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WO2017018752A1 - Dérivé buspirone et composition pharmaceutique le comprenant - Google Patents

Dérivé buspirone et composition pharmaceutique le comprenant Download PDF

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Publication number
WO2017018752A1
WO2017018752A1 PCT/KR2016/008072 KR2016008072W WO2017018752A1 WO 2017018752 A1 WO2017018752 A1 WO 2017018752A1 KR 2016008072 W KR2016008072 W KR 2016008072W WO 2017018752 A1 WO2017018752 A1 WO 2017018752A1
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Prior art keywords
formula
group
azaspiro
dione
piperidin
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PCT/KR2016/008072
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English (en)
Korean (ko)
Inventor
서홍석
심태보
이용직
윤호종
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Korea Institute of Science and Technology KIST
Korea University Research and Business Foundation
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Korea Institute of Science and Technology KIST
Korea University Research and Business Foundation
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Priority claimed from KR1020150106982A external-priority patent/KR101663543B1/ko
Priority claimed from KR1020150106981A external-priority patent/KR20170014130A/ko
Application filed by Korea Institute of Science and Technology KIST, Korea University Research and Business Foundation filed Critical Korea Institute of Science and Technology KIST
Publication of WO2017018752A1 publication Critical patent/WO2017018752A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • 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
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • 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
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

  • the present invention relates to a composition for treating and preventing blood pressure diseases, and more particularly, to a pharmaceutical composition for treating or preventing hypertension diseases.
  • Blood pressure is the pressure on the walls of blood vessels when blood flows through them. According to the name of the blood vessels arterial blood pressure, capillary blood pressure, venous blood pressure, etc. are distinguished, usually refers to arterial blood pressure. Arterial blood pressure is altered by heart rate and vascular resistance.
  • the blood pressure lowering agents which are used in the clinic and directly lower blood pressure by acting on blood vessels are diuretics, beta blockers, calcium blockers, alpha blockers, angiotensin converting enzyme inhibitors and angiotensin converting enzyme inhibitors, and angiotensin receptor blockers. It is known that all of these agents act as a mechanism to artificially drop elevated blood pressure.
  • the blood pressure when the ventricles contract and blood is pushed into the arteries is called systolic blood pressure (highest blood pressure). Even when the ventricles are expanded and the blood is not pushed out, the artery wall is elastic and compresses the blood, so the blood pressure is not zero.
  • the blood pressure at this time is called diastolic blood pressure (lowest blood pressure), and the difference between systolic blood pressure and diastolic blood pressure is called pulse pressure.
  • Increased blood pressure from the heart or decreased elasticity of arterial vessels increases pulse pressure.
  • the blood pressure reading is divided into systolic and diastolic blood pressure.
  • Normal systolic blood pressure is 120 mmHg
  • diastolic blood pressure is 80 mmHg
  • average arterial pressure is 100 mmHg
  • pulse pressure is about 40 mmHg, but there are some differences.
  • hypertension may vary slightly from person to person, but generally refers to a case in which systolic blood pressure is 140 mmHg or more or diastolic blood pressure is 90 mmHg or more in an adult 18 years or older.
  • Hypertension can be broadly classified into two types. The cause of the disease is known and hypertension is caused by the occurrence of secondary hypertension, and the cause of the disease is not found is called primary (hypertension) hypertension. About 95% of all hypertensive patients are essential hypertension. The underlying cause of essential hypertension is not clear, but it is thought to be due to an increase in cardiac output (a volume of blood ejected from the heart for 1 minute) or an increase in peripheral vascular resistance.
  • Risk factors associated with hypertension include environmental and psychological factors such as family history of high blood pressure, drinking, smoking, aging, lack of exercise, obesity, salty eating habits, and stress.
  • the primary hypertension is included in the essential hypertension, and the causes of primary hypertension have been mentioned so far because of genetic predisposition and environmental predisposition, but none of them explain the etiology of hypertension correctly. Recently, it is estimated that blood pressure will rise due to the multiple factors associated with these predispositions. Even though the primary hypertension is well controlled, the prevention effect of accidents and cardiac insufficiency of cardiovascular disease lowers the relative risk by 20-50%, which is not very effective.
