BENZOYLPROPIONIC ACID ESTER DERIVATIVES

Abstract: Benzoylpropionic acid ester derivatives of formula (I) wherein R is C1-C4 alkyl or benzyl, and the pharmaceutically acceptable salts thereof, which act as kynurenine-3-hydroxylase enzyme inhibitors and are useful in the treatment of neurodegenerative diseases. A process for preparing compounds of formula (I) and pharmaceutical compositions comprising them are also described.

Description: Title BENZOYLPROPIONIC ACID ESTER DERIVATIVES The present invention relates to benzoylpropionic acid esters derivatives, to their pharmaceutically acceptable salts, to a process for their preparation and to pharmaceutical compositions comprising them Our previous International patent application WO 95/03271 refers to 2 -amιno-4 -phenyl -4 -oxo-butyric acid derivatives of formula (IA) and pharmaceutically acceptable salts thereof, wherein each of the groups X and Y is, independently, hydrogen, halogen, trifluoromethyl , hydroxy, C- L -Cg alkyl, benzyl, C 6 -C 10 aryl, -OR', -SR' , -SOR' , -S0 2 R' in which R' is -C 5 alkyl or benzyl , and R is hydroxy, ammo, hydroxylamme , -OR', -NHR' , -N(R') 2 or -NHOR' m which R' is as defined above; provided that R is not hydroxy when: (1) X and Y are simultaneously hydrogen, or (11) X and Y are m positions 3 and 4 of the phenyl ring and are simultaneously a hydroxy group or a -OR' group in which R' is methyl, or (m) one of the X and Y groups is hydrogen and the othei is in position 4 of the phenyl ring and is hydroxy, chlorine, fluorine, methyJ , n-propyl or ethoxy, either as single isomers or as racemic mixture In WO 95/03271 the compounds of formula (IA) are described as effective inhibiting the activity of the enzymes kynurenmase and/or kynurenme- 3 -hydroxylase which are involved in the metabolic pathway of kynuren eε leading to the formation of quinolmic acid, a tryptophan neurotoxic metabolite with excitatory activity in the mammalian cential nervous system The compounds of formula (IA) may, in general, be employed in the prevention and/oi treatment ol a variety of nervous system diseases related to a deranged production of quinolmic acid or excessive activation of neurotransmission mediated by N methyl -D-aspartic acid, such as, for instance, neurodegenera ive pathologies including, for example, Hunt gton's chorea, Alzheimer's disease, Parkinson's disease, dementia caused by acquired immunodeficiency syndrome (AIDS), multi - infarctual dementia, cerebral ischemia, cerebral hypoxia and epilepsy The compounds of formula (IA) are, in general, soluble in aqueous vehicles suitable for parenteral administration The most commonly used route of administration to a patient of a neuroprotective compound for the treatment of, for example, a cerebral lschemic event is the intravenous (l.v.) route; usually, a single bolus, followed by slow rate infusion of a neuroprotective agent is administered to a patient in need of it. Therefore, the use of these compounds for pharmacological therapy is significantly influenced by their solubility with reference, in particular, to mjectable media Accordingly, it is an object of the present invention to provide compounds wich are strong inhibitors of the enzyme kynurenme- 3 -hydroxylase and possess good solubility. It has now been surprisingly found that certain benzoylpropionic acid esters derivatives, which represent a selected class of compounds of formula (IA) not specifically disclosed in WO95/03271, possess excellent solubility in aqueous media and are effective inhibitors of the enzyme Kynurenme- 3 -hydroxylase These novel derivatives, which are are considerably more soluble than the corresponding α-amino acids derivatives disclosed m WO 9b/03271 are particularly useful for mjectable administration purposes, thus allowing the use of different routes and regimen of administration. In accordance with the present invention, there are provided optically active or racemic substituted