WO1998043964A1 - Derives de 2-[(3-substitue)-5-isoxazolylmethylamino]alkanamide - Google Patents

Derives de 2-[(3-substitue)-5-isoxazolylmethylamino]alkanamide Download PDF

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Publication number
WO1998043964A1
WO1998043964A1 PCT/EP1998/001928 EP9801928W WO9843964A1 WO 1998043964 A1 WO1998043964 A1 WO 1998043964A1 EP 9801928 W EP9801928 W EP 9801928W WO 9843964 A1 WO9843964 A1 WO 9843964A1
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WIPO (PCT)
Prior art keywords
compound
propanamide
isoxazol
hydrogen
formula
Prior art date
Application number
PCT/EP1998/001928
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English (en)
Inventor
Paolo Pevarello
Manuela Villa
Raffaella Amici
Patricia Salvati
Mario Varasi
Original Assignee
Newron Pharmaceuticals 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 Newron Pharmaceuticals S.P.A. filed Critical Newron Pharmaceuticals S.P.A.
Priority to AU70430/98A priority Critical patent/AU7043098A/en
Publication of WO1998043964A1 publication Critical patent/WO1998043964A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D261/12—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D261/14—Nitrogen atoms

Definitions

  • the present invention relates to novel 2- [ (3 -substituted) - 5-isoxazolylmethylamino] alkanamide ⁇ , to their use as therapeutic agents, to a process for their preparation and to pharmaceutical compositions containing them. It has been found that novel 2- [ (3-substituted) -5- isoxazolylmethylamino] alkanamide derivatives as herein defined have valuable biological properties, in particular as antiepileptic, anti-Parkinson, neuroprotective, anti- depressant, antispastic and/or hypnotic agent.
  • the present invention provides compounds having the following formula (I)
  • n is zero or an integer of 1 to 3 ;
  • X is 0, S or NH; each of R and R independently is hydrogen, alkyl, halogen, hydroxy, ⁇ d alkoxy or trifluoromethyl ; each of R 2 , R 5 and R 6 independently is hydrogen or C- ⁇ C g alkyl .- each of R 3 and R 4 independently is hydrogen, alkyl or R 3 and R 4 taken together with the adjacent carbon atom form a
  • the pharmaceutically acceptable salts of the compounds of formula (I) include acid addition salts with inorganic, e.g. hydrochloric, hydrobromic, sulphuric, and phosphoric acids, or organic, e.g. acetic, propionic, lactic, oxalic, malic, maleic, tartaric, citric, benzoic, mandelic, salicylic, alkylsulfonic and fumaric acids.
  • inorganic e.g. hydrochloric, hydrobromic, sulphuric, and phosphoric acids
  • organic e.g. acetic, propionic, lactic, oxalic, malic, maleic, tartaric, citric, benzoic, mandelic, salicylic, alkylsulfonic and fumaric acids.
  • the compounds of the formula (I) may also form pharmaceutically acceptable solvates, such as mono-, di- or tri-hydrates, which are also object of the present invention.
  • the alkyl and alkoxy groups may be branched or straight groups .
  • a C- L -Cg alkyl group is preferably a C 1 -C 4 alkyl group, in particular methyl, ethyl, n - and iso-propyl, n - , iso- , sec- and tert-butyl, more preferably methyl or ethyl.
  • Representative examples of Ci- j alkoxy groups include methoxy or ethoxy.
  • a halogen atom is e.g. chlorine, fluorine, bromine, in particular chlorine and fluorine, more preferably fluorine.
  • a C 3 -C 7 cycloalkyl group is, for instance, a cyclopropyl
  • Compounds of formula (I) contain an asymmetric carbon atom and have optical 1 and d isomers. These compounds can be used as the dl racemate or the d- and 1-isomer can be separately synthesized from optically pure starting material or separated from the racemate in a conventional manner.
  • the present invention also include within its scope both the metabolites and the pharmaceutically acceptable bio- precursors (otherwise known as pro-drugs) of the compounds of formula (I) .
  • Preferred compounds of the invention are the compounds of formula (I) wherein n is 1 or 2 ; R is hydrogen; R is hydrogen or halogen; each of R 2 , R 3 , R 4 , R 5 and R 6 independently is hydrogen or C x -C 4 alkyl; and the pharmaceutically acceptable salts thereof .
  • More preferred compounds of the invention are the compounds of formula (I) , wherein n is 1;
  • X is 0 or NH
  • R x is hydrogen or halogen
  • R 3 is C x -C 4 alkyl
  • R 4 is hydrogen or C x -C 4 alkyl
  • R, R 2 , R 5 and R 6 are hydrogen; and the pharmaceutically acceptable salts thereof.
  • Examples of specific compounds of the invention are: 2-[3- (3-fluorobenzyloxy) isoxazol-5-ylmethylamino] propanamide ;
