CA2258074A1 - Benzoylpropionic acid ester derivatives - Google Patents
Benzoylpropionic acid ester derivatives Download PDFInfo
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- CA2258074A1 CA2258074A1 CA002258074A CA2258074A CA2258074A1 CA 2258074 A1 CA2258074 A1 CA 2258074A1 CA 002258074 A CA002258074 A CA 002258074A CA 2258074 A CA2258074 A CA 2258074A CA 2258074 A1 CA2258074 A1 CA 2258074A1
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- C07—ORGANIC CHEMISTRY
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- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/34—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
- C07C229/36—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings with at least one amino group and one carboxyl group bound to the same carbon atom of the carbon skeleton
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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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
CA 022~8074 1998-12-10 W O 98/03469 PCT~P97/03S88 Title ~ BENzoyrlpRopIoNIc ACID ESTF.~ DERIVATIVES
s 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
l0 95/03271 refers to 2-amino-4-phenyl-4-oxo-butyric acid derivatives of formula (IA) O NH
~ 2 Y (IA) and pharmaceutically acceptable salts thereof, wherein each of the groups X and Y is, independently, hydrogen, halogen, trifluoromethyl, hydroxy, C1-C5 alkyl, benzyl, C6-C1~
aryl, -OR', -SR', -SOR', -SO2R' in which R' is C1-Cs alkyl or benzyl; and R is hydroxy, amino, hydroxylamine, -OR', -NHR', -N(R') 2 or -NHOR' in which R' is as defined above provided that R is not hydroxy when:
(i) X and Y are simultaneously hydrogen; or (ii) X and Y are in positions 3 and 4 of the phenyl ring and are simultaneously a hydroxy group or a -OR' group in which R' is methyl; or CA 022~8074 1998-12-10 W O g8/03469 PCTAEP97/03S88 (iii)one of the X and Y groups is hydrogen and the other is in position 4 of the phenyl ring and is hydroxy, chlorine, fluorine, methyl, n-propyl or methoxy, either as single isomers or as racemic mixture.
In WO 95/03271 the compounds of formula (IA) are described as effective in inhibiting the activity of the enzymes kynureninase and/or kynurenine-3-hydroxylase which are involved in the metabolic pathway of kynurenines leading to the formation of quinolinic acid, a tryptophan neurotoxlc metabolite with excitatory activity in the mammalian central nervous system. The compounds of formula (IA) may, ln general, be employed in the prevention and/or treatment of a variety of nervous system diseases related to a deranged production of quinolinic acid or excessive activation of neurotransmission mediated by N-methyl-D-aspartic acid, such as, for instance, neurodegenerative pathologies including, for example, Huntington'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 ischemic event is the intravenous (i.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 CA 022~8074 1998-12-lo W 098/03469 PCTA~P97/03588 solubility with reference, in particular, to injectable media.
Accordingly, it is an object of the present invention to provide compounds wich are strong inhibitors of the enzyme kynurenine-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 W095/03271, possess excellent solubility in aqueous media and are effective inhibitors of the enzyme Kynurenine-3-hydroxylase.
These novel derivatives, which are are considerably more soluble than the corresponding a-amino acids derivatives disclosed in WO 95/03271 are particularly useful for injectable 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) --J~ r~~
Cl ~ ~
C1 (I) wherein R is Cl- C4 alkyl or benzyl, and the pharmaceutically acceptable salts thereof.
CA 022~8074 1998-12-lo A Cl- C4 alkyl group may be a branched or straight chain group, typlcally methyl, ethyl, isopropyl or preferably tert-butyl.
The compounds of formula (I) possess an asymmetric carbon atom in the asterisked position and can therefore exist either as individual optical isomers or as racemic mixture.
