WO2025007697A1 - 5-氨基-1-烷基-1h-1,2,3-三氮唑-4-甲酰胺类化合物及其制备和应用 - Google Patents

5-氨基-1-烷基-1h-1,2,3-三氮唑-4-甲酰胺类化合物及其制备和应用 Download PDF

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WO2025007697A1
WO2025007697A1 PCT/CN2024/097787 CN2024097787W WO2025007697A1 WO 2025007697 A1 WO2025007697 A1 WO 2025007697A1 CN 2024097787 W CN2024097787 W CN 2024097787W WO 2025007697 A1 WO2025007697 A1 WO 2025007697A1
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alkyl
amino
compound
triazole
preparation
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崔孙良
黄言新
徐层林
陈忠
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Zhejiang University
Zhejiang Chinese Medical University
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Zhejiang University
Zhejiang Chinese Medical University
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    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
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    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A—HUMAN NECESSITIES
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings

Definitions

  • the present invention relates to the field of pharmaceutical chemistry, and in particular to a class of 5-amino-1-alkyl-1H-1,2,3-triazole-4-carboxamide compounds and a preparation method and application thereof.
  • Ion channels are an important class of drug targets. As a class of transmembrane proteins, ion channels contain water pores formed by multiple subunits, which can regulate the influx or efflux of different ions across the cell membrane when ligands bind or voltage changes. Ion channels function as basic excitatory or inhibitory units in the cell membranes of many tissues, including nerves, muscles, and glands. When the channel is open, the influx or efflux of ions generates various electrical signals, which promote a large number of cellular activities and basic physiological processes. Ion channels not only affect neurotransmitter release, muscle contraction, and glandular secretion, but also play a key role in learning and memory, cell volume maintenance, and homeostasis.
  • Ion channel dysfunction or ion channelopathy is associated with impaired pain perception, inflammatory response, diabetes, and tumor cell proliferation and migration.
  • abnormal ion channels are associated with many neurological diseases and arrhythmias, including anxiety, insomnia, epilepsy, schizophrenia, Parkinson's disease and Alzheimer's disease, as well as long/short QT syndrome. Therefore, ion channels are an important class of drug targets.
  • the patent specification with publication number CN113717133A discloses a class of 3-amido-N-arylbenzamide compounds and their use in the preparation of anti-epileptic therapeutic drugs.
  • the patent specification with publication number CN114044757A discloses a class of triazole-4-(N-substituted carboxamide)-5-triazene compounds and their preparation methods and their use in the preparation of anti-epileptic drugs. Neither of these two prior arts reports the drug effects in the lamotrigine resistance model, and does not involve the solution of the drug resistance problem.
  • triazole-4-(N-substituted carboxamide)-5-triazene compounds disclosed in the patent specification with publication number CN114044757A contain triazene groups, which makes these compounds have biological toxicity and difficult to pass in terms of drug safety.
  • the present invention changes the necessary triazene-containing core structure in CN114044757A, discards the triazene structure with potential biological toxicity, and replaces it with an amino group, designs and synthesizes a class of non-biologically toxic 5-amino-1-alkyl-1H-1,2,3-triazole-4-carboxamide compounds, and unexpectedly finds that this class of new structural compounds still has obvious electrophysiological activity and can show inhibitory activity on sodium and other ion channels.
  • PTZ pentylenetetrazol acute epilepsy attack model
  • MES maximum electric shock epilepsy attack model
  • lamotrigine resistance model some compounds have more potent anti-epileptic efficacy, can significantly reduce the grade of epilepsy attacks, and improve epilepsy. It has good anti-epileptic efficacy in the lamotrigine-resistant model and has good development prospects.
  • the present invention provides a class of 5-amino-1-alkyl-1H-1,2,3-triazole-4-carboxamide compounds, pharmaceutically acceptable salts thereof, or racemic mixtures, hydrates, solvates, prodrugs, enantiomers, diastereomers, and tautomers thereof.
  • the 5-amino-1-alkyl-1H-1,2,3-triazole-4-carboxamide compounds have the general structural formula shown in the following formula (1):
  • R1 is a substituted or unsubstituted aromatic ring, wherein the aromatic ring is a benzene ring or an aromatic heterocyclic ring, wherein the substituent on the aromatic ring contains a fluorine atom and is independently selected from halogen, nitro, amino, hydroxyl, cyano, alkoxy, thiol, carboxyl, ester, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C1-6 cycloalkyl, substituted or unsubstituted C1-6 heterocycloalkyl, substituted or unsubstituted C4-10 aryl, substituted or unsubstituted C1-8 heteroaryl, C2-10 alkenyl, C 2-10 alkynyl, alkyl monosubstituted amine, alkyl disubstituted amine, alkoxy, alkylcarbonyloxy, cycloalkylcarbonyloxy, heteroarylcarbonyloxy, al
  • R2 and R3 are the same or different, and are independently selected from hydrogen, substituted or unsubstituted C1 - C4 alkyl, substituted or unsubstituted phenyl, the substituent on the C1-C4 alkyl is methoxyl, hydroxyl; or R2 , R3 and N connecting R2 and R3 form a six-membered ring, and the six-membered ring contains N, C and O.
  • the 5-amino-1-alkyl-1H-1,2,3-triazole-4-carboxamide compound may also have a general structural formula as shown in the following formula (2):
  • R 1 represents one or more substituents on the benzene ring or pyridine ring, independently selected from one or more of H, halogen, C 1 -C 6 alkoxy, hydroxyl, cyano, amino, thienyl, pyrazolyl, and pyridinone;
  • R2 and R3 are independently selected from hydrogen, substituted or unsubstituted C1 - C4 alkyl, C3 -C6 cycloalkyl, phenyl, and the substituent on the C1 - C4 alkyl is one or more of phenyl, ester, and hydroxyl; or R2 , R3 and N connecting R2 and R3 form a substituted or unsubstituted six -membered ring, the six-membered ring is composed of N and C or N, C and O, and the substituent on the six-membered ring is C1 - C4 alkyl.
  • 5-amino-1-alkyl-1H-1,2,3-triazole-4-carboxamide compound can be selected from any one of the following compounds 1-32:
  • the present invention also provides a method for preparing the 5-amino-1-alkyl-1H-1,2,3-triazole-4-carboxamide compounds.
  • the present invention can adopt reaction route I to synthesize compound 1-32;
  • Reaction Scheme I includes the following process:
  • Ethyl cyanoacetate A reacts with benzyl azide compound B in DMF with NaH as base to generate substituted 5-amino-1-alkyl-1H-1,2,3-triazole-4-carboxylate compound C, which is then hydrolyzed and acidified under the action of NaOH to generate carboxylic acid compound D, which then undergoes condensation reaction with amine compound E under the promotion of condensation reagent HATU to generate target compound 1-32.
  • At least one triazole compound, a pharmaceutically acceptable salt thereof, or a racemic mixture, hydrate, solvate, prodrug, enantiomer, diastereomer, or tautomer thereof prepared according to the above method can be purified by column chromatography, high performance liquid chromatography, crystallization, or other appropriate methods.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising at least one of a pharmaceutically acceptable carrier and an excipient, and the 5-amino-1-alkyl-1H-1,2,3-triazole-4-carboxamide compound, a pharmaceutically acceptable salt thereof, or a racemic mixture thereof, a hydrate, a solvate, a prodrug, an enantiomer, a diastereomer, or a tautomer.
  • a pharmaceutically acceptable carrier refers to a carrier that is compatible with the active ingredient (5-amino-1-alkyl-1H-1,2,3-triazole-4-carboxamide compound, a pharmaceutically acceptable salt thereof, or a racemic mixture thereof, a hydrate, a solvate, a prodrug, an enantiomer, a diastereomer, a tautomer) in the composition (in some embodiments, can stabilize the active ingredient) and is harmless to the treated individual.
  • the active ingredient 5-amino-1-alkyl-1H-1,2,3-triazole-4-carboxamide compound, a pharmaceutically acceptable salt thereof, or a racemic mixture thereof, a hydrate, a solvate, a prodrug, an enantiomer, a diastereomer, a tautomer
  • Excipients may be selected from a combination of one or more of excipients, diluents, fillers, salts, disintegrants, binders, lubricants, glidants, wetting agents, controlled release matrices, colorants, flavoring agents, buffers, stabilizers, solubilizers, and the like.
  • compositions comprising the 5-amino-1-alkyl-1H-1,2,3-triazole-4-carboxamide compounds described herein, their pharmaceutically acceptable salts, or their racemic mixtures, hydrates, solvates, prodrugs, enantiomers, diastereomers, tautomers can be administered in various known ways, such as orally, topically, rectally, parenterally, by inhalation or implantation.
  • the pharmaceutical composition can be prepared into various types of dosage unit forms, such as tablets, pills, powders, liquid preparations, suspensions, emulsions, granules, capsules, suppositories and injections (solutions and suspensions).
  • any excipient known and widely used in the art may be used.
  • carriers such as lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose and silicic acid; binders such as water, ethanol, propanol, ordinary syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose and potassium phosphate, polyvinyl pyrrolidone, etc.
  • disintegrants such as dry starch, sodium alginate, agar powder and kelp powder, sodium bicarbonate, calcium carbonate, fatty acid esters of polyethylene sorbitan, sodium lauryl sulfate, monoglyceride of stearic acid, starch and lactose, etc.
  • disintegration inhibitors such as white sugar, glyceryl tristearate, coconut oil and hydrogenated oil
  • adsorption promoters such as quaternary am
  • any excipient known and widely used in the art can be used, for example, carriers such as lactose, starch, coconut oil, hardened vegetable oil, kaolin and talc, etc.; binders such as gum arabic powder, tragacanth powder, gelatin and ethanol, etc.; disintegrants such as agar and kelp powder, etc.
  • any excipient known and widely used in the art may be used, for example, polyethylene glycol, coconut oil, higher alcohols, esters of higher alcohols, gelatin and semi-synthetic glycerides and the like.
  • the solution or suspension can be sterilized (preferably by adding an appropriate amount of sodium chloride, glucose or glycerol, etc.) to prepare an injection with an osmotic pressure equal to that of blood.
  • any commonly used carrier in the art can also be used, for example, water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol and fatty acid esters of polyethylene sorbitan, etc.
  • common solvents, buffers and analgesics, etc. can also be added.
  • the administration method of the pharmaceutical composition is not particularly limited.
  • Various dosage forms of preparations can be selected for administration according to the patient's age, gender, and other conditions and symptoms.
  • tablets, pills, solutions, suspensions, emulsions, granules or capsules can be administered orally; injections can be administered alone or mixed with injection delivery fluids (such as glucose solutions and amino acid solutions) for intravenous injection; suppositories are administered to the rectum.
  • the present invention also provides a method for regulating ion channel function, which comprises using an effective amount of 5-amino-1-alkyl-1H-1,2,3-triazole-4-carboxamide compounds, pharmaceutically acceptable salts thereof, or racemic mixtures, hydrates, solvates, prodrugs, enantiomers, diastereomers, and tautomers thereof.
  • the present invention also provides a method for regulating ion channel function, which comprises using an effective amount of a pharmaceutical composition to regulate ion channel function, wherein the pharmaceutical composition comprises at least one of a pharmaceutically acceptable carrier and an excipient, and the 5-amino-1-alkyl-1H-1,2,3-triazole-4-carboxamide compound, a pharmaceutically acceptable salt thereof, or a racemic mixture thereof, a hydrate, a solvate, a prodrug, an enantiomer, a diastereomer, or a tautomer thereof.
  • the pharmaceutical composition comprises at least one of a pharmaceutically acceptable carrier and an excipient, and the 5-amino-1-alkyl-1H-1,2,3-triazole-4-carboxamide compound, a pharmaceutically acceptable salt thereof, or a racemic mixture thereof, a hydrate, a solvate, a prodrug, an enantiomer, a diastereomer, or a tautomer thereof.
  • the present invention also provides a method for treating a disease in an individual that is responsive to modulation of ion channel function, comprising administering to an individual in need thereof an amount of a 5-amino-1-alkyl-1H-1,2,3-triazole-4-carboxamide compound, a pharmaceutically acceptable salt thereof, or a racemic mixture thereof, hydrate, solvate, prodrug, enantiomer, diastereomer, or tautomer that is effective in modulating ion channel function.
  • the present invention also provides a method for treating a disease in an individual that is responsive to regulation of ion channel function, comprising administering to an individual in need thereof a pharmaceutical composition in an amount that can effectively regulate ion channel function, wherein the pharmaceutical composition comprises at least one of a pharmaceutically acceptable carrier and an excipient, and the 5-amino-1-alkyl-1H-1,2,3-triazole-4-carboxamide compound, a pharmaceutically acceptable salt thereof, or a racemic mixture thereof, a hydrate, a solvate, a prodrug, an enantiomer, a diastereomer, or a tautomer thereof.
  • the present invention also provides the use of the 5-amino-1-alkyl-1H-1,2,3-triazole-4-carboxamide compound, its pharmaceutically acceptable salt, or its racemic mixture, hydrate, solvate, prodrug, enantiomer, diastereomer, tautomer, or the pharmaceutical composition in the preparation of ion channel blockers.
  • the present invention also provides the use of the 5-amino-1-alkyl-1H-1,2,3-triazole-4-carboxamide compound, its pharmaceutically acceptable salt, or its racemic mixture, hydrate, solvate, prodrug, enantiomer, diastereomer, tautomer, or the pharmaceutical composition in the preparation of a medicament for treating ion channel-related diseases.
  • the ion channel of the present invention may be a sodium ion channel.
  • the ion channel-related diseases include central nervous system diseases, inflammatory diseases, autoimmune diseases, cancer, infectious diseases, cardiovascular and cerebrovascular diseases, etc.
  • the central nervous system diseases include epilepsy, Parkinson's disease, Alzheimer's disease, anxiety, depression, schizophrenia, etc.
  • Inflammatory diseases refer to pathological conditions that result in an inflammatory response, particularly due to chemotaxis of neutrophils.
