US20060142276A1 - Therapeutic agent for senile dementia - Google Patents

Therapeutic agent for senile dementia Download PDF

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US20060142276A1
US20060142276A1 US10/562,039 US56203905A US2006142276A1 US 20060142276 A1 US20060142276 A1 US 20060142276A1 US 56203905 A US56203905 A US 56203905A US 2006142276 A1 US2006142276 A1 US 2006142276A1
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therapeutic
group
formula
cognitive dysfunctions
preventive agent
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Yukihiro Ohno
Takeo Ishiyama
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Sumitomo Pharma Co Ltd
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Sumitomo Dainippon Pharma Co Ltd
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Assigned to DAINIPPON SUMITOMO PHARMA CO. LTD. reassignment DAINIPPON SUMITOMO PHARMA CO. LTD. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: OHNO, YUKIHIRO, ISHIYAMA, TAKEO
Publication of US20060142276A1 publication Critical patent/US20060142276A1/en
Priority to US12/140,927 priority Critical patent/US8148379B2/en
Priority to US13/409,075 priority patent/US8552000B2/en
Abandoned legal-status Critical Current

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    • 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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a therapeutic agent for dementia, more particularly, a therapeutic agent for dementia, which comprises as an active ingredient an imide derivative.
  • Senile dementia is divided broadly into the Alzheimer type dementia and the cerebrovascular dementia, and about 80% of the patients of senile dementia can be classified into these categories. As the population rapidly ages, the number of the patients of senile dementia demonstrates an upward trend in these days. In Japan, it is speculated that about 7% of the people 65 years old or over show the symptoms of dementia, and hence, it is an urgent need to develop an excellent therapeutic agent for dementia.
  • the Alzheimer type dementia is accompanied by senile plaque and neurofibrillary tangle, and it is pathologically characterized by encephalatrophy caused by significant neuronal death.
  • Alzheimer's disease In familial Alzheimer's disease, several gene mutations have been identified, whereby a leading hypothesis for neuronal pathogenetic mechanism thereof has been speculated, but the most of cases are sporadic, and hence, it may be said that Alzheimer's disease is still a disease of unknown cause. Accordingly, at the present, there is no radical therapeutic method for inhibiting neurodegeneration.
  • the Alzheimer type dementia shows as core symptoms cognition dysfunctions such as disorders of memory, faculty of orientation, attention, etc., and it is also accompanied by peripheral symptoms such as psychotic manifestations or abnormal behavior problems (e.g., depression, aggressive attack, delusion, etc.).
  • acetylcholine esterase inhibitors are also effective to not only core symptoms but also peripheral symptoms.
  • neurotransmitter acetylcholine is supplemented by inhibiting acetylcholine-degrading enzyme, while acetylcholine neuronal cells, which are closely-linked with cognitive function, are especially disturbed in Alzheimer's disease and neurotransmitter acetylcholine is reduced.
  • the cerebrovascular dementia is a disease which develops owing to cerebrovascular disorders, and at the moment, there is no cure for core symptoms thereof.
  • acetylcholine esterase inhibitors have been done, and it has become apparent that these medicaments are also effective to cerebrovascular dementia.
  • a therapeutic agent having a similar therapeutic mechanism to the Alzheimer's disease such as acetylcholine esterase inhibitors may be effective even to cerebrovascular dementia (e.g., Rinsho-Seishinigaku (i.e., Clinical Psychiatry), 31 (10): 1189-1193 (2002)).
  • JP Patent No. 2800953 discloses imide derivatives showing an excellent antipsychotic activity and anxiety reducing activity, but it has never indicated whether or not those derivatives show effects on senile dementia.
  • the present invention provides a therapeutic agent for senile dementia. More particularly, the present invention provides a therapeutic agent effective to both of the core symptoms and the peripheral symptoms of senile dementia.
  • the present inventors have intensively studied in order to solve the above problems, and found that the imide compound of the present invention exhibits a therapeutic effect in cognitive/memory disturbance models produced by acetylcholine receptor blocker, which are representative animal models for senile dementia, and finally they have accomplished the present invention.
