EP1781602A1 - 4-sulfonyl-substituted benzoylalanine derivatives useful as kynurenine-aminotransferase inhibitors - Google Patents

4-sulfonyl-substituted benzoylalanine derivatives useful as kynurenine-aminotransferase inhibitors

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Publication number
EP1781602A1
EP1781602A1 EP05775813A EP05775813A EP1781602A1 EP 1781602 A1 EP1781602 A1 EP 1781602A1 EP 05775813 A EP05775813 A EP 05775813A EP 05775813 A EP05775813 A EP 05775813A EP 1781602 A1 EP1781602 A1 EP 1781602A1
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Prior art keywords
compounds
benzoylalanine
alkyl
ethylsulfonyl
preparation
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German (de)
French (fr)
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Roberto Pellicciari
Robert Schwarcz
Paolo Guidetti
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
    • C07C317/48—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton the carbon skeleton being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • 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

Definitions

  • the present invention relates to benzoylalanine derivatives inhibiting the enzyme kynurenine aminotransferase.
  • Glutamate and nicotinic acetylcholine receptors are fundamentally involved in several cognitive processes. In principle, it is desirable to increase neurotransmission through these receptors to achieve physiological or clinical cognitive improvement.
  • Studies in animals indicate that increases in glutamate and acetylcholine receptor function will prove especially beneficial in several psychiatric diseases including schizophrenia, depression, bipolar illness, attention-deficit disorder, obsessive-compulsive disorder, drug addiction, and mental retardation and other neurodevelopmental disorders. Such increases will also provide substantial advantages in situations that require neuronal regeneration and synaptic plasticity.
  • Excitatory neurotransmission .through glutamate and acetylcholine receptors can be enhanced by reducing the formation and levels of kynurenic acid, a tryptophan metabolite that normally inhibits glutamatergic and cholinergic function in the brain.
  • kynurenic acid a tryptophan metabolite that normally inhibits glutamatergic and cholinergic function in the brain.
  • specific inhibitors of the major kynurenic acid-producing enzyme, kynurenine aminotransferase (KAT II) were synthesized and tested in vitro and in vivo.
  • the present invention relates to compounds of formula (I)
  • R is Cj-C 6 alkyl or C 5 -C 6 cycloalkyl; R' is hydrogen or an amino group;
  • R" is hydrogen, halogen, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl; and the pharmaceutically acceptable esters thereof.
  • a preferred class of compounds of formula (I) is that in which R is
  • Ci-C 6 alkyl preferably ethyl.
  • Further preferred classes of compounds of formula (I) are those in which:
  • R is Cj-C 6 alkyl and R" is hydrogen; R is Ci-C 6 alkyl and R" is halogen.
  • Halogen herein means a halogen selected from fluorine, chlorine, bromine and iodine; preferably chlorine.
  • the compounds of formula (I) can be prepared according to conventional methods; particularly advantageous is the process involving the reaction of a trialkyl-(4-alkylthio)-phenyl stannane with (S)-3- benzoyloxycarbonyl-5-oxo-4-oxazolidine-acetic acid chloride, the oxidation of the thioether and the hydrolysis of the oxazolidine to give the amino acid.
  • the compounds of formula (I) inhibit the kynurenine aminotransferase at IC 50 ranging from 2 to 25 ⁇ M, and proved particularly selective for this enzyme (inhibition of kynurenine 3-hydroxylase and kynureninase, other enzymes involved in the kynurenine pathway, is only observed at values above 2000 ⁇ M).
  • the compounds of the invention can be used for the preparation of pharmaceutical compositions for the treatment of psychiatric and neurodegenerative diseases, in particular schizophrenia, depression, bipolar illness, attention-deficit disorder, obsessive-compulsive disorder, drug addiction, mental retardation, Parkinson's disease, Alzheimer's disease, cognitive disorders in neurodegenerative and seizure disorders, age-related cognitive deficit, cognitive disorders in children, as well as for the stimulation of neuronal regeneration in neurodegenerative and seizure disorders, and after cell transplantation.
  • psychiatric and neurodegenerative diseases in particular schizophrenia, depression, bipolar illness, attention-deficit disorder, obsessive-compulsive disorder, drug addiction, mental retardation, Parkinson's disease, Alzheimer's disease, cognitive disorders in neurodegenerative and seizure disorders, age-related cognitive deficit, cognitive disorders in children, as well as for the stimulation of neuronal regeneration in neurodegenerative and seizure disorders, and after cell transplantation.
  • compositions can be prepared according to methods commonly known to those skilled in the art, in particular according to what described in Remington's Pharmaceutical Sciences Handbook, XVII Ed. Mack Pub., N.Y., U.S.A.
  • the invention is further illustrated by the following example and pharmacological section.
  • the aqueous phase is acidified with 6N HCl and extracted with AcOEt.
  • the organic phase is then dried over dry Na 2 SO 4 , filtered through paper filter and concentrated in rotary evaporator.
  • the product is finally crystallized from diisopropyl ether to obtain 9.3 g of a crystalline white solid. Yield: 77%.
  • Test compounds were added in 20 ⁇ l aliquots at the beginning of the incubation period to examine interference with enzyme activity.
  • Kynurenine 3-hydroxylase and kynureninase activities were determined in rat liver homogenate according to established procedures.
  • Microdialysis was performed in the hippocampus of unanesthetized male rats (200-220 g) according to established procedures.
  • tested compounds (Ia) and (Ib) gave the following results (IC 50 values are expressed ⁇ M):
  • Kynurenine 3 -hydroxylase >2000 Kynureninase: >2000
  • Kynureninase >2000 Compound (Ia) was tested in the rat brain in vivo and found to reduce the extracellular concentration of kynurenic acid in the hippocampus. In quantitative terms, this reduction was similar to that observed after the in vivo administration of known cognition-enhancing drugs such as d-amphetamine and methylphenidate. Such decreases in hippocampal kynurenic acid levels are known to enhance the activity of of/ nicotinic acetylcholine receptors (Alkondon et al., J. Neurosci., 24: 4635-4648, 2004).
  • Compound (Ia) can therefore increase cholinergic function in vivo, thus being clinically useful for the treatment of cognitive deficits and aging-related pathophysiologies.

