CN112225695A - Oxynitride and preparation method and application thereof - Google Patents
Oxynitride and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses an oxynitride, a preparation method and application thereof. Specifically, the invention discloses a nitrogen oxide compound shown as a formula (I) or a pharmaceutically acceptable salt thereof, wherein the nitrogen oxide compound has better NaV1.8 blocking activity;
Description
Technical Field
The invention relates to an oxynitride, a preparation method and application thereof.
Background
Pain is one of the most common symptoms in the clinic, the fifth vital sign following respiration, pulse, blood pressure and body temperature, and seriously affects the quality of life of the patient. Statistically, the worldwide analgesic market in 2018 is about $ 360 billion, and is expected to reach $ 560 billion in 2023. The acute moderate-severe degree mainly depends on opioid drugs, accounts for about two thirds of the market share of analgesics, and will steadily increase with an annual compound growth rate of 2.5% in the future. The number of chronic pain patients mainly suffering from neuropathic pain (neuropathic pain) and arthritis pain is increasing year by year, and the market is expected to show about 18% of annual composite growth rate and is a main driving force for driving the global pain market to continuously grow in the next decade.
Neuropathic pain is a chronic pain that results from injury or disease to the peripheral somatosensory nervous system and its symptoms include spontaneous pain and allodynia from normal, harmless stimuli. Common causes of neuropathic pain include: diabetes, herpes zoster, spinal cord injury, stroke, multiple sclerosis, cancer, HIV infection, lumbar or cervical radiculoneuropathy, and traumatic or post-operative nerve damage, among others. Osteoarthritis, also known as degenerative arthritis, is a bone joint cartilage degradation caused by various factors, which can cause the surface of joint bone to be uneven and possibly form bone spurs, and the clinical manifestations are mainly joint pain and joint stiffness. The long-term pain not only affects the sleeping, working and living abilities of the patients, but also increases the incidence of emotional disorders such as depression or anxiety, thereby bringing heavy economic burden to the families and the society of the patients.
According to data published by the International society for pain, neuropathic pain Special group (NeuPSIG), the prevalence of neuropathic pain is about 3.3% -8.2%. According to the calculation, at least more than 5 million patients exist in China. In 2017 there were 3050 thousands of neuropathic pain patients in the five major markets of the united states, japan and the european union (france, germany, italy, spain and the uk) and there was a rising trend year by year. Neuropathic pain is one of the most difficult conditions to treat, and most current treatment regimens are still unsatisfactory. It has been reported that only 14.9% of outpatients who can timely relieve pain by drug therapy, i.e., about 85% of painful patients, are not treated with timely and effective drugs, and thus some patients have to seek surgical intervention. The first-line drugs currently used clinically for the treatment of neuropathic pain are mainly calcium channel modulators (such as pregabalin and gabapentin), tricyclic antidepressants and 5-hydroxytryptamine and norepinephrine reuptake inhibitors (such as anticonvulsants and antidepressant drugs including duloxetine and venlafaxine). These drugs have limited efficacy and are associated with various adverse reactions. Duloxetine is one of first-line medicines for treating neuropathic pain, and main side effects comprise gastrointestinal tract reaction, nausea, somnolence, dry mouth, hyperhidrosis, dizziness and the like, so that the medicine withdrawal rate reaches 15% -20%. The antiepileptic drugs gabapentin and pregabalin are main drugs for treating neuropathic pain, and can cause a plurality of adverse reactions such as dizziness, somnolence, peripheral edema, weight gain, weakness, headache, dry mouth and the like. It has also been found in recent years that pregabalin causes a very small proportion of patients to develop suicidal ideation and self-injurious behaviour associated with drug use.
The number of osteoarthritis patients is huge, more than 4 hundred million osteoarthritis patients are expected to exist in the world at present, and the number of osteoarthritis patients in China is estimated to be in the hundreds of millions. There is also no effective treatment for osteoarthritis pain at present. There are physiotherapy, pharmacotherapy and surgical treatment in clinic. Physical therapy includes thermal therapy, hydrotherapy, ultrasound, massage and the like, and auxiliary appliances reduce joint pressure and relieve pain, but the effect is limited, and most of the physical therapy still needs to rely on medicines for treatment. These drugs all have various degrees of side effects. Non-steroidal anti-inflammatory drugs are indicated for mild to moderate pain, but also have gastrointestinal side effects and risk in the cardiovascular and cerebrovascular areas. Opioid analgesics are used for severe pain, but have significant side effects such as nausea, vomiting, constipation and drug dependence, and are not suitable for long-term administration. Therefore, the research and development of a new target-targeted mechanism and a safe and effective analgesic drug meet the unmet clinical requirements, and have important economic and social meanings.
Recent research results have gradually revealed that the sodium ion channel subtype 1.8 (nav 1.8) plays an important role in the generation and transmission of pain sensation. NaV1.8 is a voltage-gated sodium ion channel, mainly expressed in afferent neurons including sensory neurons, by controlling sodium ion entry and exit from cells, in the maintenance of nociceptive sensory neuron excitability, action potential release and persistence, and pain sensitivity regulation, play an important role. Paroxysmal pain due to small fiber neuropathy (damage to a δ fibers mainly responsible for pain transmission and non-medullary fiber C fibers) occurs in patients with nav1.8 activating mutations. Diseases such as chronic inflammation and diabetes can cause the increase of NaV1.8 expression or the change of properties to sensitize nociceptive neurons, and cause various pains. However, NaV1.8 knockout mice are not sensitive to pain.