  • diseases include inflammatory skin diseases (including psoriasis and atopic dermatitis); systemic scleroderma and sclerosis; reactions associated with inflammatory bowel disease (e.g., Crohn's disease and ulcerative colitis); ischemia-reperfusion injury, including tissue reperfusion injury caused by surgery, myocardial ischemia such as myocardial infarction, cardiac arrest, reperfusion after cardiac surgery, and abnormal contractile responses of coronary vessels after percutaneous transluminal coronary angioplasty, tissue reperfusion injury after stroke and abdominal aortic aneurysm surgery; cerebral edema secondary to stroke; cranial trauma; hemorrhagic stroke Acute lung injury; asphyxia; adult respiratory distress syndrome; Behcet's disease; dermatomyositis; polymyositis; multiple sclerosis; dermatitis; meningitis
  • Autoimmune diseases are diseases or conditions caused by the body's immune response to its own antigens, which results in damage to its own tissues or organs.
  • autoimmune diseases include, but are not limited to, chronic obstructive pulmonary disease, allergic rhinitis, lupus erythematosus, myasthenia gravis, multiple sclerosis (MS), rheumatoid arthritis, psoriasis, inflammatory bowel disease, asthma, idiopathic thrombocytopenic purpura, and myeloproliferative diseases such as myelofibrosis and polycythemia vera/essential thrombocythemia myelofibrosis.
  • the inflammatory diseases and autoimmune diseases include rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), allergic rhinitis, asthma, lupus erythematosus, psoriasis and multiple sclerosis.
  • COPD chronic obstructive pulmonary disease
  • Non-limiting examples of solid tumors include pancreatic cancer; bladder cancer: colorectal cancer: breast cancer, including metastatic breast cancer; prostate cancer, including androgen-dependent and androgen-independent prostate cancer; kidney cancer, including, for example, metastatic renal cell carcinoma; hepatocellular carcinoma; lung cancer, including, for example, non-small cell lung cancer (NSCLC), bronchioloalveolar carcinoma (BAC), and lung adenocarcinoma; ovarian cancer, including, for example, progressive epithelial cancer or primary peritoneal cancer; cervical cancer; gastric cancer; esophageal cancer; head and neck cancer, including, for example, head and neck squamous cell carcinoma; skin cancer, including, for example, malignant melanoma: neuroendocrine cancer, including metastatic neuroendocrine tumors: brain tumors, including, for example, gliomas, anaplastic oligodendrogliomas, adult glioblastoma multiforme, and adult anaplastic astrocytomas; bone
  • Non-limiting examples of hematologic malignancies include acute myeloid leukemia (AML); chronic myeloid leukemia (CML), including accelerated phase CML and CML blast phase (CML-BP); acute lymphocytic leukemia (ALL); chronic lymphocytic leukemia (CLL); Hodgkin's lymphoma; non-Hodgkin's lymphoma (NHL), including follicular lymphoma and mantle cell lymphoma; B-cell lymphoma; T-cell lymphoma; multiple myeloma (MM); Waldenstrom's macroglobulinemia; myelodysplastic syndrome, including refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, and refractory anemia with excess blasts combined with acute transformation; and myeloproliferative syndrome.
  • AML acute myeloid leukemia
  • CML chronic myeloid leukemia
  • the cancer can be selected from leukemia, multiple myeloma (MM), lymphoma;
  • the leukemia is acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL) and chronic myeloid leukemia (CML);
  • the lymphoma is Hodgkin's lymphoma, non-Hodgkin's lymphoma (NHL), mantle cell lymphoma (MCL), follicular lymphoma, B cell lymphoma, T Diffuse large B-cell lymphoma (DLBCL).
  • infectious diseases include bacterial infection, fungal infection, viral infection, parasitic infection and the like.
  • cardiovascular and cerebrovascular diseases include acute heart failure, hypotension, hypertension, angina pectoris, myocardial infarction, cardiomyopathy, congestive heart failure, atherosclerosis, coronary heart disease, restenosis and vascular stenosis, as well as traumatic brain injury, stroke, ischemia-reperfusion injury, etc.
  • the present invention also provides the use of the 5-amino-1-alkyl-1H-1,2,3-triazole-4-carboxamide compound, its pharmaceutically acceptable salt, or its racemic mixture, hydrate, solvate, prodrug, enantiomer, diastereomer, tautomer, or the pharmaceutical composition in the preparation of anesthetics.
  • the compound of formula (1) described herein and/or its pharmaceutically acceptable salt can be used in combination with other active ingredients for the treatment of central nervous system diseases, inflammatory diseases, autoimmune diseases, cancer, infectious diseases or cardiovascular and cerebrovascular diseases and the preparation of anesthetics.
  • the compound of formula (1) and/or its pharmaceutically acceptable salt can be used separately from other active ingredients or prepared into a compound preparation.
  • Other active ingredients refer to those known effective ingredients for treating diseases related to ion channel function.
  • a hyphen ("-") that is not between two letters or symbols indicates the point of attachment of a substituent.
  • -O(C 1-4 alkyl) refers to a C 1-4 alkyl group that is attached to the rest of the molecule through an oxygen atom.
  • the "-" may be omitted.
  • alkyl refers to a straight or branched saturated alkyl group containing 1 to 18 carbon atoms, such as 1 to 12 carbon atoms, such as 1 to 6 carbon atoms, and such as 1 to 4 carbon atoms.
  • C 1-6 alkyl is within the scope of “alkyl” and represents the alkyl group having 1 to 6 carbon atoms.
  • alkyl groups include, but are not limited to, methyl (“Me”), ethyl (“Et”), n-propyl (“n-Pr”), isopropyl (“i-Pr”), n-butyl (“n-Bu”), isobutyl (“i-Bu”), sec-butyl (“s-Bu”), and tert-butyl (“t-Bu”).
  • halo refers to fluoro, chloro, bromo and iodo
  • halogen refers to fluorine, chlorine, bromine and iodine
  • haloalkyl refers to an alkyl group as defined herein in which one or more hydrogen atoms, such as 1, 2, 3, 4 or 5 hydrogen atoms, are replaced by halogen atoms, and when more than one hydrogen atom is replaced by a halogen atom, the halogen atoms may be the same as or different from each other.
  • the term “haloalkyl” as used herein refers to an alkyl group as defined herein in which two or more hydrogen atoms, such as 2, 3, 4 or 5 hydrogen atoms, are replaced by halogen atoms, wherein the halogen atoms are the same as each other.
  • haloalkyl refers to an alkyl group as defined herein in which two or more hydrogen atoms, such as 2, 3, 4 or 5 hydrogen atoms, are replaced by halogen atoms, wherein the halogen atoms are the same as each other.
  • haloalkyl refers to an alkyl group as defined herein in which two or more hydrogen atoms, such as 2, 3, 4 or 5 hydrogen atoms, are replaced by halogen atoms, wherein the halogen atoms are different from each other. Examples of haloalkyl groups include, but are not limited to , -CF3 , -CHF2 , -CH2CF3 , and the like .
  • alkoxy refers to the group -O-alkyl, wherein alkyl is as defined above.
  • alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy and hexyloxy, including their isomers.
  • aryl refers to a carbocyclic hydrocarbon group consisting of one or more rings fused together containing 6 to 14 ring carbon atoms, for example 6 to 12 ring carbon atoms, wherein at least one ring is an aromatic ring and the other rings are not heteroaryl as defined below, and the point of attachment may be on the aromatic ring or on the other rings.
  • aryl include, but are not limited to, phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, indenyl, indanyl, azulenyl, preferably phenyl.
  • aryl or “aromatic” follows Huckel's rule, where the number of ⁇ electrons is equal to 4n+2, and n is zero or any positive integer up to 6.
  • heteroaryl or “heteroaromatic” refers to a 4- to 12-membered monocyclic, bicyclic and tricyclic, saturated and partially unsaturated ring selected from the group consisting of at least one, e.g., 1-4, further e.g., 1-3, or further e.g., 1 or 2, heteroatoms selected from O, S, and N, and at least one carbon atom.
  • the point of attachment of the heteroaryl group may be on a heteroatom or on carbon.
  • Heteroaryl or “heteroaromatic” also refers to a monocyclic ring containing at least one heteroatom selected from O, S, and N; or a fused ring wherein at least one ring contains at least one heteroatom selected from O, S, and N and the other ring is not a heteroaryl or aryl group, and the point of attachment may be on the heteroaryl group or on the other ring.
  • heteroaryl refers to:
  • a monocyclic aromatic hydrocarbon radical having 5, 6 or 7 ring atoms, for example having 6 ring atoms, which comprises in the ring one or more, for example 1, 2 or 3, for example 1 or 2, ring heteroatoms independently selected from N, O and S, the remaining ring atoms being carbon atoms: and
  • Bicyclic aromatic hydrocarbon groups having 8-12 ring atoms, for example having 9 or 10 ring atoms, which contain one or more, for example 1, 2, 3 or 4, for example 1 or 2, ring heteroatoms independently selected from N, O and S in the ring, the remaining ring atoms being carbon atoms, wherein at least one ring is an aromatic ring.
  • bicyclic heteroaryl groups include 5-6 membered heteroaryl rings fused to 5-6 membered cycloalkyl rings, heteroaryl rings or aryl rings, wherein the point of attachment may be on the heteroaryl ring or on the cycloalkyl ring/heteroaryl ring/aryl ring.
  • Heteroaryl also includes those wherein the N ring heteroatom is in the form of an N-oxide, for example N-oxidized pyrimidinyl.
  • the ring heteroatom in the above heteroaryl is a N atom, and such heteroaryl is referred to as a "nitrogen-containing heteroaryl".
  • Nitrogen-containing heteroaryl also includes those heteroaryl groups in which the N ring heteroatom is in the form of an N-oxide, for example Pyridinyl N-oxide.
  • heteroaryl groups include, but are not limited to, pyridyl, pyridyl N-oxide; pyrazinyl; pyrimidinyl; pyrazolyl; imidazolyl; oxazolyl; isoxazolyl; thiazolyl; isothiazolyl; thiadiazolyl; tetrazolyl; triazolyl; thienyl; furanyl; pyranyl; pyrrolyl; pyridazinyl; benzo[d]thiazolyl; benzodioxaropentyl, such as benzo[d][1,3]dioxaropentyl; benzoxazolyl, such as benzo[d]oxazolyl; imidazopyridyl, such as imidazo[1,2-a]pyridyl; triazolopyridyl, such as [l,2,4]triazolo[4,3-a]pyridyl and
  • nitrogen-containing heteroaryl groups include, but are not limited to, pyrrolyl; pyrazolyl; imidazolyl; pyridinyl; pyrazinyl; pyrimidinyl, N-oxidized pyrimidinyl; pyridazinyl; pyrrolopyrimidinyl, such as pyrrolo[3,4-d]pyrimidinyl, 7H-pyrrolo[2,3-d]pyrimidinyl; purinyl, such as 9H-purinyl and 7H-purinyl; quinolyl; indolyl; and indazolyl.
  • hydroxyl refers to an -OH group.
  • thiol refers to a -SH group.
  • carboxy refers to a -C(O)-OH group.
  • amino refers to a -NH2 group.
  • cyano refers to a -CN group.
  • substituted or “substituted by” as used herein means that one or more hydrogen atoms on a given atom or group are replaced by one or more substituents selected from a given group, provided that the normal valency of the given atom is not exceeded.
  • substituted with one or more substituents means that one or more hydrogen atoms on a given atom or group are independently replaced with one or more substituents selected from a given group. In some embodiments, "substituted with one or more substituents” means that a given atom or group is replaced with 1, 2, 3 or 4 substituents independently selected from a given group.
  • 5-amino-1-alkyl-1H-1,2,3-triazole-4-carboxamide compounds may contain one or more chiral centers and thus exist as two or more stereoisomers. Racemic mixtures of these isomers, single isomers and mixtures enriched in one enantiomer, and when there are two chiral centers, the isomers may be present as two or more stereoisomers. The diastereomers and the mixtures enriched with specific diastereomers at the center are all within the scope of the present invention.
  • the present invention includes all single stereoisomers (e.g., enantiomers), racemic mixtures or partially resolved mixtures of 5-amino-1-alkyl-1H-1,2,3-triazole-4-carboxamide compounds, and, where appropriate, their single tautomers.
  • the present invention also provides a pharmaceutically acceptable salt of a 5-amino-1-alkyl-1H-1,2,3-triazole-4-carboxamide compound.
  • “Pharmaceutically acceptable salt” refers to a derivative of the disclosed compound wherein the parent compound is modified by converting an existing acid or base moiety into its salt form.
  • Pharmaceutically acceptable salts include, but are not limited to, acid addition salts formed by 5-amino-1-alkyl-1H-1,2,3-triazole-4-carboxamide compounds and inorganic or organic acids, and pharmaceutically acceptable salts also include base addition salts formed by 5-amino-1-alkyl-1H-1,2,3-triazole-4-carboxamide compounds with acidic groups and pharmaceutically acceptable cations.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing basic or acidic moieties by conventional chemical methods. In general, these salts can be prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of an appropriate base or acid in water or an organic solvent or a mixture of the two.
  • solvate is intended to include stoichiometric or non-stoichiometric solvent addition forms. If the solvent is water, the solvate formed is a hydrate, and when the solvent is ethanol, the solvate formed is an ethanolate.
  • prodrug refers to a compound that is an inactive precursor of a compound and is converted into its active form in vivo through normal metabolic pathways.
  • a prodrug can be converted into a pharmacologically active form by hydrolysis of, for example, an ester or amide bond, thereby introducing or exposing a functional group on the resulting product.
  • a prodrug can be designed to react with an endogenous compound to form a water-soluble conjugate that further enhances the pharmacological properties of the compound, such as increasing the circulation half-life.
  • a prodrug can be designed to have a functional group covalently modified by, for example, glucuronic acid, sulfate, glutathione, amino acids, or acetate.
  • the resulting conjugate can be passivated and excreted in the urine, or rendered more effective than the parent compound.
  • High molecular weight conjugates can also be excreted in the bile, cleaved by enzymes and released back into the circulation, thereby effectively increasing the biological half-life of the originally administered compound.
  • subject refers to any animal, including mammals and non-mammals, preferably rats, mice, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses or primates, and most preferably humans.
