4-(Phenyl-(Piperidin-4-ylidene-Methyl)-Benzamide Derivatives and Their Use for the Treatment of Pain

专利摘要:
The present disclosure discloses and claims the compounds of formula (I) as well as their pharmaceutically acceptable salts and their use in pharmaceutical compositions and therapies, particularly in the management of pain, anxiety and functional gastrointestinal disorders : <Formula I> Wherein R 1 is phenyl, pyridinyl, pyrrolyl, thienyl, furanyl, imidazolyl, triazolyl and pyridyl-N-oxide, wherein each R 1 phenyl ring and R 1 heteroaromatic The ring is optionally and independent by 1, 2 or 3 substituents selected from straight and branched C 1 -C 6 alkyl, NO 2 , CF 3 , C 1 -C 6 alkoxy, chloro, fluoro, bromo and iodo May be further substituted with substitution on the phenyl ring and the heteroaromatic ring may occur at any position on the ring system).
公开号:KR20030094424A
申请号:KR10-2003-7014945
申请日:2002-05-16
公开日:2003-12-11
发明作者:윌리암 브라운；크리스토퍼 왈폴；종용 웨이
申请人:아스트라제네카 아베；
IPC主号:

专利说明:

4- (phenyl-piperidine-4-ylidene-methyl) -benzamide derivatives and their use for the treatment of pain, anxiety or gastrointestinal disorders {4- (Phenyl- (Piperidin-4-ylidene-Methyl) -Benzamide Derivatives and Their Use for the Treatment of Pain, Anxiety or Gastrointestinal Disorders}
[2] The δ receptor has been shown to play a role in many body functions, such as the circulatory system and pain system. Thus, ligands for δ receptors may have potential use as anesthetics and / or anti-hypertensive agents. In addition, ligands for δ receptors have also been shown to possess immunomodulatory activity.
[3] Currently, at least three different opioid receptor populations (μ, δ, and κ) have been identified, all of which are distinct in both the central and peripheral nervous systems of many species, including humans. Pain was observed in various animal models in which one or more of these receptors were activated.
[4] Almost without exception, the currently available opiate δ ligands are peptides by nature and are unsuitable for administration by the systemic route. One example of a non-peptidic δ-agonist is SNC80 (Bilsky E. J. et al., Journal of Pharmacology and Experimental Therapeutics, 273 (1), pp. 359-366 (1995)). However, there is still a need for selective δ-agonists with improved selectivity as well as adverse side effects profiles.
[5] Therefore, the fundamental task of the present invention was to find a new anesthetic that not only improved the anesthetic effect and side effect profile as well as improved systemic efficacy compared to current μ agonists.
[6] Conventional anesthetics already identified in the art have many disadvantages in that they are poorly pharmacokinetic and not anesthetized when administered via the systemic route. It has also been demonstrated that δ agonist compounds, which have been described as preferred in the art, have a significant convulsive effect when administered systemically.
[7] In the context of the present invention, Applicants have found certain compounds that exhibit surprisingly improved properties such as improved δ-agonist efficacy, in vivo efficacy, pharmacokinetic properties, bioavailability, in vitro stability and / or low toxicity. Revealed them.
[8] Summary of the Invention
[9] The novel compounds according to the invention are defined by the formula
[10]
[11] Where
[12] R ¹ is
[13]
[14]
[15] Selected from any one of
[16] Wherein each R ¹ phenyl ring and R ¹ heteroaromatic ring is derived from straight and branched C ₁ -C ₆ alkyl, NO ₂ , CF ₃ , C ₁ -C ₆ alkoxy, chloro, fluoro, bromo and iodo And optionally, independently, may be further substituted by 1, 2 or 3 substituents independently selected. Substitution on the phenyl ring and heteroaromatic ring may occur at any position on the ring system.
[17] A further embodiment of the invention is a compound of formula I, wherein R ¹ is as defined above and each R ¹ phenyl ring and R ¹ heteroaromatic ring may be independently further substituted by a methyl group.
[18] A further embodiment of the invention relates to compounds of formula I wherein R ¹ is phenyl, pyrrolyl, pyridinyl, thienyl or furanyl, optionally bearing one or two preferred substituents on R ¹ phenyl or R ¹ heteroaromatic rings. Compound.
[19] Another embodiment of the invention is a compound of formula I, wherein R ¹ is phenyl, pyrrolyl or pyridinyl, optionally bearing one or two preferred substituents on R ¹ phenyl or R ¹ heteroaromatic ring.
[20] Another embodiment of the invention is a compound of Formula I, wherein R ¹ is thienyl or furanyl, optionally bearing one or two preferred substituents on the R ¹ heteroaromatic ring.
[21] Also included in the scope of the present invention are salts and enantiomers of the compounds of formula (I).
[22] When R ¹ phenyl ring and R ¹ heteroaromatic ring (s) are substituted, preferred substituents are independently selected from any one of CF ₃ , methyl, iodo, bromo, fluoro and chloro.
[23] In reaction step A of Scheme 2, an intermediate compound of Formula II is reacted with 8-quinoline boronic acid using a palladium catalyst, for example, Pd (PPh ₃ ) ₄ , in the presence of a base such as Na ₂ CO ₃ to formula III After obtaining a compound of deprotection under standard conditions
[24] i) a compound of the formula R ¹ -CH ₂ -X wherein R ¹ is as defined above and X is halogen, preferably bromine or chlorine and a suitable base or