Abstract

The invention relates to compounds of formula (I), in which R, R' and R' are as defined in the disclosure and the pharmaceutically acceptable esters thereof. The compounds of the invention reduce the synthesis of kynurenic acid thus inhibiting the enzyme kynurenine aminotransferase and can be used for the preparation of medicaments for the treatment of those psychiatric and neurological diseases which benefit from an increase in glutamatergic and/or cholinergic neurotransmission, such as depression, bipolar illness, anxiety, Alzheimer's disease. Furthemore, the compounds of the invention are useful for stimulating attention, memory and other cognitive processes in normal individuals of any age, including children, adolescents and the elderly.

Description

4-SULFONYL-SUBSTITUTED BENZOYLALANINE DERIVATIVES USEFUL AS KYNURENINE- AMINOTRANSFERASE INHIBITORS
FIELD OF THE INVENTION
The present invention relates to benzoylalanine derivatives inhibiting the enzyme kynurenine aminotransferase.
TECHNOLOGICAL BACKGROUND Glutamate and nicotinic acetylcholine receptors are fundamentally involved in several cognitive processes. In principle, it is desirable to increase neurotransmission through these receptors to achieve physiological or clinical cognitive improvement. Studies in animals indicate that increases in glutamate and acetylcholine receptor function will prove especially beneficial in several psychiatric diseases including schizophrenia, depression, bipolar illness, attention-deficit disorder, obsessive-compulsive disorder, drug addiction, and mental retardation and other neurodevelopmental disorders. Such increases will also provide substantial advantages in situations that require neuronal regeneration and synaptic plasticity. Excitatory neurotransmission .through glutamate and acetylcholine receptors can be enhanced by reducing the formation and levels of kynurenic acid, a tryptophan metabolite that normally inhibits glutamatergic and cholinergic function in the brain. To this end, specific inhibitors of the major kynurenic acid-producing enzyme, kynurenine aminotransferase (KAT II), were synthesized and tested in vitro and in vivo.
Compounds able to reduce the formation of kynurenic acid, inter alia some benzoylalanine derivatives, have recently been described, for example in WO 9,503,271 and US 5,708,030.
It has now been found that some benzoylalanine derivatives are inhibitors of the synthesis of the kynurenic acid particularly effective thanks to their ability to inhibit the enzyme kynurenine aminotransferase. DISCLOSURE OF THE INVENTION
The present invention relates to compounds of formula (I)
in which
R is Cj-C6 alkyl or C5-C6 cycloalkyl; R' is hydrogen or an amino group;
R" is hydrogen, halogen, C1-C6 alkyl or C3-C6 cycloalkyl; and the pharmaceutically acceptable esters thereof. A preferred class of compounds of formula (I) is that in which R is
Ci-C6 alkyl, preferably ethyl. Further preferred classes of compounds of formula (I) are those in which:
R is Cj-C6 alkyl and R" is hydrogen; R is Ci-C6 alkyl and R" is halogen. "Halogen" herein means a halogen selected from fluorine, chlorine, bromine and iodine; preferably chlorine.
