EP1529030A2 - Derives de l'acide r(+)-2-amino-3-hydroxypropanoique a action glycinergique - Google Patents

Derives de l'acide r(+)-2-amino-3-hydroxypropanoique a action glycinergique

Info

Publication number
EP1529030A2
EP1529030A2 EP03758195A EP03758195A EP1529030A2 EP 1529030 A2 EP1529030 A2 EP 1529030A2 EP 03758195 A EP03758195 A EP 03758195A EP 03758195 A EP03758195 A EP 03758195A EP 1529030 A2 EP1529030 A2 EP 1529030A2
Authority
EP
European Patent Office
Prior art keywords
amino
pharmaceutically acceptable
acceptable salts
phenyl
alkyl
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP03758195A
Other languages
German (de)
English (en)
French (fr)
Inventor
Kathleen Clarence-Smith
Jean-Marie Georges Contreras
Laurence Nathalie Deyon
Camille Georges Wermuth
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Prestwick Pharmaceuticals Inc
Original Assignee
Prestwick Pharmaceuticals Inc
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 Prestwick Pharmaceuticals Inc filed Critical Prestwick Pharmaceuticals Inc
Publication of EP1529030A2 publication Critical patent/EP1529030A2/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • C07C229/04—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 being acyclic and saturated
    • C07C229/22—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 being acyclic and saturated the carbon skeleton being further substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring

Definitions

  • the present invention relates to the use of derivatives of R (+) acid -
  • 2-amino-3-hydroxypropanoic acid for the preparation of medicaments intended for treating diseases of the central nervous system (CNS) due to reduced glycinergic transmission, pharmaceutical compositions comprising new derivatives of R (+) - 2-amino acid -3-hydroxypropanoic as active ingredients, as well as new compounds derived from R (+) - 2- amino-3-hydroxypropanoic acid.
  • Substances capable of strengthening glycinergic transmission are therefore capable of improving the cognitive and memory disorders which accompany these diseases.
  • glycine is one of the most potent agonists at the NMDA receptor glycine site and that other D-amino acids, including D-serine, are very good agonists, albeit with lower affinity than that of glycine.
  • Document US 6,228,875 shows that neuropsychiatric diseases characterized by a deficit in neurotransmission by the NMDA receptor can be alleviated by a compound acting as an agonist of the glycine site on the NMDA receptor.
  • said document cites in particular D-serine, esters of D-serine, alkylated D-serine or precursors of D-serine.
  • D-serine administered at a dose of 2 g / day, is effective in the treatment of schizophrenia even in patients who respond poorly to treatment with conventional antipsychotic drugs.
  • R (+) - 2-amino-3-hydroxypropanoic acid substituted on nitrogen by a (C 3 -C 6 ) alkenyl, 3-oxo (C 5 -C 6) group ) alkyl, 3-oxo (C 4 -C 6 ) alken-2-yl, phenyl (C ⁇ -C 6 ) alkyl, phenyl (C 2 - C 6 ) alkenyl, gem-diphenyl (C 1 -C 6 ) alkyl, gem-diphenyl (C 2 -C 6 ) alkenyl, (Ci- C 6 ) alkanoyl, 2-aminopropionyl optionally N-substituted, 2,6-diamino-n-hexanoyl optionally N, N'-disubstituted, phenyl (C ⁇ .
  • C 6 ) alkylidene or gem-diphenyl (C ⁇ -C 6 ) alkylidene, while containing a lower amount of D-serine is capable of improving glycinergic transmission in patients suffering from CNS diseases due to reduced glycinergic transmission, in particular suffering from autism, schizophrenia or Alzheimer's disease, at doses much lower than those used for glycine and at most at the same level as those used for D-serine.
  • Ra is hydrogen
  • Ra ' is hydrogen
  • N-benzyloxycarbonyl-R (+) - 2-aminopropionyle N-benzyloxycarbony.lS (-) - 2- aminopropionyle, R (+) - 2,6-diamino- / 7-hexanoyl, S (-) - 2,6 diamino- ⁇ -hexanoyl,
  • Ra ' together, are a phenyl (C 1 -C 6 ) alkylidene or gem-dipheny group ⁇ Cr
  • Ra is hydrogen, a (CrC 6 ) straight or branched chain alkyl group or a (C 3 -C 6 ) cycloalkyl (C 1 -C 6 ) group alkyl, phenyl (C ⁇ -C 2 ) alkyl, phenacetyl or phenyl , the phenyl group or groups present in the substituents Ra, Ra 'and Ra "being unsubstituted or substituted by a halogen atom or by a hydroxy group, (C ⁇ .
  • CNS due to reduced glycinergic transmission including the treatment of autism, schizophrenia and Alzheimer's disease.
  • Ra ′ is a gem-diphenyl (C 1 -C 6 ) alkyl group
  • Ra ′ is a ⁇ -diphenyl (C 2 -C 6 ) alkyl group
  • the activity of these products was evaluated in a predictive test for this type of activity which consists in evaluating the locomotor activity of animals. It is carried out on groups of 10 mice having received the test compounds per os (8 mg / kg) 15 minutes before the injection of phencyclidine (4 mg / kg). Animals are placed in an "open field" divided into 9 equal squares. A camera records their activity for 25 minutes, the locomotor activity being expressed in number of tiles crossed per minute.
  • the compounds of formula I are administered to the patient who requires an increase in glycinergic transmission at a daily dose which does not exceed 10 g per day and which is advantageously between 200 and 7500 mg and more preferably between 250 - 5000 mg.
  • the preferred doses, 500 to 3000 mg or 750 to 2000 mg allow a good improvement in glycinergic transmission and also an improvement in the negative symptoms of schizophrenia, symptoms of Alzheimer's disease and behavior in autism.
  • the compounds useful as active principles intended to improve glycinergic transmission are included in pharmaceutical compositions formulated in dosage units containing from 10 mg to 1200 mg, advantageously from 50 to 1000 mg of active principle.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising, as an active ingredient, a pharmacologically effective dose of an R (+) - 2-amino-3-hydroxypropanoic acid derivative of formula II
  • Rb is hydrogen, Rb 'is hydrogen, (C 3 - C 6 ) alkenyl, 3-oxo (C 4 -C 6 ) alkyl, 3-oxo (C 4 -C 6 ) alken-2- yl, with straight or branched chains, a phenyl (C 1 -C 6 ) alkyl, phenyl (C 2 -C 6 ) alkenyl, (C 2 - C 6 ) alkanoyl, gem-diphenyl (C ⁇ -C 6 ) alkyl group, gem-diphenyl (C 2 -C 6 ) alkenyl, (C 3 - C 6 ) alkenoyl, N- (C 2 -C 6 ) alkanoyl-R (+) - 2-aminopropionyl, N- (C 2 -C 6 ) alkanoyl-S (-) -2-aminopropionyle, N-benzyloxycarbonyl-R (+
  • Rb and Rb 'are both H then Rb "is other than hydrogen, methyl , ethyl or unsubstituted benzyl and that, when Rb is hydrogen and Rb 'is unsubstituted benzyl, an N-benzyloxycarbonyl-S (-) - 2-aminopropionyl, R (+) - 2-aminopropionyl or S (-) -2-aminopropionyl, then Rb "is other than hydrogen; or one of its pharmaceutically acceptable salts, mixed with a pharmaceutically acceptable excipient.
  • the active principle can be administered in the most appropriate dosage unit in admixture with conventional pharmaceutical excipients, in animals and animals humans.
  • Suitable unit administration forms include oral forms such as tablets, capsules, powders, granules and oral solutions or suspensions, sublingual and oral administration forms or parenteral or rectal administration forms .
  • the present invention provides new derivatives of R (+) - 2-amino-3-hydroxypropanoic acid of formula III