[25] ii) a compound of the formula R ¹ -CHO, wherein R ¹ is as defined above and a suitable reducing agent
[26] Alkylation with yields compounds of formula (I):
[27]
[28]
[29] Wherein PG is a urethane protecting group such as Boc or CBZ or benzyl or substituted benzyl protecting group such as 2,4-dimethoxybenzyl.
[30] Suitable bases for use in the standard alkylation step i) include, but are not limited to, triethylamine and potassium carbonate.
[31] Suitable reducing agents for use in standard reduction step ii) include, but are not limited to, sodium cyanoborohydride and sodium triacetoxyborohydride.
[32] The novel compounds of the present invention are useful in therapy, and in particular for the treatment of various pain conditions such as chronic pain, neuropathic pain, acute pain, cancer pain, pain caused by rheumatoid arthritis, migraine headaches, visceral pain and the like. However, this list should not be construed in a limiting sense.
[33] The compounds of the present invention are useful as immunomodulators, in particular autoimmune diseases such as arthritis, skin transplants, organ transplants and diseases requiring similar surgery, collagen diseases, various allergic immunomodulators, and also as anti-tumor and anti-viral agents. useful.
[34] The compounds of the present invention are useful in disease states with or associated with degeneration or dysfunction of opioid receptors. This may include the use of isotopically labeled compounds of the invention in imaging applications and diagnostic techniques such as positron emission tomography (PET).
[35] Compounds of the invention include diarrhea, depression, anxiety and stress-related disorders such as post-traumatic stress disorder, panic disorder, generalized anxiety disorder, interphobia and obsessive compulsive disorder; Urinary incontinence, various mental disorders, cough, pulmonary edema, various gastrointestinal disorders, for example, functional gastrointestinal disorders such as constipation, irritable bowel syndrome and functional dyspepsia, Parkinson's disease and other movement disorders, traumatic brain injury, stroke, cardioprotection after myocardial infarction It is useful in the treatment of sympathetic nervous system disorders such as drug intoxication and hypertension, including spinal injury and abuse of alcohol, nicotine, opioids and other drugs.
[36] The compounds of the present invention are useful as anesthetics for use during general anesthesia and during monitored anesthetic conditions. Often combinations of agents with different properties are used to balance the effects required to maintain anesthesia (eg memory loss, painlessness, muscle relaxation and sedation). Such combinations include inhalation anesthetics, sleeping pills, anxiety medications, neuromuscular blockers and opioids.
[37] Also included in the scope of the invention is the use of any compound of formula (I) in the manufacture of a medicament for treating any of the conditions discussed above.
[38] A further aspect of the present invention is a method of treating a subject suffering from that condition by administering an effective amount of a compound of Formula I above to a patient in need of treatment of any of the conditions discussed above.
[39] A further aspect of the invention is the intermediate of formulas II and III:
[40]
[41] Wherein PG is a urethane protecting group such as Boc or CBZ or benzyl or substituted benzyl protecting group such as 2,4-dimethoxybenzyl.
[42] Manufacturing method
[1] The present invention relates to novel compounds, methods for their preparation, their use and pharmaceutical compositions comprising said novel compounds. The novel compounds are useful for therapy, in particular for the treatment of pain, anxiety and functional gastrointestinal disorders.
[43] Hereinafter, the present invention will be described in more detail with reference to the following examples, which are not intended to limit the present invention.
[44]
[45] Intermediate 2: 4- (dimethoxy-phosphorylmethyl) -benzoic acid methyl ester
[46] A mixture of starting material 1 (11.2 g, 49 mmol) and trimethyl phosphite (25 mL) was refluxed under N ₂ for 5 hours. Excess trimethyl phosphite was removed via co-distillation with toluene to afford compound 2 in quantitative yield:
[47]
[48] Intermediate 3: 4- (t-methoxycarbonyl-benzylidene) -piperidine-1-carboxylic acid tert-butyl ester
[49] To a solution of 2 in dry THF (200 mL) was added lithium diisopropylamide (32.7 mL, 1.5 M in hexane, 49 mmol) dropwise at -78 ° C. The reaction mixture was then warmed to room temperature before N-tert-butoxycarbonyl-4-piperidone (9.76 g, 49 mmol in 100 mL of dry THF) was added. After 12 hours, the reaction mixture was quenched with water (300 mL) and extracted with ethyl acetate (3 x 300 mL). The combined organic phases were dried over MgSO ₄ and evaporated to afford the crude product which was purified by flash chromatography to give 3 as a white solid (5.64 g, 35%):
[50]
[51] Intermediate 4: 4-Bromo-4- [bromo- (4-methoxycarbonyl-phenyl) -methyl] -piperidine-1-carboxylic acid tert-butyl ester
