CN118021777A - Amide derivatives, pharmaceutical compositions containing them and their use - Google Patents

Abstract

The present invention provides the use of the following compound (I) or a pharmaceutically acceptable salt, ester, optical isomer, tautomer, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, chelate, complex, clathrate, or prodrug thereof as potassium channel modulator, and pharmaceutical compositions containing the compound of the invention.

Description

Amide derivatives, pharmaceutical compositions containing them and their use

Technical Field

The invention belongs to the technical field of chemistry and biological medicine, and in particular relates to an amide derivative, a preparation method and application thereof

Background

The Kv7 potassium channel is a voltage-dependent potassium ion channel and has the characteristics of low threshold activation, slow activation and non-deactivation. The Kv7 potassium channel has five family members (Kv 7.1-Kv7.5, or KCNQ1-KCNQ 5), all of which have a similar structure, i.e., one functional channel is composed of four subunits, each comprising six transmembrane segments (S1S 6). S1-S4 are voltage sensing areas, and have important roles in sensing membrane potential change, controlling conformational change and the like; S5-S6 are the main components of the channel pore region, and are the main combination and action regions of potassium channel openers. KV7.1 potassium channel is a non-neuronal pathway distributed in peripheral tissues and expressed in the heart to mediate myocardial Iks, whose mutation can lead to Long Q T syndrome. Kv7.2/Kv7.3 potassium channel is the basis of neuron M current, widely distributed in the nervous system, and has various physiological activities. Type 2 voltage-gated potassium ion channels (abbreviated as KCNQ 2) are predominantly expressed in the nervous system, which assemble with type 3 voltage-gated potassium ion channels (KCNQ 3) into heterotetramers, which together mediate M-current (IKM). IKM is a slow-activation, slow-deactivation, and non-deactivation current that plays an important role in maintaining resting membrane potential, reducing intrinsic discharge triggered by excitatory stimuli, and repeating action potential discharge. Mutations in the KCNQ2 gene were first discovered in 1998 in the family of benign familial neonatal convulsions patients, revealing the correlation of KCNQ2 channels with epileptic disease. A large number of clinical studies have found that KCNQ2 gene mutation is associated with seizures of diseases such as epilepsy, benign familial neonatal convulsions or neonatal epileptic encephalopathy, peripheral nerve hyperexcitability (PNH or myotonic or neuromuscular tonic). The expression of KCNQ2 channels in the various levels of neurons of the pain-sensing conduction pathway and in the brain region involved in pain suggests the possibility of KCNQ2 channels as analgesic targets. Functional experiments prove that in models of neuropathic pain, osteoarthritis pain, bone cancer pain and the like, the expression quantity of KCNQ2 is down-regulated, and the KCNQ2 channel is activated to relieve neuropathic pain and fibromyalgia. In addition, the modulation of KCNQ2 channel activity is also associated with neurological diseases such as parkinson's disease, ischemia, schizophrenia, smooth muscle disease and depression. Given the important role IKM has in controlling neuronal excitability in the central and peripheral nervous systems, KCNQ2 channels are considered as important pharmacological targets for the development of new drugs for neurological and metabolic diseases, and the development of KCNQ2 channel modulators has potential application value for the treatment of pain, epilepsy or neurological diseases. The KCNQ2 inhibitors reported so far have linopirdine, XE-991, DMP-543, UCL2077, ML252, HN38 and other compounds, and the common defect of the compounds is lack of subtype selectivity among the interior of KCNQ family members. KCNQ4 potassium channels are highly expressed in the outer hair cells of the cochlear and brain stem auditory nuclei, and mutations thereof may lead to hereditary hearing loss. KCNQ5 potassium channels are highly expressed in skeletal muscle and brain, and mutations thereof may cause retinopathy and the like.

Retigabine is an agonist of potassium ion channels and is approved to be marketed in 2011 as a novel antiepileptic drug for the adjuvant treatment of partial seizure, but poor target selectivity causes a series of side effects such as retinal pigment deposition, skin discoloration, urinary retention, etc. A series of compounds with different skeletons such as BMS-204352, ICA-069673, NH29, znPy, ML213 and the like are reported to activate KCNQ2 channels, and partial compounds show anticonvulsant effect in a mouse seizure model, but a great deal of preclinical data is still lacking, and considering that most of the new molecules do not start clinical trials, or molecules like ICA-069673 enter clinical phase II research, whether they enter the market successfully or not can not be predicted at present because tolerance, pharmacokinetics and the like cannot be subjected to the next clinical study.

Disclosure of Invention

At present, there are many small molecule agonists of potassium ion channels other than retigabine on the market, but there are no other products that have been successfully marketed. By means of computer aided medicine design, rational design and modification, we find one kind of small molecule regulator with new skeleton potassium channel and complete the research of in vitro and in vivo activity. In order to solve the above problems of the prior art, the inventors have intensively studied and found that certain compounds have a potassium channel modulator effect, and preliminary results of pharmacological activity tests show that they can significantly increase the current of KCNQ2 channels and open KCNQ2 channels at lower voltages.

Specifically disclosed is the use of an amide compound represented by the formula (I) below or a pharmaceutically acceptable salt, ester, optical isomer, tautomer, stereoisomer, polymorph, solvate, N-oxide, isotopically-labeled compound, metabolite, chelate, complex, clathrate, or prodrug thereof as a potassium ion channel agonist,

Ar is selected from the following groups:

indicating the location of the connection.