With the determination of the position of Nav1.8 in chronic pain, the research on drugs based on the target spot is hot, at present, one small molecular blocker is in the clinical stage 2 internationally, other small molecular blockers and antibodies are developed before clinical application, and no other new drug research and development aiming at the target spot is available at home. At the front end of the development, the small molecule NaV1.8 blocker VX-150 of Futai (Vertex) Inc. in USA, phase 2 clinical trials have been conducted on patients with osteoarthritis, acute pain and pain caused by small fiber neuropathy, and all three studies have obtained positive results, indicating that inhibition of NaV1.8 activity can relieve a variety of pain including neuropathic pain. VX-150 has now obtained us FDA breakthrough therapy approval for the treatment of moderate to severe pain, again demonstrating that nav1.8 is a potential target for analgesia. In addition, the action mechanism and the second-phase clinical experiment of the NaV1.8 retarder show that the NaV1.8 retarder is widely applicable to various pains such as neuropathic pain, osteoarthritis pain, acute injury pain and the like; the safety is relatively high, no addiction exists, and the gastrointestinal side effects and the cardiovascular and cerebrovascular side effects of the non-steroidal anti-inflammatory drugs do not exist; can be used in combination with other analgesics to enhance therapeutic effect and reduce side effects.
Disclosure of Invention
The invention aims to solve the technical problem that the existing NaV1.8 retarder is few in types, and therefore, the invention provides an oxynitride and a preparation method and application thereof. The oxynitride compound has a good NaV1.8 blocking activity.
The invention provides a nitroxide compound shown in formula (I) or a pharmaceutically acceptable salt thereof,
wherein the content of the first and second substances,
R1selected from H, F, Cl, OH or NH2；
R2Selected from H, F, Cl, Br, I, OH, NH2、C1-C3Alkyl or C1-C3Alkoxy of (a), said C1-C3Alkyl or C1-C3Is optionally substituted with 1,2 or 3 halogens;
R3selected from H, F, Cl, Br, I, OH, NH2、C1-C3Alkyl or C1-C3Alkoxy of (a), said C1-C3Alkyl or C1-C3Is optionally substituted with 1,2 or 3 halogens;
R4selected from H, F, Cl, OH, NH2、C1-C3Alkyl or C1-C3Alkoxy of (a), said C1-C3Alkyl or C1-C3Is optionally substituted with 1,2 or 3 halogens;
x is selected from-CH2-or-O-;
y is selected from-CH2-or-O-;
z is selected from-CH2-、-CH2CH2-or-O-;
and, when Y is selected from-O-, neither X nor Z is selected from-O-;
t is selected from N or CH.
In one embodiment, in the nitroxide compound of formula (i) or its pharmaceutically acceptable salt, certain groups are defined as follows, and the definition of the unrelated group is as described in any of the preceding embodiments (hereinafter referred to as "in one embodiment"):
when T is selected from CH, the amide bond is linked to N+-O-Meta position of (b).
In one embodiment, when T is selected from CH, the amide linkage is to N+-O-And (4) contraposition.
In one embodiment, when T is selected from N, the amide linkage is to N+-O-Meta or para of (a).
In a certain embodiment, R2Selected from H, F, Cl, Br, I, OH, NH2Methyl, trifluoromethyl, methoxy or trifluoromethoxy.
In a certain embodiment, R3Selected from H, F, Cl, Br, I, OH, NH2Methyl, trifluoromethyl, methoxy or trifluoromethoxy.
In a certain embodiment, R4Selected from H, F, Cl, OH, NH2Methyl, trifluoromethyl or trifluoromethoxy.
In one embodiment, X is selected from-CH2-, Y is selected from-CH2-, Z is selected from-CH2-。
In one embodiment, X is selected from-O-, and Y is selected from-CH2-, Z is selected from-CH2-。
In one embodiment, X is selected from-CH2-, Y is selected from-O-, and Z is selected from-CH2-。
In one embodiment, X is selected from-CH2-, Y is selected from-CH2-, Z is selected from-O-.
In one embodiment, X is selected from-O-, and Y is selected from-CH2-, Z is selected from-O-.
In one embodiment, X is selected from-CH2-, Y is selected from-CH2-, Z is selected from-CH2CH2-。
In one embodiment, the nitroxide compound of formula (i) or a pharmaceutically acceptable salt thereof is any one of the following compounds:
the invention also provides a pharmaceutical composition, which comprises the substance X and pharmaceutic adjuvants; the substance X is the oxynitride shown in the formula (I) or pharmaceutically acceptable salt thereof.
The invention also provides the application of the substance X in the preparation of the voltage-gated sodium channel blocker; the substance X is the oxynitride shown in the formula (I) or pharmaceutically acceptable salt thereof.
In one version of the application, the voltage-gated sodium channel can be nav 1.8.
In one embodiment of the use, the voltage-gated sodium channel blocker can be a voltage-gated sodium channel blocker used in vitro.
The invention also provides the application of the substance X in preparing the medicament; the drug is used for inhibiting a voltage-gated sodium channel; the substance X is the oxynitride shown in the formula (I) or pharmaceutically acceptable salt thereof.
In one version of the application, the voltage-gated sodium channel can be nav 1.8.
The invention also provides the application of the substance X in preparing the medicament; the substance X is the oxynitride shown in the formula (I) or pharmaceutically acceptable salt thereof; the medicament is used for treating one or more of the following diseases: chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, primary pain, post-operative pain, visceral pain, multiple sclerosis, summerhorn-marmottle syndrome, incontinence and arrhythmia.
In one version of the use, the intestinal pain may be inflammatory bowel disease pain, crohn's disease pain or interstitial cystitis pain.
In one version of the use, the neuropathic pain may be post-herpetic neuralgia, diabetic neuralgia, painful HIV-associated sensory neuropathy, trigeminal neuralgia (e.g., trigeminal autonomic headache), mouth burn syndrome, post-amputation pain, phantom pain, painful neuroma, traumatic neuroma, Morton's neuroma, nerve crush injury, spinal stenosis, carpal tunnel syndrome, radiculopathy, sciatica, avulsion, brachial plexus avulsion, complex regional pain syndrome, drug therapy induced neuralgia, cancer chemotherapy induced neuralgia, anti-retroviral therapy induced neuralgia, post-spinal cord injury pain, primary small-fiber neuropathy, or primary sensory neuropathy.
In one embodiment of the use, the musculoskeletal pain may be osteoarthritis pain, back pain, cold pain, burn pain, or dental pain.
In one embodiment of the use, the inflammatory pain may be rheumatoid arthritis pain or vulvodynia.
In one version of the use, the primary pain may be fibromyalgia.
The following terms and symbols used in the present invention have the meanings as described below, unless otherwise indicated in the context.