[52] To a mixture of 3 (5.2 g, 16 mmol) and K ₂ CO ₃ (1.0 g) in dry dichloromethane (200 mL) was added bromine solution (2.9 g, 18 mmol) in 30 mL of CH ₂ Cl ₂ at 0 ° C. . After 1.5 hours at room temperature, K ₂ CO ₃ was filtered and the solution was condensed. The residue was then dissolved in ethyl acetate (200 mL), washed with water (200 mL), 0.5 M HCl (200 mL) and brine (200 mL) and dried over MgSO ₄ . The solvent was removed to give crude product which was recrystallized from methanol to give 4 as a white solid (6.07 g, 78%).
[53]
[54] Intermediate 5: 4- [Bromo- (4-carboxy-phenyl) -methylene] -piperidine-1-carboxylic acid tert-butyl ester
[55] A solution of 4 (5.4 g, 11 mmol) in methanol (300 mL) and 2.0 M NaOH (100 mL) was heated at 40 ° C. for 3 hours. The solid was collected via filtration and dried overnight under vacuum. The dry salt was dissolved in 40% acetonitrile / water and adjusted to pH 2 with concentrated HCl. Through filtration, product 5 (3.8 g, 87%) was isolated as a white powder.
[56]
[57] Intermediate 6: 4- [Bromo- (4-diisopropylcarbamoyl-phenyl) -methylene] -piperidine-1-carboxylic acid tert-butyl ester
[58] Diisopropylamine (71.10 mL, 0.510 mol, 4.0 equiv) and 2- (1H-benzotriazole) at room temperature in a dilute suspension of acid (5) (50.27 g, 0.127 mol, 1.0 equiv) in ethyl acetate (350 mL) -1-yl) -1,1,3,3-tetra-methylruroniumtetrafluoroborate (TBTU, 44.90 g, 0.140 mol, 1.1 equiv) was added. After stirring the resulting pale white suspension for 2 days, water (200 mL) was added to quench the reaction and the two phases were separated. The organic phase was back extracted twice with dichloromethane (100 mL). The combined organic phases were washed with 1 M aqueous HCl solution (150 mL) and brine (100 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a light yellow oil. The crude product was recrystallized in tert-butyl methyl ether (300 mL). The filtrate was purified by flash chromatography eluting with 30% ethyl acetate in hexanes and recrystallized in an ethyl acetate: hexane (10: 90) mixture. The white solid product was combined (47.28 g, 78%).
[59]
[60] Intermediate 7: 4- [1- (4-Diisopropylcarbamoyl-phenyl) -1-quinolin-8-yl-methylene] -piperidine-1-carboxylic acid tert-butyl ester
[61] To a solution of bromine 6 (10.75 g, 22.47 mmol, 1.0 equiv) in toluene (150 mL) at room temperature was added 8-quinolineboronic acid (4.66 g, 26.92 mmol, 1.2 equiv) followed by ethanol (30 mL) and Sodium carbonate (2 M aqueous solution, 28.1 mL, 56.18 mmol, 2.5 equiv) was added. After purging the system with nitrogen for 15 minutes, tetrakis (triphenylphosphine) palladium (0) (1.87 g, 1.62 mmol, 0.072 equiv) was added to the mixture and brought to 90 ° C. After stirring overnight, the reaction was cooled to room temperature and quenched with water (100 mL) to separate the phases. The organic phase was washed with water (100 mL) and then brine (50 mL), dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography eluting with 50% ethyl acetate in hexanes (7.57 g, 64%).
[62] Intermediate 8: N, N-diisopropyl-4- (1-piperidin-4-ylidene-1-quinolin-8-yl-methyl) -benzamide
[63] To a solution of carbamate (7) (7.57 g, 14.34 mmol, 1.0 equiv) in dichloromethane (120 mL) was added trifluoroacetic acid (TFA) (11.05 mL, 143.4 mmol, 10.0 equiv) at room temperature. After stirring for 2.5 hours, the reaction was quenched by the addition of 2 M aqueous sodium hydroxide solution (80 mL). Separated the phases. The aqueous phase was back extracted three times with dichloromethane (50 mL). The organic phases were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to give 5.84 g (95%) of the desired compound.
[64] An aliquot (375 mg, 0.88 mmol) of deprotected amine was purified by flash chromatography eluting with 5% methanol in dichloromethane. The fractions were concentrated under reduced pressure and diluted in diethyl ether and dichloromethane. To this mixture was added 1M HCl solution in diethyl ether (4 mL, about 3.5 equiv). The resulting mixture was then concentrated under reduced pressure. The white solid was triturated with diethyl ether and concentrated under reduced pressure to give 350 mg of intermediate (8) as a hydrochloride salt.
[65] Examples 1 to 12 were synthesized according to the general synthesis method shown below.
[66]
[67] The synthesis method of Example 1 below is typical:
[68]
[69] Example 1: 4- [1- (1-benzyl-piperidin-4-ylidene) -1-quinolin-8-yl-methyl] -N, N-diisopropyl-benzamide
[70] To a solution of amine 8 (451 mg, 1.05 mmol, 1.0 equiv) in tetrahydrofuran (20 mL) was added benzaldehyde (129 μl, 1.27 mmol, 1.2 equiv) at room temperature. After stirring for 10 minutes, sodium triacetoxyborohydride (292 mg, 1.38 mmol, 1.3 equiv) was added to the solution. After stirring overnight, the reaction mixture was diluted with dichloromethane (10 mL) and 2 M aqueous sodium hydroxide solution (15 mL). The phases were separated and the organic phase was washed with brine (15 mL). The aqueous phase was back extracted three times with dichloromethane (15 mL). The organic phases were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography eluting with 5% methanol in dichloromethane. The fractions were concentrated under reduced pressure and diluted in diethyl ether and dichloromethane. To this mixture was added 1M HCl solution in diethyl ether (4 mL, about 3.5 equiv). The resulting mixture was then concentrated under reduced pressure. The white solid was triturated with diethyl ether and concentrated under reduced pressure to give Example 1 (283 mg, 41%).
[71]