benzoylpropionic acid esters derivatives of formula (I) wherein R is C- L -C, alkyl or benzyl, and the pharmaceutically acceptable salts thereof. A C-,-C 4 alkyl group may be a branched oi straight chain group, typically methyl, ethyl, isopropyl 01 preferably tert butyl . The compounds of formula (I) possess an asymmetric carbon atom m the asterisked position and can therefore exist either as individual optical isomers or as racemic mixture The scope of the present invention encompasses both t he individual optical isomers and the racemic mixture ol the formula (I) compounds The pharmaceutically acceptable salts of the compounds of formula (I) include salts with pharmaceutically acceptable acids, either inorganic acids, such as, e g , hydrochloi IC , hydrobromic, nitric or sulphuric acid or organic acids, such as, e g , citric, tartaric, maleic, fumaric, methanesulfonic or ethanesulfonic acid Preferred salts according to the invention are hydrochlorides . Specific examples of compounds of formula (I) according to this invention are the following 2 -ammo-4 -oxo-4 -( 3 ', 4 ' -dichlorophenyl ) butanoic acid methyl ester, 2-ammo-4 -oxo-4 - (3 ', 4 ' -dichlorophenyl) butanoic acid ethyl ester, 2-ammo-4-oxo-4- (3 ', 4 ' -dichlorophenyl) butanoic acid i-propyl ester; 2-ammo-4 -oxo-4- (3 ', 4 ' -dichlorophenyl) butanoic acid tert- butyl ester; 2-ammo-4 -oxo-4 - (3 ', 4 ' -dichlorophenyl) butanoic acid benzyl ester, and their pharmaceutically acceptable salts, in particular their hydrochloride salts. A compound of formula (I) may be prepared by a process which comprises : a) reacting a compound of formula (II) with a compound of formula (III either as a single (R) or (S) enantiomer or as racemic mixture, wherein Rj is hydrogen, methyl, trifluoromethyl , C^-Cg alkoxy or benzyloxy, to form a compound of formula (IV) (IV) either as a single (R) or (S) enantiomer or as racemic mixture wherein R_ is as defined above; b) converting a compound of formula (IV) either as a single (R) or (S) enantiomer or as racemic mixture into a single (R) or (S) enantiomer or racemic mixture of the compound of formula (V) or of formula (VI) wherein R and R_ are as defined above, and c) converting the compound of formula (V) or of formula (VI) into a compound of formula (I) or a pharmaceutically acceptable salt thereof. In the above formulae (III) and (IV) R x is preferably trifluoromethyl or C^C^ alkoxy, in particular methoxy, ethoxy or tert-butoxy. The reaction of a compound of formula (II) with a compound of formula (III) as described under step a) may be carried out according to known methods (see, for example, J.E. Nordlander, J. Org. Chem., 5_Q, 3619-22, 1985 and D.G. Melillo, J. Org. Chem. 5_2, 5143-50, 1987) ; for example, the reaction may be performed in the presence of a suitable Lewis acid catalyst, in an inert solvent such as, e.g., dichloromethane or dichloroethane , nitromethane , cyclohexane or heptane, or using an excess of 1 , 2-dichlorobenzene , used in this case as reagent and as solvent; at a temperature ranging from about -5°C to about 60°C; optionally in the presence of a cosolvent such as, for example, nitromethane . A suitable Lewis acid may be, e.g., anhydrous aluminium trichoride, anhydrous tin dichloride, titanium tetrachloride or zinc dichloride, typically aluminium trichloride. The conversion of a compound of formula (IV) into the compound of formula (V) as described under step b) may be carried out according to known procedures under either acidic or alkaline hydrolytic conditions. Alkaline hydrolysis may be performed by an alkali metal hydroxide such as, e.g., lithium, sodium or potassium hydroxide or sodium carbonate, in a suitable solvent such as, e.g., aqueous methanol or ethanol, at a temperature ranging from about 0°C to about 50°C. Acidic hydrolysis may be catalysed by an inorganic acid such as, e.g., hydrochloric acid, at a temperature ranging from about 60°C to about 110°C, for a time which may vary