EP1061952A2 - Kombination von inverse agonisten des gaba-a alpha-5 rezeptor subtyps und acetylcholinesterase-inhibitoren - Google Patents

Kombination von inverse agonisten des gaba-a alpha-5 rezeptor subtyps und acetylcholinesterase-inhibitoren

Info

Publication number
EP1061952A2
EP1061952A2 EP99909095A EP99909095A EP1061952A2 EP 1061952 A2 EP1061952 A2 EP 1061952A2 EP 99909095 A EP99909095 A EP 99909095A EP 99909095 A EP99909095 A EP 99909095A EP 1061952 A2 EP1061952 A2 EP 1061952A2
Authority
EP
European Patent Office
Prior art keywords
inverse agonist
combination
gabaa
acetylcholinesterase inhibitor
receptor subtype
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Withdrawn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
EP99909095A
Other languages
English (en)
French (fr)
Inventor
Gerard Raphael Dawson
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.)
Organon Pharma UK Ltd
Original Assignee
Merck Sharp and Dohme 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 Merck Sharp and Dohme Ltd filed Critical Merck Sharp and Dohme Ltd
Publication of EP1061952A2 publication Critical patent/EP1061952A2/de
Withdrawn legal-status Critical Current

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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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • 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
    • A61P25/28—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

