WO2021080312A1 - 인지 장애의 예방, 경감 또는 치료, 또는 인지 기능 향상을 위한 이미다조피리미딘 또는 이미다조트리아진 화합물의 용도 - Google Patents
인지 장애의 예방, 경감 또는 치료, 또는 인지 기능 향상을 위한 이미다조피리미딘 또는 이미다조트리아진 화합물의 용도 Download PDFInfo
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- WO2021080312A1 WO2021080312A1 PCT/KR2020/014399 KR2020014399W WO2021080312A1 WO 2021080312 A1 WO2021080312 A1 WO 2021080312A1 KR 2020014399 W KR2020014399 W KR 2020014399W WO 2021080312 A1 WO2021080312 A1 WO 2021080312A1
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- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
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- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/27—Esters, e.g. nitroglycerine, selenocyanates of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
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- 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
- A61K31/4458—Non condensed piperidines, e.g. piperocaine only substituted in position 2, e.g. methylphenidate
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- 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
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- 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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
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- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Definitions
- the present invention is an imidazopyrimidine or imidazotriazine compound of the following formula (1), or a pharmaceutically acceptable salt, solvate, or Regarding the use of luggage:
- the human brain has the ability to acquire, store, and retrieve information over decades. This collection of information, that is, learning, changes the physiological state of specific neurons in the process of encoding memory. These physiological changes are changes in cell activity by learning that become part of the neural code for that memory. The change may occur through the expression or function of ion channels that cause neurons to excite more or less, resulting in an increase or decrease in action potential, or more indirectly through changes in other electrical signals. have. Learning can proceed with the process of nerve growth through a new connection, or, conversely, can proceed with a nerve retraction process that removes the existing connection.
- learning can proceed with the adaptation process of cellular signals through changes in the overall ability of neurons to integrate different types of signals, and can lead to morphological and functional changes of synapses that increase or decrease the ability of neurons. have.
- Molecular and cellular engrams generated by all neurons involved in this learning act as guides that enable memory information to be retrieved later.
- the interconnection of the cells connected between the concepts is strengthened through a simplification process according to the perceptual concept and is managed logically and efficiently.
- the efficiency of brain capacity is further increased through the process of forgetting that memory traces that are not used or used frequently are deleted.
- the cognitive process is the entire process of creating and managing memory traces so that information on events or contents experienced before can be recalled and re-acknowledged later (Davis & Zhong, 2017, “The Biology of Forgetting-A Perspective” Neuron. Aug 2;95(3):490-503).
- Improving cognitive function is a direction in which a new connection is formed well in the process of nerve growth in the acquisition, storage, and retrieval of information, strengthens the adaptation process of cellular signals, or makes the interconnection of cells connected between concepts more logical. As a result, the cell's activity takes place. Or the process of forgetting, that is, the natural decay of living organisms causes the necessary memory traces to decline, similar memory traces that hinder the proper retrieval of desired information, or recognizing the direction in which memory retrieval becomes difficult due to changes in the structure of the memory traces. It is not to be hindered.
- Cognitive impairment is a neurological disorder in which memory, attention, language ability, and judgment are deteriorated in the cognitive process, and varies from very mild to severe. The ability to perform daily activities is preserved and instrumental activities are possible, but a case in which cognitive function is poor is called mild cognitive impairment, and a condition in which cognitive function is deteriorated to the extent that it interferes with daily life. It is called dementia. Mild cognitive impairment can occur as a transient disorder in the process of developing dementia. In addition, cognitive impairment is considered as risk factors such as aging, heredity, and cardiovascular disease.
- the present invention is to provide a method for preventing, alleviating or treating cognitive disorders, or improving cognitive function.
- the present invention provides an imidazopyrimidine or imidazotriazine compound of Formula 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof, for the prevention, alleviation or treatment of cognitive disorders, or cognitive function. It is intended to provide a use for use for improvement:
- the present invention comprises a therapeutically effective amount of an imidazopyrimidine or imidazotriazine compound of Formula 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof, for the prevention, alleviation or treatment of cognitive disorders, Or it provides a drug for improving cognitive function:
- X is CH or N
- Z is O or S
- R 1 is halo, C 1 -C 5 alkyl, C 1 -C 5 alkoxy, C 1 -C 5 alkylthio, amino, di(C 1 -C 5 alkyl)amino, cyano, formyl, halo-C 1 -C 5 alkyl, hydroxy-C 1 -C 5 alkyl, C 1 -C 5 alkoxy-C 1 -C 5 alkyl, carbamoyloxy-C 1 -C 5 alkyl, C 1 -C 5 alkyl-C(O )OC 1 -C 5 alkyl, 5 or 6 membered heterocycloalkyl-C 1 -C 5 alkyl and di(C 1 -C 5 alkyl)amino- having 1-3 heteroatoms selected from N, O and S C 6 -C 12 aryl unsubstituted or substituted with one or more substituents selected from C 1 -C 5 alkyl; Or 1 selected from N, O and S, un
- R 2 is C 6 -C 12 aryl unsubstituted or substituted with one or more substituents selected from halo, deuterium, hydroxy and C 1 -C 5 alkyl; Or 5 to 12 membered unsaturated heterocyclyl having 1-3 heteroatoms selected from N, O and S, unsubstituted or substituted with one or more substituents selected from halo and C 1 -C 5 alkyl.
- the present invention comprises a therapeutically effective amount of the imidazopyrimidine or imidazotriazine compound of Formula 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof, and additionally a pharmaceutically acceptable carrier It provides a pharmaceutical composition for preventing, alleviating or treating cognitive disorders, or improving cognitive function, comprising at least one kind.
- the present invention comprises administering a therapeutically effective amount of the imidazopyrimidine or imidazotriazine compound of Formula 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof to a subject to be treated, cognitive impairment It provides a method for preventing, alleviating or treating or improving cognitive function.
- the present invention uses the imidazopyrimidine or imidazotriazine compound of Formula 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof to prevent, alleviate or treat cognitive disorders, or improve cognitive function. It provides a use for use in the treatment of
- R 1 is halo, hydroxy, C 1 -C 5 alkyl, C 1 -C 5 alkoxy, C 1 -C 5 alkylthio, amino, di(C 1- C 5 alkyl) amino, cyano, formyl, halo-C 1 -C 5 alkyl, hydroxy-C 1 -C 5 alkyl, C 1 -C 5 alkoxy-C 1 -C 5 alkyl, carbamoyloxy-C Phenyl unsubstituted or substituted with 1 to 3 substituents selected from 1 -C 5 alkyl and C 1 -C 5 alkyl-C(O)OC 1 -C 5 alkyl; Or selected from N, O and S, unsubstituted or substituted with 1 to 3 substituents selected from halo, hydroxy, C 1 -C 5 alkyl, C 1 -C 5 alkoxy and halo-C 1 -C 5 alkyl Is
- R 2 is phenyl unsubstituted or substituted with 1 to 5 substituents selected from halo, deuterium, hydroxy and C 1 -C 5 alkyl; Or 5 or 6 membered heteroaryl having 1-3 heteroatoms selected from N, O and S, unsubstituted or substituted with 1 to 3 substituents selected from halo and C 1 -C 5 alkyl.
- X is CH or N
- Z is O
- R 1 is halo, hydroxy, C 1 -C 5 alkyl, C 1 -C 5 alkoxy, C 1 -C 5 alkylthio, amino, di(C 1 -C 5 alkyl)amino, cyano, formyl, halo -C 1 -C 5 alkyl, hydroxy-C 1 -C 5 alkyl, C 1 -C 5 alkoxy-C 1 -C 5 alkyl, carbamoyloxy-C 1 -C 5 alkyl and C 1 -C 5 alkyl- Phenyl unsubstituted or substituted with 1 to 3 substituents selected from C(O)OC 1 -C 5 alkyl; Or selected from N, O and S, unsubstituted or substituted with 1 or 2 substituents selected from halo, hydroxy, C 1 -C 5 alkyl, C 1 -C 5 alkoxy and halo-C 1 -C 5 alkyl 5 to 9 membered unsatur
- R 2 is phenyl unsubstituted or substituted with 1 to 5 substituents selected from halo, deuterium, hydroxy and C 1 -C 5 alkyl; Or a 6-membered heteroaryl having 1 or 2 nitrogen atoms, unsubstituted or substituted with 1 or 2 substituents selected from halo and C 1 -C 5 alkyl.