from about 4 hours to about 12 hours. The conversion of a compound of formula (V) into a compound of formula (I) as described under step c) may be carried out following known procedures. For example, a compound of formula (V) can be converted into a compound of formula (I) by heating a compound of formula (V) either as free amino acid or as its inorganic salt, e.g. the hydrochloride, with the corresponding alcohol, e.g. methanol or ethanol, at the presence of a suitable catalyst, e.g. anhydrous hydrochloric acid. A compound of formula (IV) may be converted into a compound of formula (VI) using known method for esterification of protected amino acids. For example, such an esterification reaction can be carried out via a reactive intermediate of the carboxylic acid, which may be isolated or not, by reaction with the appropriate alcohol of formula ROH m which R is as defined above. The reaction can be carried out m a customary solvent, e.g. dichloromethane , tetrahydrofuran, toluene, or in the presence of an excess of the alcohol itself, at a temperature which may range from about -20°C to about 50°C. Intermediate reactive derivatives of the carboxylic acid may be, for example, acid halides, e.g. chloride, mixed anhydrides, e.g. etoxycarbonyl or ISO- butyloxy anhydride, or a suitable reactive intermediate obtained m si tu , for example, by reaction with a diimidc, e.g. dicyclohexylcarbodi-imide or carbonyl diimidazole The esterification reaction may be also caiπed out by treatment of a compound of formula (IV) with a suitable alkylatmg agent of formula R-X in which R is as defined above, and X is an suitable leaving group such as, e.g a halogen atom, preferably iodine or bromine, or a sul ate ester, m the presence of an inorganic base, e g potassium carbonate or bicarbonate, or in the presence of an organic base, e.g. diazabicycloundecene (DBU) , in a suitable solvent, e.g. dimethylformamide , at a reaction temperature that may range from about 0°C to about 60°C. A compound of formula (IV) wherein R_ is tert-butoxy or benzyloxy may preferably be obtained from a compounα of formula (V) wherein R_ is different from tert-butoxy or benzyloxy by usual and well known methods of nitrogen protection of amino acids; this compound of formula (IV) may be converted into a compound of formula (VI) as above described . A compound of formula (VI) may be converted into a compound of formula (I), for example, by mild basic hydrolysis of the nitrogen protecting group when it is a tπfluoro- acetyl group, mild acid hydrolysis when it is a tert- butoxycarbonyl group or hydrogenolysis when it is a benzyloxycarbonyl protecting group. The compounds of formula (II) and (III) are known compounds or may be obtained by known procedures . The compounds of formula (I) are active as kynurenme- 3 - hydroxylase enzyme inhibitors exhibiting a broad spectrum of CNS related activities pertaining to the metabolic pathway of kynurenines leading to the formation of quinolmic acid They can therefore be useful, e.g., in the prevention and/or treatment of a variety of nervous system diseases related to a deranged production of quinolmic acid or excessive activation of neurotransmission mediated by N-methyl-D- aspartic acid, such as, e g neurodegenerative pathologies including, e.g., Huntmgton's chorea, Alzheimer's disease, Parkinson's disease, dementia caused by acquired immunodeficiency syndrome (AIDS), multi mfarctual dementia, cerebral ischemia, cerebral hypoxia and epilepsy A mammal, comprising humans, in need of a kynurenme- 3- hydroxylase enzyme inhibitors may thus be treated by a method which comprises the administration thereto of a therapeutically effective amount of a compound of formula (I) or pharmaceutically acceptable salt thereof. The condition of the human or animal can thereby be improved The efficacy of the compounds of formula (I) m the inhibition of the enzyme kynurenme-3 -hydroxylase has been evaluated m rat liver