CN113045487A - Selective sodium channel regulator and preparation and application thereof - Google Patents

Selective sodium channel regulator and preparation and application thereof Download PDF

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Publication number
CN113045487A
CN113045487A CN202011580854.3A CN202011580854A CN113045487A CN 113045487 A CN113045487 A CN 113045487A CN 202011580854 A CN202011580854 A CN 202011580854A CN 113045487 A CN113045487 A CN 113045487A
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substituted
unsubstituted
pain
compound
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李傲
姚元山
P·K·贾达夫
曹国庆
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Minghui Pharmaceutical Hangzhou Co ltd
Minghui Pharmaceutical Shanghai Co ltd
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Minghui Pharmaceutical Hangzhou Co ltd
Minghui Pharmaceutical Shanghai Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/14—Antitussive agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics

Abstract

The invention provides a compound as a selective sodium channel regulator and a synthesis and use method thereof, and particularly provides a compound as shown in a formula (I), a preparation method thereof and application thereof as the selective sodium channel regulator. The compounds exhibit excellent activity as sodium channel modulators.

Description

Selective sodium channel regulator and preparation and application thereof
Technical Field
The invention relates to a compound as a selective sodium channel regulator, an isomer, a solvate, a salt of the compound, a medicament taking the compound or the salt as an active ingredient, and application thereof in medicaments for treating and/or preventing target diseases related to sodium channel regulation, such as pain.
Background
Pain is a protective mechanism that protects healthy animals from tissue damage and prevents further damage to the damaged tissue. Nevertheless, there are many cases where pain persists beyond its usefulness, or where patients would benefit from pain suppression.
Neuropathic pain is a form of chronic pain caused by injury to sensory nerves, and can be divided into two categories, pain caused by injury to nerve metabolism and pain caused by injury to nerve continuity. Metabolic injury pain indications include post-herpetic neuropathy, diabetic neuropathy and drug-induced neuropathy. The pain indications caused by the continuous damage of the nerve comprise nerve entrapment injuries such as amputation pain, postoperative nerve injury pain and neuropathic back pain.
Voltage-gated sodium channels (Nav's) are involved in pain signaling. Nav are biological mediators of electrical signal transduction because they mediate the rapid ascending of action potentials of many excitable cell types (e.g., neurons, skeletal muscle cells, cardiac muscle cells). The role of these channels in normal physiology, pathological states caused by mutations in the sodium channel genes, preclinical work in animal models, and evidence of the clinical pharmacology of known sodium channel modulators suggest a central role for Nav's in pain perception. Nav's mediate the rapid upward movement of action potentials of many excitable cell types (e.g., neurons, skeletal muscle cells, cardiac muscle cells) and are therefore involved in the initiation of signaling in these cells. Antagonists that reduce Nav's current may prevent or reduce neural signals due to the role of Nav's in the initiation and propagation of neuronal signals, and Nav's are considered a possible target for pain relief where hyperexcitability is observed. Several clinically useful analgesics have been identified as inhibitors of Nav's. Local anesthetics such as lidocaine block pain by inhibiting Nav channels, and other compounds such as carbamazepine, lamotrigine and tricyclic antidepressants have been shown to be effective in relieving pain by sodium channel inhibition.
Nav's form voltage-gated ion channel superfamily subfamily, and contain 9 isoforms, named Nav1.1-Nav1.9. The tissue localization of the nine isoforms varied. Nav1.4 is skeletal muscle of the main sodium channel, Nav1.5 is myocardial cells of the main sodium channel. Nav 1.7, 1.8 and 1.9 mainly located in the peripheral nervous system, while Nay 1.1, 1.2, 1.3 and 1.6 is central and peripheral nervous system found in the neural channel. The functional behavior of the nine isoforms is similar, but differs in specific aspects of voltage-dependent and kinetic behavior.
The Nav1.8 channel is determined as a possible target for analgesia, and is proved to be a carrier of sodium current, maintains action potential emission of neurons in small dorsal root ganglia, and also participates in spontaneous signal emission of damaged neurons, such as driving neuropathic pain and the like. A major drawback of some known Nav's inhibitors is their poor therapeutic window, which may be the result of their lack of isoform selectivity. Since Navl.8 is primarily restricted to pain-sensing neurons, selective Nav1.8 blockers are unlikely to induce the adverse effects common to non-selective Nav's blockers. Therefore, the field still needs to develop new Nav1.8 selective inhibitors.
