Classifications

• • 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
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
• • 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
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
• • 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
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

• the present invention relates to a therapeutic agent for dementia caused by the combined use of a pyrazoloquinoline derivative having phosphodiesterase 9 (PDE9) inhibitory activity or a pharmaceutically acceptable salt thereof and donepezil or a pharmaceutically acceptable salt thereof.
• PDE9 phosphodiesterase 9
• the pyrazoloquinoline derivative represented by the formula (I) (hereinafter referred to as “compound (I)”) has an inhibitory action on phosphodiesterase 9 (PDE9) and is expected to improve the cognitive function in Alzheimer's disease. (Patent Document 1).
• donepezil represented by the formula (II) (hereinafter referred to as “compound (II)”) has an acetylcholinesterase inhibitory action and has been reported to have an effect on Alzheimer's disease and Lewy body dementia ( Non-patent documents 1, 2, and 3).
• galantamine, rivastigmine, which is an acetylcholinesterase inhibitor, and memantine, which is an NMDA receptor antagonist, have been approved for the treatment of Alzheimer's disease.
• Donepezil is indicated for mild to severe Alzheimer's disease.
• peripheral symptoms such as excitement, anxiety, emotionlessness, delusion, depression, derepression, hallucinations, irritability, abnormal behavior, and apathy (BPSD) : Effect on behavioral and psychological symptoms of mentia) has also been reported (see Non-Patent Documents 4 and 5).
• Galantamine and rivastigmine are indicated for mild to moderate Alzheimer's disease (see Non-Patent Documents 6 and 7).
• Memantine has been reported to be effective for moderate to advanced cognitive function of Alzheimer's disease and BPSD (excitability, irritability, aggression, behavioral disorder) (see Non-Patent Documents 8 and 9). Although acetylcholinesterase inhibitors cannot be used together, any acetylcholinesterase inhibitor and memantine can be used together. In the Dementia Guidelines 2010, acetylcholinesterase inhibitors are recommended for the core symptoms of Alzheimer's disease. One of donepezil, galantamine, and rivastigmine should be selected first, and if there is a problem with its efficacy or tolerability There is a guideline to change to an acetylcholinesterase inhibitor. If the effect of an acetylcholinesterase inhibitor is insufficient or if there is a problem with tolerability, combination with memantine or replacement with memantine is considered.
• Non-Patent Document 10 Memantine can be selected for patients with moderate to severe Alzheimer's disease when acetylcholinesterase inhibitors are not used because of side effects and tolerability, but there are currently effective treatments for other patients. Not. For patients with inadequate effects, an acetylcholinesterase inhibitor and memantine can be used together, but the effects of these combinations have been reported (see Non-Patent Document 11), but there is no effect of the combination. There are also reports (see Non-Patent Document 12), and opinions are divided.
• the present invention relates to ⁇ 1> to ⁇ 19.3> below.
• ⁇ 4> The therapeutic agent according to any one of ⁇ 1> to ⁇ 3>, wherein the Alzheimer's disease is mild, moderate or severe Alzheimer's disease.
• a therapeutic agent for Alzheimer's disease or Lewy body dementia which is administered simultaneously or separately with a pharmaceutically acceptable salt thereof.
• ⁇ 8> The therapeutic agent according to any one of ⁇ 5> to ⁇ 7>, wherein the Alzheimer's disease is mild, moderate or severe Alzheimer's disease.
• ⁇ 12> The therapeutic agent according to any one of ⁇ 9> to ⁇ 11>, wherein the Alzheimer's disease is mild, moderate or severe Alzheimer's disease.
• donepezil represented by formula (II) for the treatment of Alzheimer's disease or Lewy body dementia in combination with a pharmaceutically acceptable salt thereof Or a pharmaceutically acceptable salt thereof.
• ⁇ 13.3> Donepezil or a pharmaceutically acceptable salt thereof according to any one of ⁇ 13> to ⁇ 13.2>, wherein the Alzheimer's disease is mild, moderate or severe Alzheimer's disease.
• ⁇ 15.3> The method according to any one of ⁇ 15> to ⁇ 15.2>, wherein the Alzheimer's disease is mild, moderate or severe Alzheimer's disease.
• ⁇ 18.3> Use of donepezil or a pharmaceutically acceptable salt thereof according to any one of ⁇ 18> to ⁇ 18.2>, wherein the Alzheimer's disease is mild, moderate or severe Alzheimer's disease.
• the present invention relates to a combination of a pyrazoloquinoline derivative represented by formula (I) having a PDE9 inhibitory action or a pharmaceutically acceptable salt thereof and donepezil having a acetylcholinesterase inhibitory action or a pharmaceutically acceptable salt thereof.
• a therapeutic agent for Alzheimer's disease and Lewy body dementia Compared to the case of using alone, the therapeutic agent by such combination shows a remarkable cognitive function improving action in an animal model and has applicability as a therapeutic agent for Alzheimer's disease and dementia with Lewy bodies.
• the “pharmaceutically acceptable salt” in the present specification is not particularly limited as long as it forms a salt with the compound according to the present invention, and specifically, for example, an inorganic acid salt or an organic acid salt. Or acid addition salts, such as acidic amino acid salt, are mentioned.
• the “pharmaceutically acceptable salt” means that an acid for one molecule of the compound is formed in the formed salt as long as the salt is formed in an appropriate ratio.
• the number of molecules is not particularly limited, but in one embodiment, the acid is about 0.1 to about 5 molecules per molecule of the compound, and in another embodiment, the acid is about 0.001 molecule per molecule of the compound. In another embodiment, the acid is about 0.5, about 1, or about 2 molecules per molecule of the compound.
• the inorganic acid salt include hydrochloride, hydrobromide, sulfate, nitrate, phosphate and the like.
• Specific examples of the organic acid salt include, for example, acetate. Succinate, fumarate, maleate, tartrate, citrate, lactate, stearate, benzoate, methanesulfonate, p-toluenesulfonate, benzenesulfonate, etc. It is done.
• acidic amino acid salts include aspartate and glutamate.
• the pharmaceutical composition according to the present invention comprises compound (I) or a pharmaceutically acceptable salt thereof and / or compound (II) or a pharmaceutically acceptable salt thereof as a pharmaceutically acceptable additive. It can manufacture by mixing with.
• the pharmaceutical composition according to the present invention can be produced according to a known method such as the method described in the 16th revised Japanese Pharmacopoeia General Rules for Preparations.
• the pharmaceutical composition according to the present invention can be appropriately administered to a patient according to its dosage form.
• the dose of compound (I) or a pharmaceutically acceptable salt thereof and compound (II) or a pharmaceutically acceptable salt thereof according to the present invention is the degree of symptoms, age, sex, body weight, dosage form ⁇ Depending on the type of salt, specific type of disease, etc., in general, for adults, about 30 ⁇ g to 10 g by oral administration per day, 100 ⁇ g to 5 g as one aspect, 100 ⁇ g as another aspect 1 g is administered by injection in an amount of about 30 ⁇ g to 1 g, in one embodiment, 100 ⁇ g to 500 mg, and in another embodiment, 100 ⁇ g to 300 mg, each in one or several divided doses.
• Compound (I) can be produced, for example, by the method described in Patent Document 1.
• Scopolamine is a muscarinic receptor inhibitor that blocks transmission in the acetylcholine nervous system.
• the acetylcholine nervous system is involved in memory and attention, etc.
• Healthy people and animals treated with scopolamine show dementia-like amnesia and are used to treat cognitive impairment in Alzheimer's disease and Lewy body dementia (Snyder et al., Alzheimer's & Dementia 1 (2005) 126-135, Sambeth et al., European Journal of Pharmacology, vol. 572 (2007) 59. 2007) p.
• Scopolamine (Wako Pure Chemical Industries) was administered subcutaneously at a dose of 0.7 mg / kg 30 minutes before T1.
• T1 the rats were habituated to an empty test apparatus for 3 minutes and then placed in the waiting room.
• T2 a retention trial
• T1 familiar object
• T1 familiar object
• T2 rat behavior was photographed with a digital video camera, and the total search time for each object was manually measured using a stopwatch. The behavior in which the rat approached the nose within 2 cm of the object and the nose was directed toward the object was defined as the search behavior.
• novel object search ratio of T2 is regarded as an amnestic index that reflects discrimination between a known object and a novel object.
• the rats in the pathological control group showed a significant decrease in the novel object search rate compared to the rats in the normal control group. This means that scopolamine induced memory impairment in rats.
• Compound (I) showed a significant improvement effect of the novel object search rate at 3.3 mg / kg (Table 2), but no significant effect at 1 mg / kg (Table 1).
• Donepezil hydrochloride showed a significant improvement effect of the novel object search rate at 0.3 mg / kg (Table 4), but did not show a significant effect at 0.03 mg / kg (Table 3).