  • an antihypertensive agent that has an effect of lowering blood pressure by acting on blood vessels as a treatment for existing hypertension patients
  • diuretics, beta-blockers, calcium blockers, alpha blockers, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, etc. as discussed above.
  • these agents previously known as antihypertensive drugs, act only as a mechanism to artificially lower elevated blood pressure, and these drugs are taken without considering the effects on other conditions for patients with other conditions as well as hypertension.
  • There was a problem In particular, if patients with other conditions in addition to hypertension, taking the drug randomly just because it is effective in the treatment of hypertension, there is a problem that there is a high risk of causing side effects.
  • buspirone is known only as a therapeutic agent for anxiety neurosis, and has been taken only by patients with stress-related diseases that operate complex mechanisms that develop into mental and physical abnormalities, but its use has not been found in a variety of ways. There is a problem that there is much lack of research to use for other purposes. In order to solve the problems as described above, further studies on buspirone should also be preceded, but there is a problem that these studies are lacking so far, although studies to develop and utilize another derivative of buspyron have to be made sufficiently.
  • Patent Document 1 only discloses a benzopyrin derivative that has the effect of treating hypertension .
  • an object of the present invention is to provide a boostron, buspyrone derivatives that can diversify the utilization of the buspyron. It is also an object of the present invention to provide a pharmaceutical composition capable of preventing and treating hypertension.
  • the purpose of the present invention is to provide a pharmaceutical composition that can be taken by patients who have other conditions with hypertension by utilizing a substance having a therapeutic effect on other conditions in the treatment of hypertension. It is also an object to provide a pharmaceutical composition capable of preventing and treating hypertension by identifying a new cause of essential hypertension or primary hypertension, rather than artificially lowering blood pressure.
  • Buspyron derivatives according to one feature of the present invention for solving the above problems is represented by the following [Formula 1] or [Formula 1-1].
  • X is NH or CH 2
  • Y is oxygen or CH 2 ;
  • A is an aryl group having 6 (C 6 ) carbon atoms, or a hexagonal or hexavalent heteroaryl group containing 1-3 nitrogen atoms, or a pentagonal or hexagonal group containing 1-3 nitrogen or oxygen atoms Is a heterocycloalkyl group;
  • any one selected from the group consisting of the aryl group, a heteroaryl group and a heterocycloalkyl group are alkoxy groups, the carbon number of the alkyl group, having 1 to 8 (C 1 -C 8) having a carbon number of 1 to 8 (C 1 -C 8) Substituted or unsubstituted with any one or more substituents selected from the group consisting of 1 to 8 (C 1 -C 8 ) haloalkyl groups and alkoxycarbonyl groups having 1 to 8 (C 1 -C 8 );
  • R a is hydrogen, or is or a halogen atom, or is an alkyl group having 1 to 8 (C 1 -C 8), or -NHC (O) R 3, or is -NR 3 R 4, and;
  • R 3 or R 4 is hydrogen or an alkyl group having 1 to 8 carbon atoms (C 1 -C 8 ).
  • Y ' is oxygen or CH 2 ;
  • a ′ is each an aryl group having 6 (C 6 ) carbon atoms, or a hexagonal or hexavalent heteroaryl group containing 1-3 nitrogen atoms, or a pentagonal group containing 1-3 nitrogen or oxygen atoms or Hexagonal heterocycloalkyl group;
  • any one selected from the group consisting of the aryl group, a heteroaryl group and a heterocycloalkyl group are alkoxy groups, the carbon number of the alkyl group, having 1 to 8 (C 1 -C 8) having a carbon number of 1 to 8 (C 1 -C 8) Substituted or unsubstituted with any one or more substituents selected from the group consisting of 1 to 8 (C 1 -C 8 ) haloalkyl groups and alkoxycarbonyl groups having 1 to 8 (C 1 -C 8 );
  • R a ' is hydrogen, or is or a halogen atom, or is an alkyl group having 1 to 8 (C 1 -C 8), or -NHC (O) R 3, or is -NR 3 R 4, and;
  • R 3 or R 4 is hydrogen or an alkyl group having 1 to 8 carbon atoms (C 1 -C 8 ).
  • the pharmaceutical composition for the treatment and prevention of hypertension diseases contains a buspyrone derivative represented by the above [Formula 1] or [Formula 1-1] or a pharmaceutically acceptable salt thereof as an active ingredient. .