The invention also provides an application of the amide compound shown in the formula (I) or pharmaceutically acceptable salt, ester, optical isomer, tautomer, stereoisomer, polymorph, solvate, N-oxide, isotopically-labeled compound, metabolite, chelate, complex, clathrate or prodrug thereof in preparing medicines for treating or relieving diseases related to potassium ion channels,

Ar is selected from the following groups:

indicating the location of the connection.

In the present invention, the above-mentioned "potassium ion channel" is preferably a type 2 voltage-gated potassium ion channel KCNQ2, sometimes also referred to as a voltage-gated potassium ion channel KCNQ2, or simply KCNQ2 channel.

In general, potassium channel related disorders refer to central nervous system diseases or disorders including narcolepsy, anxiety, neuropathic pain and migraine, neurodegenerative disorders, stroke, cocaine abuse, nicotine withdrawal symptoms, ethanol withdrawal symptoms, tinnitus and Alzheimer's disease, depression, sleep disorders during aging, and neurodevelopmental disorders. Wherein the seizure disorder is selected from the group consisting of acute seizure disorders, convulsions, status epilepticus, epilepticus such as epileptic syndromes and seizures, neonatal spasms, neonatal seizures, benign familial neonatal seizures (KCNQ 2-BFNE), epileptic encephalopathy (KCNQ 2-NEE), benign familial neonatal convulsions type 1 (BFNC), benign familial neonatal seizures 1 (BFNS 1), neonatal seizures associated with hypoxic ischemic injury, epileptic spasms, epileptic encephalopathy, early infant epileptic encephalopathy 7 (EIEE 7), early infant epileptic encephalopathy with mental retardation, generalized tonic seizures, pale bulb disorder, apneas, cerebral edema, dystonias, facial erythema, hypotonia, epileptic seizures, callus dyscrasia, hyperrhythmic disorders, focal clonic seizures, generalized tonic seizures, myofiber seizures, spastic flaccid paralysis and myofiber limb twitches;

The anxiety disorder is selected from anxiety and diseases and disorders associated with: panic attacks, agoraphobia, panic disorder with agoraphobia, panic disorder without agoraphobia, agoraphobia without history of panic disorder, specific phobia, social phobia and other specific phobia, obsessive compulsive disorder, post-traumatic stress disorder, acute stress disorder, generalized anxiety disorder, anxiety disorder caused by general somatic disorders, substance-induced anxiety disorder, bid farewell anxiety disorder, accommodation disorder, presentation anxiety, eras disorder, anxiety disorder caused by general somatic disorders and substance-induced anxiety disorder and anxiety disorder without specific comments;

The neuropathic pain and migraine pain is selected from the group consisting of allodynia, hyperalgesic pain, phantom pain, neuropathic pain associated with diabetic neuropathy, neuropathic pain associated with trigeminal neuralgia, neuropathic pain associated with sciatica, and neuropathic pain associated with migraine; or alternatively, the first and second heat exchangers may be,

The neurodegenerative disease is selected from Alzheimer's disease, huntington's chorea, multiple sclerosis, amyotrophic lateral sclerosis, creutzfeld-Jakob's, parkinson's disease, encephalopathy caused by AIDS or induced by rubella virus, herpes virus, borrelia or unknown pathogen infection, trauma-induced neurodegenerative lesions, neuronal hyperexcitatory states such as in drug withdrawal or intoxication symptoms, and neurodegenerative diseases of the peripheral nervous system such as polyneuropathy and polyneuritis.

The depression is selected from bipolar depression, post partum depression, major depression, mental depression, atypical depression, mental depression, refractory depression, huntington's disease-related depression, multiple sclerosis-related depression, or anxiety-related depression.

The neurodevelopmental disorder is selected from the group consisting of developmental delay, intellectual impairment, non-syndromic intellectual impairment, autism Spectrum Disorder (ASD).

Whether the pharmacological activity of the compounds of the present invention is related to a potassium ion channel-related disease is based on the results of the existing pharmacological experiments and the speculation of the existing knowledge system, however, whether such mechanism speculation is correct or not does not affect the pharmacological effects of the present invention, that is, the present invention provides the use of an amide compound represented by the above formula (I) or a pharmaceutically acceptable salt, ester, optical isomer, tautomer, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, chelate, complex, clathrate, or prodrug thereof, for the preparation of a medicament for preventing or treating a disease selected from the group consisting of narcotic diseases, anxiety, neuropathic pain and migraine, neurodegenerative diseases, stroke, cocaine abuse, nicotine withdrawal symptoms, ethanol withdrawal symptoms, tinnitus and alzheimer's disease, depression, sleep disorders during aging, neurodevelopment disorders, the specific examples of the diseases are the same as described above, and the administration dose of the compound of the formula (I) is not described in detail, and is 0.1 to 50mg/kg.

The invention provides a pharmaceutical composition, which comprises a prophylactically or therapeutically effective amount of a compound shown in the formula (I) or pharmaceutically acceptable salt, ester, optical isomer, tautomer, stereoisomer, polymorph, solvate, N-oxide, isotopically-labeled compound, metabolite, chelate, complex, inclusion compound or prodrug thereof and a pharmaceutically acceptable carrier, wherein the dosage form of the pharmaceutical composition is an oral dosage form or an injection,

The oral dosage forms include capsules, tablets, pills, powders and granules. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures,

The injection comprises a physiologically acceptable sterile aqueous or anhydrous solution, dispersion, suspension or emulsion, and a compound of formula (I) or a pharmaceutically acceptable salt, ester, optical isomer, tautomer, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, chelate, complex, clathrate, or prodrug thereof for redissolving into a sterile injectable solution or dispersion.