- R 1 is halo, hydroxy, C 1 -C 5 alkyl, C 1 -C 5 alkoxy, C 1 -C 5 alkylthio, amino, di(C 1 -C 5 alkyl)amino, cyano, formyl, halo -C 1 -C 5 alkyl, hydroxy-C 1 -C 5 alkyl, C 1 -C 5 alkoxy-C 1 -C 5 alkyl, carbamoyloxy-C 1 -C 5 alkyl and C 1 -C 5 alkyl- Phenyl unsubstituted or substituted with 1 to 3 substituents selected from C(O)OC 1 -C 5 alkyl; 1,3-benzodioxolyl unsubstituted or substituted with 1 or 2 halo; Or pyridyl or pyrimidinyl unsubstituted or substituted with 1 or 2 substituents selected from halo, hydroxy, C 1 -C 5 al
- R 2 is phenyl unsubstituted or substituted with 1 to 5 substituents selected from halo, deuterium, hydroxy and C 1 -C 5 alkyl; Or pyridyl unsubstituted or substituted with 1 or 2 substituents selected from halo and C 1 -C 5 alkyl.
- X is CH
- Z is O
- R 1 is halo, hydroxy, C 1 -C 5 alkyl, C 1 -C 5 alkoxy, C 1 -C 5 alkylthio, amino, halo-C 1 -C 5 alkyl, hydroxy-C 1 -C 5 alkyl And phenyl unsubstituted or substituted with 1 to 3 substituents selected from C 1 -C 5 alkoxy-C 1 -C 5 alkyl;
- R 2 is pyridyl unsubstituted or substituted with 1 or 2 substituents selected from halo and C 1 -C 5 alkyl.
- Representatives of the compounds of formula 1 according to the present invention include:
- representatives of the compounds of formula 1 according to the present invention include:
- the preparation of the imidazopyrimidine or imidazotriazine compound of Formula 1 can be carried out by using known compounds or compounds that can be easily prepared from those of ordinary skill in the art for compound synthesis. Can be manufactured.
- the method for preparing the compound of Formula 1 is described in detail in International Publication No. WO 2016/137260 A1, and the document is incorporated herein by reference.
- the compound of Formula 1 may be chemically synthesized by the method described in the above document, but this is only to present one exemplary method, and the order of unit operations may be selectively changed as necessary, and the scope of the invention I'm not trying to limit it.
- the imidazopyrimidine or imidazotriazine compound of Formula 1 may be used to prevent, alleviate or treat cognitive disorders, or to improve cognitive function.
- the imidazopyrimidine or imidazotriazine compound of Formula 1 can also be applied to the prevention, alleviation or treatment of cognitive disorder symptoms.
- Symptoms of cognitive impairment include decreased memory, decreased attention, decreased speech ability, decreased spatiotemporal ability, decreased reasoning ability, decreased judgment, unorganized thinking, slow thinking, difficulty understanding, low concentration, loss of ability to solve problems, poor memory, It can occur in various ways, such as difficulty in expressing thoughts, difficulty in integrating thoughts, senses, and actions, or in erasing inappropriate thinking. These symptoms are manifested by repetition of the same words, repetition of the same question, difficulty in conveying content due to loss, loss, inaccurate names, memory of time or place, etc.
- the imidazopyrimidine or imidazotriazine compound of Formula 1 may be used for alleviation or treatment of diseases associated with cognitive disorders.
- Diseases related to the cognitive impairment include mild cognitive impairment, Alzheimer's disease, Alzheimer type dementia, presenile dementia, and early onset Alzheimer's disease. ), senile dementia, Lewy body corpuscle dementia, micro-infarct dementia, AIDS-related dementia, HIV-dementia, Lewy body corpuscle dementia Dementia associated with Lewy bodies, Down's syndrome associated dementia, Pick's disease, residual short-term memory impairment, age-related cognitive impairment (age-associated) cognitive disorder, age associated memory impairment, drug-associated cognitive disorder, immunodeficiency syndrome-associated cognitive disorder, cognitive impairment associated with vascular disease (vascular disease-associated cognitive impairment), Cognitive Impairment Associated With Schizophrenia, Parkinson's disease-associated cognitive impairment, Cognitive disorders associated with epilepsy. ated with epilepsy, depression-associated cognitive disorder, cognitive disorders associated with bipolar dosorder, obsessive compulsive disorder-associated cognitive disorder, trauma Post-traumatic stress disorder, attention deficit disorder, attention deficit hyperactivity disorder, and learning deficit disorder.
- the disease related to the cognitive impairment is mild cognitive impairment, Alzheimer's disease, Alzheimer's type dementia, elderly dementia, early onset Alzheimer's disease, senile dementia, early memory loss disorder, age-related cognitive impairment, age-related memory impairment. , Drug-related cognitive impairment and schizophrenia-related cognitive impairment.
- the pharmaceutical or pharmaceutical composition of the present invention may be used to prevent, alleviate or treat the cognitive disorder disease, but the scope of the present invention is not limited to the disease.
- the pharmaceutical or pharmaceutical composition of the present invention can be used to prevent, alleviate or treat symptoms of cognitive impairment, and the symptoms include lowering attention, lowering speech ability, lowering spatiotemporal ability, lowering reasoning ability, and lowering judgment, It is not limited thereto.
- the efficacy of the compound of Formula 1 on cognitive impairment can be confirmed using a known model.
- an animal model related to the prevention and treatment of cognitive disorders an animal model in which cognitive ability is lowered by administering a cognitive inhibitor can be used, and as an animal model for improving cognitive function, natural oblivion occurs over time.
- the natural oblivion model can be used.
- an animal model in which cognitive ability is lowered by treatment with dizocilpine (MK-801) is a model widely used as a means to verify drug efficacy for the development of therapeutic agents for cognitive disorders (NMWJ de Bruin et al., Neurobiology of learning and memory , 2016, Vol. 133, p. 100-117).
- the natural oblivion rat model is also used as a means to verify drug efficacy for the development of cognitive function improvement (MV King et al., Neuropharmacology 47 (2004) 195-204 ) .
- the dosage of the imidazopyrimidine or imidazotriazine compound of Formula 1 for the prevention, alleviation or treatment of the disease will generally vary depending on the severity of the disease, the body weight and the metabolic state of the subject to be treated.
- a "therapeutically effective amount" for an individual patient means an amount sufficient to achieve the aforementioned pharmacological effect, ie a therapeutic effect.
- the therapeutically effective amount of the compound of formula 1 when administered to mammals, including humans, 0.1 to 500 mg/kg (body weight) per day, preferably 0.5 to 100 mg/kg (body weight), may be included in the pharmaceutical composition, and these pharmaceutical compositions are administered in divided doses once or twice a day Can be.
- the compounds of the present invention can be administered by conventional methods used for administration of therapeutic agents, such as oral, parenteral, intravenous, intramuscular, subcutaneous or rectal administration.
- the pharmaceutical or pharmaceutical composition according to an embodiment of the present invention comprises a therapeutically effective amount of an imidazopyrimidine or imidazotriazine compound of the present invention, a pharmaceutically acceptable salt, solvate, hydrate, and combinations thereof. It may include a compound selected from the group consisting of.
- the pharmaceutically acceptable salts include addition salts of acids or bases and stereochemically isomeric forms thereof.
- the salt includes any salt that maintains the activity of the parent compound in the object to be administered and does not cause undesirable effects, and is not particularly limited.
- Such salts include inorganic and organic salts, for example acetic acid, nitric acid, aspartic acid, sulfonic acid, sulfonic acid, maleic acid, glutamic acid, formic acid, succinic acid, phosphoric acid, phthalic acid, tannic acid, tartaric acid, hydrobromic acid.
- alkali and alkaline earth metal salts such as ammonium salt, lithium salt, sodium salt, potassium salt, magnesium salt and calcium salt, for example, benzathine, N-methyl-D- And salts with organic bases such as glucamine and hydrabamine salts, and salts with amino acids such as arginine and lysine.
- the salt form can also be converted to the free form by treatment with a suitable base or acid.
- additional salt includes a compound of formula 1 and a solvate which salts thereof may form. Such solvates are, for example, hydrates, alcoholates.
- the pharmaceutical or pharmaceutical composition according to an embodiment of the present invention may be for oral administration or parenteral administration, and preferably may be for oral administration.
- parenteral administration it may be for parenteral administration such as intravenous injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, endothelial administration, topical administration, intranasal administration, vaginal administration, intrapulmonary administration, or rectal administration.
- parenteral administration the pharmaceutical or pharmaceutical composition of the present invention is formulated in the form of powders, granules, tablets, pills, dragees, capsules, solutions, gels, syrups, suspensions, wafers, etc. according to methods known in the art. It can be angry.