  • the compounds of the present invention which are derivatives of N-substitution of R (+) - 2-amino-3-hydroxypropanoic acid, or of its esters, and their pharmaceutically acceptable salts, are synthesized according to conventional methods of preparation of amino acid esters or N-substituted derivatives of amino acids and their esters.
  • esters of R (+) - 2-amino-3-hydroxypropanoic acid can be obtained by reaction of a functional derivative of D-serine with the alcohol or the esterifying phenol or by saponification in position 4 of ( R) -3-tert-butoxycarbonyl-2,2-dimethyloxazolidine-4-methyl or ethyl carboxylate, esterification of (R) -3-tert-butoxycarbonyl-2,2-dimethyloxazolidine-4-carboxylic acid by reaction of a functional derivative thereof with alcohol or the esterifying phenol in the presence of a proton sensor, for example of a tertiary base such as 4-dimethylaminopyridine, methylmorpholine, ethylmorpholine or diisopropylamine , and saponification of the tert-butyl ester with trifluoroacetic acid which at the same time involves the decomposition of the oxazolidinic ring and the formation of the desired este
  • N-monosubstitution can be carried out by reaction of the ester of R (+) - 2-amino-3-hydroxypropanoic acid with a halide of formula:
  • a tertiary organic base such as 4-dimethylaminopyridine, 4-methyl- or 4-ethylmorpholine
  • an inorganic base such as an alkaline bicarbonate such as sodium hydrogencarbonate.
  • the corresponding acyl halide can be replaced by another functional derivative such as a mixed anhydride, an active ester or the free acid, suitably activated by example with dicyclohexylcarbodiimide. If the alkanoyl group is substituted on the alkyl by an amino group, this will be suitably protected by one of the conventional protecting groups for peptide chemistry, for example by a benzyloxycarbonyl group.
  • Ra ', Rb' or R ' are other than an alkanoyl group, can be replaced by a compound of formula Ra'-X (IVa'), Rb'-X . (IVb ') or R'-X (IV)
  • X represents a leaving group such as an alkanesulphonyloxy radical such as methanesulphonyloxy or a benzenesulphonyloxy radical unsubstituted or substituted on the benzene ring preferably by a methyl group such as -toluenesulphonyloxy.
  • the compounds having the formula I, II or III where Ra and Ra ', or Rb and Rb', or R and R ', together, are a gem-diphenyl (CrC 6 ) alkylidene group are prepared by reaction of D-serine or one of its esters with a benzophenone, when the desired product has the formula I, II or III where Ra and Ra ', or Rb and Rb', or R and R ', together, are a group gem-diphenyl (C ⁇ ) alkyl (diphenylmethyl), or with a gem-diphenyl (C 2 -C 6 ) carboxaldehyde, when the desired product has the formula I, II or III where Ra and Ra ', or Rb and Rb' , or R and R ', together, are a gem-diphenyl (C 2 -C 6 ) alkyl group, under the conditions for the preparation of Schiff bases.
  • phenyl used in the general description above, includes any phenyl group, unsubstituted or substituted by a halogen atom or by a hydroxy group, (CrC 3 ) alkoxy, cyano, nitro or acetyl.
  • the N-substituted derivative thus obtained is an intermediate which is saponified to prepare a compound of formula I, II or III where Ra ", Rb "or R” is hydrogen, while the N-substituted derivative thus obtained is the product final, if an ester other than the methyl or ethyl ester was used as the starting compound.
  • the R (+) - 2-amino-3-hydroxypropanoic acid derivatives can be isolated in free form or from their chemically or pharmaceutically acceptable salts.
  • the salts may be those with mineral or organic bases, for example sodium hydroxide or trometamol, or with mineral or organic acids such as the hydrochloride or trifluoroacetate.
  • the chemically or pharmaceutically acceptable salts form part of the invention.
  • the expression “chemically acceptable” refers to the salts of the compounds of formula I, useful for the isolation or the purification of the new products.
  • Cyclopropylmethyl 2- (R) -amino-3-hydroxypropanoate hydrochloride Cool the cyclopropylcarbinol (15 mL) to 0 ° C and add acetyl chloride (1.37 mL). After 10 minutes of stirring at 0 ° C, add the D-serine (750 mg) and bring the solution to reflux for 2 hours. Concentrate the reaction mixture, take up with a saturated potassium carbonate solution and extract with ethyl acetate. Dry the organic phase on MgSO, filter and concentrate. Take up the product in a minimum of methanol and add a solution of IN hydrochloric acid in ether. Evaporate the solvent in vacuo to obtain the desired product as a brown solid (250 mg). Melting point: 112-118 ° C.
  • R (+) - N- (4,4-diphenyl) butyl-2-amino-3-hydroxypropanoic acid hydrochloride At 0 ° C, dissolve R (+) - N- (4,4-diphenyl) butyl Methyl -2-amino-3-hydroxypropanoate (600 mg) in a THF / H 2 O mixture (3/1; 20 mL) and add a 5N sodium hydroxide solution (0.7 mL). After 15 minutes at 0 ° C, allow the reaction mixture to return to room temperature. After 45 minutes, cool the mixture again to 0 ° C, add a solution of IN hydrochloric acid (4 mL) and then concentrate in vacuo.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Psychiatry (AREA)
  • Hospice & Palliative Care (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Peptides Or Proteins (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
EP03758195A 2002-08-14 2003-08-01 Derives de l'acide r(+)-2-amino-3-hydroxypropanoique a action glycinergique Withdrawn EP1529030A2 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
FR0210306A FR2843590B1 (fr) 2002-08-14 2002-08-14 Derives de l'acide r(+)-2-amino-3-hydroxypropanoique a action glycinergique
FR0210306 2002-08-14
PCT/FR2003/002447 WO2004016580A2 (fr) 2002-08-14 2003-08-01 Derives de l'acide r(+)-2-amino-3-hydroxypropanoique a action glycinergique