In preliminary pharmacological experiments, the compounds of the invention have the application as potassium ion channel modulators, in summary, the invention also provides the application of the compounds and various derivative substances (pharmaceutically acceptable inorganic or organic salts, hydrates or solvates) thereof and the like in preparing medicaments for relieving and treating diseases related to potassium ion channels, wherein the medicaments comprise the compounds as main active ingredients.

Specific examples and preferred examples of each group in the compound of the present invention, and specific examples of the compound of the present invention are the same as those of each group in the compound for the above-mentioned medical use, and preferred examples of the compound are not described here in detail.

The present invention also provides a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, optical isomer, tautomer, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, chelate, complex, clathrate, or prodrug thereof, and a pharmaceutically acceptable carrier, the pharmaceutical composition preferably being a solid formulation, semi-solid formulation, liquid formulation, or gaseous formulation.

In one embodiment of the invention, the pharmaceutical composition is in the form of oral dosage form or injection, and the oral dosage form comprises capsules, tablets, pills, powder and granules. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures; the injectable formulation comprises a physiologically acceptable sterile aqueous or anhydrous solution, dispersion, suspension or emulsion, and a sterile powder of a compound of the invention or a pharmaceutically acceptable salt, ester, optical isomer, tautomer, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, chelate, complex, clathrate, or prodrug thereof for redissolving into a sterile injectable solution or dispersion.

Compared with the prior art, the invention has the following advantages:

compared with retigabine, the compound has a brand new skeleton type, has more stable physicochemical properties, is not easy to oxidize, and generates side effects such as pigmentation and the like. The retigabine has a triamine benzene ring in the structure, has unstable physicochemical properties and is easy to oxidize. Current studies generally suggest that oxidation of retigabine is the primary cause of pigmentation, and therefore many retigabine analogues have been engineered on the triamine benzene ring to improve their stability.

Detailed Description

The other elements of the present invention will be described in more detail below.

Definition of the definition

Unless defined otherwise hereinafter, all technical and scientific terms used herein are intended to be identical to what is commonly understood by one of ordinary skill in the art. References to techniques used herein are intended to refer to techniques commonly understood in the art, including variations of those that are obvious to those skilled in the art or alternatives to equivalent techniques. While the following terms are believed to be well understood by those skilled in the art, the following definitions are set forth to better explain the present invention.

In the present invention,

The terms "comprising," "including," "having," "containing," or "involving," and other variations thereof herein, are inclusive (inclusive) or open-ended and do not exclude additional unrecited elements or method steps.

The term "pediatric patient" as used herein refers to a patient less than 16 years of age at the time of diagnosis or treatment. The term "child" can also be divided into the following subclasses: neonates (from birth to first month of birth); infants (1 month to two years); children (2 to 12 years); teenagers (12 to 21 years old (up to but not including 22 years of birth)). Berhman RE, kliegman R, arvin AM, nelson we. Nelson textbook, 15 th edition. Philadelphia: w.b. samanders company, 1996; rudolph AM, et al. Pediatric version 21 of rudoffer. New York: mcGrow-Hill, 2002; and Avery MD, first LR. Pediatric medicine, second edition. Balm: williams & Wilkins;1994.

As used herein, an "effective amount" of a compound refers to an amount sufficient to down-regulate or agonize potassium ion channels.

As used herein, a "therapeutically effective dose" of a compound refers to an amount sufficient to ameliorate or somehow reduce symptoms, stop or reverse progression of a disease, or down-regulate or agonize potassium ion channels. Such doses may be administered as a single dose or may be administered according to a regimen so as to be effective.

As used herein, "treating" refers to ameliorating or otherwise altering the condition, disorder, or symptom or pathology of a disease in a patient in any manner.

As used herein, "ameliorating a symptom of a particular disease by use of a particular compound or pharmaceutical composition" refers to any reduction, whether permanent or temporary, persistent or temporary, attributable to or associated with the use of the composition.

By "pharmaceutically acceptable salts" is meant salts of the compounds of the present invention which are safe and effective when used in the human or animal body. Salts of the compounds may be obtained by dissolving the corresponding addition salts in pure solution or in a suitable inert solvent with sufficient amounts of base or acid. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia, magnesium salts, and the like, and pharmaceutically acceptable acid addition salts include inorganic and organic acid salts including hydrochloric acid, hydrobromic acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, monohydrogen sulfate, acetic acid, maleic acid, malonic acid, succinic acid, fumaric acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, methanesulfonic acid, and the like (see Berge et al, "Pharmaceutical Salts", journal of Pharmaceutical Science 66:1-19 (1977)).

The present invention encompasses all possible crystalline forms or polymorphs of the compounds of the present invention, which may be single polymorphs or mixtures of any ratio of more than one polymorphs.

It will also be appreciated that certain compounds of the invention may exist in free form for use in therapy or, where appropriate, in the form of pharmaceutically acceptable derivatives thereof. In the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, N-oxides, metabolites, chelates, complexes, clathrates or prodrugs which, upon administration to a patient in need thereof, are capable of providing the compounds of the present invention, or metabolites or residues thereof, directly or indirectly. Thus, when reference is made herein to "a compound of the invention" it is also intended to encompass the various derivative forms of the compounds described above.