  • the present invention has the following beneficial effects: the 5-amino-1-alkyl-1H-1,2,3-triazole-4-carboxamide compounds, pharmaceutically acceptable salts thereof, or racemic mixtures, hydrates, solvates, prodrugs, enantiomers, diastereomers, and tautomers thereof of the present invention have high pharmaceutical activity and are non-biotoxic.
  • the drug has good safety and can overcome the problem of drug resistance of existing drugs.
  • Figure 1 is a graph showing the test results of the inhibitory activity of compounds 1, 2, 3, 7, 11, 14, 15, 22, and 26 on sodium ion channels.
  • FIG. 2 is a graph showing the results of measuring the effects of control drugs and compounds 1 and 2 on the pentylenetetrazol acute epileptic seizure model (PTZ).
  • PTZ pentylenetetrazol acute epileptic seizure model
  • FIG3 is a graph showing the results of measuring the effects of the control drug and compounds 1 and 2 on the maximum electric shock epileptic seizure model.
  • FIG. 4 is a graph showing the results of the evaluation of the anti-epileptic efficacy of the control drug and the compound of the present invention in the lamotrigine-resistant model.
  • FIG5 is a graph showing the anti-epileptic efficacy results of the oral administration experiment of the control drug and compounds 1, 2, and 11 in the lamotrigine resistance model.
  • FIG6 is a diagram showing the safety evaluation results of compounds 1 and 2.
  • the 5-amino-1-alkyl-1H-1,2,3-triazole-4-carboxamide compounds of the present invention are prepared by the following route:
  • Step 1 Place 600 mg of sodium hydride in a dry 100 mL two-necked bottle, place a reflux tube on the two-necked bottle, and protect with argon. Add 20 mL of anhydrous DMF to the two-necked bottle at 0°C and stir for 10 minutes. Then add 2.26 g of cyano Ethyl acetate A (20 mmol) was dissolved in 10 mL of anhydrous DMF, added dropwise into the two-necked bottle using a syringe, and stirred at 0°C for 15 min.
  • Step 2 1.7 g of 2,6-difluorobenzyl azide B (10 mmol) was dissolved in 10 mL of anhydrous DMF and added dropwise to the above two-necked bottle at 0°C. The reaction system was then moved to 65°C and stirred for 5 h. After the reaction was completed, the solvent was removed under reduced pressure. Column chromatography was performed using silica gel as the stationary phase and dichloromethane/methanol system as the eluent to obtain 1.7 g of white solid intermediate C with a yield of 65%.
  • Step 3 Place 1.7 g of intermediate C (6.5 mmol) in a 100 mL beaker, add 20 mL of 5% sodium hydroxide aqueous solution, and stir at room temperature until clear. Then add 10% hydrochloric acid to the beaker to adjust the pH to 2-3, and a large amount of white solid precipitates. Filter the reaction solution and drain the residue under reduced pressure. Then extract the filtrate three times with ethyl acetate, wash with saturated sodium chloride solution, dry with anhydrous sodium sulfate, remove the solvent under reduced pressure to obtain a white solid, combine with the residue, and drain. A total of 1.4 g of intermediate D was obtained, with a yield of 84%, and a combined yield of 55% in two steps.
  • Step 4 Place 1 g of intermediate D (4.5 mmol) and 2.85 g of HATU (6.7 mmol) in a 50 mL dry two-necked flask, inject 25 mL of DMF and 2.5 mL of DIPEA (N, N-diisopropylethylamine, 14 mmol) and 0.5 mL of ammonia water, and stir overnight at room temperature. After the reaction is completed, 25 mL of water is added to the reaction solution, and dichloromethane is extracted 3 times. The organic phase is washed once with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and the solvent is removed under reduced pressure.
  • DIPEA N, N-diisopropylethylamine, 14 mmol
  • This experiment mainly used 6-8 week old male C57BL/6 wild type (WT) mice.
  • DMSO dimethyl sulfoxide
  • the laboratory used cerebrospinal fluid to dilute and prepare gradient concentrations of 1 ⁇ M, 3 ⁇ M, 10 ⁇ M, 30 ⁇ M, 60 ⁇ M, 100 ⁇ M, etc.
  • Cerebrospinal fluid formula (unit mM): 125NaCl, 2.5KCl, 2CaCl 2 , 1.25NaH 2 PO 4 , 1MgCl 2 , 25NaHCO 3 , 10D-glucose, pH adjusted to 7.4 with HCl.
  • mice After the mice were anesthetized with isoflurane, they were quickly decapitated and the brains were removed.
  • the brain tissues were then sliced and quickly placed in a slicing solution that was previously saturated with a mixture of 95% oxygen and carbon dioxide at 4°C.
  • the brain tissues containing the hippocampus were then quickly cut into 300 ⁇ m slices using a vibrating slicer and incubated in artificial cerebrospinal fluid that was oxygenated at a constant temperature of 34°C. After one hour of incubation, the slices were used for subsequent experiments.
  • the electrophysiological recording adopts the whole-cell voltage clamp mode.
  • the glass microelectrode for recording is pulled by the microelectrode pulling instrument with an impedance of 6-8M ⁇ to record the glutamatergic neurons of hippocampal CA1.
  • This experiment mainly observes the effect of a series of small molecule compounds on the amplitude of the maximum open current (I Na-Max ) of the sodium ion channel of hippocampal glutamatergic neurons.
  • I Na-Max maximum open current
  • the recording cell is first held at -70mV for 300ms, and then the holding voltage is immediately stepped to -10mV. for 15ms.
  • the sodium current of the sodium channel under the depolarization voltage change is recorded, which is I Na-Max .
  • the I Na-Max of the hippocampal glutamatergic neurons in the baseline state is first recorded, and then different gradient concentrations of compounds are perfused to investigate the inhibitory effect of the compounds on the amplitude of I Na-Max .
  • the compounds that can effectively inhibit the sodium current (inhibition rate greater than 20%) are subjected to the second round of IC 50 determination.
  • concentration gradients of 1 ⁇ M, 3 ⁇ M, 10 ⁇ M, 30 ⁇ M, and 100 ⁇ M were set to screen the IC50 of the effect on sodium channels. According to the inhibition efficiency of the compound at each concentration (the difference in the amplitude of I Na-Max before and after administration divided by the amplitude of I Na-Max in the basal state), the concentration-drug effect curve was drawn and the IC50 value was calculated.
  • mice adult male ICR mice weighing 25-30 g were used. The mice were randomly divided into the following groups according to their weight: solvent group, Rufinamide positive control group, VPA positive control group and different compound groups (Rufinamide and candidate compounds were 50 mg/kg, VPA was 300 mg/kg), with 5-6 ICR male mice in each group.
  • solvent or drug was given by gavage, and 100 mg/kg PTZ was injected intraperitoneally 1 hour later. Immediately afterwards, the epileptic seizures of the mice were observed and recorded, and the observation time was 30 minutes.
  • the behavioral evaluation grading standard is: Grade 0: no obvious reaction; Grade 1: absence and dullness, ear and face twitching; Grade 2: whole body twitching, no forelimb lifting; Grade 3: one or both forelimbs lifted; Grade 4: one side of the body fell to the side with convulsions; Grade 5: fell to the ground on the back, or whole body tonic-clonic seizure; Grade 6: death after tonic seizure.
  • the grade of epileptic seizures in each mouse ( Figure 2a), the time from the start of drug administration to the second level seizure latency (Figure 2b), the fourth level seizure latency (Figure 2c), the sixth level seizure latency (Figure 2d) and the survival rate of mice ( Figure 2e) were recorded. From the experimental results, compounds 1 and 2 showed good anti-epileptic efficacy, which was better than Rufinamide.
  • This experiment mainly used 2- to 4-month-old adult male C57BL/6 wild-type (WT) mice.
  • mice were anesthetized by intraperitoneal injection of 1% sodium pentobarbital (60 mg/kg).
  • the double-helix electrode used for electrical stimulation to induce epileptic seizures and EEG recording was implanted in the right ventral hippocampus CA3.
  • the double-helix electrode was wound with a double strand of polytetrafluoroethylene-covered stainless steel wire. The insulation layer was scraped off 0.5mm at the end, and the maximum distance between the tops did not exceed 0.5mm.
  • the electrode implantation speed should not be too fast (50-100 ⁇ m/min). After the electrode was implanted, it was fixed with dental cement. After the cement was completely dry, the spiral was unwound and the outer insulation layer of the electrode was removed with tweezers.
  • the electrodes were connected to the micro sockets by soldering and fixed with medical dental cement.
  • the EEG was recorded with the Neuroscan system, and the stimulation current (unidirectional square wave pulse, 20 Hz, 1 ms/pulse, duration 2 s) was started from 40 ⁇ A and increased by 20 ⁇ A every 1 min until an afterdischarge duration (ADD) of at least 5 s was induced.
  • the current intensity at this time was defined as the ADT of the animal and used for grouping.
  • Parameters of rapid electrical ignition 1ms square wave pulse, 20Hz stimulation frequency, 400 ⁇ A suprathreshold stimulation intensity, 2s duration.
  • a subconvulsive dose of 5mg/kg lamotrigine was intraperitoneally administered, and an electrical stimulation was given after a 30-minute rest, and another electrical stimulation was given half an hour later. The above process was repeated 3 times a day, with 6 electrical stimulations per day until complete ignition.
  • the severity of behavior was judged according to the Racine classification system, grade 1: facial twitching; grade 2: nodding; grade 3: unilateral forelimb clonic seizure; grade 4: bilateral forelimb clonic seizure; grade 5: bilateral forelimb clonic seizure accompanied by unbalanced fall.
  • seizure grades 1-3 are considered FS, while grades 4-5 are considered GS. Animals with 3 consecutive grade 5 seizures are considered to be completely ignited.
  • the safety of compounds 1 and 2 was evaluated using adult male ICR mice weighing 25-30g. The mice were randomly divided into treatment groups and blank groups according to their weight, with 5-6 ICR male mice in each group. During the experiment, the solvent or drug was gavaged for three consecutive weeks at a dose of 100 mg/kg, and the weight changes (Figure 6a), exercise capacity (Figure 6b- Figure 6e) and blood routine indicators (Figure 6f- Figure 6k) of the mice were examined. The experimental results showed that compounds 1 and 2 had no damage to the weight gain and exercise capacity of mice under continuous administration of 100 mg/kg, and the blood routine indicators were also within the normal range, indicating that compounds 1 and 2 have good safety.

