EP1423146A1 - Composition pour le traitement de la maladie de parkinson contenant un antagoniste du recepteur cb1 et un produit qui active la neurotransmission dopaminergique dans le cerveau - Google Patents

Composition pour le traitement de la maladie de parkinson contenant un antagoniste du recepteur cb1 et un produit qui active la neurotransmission dopaminergique dans le cerveau

Info

Publication number
EP1423146A1
EP1423146A1 EP02774886A EP02774886A EP1423146A1 EP 1423146 A1 EP1423146 A1 EP 1423146A1 EP 02774886 A EP02774886 A EP 02774886A EP 02774886 A EP02774886 A EP 02774886A EP 1423146 A1 EP1423146 A1 EP 1423146A1
Authority
EP
European Patent Office
Prior art keywords
methyl
azetidine
methylsulfonyl
methylene
chlorophenyl
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.)
Ceased
Application number
EP02774886A
Other languages
German (de)
English (en)
French (fr)
Inventor
Jésus Benavides
Daniel Boccio
Yvette Henin
Odile Piot-Grosjean
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.)
Aventis Pharma SA
Original Assignee
Aventis Pharma SA
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 Aventis Pharma SA filed Critical Aventis Pharma SA
Publication of EP1423146A1 publication Critical patent/EP1423146A1/fr
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
    • 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
    • A61P25/14—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
    • A61P25/18—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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the invention relates to the combination of one or more CB1 receptor antagonists and one or more products which activate dopaminergic neurotransmission in the brain, the pharmaceutical compositions containing them and their use for the treatment of Parkinson's disease.
  • CBl receptor antagonists have been developed for the treatment of schizophrenia (D. KENDALL, Curr. Opin. Cent. Peripher. Nerv. Syst. Invest. Drugs, 2 (1), 112-122, 2000), for their action on food intake (G. COLOMBO et al., Life Sciences, 63 (8), 113-117 (1998); J. SIAMAND et al., Behavioral 15 Pharmacol., 9, 179-181 (1998)), for the treatment of Parkinson's disease, epilepsy, migraine, stress (G. GERDEMAN, DM. LOVINGER, J. Neurophysiol, 85 (1), 468-471, 2001; WO0046209).
  • Parkinson's disease results from a chronic and progressive neurological disorder. It is based on a dopamine deficit, a relative excess in acetylcholine and is 0 associated with a destruction of dopaminergic neurons which participate in the control of motor activities (H. LULLMANN et al., Pocket Atlas of Pharmacology, 2 ° Ed, Médecine- Sciences, Flammarion, ISBN2-257-12119-8).
  • the treatment of Parkinson's disease is mainly pharmacological and uses various drugs intended to increase the amount of dopamine present in the brain.
  • levodopa a precursor of dopamine converted to dopamine by dopa-decarboxylase
  • Levodopa remains the first treatment today choice of Parkinson's disease and initially gives good results but after several years, we observe in the majority of patients fluctuation of response ('on-off effect), a decrease in its effectiveness as the disease progresses (wearing-off effect, deterioration at the end of the dose), and especially dyskinesias (involuntary abnormal movements). A state of psychosis can also be observed.
  • drugs such as dopamine agonists are also recommended alone or in combination with levodopa and are mainly intended to minimize the undesirable effects thereof.
  • blood-brain cells have been developed and prescribed in combination with levodopa. Significant side effects have also been observed with these therapies.
  • a dopamine precursor in addition to levodopa, a dopamine precursor, the following products may be mentioned among the dopamine agonists: bromocriptine (Novartis), cabergoline (Pharmacia Corp.) adrogolide (Abbott Laboratories), BAM-1110 (Maruko Seiyaku Co Ltd), Duodopa ® (Neopharma), L-dopa, dopadose (Neopharma), CHF1512 (Chiesi), PNU-95666 (Pharmacia & Upjohn), ropinirole (GlaxoSmithKline Beecham), pramipexole (Boehringer Ingelheim) rotigotine (Discovery Therapeutics, Lohmann Therapy System), spheramine (Therapy System), Titan Pharmaceuticals), TV1203 (Teva pharmaceutical), uridine (Polifarma) Among the MAO B inhibitors, mention may be made of: rasagiline (Teva Pharmaceutical frid.) Se
  • tolcapone (Roche) and entacapone (Orion Pharma).
