052 g) in THF / H20 (4 ml, 3/1) at room temperature, add LIOH (0.01 g) and stirring is continued for 30 minutes. THF is evaporated and H20 (2 ml) is added. The resulting solution is washed with diethyl ether (2 x 50 ml). The aqueous phase is acidified to pH = 4 with 10% HCl and the product is filtered and washed with water (10 ml) and dried under vacuum at 60 ° C for 12 hours to obtain 5,7-dichloro- 4- (2-Oxo-l- (pyridin-3-yl) -pyrrolidin-3-ylidene) -1,2,3,4-tetrahydro-2-quinoline carboxylic acid (0.033 g) as a yellow solid. The solid is dissolved in IMS (5% methanol in ethanol) (5 ml) and an IN NaOH solution is added. After 5 minutes, the solvent is evaporated and the solid is triturated with diethyl ether (5 ml), filtered, dried under vacuum for 12 hours to give the title compound (0.01 g) as a yellow solid, m.p. : > 200 ° NMR (DMSO) d (ppm) 7.74 (d, 2H); 7.39 (t, 2H); 7.15 (t, 1H); 6.76 (d, 1H); 6.51 (d, 1H); 6.20 (m, 1H); 4.63 (dd, 1H), 3.78 (m, 2H); 3.41 (dd, 1H); 3.18 (m, 1H); 2.35 (dd, 1H); 1.81 (t, 1H). IR (nujol: 3363, 1688, 1630, 1586 cm -i E p e 31 7 -. 7 -. 7-Chloro -4- (i-phenyl- •? 3 -pyrrolin-2-one -3i D-1,2,3,4-tetrahydroqu: inolin- • 2-carboxylate of (±) -Ethyl ( 31a) 7-Chloro -4- (2-oxo-1- • phenyl-3-pyrro.lidinylidene) -1,2,3,4-tetrahydro-2-quinol-incarboxylate of (±) -Ethyl (31b) To a solution of intermediate 4 (2.2 g) in DMF (50 ml) are added (Pd (PPh3) (244 mg) and TEA (1.2 ml) and the resulting solution is heated at 110 ° C for 2 hours. The crude product is poured into 200 ml of ethyl acetate and washed first with a saturated solution of NH 4 Cl (2 x 150 ml), then with water and brine.The organic phase is dried and concentrated to give the crude product. column chromatography (cyclohexane / dichloromethane / ethyl acetate 50/40/10) Rf = 0.41 gave the title compound 31a (540 mg) as a discolored white solid. m.p. = 150-153 ° C NMR (DMSO) 5 (ppm) 7.80 (m, 2H), 7.39 (m, 2H), 7.12 (m, 1H), 6.83 (d, 1H), 6.77 (d, 1H), 6.69 (m, 1H), 6. 48 (dd, 1H), 6.45 (s, 1H), 4.48 (m, 2H), 4.15 (m, 2H), 3.94 (, 1H), 3.82 (m, 1H), 2.34 (, 1H), 1.97 (m, 1H), 1.20 (t, 3H) IR (Nujol) (cm "1) 3385, 1728, 1680 and the title compound 31b (475 mg) Rf = 0.29 as a yellow solid mp = 152-156 ° C NMR (DMSO) d (ppm) 7.72 (, 2H), 7.39 (m, 2H), 7.20 (d, 1H), 7.16 (m, 1H), 6.98 (d, 1H), 6.74 (d, 1H), 6. 57 (dd, 1H), 4.29 (dd, 1H), 4.21 (m, 1H), 4.02 (m, 1H), 3.93 (m, 1H), 3.82 (m, 1H), 3.69 (m, 1H), 3.20 (m, 1H), 2.92 (m, 2H), 0.93 (t, 3H) Example 31a 7-Chloro-4- (l-phenyl-? 3-pyrrolin-2-one-3-yl) -1,2,3,4-tetrahydroquinoline-2-carboxylate of (±) -Ethyl To a solution of intermediate 4a (0.1 g) in dry DMF (5 ml) are added Pd (OAc) 2 (10 mg) and TEA (0.026 ml). The mixture is heated at 110 ° C for 2 hours, then diluted with a saturated solution of NH 4 Cl and extracted with ethyl acetate. (2x10 ml). The solvent is evaporated and the crude product is purified by flash chromatography (Cyclohexane / EA 8: 2) to give the title compound as a white solid (40 mg).

Example 31b 7-Chloro-4- (2-oxo-l-phenyl-3-pyrrolidinylidene)) -1, 2, 3, 4-tetrahydro-2-quinolinecarboxylate of (±) -Ethyl To a solution of intermediate 4b (370 g) in toluene (5.2 lit), triethylamine is added (248 ml), triphenylphosphine (7.4 g) and PdCl 2 (2.52 g).