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Abstract

本发明公开了一类具有式（1）所示结构通式的5-氨基-1-烷基-1H-1,2,3-三氮唑-4-甲酰胺类化合物，其药学上可接受的盐，或其外消旋混合物、水合物、溶剂合物、前药、对映异构体、非对映异构体、互变异构体。本发明还公开了含有式（1）化合物的药物组合物，以及式（1）化合物、其药学上可接受的盐、或其外消旋混合物、水合物、溶剂合物、前药、对映异构体、非对映异构体、互变异构体，或所述的药物组合物在制备用于治疗对调节离子通道功能有响应的疾病的药剂中的应用。

Description

5-氨基-1-烷基-1H-1,2,3-三氮唑-4-甲酰胺类化合物及其制备和应用 技术领域
本发明涉及药物化学领域，具体涉及一类5-氨基-1-烷基-1H-1,2,3-三氮唑-4-甲酰胺类化合物及其制备方法和应用。
背景技术
离子通道是一类重要的药物靶点，离子通道作为一类跨膜蛋白，含有由多个亚基形成的水孔，可调节不同离子在配体结合或电压变化时穿过细胞膜的内流或外排。离子通道在许多组织(包括神经、肌肉和腺体)的细胞膜中作为基本的兴奋或抑制单位发挥作用。当通道打开时，离子的内流或外排产生各种电信号，促进了大量的细胞活动和基本的生理过程。离子通道不仅影响神经递质释放、肌肉收缩和腺体分泌，而且在学习记忆、细胞体积维持和体内平衡中起着关键作用。离子通道功能障碍或离子通道病变与痛觉受损、炎症反应、糖尿病以及肿瘤细胞增殖和迁移有关。此外，异常的离子通道与许多神经系统疾病和心律失常有关，包括焦虑、失眠、癫痫、精神分裂症、帕金森病和阿尔茨海默病，以及长/短QT间期综合征。因此，离子通道是一类重要的药物靶标。
申请人在先前的研究中报道了两类可用于治疗癫痫的化合物。公开号为CN113717133A的专利说明书公开了一类3-酰胺基-N-芳基苯甲酰胺类化合物及其在制备抗癫痫治疗药中的应用。公开号为CN114044757A的专利说明书公开了一类三氮唑-4-(N-取代甲酰胺)-5-三氮烯类化合物及其制备方法和在制备抗癫痫药物中的应用。这两篇现有技术均未报道拉莫三嗪耐药模型中的药物效果，不涉及耐药性问题的解决。此外，公开号为CN114044757A的专利说明书公开的三氮唑-4-(N-取代甲酰胺)-5-三氮烯类化合物中由于含有三氮烯基团，使得这类化合物具有生物毒性，在药物安全性方面难以过关。
本发明通过对CN114044757A中所必要的含三氮烯的母核结构进行特征改变，舍弃具有潜在生物毒性的三氮烯结构，替换为氨基，设计合成了一类无生物毒性的5-氨基-1-烷基-1H-1,2,3-三氮唑-4-甲酰胺类化合物，且意外发现该类新结构化合物仍具有明显的电生理活性，对钠等离子通道可表现出抑制活性。在癫痫的动物模型中，包括戊四唑急性癫痫发作模型(PTZ)、最大电休克癫痫发作模型(MES)、拉莫三嗪耐药模型，部分化合物具有更为强效的抗癫痫药效，能显著降低癫痫发作等级，提高癫痫发 作潜时，并且在拉莫三嗪耐药模型中依然具有良好的抗癫痫药效，具有良好的开发前景。
发明内容
本发明提供了一类5-氨基-1-烷基-1H-1,2,3-三氮唑-4-甲酰胺类化合物、其药学上可接受的盐，或其外消旋混合物、水合物、溶剂合物、前药、对映异构体、非对映异构体、互变异构体，所述的5-氨基-1-烷基-1H-1,2,3-三氮唑-4-甲酰胺类化合物具有如下式(1)所示结构通式：
式(1)中：
R1为取代或未取代的芳环，所述的芳环为苯环或芳香杂环，所述芳环上的取代基包含氟原子，并独立地选自卤素、硝基、氨基、羟基、氰基、烷氧基、巯基、羧基、酯基、取代或未取代的C1-6烷基、取代或未取代的C1-6环烷基、取代或未取代的C1-6杂环烷基、取代或未取代的C4-10芳基、取代或未取代的C1-8杂芳基、C2-10烯基、C2-10炔基、烷基单取代胺基、烷基双取代胺基、烷氧基、烷基羰氧基、环烷基羰氧基、杂芳基羰氧基、烷氧基羰基、环烷氧基羰基、杂芳氧基羰基、烷基羰胺基、环烷基羰胺基、杂芳基羰胺基、胺基羰基、烷氧甲酰胺基、烷巯基、羟基烷氧基、糖残基、磺酸基、磷酸基、多羟基烷氧基羰基、羧基烷氧基、羧基烷基甲酰氧基中的一个或多个；
R2和R3相同或不同，各自独立地选自氢、取代或未取代的C1～C4烷基、取代或未取代的苯基，所述C1～C4烷基上的取代基为甲氧酰基、羟基；或者R2、R3与连接R2和R3的N形成六元环，所述六元环中含有N、C和O。
所述的5-氨基-1-烷基-1H-1,2,3-三氮唑-4-甲酰胺类化合物还可以具有如下式(2)所示结构通式：
式(2)中：
表示苯环或吡啶环；
R1表示所述苯环或吡啶环上的一个或多个取代基，分别独立选自H、卤素、C1～C6烷氧基、羟基、氰基、氨基、噻吩基、吡唑基、吡啶啉酮中的一个或多个；
R2和R3分别独立选自氢、取代或未取代的C1～C4烷基、C3～C6环烷基、苯基，所述C1～C4烷基上的取代基为苯基、酯基、羟基中的一个或多个；或者R2、R3与连接R2和R3的N形成取代或未取代的六元环，所述六元环由N、C连接组成或由N、C和O连接组成，所述六元环上的取代基为C1～C4烷基。
进一步的，所述的5-氨基-1-烷基-1H-1,2,3-三氮唑-4-甲酰胺类化合物可选自以下化合物1-32中的任一种：


本发明还提供了所述的5-氨基-1-烷基-1H-1,2,3-三氮唑-4-甲酰胺类化合物的制备方法。
本发明可采用反应路线I合成化合物1-32；
反应路线I包括以下过程：
氰基乙酸乙酯A与苄基叠氮类化合物B在DMF中，NaH作碱的情况下，反应生成取代5-氨基-1-烷基-1H-1,2,3-三氮唑-4-甲酸酯类化合物C，然后在NaOH作用下水解、酸化生成羧酸类化合物D，接着在缩合试剂HATU的促进下，与胺类化合物E发生缩合反应，生成目标化合物1-32。
按照上述方法制备得到的至少一种三氮唑类化合物、其药学上可接受的盐，或其外消旋混合物、水合物、溶剂合物、前药、对映异构体、非对映异构体、互变异构体可以通过柱色谱、高效液相色谱、结晶或其他适当的方法进行纯化。
本发明还提供了一种药物组合物，包含可药用的载体、辅料中的至少一种，以及所述的5-氨基-1-烷基-1H-1,2,3-三氮唑-4-甲酰胺类化合物、其药学上可接受的盐、或其外消旋混合物、水合物、溶剂合物、前药、对映异构体、非对映异构体、互变异构体。
药学上可接受的载体(即可药用的载体)是指能与组合物中的活性成分(5-氨基-1-烷基-1H-1,2,3-三氮唑-4-甲酰胺类化合物、其药学上可接受的盐、或其外消旋混合物、水合物、溶剂合物、前药、对映异构体、非对映异构体、互变异构体)相容(在一些实施方案中，能稳定活性成分)并且对所治疗的个体无害的载体。辅料可选自赋形剂、稀释剂、填充剂、盐、崩解剂、黏合剂、润滑剂、助流剂、润湿剂、控制释放基质、着色剂、调味剂、缓冲剂、稳定剂、增溶剂等中的一种或多种的组合。
包含本文所述的5-氨基-1-烷基-1H-1,2,3-三氮唑-4-甲酰胺类化合物、其药学上可接受的盐、或其外消旋混合物、水合物、溶剂合物、前药、对映异构体、非对映异构体、互变异构体的药物组合物可以以各种已知的方式例如口服、局部、直肠、肠胃外、吸入或植入等方式施用。
根据治疗目的，可将药物组合物制成各种类型的给药单位剂型，如片剂、丸剂、粉剂、液体制剂、悬浮液、乳液、颗粒剂、胶囊、栓剂和针剂(溶液及悬浮液)等。
为了使片剂形式的药物组合物成形，可使用本领域任何已知并广泛使用的赋形剂。 例如，载体，如乳糖、白糖、氯化钠、葡萄糖、尿素、淀粉、碳酸钙、高岭土、结晶纤维素和硅酸等；粘合剂，如水、乙醇、丙醇、普通糖浆、葡萄糖溶液、淀粉溶液、明胶溶液，羧甲基纤维素、紫胶、甲基纤维素和磷酸钾、聚乙烯吡咯烷酮等；崩解剂，如干淀粉、藻酸钠、琼脂粉和海带粉，碳酸氢钠、碳酸钙、聚乙烯脱水山梨醇的脂肪酸酯、十二烷基硫酸钠、硬脂酸单甘酯、淀粉和乳糖等；崩解抑制剂，如白糖、甘油三硬脂酸酯、椰子油和氢化油；吸附促进剂，如季胺碱和十二烷基硫酸钠等；润湿剂，如甘油、淀粉等；吸附剂，如淀粉、乳糖、高岭土、膨润土和胶体硅酸等；以及润滑剂，如纯净的滑石，硬脂酸盐、硼酸粉和聚乙二醇等。还可以根据需要选用通常的涂渍材料制成糖衣片剂、涂明胶膜片剂、肠衣片剂、涂膜片剂、双层膜片剂及多层片剂。
为了使丸剂形式的药物组合物成形，可使用本领域任何己知的并广泛使用的赋形剂，例如，载体，如乳糖，淀粉，椰子油，硬化植物油，高岭土和滑石粉等；粘合剂，如阿拉伯树胶粉，黄蓍胶粉，明胶和乙醇等；崩解剂，如琼脂和海带粉等。
为了使栓剂形式的药物组合物成形，可使用本领域任何已知并广泛使用的赋性剂，例如，聚乙二醇，椰子油，高级醇，高级醇的酯，明胶和半合成的甘油酯等。
为了制备针剂形式的药物组合物，可将溶液或悬浮液消毒后(最好加入适量的氯化钠，葡萄糖或甘油等)，制成与血液等渗压的针剂。在制备针剂时，也可使用本领域内任何常用的载体，例如，水，乙醇，丙二醇，乙氧基化的异硬脂醇，聚氧基化的异硬脂醇和聚乙烯脱水山梨醇的脂肪酸酯等。此外，还可加入通常的溶解剂、缓冲剂和止痛剂等。
本发明中，所述药物组合物的给药方法没有特殊限制。可根据病人年龄、性别和其它条件及症状，选择各种剂型的制剂给药。例如，片剂、丸剂、溶液、悬浮液、乳液、颗粒剂或胶囊口服给药；针剂可以单独给药，或者和注射用输送液(如葡萄糖溶液及氨基酸溶液)混合进行静脉注射；栓剂为给药到直肠。
另一方面，本发明还提供了一种调节离子通道功能的方法，其包括使用有效量的5-氨基-1-烷基-1H-1,2,3-三氮唑-4-甲酰胺类化合物、其药学上可接受的盐、或其外消旋混合物、水合物、溶剂合物、前药、对映异构体、非对映异构体、互变异构体。
另一方面，本发明还提供了一种调节离子通道功能的方法，其包括使用有效量的药物组合物调节离子通道功能，所述药物组合物包含可药用的载体、辅料中的至少一种，以及所述的5-氨基-1-烷基-1H-1,2,3-三氮唑-4-甲酰胺类化合物、其药学上可接受的盐、或其外消旋混合物、水合物、溶剂合物、前药、对映异构体、非对映异构体、互变异构体。
另一方面，本发明还提供了一种治疗个体中对调节离子通道功能有响应的疾病的方法，其包括给需要其的个体施用能有效调节离子通道功能的量的5-氨基-1-烷基-1H-1,2,3-三氮唑-4-甲酰胺类化合物、其药学上可接受的盐、或其外消旋混合物、水合物、溶剂合物、前药、对映异构体、非对映异构体、互变异构体。
另一方面，本发明还提供了一种治疗个体中对调节离子通道功能有响应的疾病的方法，其包括给需要其的个体使用能有效调剂离子通道功能的量的一种药物组合物，所述药物组合物包含包含可药用的载体、辅料中的至少一种，以及所述的5-氨基-1-烷基-1H-1,2,3-三氮唑-4-甲酰胺类化合物、其药学上可接受的盐、或其外消旋混合物、水合物、溶剂合物、前药、对映异构体、非对映异构体、互变异构体。
本发明还提供了所述的5-氨基-1-烷基-1H-1,2,3-三氮唑-4-甲酰胺类化合物、其药学上可接受的盐，或其外消旋混合物、水合物、溶剂合物、前药、对映异构体、非对映异构体、互变异构体，或所述的药物组合物在制备离子通道阻滞剂中的应用。
本发明还提供了所述的5-氨基-1-烷基-1H-1,2,3-三氮唑-4-甲酰胺类化合物、其药学上可接受的盐，或其外消旋混合物、水合物、溶剂合物、前药、对映异构体、非对映异构体、互变异构体，或所述的药物组合物在制备用于治疗离子通道相关的疾病的药剂中的应用。
本发明所述离子通道可为钠离子通道。
所述的离子通道相关的疾病包括中枢神经系统疾病、炎症性疾病、自身免疫性疾病、癌症、感染性疾病、心脑血管疾病等。
所述的中枢神经系统疾病为癫痫、帕金森、阿兹海默症、焦虑症、抑郁症、精神分裂症等。
炎症性疾病指的是导致炎症反应的病理状态，尤其是由于嗜中性粒细胞趋化引起的。这种疾病的例子包括炎性皮肤疾病(包括银屑病和特应性皮炎)；系统性硬皮病和硬化症；与炎性肠病(例如克罗恩病和溃疡性结肠炎)有关的反应；缺血再灌注损伤，包括手术引起组织再灌注损伤、心肌缺血如心肌梗死、心脏骤停、心脏术后再灌注和经皮冠状动脉成形术后冠脉血管的异常收缩反应、中风和腹主动脉瘤手术组织再灌注损伤；中风继发脑水肿；颅外伤；失血性休克；室息；成人呼吸窘迫综合征；急性肺损伤；白塞氏病；皮肌炎；多发性肌炎；多发性硬化症；皮炎；脑膜炎；脑炎；葡萄膜炎；骨关节炎；狼疮性肾炎；自身免疫性疾病如类风湿性关节炎；舍格林氏综合征；脉管炎；涉及白细胞渗出的疾病；败血症或创伤继发中枢神经系统炎症性疾病、多器官损伤综合征：酒精性肝炎；细菌性肺炎；抗原-抗体复合物介导的疾病，包括肾小球 肾炎：脓血症：结节病；组织/器官移植引起的免疫病理反应；肺部炎症，包括胸膜炎、肺泡炎、脉管炎、肺炎、慢性支气管炎、支气管扩张、弥漫性泛细支气管炎、过敏性肺炎、特发性肺纤维化以及囊性纤维化等。
自身免疫性疾病是指机体对自身抗原发生免疫反应而导致自身组织或器官损害所引起的疾病或病症。自身免疫性疾病的例子包括但不限于：慢性阻塞性肺病、变应性鼻炎、红斑狼疮、重症肌无力、多发性硬化(MS)、类风湿性关节炎、银屑病、炎性肠病、哮喘和特发性血小板减少性紫瘢以及骨髓增生性疾病，例如骨髓纤维化、真性红细胞增多症/原发性血小板增多症性骨髓纤维化。
所述的炎症性疾病、自身免疫性疾病包括类风湿性关节炎、慢性阻塞性肺病(COPD)、变应性鼻炎、哮喘、红斑狼疮、银屑病和多发性硬化。
包括皮肤、组织、器官、骨骼、软骨、血液和血管的癌症，其既包括原发性癌症，也包括转移性癌症。
实体瘤的非限制性例子包括胰腺癌；膀胱癌：结肠直肠癌：乳腺癌，包括转移性乳腺癌；前列腺癌，包括雄性激素依赖性和非雄性激素依赖性前列腺癌；肾癌，包括例如转移性肾细胞癌；肝细胞癌；肺癌，包括例如非小细胞肺癌(NSCLC)、细支气管肺泡癌(BAC)和肺腺癌；卵巢癌，包括例如进行性上皮癌或原发性腹膜癌；宫颈癌；胃癌；食道癌；头颈癌，包括例如头颈部鳞状细胞癌；皮肤癌，包括例如恶性黑素瘤：神经内分泌癌，包括转移性神经内分泌瘤：脑瘤，包括例如神经胶质瘤、间变性少突神经胶质瘤、成人多形性成胶质细胞瘤和成人间变型星形细胞瘤；骨癌；软组织肉瘤：和甲状腺癌。