The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
The term "alkyl" refers to a straight or branched chain saturated monovalent hydrocarbon radical having 1 to 3 carbon atoms, for example having 1,2 or 3 carbon atoms. For example, "C1~C3The "alkyl group" of (a) represents an alkyl group having 1 to 3 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl such as n-propyl (n-Pr) or isopropyl (i-Pr), butyl such as n-butyl (n-Bu), isobutyl (i-Bu), and the like. Whether the term "alkyl" is used alone or asThis definition applies to moieties that are other groups such as haloalkyl, alkoxy, and the like.
The term "alkoxy" denotes an alkyl group attached to the rest of the molecule through one oxygen atom. C1~C3Examples of alkoxy groups of (a) include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.
The term "pharmaceutically acceptable" refers to non-toxic, biologically tolerable, and suitable for administration to an individual.
The term "pharmaceutically acceptable salt" refers to non-toxic, biologically tolerable acid or base addition salts of nitroxides of formula (i) suitable for administration to a subject, including but not limited to: acid addition salts of nitroxides of formula (I) with inorganic acids, such as hydrochloride, hydrobromide, carbonate, bicarbonate, phosphate, sulfate, sulfite, nitrate, and the like; and the acid addition salts of nitroxides of formula (I) with organic acids, such as formate, acetate, malate, maleate, fumarate, tartrate, succinate, citrate, lactate, methanesulfonate, p-toluenesulfonate, 2-hydroxyethanesulfonate, benzoate, salicylate, stearate and salts of formula HOOC- (CH)2)nSalts with alkanedicarboxylic acids of-COOH (wherein n is 0 to 4), and the like. "pharmaceutically acceptable salts" also include the base addition salts of nitroxides of formula (I) bearing acidic groups with pharmaceutically acceptable cations such as sodium, potassium, calcium, aluminum, lithium and ammonium.
Furthermore, if the compounds according to the invention are obtained in the form of an acid addition salt, their free base form can be obtained by basifying a solution of the acid addition salt. Conversely, if the product is in the form of the free base, its acid addition salts, particularly the pharmaceutically acceptable acid addition salts, can be obtained according to the conventional procedures for preparing acid addition salts from basic compounds by dissolving the free base in a suitable solvent and treating the solution with an acid. Those skilled in the art will be able to determine, without undue experimentation, the various synthetic procedures that may be used to prepare non-toxic, pharmaceutically acceptable acid addition salts.
The term "treatment" refers to the administration of one or more pharmaceutical substances, in particular the present nitroxides of formula (I) and/or their pharmaceutically acceptable salts, to an individual suffering from a disease or having symptoms of said disease, for the purpose of curing, alleviating, altering, curing, ameliorating, improving or affecting said disease or symptoms of said disease.
The terms "treating", "contacting" and "reacting" when referring to a chemical reaction refer to the addition or mixing of two or more reagents under appropriate conditions to produce the indicated and/or desired product. It will be appreciated that the reaction that produces the indicated and/or the desired product may not necessarily result directly from the combination of the two reagents that were initially charged, i.e., one or more intermediates that are formed may be present in the mixture that ultimately result in the formation of the indicated and/or the desired product.
Technical and scientific terms used herein that are not specifically defined have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.
The reagents and starting materials used in the present invention are commercially available.
The positive progress effects of the invention are as follows: the oxynitride has better NaV1.8 blocking activity.
Detailed Description
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures in the following examples, if no specific conditions are indicated, are generally carried out according to the conditions customary for such reactions, or according to the conditions recommended by the manufacturer. Unless otherwise indicated, percentages and parts are percentages and parts by weight. Unless otherwise specified, the ratio of liquids is by volume.
The test materials and reagents used in the following examples are commercially available without specific reference.
In the following examples of the present invention,1the H-NMR spectra were recorded on a Bluker AVANCE III HD 400MHz NMR spectrometer;13C-NMR spectra were recorded on a Bluker AVANCE III HD 400MHz NMR spectrometer with chemical shifts expressed in delta (ppm); mass spectra were recorded on a mass spectrometer of Agilent 1260 (ESI) or Shimadzu LCMS-2020 (ESI) or Agilent 6215 (ESI); reverse phase preparative HPLC separation is a fully automated purification system (Xitinate) with Agilent 1290 UV guidance®Prep C18 OBDTM 21.2 x 250mm 10 μm column) or a fully automated purification system (xBridge GX281 uv-guided by Gilson GX 281)®Prep C18 OBDTM 19 x 250mm 10 μm column) or Waters QDa directed full automatic purification system (SunFire)®Prep C18 OBD 29 x 250mm 10 μm column).