The scope of the present invention encompasses both the individual optical isomers and the racemic mixture of the lo 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., hydrochloric, 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) accordlng to this invention are the following:
s 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
l0 95/03271 refers to 2-amino-4-phenyl-4-oxo-butyric acid derivatives of formula (IA) O NH
~ 2 Y (IA) and pharmaceutically acceptable salts thereof, wherein each of the groups X and Y is, independently, hydrogen, halogen, trifluoromethyl, hydroxy, C1-C5 alkyl, benzyl, C6-C1~
aryl, -OR', -SR', -SOR', -SO2R' in which R' is C1-Cs alkyl or benzyl; and R is hydroxy, amino, hydroxylamine, -OR', -NHR', -N(R') 2 or -NHOR' in which R' is as defined above provided that R is not hydroxy when:
(i) X and Y are simultaneously hydrogen; or (ii) X and Y are in positions 3 and 4 of the phenyl ring and are simultaneously a hydroxy group or a -OR' group in which R' is methyl; or CA 022~8074 1998-12-10 W O g8/03469 PCTAEP97/03S88 (iii)one of the X and Y groups is hydrogen and the other is in position 4 of the phenyl ring and is hydroxy, chlorine, fluorine, methyl, n-propyl or methoxy, either as single isomers or as racemic mixture.
In WO 95/03271 the compounds of formula (IA) are described as effective in inhibiting the activity of the enzymes kynureninase and/or kynurenine-3-hydroxylase which are involved in the metabolic pathway of kynurenines leading to the formation of quinolinic acid, a tryptophan neurotoxlc metabolite with excitatory activity in the mammalian central nervous system. The compounds of formula (IA) may, ln general, be employed in the prevention and/or treatment of a variety of nervous system diseases related to a deranged production of quinolinic acid or excessive activation of neurotransmission mediated by N-methyl-D-aspartic acid, such as, for instance, neurodegenerative pathologies including, for example, Huntington'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 ischemic event is the intravenous (i.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 CA 022~8074 1998-12-lo W 098/03469 PCTA~P97/03588 solubility with reference, in particular, to injectable media.
Accordingly, it is an object of the present invention to provide compounds wich are strong inhibitors of the enzyme kynurenine-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 W095/03271, possess excellent solubility in aqueous media and are effective inhibitors of the enzyme Kynurenine-3-hydroxylase.
These novel derivatives, which are are considerably more soluble than the corresponding a-amino acids derivatives disclosed in WO 95/03271 are particularly useful for injectable 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) --J~ r~~
Cl ~ ~
C1 (I) wherein R is Cl- C4 alkyl or benzyl, and the pharmaceutically acceptable salts thereof.
CA 022~8074 1998-12-lo A Cl- C4 alkyl group may be a branched or straight chain group, typlcally methyl, ethyl, isopropyl or preferably tert-butyl.
The compounds of formula (I) possess an asymmetric carbon atom in the asterisked position and can therefore exist either as individual optical isomers or as racemic mixture.
The scope of the present invention encompasses both the individual optical isomers and the racemic mixture of the lo 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., hydrochloric, 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) accordlng to this invention are the following:
2-amino-4-oxo-4-(3',4'-dichlorophenyl)butanoic acid methyl ester;
2-amino-4-oxo-4-(3',4'-dlchlorophenyl)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;
.
CA 02258074 1998-12-lo W O 98/03469 PCT~P97/03588 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) Cl ~
Cl (II) with a compound of formula (III) Rl ~ N ~ O
(III) either as a single (R) or (S~ enantiomer or as racemic mixture, wherein Rl is hydrogen, methyl, trifluoromethyl, C1-C6 alkoxy or benzyloxy, to form a compound of formula (IV) O HN ~ O
,/, ~ ; OH
Cl ~ ~
Cl (IV) , CA 022~8074 1998-12-10 either as a single (~) or (S) enantiomer or as racemic mixture wherein R1 is as defined above;
b) converting a compound of formula (IV3 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) ~ 3 ~ . OH ~ ~ O~R
Cl (V) Cl (VI) wherein R and Rl 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) Rl is preferably trifluoromethyl or C1-C6 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., 50, 36l9-22, l985 and D.G.
Melillo, J. Org. Chem. 52, 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 2s or heptane, or using an excess of l,2-dichlorobenzene, used in this case as reagent and as solvent; at a temperature CA 022~8074 1998-12-10 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.
o 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 '0 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.
'5 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 . .