Furthermore, the following compounds are particularly preferred: (S)-4-ethylsulfonyl benzoylalanine (Ia); (S)-2-amino-4-ethylsulfonyl benzoylalanine (Ib); (S)-3-chloro-4-ethylsulfonyl benzoylalanine (Ic);
(S)-2-amino-5-chloro-4-ethylsulfonyl benzoylalanine (Id). The compounds of formula (I) can be prepared according to conventional methods; particularly advantageous is the process involving the reaction of a trialkyl-(4-alkylthio)-phenyl stannane with (S)-3- benzoyloxycarbonyl-5-oxo-4-oxazolidine-acetic acid chloride, the oxidation of the thioether and the hydrolysis of the oxazolidine to give the amino acid. The compounds of formula (I) inhibit the kynurenine aminotransferase at IC50 ranging from 2 to 25 μM, and proved particularly selective for this enzyme (inhibition of kynurenine 3-hydroxylase and kynureninase, other enzymes involved in the kynurenine pathway, is only observed at values above 2000 μM). Therefore, the compounds of the invention can be used for the preparation of pharmaceutical compositions for the treatment of psychiatric and neurodegenerative diseases, in particular schizophrenia, depression, bipolar illness, attention-deficit disorder, obsessive-compulsive disorder, drug addiction, mental retardation, Parkinson's disease, Alzheimer's disease, cognitive disorders in neurodegenerative and seizure disorders, age-related cognitive deficit, cognitive disorders in children, as well as for the stimulation of neuronal regeneration in neurodegenerative and seizure disorders, and after cell transplantation.
The pharmaceutical compositions can be prepared according to methods commonly known to those skilled in the art, in particular according to what described in Remington's Pharmaceutical Sciences Handbook, XVII Ed. Mack Pub., N.Y., U.S.A.
The invention is further illustrated by the following example and pharmacological section.
EXAMPLE (S)-4-Ethylsuifbnyl benzoylalanine
Preparation 1. Synthesis of trimethyl-4-(ethyIthio-phenyl) stannane
A solution of l-bromo-4-ethylthio benzene (3.1 g, 13.82 mmoles) in anhydrous THF (42.09 ml) is added with 2.5 eq of 1.6 M tBuLi in pentane (21.4 ml), under magnetic stirring and argon inert atmosphere, at -78°C. The mixture turns yellow. The mixture is reacted at -78°C for an hour, then added with 2.18 eq of a IM solution Of Me3SnCl in THF (30.13 ml), under the same conditions as above, then it is slowly cooled to room temperature and reacted under these conditions for 3 hrs, monitoring the progress of the reaction by TLC (petroleum etherrEtOAc = 8:2) in which the stannylation product shows Rf higher than the starting bromo-derivative. The mixture is subsequently poured onto ice and extracted with AcOEt. The organic phase is dried over dry Na2SO4, filtered through paper filter and concentrated in rotary evaporator. The residue is purified by flash chromatography on silica gel, eluting with petroleum ether. 2.78 g of a clear pale yellow oil are obtained. Yield: 65.01%.