Pharmaceutically acceptable salts of the compounds of the invention include acid addition salts and base addition salts thereof, including but not limited to salts containing hydrogen or coordination bonds.

Suitable acid addition salts are formed from acids that form pharmaceutically acceptable salts. Examples include acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate/carbonate, bisulfate/sulfate, borate, camphorsulfonate, citrate, cyclamate, ethanedisulfonate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hyparate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthoate (naphthylate), 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate, and xinafoate (xinofoate).

Suitable base addition salts are formed from bases that form pharmaceutically acceptable salts. Examples include aluminum salts, arginine salts, benzathine salts, calcium salts, choline salts, diethylamine salts, diethanolamine salts, glycine salts, lysine salts, magnesium salts, meglumine salts, ethanolamine salts, potassium salts, sodium salts, tromethamine salts, and zinc salts.

For a review of suitable salts see Stahl, wermpuh, "Handbook of Pharmaceutical Salts: properties, selection, and Use (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds of the invention are known to those skilled in the art.

As used herein, the term "ester" means an ester derived from each of the compounds of the general formula in the present application, including physiologically hydrolyzable esters (compounds of the present application that can be hydrolyzed under physiological conditions to release the free acid or alcohol form). The compounds of the application may themselves be esters.

The compounds of the invention may be present in the form of solvates (preferably hydrates) wherein the compounds of the invention comprise a polar solvent as a structural element of the compound lattice, in particular for example water, methanol or ethanol. The polar solvent, in particular water, may be present in stoichiometric or non-stoichiometric amounts.

Those skilled in the art will appreciate that not all nitrogen-containing heterocycles are capable of forming N-oxides, as nitrogen requires available lone pairs to oxidize to oxides; those skilled in the art will recognize nitrogen-containing heterocycles capable of forming N-oxides. Those skilled in the art will also recognize that tertiary amines are capable of forming N-oxides. Synthetic methods for preparing N-oxides of heterocycles and tertiary amines are well known to those skilled in the art and include oxidizing heterocycles and tertiary amines with peroxyacids such as peracetic acid and m-chloroperoxybenzoic acid (MCPBA), hydrogen peroxide, alkyl hydroperoxides such as t-butyl hydroperoxide, sodium perborate, and dioxiranes (dioxirane) such as dimethyl dioxirane. These methods for preparing N-oxides have been widely described and reviewed in the literature, see for example: T.L. Gilchrist, comprehensive Organic Synthesis, vol.7, pp 748-750; katritzky and a.j. Boulton, eds., ACADEMIC PRESS; and g.w.h.cheeseman and e.s.g.werstiuk, ADVANCES IN Heterocyclic Chemistry, vol.22, pp 390-392, a.r.katritzky and a.j.boulton, eds., ACADEMIC PRESS.

Also included within the scope of the invention are metabolites of the compounds of the invention, i.e., substances that form in vivo upon administration of the compounds of the invention. Such products may result from, for example, oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, etc. of the compound being administered. Accordingly, the present invention includes metabolites of the compounds of the present invention, including compounds made by a process of contacting a compound of the present invention with a mammal for a time sufficient to produce the metabolites thereof.

The invention further includes within its scope prodrugs of the compounds of the invention, which are certain derivatives of the compounds of the invention which may themselves have little or no pharmacological activity, which, when administered into or onto the body, may be converted into the compounds of the invention having the desired activity by, for example, hydrolytic cleavage. Typically such prodrugs will be functional derivatives of the compounds which are readily convertible in vivo into the desired therapeutically active compound. Additional information regarding the use of prodrugs can be found in "Pro-drugs as Novel DELIVERY SYSTEMS", vol.14, ACS Symposium Series (T.Higuchi and V.stilla). Prodrugs of the invention may be prepared, for example, by replacing the appropriate functional groups present in the compounds of the invention with certain moieties known to those skilled in the art as "pro-moieties" (e.g., "Design of Prodrugs", described in H. Bundgaard (Elsevier, 1985) ".

The invention also encompasses compounds of the invention containing a protecting group. During any process for preparing the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules of interest, thereby forming a chemically protected form of the compounds of the present invention. This can be achieved by conventional protecting groups, for example those described in T.W.Greene & P.G.M.Wuts, protective Groups in Organic Synthesis, john Wiley & Sons,1991, which references are incorporated herein by reference. The protecting group may be removed at a suitable subsequent stage using methods known in the art.

The chemical structures described above in the present invention include labels of different isotopes of each element, for example, the compound of formula (I) may be a deuterated compound of formula (I), and are not described in detail.

The term "about" means within + -10%, preferably within + -5%, more preferably within + -2% of the stated value.

Specific examples of the compounds of the present invention are as follows:

Typical compounds of the invention include, but are not limited to, compounds in the tables above, compound nomenclature in the invention following systematic nomenclature, or nomenclature using ChemDraw software.

Examples

The method of the present invention will be described by way of specific examples, so that the technical solution of the present invention can be understood and grasped more easily, but the present invention is not limited thereto.

The ¹ H NMR spectra in the examples below were determined using a Bruker instrument (400 MHz) and the chemical shifts were expressed in ppm. Tetramethylsilane internal standard (0.00 ppm) was used. ¹ H NMR representation method: s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet, br=broad, dd=doublet of doublet, dt=doublet of triplet. If coupling constants are provided, they are in Hz.

