• 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:
    Piperidine derivative compounds as inhibitors of PDE8A. The present invention relates to piperidine derivatives as inhibitors of the PDE8A enzyme. These compounds, therefore, are useful for the manufacture of a medicament for the treatment and/or prevention of diseases in which PDE8A is involved, such as neurodegenerative and/or neurological diseases, among which are Alzheimer's and Parkinson's. (Machine-translation by Google Translate, not legally binding)
    公开号:ES2696516A1
    申请号:ES201730924
    申请日:2017-07-12
    公开日:2019-01-16
    发明作者:Ayuso-Gontán Carmen Gil；Gil Ana Martínez；Pérez Victor Sebastián；Diaz Julie C Herrera
    申请人:Consejo Superior de Investigaciones Cientificas CSIC；
    IPC主号:
    专利说明:

    [0001]
    [0002] Piperidine derivative compounds as PDE8A inhibitors
    [0003]
    [0004] The present invention relates to inhibitors of the PDE8A enzyme and its use for the treatment of neurodegenerative and / or neurological diseases such as Alzheimer's and Parkinson's. Therefore, the invention could be framed in the field of pharmaceutical chemistry.
    [0005]
    [0006] BACKGROUND OF THE INVENTION
    [0007] The guanosine and cyclic 3 ', 5' adenosine monophosphate compounds (cAMP and cGMP) are the second messengers that mediate the response of cells to a wide variety of hormones and neurotransmitters and modulate many metabolic processes. Phosphodiesterases (PDE) are the only enzymes that hydrolyze these cyclic nucleotides and thus play crucial roles in the physiological processes that involve the signaling pathway of these nucleotides. Phosphodiesterase-8 (PDE8) is a cAMP-specific enzyme and plays an important role in many biological processes, including T-cell activation, testosterone production, adrenocortical hyperplasia and thyroid function. See Wang et al., Biochemistry, 2008, 47 (48), 12760-8.
    [0008]
    [0009] Selective PDE inhibitors have been widely studied as therapeutic agents for the treatment of various human diseases (Maurice, DH et al., Nat. Rev. Drug Discov., 2014, 13, 290-314). For example, substituted triazolopyrimidine is disclosed in WO2011058478 as inhibitors of the PDE8 enzyme and its application in the treatment of neurodegenerative and / or neurological diseases, such as Alzheimer's.
    [0010] In the following publication: Michael P. DeNinno et al. "1,5-Substituted nipecotic amides: Selective PDE8 inhibitors displaying diastereomer-dependent microsomal stability" Bioorganic & Medicinal Chemistry Letters 21 (2011) 3095-3098, compounds are disclosed as inhibitors of PDE8B that could have utility in the treatment of diabetes.
    [0011]
    [0012] The present invention relates to piperidine derivatives as inhibitors of the PDE8A enzyme useful for the treatment of diseases neurodegenerative and / or neurological where this enzyme is overexpressed. Therefore, an alternative or improvement to the already known compounds for the treatment of this type of diseases is presented.
    [0013]
    [0014] DESCRIPTION OF THE INVENTION
    [0015] The present invention presents a family of compounds that possess the ability to inhibit the enzyme PDE8A in micromolar order, being useful for the treatment of neurological and / or neurodegenerative diseases mediated by said enzyme.
    [0016]
    [0017] In a first aspect, the present invention relates to the use of a compound of formula (I) or any of its isomers or pharmaceutically acceptable salts thereof
    [0018]
    [0019]
    [0020]
    [0021] where
    [0022] R1 is selected from - (O) -C1-C3 alkyl and -NH- (CH2) n-R1 ';
    [0023] n is a value between 0 and 2 and
    [0024] R1 'is an aryl optionally substituted by a - (O) -C1-C3 alkyl, by a halogen selected from fluorine, chlorine, bromine and iodine or by a C1-C3 alkyl,
    [0025] R2 is an aryl optionally substituted by a C1-C3 alkyl or by a halogen selected from fluorine, chlorine, bromine and iodine,
    [0026] R3 is a C1-C3 alkyl,
    [0027] with the proviso that when R1 is -NH- (CH2) n-R1 ', the compound is the R-isomer, for the treatment or prevention of neurodegenerative and / or neurological diseases mediated by the enzyme PDE8A.
    [0028]
    [0029] In a preferred embodiment of the present invention, R1 is -NH- (CH2) n-R1 '(R1' as defined above) and n is a value between 1 and 2, more preferably 1.
    [0030]
    [0031] In a preferred embodiment of the present invention, R1 is -NH- (CH2) n -R1 ', n is 1 and R1 'is a phenyl optionally substituted by a - (O) -C1-C3 alkyl or by a halogen selected from fluorine, chlorine, bromine and iodine.
    [0032] In a more preferred embodiment R1 'is unsubstituted phenyl.
    [0033]
    [0034] In another more preferred embodiment R1 'is meta- or para-methoxyphenyl.
    [0035]
    [0036] In another more preferred embodiment R1 'is meta- or para-chlorophenyl.
    [0037]
    [0038] In a preferred embodiment of the present invention R1 is - (O) -C1-C3 alkyl, more preferably R1 is -O-ethyl.
    [0039]
    [0040] In another preferred embodiment of the present invention R2 is a phenyl.
    [0041] In another preferred embodiment of the present invention R2 is a is a phenyl substituted by C1-C3 alkyl, preferably methyl; preferably the substitution by C1-C3 alkyl is meta- position and more preferably R2 is a meta-methylphenyl.
    [0042]
    [0043] In another preferred embodiment of the present invention R2 is a phenyl substituted by a halogen, preferably fluorine; more preferably the halogen substitution is in the ortho position and more preferably R2 is an orfo-fluorophenyl.
    [0044]
    [0045] In another preferred embodiment of the present invention, R1 is -NH- (CH2) n -R1 ', where n1 and R1' are a phenyl optionally substituted by a - (O) -C1-C3 alkyl or by a halogen selected from fluorine , chlorine, bromine and iodine, more preferably R1 'is selected from unsubstituted phenyl, meta- or para-methoxyphenyl and meta- or para-chlorophenyl, and R2 is an ortho-fluorophenyl.
    [0046]
    [0047] In another preferred embodiment of the present invention, R1 is -NH- (CH2) n -R1 ', where n1 and R1' are a phenyl optionally substituted by a - (O) -C1-C3 alkyl or by a halogen selected from fluorine , chlorine, bromine and iodine, more preferably R1 'is selected from unsubstituted phenyl, meta- or para-methoxyphenyl and meta- or para-chlorophenyl, and R2 is a meta-methylphenyl.