Definitions

  • the present invention relates to a combination of an acetylcholinesterase inhibitor and an inverse agonist of the GABAA s receptor subtype, and the use of the combination in treating neurodegenerative conditions such as Alzheimer's Disease.
  • Alzheimer's Disease is a poorly understood neurodegenerative condition mainly affecting the elderly but also younger people who are generally genetically predispositioned to it.
  • One postulated method of treatment comprises the administration of acetylcholinesterase inhibitors which act on the cholinergic system.
  • this method suffers from the disadvantages that these compounds induce a range of side-effects including diarrhoea, salivation and nausea.
  • the present invention provides a new and surprisingly effective synergistic combination of an acetylcholinesterase inhibitor and an inverse agonist of the GABAA ⁇ g receptor subtype for separate, sequential or simultaneous administration.
  • the present invention provides a greater than expected improvement in the condition of subjects suffering from a neurodegenerative with an associated cognitive deficit, such as Alzheimer's Disease or Parkinson's disease, or from a cognitive deficit which may arise from a normal process such as aging or from an abnormal process such as injury, than would be expected from administration of the active ingredients alone.
  • the combination allows for a lower overall dose of each of the active ingredients to be administered thus reducing side effects and decreasing any reduction in the effectiveness of each of the active ingredients over time.
  • Acetylcholinesterase inhibitors which may be used include any which are known to the skilled person. Examples are physostigmine, neostigmine, edrophonium and its chloride, pyridostigmine and its bromide, eptastigmine.and its tartrate, galanthamine and its hydrochloride and hydrobromide, metrifonate, tacrine and its hydrochloride, eseridine and its salicylate, suronacrine and its maleate, velnacrine and its maleate, amiridine and its hydrochloride, 7- methoxy tacrine, SM-10888 and its citrate, phenserine and its tartrate, ENA-713, donepezil and its hydrochloride, TAK-147, CP-118954, huperzine A and zifrosilone.
  • any inverse agonist of the GABAA as receptor subtype may be used which fulfills the criteria of WO-A-9625948.
  • the inverse agonist may be either binding selective for the 0:5 subtype or functionally selective, or both.
  • the inverse agonist is preferably an antagonist, or has insignificant agonist or inverse agonist properties at the other GABAA receptor subtypes when measured in oocytes as described in WO-A-9625948.
  • the inverse agonist preferably has a functional efficacy at the g receptor subunit of less than -20% and functional efficacies at the ⁇ i, ⁇ .2, and 0:3 receptor subunits of between -20 and +20%.
  • functional efficacy is meant the percentage modulation of the EC20 response produced by GABA, upon coadministration of the inverse agonist, in oocytes expressing GABAA receptor channels containing the ⁇ receptor subunit under test. Details of this measurement are given in WO-A-9625948.
  • the inverse agonist preferably binds selectively to GABAA receptors containing the as subunit 10, 25 and particularly 50 times compared to GABAA receptors subunits containing the ⁇ i, 0:2 or 0:3 subunits. Preferably this binding selectivity is shown over all these subunits.
  • a preferred class of inverse agonists which are disclosed in WO-A-9850385, are of formula I:
  • R 1 is hydrogen, halogen or CN or a group C ⁇ -4alkyl, C2-4alkenyl, C2-4alkynyl, Ci. alkoxy, C2-4alkenyloxy or C 2 -4alkynyloxy, each of which groups is unsubstituted or substituted with one or two halogen atoms or with a pyridyl or phenyl ring each of which rings may be unsubstituted or independently substituted by one or two halogen atoms or nitro, cyano, amino, methyl or CF3 groups;
  • R 2 is hydrogen, halogen or CN or a group C ⁇ -4alkyl, C2- 4 alkenyl,
  • L is 0, S or NR n where R n is H, Cj- ⁇ alkyl or C3-6cycloalkyl;
  • X is a 5-membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms independently chosen from oxygen, nitrogen and sulphur, at most one of the heteroatoms being oxygen or sulphur, or a 6-membered heteroaromatic ring containing 1, 2 or 3 nitrogen atoms, the 5- or 6-membered heteroaromatic ring being optionally fused to a benzene ring and the heteroaromatic ring being optionally substituted by R x and/or R ' and/or R*, where R x is halogen, R 3 , OR*, OCOR 3 , NR R 5 , NR COR 5 , tri(C 1 - 6 alkyl)silylC 1 -6alkoxyC 1 - alkyl ) CN or R 9 , is halogen, R 3 , OR 3 , OCOR 3 , NR 4 R 5 , NR 4 COR 5 or CN and R* is R 3 , OR 3 or OCOR
  • Y is optionally branched Cj. 4 alkylidene optionally substituted by an oxo group or Y is a group (CH 2 )jO wherein the oxygen atom is nearest the group X and j is 2, 3 or 4;
  • Z is a 5-membered heteroaromatic ring containing 1, 2 or 3 heteroatoms independently selected from oxygen, nitrogen and sulphur, at most one of the heteroatoms being oxygen or sulphur and providing that when two of the heteroatoms are nitrogen an oxygen or sulphur atom is also present and that when one of the atoms is oxygen or sulphur then at least one nitrogen atom is present, or a 6-membered heteroaromatic ring containing 2 or 3 nitrogen atoms, Z being optionally substituted by R v and/or R w , where R v is halogen, R G , NR 7 R 8 , NR 7 COR 8 , CN, furyl, thienyl, phenyl, benzyl, pyridyl or a 5-membered heteroaromatic ring containing at least one nitrogen atom and optionally 1, 2 or 3 other heteroatoms independently selected from oxygen, nitrogen and sulphur, at most one of the other heteroatoms being oxygen or
