• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    Modulating compounds of the dream calcium neuronal sensor and its therapeutic uses. The present invention relates to a group of compounds with a structural core derived from phenylacetamide with the following formula (I): {image-01} Having modulation capacity of the dream neuronal calcium sensor, so that the present invention also refers to the use of these compounds for the treatment or prevention of disorders or diseases where the dream levels are above or below the levels considered physiologically normal. (Machine-translation by Google Translate, not legally binding)
    公开号:ES2578377A1
    申请号:ES201431898
    申请日:2014-12-22
    公开日:2016-07-26
    发明作者:Marta GUTIÉRREZ RODRÍGUEZ；Pilar CERCOS PITA；Mª Mercedes MARTÍN MARTÍNEZ；Mª Rosario HERRANZ HERRANZ；Mª Teresa GARCÍA LÓPEZ；Mª Carmen VALENZUELA MIRANDA；José Ramón NARANJO ORIVIO；Britt Mellstrom；José Manuel DOPAZO SANTOS；Paz GONZÁLEZ PÉREZ
    申请人:Consejo Superior de Investigaciones Cientificas CSIC；Universidad Autonoma de Madrid；Centro de Investigacion Biomedica en Red de Enfermedades Neurodegenerativas CIBERNED；
    IPC主号:
    专利说明:

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    In another preferred embodiment, R5 is H.
    In another preferred embodiment, R5 is an optionally substituted phenyl and R6 is H.
    In a more preferred embodiment, R5 is a phenyl substituted by a C1-C4 alkyl. In an even more preferred embodiment, R5 is selected from 2-methyl-phenyl, 4-n-butylphenyl or 4-tert-butyl-phenyl.
    In another preferred embodiment, R5 is a C2-C4 alkyne and more preferably ethynyl.
    In another preferred embodiment, R6 is an optionally substituted phenyl and R5 is H. In a more preferred embodiment, R6 is a phenyl substituted by a C1-C4 alkyl. In a still more preferred embodiment, R6 is selected from 2-methyl-phenyl, 4-n-butyl-phenyl
    or 4-tert-butyl-phenyl.
    In another preferred embodiment, R5 and R6 form together with the phenyl to which a naphthalene group is attached.
    In another preferred embodiment, the compound of formula (I) described above is selected from the following list:
    - 2- [2- (3,4-Dichlorophenyl) acetylamino] -4-methoxybenzoic acid, (7)
    - 4-Chloro-2- [2- (3-phenoxyphenyl) acetylamino] benzoic acid, (9)
    - 4-Chloro-2- [2- (4-chloro-2-fluorophenyl) acetylamino] benzoic acid, (10)
    Methyl -4-chloro-2- [2- (3,4-dichlorophenyl) acetylamino] benzoate, (13)
    - 4-Chloro-2- [2- (3,4-dihydroxyphenyl) acetylamino] benzoic acid, (15)
    - 4-Chloro-2- [3- (3,4-dichlorophenyl) propanoylamino] benzoic acid, (16)
    -4-chloro-2- [2- (3,4-dichlorophenyl) acetylamino] -N-methylbenzamide, (21)
    - 3- [2- (3-Phenoxyphenyl) acetylamino] -2-naphthoic acid, (22)
    - 3- [3- (3- (3,4-Dichlorophenyl) propanoylamino)] - 2-naphthoic acid, (23)
    - 4-Bromo-2- [2- (3,4-dichlorophenyl) acetylamino] benzoic acid, (32)
    - 2- [2- (3,4-Dichlorophenyl) acetylamino] -5- (4’-n-butylphenyl) benzoic acid, (34)
    - 2- [2- (3,4-Dichlorophenyl) acetylamino] -4- (4’-n-butylphenyl) -benzoic acid, (35)
    - 2- [2- (3,4-Dichlorophenyl) acetylamino] -5- (4’-tert-butylphenyl) -benzoic acid, (36)
    - 2- [2- (3,4-Dichlorophenyl) acetylamino] -5- (2’-methylphenyl) -benzoic acid, (37)
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    of a disease or disorder in which the DREAM protein has altered levels of expression.
    In the present invention, the expression "DREAM protein expression levels are altered" refers to the fact that in the target tissue or cell being treated the amount of DREAM protein in said target cell or tissue is above or below the levels that are considered physiologically normal; DREAM protein expression can be measured by techniques widely known to those skilled in the art, and therefore the measurement of both protein and messenger RNA levels can be referred to. This abnormal level of DREAM affects the signaling pathways in which this protein is involved, leading to different dysfunctions that result in symptoms associated with different pathologies. The compounds of formula (I) of the present invention are capable of modulating the function of DREAM so that abnormal levels of DREAM do not affect the signaling pathways.
    In a preferred embodiment, the disease or disorder in which DREAM protein expression levels are altered is selected from neurodegenerative diseases, cognitive disorders, sensory perception disorders, inflammatory response disorders and auto-inflammatory diseases.
