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WO2018155954A1 - Nouveau composé d'urée d'aryle de phénylpipérazine et composition pharmaceutique le contenant - Google Patents

Nouveau composé d'urée d'aryle de phénylpipérazine et composition pharmaceutique le contenant Download PDF

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WO2018155954A1
WO2018155954A1 PCT/KR2018/002256 KR2018002256W WO2018155954A1 WO 2018155954 A1 WO2018155954 A1 WO 2018155954A1 KR 2018002256 W KR2018002256 W KR 2018002256W WO 2018155954 A1 WO2018155954 A1 WO 2018155954A1
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compound
formula
carbon atoms
group
acceptable salt
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Korean (ko)
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천승훈
김경만
차오용카이
신찬영
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Shenzen Linglan Bio-Pharmaceutical Technology Co Ltd
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Shenzen Linglan Bio-Pharmaceutical Technology Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/04—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • 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
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine 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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin

Definitions

  • the present invention relates to novel phenylpiperazine aryl urea derivative compounds.
  • Dopamine nervous system dysfunction causes a variety of neuropsychiatric diseases, such as social phobia, Tourette's syndrome, Parkinson's disease, hyperactivity disorder, schizophrenia, bipolar disorder, and drug or alcohol dependence.
  • neuropsychiatric diseases such as social phobia, Tourette's syndrome, Parkinson's disease, hyperactivity disorder, schizophrenia, bipolar disorder, and drug or alcohol dependence.
  • Parkinson's disease is caused by the progressive loss of dopamine neurons in the substantia nigra of the brain, and chronic progressive degenerative of the nervous system, characterized by stability, stiffness, locomotion (slowness) and postural instability. Disease. Parkinson's disease is estimated to be about 1% of the population over age 60.
  • Schizophrenia is a type of chronic mental disorder that prevents integrated normal thinking because of the overall impairment of the thinking system and emotional responses. In Korea, it was called schizophrenia until 2010. Schizophrenia causes symptoms due to excessive dopamine activity due to excessive secretion of dopamine or an increase in dopamine receptors in the limbic system of the brain.
  • Substance abuse refers to the use of illegal drugs or legal drugs, such as neurostabilizers, without medical supervision.
  • Medically defined substance abuse is regarded as a condition in which an individual's health is compromised by the regular and excessive use of certain substances, threatens interpersonal relationships, and paralyzes society itself in the process.
  • drug abuse the amount of dopamine in the septal nucleus of the brain is increased.
  • the increase in dopamine in the septal nucleus of the septum is much more rapid in the case of drug abuse than in the natural compensation.
  • Bipolar disorder is a type of mood disorder, often referred to as 'manic depression'. Manic episodes and depressive episodes, which cause a variety of symptoms associated with abnormally elevated mood, may appear independently or in combination. Bipolar disorder is caused by excessive secretion of dopamine.
  • L-Dopa is currently commonly used to treat Parkinson's disease. Parkinson's disease slows the progress and alleviates clinical symptoms, but prolonged use of side effects include involuntary exercise and vomiting.
  • Treatment for schizophrenia, drug abuse, and bipolar disorder is a disease caused by an increase in dopamine, so dopamine blockers are basically used.
  • dopamine blockers are basically used.
  • excessive inhibition of dopamine inhibits the reticular system that regulates basal metabolism, body temperature control, and vascular movement, resulting in side effects such as anticholinergic action and sympathetic block. Therefore, there is a need for the development of a new drug that can replace the existing drugs.
  • the present invention aims to provide a novel phenylpiperazine aryl urea compound and a pharmaceutical composition comprising the same.
  • R 1 and R 2 are each independently hydrogen, halogen, an alkyl group having 1 to 4 carbon atoms, an alkyl group having 1 to 4 carbon atoms substituted with halogen, or an alkoxy group having 1 to 4 carbon atoms;
  • Ar is a substituted or unsubstituted aryl group having 5 to 10 carbon atoms, or a heteroaryl group having 5 to 10 carbon atoms;
  • n is an integer of 1 or 2.
  • R 1 , R 2 , Ar and n are as defined in claim 1, respectively.