血液系统恶性肿瘤的非限制性例子包括急性髓性白血病(AML)；慢性髓性白血病(CML)，包括加速期CML和CML急变期(CML-BP)：急性淋巴细胞白血病(ALL)；慢性淋巴细胞白血病(CLL)；霍奇金淋巴瘤；非霍奇金淋巴瘤(NHL)，包括滤泡型淋巴瘤和套细胞淋巴瘤；B细胞淋巴瘤；T细胞淋巴瘤；多发性骨髓瘤(MM)；瓦尔登斯特伦巨球蛋白血症；骨髓增生异常综合征，包括顽固性贫血、环状铁粒幼细胞顽固性贫血、过量芽细胞顽固性贫血和过量芽细胞顽固性贫血合并急性转化；以及骨髓增生综合征。
一些实施方案中，典型的，所述的癌症可选自白血病、多发性骨髓瘤(MM)、淋巴瘤；所述的白血病为急性淋巴细胞白血病(ALL)、急性髓性白血病(AML)、慢性淋巴细胞白血病(CLL)和慢性髓性白血病(CML)；所述的淋巴瘤为霍奇金淋巴瘤、非霍奇金淋巴瘤(NHL)、套细胞淋巴瘤(MCL)、滤泡型淋巴瘤、B细胞淋巴瘤、T 细胞淋巴瘤、弥散性大B细胞淋巴瘤(DLBCL)。
所述的感染性疾病包括细菌性感染、真菌性感染、病毒性感染、寄生虫感染等。
所述的心脑血管疾病包括急性心力衰竭、低血压、高血压、心绞痛、心肌梗塞、心肌病、充血性心力衰竭、动脉粥样硬化、冠心病、再狭窄和血管狭窄，以及外伤性脑损伤、中风、缺血再灌注损伤等。
本发明还提供了所述的5-氨基-1-烷基-1H-1,2,3-三氮唑-4-甲酰胺类化合物、其药学上可接受的盐，或其外消旋混合物、水合物、溶剂合物、前药、对映异构体、非对映异构体、互变异构体，或所述的药物组合物在制备麻醉剂中的应用。
此外，本文所述的式(1)的化合物和/或其药学上可接受的盐可与其它的活性成分联合用药，用于治疗中枢神经系统疾病、炎症性疾病、自身免疫性疾病、癌症、感染性疾病或心脑血管疾病以及制备麻醉剂。式(1)的化合物和/或其药学上可接受的盐可与其它的活性成分分开用药或制成复方制剂。其它的活性成分是指那些已知的治疗与离子通道功能相关的疾病的有效的成分。
定义
本申请中所用的下列单词、短语和符号具有如下所述的含义，其所处的上下文中另有说明的除外。
不在两个字母或符号之间的短横(“-”)表示取代基的连接位点。例如，-O(C1-4烷基)是指通过氧原子与分子的其余部分连接的C1-4烷基。然而，当取代基的连接位点对本领域技术人员来说是显而易见的时候，例如，卤素取代基，“-”可以被省略。
本文所用的术语“烷基”是指含有1-18个碳原子、例如1-12个碳原子、再例如1-6个碳原子、再例如1-4个碳原子的直链或支链的饱和烷基。例如，“C1-6烷基”在“烷基”的范围内，表示所述的具有1-6个碳原子的烷基。烷基的例子包括但不限于甲基(“Me”)、乙基(“Et”)、正丙基(“n-Pr”)、异丙基(“i-Pr”)、正丁基(“n-Bu”)、异丁基(“i-Bu”)、仲丁基(“s-Bu”)和叔丁基(“t-Bu”)。
本文所用的术语“卤代”是指氟代、氯代、溴代和碘代，“卤素”是指氟、氯、溴和碘。
本文所用的术语“卤代烷基”是指其中一个或多个氢原子、例如1、2、3、4或5个氢原子被卤素原子替代的本文所定义的烷基，并且当超过一个氢原子被卤素原子替代时，所述卤素原子可以彼此相同或不同。在一个实施方案中，本文所用的术语“卤代烷基”是指其中两个或更多个氢原子、例如2、3、4或5个氢原子被卤素原子替代的本文所定义的烷基，其中所述卤素原子彼此相同。在另一个实施方案中，本文所用 的术语“卤代烷基”是指其中两个或更多个氢原子、例如2、3、4或5个氢原子被卤素原子替代的本文所定义的烷基，其中所述卤素原子彼此不同。卤代烷基的例子包括但不限于-CF3、-CHF2、-CH2CF3等。
本文所用的术语＂烷氧基”是指基团-O-烷基，其中烷基如上文所定义。烷氧基的例子包括但不限于甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、戊氧基和已氧基，包括它们的异构体。
本文所用的术语“芳基”是指由一个环或多个环稠合组成的含有6-14个环碳原子，例如6-12个环碳原子的碳环烃基，其中至少一个环是芳族环并且其它环不是如下文所定义的杂芳基，其连接点可以在芳族环上或在其它环上。芳基的例子包括但不限于苯基、萘基、1,2,3,4-四氢萘基、茚基、茚满基、薁基，优选苯基。
如本文所用，“芳基”或“芳族的”遵循休克尔规则，其中π电子数等于4n+2，n为零或任何最多为6的正整数。
本文所用的术语“杂芳基”或“杂芳的”是指选自4至12元单环的、双环的和三环的、饱和的和部分不饱和的环，其除了包含至少一个、例如1-4个、再例如1-3个或再例如1或2个选自O、S和N的杂原子外，还包含至少一个碳原子。杂芳基的连接点可以在杂原子上或在碳上。”杂芳基”或“杂芳的”也指单环，其包含至少一个选自O、S和N的杂原子；或者是稠环，其中至少一个环包含至少一个选自O、S和N的杂原子并且其它环不是杂芳基或芳基，其连接点可以在杂芳上或在其它环上。
本文所用的术语“杂芳基”是指：
具有5、6或7个环原子、例如具有6个环原子的单环芳族烃基，其在环中包含一个或多个、例如1、2或3个、例如1或2个独立地选自N、O和S的环杂原子，其余环原子是碳原子：和
有8-12个环原子、例如具有9或10个环原子的二环芳族烃基，其在环中包含一个或多个、例如1、2、3或4个、例如1或2个独立地选自N、O和S的环杂原子，其余环原子是碳原子，其中至少一个环是芳族环。例如，二环杂芳基包括与5-6元环烃基环、杂芳基环或芳基环稠合的5-6元杂芳基环，其中连接点可以在杂芳基环上或在环烷基环/杂芳基环/芳基环上。
杂芳基也包括其中的N环杂原子是N-氧化物形式的那些杂芳基，例如N-氧化嘧啶基。
在一些实施方案中，上述杂芳基中的环杂原子是N原子，这类杂芳基称为“含氮杂芳基”。含氮杂芳基也包括其中的N环杂原子是N-氧化物形式的那些杂芳基，例如 N-氧化吡啶基。
杂芳基的例子包括但不限于：吡啶基、N-氧化吡啶基；吡嗪基；嘧啶基；吡唑基；咪唑基；恶唑基；异恶唑基；噻唑基；异噻唑基；噻二唑基；四唑基；三唑基；噻吩基；呋喃基；吡喃基；吡咯基；哒嗪基；苯并[d]噻唑基；苯并间二氧杂芳戊烯基，例如苯并[d][1,3]间二氧杂芳戊烯基；苯并恶唑基，例如苯并[d]恶唑基；咪唑并吡啶基，例如咪唑并[1,2-a]吡啶基；三唑并吡啶基，例如[l,2,4]三唑并[4,3-a]吡啶基和[1,2,4]三唑并[1,5-a]吡啶基；吲唑基；2H-吲唑基；吡咯并嘧啶基，例如吡咯并[3,4-d]嘧啶基、7H-吡咯并[2,3-d]嘧啶基；吡唑并嘧啶基，例如吡唑并[1,5-a]嘧啶基；四唑并吡啶基，例如四唑并[1,5-a]吡啶基；苯并噻吩基；苯并呋喃基；苯并咪唑啉基；吲哚基；吲哚啉基；嘌呤基，例如9H-嘌呤基和7H-嘌呤基；喹啉基；异喹啉基；1,2,3,4-四氢喹啉基和1,2,3,4-四氢异喹啉基。
含氮杂芳基的实例包括但不限于：吡咯基；吡唑基；咪唑基；吡啶基；吡嗪基；嘧啶基、N-氧化嘧啶基；哒嗪基；吡咯并嘧啶基，例如吡咯并[3,4-d]嘧啶基、7H-吡咯并[2,3-d]嘧啶基；嘌呤基，例如9H-嘌呤基和7H-嘌呤基；喹啉基；吲哚基；以及吲唑基。
本文所述的术语“羟基”是指-OH基团。
本文所用的术语“巯基”是指-SH基团。
本文所用的术语“羧基”是指-C(O)-OH基团。
本文所用的术语“氨基”是指-NH2基团。
本文所用的术语“氰基”是指-CN基团。
如果本文的某个结构式包含星号“*”，则该结构式所表示的化合物为消旋体。
本文所用的术语“被取代的”或“被·····取代”意指给定原子或基团上的一个或多个氢原子被一个或多个选自给定取代基替换，条件是不超过该给定原子的正常化合价。
本文所用的术语“被一个或多个取代基取代”意指给定的原子或基团上的一个或多个氢原子独立地被一个或多个选自给定基团的取代基替换。在一些实施方案中，“被一个或多个取代基取代”意指给定的原子或基团被l、2、3或4个独立地选自给定基团的取代基取代。
本领域技术人员应当理解的是，一些5-氨基-1-烷基-1H-1,2,3-三氮唑-4-甲酰胺类化合物可以包含一个或多个手性中心，因此存在两个或更多个立体异构体。这些异构体的外消旋混合物、单个异构体和一种对映异构体富集的混合物，以及当有两个手性 中心时的非对映异构体和特定的非对映异构体部分富集的混合物均在本发明的范围内。本领域技术人员还应当理解的是，本发明包括5-氨基-1-烷基-1H-1,2,3-三氮唑-4-甲酰胺类化合物的所有单个立体异构体(例如对映异构体)、外消旋混合物或部分拆分的混合物，以及在适当的情况下，包括其单个互变异构体。
本发明也提供了5-氨基-1-烷基-1H-1,2,3-三氮唑-4-甲酰胺类化合物的一种药学上可接受的盐，“药学上可接受的盐”是指所公开化合物的衍生物，其中母体化合物通过使现有酸或碱部分转化成其盐形式而得到改性。
药学上可接受的盐包括但不限于：5-氨基-1-烷基-1H-1,2,3-三氮唑-4-甲酰胺类化合物与无机酸或有机酸形成的酸加成盐，药学上可接受的盐也包括带有酸性基团的5-氨基-1-烷基-1H-1,2,3-三氮唑-4-甲酰胺类化合物与药学上可接受的阳离子形成的碱加成盐。本发明的药学上可接受的盐可通过常规化学方法自含有碱性或酸性部分的母体化合物合成。一般来说，这些盐可通过使这些化合物的游离酸或碱形式与化学计算量的适当碱或酸在水或有机溶剂或两者的混合物中反应来制备。
术语“溶剂合物”意指包含化学计量的或非化学计量的溶剂加成形式。如果溶剂是水，则形成的溶剂合物是水合物，当溶剂是乙醇时，则形成的溶剂合物是乙醇合物。
术语“前药”指为化合物的非活性前体，在体内通过正常代谢途径转化为其活性形式的化合物。为了说明，可通过水解(例如)酯或酰胺键将前药转化为药理学活性形式，从而引入或暴露所生成的产物上的官能团。可将前药设计为与内源化合物反应以形成进一步增强化合物的药理学性质，例如增加循环半衰期的水溶性轭合物。或者，可将前药设计为官能团受(例如)葡糖醛酸、硫酸盐、谷胱甘肽、氨基酸或醋酸盐共价修饰。所生成的轭合物可被钝化且排于尿中，或致使其比母体化合物更有效。高分子量轭合物也可排于胆汁中，受酶裂解并释放回循环中，从而有效增加原先施用化合物的生物半衰期。
本文所用的属于“个体”是指任何动物，包括哺乳动物和非哺乳动物，其中优选为大鼠、小鼠、其他啮齿动物、兔、狗、猫、猪、牛、绵羊、马或灵长类动物，且最优选为人类。
本文所用的未具体定义的技术和科学术语具有本发明所属领域的技术人员通常理解的含义。
本发明与现有技术相比，有益效果有：本发明的5-氨基-1-烷基-1H-1,2,3-三氮唑-4-甲酰胺类化合物、其药学上可接受的盐，或其外消旋混合物、水合物、溶剂合物、前药、对映异构体、非对映异构体、互变异构体，在具有高药物活性的同时无生物毒性， 用药安全性好，且可克服现有药物耐药性问题。
附图说明
图1为化合物1、2、3、7、11、14、15、22、26对钠离子通道抑制活性测试结果图。
图2为对照药物和化合物1、2对戊四唑急性癫痫发作模型(PTZ)的作用测定结果图。
图3为对照药物和化合物1、2对最大电休克癫痫发作模型的作用测定结果图。
图4为对照药物和本发明化合物拉莫三嗪耐药模型抗癫痫药效评价结果图。
图5为对照药物和化合物1、2、11拉莫三嗪耐药模型的灌胃给药实验抗癫痫药效结果图。
图6为化合物1、2安全性评价结果图。
具体实施方式
下面结合附图及具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。
本发明的5-氨基-1-烷基-1H-1,2,3-三氮唑-4-甲酰胺类化合物采用如下路线进行制备：
制备实施例1:化合物1的制备
步骤1：将600mg氢化钠置于干燥100mL两口瓶中，两口瓶上架回流管，氩气保护。在0℃下，向两口瓶中加入20mL无水DMF，搅拌10分钟。再将2.26g氰基 乙酸乙酯A(20mmol)溶于10mL无水DMF，用注射器滴加入两口瓶中，0℃下搅拌15min。
步骤2：将1.7g的2,6-二氟苄基叠氮B(10mmol)溶于10mL无水DMF，0℃下滴加入上述的两口瓶中。随后将反应体系移至65℃下搅拌5h。反应结束后，减压除去溶剂。使用硅胶为固定相，二氯甲烷/甲醇体系为洗脱剂进行柱色谱分离纯化，得到1.7g白色固体中间体C，收率65％。
步骤3：将1.7g的中间体C(6.5mmol)置于100mL烧杯中，加入20mL 5％氢氧化钠水溶液，室温下搅拌至澄清。随后向烧杯中滴加10％盐酸调节pH至2～3，有大量白色固体析出。将反应液过滤，滤渣减压抽干。再将滤液用乙酸乙酯萃取三次，饱和氯化钠溶液洗涤，无水硫酸钠干燥，减压除去溶剂，得到白色固体，与滤渣合并，抽干。共得到1.4g中间体D，收率84％，两步合并收率55％。
步骤4：将1g的中间体D(4.5mmol)，2.85g的HATU(6.7mmol)置于50mL干燥二口瓶中，注入25mL DMF和2.5mL DIPEA(N,N-二异丙基乙胺，14mmol)以及0.5mL氨水，室温下搅拌过夜。反应结束后，反应液中加入25mL水，二氯甲烷萃取3次，有机相用饱和氯化钠水溶液洗涤一次，无水硫酸钠干燥，减压除去溶剂。使用硅胶为固定相，二氯甲烷/甲醇体系为洗脱剂进行柱色谱分离纯化，得到850mg白色固体5-氨基-(2，6-二氟苄基)-1H-1,2,3-三氮唑-4-甲酰胺，收率70％。
产品物理性质及谱图数据如下：白色固体；mp:212.7℃；1H NMR(400MHz,DMSO-d6)δ7.49(m,1H),7.41(s,1H),7.15(t,J＝8.0Hz,2H),7.08(s,1H),6.44(s,2H),5.39(s,2H)；13C NMR(101MHz,DMSO-d6)δ164.23,160.83(dd,J＝249.0,7.7Hz),144.95,131.21(t,J＝10.4Hz),121.29,112.04–111.61(m),111.25(t,J＝19.0Hz),36.93；19F NMR(376MHz,DMSO-d6)δ-114.35.