  • the compounds of the invention and the salts thereof can be obtained by a process comprising: a) reaction of a compound of formula (II)
  • the reaction of a compound of formula (II) with a compound of formula (III) to give a compound of formula (I) or (IV) is a reductive amination reaction which can be carried out according to well known methods .
  • a reductive amination reaction which can be carried out according to well known methods .
  • it may be performed under nitrogen atmosphere, in a suitable organic solvent, such as an alcohol, e.g. a C 1 -C 4 alkanol, in particular methanol , or in acetonitrile, at a temperature ranging from about 0°C to about 40°C, in the presence of a reducing agent, the most appropriate being sodium cyanoborohydride .
  • a suitable organic solvent such as an alcohol, e.g. a C 1 -C 4 alkanol, in particular methanol , or in acetonitrile, at a temperature ranging from about 0°C to about 40°C, in the presence of a reducing agent, the most appropriate
  • the halogen W is preferably iodine.
  • the alkylation reaction of a compound of formula (IV) with a compound of formula (V) can be carried out in a suitable organic solvent, such as a C 1 -C 4 alcohol, e.g. methanol , ethanol or isopropanol, in particular in ethanol, at a temperature ranging from about 0°C to about 50 °C.
  • a suitable solvent such as a C- L -C 4 alcohol, e.g.
  • a compound of the invention can be converted, as stated above, into another compound of the invention by known methods.
  • Process-variant b) above may be regarded as an example of optional conversion of a compound of the invention into another compound of the invention.
  • An isomer, e.g., a d- or 1-isomer of a compound of the invention can be separately synthesized from optically pure starting material or separated from a racemate in a conventional manner.
  • a compound of formula (II) can be obtained from reduction of a compound of formula (VII)
  • R, R l t X and n are as defined above and R 7 is a lower alkyl, typically C x -C 4 alkyl.
  • Transformation to aldehyde can be achieved using a suitable reducing agent such as i-Bu 2 AlH, LiAlH 4 , NaAlH 4 , preferably i-Bu 2 AlH in toluene at about -75°C.
  • a suitable reducing agent such as i-Bu 2 AlH, LiAlH 4 , NaAlH 4 , preferably i-Bu 2 AlH in toluene at about -75°C.
  • a compound of formula (VII) can be obtained reacting a compound of formula (VIII)
  • A is OH, halogen or a leaving group such as mesyloxy, tosyloxy or trifluoroacetate and R 7 is as defined above, with a compound of formula (IX)
  • (VIII) A is OH and in the compound of formula (IX) E is halogen or a leaving group such as mesyloxy, tosyloxy or trifluoroacetate.
  • a suitable base such as anhydrous potassium carbonate, sodium carbonate, triethylamine, pyridine, diisopropylethylamine, etc.
  • a suitable solvent such as ethanol,
  • the compounds of the invention are active on the central nervous system (CNS) and can be used in therapy, for example as antiepileptics, in the treatment of Parkinson's disease and as neuroprotective agents, e.g. preventing or treating neuronal loss associated with stroke, hypoxia, ischemia, CNS trauma, hypoglycaemia or surgery and in treating and preventing neurodegenerative diseases such as Alzheimer's disease, amyotrophic lateral sclerosis, Down's syndrome, Huntington's disease, dementia caused by acquired immunodeficiency syndrome (AIDS) , infarctual dementia; they can also be used as antidepressants, hypnotics and antispastic agents and in treating ocular damage, rethinopaty and infections or inflammations in the brain.
  • CNS central nervous system
  • the activity on the CNS of the compounds of the invention was evaluated on the basis of pharmacological methods, such as, for example, the antagonism of convulsions and lethality induced by intravenous injection of bicuculline in mice (Antiepileptic Drugs, D.M. Woodbury et al . eds . , 2nd edition, Raven Press, New York, 1982) , or the antagonism of maximal electroshock seizures (MES) (Woodbury, L.A. and Davenport, V.D., Arch. Int. Pharmacodyn. Ther. 92; 97-104, 1952).
  • MES maximal electroshock seizures
  • a patient is treated according to the present invention by a method comprising administering to the patient an effective amount of one of the compounds of the invention.
  • the present compounds can be used to treat disorders of the central nervous system, for example epilepsy or Parkinson's disease; or as neuroprotective agents, and in preventing neurodegenerative diseases or treating a patient suffering therefrom, as antidepressants, hypnotics, anti-spastic agents and for the treatment of ocular damage or rethinopaty and infections or inflammations in the brain.