The resulting solution is heated to 100 ° C and stirred for 2 h. The suspension is cooled to 20-25 ° C and toluene (2.6 ml) is added. The reaction mixture is washed with 8% NH 4 Cl (3x5.2 lit) and water (5.2 lit). The organic layer is filtered on a celite pad and washed with toluene (1 lit); then it is distilled under vacuum (T = 50 ° C, P = 60 mbar) to reach 6.3 lit. After cooling to T = 20-25 ° C, isooctane (5.2 lit) is added dropwise during 30 minutes. The precipitate is stirred for 2h 30 minutes then it is filtered and washed with a 1/1 toluene / isooctane mixture (1.851it). The yellow solid is dried in vacuum at T = 40 ° C for 18 h to obtain the title compound as a yellow solid 210 g. m.p. 160-162 ° C NMR (DMSO): 7.72 (m, 2H); 7.39 (m, 2H); 7.20 (d, 2H); 7.15 (m, 2H); 6.96 (dd, 1H); 6.74 (d, 1H); 6.57 (dd, 1H); 4.29 (dd, 1H); 4.21 (m, 1H); 4.02 (m, 1H); 3.93 (m, 1H); 3.82 (m, 1H), 3.69 (m, 1H); 3.20 (m, 1H); 2.92 (m, 2H); 2.92 (m, 2H); 0.93 (t, 3H).

Examples of Pharmacy A. Capsules / Tablets Active ingredient 20.0 mg Starch 1500 2.5 mg Microcrystalline Cellulose 200.0 mg Croscarmellose Sodium 6.0 mg Magnesium Stearate 1.5 mg The active ingredient is combined with the other excipients. The mixture can be used to fill the gelatin capsules or compressed to form tablets using appropriate punches. The tablets can be coated using conventional techniques and coatings.

B. Tablets Active ingredient 20.0 mg Lactose 200.0 mg Microcrystalline cellulose 70.0 mg Povidone 25.0 mg Croscarmellose Sodium 6.0 mg Magnesium stearate 1.5 mg The active ingredient is combined with lactose, microcrystalline cellulose and part of croscarmellose sodium. The mixture is granulated with povidone after dispersion in a suitable solvent (ie water). The granule, after drying and grinding, is combined with the remaining excipients. The mixture can be compressed using appropriate punches and the tablets are coated using conventional techniques and coatings. c) Bolo Active ingredient 0.1-32 mg / ml Sodium phosphate 1.0-50.0 mg / ml Water for injection c.a. up to 1 ml The formulation can be packed in glass ampoules or ampoules and syringes with a rubber stopper and a plastic / metal overlay (ampoules only).

D) Infusion Active ingredient 0.01-3.2 mg / ml 5% dextrose injection q.s. up to 100 ml The formulation can be packed in glass ampoules or a plastic bag. The affinity of the compound of the invention towards the strychnine-insensitive glycine binding site is determined using the procedure of Kishimoto H. et al J.

The pki values obtained with the representative compounds of the invention are given in the following table. tEj emplo pki No 1 .1 14 7.9 15 7.73 16 7.8 17 8.7 18 7.78 19 8.9 21 7.1 22 7.9 24 7.8 25 7.15 30 7.7 29 8.7 The ability of the compounds of the invention to inhibit pain in mice has been evaluated in the formalin test as described by Dubuisson and Dennis (Pain, 1977, 4: 161-174). In this test 20 μl of 1% formalin are injected into the plantar surface of the left rear claw of the mouse. The amount of time, in seconds, that the animals consume by licking the claw or paw injected during the first 5 minutes (initial phase) and then from 20 to 60 minutes (final phase) after the formalin, was used as a measurement of the Pain intensity. The compounds of the invention were orally administered for 1 hour before the formalin injection. From these results, the dose required to reduce the licking time by 50% expressed as mg / kg is referred to as the value of ED5os- Representative results obtained for the compounds of the invention when given by oral administration, are provided in the next table. j. Do not . ED50 (mg / kg po) 2 1 0. 1 4 17 0. 3 2 0. 03 No undesirable effect has been observed when the compounds of the invention have been administered to mice at pharmacologically active doses.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that. it is clear from the present description of the invention. Having described the invention as above, the content of the following is claimed as property.