CA 022~8074 1998-12-1o W O 98/03469 PCT~EP97/03588 intermediate of the carboxylic acid, which may be isolated or not, by reaction with the appropriate alcohol of formula ROH
in which R is as defined above. The reaction can be carried out in 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 intermediateobtained in si tu, for example, by reaction with a diimide, e.g. dicyclohexylcarbodiimide or carbonyl diimldazole.
The esterification reaction may be also carried out by treatment of a compound of formula (IV) with a suitable alkylating 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 sulfate ester, in 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 R1 is tert-butoxy or benzyloxy may preferably be obtained from a compound of formula (V) wherein Rl 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 CA 022~8074 1998-12-10 of the nitrogen protecting group when it is a trifluoro-acetyl group, mild acid hydrolysis when it is a tert-butoxycarbonyl group or hydrogenolysis when it is a benzyloxycarbonyl protecting group.
s 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 kynurenine-3-hydroxylase enzyme inhibitors exhibiting a broad spectrum of CNS related activities pertaining to the metabolic pathway of o kynurenines leading to the formation of quinolinic 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 quinolinic acid or excessive activation of neurotransmission mediated by N-methyl-D-aspartic acid, such as, e.g. neurodegenerative pathologiesincludlng, e.g., Huntington's chorea, Alzheimer's disease, Parkinson's disease, dementia caused by acquired immunodeficiency syndrome (AIDS), multi infarctual dementia, cerebral ischemia, cerebral hypoxia and epilepsy.
A mammal, comprising humans, in need of a kynurenine-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) in the inhibition of the enzyme kynurenine-3-hydroxylase has been evaluated in rat liver mitochondrial extract as reported below, according to: "A Radiometric Assay for Kynurenine 3-Hydroxylase Based on the Release of H2O during Hydroxylationof L-(3,5- H)Kynurenine"; Joel B.Erickson, Ellen M.Flanagan, CA 022~8074 1998-12-10 Suzanne Russo, and John F.Reinhard.Jr.; Analytical Biochem.
(1992), 205, 257-262) with minor modifications.
The assay for kynurenine 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.
I0 The assay for kynurenine 3-hydroxylase activity was carried out at 37~C for a time of 30 min. The reaction mixture of a total volume of lO0 ml was constituted of 44 mg of suspended extract, 100 mM Tris/Cl buffer pH 8.1, 10 mM EDTA, 100 mM
KCl, 0.8 mM NADPH, 0.025 mM L-Kynurenine, 0.5 mCi L-(3,5-3H)Kynurenine (10 Ci/mmol) and 10 ml of differentconcentration of inhibitor solutions. After the incubation the reaction was terminated by the addition of l mL of 7.5~
(w/v) activated charcoal, vortexed and centrifugated for 7 min.
A 500 ml aliquot of supernatant was counted by scintillation spectroscopy in 5 ml of liquid scintillation.
As an example, the compounds of the present invention:
(R,S)-Methyl 2-amlno-4-oxo-4-(3',4'-dichlorophenyl) butanoate hydrochloride (PNU 157678)*;
(S)-Methyl 2-amino-4-oxo-4-(3',4'-dichlorophenyl) butanoate hydrochloride (PNU 161145)*;
(R)-Methyl 2-amino-4-oxo-4-(3',4'-dichlorophenyl) butanoate hydrochloride (PNU 161144)*;
(R,S)-Ethyl 2-amino-4-oxo-4-(3',4'-dichlorophenyl) butanoate hydrochloride (PNU 161250)*;
CA 022~8074 1998-12-10 W O 98103469 PCT~EP97/03588 (R,S)-Isopropyl 2-amino-4-oxo-4-(3',4'-dichlorophenyl) butanoate hydrochloride (PNU 161248)*; and (R,S)- Benzyl 2-amino-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 in the following Table 1.
Table 1 COMPOUND INHIBITION AT 100~M
PNU 157678 97~ (IC5Q= 0. 51~M) 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, in the form of tablets, capsules, sugar or film coated tablets, liquid solutions or lS 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 intravenal infusion, more preferably by slow i.v. infusion.