  • disorders of the central nervous system for example epilepsy or Parkinson's disease
  • neuroprotective agents and in preventing neurodegenerative diseases or treating a patient suffering therefrom, as antidepressants, hypnotics, anti-spastic agents and for the treatment of ocular damage or rethinopaty and infections or inflammations in the brain.
  • the condition of a patient may thus be improved.
  • 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 suspensions,- rectally in the form of suppositories; parenterally, e.g. intramuscularly, or by intravenous injection or infusion.
  • the dosage depends on the age, weight, conditions of the patient and on the administration route; for example, the dosage adopted for oral administration to adult humans e.g. for the representative compound of the invention
  • 2-[3-(3- fluorobenzyloxy) -isoxazol-5-ylmethylamino]-propanamide may range from about 1 to about 500 mg pro dose, from 1 to 5 times daily.
  • the invention includes pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, as an active principle, in association with a pharmaceutically acceptable excipient (which can be a carrier or a diluent) .
  • a pharmaceutically acceptable excipient which can be a carrier or a diluent
  • compositions containing the compounds of the invention are usually prepared following conventional methods and are administered in a pharmaceutically suitable form.
  • the solid oral forms may contain, together with the active compound, diluents, e.g. lactose, dextrose, saccharose, cellulose, corn starch or potato starch; lubricants, e.g. silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols; binding agents, e.g. starches, arabic gums, gelatin, methylcellulose, carboxymethylcellulose or polyvinyl pyrrolidone; disaggregating agents, e.g.
  • diluents e.g. lactose, dextrose, saccharose, cellulose, corn starch or potato starch
  • lubricants e.g. silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols
  • binding agents e.g. starches, arabic gums, gelatin, methylcellulose, carboxymethylcellulose or polyvinyl pyrrol
  • a starch alginic acid, alginate ⁇ or sodium starch glycolate,- effervescing mixtures; dyestuffs,- sweeteners; wetting agents such as lecithin, polysorbates, laurylsulphates ; and, in general, non-toxic and pharmacologically inactive substances used in pharmaceutical formulations.
  • Said pharmaceutical preparations may be manufactured in known manner, for example, by means of mixing, granulating, tabletting, sugar-coating, or film-coating processes.
  • the liquid dispersion for oral administration may be e.g. syrups, emulsions and suspension.
  • the syrups may contain as carrier, for example, saccharose or saccharose with glycerin and/or mannitol and/or sorbitol .
  • the suspension and the emulsion may contain as carrier, for example, a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol .
  • the suspension or solutions for intramuscolar injections may contain, together with the active compound, a pharmaceutically acceptable carrier, e.g. sterile water, olive oil, ethyl oleate, glycols, e.g. propylene glycol, and, if desired, a suitable amount of lidocaine hydrochloride .
  • a pharmaceutically acceptable carrier e.g. sterile water, olive oil, ethyl oleate, glycols, e.g. propylene glycol, and, if desired, a suitable amount of lidocaine hydrochloride .
  • the solutions for intravenous injections or infusion may contain as carrier, for example, sterile water or preferably they may be in the form of sterile, aqueous, isotonic saline solutions.
  • the suppositories may contain together with the active compound a pharmaceutically acceptable carrier, e.g. cocoa butter, polyethylene glycol, a polyoxyethylene sorbitan fatty acid ester surfactant or lecithin.
  • a pharmaceutically acceptable carrier e.g. cocoa butter, polyethylene glycol, a polyoxyethylene sorbitan fatty acid ester surfactant or lecithin.
  • Methyl 3- (3-fluorobenzyloxy) -5-isoxazolecarboxylate (1) Methyl 3-hydroxy-5-isoxazolecarboxylate (5.0 g; 0.035 mol) was dissolved in acetone (90 ml) under nitrogen, K 2 C0 3 (9.4 g,- 0.068 mol) was added and the mixture was heated to reflux for one hour. After addition of KI (a catalitic amount), 3-fluorobenzylchloride (6.3 ml, 0.053 mol) was added dropwise and the mixture was stirred at reflux for 5 hours.
  • preparation can be made of capsules having the following composition:

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

Nouveaux 2-[(3-substitué)-5-isoxazolylméthylamino]alkanamides représentés par la formule suivante (I) dans laquelle: n est zéro ou un entier de 1 à 3; X représente O, S ou NH; chacun de R et R1, qui sont semblables ou différents, représente hydrogène, alkyle C1-C6, halogène, hydroxy, alkoxy C1-C4 ou trifluorométhyle; chacun de R2, R5 et R6, qui sont semblables ou différents, représente hydrogène ou alkyle C1-C6; chacun de R3 et R4, qui sont semblables ou différents, représente hydrogène ou alkyle C1-C6 et R3 et R4 pris ensemble avec l'atome de carbone contigu, constituent un noyau cycloalkyle C3-C7; ainsi que leurs sels acceptables sur le plan pharmaceutique, jouant un rôle efficace en tant qu'agents contre des troubles du système nerveux central.
PCT/EP1998/001928 1997-04-03 1998-03-27 Derives de 2-[(3-substitue)-5-isoxazolylmethylamino]alkanamide WO1998043964A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU70430/98A AU7043098A (en) 1997-04-03 1998-03-27 2-{(3-substituted)-5-isoxazolylmethylamino}alkanamide derivatives

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9706730.0 1997-04-03
GBGB9706730.0A GB9706730D0 (en) 1997-04-03 1997-04-03 2-[(3-substituted)-5-Isoxazolymethylaminojalkanamid derivatives

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999026614A1 (fr) * 1997-11-21 1999-06-03 Euro-Celtique S.A. 2-aminoacetamides substitues et leur utilisation
US6281211B1 (en) 1999-02-04 2001-08-28 Euro-Celtique S.A. Substituted semicarbazides and the use thereof
EP1742904A2 (fr) * 2004-05-06 2007-01-17 The Regents Of The University Of California Enaminones substitues, leurs derives et leur utilisation
USRE40259E1 (en) 1997-12-31 2008-04-22 Newron Pharmaceuticals, S.P.A. Alpha-aminoamide derivatives useful as analgesic agents
US7393872B2 (en) 1999-04-09 2008-07-01 Euro-Celtique S.A. Sodium channel blocker compositions and the use thereof
US7709523B2 (en) 2003-01-16 2010-05-04 Newron Pharmaceuticals Spa Alpha-aminoamide derivatives useful as antimigraine agents
US8084447B2 (en) 2001-09-03 2011-12-27 Newron Pharmaceuticals S.P.A. Pharmaceutical composition comprising gabapentin or an analogue thereof and an α-aminoamide and its analgesic use