制备实施例2:化合物2的制备
更换相应底物，制备方法同制备实施例1，柱层析得白色固体2，收率75％。
产品物理性质及谱图数据如下：白色固体；mp:211.4℃；1H NMR(400MHz,DMSO-d6)δ7.98(q,J＝4.7Hz,1H),7.48(m,1H),7.20-7.08(m,2H),6.40(s,2H),5.39 (s,2H),2.71(d,J＝4.7Hz,3H)；13C NMR(101MHz,DMSO-d6)δ162.58,160.81(dd,J＝249.2,7.4Hz),144.54,131.20(t,J＝10.4Hz),121.46,112.28–111.41(m),111.23(t,J＝19.2Hz),36.93,25.10；19F NMR(376MHz,DMSO-d6)δ-114.36.
制备实施例3:化合物3的制备
更换相应底物，制备方法同制备实施例1，柱层析得白色固体3，收率68％。
产品物理性质及谱图数据如下:白色固体；mp:147.5℃；1H NMR(400MHz,DMSO-d6)δ7.49(m,1H),7.16(t,J＝8.0Hz,2H),6.62(s,2H),5.39(s,2H),3.47(s,3H),2.94(s,3H)；13C NMR(101MHz,DMSO-d6)δ162.46,160.85(dd,J＝248.5,7.7Hz),146.78,131.25(t,J＝10.3Hz),121.99,111.88(d,J＝6.0Hz),111.70(d,J＝5.4Hz),111.33–110.93(m),37.89,36.90；19F NMR(376MHz,DMSO-d6)δ-114.18.
制备实施例4:化合物4的制备
更换相应底物，制备方法同制备实施例1，柱层析得白色固体4，收率77％。
产品物理性质及谱图数据如下：白色固体；mp:177.9℃；1H NMR(400MHz,DMSO-d6)δ7.49(m,1H),7.16(t,J＝8.1Hz,2H),6.67(s,2H),5.40(s,2H),3.61(dt,J＝8.3,6.6Hz,4H)；13C NMR(101MHz,Chloroform-d)δ161.81,161.39(dd,J＝250.3,7.5Hz),146.29,131.47(t,J＝10.5Hz),123.65,112.64–111.10(m),110.01,67.14,42.59,37.52；19F NMR(376MHz,DMSO-d6)δ-114.15.
制备实施例5:化合物5的制备
更换相应底物，制备方法同制备实施例1，柱层析得白色固体5，收率74％。
产品物理性质及谱图数据如下：白色固体；mp:144.3℃；1H NMR(400MHz,DMSO-d6)δ7.49(m,1H),7.16(t,J＝8.0Hz,2H),6.64(s,2H),5.40(s,2H),3.94(d,J＝277.4Hz,4H),2.33(t,J＝5.0Hz,4H),2.19(s,3H)；13C NMR(101MHz,Chloroform-d)δ161.4(dd,J＝249.8,8.0Hz),161.71,146.25,131.43(t,J＝8.4Hz),123.80,112.19–111.76(m),110.11,55.58,46.05,42.14,37.50；19F NMR(376MHz,DMSO-d6)δ-114.17.
制备实施例6:化合物6的制备
更换相应底物，制备方法同制备实施例1，柱层析得白色固体6，收率72％。
产品物理性质及谱图数据如下：白色固体；mp:156.7℃；1H NMR(400MHz,DMSO-d6)δ8.04(m,1H),7.48(m,1H),7.28–6.90(m,2H),6.40(s,2H),5.39(s,2H),3.21(qd,J＝7.0,3.8Hz,2H),1.06(dt,J＝7.3,3.3Hz,3H)；13C NMR(101MHz,DMSO-d6)δ161.90,160.82(dd,J＝249.7,6.9Hz),144.65,131.22(t,J＝10.5Hz),121.43,112.00–111.65(m),36.93,32.75,15.20；19F NMR(376MHz,DMSO-d6)δ-114.23.
制备实施例7:化合物7的制备
更换相应底物，制备方法同制备实施例1，柱层析得白色固体7，收率72％。
产品物理性质及谱图数据如下：白色固体；mp:162.6℃；1H NMR(400MHz, DMSO-d6)δ8.64(t,J＝6.4Hz,1H),7.51(m,1H),7.31(d,J＝4.3Hz,4H),7.26–7.11(m,3H),6.47(s,2H),5.42(s,2H),4.41(d,J＝6.3Hz,2H)；13C NMR(101MHz,DMSO-d6)δ162.08,160.39(dd,J＝250.5,8.1Hz),144.81,140.17,131.22(t,J＝10.6Hz),128.15,127.25,126.57,121.20,111.92,111.68,111.22(t,J＝19.1Hz),41.48,36.92；19F NMR(376MHz,DMSO-d6)δ-114.17.
制备实施例8:化合物8的制备
更换相应底物，制备方法同制备实施例1，柱层析得白色固体8，收率69％。
产品物理性质及谱图数据如下：白色固体；mp:152.4℃；1H NMR(400MHz,DMSO-d6)δ8.09(d,J＝4.5Hz,1H),7.48(m,1H),7.15(t,J＝8.1Hz,2H),6.44(s,2H),5.39(s,2H),2.77(tq,J＝8.5,4.2Hz,1H),0.71–0.47(m,4H)；13C NMR(101MHz,DMSO-d6)δ163.79,161.29(dd,J＝249.1,7.8Hz),145.18,131.69(t,J＝10.3Hz),112.49–112.10(m),111.75(t,J＝19.2Hz),37.44,22.53,6.18；19F NMR(376MHz,DMSO-d6)δ-114.24.
制备实施例9:化合物9的制备
更换相应底物，制备方法同制备实施例1，柱层析得9，收率67％。
产品物理性质及谱图数据如下：白色固体；mp:180.2℃；1H NMR(400MHz,DMSO-d6)δ8.38(t,J＝6.1Hz,1H),7.51(m,1H),7.19(t,2H),6.49(s,2H),5.42(s,2H),3.95(d,J＝6.1Hz,2H),3.65(s,3H)；13C NMR(101MHz,DMSO-d6)δ170.54,162.36,160.81(dd,J＝251.5,7.8Hz),131.24(t,J＝10.4Hz),120.85,112.07–111.63(m),111.46–110.94(m),51.67,40.20,36.95；19F NMR(376MHz,DMSO-d6)δ-114.25.
制备实施例10:化合物10的制备
更换相应底物，制备方法同制备实施例1，柱层析得白色固体10，收率73％。
产品物理性质及谱图数据如下：白色固体；mp:223.3℃；1H NMR(400MHz,DMSO-d6)δ7.55–7.26(m,4H),7.24–6.89(m,1H),6.50(s,2H),5.40(d,J＝1.6Hz,2H)；13C NMR(101MHz,DMSO-d6)δ164.25,161.33(d,J＝250.0Hz),145.06,134.72(d,J＝5.2Hz),131.32(d,J＝10.0Hz),125.69(d,J＝3.4Hz),121.19,120.96(d,J＝17.5Hz),114.76(d,J＝22.2Hz),40.46(d,J＝3.8Hz)；19F NMR(376MHz,DMSO-d6)δ-112.68.
制备实施例11:化合物11的制备
更换相应底物，制备方法同制备实施例1，柱层析得白色固体11，收率71％。
产品物理性质及谱图数据如下：白色固体；mp:201.9℃；1H NMR(400MHz,DMSO-d6)δ7.49(s,1H),7.33(m,1H),7.20–7.03(m,3H),6.45(s,2H),5.45(s,2H)；13C NMR(101MHz,DMSO-d6)δ164.71,160.49(dd,J＝248.9,12.5Hz),145.47,131.22(dd,J＝9.9,5.6Hz),122.10,119.85(dd,J＝15.3,3.7Hz),112.36–112.03(m),104.65(t,J＝25.7Hz),42.88；19F NMR(376MHz,DMSO-d6)δ-110.22,-112.70.
制备实施例12:化合物12的制备
更换相应底物，制备方法同制备实施例1，柱层析得白色固体12，收率70％。
产品物理性质及谱图数据如下：白色固体；mp:197.6℃；1H NMR(400MHz,DMSO-d6)δ7.49(m,2H),7.29(m,1H),7.11(s,1H),7.03(t,J＝8.2Hz,1H),6.44(s,2H),5.45(s,2H)；13C NMR(101MHz,DMSO-d6)δ164.19,159.74(d,J＝250.4Hz),145.05,133.44(d,J＝10.3Hz),130.49(d,J＝4.9Hz),124.93(d,J＝3.7Hz),122.22(d,J＝15.2Hz),121.61,116.18(d,J＝24.5Hz),42.44；19F NMR(376MHz,DMSO-d6)δ-114.18.
制备实施例13:化合物13的制备
更换相应底物，制备方法同制备实施例1，柱层析得白色固体13，收率72％。
产品物理性质及谱图数据如下：白色固体；mp:164.3℃；1H NMR(400MHz,DMSO-d6)δ7.88(t,J＝5.9Hz,1H),7.48(m,1H),7.15(t,J＝8.0Hz,2H),6.43(s,2H),5.40(s,2H),4.72(t,J＝5.4Hz,1H),3.46(q,J＝5.9Hz,2H),3.28(q,J＝6.2Hz,2H)；13C NMR(101MHz,DMSO-d6)δ162.67,161.30(dd,J＝249.1,7.6Hz),145.17,131.71(t,J＝10.5Hz),121.77,112.47–112.10(m),111.75(t,J＝19.0Hz),60.50,41.26,37.45；19F NMR(376MHz,DMSO-d6)δ-114.13.
制备实施例14:化合物14的制备
更换相应底物，制备方法同制备实施例1，柱层析得白色固体14，收率72％。
产品物理性质及谱图数据如下：白色固体；mp:194.5℃；1H NMR(400MHz,DMSO-d6)δ10.02(s,1H),7.81(d,J＝8.6Hz,2H),7.52(m,1H),7.31(t,2H),7.19(t,2H),7.06(t,1H),6.67(s,2H),5.48(s,2H)；13C NMR(101MHz,DMSO-d6)δ161.31(dd,J＝249.5,8.1Hz),161.21,146.04,139.45,131.70(d,J＝10.2Hz),128.98,123.54,121.65,120.50,112.96–112.03(m),111.72,37.56；19F NMR(376MHz,DMSO-d6)δ-114.25.
制备实施例15:化合物15的制备
更换相应底物，制备方法同制备实施例1，柱层析得白色固体15，收率71％。
产品物理性质及谱图数据如下：白色固体；mp:193.3℃；1H NMR(400MHz,DMSO-d6)δ8.34(m,1H),7.77(m,1H),7.46(dt,J＝8.8,4.5Hz,2H),7.07(s,1H),6.33(s,2H),5.60(s,2H)；13C NMR(101MHz,DMSO-d6)δ164.83,157.26(d,J＝256.7Hz),146.21,145.70(d,J＝5.3Hz),143.18(d,J＝14.7Hz),125.58(d,J＝3.8Hz),124.09(d,J＝17.9Hz),122.02,45.54；19F NMR(376MHz,DMSO-d6)δ-125.88.
制备实施例16:化合物16的制备
更换相应底物，制备方法同制备实施例1，柱层析得白色固体16，收率74％。
产品物理性质及谱图数据如下：白色固体；mp:177.1℃；1H NMR(400MHz,DMSO-d6)δ8.60(d,J＝1.7Hz,1H),8.39(d,J＝4.8Hz,1H),7.50(s,1H),7.14(s,1H),6.86(t,J＝5.7Hz,1H),6.48(s,2H),5.58(s,2H)；13C NMR(101MHz,DMSO-d6)δ164.64,157.34(d,J＝255.8Hz),146.83(d,J＝5.3Hz),145.78,138.14(d,J＝22.6Hz),132.34(d,J＝12.3Hz),123.26,122.14,42.80；19F NMR(376MHz,DMSO-d6)δ-125.67.
制备实施例17:化合物17的制备
更换相应底物，制备方法同制备实施例1，柱层析得白色固体17，收率72％。
产品物理性质及谱图数据如下：白色固体；mp:172.1℃；1H NMR(400MHz, DMSO-d6)δ7.39(m,2H),7.04(s,1H),6.91(d,J＝8.4Hz,1H),6.85(t,J＝8.5Hz,1H),6.25(s,2H),5.24(s,2H),3.81(s,3H)；13C NMR(101MHz,DMSO-d6)δ164.30,161.25(d,J＝245.5Hz),158.45(d,J＝7.7Hz),144.85,130.70(d,J＝10.6Hz),121.22,110.70(d,J＝17.1Hz),107.71(d,J＝22.0Hz),107.41(d,J＝2.5Hz),56.32,37.43；19F NMR(376MHz,DMSO-d6)δ-116.36.