- the pharmaceutical composition according to one embodiment may be formulated as an uncoated tablet, or coated with an active agent or to be protected from degradation in the stomach.
- the composition may be administered by any device capable of moving the active substance to the target cell.
- the route of administration may vary depending on the general condition and age of the subject to be treated, the nature of the treatment condition and the active ingredient selected.
- a suitable dosage of the drug or pharmaceutical composition according to an embodiment of the present invention may include formulation method, mode of administration, age, weight, sex, pathological condition, food, administration time, route of administration, excretion rate, and response sensitivity. It varies by factors, and usually a skilled practitioner can easily determine and prescribe an effective dosage for the desired treatment or prophylaxis.
- the pharmaceutical composition according to an embodiment may be administered in one or several doses, for example, it may be administered once to four times a day.
- the pharmaceutical composition according to an embodiment may contain 0.1 to 500 mg/kg (body weight) of the compound of Formula 1, preferably 0.5 to 100 mg/kg (body weight).
- the drug or pharmaceutical composition according to an embodiment of the present invention is prepared by using a pharmaceutically acceptable carrier and/or excipient according to a method that can be easily carried out by a person having ordinary knowledge in the art. It can be prepared in a unit dosage form by formulation, or can be prepared by incorporating it into a multi-dose container.
- the formulation may be in the form of a solution, suspension, or emulsion in an oil or aqueous medium, or may be in the form of an extract, powder, granule, tablet or capsule, and may additionally include a dispersant or a stabilizer.
- the pharmaceutical composition may be administered in the form of a suppository, spray, ointment, cream, gel, inhalant or skin patch.
- the pharmaceutical composition may be prepared for mammalian administration, more preferably for human administration.
- Pharmaceutically acceptable carriers may be solid or liquid, and excipients, antioxidants, buffers, bacteriostatic agents, dispersants, adsorbents, surfactants, binders, preservatives, disintegrants, sweetening agents, flavoring agents, lubricants, release controlling agents, wetting agents, It may be one or more selected from stabilizers, suspending agents and lubricants.
- the pharmaceutically acceptable carrier may be selected from saline, sterile water, Ringer's solution, buffered saline, dextrose solution, maltodextrin solution, glycerol, ethanol, and mixtures thereof.
- suitable fillers include sugars (e.g. dextrose, sucrose, maltose and lactose), starches (e.g. corn starch), sugar-alcohols (e.g. mannitol, sorbitol, maltitol, erythritol and Xylitol), starch hydrolysates (eg, dextrin and maltodextrin), cellulose or cellulose derivatives (eg, microcrystalline cellulose), or mixtures thereof, but are not limited thereto.
- sugars e.g. dextrose, sucrose, maltose and lactose
- starches e.g. corn starch
- sugar-alcohols e.g. mannitol, sorbitol, maltitol, erythritol and Xylitol
- starch hydrolysates eg, dextrin and maltodextrin
- cellulose or cellulose derivatives eg, micro
- magnesium aluminum silicate, povidone, copovidone, methylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, gelatin, gums, water Cross, starch paste, or a mixture thereof may be used, but is not limited thereto.
- suitable preservatives include benzoic acid, sodium benzoate, benzyl alcohol, butylated hydroxyanisole, butylated hydroxytoluene, chlorbutol, gallate, hydroxybenzoate, EDTA, or mixtures thereof. May be used, but is not limited thereto.
- starch glycolate sodium salt cross-linked polyvinyl pyrrolidone, cross-linked carboxymethylcellulose, starch, microcrystalline cellulose, or a mixture thereof may be used. However, it is not limited thereto.
- sucralose as a suitable sweetening agent, sucralose, saccharin, sodium or potassium or calcium saccharin, acesulfame potassium or sodium cyclamate, mannitol, fructose, sucrose, maltose, or a mixture thereof may be used, but Not limited.
- silica, colloidal silicon dioxide, talc, or the like may be used as an appropriate glidant, but is not limited thereto.
- long-chain fatty acids and salts thereof such as magnesium stearate and stearic acid, talc, glyceride wax, or mixtures thereof may be used, but are not limited thereto.
- the imidazopyrimidine or imidazotriazine compound of Formula 1 may be used in combination with an additional drug for preventing, alleviating or treating cognitive disorders, or improving cognitive function.
- the pharmaceutical or pharmaceutical composition of the present invention may be a combination preparation comprising the imidazopyrimidine or imidazotriazine compound of Formula 1 and such additional drugs as a therapeutically effective amount of the active ingredient.
- Such additional drugs include, for example, dimethylamylamine, methylphenidate, amphetamine, tacrine, rivastigmine, galantamine, and donepezil ( donepezil), memantine, tolcapone, levodopa, atomoxetine, clonidine, pramipexole, guanfacine and fexofenadine.
- dimethylamylamine, methylphenidate, amphetamine, tacrine, rivastigmine, galantamine, and donepezil ( donepezil) memantine, tolcapone, levodopa, atomoxetine, clonidine, pramipexole, guanfacine and fexofenadine.
- memantine tolcapone
- levodopa atomoxetine
- clonidine clonidine
- pramipexole guanfacine
- the pharmaceutical or pharmaceutical composition according to an embodiment of the present invention is dimethylamylamine, methylphenidate, amphetamine, tacrine, rivastigmine, galantamine, donepezil, memantine, tolcapone, levodopa, atomok It may further include one or more drugs selected from the group consisting of cetin, clonidine, pramipexole, guanfacin, and fexofenadine.
- the blending weight ratio (a:b) of component (b)] is, for example, 1,000:1 to 1:1,000, or 500:1 to 1:500, or 100:1 to 1:100, or 50:1 to 1: 50, or may be in the range of 10:1 to 1:10, but is not limited thereto.
- treat As used herein, the terms “treat”, “treating” and “treatment” are to eliminate all or part of the disease and/or its accompanying symptoms.
- the term "subject” is an animal, preferably a mammal (e.g., primates (e.g., humans), cattle, sheep, goats, horses, dogs , Cat, rabbit, rat, mouse, etc.), most preferably human.
- primates e.g., humans
- cattle, sheep, goats horses, dogs , Cat, rabbit, rat, mouse, etc.
- most preferably human most preferably human.
- the term "therapeutically effective amount” is sought by a researcher, veterinarian, physician or other clinician, and includes alleviating the symptoms of the disease or disorder being treated. It means the amount of active compound or pharmaceutical agent that induces a reaction.
- composition includes products comprising a specified amount of the specified ingredients and any product produced directly or indirectly from a combination of the specified amounts of the specified ingredient.
- cogntive disorder refers to the cognitive function or cognitive domain of an animal, such as working memory, attention and arousal, language learning and memory, visual learning and memory, reasoning and problem solving, For example, it refers to impairments that indicate atrophy in executive function, task processing speed, and/or social cognition.
- cognitive impairments include attention deficit, unorganized thinking, slow thinking, difficulty understanding, low concentration, loss of ability to solve problems, poor memory, difficulty expressing thoughts and/or difficulty in integrating thinking, sensory and behavior, or inadequate It is known to indicate the difficulty of erasing accidents, and can be used interchangeably with the term “cognitive deficit”.
- the pharmaceuticals and pharmaceutical compositions according to the present invention can effectively prevent, alleviate or treat cognitive disorders, or improve cognitive function.
- FIG. 1 is a result showing the effect of test compounds (0.03, 0.1, 0.3 mg/kg) on an object recognition test in a rat model whose cognitive ability was degraded by disosilpin treatment.
- Figure 2 is a result showing the effect of the test compound (0.1, 0.3, 1 mg/kg) on the Y-maze test in a rat model whose cognitive ability is lowered by disosilpin treatment.
- 3 is a result showing the effect of a test compound (0.1, 0.3 mg/kg) on an object recognition test in a rat model for natural forgetting.
- Example 1 Effect on object recognition test in rat model with reduced cognitive ability by disosilpin treatment
- an animal model for cognitive impairment an animal model in which cognitive ability was decreased by administration of a cognitive inhibitor, dizosilpine, was used.
- mice Male rats (Wistar, 4 weeks old, Orient Bio Co., Ltd.) were purchased and bred acclimated for at least 1 week in an animal breeding room. Experimental animals were raised in a controlled environment (12 hours of illumination/12 hours of non-illumination) and maintained at 19 to 25°C and relative humidity of 30 to 70%, and in an environment where water and food can be freely ingested, the Animal Experiment Ethics Committee (Institutional Animal Care and Use Committee (IACUC)) in accordance with the laboratory animal care standards, it was stored and managed. Rats were stabilized for more than a week and then used for object recognition tests. Rats were randomly divided into groups and the test was performed under lighting.