    In a more preferred embodiment, the disease or disorder in which DREAM protein expression levels are altered is selected from Alzheimer's disease and other dementias, schizophrenia, Huntington's disease, dyskinesia, depression, disorders associated with syndrome. Down, chronic pain, neuropathic pain, allodynia, atherosclerosis, type-2 diabetes, rheumatoid arthritis, gout or acute lung inflammation.
    For application in therapy, the compounds of formula (I), their isomers, salts or solvates, will preferably be found in a pharmaceutically acceptable form.
    or substantially pure, that is, having a pharmaceutically acceptable level of purity excluding normal pharmaceutical additives such as diluents and carriers, and not including material considered toxic at normal dosage levels. The purity levels for the active ingredient are preferably
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    Another aspect of the invention relates to a method of treating a disease.
    or disorder in which the expression levels of the DREAM protein are altered comprising the administration of a therapeutically effective amount of a compound of formula (I) as described above.
    In the sense used in this description, the term "therapeutically effective amount" refers to the amount of the agent or compound capable of developing the therapeutic action determined by its pharmacological properties, calculated to produce the desired effect and, in general, will be determined, among other causes, due to the characteristics of the compounds, as well as the age, condition of the patient, the severity of the alteration or disorder, and the route and frequency of administration.
    In a preferred embodiment, the disease or disorder in which DREAM protein expression levels are altered is selected from neurodegenerative diseases, cognitive disorders, sensory perception disorders, inflammatory response disorders and auto-inflammatory diseases.
    In a more preferred embodiment, the disease or disorder in which DREAM protein expression levels are altered is selected from Alzheimer's disease and other dementias, schizophrenia, Huntington's disease, dyskinesia, depression, disorders associated with syndrome. Down, chronic pain, neuropathic pain, allodynia, atherosclerosis, type-2 diabetes, rheumatoid arthritis, gout or acute lung inflammation.
    The compounds and compositions of this invention can be used with other drugs to provide a combination therapy. The other drugs may be part of the same composition, or they may be provided as a separate composition for administration at the same time or at a different time.
    Throughout the description and the claims the word "comprises" and its variants are not intended to exclude other technical characteristics, additives, components or steps. For those skilled in the art, other objects, advantages and features of the invention will be derived partly from the description and partly from the practice of the
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    Method D To a solution of the corresponding amine (0.7 mmol) in DMF (2 mL), 2.2 mmol of DIPEA or NMM are added. The solution is stirred at room temperature for 10 min. A coupling agent (1.1 mmol, HATU, COMU, PyAOP-HOAt, EDC, DIC, HOBt) and the corresponding acid (1.1 mmol) are then added. After 12 h of stirring at room temperature, the solvent is removed under reduced pressure. The reaction crude is suspended in water, acidified with 1N HCl until pH = 3 or 4, extracted with AcOEt (3 x 15 mL) and washed with a saturated NaCl solution (3 x 15 mL). The organic phase is dried over Na2SO4 and the solvent is evaporated to dryness. The resulting residue is purified by medium pressure chromatography.
    Functionalization of the aryl ring. General procedure. Cross coupling technology allows an aryl ring to be functionalized through reactions catalyzed by a transition metal. For example, a Suzuki coupling can be carried out using aryl bromide and a boronic acid coupling partner. Alternatively, couplings between a terminal acetylene and an aryl halide can be carried out by the Sonogashira reaction.
    to. Suzuki Coupling In a microwave tube, an aryl halide (0.4 mmol), the corresponding boronic acid derivative (0.6 mmol), K2CO3 (2.6 mmol), [Pd (PPh3) 4] ( 2% by weight) and 7 mL of a THF / H2O mixture (4/1). The reaction mixture is purged with argon and heated by irradiating at 125 ° C for 15 min in a microwave reactor. Then, 0.6 mmol more of the corresponding boronic acid is added and the procedure described is repeated again. The solvent is removed to dryness, water is added and extracted with DCM (3 x 10 mL). The organic phases are washed with H2O (3 × 10 mL), dried over Na2SO4, and concentrated under reduced pressure. The reaction crude is purified by medium pressure chromatography.
    b. Sonogashira reaction In a sealed tube of 25 mL capacity, the corresponding brominated derivative (0.22 mmol), CuI (0.06 mmol), [Pd (PPh3) 4] (20% by weight), Et3N ( 1.74 mmol), trimethylsilyl alkyl (0.67 mmol) and 1.5 mL of a THF / DMF mixture (10/3). The reaction mixture is heated at 45 ° C for 12 h. The solvent is evaporated to dryness and the


    residue is extracted with AcOEt (3 × 10 mL). The organic phases are washed with H2O (3 × 10 mL), dried over Na2SO4, and concentrated under reduced pressure. The reaction crude is purified by medium pressure chromatography (hexane / AcOEt).