Claims (20)

1. A compound of the formula (I) (l) or a salt or metabolically non-toxic labile esters thereof, characterized in that Y represents a carbon atom; Z is the CH group which is attached to the group Y by means of a double bond and X is CH or Z is methylene or NRn and X is a carbon atom attached to the group Y by means of a double bond; A represents an alkylene chain with 1 to 2 carbon atoms and which can be substituted by one or two groups selected from alkyl having 1 to 6 carbon atoms optionally substituted by hydroxy, amino, C? -4alkylamino or C_? The dialkyl amino or such chain may be substituted by the group = 0; R represents a halogen atom or an alkyl group with 1 to 4 carbon atoms; Ri represents a hydrogen, a halogen atom or an alkyl group with 1 to 4 carbon atoms; R2 represents phenyl which may be substituted with up to 3 groups selected from halogen, hydrogen, or (CH2) nR3 wherein R3 is COR, NR5R5, NHCOR7, NHCORgRs or the NH group S02 Rio or R2 is a heteroaryl group of 5 elements which contains 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen; or a 6-membered heteroaryl group containing 1 to 3 nitrogen atoms R 4 represents an amino, a hydroxyl or an alkoxy group with C 1-4 or R 5 and R 6 each independently represent hydrogen or an alkyl group with C 1-4 or R 5 and together with the nitrogen atom to which they are attached represent a saturated 5-7-element heterocyclic group, optionally containing an additional heteroatom selected from oxygen, sulfur or nitrogen R7 represents a hydrogen atom or alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, or phenyl; R8 represents hydrogen or an alkyl group with 1 to 4 carbon atoms; Rg represents hydrogen, alkyl having 1 to 4 carbon atoms optionally substituted (optionally substituted by one or more hydroxy carbyl and amino groups), phenyl; Rn represents hydrogen or an alkyl group with 1 to 4 carbon atoms; Rio represents hydrogen, alkyl having 1 to 4 carbon atoms or a nitrogen protecting group, n is zero or an integer from 1 to 2;

2. A compound according to claim 1, characterized in that R is chlorine and Ri is hydrogen or a chlorine atom.

3. A compound according to claim 1 or 2, characterized in that A is a chain selected from -CH -, - (CH2) 2- or C = 0.

4. A compound according to any of claims 1-3, characterized in that Z is CH which is attached to the group Y by means of a double bond, a methyl group or an NH group.

5. A compound according to any of claims 1-4, characterized in that R2 is a group selected from phenyl (optionally substituted by acetylamino, methanesulfonylamino) or 3-pyridyl.

6. A compound according to any of claims 1-5, characterized in that R2 represents phenyl.

7. a compound according to any of claims 1-6, characterized in that A is a chain selected from -CH2-, - (CH2) 2, and Z is the CH group which is attached to the group Y by means of a double bond , or a methylene group, or A is C = 0 and Z is an NH group, R is chlorine, Ri is chlorine or hydrogen and R2 is phenyl (optionally substituted by acetylamino or methanesulphonylamino) or 3-pyridyl.

8. (±) 7-Chloro-4- (2-oxo-l-phenyl-3-pyrrolidinylidene) -1,2,3,4-tetrahydro-2-quinolinecarboxylic acid, physiologically acceptable salts or metabolically non-toxic labile esters thereof. TD

9. The ± 7-Chloro-4- (2-oxo-l-phenyl-3-pyrrolidinylidene) -1,2,3,4-tetrahydro-2-quinolinecarboxylate sodium. 5

10. 7-Chloro-4- (2-oxo-l-phenyl-3-pyrrolidinylidene) -1,2,4,4-tetrahydro-2-quinolinecarboxylate of (-) sodium. 0

11. (+) 7-Chloro-4- (1-phenyl-3-pyrrolin-2-one-3-yl) -1,2,3,4-tetrahydro-2-quinolinecarboxylic acid, physiologically acceptable salts or labile esters metabolically non-toxic thereof.

12. The (±) 7-chloro-4- (l-phenyl-β-pyrrolin-2-one-3-yl) -1,2,3,4-tetrahydro-2-quinolinecarboxylate sodium.

13. 7-Chloro-4- (1-phenyl-3-pyrrolin-2-one-3-yl) -1,2,4,4-tetrahydro-2-quinolinecarboxylate of (-) sodium.

14. 7-Chloro-4- (1-phenyl-3-pyrrolin-2-one-3-yl) -1,2,4,4-tetrahydroquinoline-2-carboxylate of (+) sodium.