- IACUC Institutionional Animal Care and Use Committee
- NMDA N-methyl-D-aspartate
- Dizosilpine (purchased from Sigma) was newly prepared by dissolving in physiological saline used as a vehicle, and 30 minutes before training, a dose of 0.1 mg/kg was administered subcutaneously in a volume of 1 ml per 1 kg of rat body weight. As a control group, only physiological saline was administered.
- test compound was dissolved in 5% DMSO (dimethyl sulfoxide) in 10% Cremophor, and in a volume of 1 ml per 1 kg of rat body weight, 0.03, 0.1, 0.3 mg/kg doses were administered orally 1 hour before training. Became. As a control, only vehicle (5% DMSO in 10% Cremophor) was administered.
- 5% DMSO dimethyl sulfoxide
- the rats were each handled by the experimenter for at least 3 minutes, and the box acclimation for 3 minutes was performed twice in an empty box before the experiment.
- the rats were trained in a box.
- the training was carried out by exposure to two identical plastic cylinders or a box of stainless steel square pyramids.
- One hour after training, the test was conducted in a box containing one plastic cylinder and one stainless steel square pyramid.
- the time the rats explored each object was measured. Rats trained in a box with two plastic cylinders used a stainless steel pyramid as a new object, and a rat trained in a box with two stainless steel cylinders had a plastic cylinder.
- the test results were analyzed with a new object.
- the recognition index was calculated based on the time the object was searched, and the data on the cognitive index between groups were analyzed by one-way analysis of variance (ANOVA) and Dunnett's multiple comparison test, and p. In the case of ⁇ 0.05, the effect was defined as significant. All results were expressed as mean values ⁇ SEM.
- the cognitive index of the negative control group treated with only dizosilpine was 49.77 ⁇ 1.03 seconds, and a significant decrease in cognitive function was observed compared to the cognitive index of 63.29 ⁇ 1.56 seconds in the positive control vehicle group (P ⁇ 0.001).
- the test compound was administered to disosilpine, significant recovery of cognitive function was observed in the 0.1 mg/kg administration group and the 0.3 mg/kg administration group, respectively, in 57.95 ⁇ 1.8 seconds and 57.62 ⁇ 1.89 seconds compared to the negative control group whose cognitive function was degraded. Showed (all P ⁇ 0.01).
- Table 1 summarizes the results of the analysis of the cognitive index of the test compound for the object recognition test in the rat model whose cognitive ability was degraded by disosilpin treatment.
- Example 2 Effect on the Y-shaped maze experiment in a rat model with reduced cognitive ability by disosilpin treatment
- Rats Male rats (Wistar, 4 weeks old, Orient Bio Co., Ltd.) were purchased and bred acclimated for at least 1 week in an animal breeding room. Experimental animals were raised in a controlled environment (12 hours of illumination/12 hours of non-illumination) and maintained at 19 to 25°C and relative humidity of 30 to 70%, and in an environment where water and food can be freely ingested, the Animal Experiment Ethics Committee It was stored and managed according to the laboratory animal care standards of. Rats were stabilized for more than a week and then used in a Y-shaped maze experiment. Rats were randomly divided into groups and the test was performed under lighting.
- Dizosilpine (purchased from Sigma) was newly prepared by dissolving in physiological saline used as a vehicle, and 30 minutes before training, a dose of 0.1 mg/kg was administered subcutaneously in a volume of 1 ml per 1 kg of rat body weight. As a control group, only physiological saline was administered.
- test compound was dissolved in 5% DMSO in 9.5% Cremophor, and was administered orally 1 hour before training in a volume of 5 ml per 1 kg of rat body weight, 0.1, 0.3, and 1 mg/kg dose.
- 5% DMSO in vehicle (9.5% Cremophor) was administered.
- the rats were handled by the experimenter for 3 minutes for 2 days, and the Y-shaped maze experiment was conducted the next day.
- a vehicle or test compound was administered intraperitoneally 1 hour before the experiment, and vehicle or dizosilpine was administered subcutaneously 30 minutes before the experiment, and then the rat was placed at the end of one arm in the Y-shaped maze. It was allowed to move and lasted for 5 minutes.
- the three arms positioned at the same angle in the Y-shaped maze were 45 cm long, 10 cm wide, and 20 cm high. The case of rats visiting three different cancers in succession was defined as an alternation behavior.
- the alternation rate was calculated by grasping the alternation behavior based on the visit record of each arm of the rat, and the data on the alternation rate between groups were analyzed by one-way ANOVA and Dunnett's multiple comparison method. When p ⁇ 0.05, the effect was defined as significant. All results were expressed as mean values ⁇ SEM.
- the shift ratio of the negative control group treated with only dizosilpine was 49.2 ⁇ 5.3 seconds, and a significant decrease in cognitive function was observed compared to the shift ratio of 70.1 ⁇ 2.8 seconds in the positive control vehicle group (P ⁇ 0.001).
- the shift ratio to the 0.1 mg/kg administration group was 67.3 ⁇ 3.5 seconds, which showed a significant recovery of cognitive function compared to the negative control group with decreased cognitive function (P ⁇ 0.001).
- the alternating ratio of the test compound 0.3 mg/kg administration group was 57.3 ⁇ 5.7 seconds, showing a tendency toward recovery of cognitive function when compared to the control group with decreased cognitive function.
- Table 2 summarizes the results of the analysis of the shift ratio of the test compound to the Y-shaped maze experiment in the rat model with reduced cognitive ability by disosilpin treatment.
- Example 3 Effect on object recognition test in rat model in which natural oblivion occurred
- Rats Male rats (Wistar, 4 weeks old, Orient Bio Co., Ltd.) were purchased and bred acclimated for at least 1 week in an animal breeding room. Experimental animals were raised in a controlled environment (12 hours of illumination/12 hours of non-illumination) and maintained at 19 to 25°C and relative humidity of 30 to 70%, and in an environment where water and food can be freely ingested, the Animal Experiment Ethics Committee It was stored and managed according to the laboratory animal care standards of. Rats were stabilized for more than a week and then used for object recognition tests. Rats were randomly divided into groups and the trial was conducted under lighting.
- test compound was dissolved in 5% DMSO in 10% cremophor and administered orally at a dose of 1 mg/kg 1 hour before training.
- vehicle only 5% DMSO in 10% Cremophor was administered.
- the rats were each handled by the experimenter for at least 3 minutes, and the box acclimation for 3 minutes was performed twice in an empty box before the experiment.
- the rats were put in a box and trained.
- the training was carried out by exposure to two identical plastic cylinders or a box of stainless steel square pyramids.
- the test was carried out in a box containing one plastic cylinder and one stainless steel square pyramid.
- the time the rats explored each object was measured, and the rat trained in a box with two plastic cylinders used a stainless steel pyramid as a new object, and the rat trained in a box with two stainless steel cones was a plastic cylinder.
- the test results were analyzed.
- Cognitive index was calculated based on the time of searching for the object, and the data on the cognitive index between groups were analyzed by one-way ANOVA and Dunnett's multiple comparison method, and the effect was defined as significant when p ⁇ 0.05. All results were expressed as mean values ⁇ SEM.
- the cognitive index in the vehicle group as the control group was 48.61 ⁇ 1.87 seconds, and there is no difference from the cognitive index 50 when searching for the exact same time period without distinguishing between an existing object and a new object. During the period, it was confirmed that sufficient natural oblivion occurred.
- the cognitive indices were 56.57 ⁇ 2.37 seconds and 59.77 ⁇ 2.64 seconds, respectively, showing a significant difference compared to the control group in which natural oblivion occurred (P ⁇ 0.05, P ⁇ , respectively) 0.01).
- Table 3 summarizes the results of the cognitive index analysis of the test compound (0.1 mg/kg, 0.3 mg/kg) for the object recognition test in the rat model in which natural oblivion occurred.
- the cognitive index in the vehicle group which is the control group, is 51.20 ⁇ 2.61 seconds, and there is no difference from the cognitive index 50, which is the case of searching for the exact same time without distinguishing between an existing object and a new object. During the period, it was confirmed that sufficient natural oblivion occurred.
- the cognitive index was 60.91 ⁇ 2.72 seconds, which was a significant difference compared to the control group in which natural oblivion occurred (P ⁇ 0.01), and the cognitive index was 56.20 ⁇ in the group administered with the test compound 3 mg/kg. It shows that natural forgetting is alleviated when compared to the control group in which natural forgetting occurred in 2.27 seconds.