Wherein, the Chinese names of the reagent represented by chemical formula or English letter abbreviation are as follows:
AcOH represents acetic acid; AlCl3Represents aluminum trichloride; aq represents an aqueous solution; ar represents argon; b is2Pin2Represents pinacol diboron; BBr3Represents boron tribromide; BH3Represents borane; (Boc)2O represents di-tert-butyl dicarbonate; br represents a broad peak; DEG C represents centigrade degree; CD (compact disc)3OD represents deuterated methanol; CDCl3Represents deuterated chloroform; conc. represents the concentration; (COCl)2Represents oxalyl chloride; cs2CO3Represents cesium carbonate; CuCl represents cuprous chloride; CuI represents cuprous iodide; d represents a doublet; DCM represents dichloromethane; dioxane or 1,4-Dioxane represents Dioxane; DIPEA or DIEA represents N, N-diisopropylethylamine; DMAP for 4-dimethylaminopyridine; DMF represents dimethylformamide; DMSO represents dimethyl sulfoxide; EA or EtOAc stands for ethyl acetate; ESI stands for electrospray ionization; et (Et)3SiH represents triethylsilane; g represents g; h2O represents water; HATU represents 1- [ bis (dimethylamino) methylene]-1H-1,2, 3-triazolo [4,5-b]Pyridinium 3-oxide hexafluorophosphate; HCl represents hydrogen chloride; HCl aq. represents hydrochloric acid; HOBt represents 1-hydroxybenzotriazole; HPLC for high performance liquid chromatography; k2CO3Represents potassium carbonate; KOAc represents potassium acetate; LDA represents a hetero atomLithium propylamine; LC-MS stands for liquid chromatography-mass spectrometry; LiHMDS stands for lithium bis (trimethylsilyl) amide; LiOH represents lithium hydroxide; m represents a multiplet; m/z represents mass-to-charge ratio; m-CPBA represents m-chloroperoxybenzoic acid; MeCN, ACN or CH3CN represents acetonitrile; MeOH represents methanol; MeONa represents sodium methoxide; min represents min; mg represents mg; mL represents mL; mmol represents millimole; n is a radical of2Represents nitrogen; na (Na)2CO3Represents sodium carbonate; NaBH4Represents sodium borohydride; NaCl represents sodium chloride; NaHCO 23Represents sodium bicarbonate; NaOH represents sodium hydroxide; na (Na)2SO4Represents sodium sulfate; NaH2PO4Represents sodium dihydrogen phosphate; NBS represents N-bromosuccinimide; n-BuLi represents n-butyllithium; NH (NH)4Cl represents ammonium chloride; NMP stands for N-methyl-2-pyrrolidone; PBr3Represents phosphorus tribromide; pd (dppf) Cl2Or PdCl2(dppf) represents 1, 1' -bis (diphenylphosphino) ferrocene palladium dichloride; pd (OAc)2Represents palladium acetate; PE represents petroleum ether; CaCl2Represents calcium chloride; KCl represents potassium chloride; HEPES represents 4-hydroxyethylpiperazine ethanesulfonic acid; MgCl2Represents magnesium chloride; glucose represents Glucose; CsCl represents cesium chloride; EGTA stands for ethylene glycol bis (2-aminoethyl ether) tetraacetic acid; CsF represents cesium fluoride; CsOH represents cesium hydroxide; RT or RT represents room temperature; s represents a single peak; SOCl2Represents thionyl chloride; t represents a triplet; TFA represents trifluoroacetic acid; TLC for thin layer chromatography; THF represents tetrahydrofuran; toluene or tol, for Toluene; UV stands for ultraviolet.
Example A1
Step 1, synthesis of intermediate 1-2:
reacting 2-fluoro-6- (trifluoromethyl) aniline(Compound 1-1, 5 g, 27.93 mmol), NBS (4.97 g, 27.93 mmol) and AcOH (2 mL) were added to ACN (25 mL), and stirred at room temperature for 1.5 hours. The reaction was concentrated, water was added, extracted with EtOAc (30 mL. times.3), and the organic phase was extracted with Na2SO4Drying through a normal phase column (EtOAc/PE = 10%) afforded 6g of intermediate 1-2 in 81% yield. The purity of the absorption peak at UV254 is 99%.
And 2, synthesizing intermediates 1-3:
intermediate 1-2 (1 g, 3.88 mmol), (Boc)2O (2.5 g, 11.63 mmol) and DMAP (473 mg, 3.88 mmol) were added to ACN (10 mL) and stirred at room temperature for 16 hours. Adding saturated NH to the reaction solution4Cl solution, extracted with EtOAc (10 mL. times.3), organic phase with Na2SO4Drying through a normal phase column (EtOAc/PE = 10% -30%) gave 2 g of intermediates 1-3 in 93% yield. LC-MS: m/z 938.7 (2M + Na)+。
And 3, synthesizing intermediates 1-4:
intermediate 1-3 (1.8 g, 3.93 mmol) was added to THF (30 mL), the reaction was cooled to-78 deg.C, LDA (2M, 2.9 mL, 5.90 mmol) was added to the reaction, and stirring was continued for 0.5 h. Ethyl oxychloride (938 mg, 8.65 mmol) was added to the reaction mixture at-78 ℃ and stirring continued at room temperature for 1 h. Adding saturated NH to the reaction solution4Cl solution, extracted with EtOAc (30 mL x 3), organic phase with Na2SO4Drying, passing through a normal phase column (EtOAc/PE = 10% -30%) gave 1.9 g of intermediates 1-4, 82% yield. LC-MS: m/z 1082.8 (2M + Na)+。
And 4, synthesizing intermediates 1-5:
intermediate 1-4 (1.8 g, 3.40 mmol), TFA (10 mL) and DCM (40 mL) were added to a 250 mL single-neck flask at room temperature and reacted for 4 h at room temperature. The reaction was concentrated and passed through a normal phase column (EtOAc/PE = 10% -30%) to give 1.1g of intermediates 1-5 in 98% yield. LC-MS: m/z 331.9 (M + H)+。
And 5, synthesizing intermediates 1-7:
intermediate 1-5 (1 g, 3.03 mmol)Adding into ACN (10 mL), and adding tert-butyl nitrite (compound 1-6, 406 mg, 3.94 mmol), CuCl2·H2O (670 mg, 3.94 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 2 hours. The reaction was concentrated, water was added, extracted with EtOAc (10 mL. times.3), and the organic phase was extracted with Na2SO4Drying through a normal phase column (EtOAc/PE = 10% -30%) gave 330 mg of intermediate 1-7, 31% yield.
And 6, synthesizing intermediates 1-8:
intermediates 1-7 (310 mg, 0.89 mmol), NaOH (177 mg, 4.43 mmol) were added to H2A mixture of O (3 mL), MeOH (6 mL), and THF (3 mL) was stirred at room temperature for 6 hours. Adding 2M hydrochloric acid to the reaction solution, adjusting pH to acidity, concentrating the reaction solution, adding water, extracting with EtOAc (10 mL. times.3), and extracting the organic phase with Na2SO4Drying and concentration gave 240 mg of intermediate 1-8 in 84% yield.