~0 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 CA 022~8074 1998-12-10 W O 98/03469 PCTrEP97/03588 lmg to lOOOmg per kg per day, peferably from 50mg to 400mg per kg.
The present invention includes in 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 o methods and may be administered in a pharmaceutically sultable 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 s invention.
Example 1 (R.S~-Methyl 2-amino-4-oxo-4-(3'.4'-dichlorophenyl~ butanoate hydrochloride.
To an ice cooled saturated solution of anhydrous hydrochloric acid in methanol (400 ml),(R,S)-2-amino-4-oxo-(3~,4'-dichlorophenyl)butanoic acid hydrochloride (4.4 g; 14.7 mmol, preparation described in WO 95/03271) was added, the 2s 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.
CA 022~8074 1998-12-lo ~ 3 Microanalysis:
calcd. for CllHl2Cl3NO3: 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-amino-~-oxo-4-(3'.4'-dichlorophenyl) butanoate hydrochloride (yield 67~) Colorless solid, mp. 147-150~C (Ethyl ether), calcd. for Cl3Hl6Cl3NO3: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 Cl3Hl6Cl3NO3 : 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-amino-4-oxo-(3',4'-dichlorophenyl) butanoic acid hydrochloride and methanol (yield 92~).
mp.170-171~C (Ethyl ether) [a]D= + 34.5~ (MeOH, c=0.88) CA 022~8074 1998-12-lo '~4 Microanalysis:
calcd. for C1lH12Cl3NOl:C 42.3; H 3.87; N 4.48; Cl 34.08 Found : 42.25; 3.92 ; 4.50 ; 33.46.
S Example 3 (R)-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 (R)-2-amino-4-oxo-(3',4'-l0 dichlorophenyl) butanoic acid hydrochloride and methanol (yield 9o~).
mp. 171/172~C (Ethyl ether) [(xlD= -33.9o (MeOH, c=1) Microanalysis:
calcd. for CllHl2Cl3NO3: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-amino-4-oxo-4-(3'.4'-dichlorophenyl)butanoic acid hydrochloride.
To a stirred suspension of (S)-2-[(trifluoroacety)amino]-4-oxo-4-(3',4'-dichloro phenyl)butanoic acid (2.2 g; 6 mmol) in 6N HCl (80 mL), glacial acetic acid (40 mL) was added on stirring at 50~C, the resulting mixture was heated to 80~C
2s 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 min., then cooled to room temperature and filtered, the colorless crystals of the hydrochloride were recrystallized from ethanol/ethyl acetate .... . .
CA 022~8074 1998-12-10 W O 98/03469 PCT~P97/03588 ~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 (C6H3Cl2CO).
s H NMR ( 200 MHz, DMSO-d6) â : 3.78 (d, 2H, CH2); 4.38 (m, lH, CH); 7.67 (d, lH, H6, ); 7.98 (dd, lH, Hs~ ); 8.20 (d, lH, H2,);
8.50 (~road s, 3H, -NH3); 13.80 ( broad s, lH, COOH).
Example 5 10 (R) -2-amino-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)amino]-4-oxo-4-(3',4'-dichlorophenyl) lS butanoic acid (yield 85%).
mp.192-193~C;
[~D = - 36.4~ (Abs. ethanol, c= 1.0).
Example 6 (S)-2-~(trifluoroacety)amino~-4-oxo-4-(3',4'-dichlorophenyl) butanoic acid .
To a mechanically stirred suspension of (R,S)-N-(trifluoroacetyl)aspartic anhydride ( D.S. Nordlander J.Org.Chem., 50, 3619-3622,(1985)),(4 g, 0.018 mol.) in 1,2-dichlorobenzene (12 mL), AlCl3 (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 30-40OC. Hexane was added and after 30 min. stirring a yellow CA 022~8074 1998-12-10 W O 98/03469 PCT~P97/03588 ~6 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 (EI) m/z: 357 (M); 339 (M- H2O); 173 (C6HsCl2-CO).
lH NMR ( 200 MHz, DMSO-d6) ~ : 3.60 (d, 2H, C~2); 4.77 (q, lH, CH); 7.79 (d, lH, H6,); 7.93 (dd, lH, Hsl ); 8.18 (d, lH, H2);
9.72 (d, lH, NH); 13.10 (s, lH, 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;
La]D= - 17.3~ (Abs. ethanol, c= 1.05).