[72] Elemental Analysis: Found C, 62.95; H, 7.08; N, 6.19. Calcd for C ₃₅ H ₃₉ N ₃ 0 x 2.9HCl x 2.5H ₂ 0. C, 62.89; H, 7.07; N, 6.29%.
[73] Examples 2-12 were prepared similarly. Analytical data for Examples 1-12 are shown in Table 1 below:
[74]
[75]
[76]
[77] Pharmaceutical composition
[78] The novel compounds according to the invention can be administered by oral, intramuscular, subcutaneous, topical, nasal, intraperitoneal, intrathoracic, intravenous, epidural, intradural, intraventricular administration and joint injection.
[79] Preferred routes of administration are oral, intravenous or intramuscular administration.
[80] Dosage depends on the route of administration, the severity of the disease, the age and weight of the patient and other factors normally considered by the attending physician, with the individual regimen and dosage levels determined to be most suitable for the particular patient. do.
[81] Inert, pharmaceutically acceptable carriers for preparing pharmaceutical compositions from the compounds of the present invention may be solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets, and suppositories.
[82] The solid carrier may be one or more substances that may also act as diluents, flavors, solubilizers, lubricants, suspending agents, binders, or tablet disintegrating agents, or may be encapsulating materials.
[83] In powders, the carrier is a finely divided solid which is present in a mixture with the finely divided active component. In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
[84] To prepare the suppository composition, a low-melting wax, for example a mixture of fatty acid glycerides and cocoa butter, is first melted and the active ingredient is dispersed therein through stirring or the like. The molten homogeneous mixture is then poured into a mold of convenient size and cooled to solidify.
[85] Suitable carriers are magnesium carbonate, magnesium stearate, talc, lactose, sugars, pectin, dextrin, starch, tragacanth, methyl cellulose, carboxymethyl cellulose sodium, low melt wax, cocoa butter and the like.
[86] Salts include, but are not limited to, pharmaceutically acceptable salts. Examples of pharmaceutically acceptable salts within the scope of the present invention include acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium acetate, chamlate, carbonate, chloride, citrate, dihydrochloride , Edetate, edysylate, estolate, ecylate, fumarate, glucaptate, gluconate, glutamate, glycolylarsanylate, hexylsorbinate, hydrabamine, hydrobromide, hydrochloride, hydride Loxynaphthoate, isethionate, lactate, lactobionate, maleate, maleate, mandelate, mesylate, methyl bromide, methylnitrate, methylsulfate, no mate, naphsylate, nitrate, pamo Eates (embonates), Pantothenates, Phosphates / Diphosphates, Polygalacturonates, Sal Salicylate, stearate, a sub-acetate, succinate, sulfate, carbonate carbon, tartrate, such as Theo clay agent.
[87] Examples of pharmaceutically unacceptable salts within the scope of the present invention include hydroiodide, percholate and tetrafluoroborate. Pharmaceutically unacceptable salts may be useful because of their advantageous physical and / or chemical properties such as crystallinity and the like.
[88] Preferred pharmaceutically acceptable salts are hydrochloride, sulfate and bitartrate. Hydrochloride and sulfate salts are particularly preferred.
[89] The term composition is intended to include preparations of the active ingredient and encapsulation material as a carrier, wherein a capsule is provided in which the carrier surrounds and is associated with the active ingredient (whether or not another carrier is present). Similarly, cachets are included.
[90] Tablets, powders, cachets, and capsules can be used as solid dosage forms suitable for oral administration.
[91] Liquid compositions include solutions, suspensions, and emulsions. Sterile water or water-propylene glycol solutions of the active compounds may be mentioned as an example of a liquid formulation suitable for parenteral administration. The liquid composition may be formulated as a solution in aqueous polyethylene glycol solution.
[92] Aqueous solutions for oral administration can be prepared by dissolving the active ingredient in water and adding suitable colorants, flavors, stabilizers and thickeners as necessary. Oral aqueous suspensions can be prepared by dispersing the finely divided active component in water with viscous substances such as natural synthetic rubber, resins, methyl cellulose, carboxymethyl cellulose sodium and other suspending agents known in the pharmaceutical formulation art. have.
[93] The pharmaceutical composition is preferably in unit dosage form. In this form, the composition is divided into unit doses containing appropriate amounts of active ingredients. Unit dosage forms can be packaged preparations, such as packaged tablets, capsules and powders in vials or ampoules, wherein the preparations are contained in discrete amounts in a package. In addition, the unit dosage form may be a capsule, cachet or tablet itself or any suitable number of any of the above packaged forms.
[94] Biological assessment
[95] In vitro model
[96] Cell culture
[97] A. Human 293S cells expressing cloned human μ, δ and κ receptors and resistant to neomycin were treated with calcium-free DMEM, 10% FBS, 5% BCS, 0.1% Pluronic at 37 ° C. and 5% CO ₂ . (Pluronic) was grown in suspension in shake flasks containing F-68 and 600 μg / mL Geneticin.