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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)
• Neurosurgery (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Biomedical Technology (AREA)
• Epidemiology (AREA)
• Neurology (AREA)
• Psychiatry (AREA)
• Hospice & Palliative Care (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Organic Chemistry (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)

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• 2018
  • 2018-05-30 RU RU2019135834A patent/RU2019135834A/ru unknown
  • 2018-05-30 CA CA3060030A patent/CA3060030A1/en active Pending
  • 2018-05-30 CN CN201880030220.5A patent/CN110603040B/zh active Active
  • 2018-05-30 ES ES18810578T patent/ES2980131T3/es active Active
  • 2018-05-30 JP JP2019521248A patent/JP7079777B2/ja active Active
  • 2018-05-30 WO PCT/JP2018/020638 patent/WO2018221545A1/ja not_active Ceased
  • 2018-05-30 SG SG11201909595V patent/SG11201909595VA/en unknown
  • 2018-05-30 EP EP18810578.7A patent/EP3632439B1/en active Active
  • 2018-05-30 KR KR1020197033197A patent/KR102627787B1/ko active Active
  • 2018-05-30 US US16/607,402 patent/US11833146B2/en active Active
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  • 2018-05-30 AU AU2018276565A patent/AU2018276565A1/en not_active Abandoned
  • 2018-05-30 BR BR112019023569-8A patent/BR112019023569A2/pt not_active IP Right Cessation
• 2022
  • 2022-05-23 JP JP2022083947A patent/JP7288999B2/ja active Active

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