    [0048]
    [0049] In a preferred embodiment of the present invention R1 is - (O) -C1-C3 alkyl, preferably -O-ethyl and R2 is an unsubstituted phenyl.
    [0050] In a preferred embodiment of the present invention R1 is- (O) -C1-C3 alkyl, preferably -O-ethyl and R2 is a phenyl substituted by a C1-C3 alkyl, more preferably R2 is mepha-methylphenyl.
    [0051]
    [0052] In a preferred embodiment of the present invention R3 is methyl.
    [0053]
    [0054] In a more preferred embodiment of this first aspect, the invention relates to the use of the compounds of formula (I) selected from the list comprising:
    [0055] - (R) -W-benzyl-1 - ((2- (2-fluorophenyl) -5-methyloxazol-4-yl) methyl) piperidine-3-carboxamide;
    [0056] - (R) -1 - ((2- (2-fluorophenyl) -5-methyloxazol-4-yl) methyl) -W- (3-methoxybenzyl) piperidine-3-carboxamide;
    [0057] - (R) -W- (3-chlorobenzyl) -1 - ((2- (2-fluorophenyl) -5-methyloxazol-4-yl) methyl) piperidine-3-carboxamide;
    [0058] - (R) -W- (4-chlorobenzyl) -1 - ((2- (2-fluorophenyl) -5-methyloxazol-4-yl) methyl) piperidine-3-carboxamide;
    [0059] - (R) -1 - ((5-methyl-2- (m-tolyl) oxazol-4-yl) methyl) piperidine-3-carboxylic acid ethyl ester;
    [0060] - 1 - ((5-methyl-2- (m-tolyl) oxazol-4-yl) methyl) piperidine-3-carboxylic acid ethyl ester;
    [0061] - (R) -1 - ((5-methyl-2-phenyloxazol-4-yl) methyl) piperidine-3-carboxylic acid ethyl ester and
    [0062] - 1 - ((5-Methyl-2-phenyloxazol-4-yl) methyl) piperidine-3-carboxylic acid ethyl ester.
    [0063]
    [0064] A second aspect of the invention relates to the use of a compound of formula (II) or any of its isomers or pharmaceutically acceptable salts thereof:
    [0065]
    [0066]
    [0067]
    [0068] Formula (II)
    [0069] where
    [0070] R1 is - (O) -C1-C3 alkyl,
    [0071] R2 is an aryl optionally substituted by a C1-C3 alkyl,
    [0072] R3 is a C1-C3 alkyl,
    [0073] for the preparation of a medication.
    [0074]
    [0075] In a preferred embodiment of this second aspect of the present invention, R1 is -O-ethyl.
    [0076]
    [0077] In another preferred embodiment of this second aspect of the present invention, R3 is a methyl.
    [0078]
    [0079] In another preferred embodiment of this second aspect of the present invention, R 2 is an unsubstituted phenyl.
    [0080]
    [0081] In another preferred embodiment of this second aspect of the present invention, R 2 is a phenyl substituted by a C 1 -C 3 alkyl, more preferably R 2 is mepha-methylphenyl.
    [0082]
    [0083] In a preferred embodiment of this second aspect of the present invention, the compound of formula (II) is a racemic mixture.
    [0084]
    [0085] In a preferred embodiment of this second aspect of the present invention, the compound of formula (II) is the R-isomer.
    [0086]
    [0087] In a more preferred embodiment of this second aspect, the invention relates to the use of the compounds of formula (II) selected from the list comprising:
    [0088] - (R) -1 - ((5-methyl-2- (m-tolyl) oxazol-4-yl) methyl) piperidine-3-carboxylic acid ethyl ester;
    [0089] - 1 - ((5-methyl-2- (m-tolyl) oxazol-4-yl) methyl) piperidine-3-carboxylic acid ethyl ester;
    [0090] - (R) -1 - ((5-methyl-2-phenyloxazol-4-yl) methyl) piperidine-3-carboxylic acid ethyl ester and
    [0091] - 1 - ((5-Methyl-2-phenyloxazol-4-yl) methyl) piperidine-3-carboxylic acid ethyl ester.
    [0092]
    [0093] The compounds of the present invention, both of general formula (I) and of general formula (II) are inhibitors of the PDE8A enzyme, therefore, these compounds are used for the treatment and / or prevention of diseases in which it is involved this enzyme.
    [0094] Neurodegenerative and / or neurological diseases can be selected from the list comprising, but not limited to, Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, cerebral ischemia, post-encephalitic parkinsonisms, dystonia, Tourette's syndrome, pathologies of periodic limbic movements, restless legs syndrome, epilepsy and combinations thereof.
    [0095]
    [0096] A third aspect of the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or (II) together with a pharmaceutically acceptable carrier or excipient.
    [0097]
    [0098] In general, the therapeutically effective amount of the compound of formula (I) or (II) to be administered will depend, among other factors, on the individual to be treated, on the severity of the disease that said individual suffers, on the form of administration chosen, etc. For this reason, the doses mentioned in this invention should only be considered as guidelines for the person skilled in the art, and he should adjust the doses according to the variables mentioned above. However, a compound of formula (I) or (II) can be administered one or more times a day, for example, 1, 2, 3 or 4 times a day, in a typical total daily amount comprised between 0.1 and 1000. mg / kg body mass / day, preferably 10 mg / kg body mass / day.
    [0099]
    [0100] A final aspect of the present invention relates to the following compounds of formula (I):
    [0101] - (R) -W-benzyl-1 - ((2- (2-fluorophenyl) -5-methyloxazol-4-yl) methyl) piperidine-3-carboxamide;
    [0102] - (R) -1 - ((2- (2-fluorophenyl) -5-methyloxazol-4-yl) methyl) -W- (3-methoxybenzyl) piperidine-3-carboxamide;
    [0103] - (R) -W- (3-chlorobenzyl) -1 - ((2- (2-fluorophenyl) -5-methyloxazol-4-yl) methyl) piperidine-3-carboxamide;
    [0104] - (R) -W- (4-chlorobenzyl) -1 - ((2- (2-fluorophenyl) -5-methyloxazol-4-yl) methyl) piperidine-3-carboxamide;
    [0105] - (R) -1 - ((5-methyl-2- (m-tolyl) oxazol-4-yl) methyl) piperidine-3-carboxylic acid ethyl ester;
    [0106] - 1 - ((5-methyl-2- (m-tolyl) oxazol-4-yl) methyl) piperidine-3-carboxylic acid ethyl ester;
    [0107] - (R) -1 - ((5-methyl-2-phenyloxazol-4-yl) methyl) piperidine-3-carboxylic acid ethyl ester;
    [0108] - 1 - ((5-Methyl-2-phenyloxazol-4-yl) methyl) piperidine-3-carboxylic acid ethyl ester.