Disclosure of Invention
The invention aims to provide a Nav1.8 selective inhibitor.
In a first aspect of the present invention, there is provided a compound represented by the following formula (I), and isomers, solvates or pharmaceutically acceptable salts thereof:
Figure BDA0002865208870000021
l is selected from the group consisting of: s (O)p，O，NR5CO or C (R)6)R7；
Cyc is selected from: 5-6 membered heteroaryl, the heteroatoms of which are independently selected from O, N or S (O)p；
R1Selected from the group consisting of: hydrogen, deuterium, ═ O, halogen, CHF2，CF3，CD3，OCF3，OCH3，OCD3Cyano, nitro, hydroxy, amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, 1 or 2 nonadjacent carbon atoms being replaced by O or NR5An alternative C1-C6 alkyl group, a substituted or unsubstituted C3-C6 cycloalkyl group, a substituted or unsubstituted C4-C6 heterocyclyl group, said heteroatoms independently selected from O, N or S (O)p(ii) a Or two adjacent R1And the atoms to which they are attached form a substituted or unsubstituted 5-6 membered carbocyclic or heterocyclic ring;
R2selected from the group consisting of: 0 to 4R1Substituted C3-C6 cycloalkyl, 0-4R1Substituted C4-C6 heterocyclyl, 0-4R1Substituted 6-10 membered aryl, 0-4R1Substituted 5-10 membered heteroaryl; wherein two adjacent R are1May form a 5-to 6-membered carbocyclic or heterocyclic ring together with the ring atoms to which they are attached;
R4selected from the group consisting of: hydrogen, deuterium, halogen, hydroxy, amino, cyano, substituted or unsubstituted C1-C4 alkyl, 1 or 2 non-adjacent carbon atoms being replaced by O or NR5Substituted C1-C4 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstitutedUnsubstituted C4-C6 heterocyclyl, said heteroatoms being independently selected from O, N or S (O)p；
n is selected from the group consisting of: 0, 1,2,3 or 4;
p is selected from the group consisting of: 0, 1 or 2;
R5selected from the group consisting of: hydrogen, substituted or unsubstituted C1-C6 alkyl, C1-C6 alkyl wherein 1 or 2 non-adjacent carbon atoms are replaced by O or NH, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C4-C6 heterocyclyl, said heteroatoms being independently selected from O, N or S (O)p；
R6And R7Each independently selected from: hydrogen, substituted or unsubstituted C1-C4 alkyl, 1 or 2 non-adjacent carbon atoms being replaced by O or NR5An alternative C1-C4 alkyl group, a substituted or unsubstituted C3-C6 cycloalkyl group, a substituted or unsubstituted C4-C6 heterocyclyl group, said heteroatoms independently selected from O, N or S (O)p(ii) a Or R6And R7A carbocyclic ring having C3-C6 atoms or a heterocyclic ring having C4-C6 atoms attached thereto;
unless otherwise specified, "substituted" means substituted with one or more (e.g., 2,3, 4, etc.) substituents selected from the group consisting of: halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, halogenated C3-C8 cycloalkyl, oxo, -CN, hydroxy, amino, carboxy, amide, sulfonamide, sulfone; a group selected from the group consisting of unsubstituted or substituted with one or more substituents: a C6-C10 aryl group, a halogenated C6-C10 aryl group, a 5-10 membered heteroaryl group having 1-3 heteroatoms selected from N, S and O, a halogenated 5-10 membered heterocyclyl group having 1-3 heteroatoms selected from N, S and O, and said substituents are selected from the group consisting of: halogen, C1-C6 alkyl, C1-C6 alkoxy, ═ O.
In another preferred embodiment, R4Selected from the group consisting of: hydrogen, halogen, hydroxy, substituted or unsubstituted C1-C4 alkyl.