The mass spectrum is measured by an LC/MS instrument, and the ionization mode is ESI.

High performance liquid chromatograph model: agilent 1260, siemens flying U3000; chromatographic column model: waters xbrige C18 < 18 > (4.6X105 mm,3.5 μm); mobile phase: ACN, B Water (0.1% H ₃PO₄); flow rate: 1.0mL/min; gradient ：5％A for 1min,increase to 20％A within 4min,increase to 80％Awithin 8min,80％Afor 2min,back to 5％Awithin 0.1min; wavelength: 220nm; column incubator: 35 ℃.

The thin layer chromatography silica gel plate is a smoke table yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification of the silica gel plate used by the Thin Layer Chromatography (TLC) is 0.2mm-0.3mm, and the specification of the thin layer chromatography separation and purification product is 0.4mm-0.5mm.

Column chromatography generally uses tobacco stage yellow sea silica gel 200-300 mesh silica gel as carrier.

In the examples below, all temperatures are degrees celsius unless otherwise indicated, and unless otherwise indicated, the various starting materials and reagents are either commercially available or synthesized according to known methods, and are used without further purification, and unless otherwise indicated, commercially available manufacturers include, but are not limited to, chinese pharmaceutical group limited, belvedere technology limited, tendril (Shanghai) chemical industry development limited, shanghai Pichia pharmaceutical technology limited, shanghai michelel chemical technology limited, and the like.

CD ₃ OD: deuterated methanol

CDCl ₃: deuterated chloroform

DMSO-d ₆: deuterated dimethyl sulfoxide

Pd ₂(dba)₃: tris (dibenzylideneacetone) dipalladium

Pd (dppf) Cl ₂: [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride

XantPhos:4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene

XPhos: 2-dicyclohexylphosphorus-2, 4, 6-triisopropylbiphenyl

HATU:2- (7-Oxybenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate

TLC: thin layer chromatography

HPLC: high performance liquid chromatography

Purity: purity of

The hydrogen atmosphere is defined as the reaction flask being connected to a hydrogen balloon of about 1L volume.

The examples are not particularly described, and the solution in the reaction is an aqueous solution.

The examples are not specifically described, and the reaction temperature is room temperature and is 20℃to 30 ℃.

The monitoring of the progress of the reaction in the examples employed Thin Layer Chromatography (TLC), the developing reagent used for the reaction, the system of eluent for column chromatography employed for purifying the compound or the developing reagent system of thin layer chromatography included: a: petroleum ether and ethyl acetate systems; b: methylene chloride and methanol systems; c: n-hexane: ethyl acetate; the volume ratio of the solvent is different according to the polarity of the compound, and can be adjusted by adding a small amount of acidic or alkaline reagent, such as acetic acid or triethylamine.

Pharmaceutical chemistry experiment

Example 1

N- (1, 2-Dihydroacenaphthylen-5-yl) -4-fluorobenzamide 1

First step 1, 2-Dihydroacenaphthene-5-amine 1b

5-Nitroacenaphthene 1a (1.00 g,5.02 mmol) was dissolved in ethanol (20 mL), wet palladium on carbon (0.15 g, 10%) was added at room temperature, hydrogen was displaced three times, after stirring overnight at room temperature under a hydrogen balloon, TLC showed the starting material disappeared, celite was filtered, ethanol (60 mL) was washed, the filtrate was concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=50/1-20/1) to give the title compound 1b (0.60 g, 71% yield) as a white solid.

LC-MS:m/z＝170.1[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ7.70(d,J＝8.4Hz,1H),7.31-7.25(m,1H),7.18(d,J＝6.8Hz,1H),7.00(d,J＝7.2Hz,1H),6.60(d,J＝7.2Hz,1H),5.39(s,2H),3.31-3.25(m,2H),3.21-3.15(m,2H).

Second step N- (1, 2-Dihydroacenaphthylen-5-yl) -4-fluorobenzamide 1

Compound 1b (450 mg,2.66 mmol) was dissolved in dichloromethane (10 mL), 4-fluorobenzoic acid (480 mg,3.46 mmol) was added at room temperature, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (660 mg,3.46 mmol) and 4-dimethylaminopyridine (33 mg,0.27 mmol) were added and after stirring at room temperature for 1 hour, TLC showed the disappearance of starting material, the reaction solution was quenched with water (20 mL), dichloromethane extracted (20 mL x 3), the organic phases were combined, washed with dilute hydrochloric acid (30 mL, 1N), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=30/1-5/1) to give a white solid, which was slurried with methyl tert-butyl ether (8 mL) and filtered to give the title compound 1 (580 mg, 75% yield) as a white solid.

LC-MS:m/z＝292.1[M+H]⁺(99.37％purity,220nm)

¹H NMR(400MHz,DMSO-d₆)δ10.34(s,1H),8.15(dd,J＝8.4,5.2Hz,2H),7.62(d,J＝8.4Hz,1H),7.55(d,J＝7.2Hz,1H),7.49-7.45(m,1H),7.42-7.36(m,2H),7.35-7.32(m,2H),3.42-3.32(m,4H).