  • the subject of the invention is therefore the combination of one or more products activating dopaminergic neurotransmission in the brain and of one or more CBl antagonist azetidine derivatives of formula I:
  • R represents a chain
  • Ri represents a methyl or ethyl radical
  • R 2 represents either an aromatic chosen from phenyl, naphthyl or indenyl, these aromatics being unsubstituted or substituted by one or more halogen, alkyl, alkoxy, -CO-alk, hydroxy, -COOR5, formyl, trifluoromethyl, trifluoromethylsulfanyl, trifluoromethoxy , nitro, - R 6 R 7 , -CO- H-NR 6 R 7 , -N (alk) COOR 8 , cyano, -CO HR9, -CO-NR 16 R 17 , alkylsulfanyl, hydroxyalkyl, -O-alk-NR 12 R 13 or alkylthioalkyl or a heteroaromatic chosen from benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromannyl,
  • R 3 and R identical or different, represent either an aromatic chosen from phenyl, naphthyl or indenyl, these aromatics being unsubstituted or substituted by one or more halogen, alkyl, alkoxy, formyl, hydroxy, trifluoromethyl, trifluoromethoxy, -CO-alk , cyano, -COOR 5 , -CONRioR ⁇ , -CO-NH-NR 6 R 7 , alkylsulfanyl, hydroxyalkyl, or alkylthioalkyl; or a heteroaromatic chosen from the benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromannyl, 2,3-dihydrobenzofuryl, 2,3-dihydrobenzothienyl, furyl, isochromannyl, isoquinolyl, pyrrolyl, quinolyl, 1,2,3,4-tetrahydroisoquiny
  • R 5 is an alkyl or phenyl radical optionally substituted by one or more halogen atoms
  • R 6 and R 7 identical or different, represent a hydrogen atom or an alkyl, -COOalk, cycloalkyl, alkylcycloalkyl, -alk-O-alk, hydroxyalkyl radical or alternatively R 6 and R form together with the nitrogen atom to which they are attached a saturated or unsaturated mono or bicyclic heterocycle having 3 to 10 members, optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen and being optionally substituted by one or more alkyl radicals, -COalk, -COOalk, -CO-NHalk, -CS-NHalk, -CO-alk-NR 14 R ⁇ 5 , oxo, hydroxyalkyle, -alk-O-alk, -CO-NH 2 ,
  • R 8 represents an alkyl radical
  • R 9 represents a hydrogen atom or an alkyl or alkyl radical substituted by dialkylamino, phenyl, cycloalkyl (optionally substituted by -COOalk) or a mono or bicyclic heterocycle saturated or unsaturated having 3 to 10 members, optionally containing one or more heteroatoms chosen from oxygen, sulfur and nitrogen and being optionally substituted by one or more alkyl radicals,
  • Rio and Ru identical or different, represent a hydrogen atom or an alkyl radical or Rio and Ru together with the nitrogen atom to which they are attached form a saturated mono or bicyclic heterocycle having 3 to 10 members, optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen and being optionally substituted by an alkyl radical,
  • R ⁇ 2 and R ⁇ 3 identical or different, represent a hydrogen atom or an alkyl or cycloalkyl radical, or else Rj 2 and R ⁇ 3 together with the nitrogen atom to which they are attached form a saturated mono or bicyclic heterocycle having 3 with 10 links, possibly containing another heteroatom chosen from oxygen, sulfur and nitrogen and being optionally substituted by an alkyl radical, -COalk, -COOalk, -CO-NHalk, -CS-NHalk, -CO-alk-NR ⁇ 4 R ⁇ 5 or a saturated mono or bicyclic heterocycle having 3 to 10 members and containing a heteroatom chosen from oxygen, sulfur and nitrogen,
  • R ⁇ 4 and R 15 identical or different, represent a hydrogen atom or an alkyl or -COOalk radical
  • alk represents an alkyl or alkylene radical
  • alkyl and alkylene radicals and portions and the alkoxy radicals and portions are in straight or branched chain and contain 1 to 6 carbon atoms
  • salts of azetidine derivatives the following salts may be cited: benzenesulfonate, hydrobromide, hydrochloride, citrate, ethanesulfonate, fumarate, gluconate, iodate, isethionate, maleate, methanesulfonate, methylene-bis- ⁇ -oxynaphtoate, nitrate , oxalate, pamoate, phosphate, salicylate, succinate, sulfate, tartrate, theophyllinacetate and p-toluenesulfonate.
  • Tables 1 and 2 demonstrate the synergistic effect of the association.
  • Table 1 concerns the ip administration of the CBl antagonist and Table 2 concerns the po administration of the CBl antagonist
  • the antagonist product CBl (1.5 mg / kg i.p., 2 ml / kg) and quinpirole (62.5 ⁇ g / kg i.p., 1 ml / kg) are co-administered 18 hours after the injection of reserpine.
  • the recording of motor activity begins 5 minutes after the co-administration of the products and lasts 1 hour.