  • Buspiron derivatives according to the present invention is a invention that expands the scope of the use of buspyrone revealed that there is a new use for the treatment of busphyron, known to have a therapeutic effect on a stressful disease.
  • busphyron known to have a therapeutic effect on a stressful disease.
  • these pyrphyron or buspyron oils have a therapeutic effect on hypertension, and thus the invention is suitable for taking patients with both stress and hypertension.
  • the two conditions simultaneously have to take the drugs that have a therapeutic effect at the same time the therapeutic effect is more excellent for the patients who were severely limited in the range of the drug due to the concern of side effects.
  • FIG. 1 is a graph showing the results of measuring systolic blood pressure in the SHR control group, buspirone administration group, and YHJ 07159 administration group, respectively, as a result of Experimental Example 1;
  • Figure 2 is a graph showing the results of measuring diastolic blood pressure in the SHR control group, buspirone administration group, the YHJ 07159 administration group of the buspyron derivative as a result of Experimental Example 2, respectively.
  • FIG. 3 shows the results of measurement of heart rate in the SHR control group, the buspirone-administered group, and the YHJ 07159-administered group of the buspyrone derivatives as the results of Experimental Example 3, respectively.
  • FIG. 5 shows the results of measuring whether or not the weight of the heart is reduced in the SHR control group, the buspirone-administered group, and the YHJ 07159-administered group, which is a buspyron derivative, as the results of Experimental Example 4, respectively.
  • FIG. 6 shows the results of measuring whether or not the SHR control group, the buspirone administration group, and the YHJ 07159 administration group of the buspyron derivative, respectively, as a result of Experiment 4 reduce the body weight index.
  • AMPK ATP-activated protein kinase
  • the present inventors have made extensive efforts to develop a pharmaceutical composition having excellent therapeutic and prophylactic effects using a booster, a new boosteron derivative having diversified the use of the booster, and a metabolic improvement in hypertension among blood pressure diseases. According to the present invention, the present invention was completed by finding a pharmaceutical composition for the treatment and prevention of busphyron, busphyron derivatives and hypertension.
  • the present invention can repair or prevent hypertension by fundamentally modifying the cause of essential hypertension or primary hypertension by restoring intracellular AMPK and normalizing metabolic action.
  • buspyron derivative according to the present invention may be represented by the following [Formula 1] or [Formula 2].
  • X is NH or CH 2
  • Y is oxygen or CH 2 ;
  • A is an aryl group having 6 (C 6 ) carbon atoms, or a hexagonal or hexavalent heteroaryl group containing 1-3 nitrogen atoms, or a pentagonal or hexagonal group containing 1-3 nitrogen or oxygen atoms Is a heterocycloalkyl group;
  • any one selected from the group consisting of the aryl group, a heteroaryl group and a heterocycloalkyl group are alkoxy groups, the carbon number of the alkyl group, having 1 to 8 (C 1 -C 8) having a carbon number of 1 to 8 (C 1 -C 8) Substituted or unsubstituted with any one or more substituents selected from the group consisting of 1 to 8 (C 1 -C 8 ) haloalkyl groups and alkoxycarbonyl groups having 1 to 8 (C 1 -C 8 );
  • R a is hydrogen, or is or a halogen atom, or is an alkyl group having 1 to 8 (C 1 -C 8), or -NHC (O) R 3, or is -NR 3 R 4, and;
  • R 3 or R 4 is hydrogen or an alkyl group having 1 to 8 carbon atoms (C 1 -C 8 ).
  • Y ' is oxygen or CH 2 ;
  • a ′ is each an aryl group having 6 (C 6 ) carbon atoms, or a hexagonal or hexavalent heteroaryl group containing 1-3 nitrogen atoms, or a pentagonal group containing 1-3 nitrogen or oxygen atoms or Hexagonal heterocycloalkyl group;
  • any one selected from the group consisting of the aryl group, a heteroaryl group and a heterocycloalkyl group are alkoxy groups, the carbon number of the alkyl group, having 1 to 8 (C 1 -C 8) having a carbon number of 1 to 8 (C 1 -C 8) Substituted or unsubstituted with any one or more substituents selected from the group consisting of 1 to 8 (C 1 -C 8 ) haloalkyl groups and alkoxycarbonyl groups having 1 to 8 (C 1 -C 8 );
  • R a ' is hydrogen, or is or a halogen atom, or is an alkyl group having 1 to 8 (C 1 -C 8), or -NHC (O) R 3, or is -NR 3 R 4, and;
  • R 3 or R 4 is hydrogen or an alkyl group having 1 to 8 carbon atoms (C 1 -C 8 ).