Example 8 Benzyl (R S)-2-amino-4-oxo-4-(3' 4'-dichlorophenyl)butanoate hydrochlor;de 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 , . . .... .
CA 022~8074 1998-12-10 '~
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.194-198~C.
Microanalysis:
calcd. for Cl7Hl7C13NO3: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-amino-4-oxo-4-(3'.4'-dichlorophenyl)butanoate.
To a stirred solution of (R,S)-N-t-butoxycarbonyl-2-amino-4-oxo-4-(3',4'-dichlorophenyl)butanoic acid (2.1 g; 5.8 mmol)in dry DMF (16 mL), ethyldiisopropylamine (l.9 mL) was added at room temperature. The resulting solution was stirred at r.t.
5 min., then benzylbromide (0.86 mL) 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 mL)and 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) in water (15 mL) and t-butanol (7 mL), lN NaOH (21 CA 022~8074 1998-12-10 W O 98/03469 PCT~EP97/03588 -1~
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 mL), and the pH was adjusted to 3 by slow addition of 0.5 M
KHSO4. 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:
lS 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.
. .
2-amino-4-oxo-4-(3',4'-dlchlorophenyl)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;
.
CA 02258074 1998-12-lo W O 98/03469 PCT~P97/03588 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) Cl ~
Cl (II) with a compound of formula (III) Rl ~ N ~ O
(III) either as a single (R) or (S~ enantiomer or as racemic mixture, wherein Rl is hydrogen, methyl, trifluoromethyl, C1-C6 alkoxy or benzyloxy, to form a compound of formula (IV) O HN ~ O
,/, ~ ; OH
Cl ~ ~
Cl (IV) , CA 022~8074 1998-12-10 either as a single (~) or (S) enantiomer or as racemic mixture wherein R1 is as defined above;
b) converting a compound of formula (IV3 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) ~ 3 ~ . OH ~ ~ O~R
Cl (V) Cl (VI) wherein R and Rl 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) Rl is preferably trifluoromethyl or C1-C6 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., 50, 36l9-22, l985 and D.G.
Melillo, J. Org. Chem. 52, 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 2s or heptane, or using an excess of l,2-dichlorobenzene, used in this case as reagent and as solvent; at a temperature CA 022~8074 1998-12-10 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.
o 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 '0 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.
'5 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 . .
CA 022~8074 1998-12-1o W O 98/03469 PCT~EP97/03588 intermediate of the carboxylic acid, which may be isolated or not, by reaction with the appropriate alcohol of formula ROH
in which R is as defined above. The reaction can be carried out in 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 intermediateobtained in si tu, for example, by reaction with a diimide, e.g. dicyclohexylcarbodiimide or carbonyl diimldazole.
The esterification reaction may be also carried out by treatment of a compound of formula (IV) with a suitable alkylating 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 sulfate ester, in 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 R1 is tert-butoxy or benzyloxy may preferably be obtained from a compound of formula (V) wherein Rl 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 CA 022~8074 1998-12-10 of the nitrogen protecting group when it is a trifluoro-acetyl group, mild acid hydrolysis when it is a tert-butoxycarbonyl group or hydrogenolysis when it is a benzyloxycarbonyl protecting group.
s 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 kynurenine-3-hydroxylase enzyme inhibitors exhibiting a broad spectrum of CNS related activities pertaining to the metabolic pathway of o kynurenines leading to the formation of quinolinic 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 quinolinic acid or excessive activation of neurotransmission mediated by N-methyl-D-aspartic acid, such as, e.g. neurodegenerative pathologiesincludlng, e.g., Huntington's chorea, Alzheimer's disease, Parkinson's disease, dementia caused by acquired immunodeficiency syndrome (AIDS), multi infarctual dementia, cerebral ischemia, cerebral hypoxia and epilepsy.