1H-NMR (CDCl3, 200 MHz) δ: 0.36 (s, 9H, (CHO1Sn); 1.39 (t, 3H, J - 5.34, CH1CH2S); 3.01 (q, 2H, J1 = 7.38 Hz, J2 = 14.7 Hz, CH^CH2S); 3÷7.6 (2m, 4H, Ar). IR (CHCl3); 3059.03; 2972.73; 2925.97; 4868.56; 1885.56; 1631.48;
1566,4; 1471.42; 1447.31 ; 1386.09; 1264.59; 1 180.22; 1111.28; 1091.99; 1068.85; 1005.21 ; 969.055.
Preparation 2. Synthesis of (S)-N-benzyloxycarbonyl-aspartic acid
A solution Of NaHCO3 (18 g, 210 mmoles) in 258 ml of bidistilled H2O is added with (S)-aspartic acid (10 g, 75 mmoles). The solution is cooled to
O0C, then added with 1.7 eq of benzyl chloroformate (18.2 ml, 127.5 mmoles) under magnetic stirring. The mixture is warmed at room temperature and reacted under these condition for 2 days. Subsequently, the mixture is washed with ether and the aqueous phase is acidified with 6N HCl, then extracted with AcOEt. Finally, the organic phase is dried over dry Na2SO4, filtered through paper filter and concentrated in rotary evaporator. 17 g of product in the form of a transparent, colourless gluey residue are obtained. Yield: 85%.
1H-NMR (CDCl3, 200 MHz) δ: 2.52÷3.1 (m, 2H, CH2CO2H); 4.3÷4.6 (m, IH, CH(NHCbZ)(CO2H); 4.59÷5.1(m, 2H, CH2Ph); 6 (d, IH, NH); 7.17÷7.25 (m, 5H, Ar); 10.2 (2H, bromine, CO2H)
Preparation 3. Synthesis of (S)-3-benzyloxycarbonyl-5-oxo-4- oxazolidine-acetic acid
(S)-N-Benzyloxycarbonyl aspartic acid (11.55 g, 43.22 mmoles) is suspended in dry benzene (360 ml), under argon inert atmosphere, with magnetic stirring and drying system. The mixture is refluxed to complete dissolution of the acid, added with 1.66 eq of paraformaldehyde (3.15 g, 71.74 mmoles) and 0.052 eq of pTOH (427.5 mg, 2.247 mmoles), then refluxed for 3 hrs removing the formed H2O and monitoring the reaction by TLC (CH2Cl2:MeOH = 9: 1). The mixture is cooled at room temperature and washed with 5% NaHCO3. The aqueous phase is acidified with 6N HCl and extracted with AcOEt. The organic phase is then dried over dry Na2SO4, filtered through paper filter and concentrated in rotary evaporator. The product is finally crystallized from diisopropyl ether to obtain 9.3 g of a crystalline white solid. Yield: 77%.
M.p. (Kofler): 78°-82°C
Specific rotatory power: +130.4360
1H-NMR (CDCl3, 200 MHz) δ: 2.83(3.2 (m, 2H, CH2CO2H); 4.33÷4.36 (m, IH, CH(NCbZ)(CO); 4.87 (bromine, IH, CH2-CO2H).; 5.11÷5.13 (d, 2H, CH2Ph); 5.19 (bromine, IH, CJL-heteroc); 5.439 (d, IH, J = 3.53 hrsz; CH2-heteroc); 7.26 (7.34 (m, 5H, Ar).
13C-NMR (CDCl3, 50 MHz) δ: 33.947; 34.732; 52.038; 67.834; 78.691 ; 128.227; 128.460; 128.673; 136.272; 153.360; 172.369; 173.117. Preparation 4. Synthesis of (S)-3-benzyloxycarbonyl-5-oxo-4- oxazolidine-acetic acid chloride
A suspension of (S)-3-benzyloxycarbonyl-5-oxo-4-oxazolidine-acetic acid (1.5 g, 5.37 mmoles) in anhydrous toluene (11 ml) is added with an excess of freshly distilled SOCl2 (1 1 ml), under magnetic stirring and argon inert atmosphere, at room temperature. The resulting yellow solution is reacted under these conditions for 3 hrs, then concentrated in rotary evaporator (previously dried) and the resulting yellow oily residue is immediately used for the subsequent reaction. Preparation 5. Synthesis of (S)-4-[2-(4-ethylthio-phenyl)-2-oxa- oxazolidine-3-carboxyIic acid benzyl ester