In another preferred embodiment, R is1Selected from the group consisting of: hydrogen, deuterium, halogen, CF3，CD3，OCF3，OCH3，OCD3，CN。
In another preferred embodiment, theR is as described2Selected from the group consisting of: phenyl, pyridyl, pyrimidinyl, pyrazinyl; wherein, R is2May also be substituted by one or more R1And (4) substitution.
In another preferred embodiment, R is5Selected from the group consisting of: hydrogen, unsubstituted or halogenated C1-C6 alkyl, C1-C6 alkyl in which 1 or 2 nonadjacent carbon atoms are replaced by O or NH.
In another preferred embodiment, R is6And R7Each independently selected from: hydrogen, substituted or unsubstituted C1-C4 alkyl, 1 or 2 non-adjacent carbon atoms being replaced by O or NR5An alternative C1-C4 alkyl, substituted or unsubstituted C3-C6 cycloalkyl.
In another preferred embodiment, R is8Selected from: hydrogen, substituted or unsubstituted C1-C4 alkyl.
In another preferred embodiment, the compound of formula (I) has the structure shown in formula (II) below:
Figure BDA0002865208870000041
wherein G is N or N+-O-，
In another preferred embodiment, the compound of formula (I) has the structure shown below:
Figure BDA0002865208870000042
in another preferred embodiment, L is O.
In another preferred embodiment, the compound has the structure shown in the following formula (III):
Figure BDA0002865208870000051
in another preferred embodiment, the compound of formula (I) has the structure shown below:
Figure BDA0002865208870000052
wherein Ra, Rb, Rc and Rd are independently selected from the following groups: hydrogen, deuterium, halogen, CHF2，CF3，CD3，OCF3，OCH3，OCD3Cyano, nitro, hydroxy, amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, 1 or 2 nonadjacent carbon atoms being replaced by O or NR5An alternative C1-C6 alkyl group, a substituted or unsubstituted C3-C6 cycloalkyl group, a substituted or unsubstituted C4-C6 heterocyclyl group, said heteroatoms independently selected from O, N or S (O)p。
In another preferred embodiment, Ra, Rb, Rc and Rd are each independently selected from the group consisting of: hydrogen, deuterium, halogen, CF3，CD3，OCF3，OCH3，OCD3，CN。
In another preferred embodiment, the compound is selected from the group consisting of:
Figure BDA0002865208870000053
Figure BDA0002865208870000061
Figure BDA0002865208870000071
in a second aspect of the invention, there is provided a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound, isomer, solvate or pharmaceutically acceptable salt or hydrate thereof according to the first aspect of the invention.
In another preferred embodiment, the pharmaceutical composition is used in a method of treating, ameliorating or preventing a disease or disorder associated with sodium channel modulation; preferably, the disease or condition is pain.
In another preferred embodiment, the pain or disease is selected from the group consisting of: chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, post-operative pain, visceral pain, multiple sclerosis, peroneal muscular atrophy (Charcot-Marie-Tooth syndrome), incontinence, pathological cough, or cardiac arrhythmia.
In another preferred embodiment, the treatment comprises reducing the severity of pain in the patient.
In another preferred embodiment, the neuropathic pain comprises post-herpetic neuralgia.
In another preferred embodiment, the neuropathic pain comprises idiopathic small-fiber neuropathy.
In another preferred embodiment, the musculoskeletal pain comprises osteoarthritis pain.
In another preferred embodiment, the acute pain comprises acute post-operative pain.
In another preferred embodiment, the post-operative pain comprises a bunion removal pain or an abdominoplasty pain.
In a third aspect of the invention, there is provided a use of a compound of the first aspect of the invention, or a pharmaceutically acceptable salt or hydrate thereof, for the manufacture of a pharmaceutical composition for the treatment, alleviation or prevention of a disease associated with sodium channel modulation; preferably, the disease or condition is pain.
In another preferred embodiment, the pain or disease is selected from the group consisting of: chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, post-operative pain, visceral pain, multiple sclerosis, peroneal muscular atrophy (Charcot-Marie-Tooth syndrome), incontinence, pathological cough, or cardiac arrhythmia.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.