[98] B. Mice and rat brains were weighed and rinsed in ice cold PBS (containing 2.5 mM EDTA, pH 7.4). Brains were cooled in ice-cold lysis buffer (50 mM Tris, pH 7.0, 2.5 mM EDTA, immediately before use, DMSO: 0.5 M phenylmethylsulfonyl fluoride stock in ethanol so that the concentration of phenylmethylsulfonyl fluoride was 0.5 mM. Added) homogenized with polytron for 15 seconds (mouse) or for 30 seconds (rat).
[99] Manufacture of membrane
[100] Cells are pelleted and resuspended in lysis buffer (50 mM Tris, pH 7.0, 2.5 mM EDTA, 0.1 M PMSF stock in ethanol just prior to use, with a concentration of 0.1 mM PMSF) and incubated on ice for 15 minutes. After that, it was homogenized with polytron for 30 seconds. The suspension was spun at 1000 g (max) at 4 ° C. for 10 minutes. The supernatant was left on ice and the pellet was resuspended and spun as above. The supernatants obtained from these two revolutions were combined and spun at 46,000 g (max) for 30 minutes. The pellet was resuspended in cold Tris buffer (50 mM Tris / Cl, pH 7.0) and spun again. The final pellet was resuspended in membrane buffer (50 mM Tris, 0.32 M sucrose, pH 7.0). Aliquots (1 mL) in polypropylene tubes were frozen in dry ice / ethanol and stored at −70 ° C. until use. Protein concentration was determined by a modified Lowry assay using sodium dodecyl sulphate.
[101] Binding analysis
[102] The membrane was thawed at 37 ° C. to cool on ice and passed through a 25-gauge needle three times to bind buffer (50 mM Tris, 3 mM MgCl ₂ , 1 mg / mL BSA (Sigma A-7888), pH 7.4 , Filtered through a 0.22 m filter and stored at 4 ° C. 5 μg / mL aprotinine, 10 μM bestatin, 10 μM diprotein A freshly added, no DTT). 100 μl aliquots were added to an ice cold 12 × 75 mm polypropylene tube containing 100 μl of appropriate radioligand and 100 μl of various concentrations of test compound. Total (TB) binding and nonspecific (NS) binding were measured in each case in the absence and presence of 10 μM naloxone. After vortexing the tube and incubating at 25 ° C. for 60-75 minutes, the contents were quickly vacuum-filtered through a GF / B filter (Whatman product) pre-soaked in 0.1% polyethyleneimine for at least 2 hours. Washed with about 12 mL of ice-cold wash buffer (50 mM Tris, pH 7.0, 3 mM MgCl ₂ ) per tube. After the filter was soaked in a minivial containing 6 to 7 mL of scintillation solution for 12 hours or more, the radioactivity (dpm) remaining in the filter was measured by a beta counter. When the assay was performed on plates with 96 deep wells, it was filtered (96) with 96 single filters soaked in PEI, washed with 1 mL wash buffer and dried in an oven at 55 ° C. for 2 hours. 50 μl of MS-20 scintillation fluid per well was added to the filter plate, followed by counting on TopCount (Packard).
[103] Functional analysis
[104] The agonist activity of the compound was measured by measuring the extent to which the compound receptor complex activates the binding of G-protein (receptor coupled) and GTP. In GTP binding assays, GTP [γ] ³⁵ S was combined with membranes of HEK-293S cells expressing test compounds and cloned human opioid receptors or membranes of homogenized rats and brains of mice. Agonists stimulate GTP [γ] ³⁵ S binding in these membranes. EC ₅₀ and E _max values of the compounds are determined from dose-response curves. Right shift of the dose response curve by the antagonist naltrindol demonstrates that agonist activity is mediated through the δ receptor.
[105] Methods for Rat Brain GTP
[106] Rat brain membranes were thawed at 37 ° C. and passed three times through flat 25-gauge needles, and with GTPγS binder (50 mM HEPES, 20 mM NaOH, 100 mM NaCl, 1 mM EDTA, 5 mM MgCl ₂ , pH 7.4, Fresh 1 mM DTT, added 0.1% BSA). The final 120 μM GDP was added to the membrane dilution. The EC ₅₀ and E _max of the compound were 10-point dose-response performed in 300 μl containing an appropriate amount of membrane protein (20 μg / well) and 100000 to 130000 dpm (0.11 to 0.14 nM) GTPγ ³⁵ S per well. Evaluation was made from the curves. Basal and maximal stimulus binding was determined in the absence and presence of 3 μM SNC-80.
[107] Data analysis
[108] Specific binding (SB) was calculated as TB-NS and SB in the presence of various test compounds was expressed as a percentage of control SB. While replacing specifically bound radioligands, IC ₅₀ values and Hill coefficients (n _H ) for ligands can be obtained from a logit plot or curve plot program such as Ligand, GraphPadprism. (GraphPad Prism), SigmaPlot or ReceptorFit. K _i values were calculated from the Cheng-Prussoff equation. The mean ± SEM values of IC ₅₀ , K _i and n _H values were recorded for ligands tested in three or more replacement curves. Biological data of the compounds of the invention are reported in Table 2 below:
[109]
[110] Receptor Saturation Experiment
[111] Radioligand K _δ values were determined by binding assays on cell membranes using appropriate radioligands (where possible the amount of radioligand required is 10 times or less) in the concentration range of 0.2-5 times the K _δ estimate. Specific radioligand bonds are shown as pmol / membrane protein (mg). K _δ and B _max values in individual experiments were obtained from the nonlinear plots of radioligand (B) to free radioligand (F) (nM) specifically bound in each experiment according to the 1-site model.