  • At least one prophylactic or therapeutic pharmaceutical composition selected from the group consisting of Parkinson's disease, drug abuse, schizophrenia and bipolar disorder comprising any one of the compounds 1 to 5 or a pharmaceutically acceptable salt thereof.
  • the phenylpiperazine aryl urea compound according to the present invention is a novel substance and acts as an agonist for the dopamine D 3 receptor, thereby preventing or treating Parkinson's disease, drug abuse, schizophrenia or bipolar disorder.
  • the present invention provides a compound of Formula 1 or a pharmaceutically acceptable salt thereof:
  • R 1 and R 2 are each independently hydrogen, halogen, an alkyl group having 1 to 4 carbon atoms, an alkyl group having 1 to 4 carbon atoms substituted with halogen, or an alkoxy group having 1 to 4 carbon atoms;
  • Ar is a substituted or unsubstituted aryl group having 5 to 10 carbon atoms, or a heteroaryl group having 5 to 10 carbon atoms;
  • n is an integer of 1 or 2.
  • the compound represented by Chemical Formula 1 is a phenylpiperazine aryl urea compound.
  • the compound represented by Formula 1 may form a pharmaceutically acceptable salt.
  • pharmaceutically acceptable salts are not particularly limited to those commonly used in the art to which the present invention pertains, such as inorganic and organic acid addition salts of compounds.
  • it may be an addition salt of an inorganic acid such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, nitrous acid, phosphorous acid, perchloric acid or bromic acid, and may be acetic acid, methanesulfonic 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, said, oxalic acid, benzoic acid, embonic acid, aspartic acid or glutamic acid.
  • halogen means fluorine (F), chlorine (Cl), bromine (Br) or iodine (I), unless stated otherwise.
  • alkyl group means a straight or branched saturated hydrocarbon group. Unless defined otherwise, it may be an alkyl group having 1 to 10 carbon atoms, preferably an alkyl group having 1 to 4 carbon atoms.
  • Alkyl groups are, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 2-methylbutyl, 3-methylbutyl, 1,2-dimethylpropyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, 2-hexyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1 , 2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 1,1-dimethyl
  • an alkyl group having 1 to 4 carbon atoms substituted with halogen refers to having one or more hydrogen atoms substituted with halogen in an alkyl group having 1 to 4 carbon atoms.
  • alkoxy group refers to an alkyl group bonded through an oxygen atom. Unless defined otherwise, it may be an alkoxy having 1 to 10 carbon atoms, preferably an alkoxy group having 1 to 4 carbon atoms.
  • Alkoxy groups are, for example, methoxy, ethoxy, n-propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, 1,1-dimethylethoxy, n-pentoxy , 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 2,2-dimethylpropoxy, 1 ethylpropoxy, hexoxy , 1-methylpentoxy, 2-methylpentoxy, 3-methylpentoxy, 4-methylpentoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2 , 2-dimethylbutoxy, 2,3-dimethylbutoxy, 3,3-dimethylbutoxy, 1-ethylbutoxy, 2-ethylbutoxy, 1,1,2-trimethylpropoxy, 1,2,2 -Trimethylpropoxy, 1-ethyl-1-methylpropoxy or 1-ethyl-2-methylpropoxy and the like.
  • aryl group means a monocyclic or polycyclic aromatic hydrocarbon group. Unless defined otherwise, it may be an aryl group having 5 to 18 carbon atoms, preferably an aryl group having 5 to 10 carbon atoms.
  • Aryl groups include, for example, phenyl, naphthyl, anthracenyl, phenanthrenyl, naphthacenyl, chrysenyl, pyrenyl and the like.
  • heteroaryl group means that the carbon atom of the aryl group defined above is substituted with one or more hetero atoms.
  • the hetero atom may be O, N or S. Unless defined otherwise, it may be a heteroaryl group having 5 to 18 carbon atoms, preferably a heteroaryl group having 5 to 10 carbon atoms.
  • Heteroaryl groups are, for example, furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, benzofuranyl, benzothiazolyl, benzoimidazolyl, pyridyl, quinolinyl, acridinyl, Pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, imidazolyl, pyrazolyl, indolyl, purinyl, indazolyl, benzotriazolyl, 1,2,3-triazolyl, 1,3,4-tria Zolyl or carbazolyl and the like.