    Saponification of the ester group. General procedure
    To a solution of the corresponding ester (0.09 mmol) in 1.2 mL of THF and 0.6 mL of MeOH, a solution of 2N NaOH (0.2 mL) is added dropwise. After 12 h of stirring at room temperature, the solvent is removed under reduced pressure, water is added and acidified with 1N HCl at pH 3 or 4. The aqueous phase is extracted with AcOEt (3 x 10 mL). The organic extracts are washed with water and saturated NaCl solution, dried over Na2SO4, the solvent is removed to dryness and lyophilized. The product is obtained pure without the need for additional purifications.
    Detailed description of the new compounds prepared:
    2- [2- (3,4-Dichlorophenyl) acetylamino] -4-methoxybenzoic acid. (7) White amorphous solid. Rdto. 60% 1H-NMR (300 MHz, DMSO-d6) G: 3.78 (3H, s), 3.71 (2H, s), 6.69 (1H, dd, J = 8.9, 2.6 Hz), 7.34 (1H, dd, J = 8.3 , 2.1 Hz), 7.60 (1H, d, J = 8.3 Hz), 7.65 (1H, d, J = 2.1 Hz), 7.90 (1H, d, J = 8.9 Hz), 8.18 (1H, d, J = 2.6 Hz),
    11.33 (1H, s), 13.26 (1H, s). 13C-NMR (75 MHz, DMSO-d6) G: 43.0, 55.4, 104.4, 108.3, 108.6, 129.6, 130.2, 130.5, 130.9, 131.8, 132.9, 135.7, 142.7, 163.5, 168.9, 169.2. LC-MS (m / z): 354.4 ([M + H] +).
    4-Chloro-2- [2- (3-phenoxyphenyl) acetylamino] benzoic acid. (9) White crystalline solid. Rdto. 16% 1H-NMR (300 MHz, DMSO-d6) G: 3.80 (2H, s), 6.93 (1H, ddd, J = 8.2, 2.5, 0.9 Hz), 7.02 (3H, m), 7.12 (2H, m), 7.21 (1H, dd, J = 8.6, 2.2 Hz), 7.36 (3H, m), 7.96 (1H, d, J = 8.6 Hz), 8.63 (1H, d, J = 2.2 Hz), 11.21 (1H, s ),
    13.87 (1H, s). 13C-NMR (75 MHz, DMSO-d6) G: 44.5, 115.3, 118.9, 119.4, 120.4, 123.0, 123.7, 125.3, 130.4, 130.6, 133.2, 136.8, 138.8, 142.1, 157.1, 169.0, 170.2. LC-MS:
    382.5 ([M + H] +).
    4-Chloro-2- [2- (4-chloro-2-fluorophenyl) acetylamino] benzoic acid. (10) White crystalline solid. Rdto. 24% 1H-NMR (300 MHz, DMSO-d6) G: 3.86 (2H, s), 7.20 (1H, dd, J = 8.6, 2.2 Hz), 7.25 (1H, m), 7.32 (1H, m), 7.36 ( 1H, m), 7.94 (1H, d, J = 8.6
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    (1H, d, J = 2.2 Hz), 11.19 (1H, s). 13C-NMR (75 MHz, DMSO-d6) G: 29.9, 38.7, 115.7, 119.8, 123.2, 129.3, 129.6, 131.0, 131.4, 133.5, 139.1, 142.3, 142.6, 169.1, 171.3. LC-MS (m / z): 372.1 ([M + H] +).
    4-chloro-2- [2- (3,4-dichlorophenyl) acetylamino] -N-methylbenzamide. (21) White amorphous solid. Rdto. 23% 1H-NMR (400 MHz, DMSO-d6) G: 2.76 (3H, d, J = 4.5 Hz), 3.80 (2H, s), 7.23 (1H, dd, J = 8.5, 2.2 Hz), 7.33 ( 1H, dd, J = 8.3, 2.1 Hz), 7.60 (1H, d, J = 8.3 Hz), 7.63 (1H, d, J = 2.1 Hz), 7.71 (1H, d, J = 8.5 Hz), 8.45 ( 1H, d, J =
    2.2 Hz), 8.76 (1H, d, J = 4.5 Hz), 11.51 (1H, s). 13C-NMR (100 MHz, DMSO-d6) G: 26.9, 43.2, 120.3, 120.4, 123.6, 130.3, 130.7, 131.1, 131.5, 132.4, 136.7, 136.7, 140.5, 168.2, 169.5. LC-MS (m / z): 371.1 ([M + H] +).
