AU2846499A - Combination of a gaba-a alpha 5 inverse agonist and an acetylcholinesterase inhibitor - Google Patents
Combination of a gaba-a alpha 5 inverse agonist and an acetylcholinesterase inhibitor Download PDFInfo
- Publication number
- AU2846499A AU2846499A AU28464/99A AU2846499A AU2846499A AU 2846499 A AU2846499 A AU 2846499A AU 28464/99 A AU28464/99 A AU 28464/99A AU 2846499 A AU2846499 A AU 2846499A AU 2846499 A AU2846499 A AU 2846499A
- Authority
- AU
- Australia
- 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.)
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- 229960003692 gamma aminobutyric acid Drugs 0.000 description 1
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- 125000003707 hexyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
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- LULNWZDBKTWDGK-UHFFFAOYSA-M neostigmine bromide Chemical compound [Br-].CN(C)C(=O)OC1=CC=CC([N+](C)(C)C)=C1 LULNWZDBKTWDGK-UHFFFAOYSA-M 0.000 description 1
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- 125000004430 oxygen atom Chemical group O* 0.000 description 1
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- 239000008024 pharmaceutical diluent Substances 0.000 description 1
- LFSXCDWNBUNEEM-UHFFFAOYSA-N phthalazine Chemical compound C1=NN=CC2=CC=CC=C21 LFSXCDWNBUNEEM-UHFFFAOYSA-N 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
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- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- 229960002290 pyridostigmine Drugs 0.000 description 1
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- 125000000168 pyrrolyl group Chemical group 0.000 description 1
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- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
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- 239000001593 sorbitan monooleate Substances 0.000 description 1
- 235000011069 sorbitan monooleate Nutrition 0.000 description 1
- 229940035049 sorbitan monooleate Drugs 0.000 description 1
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- 235000012222 talc Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
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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
Landscapes
- 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)
- Neurosurgery (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (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)
Description
WO 99/47131 - 1 - PCT/GB99/00778 COMBINATION OF A GABA-A ALPHA 5 INVERSE AGONIST AND AN ACETYLCHOLINESTERASE INHIBITOR The present invention relates to a combination of an acetylcholinesterase 5 inhibitor and an inverse agonist of the GABAA c5 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 10 generally genetically predispositioned to it. One postulated method of treatment comprises the administration of acetylcholinesterase inhibitors which act on the cholinergic system. However this method suffers from the disadvantages that these compounds induce a range of side-effects including diarrhoea, salivation 15 and nausea. The present invention provides a new and surprisingly effective synergistic combination of an acetylcholinesterase inhibitor and an inverse agonist of the GABAA cX5 receptor subtype for separate, sequential or simultaneous administration. 20 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 25 process such as injury, than would be expected from administration of the active ingredients alone. Further, 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. 30 Acetylcholinesterase inhibitors which may be used include any which are known to the skilled person. Examples are physostigmine, WO 99/47131 - 2 - PCT/GB99/00778 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, 5 velnacrine and its maleate, amiridine and its hydrochloride, 7 methoxytacrine, 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 ac5 receptor subtype may be used 10 which fulfills the criteria of WO-A-9625948. The inverse agonist may be either binding selective for the a5 subtype or functionally selective, or both. Thus the inverse agonist is preferably an antagonist, or has insignificant agonist or inverse agonist properties at the other GABAA a receptor subtypes when measured in oocytes as described in 15 WO-A-9625948. Thus the inverse agonist preferably has a functional efficacy at the c receptor subunit of less than -20% and functional efficacies at the aXi, a2, and C3 receptor subunits of between -20 and +20%. By functional efficacy is meant the percentage modulation of the EC 2 o response produced 20 by GABA, upon coadministration of the inverse agonist, in oocytes expressing GABAA receptor channels containing the a 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 a5 subunit 10, 25 and particularly 50 times compared to 25 GABAA receptors subunits containing the xi, a2 or a3 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: WO 99/47131 - 3 - PCT/GB99/00778 N-N R Z N L-Y-X wherein: RI is hydrogen, halogen or CN or a group C1-4alkyl, C2.
4 alkenyl, 5 C2.
4 alkynyl, C1.