Example 2

N- (1, 2-Dihydroacenaphthylen-5-yl) -3, 4-difluorobenzamide 2

/>

First step 3, 4-difluorobenzoic acid 2b

3, 4-Difluorobenzaldehyde 2a (500 mg,3.51 mmol) was dispersed in a mixed solution of acetone and water (5 mL/2 mL), sodium chlorite (636 mg,7.03 mmol) and sulfamic acid (1.02 g,10.55 mmol) were added at room temperature, and stirred at room temperature for 2 hours. TLC detection showed complete reaction. The reaction mixture was quenched with water (10 mL), extracted with ethyl acetate (10 mL), washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, and concentrated to give the title compound 2b (510 mg, crude) as a white solid, which was directly taken into the next reaction.

Second step N- (1, 2-Dihydroacenaphthylen-5-yl) -3, 4-difluorobenzamide 2

Compound 1b (50 mg,0.29 mmol) and 3, 4-difluorobenzoic acid 2b (70 mg, crude) were dissolved in dichloromethane (5 mL), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (84 mg,0.44 mmol) and catalytic amount of 4-dimethylaminopyridine (5 mg) were added at room temperature and stirred at room temperature for 1 hour. TLC detection showed complete reaction. The reaction solution was neutralized with saturated aqueous sodium hydrogencarbonate (5 mL), the excess 3, 4-difluorobenzoic acid starting material was extracted with methylene chloride (20 mL), washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was slurried with methanol (1 mL) to give the title compound 2 (47.0 mg, yield 51%)

LC-MS：m/z＝310.1[M+H]⁺；(99.64％purity,220nm)

¹H NMR(400MHz,DMSO-d₆)δ10.42(s,1H),8.16-8.11(m,1H),7.97(s,1H),7.66-7.61(m,2H),7.54(d,J＝7.6Hz,1H),7.50-7.46(m,1H),7.35-7.33(m,2H),3.40-3.34(m,4H).

Examples 3 to 8

Table 2 the compounds of examples 3-8 were synthesized with reference to the second step synthesis of examples 1 and 2, except that different substituted benzoic acid starting materials were charged in each example, see table 2 below.

Pharmacological experiment part modulation of type 2 voltage-gated potassium channel KCNQ2 channel currents in mammalian expression systems by the compounds of the invention

Experimental method

1. Plasmid preparation

The gene of human source voltage-gated potassium ion channel KCNQ2 (NP-004509.2) was cloned into pIRES2-EGFP expression vector and heterologously expressed in CHO-K1 cells.

2. Cell culture and transfection

CHO-K1 cells (purchased from cell bank of China academy of sciences) were cultured using DMEM/F12 medium, 10% fetal bovine serum was added, and cultured in a carbon dioxide incubator (5% CO ₂ ℃ C.). The cells are digested by 25% pancreatin when passaged, and when the cell density reaches 80% -100%, the transfection plasmid is carried out by referring to Lipofectamine 300 experimental operation instruction book: tube A was filled with OPTI-MEM 125. Mu.L and lip 3000. Mu.L; tube B was filled with OPTI-MEM 125. Mu.L, plasmid 2.5. Mu.g, P3000. Mu.L, tube A and tube B were mixed, left to stand for 15min, and then added dropwise to 6-well plates, after 24h transfection, cells were digested with pancreatin, centrifuged, resuspended in extracellular fluid and added dropwise to dishes, and cells with green fluorescent markers were selected for electrophysiological testing.

3. Whole cell patch clamp experiment

The whole-cell electrophysiological experiment record is carried out at the room temperature of 23-25 ℃ by adopting a HEKA EPC10 patch clamp amplifier, the filtering is 1kHz, and the sampling frequency is 10kHz. The patch clamp electrode is drawn by a horizontal electrode drawing instrument P-97 through a multi-step program, and the resistance is 3-5 MΩ. Extracellular fluid used for cell recording was 145mM NaCl, 5mM KCl, 1mM CaCl ₂、3mM MgCl₂, 10mM HEPES (pH 7.4, adjusted with NaOH), intracellular fluid was 150mM KCl, 3mM MgCl ₂, 5mM EGTA, 10mM HEPES (pH 7.3, adjusted with KOH). After sealing and rupture of the membrane, the voltage is clamped at-80 mV, then a Step record mode is adopted, a series of depolarization voltages ranging from-90 mV to +60mV (increasing every 10mV and one sweep every 2 s) are given to draw outward current, and then a super-polarized voltage of-120 mV is given to draw tail current and record. Then, the Ramp recording mode is started, extracellular fluid is firstly recorded under the voltage of-10 mV, and a compound (triazole derivative provided by the invention is used as a potassium ion channel regulator) is administered after the channel current is stable. The administration time is at least 3min, and finally, after the drug action is stable, the cell is washed back by extracellular fluid. The rapid drug delivery system was RSC-200 at a rate of about 0.2mL/min.

4. Data analysis and statistics

Data analysis and mapping were performed using software such as Clampfit 10.4, GRAPHPAD PRISM 8.0.2. The specific statistical method is as follows:

(1) And (5) carrying out statistics on the drug effect. The effect of the drug was judged by recording the steady outward current at-10 mV before and after test dosing. The mean steady current before administration was designated as I _control and the mean steady current after administration was designated as I. The effect of the drug on the channel is denoted as I/I _control.

(2) Dose-response curve fitting of the drug. Fitting was performed with the formula e=e _max/(1+(EC₅₀/C)^P, where EC ₅₀ is the drug concentration that produced half the maximum response, P is Hill coefficient, and C is drug concentration.