Detailed Description
The present inventors have conducted extensive and intensive studies for a long time and have unexpectedly found a compound represented by the formula (I). The compounds have unexpected activity in modulating cytokines and/or interferons and are useful in the treatment of diseases mediated by cytokines and/or interferons. The compounds have unexpected activity on Nav1.8 and excellent selectivity on other Navs subtypes, and can be used for treating, relieving or preventing Nav 1.8-related diseases. Based on the above findings, the inventors have completed the present invention.
Definition of
As used herein, the term "alkyl" includes straight or branched chain alkyl groups. E.g. C1-C4Alkyl represents a straight or branched chain alkyl group having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, and the like.
As used herein, the term "C3-C8Cycloalkyl "refers to cycloalkyl groups having 3 to 8 carbon atoms. It may be a single ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or the like. Also bicyclic, e.g., bridged, fused or spiro forms.
As used herein, the term "C6-C10Aryl "means an aryl group having 6 to 10 carbon atoms, for example, phenyl or naphthyl and the like.
As used herein, the term "5-10 membered heteroaryl having 1-3 heteroatoms selected from the group consisting of N, S and O" refers to a cyclic aromatic group having 5-10 atoms and wherein 1-3 atoms are heteroatoms selected from the group consisting of N, S and O. It may be a single ring or a condensed ring form. Specific examples may be pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3) -triazolyl and (1,2,4) -triazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl and the like.
Unless specifically stated to be "substituted or unsubstituted", the groups of the present invention may be selected fromSubstituted with a substituent of group (d): halogen, nitrile group, nitro group, hydroxyl group, amino group, C1-C6Alkyl-amino, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Alkoxy, halo C1-C6Alkyl, halo C2-C6Alkenyl, halo C2-C6Alkynyl, halo C1-C6Alkoxy, allyl, benzyl, C6-C12Aryl radical, C1-C6alkoxy-C1-C6Alkyl radical, C1-C6Alkoxy-carbonyl, phenoxycarbonyl, C2-C6Alkynyl-carbonyl, C2-C6Alkenyl-carbonyl, C3-C6Cycloalkyl-carbonyl, C1-C6Alkyl-sulfonyl, and the like.
As used herein, "halogen" or "halogen atom" refers to F, Cl, Br, and I. More preferably, the halogen or halogen atom is selected from F, Cl and Br. "halogenated" means substituted with an atom selected from F, Cl, Br, and I.
Unless otherwise specified, the structural formulae depicted herein are intended to include all isomeric forms (e.g., enantiomers, diastereomers and geometric isomers (or conformational isomers)): for example, R, S configuration containing an asymmetric center, (Z), (E) isomers of double bonds, and the like. Thus, individual stereochemical isomers of the compounds of the present invention or mixtures of enantiomers, diastereomers or geometric isomers (or conformers) thereof are within the scope of the present invention.
As used herein, the term "hydrate" refers to a complex formed by the coordination of a compound of the present invention with water.
The compounds of the present application may be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combinations of the specific embodiments with other chemical synthetic methods, and equivalents known to those skilled in the art, with preferred embodiments including, but not limited to, the examples of the present application.
This applicationThe solvents used are commercially available. Abbreviations used in this application are as follows: aq represents an aqueous solution; HATU represents O- (7-azabenzotriazol-1-yl) -N, N' -tetramethyluronium hexafluorophosphate; EDC stands for N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride; m-CPBA represents 3-chloroperoxybenzoic acid; eq represents equivalent, equivalent; CDI represents carbonyldiimidazole; DCM represents dichloromethane; PE represents petroleum ether; DIAD represents diisopropyl azodicarboxylate; DMF represents N, N-dimethylformamide; DMSO represents dimethyl sulfoxide; EtOAc for ethyl acetate; EtOH stands for ethanol; MeOH represents methanol; cbz represents benzyloxycarbonyl, an amino protecting group; boc represents tert-butyloxycarbonyl, an amino protecting group; HOAc represents acetic acid; NaCNBH3Represents sodium cyanoborohydride; r.t. represents room temperature; THF represents tetrahydrofuran; TFA represents trifluoroacetic acid; DIPEA stands for diisopropylethylamine; boc2O represents di-tert-butyl dicarbonate; LDA stands for lithium diisopropylamide.
The compound is artificially synthesized or
Figure BDA0002865208870000101
The software names, and the commercial compounds are under the supplier catalog name.