    3- [2- (3-Phenoxyphenyl) acetylamino] -2-naphthoic acid. (22) White amorphous solid. Rdto. 61% 1H-NMR (400 MHz, DMSO-d6) G: 3.79 (2H, s), 6.92 (1H, ddd, J = 8.2, 2.5, 0.9 Hz), 7.01 (2H, m), 7.05 (1H, t, J = 2.5 Hz), 7.10 (1H, tt, J = 7.7, 1.1 Hz), 7.15 (1H, dt, J = 8.2, 0.9 Hz), 7.36 (3H, m), 7.45 (1H, ddd, J = 8.1, 6.9, 1.1 Hz), 7.58 (1H, ddd, J = 8.1, 6.9, 1.1 Hz), 7.84 (1H, d, J = 8.1 Hz), 7.99 (1H, d, J = 8.1 Hz), 8.65 (1H, s), 8.92 (1H, s), 11.11 (1H, s). 13C-NMR (100 MHz, DMSO-d6) G: 44.3, 116.6, 117.3, 117.4, 118.5, 120.0, 123.4, 124.9, 125.6, 127.1, 128.2, 129.1, 129.3, 130.0, 130.2, 133.1, 135.5, 136.0, 137.0 , 156.7, 169.3, 169.4. LC-MS (m / z): 398.2 ([M + H] +).
    3- [3- (3- (3,4-Dichlorophenyl) propanoylamino)] - 2-naphthoic acid. (23) White amorphous solid. Rdto. 71% 1H-NMR (400 MHz, DMSO-d6) G: 2.79 (2H, s), 2.97 (2H, s), 7.30 (1H, dd, J = 8.3; 2.0 Hz), 7.47 (1H, td, J = 8.1 , 6.9 Hz), 7.53 (1H, t, J = 8.3 Hz), 7.59 (1H, m), 7.86 (1H, d, J = 8.1 Hz), 8.01 (1H, d, J = 8.1 Hz), 8.67 ( 1H, s), 8.88 (1H, s), 11.15 (1H, s). 13C-NMR (100 MHz, DMSO-d6) G: 29.6, 38.2, 116.7, 117.7, 125.5, 127.1, 128.2, 128.6, 129.0, 129.2, 130.4, 130.5, 130.8, 133.1, 135.5, 135.9, 142.3, 169.5, 170.1 . LC-MS (m / z): 388.2 ([M + H] +).
    4-Bromo-2- [2- (3,4-dichlorophenyl) acetylamino] benzoic acid. (32) White amorphous solid. Rdto. 69% 1H-NMR (400 MHz, DMSO-d6) G: 3.85 (2H, s), 7.36 (2H, dd, J = 8.4, 2.0 Hz), 7.61 (1H, d, J = 8.4 Hz), 7.66 (1H, d, J = 2.0 Hz), 7.87 (1H, d, J = 8.4 Hz), 8.74 (1H, d, J = 2.0 Hz), 11.15 (1H, s). 13C-NMR (100 MHz, DMSO-d6) G:
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    Hz), 8.03 (1H, d, J = 8.2 Hz), 8.83 (1H, d, J = 1.8 Hz), 11.21 (1H, s). 13C-NMR (100 MHz, DMSO-d6) G: 42.9, 115.4, 117.9, 121.1, 126.9, 128.6, 129.1, 129.7, 130.3, 130.5, 130.9, 131.8, 131.9, 135.9, 138.9, 141.1, 145.4, 169.0, 169.2 . LC-MS (m / z): 400.1 ([M + H] +).
    2- [2- (3,4-Dichlorophenyl) acetylamino] -4- (2’-methylphenyl) benzoic acid. (40) White amorphous solid. Rdto. 85% 1H-NMR (400 MHz, DMSO-d6) G: 2.23 (3H, s), 3.84 (2H, s), 7.13 (1H, dd, J = 8.1, 1.8 Hz), 7.20 (1H, m), 7.27 ( 3H, m), 7.36 (1H, dd, J = 8.3,
    2.1 Hz), 7.61 (1H, d, J = 8.3 Hz), 7.67 (1H, d, J = 2.1 Hz), 8.01 (1H, d, J = 8.1 Hz), 8.49 (1H, d, J = 1.8 Hz ), 11.20 (1H, s). 13C-NMR (100 MHz, DMSO-d6) G: 20.1, 42.9, 115.1, 120.5, 123.5, 126.1, 128.0, 129.1, 129.7, 130.3, 130.5, 130.9, 131.0, 131.9, 134.6, 135.9, 140.2, 140.4, 146.8 , 168.9, 169.2. LC-MS (m / z): 414.2 ([M + H] +).