[112] Measurement of mechanical allodynia using the Von Frey test method
[113] Testing was conducted between 08:00 and 16:00 hours using the method described by Chaplan et al. (1994). In order to gain access to the paws of the rats, the rats were confined in a Plexiglas cage with a barbed wire and allowed to acclimate for 10 to 15 minutes. The central flat area except the less sensitive foot pad in the left hind paw was taken as the test area. The feet were irritated with a series of 8 von Frey Fleece (0.41, 0.69, 1.20, 2.04, 3.63, 5.50, 8.51, and 15.14 g; Stoelting, Illinois, USA) with increasing logarithmic stiffness. The von Frey hair was placed vertically on the flat surface of the foot under the barbed wire floor and held there for about 6-8 seconds with sufficient force to slightly twist the foot. The case of taking off immediately was recorded as a positive reaction. Flinching as soon as the hair was removed was also considered positive. Moving was considered an ambiguous response, in which case the stimulus was repeated.
[114] Test protocol
[115] One day after the operation, FCA-treated group animals were tested. 50% of the escape reflex threshold was measured using Dixon's up-down method (1980). The test was started with 2.04 g hair with moderate stiffness. It was continuously stimulated continuously with increasing or decreasing stiffness. If there was no response to the first hair selected, the stimulus was stronger. If the foot was released, the next weak stimulus was selected. The optimal threshold by this method was calculated as six responses near the 50% threshold, and when the first change in the reaction occurred, for example when the threshold was first crossed, the six responses began to count. When the threshold was outside the range of stimulation, the values were 15.14 (normal sensitivity) or 0.41 (maximum allodynia), respectively. The pattern in which positive and negative responses were generated was applied to the table according to the convention (X = no escape reflection; O = escape reflection) and the 50% escape reflection threshold was calculated using the following equation:
[116] 50% g threshold = 10 ^{(Xf + kδ)} / 10,000
[117] Where Xf = value of the last von Freyter used (in log units); k = value of the table for aspects of positive / negative response (according to the method of Chaplan et al. (1994)), δ = mean difference between logarithms (log units), where δ = 0.224.
[118] The von Frey threshold was converted to the maximum possible effect ratio (% MPE) according to the method of Chaplan et al. (1994). The% MPE was calculated using the following equation:
[119] .
[120] Administration of Test Substance
[121] The test substance was injected into rats (subcutaneous, intraperitoneal, intravenous or oral) prior to the von Frey test and the time between administration of the test compound and the von Frey test was varied depending on the nature of the test material.
[122] Writhing test
[123] Mice were injected intraperitoneally with acetic acid to cause abdominal contractions in mice. Later, this caused the body of the mouse to stretch to its typical shape. This movement was less frequently observed when anesthetic drugs were administered and this drug was selected as a potentially good candidate.
[124] The complete and typical twisted reflexes were considered only if there was no movement of the animal, slightly depressed on the lower back and the flat side of both feet could be observed. In this assay, it was demonstrated that distortion reflection was significantly inhibited after oral administration of the compounds of the present invention at 1 to 100 μmol / kg.
[125] (i) Preparation of the Solution:
[126] Acetic acid (AcOH): 120 [mu] l of acetic acid was added to 19.88 mL of distilled water to give AcOH having a final volume of 20 mL and a final concentration of 0.6%. The solution was then mixed (vortexed) and made for injection.
[127] Compound (Drug): Each compound was prepared and dissolved in the most suitable vehicle according to standard methods.
[128] (ii) administration of solution
[129] The compound (drug) is orally, intraperitoneally (ip) or subcutaneous (sc) for 20, 30 or 40 minutes (regarding the average body weight of the mouse) for 20, 30 or 40 minutes (depending on the type and nature of the compound) prior to the test. Or intravenously (iv). When the compound is delivered to the central (intraventricular (i.c.v.) or intradural (i.t.)) a 5 μl volume is administered.
[130] Immediately prior to testing, AcOH was administered intraperitoneally (i.p.) at two sites of 10 mL / kg (considering the average body weight of the mouse).
[131] (iii) testing
[132] Animals (mouses) were observed for 20 minutes and the number of reactions (twisted reflections) was recorded to collect data at the end of the experiment. Mice were placed in individual “shoebox” shaped cages with mats. In general, four mice (one in control and three in drug administration) were observed simultaneously.
[133] For anxiety and anxiety-like symptoms, efficacy was established by the geller-seifter conflict test in rats.
[134] In the case of functional gastrointestinal disorder symptoms, rats are described in Coutinho SV et al, in American Journal of Physiology-Gastrointestinal & Liver Physiology. 282 (2): G307-16, 2002 Feb.] can establish efficacy.