- Table 4 summarizes the results of the cognitive index analysis of the test compounds (1 mg/kg, 3 mg/kg) for the object recognition test in the rat model in which natural oblivion occurred.
- test compound has a mitigating effect on natural forgetting by improving cognitive function in a normal cognitive state.
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Description
Claims (45)
- 치료학적 유효량의 하기 화학식 1의 이미다조피리미딘 또는 이미다조트리아진 화합물, 또는 이의 약제학적으로 허용가능한 염, 용매화물 또는 수화물을 포함하는, 인지 장애의 예방, 경감 또는 치료용, 또는 인지 기능 향상용 약제:[화학식 1]상기 화학식 1에서,X는 CH 또는 N이고;Z는 O 또는 S이며;R1은 할로, C1-C5 알킬, C1-C5 알콕시, C1-C5 알킬티오, 아미노, 디(C1-C5 알킬)아미노, 시아노, 포르밀, 할로-C1-C5 알킬, 히드록시-C1-C5 알킬, C1-C5 알콕시-C1-C5 알킬, 카바모일옥시-C1-C5 알킬, C1-C5 알킬-C(O)O-C1-C5 알킬, N, O 및 S로부터 선택되는 1-3개의 헤테로원자를 갖는 5 또는 6원 헤테로사이클로알킬-C1-C5 알킬 및 디(C1-C5 알킬)아미노-C1-C5 알킬로부터 선택되는 하나 이상의 치환기로 치환되거나 비치환된 C6-C12 아릴; 또는 할로, 히드록시, C1-C5 알킬, C1-C5 알콕시 및 할로-C1-C5 알킬로부터 선택되는 하나 이상의 치환기로 치환되거나 비치환된, N, O 및 S로부터 선택되는 1-5개의 헤테로원자를 갖는 5 내지 12원 불포화 헤테로사이클릴이고;R2는 할로, 중수소, 히드록시 및 C1-C5 알킬로부터 선택되는 하나 이상의 치환기로 치환되거나 비치환된 C6-C12 아릴; 또는 할로 및 C1-C5 알킬로부터 선택되는 하나 이상의 치환기로 치환되거나 비치환된, N, O 및 S로부터 선택되는 1-3개의 헤테로원자를 갖는 5 내지 12원 불포화 헤테로사이클릴이다.
- 제1항에 있어서, 상기 R1이 할로, 히드록시, C1-C5 알킬, C1-C5 알콕시, C1-C5 알킬티오, 아미노, 디(C1-C5 알킬)아미노, 시아노, 포르밀, 할로-C1-C5 알킬, 히드록시-C1-C5 알킬, C1-C5 알콕시-C1-C5 알킬, 카바모일옥시-C1-C5 알킬 및 C1-C5 알킬-C(O)O-C1-C5 알킬로부터 선택되는 1 내지 3개의 치환기로 치환되거나 비치환된 페닐; 또는 할로, 히드록시, C1-C5 알킬, C1-C5 알콕시 및 할로-C1-C5 알킬로부터 선택되는 1 내지 3개의 치환기로 치환되거나 비치환된, N, O 및 S로부터 선택되는 1-3개의 헤테로원자를 갖는 5 내지 10원 불포화 헤테로사이클릴인 것을 특징으로 하는 약제.
- 제1항에 있어서, 상기 R2가 할로, 중수소, 히드록시 및 C1-C5 알킬로부터 선택되는 1 내지 5개의 치환기로 치환되거나 비치환된 페닐; 또는 할로 및 C1-C5 알킬로부터 선택되는 1 내지 3개의 치환기로 치환되거나 비치환된, N, O 및 S로부터 선택되는 1-3개의 헤테로원자를 갖는 5 또는 6원 헤테로아릴인 것을 특징으로 하는 약제.
- 제1항에 있어서,상기 X는 CH 또는 N이고;상기 Z는 O이며;상기 R1은 할로, 히드록시, C1-C5 알킬, C1-C5 알콕시, C1-C5 알킬티오, 아미노, 디(C1-C5 알킬)아미노, 시아노, 포르밀, 할로-C1-C5 알킬, 히드록시-C1-C5 알킬, C1-C5 알콕시-C1-C5 알킬, 카바모일옥시-C1-C5 알킬 및 C1-C5 알킬-C(O)O-C1-C5 알킬로부터 선택되는 1 내지 3개의 치환기로 치환되거나 비치환된 페닐; 또는 할로, 히드록시, C1-C5 알킬, C1-C5 알콕시 및 할로-C1-C5 알킬로부터 선택되는 1 또는 2개의 치환기로 치환되거나 비치환된, N, O 및 S로부터 선택되는 1 또는 2개의 헤테로원자를 갖는 5 내지 9원 불포화 헤테로사이클릴이고;상기 R2는 할로, 중수소, 히드록시 및 C1-C5 알킬로부터 선택되는 1 내지 5개의 치환기로 치환되거나 비치환된 페닐; 또는 할로 및 C1-C5 알킬로부터 선택되는 1 또는 2개의 치환기로 치환되거나 비치환된, 1 또는 2개의 질소원자를 갖는 6원 헤테로아릴인 것을 특징으로 하는 약제.
- 제1항에 있어서,상기 R1은 할로, 히드록시, C1-C5 알킬, C1-C5 알콕시, C1-C5 알킬티오, 아미노, 디(C1-C5 알킬)아미노, 시아노, 포르밀, 할로-C1-C5 알킬, 히드록시-C1-C5 알킬, C1-C5 알콕시-C1-C5 알킬, 카바모일옥시-C1-C5 알킬 및 C1-C5 알킬-C(O)O-C1-C5 알킬로부터 선택되는 1 내지 3개의 치환기로 치환되거나 비치환된 페닐; 1개 또는 2개의 할로로 치환되거나 비치환된 1,3-벤조디옥솔일; 또는 할로, 히드록시, C1-C5 알킬, C1-C5 알콕시 및 할로-C1-C5 알킬로부터 선택되는 1 또는 2개의 치환기로 치환되거나 비치환된 피리딜 또는 피리미디닐이고,상기 R2는 할로, 중수소, 히드록시 및 C1-C5 알킬로부터 선택되는 1 내지 5개의 치환기로 치환되거나 비치환된 페닐; 또는 할로 및 C1-C5 알킬로부터 선택되는 1 또는 2개의 치환기로 치환되거나 비치환된 피리딜인 것을 특징으로 하는 약제.
- 제1항에 있어서,상기 X는 CH이고;상기 Z는 O이며;상기 R1은 할로, 히드록시, C1-C5 알킬, C1-C5 알콕시, C1-C5 알킬티오, 아미노, 할로-C1-C5 알킬, 히드록시-C1-C5 알킬 및 C1-C5 알콕시-C1-C5 알킬로부터 선택되는 1 내지 3개의 치환기로 치환되거나 비치환된 페닐이고;상기 R2는 할로 및 C1-C5 알킬로부터 선택되는 1 또는 2개의 치환기로 치환되거나 비치환된 피리딜인 것을 특징으로 하는 약제.
- 제항에 있어서, 화학식 1의 이미다조피리미딘 또는 이미다조트리아진 화합물이 다음의 화합물로부터 선택되는 것을 특징으로 하는 약제:6-(4-플루오로페닐)-2-(피리딘-2-일옥시메틸)이미다조[1,2-a]피리미딘;6-[4-플루오로-2-(트리플루오로메틸)페닐]-2-(2-피리딜옥시메틸)이미다조[1,2-a]피리미딘;6-(4-플루오로-2-메틸-페닐)-2-[(5-플루오로-2-피리딜)옥시메틸)이미다조[1,2-a]피리미딘;6-(4-플루오로페닐)-2-[(5-플루오로-2-피리딜)옥시메틸)이미다조[1,2-a]피리미딘;[5-플루오로-2-[2-(2-피리딜옥시메틸)이미다조[1,2-a]피리미딘-6-일]페닐]메탄올; 및6-[4-플루오로-2-(플루오로메틸)페닐]-2-(2-피리딜옥시메틸)이미다조[1,2-a] 피리미딘.
- 제1항에 있어서, 인지 장애 증상에 대한 예방, 경감 또는 치료에 사용되는 약제.
- 제8항에 있어서, 인지 장애 증상이 주의력 저하, 언어능력 저하, 시공간능력 저하, 추리능력 저하 또는 판단력 저하인 약제.