    2- [2- (3,4-Dichlorophenyl) acetylamino] -4- (4’-n-butylphenyl) -benzoic acid. (35) White amorphous solid. Rdto. 94% 1H-NMR (400 MHz, DMSO-d6) G: 0.90 (3H, t, J = 7.3 Hz), 1.31 (2H, sx, J = 7.3 Hz), 1.57 (2H, q, J = 7.3 Hz), 2.62 (2H, t, J = 7.3 Hz), 3.87 (2H, s), 7.31 (2H, d, J = 8.3 Hz), 7.38 (1H, dd, J = 8.3, 2.0 Hz), 7.43 (1H, dd, J = 8.3,
    1.9 Hz), 7.57 (2H, d, J = 8.3 Hz), 7.62 (1H, d, J = 8.3 Hz), 7.68 (1H, d, J = 2.0 Hz), 8.01 (1H, d, J = 8.3 Hz ), 8.82 (1H, d, J = 1.9 Hz), 11.21 (1H, s). 13C-NMR (100 MHz, DMSOd6) G: 13.8, 21.8, 33.0, 34.5, 42.9, 115.0, 117.6, 120.8, 126.7, 129.1, 129.7, 130.3, 130.6, 130.9, 131.8, 131.9, 135.9, 136.2, 141.2, 143.0 , 145.4, 168.9, 169.3. LC-MS (m / z): 456.1 ([M + H] +).
    2- [3- (3,4-Dichlorophenyl) propanoylamino) -5-phenylbenzoic acid. (61) White amorphous solid. Rdto. 99% 1H-NMR (400 MHz, DMSO-d6) G: 2.76 (2H, t, J = 7.5 Hz), 2.93 (2H, t, J = 7.5 Hz), 7.27 (1H, dd, J = 8.3, 2.1 Hz) , 7.35 (1H, tt, J = 7.6, 1.1 Hz), 7.45 (2H, t, J = 7.6 Hz), 7.51 (1H, d, J = 8.3 Hz), 7.56 (1H, d, J = 2.1 Hz) , 7.64 (2H, dd, J = 7.6, 1.1 Hz), 7.88 (1H, dd, J = 8.7, 2.4 Hz), 8.19 (1H, d, J = 2.4 Hz), 8.52 (1H, d, J = 8.7 Hz), 11.20 (1H, s). 13C-NMR (100 MHz, DMSO-d6) G: 30.2, 38.4, 117.9, 121.4, 127.0, 128.2, 129.3, 129.4, 129.6, 129.7, 131.0, 131.2, 131.5, 132.7, 134.9, 139.4, 140.5, 142.8, 170.0 , 170.9. LC-MS: 414.1 (M + H) +. LC-MS (m / z): 414.2 ([M + H] +).
    2- [3- (3,4-Dichlorophenyl) propanoylamino] -5- (2’-methylphenyl) benzoic acid. (44)


    White amorphous solid. Rdto. 66% 1H-NMR (400 MHz, DMSO-d6) G: 2.23 (3H, s), 2.78 (2H, t, J = 7.5 Hz), 2.96 (2H, t, J = 7.5 Hz), 7.21 (1H, m) , 7.29 (4H, m), 7.54 (1H, d, J =
    8.2 Hz), 7.58 (1H, d, J = 2.0 Hz), 7.59 (1H, dd, J = 8.5, 2.2 Hz), 7.88 (1H, d, J = 2.2 Hz), 8.51 (1H, d, J = 8.5 Hz), 11.16 (1H, s), 13.68 (1H, s). 13C-NMR (100 MHz, DMSOd6) G: 20.1, 29.5, 38.1, 116.7, 120.0, 126.1, 127.5, 128.6, 128.9, 129.4, 130.4, 130.4, 130.5, 130.8, 131.1, 134.4, 134.7, 135.3, 139.4, 139.8 , 142.1, 169.3, 170.2. LC-MS (m / z): 428.2 ([M + H] +).
    2- [3- (3,4-Dichlorophenyl) propanoylamino] -5- (4’-tert-butylphenyl) benzoic acid. (43) White amorphous solid. Rdto. 91% 1H-NMR (400 MHz, DMSO-d6) G: 1.31 (3H, s), 2.77 (2H, t, J = 7.5 Hz), 2.95 (2H, t, J = 7.5 Hz), 7.29 (1H, dd, J = 8.3, 2.1 Hz), 7.48 (2H, d, J = 8.4 Hz), 7.53 (1H, d, J = 8.3 Hz), 7.58 (3H, m), 7.88 (1H, dd, J = 8.7, 2.3 Hz), 8.19 (1H, d, J = 2.3 Hz), 8.53 (1H, d, J = 8.7 Hz), 11.10 (1H, s), 13.70 (1H, s). 13C-NMR (100 MHz, DMSO-d6) G: 29.6, 31.2, 34.4, 38.3, 117.2, 120.7, 125.8, 126.0, 128.5, 128.9, 130.4, 130.5, 130.8, 131.9, 134.2, 135.9, 139.6, 142.1, 150.0 , 169.3, 170.2. LC-MS (m / z): 470.3 ([M + H] +).