And 7, synthesizing intermediates 1-9:
intermediate 1-8 (240 mg, 0.75 mmol), 3-aminopyridine (105 mg, 1.12 mmol), HATU (568 mg, 1.50 mmol) and DIEA (289 mg, 2.24 mmol) were added to DMF (2.5 mL) and the reaction was allowed to react at room temperature for 16 h. LC-MS showed the reaction was complete. Adding NH to the reaction solution4Cl solution (40 mL), extracted with EtOAc (10 mL. times.3), and the organic phase washed 3 times with water and Na2SO4Drying, spin-drying and passage through a normal phase column (EtOAc/PE = 50%) gave 250 mg of intermediates 1-9 in 79% yield. LC-MS: m/z 398.9 (M + H)+。
And 8, synthesizing intermediates 1-11:
at room temperature, compound 1-10 (p-fluorophenol, 200 mg, 1.78 mmol) was added to a 25-mL single-neck flask, DMF (5 mL) and pyridine (169 mg, 2.14 mmol) were added, the temperature was reduced to 0 ℃, 3-chloropropionyl chloride (226.5 mg, 1.78 mmol) was added dropwise, and the reaction was carried out at room temperature for 4 hours. Sampling TLC to detect the completion of the reaction, adding water into the reaction solution, extracting with EA (100 mL. times.3), and performing column chromatography on the positive phase column (EtOAc/PE = 0% -60%) to obtain 300 mg of intermediate 1-11, wherein the yield is as follows: 83 percent.1H NMR（400 MHz，DMSO-d 6 ）δ 7.31 – 7.22（m，2H），7.20 - 7.16（m，2H），3.91（t，J = 6.3 Hz，2H），3.11（t，J = 6.3 Hz，2H）。
Step 9, synthesis of intermediates 1-12:
intermediate 1-11 (200 mg, 0.99 mmol) and AlCl were added to a 25 ml microwave tube at room temperature3(395 mg, 2.97 mmol), heating to 100 ℃, stirring for 15min, heating to 180 ℃, stirring for 3 hours, cooling to room temperature, adding 5 mL of EA, stirring uniformly, adding into water, EA (100 mL × 3) extracting, column chromatography (EtOAc/PE = 0% -100%) to obtain 80 mg of intermediate 1-12, yield: 49 percent.1H NMR（400 MHz，DMSO-d 6 ）δ 10.00（s，1H），7.30（t，J = 8.7 Hz，1H），6.74（dd，J = 8.8，3.5 Hz，1H），3.04 – 2.97（m，2H），2.63 – 2.56（m，2H）。
Step 10, synthesis of intermediates 1-13:
intermediate 1-12 (40 mg, 0.24 mmol), TFA (5 mL) and Et were added to a 25 mL single-necked flask at room temperature3SiH (70 mg, 0.60 mmol). The temperature is raised to 80 ℃ for reaction for 16 hours. After the reaction, concentrate to dryness under reduced pressure, add water, EA (100 mL × 3), extract, dry the organic phase, concentrate and column chromatographe (EtOAc/PE = 0% -80%) to give 20 mg of intermediate 1-13, yield: and 55 percent.1H NMR（400 MHz，DMSO-d 6 ）δ 9.08（s，1H），6.69（t，J = 8.6 Hz，1H），6.52-6.49（m，1H），2.80（t，J = 7.4 Hz，2H），2.72（t，J = 7.3 Hz，2H），1.98（dt，J = 12.7，6.4 Hz，2H）。
Step 11, synthesis of intermediates 1-14:
to a 25 mL single-neck flask, intermediates 1 to 9 (100 mg, 0.25 mmol), intermediates 1 to 13 (42 mg, 0.28 mmol), CuI (4.8 mg, 0.025 mmol), cesium carbonate (123.0 mg, 0.38 mmol) and toluene (5 mL) were added at room temperature, and after completion of the addition, the reaction was carried out at 100 ℃ for 5 hours. Cooling to room temperature, concentrating, adding ethyl acetate (50 mL), washing with water, washing with saturated salt solution, and adding Na2SO4Drying, concentrating, and making into powderPassage through a normal phase column (EtOAc/PE = 10% -70%) yielded 70 mg of intermediates 1-14 in 59% yield. LC-MS: m/z 469.0 (M + H)+。
Step 12, synthesis of example a 1:
to a 25 mL single-neck flask were added intermediates 1-14 (70 mg, 0.15 mmol), DCM (5 mL) and m-CPBA (38.65 mg, 0.22 mmol) at room temperature. The reaction was carried out at room temperature for 2 hours. The reaction was complete, diluted with DCM (3 mL), washed with saturated sodium bicarbonate water and the organic phase was Na2SO4Drying and concentration gave 26.53 mg of example A1, 37% yield. LC-MS: m/z 484.9 (M + H)+；1H NMR（400 MHz，DMSO-d 6 ）δ 11.38（s，1H），8.60（s，1H），8.04（d，J = 5.7 Hz，1H），7.47 – 7.38（m，2H），7.12（s，1H），7.09 – 6.95（m，2H），2.89（t，J = 7.5 Hz，2H），2.75（t，J = 7.4 Hz，2H），2.03（p，J = 7.6 Hz，2H）。
Example A2
Step 1, synthesis of an intermediate 2-2:
to a 250 ml three-necked flask, compound 2-1 (2-bromo-1, 4-difluorobenzene, 15 g, 77.72 mmol), 100 ml of tetrahydrofuran was added at room temperature. After nitrogen gas was replaced, the temperature was lowered to-65 ℃ and LDA (10.82 g, 101.04 mmol) was slowly added dropwise, followed by reaction for 30 minutes after completion of the addition. DMF (17.04 g, 233.17 mmol) was then added slowly dropwise, followed by reaction for 2 hours. Adding 5 mL of saturated ammonium chloride to quench the reaction, adding 250 mL of ethyl acetate to extract, washing with water, washing with saturated salt water, drying an organic phase, filtering, and performing normal phase column chromatography (EA/PE = 0% -100%) to obtain 11.5 g of a white solid with the yield of 67%.1H NMR（400 MHz，CDCl3）δ 10.34（s，1H），7.34（ddd，J = 9.2，7.4，4.5 Hz，1H），7.16（td，J = 9.3，4.0 Hz，1H）。
Step 2, synthesizing an intermediate 2-3:
intermediate 2-2 (5 g, 22.62 mmol), methanol (50 mL) and sodium methoxide (1.34 g, 24.89 mmol) were added to a 100 mL single-neck flask at room temperature and stirred for 2 hours. Adding 50 mL of water, adding 100 mL of ethyl acetate for extraction, washing with water, washing with saturated salt water, drying an organic phase, filtering, performing normal phase column chromatography (EA/PE = 0% -100%), and performing spin drying to obtain 3.5 g of an intermediate 2-3 with the yield of 66%. LC-MS: m/z =233.2 (M + 1)+。