4 alkoxy, C2.4alkenyloxy or C2.4alkynyloxy, 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 CF 3 groups; 10 R 2 is hydrogen, halogen or CN or a group C1.4alkyl, C2-4alkenyl, C2.4alkynyl, C1.4alkoxy, C2-4alkenyloxy or C2-4alkynyloxy each of which groups is unsubstituted or substituted with one or two halogen atoms; L is 0, S or NRn where Rn is H, C1.6alkyl or C3.6cycloalkyl; X is a 5-membered heteroaromatic ring containing 1, 2, 3 or 4 15 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 Rx and/or RY 20 and/or Rz, where Rx is halogen, R3, OR 3 , OCOR 3 , NR 4
R
5 , NR 4
COR
5 , tri(Cl6alkyl)silylC.GalkoxyCl 4 alkyl, CN or R 9 , Ry is halogen, R 3 , OR 3 ,
OCOR
3 , NR 4
R
5 , NR 4 COR5 or CN and Rz is R 3 , OR3 or OCOR 3 , where R3 is Ci.calkyl, C2.6alkenyl, C2.6alkynyl, C3.6cycloalkyl, hydroxyC1.6alkyl and R 3 is optionally mono, di- or tri-fluorinated, R 4 and R5 are each independently 25 hydrogen, CIcalkyl, C2.6alkenyl, C2.6alkynyl, C3.ccycloalkyl or CF 3 or R4 and R5, 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, and R 9 is benzyl or an aromatic ring containing either 6 WO 99/47131 - 4 - PCT/GB99/00778 atoms, 1, 2 or 3 of which are optionally nitrogen, or 5 atoms, 1, 2 or 3 of which are independently chosen from oxygen, nitrogen and sulphur, at most one of the atoms being oxygen or sulphur, and R 9 is optionally substituted by one, two or three substituents independently chosen from 5 halogen atoms and C1.4alkyl, C2-4alkenyl, C2.4alkynyl, C1.4alkoxy, C2.4alkenyloxy and C2.4alkynyloxy groups each of which groups is unsubstituted or substituted by one, two or three halogen atoms, and when X is a pyridine derivative, the pyridine derivative is optionally in the form of the N-oxide and providing that when X is a tetrazole derivative it 10 is protected by a C1.4alkyl group; or X is phenyl optionally substituted by one, two or three groups independently selected from halogen, cyano, C 1 . 6alkyl, C2.6alkenyl, C2.salkynyl and C3.cycloalkyl; Y is optionally branched C1.4alkylidene optionally substituted by an oxo group or Y is a group (CH 2 )jO wherein the oxygen atom is nearest the 15 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 20 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 Rv and/or Rw, where Rv is halogen, RG, NR 7
R
8 , NR 7
COR
8 , CN, furyl, thienyl, phenyl, benzyl, pyridyl or a 5-membered heteroaromatic ring containing at 25 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 sulphur and Rw is R 6 or CN;
R
6 is C1.6alkyl, C2.6alkenyl, C2.Galkynyl, C3.6cycloalkyl, hydroxyC1.
6 alkyl, C1.alkoxy, C2.6alkenyloxy, C2.6alkynyloxy, CH 2 F or CF 3 ; 30 and WO 99/47131 - 5 - PCT/GB99/00778 R7 and R 8 are each independently hydrogen, C1.6alkyl, C2.salkenyl, C2- 6 alkynyl, C3.6cycloalkyl or CF 3 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; 5 or a pharmaceutically acceptable salt thereof. As used herein, the expression "Cl6alkyl" 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 "Cl4alkyl", "C24alkenyl", 10 "C2.alkenyl", "hydroxyCl-6alkyl", "C24alkyl" and "C2.6alkynyl" are to be construed in an analogous manner. The expression "C3.6cycloalkyl" 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, 15 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. 20 The term "halogen" as used herein includes fluorine, chlorine, bromine and iodine, of which fluorine and chlorine are preferred. As used herein the term "C1.6alkoxy" includes methoxy and ethoxy groups, and straight-chained, branched and cyclic propoxy, butoxy, pentoxy and hexoxy groups, including cyclopropylmethoxy. Derived 25 expressions such as "C2-6alkenyloxy", "C2.6alkynyloxy", "C1.4alkoxy", "C2.4alkenyloxy" and "C2.4alkyloxy" should be construed in an analogous manner. Four particular compounds which can be used are: 6-(1-methylimidazol-4-yl)methyloxy-3-(5-methylisoxazol-3-yl)-1,2,4 30 triazolo[3,4-a]phthalazine; WO 99/47131 - 6 - PCT/GB99/00778 3-(5-methylisoxazol-3-yl)-6-(1-methyl- 1,2,3-triazol-4-yl)methyloxy- 1,2,4 triazolo[3,4-a]phthalazine; 3-(5-methylisoxazol-3-yl)-6-(2-pyridyl)- 1,2,4-triazolo[3,4-a]phthalazine; and 5 3-(5-methylisoxazol-3-yl)-6-(1-methylimidazol-4-yl)- 1,2,4-triazol-3 ylmethyloxy- 1,2,4-triazolo[3,4-a]phthalazine. The second of the above compounds is particularly favoured. The present invention also provides a pharmaceutical composition comprising an acetylcholinesterase inhibitor, an inverse agonist of the 10 GABAA a5 receptor subtype and a pharmaceutically acceptable carrier. There is also provided 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 15 ax5 receptor subtype and a second pharmaceutically acceptable carrier for simultaneous, sequential or separate administration. There is further provided a combination of an acetylcholinesterase inhibitor and an inverse agonist of the GABAA a5 receptor subtype for use in a method of treatment of the human body, particularly for the 20 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. 25 There is also provided the use of a combination of an acetylcholinesterase inhibitor and an inverse agonist of the GABAA c5 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 30 aging or of an abnormal process such as injury. The treatment of Alzheimer's Disease is particularly preferred.