Publications (1)

Publication Number Publication Date
EP1529030A2 true EP1529030A2 (fr) 2005-05-11

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ID=30775996

Family Applications (1)

Application Number Title Priority Date Filing Date
EP03758195A Withdrawn EP1529030A2 (fr) 2002-08-14 2003-08-01 Derives de l'acide r(+)-2-amino-3-hydroxypropanoique a action glycinergique

Country Status (19)

Country Link
US (1) US7488755B2 (xx)
EP (1) EP1529030A2 (xx)
JP (1) JP2005535715A (xx)
KR (2) KR100756138B1 (xx)
CN (1) CN1675169A (xx)
AU (1) AU2003274213B2 (xx)
BR (1) BR0313740A (xx)
CA (1) CA2497347A1 (xx)
CR (1) CR7736A (xx)
EA (1) EA010417B1 (xx)
FR (1) FR2843590B1 (xx)
GE (1) GEP20074194B (xx)
IL (1) IL166778A0 (xx)
MX (1) MXPA05001761A (xx)
NO (1) NO20050961L (xx)
NZ (1) NZ538633A (xx)
PL (1) PL375413A1 (xx)
UA (1) UA80559C2 (xx)
WO (1) WO2004016580A2 (xx)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9199916B2 (en) * 2011-11-10 2015-12-01 Ramamohan Rao Davuluri Process for the preparation of (R)-N-benzyl-2-acetamido-3-methoxypropionamide

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH03236315A (ja) * 1989-12-05 1991-10-22 Nippon Oil & Fats Co Ltd 抗精神病薬
US5332758A (en) * 1990-07-13 1994-07-26 Kanebo, Ltd. Collagen metabolism ameliorant and its use
ES2036926B1 (es) * 1991-08-08 1994-01-16 Uriach & Cia Sa J "procedimiento para la obtencion de derivados de la (2-alquil-3-piridil)metilpiperazina".
GB9425730D0 (en) 1994-12-20 1995-02-22 Nycomed Pharma As Compounds
ATE320804T1 (de) * 1995-12-07 2006-04-15 Daniel C Javitt Behandlung negativer und kognitiver symptome der schizophrenie mit antagonisten der glycinaufnahme
IT1283489B1 (it) * 1996-07-23 1998-04-21 Chiesi Farma Spa Ammidi di alfa-amminoacidi,loro preparazione e loro impiego terapeutico
AU765603C (en) * 1998-04-14 2004-08-05 General Hospital Corporation, The Methods for treating neuropsychiatric disorders
GB2410947B (en) 2004-02-11 2008-09-17 Cambridge Lab Ltd Pharmaceutical compounds

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2004016580A2 *

Also Published As

Publication number Publication date
NO20050961L (no) 2005-04-28
FR2843590B1 (fr) 2007-10-05
PL375413A1 (en) 2005-11-28
WO2004016580A2 (fr) 2004-02-26
MXPA05001761A (es) 2005-04-25
JP2005535715A (ja) 2005-11-24
KR20070067250A (ko) 2007-06-27
FR2843590A1 (fr) 2004-02-20
CA2497347A1 (en) 2004-02-26
IL166778A0 (en) 2006-01-15
NZ538633A (en) 2007-10-26
WO2004016580A3 (fr) 2004-04-08
KR100756138B1 (ko) 2007-09-05
EA200500333A1 (ru) 2005-08-25
CN1675169A (zh) 2005-09-28
KR100890674B1 (ko) 2009-03-26
BR0313740A (pt) 2005-07-19
UA80559C2 (en) 2007-10-10
GEP20074194B (en) 2007-09-10
AU2003274213A1 (en) 2004-03-03
EA010417B1 (ru) 2008-08-29
CR7736A (es) 2008-10-10
US7488755B2 (en) 2009-02-10
AU2003274213B2 (en) 2008-03-13
US20050261372A1 (en) 2005-11-24
KR20050055697A (ko) 2005-06-13

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