    [0109]
    [0110] The compounds of the present invention of formula (I) and formula (II) have the ability to cross the blood-brain barrier, as shown in the examples below. This supposes an additional advantage of the compounds to the time to use them in therapeutic treatments of diseases related to the central nervous system, such as neurodegenerative and / or neurological diseases.
    [0111]
    [0112] The compounds of the invention represented by the formula (I) or the formula (II) may be in crystalline form as free compounds or as solvates and both forms are intended to be within the scope of the present invention. In this sense, the term "solvate", as used herein, includes both pharmaceutically acceptable solvates, ie, solvates of the compound of formula (I) and (II) which can be used in the manufacture of a medicament, as solvates pharmaceutically acceptable, which may be useful in the preparation of solvates or pharmaceutically acceptable salts. The nature of the pharmaceutically acceptable solvate is not critical as long as it is pharmaceutically acceptable. In a particular embodiment, the solvate is a hydrate. The solvates can be obtained by conventional solvation methods well known to those skilled in the art.
    [0113]
    [0114] The compounds of formula (I) or of formula (II) for therapeutic use are prepared in solid form or aqueous suspension, in a pharmaceutically acceptable diluent. These preparations can be administered by any appropriate route of administration, for which said preparation will be formulated in the pharmaceutical form appropriate to the chosen administration route. In a particular embodiment, the administration of the compound of formula (I) or of formula (II) is carried out orally, topically, rectally or parenterally (including subcutaneously, intraperitoneally, intradermally, intramuscularly, intravenously, etc.). A review of the different pharmaceutical forms of drug administration and of the excipients necessary for obtaining them can be found, for example, in the "Galenic Pharmacy Treaty", C. Faulí i Trillo, 1993, Luzán 5, S.A. Editions, Madrid, or in other habitual or similar ones of the Spanish Pharmacopoeias and in the United States.
    [0115]
    [0116] The compounds described in the present invention, their pharmaceutically acceptable salts, solvates as well as the pharmaceutical compositions containing them can be used together with other additional drugs to provide a combination therapy. Said additional drugs can be part of the same pharmaceutical composition or, alternatively, they can be provided in the form of a separate composition for simultaneous administration or not to that of the pharmaceutical composition comprising a compound of formula (I) or of formula (II), or a pharmaceutically acceptable salt or solvate thereof.
    [0117]
    [0118] Unless otherwise indicated, the compounds of the invention also include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having said structure, with the exception of the substitution of a hydrogen by a deuterium or by tritium, or the substitution of a carbon for a carbon enriched in 13C or 14C or a nitrogen enriched in 15N, are within the scope of this invention.
    [0119]
    [0120] In the present invention, the term "C1-C3 alkyl" refers, in the present invention, to hydrocarbon chain, linear or branched chain residues, having from 1 to 3 carbon atoms and which are attached to the rest of the molecule by a single bond, for example, propyl, ethyl, methyl, isopropyl, undecanoyl, heptadecanoyl, octadecanoyl, etc. These alkyl radicals may be optionally substituted at one or more positions by one or more groups such as hydroxyl, amines, amides, oxo, cyano, halogens, aryl, etc.
    [0121]
    [0122] The term "aryl" refers in the present invention to an aromatic carbocyclic chain, having from 6 to 12 carbon atoms, being able to be single or multiple ring, in the latter case with separate and / or condensed rings. non-limiting, aryl is a phenyl group.
    [0123]
    [0124] The term "treatment or prevention" as used herein, unless otherwise indicated, means reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which it is applied in such terms, one or more symptoms of such disorder or condition.
    [0125]
    [0126] The term "excipients, adjuvants and / or vehicles" refers to molecular entities or substances with which the active ingredient is administered Such pharmaceutical excipients, adjuvants or vehicles can be sterile liquids, such as waters and oils, including those of petroleum or of animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like, excipients, disintegrants, wetting agents or diluents. describe suitable excipients and pharmaceutical vehicles in "Remington's Pharmaceutical Sciences" by EW Martin.
    [0127]
    [0128] Throughout the description and the claims the word "comprises" and its variants do not intend to exclude other technical characteristics, additives, components or steps. For those skilled in the art, other objects, advantages and characteristics of the invention will emerge partly from the description and partly from the practice of the invention. The following examples are provided by way of illustration, and are not intended to be limiting of the present invention.
    [0129]
    [0130] EXAMPLES
    [0131]
    [0132] The invention will now be illustrated by means of tests carried out by the inventors, which show the effectiveness of the product of the invention.
    [0133]
    [0134] Example 1: General procedure for the synthesis of ^ -substituted piperidinecarboxamide derivatives (compounds 1 to 5):
    [0135]
    [0136] The synthesis of this family of compounds was carried out by a synthetic route consisting of 4 steps from the commercial 3-piperidinecarboxylic acid (Scheme 1). The first stage of synthesis consists of the protection reaction of the amino group of the piperidine (a) to obtain the piperidine derivative ^ -protected with the protective group (GP) Boc. From this initial stage the carboxylic acid is transformed into amide by reaction with the corresponding amine (b). Finally, the deprotection of the amine (c) followed by the W-alkylation with the corresponding alkyl halide (d) allows obtaining the final product.
    [0137]
    [0138]
    [0139]
    [0140]
    [0141] Scheme 1. Synthetic route to obtain the new 1.3 disubstituted derivatives proposed.
    [0142] The corresponding substituted carboxamide derivative (1eq.) Is added to a 25 mL flask and dissolved in 5 mL of dichloromethane. Once dissolved, trifluoroacetic acid (4 eq.) Is added at room temperature and the stirring for 2 hours. Then, the solvent is removed under reduced pressure. The residue is dissolved in dimethylformamide (DMF), transferred to a microwave vial, diisopropylethylamine (DIPEA) (4eq.) And the corresponding halide (1 eq.) Are added. It is subjected to microwave irradiation for 1 hour and 10 minutes at 130 ° C. The reaction crude is then added to 30 ml of a NaClsat solution and extracted with ethyl acetate (3x25 ml). The organic phase is dried over anhydrous MgSO 4, filtered and the solvent is evaporated under reduced pressure. The reaction crude is purified by chromatography of the eluent mixture indicated in each case.