Pharmaceutical compositions and methods of administration
Since the compound of the present invention has excellent activity as a sodium channel modulator, the compound of the present invention and various crystalline forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates thereof, and a pharmaceutical composition containing the compound of the present invention as a main active ingredient can be used for the prevention and/or treatment (stabilization, alleviation or cure) of a disease or disorder associated with a sodium channel, such as pain and the like.
The pharmaceutical compositions of the present invention comprise a safe and effective amount of a compound of the present invention in combination with a pharmaceutically acceptable excipient or carrier. Wherein "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000mg of a compound of the invention per dose, more preferably, 1-200mg of a compound of the invention per dose. Preferably, said "dose" is a capsule or tablet.
"pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. By "compatible" is meant herein that the components of the composition are capable of intermixing with and with the compounds of the present invention without significantly diminishing the efficacy of the compounds. Examples of pharmaceutically acceptable carrier moieties are cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), and the like
Figure BDA0002865208870000102
) Wetting agents (e.g., sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.
The mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, parenteral (intravenous, intramuscular, subcutaneous or topical).
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, for example, glycerol; (d) disintegrating agents, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) absorption accelerators, e.g., quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glycerol monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.
Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shells such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be delayed in release in a certain part of the digestive tract. Examples of embedding components which can be used are polymeric substances and wax-like substances. If desired, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly employed in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of such materials and the like.
In addition to these inert diluents, the compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols and suitable mixtures thereof.
The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable therapeutic agents.
When administered in combination, the pharmaceutical composition further comprises one or more (2, 3, 4, or more) other pharmaceutically acceptable therapeutic agents. One or more (2, 3, 4, or more) of such other pharmaceutically acceptable therapeutic agents may be used simultaneously, separately or sequentially with a compound of the invention for the prevention and/or treatment of cytokine and/or interferon mediated diseases.
When the pharmaceutical composition is used, a safe and effective amount of the compound of the present invention is suitable for mammals (such as human beings) to be treated, wherein the administration dose is a pharmaceutically-considered effective administration dose, and for a human body with a weight of 60kg, the daily administration dose is usually 1 to 2000mg, preferably 1 to 500 mg. Of course, the particular dosage will depend upon such factors as the route of administration, the health of the patient, and the like, and is within the skill of the skilled practitioner.
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 which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are by weight.
Examples
Example 1
Figure BDA0002865208870000121
Figure BDA0002865208870000131
First step of
Compound 1a (10.00g, 38.90mmol) and potassium carbonate (16.10g, 116.72mmol) were dissolved in N, N-dimethylformamide (100mL) under nitrogen, and methyl iodide (8.30g, 58.35mmol) was added and the reaction was carried out at room temperature for 2 hours. After the reaction was completed, water (50mL) was added to quench the reaction, ethyl acetate (50mL) was added, the mixture was separated, the aqueous phase was extracted with ethyl acetate (30mL × 3), the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 1b (12.00g) in yield: 99 percent.
1H NMR(400MHz,DMSO-d6)δ7.66(dd,J＝8.7,0.4Hz,1H),7.10(d,J＝2.6Hz,1H),6.91–6.84(m,1H),3.85(s,3H).
Second step of
To a solution of compound 1b (12.00g, 44.28mmol) in tetrahydrofuran (100mL) was slowly added dropwise a solution of n-butyllithium in tetrahydrofuran (2.5M, 20mL, 0.50mmol) at-78 deg.C under nitrogen. Stirring was continued for 30 minutes after the addition was complete. Triisopropyl borate (11.66g, 62.00mmol) was added dropwise to the above reaction solution at-78 ℃ and reacted at this temperature for 2 hours. After the reaction was completed, the pH was adjusted to 4 to 5 with 1N diluted hydrochloric acid (60mL), ethyl acetate (50mL) was added, liquid separation was performed, the aqueous phase was extracted with ethyl acetate (30mLx 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude product 1c (6.00g), yield: 42 percent.
1H NMR(400MHz,CDCl3)δ7.85(d,J＝8.2Hz,1H),6.88(d,J＝8.2Hz,1H),6.72(s,1H),5.78(s,2H),3.93(s,3H).