  • buspyrone derivatives represented by the above [Formula 1] or [Formula 1-1] are compounds having a linkage and a substituent specific to 8-azaspiro [4.5] decaine-7,9-dione which is a specific basic base.
  • halogen atom means chloro, fluoro, bromo, iodine.
  • the 'alkyl group' means methyl, ethyl, n-propyl, i-propyl, cyclopropyl, n-butyl, i-butyl, t-butyl, cyclobutyl, cyclopropylmethyl, n-pentyl, i-pentyl, Having from 1 to 8 carbon atoms including neopentyl, t-pentyl, cyclopentyl, cyclobutylmethyl, n-hexyl, i-hexyl, cyclohexyl, cyclopentylmethyl, heptyl, cyclohexylmethyl, octyl and the like Linear, branched or cyclic aliphatic saturated hydrocarbon groups.
  • aryl group refers to a monocyclic, bicyclic, or tricyclic aromatic hydrocarbon group having 6 to 15 carbon atoms, including phenyl, naphthyl, anthranilyl, phenanthryl, and the like.
  • heteroaryl group refers to pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxdiazolyl, thiadiazolyl , Tetrazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, indolyl, isoindolyl, benzofuranyl, benzofurazanyl, dibenzofuranyl, isobenzofuranyl, indazolyl, benzimida Zolyl, benzoxazolyl, benzisooxazolyl, benzothiazolyl, dibenzothiophenyl, naphthyridyl, benzisothiazolyl, quinolinyl, isoquinolinyl, quinoxalin
  • heterocycloalkyl group means a pentagonal or hexagonal aliphatic heterohydrocarbon ring group including one or more heteroatoms selected from N and O, including morpholinyl, piperidinyl, piperazinyl, and the like. do.
  • the molecular weight of the buspyrone derivatives according to the present invention may preferably correspond to 350-550.
  • the compound represented by the above [Formula 1] or [Formula 1-1] may be prepared by the production method represented by the following scheme 1.
  • the compound represented by [Formula 1-1] may also be synthesized by the same synthesis method as in Scheme 1.
  • step 1 is performed at room temperature in the presence of organic acids such as trifluoroacetic acid or inorganic acids such as hydrochloric acid and sulfuric acid.
  • organic acids such as trifluoroacetic acid or inorganic acids such as hydrochloric acid and sulfuric acid.
  • the reaction solvent a conventional organic solvent containing dichloromethane, tetrahydrofuran, dioxane, N, N-dimethylformamide, N, N-dimethylsulfoxide, 2-butanol, 2-pentanol, and the like can be used. .
  • the second process proceeds through an amination reaction at high temperature in the presence of a base.
  • a base organic bases such as amines, organic bases such as potassium carbonate and the like are used.
  • the reaction solvent a conventional organic solvent containing N, N-dimethylsulfoxide, tetrahydrofuran, dioxane, N, N-dimethylformamide, 2-butanol, 2-pentanol and the like can be used.
  • the reaction temperature is in the range from 50 ° C. to 200 ° C., preferably from 80 ° C. to 150 ° C.
  • Buspirone commonly called BuSpar, Buspiron and Buspisal
  • Buspiron is chemically similar to anti-anxiety Piperazine and Azapirone, but with less antidepressant effects.
  • Buspiron was certified by the US Food and Drug Administration in 1986, and became generic in 2001. These symptoms are known to be applied to general anxiety disorder, selective serotonin reuptake inhibitor treatment, to suppress depression or anxiety, and to increase spatial learning ability and spatial memory after trauma to the brain.
  • Buspyron has been reported to be effective in the treatment of mental stress disorder in the past, there is little reported that it is also effective in other conditions in addition to mental stress disorder. There is no disclosure or suggestion in the existing literature about the therapeutic effect, especially with regard to hypertension.