    [0143]
    [0144] (R) -W-benzM - ((5-methyl-2- (m-tolyl) oxazol-4-yl) methyl) piperidine-3-carboxamide (1)
    [0145]
    [0146] Reagents: 1- (R) - (3- (benzylcarbamoyl) piperidine) tere-butyl carboxylate (300 mg, 0.95 mmol), trifluoroacetic acid (0.29 mL, 3.8 mmol), dichloromethane (5 mL). DIPEA (0.65 mL, 3.76 mmol), 4- (chloromethyl) -5-methyl-2- (m-tolyl) oxazole (210 mg, 0.95 mmol) and DMF (5 mL). Purification: IsoleraOne equipment, using a mixture of AcOEt / Methanol (9: 1) as eluents, obtaining an oil. Yield: 229 mg (54%). 1 H-NMR (300 MHz, Acetone- ^): 57.83-7.65 (m, 2H), 7.40-7.06 (m, 7H), 4.42-4.23 (m, 2H) , 3.52 3.33 (m, 2H), 2.84-2.66 (m, 2H), 2.51 (m, 2H), 2.37 (s, 7H), 1.82-1, 56 (m, 4H). 13 C-NMR (75 MHz, Methanol-ck): 5177.2, 161.5, 148.5, 140.3, 140.1, 133.2, 132.4, 130.1, 129.7, 128, 6, 128.5, 128.3, 127.7, 124.4, 56.4, 54.9, 54.2, 44.1, 44.0, 28.5, 25.0, 21.6, 10.4. HRMS (ESI) calcd (C 25 H 29 N 3 O 2): 403.2264, found [M + H] +: 404.2337.
    [0147]
    [0148] (R) -W-benzyl-1 - ((2- (2-fluorophenyl) -5-methyloxazol-4-yl) methyl) piperidine-3-carboxamide (2)
    [0149] Reagents: 1- (R) - (3- (benzylcarbamoyl) piperidine) tere-butyl carboxylate (300 mg, 0.95 mmol), trifluoroacetic acid (0.29 mL, 3.8 mmol), dichloromethane (5 mL) . DIPEA (0.65 mL, 3.76 mmol), 4- (chloromethyl) -2- (2-fluoromethyl) -5-methyloxazole (210 mg, 0.95 mmol) and DMF (5 mL). Purification: IsoleraOne equipment, using a mixture of AcOEt / Methanol (9: 1) as eluents, obtaining an oil. Yield: 135 mg (45%). 1 H-NMR (300 MHz, CDCl 3): 57.94-7.80 (m, 1H), 7.46-7.31 (m, 1H), 7.18-7.07 (m, 7H), 4.51 - 4.28 (m, 2H), 3.53 - 3.24 (m, 2H), 3.07 - 2.77 (m, 2H), 2.59 - 2.50 (m, 1H ), 2.29 (s, 5H), 2.06-1.91 (m, 1H), 1.78-1.51 (m, 3H). 13 C-NMR (75 MHz, CDCl3): 5 174.9, 159.8 (d, J = 255.2 Hz), 156.2 (d, J = 4.7 Hz), 146.6, 139.2, 132.1, 131.6 ( d, J = 8.1 Hz), 129.4 (d, J = 1.7 Hz), 128.4, 127.3, 126.9, 124.3 (d, J = 3.7 Hz), 116.8 (d, J = 21.5 Hz), 115.8 (d, J = 13.4 Hz) 54.3, 54.2, 53.4, 43.0, 42.8, 27.1 , 22.8, 10.2. HRMS (ESI) calcd (C 24 H 26 FN 3 O 2): 407.2024, found [M + H] +: 408.2096.
    [0150]
    [0151] (R) -1 - ((2- (2-fluorophenyl) -5-methyloxazol-4-yl) methyl) -W- (3-methoxybenzyl) piperidine-3-carboxamide (3)
    [0152] Reagents: (R) -3 - ((3-methoxybenzyl) carbamoyl) piperidine-1-carboxylic acid tert -butyl ester (315 mg, 0.90 mmol), trifluoroacetic acid (0.28 mL, 3.62 mmol), dichloromethane (5 mL). DIPEA (0.6 mL, 3.62 mmol), 4- (chloromethyl) -2- (2-fluorophenyl) -5-methyloxazole (203 mg, 0.90 mmol) and DMF (5 mL). Purification: chromatographic column, using a mixture of AcOEt / Methanol (9: 1) as eluents, obtaining a yellow oil. Yield: 105.5 mg (26.5%)
    [0153] 1 H-NMR (300 MHz, CDCfe): 57.94-7.80 (m, 1H), 7.46-7.31 (m, 1H), 7.18-7.07 (m, 7H), 4.51 - 4.28 (m, 2H), 3.53 - 3.24 (m, 2H), 3.07 - 2.77 (m, 2H), 2.59 - 2.50 (m, 1H ), 2.29 (s, 5H), 2.06-1.91 (m, 1H), 1.78-1.51 (m, 3H). 13 C NMR (75 MHz, CDCfe) 5 175.1, 159.6 (d, J = 257.9 Hz), 159.6, 156.3 (d, J = 4.6 Hz), 146.5, 140.7, 132.3, 131.5 (d, J = 8.4 Hz), 129.3, 129.3 (d, J = 1.9 Hz), 124.2 (d, J = 3, 7 Hz), 119.4, 116.7 (d, J = 21.5 Hz), 115.7 (d, J = 11.0 Hz), 112.6, 112.4, 55.0, 54.2, 54.0, 53.2, 42.7, 41.5, 27.0, 22.7, 10.2. HRMS (ESI) calcd (C25H28FN3O3): 437.2148, found [M + H] +: 438.2187.