  • Ar of the present invention is a substituted or unsubstituted aryl group having 5 to 10 carbon atoms, or a heteroaryl group having 5 to 10 carbon atoms.
  • the aryl group having 5 to 10 carbon atoms may be substituted with an aryl group.
  • the aryl group may be a phenyl group.
  • R 1 and R 2 are independently hydrogen, halogen, alkyl group having 1 to 4 carbon atoms, alkyl group having 1 to 4 carbon atoms substituted with halogen or alkoxy group having 1 to 4 carbon atoms.
  • R 1 and R 2 may be independently an alkyl group having 1 to 4 carbon atoms substituted with hydrogen, halogen or halogen. More preferably, R 1 is halogen or an alkyl group having 1 to 4 carbon atoms substituted with halogen, R 2 may be hydrogen, halogen or an alkyl group having 1 to 4 carbon atoms substituted with halogen.
  • D 3 receptor selectivity is excellent.
  • the halogen of R 1 and R 2 may be independently of each other F or Cl.
  • the aryl group or heteroaryl group may have two aromatic rings.
  • An aryl group or heteroaryl group having two aromatic rings is, for example, naphthyl, benzofuranyl, benzothiazolyl, benzoimidazolyl, quinolinyl, indolyl, indazolyl, benzotriazolyl and the like.
  • the heteroaryl group having two aromatic rings may include one or more heteroatoms N or S.
  • benzothiazolyl benzoimidazolyl, quinolinyl, indolyl, indazolyl, benzotriazolyl and the like.
  • Ar may be quinolinyl or benzothiazolyl.
  • D 3 receptor selectivity is excellent.
  • n is 1 or 2.
  • D 3 receptor selectivity is excellent.
  • the compound represented by Formula 1 according to the present invention is more specifically illustrated as follows.
  • the present invention comprises the steps of reacting the Ar-NH 2 compound to which Ar of formula 1 is bonded and carbonyldiimidazole or phosgene; And it provides a method of preparing a compound represented by the formula (1) or a pharmaceutically acceptable salt thereof comprising the step of reacting the reaction product with a compound represented by the formula (2) to obtain a compound represented by the formula (1) :
  • R 1 , R 2 , Ar and n are as defined in claim 1, respectively).
  • the step of reacting a compound Ar-NH 2 wherein Ar is a combination of the above formula (1) and carbonyldiimidazole or phosgene comprises the steps of dissolving the Ar-NH 2 compound in a solvent; Dissolving carbonyldiimidazole or phosgene in a solvent; And reacting the Ar-NH 2 solution with the carbonyldiimidazole solution.
  • the solvent usable for the reaction is not particularly limited, but may be a solvent capable of dissolving the compounds.
  • the solvent is dichloromethane, chloroform, dimethyl sulfoxide (DMSO), diethylene glycol monomethyl ether, N, N-dimethylformamide, tetrahydrofuran, acetonitrile, methanol, ethanol , Propanol, butanol, toluene, or the like, or may be used by mixing two or more solvents.
  • the step of reacting the Ar-NH 2 solution and the carbonyldiimidazole solution may specifically include adding one solution to another solution in a dropwise manner and then stirring the solution. After the reaction of the mixture is completed may further comprise the step of separating the reaction product from the mixture.
  • the reaction temperature in the step of reacting the Ar-NH 2 compound bonded Ar of Formula 1 with carbonyldiimidazole or phosgene may be 0 to 100 ° C, preferably 0 ° C to room temperature.
  • the step of reacting the reaction product and the compound represented by the formula (2) to obtain a compound represented by the formula (1) is specifically the reaction product, the solvent, the compound represented by the formula (2) and N, N-diisopropylethylamine (N, N-Diisopropylethylamine, DIEA) or 2,2,6,6-tetramethylpiperidine (2,2,6,6-tetramethylpiperidine) may be reacted.
  • Reacting the reaction product and the compound represented by the following Chemical Formula 2 may specifically be carried out by reflux reaction.