  • R G is Ci- ⁇ alkyl, C2-6alkenyl, C2-6alkynyl, C3-Gcycloalkyl, hydroxyd-calkyl, Ci-calkoxy, C2 c,alkenyloxy, C2-6alkynyloxy, CH2F or CF3; and R 7 and R 8 are each independently hydrogen, Ci-ealkyl, C2- G alkenyl, C2-6alkynyl, C3-Gcycloalkyl or CF3 or R 7 and R 8 , together with the nitrogen atom to which they are attached, form a 4-7 membered heteroaliphatic ring containing the nitrogen atom as the sole heteroatom; or a pharmaceutically acceptable salt thereof.
  • d-Galkyl includes methyl and ethyl groups, and straight-chained and branched propyl, butyl, pentyl and hexyl groups. Particular alkyl groups are methyl, ethyl, n-propyl, isopropyl and t-butyl. Derived expressions such as “C2-4alkenyl”, “C 2 -6alkeny_”, “hydroxyCi-calkyl", “C 2 -4alkyl” and "C 2 . 6 alkyny_” are to be construed in an analogous manner.
  • C3-Gcycloalkyl as used herein includes cyclic propyl, butyl, pentyl and hexyl groups such as cyclopropyl and cyclohexyl.
  • Suitable 5- and 6-membered heteroaromatic rings include pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, oxadiazolyl and thiadiazolyl groups.
  • a suitable 5-membered heteroaromatic ring containing four nitrogen atoms is tetrazolyl.
  • Suitable 6-membered heteroaromatic rings containing three nitrogen atoms include 1,2,4-triazine and 1,3,5-triazine.
  • halogen as used herein includes fluorine, chlorine, bromine and iodine, of which fluorine and chlorine are preferred.
  • Ci- ⁇ alkoxy includes methoxy and ethoxy groups, and straight-chained, branched and cyclic propoxy, butoxy, pentoxy and hexoxy groups, including cyclopropylmethoxy. Derived expressions such as “C2-6alkenyloxy”, “C2-6alkynyloxy”, “C 1 - 4 alkoxy”,
  • the present invention also provides a pharmaceutical composition comprising an acetylcholinesterase inhibitor, an inverse agonist of the GABAA 0.5 receptor subtype and a pharmaceutically acceptable carrier.
  • a kit of parts comprising a first pharmaceutical composition comprising an acetylcholinesterase inhibitor and a first pharmaceutically acceptable carrier and a second pharmaceutical composition comprising an inverse agonist of the GABAA 0.5 receptor subtype and a second pharmaceutically acceptable carrier for simultaneous, sequential or separate administration.
  • a combination of an acetylcholinesterase inhibitor and an inverse agonist of the GABAA 0.5 receptor subtype for use in a method of treatment of the human body, particularly for the treatment of a neurodegenerative disorder with associated cognitive deficit such as Alzheimer's Disease or Parkinson's disease, or of a cognitive deficit arising from a normal process such as aging or of an abnormal process such as injury.
  • the combination is particularly beneficial in the treatment of Alzheimer's Disease.
  • a combination of an acetylcholinesterase inhibitor and an inverse agonist of the GABAA s receptor subtype in the manufacture of a medicament for the treatment of a neurodegenerative disorder such as Alzheimer's Disease or Parkinson's disease, or of a cognitive deficit arising from a normal process such as aging or of an abnormal process such as injury.
  • the treatment of Alzheimer's Disease is particularly preferred.
  • a method of treatment of a subject suffering from a neurodegenerative disorder such as Alzheimer's Disease or Parkinson's disease, or a cognitive deficit arising from a normal process such as aging or an abnormal process such as injury, which comprises administering to that subject a therapeutically effective amount of a combination of an acetylcholinesterase inhibitor and an inverse agonist of the GABAA 0.5 receptor subtype.
  • a neurodegenerative disorder such as Alzheimer's Disease or Parkinson's disease
  • a cognitive deficit arising from a normal process such as aging or an abnormal process such as injury
  • the treatment of Alzheimer's Disease is particularly preferred.
  • compositions of the present invention are preferably in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, transdermal patches, auto-injector devices or suppositories; for oral, parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation.
  • a pharmaceutical carrier e.g.
  • This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of each active ingredient of the present invention.
  • Typical unit dosage forms contain from 1 to 100 mg, for example 1, 2, 5, 10, 25, 50 or 100 mg, of each active ingredient.
  • the tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
  • the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
  • liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
  • Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.
  • a suitable dosage level is about 0.01 to 250 mg/kg per day, preferably about 0.01 to 100 mg/kg per day, and especially about 0.01 to 5 mg/kg of body weight per day of each active ingredient.
  • the compounds may be administered on a regimen of 1 to 4 times per day. In some cases, however, dosage outside these limits may be used.
  • the synergistic effect of the combination of the present invention can be shown, for example, by comparing the combined dosage of the combination with dosages of the same amount of each of the active ingredients separately on subjects using the Mini-Mental State Examination (MMSE) as described in Folstein and Folstein J. Psychiat. Res., 1975, 12, 189-198 or a variant thereof as discussed in Tombaugh and Mclntyre, JAGS, 1992, 40, 922-935.
  • MMSE Mini-Mental State Examination