(3) Conductance-voltage curve (G-V curve) statistics. The effect of the voltage sensitivity of the channel itself or the test drug on the voltage sensitivity of the channel was counted by recording the tail current induced by a set of depolarizing voltages (-90 mV to +60mV, increasing every 10 mV) momentarily hyperpolarized to-120 mV. The G/G _max at each voltage was counted normalized to the calculated maximum conductance G _max. The boltzmann equation is used: g=g _min+(G_max-G_min)/(1+exp(V-V_1/2)/S), G _max is the maximum conductance, G _min is the minimum conductance, V _1/2 is the voltage at which 50% of the maximum conductance is reached, and S is the slope factor.

Statistical analysis of the data was performed using paired t-test (Student' S PAIRED T TEST), all experimental data were expressed as mean ± standard error (mean ± s.e.m.), and differences between the two groups were considered statistically significant at P < 0.05.

The test results are shown in Table 3.

TABLE 3 test of the effect of the compounds of the invention on the voltage-gated potassium channel KCNQ2 channel current at a concentration of 10. Mu.M

N represents the same number of experiments performed under the same experimental conditions at different times, respectively.

Nd represents no statistics.

Conclusion: in this experiment, it was tested that some compounds of the present invention increased the potassium current of the voltage-gated potassium channel KCNQ2 channel, making the channel more sensitive to low voltages, i.e., allowing the voltage-gated potassium channel KCNQ2 channel to open at lower voltages. It is expected that the activity of the neuronal network can be regulated, and thus the compounds of the present invention can be effectively used for the treatment of diseases such as etc. which regulate the activity of neurons.

However, other mechanisms may exist for various activities of the compounds of the present invention, and the speculation of the mechanism in the present invention is correct or not, without affecting the specific active effects of the compounds of the present invention. The therapeutic use in the treatment or alleviation of the relevant diseases is not limited to the embodiments described above, i.e. it does not mean that the invention has to be carried out in dependence of the embodiments described above. It should be apparent to those skilled in the art that any modification of the present invention, equivalent substitution of raw materials for the product of the present invention, addition of auxiliary components, selection of specific modes, etc., falls within the scope of the present invention and the scope of disclosure.

The preferred embodiments of the present invention have been described in detail above, but the present invention is not limited to the specific details of the above embodiments, and various simple modifications can be made to the technical solution of the present invention within the scope of the technical concept of the present invention, and all the simple modifications belong to the protection scope of the present invention.

In addition, the specific features described in the above embodiments may be combined in any suitable manner, and in order to avoid unnecessary repetition, various possible combinations are not described further.

Claims (10)

1. The use of an amide compound of formula (I) or a pharmaceutically acceptable salt, ester, optical isomer, tautomer, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, chelate, complex, clathrate, or prodrug thereof as potassium channel modulator,

Ar is selected from the following groups:

indicating the location of the connection.

2. The use of an amide compound of formula (I) or a pharmaceutically acceptable salt, ester, optical isomer, tautomer, stereoisomer, polymorph, solvate, N-oxide, isotopically-labeled compound, metabolite, chelate, complex, clathrate, or prodrug thereof in the manufacture of a medicament for treating or ameliorating a disorder associated with potassium ion channels,

Ar is selected from the following groups:

indicating the location of the connection.

3. The use according to claim 2, wherein the potassium channel related disease is selected from central nervous system diseases or disorders.

4. The use according to claim 3, wherein the central nervous system disease or disorder is selected from the group consisting of narcolepsy, anxiety, neuropathic pain and migraine, neurodegenerative diseases, stroke, cocaine abuse, nicotine withdrawal symptoms, ethanol withdrawal symptoms, tinnitus and alzheimer's disease, depression, sleep disorders during aging, neurodevelopmental disorders.

5. The use according to claim 4, wherein,

The seizure disorders are selected from the group consisting of acute seizure disorders, convulsions, status epilepticus, epilepsy disorders such as epileptic syndromes and seizures, neonatal spasms, neonatal seizures, benign familial neonatal seizures (KCNQ 2-BFNE), epileptic encephalopathy (KCNQ 2-NEE), benign familial neonatal convulsions type 1 (BFNC), benign familial neonatal seizures 1 (BFNS 1), neonatal seizures associated with hypoxic ischemic injury, epileptic spasms, epileptic encephalopathy, early infant epileptic encephalopathy 7 (EIEE 7), early infant epileptic encephalopathy with mental retardation, generalized tonic seizures, pale globular abnormal conditions, apneas, cerebral edema, dystonia, facial erythema, hypotonia, epileptic seizures, calluses, hyperrhythmic disorders, focal clonic seizures, generalized tonic clonic seizures, myofiber seizures, sexual parvulus and myofiber spasms;

The anxiety disorder is selected from anxiety and diseases and disorders associated with: panic attacks, agoraphobia, panic disorder with agoraphobia, panic disorder without agoraphobia, agoraphobia without history of panic disorder, specific phobia, social phobia and other specific phobia, obsessive compulsive disorder, post-traumatic stress disorder, acute stress disorder, generalized anxiety disorder, anxiety disorder caused by general somatic disorders, substance-induced anxiety disorder, bid farewell anxiety disorder, accommodation disorder, presentation anxiety, eras disorder, anxiety disorder caused by general somatic disorders and substance-induced anxiety disorder and anxiety disorder without specific comments;

The neuropathic pain and migraine pain is selected from the group consisting of allodynia, hyperalgesic pain, phantom pain, neuropathic pain associated with diabetic neuropathy, neuropathic pain associated with trigeminal neuralgia, neuropathic pain associated with sciatica, and neuropathic pain associated with migraine; or alternatively, the first and second heat exchangers may be,