  • the antagonist product CBl (3 mg / kg ip, 2 ml / kg) and levodopa (120 mg / kg + benserazide 50 mg / kg ip, 5 ml / kg) are co-administered.
  • Benserazide is an inhibitor of peripheral dopa-decarboxylase, which allows levodopa to cross the blood-brain barrier before it is transformed into dopamine.
  • the recording of motor activity begins 5 minutes after co-administration and lasts 2.5 hours. Table 1
  • Example 1 l- [bis (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) - methylene] azetidine)
  • SR141716A N- (piperidin-l-yl) -5 (4-chlorophenyl ) -l- (2,4-dichlorophenyl) -4- methyl- 1 H-pyrazole-3 -carboxamidehydrochloride
  • the oral studies are carried out in a hydrophobic solvent of Labrafil / Labrasol formulation (40/60%, w / w). These products are administered (in a volume of lml / kg) one hour before the dopaminergic agonist.
  • the recording of locomotor activity begins 5 min after the intra-peritoneal injection of the dopaminergic agonist and lasts 1 hour.
  • the dopamine agonist Dl is Cl-APB at 0.3 mg / kg.
  • the dopamine agonist D2 is quinpirole at O.lmg.kg.
  • Example 1 l- [bis (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) - methylene] azetidine)
  • SR141716A N- (piperidin-l-yl) -5 (4-chlorophenyl ) -l- (2,4-dichlorophenyl) -4- methyl- 1 H-pyrazole-3 -carboxamidehydrochloride ANOVA + Dunnett: * p ⁇ 0.05, ** p ⁇ 0.01
  • the compounds of the combination can be used orally, parenterally, transdermally or rectally either simultaneously or separately or over a period of time.
  • the present invention also relates to pharmaceutical compositions containing the combination of one or more products which activate dopaminergic neurotransmission in the brain and one or more CBl receptor antagonists as defined above with a pharmaceutically acceptable vehicle.
  • compositions for oral administration tablets, pills, powders (gelatin capsules, cachets) or granules can be used.
  • the active ingredients are mixed with one or more inert diluents, such as starch, cellulose, sucrose, lactose or silica, under current argon.
  • these compositions can also comprise substances other than diluents, for example one or more lubricants such as magnesium stearate or talc, a dye, a coating (dragees) or a varnish.
  • compositions for oral administration use may be made of pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs containing inert diluents such as water, ethanol, glycerol, vegetable oils or oil paraffin.
  • inert diluents such as water, ethanol, glycerol, vegetable oils or oil paraffin.
  • These compositions can include substances other than diluents, for example wetting, sweetening, thickening, flavoring or stabilizing products.
  • the sterile compositions for parenteral administration can preferably be aqueous or non-aqueous solutions, suspensions or emulsions.
  • solvent or vehicle water, propylene glycol, polyethylene glycol, vegetable oils, in particular olive oil, injectable organic esters, for example ethyl oleate or other organic solvents can be used. suitable.
  • These compositions can also contain adjuvants, in particular wetting, isotonizing, emulsifying, dispersing and stabilizing agents. Sterilization can be done in several ways, for example by aseptic filtration, by incorporating sterilizing agents into the composition, by irradiation or by heating. They can also be prepared in the form of sterile solid compositions which can be dissolved at the time of use in sterile water or any other sterile injectable medium.
  • compositions for rectal administration are suppositories or rectal capsules which contain, in addition to the active product, excipients such as cocoa butter, semisynthetic glycerides or polyethylene glycols.
  • the pharmaceutical compositions containing the association as defined above generally contain 0.1 to 500 mg of the antagonist CBl.
  • the present invention also relates to the method of treatment of Parkinson's disease which consists in administering to the patient a combination or a composition pharmaceutical containing the combination as defined above either simultaneously or separately or in a spread over time.
  • the doses depend on the desired effect, on the duration of the treatment and on the route of administration used; they are generally from 0.1 to 500 mg per day orally for an adult of the antagonist CB 1.
  • the doctor will determine the appropriate dosage based on age, weight and all other factors specific to the subject to be treated.