权利要求:
Claims (15)
[1" claim-type="Currently amended] A compound of formula I and salts thereof
<Formula I>

Where
R ¹ is


Selected from any one of
Wherein each R ¹ phenyl ring and R ¹ heteroaromatic ring is derived from straight and branched C ₁ -C ₆ alkyl, NO ₂ , CF ₃ , C ₁ -C ₆ alkoxy, chloro, fluoro, bromo and iodo And may be further substituted independently by one, two or three substituents independently selected.
[2" claim-type="Currently amended] The compound of claim 1, wherein each R ¹ phenyl ring and R ¹ heteroaromatic ring is optionally and independently selected by one, two or three substituents independently selected from methyl, CF ₃ , chloro, fluoro, bromo and iodo Compound which may be further substituted by.
[3" claim-type="Currently amended] The compound of claim 1, wherein each R ¹ phenyl ring and R ¹ heteroaromatic ring can be independently further substituted by a methyl group.
[4" claim-type="Currently amended] The compound of claim 1, wherein R ¹ is phenyl, pyrrolyl, pyridinyl, thienyl, or furanyl.
[5" claim-type="Currently amended] The method according to claim 1 or 2,
4- [1- (1-benzyl-piperidin-4-ylidene) -1-quinolin-8-yl-methyl] -N, N-diisopropyl-benzamide;
N, N-diisopropyl-4- [1- (1-pyridin-2-ylmethyl-piperidin-4-ylidene) -1-quinolin-8-yl-methyl] -benzamide,
N, N-diisopropyl-4- [1- (1-pyridin-4-ylmethyl-piperidin-4-ylidene) -1-quinolin-8-yl-methyl] -benzamide,
N, N-diisopropyl-4- [1-quinolin-8-yl-1- (1-thiophen-2-ylmethyl-piperidin-4-ylidene) -methyl] -benzamide,
N, N-diisopropyl-4- [1-quinolin-8-yl-1- (1-thiophen-3-ylmethyl-piperidin-4-ylidene) -methyl] -benzamide,
N, N-diisopropyl-4- [1-quinolin-8-yl-1- (1-furan-3-ylmethyl-piperidin-4-ylidene) -methyl] -benzamide,
N, N-diisopropyl-4- [1-quinolin-8-yl-1- (1-furan-2-ylmethyl-piperidin-4-ylidene) -methyl] -benzamide,
N, N-diisopropyl-4- [1-quinolin-8-yl-1- (1-pyrrole-2-ylmethyl-piperidin-4-ylidene) -methyl] -benzamide,
N, N-diisopropyl-4- {1- [1- (4-bromo-benzyl) -piperidin-4-ylidene] -1-quinolin-8-yl-methyl} -benzamide,
4- {1- [1- (1H-imidazol-2-ylmethyl) -piperidin-4-ylidene] -1-quinolin-8-yl-methyl} -N, N-diisopropylbenzamide ,
N, N-diisopropyl-4- {1- [1- (4-methoxy-benzyl) -piperidin-4-ylidene] -1-quinolin-8-yl-methyl} -benzamide and
N, N-diisopropyl-4- [1-quinolin-8-yl-1- (1-thiazol-2-ylmethyl-piperidin-4-ylidene) -methyl] -benzamide
A compound selected from any one of.
[6" claim-type="Currently amended] 6. The compound according to claim 1, in the form of a hydrochloride, dihydrochloride, sulfate, tartrate, ditrifluoroacetate or citrate salt.
[7" claim-type="Currently amended] The compound of any one of claims 1-4 for use in therapy.
[8" claim-type="Currently amended] Use of a compound of formula I according to claim 1 in the manufacture of a medicament for use in treating pain, anxiety or functional gastrointestinal disorders.
[9" claim-type="Currently amended] A pharmaceutical composition comprising the compound of formula I of claim 1 as an active ingredient and a pharmaceutically acceptable carrier.
[10" claim-type="Currently amended] A method of treating pain by administering an effective amount of a compound of formula I of claim 1 to a subject in need thereof.
[11" claim-type="Currently amended] A method of treating functional gastrointestinal disorders by administering an effective amount of a compound of formula (I) of claim 1 to a subject suffering from functional gastrointestinal disorders.
[12" claim-type="Currently amended] A method of treating anxiety by administering an effective amount of a compound of Formula (I) of claim 1 to a subject with anxiety.
[13" claim-type="Currently amended] A) A compound of formula II is reacted with 8-quinoline boronic acid using a palladium catalyst such as Pd (PPh ₃ ) ₄ in the presence of a base such as Na ₂ CO ₃ to obtain a compound of formula III Deprotection under conditions and alkylation with compounds of formula R ¹ -CHO under reducing conditions to give compounds of formula I