mitochondrial extract as reported below, according to "A Radiometnc Assay for Kynurenme 3- Hydroxylase Based on the Release of H 2 0 during Hydroxylation of L-(3,5- H) Kynurenme" , Joel B.Erickson, Ellen M.Flanagan, Λ Suzanne Russo, and John F . Remhard . Jr ; Analytical Biochem (1992), 205, 257-262) with minor modifications The assay for kynurenme 3 -hydroxylase was based on the enzymatic synthesis of tritiated water during the hydroxylation reaction. Radiolabeled water was quantified following selective adsorption of the isotopic substrate and its metabolite with activated charcoal . Rat liver mitochondrial extract was used as enzymatic preparation for this assay. The assay for kynurenme 3 -hydroxylase activity was carried out at 37°C for a time of 30 mm. The reaction mixture of a total volume of 100 ml was constituted of 44 mg of suspended extract, 100 mM Tris/Cl buffer pH 8.1 , 10 mM EDTA, 100 mM KC1, 0.8 mM NADPH, 0.025 mM L- Kynurenme , 0 5 Ci L (3, H) Kynurenme (10 Ci/m ol) and 10 ml of different concentration of inhibitor solutions After the incubation the reaction was terminated by the addition of 1 mL of 7 5% (w/v) activated charcoal, vortexed and centrifugated foi 7 min. A 500 ml aliquot of supernatant was counted by scintillation spectroscopy m 5 ml of liquid scintillation. As an example, the compounds of the present invention (R,S) -Methyl 2-amino-4 -oxo-4 - (3 ', 4 ' -dichlorophenyl) butanoate hydrochloride (PNU 157678)*; (S) -Methyl 2-amιno-4-oxo-4 - (3 ', 4 ' -dichlorophenyl ) butanoate hydrochloride (PNU 161145)*; (R) -Methyl 2-amino-4-oxo-4 - (3 ', ' -dichlorophenyl ) butanoate hydrochloride (PNU 161144)*; (R,S) -Ethyl 2-amino-4-oxo-4- (3 ', 4 ' -dichlorophenyl ) butanoate hydrochloride (PNU 161250)*; ΛΛ (R, S) -Isopropyl 2 -ammo- 4 -oxo-4- (3 ' , 4 ' -dichlorophenyl) butanoate hydrochloride (PNU 161248)*; and (R, S) -Benzyl 2 -am o-4 -oxo-4 - ( 3 ' , 4 ' -dichlorophenyl ) butanoate hydrochloride (PNU 161252)*; have been tested according to the method described above and. the obtained results are reported m the following Table 1. Table 1 INHIBITION AT lOOμM COMPOUND PNU 157678 97% (IC 5P = 0.51μM) PNU 161145 97.2% PNU 161144 90.8% PNU 161250 97.7% PNU 161248 96.2% PNU 161248 97.4% * INTERNAL CODE The compounds of the invention can be administered in a variety of dosage forms, e.g. orally, the form of tablets, capsules, sugar or film coated tablets, liquid solutions or suspensions; rectally, in the form of suppositories; parenterally, e.g. intramuscularly, or by intravenous injection or infusion; topically, e.g. in the form of creams. Preferably they are administered by travenal infusion, more preferably by slow l.v. infusion. The dosage depends on the age, weight, conditions of the patient and administration route. For example, a suitable dosage for oral administration to adult humans may be from ΛV lmg to lOOOmg per kg per day, peferably from 50mg to 400mg per kg The present invention includes its scope also pharmaceutical compositions comprising an optically active or a racemic compound of formula (I), or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable non-toxic carrier and/or diluent The pharmaceutical compositions containing the compounds of the invention are usually prepared following conventional methods and may be administered in a pharmaceutically suitable form Example of pharmaceutically suitable preparations can be found in the specification of WO 95/03271. The following examples illustrate but do not limit the invention Example 1 (R.S) -Methyl 2 -amιno- -oxo- - (3 '.4 ' -dichlorophenyl ) butanoate hydrochloride . To an ice cooled saturated solution of anhydrous hydrochloric acid m methanol (400 ml) , (R, S) -2-ammo-4 -oxo- (3 ' , 4 ' - dichlorophenyl ) butanoic acid hydrochloride (4.4 g; 14.7 mmol , preparation described m WO 95/03271) was added, the resulting stirred suspension was allowed to came to room temperature, then refluxed over 12 hours. The so obtained solution was concentrated under reduced pressure to an oily material which was coevaporated twice from methanol The residue was taken up with dry ethyl ether to afford the titled compound as colorless crystals (3.6 g; 78%) mp. 170-171°C Microanalysis : calcd for C 11 H 12 C1 3 N0 3 : C 42.3 ; H 3.87 , N 4.48 , Cl 34 08 Found : 42.25; 3.87 , 4.48 , 33 59 The following compounds: (R, S) -Ethyl 2-ammo-4-oxo-4- (3 ' , 4 ' -dichlorophenyl) butanoate hydrochloride (yield 67%) Colorless solid, mp . 