15. A compound characterized in that it is selected from: Acid. { + _) -7-chloro-4- (1- (3-pyridin) -? 3-pyrrolin-2-one-3-yl) -1,2,4,4-tetrahydroquinoline-2-carboxylic acid (+ _) -7-chloro-4- (1-phenyl-3-5,6-dihydro-pyridin-2-one-3-yl) -1,2,3,4-tetrahydroquinoline-2-carboxylic acid (+ _) -5 , 7-dichloro-4- (l-phenyl-? 3-pyrrolin-2-one-3-yl) -1,2,3,4-tetrahydroquinoline-2-carboxylic acid, (+/-) -7-chloro-4 - (1- (4-acetylamino) -l-phenyl-? 3-pyrrolin-2-one-3-yl) -1,2,3,4-tetrahydroquinoline-2-carboxylic acid, (+/-) 7-chloro- 4- (1- (4-methanesulfonylamino) -1-phenyl-? 3-pyrrolin-2-one-3-yl) -1,2,3,4-tetrahydroquinoline-2-carboxylic acid, Acid (±) -7-chloro- 4- (2-Oxo-l-phenyl-3-piperidinylidene) -1,2,3,4-tetrahydro-2-quinolinecarboxylic acid. { + _) -7-chloro-4- (2, 5-dioxo-l-phenyl-imidazolidin-4-ylidene)) -1, 2, 3, 4-tetrahydro-2-quinolinecarboxylic, (+ _) -7- chloro-4- (2-oxo-l- (pyridin-3-yl) -pyrrolidin-3-ylidene) -1,2,3,4-tetrahydro-2-quinolinecarboxylate. , (+ _) -7-Chloro-4- (2-oxo-l- (4-acetylamino) phenyl-pyrrolidin-3-ylidene) -1,2,3,4-tetrahydro-2-quinolinecarboxylic acid, acid A) 7-chloro-4- (2-oxo-l- ((4-methanesulfonyl amino) phenyl-pyrrolidin-3-ylidene) -1,2,3,4-tetrahydro-2-quinolinecarboxylic acid, 5,7,7-dichloroic acid -4- (2-oxo-l- (phenyl) -pyrrolidin-3-ylidene) -1, 2, 3, 4-tetrahydro-2-quinoline carboxylic acid, 5,7-dichloro-4- (2-oxo- l- (phenyl) -? 3-pyrrolin-2-one-3-yl) -1,2,4,4-tetrahydro-2-quinoline-2-carboxylic acid and the physiologically acceptable salts (for example salts of sodium), metabolically non-toxic labile esters or enantiomers thereof.

16. A compound according to any of claims 1-15 for use in therapy.

17. The use of a compound according to any of claims 1-15 in the manufacture of a therapeutic agent to antagonize the effects of the excitatory amino acids on the NMDA receptor complex.

18. A pharmaceutical composition, characterized in that it comprises a compound according to any of claims 1-15 in admixture with one or more physiologically acceptable carriers or excipients.

19. A method of treatment of a mammal including the human, for the conditions wherein the antagonization of the effects of the excitatory amino acids on the NMDA receptor complex is of therapeutic benefit, characterized in that it comprises the administration of an effective amount of a compound according to any of claims 1 to 16.

20. A process for the preparation of the compounds according to any of claims 1-15, characterized in that it comprises cyclizing a compound of the formula (II) in which R, Ri, R2, A, X, Y, Z have the meanings defined in claim 1 and R 2 is a carboxylic protecting group, R 13 represents a bromine or iodine atom, R 14 represents hydrogen or a nitrogen protecting group, 00 followed where necessary or desirable by one or more of the following steps: (i) removal of the protecting group, (ii) isolation of the compound as a salt thereof, (iii) conversion of a compound of the formula (I) or a salt thereof in a metabolically labile ester thereof; (iv) separation of a compound of the formula (I) or a derivative thereof into enantiomers thereof. SUMMARY The compounds of the formula (I) or a salt or metabolically non-toxic labile esters thereof, wherein Y represents a carbon atom; Z is the CH group which is attached to the group Y by • means of a double bond and X is CH or Z is methylene or NRn and X is a carbon atom attached to the group Y by means of a double bond; A represents an alkylene chain with 1 to 2 carbon atoms and which can be substituted by one or two groups selected from alkyl having 1 to 6 carbon atoms optionally substituted by hydroxy, amino, C? -4alkylamino or C_? _4 dialkyl amino or such a chain may be substituted by the group = 0; R represents a halogen atom or an alkyl group with 1 to 4 carbon atoms; 7R? represents a hydrogen, a halogen atom or an alkyl group with 1 to 4 carbon atoms; R2 represents optionally substituted phenyl, a 5-membered heteroaryl group containing 1 to 3 heteroatoms selected from oxygen, sulfur, and nitrogen or a 6-membered heteroaryl group containing 1 to 3 nitrogen atoms, processes for their preparation and their use as glycine antagonists.