A solution of (S)-3-benzyloxycarbonyl-5-oxo-4-oxazolidine-acetic acid chloride (1.58 g, 5.37 mmoles) in anhydrous THF (40 ml) is added with trimethyl-4-(ethylsulfinyl-phenyl) stannane (1.43 g, 4.75 mmoles), 0.063 eq of dry K2CO3 (41 mg, 0.299 mmoles), 1.322 eq of dry DPA (1.09 ml,
6.28 mmoles) and 0.05 eq of Pd2dba»CHCl3, under magnetic stirring and argon inert atmosphere, at room temperature. The resulting black mixture is reacted at room temperature for about 16 h, monitoring the progress of the reaction by TLC (petroleum ether:EtOAc = 7:3), then is diluted with ether, filtered and the filtrate is washed with 10% K2CO3, H2O and brine. The organic phase is dried over dry Na2SO4, filtered through paper filter and concentrated in rotary evaporator. The residue is finally purified by flash chromatography on silica gel. 606 mg of unreacted stannane and 217 mg of the reduction product (mercaptan) are obtained, and 378 mg of coupling product are finally eluted with petroleum ether:EtOAc = 7:3. Yield: 28%.
IR (CHCl3): 2970.8; 2926.45; 1797.33; 1675.36; 1290.63; 1183.11.
1H-NMR (CDCl3, 200 MHz) δ: 1.37 (t, 3H, J = 7.4 Hz, CH3CH2S);
2.97÷3.08 (q, 2H, Jl = 7.4 Hz, J2 = 14.8 Hz, CH3CH2S); 3.48÷4.17 (m, 2H, CH2(CO); 4.44 (bromine, IH, CH(NHCbz)(CO); 5.05÷5.26 (m, 2H, CH2Ph);
5.47÷5.57 (m, 2H, CH2-heteroc); 7.261÷7.829 (m, 9H, Ar).
13C-NMR (CDCl3, 50 MHz) δ: 13.835; 27.259; 38.449; 51.161 ; 67.865; 126.125; 128.271 ; 128.613; 128.695; 131.988; 135,384; 146.172; 152.650; 172.439; 195.463. Preparation 6. Synthesis of (S)-4-[2-(4-ethylsulfonyl-phenyl)-2-oxa- oxazolidine-3-carboxylic acid benzyl ester
A solution of (S)-4-[2-(4-ethylsulfinyl-phenyl)-2-oxa-oxazolidine-3- carboxylic acid ester benzyl (150 mg, 0.3765 mmoles) in CHCl3 is slowly added with 1 ,7 eq of 77% mCPBA (143.44 mg, 0.640 mmoles). The mixture is reacted at room temperature for about 16 hrs monitoring the progress of the reaction by TLC (petroleum ether.ΕtOAc = 5:5). At the beginning of the reaction, both the sulfone and the sulfoxide intermediate form, the latter being much more polar than the sulfone. After the starting product and the sulfoxide have completely disappeared, the mixture is washed with a NaHCO3 saturated solution, IN NaOH and brine. The organic phase is dried over dry Na2SO4, filtered through paper filter and concentrated in rotary evaporator. 147 mg of a white solid are obtained. Yield: 90.49%. M.p. (Kofler): 55°-59°C.
IR (CHCl3): 3054.69; 2974.66; 2925.48; 2870.52; 1572.66; 1479.62; 1447.31 ; 1378.85; 1262.18; 1188.9; 1102.6; 1060.17; 1012.93; 968.573.
1H-NMR (CDCl3, 200 MHz) δ: 1.28 (t, 3H, J = 6.53 hrsz, CH1CH9SO7); 3.09÷3.20 (q, 2H, J1 = 6.76 Hz, J2 = 14.08 Hz, CH3CH1SO2); 3.56÷4.25 (m, 2H, CH1(CO); 4.50 (bromine, IH, CH(NHCbz)(CO); 5.06÷5.25 (m, 2H, CH2Ph); 5.38÷5.6Q (m, 2H, CH2-heteroc); 7.261÷7.899 (m, 9H, Ar).
13C-NMR (CDCl3, 50 MHz) δ: 8.01 ; 39.5; 51 ; 51.5; 68.25; 78.25; 128.271 ; 128.81 ; 134.5; 139.5; 150.25; 170.3.