WO 99/47131 - 7 - PCT/GB99/00778 There is also disclosed 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 5 administering to that subject a therapeutically effective amount of a combination of an acetylcholinesterase inhibitor and an inverse agonist of the GABAA cL5 receptor subtype. The treatment of Alzheimer's Disease is particularly preferred. The pharmaceutical compositions of the present invention are 10 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. For 15 preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums or surfactants such as sorbitan monooleate, polyethylene glycol, and other 20 pharmaceutical diluents, e.g. water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the 25 composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. 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 30 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 WO 99/47131 - 8 - PCT/GB99/00778 coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, 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 5 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. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as 10 shellac, cetyl alcohol and cellulose acetate. The 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 15 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. 20 For the treatment of a neurodegenerative condition, 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 25 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 30 Examination (MMSE) as described in Folstein and Folstein J. Psychiat.
WO 99/47131 - 9 - PCT/GB99/00778 Res., 1975, 12, 189-198 or a variant thereof as discussed in Tombaugh and McIntyre, JAGS, 1992, 40, 922-935.
Claims (8)
1. A combination of an acetylcholinesterase inhibitor and an inverse agonist of the GABAA a.5 receptor subtype for separate, sequential or 5 simultaneous aministration.
2. A combination according to claim 1 wherein the inverse agonist has a functional efficacy at the C receptor subtype of less than 20%, and a functional efficacy at the ai, a2 and X3 receptor subtypes of between -20 10 and +20 %.
3. A combination according to claim 1 or 2 wherein the inverse agonist has a binding ration of greater than 10:1 to GABAA receptors containing the aX receptor subtype compared to GABAA receptors containing the ai, a2 15 or X3 subtypes.
4. A combination according to claim 1 wherein the inverse agonist is 3-(5-methylisoxazol-3-yl)-6-(1-methyl-1,2,3-triazol-4-yl)methyloxy-1,2,4 triazolo[3,4-ajphthalazine. 20
5. A combination according to any one of the preceding claims wherein the acetylcholinesterase inhibitor is selected from physostigmine bromide, eptastigmine and its tartrate, galanthamine and its hydrochloride and hydrobromide, metrifonate, tacrine and its hydrochloride, eseridine and its 25 salicylate, suronacrine and its maleate, velnacrine and its maleate, amiridine and its hydrochloride, 7-methoxytacrine, SM-10888 and its citrate, phenserine and its tartrate, ENA-713, donepezil and its hydrochloride, TAK-147, CP-118954, huperzine A and zifrosilone. WO 99/47131 - 11 - PCT/GB99/00778
6. A pharmaceutical composition comprising a combination as defined if any one of claims 1 to 5 and a pharmaceutically acceptable carrier for simultaneous administration. 5
7. 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 U5 receptor subtype and a second pharmaceutically acceptable carrier for simultaneous, separate or 10 sequential administration.