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
EP99909095A 1998-03-16 1999-03-16 Kombination von inverse agonisten des gaba-a alpha-5 rezeptor subtyps und acetylcholinesterase-inhibitoren Withdrawn EP1061952A2 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GB9805561 1998-03-16
GBGB9805561.9A GB9805561D0 (en) 1998-03-16 1998-03-16 A combination of therapeutic agents
PCT/GB1999/000778 WO1999047131A2 (en) 1998-03-16 1999-03-16 Combination of a gaba-a alpha 5 inverse agonist and an acetylcholinesterase inhibitor

Publications (1)

Publication Number Publication Date
EP1061952A2 true EP1061952A2 (de) 2000-12-27

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ID=10828631

Family Applications (1)

Application Number Title Priority Date Filing Date
EP99909095A Withdrawn EP1061952A2 (de) 1998-03-16 1999-03-16 Kombination von inverse agonisten des gaba-a alpha-5 rezeptor subtyps und acetylcholinesterase-inhibitoren

Country Status (6)

Country Link
EP (1) EP1061952A2 (de)
JP (1) JP2002506815A (de)
AU (1) AU753077B2 (de)
CA (1) CA2323618A1 (de)
GB (1) GB9805561D0 (de)
WO (1) WO1999047131A2 (de)

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US6271241B1 (en) 1999-04-02 2001-08-07 Neurogen Corporation Cycloalkyl and aryl fused aminoalkyl-imidazole derivatives: modulators and GLP-1 receptors
US6380210B1 (en) 1999-04-02 2002-04-30 Neurogen Corporation Heteroaryl fused aminoalkyl-imidazole derivatives: selective modulators of GABAa receptors
US6627624B1 (en) 1999-04-02 2003-09-30 Neurogen Corporation Aryl fused aminoalkyl-imidazole derivatives: selective modulators of GABAa receptors
US6281237B1 (en) 1999-04-02 2001-08-28 Neurogen Corporation N-phenyl benzimidazolecarboxamide and N-phenyl indolecarboxamide derivatives
WO2001092257A1 (en) 2000-05-26 2001-12-06 Neurogen Corporation Oxo-imidazopyrimidine-carboxamides and their use as gaba brain receptor ligands
AU2001273639A1 (en) 2000-06-26 2002-01-08 Neurogen Corporation Aryl fused substituted 4-oxy-pyridines
US20020151591A1 (en) * 2000-10-17 2002-10-17 Anabella Villalobos Combination use of acetylcholinesterase inhibitors and GABAa inverse agonists for the treatment of cognitive disorders
IL159811A0 (en) 2001-07-13 2004-06-20 Neurogen Corp Heteroaryl substituted fused bicyclic heteroaryl compounds as gabaa receptor ligands
MXPA05006940A (es) * 2002-12-24 2006-02-22 Neurochem Int Ltd Formulaciones terapeuticas para el tratamiento de enfermedades relacionadas con beta - amiloide.
GB0322140D0 (en) * 2003-09-22 2003-10-22 Pfizer Ltd Combinations
TW200533371A (en) * 2004-04-15 2005-10-16 Dainippon Pharmaceutical Co Medicament comprising a combination of an acetylcholinesterase inhibitor and a 5-substituted-3-oxadiazolyl-1,6-naphthyridin-2(1h)-one derivative
CA2566204A1 (en) * 2004-05-14 2005-12-01 The Johns Hopkins University Method for improving cognitive function by co-administration of a gabab receptor antagonist and an acetylcholinesterase inhibitor
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US9126987B2 (en) 2006-11-30 2015-09-08 Probiodrug Ag Inhibitors of glutaminyl cyclase
JP5930573B2 (ja) 2007-03-01 2016-06-15 プロビオドルグ エージー グルタミニルシクラーゼ阻害剤の新規使用
JP5667440B2 (ja) 2007-04-18 2015-02-12 プロビオドルグ エージー グルタミニルシクラーゼ阻害剤としてのチオ尿素誘導体
PL2475428T3 (pl) 2009-09-11 2015-12-31 Probiodrug Ag Pochodne heterocykliczne jako inhibitory cyklazy glutaminowej
EA037187B1 (ru) 2010-02-09 2021-02-17 Дзе Джонс Хопкинс Юниверсити Способ и композиция для лечения когнитивного расстройства
EP2542549B1 (de) 2010-03-03 2016-05-11 Probiodrug AG Glutaminylcyclase-hemmer
US8269019B2 (en) 2010-03-10 2012-09-18 Probiodrug Ag Inhibitors
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WO2014078568A1 (en) 2012-11-14 2014-05-22 The Johns Hopkins University Methods and compositions for treating schizophrenia
US11160785B2 (en) 2013-03-15 2021-11-02 Agenebio Inc. Methods and compositions for improving cognitive function
US10806717B2 (en) 2013-03-15 2020-10-20 The Johns Hopkins University Methods and compositions for improving cognitive function
MX384391B (es) 2015-05-22 2025-03-14 Agenebio Inc Composiciones farmacéuticas de levetiracetam de liberación extendida.
KR101743960B1 (ko) * 2015-07-06 2017-06-08 서울대학교산학협력단 G단백질 결합형 수용체19 작용제를 유효성분으로 함유하는 알츠하이머 질환 또는 치매를 예방, 치료 또는 지연하기 위한 약학적 조성물
ES2812698T3 (es) 2017-09-29 2021-03-18 Probiodrug Ag Inhibidores de glutaminil ciclasa

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Also Published As

Publication number Publication date
WO1999047131A2 (en) 1999-09-23
WO1999047131A3 (en) 1999-11-04
GB9805561D0 (en) 1998-05-13
CA2323618A1 (en) 1999-09-23
AU2846499A (en) 1999-10-11
JP2002506815A (ja) 2002-03-05
AU753077B2 (en) 2002-10-10

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