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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• 2001
  • 2001-08-29 FR FR0111201A patent/FR2829027A1/fr active Pending
• 2002
  • 2002-08-27 AR ARP020103212A patent/AR036303A1/es not_active Application Discontinuation
  • 2002-08-28 IL IL16055802A patent/IL160558A0/xx unknown
  • 2002-08-28 MX MXPA04001848A patent/MXPA04001848A/es unknown
  • 2002-08-28 JP JP2003522575A patent/JP2005505539A/ja not_active Abandoned
  • 2002-08-28 EP EP02774886A patent/EP1423146A1/fr not_active Ceased
  • 2002-08-28 WO PCT/FR2002/002945 patent/WO2003018060A1/fr not_active Ceased
  • 2002-08-28 CA CA002458855A patent/CA2458855A1/en not_active Abandoned
• 2004
  • 2004-02-25 US US10/786,483 patent/US7105504B2/en not_active Expired - Fee Related

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