A mammal, comprising humans, in need of a kynurenine-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) in the inhibition of the enzyme kynurenine-3-hydroxylase has been evaluated in rat liver mitochondrial extract as reported below, according to: "A Radiometric Assay for Kynurenine 3-Hydroxylase Based on the Release of H2O during Hydroxylationof L-(3,5- H)Kynurenine"; Joel B.Erickson, Ellen M.Flanagan, CA 022~8074 1998-12-10 Suzanne Russo, and John F.Reinhard.Jr.; Analytical Biochem.
(1992), 205, 257-262) with minor modifications.
The assay for kynurenine 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.
I0 The assay for kynurenine 3-hydroxylase activity was carried out at 37~C for a time of 30 min. The reaction mixture of a total volume of lO0 ml was constituted of 44 mg of suspended extract, 100 mM Tris/Cl buffer pH 8.1, 10 mM EDTA, 100 mM
KCl, 0.8 mM NADPH, 0.025 mM L-Kynurenine, 0.5 mCi L-(3,5-3H)Kynurenine (10 Ci/mmol) and 10 ml of differentconcentration of inhibitor solutions. After the incubation the reaction was terminated by the addition of l mL of 7.5~
(w/v) activated charcoal, vortexed and centrifugated for 7 min.
A 500 ml aliquot of supernatant was counted by scintillation spectroscopy in 5 ml of liquid scintillation.
As an example, the compounds of the present invention:
(R,S)-Methyl 2-amlno-4-oxo-4-(3',4'-dichlorophenyl) butanoate hydrochloride (PNU 157678)*;
(S)-Methyl 2-amino-4-oxo-4-(3',4'-dichlorophenyl) butanoate hydrochloride (PNU 161145)*;
(R)-Methyl 2-amino-4-oxo-4-(3',4'-dichlorophenyl) butanoate hydrochloride (PNU 161144)*;
(R,S)-Ethyl 2-amino-4-oxo-4-(3',4'-dichlorophenyl) butanoate hydrochloride (PNU 161250)*;
CA 022~8074 1998-12-10 W O 98103469 PCT~EP97/03588 (R,S)-Isopropyl 2-amino-4-oxo-4-(3',4'-dichlorophenyl) butanoate hydrochloride (PNU 161248)*; and (R,S)- Benzyl 2-amino-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 in the following Table 1.
Table 1 COMPOUND INHIBITION AT 100~M
PNU 157678 97~ (IC5Q= 0. 51~M) 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, in the form of tablets, capsules, sugar or film coated tablets, liquid solutions or lS 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 intravenal infusion, more preferably by slow i.v. infusion.
~0 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 CA 022~8074 1998-12-10 W O 98/03469 PCTrEP97/03588 lmg to lOOOmg per kg per day, peferably from 50mg to 400mg per kg.
The present invention includes in 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 o methods and may be administered in a pharmaceutically sultable 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 s invention.
Example 1 (R.S~-Methyl 2-amino-4-oxo-4-(3'.4'-dichlorophenyl~ butanoate hydrochloride.
To an ice cooled saturated solution of anhydrous hydrochloric acid in methanol (400 ml),(R,S)-2-amino-4-oxo-(3~,4'-dichlorophenyl)butanoic acid hydrochloride (4.4 g; 14.7 mmol, preparation described in WO 95/03271) was added, the 2s 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.
CA 022~8074 1998-12-lo ~ 3 Microanalysis:
calcd. for CllHl2Cl3NO3: 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-amino-~-oxo-4-(3'.4'-dichlorophenyl) butanoate hydrochloride (yield 67~) Colorless solid, mp. 147-150~C (Ethyl ether), calcd. for Cl3Hl6Cl3NO3: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 Cl3Hl6Cl3NO3 : 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-amino-4-oxo-(3',4'-dichlorophenyl) butanoic acid hydrochloride and methanol (yield 92~).
mp.170-171~C (Ethyl ether) [a]D= + 34.5~ (MeOH, c=0.88) CA 022~8074 1998-12-lo '~4 Microanalysis:
calcd. for C1lH12Cl3NOl:C 42.3; H 3.87; N 4.48; Cl 34.08 Found : 42.25; 3.92 ; 4.50 ; 33.46.
