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WO2011070579A1 - Procédés d'amélioration des fonctions cognitives - Google Patents

Procédés d'amélioration des fonctions cognitives Download PDF

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Publication number
WO2011070579A1
WO2011070579A1 PCT/IL2010/001041 IL2010001041W WO2011070579A1 WO 2011070579 A1 WO2011070579 A1 WO 2011070579A1 IL 2010001041 W IL2010001041 W IL 2010001041W WO 2011070579 A1 WO2011070579 A1 WO 2011070579A1
Authority
WO
WIPO (PCT)
Prior art keywords
conjugate
subject
moiety
cns
cognitive
Prior art date
Application number
PCT/IL2010/001041
Other languages
English (en)
Inventor
Yona Geffen
Kinneret Savitsky
Abraham Nudelman
Ada Rephaeli
Irit Gil-Ad
Abraham Weizman
Original Assignee
Biolinerx Ltd.
Bar-Ilan University
Ramot At Tel-Aviv University Ltd.
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 Biolinerx Ltd., Bar-Ilan University, Ramot At Tel-Aviv University Ltd. filed Critical Biolinerx Ltd.
Priority to BR112012013639A priority Critical patent/BR112012013639A2/pt
Priority to JP2012542686A priority patent/JP2013513600A/ja
Priority to AU2010329440A priority patent/AU2010329440A1/en
Priority to MX2012006566A priority patent/MX2012006566A/es
Priority to CA2782514A priority patent/CA2782514A1/fr
Priority to CN2010800629437A priority patent/CN102762211A/zh
Priority to EP10835610A priority patent/EP2509603A1/fr
Publication of WO2011070579A1 publication Critical patent/WO2011070579A1/fr
Priority to IL220242A priority patent/IL220242A0/en

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
    • C07D279/14—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems
    • C07D279/18—[b, e]-condensed with two six-membered rings
    • C07D279/22—[b, e]-condensed with two six-membered rings with carbon atoms directly attached to the ring nitrogen atom
    • C07D279/24—[b, e]-condensed with two six-membered rings with carbon atoms directly attached to the ring nitrogen atom with hydrocarbon radicals, substituted by amino radicals, attached to the ring nitrogen atom
    • C07D279/26—[b, e]-condensed with two six-membered rings with carbon atoms directly attached to the ring nitrogen atom with hydrocarbon radicals, substituted by amino radicals, attached to the ring nitrogen atom without other substituents attached to the ring system
    • 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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular 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
    • 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
    • A61P25/18—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
    • A61P25/24—Antidepressants
    • 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
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • 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
    • 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

Definitions

  • WO 2008/010222 describes novel compositions composed of GABA agonists conjugated to CNS-acting analgesic drugs capable of crossing the BBB.
  • WO 2008/010222 describes conjugates of anti-parkinsonian drugs such as L- DOPA and GABA agonists and their use in treating neurodegenerative diseases. SUMMARY OF THE INVENTION
  • the subject is identified as having cognitive impairment or dysfunction following a treatment with a CNS-acting drug.
  • a pharmaceutically acceptable salt of the conjugate is used.
  • FIG. 4 is bar chart illustrating the effect of administrating picrotoxin (0.25, 0.5 and 1 mg/kg) on the percent correct response (pressing the correct lever) in the PCP- induced reversal learning task. Data are expressed as mean ⁇ SEM. Significant differences between picrotoxin-treated and vehicle-treated groups are marked by "*" (PO.05) and "**" (PO.01), based on ANOVA followed by Dunnett's t- test.
  • BL-1020 perphenazine 4-aminobutyrate
  • a moiety having CNS activity therefore describes agents capable of (i) crossing the blood-brain barrier (BBB), (ii) acting on the central nervous system (CNS) and (iii) exerting a therapeutic activity in the CNS (exerting a CNS activity).
  • BBB blood-brain barrier
  • CNS central nervous system
  • a suitable CNS-acting drug can be, for example, an anxiolytic drug such as, but not limited to, benzodiazepines, phenothiazines and butyrophenones, an MAO inhibitor, an anti-depressant, an anti-convulsant, an anti-parkinsonian drug, an analgesic and an acetylcholine esterase inhibitor.
  • the CNS-acting drug can be tricyclic, bicyclic or monocyclic.
  • thioalkoxy describes both a -S-alkyl group, and a -S-cycloalkyl group, as defined herein.
  • covalently linking the first moiety and the second moiety via an alkyloxy carboxylic ester bond is particularly useful in cases where the second moiety includes a free carboxylic acid group, since it avoids the formation of the typically unstable anhydride conjugate.
  • the subject can be, but is not limited to, a subject having a cognitive impairment or dysfunction.
  • the subject has a cognitive impairment or dysfunction which is associated with a CNS disease or disorder, and the subject is afflicted with the CNS disease or disorder.
  • an amount effective for improving cognitive function can be higher than, lower than or the same as a therapeutically effective amount of the conjugate as determined for the disease or disorder in the subject.
  • the subject has a CNS disease or- disorder, and is treated with a CNS-acting drug, and, following treatment with the CNS-acting drug, evaluating the cognitive parameters of the subject is effected.
  • subjects identified as being in need for improving a cognitive function are administered with a conjugate as described herein, either in combination with the CNS-acting drug or as a substituting therapy.
  • the conjugate of the present embodiments may be utilized as a prophylactic treatment for preventing onset or inhibiting progression of a cognitive impairment or dysfunction in a subject prone or predisposed to cognitive impairment or dysfunction.
  • the subject is diagnosed for having a bipolar disorder, Alzheimer's disease, Huntington's disease, multiple sclerosis, Parkinson's disease, brain injury, stroke, age-related disease or disorder or epilepsy.
  • pharmaceutically acceptable carrier refers to a carrier or a diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.
  • An adjuvant is included under these phrases.
  • compositions of the present invention may also be formulated in rectal compositions such as suppositories or retention enemas, using, e.g., conventional suppository bases such as cocoa butter or other glycerides.
  • a conjugate as described herein in the preparation of a medicament (e.g. a pharmaceutical composition as described herein) for improving a cognitive function, preventing onset of inhibiting progression of a cognitive impairment or dysfunction., and/or for improving a cognitive function in a subject identified as being in need for improving a cognitive function upon evaluating cognitive parameters of the subject.
  • a medicament e.g. a pharmaceutical composition as described herein
  • a conjugate comprising a first moiety having GABA agonist activity and a second moiety having CNS activity being covalently linked to said first moiety, or of a pharmaceutically acceptable salt of the conjugate in the manufacture of a medicament for treating a cognitive impairment associated with schizophrenia in a subject in need thereof, as described herein