And 3, synthesizing intermediates 2-4:
adding the intermediate 2-3 (2.5 g, 10.73 mmol) into a reaction bottle, adding (methoxymethyl) triphenyl phosphonium chloride (4.95 g, 16.09 mmol) and 30 mL of tetrahydrofuran, cooling to-65 ℃, slowly adding LiHMDS (1.8 g, 11.80 mmol) dropwise, reacting at-65 ℃ for 1 hour, raising the temperature to room temperature, adding 30 mL of water for quenching, adding 100 mL of ethyl acetate for extraction, washing an organic phase with saturated saline, drying and filtering. After concentration, the mixture was passed through a normal phase column (EA/PE = 10% -100%) to obtain 2.6g of intermediate 2-4 with a yield of 66%. LC-MS: m/z =260.9 (M + 1)+。
And 4, synthesizing intermediates 2-5:
at room temperature, adding 2-4 (2.6 g, 9.96 mmol) of intermediate and 30 mL of tetrahydrofuran into a 100 mL single-neck bottle, then slowly dropwise adding 10 mL of 3 mol/L hydrochloric acid, reacting at room temperature for 2 hours, adding 50 mL of water, adding 100 mL of ethyl acetate, washing with water, washing with saturated salt water, drying, filtering, concentrating, and performing normal phase column chromatography (EA/PA = 0-100%) to obtain 1.5 g of 2-5 of intermediate with the yield of 65%.1H NMR（400 MHz，CDCl3）δ 9.59（t，J = 1.4 Hz，1H），7.00（dd，J = 8.9，8.1 Hz，1H），6.74（dd，J = 9.1，4.1 Hz，1H），3.88（d，J = 1.2 Hz，2H），3.73（s，3H）。
And 5, synthesizing intermediates 2-6:
intermediate 2-5 (1.5 g, 6.07 mmol) was added to a 100 mL single neck flask at room temperature20 mL of water methanol and sodium borohydride (459.39 mg, 12.14 mmol) were reacted at room temperature for 1 hour, 30 mL of water was added, 100 mL of ethyl acetate was added, the mixture was washed with water and saturated brine, dried, filtered, concentrated, and subjected to normal phase column chromatography (EA/PE = 0-100%) to obtain 1.13 g of intermediate 2-6 with a yield of 85%.1H NMR（400 MHz，DMSO-d 6 ）δ 9.39（s，1H），6.85 – 6.76（m，1H），6.21（dd，J = 8.8，3.2 Hz，1H），4.59（t，J = 8.7 Hz，2H），3.35（s，3H），3.09（t，J = 8.6 Hz，2H）。
And 6, synthesizing intermediates 2-7:
to a 100 mL single-neck flask were added intermediate 2-6 (1.13 g, 4.54 mmol), toluene 15 mL, 2- (di-tert-butylphosphino) -2' - (N, N-dimethylamino) biphenyl (41 mg, 0.12 mmol), palladium acetate (27 mg, 0.12 mmol), and cesium carbonate (1.75 g, 9.07 mmol) at room temperature. The reaction was carried out at 80 ℃ overnight. 50 mL of water was added, 100 mL of ethyl acetate was added, the mixture was washed with water, washed with saturated brine, dried, filtered, concentrated, and subjected to normal phase column chromatography (EA/PE = 0-100%) to obtain 570 mg of intermediate 2-7 with a yield of 53%.1H NMR（400 MHz，CDCl3）δ 6.85（dd，J = 10.0，9.1 Hz，1H），6.26（dd，J = 8.9，2.9 Hz，1H），4.67（t，J = 8.8 Hz，2H），3.80（s，3H），3.22 – 3.14（m，2H）。
And 7, synthesizing intermediates 2 to 8:
at room temperature, adding the intermediate 2-7 (250 mg, 1.49 mmol), dichloromethane 10 mL, a dichloromethane solution of boron tribromide (1 mol/L, 3 mL) into a 50 mL single-neck flask, reacting at room temperature for 1 hour, adding water 30 mL, adding dichloromethane 20 mL, washing with water, washing with saturated saline, drying, filtering, concentrating, and performing normal phase column chromatography (EA/PE = 0-100%) to obtain 113 mg of the intermediate 2-8 with the yield of 85%. LC-MS: m/z =155.4 (M + 1)+。
And 8, synthesizing intermediates 2-9:
at room temperature, 2,6, 6-tetramethylpiperidine (10.7 g, 75.55 mmol) and 100 mL of anhydrous tetrahydrofuran were added to a 250 mL single-neck flask, and n-butyllithium (47) was added dropwise thereto by cooling to 0 deg.CmL, 75.55 mmol, 1.6M n-hexane solution), stirring at 0 ℃ for 30 minutes after the addition is completed, and removing the ice-water bath. Changing into a dry ice acetone bath, cooling to-78 ℃, dropwise adding 1-chloro-4-fluoro-2- (trifluoromethyl) benzene (10 g, 50.37 mmol), stirring for 2 hours after dropwise adding, pouring the reaction solution into dry ice, naturally heating to room temperature, adding 200 mL of 1N hydrochloric acid, adding 400 mL of ethyl acetate, washing with water, washing with saturated sodium chloride, drying, and concentrating to obtain 9 g of intermediate 2-9 with the yield of 74%.1H NMR（400 MHz，CDCl3）δ 8.15（d，J = 6.2 Hz，1H），7.56（d， J = 10.0 Hz，1H）。
And 9, synthesizing intermediates 2-10:
at room temperature, adding the intermediate 2-9 (200 mg, 0.825 mmol), DMF (5 mL), HATU (375 mg, 0.989 mmol), stirring for half an hour, adding 3-aminopyridine (78 mg, 0.825 mmol), DIEA (128 mg, 0.989 mmol), stirring for 16 hours at room temperature, adding 50 mL of water, adding 150 mL of ethyl acetate for extraction, washing with water, washing with saturated saline, drying an organic phase, filtering, performing normal phase column chromatography (EA/PE = 0% -100%), and performing spin drying to obtain 250 mg of the intermediate 2-10 with the yield of 95%. LC-MS: m/z =319.0 (M + 1)+。
Step 10, synthesis of intermediate 2-11:
to a 50 mL single-necked flask, intermediate 2-10 (60 mg, 0.188 mmol), DMF (5 mL), intermediate 2-8 (29 mg, 0.188 mmol), cesium carbonate (120 mg, 0.282 mmol) was added at room temperature. The reaction was carried out at 100 ℃ for 5 hours. 30 mL of water was added, 20 mL of ethyl acetate was added, washed with water, washed with saturated brine, dried, filtered, concentrated, and subjected to normal phase column chromatography (EA/PE = 0-100%) to obtain 62 mg of intermediate 2-11 with a yield of 85%. LC-MS: m/z =453.1 (M + 1)+。