S Example 3 (R)-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 (R)-2-amino-4-oxo-(3',4'-l0 dichlorophenyl) butanoic acid hydrochloride and methanol (yield 9o~).
mp. 171/172~C (Ethyl ether) [(xlD= -33.9o (MeOH, c=1) Microanalysis:
calcd. for CllHl2Cl3NO3: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-amino-4-oxo-4-(3'.4'-dichlorophenyl)butanoic acid hydrochloride.
To a stirred suspension of (S)-2-[(trifluoroacety)amino]-4-oxo-4-(3',4'-dichloro phenyl)butanoic acid (2.2 g; 6 mmol) in 6N HCl (80 mL), glacial acetic acid (40 mL) was added on stirring at 50~C, the resulting mixture was heated to 80~C
2s 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 min., then cooled to room temperature and filtered, the colorless crystals of the hydrochloride were recrystallized from ethanol/ethyl acetate .... . .
CA 022~8074 1998-12-10 W O 98/03469 PCT~P97/03588 ~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 (C6H3Cl2CO).
s H NMR ( 200 MHz, DMSO-d6) â : 3.78 (d, 2H, CH2); 4.38 (m, lH, CH); 7.67 (d, lH, H6, ); 7.98 (dd, lH, Hs~ ); 8.20 (d, lH, H2,);
8.50 (~road s, 3H, -NH3); 13.80 ( broad s, lH, COOH).
Example 5 10 (R) -2-amino-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)amino]-4-oxo-4-(3',4'-dichlorophenyl) lS butanoic acid (yield 85%).
mp.192-193~C;
[~D = - 36.4~ (Abs. ethanol, c= 1.0).
Example 6 (S)-2-~(trifluoroacety)amino~-4-oxo-4-(3',4'-dichlorophenyl) butanoic acid .
To a mechanically stirred suspension of (R,S)-N-(trifluoroacetyl)aspartic anhydride ( D.S. Nordlander J.Org.Chem., 50, 3619-3622,(1985)),(4 g, 0.018 mol.) in 1,2-dichlorobenzene (12 mL), AlCl3 (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 30-40OC. Hexane was added and after 30 min. stirring a yellow CA 022~8074 1998-12-10 W O 98/03469 PCT~P97/03588 ~6 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 (EI) m/z: 357 (M); 339 (M- H2O); 173 (C6HsCl2-CO).
lH NMR ( 200 MHz, DMSO-d6) ~ : 3.60 (d, 2H, C~2); 4.77 (q, lH, CH); 7.79 (d, lH, H6,); 7.93 (dd, lH, Hsl ); 8.18 (d, lH, H2);
9.72 (d, lH, NH); 13.10 (s, lH, 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;
La]D= - 17.3~ (Abs. ethanol, c= 1.05).
Example 8 Benzyl (R S)-2-amino-4-oxo-4-(3' 4'-dichlorophenyl)butanoate hydrochlor;de 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 , . . .... .
CA 022~8074 1998-12-10 '~
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.194-198~C.
Microanalysis:
calcd. for Cl7Hl7C13NO3: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-amino-4-oxo-4-(3'.4'-dichlorophenyl)butanoate.
To a stirred solution of (R,S)-N-t-butoxycarbonyl-2-amino-4-oxo-4-(3',4'-dichlorophenyl)butanoic acid (2.1 g; 5.8 mmol)in dry DMF (16 mL), ethyldiisopropylamine (l.9 mL) was added at room temperature. The resulting solution was stirred at r.t.
5 min., then benzylbromide (0.86 mL) 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 mL)and 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) in water (15 mL) and t-butanol (7 mL), lN NaOH (21 CA 022~8074 1998-12-10 W O 98/03469 PCT~EP97/03588 -1~
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 mL), and the pH was adjusted to 3 by slow addition of 0.5 M
KHSO4. 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:
lS 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 (9)
1'. An optically active or racemic substituted benzoylpropionic acid ester derivative of formula (I) wherein R is C1-C4 alkyl or benzyl, or a pharmaceutically acceptable salt thereof.