A process for preparing a compound of formula I, comprising:
<Formula II>

<Formula III>

Wherein PG is a urethane protecting group such as Boc or CBZ or benzyl or substituted benzyl protecting group such as 2,4-dimethoxybenzyl.
[14" claim-type="Currently amended] A compound of formula II:
<Formula II>

Wherein PG is a urethane protecting group such as Boc or CBZ or benzyl or substituted benzyl protecting group such as 2,4-dimethoxybenzyl.
[15" claim-type="Currently amended] A compound of formula III:
<Formula III>

Wherein PG is a urethane protecting group such as Boc or CBZ or benzyl or substituted benzyl protecting group such as 2,4-dimethoxybenzyl.

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同族专利:

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公开号 | 公开日

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AR033757A1|2004-01-07|

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HU0400975A2|2004-08-30|

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EP1395575B1|2006-07-19|

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EE200300542A|2004-02-16|

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JP2005508858A|2005-04-07|

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SE0101768D0|2001-05-18|

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DE60213234D1|2006-08-31|

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IL158632D0|2004-05-12|

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IS7025A|2003-11-11|

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AT333452T|2006-08-15|

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NO20035117D0|2003-11-17|

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WO2002094811A1|2002-11-28|

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BR0209668A|2004-04-20|

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SK13942003A3|2004-04-06|

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CA2446154A1|2002-11-28|

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RU2003131969A|2005-05-10|

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CZ20033088A3|2004-05-12|

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PL366388A1|2005-01-24|

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DE60213234T2|2007-06-14|

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CO5540321A2|2005-07-29|

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US6838468B2|2005-01-04|

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ZA200308636B|2005-06-21|

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US20040147553A1|2004-07-29|

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EP1395575A1|2004-03-10|

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BG108329A|2004-12-30|

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CN1527828A|2004-09-08|

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MXPA03010437A|2004-03-09|

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ES2268037T3|2007-03-16|

引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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法律状态:
2001-05-18|Priority to SE0101768A

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2001-05-18|Priority to SE0101768-0

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2002-05-16|Application filed by 아스트라제네카 아베

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2002-05-16|Priority to PCT/SE2002/000947

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2003-12-11|Publication of KR20030094424A

优先权:

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申请号 | 申请日 | 专利标题

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SE0101768A|SE0101768D0|2001-05-18|2001-05-18|Novel compounds|

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SE0101768-0|2001-05-18|

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PCT/SE2002/000947|WO2002094811A1|2001-05-18|2002-05-16|4--benzamide derivatives and their use for the treatment of pain, anxiety or gastrointestinal disorders|