  • the buspyron derivatives according to [Formula 1] or [Formula 1-1] have an effect on lowering blood pressure by acting on peripheral blood vessels, thereby treating and preventing hypertension.
  • Such a python derivative according to [Chemical Formula 1] or [Chemical Formula 1-1] is capable of directly lowering blood pressure by directly reacting with blood in a blood vessel, and further expressing the expression of ATP-activated protein kinase (AMPK) in muscle cells. The blood pressure in the blood vessels can be lowered while increasing.
  • AMPK ATP-activated protein kinase
  • the ATP-activated protein kinase is known to be a substance that decreases the weight while being expressed in muscle cells when blood pressure decreases, in other words, the ATP-activated protein kinase (AMPK) is not properly expressed in muscle cells.
  • AMPK ATP-activated protein kinase
  • mitochondria such as metabolic activity is not smooth, blood pressure around blood vessels will be forced to rise. Therefore, in the present invention, paying attention to the above mechanism, by increasing the expression of ATP-activated protein kinase (AMPK) in the muscle when the muscle of the buspyron derivatives represented by the above [Formula 1] or [Formula 1-1] to the muscle cells This can metabolically lower blood pressure in blood vessels.
  • this mechanism or mechanism by lowering the blood pressure through this mechanism or mechanism, it is artificially lowered blood pressure (direct response to blood in the blood vessels by lowering blood pressure by regulating blood flow) to treat hypertension with a mechanism distinct from other conventional hypertension drugs It may be to prevent.
  • such mechanisms or mechanisms may be identified to lower blood pressure by identifying the cause of primary or primary hypertension, thereby treating or preventing hypertension.
  • a pharmaceutical composition for the treatment and prevention of hypertension diseases comprises a buspyrone derivative represented by the above [Formula 1] or [Formula 1-1] or a pharmaceutically acceptable salt thereof as an active ingredient.
  • a pharmaceutical composition for the treatment and prevention of hypertension diseases comprises a buspyrone derivative represented by the above [Formula 1] or [Formula 1-1] or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the buspyron derivatives represented by the above [Formula 1] or [Formula 1-1] increase the expression of ATP-activated protein kinase (AMPK) in muscle as discussed above, thereby lowering blood pressure in blood vessels. will be.
  • AMPK ATP-activated protein kinase
  • the present pharmaceutical composition is to treat and prevent hypertension diseases through this mechanism or mechanism.
  • the pharmaceutical composition for the treatment and prevention of hypertension diseases may contain not only the buspirone derivative represented by the above [Formula 1] or [Formula 1-1], but also a pharmaceutically acceptable salt thereof as an active ingredient.
  • a pharmaceutically acceptable salt there is no particular limitation, as one example of the pharmaceutically acceptable salt, all of them are to increase the solubility of the buspyrone derivatives represented by the above [Formula 1] or [Formula 1-1].
  • acid addition salts may be used.
  • the pharmaceutically acceptable salt is low toxicity to the human body and should not adversely affect the biological activity and physicochemical properties of the parent compound.
  • the free acid that can be used to prepare the pharmaceutically acceptable salt can be divided into inorganic and organic acids.
  • the inorganic acid may be hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, perchloric acid, bromic acid, or the like.
  • Organic acids include acetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, fumaric acid, maleic acid, malonic acid, phthalic acid, succinic acid, lactic acid, citric acid, citric acid, gluconic acid, tartaric acid, salicylic acid, malic acid, oxalic acid, Benzoic acid, embonic acid, aspartic acid, glutamic acid and the like can be used.
  • Organic bases that can be used for the preparation of organic base addition salts are tris (hydroxymethyl) methylamine, dicyclohexylamine and the like.
  • Amino acids that can be used to prepare amino acid addition bases are natural amino acids such as alanine, glycine and the like.
  • the buspyrone derivatives according to the present invention may include all hydrates and solvates as well as pharmaceutically acceptable salts.
  • the hydrate or solvate is dissolved in a compound which can be mixed with water such as methanol, ethanol, acetone, 1,4-dioxane, and then the free acid or the compound represented by the above [Formula 1] or [Formula 1-1] After the free base is added it may be crystallized or recrystallized. In such cases, solvates (particularly hydrates) may be formed.