8. A method of treatment of a subject suffering from a neurodegenerative disorder or a cognitive deficit comprising administering to that subject a therapeutically effective amount of a combination of an 15 acetylcholinesterase inhibitor and an inverse agonist of the GABAA a5 receptor subtype.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GBGB9805561.9A GB9805561D0 (en) | 1998-03-16 | 1998-03-16 | A combination of therapeutic agents |
GB9805561 | 1998-03-16 | ||
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 (2)
Publication Number | Publication Date |
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AU2846499A true AU2846499A (en) | 1999-10-11 |
AU753077B2 AU753077B2 (en) | 2002-10-10 |
Family
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Family Applications (1)
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AU28464/99A Ceased AU753077B2 (en) | 1998-03-16 | 1999-03-16 | Combination of a GABA-A alpha 5 inverse agonist and an acetylcholinesterase inhibitor |
Country Status (6)
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EP (1) | EP1061952A2 (en) |
JP (1) | JP2002506815A (en) |
AU (1) | AU753077B2 (en) |
CA (1) | CA2323618A1 (en) |
GB (1) | GB9805561D0 (en) |
WO (1) | WO1999047131A2 (en) |
Families Citing this family (28)
Publication number | Priority date | Publication date | Assignee | Title |
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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 |
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 |
US6723332B2 (en) | 2000-05-26 | 2004-04-20 | Neurogen Corporation | Oxomidazopyridine-carboxamides |
WO2002000623A2 (en) | 2000-06-26 | 2002-01-03 | 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 |
WO2004058239A1 (en) * | 2002-12-24 | 2004-07-15 | Neurochem (International) Limited | Therapeutic formulations for the treatment of beta-amyloid related diseases |
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 |
WO2005112946A1 (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 |
WO2008055945A1 (en) | 2006-11-09 | 2008-05-15 | Probiodrug Ag | 3-hydr0xy-1,5-dihydr0-pyrr0l-2-one derivatives as inhibitors of glutaminyl cyclase for the treatment of ulcer, cancer and other diseases |
SI2091948T1 (en) | 2006-11-30 | 2012-07-31 | Probiodrug Ag | Novel inhibitors of glutaminyl cyclase |
ZA200905537B (en) | 2007-03-01 | 2010-10-27 | Probiodrug Ag | New use of glutaminyl cyclase inhibitors |
EP2142514B1 (en) | 2007-04-18 | 2014-12-24 | Probiodrug AG | Thiourea derivatives as glutaminyl cyclase inhibitors |
ES2548913T3 (en) | 2009-09-11 | 2015-10-21 | Probiodrug Ag | Heterocyclic derivatives such as glutaminyl cyclase inhibitors |
US20110212928A1 (en) | 2010-02-09 | 2011-09-01 | The Johns Hopkins University | Methods and compositions for improving cognitive function |
JP6026284B2 (en) | 2010-03-03 | 2016-11-16 | プロビオドルグ エージー | Inhibitors of glutaminyl cyclase |
JP5688745B2 (en) | 2010-03-10 | 2015-03-25 | プロビオドルグ エージー | Heterocyclic inhibitor of glutaminyl cyclase (QC, EC 2.3.2.5) |
WO2011131748A2 (en) | 2010-04-21 | 2011-10-27 | Probiodrug Ag | Novel inhibitors |
WO2012123563A1 (en) | 2011-03-16 | 2012-09-20 | Probiodrug Ag | Benz imidazole derivatives as inhibitors of glutaminyl cyclase |
EP2919788A4 (en) | 2012-11-14 | 2016-05-25 | Univ Johns Hopkins | Methods and compositions for treating schizophrenia |
US10806717B2 (en) | 2013-03-15 | 2020-10-20 | The Johns Hopkins University | Methods and compositions for improving cognitive function |
ES2881081T3 (en) | 2013-03-15 | 2021-11-26 | Agenebio Inc | Procedures and compositions to improve cognitive function |
JP6899043B2 (en) | 2015-05-22 | 2021-07-07 | エージンバイオ, インコーポレイテッド | Sustained release pharmaceutical composition of levetiracetam |
KR101743960B1 (en) * | 2015-07-06 | 2017-06-08 | 서울대학교산학협력단 | G 19 Pharmaceutical composition for preventing treating or retarding Alzheimers disease or dementia comprising G protein-Coupled Receptor19 agonist as an active ingredient |
EP3461819B1 (en) | 2017-09-29 | 2020-05-27 | Probiodrug AG | Inhibitors of glutaminyl cyclase |
Family Cites Families (3)
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US4647580A (en) * | 1985-07-18 | 1987-03-03 | Syntex (U.S.A.) Inc. | Treatment of Alzheimer's disease |
GB9503601D0 (en) * | 1995-02-23 | 1995-04-12 | Merck Sharp & Dohme | Method of treatment and method of manufacture of medicament |
AU724076B2 (en) * | 1996-07-25 | 2000-09-14 | Merck Sharp & Dohme Limited | Substituted triazolo pyridazine derivatives as inverse agonists of the GABAAalpha5 receptor subtype |
-
1998
- 1998-03-16 GB GBGB9805561.9A patent/GB9805561D0/en not_active Ceased
-
1999
- 1999-03-16 CA CA002323618A patent/CA2323618A1/en not_active Abandoned
- 1999-03-16 EP EP99909095A patent/EP1061952A2/en not_active Withdrawn
- 1999-03-16 WO PCT/GB1999/000778 patent/WO1999047131A2/en not_active Application Discontinuation
- 1999-03-16 AU AU28464/99A patent/AU753077B2/en not_active Ceased
- 1999-03-16 JP JP2000536371A patent/JP2002506815A/en not_active Withdrawn
Also Published As
Publication number | Publication date |
---|---|
WO1999047131A2 (en) | 1999-09-23 |
JP2002506815A (en) | 2002-03-05 |
WO1999047131A3 (en) | 1999-11-04 |
CA2323618A1 (en) | 1999-09-23 |
GB9805561D0 (en) | 1998-05-13 |
AU753077B2 (en) | 2002-10-10 |
EP1061952A2 (en) | 2000-12-27 |
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