- 제1항에 있어서, 인지 장애와 관련된 질환의 경감 또는 치료에 사용되는 약제.
- 제10항에 있어서, 인지 장애와 관련된 질환은 경도 인지 장애(mild cognitive impairment), 알츠하이머병(Alzheimer's disease), 알츠하이머형 치매(Alzheimer type dementia), 초로성 치매(presenile dementia), 초기 발병 알츠하이머병(early onset Alzheimer's disease), 노인성 치매(senile dementia), 루이소체 치매(Lewy body corpuscle dementia), 미세 경색 치매(micro-infarct dementia), AIDS-관련 치매(AIDS-related dementia), HIV-치매(HIV-dementia), 루이체 관련된 치매(dementia associated with Lewy bodies), 다운 증후군 관련된 치매(Down's syndrome associated dementia), 피크병(Pick's disease), 조기 기억 상실 장애(recent short-term memory impairment), 나이-관련 인지 장애(age-associated cognitive disorder), 나이 관련 기억 손상(age associated memory impairment), 약물-관련 인지 장애(drug-associated cognitive disorder), 면역 결핍 증후군과 관련된 인지 장애(immunodeficiency syndrome-associated cognitive disorder), 혈관질환과 관련된 인지 장애(vascular disease-associated cognitive impairment), 정신 분열증과 관련된 인지 장애(cognitive impairment associated with schizophrenia), 파킨슨병과 관련된 인지 장애(Parkinson's disease-associated cognitive impairment), 뇌전증과 관련된 인지 장애(cognitive disorders associated with epilepsy), 우울증과 관련된 인지 장애(depression-associated cognitive disorder), 양극성 장애와 관련된 인지 장애(cognitive disorders associated with bipolar dosorder), 강박 장애와 관련된 인지 장애(obsessive compulsive disorder-associated cognitive disorder), 외상 후 스트레스 장애(post-traumatic stress disorder), 주의력 결핍 장애(attention deficit disorder), 주의력 결핍 과잉 행동 장애(attention deficit hyperactivity disorder) 및 학습 결핍증(learning deficit disorder)로 이루어진 군으로부터 선택되는 약제.
- 제11항에 있어서, 인지 장애와 관련된 질환은 경도 인지 장애, 알츠하이머병, 알츠하이머형 치매, 초로성 치매, 초기 발병 알츠하이머병, 노인성 치매, 조기 기억 상실 장애, 나이-관련 인지 장애, 나이 관련 기억 손상, 약물 관련 인지 장애 및 정신분열증과 관련된 인지 장애로 이루어진 군으로부터 선택되는 약제.
- 제1항에 있어서, 포유 동물 투여용으로 제조된 것인 약제.
- 제1항에 있어서, 0.1 내지 500 mg/㎏(체중)의 화학식 1의 이미다조피리미딘 또는 이미다조트리아진 화합물을 포함하는 약제.
- 제1항에 있어서, 경구 투여용, 또는 정맥내 주입, 피하 주입, 근육 주입, 복강 주입, 내피 투여, 국소 투여, 비내 투여, 질내 투여, 폐내 투여 및 직장내 투여로 이루어진 군으로부터 선택되는 비경구 투여용인 약제.
- 제1항에 있어서, 디메틸아밀아민, 메틸페니데이트, 암페타민, 타크린, 리바스티그민, 갈란타민, 도네페질, 메만틴, 톨카폰, 레보도파, 아토목세틴, 클로니딘, 프라미펙솔, 구안파신 및 펙소페나딘으로 이루어진 군으로부터 선택된 하나 이상의 약물을 더 포함하는 약제.
- 치료학적 유효량의 하기 화학식 1의 이미다조피리미딘 또는 이미다조트리아진 화합물, 또는 이의 약제학적으로 허용가능한 염, 용매화물 또는 수화물을 포함하고, 추가로 약제학적으로 허용되는 담체를 1종 이상 포함하는, 인지 장애의 예방, 경감 또는 치료용, 또는 인지 기능 향상용 약제학적 조성물:[화학식 1]상기 화학식 1에서,X는 CH 또는 N이고;Z는 O 또는 S이며;R1은 할로, C1-C5 알킬, C1-C5 알콕시, C1-C5 알킬티오, 아미노, 디(C1-C5 알킬)아미노, 시아노, 포르밀, 할로-C1-C5 알킬, 히드록시-C1-C5 알킬, C1-C5 알콕시-C1-C5 알킬, 카바모일옥시-C1-C5 알킬, C1-C5 알킬-C(O)O-C1-C5 알킬, N, O 및 S로부터 선택되는 1-3개의 헤테로원자를 갖는 5 또는 6원 헤테로사이클로알킬-C1-C5 알킬 및 디(C1-C5 알킬)아미노-C1-C5 알킬로부터 선택되는 하나 이상의 치환기로 치환되거나 비치환된 C6-C12 아릴; 또는 할로, 히드록시, C1-C5 알킬, C1-C5 알콕시 및 할로-C1-C5 알킬로부터 선택되는 하나 이상의 치환기로 치환되거나 비치환된, N, O 및 S로부터 선택되는 1-5개의 헤테로원자를 갖는 5 내지 12원 불포화 헤테로사이클릴이고;R2는 할로, 중수소, 히드록시 및 C1-C5 알킬로부터 선택되는 하나 이상의 치환기로 치환되거나 비치환된 C6-C12 아릴; 또는 할로 및 C1-C5 알킬로부터 선택되는 하나 이상의 치환기로 치환되거나 비치환된, N, O 및 S로부터 선택되는 1-3개의 헤테로원자를 갖는 5 내지 12원 불포화 헤테로사이클릴이다.
- 제17항에 있어서, 인지 장애 증상에 대한 예방, 경감 또는 치료에 사용되는 약제학적 조성물.
- 제18항에 있어서, 인지 장애 증상이 주의력 저하, 언어능력 저하, 시공간능력 저하, 추리능력 저하 또는 판단력 저하인 약제학적 조성물.
- 제17항에 있어서, 인지 장애와 관련된 질환의 경감 또는 치료에 사용되는 약제학적 조성물.
- 제20항에 있어서, 인지 장애와 관련된 질환은 경도 인지 장애(mild cognitive impairment), 알츠하이머병(Alzheimer's disease), 알츠하이머형 치매(Alzheimer type dementia), 초로성 치매(presenile dementia), 초기 발병 알츠하이머병(early onset Alzheimer's disease), 노인성 치매(senile dementia), 루이소체 치매(Lewy body corpuscle dementia), 미세 경색 치매(micro-infarct dementia), AIDS-관련 치매(AIDS-related dementia), HIV-치매(HIV-dementia), 루이체 관련된 치매(dementia associated with Lewy bodies), 다운 증후군 관련된 치매(Down's syndrome associated dementia), 피크병(Pick's disease), 조기 기억 상실 장애(recent short-term memory impairment), 나이-관련 인지 장애(age-associated cognitive disorder), 나이 관련 기억 손상(age associated memory impairment), 약물-관련 인지 장애(drug-associated cognitive disorder), 면역 결핍 증후군과 관련된 인지 장애(immunodeficiency syndrome-associated cognitive disorder), 혈관질환과 관련된 인지 장애(vascular disease-associated cognitive impairment), 정신 분열증과 관련된 인지 장애(cognitive impairment associated with schizophrenia), 파킨슨병과 관련된 인지 장애(Parkinson's disease-associated cognitive impairment), 뇌전증과 관련된 인지 장애(cognitive disorders associated with epilepsy), 우울증과 관련된 인지 장애(depression-associated cognitive disorder), 양극성 장애와 관련된 인지 장애(cognitive disorders associated with bipolar dosorder), 강박 장애와 관련된 인지 장애(obsessive compulsive disorder-associated cognitive disorder), 외상 후 스트레스 장애(post-traumatic stress disorder), 주의력 결핍 장애(attention deficit disorder), 주의력 결핍 과잉 행동 장애(attention deficit hyperactivity disorder) 및 학습 결핍증(learning deficit disorder)로 이루어진 군으로부터 선택되는 약제학적 조성물.
- 제21항에 있어서, 인지 장애와 관련된 질환은 경도 인지 장애, 알츠하이머병, 알츠하이머형 치매, 초로성 치매, 초기 발병 알츠하이머병, 노인성 치매, 조기 기억 상실 장애, 나이-관련 인지 장애, 나이 관련 기억 손상, 약물 관련 인지 장애 및 정신분열증과 관련된 인지 장애로 이루어진 군으로부터 선택되는 약제학적 조성물.