    2- [3- (3,4-Dichlorophenyl) propanoylamino] -5- (4’-n-butylphenyl) benzoic acid. (38) White amorphous solid. Rdto. 91% 1H-NMR (400 MHz, DMSO-d6) G: 0.90 (3H, t, J = 7.3 Hz), 1.32 (2H, sx, J = 7.3 Hz), 1.57 (2H, q, J = 7.3 Hz), 2.69 (2H, t, J = 7.3 Hz), 2.77 (2H, t, J = 7.5 Hz), 2.95 (2H, t, J = 7.5 Hz), 7.29 (3H, m), 7.53 (1H, d, J = 8.3 Hz), 7.56 (2H, d, J = 8.2 Hz), 7.58 (1H, d, J = 2.0 Hz), 7.88 (1H, dd, J = 8.7, 2.3 Hz), 8.19 (1H, d, J = 2.3 Hz), 8.53 (1H, d, J = 8.7 Hz), 11.10 (1H, s), 13.76 (1H, s). 13C-NMR (100 MHz, DMSO-d6) G: 13.8, 21.8, 29.5, 33.1, 34.4, 38.2, 117.2, 120.7, 126.2, 128.5, 128.6, 128.9, 129.0, 130.4, 130.5, 130.8, 131.8, 134.2, 136.1 , 139.6, 141.8, 142.2, 169.4,
    170.2. LC-MS (m / z): 470.2 ([M + H] +).
    2- [3- (3,4-Dichlorophenyl) propanoylamino] -4-phenylbenzoic acid. (41) White amorphous solid. Rdto. 89% 1H-NMR (400 MHz, DMSO-d6) G: 2.79 (2H, t, J = 7.5 Hz), 2.96 (2H, t, J = 7.4 Hz), 7.30 (1H, dd, J = 8.3, 2.1 Hz) , 7.44 (1H, m), 7.50 (4H, m),
    7.58 (1H, d, J = 2.1 Hz), 7.67 (2H, dd, J = 8.2, 1.3 Hz), 8.05 (1H, d, J = 8.3 Hz), 8.81 (1H, d, J = 1.8 Hz), 11.20 (1H, s). 13C-NMR (100 MHz, DMSO-d6) G: 29.4, 38.2, 115.3, 117.9, 120.9, 126.9, 128.6, 128.7, 128.9, 129.2, 130.4, 130.5, 130.8, 131.8, 139.0, 141.2, 142.1, 145.4, 169.3 , 170.4. LC-MS (m / z): 414.2 ([M + H] +).


    2- [3- (3,4-Dichlorophenyl) propanoylamino] -4- (2’-methylphenyl) benzoic acid. (45) White amorphous solid. Rdto. 94% 1H-NMR (400 MHz, DMSO-d6) G: 2.24 (3H, s), 2.77 (2H, t, J = 7.5 Hz), 2.93 (2H, t, J = 7.5 Hz), 7.12 (1H, dd, J = 8.1, 1.8 Hz), 7.21 (1H, m),
    7.29 (2H, dd, J = 8.2, 2.1Hz), 7.32 (2H, m), 7.52 (1H, d, J = 8.2 Hz), 7.56 (1H, d, J =
    5 2.1 Hz), 8.02 (1H, d, J = 8.1 Hz), 8.47 (1H, d, J = 1.8 Hz), 11.17 (1H, s). 13C-NMR (100 MHz, DMSO-d6) G: 20.1, 29.4, 38.2, 114.9, 120.4, 123.3, 126.1, 128.0, 128.6, 128.9, 129.1, 130.4, 130.5, 130.5, 130.7, 131.0, 134.6, 140.2, 140.0 , 140.5, 142.1, 169.3,
    170.3. LC-MS (m / z): 428.2 ([M + H] +).
    10 2- [3- (3,4-Dichlorophenyl) propanoylamino] -4- (4’-n-butylphenyl) benzoic acid. (64) White amorphous solid. Rdto. 89% 1H-NMR (400 MHz, DMSO-d6) G: 0.90 (3H, t, J = 7.3 Hz), 1.32 (2H, sx, J = 7.3 Hz), 1.57 (2H, q, J = 7.3 Hz), 2.63 (2H, t, J = 7.3 Hz), 2.79 (2H, t, J = 7.5 Hz), 2.96 (2H, t, J = 7.5 Hz), 7.29 (1H, dd, J = 8.2, 2.1 Hz), 7.33 (2H, d, J = 8.3 Hz), 7.42 (1H, dd, J = 8.3, 1.9 Hz), 7.53 (1H, d, J = 8.2 Hz), 7.58 (2H, d, J = 8.3
    15 Hz), 7.58 (1H, d, J = 2.1 Hz), 8.03 (1H, d, J = 8.3 Hz), 8.80 (1H, d, J = 1.9 Hz), 11.19 (1H, s), 13.59 (1H , s). 13C-NMR (100 MHz, DMSO-d6) G: 13.8, 21.8, 29.4, 33.0, 34.5, 38.2, 114.9, 117.6, 120.6, 126.7, 128.6, 128.9, 129.1, 130.4, 130.5, 130.8, 131.8, 136.3, 141.2 , 142.1, 143.0, 145.4, 169.3, 170.4. LC-MS (m / z): 470.3 ([M + H] +).