    [0154]
    [0155] (R) -W- (3-chlorobenzyl) -1 - ((2- (2-fluorophenyl) -5-methyloxazol-4-yl) methyl) piperidine-3-carboxamide (4)
    [0156] Reagents: (R) -3 - ((3-chlorobenzyl) carbamoyl) piperidine-1-carboxylic acid tert -butyl ester (280 mg, 0.81 mmol), trifluoroacetic acid (0.23 mL, 3.08 mmol), dichloromethane (5 mL). DIPEA (0.5 mL, 3.08 mmol), 4- (chloromethyl) -2- (2-fluorophenyl) -5-methyloxazole (174 mg, 0.77 mmol) and DMF (5 mL). Purification: chromatographic column, using a mixture of AcOEt / Methanol (9: 1) as eluents, obtaining a yellow oil. Yield: 74 mg (21%). 1 H NMR (300 MHz, CDCh) 57.81 (td, J = 8.0, 1.8 Hz, 1H), 7.40-7.30 (m, 1H), 7.17-7.05 ( m, 3H), 7.04-6.95 (m, 3H), 4.40-4.33 (m, 2H), 3.55-3.23 (m, 2H), 3.07-2, 85 (m, 2H), 2.60 - 2.50 (m, 1H), 2.29 (s, 5H), 2.07 - 1.95 (m, 1H), 1.80 - 1.50 ( m, 3H). 13 C NMR (75 MHz, CDCl 3) 5175.1, 159.6 (d, J = 256.4 Hz), 156.2 (d, J = 4.6 Hz), 146.3, 141.2, 133.9 , 132.2, 131.4 (d, J = 8.4 Hz), 129.4, 129.0 (d, J = 1.9 Hz), 126.9, 126.7, 124.9, 124 , 0 (d, J = 3.7 Hz), 116.6 (d, J = 21.5 Hz), 115.4 (d, J = 10.9 Hz), 54.2, 53.6, 53 , 0.41.9, 41.2, 26.8, 22.5, 10.0. HRMS (ESI) calcd (C24H25ClFN3O2): 441.1616, found [M + H] +: 442.1652.
    [0157]
    [0158] (R) -W- (4-chlorobenzyl) -1 - ((2- (2-fluorophenyl) -5-methyloxazol-4-yl) methyl) piperidine-3-carboxamide (5)
    [0159] Reagents: tere-butyl (R) -3 - ((4-chlorobenzyl) carbamoyl) piperidine-1-carboxylate (273 mg, 0.77 mmol), trifluoroacetic acid (0.23 mL, 3.09 mmol), dichloromethane (5 mL). DI PEA (0.54 mL, 3.09 mmol), 4- (chloromethyl) -2- (2-fluorophenyl) -5-methyloxazole (174 mg, 0.77 mmol) and DMF (5 mL). Purification: chromatographic column, using a mixture of AcOEt / Methanol (9: 1) as eluents, obtaining a yellow oil. Yield: 88.5 mg (26%). 1 H NMR (300 MHz, CDCfe) 57.83 (td, J = 7.9, 1.8 Hz, 1H), 7.42-7.32 (m, 1H), 7.19-7.09 ( m, 2H), 7.08-7.01 (m, 4H), 4.39-4.33 (m, 2H), 3.54-2.122 (m, 2H), 3.07-2, 84 (m, 2H), 2.55 (m, 1H), 2.28 (s, 5H), 2.04-1.95 (m, 1H), 1.73-1.50 (m, 3H) .13 C-NMR (75 MHz, CDCfe) 5 175.2, 159.7 (d, J = 256.4 Hz), 156.3 (d, J = 4.8 Hz), 146.5, 137, 8, 132.4, 131.7 (d, J = 8.4 Hz), 129.1 (d, J = 1.8 Hz), 128.4, 128.4, 124.3 (d, J = 3.7 Hz), 116.8 (d, J = 21.4 Hz), 115.6 (d, J = 10.9 Hz), 54.4, 53.7, 53.1, 42.0, 41.3, 27.0, 22.6, 10.2. HRMS (ESI) calcd (C24H25CFN3O2): 441.1619, found [M + H] +: 442.1676.
    [0160]
    [0161] Example 2: General procedure for the synthesis of ^ -substituted ethyl piperidine-3-carboxylate derivatives (compounds 6 to 9):
    [0162]
    [0163] The corresponding ethyl piperidine-3-carboxylate (1 equiv) is dissolved in 5 mL of acetonitrile, with K2CO3 (1.2 equiv) and the oxazole derivative (1 equiv) being added. The reaction mixture is heated under microwave irradiation for 75 min at 95 ° C. After this time, an extraction with 3x15mL ethyl acetate is carried out. The organic phase is dried over anhydrous MgSO 4, filtered and the solvent is evaporated under reduced pressure. The reaction crude is purified by chromatography using a mixture of Hexane: AcOEt as eluents.
    [0164]
    [0165] (R) -1 - ((5-Methyl-2- (m-tolyl) oxazol-4-yl) methyl) piperidine-3-carboxylic acid ethyl ester (6) Reagents: ethyl (R) -piperidine-3-carboxylate (0.398 mg, 2.59 mmol), acetonitrile (5 mL), potassium carbonate (429 mg, 3.11 mmol), 4- (chloromethyl) -5-methyl-2- (m-tolyl) oxazole (600 mg, 2.71 mmol). Purification: chromatographic column, using a mixture of Hexane: AcOEt (9: 1) as eluents, obtaining a yellow oil. Performance: 492 mg (56%). 1 H NMR (300 MHz, CDCl 3) 57.85 (s, 1H), 7.78 (d, J = 7.7 Hz, 1H), 7.28 (t, J = 7 , 7 Hz, 1H), 7.21 (d, J = 7.4 Hz, 1H), 4.10 (q, J = 7.1 Hz, 2H), 3.45 (s, 2H), 3, 13-3.02 (m, 1H), 2.93-2.80 (m, 1H), 2.62 (m, 1H), 2.38 (s, 3H), 2.36 (s, 3H) , 2.25-2.04 (m, 1H), 2.04 - 1.88 (m, 2H), 1.79-1.51 (m, 2H), 1.50 - 1.35 (m, 1H), 1.22 (t, J = 7.1 Hz, 3H). 13 C NMR (75 MHz, CDCl 3) 5 174.3, 159.7, 146.2, 138.4, 132.3, 130.7, 128.6, 127.6, 126.7, 123.2, 60.3, 55.3, 53.9, 53.5, 41.8, 27.0, 24.5, 21.4, 14.2, 10.5.