制备实施例18:化合物18的制备
更换相应底物，制备方法同制备实施例1，柱层析得白色固体18，收率75％。
产品物理性质及谱图数据如下：白色固体；mp:157.4℃；1H NMR(400MHz,DMSO-d6)δ7.52–7.43(m,1H),7.09(m,2H),6.88(dd,J＝12.2,2.5Hz,1H),6.79(dd,J＝8.6,2.5Hz,1H),6.40(s,2H),5.37(s,2H),3.77(s,3H)；13C NMR(101MHz,DMSO-d6)δ164.75,161.08(d,J＝245.9Hz),161.01(d,J＝11.0Hz),145.33,130.90(d,J＝5.8Hz),122.08,115.00(d,J＝15.4Hz),110.87(d,J＝2.9Hz),102.15(d,J＝24.9Hz),56.19,42.91(d,J＝2.9Hz)；19F NMR(376MHz,DMSO-d6)δ-115.13.
制备实施例19:化合物19的制备
更换相应底物，制备方法同制备实施例1，柱层析得白色固体19，收率67％。
产品物理性质及谱图数据如下：白色固体；mp:220.8℃；1H NMR(400MHz,DMSO-d6)δ9.97(s,1H),7.42(s,1H),7.07(s,1H),6.95(t,J＝8.6Hz,1H),6.58(d,J＝10.3Hz,2H),6.34(s,2H),5.30(s,2H)；13C NMR(101MHz,DMSO-d6)δ164.78,161.05(d,J＝245.0Hz),159.37(d,J＝11.5Hz),145.29,130.97(d,J＝5.9Hz),122.08,113.29(d, J＝15.3Hz),112.45–111.32(m),103.11(d,J＝23.4Hz),42.96；19F NMR(376MHz,DMSO-d6)δ-116.08.
制备实施例20:化合物20的制备
更换相应底物，制备方法同制备实施例1，柱层析得白色固体20，收率69％。
产品物理性质及谱图数据如下：白色固体；mp:222.2℃；1H NMR(400MHz,DMSO-d6)δ10.53(d,J＝1.7Hz,1H),7.36(s,1H),7.20(m,1H),7.03(s,1H),6.72(d,J＝8.2Hz,1H),6.70–6.63(m,1H),6.22(s,2H),5.21(s,2H)；13C NMR(101MHz,DMSO-d6)δ164.77,162.28(d,J＝245.5Hz),157.38(d,J＝7.7Hz),145.16,130.77(d,J＝10.7Hz),121.79,111.83,109.83(d,J＝17.2Hz),106.40(d,J＝21.8Hz),38.17；19F NMR(376MHz,DMSO-d6)δ-116.20.
制备实施例21:化合物21的制备
更换相应底物，制备方法同制备实施例1，柱层析得白色固体21，收率71％。
产品物理性质及谱图数据如下：白色固体；mp:185.6℃；1H NMR(400MHz,DMSO-d6)δ7.46(s,1H),7.38(m,1H),7.27–7.14(m,2H),7.10(s,1H),7.00(td,J＝7.7,1.8Hz,1H),6.42(s,2H),5.46(s,2H).13C NMR(101MHz,DMSO-d6)δ164.25,159.83(d,J＝246.1Hz),145.08,130.00(d,J＝8.1Hz),129.20(d,J＝3.9Hz),124.65(d,J＝3.5Hz),122.93(d,J＝14.8Hz),121.59,115.46(d,J＝20.7Hz),42.80(d,J＝4.4Hz)；19F NMR(376MHz,DMSO-d6)δ-117.60.
制备实施例22:化合物22的制备
更换相应底物，制备方法同制备实施例1，柱层析得白色固体22，收率70％。
产品物理性质及谱图数据如下：白色固体；mp:236.1℃；1H NMR(400MHz,DMSO-d6)δ7.83-7.77(m,1H),7.67–7.62(m,2H),7.41(s,1H),7.10(s,1H),6.53(s,2H),5.49(s,2H)；13C NMR(101MHz,DMSO-d6)δ164.69,160.82(d,J＝249.6Hz),145.75,132.24(d,J＝9.3Hz),130.28(d,J＝3.4Hz),126.09(d,J＝18.0Hz),121.79(d,J＝6.6Hz),121.60,116.63(d,J＝3.9Hz),114.63(d,J＝5.4Hz),42.08；19F NMR(376MHz,DMSO-d6)δ-113.31.
制备实施例23:化合物23的制备
更换相应底物，制备方法同制备实施例1，柱层析得白色固体23，收率72％。
产品物理性质及谱图数据如下：白色固体；mp:210.1℃；1H NMR(400MHz,DMSO-d6)δ7.94(d,J＝9.9Hz,1H),7.72(d,J＝8.0Hz,1H),7.51(s,1H),7.15(s,1H),7.09(t,J＝7.7Hz,1H),6.50(s,2H),5.59(s,2H)；13C NMR(101MHz,DMSO-d6)δ164.64,159.73(d,J＝249.3Hz),145.70,130.42(d,J＝4.6Hz),129.82,129.73–129.55(m),122.14,119.92(d,J＝25.0Hz),117.98(d,J＝2.6Hz),112.68(d,J＝9.7Hz),43.34；19F NMR(376MHz,DMSO-d6)δ-114.32.
制备实施例24:化合物24的制备
更换相应底物，制备方法同制备实施例1，柱层析得白色固体24，收率65％。
产品物理性质及谱图数据如下：白色固体；mp:214.8℃；1H NMR(400MHz,DMSO-d6)δ7.57(d,J＝7.1Hz,2H),7.43(s,1H),7.10(s,1H),6.46(s,2H),5.37(s,2H)；13C NMR(101MHz,DMSO-d6)δ164.66,161.25(dd,J＝253.0,8.7Hz),145.45,122.64(t,J＝12.7Hz),121.79,116.72–115.34(m),111.62(t,J＝19.4Hz),37.30；19F NMR(376MHz,DMSO-d6)δ-112.08.
制备实施例25:化合物25的制备
更换相应底物，制备方法同制备实施例1，柱层析得白色固体25，收率67％。
产品物理性质及谱图数据如下：白色固体；mp:217.5℃；1H NMR(400MHz,DMSO-d6)δ7.38(s,1H),7.05(s,1H),6.27(s,2H),6.19(d,J＝10.3Hz,2H),5.85(s,2H),5.14(s,2H)；13C NMR(101MHz,DMSO-d6)δ164.79,162.31(dd,J＝243.5,11.5Hz),151.96(t,J＝14.4Hz),145.07,121.86,97.30(t,J＝20.5Hz),96.58–95.18(m),37.24；19F NMR(376MHz,DMSO-d6)δ-115.83.
制备实施例26:化合物26的制备
更换相应底物，制备方法同制备实施例1，柱层析得白色固体26，收率67％。
产品物理性质及谱图数据如下：白色固体；mp:212.4℃；1H NMR(400MHz,DMSO-d6)δ7.90(d,J＝6.8Hz,2H),7.44(s,1H),7.12(s,1H),6.51(s,2H),5.49(s,2H)；164.64,161.47(dd,J＝249.7,8.6Hz),145.70,130.44,124.66(t,J＝12.7Hz),123.79,115.34-115.07(m),112.63(t,J＝27.5Hz),43.33；19F NMR(376MHz,DMSO-d6)δ-114.52.
制备实施例27:化合物27的制备
更换相应底物，制备方法同制备实施例1，柱层析得白色固体27，收率76％。
产品物理性质及谱图数据如下：白色固体；mp:260.8℃；1H NMR(400MHz,DMSO-d6)δ7.73(d,J＝3.6Hz,1H),7.69(d,J＝5.0Hz,1H),7.60–7.45(m,2H),7.43(s,1H),7.28–7.15(m,1H),7.10(s,1H),6.46(s,2H),5.41(s,2H)；13C NMR(101MHz,DMSO-d6)δ164.71,161.64(dd,J＝248.7,9.0Hz),145.43,140.82,137.25,129.27,128.26,126.69,121.82,110.32(t,J＝19.6Hz),109.55–108.20(m),37.40；19F NMR(376MHz,DMSO-d6)δ-113.47.
制备实施例28:化合物28的制备
更换相应底物，制备方法同制备实施例1，柱层析得白色固体28，收率73％。
产品物理性质及谱图数据如下：白色固体；mp:248.8℃；1H NMR(400MHz,DMSO-d6)δ13.11(s,1H),8.37(s,1H),8.07(s,1H),7.51–7.36(m,3H),7.08(s,1H),6.42(s,2H),5.36(s,2H)；13C NMR(101MHz,DMSO-d6)δ164.73(s),161.86(dd,J ＝248.5,8.8Hz),145.37,137.39,127.32,125.38,121.83,119.73,110.03–106.85(m),37.38；19F NMR(376MHz,DMSO-d6)δ-114.78.
制备实施例29:化合物29的制备
更换相应底物，制备方法同制备实施例1，柱层析得白色固体29，收率56％。
产品物理性质及谱图数据如下：白色固体；mp:215.7℃；1H NMR(400MHz,DMSO-d6)δ7.70(m,1H),7.52(m,1H),7.45–7.35(m,3H),7.08(s,1H),6.51(s,1H),6.48(s,2H),6.34(t,J＝6.7Hz,1H),5.45(s,2H)；13C NMR(101MHz,DMSO-d6)δ164.68,161.26,160.86(dd,J＝248.9,9.1Hz),145.51,142.70,141.51,139.01,121.79,121.12,113.63–110.28(m),108.53,106.42,37.31；19F NMR(376MHz,DMSO-d6)δ-113.15.
制备实施例30:化合物30的制备
更换相应底物，制备方法同制备实施例1，柱层析得白色固体30，收率67％。
产品物理性质及谱图数据如下：白色固体；mp:204.4℃；1H NMR(400MHz,DMSO-d6)δ7.36(s,1H),7.20(dd,J＝9.0,1.8Hz,1H),7.14(s,1H),7.04(s,1H),6.27(s,2H),5.20(s,2H),3.83(s,3H)；13C NMR(101MHz,DMSO-d6)δ164.77,161.61(d,J＝249.6Hz),159.51(d,J＝8.7Hz),145.40,122.96(d,J＝13.4Hz),121.71,111.97,111.71,110.95(d,J＝17.3Hz),57.36,37.71；19F NMR(376MHz,DMSO-d6)δ-112.08.
制备实施例31:化合物31的制备
更换相应底物，制备方法同制备实施例1，柱层析得白色固体31，收率72％。
产品物理性质及谱图数据如下：白色固体；mp:237.1℃；1H NMR(400MHz,DMSO-d6)δ7.53(m,1H),7.47(t,J＝1.2Hz,1H),7.37(s,1H),7.06(s,1H),6.36(s,2H),5.29(s,2H),3.87(s,3H)；13C NMR(101MHz,DMSO-d6)δ164.72,161.24(d,J＝248.0Hz),159.36(d,J＝8.4Hz),145.55,121.67,118.12,117.19(d,J＝16.8Hz),113.29(d,J＝13.3Hz),112.66(d,J＝27.0Hz),112.15,57.60,37.82；19F NMR(376MHz,DMSO-d6)δ-113.61.
制备实施例32:化合物32的制备
更换相应底物，制备方法同制备实施例1，柱层析得白色固体32，收率70％。
产品物理性质及谱图数据如下：白色固体；mp:226.7℃；1H NMR(400MHz,DMSO-d6)δ7.68–7.61(m,2H),7.37(s,1H),7.20–7.14(m,2H),7.12(s,1H),7.05(s,1H),6.28(s,2H),5.24(s,2H),3.90(s,3H)；13C NMR(101MHz,DMSO-d6)δ164.81,162.02(d,J＝245.0Hz),159.29(d,J＝8.7Hz),145.37,142.25,136.81(d,J＝11.7Hz),129.07,127.42,125.95,121.76,110.23(d,J＝17.5Hz),105.30(d,J＝24.2Hz),104.93,57.01,37.87；19F NMR(376MHz,DMSO-d6)δ-113.47.