  • the present invention relates to the following:
  • FIG. 1 shows the effects of the imide derivative on rats in one step-through passive avoidance test where the acetylcholine receptor blocker scopolamine was used for inducing amnesia, and indicates the step-through latency during the training (*: P ⁇ 0.05 vs the group treated with 0.5% MC+scopolamine (Steel's test)).
  • FIG. 2 shows the effects of the imide derivatives on rats in one step-through passive avoidance test where the acetylcholine receptor blocker scopolamine was used for inducing amnesia, and indicates the step-through latency during the test (*: P ⁇ 0.05 vs the group treated with 0.5% MC+scopolamine (Steel's test), #: ⁇ 0.01 vs the group treated with 0.5% MC+saline solution (Mann-Whitney test)).
  • the lower alkylene for Z and A includes, for example, ones having not more than 3 carbon atoms such as methylene, ethylene, trimethylene, etc.
  • the hydrocarbon ring for Z and A includes, for example, a cycloalkane or cycloalkene having not more than 7 carbon atoms.
  • the cycloalkane having not more than 7 carbon atoms includes, for example, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, etc.
  • the cycloalkene having not more than 7 carbon atoms includes, for example, cyclopentene, cyclohexene, cycloheptene, etc.
  • the hydrocarbon ring being cross-linked with a lower alkylene or an oxygen atom for Z and A includes, for example, rings having not more than 10 carbon atoms such as bicyclo[1.1.1]pentane, bicyclo[2.1.1]hexane, bicyclo[2.1.1]hex-2-ene, bicyclo[2.2.1]heptane, bicyclo[2.2.1]hept-2-ene, bicyclo[2.2.2]octane, bicyclo[2.2.2]oct-2-ene, bicyclo[4.1.1]octane, bicyclo-[4.1.1]oct-2-ene, bicyclo[4.1.1]oct-3-ene, bicyclo[3.2.1]octane, bicyclo-[3.2.1]oct-2-ene, bicyclo[3.2.1]oct-3-ene, bicyclo[3.2.1]oct-6-ene, bicyclo-[3.2.2]nonane, bicyclo[
  • the aromatic hydrocarbon ring for Z includes, for example, ones having not more than 10 carbon atoms such as phenyl ring, naphthyl ring, etc.
  • the binding position of the hydrocarbon ring for A includes, for example, -1, 1-, -1,2-, -1,3-, -1,4-, etc.
  • the aromatic hydrocarbon group for —Ar includes, for example, ones having not more than 10 carbon atoms such as phenyl, naphthyl, etc.
  • the aromatic heterocyclic group for —Ar includes, for example, an aromatic heteromonocyclic group and an aromatic heterobicyclic group.
  • the aromatic heteromonocyclic group includes, for example, ones having not more than 6 carbon atoms, and further having the same or different 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, such as pyridyl, pyrimidinyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, furyl, imidazolyl, etc.
  • the aromatic heterobicyclic group includes, for example, ones having not more than 10 carbon atoms, and further having the same or different 1 to 5 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, such as benzolog-fused rings (e.g., benziso-thiazolyl, benzisoxazolyl, benzofuryl, quinolyl, isoquinolyl, indolyl, indazolyl, benzimidazolyl, benzoxazolyl, etc.), naphthyridinyl, puteridinyl, thienofuranyl, imidazothiophen-yl, imidazofuranyl, etc.
  • benzolog-fused rings e.g., benziso-thiazolyl, benzisoxazolyl, benzofuryl, quinolyl, isoquinolyl, indolyl, indazolyl, benzimidazolyl, benzox
  • the alkyl includes, for example, ones having not more than 6 carbon atoms, and preferably lower alkyl groups having not more than 4 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, butyl, etc.
  • the lower alkyl includes, for example, ones having not more than 4 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, butyl, etc.
  • the lower alkoxy includes, for example, ones having not more than 4 carbon atoms, such as methoxy, ethoxy, propoxy, 2-propoxy, butoxy, etc.
  • the halogen atom is fluorine, chlorine, bromine, iodine.
  • the present compound [1] may have stereoisomers and/or an optical isomer.
  • the present invention also includes a mixture of these isomers or each isolated isomer.
  • the preferable group for —Ar is an aromatic heterobicyclic group, or naphthyl, benzoyl, phenoxy or phenylthio (in these cases, G is N, CH, or COH), or biphenylmethylidene (in this case, G is a carbon atom), where said aromatic heterobicyclic group, naphthyl, benzoyl, phenoxy, phenylthio and biphenylmethylidene may optionally be substituted by at least one group selected from a lower alkyl, a lower alkoxy and a halogen atom.
  • the more preferable group for —Ar is a benzolog-fused ring, naphthyl, benzoyl, phenoxy, or phenyl (said benzolog-fused ring, naphthyl, benzoyl, phenoxy, and phenylthio may optionally be substituted by at least one group selected from a lower alkyl, a lower alkoxy and a halogen atom), and in this case, G is N, CH or COH.