  • the reaction temperature in the step of reacting may be 0 to 100 °C, preferably 0 °C to room temperature.
  • After the reaction of the mixture is completed may include the step of separating the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof from the mixture.
  • some compounds of Formula 1 of the present invention may be prepared as in Scheme 1 below.
  • each of Compounds 1a to 1l may be reacted with Compound 2 to prepare Compounds 3a to 3l, respectively.
  • the kind of base (K 2 CO 3 ), catalyst (NaI) and solvent (acetonitrile) in the reaction is not particularly limited.
  • compounds 4a to 4l may be prepared by adding a reducing agent (hydrazine, hydrazine) to each of the compounds 3a to 3l.
  • a reducing agent hydrazine, hydrazine
  • the kind of reducing agent (hydrazine) and solvent (ethanol) in the reaction is not particularly limited.
  • Ar-NH 2 compound to which Ar is bonded to Chemical Formula 1 and carbonyldiimidazole or phosgene are reacted, followed by reacting the reaction product with each of Compounds 4a to 4l to Compounds 5a to 5l (5a to 5a). 5l), 6a-6l, 7a-7l, 8a-8l, 9a-9l, 10a-10l, 11a-11l and 12a-12l.
  • the method comprising dissolving the compound Ar-NH 2 wherein Ar is a combination of Formula 1 with carbonyldiimidazole is particularly the Ar-NH 2 which already reacting imidazole or phosgene compound in a solvent; Dissolving carbonyldiimidazole or phosgene in a solvent; And reacting the Ar-NH 2 solution with the carbonyldiimidazole solution.
  • the solvent usable for the reaction is not particularly limited, but may be a solvent capable of dissolving the compounds.
  • the step of reacting the Ar-NH 2 solution and the carbonyldiimidazole solution may specifically include adding one solution to another solution in a dropwise manner and then stirring the solution. After the reaction of the mixture is completed may further comprise the step of separating the reaction product from the mixture.
  • Reacting the reaction product with each of the compounds 4a to 4l is specifically the reaction product, the solvent, any one of the compounds 4a to 4l and N, N-Diisopropylethylamine (DIEA) or 2,2,6,6-tetramethylpiperidine may be a reaction of 2,2,6,6-tetramethylpiperidine.
  • Reacting the reaction product with each of the compounds 4a to 4l may be specifically to reflux the reaction.
  • the compounds 5a to 5l (5a to 5l), 6a to 6l, 7a to 7l, 8a to 8l, 9a to 9l, 10a to 10l, 11a to 11l or 12a to 12l are separated from the mixture, respectively. It may include the step.
  • organic bases such as trimethylamine (TMA), triethylamine (TEA), diisopropylethylamine and pyridine; Or sodium carbonate (Na 2 CO 3)
  • TMA trimethylamine
  • TEA triethylamine
  • NaH sodium hydride
  • the solvent used in the reaction is dichloromethane, chloroform, dimethyl sulfoxide (DMSO), diethylene glycol monomethyl ether (DGME), N, N-dimethylformamide, tetrahydrofuran, acetonitrile, methanol, ethanol, propanol , Butanol or toluene, and the like.
  • the reaction may include the process of reflux.
  • the reaction temperature may be 0 to 150 ° C, preferably 0 ° C to room temperature.
  • the reaction may be carried out by adding or not adding a catalyst such as NaI, KI, or the like.
  • the present invention provides at least one prophylactic or therapeutic pharmaceutical composition selected from the group consisting of Parkinson's disease, drug abuse, schizophrenia and bipolar disorder comprising a compound of the present invention or a pharmaceutically acceptable salt thereof.
  • the compounds of the present invention show high selectivity for dopamine D 3 receptors and can act as D 3 receptor agonists to prevent or treat Parkinson's disease, drug abuse, schizophrenia or bipolar disorder.
  • Dopamine receptors exist in five subtypes, all of which belong to the G protein coupled receptor, which is a D 2 like group (D 2 , D 3 and D 4 receptors) and a D 1 like group (D 1 and D 5). Receptors). Among these, D 1 like group receptors stimulate adenylate cyclase and D 2 like group receptors inhibit it. These receptors are distributed differently depending on the tissue. Unlike the D 2 receptor, which is expressed at high density in the basal ganglia that regulates motor function, the D 3 receptor is mainly expressed in the limbic system, which plays an important role in the regulation of human emotion or emotion.