147-150°C (Ethyl ether), calcd for C 13 H 16 C1 3 N0 3 : C 44.13; H 4.32 , N 4.29 ; Cl 32 57 Found - 42.53; 4.40 , 4.04 , 33 47, and (R, S) -Isopropyl 2 -amino-4 -oxo-4 - (3 ' .4 ' -dichlorophenyl) butanoate hydrochloride . (yield 77%) Colorless solid, mp . 169-173°C (Ethyl ether) , calcd for C 13 H 1€ C1 3 N0 3 : C 45.83; H 4.73 ; N 4 11 , Cl 31 23 Found 42.32; 4 76 ; 4.04 ; 30.99, were prepared according to the above procedure, using ethanol or isopropanol respectively instead of methanol Example 2 (S) -Methyl 2 -amino-4 -oxo-4 - (3' ,4' -dichlorophenyl) butanoate hydrochloride. Following the procedure described in Example 1, the title compound was prepared starting from (S) -2-ammo-4 -oxo- ( 3 ' , 4 ' - dichlorophenyl) butanoic acid hydrochloride and methanol (yield 92%) . mp.l70-17l°C (Ethyl ether) [α] D = + 34.5° (MeOH, c=0.88) Microanalysis ■ calcd. for C^H^Cl j NO-, : C 42.3 ; H 3.87 ; N 4.48 ; Cl 34 08 Found : 42.25, 3.92 , 4.50 ; 33.46 Example 3 (R) -Methyl 2-ammo-4 -oxo-4 -( 3 '.4 ' -dichlorophenyl ) butanoate hydrochloride . Following the procedure described in Example 1, the title compound was prepared starting from (R) -2 -ammo-4 -oxo- ( 3 ' , 4 ' dichlorophenyl) butanoic acid hydrochloride and methanol (yield 90%) . mp. 171/172°C (Ethyl ether) [α] D = -33.9° (MeOH, c = l) Microanalysis : calcd. for C 1X H 12 C1 3 N0 : C 42.3 ; H 3.87 ; N 4.48 , Cl 34.08 Found : 42.15, 3.93 ; 4 48 ; 33.76 Example 4 (S) -2 -ammo- 4 -oxo- 4 - (3 ' .4 ' -dichlorophenyl) butanoic acid hydrochloride. To a stirred suspension of (S) -2 -f (trifluoroacety) ammo]-4 - oxo-4 - (3 ', 4 ' -dichloro phenyl ) butanoic acid (2.2 g,- 6 mmol) in 6N HCl (80 mL) , glacial acetic acid (40 L) was added on stirring at 50°C, the resulting mixture was heated to 80°C for 2h. The solvents were removed under reduced pressure and the residue was suspended in ethyl acetate, at 50 °C. The suspension was stirred at 80°C 10 mm., then cooled to room temperature and filtered, the colorless crystals of the hydrochloride were recrystallized from ethanol/ethyl acetate - 5 to provide the pure titled compound (1.8 g, 86%) as colorless prisms, mp . 215-216 °C. MS (FAB) m/z: 262 (M) ; 217.6 (M -COOH) ; 189 (M -COOH - HCN) ; 173 (C 6 H 3 C1 2 C0) . 1 ]r\ NMR ( 200 MHz, DMSO-d G ) δ : 3.78 (d, 2H, CH 2 ) ; 4.38 (m, 1H, CH) ; 7.67 (d, 1H , H 6 ) ; 7.98 (dd, 1H, H s .) ; 8.20 (d, 1H, H 2 ,) ; 8.50 (broad s, 3H, -Ntf- ) ; 13.80 ( broad s, 1H, COOH) . Example 5 (R) -2-ammo-4-oxo-4- (3 ' , 4 ' -dichlorophenyl) butanoic acid hydrochloride . Following the procedure described in Example 4, the title compound was prepared starting from (R)-2- [ (trifluoroacety) ammo]-4 -oxo-4 - ( 3 ' , 4 ' -dichlorophenyl) butanoic acid (yield 85%) . mp.192-193°C; [αj D = - 36.4° (Abs. ethanol, c= 1.0). Example 6 (S) -2-[ (trifluoroacety) amιno]-4 -oxo-4 - (3 ' .4 ' -dichlorophenyl) butanoic acid . To a mechanically stirred suspension of (R,S)-N- (tπfluoroacetyl) aspartic anhydride ( D.S. Nordlander J. Org. Chem., 50, 3619-3622 , (1985) ), (4 g, 0.018 mol.) in 1,2- dichlorobenzene (12 mL) , AlCl 3 (7,2 g, 0.054 mol) was added portionwise, under nitrogen atmosphere, at 0°C. The resulting slurry was stirred 10 min. at 0°C then warmed to 60°C for 7 h. The reaction mixture was then inverse-quenched by addition of ice and 37% HCl , maintaining the temperature below SO- 40°C. Hexane was added and after 30 min. stirring a yellow Λ(> solid was formed, the mixture was poured into 2 N HCl and the resulting suspension was strirred for 20 min., filtered and the solid washed twice with hexane, to afford the crude N- trifluoroacetyl amino acid. Recrystallization from ethyl ether provided the pure titled compound (5.02 g, 78%) as a colorless solid melting at 174-175°C. MS (FAB) m/z: 358.2 (M+H) MS (El) m/z: 357 (M) ; 339 (M- H ? 