    [0166]
    [0167] 1 - ((5-Methyl-2- (m-tolyl) oxazol-4-yl) methyl) piperidine-3-carboxylic acid ethyl ester (7) Reagents: ethyl piperidin-3-carboxylic acid (0.313 mL, 2.04 mmol ), acetonitrile (5 mL), potassium carbonate (337 mg, 2.45 mmol), 4- (chloromethyl) -5-methyl-2- (m-tolyl) oxazole (450 mg, 2.04 mmol). Purification: chromatographic column, using a mixture of Hexane: AcOEt (9: 1) as eluents, obtaining a yellow oil. Yield: 535 mg (76.5%). 1 H NMR (300 MHz, CDCh) 57.85 (s, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.29 (t, J = 7.6 Hz, 1H), 7.21 (d, J = 7.49 Hz, 1H), 4.10 (q, J = 7.1 Hz, 2H), 3.45 (s, 2H), 3.13-3.00 (m , 1H), 2.85 (d, J = 11.1 Hz, 1H), 2.69-2.52 (m, 1H), 2.38 (s, 3H), 2.36 (s, 3H) , 2.26-2.04 (m, 1H), 1.98 (m, 2H), 1.79-1.50 (m, 2H), 1.51-1.30 (m, 1H), 1 , 22 (t, J = 7.1 Hz, 3H). 13 C NMR (75 MHz, CDCh) 5 174.3, 159.6, 146.0, 138.3, 132.4, 130.6, 128.5, 127.6, 126.7, 123.1, 60.2, 55.3, 53.9, 53.4, 41.8, 27.0, 24.4, 21.3, 14.2, 10.4. HRMS (ESI) calcd (C24H25CFN3O2): 343.20162, found [M + H] +: 343.20165
    [0168]
    [0169] (R) -1 - ((5-Methyl-2-phenyloxazol-4-yl) methyl) piperidine-3-carboxylic acid ethyl ester (8) Reagents: ethyl (R) -piperidine-3-carboxylate (0.221 mL, 1 , 44 mmol), acetonitrile (5 mL), potassium carbonate (165.5 mg, 1.78 mmol), 4- (chloromethyl) -5-methyl-2-phenyloxazole (300 mg, 1.44 mmol). Purification: chromatographic column, using a mixture of Hexane: AcOEt (9: 1) as eluents, obtaining a yellow oil. Yield: 348.5 mg (73.8%). 1 H NMR (300 MHz, CDCh) 58.01-7.86 (m, 2H), 7.41-7.25 (m, 3H), 4.03 (q, J = 7.1 Hz, 2H) , 3.38 (s, 2H), 3.06-2.94 (m, 1H), 2.86-2.73 (m, 1H), 2.62-2.46 (m, 1H), 2 , 36 (s, 3H) 2.12 (t, J = 10.8 Hz, 1H), 2.03-1.75 (m, 2H), 1.73-1.44 (m, 2H), 1 , 44-1.24 (m, 1H), 1.15 (t, J = 7.1 Hz, 3H) .13 C NMR (75 MHz, CDCh) 5 174.3, 159.5, 146.2, 132.6, 129.8, 128.6, 127.8, 126.1, 60.3, 55.4, 54.0, 53.5, 41.9, 27.1.24.5, 14, 3, 10.5.
    [0170]
    [0171] Ethyl 1 - ((5-methyl-2-phenyloxazol-4-yl) methyl) piperidine-3-carboxylate (9) Reagents: ethyl piperidin-3-carboxylate (0.296 mL, 1.92 mmol), acetonitrile (5) mL), potassium carbonate (317 mg, 2.30 mmol), 4- (chloromethyl) -5-methyl-2-phenyloxazole (400 mg, 1.92 mmol). Purification: chromatographic column, using a mixture of Hexane: AcOEt (9: 1) as eluents, obtaining a yellow oil. Yield: 543 mg (86%). 1 H NMR (300 MHz, CDCfe) 57.95-7.85 (m, H12, 2H), 7.36-7.20 (m, 3H), 4.00 ( q, J = 7.1 Hz, 2H), 3.35 (s, 2H), 3.03-2.91 (m, 1H), 2.80-2.70 (m, 1H), 2.51 (tt, J = 10.6, 3.8 Hz, 1H), 2.25 (s, 3H), 2.10 (t, J = 10.7 Hz, 1H), 2.02-1.78 ( m, 2H), 1.68-1.42 (m, 2H), 1.40-1.23 (m, 1H), 1.11 (t, J = 7.1 Hz, 2H) .13 C NMR (75 MHz, CDCl 3) 5174.0, 159.2, 145.9, 132.4, 129.6, 128.4, 127.5, 125.9, 60.0, 55.2, 53.7, 53.3, 41.6, 26.8, 24.3, 14.0, 10.2.
    [0172]
    [0173] Example 3: Measurement of PDE8A inhibition
    [0174]
    [0175] The measurement of the inhibition of PDE8A was carried out using a commercial kit for measuring phosphodiesterase activity.
    [0176] The compounds of the present invention (examples 1 and 2) were evaluated. For this, said compounds were incubated (in a concentration range of 0.1 nM to 100 pM) in the presence of 0.02 U / well of PDE8A and 0.05 pCi of [3 H] cAMP, during 20 min at 30 ° C in the test buffer supplied with the kit (total volume per well = 100 pL). At the end of this time, 50 pL of a suspension of 20 mg / mL of glass silicate SPA microspheres was added and kept stirring at room temperature for 60 minutes. The plate was allowed to stand for 20 min and the radioactivity was detected in a scintillation detector. In all trials two points were included in the absence of PDE8A (blank / negative control) and two spots with PDE8A in the absence of inhibitors (positive control).
    [0177] Analysis of the data: All the compounds were initially evaluated at the concentration of 10 pM and the percent inhibition of PDE8A was calculated according to the following formula:
    [0178] % inhibition = ((cpm control - cpm sample) x 100) / (cpm control - white cpm) For those compounds with% inhibition values greater than 45% their inhibitory potency (IC50) was calculated by constructing a concentration-response curve, following the protocol explained above (concentration of the analyzed compound from 0.1 nM to 100 pM). The data was adjusted with software using a non-linear adjustment.
    [0179]
    [0180] The data obtained are shown in Table 1:
    [0181]
    [0182] Table 1. Inhibitory concentration 50 (IC50) of the compound PDE8A enzyme synthesized (1-9)
    [0183]
    [0184]
    [0185]
    [0186]
    [0187] Example 4: Prediction of the blood-brain barrier passage
    [0188] An essential requirement that must be fulfilled by drugs intended for the treatment of neurodegenerative diseases is the ability to cross the blood-brain barrier (BHE) since, otherwise, they could not act on the target of interest. Therefore, for compounds that are not permeable or located in the area of uncertainty, it may be necessary that their pharmaceutical formulation be adequately transported by methods known to a person skilled in the art, such as, for example, by encapsulation. This ability can be predicted in vitro using a method known by the acronym PAMPA ( Parallel Artificial Membrane Permeability Assay) described by Di et al (Di, L., Kerns, EH, Fan, K., McConnell, OJ, Carter, GT Eur. J. Med. Chem., 2003, 38 (3), 223-232) and that has subsequently been fine-tuned in our research group. This method allows to predict the effective permeability through artificial membranes through a passive diffusion process.
