WO1998003469A1 - Derives d'esters d'acide benzoylpropionique - Google Patents

Derives d'esters d'acide benzoylpropionique Download PDF

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Publication number
WO1998003469A1
WO1998003469A1 PCT/EP1997/003588 EP9703588W WO9803469A1 WO 1998003469 A1 WO1998003469 A1 WO 1998003469A1 EP 9703588 W EP9703588 W EP 9703588W WO 9803469 A1 WO9803469 A1 WO 9803469A1
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WO
WIPO (PCT)
Prior art keywords
compound
formula
oxo
dichlorophenyl
amino
Prior art date
Application number
PCT/EP1997/003588
Other languages
English (en)
Inventor
Mario Varasi
Antonio Giordani
Massimo Cini
Carmela Speciale
Alberto Bianchetti
Original Assignee
Pharmacia & Upjohn S.P.A.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Pharmacia & Upjohn S.P.A. filed Critical Pharmacia & Upjohn S.P.A.
Priority to EP97937467A priority Critical patent/EP0915830A1/fr
Priority to AU40096/97A priority patent/AU4009697A/en
Priority to JP10506490A priority patent/JP2000515143A/ja
Publication of WO1998003469A1 publication Critical patent/WO1998003469A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • 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
    • 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
    • A61P25/08—Antiepileptics; Anticonvulsants
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • 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
  • 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
  • the compounds of formula (IA) are, in general, soluble in aqueous vehicles suitable for parenteral administration
  • 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 .
  • Preferred salts according to the invention are hydrochlorides .
  • R x is preferably trifluoromethyl or C ⁇ C ⁇ alkoxy, in particular methoxy, ethoxy or tert-butoxy.
  • 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.
  • 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.
  • step c) 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.
  • 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 (V) either as free amino acid or as its inorganic salt, e.g. the hydrochloride
  • the corresponding alcohol e.g. methanol or ethanol
  • a suitable catalyst e.g. anhydrous hydrochloric acid
  • the esterification reaction may be also cai ⁇ ed 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 compoun ⁇ 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 t ⁇ fluoro- 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
  • 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 .
  • Capsule each weighing 0.230 g and containing 50 mg of the active substance can be prepared as follows: Composition for 500 capsules:
  • 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.

Landscapes

  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical & Material Sciences (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Psychology (AREA)
  • Pain & Pain Management (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Cette invention se rapporte à des dérivés d'esters d'acide benzoylpropionique représentés par la formule (I), où R représente alkyle C1-C4 ou benzyle, et aux sels de ces dérivés acceptables sur le plan pharmaceutique, qui agissent comme inhibiteurs de l'enzyme kynurénine-3-hydroxylase et sont utiles dans le traitement des maladies neuro-dégénératives. Cette invention présente également un procédé pour préparer des composés représentés par la formule (I) et des compositions pharmaceutiques comprenant ces composés.
PCT/EP1997/003588 1996-07-23 1997-07-03 Derives d'esters d'acide benzoylpropionique WO1998003469A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP97937467A EP0915830A1 (fr) 1996-07-23 1997-07-03 Derives d'esters d'acide benzoylpropionique
AU40096/97A AU4009697A (en) 1996-07-23 1997-07-03 Benzoylpropionic acid ester derivatives
JP10506490A JP2000515143A (ja) 1996-07-23 1997-07-03 ベンゾイルプロピオン酸エステル誘導体

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
WO1998003469A1 true WO1998003469A1 (fr) 1998-01-29

Family

ID=10797362

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1997/003588 WO1998003469A1 (fr) 1996-07-23 1997-07-03 Derives d'esters d'acide benzoylpropionique

Country Status (8)

Country Link
EP (1) EP0915830A1 (fr)
JP (1) JP2000515143A (fr)
AR (1) AR007946A1 (fr)
AU (1) AU4009697A (fr)
CA (1) CA2258074A1 (fr)
GB (1) GB9615441D0 (fr)
WO (1) WO1998003469A1 (fr)
ZA (1) ZA976429B (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103554006A (zh) * 2009-09-11 2014-02-05 伊文蒂瓦公司 吲哚衍生物作为nurr-1激活剂用作治疗帕金森病的药剂的用途

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995003271A1 (fr) * 1993-07-23 1995-02-02 Pharmacia S.P.A. Derives de l'acide 2-amino-4-phenyl-4-oxobutyrique, ayant une activite inhibitrice de la cynureninase et/ou de la cynurenine-3-hydroxylase

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995003271A1 (fr) * 1993-07-23 1995-02-02 Pharmacia S.P.A. Derives de l'acide 2-amino-4-phenyl-4-oxobutyrique, ayant une activite inhibitrice de la cynureninase et/ou de la cynurenine-3-hydroxylase

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
SPECIALE, CARMELA ET AL: "(R,S)-3,4-dichlorobenzoylalanine (FCE 28833A) causes a large and persistent increase in brain kynurenic acid levels in rats", EUR. J. PHARMACOL. (1996), 315(3), 263-267 CODEN: EJPHAZ;ISSN: 0014-2999, 1996, XP002043986 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103554006A (zh) * 2009-09-11 2014-02-05 伊文蒂瓦公司 吲哚衍生物作为nurr-1激活剂用作治疗帕金森病的药剂的用途

Also Published As

Publication number Publication date
EP0915830A1 (fr) 1999-05-19
CA2258074A1 (fr) 1998-01-29
ZA976429B (en) 1998-02-18
AR007946A1 (es) 1999-11-24
GB9615441D0 (en) 1996-09-04
JP2000515143A (ja) 2000-11-14
AU4009697A (en) 1998-02-10

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