  • Parkinson's disease, drug abuse, Johyun increase or there is when the treatment for bipolar disorder using the low selectivity drugs for D 2 receptors and D 3 receptors, simultaneously with the desired therapeutic effect observed adverse effects on motor function, the former D 3 It is expressed by blocking the receptor and the latter is caused by blocking the D 2 receptor.
  • drugs that selectively act on the D 3 receptor are thought to improve the side effects of existing therapeutics.
  • Parkinson's disease is caused by the progressive loss of dopamine neurons in the substantia nigra of the brain, and chronic progressive degenerative of the nervous system, characterized by stability, stiffness, locomotion (slowness) and postural instability. Disease.
  • Schizophrenia is a symptom caused by excessive dopamine activity due to excessive secretion of dopamine or an increase in dopamine receptors in the limbic system of the brain. Representative symptoms include delusions, hallucinations, and confusion.
  • the D 2 receptor and the D 3 receptor are the main targets of currently used schizophrenia.
  • the amount of dopamine in the septal nucleus of the brain is increased.
  • the increase in dopamine in the septal nucleus of the septum is much more rapid in the case of drug abuse than in the natural compensation.
  • Bipolar disorder is a type of mood disorder, commonly referred to as 'manic depression', and excessive secretion of dopamine may be one cause of bipolar disorder.
  • Dopamine nervous system dysfunction causes various neuropsychiatric diseases. Recently, dopamine D 3 receptor agonists have been reported to have therapeutic effects on Parkinson's disease, drug abuse, schizophrenia and bipolar disorder.
  • 6-OHDA 6-hydroxydopamine (6-hydroxhdopamine)
  • CDI carbonyldiimidazole
  • MeCN acetonitrile (CH 3 CN, acetonitrile)
  • HEK-293 cells expressing the D 2 receptor (D 2 R) or D 3 receptor (D 3 R) were prepared and [ 3 H] -sulpiride that binds to both D 2 R and D 3 R The cells were treated.
  • [3 H] - concentration of sulpiride are cells expressing D 2 R is 2.2 nM, cells expressing D R 3 is treated with 7.2 nM.
  • Other groups include [3 H] - was treated with sulpiride (sulpiride) and carried by each of the compounds (100 nM) or its hydrochloride synthesized in Examples 1 to 16.
  • the top 10 compounds with superior binding to D 3 R compared to the control [ 3 H] -sulfide were 5dHCl, 5iHCl, 5a, 5hHCl, 5gHCl, 5aHCl, 5g, 5e, 5k HCl, followed by 5k.
  • the top 10 compounds with superior binding to D 2 R compared to the control [ 3 H] -sulfide were 5dHCl, 6bHCl, 6c, 6e, 6b, 6eHCl, 5gHCl, 5a, 5g, In order of 5h HCl.
  • the top ten compounds with large differences in substitution rate between D 2 R and D 3 R were 5i.HCl, 5k.HCl, 5a.HCl, 5f.HCl, 5k, 5h, 5e, 5h.HCl. In order of 5f and 5j.
  • the sulpiride (sulpiride) - D 2 receptor (D 2 R) or D 3 receptors (D 3 R) for expressing prepare the HEK-293 cells, and combining all of the D 2 R and D 3 R [3 H]
  • the cells were treated.
  • [3 H] - concentration of sulpiride are cells expressing D 2 R is 2.2 nM, cells expressing D R 3 is treated with 7.2 nM.
  • Another experimental group was treated with [ 3 H] -sulpiride and each compound synthesized in Examples 1-18 (1 nM, 10 nM, 100 nM, 1 ⁇ M, 10 ⁇ M and 100 ⁇ M) together.
  • Ki Inhibitory constant
  • the smaller the Ki value means that the compound is a better binding to the receptor, and means that the Ki values of the difference between D 2 and D 3 R R larger greater selectivity between D 2 and D 3 R R.