Preparation 7. Synthesis of (S)-4-ethyIsulfonyl benzoylalanine A suspension of (S)-4-[2-(4-ethylsulfonyl-phenyl)-2-oxa-oxazolidine-3- carboxylic acid ester benzyl (130 mg, 0.301 mmoles) in 6N HCl (15 ml) is refluxed under magnetic stirring for 12 hrs. The reaction is monitored by TLC RP-8 (H2θ:MeCN = 8:2). The yellow solution is cooled at room temperature and washed with CHCl3. The aqueous phase is concentrated in rotary evaporator and the amino acid is purified and neutralized by means of a 50Wx2x200 cation exchange resin, eluting with a 10% pyridine aqueous solution. 311 mg of a pale brown solid are obtained. Yield: 95%. [α]: +20.6640 HPLC: [Merck, Lichrospher 100-RP 18, 200x4.5; flow 0.7/min; eluent: H2O (+0.01% TFA): CH3CN - 60:40]
Purity: 97%
1H-NMR (CDCl3, 400 MHz) δ: 1.07 (t, 3H, J = 7.05 Hz, CH3CH2SO2); 3.20÷3.30 (q, 2H, J1 = 7.326 Hz, J1 = 14.69 Hz, CH3CH2SO2); 3.8 (d, 2H, J = 5.01 Hz, CH2(CO); 4.41 (t, IH, J = 5.25 Hz, CH(NH2)(CO2H); 7.89 (d, 2H, J = 8.27, Ar); 8.07 (d, 2H, J = 8.31 Hz, Ar).
13C-NMR (CDCl3, 100 MHz) δ: 6.2; 38.646; 48.780; 49.742; 128.473; 129.191 ; 139.273; 141.086; 171.492; 197.920. PHARMACOLOGICAL SECTION
For the measurement of KAT II activity, 100 μl of partially purified rat liver enzyme were incubated (2 hrs, 370C) with 100 μl of 150 mM Tris-acetate (pH 7.0), 2 μM (2.5 nCi) [3H]-kynurenine, 1 mM pyruvate and 80 μM pyridoxal-5 '-phosphate. Blanks were obtained using denatured protein preparations. The reaction was terminated by the addition of 25 μl of 30% (w/v) trichloroacetic acid. 1 ml of 0.1 M HCl was added, and the denatured protein was removed by centrifugation. 1 ml of the supernatant was applied to a Dowex 50 W H+ cation exchange column, which was then washed with 1 ml of 0.1 M HCl, followed by 1 ml of ultrapure water. [3H]-KYNA was subsequently eluted with 2 x 1 ml of ultrapure water, and radioactivity was quantified by liquid scintillation spectrometry.
Test compounds were added in 20 μl aliquots at the beginning of the incubation period to examine interference with enzyme activity.
Kynurenine 3-hydroxylase and kynureninase activities were determined in rat liver homogenate according to established procedures.
Microdialysis was performed in the hippocampus of unanesthetized male rats (200-220 g) according to established procedures.
More particularly, tested compounds (Ia) and (Ib) gave the following results (IC50 values are expressed μM):
(Ia)
KAT II: 2.8
Kynurenine 3 -hydroxylase: >2000 Kynureninase: >2000
(Ib)
KAT II: 1.2
Kynurenine 3 -hydroxylase: 1002
Kynureninase: >2000 Compound (Ia) was tested in the rat brain in vivo and found to reduce the extracellular concentration of kynurenic acid in the hippocampus. In quantitative terms, this reduction was similar to that observed after the in vivo administration of known cognition-enhancing drugs such as d-amphetamine and methylphenidate. Such decreases in hippocampal kynurenic acid levels are known to enhance the activity of of/ nicotinic acetylcholine receptors (Alkondon et al., J. Neurosci., 24: 4635-4648, 2004).
Compound (Ia) can therefore increase cholinergic function in vivo, thus being clinically useful for the treatment of cognitive deficits and aging-related pathophysiologies.