2. An optically active or racemic substituted benzoylpropionic acid ester derivative as claimed in claim 1 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.
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) with a compound of formula (III) either as a single (R) or (S) enantiomer or as racemic mixture, wherein R1 is hydrogen, methyl, trifluoromethyl, C1-C6 alkoxy or benzyloxy, to form a compound of formula (IV) either as a single (R) or (S) enantiomer or as racemic mixture wherein R1 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 R1 are as defined in claim 1 c) converting the compound of formula (V) or of formula (VI) into a compound of formula (I) or a pharmaceuticaly acceptable salt thereof.
4. A process for the preparation of a compound as claimed in claim 1 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 R1 is hydrogen, methyl, trifluoromethyl, C1-C6 alkoxy or benzyloxy, to form a compound of formula (IV) either as a single (R) or (S) enantiomer or as racemic mixture wherein R1 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 R1 are as defined in claim 1 c) converting the compound of formula (V) or of formula (VI) into a compound of formula (I) or a pharmaceuticaly 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 kynurenine 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 quinolinic acid.
8. A compound as claimed in claim 7, wherein the nervous system disease is a neurodegenerative disease.
9. A compound as claimed in claim 8, wherein the neurodegenerative disease is selected from Huntington's chorea, Alzheimer's disease, Parkinson's disease, dementia caused by acquired immunodeficiency syndrome (AIDS), multi infarctual dementia, cerebral ischemia, cerebral hypoxia and epilepsy.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB9615441.4A GB9615441D0 (en) | 1996-07-23 | 1996-07-23 | Benzoylpropionic acid ester derivatives |
| GB9615441.4 | 1996-07-23 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2258074A1 true CA2258074A1 (en) | 1998-01-29 |
Family
ID=10797362
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002258074A Abandoned CA2258074A1 (en) | 1996-07-23 | 1997-07-03 | Benzoylpropionic acid ester derivatives |
Country Status (8)
| Country | Link |
|---|---|
| EP (1) | EP0915830A1 (en) |
| JP (1) | JP2000515143A (en) |
| AR (1) | AR007946A1 (en) |
| AU (1) | AU4009697A (en) |
| CA (1) | CA2258074A1 (en) |
| GB (1) | GB9615441D0 (en) |
| WO (1) | WO1998003469A1 (en) |
| ZA (1) | ZA976429B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2950053B1 (en) * | 2009-09-11 | 2014-08-01 | Fournier Lab Sa | USE OF BENZOIC INDOLE DERIVATIVES AS NURR-1 ACTIVATORS FOR THE TREATMENT OF PARKINSON'S DISEASE |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1265101B1 (en) * | 1993-07-23 | 1996-10-30 | Erba Carlo Spa | DERIVATIVES OF 2-AMINO-4-PHENYL-4-BUTYRIC BONE ACID |
-
1996
- 1996-07-23 GB GBGB9615441.4A patent/GB9615441D0/en active Pending
-
1997
- 1997-07-03 CA CA002258074A patent/CA2258074A1/en not_active Abandoned
- 1997-07-03 JP JP10506490A patent/JP2000515143A/en not_active Withdrawn
- 1997-07-03 AU AU40096/97A patent/AU4009697A/en not_active Abandoned
- 1997-07-03 WO PCT/EP1997/003588 patent/WO1998003469A1/en not_active Application Discontinuation
- 1997-07-03 EP EP97937467A patent/EP0915830A1/en not_active Ceased
- 1997-07-21 ZA ZA9706429A patent/ZA976429B/en unknown
- 1997-07-22 AR ARP970103274A patent/AR007946A1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| AR007946A1 (en) | 1999-11-24 |
| EP0915830A1 (en) | 1999-05-19 |
| GB9615441D0 (en) | 1996-09-04 |
| AU4009697A (en) | 1998-02-10 |
| ZA976429B (en) | 1998-02-18 |
| WO1998003469A1 (en) | 1998-01-29 |
| JP2000515143A (en) | 2000-11-14 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Dead |