    Methyl (2R) -2- [2- (3,4-dichlorophenyl) acetylamino] -3- (1-trityl-1H-imidazol-4-yl) propanoate.
    (62)
    White amorphous solid. Rdto. 71% 1H-NMR (300 MHz, CD3Cl) G: 2.91 (1H, dd, J = 14.7,
    4.5 Hz), 3.00 (1H, dd, J = 14.7, 5.8 Hz), 3.51 (3H, s), 4.04 (1H, d, J = 14.3 Hz), 4.06 25 (1H, d, J = 14.3 Hz), 4.66 (1H, ddd, J = 7.8, 5.8, 4.5 Hz), 6.50 (1H, s), 6.99 (6H, m), 7.09 (1H, dd, J = 8.2, 2.1 Hz), 7.19 (1H, s), 7.28 (10H, m), 7.37 (1H, d, J = 2.1 Hz),
    7.68 (1H, d, J = 7.8 Hz). 13C-NMR (75 MHz, CD3Cl) G: 28.0, 41.0, 51.4, 52.0, 75.0, 119.0, 119.1, 119.3, 127.3, 128.0, 129.0, 129.7, 130.0, 130.5, 131.0, 134.5, 136.5, 141.0, 169.0, 171.0 . LC-MS (m / z): 599.1 ([M + H] +).
    30

    Example 2. Tests of the effect of the compounds of the invention on the modulation of the Kv4.3 channel by DREAM.
    The new compounds synthesized according to this invention have been evaluated in vitro in voltage fixation assays in CHO cells transiently transfected with cDNA encoding Kv4.3 only or Kv4.3 in the presence of DREAM (Kv4.3 + DREAM) using the patch-clamp technique Some of the compounds inhibit the modulation of Kv4.3 channels by DREAM. For any of the compounds evaluated, this effect is selective and is observed only in the presence of the DREAM channel modulator. Thus, as seen in Figure 1B, compounds (35) and (42) inhibit the Kv4.3 current only in the presence of DREAM, measured as% decrease in the amount of charge that the membrane passes through and estimated from of the integral of the current. However, (62) does not show selectivity, joining the channel in the absence of DREAM, since it similarly inhibits the current generated by the Kv4.3 channels than that of the Kv4.3 channels in the presence of DREAM. Figure 1A shows a representative example of the effects of (35) (100 nM) on Kv4.3 or Kv4.3 + DREAM channels. Panel B of Figure 1 shows a bar chart comparing the current inhibitory effect Kv4.3 and Kv4.3 + DREAM produced by (35),
    (42) and (62) at 100nM. Example 3: Neuroprotective effect of the compounds of the invention on Q111DR cells
    In an immortalized cell line of STHdhQ111 / Q111 mouse striatum infected with lentivirus expressing the complete human DREAM protein (Q111DR) the neuroprotective effect of the compounds against H2O2-mediated necrosis and staurosporin-mediated apoptosis was studied.
    A representative example of the ability of the compounds to inhibit the release of the enzyme lactate dehydrogenase is shown in Figure 2, which is a reflection of their inhibitory effect on cell death produced by oxidative stress in response to exposure to H2O2. The lower LDH release and therefore the neuroprotective effect of the compound (62) is evident.