The neurodegenerative disease is selected from Alzheimer's disease, huntington's chorea, multiple sclerosis, amyotrophic lateral sclerosis, creutzfeld-Jakob's, parkinson's disease, encephalopathy caused by AIDS or induced by rubella virus, herpes virus, borrelia or unknown pathogen infection, trauma-induced neurodegenerative lesions, neuronal hyperexcitatory states such as in drug withdrawal or intoxication symptoms, and neurodegenerative diseases of the peripheral nervous system such as polyneuropathy and polyneuritis;

The depression is selected from bipolar depression, post partum depression, major depression, mental depression, atypical depression, mental depression, refractory depression, huntington's disease-related depression, multiple sclerosis-related depression, or anxiety-related depression;

The neurodevelopmental disorder is selected from the group consisting of developmental delay, intellectual impairment, non-syndromic intellectual impairment, autism Spectrum Disorder (ASD).

6. Use of an amide compound represented by formula (I) or a pharmaceutically acceptable salt, ester, optical isomer, tautomer, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, chelate, complex, clathrate, or prodrug thereof for the preparation of a medicament for preventing or treating a disease selected from the group consisting of narcotic diseases, anxiety, neuropathic pain and migraine, neurodegenerative diseases, stroke, cocaine abuse, nicotine withdrawal symptoms, ethanol withdrawal symptoms, tinnitus and Alzheimer's disease, depression, sleep disorders during aging, neurodevelopmental disorders,

Ar is selected from the following groups:

indicating the location of the connection.

7. The use according to claim 6, wherein,

The seizure disorders are selected from the group consisting of acute seizure disorders, convulsions, status epilepticus, epilepsy disorders such as epileptic syndromes and seizures, neonatal spasms, neonatal seizures, benign familial neonatal seizures (KCNQ 2-BFNE), epileptic encephalopathy (KCNQ 2-NEE), benign familial neonatal convulsions type 1 (BFNC), benign familial neonatal seizures 1 (BFNS 1), neonatal seizures associated with hypoxic ischemic injury, epileptic spasms, epileptic encephalopathy, early infant epileptic encephalopathy 7 (EIEE 7), early infant epileptic encephalopathy with mental retardation, generalized tonic seizures, pale globular abnormal conditions, apneas, cerebral edema, dystonia, facial erythema, hypotonia, epileptic seizures, calluses, hyperrhythmic disorders, focal clonic seizures, generalized tonic clonic seizures, myofiber seizures, sexual parvulus and myofiber spasms;

The anxiety disorder is selected from anxiety and diseases and disorders associated with: panic attacks, agoraphobia, panic disorder with agoraphobia, panic disorder without agoraphobia, agoraphobia without history of panic disorder, specific phobia, social phobia and other specific phobia, obsessive compulsive disorder, post-traumatic stress disorder, acute stress disorder, generalized anxiety disorder, anxiety disorder caused by general somatic disorders, substance-induced anxiety disorder, bid farewell anxiety disorder, accommodation disorder, presentation anxiety, eras disorder, anxiety disorder caused by general somatic disorders and substance-induced anxiety disorder and anxiety disorder without specific comments;

The neuropathic pain and migraine pain is selected from the group consisting of allodynia, hyperalgesic pain, phantom pain, neuropathic pain associated with diabetic neuropathy, neuropathic pain associated with trigeminal neuralgia, neuropathic pain associated with sciatica, and neuropathic pain associated with migraine; or alternatively, the first and second heat exchangers may be,

The neurodegenerative disease is selected from Alzheimer's disease, huntington's chorea, multiple sclerosis, amyotrophic lateral sclerosis, creutzfeld-Jakob's, parkinson's disease, encephalopathy caused by AIDS or induced by rubella virus, herpes virus, borrelia or unknown pathogen infection, trauma-induced neurodegenerative lesions, neuronal hyperexcitatory states such as in drug withdrawal or intoxication symptoms, and neurodegenerative diseases of the peripheral nervous system such as polyneuropathy and polyneuritis;

The depression is selected from bipolar depression, post partum depression, major depression, mental depression, atypical depression, mental depression, refractory depression, huntington's disease-related depression, multiple sclerosis-related depression, or anxiety-related depression;

The neurodevelopmental disorder is selected from the group consisting of bradykinesia, dysnoesia, non-syndromic dysnoesia, autism spectrum disorder ASD.

8. The use or use according to any one of claims 1 to 7, wherein the compound of formula (I) is administered at a dose of 0.1 to 50mg/kg.

9. A pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, optical isomer, tautomer, stereoisomer, polymorph, solvate, N-oxide, isotopically-labeled compound, metabolite, chelate, complex, clathrate, or prodrug thereof, and a pharmaceutically acceptable carrier,

Ar is selected from the following groups:

indicating the location of the connection.

10. The pharmaceutical composition of claim 9, wherein the pharmaceutical composition is in the form of an oral dosage form or an injection,

The oral dosage forms include capsules, tablets, pills, powders and granules, the liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures,

The injection comprises a physiologically acceptable sterile aqueous or anhydrous solution, dispersion, suspension or emulsion, and a compound of formula (I) or a pharmaceutically acceptable salt, ester, optical isomer, tautomer, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, chelate, complex, clathrate, or prodrug thereof for redissolving into a sterile injectable solution or dispersion.