Step 11, synthesis of example a 2:
intermediate 2-11 (60 mg, 0.132 mmol), dichloromethane 15 mL, m-CPBA (45.41 mg, 0.264 mmol) were added to a 25 mL single-neck flask at room temperature. Reacting at room temperature for 3 hours, removing the solvent under reduced pressure, adding 50 mL of ethyl acetate, washing with saturated sodium bicarbonate water, drying, concentrating, and preparing by a reversed phase chromatographic column to obtain 24.12mg of example A2. Yield: 38 percent. LC-MS: m/z 469.1 (M + H)+。1H NMR（400 MHz，DMSO-d 6 ）δ 11.31（s，1H），8.25（d，J = 26.1 Hz，1H），8.08（s，1H），7.78（m 1H），7.34（m，1H），7.22（m，1H），7.07（m，2H），6.78（m，1H），4.65（m，2H），3.22 – 2.88（m，2H）。
In analogy to the synthesis of examples a1 and a2, the following examples A3 to a5 were synthesized as shown in table 1 below:
table 1: examples A3-A5 structural formulae and analytical data thereof
Example B1: test experiment for blocking activity of compound of the invention on sodium ion channel 1.8 (NaV1.8)
1. The test method comprises the following steps: the patch clamp technique detects the effect of compounds on the 1.8 subtype current of voltage-gated sodium ion channels (NaV).
2. Formulation and analysis of the formulations administered.
2.1. The preparation method of the stock solution of the administration preparation comprises the following steps:
comparison: an appropriate volume of DMSO was weighed out as a stock solution.
Test compounds: compounds were weighed to the appropriate mass (actual = theoretical concentration x volume x molecular weight/purity), the volume of DMSO required was calculated according to the formula, and then the final DMSO mass required was converted. The powder was then dissolved with a weighed amount of DMSO. The actual stock solution concentration was calculated from the final DMSO usage, and generally the actual stock solution concentration was slightly different from the theoretical concentration.
2.2. The preparation method and the concentration of the working solution of the drug administration preparation are as follows:
prior to NaV channel current testing, control and test compound stocks were diluted into 10 mL of extracellular fluid as working fluid and sonicated for 20 min.
3. And (4) an experimental system.
3.1. Cell culture:
1) the CHO cell line stably expressing the Nav1.8 channel has the following specific information: SCN 10A: NM _ 006514.
2) The cells were cultured in HAM' S/F-12 medium containing 10% fetal bovine serum and 10 μ g/mL Blastidin, 200 μ g/mL Hygromycin B and 100 μ g/mL Zeocin at 37 ℃ with a carbon dioxide concentration of 5%.
3) Cell passage: the old medium was removed and washed once with PBS, then 1 mL of 0.25% -Trypsin-EDTA solution was added and incubated at 37 ℃ for 1.5 min. When the cells detached from the bottom of the dish, 5 mL of complete medium pre-warmed at 37 ℃ was added. The cell suspension was gently pipetted with a pipette to separate the aggregated cells. The cell suspension was transferred to a sterile centrifuge tube and centrifuged at 1000 rpm for 5min to collect the cells. Expanding or maintaining the culture, the cells are seeded on 6 cm cell culture dishes, each cell culture dish is seeded with cells in an amount of 2.5 x 105cells (final volume: 5 mL).
4) To maintain the electrophysiological activity of the cells, the cell density must not exceed 80%.
5) Patch clamp assay, cells were detached with 0.25% -Trypsin-EDTA at 8 × 10 per well before assay3The density of the cells was inoculated into a 24-well plate previously covered with a cover glass (final volume: 500. mu.L), tetracycline was added, and the experimental examination was performed the next day.
3.2. The electrophysiological solution:
1) extracellular fluid: 140 mM NaCl, 3.5 mM KCl, 2 mM CaCl2，10 mM HEPES，1.25 mM NaH2PO4，1 mM MgCl2，10 mM Glucose，pH=7.4（NaOH）。
2) Intracellular fluid: 50mM CsCl, 10 mM NaCl, 10 mM HEPES, 20 mM EGTA, 60 mM CsF, pH =7.2 (CsOH).
4. Test methods.
4.1. The apparatus is shown in table 2 below:
table 2: instrument vendor and model
4.2. And (3) patch clamp detection:
the voltage stimulation protocol for whole-cell patch-clamp recording of Nav channel currents was as follows: the membrane potential of the cells was first clamped at-130 mV, and then the voltage was stepped to-40 mV or-20 mV for 8s at 10 mV step intervals. The clamp voltage was maintained at-120 mV and data acquisition was repeated every 20 seconds. The peak amplitude of the inward current is measured to determine the semi-inactive voltage.
The cell clamping potential was set at-120 mV. The resting and semi-inactivating inhibition of sodium current was measured using a double pulse mode. The double pulse pattern was completed by two 0 mV depolarization test pulses (TP 1 and TP 2) lasting 50 ms. The conditioned voltage between the two depolarization pulses was set around the semi-inactivation voltage (duration 8 s). Prior to the administration of the second depolarization pulse, the cell membrane potential was clamped to-120 mv for 20ms to allow unbound compounds and channels in the inactivated state to recover. Data was collected repeatedly at 20s intervals and the current peaks at the two test pulses were measured.