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Pain & Pain Management (AREA)
  • Immunology (AREA)
  • Psychiatry (AREA)
  • Epidemiology (AREA)
  • Rheumatology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Pulmonology (AREA)
  • Psychology (AREA)
  • Hospice & Palliative Care (AREA)
  • Transplantation (AREA)
  • Cardiology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Dermatology (AREA)
  • Otolaryngology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne des conjugués comprenant un premier fragment ayant une activité agoniste de GABA et un deuxième fragment ayant une activité sur le SNC étant lié de façon covalente au premier fragment, pour utilisation dans l'amélioration de la fonction cognitive, et dans la prévention de l'apparition ou l'inhibition de l'évolution d'un trouble ou dysfonctionnement cognitif. La présente invention concerne en outre des procédés utilisant ces conjugués et des articles de fabrication comprenant ces conjugués.
PCT/IL2010/001041 2009-12-09 2010-12-09 Procédés d'amélioration des fonctions cognitives WO2011070579A1 (fr)

Priority Applications (8)

Application Number Priority Date Filing Date Title
BR112012013639A BR112012013639A2 (pt) 2009-12-09 2010-12-09 "métodos pára melhorar funções congnitivas"
JP2012542686A JP2013513600A (ja) 2009-12-09 2010-12-09 認知機能改善方法
AU2010329440A AU2010329440A1 (en) 2009-12-09 2010-12-09 Methods of improving cognitive functions
MX2012006566A MX2012006566A (es) 2009-12-09 2010-12-09 Metodo para mejorar las funciones cognoscitivas.
CA2782514A CA2782514A1 (fr) 2009-12-09 2010-12-09 Procedes d'amelioration des fonctions cognitives
CN2010800629437A CN102762211A (zh) 2009-12-09 2010-12-09 改善认知功能的方法
EP10835610A EP2509603A1 (fr) 2009-12-09 2010-12-09 Procédés d'amélioration des fonctions cognitives
IL220242A IL220242A0 (en) 2009-12-09 2012-06-07 Methods of improving cognitive functions

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US26788309P 2009-12-09 2009-12-09
US61/267,883 2009-12-09

Publications (1)

Publication Number Publication Date
WO2011070579A1 true WO2011070579A1 (fr) 2011-06-16

Family

ID=44145173

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IL2010/001041 WO2011070579A1 (fr) 2009-12-09 2010-12-09 Procédés d'amélioration des fonctions cognitives

Country Status (9)

Country Link
US (1) US8975251B2 (fr)
EP (1) EP2509603A1 (fr)
JP (1) JP2013513600A (fr)
CN (1) CN102762211A (fr)
AU (1) AU2010329440A1 (fr)
BR (1) BR112012013639A2 (fr)
CA (1) CA2782514A1 (fr)
MX (1) MX2012006566A (fr)
WO (1) WO2011070579A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115350172A (zh) * 2022-08-12 2022-11-18 昆明医科大学 Gabapentin对AD情景记忆改善的应用

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US8975251B2 (en) 2015-03-10
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