  • the compounds of the present invention may also include stoichiometric solvates, including hydrates, in addition to various amounts of water-containing compounds that may be prepared by methods such as lyophilization.
  • the buspyron derivatives or pharmaceutically acceptable salts thereof represented by the above [Formula 1] or [Formula 1-1] are not particularly limited, but preferably 1-80 wt% based on 100 parts by weight of the total composition. It is preferably included in the portion, more preferably 20 to 60 parts by weight. When included in less than 1 part by weight of the buspyrone derivatives or pharmaceutically acceptable salts thereof represented by the above [Formula 1] or [Formula 1-1], it is difficult to fully express the blood pressure lowering effect to be achieved in the present invention is preferred.
  • the amount of the buspyrone derivative or the pharmaceutically acceptable salt thereof represented by the above [Formula 1] or [Formula 1-1] exceeds 80 parts by weight, the content of the remaining substances for preparing a pharmaceutical application product It is not preferable because it can be limited. In addition, even if the blood pressure lowering effect can be sufficiently achieved, it is not economical because it contains more than necessary amount.
  • the method of administering the pharmaceutical composition for the treatment and prevention of hypertension diseases is not particularly limited, but preferably injected into an artery or vein, subcutaneously, rectally, nasal, or any other parenteral. More preferably, it is preferably injected into an artery or vein, orally or directly into muscle cells.
  • the chosen level of administration of the composition will depend on the activity of the compound, the route of administration, the severity of the condition being treated and the condition and previous history of the patient being treated. However, it is within the knowledge of the art to start with a dose of the compound at a lower level than required to achieve the desired therapeutic effect, and gradually increase the dosage until the desired effect is achieved, with the preferred dosage being age, sex , Body shape and weight.
  • the composition may be further processed before being formulated into a pharmaceutically acceptable pharmaceutical formulation, and may preferably be ground or ground into smaller particles.
  • the composition will also vary depending on the condition and the patient being treated, but this can be determined non-originally.
  • the buspyron derivative represented by the above [Formula 1] or [Formula 1-1] or a pharmaceutically acceptable salt thereof can react directly with blood in the blood vessel to lower the blood pressure,
  • AMPK ATP-activated protein kinase
  • by lowering the blood pressure through this mechanism or mechanism it is artificially lowered blood pressure (direct response to blood in the blood vessels by lowering blood pressure by regulating blood flow) to treat hypertension with a mechanism distinct from other conventional hypertension drugs It may be to prevent.
  • the mechanism or mechanism is to identify and lower the blood pressure, thereby identifying the cause of essential or primary hypertension may be to treat or prevent hypertension. Therefore, even through such a mechanism or mechanism, in the present invention, the buspyrone derivative represented by the above [Formula 1] or [Formula 1-1], or a pharmaceutically acceptable salt thereof, lowers the blood pressure and is effective in treating and preventing hypertension. It can be seen that.
  • the pharmaceutical composition according to the present invention acts metabolically to lower blood pressure in blood vessels, thereby treating or preventing hypertension, which is represented by the above [Formula 1] or [Formula 1-1] or a pharmaceutically acceptable buspiron derivative.
  • Possible salts thereof can lower the blood pressure of systolic 180-200 mmHg to 140-170 mmHg when blood vessels are treated with 5 mg / Kg / d.
  • the buspirone derivative represented by the above [Formula 1] or [Formula 1-1] or a pharmaceutically acceptable salt thereof may increase the blood pressure of the diastolic device 100-120 mmHg by 60-60 when 5 mg / Kg / d is treated in the blood vessel. The blood pressure can be lowered to 90 mmHg.
  • the hypertension diseases are essential hypertension, hypertensive heart disease, hypertensive kidney disease, secondary hypertension, atherosclerosis disease, coronary artery stenosis, thrombosis, arterial embolism, atherosclerosis, cerebrovascular disease, cerebral infarction, stroke, electroencephalopathy Obstruction or stenosis, occlusion or narrowing of the cerebral artery, renal vascular disease, peripheral vascular disease, giant cell arteritis, Takayasu's arteritis, Kawasaki's disease, nodular polyangitis aneurysm, nodular polyangiitis arterial detachment, varicose vein, thrombophlebitis and venous thrombosis It may be any one selected from the group consisting of.