    image19
    权利要求:
    Claims (4)
    [1]
    image 1
    image2
    image3
    image4
    image5
    image6

    [38]
    38. Use of a compound of formula (I) according to the preceding claim which is selected from the following list:
    - 4-Chloro-2- [2- (3,4-dichlorophenyl) acetylamino] benzoic acid,
    - 2- [2- (3,4-Dichlorophenyl) acetylamino] -4-methoxybenzoic acid,
    - 4-Chloro-2- [2- (3-phenoxyphenyl) acetylamino] benzoic acid,
    - 4-Chloro-2- [2- (4-chloro-2-fluorophenyl) acetylamino] benzoic acid,
    Methyl -4-chloro-2- [2- (3,4-dichlorophenyl) acetylamino] benzoate,
    - 4-Chloro-2- [2- (3,4-dihydroxyphenyl) acetylamino] benzoic acid,
    - 4-Chloro-2- [3- (3,4-dichlorophenyl) propanoylamino] benzoic acid,
    - 3- [2- (3,4-Dichlorophenyl) acetylamino] -2-naphthoic acid,
    -4-chloro-2- [2- (3,4-dichlorophenyl) acetylamino] -N-methylbenzamide,
    - 3- [2- (3-Phenoxyphenyl) acetylamino] -2-naphthoic acid,
    - 3- [3- (3- (3,4-Dichlorophenyl) propanoylamino)] - 2-naphthoic acid,
    - 4-Bromo-2- [2- (3,4-dichlorophenyl) acetylamino] benzoic acid,
    - 2- [2- (3,4-Dichlorophenyl) acetylamino] -5- (4’-n-butylphenyl) benzoic acid,
    - 2- [2- (3,4-Dichlorophenyl) acetylamino] -4- (4’-n-butylphenyl) -benzoic acid,
    - 2- [2- (3,4-Dichlorophenyl) acetylamino] -5- (4’-tert-butylphenyl) -benzoic acid,
    - 2- [2- (3,4-Dichlorophenyl) acetylamino] -5- (2’-methylphenyl) -benzoic acid,
    - 2- [3- (3,4-Dichlorophenyl) propanoylamino] -5- (4’-n-butylphenyl) benzoic acid,
    - 2- [2- (3,4-Dichlorophenyl) acetylamino] -4-phenylbenzoic acid,
    - 2- [2- (3,4-Dichlorophenyl) acetylamino] -4- (2’-methylphenyl) benzoic acid,
    - 2- [3- (3,4-Dichlorophenyl) propanoylamino] -4-phenylbenzoic acid,
    - 2- [2- (3,4-Dichlorophenyl) acetylamino] -5-phenylbenzoic acid,
    - 2- [3- (3,4-Dichlorophenyl) propanoylamino] -5- (4’-tert-butylphenyl) benzoic acid,
    - 2- [3- (3,4-Dichlorophenyl) propanoylamino] -5- (2’-methylphenyl) benzoic acid,
    - 2- [3- (3,4-Dichlorophenyl) propanoylamino] -4- (2’-methylphenyl) benzoic acid,
    - 2- [2- (3,4-Dichlorophenyl) acetylamino] -4-ethynylbenzoic acid,
    Methyl -2- [2- (3,4-dichlorophenyl) acetylamino] -5-phenylbenzoate,
    Methyl -2- [2- (3,4-dichlorophenyl) acetylamino] -5- (2’-methylphenyl) benzoate,
    Methyl -2- [2- (3,4-dichlorophenyl) acetylamino] -5- (4’-tert-butylphenyl) benzoate,
    Methyl -2- [2- (3,4-dichlorophenyl) acetylamino] -5- (4’-n-butylphenyl) benzoate,
    Methyl -2- [2- (3,4-dichlorophenyl) acetylamino] -4-phenylbenzoate,
    Methyl -2- [2- (3,4-dichlorophenyl) acetylamino] -4- (2’-methylphenyl) benzoate,
    37

    Methyl -2- [2- (3,4-dichlorophenyl) acetylamino] -4- (4’-n-butylphenyl) benzoate,
    Methyl -2- [3- (3,4-dichlorophenyl) propanoylamino] -5-phenylbenzoate,
    -2- [3- (3,4-Dichlorophenyl) propanoylamino] -5- (2’-methylphenyl) methyl benzoate,
    Methyl -2- [3- (3,4-dichlorophenyl) propanoylamino] -5- (4'-n-butylphenyl) benzoate, 5 -2- [3- (3,4-dichlorophenyl) propanoylamino] -4-phenylbenzoate of methyl,
    -2- [3- (3,4-Dichlorophenyl) propanoylamino] -4- (2’-methylphenyl) methyl benzoate,
    Methyl -2- [3- (3,4-dichlorophenyl) propanoylamino] -4- (4’-n-butylphenyl) benzoate,
    -2- [3- (3,4-Dichlorophenyl) propanoylamino) -5-phenylbenzoic acid,
    - (2R) -2- [2- (3,4-Dichlorophenyl) acetylamino] -3- (1-trityl-1H-imidazol-4-yl) propanoate 10,
    -N- (2-benzoylphenyl) -2- (3,4-dichlorophenyl) acetamide and
    - 2- [3- (3,4-Dichlorophenyl) propanoylamino] -4- (4’-n-butylphenyl) benzoic acid.
    [39]
    39. Use of a compound of formula (I) according to any of claims 37
    15 or 38 for the manufacture of a medicament for the treatment of a disease or disorder in which the DREAM protein has altered expression levels.
    [40]
    40. Use according to the preceding claim wherein the disease or disorder in which
    20 DREAM protein expression levels are altered, it is selected from neurodegenerative diseases, cognitive disorders, sensory perception disorders, inflammatory response disorders and autoinflammatory diseases.
    Use according to the preceding claim wherein the disease or disorder in which the expression levels of the DREAM protein are altered is selected from Alzheimer's disease and other dementias, schizophrenia, Huntington's disease, dyskinesia, depression, associated disorders. Down syndrome, chronic pain, neuropathic pain, allodynia, atherosclerosis, type-2 diabetes, arthritis
    30 rheumatoid, gout, or acute pulmonary inflammation.
    38
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