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  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Neurology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Neurosurgery (AREA)
  • Psychiatry (AREA)
  • Psychology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
EP02774886A 2001-08-29 2002-08-28 Composition pour le traitement de la maladie de parkinson contenant un antagoniste du recepteur cb1 et un produit qui active la neurotransmission dopaminergique dans le cerveau Ceased EP1423146A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
FR0111201A FR2829027A1 (fr) 2001-08-29 2001-08-29 Association avec un antagoniste du recepteur cb1, les compositions pharmaceutiques les contenant et leur utilisation pour le traitement de la maladie de parkinson
FR0111201 2001-08-29
PCT/FR2002/002945 WO2003018060A1 (fr) 2001-08-29 2002-08-28 Composition pour le traitement de la maladie de parkinson contenant un antagoniste du recepteur cb1 et un produit qui active la neurotransmission dopaminergique dans le cerveau

Publications (1)

Publication Number Publication Date
EP1423146A1 true EP1423146A1 (fr) 2004-06-02

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ID=8866793

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EP02774886A Ceased EP1423146A1 (fr) 2001-08-29 2002-08-28 Composition pour le traitement de la maladie de parkinson contenant un antagoniste du recepteur cb1 et un produit qui active la neurotransmission dopaminergique dans le cerveau

Country Status (9)

Country Link
US (1) US7105504B2 (enExample)
EP (1) EP1423146A1 (enExample)
JP (1) JP2005505539A (enExample)
AR (1) AR036303A1 (enExample)
CA (1) CA2458855A1 (enExample)
FR (1) FR2829027A1 (enExample)
IL (1) IL160558A0 (enExample)
MX (1) MXPA04001848A (enExample)
WO (1) WO2003018060A1 (enExample)

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US7129239B2 (en) 2002-10-28 2006-10-31 Pfizer Inc. Purine compounds and uses thereof
US7247628B2 (en) 2002-12-12 2007-07-24 Pfizer, Inc. Cannabinoid receptor ligands and uses thereof
US7329658B2 (en) 2003-02-06 2008-02-12 Pfizer Inc Cannabinoid receptor ligands and uses thereof
US7176210B2 (en) 2003-02-10 2007-02-13 Pfizer Inc. Cannabinoid receptor ligands and uses thereof
AR044007A1 (es) * 2003-04-11 2005-08-24 Newron Pharmaceuticals Inc Metodos para el tratamiento de la enfermedad de parkinson
US7268133B2 (en) 2003-04-23 2007-09-11 Pfizer, Inc. Patent Department Cannabinoid receptor ligands and uses thereof
US7145012B2 (en) 2003-04-23 2006-12-05 Pfizer Inc. Cannabinoid receptor ligands and uses thereof
US7141669B2 (en) 2003-04-23 2006-11-28 Pfizer Inc. Cannabiniod receptor ligands and uses thereof
US7232823B2 (en) 2003-06-09 2007-06-19 Pfizer, Inc. Cannabinoid receptor ligands and uses thereof
KR20060019587A (ko) 2003-06-11 2006-03-03 머크 앤드 캄파니 인코포레이티드 치환된 3-알킬 및 3-알케닐 아제티딘 유도체
EP1498122A1 (en) * 2003-07-18 2005-01-19 Aventis Pharma S.A. Semi-solid systems containing azetidine derivatives
EP1498123A1 (en) * 2003-07-18 2005-01-19 Aventis Pharma S.A. Emulsifying systems containing azetidine derivatives
MX2007016508A (es) 2005-06-30 2008-03-04 Prosidion Ltd Agonistas del receptor acoplado a la proteina g.
US7906652B2 (en) 2005-11-28 2011-03-15 Merck Sharp & Dohme Corp. Heterocycle-substituted 3-alkyl azetidine derivatives
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AR064735A1 (es) 2007-01-04 2009-04-22 Prosidion Ltd Agonistas de gpcr y composicion farmaceutica en base al compuesto
GB0700122D0 (en) 2007-01-04 2007-02-14 Prosidion Ltd GPCR agonists
PE20081849A1 (es) 2007-01-04 2009-01-26 Prosidion Ltd Derivados de piperidin-4-il-propoxi-benzamida como agonistas de gpcr
US20100048625A1 (en) 2007-01-04 2010-02-25 Matthew Colin Thor Fyfe Piperidine gpcr agonists
RS52065B (sr) 2007-01-04 2012-06-30 Prosidion Ltd Piperidinski gpcr agonisti
GB0720390D0 (en) 2007-10-18 2007-11-28 Prosidion Ltd G-Protein coupled receptor agonists
GB0720389D0 (en) 2007-10-18 2008-11-12 Prosidion Ltd G-Protein Coupled Receptor Agonists

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US20020177593A1 (en) * 1998-09-30 2002-11-28 Yuji Ishihara Agents and crystals for improving excretory potency of urinary bladder
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Also Published As

Publication number Publication date
US20050107356A1 (en) 2005-05-19
FR2829027A1 (fr) 2003-03-07
JP2005505539A (ja) 2005-02-24
CA2458855A1 (en) 2003-03-06
WO2003018060A1 (fr) 2003-03-06
US7105504B2 (en) 2006-09-12
MXPA04001848A (es) 2004-06-15
IL160558A0 (en) 2004-07-25
AR036303A1 (es) 2004-08-25

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