  • the pharmaceutical composition according to the present invention enables the treatment and prevention of hypertension diseases by lowering blood pressure in blood vessels as described above.
  • the compound according to Example 1 represented by Chemical Formula 4 was prepared through the following preparation process.
  • Step 1 tert-butyl 4- (4-hydroxybutyl) piperidine-1-carboxylate
  • Step 3 tert-Butyl 4- (4- (7,9-dioxo-8-azaspiro [4.5] decan-8-yl) butyl) piperidine-1-carboxylate
  • Step 4 8- (4- (1- (pyrimidin-2-yl) piperidin-4-yl) butyl) -8-azaspiro [4.5] decaine-7,9-dione
  • Examples 2 to 21 were prepared through the process of Scheme 1 below. Specifically, Examples 2 to 21 through amination reaction under basic conditions between various aryl / heteroaryl compounds in the same manner as in Step 4 of Example 1 in Formula 2 synthesized similarly to Preparation Example 1 above The target compounds according to the above could be synthesized respectively.
  • novel compound represented by Formula 1 according to the present invention can be formulated in various forms according to the purpose.
  • the following illustrates some formulation methods containing the compound represented by Formula 1 according to the present invention as an active ingredient, but the present invention is not limited thereto.
  • Injectables were prepared by containing 100 mg as the active ingredient, 180 mg of mannitol, 26 mg of Na2HPO4-12H2O and 2974 mg of distilled water.
  • Spontaneously Hypertensive Rat (hereinafter referred to as 'SHR') is an experimental animal expressing hereditary hypertension, and hypertension most similar to that of human primary hypertension.
  • SHR is an animal inbred from Wistar stock and developed by Okamoto and Aoki et al. (7-8). Usually, blood pressure begins to rise regardless of Na + or Cl ⁇ at 4-6 weeks of age, and hypertension is expressed in 8-12 weeks. Since SHR is frequently accompanied by hypertensive target organ damage such as cardiac hypertrophy, heart failure, and renal impairment, SHR is a model animal of hypertension with essential hypertension, especially heart disease, and has been widely used for the cause of hypertension and related studies. It is not revealed.
  • buspirone-administered group (7 mg administered 1 mg / d, 7 mg administered 5 mg / d, 7 mg administered 10 mg / d), YHJ 07159 corresponding to a derivative of buspirone (Example 1 Buspiron derivatives prepared according to '(6 mice administered 1 mg / d, 7 administrations of 5 mg / d, 6 administrations of 10 mg / d), and the rest of the control group (7) divided into 4 weeks and 5
  • buspirone and YHJ 07159 were administered for 5 weeks using drinking water from 5 weeks of age. The rest of the control animals were bred with drug-free water.
  • the systolic blood pressure was measured in the SHR control group, the buspirone-administered group, and the YHJ 07159-administered group, respectively, and the results are shown in FIGS. 1 and 1 below (in Table 1, the buspirone-administered group was designated as 'buspirone', and YHJ 07159).
  • the administration group was indicated as 'new drug'. Until the 1-4th parking after the administration of the drug, the blood pressure increased over time in the buspirone group and the YHJ 07159 group compared to the SHR control group, but it was significant in the control group and the drug group (the buspirone group and the YHJ 07159 group). There was no difference in blood pressure.
  • the diastolic blood pressure was measured in the SHR control group, the buspirone-administered group, and the YHJ 07159-administered group, respectively, and the results thereof are shown in FIGS. 2 and 2 below (in Table 2, the Buspirone-administered group was designated as 'buspirone', and YHJ 07159). The administration group was indicated as 'new drug'. In diastolic blood pressure, there was no significant difference in blood pressure between the buspirone and YHJ 07159 groups compared to the SHR control group.
  • the blood pressure lowering effect was higher in the high-pirus buspirone group and the YHJ 07159 group than 5 mg / kg / d.
  • the heart rate of each group was measured and compared, and the results thereof are shown in FIG. 3 and Table 3 (in Table 3, the buspirone-administered group was expressed as 'buspirone', and the YHJ 07159-administered group was expressed as 'new drug'). . On the other hand, in the case of heart rate, no difference was observed between both groups before and after drug treatment.