0); 173 (C G H B Cl ? -CO) . X H NMR ( 200 MHz, DMS0-d 6 ) δ : 3.60 (d, 2H, CH 2 ); 4.77 (q, 1H, CH) ; 7.79 (d, 1H, H 6 , ) ; 7.93 (dd, 1H, H ς , ) ; 8.18 (d, 1H, H 2 , ) ; 9.72 (d, 1H, NH) ; 13.10 (s, 1H , COOH) . Example 7 (R) -2-[(trifluoroacety) amino]-4 -oxo- 4 - (3 ' .4 ' -dichlorophenyl) butanoic acid . Following the procedure described in Example 6, the title compound was prepared starting from (R) -N- ( trifluoroacetyl ) aspartic anhydride as colorless prisms (yield 60%) mp. 154 °C; [α] D = - 17.3° (Abs. ethanol, c= 1.05). Example 8 Benzyl (R.S) -2-amino-4-oxo-4- (3' .4' -dichlorophenyl) butanoate hydroch oride. To a stirred ice-cooled solution of 4N hydrochloric acid in dry dioxane (15 mL) , benzyl (R, S) -N- tertbutoxy carbonyl-2- amino-4-oxo-4- (3 ', 4 ' -dichlorophenyl) butanoate (1.8 g; 4 mmol) was added. The resulting solution was allowed to warm to room temperature then heated to 50°C for 2 hours. The resulting reaction mixture was concentrated to on oily material which was coevaporated twice from dry dioxane. The resulting residue was taken up with dry ethyl ether to afford the pure titled compound as colorless crystals (1.27g; 79%) . mp.l94-198°C. Microanalysis : calcd. for C 17 H 17 C1 3 N0 : C 52.39; H 4.40 ; N 3.59 ; Cl 27.30 Found : 52.44; 4.19 ; 3.60 ; 27.31 Example 9 (R, S) -N- t -butoxycarbonyl 2 -ammo-4 -oxo-4 - (3 ' .4 ' dichlorophenyl ) butanoate . To a stirred solution of (R, S) -N- t -butoxycarbonyl -2-amιno-4 - oxo-4 - (3 ', 4 ' -dichlorophenyl ) butanoic acid (2.1 g; 5.8 mmoD dry DMF (16 mL) , ethyldiisopropylamme (1 9 mL) was added at room temperature. The resulting solution was stirred at r.t. 5 mm., then benzylbromide (0.86 L) dissolved in dry DMF (4 mL) was added on stirring at r.t.. The resulting reaction mixture was stirred at r.t. over 3 hrs , then diluted with water (200 mDand extracted with diethyl ether The combined organic extracts were washed with brine dried and concentrated, under reduced pressure, to an oil. Crystallization from pentane afforded the pure titled compound (1.85 g, 73%) as colorless solid melting at 87-89°C. Example 10 (R.S) -N- t -butoxycarbonyl- 2 -amino-4-oxo-4 - (3 ' .4' - dichlorophenyl) butanoic acid. To a solution of (R, S) -2 -amino-4 -oxo- (3 ' , 4 ' - dichlorophenyl) butanoic acid hydrochloride (WO 95/03271) (3 g, 10 mmol) m water (15 mL) and t-butanol (7 mL) , IN NaOH (21 λ mL) was added on stirring at r.t., followed by dropwise addition of di- t-butyldicarbonate (2.18 g, 0.01 mol) dissolved in t-butanol (6 mL) . The resulting reaction mixture was stirred at r.t. overnight, then diluted with water (70 L) , and the pH was adjusted to 3 by slow addition of 0.5 M KHS0 4 . The resulting mixture was extracted with ethyl acetate, washed with brine, dried and concentrated, under reduced pressure, to a colorless solid, which was taken up with pentane and filtered to provide the pure titled compound ( 2.1 g, 58%) as amorphous solid. Example 11 Capsule, each weighing 0.230 g and containing 50 mg of the active substance can be prepared as follows: Composition for 500 capsules: (R,S) -Methyl 2-amino-4 -oxo-4 - (3 ', 4 ' -dichlorophenyl ) butanoate hydrochloride 25 g Lactose 80 g Corn starch 5 g Magnesium stearate 5 g This formulation can be incapsulated in two hard gelating capsules of two pieces each with each capsule weighing 0.230g. Example 12 Intramuscular injection of 50 mg/ml A pharmaceutical injectable composition can be manufactured dissolving 50 g of (R,S) -Methyl 2-amino-4 -oxo-4 - (3 ' , 4 ' - dichlorophenyl) butanoate hydrochloride in sterile water (1000 ml) and sealed in 1-5 ml ampoules.