Claims

1. Compounds of formula (I)
in which
R is Ci-C6 alkyl or C5-C6 cycloalkyl; R' is hydrogen or an amino group;
R" is hydrogen, halogen, C1-C6 alkyl or C3-C6 cycloalkyl and the pharmaceutically acceptable esters thereof.
2. Compounds as claimed in claim 1 wherein R is C1-C6 alkyl.
3. Compounds as claimed in claim 2 in which R is ethyl.
4. Compounds as claimed in claim 1 wherein R is C1-C6 alkyl and R" is hydrogen.
5. Compounds as claimed in claim 1 wherein R is CpC6 alkyl and R" is halogen.
6. A compound as claimed in claim 1, selected from: (S)-4-ethylsulfonyl benzoylalanine (Ia); (S)-2-amino-4-ethylsulfonyl benzoylalanine (Ib); (S)-3-chloro-4-ethylsulfonyl benzoylalanine (Ic);
(S)-2-amino-5-chloro-4-ethylsulfonyl benzoylalanine (Id).
7. Pharmaceutical compositions containing a compound of any one of claims 1-6 in admixture with suitable excipients and/or carriers.
8. The use of a compound of any one of claims 1-6 for the preparation of pharmaceutical compositions for the preparation of a medicament for the treatment of those psychiatric and neurological diseases which benefit from an increase in glutamatergic and/or cholinergic neurotransmission.
9. The use as claimed in claim 8 in which said diseases comprise schizophrenia, bipolar illness, depression, anxiety, Alzheimer's disease.
10. The use of a compound of claims 1-6 for the preparation of pharmaceutical compositions for stimulating attention, memory and other cognitive processes in normal individuals of any age, including children, adolescents and the elderly.
EP05775813A 2004-08-06 2005-08-02 4-sulfonyl-substituted benzoylalanine derivatives useful as kynurenine-aminotransferase inhibitors Withdrawn EP1781602A1 (en)

Applications Claiming Priority (2)

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IT001626A ITMI20041626A1 (en) 2004-08-06 2004-08-06 QUINURENIN-AMINO-TRANSFERASE INHIBITORS
PCT/EP2005/008356 WO2006013085A1 (en) 2004-08-06 2005-08-02 4-sulfonyl-substituted benzoylalanine derivates useful as kynurenine-aminotransferase inhibitors

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CN107417558A (en) 2013-03-14 2017-12-01 维斯塔津治疗公司 Method for synthesis of chiral kynurenin compound
EP3049389B1 (en) 2013-09-26 2019-08-07 CHDI Foundation, Inc. Kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use thereof
EP3049077A4 (en) 2013-09-26 2017-02-15 CHDI Foundation, Inc. Kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use thereof

Family Cites Families (2)

* Cited by examiner, † Cited by third party
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
US5519055A (en) * 1993-08-06 1996-05-21 University Of Maryland At Baltimore Substituted kynurenines and process for their preparation

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
PELLICCIARI ET AL: "Modulators of the Kynurenine Pathway of Tryptophan Metabolism: Synthesis and Preliminary Biological Evaluation of (S)-4-(Ethylsulfonyl)benzoylalanine, a Potent and Selective Kynurenine Aminotransferase II (KAT II) Inhibitor", CHEM. MED. CHEM., vol. 1, 2006, pages 528 - 531 *
See also references of WO2006013085A1 *

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