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0371876A1 (fr) * 1988-11-30 1990-06-06 Novapharme Composés isoxazoles et isoxazolines à activité anticonvulsivante, procédé de préparation et compositions thérapeutiques les contenant
WO1994022808A1 (fr) * 1993-04-01 1994-10-13 Farmitalia Carlo Erba Srl Derives (arylalcoxybenzyl)aminopropanamidiques substitues, leur preparation et leur utilisation comme agents antiepileptiques, neuro-protecteurs et antidepressifs

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0371876A1 (fr) * 1988-11-30 1990-06-06 Novapharme Composés isoxazoles et isoxazolines à activité anticonvulsivante, procédé de préparation et compositions thérapeutiques les contenant
WO1994022808A1 (fr) * 1993-04-01 1994-10-13 Farmitalia Carlo Erba Srl Derives (arylalcoxybenzyl)aminopropanamidiques substitues, leur preparation et leur utilisation comme agents antiepileptiques, neuro-protecteurs et antidepressifs

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7872127B2 (en) 1997-11-21 2011-01-18 Purdue Neuroscience Company Substituted 2-aminoacetamides and the use thereof
WO1999026614A1 (fr) * 1997-11-21 1999-06-03 Euro-Celtique S.A. 2-aminoacetamides substitues et leur utilisation
US6479484B1 (en) 1997-11-21 2002-11-12 Euro-Celtique S.A. Substituted 2-aminoacetamides and the use thereof
US6500825B2 (en) 1997-11-21 2002-12-31 Euro-Celtique S.A. Substituted 2-aminoacetamides and the use thereof
US8426431B2 (en) 1997-11-21 2013-04-23 Purdue Neuroscience Company Substituted 2-aminoacetamides and the use thereof
US7091210B2 (en) 1997-11-21 2006-08-15 Purdue Neuroscience Company Substituted 2-aminoacetamides and the use thereof
US7541465B2 (en) 1997-11-21 2009-06-02 Purdue Neuroscience Company Substituted 2-aminoacetamides and the use thereof
USRE40259E1 (en) 1997-12-31 2008-04-22 Newron Pharmaceuticals, S.P.A. Alpha-aminoamide derivatives useful as analgesic agents
US6281211B1 (en) 1999-02-04 2001-08-28 Euro-Celtique S.A. Substituted semicarbazides and the use thereof
US7393872B2 (en) 1999-04-09 2008-07-01 Euro-Celtique S.A. Sodium channel blocker compositions and the use thereof
US8710040B2 (en) 2001-09-03 2014-04-29 Newron Pharmaceuticals S.P.A. Pharmaceutical composition comprising gabapentin or an analogue thereof and an α-aminoamide and its analgesic use
US8084447B2 (en) 2001-09-03 2011-12-27 Newron Pharmaceuticals S.P.A. Pharmaceutical composition comprising gabapentin or an analogue thereof and an α-aminoamide and its analgesic use
US7709523B2 (en) 2003-01-16 2010-05-04 Newron Pharmaceuticals Spa Alpha-aminoamide derivatives useful as antimigraine agents
US7825278B2 (en) 2004-05-06 2010-11-02 The Regents Of The University Of California Substituted enaminones, their derivatives and uses thereof
EP1742904A4 (fr) * 2004-05-06 2007-04-18 Univ California Enaminones substitues, leurs derives et leur utilisation
EP1742904A2 (fr) * 2004-05-06 2007-01-17 The Regents Of The University Of California Enaminones substitues, leurs derives et leur utilisation

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AU7043098A (en) 1998-10-22
GB9706730D0 (en) 1997-05-21

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