Claims: Λ<z\ CLAIMS 1. An optically active or racemic substituted benzoylpropionic acid ester derivative of formula (I) wherein R is C-^d alkyl or benzyl, or a pharmaceutically acceptable salt thereof 2. An optically active or racemic substituted benzoylpropionic acid ester derivative selected from: 2-amino-4-oxo-4- (3 ', 4 ' -dichlorophenyl) butanoic acid methyl ester; 2-amino-4-oxo-4- (3 ', 4 ' -dichlorophenyl) butanoic acid ethyl ester; 2 -amino-4 -oxo-4 - (3 ', 4 ' -dichlorophenyl) butanoic acid i-propyl ester; 2-amino-4-oxo-4- (3 ', 4 ' -dichlorophenyl) butanoic acid tert- butyl ester; 2 -amino-4 -oxo-4 - (3 ', 4 ' -dichlorophenyl) butanoic acid benzyl ester; and their pharmaceutically acceptable salts. 3. A compound as claimed in claim 1 or 2 which is a pharmaceutically acceptable hydrochloride salt. 4. A process for the preparation of a compound as claimed in claim 1 which comprises: a) reacting a compound of formula (II) Cl Cl n: with a compound of formula (III! either as a single (R) or (S) enantiomer or as racemic mixture , wherein R, is hydrogen, methyl , trifluoromethyl , C-2_-C 6 alkoxy or benzyloxy, to form a compound of formula (IV) either as a single (R) or (S) enantiomer or as racemic mixture wherein R_ is as defined above,- Zλ b) converting a compound of formula (IV) either as a single (R) or (S) enantiomer or as racemic mixture into a single (R) or (S) enantiomer or racemic mixture of the compound of formula (V) or of formula (VI) wherein R and R-_ are as defined m claim 1 c) converting the compound of formula (V) or of formula (VI) into a compound of formula (I) or a phar aceuticaly acceptable salt thereof. 4 A pharmaceutical composition which comprises, as an active ingredient, a compound as claimed in claim 1 in admixture with a pharmaceutically acceptable diluent and/or carrier 5. A compound as claimed in claim 1, for use in a method of treatment of the human or animal body by therapy. 6. A compound as claimed in claim 1, for use as a kynurenme 3 -hydroxylase enzyme inhibitor. 7. A compound as claimed in claim 1, for use in the treatment of a nervous system disease related to disturbed production of quinolmic acid. 8. A compound as claimed in claim 7, wherein the nervous system disease is a neurodegenerative disease 9. A compound as claimed m claim 8, wherein the neurodegenerative disease is selected from Huntmgton's chorea, Alzheimer's disease, Parkinson's disease, dementia caused by acquired immunodeficiency syndrome (AIDS) , multi mfarctual dementia, cerebral ischemia, cerebral hypoxia and epilepsy. 10 A method of treating a mammal need of a kynurenme- 3 - hydroxylase inhibitor, the method comprising administering to said mammal a therapeutically effective amount of a compound of formula (I), as defined in claim 1, oi a pharmaceutically acceptable salt thereof.

Inventors: BIANCHETTI ALBERTO, CINI MASSIMO, GIORDANI ANTONIO, SPECIALE CARMELA, VARASI MARIO, BIANCHETTI, ALBERTO, CINI, MASSIMO, GIORDANI, ANTONIO, SPECIALE, CARMELA, VARASI, MARIO
Applicants: BIANCHETTI ALBERTO, CINI MASSIMO, GIORDANI ANTONIO, PHARMACIA & UPJOHN SPA, SPECIALE CARMELA, VARASI MARIO, BIANCHETTI, ALBERTO, CINI, MASSIMO, GIORDANI, ANTONIO, PHARMACIA & UPJOHN S.P.A., SPECIALE, CARMELA, VARASI, MARIO
Application year: 1997
Main classification: C07C229
IPC codes: A61K31, A61P9, A61P25, C07C227, C07C229