  • the top 10 compounds with superior binding strength were 5h HCl, 5h, 5a HCl, 5i, 5f, 5j, 5iHCl, 5jHCl, 5e, 5k HCl. Appeared.
  • the top 10 compounds with good binding strength were 6dHCl, 17bHCl, 6d, 5g, 5aHCl, 5hHCl, 5c, 5iHCl, 5i, 5k In order of HCl.
  • the top 10 compounds with the largest difference in Ki between D 2 R and D 3 R were 5e, 5eHCl, 17cHCl, 5k, 5f, 5j, 5h, 5jHCl, 5kHCl, and 5i. .
  • Parkinson's disease animal models were constructed using 10-week-old ICR mice (25-30 g). Zoletil (30 mg / kg) and rompun (10 mg / kg) were anesthetized by intraperitoneal injection, and 6-OHDA was injected into the striatum via stereotaxic surgery. 2 ⁇ L of 6-OHDA at 2 ⁇ g / ⁇ L dissolved in 0.02% ascorbic acid was injected into the right striatum using normal saline. Coordinates of the scanned striatum were AP + 0.3M, ML +2.2, and DV -5.0.
  • Rotarod experiment was an animal behavior experiment for measuring motor coordination using the animal model of Experimental Example 3, was carried out to measure the effect of the test drug. Two weeks after the animal model of Experiment 3 was made, a rotarod experiment was performed after intraperitoneal injection of the test drug into the animal model at a concentration of 10 mg / kg for 3 days. 10 mg / kg apomorphine (apomorphine, Sigma Chemical Co., St. Louis, Mo.) was used as a positive control.
  • Rotarod was carried out for 5 minutes to measure the number of drops (number), and the time taken from the start of the test to drop (sec) was measured.
  • Test Example 2 HCl salts of Compound 5e and Compound 5e having the largest difference in Ki value between D 2 R and D 3 R were used.
  • As a vehicle 2 ⁇ L of 0.02% ascorbic acid dissolved in saline was used.
  • R 1 and R 2 of the compounds synthesized in Examples 1 to 18 are each independently hydrogen, halogen or an alkyl group having 1 to 4 carbon atoms substituted with halogen, but R 1 and R 2 of the compound according to the present invention are independently of each other. It may be an alkyl group having 1 to 4 carbon atoms or an alkoxy group having 1 to 4 carbon atoms. Since the alkyl group having 1 to 4 carbon atoms or the alkoxy group having 1 to 4 carbon atoms is judged to be bioisostere with R 1 or R 2 of the compound synthesized in Examples 1 to 18, hydrogen, It is believed to have a similar effect to halogen or an alkyl group having 1 to 4 carbon atoms substituted with halogen.
  • Ar of the compound synthesized in Examples 1 to 18 is a heteroaryl group having 5 to 10 carbon atoms, but Compound Ar according to the present invention may be a substituted or unsubstituted aryl group having 5 to 10 carbon atoms. Since the substituted or unsubstituted aryl group having 5 to 10 carbon atoms is considered to be a bioisostere with Ar synthesized in Examples 1 to 18, effects similar to those of the heteroaryl group having 5 to 10 carbon atoms are commonly used in drug development. It is believed to have

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Abstract

La présente invention concerne un composé d'une formule chimique particulière ou un sel pharmaceutiquement acceptable de celui-ci et, plus particulièrement, un composé capable de prévenir ou de traiter la maladie de Parkinson, la surconsommation de médicaments, la schizophrénie, ou un trouble bipolaire, par action en tant qu'agoniste du récepteur D3 de la dopamine, ou à un sel pharmaceutiquement acceptable de celui-ci.
PCT/KR2018/002256 2017-02-24 2018-02-23 Nouveau composé d'urée d'aryle de phénylpipérazine et composition pharmaceutique le contenant Ceased WO2018155954A1 (fr)

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US20240018119A1 (en) * 2020-05-29 2024-01-18 Daegu-Gyeongbuk Medical Innovation Foundation Carboxamide derivative and pharmaceutical composition comprising same as active ingredient for preventing or treating mental illness

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