生物实验实施例：钠离子通道生物活性测定
1.试验动物选择
本实验主要使用6～8周龄雄性C57BL/6野生型(Wild type,WT)小鼠。
2.试剂溶液配置
小分子化合物溶液配置：将小分子化合物分别溶于二甲基亚砜(DMSO,Amresco)溶液中，配置成浓度为10mM母液，实验室利用脑脊液稀释配置为1μM、3μM、10μM、30μM、60μM、100μM等梯度浓度。
脑脊液配方(单位mM)：125NaCl,2.5KCl,2CaCl2,1.25NaH2PO4,1MgCl2,25NaHCO3,10D-glucose，用HCl将PH调至7.4。
电极内液配方(单位mM)：50CsCl,10NaCl,60CsF,2MgCl,3Mg-ATP,20EGTA,10HEPES，和10TEA，用CsOH将PH调至7.2。
3.谷氨酸能神经元上钠离子通道电流记录
小鼠用异氟烷麻醉后，迅速断头取脑，之后将脑组织修片后迅速置于4℃且先前通以95％氧气和二氧化碳混合气饱和的切片液中，之后迅速利用振动切片机将含海马的脑组织切成300μm脑片，并将脑片至于34℃恒温通氧的人工脑脊液中孵育，孵育一小时后，用以进行后续实验。
电生理记录采用全细胞电压钳模式，记录用玻璃微电极由微电极拉制仪拉制，阻抗为6～8MΩ，记录海马CA1的谷氨酸能神经元。本实验主要观察系列小分子化合物对于海马谷氨酸能神经元钠离子通道最大开放电流(INa-Max)幅值的作用。记录INa-Max时，先将记录细胞holding在-70mV,持续300ms，之后立即将Holding电压跃阶至-10mV.，持续15ms，记录钠通道在去极化电压变化情况下的钠电流，即为INa-Max。实验时先记录基线状态的海马谷氨酸能神经元的INa-Max，之后分别灌流给以不同梯度浓度的化合物，考察化合物对INa-Max幅度的抑制作用。将能有效抑制钠电流的化合物(抑制率大于20％)进行第二轮IC50测定。对第一轮筛选有效的化合物分别设置1μM、3μM、10μM、30μM、100μM浓度梯度，筛选对钠通道作用的IC50，根据各个浓度下化合物的抑制效率(给药前后INa-Max的幅度差值除以基础状态下的INa-Max幅度)，绘制浓度药效曲线，并计算IC50值。
第一轮筛选结果如下表：
在此基础上，测定化合物1、2、3、7、11、14、15、22、26对钠离子通道抑制的IC50值，从实验结果看，这些化合物对钠离子通道都具有良好的抑制活性，参见图1和下表。
动物实验实施例1：戊四唑急性癫痫发作模型(PTZ)
测定优选化合物1和2对戊四唑急性癫痫发作模型(PTZ)的作用：采用成年雄性ICR小鼠，体重25-30g。将小鼠按照体重随机分组：溶剂组、Rufinamide阳性对照组、VPA阳性对照组以及不同化合物组(Rufinamide及候选化合物为50mg/kg,VPA为300mg/kg)，每组5-6例ICR雄鼠。实验时分别灌胃给以溶剂或药物，1h后腹腔注射100mg/kg PTZ，之后立即开始观察并记录小鼠的癫痫发作情况，观察时间为30分钟。行为学评价分级标准为：0级：无明显反应；1级：失神呆滞，耳朵和面部抽动；2级：全身抽动，无前肢抬起；3级：一侧或双侧前肢抬起；4级：一侧身体侧倒伴抽搐；5级：背部着地倒地，或全身强直阵挛发作；6级：强直后死亡。记录各小鼠癫痫发作的等级(图2a)、从给药开始到2级发作潜时(图2b)、4级发作潜时(图2c)、6级发作潜时(图2d)以及小鼠存活率(图2e)。从实验结果看，化合物1、2展示了良好的抗癫痫药效，优于Rufinamide(卢非酰胺)。
动物实验实施例2：最大电休克模型(MES)
优选化合物1和2对最大电休克癫痫发作模型的作用：采用成年雄性ICR小鼠，体重25-30g。将小鼠按照体重随机分组：溶剂组、Rufinamide阳性对照组、VPA阳性对照组以及不同化合物组(Rufinamide及候选化合物为50mg/kg,VPA为300mg/kg)，每组5-6例ICR雄鼠。实验时分别灌胃给以溶剂或药物，0.5h后将最大电休克仪的刺激夹以生理盐水浸湿后，分别夹住小鼠两耳耳廓，给以电刺激，刺激频率为50Hz,刺激持续时间为0.2s，刺激电流强度为25mA。小鼠行为学评定等级：1级：跑动；2级：前肢强直；3级：后肢强直。记录小鼠在此模型中最大发作等级(图3a)、强直强直阵挛发作持续时间(图3b)以及小鼠存活率(图3c)。从实验结果看，化合物1、2展示了良好的抗癫痫药效，优于Rufinamide(卢非酰胺)。
动物实验实施例3：拉莫三嗪耐药模型(LTG)
1.耐拉莫三嗪海马电点燃难治性癫痫模型造模：
实验动物选择：
本实验主要使用2～4月龄成年雄性C57BL/6野生型(Wild type,WT)小鼠。
1.1.手术
1.1.1.麻醉
腹腔注射1％戊巴比妥钠(60mg/kg)麻醉小鼠。
1.1.2.定位
将其固定于立体定位仪上，剔除小鼠头部毛发，碘伏消毒后剪开头皮，暴露颅骨后用极少量3％双氧水擦拭，暴露前后囟，并用棉花将残留的双氧水擦干。调节立体定位仪定位前后囟高度，通过调试鼻夹使两者处于同一水平面，高度差不超过0.2mm。根据小鼠脑图谱，以前囟为原点定位目标核团，在颅骨相应位置用牙科钻钻孔。
1.1.3.电极植入
在颅骨表面分散植入四个螺钉增加颅骨粘合力，其中一个螺钉要植于感觉运动皮层记录皮层脑电，一个螺钉要植于小脑连接参考电极，颅骨远离骨缝的两侧各打一个孔仅用于固定。用于给予电刺激诱发癫痫发作和脑电记录的双螺旋电极定向植入到右侧腹侧海马CA3，双螺旋电极由双股聚四氟乙烯覆盖的不锈钢电线绕成，将末端0.5mm刮掉绝缘层，顶端分开的距离最大不超过0.5mm，电极植入速度不宜过快(50～100μm/min)，植入电极后用牙科水泥进行固定，待水泥完全干后，解螺旋并用镊子除去电极外侧绝缘层。
将电极通过焊锡与微型插座连接，并用医用牙科水泥固定。
1.2.脑电记录及阈值测定
用Neuroscan系统记录脑电，并用电刺激器刺激电流(单向方波脉冲，20Hz，1ms/pulse，持续时间为2s)从40μA开始，每隔1min增加20μA，直到诱发出至少5s的后放电时间(afterdischarge duration,ADD)为止。此时的电流强度即被定义为该动物的ADT，用于分组。
1.3.电点燃刺激及癫痫等级评价标准
快速电点燃参数：1ms方波脉冲、20Hz刺激频率、400μA阈上刺激强度、2s持续时间。点燃前腹腔给予5mg/kg亚惊厥剂量的拉莫三嗪，休息30min后给予一次电刺激，半小时后再给予一次电刺激。上诉过程每天重复3次，每天6次电刺激，直至完全点燃。行为学的严重程度根据Racine等级分类法进行判断，1级：面部抽搐；2级：点头；3级：单侧前肢阵挛发作；4级：双侧前肢阵挛发作；5级：双侧前肢阵挛发作伴随失衡倒地。通常发作等级1-3级被认为是FS，而等级4-5级被认为是GS。3次连续5级发作的动物，被认为完全点燃。
2.拉莫三嗪耐药模型药效评价
完全点燃的动物休息半小时后，分别腹腔给予急性治疗剂量的拉莫三嗪、左乙拉西坦、丙戊酸以及不同剂量梯度的优选化合物，给药半小时后进行电刺激，记录脑电并开展行为学严重程度的判断。药效测定进行三次，将给药后发作等级降低到3级及以下定义为有效，4-5级为无效。并且测定了优选化合物对发作等级的作用，等级抑制率为给药前发作等级减去给药后发作等级除以给药前发作等级。参见图4，从实验结果看，化合物1、2、11在该耐药模型中依然展示了良好的抗癫痫药效。
此外，在拉莫三嗪耐药模型的灌胃给药实验中，化合物1、2、11都展现了良好的抗癫痫药效；在200mg/kg给药剂量下，可以显著降低癫痫发作等级，治疗有效率高。实验结果见图5所示。
动物实验实施例4:安全性评价
评价化合物的安全性：对化合物1、2的安全性进行评价，采用成年雄性ICR小鼠，体重25-30g。将小鼠按照体重随机分组，分为给药组和空白组，每组5-6例ICR雄鼠。实验时分别灌胃给以溶剂或药物，连续给药三周，给药剂量为100mg/kg，考察小鼠体重变化(图6a)、运动能力(图6b-图6e)和血常规指标(图6f-图6k)。实验结果显示，化合物1、2在100mg/kg剂量连续给药下，对小鼠的体重增长和运动能力没有损伤，血常规各项指标也在正常范围内，表明化合物1、2具有良好的安全性。
此外应理解，在阅读了本发明的上述描述内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (10)

  1. 5-氨基-1-烷基-1H-1,2,3-三氮唑-4-甲酰胺类化合物、其药学上可接受的盐，或其外消旋混合物、水合物、溶剂合物、前药、对映异构体、非对映异构体、互变异构体，其特征在于，所述的5-氨基-1-烷基-1H-1,2,3-三氮唑-4-甲酰胺类化合物具有如下式(1)所示结构通式：
    式(1)中：
    R1为取代或未取代的芳环，所述的芳环为苯环或芳香杂环，所述芳环上的取代基包含氟原子，并独立地选自卤素、硝基、氨基、羟基、氰基、烷氧基、巯基、羧基、酯基、取代或未取代的C1-6烷基、取代或未取代的C1-6环烷基、取代或未取代的C1-6杂环烷基、取代或未取代的C4-10芳基、取代或未取代的C1-8杂芳基、C2-10烯基、C2-10炔基、烷基单取代胺基、烷基双取代胺基、烷氧基、烷基羰氧基、环烷基羰氧基、杂芳基羰氧基、烷氧基羰基、环烷氧基羰基、杂芳氧基羰基、烷基羰胺基、环烷基羰胺基、杂芳基羰胺基、胺基羰基、烷氧甲酰胺基、烷巯基、羟基烷氧基、糖残基、磺酸基、磷酸基、多羟基烷氧基羰基、羧基烷氧基、羧基烷基甲酰氧基中的一个或多个；
    R2和R3相同或不同，各自独立地选自氢、取代或未取代的C1～C4烷基、取代或未取代的苯基，所述C1～C4烷基上的取代基为甲氧酰基、羟基；或者R2、R3与连接R2和R3的N形成六元环，所述六元环中含有N、C和O。
  2. 5-氨基-1-烷基-1H-1,2,3-三氮唑-4-甲酰胺类化合物、其药学上可接受的盐，或其外消旋混合物、水合物、溶剂合物、前药、对映异构体、非对映异构体、互变异构体，其特征在于，所述的5-氨基-1-烷基-1H-1,2,3-三氮唑-4-甲酰胺类化合物具有如下式(2)所示结构通式：
    式(2)中：
    表示苯环或吡啶环；
    R1表示所述苯环或吡啶环上的一个或多个取代基，分别独立选自H、卤素、C1～C6烷氧基、羟基、氰基、氨基、噻吩基、吡唑基、吡啶啉酮中的一个或多个；
    R2和R3分别独立选自氢、取代或未取代的C1～C4烷基、C3～C6环烷基、苯基，所述C1～C4烷基上的取代基为苯基、酯基、羟基中的一个或多个；或者R2、R3与连接R2和R3的N形成取代或未取代的六元环，所述六元环由N、C连接组成或由N、C和O连接组成，所述六元环上的取代基为C1～C4烷基。
  3. 根据权利要求2所述的5-氨基-1-烷基-1H-1,2,3-三氮唑-4-甲酰胺类化合物、其药学上可接受的盐，或其外消旋混合物、水合物、溶剂合物、前药、对映异构体、非对映异构体、互变异构体，其特征在于，所述的5-氨基-1-烷基-1H-1,2,3-三氮唑-4-甲酰胺类化合物选自以下化合物1-32中的任一种：


  4. 根据权利要求3所述的5-氨基-1-烷基-1H-1,2,3-三氮唑-4-甲酰胺类化合物的制备方法，其特征在于，采用反应路线I合成化合物1-32；
    反应路线I包括以下过程：
    氰基乙酸乙酯A与苄基叠氮类化合物B在DMF中，NaH作碱的情况下，反应生成取代5-氨基-1-烷基-1H-1,2,3-三氮唑-4-甲酸酯类化合物C，然后在NaOH作用下水解、酸化生成羧酸类化合物D，接着在缩合试剂HATU的促进下，与胺类化合物E发生缩合反应，生成目标化合物1-32。
  5. 一种药物组合物，其特征在于，包含可药用的载体、辅料中的至少一种，以及权利要求1～3任一项所述的5-氨基-1-烷基-1H-1,2,3-三氮唑-4-甲酰胺类化合物、其药学上可接受的盐、或其外消旋混合物、水合物、溶剂合物、前药、对映异构体、非对映异构体、互变异构体。
  6. 根据权利要求1～3任一项所述的5-氨基-1-烷基-1H-1,2,3-三氮唑-4-甲酰胺类化合物、其药学上可接受的盐，或其外消旋混合物、水合物、溶剂合物、前药、对映异构体、非对映异构体、互变异构体，或根据权利要求5所述的药物组合物在制备离子通道阻滞剂中的应用。
  7. 根据权利要求1～3任一项所述的5-氨基-1-烷基-1H-1,2,3-三氮唑-4-甲酰胺类化合物、其药学上可接受的盐，或其外消旋混合物、水合物、溶剂合物、前药、对映异构体、非对映异构体、互变异构体，或根据权利要求5所述的药物组合物在制备用于治疗离子通道相关的疾病的药剂中的应用，其特征在于，所述疾病包括中枢神经系统疾病、炎症性疾病、自身免疫性疾病、癌症、感染性疾病、心脑血管疾病。
  8. 根据权利要求6或7所述的应用，其特征在于，所述离子通道为钠离子通道。
  9. 根据权利要求7所述的应用，其特征在于，所述的中枢神经系统疾病为癫痫、帕金森、阿兹海默症、焦虑症、抑郁症、精神分裂症；
    所述的炎症性疾病、自身免疫性疾病为类风湿性关节炎、慢性阻塞性肺病、变应性鼻炎、哮喘、红斑狼疮、银屑病和多发性硬化；
    所述的癌症为实体瘤或血液系统恶性肿瘤，其选自白血病、多发性骨髓瘤、淋巴瘤；所述的白血病为急性淋巴细胞白血病、急性髓性白血病、慢性淋巴细胞白血病和慢性髓性白血病；所述的淋巴瘤为霍奇金淋巴瘤、非霍奇金淋巴瘤、套细胞淋巴瘤、滤泡型淋巴瘤、B细胞淋巴瘤、T细胞淋巴瘤、弥散性大B细胞淋巴瘤；
    所述的感染性疾病为细菌性感染、真菌性感染、病毒性感染、寄生虫感染；
    所述的心脑血管疾病为急性心力衰竭、低血压、高血压、心绞痛、心肌梗塞、心肌病、充血性心力衰竭、动脉粥样硬化、冠心病、再狭窄和血管狭窄，以及外伤性脑损伤、中风、缺血再灌注损伤。
  10. 根据权利要求1～3任一项所述的5-氨基-1-烷基-1H-1,2,3-三氮唑-4-甲酰胺类 化合物、其药学上可接受的盐，或其外消旋混合物、水合物、溶剂合物、前药、对映异构体、非对映异构体、互变异构体，或根据权利要求5所述的药物组合物在制备麻醉剂中的应用。
PCT/CN2024/097787 2023-07-06 2024-06-06 5-氨基-1-烷基-1h-1,2,3-三氮唑-4-甲酰胺类化合物及其制备和应用 Ceased WO2025007697A1 (zh)

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