- 제17항에 있어서, 포유 동물 투여용으로 제조된 것인 약제학적 조성물.
- 제17항에 있어서, 0.1 내지 500 mg/㎏(체중)의 화학식 1의 이미다조피리미딘 또는 이미다조트리아진 화합물을 포함하는 약제학적 조성물.
- 제17항에 있어서, 경구 투여용, 또는 정맥내 주입, 피하 주입, 근육 주입, 복강 주입, 내피 투여, 국소 투여, 비내 투여, 질내 투여, 폐내 투여 및 직장내 투여로 이루어지는 군으로부터 선택되는 비경구 투여용인 것인 약제학적 조성물.
- 제17항에 있어서, 약제학적으로 허용되는 담체가 부형제, 항산화제, 완충액, 정균제, 분산제, 흡착제, 계면활성제, 결합제, 방부제, 붕해제, 감미제, 향미제, 활택제, 방출조절제, 습윤제, 안정화제, 현탁화제 및 윤활제에서 선택되는 1종 이상인 약제학적 조성물.
- 제17항에 있어서, 디메틸아밀아민, 메틸페니데이트, 암페타민, 타크린, 리바스티그민, 갈란타민, 도네페질, 메만틴, 톨카폰, 레보도파, 아토목세틴, 클로니딘, 프라미펙솔, 구안파신 및 펙소페나딘으로 이루어진 군으로부터 선택된 하나 이상의 약물을 더 포함하는 약제학적 조성물.
- 치료학적 유효량의 하기 화학식 1의 이미다조피리미딘 또는 이미다조트리아진 화합물, 또는 이의 약제학적으로 허용가능한 염, 용매화물 또는 수화물을 대상체에 투여하는 것을 포함하는, 대상체에서 인지 장애의 예방, 경감 또는 치료, 또는 인지 기능 향상을 하는 방법:[화학식 1]상기 화학식 1에서,X는 CH 또는 N이고;Z는 O 또는 S이며;R1은 할로, C1-C5 알킬, C1-C5 알콕시, C1-C5 알킬티오, 아미노, 디(C1-C5 알킬)아미노, 시아노, 포르밀, 할로-C1-C5 알킬, 히드록시-C1-C5 알킬, C1-C5 알콕시-C1-C5 알킬, 카바모일옥시-C1-C5 알킬, C1-C5 알킬-C(O)O-C1-C5 알킬, N, O 및 S로부터 선택되는 1-3개의 헤테로원자를 갖는 5 또는 6원 헤테로사이클로알킬-C1-C5 알킬 및 디(C1-C5 알킬)아미노-C1-C5 알킬로부터 선택되는 하나 이상의 치환기로 치환되거나 비치환된 C6-C12 아릴; 또는 할로, 히드록시, C1-C5 알킬, C1-C5 알콕시 및 할로-C1-C5 알킬로부터 선택되는 하나 이상의 치환기로 치환되거나 비치환된, N, O 및 S로부터 선택되는 1-5개의 헤테로원자를 갖는 5 내지 12원 불포화 헤테로사이클릴이고;R2는 할로, 중수소, 히드록시 및 C1-C5 알킬로부터 선택되는 하나 이상의 치환기로 치환되거나 비치환된 C6-C12 아릴; 또는 할로 및 C1-C5 알킬로부터 선택되는 하나 이상의 치환기로 치환되거나 비치환된, N, O 및 S로부터 선택되는 1-3개의 헤테로원자를 갖는 5 내지 12원 불포화 헤테로사이클릴이다.
- 제28항에 있어서, 인지 장애 증상에 대한 예방, 경감 또는 치료를 하는 방법.
- 제29항에 있어서, 인지 장애 증상이 주의력 저하, 언어능력 저하, 시공간능력 저하, 추리능력 저하 또는 판단력 저하인 방법.
- 제28항에 있어서, 인지 장애와 관련된 질환의 경감 또는 치료를 하는 방법.
- 제31항에 있어서, 인지 장애와 관련된 질환은 경도 인지 장애(mild cognitive impairment), 알츠하이머병(Alzheimer's disease), 알츠하이머형 치매(Alzheimer type dementia), 초로성 치매(presenile dementia), 초기 발병 알츠하이머병(early onset Alzheimer's disease), 노인성 치매(senile dementia), 루이소체 치매(Lewy body corpuscle dementia), 미세 경색 치매(micro-infarct dementia), AIDS-관련 치매(AIDS-related dementia), HIV-치매(HIV-dementia), 루이체 관련된 치매(dementia associated with Lewy bodies), 다운 증후군 관련된 치매(Down's syndrome associated dementia), 피크병(Pick's disease), 조기 기억 상실 장애(recent short-term memory impairment), 나이-관련 인지 장애(age-associated cognitive disorder), 나이 관련 기억 손상(age associated memory impairment), 약물-관련 인지 장애(drug-associated cognitive disorder), 면역 결핍 증후군과 관련된 인지 장애(immunodeficiency syndrome-associated cognitive disorder), 혈관질환과 관련된 인지 장애(vascular disease-associated cognitive impairment), 정신 분열증과 관련된 인지 장애(cognitive impairment associated with schizophrenia), 파킨슨병과 관련된 인지 장애(Parkinson's disease-associated cognitive impairment), 뇌전증과 관련된 인지 장애(cognitive disorders associated with epilepsy), 우울증과 관련된 인지 장애(depression-associated cognitive disorder), 양극성 장애와 관련된 인지 장애(cognitive disorders associated with bipolar dosorder), 강박 장애와 관련된 인지 장애(obsessive compulsive disorder-associated cognitive disorder), 외상 후 스트레스 장애(post-traumatic stress disorder), 주의력 결핍 장애(attention deficit disorder), 주의력 결핍 과잉 행동 장애(attention deficit hyperactivity disorder) 및 학습 결핍증(learning deficit disorder)로 이루어진 군으로부터 선택되는 방법.
- 제32항에 있어서, 인지 장애와 관련된 질환은 경도 인지 장애, 알츠하이머병, 알츠하이머형 치매, 초로성 치매, 초기 발병 알츠하이머병, 노인성 치매, 조기 기억 상실 장애, 나이-관련 인지 장애, 나이 관련 기억 손상, 약물 관련 인지 장애 및 정신분열증과 관련된 인지 장애로 이루어진 군으로부터 선택되는 방법.
- 제28항에 있어서, 상기 대상체가 포유 동물인 것을 특징으로 하는 방법.
- 제28항에 있어서, 0.1 내지 500 mg/㎏(체중)의 화학식 1의 이미다조피리미딘 또는 이미다조트리아진 화합물이 투여되는 것을 특징으로 하는 방법.
- 제28항에 있어서, 디메틸아밀아민, 메틸페니데이트, 암페타민, 타크린, 리바스티그민, 갈란타민, 도네페질, 메만틴, 톨카폰, 레보도파, 아토목세틴, 클로니딘, 프라미펙솔, 구안파신 및 펙소페나딘으로 이루어진 군으로부터 선택된 하나 이상의 약물이 추가로 투여되는 것을 특징으로 하는 방법.
- 하기 화학식 1의 이미다조피리미딘 또는 이미다조트리아진 화합물, 또는 이의 약제학적으로 허용가능한 염, 용매화물 또는 수화물의 인지 장애의 예방, 경감 또는 치료, 또는 인지 기능 향상용 용도:[화학식 1]상기 화학식 1에서,X는 CH 또는 N이고;Z는 O 또는 S이며;R1은 할로, C1-C5 알킬, C1-C5 알콕시, C1-C5 알킬티오, 아미노, 디(C1-C5 알킬)아미노, 시아노, 포르밀, 할로-C1-C5 알킬, 히드록시-C1-C5 알킬, C1-C5 알콕시-C1-C5 알킬, 카바모일옥시-C1-C5 알킬, C1-C5 알킬-C(O)O-C1-C5 알킬, N, O 및 S로부터 선택되는 1-3개의 헤테로원자를 갖는 5 또는 6원 헤테로사이클로알킬-C1-C5 알킬 및 디(C1-C5 알킬)아미노-C1-C5 알킬로부터 선택되는 하나 이상의 치환기로 치환되거나 비치환된 C6-C12 아릴; 또는 할로, 히드록시, C1-C5 알킬, C1-C5 알콕시 및 할로-C1-C5 알킬로부터 선택되는 하나 이상의 치환기로 치환되거나 비치환된, N, O 및 S로부터 선택되는 1-5개의 헤테로원자를 갖는 5 내지 12원 불포화 헤테로사이클릴이고;R2는 할로, 중수소, 히드록시 및 C1-C5 알킬로부터 선택되는 하나 이상의 치환기로 치환되거나 비치환된 C6-C12 아릴; 또는 할로 및 C1-C5 알킬로부터 선택되는 하나 이상의 치환기로 치환되거나 비치환된, N, O 및 S로부터 선택되는 1-3개의 헤테로원자를 갖는 5 내지 12원 불포화 헤테로사이클릴이다.