  • the further preferable group for —Ar is benzisothiazolyl, benzisoxazolyl, isoquinolyl, benzofuranyl, indazolyl or indolyl (said benzisothiazolyl, benzisoxazolyl, isoquinolyl, benzofuranyl, indazolyl amd indolyl may optionally be substituted by at least one group selected from a lower alkyl, a lower alkoxy and a halogen atom), and in this case, G is N, CH or COH.
  • the preferable group for Z is, for example, a group of the formula [4]: (in which —L— is a single bond or a double bond, E is a lower alkylene optionally substituted by a lower alkyl, or an oxygen atom, R 5 is a hydrogen atom or a lower alkyl, and B is a carbonyl or a sulfonyl); a group of the formula [5]: (in which —L—, E, R 5 and B are as defined above); a group of the formula [6]: (in which R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 are independently a hydrogen atom or a lower alkyl, or the adjacent two groups of R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 may combine each other to form a double bond, and B is as
  • the saturated hydrocarbon ring formed by combining R 16 and R 17 includes, for example, a cycloalkane having not more than 7 carbon atoms, such as cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, etc.
  • the preferable group for Z is, for example, a group of the formula [10]: (in which —L′— is a single bond, E is a lower alkylene optionally substituted by a lower alkyl, or an oxygen atom, R 5 is a hydrogen atom or a lower alkyl, and B is a carbonyl or a sulfonyl); a group of the formula [11]: (in which —L′—, E, R 5 and B are as defined above); a group of the formula [12]: (in which R 6 ′, R 7 ′, R 8 ′, R 9 ′, R 10 ′, R 11 ′, R 12 ′, R 13 ′, R 14 ′, R 15 ′ are independently a hydrogen atom or a lower alkyl, and B is as defined above); a group of the formula [7]: (in which R 16 , R 17 , R 5 and B are as defined above); or a group of the formula [8]: (B is
  • the imide derivative of the present invention or an acid addition salt thereof may be prepared, for example, by the method disclosed in JP Patent No. 2800953 1 as mentioned above.
  • the imide derivative of the present invention may be used in the form of a pharmaceutically acceptable acid addition salt thereof.
  • Inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, etc. or organic acids such as fumaric acid, citric acid, tartaric acid, succinic acid, etc. may be exemplified as an acid for forming addition salts.
  • the imide derivative or a pharmaceutically acceptable acid addition salt thereof, which is the active compound of the present invention may be administered at a dose suitable for necessity of each case in a conventional dosage form.
  • it can be administered orally in the form of tablets, capsules, syrups, suspension, etc. or parenterally in the form of injection preparation such as liquid preparations (e.g., solutions, emulsions, suspension, patches, etc.).
  • suitable dosage forms may be prepared by mixing an active compound with a conventional pharmaceutically acceptable carriers, excipients, binders, stabilizers, etc.
  • a conventional pharmaceutically acceptable carriers such as, but not limited to, ethylene glycol, ethylene glycol, ethylene glycol, ethylene glycol dimethacrylate, ethylene glycol dimethacrylate, ethylene glycol dimethacrylate, ethylene glycol dimethacrylate, ethylene glycol dimethoxysulfate, etc.
  • the dose and the frequency of the administration of the present therapeutic agent may vary according to the dosage forms, or the severity of the diseases to be treated.
  • the imide derivative is orally administered at a dose of 1 to 200 mg per day in an adult, which is administered once a day or divided into several dosage units.
  • the diseases to which the therapeutic agent of the present invention is effective are the Alzheimer type and the cerebrovascular dementia, more particularly, various senile dementias (e.g., dementia with Lewy bodies, dementia from Pick's disease, dementia from Creutzfeldt-Jakob disease, dementia from Huntington's chorea, dementia from Parkinson's disease, etc.) including multiple infarct dementia, dementia caused by cerebral infarction, Binswanger disease, dementia caused by stroke, amyloid angiopathy, ischemic dementia.
  • various senile dementias e.g., dementia with Lewy bodies, dementia from Pick's disease, dementia from Creutzfeldt-Jakob disease, dementia from Huntington's chorea, dementia from Parkinson's disease, etc.
  • dementias e.g., dementia with Lewy bodies, dementia from Pick's disease, dementia from Creutzfeldt-Jakob disease, dementia from Huntington's chorea, dementia from Parkinson's disease, etc.
  • multiple infarct dementia dementia caused by cerebral in