    [0189] In the first place, it is necessary to validate the method, for which 10 commercial compounds are used (specified below), whose penetration capacity in the central nervous system (CNS) is known, obtaining in this case a good linear correlation between experimental permeability values ( Pe ) and those described. The correlation line obtained following the pattern described in the literature allows to establish the limits to predict whether a compound can cross the blood-brain barrier or not. Thus, a compound is considered to be permeable to BHE (SNC +) if it has a permeability> 4.48 x 10-6 cm s-1.
    [0190] For the procedure, 3-5 mg of caffeine, desipramine, enoxacin, hydrocortisone, ofloxacin, piroxicam and testosterone, 12 mg of promazine and 25 mg of atenolol and verapamil were taken and dissolved in EtOH (1000 pL). 100 pL of these solutions were taken and EtOH (1400 pL) and phosphate buffer (PBS) pH = 7.4 (3500 pL) were added in order to reach a final EtOH concentration of 30% v / v in solution. Finally, the solutions were filtered.
    [0191] On the other hand, a solution of PBS / EtOH (70:30) was added to each well of the acceptor plate (180 pL). The donor plate was impregnated with a solution of porcine brain lipid (4 pL) dissolved in dodecane (20 mgmL-1). After 5 min, dissolution of each compound was added on this plate (180 pL).
    [0192] From compounds 1 to 9 evaluated, they were taken between 1-2 mg and dissolved in EtOH (1500 pL) and phosphate buffer (PBS) pH = 7.4 (3500 pL), filtered and added to the donor plate. With these solutions, the wavelengths at which the compounds absorb are determined and the initial absorbance levels are measured at these wavelengths using a UV absorbance reader. Each sample was analyzed from two to five wavelengths, in three wells and in two independent experiments.
    [0193] Next, the donor plate was deposited on the acceptor forming a kind of "sandwich" and allowed to incubate for 2 h and 30 min at 25 ° C. In this way, the compounds will go from the donor plate to the acceptor plate through of porcine brain lipid by passive diffusion.Then that time, the donor plate is carefully removed and the final concentration and absorbance of both the commercial and synthesized compounds are determined.The results obtained showed that the compounds evaluated (1-3 and 6-9) are able to cross the blood-brain barrier.
    权利要求:
    Claims (28)
    [1]
    1. Use of a compound of formula (I) or any of its isomers or pharmaceutically acceptable salts thereof

    [2]
    2. Use, according to claim 1, wherein R1 is -NH- (CH2) n-R1 'and n is a value between 1 and 2.
    [3]
    3. Use, according to claim 2, wherein R1 is -NH- (CH2) n-R1 'and n is 1.
    [4]
    4. Use, according to claim 3, wherein R1 'is a phenyl optionally substituted by a - (O) -C1-C3 alkyl or by a halogen selected from fluorine, chlorine, bromine and iodine.
    [5]
    5. Use, according to claim 4, wherein R1 'is unsubstituted phenyl.
    [6]
    6. Use according to claim 4, wherein R1 'is a meta- or para-methoxyphenyl.
    [7]
    7. Use, according to claim 4, wherein R1 'is a meta- or para-chlorophenyl.
    [8]
    8. Use according to any of the preceding claims, wherein R2 is an ortho- fluorophenyl.
    [9]
    9. Use, according to claims 1-7, wherein R2 is a meta-methylphenyl.
    [10]
    10. Use, according to claim 1, wherein R1 is - (O) -C1-C3 alkyl.
    [11]
    11. Use, according to claim 10, wherein R1 is -O-ethyl.
    [12]
    12. Use according to any of claims 10 or 11, wherein R2 is a phenyl substituted by C1-C3 alkyl.
    [13]
    13. Use, according to claim 12, wherein R2 is a meta-methylphenyl.
    [14]
    14. Use according to any of claims 10 or 11, wherein R2 is an unsubstituted phenyl.
    [15]
    15. Use according to any of the preceding claims, wherein R3 is methyl.
    [16]
    16. Use according to claim 1 wherein the compound of formula (I) is selected from the list comprising:
    - (R) -W-benzyl-1 - ((2- (2-fluorophenyl) -5-methyloxazol-4-yl) methyl) piperidine-3-carboxamide;
    - (R) -1 - ((2- (2-fluorophenyl) -5-methyloxazol-4-yl) methyl) -W- (3-methoxybenzyl) piperidine-3-carboxamide;
    - (R) -W- (3-chlorobenzyl) -1 - ((2- (2-fluorophenyl) -5-methyloxazol-4-yl) methyl) piperidine-3-carboxamide;
    - (R) -W- (4-chlorobenzyl) -1 - ((2- (2-fluorophenyl) -5-methyloxazol-4-yl) methyl) piperidine-3-carboxamide;
    - (R) -1 - ((5-methyl-2- (m-tolyl) oxazol-4-yl) methyl) piperidine-3-carboxylic acid ethyl ester;
    - 1 - ((5-methyl-2- (m-tolyl) oxazol-4-yl) methyl) piperidine-3-carboxylic acid ethyl ester;
    - (R) -1 - ((5-methyl-2-phenyloxazol-4-yl) methyl) piperidine-3-carboxylic acid ethyl ester and
    - 1 - ((5-Methyl-2-phenyloxazol-4-yl) methyl) piperidine-3-carboxylic acid ethyl ester.
    [17]
    17. Use, according to any of the preceding claims, wherein the diseases Neurodegenerative and / or neurological mediated by the enzyme PDE8A are selected from the group comprising Alzheimer's, Parkinson's, multiple sclerosis, amyotrophic lateral sclerosis, cerebral ischemia, post-encephalitic parkinsonisms, dystonia, Tourette's syndrome, periodic limbic movement pathologies, leg syndrome restlessness, epilepsy or combinations thereof.
    [18]
    18. Use of a compound of formula (II) or any of its isomers or pharmaceutically acceptable salts thereof:

    [19]
    19. Use according to claim 18, wherein R1 is -O-ethyl.
    [20]
    20. Use according to claim 18 or 19, wherein R3 is a methyl.
    [21]
    21. Use according to any of claims 18 to 20, wherein R2 is an unsubstituted phenyl.
    [22]
    22. Use according to any of claims 18 to 20 wherein R2 is a phenyl substituted by a C1-C3 alkyl.
    [23]
    23. Use, according to claim 22, wherein R2 is meta-methylphenyl.
    [24]
    24. Use according to any of claims 18 to 23, wherein the compound of formula (II) is a racemic mixture.
    [25]
    25. Use according to any of claims 18 to 23, wherein the compound of formula (II) is the R-isomer.
    [26]
    26. Use, according to claim 18, wherein the compound of formula (II) is selected from the list comprising:
    - (R) -1 - ((5-methyl-2- (m-tolyl) oxazol-4-yl) methyl) piperidine-3-carboxylic acid ethyl ester;
    - 1 - ((5-methyl-2- (m-tolyl) oxazol-4-yl) methyl) piperidine-3-carboxylic acid ethyl ester;
    - (R) -1 - ((5-methyl-2-phenyloxazol-4-yl) methyl) piperidine-3-carboxylic acid ethyl ester and
    - 1 - ((5-Methyl-2-phenyloxazol-4-yl) methyl) piperidine-3-carboxylic acid ethyl ester.