- 제37항에 있어서, 인지 장애 증상에 대한 예방, 경감 또는 치료용 용도.
- 제38항에 있어서, 인지 장애 증상이 주의력 저하, 언어능력 저하, 시공간능력 저하, 추리능력 저하 또는 판단력 저하인 용도.
- 제37항에 있어서, 인지 장애와 관련된 질환의 경감 또는 치료용 용도.
- 제40항에 있어서, 인지 장애와 관련된 질환은 경도 인지 장애(mild cognitive impairment), 알츠하이머병(Alzheimer's disease), 알츠하이머형 치매(Alzheimer type dementia), 초로성 치매(presenile dementia), 초기 발병 알츠하이머병(early onset Alzheimer's disease), 노인성 치매(senile dementia), 루이소체 치매(Lewy body corpuscle dementia), 미세 경색 치매(micro-infarct dementia), AIDS-관련 치매(AIDS-related dementia), HIV-치매(HIV-dementia), 루이체 관련된 치매(dementia associated with Lewy bodies), 다운 증후군 관련된 치매(Down's syndrome associated dementia), 피크병(Pick's disease), 조기 기억 상실 장애(recent short-term memory impairment), 나이-관련 인지 장애(age-associated cognitive disorder), 나이 관련 기억 손상(age associated memory impairment), 약물-관련 인지 장애(drug-associated cognitive disorder), 면역 결핍 증후군과 관련된 인지 장애(immunodeficiency syndrome-associated cognitive disorder), 혈관질환과 관련된 인지 장애(vascular disease-associated cognitive impairment), 정신 분열증과 관련된 인지 장애(cognitive impairment associated with schizophrenia), 파킨슨병과 관련된 인지 장애(Parkinson's disease-associated cognitive impairment), 뇌전증과 관련된 인지 장애(cognitive disorders associated with epilepsy), 우울증과 관련된 인지 장애(depression-associated cognitive disorder), 양극성 장애와 관련된 인지 장애(cognitive disorders associated with bipolar dosorder), 강박 장애와 관련된 인지 장애(obsessive compulsive disorder-associated cognitive disorder), 외상 후 스트레스 장애(post-traumatic stress disorder), 주의력 결핍 장애(attention deficit disorder), 주의력 결핍 과잉 행동 장애(attention deficit hyperactivity disorder) 및 학습 결핍증(learning deficit disorder)로 이루어진 군으로부터 선택되는 용도.
- 제41항에 있어서, 인지 장애와 관련된 질환은 경도 인지 장애, 알츠하이머병, 알츠하이머형 치매, 초로성 치매, 초기 발병 알츠하이머병, 노인성 치매, 조기 기억 상실 장애, 나이-관련 인지 장애, 나이 관련 기억 손상, 약물 관련 인지 장애 및 정신분열증과 관련된 인지 장애로 이루어진 군으로부터 선택되는 용도.
- 제37항에 있어서, 포유 동물 투여용인 용도.
- 제37항에 있어서, 0.1 내지 500 mg/㎏(체중)의 화학식 1의 이미다조피리미딘 또는 이미다조트리아진 화합물이 사용되는 것을 특징으로 하는 용도.
- 제37항에 있어서, 디메틸아밀아민, 메틸페니데이트, 암페타민, 타크린, 리바스티그민, 갈란타민, 도네페질, 메만틴, 톨카폰, 레보도파, 아토목세틴, 클로니딘, 프라미펙솔, 구안파신 및 펙소페나딘으로 이루어진 군으로부터 선택된 하나 이상의 약물이 추가로 사용되는 것을 특징으로 하는 용도.
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US17/770,686 US20220370461A1 (en) | 2019-10-21 | 2020-10-21 | Use of imidazopyrimidine or imidazotriazine compounds for prevention, alleviation, or treatment of cognitive disorders, or for improving cognitive function |
EP20879398.4A EP4049662A4 (en) | 2019-10-21 | 2020-10-21 | USE OF IMIDAZOPYRIMIDINE OR IMIDAZOTRIAZINE COMPOUNDS FOR THE PREVENTION, RELIEF OR TREATMENT OF COGNITIVE DISORDERS, OR TO IMPROVE COGNITIVE FUNCTION |
MX2022004741A MX2022004741A (es) | 2019-10-21 | 2020-10-21 | Uso de compuestos de imidazopirimidina o imidazotriazina para prevencion, alivio, o tratamiento de trastornos cognitivos, o para mejorar la funcion cognitiva. |
BR112022007491A BR112022007491A2 (pt) | 2019-10-21 | 2020-10-21 | Medicamento, composição farmacêutica e método para prevenção, alívio ou tratamento de distúrbio cognitivo, e, uso de um composto de imidazopirimidina ou imidazotriazina |
KR1020227016021A KR20220087474A (ko) | 2019-10-21 | 2020-10-21 | 인지 장애의 예방, 경감 또는 치료, 또는 인지 기능 향상을 위한 이미다조피리미딘 또는 이미다조트리아진 화합물의 용도 |
JP2022523521A JP2022553323A (ja) | 2019-10-21 | 2020-10-21 | 認知障害の予防、軽減又は治療、又は認知機能の改善のためのイミダゾピリミジン又はイミダゾトリアジン化合物の使用 |
AU2020370958A AU2020370958A1 (en) | 2019-10-21 | 2020-10-21 | Use of imidazopyrimidine or imidazotriazine compounds for prevention, alleviation, or treatment of cognitive disorders, or for improving cognitive function |
CA3155209A CA3155209A1 (en) | 2019-10-21 | 2020-10-21 | Use of imidazopyrimidine or imidazotriazine compounds for prevention, alleviation, or treatment of cognitive disorders, or for improving cognitive function |
CN202080089125.XA CN114929230A (zh) | 2019-10-21 | 2020-10-21 | 咪唑并嘧啶或咪唑并三嗪化合物用于预防、减轻或治疗认知障碍或者用于改善认知功能的用途 |
ZA2022/04136A ZA202204136B (en) | 2019-10-21 | 2022-04-12 | Use of imidazopyrimidine or imidazotriazine compounds for prevention, alleviation, or treatment of cognitive disorders, or for improving cognitive function |
IL292276A IL292276A (en) | 2019-10-21 | 2022-04-14 | Use of imidazopyrimidine or imidazotriazine compounds to prevent, alleviate or treat cognitive disorders or to improve cognitive function |
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EP (1) | EP4049662A4 (ko) |
JP (1) | JP2022553323A (ko) |
KR (1) | KR20220087474A (ko) |
CN (1) | CN114929230A (ko) |
AU (1) | AU2020370958A1 (ko) |
BR (1) | BR112022007491A2 (ko) |
CA (1) | CA3155209A1 (ko) |
CL (1) | CL2022001015A1 (ko) |
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2020
- 2020-10-21 CA CA3155209A patent/CA3155209A1/en active Pending
- 2020-10-21 CN CN202080089125.XA patent/CN114929230A/zh active Pending
- 2020-10-21 KR KR1020227016021A patent/KR20220087474A/ko unknown
- 2020-10-21 US US17/770,686 patent/US20220370461A1/en active Pending
- 2020-10-21 AU AU2020370958A patent/AU2020370958A1/en active Pending
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- 2020-10-21 EP EP20879398.4A patent/EP4049662A4/en active Pending
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See also references of EP4049662A4 |
Also Published As
Publication number | Publication date |
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EP4049662A4 (en) | 2023-11-01 |
US20220370461A1 (en) | 2022-11-24 |
BR112022007491A2 (pt) | 2022-07-12 |
JP2022553323A (ja) | 2022-12-22 |
MX2022004741A (es) | 2022-05-16 |
CL2022001015A1 (es) | 2023-12-15 |
AU2020370958A1 (en) | 2022-06-09 |
CN114929230A (zh) | 2022-08-19 |
KR20220087474A (ko) | 2022-06-24 |
EP4049662A1 (en) | 2022-08-31 |
IL292276A (en) | 2022-06-01 |
CA3155209A1 (en) | 2021-04-29 |
ZA202204136B (en) | 2022-12-21 |
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