  • Cardiac weight index heart weight (g) / weight (kg)
  • mice with normal blood pressure showed normal expression of activated phosphorylated ATP-activated protein kinase (pAMPK), whereas eight-week-old mice with high blood pressure had reduced pAMPK expression below 1/2, but received YHJ 07159. Due to the increase in pAMPK expression was confirmed that the blood pressure is lowered.
  • pAMPK activated phosphorylated ATP-activated protein kinase
  • ATP-activated protein kinase AMPK
  • YHJ 07159 a buspyron derivative
  • AMPK ATP-activated protein kinase
  • the present invention can be used as a pharmaceutical composition for treating or preventing hypertension.

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Abstract

La présente invention concerne un dérivé buspirone et une composition pharmaceutique le comprenant, et plus particulièrement, un nouveau dérivé buspirone et une composition pharmaceutique de traitement ou de prévention d'une maladie hypertensive. Le dérivé buspirone selon la présente invention est un nouveau dérivé buspirone qui est, en relation à la buspirone qui est connue comme ayant un effet thérapeutique sur les maladies liées au stress, efficace pour le traitement d'autres pathologies. De plus, une composition de traitement et de prévention de maladies liées à la pression sanguine selon la présente invention peut traiter ou prévenir les maladies liées à la pression sanguine telles que l'hypertension en utilisant le dérivé buspirone et est ainsi une invention qui élargit d'une manière nouvelle la portée d'utilisation de la buspirone. En particulier, un tel dérivé buspirone permet à la buspirone, qui a été utilisée uniquement pour le traitement des maladies liées au stress, d'être utilisée pour un nouvel emploi du traitement de l'hypertension. Un effet de réduction de la pression sanguine, quel que soit l'effet de stabilisation mentale, restaure l'AMPK intracellulaire et normalise les actions métaboliques sans restreindre artificiellement le mécanisme de commande de la contraction-relaxation des cellules vasculaires, corrigeant fondamentalement de là les causes de l'hypertension essentielle ou de l'hypertension primaire, et ayant ainsi un effet de traitement ou de prévention de l'hypertension.
PCT/KR2016/008072 2015-07-29 2016-07-25 Dérivé buspirone et composition pharmaceutique le comprenant Ceased WO2017018752A1 (fr)

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KR10-2015-0106981 2015-07-29
KR1020150106982A KR101663543B1 (ko) 2015-07-29 2015-07-29 부스피론 유도체 및 이를 함유하는 약학 조성물
KR1020150106981A KR20170014130A (ko) 2015-07-29 2015-07-29 혈압질환의 치료 및 예방용 약학 조성물
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4851533A (en) * 1987-03-05 1989-07-25 American Home Products Corporation 1,4-diazine derivatives
US4855302A (en) * 1986-12-11 1989-08-08 Roussel Uclaf Certain azaspirodecane compounds and a method of inducing an anxiolytic activity
US20120183600A1 (en) * 2007-01-16 2012-07-19 Chien-Hung Chen Novel composition for treating metabolic syndrome and other conditions
WO2014144130A2 (fr) * 2013-03-15 2014-09-18 Als Mountain Llc Composition pharmaceutique comprenant un activateur d'ampk et un agent sérotoninergique et procédés d'utilisation correspondants

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4855302A (en) * 1986-12-11 1989-08-08 Roussel Uclaf Certain azaspirodecane compounds and a method of inducing an anxiolytic activity
US4851533A (en) * 1987-03-05 1989-07-25 American Home Products Corporation 1,4-diazine derivatives
US20120183600A1 (en) * 2007-01-16 2012-07-19 Chien-Hung Chen Novel composition for treating metabolic syndrome and other conditions
WO2014144130A2 (fr) * 2013-03-15 2014-09-18 Als Mountain Llc Composition pharmaceutique comprenant un activateur d'ampk et un agent sérotoninergique et procédés d'utilisation correspondants

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
SHINGALA, J. R. ET AL.: "Antihypertensive Effect of 5-HT1A Agonist Buspirone and 5-HT2B Antagonists in Experimentally Induced Hypertension in Rats", PHARMACOLOGY, vol. 73, no. 3, 2005, pages 129 - 139 *

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