    [27]
    27. A pharmaceutical composition comprising a compound of formula (II) or any of its isomers or pharmaceutically acceptable salts thereof as defined in any of claims 18 to 26, together with a pharmaceutically acceptable carrier or excipient.
    [28]
    28. Compound of formula (I) as defined in claim 1 selected from the list comprising:
    - (R) -W-benzyl-1 - ((2- (2-fluorophenyl) -5-methyloxazol-4-yl) methyl) piperidine-3-carboxamide;
    - (R) -1 - ((2- (2-fluorophenyl) -5-methyloxazol-4-yl) methyl) -W- (3-methoxybenzyl) piperidine-3-carboxamide;
    - (R) -W- (3-chlorobenzyl) -1 - ((2- (2-fluorophenyl) -5-methyloxazol-4-yl) methyl) piperidine-3-carboxamide;
    - (R) -W- (4-chlorobenzyl) -1 - ((2- (2-fluorophenyl) -5-methyloxazol-4-yl) methyl) piperidine-3-carboxamide;
    - (R) -1 - ((5-methyl-2- (m-tolyl) oxazol-4-yl) methyl) piperidine-3-carboxylic acid ethyl ester;
    - 1 - ((5-methyl-2- (m-tolyl) oxazol-4-yl) methyl) piperidine-3-carboxylic acid ethyl ester;
    - (R) -1 - ((5-methyl-2-phenyloxazol-4-yl) methyl) piperidine-3-carboxylic acid ethyl ester and
    - 1 - ((5-Methyl-2-phenyloxazol-4-yl) methyl) piperidine-3-carboxylic acid ethyl ester.
    类似技术:
    公开号 | 公开日 | 专利标题
    ES2809974T3|2021-03-08|Indole carboxamide compounds useful as kinase inhibitors
    CA3001666A1|2017-04-20|Oxadiazole amine derivative compounds as histone deacetylase 6 inhibitor, and the pharmaceutical composition comprising the same
    ES2360333B1|2012-05-04|DERIVATIVES OF BIS | AMINO AND AROMATICS SYSTEMS OF SIX MEMBERS AND THEIR USE IN THE TREATMENT OF NEURODEGENERATIVE PATHOLOGIES, INCLUDING ALZHEIMER'S DISEASE
    CA2850350A1|2013-04-04|Macrocyclic lrrk2 kinase inhibitors
    ES2859510T3|2021-10-04|Pyridazinone fused tricyclic compounds useful for treating orthomyxovirus infections
    ES2878054T3|2021-11-18|Spiroheptanil hydantoins as ROCK inhibitors
    JP6843114B2|2021-03-17|Muscarine agonist
    US20190241565A1|2019-08-08|Bicyclic pyridone lactams and methods of use thereof
    US11008302B2|2021-05-18|Substituted pyridine and pyrimidines and their use as GluN2B receptor modulators
    BR112019012927A2|2020-02-18|COMPOUND, USE OF A COMPOUND, COMBINATION OF A COMPOUND, PHARMACEUTICAL COMPOSITION AND DEVICE
    WO2015178265A1|2015-11-26|Novel glutamic acid derivative and use thereof
    CA3081751A1|2019-05-09|Substituted pyrrolopyrimidine jak inhibitors and methods of making and using the same
    US20210253572A1|2021-08-19|Imidazo[1,2-b]pyridazines as trk inhibitors
    EP2968995A1|2016-01-20|Inhibitors of lrrk2 kinase activity
    US10407430B2|2019-09-10|Janus kinase 1 selective inhibitor and pharmaceutical use thereof
    ES2696516B2|2019-06-19|Piperidine derivative compounds as PDE8A inhibitors
    CA2938186C|2019-05-28|Azaindole derivative
    ES2719115T3|2019-07-08|Alkoxide substituted chromene derivatives as inhibitors of the TCR-Nck interaction
    BR112021000878A2|2021-04-13|IMIDAZO DERIVATIVES [1,2-B] PYRIDAZINE AS TRK INHIBITORS
    JP6570034B2|2019-09-04|Novel glutamic acid derivatives and uses thereof
    ES2543641T3|2015-08-20|N5- | -N3- | -3,5-piperidinedicarboxamide derivatives for use as renin inhibitors
    ES2747648T3|2020-03-11|Pyridazinone derivatives as phosphoinositide 3-kinase inhibitors
    AU2017267637A1|2018-11-15|Piperazinyl methanone NAAA inhibitors
    AU2013221406B2|2017-02-02|Peripherally restricted diphenyl purine derivatives
    US9757369B2|2017-09-12|Heterocyclic GSK-3 allosteric modulators
    同族专利:
    公开号 | 公开日
    WO2019012173A1|2019-01-17|
    ES2696516B2|2019-06-19|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    WO2010042925A2|2008-10-10|2010-04-15|Vm Discovery Inc.|Compositions and methods for treating alcohol use disorders, pain and other diseases|
    WO2011058478A1|2009-11-16|2011-05-19|Pfizer Inc.|Substituted triazolopyrimidines as pde8 inhibitors|
    法律状态:
    2019-01-16| BA2A| Patent application published|Ref document number: 2696516 Country of ref document: ES Kind code of ref document: A1 Effective date: 20190116 |
    2019-06-19| FG2A| Definitive protection|Ref document number: 2696516 Country of ref document: ES Kind code of ref document: B2 Effective date: 20190619 |
    优先权:
    申请号 | 申请日 | 专利标题
    ES201730924A|ES2696516B2|2017-07-12|2017-07-12|Piperidine derivative compounds as PDE8A inhibitors|ES201730924A| ES2696516B2|2017-07-12|2017-07-12|Piperidine derivative compounds as PDE8A inhibitors|
    PCT/ES2018/070494| WO2019012173A1|2017-07-12|2018-07-10|Piperidine-derived compounds as pde8a inhibitors|
    [返回顶部]