Experimental data were collected by EPC-10 Amplifier (HEKA) and stored in PatchMaster (HEKA) software (software version: v2x73.2).
A capillary glass tube (BF 150-86-10, Sutter Instruments) was drawn into a recording electrode using a microelectrode drawing machine (P97, Sutter Instruments). The microelectrode manipulator (MP 285) was manipulated under an inverted microscope (IX 71) to bring the recording electrode into contact with the cell and negative pressure was applied to the cell to form a G.OMEGA.seal. And carrying out rapid capacitance compensation after G omega sealing is formed, then continuously applying negative pressure to break cell membranes by suction, and forming a whole cell recording mode. Then, the compensation of the slow capacitor is carried out, and the film capacitor and the series resistor are recorded, so that the leakage compensation is not given.
Dosing was initiated when the Nav channel current recorded in whole cells stabilized, and the next concentration was measured after each drug concentration had been applied for 5 minutes (or current to stabilization), with multiple concentrations measured for each test compound. The cover glass with the cells is placed in a recording bath in an inverted microscope, and the test compound and the external fluid without the test compound are applied to the cells by flowing through the recording chamber from a low concentration to a high concentration in sequence by gravity perfusion, and the fluid exchange is performed by a vacuum pump during recording. The current detected by each cell in the compound-free external fluid served as its own control. Multiple cells were tested in independent replicates. All electrophysiological experiments were performed at room temperature.
4.3. And (3) data analysis:
the current after each drug concentration is acted and the blank control current are firstly normalized, and then the blocking rate corresponding to each drug concentration is calculated. The mean and standard error were calculated for each concentration, and all the above values were calculated using Microsoft Excel 2013. The semi-inhibitory concentration of each compound was also calculated by IGOR software using the following equation: retardation =1/[1+ (IC)50/c）h]。
Non-linear fitting of dose-dependent effects using the above equation, where c represents drug concentration, IC50H represents the Hill coefficient for the half inhibitory concentration. Curve fitting and IC50Is performed using IGOR software (software version: 6.0.1.0).
In this example, partial compounds of the invention were tested for their blocking rates at 10 nM for NaV1.8 as shown in Table 3:
table 3: blocking Rate of partial Compounds of the invention at 10 nM for NaV1.8
The compounds of the present invention, such as A1, have significant activity advantages over the two prior art compounds listed in Table 4 below.
Table 4: the compound in the prior art has the retardation rate to NaV1.8 at a certain concentration
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.
Claims (10)
1. An oxynitride compound represented by the formula (I) or a pharmaceutically acceptable salt thereof,
wherein the content of the first and second substances,
R1selected from H, F, Cl, OH or NH2；
R2Selected from H, F, Cl, Br, I, OH, NH2、C1-C3Alkyl or C1-C3Alkoxy of (a), said C1-C3Alkyl or C1-C3Is optionally substituted with 1,2 or 3 halogens;
R3selected from H, F, Cl, Br, I, OH, NH2、C1-C3Alkyl or C1-C3Alkoxy of (a), said C1-C3Alkyl or C1-C3Is optionally substituted with 1,2 or 3 halogens;
R4selected from H, F, Cl, OH, NH2、C1-C3Alkyl or C1-C3Alkoxy of (a), said C1-C3Alkyl or C1-C3Is optionally substituted with 1,2 or 3 halogens;
x is selected from-CH2-or-O-;
y is selected from-CH2-or-O-;
z is selected from-CH2-、-CH2CH2-or-O-;
and, when Y is selected from-O-, neither X nor Z is selected from-O-;
t is selected from N or CH.
2. The nitroxide compound of formula (i) or a pharmaceutically acceptable salt thereof according to claim 1, wherein when T is selected from CH, the amide bond is linked in the meta position of N + -O-;
and/or, when T is selected from N, the amide bond is linked in the meta or para position to N + -O-.
3. The nitroxide compound of formula (i) or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein R is2Selected from H, F, Cl, Br, I, OH, NH2Methyl, trifluoromethyl, methoxy or trifluoromethoxy.
4. The nitroxide compound of formula (i) or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein R is3Selected from H, F, Cl, Br, I, OH, NH2Methyl, trifluoromethyl, methoxy or trifluoromethoxy.
5. The nitroxide compound of formula (i) or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein R is4Selected from H, F, Cl, OH, NH2Methyl, trifluoromethyl or trifluoromethoxy.
6. The nitroxide compound of formula (i) or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein X is selected from-CH2-, Y is selected from-CH2-, Z is selected from-CH2-；
And/or, X is selected from-O-, and Y is selected from-CH2-, Z is selected from-CH2-；
And/or, X is selected from-CH2-, Y is selected from-O-, and Z is selected from-CH2-；
And/or, X is selected from-CH2-, Y is selected from-CH2-, Z is selected from-O-;
and/or, X is selected from-O-, and Y is selected from-CH2-, Z is selected from-O-;
and/or, X is selected from-CH2-, Y is selected from-CH2-, Z is selected from-CH2CH2-。
7. The nitroxide compound of formula (i) or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein the nitroxide compound of formula (i) is any one of the following compounds:
8. use of a substance X for the preparation of a voltage-gated sodium channel blocker or a medicament, wherein the substance X is an oxynitride compound of formula (i) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 7; the drug is a drug for inhibiting a voltage-gated sodium channel.
9. The use of claim 8, wherein the voltage-gated sodium channel is nav 1.8;
and/or the voltage-gated sodium channel blocker is a voltage-gated sodium channel blocker used in vitro.
10. Use of a substance X for the manufacture of a medicament, wherein the substance X is a nitroxide compound of formula (i) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 7;
the medicament is used for treating one or more of the following diseases: chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, primary pain, post-operative pain, visceral pain, multiple sclerosis, summerhorn-marmottle syndrome, incontinence and arrhythmia.
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