  • the therapeutic agent of the present invention shows the improving activity of cognitive dysfunctions accompanied by acetylcholine neuronal dysfunctions, and hence, it may be used in the treatment of traumatic cognitive dysfunctions, dementia in Down syndrome, schizophrenial cognitive dysfunctions, or cognitive dysfunctions accompanied by acetylcholine neuronal dysfunctions from any cause, in addition to the treatment of senile dementia.
  • 198-07901 which is an acethylcoline receptor blocker
  • saline solution manufactured by TERUMO CORPORATION
  • Compound A at a dose of 3 mg/kg or 30 mg/kg, or 0.5% MC as a control was orally administered to the animals one hour prior to the training step in the one step-through passive avoidance test, and then, scopolamine at a dose of 0.5 mg/kg or a saline solution as a control was subcutaneously administered to the animals 30 minutes prior to the training step.
  • the volume of each solution to be administered was 5 ml/kg each.
  • the one step-through passive avoidance test in rats was carried out in the following manners with using an apparatus consisting of a light-dark box and an electric stimulator (manufactured by O—hara & Co., Ltd., product no. PA-2030A) as an experimental apparatus. Namely, on Day 1, after the medicament and the agent for inducing amnesia were administered, the rats were put into the light box of the experimental apparatus where the back of each rat was directed to the dark box. Then, 10 seconds later, a guillotine door set at the border between the dark box and the light box was opened. Due to the habits of the rats, once the rats entered into the dark box, the guillotine door was quickly closed.
  • an electroconvulsive shock (0.5 mA, for 3 seconds) was given to the rats.
  • the guillotine door was opened, and after the rats spontaneously returned to the light box, the animals were transferred into the home cage.
  • the period between the time just after the guillotine door was opened and the time at which the rats entered into the dark box was measured as a step-through latency.
  • the training was terminated, and those animals were dropped in the following experiment for the reasons of training failure.
  • FIG. 1 and FIG. 2 show the effects of Compound A on the scopolamine-induced cognitive/memory dysfunction models in the one step-through passive avoidance test when it was orally administered at a dosage of 3 mg/kg or 30 mg/kg.
  • FIG. 1 shows the step-through latency during the training step
  • FIG. 2 shows the step-through latency during the test.
  • the number of the animals was 15 per group, and the data was expressed in mean ⁇ SEM.
  • the agent for inducing amnesia, scopolamine did not affect on the step-through latency during the training.
  • Compound A slightly shortened the step-through latency during the training step at a dose of 3 mg/kg.
  • the animals treated with scopolamine showed a significantly shorter step-through latency as compared to the animals treated with saline solution (cognitive/memory dysfunction inducing effect).
  • the step-through latency was significantly extended. That is, it was observed that Compound A exhibited an improving effect of scopolamine-induced cognitive/memory dysfunctions.
  • the imide derivatives may exhibit an improving activity of scopolamine-induced cognitive/memory dysfunctions, and as a result, it may become apparent that the present invention may provide a therapeutic method for senile dementia and a therapeutic agent for said method.
  • the imide derivatives may exhibit an improving activity of scopolamine-induced cognitive/memory dysfunctions, and as a result, it has become apparent that the present invention may provide a therapeutic method for senile dementia and a therapeutic agent for said method.

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US12/140,927 US8148379B2 (en) 2003-06-23 2008-06-17 Therapeutic agent for senile dementia
US13/409,075 US8552000B2 (en) 2003-06-23 2012-02-29 Therapeutic agent for senile dementia

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PCT/JP2004/009095 WO2004113333A1 (ja) 2003-06-23 2004-06-22 老人性痴呆症治療剤

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AU2004249621B2 (en) 2003-06-23 2009-08-06 Dainippon Sumitomo Pharma Co., Ltd. Therapeutic agent for senile dementia
EP2413929A4 (en) * 2009-04-02 2012-10-10 Zenyaku Kogyo Co Ltd PROCESS FOR TREATING COGNITIVE IMPAIRMENT

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US20080255148A1 (en) 2008-10-16
JPWO2004113333A1 (ja) 2006-07-27
WO2004113333A1 (ja) 2004-12-29
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CA2531980C (en) 2013-09-17
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