The third step
To a solution of compound 1c (6.00g, 25.53mmol), sodium hydroxide (1.50g, 38.30mmol), sodium bicarbonate (21.40g, 255.32mmol), acetone (100mL) and ethylenediaminetetraacetic acid (745mg, 2.60mmol) in water (100mL) at 0 deg.C was added oxone complex salt (18.17g, 28.10mmol), which was then warmed to room temperature and stirred for 2 hours. After the reaction was completed, the pH was adjusted to acidity with 2N diluted hydrochloric acid (180mL), ethyl acetate (100mL) was added for liquid separation, the aqueous phase was extracted with ethyl acetate (50mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (ethyl acetate: petroleum ether ═ 0-100%) to obtain 1d (2.30g), yield: 43 percent
1H NMR(400MHz,CDCl3)δ6.87(d,J＝8.4Hz,1H),6.73(d,J＝10.4Hz,2H),3.88(d,J＝0.6Hz,3H).
The fourth step
To a solution of compound 1e (5.00g, 27.31mmol) in anhydrous tetrahydrofuran (50mL) under nitrogen protection at-78 deg.C was slowly added dropwise a solution of lithium diisopropylamide (2.0M, 15mL, 30.00mmol) in tetrahydrofuran, and after the addition was complete, stirring was continued at-78 deg.C for 30 minutes. A solution of ethyl chloroformate (3.84g, 35.38mmol) in dry tetrahydrofuran (10mL) was added dropwise slowly to the above reaction mixture. After the dropwise addition, the obtained reaction solution was stirred at-78 ℃ for 40 minutes, naturally warmed to room temperature, and reacted for 1 hour. After the reaction was completed, the reaction was quenched with a saturated ammonium chloride solution (50mL), extracted with ethyl acetate (50mL × 3), the organic phases were combined, washed with a saturated saline solution (30mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (ethyl acetate: petroleum ether ═ 0 to 100%) to obtain 1f (3.10g), yield: 45 percent.
1H NMR(400MHz,DMSO-d6)δ8.86(s,1H),4.42(d,J＝7.1Hz,2H),1.30(t,J＝7.1Hz,3H).
The fifth step
To a solution of 1f (340mg, 1.35mmol) and 1d (280mg, 1.35mmol) in N, N-dimethylformamide (10mL) was added cesium carbonate (877mg, 2.69mmol) at 0 deg.C under nitrogen. The reaction was carried out at 0 ℃ for 1.5 hours, and then allowed to spontaneously rise to room temperature. After completion of the reaction, water (20mL) and ethyl acetate (30mL) were added, liquid separation was performed, ethyl acetate (30mL × 3) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (ethyl acetate: petroleum ether ═ 0 to 100%) to obtain 1g (300mg) with yield: 51 percent.
1H NMR(400MHz,CD3OD)δ7.94(s,1H),7.31(d,J＝8.8Hz,1H),7.11(d,J＝2.3Hz,1H),7.00-6.93(m,1H),4.40(dt,J＝8.6,6.4Hz,2H),3.79(s,3H),1.35(td,J＝7.1,1.6Hz,3H).
The sixth step
To a mixed solution of 1g (300mg, 0.68mmol) of tetrahydrofuran (15mL) and water (15mL) was added sodium hydroxide (135mg, 3.38mmol) in portions at 0 ℃ under nitrogen. After the addition was complete, the reaction was allowed to warm to room temperature and the reaction was continued for 2 hours. After the reaction was complete, the pH was adjusted to about 2 with 1N dilute hydrochloric acid, dichloromethane (30mL x3) was extracted, the organic phases were combined, washed with saturated brine (20mL x1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product 1h (290 mg).
1H NMR(400MHz,CDCl3)δ7.89(s,1H),7.21(d,J＝8.4Hz,1H),6.87(s,2H),3.78(s,3H).
Seventh step
After dissolving 1h (100mg, 0.24mmol) in N, N-dimethylformamide (2mL), adding 1i (30mg, 0.24mmol), 2- (7-benzotriazole oxide) -N, N' -tetramethyluronium hexafluorophosphate (137mg, 0.36mmol), N-diisopropylethylamine (93mg, 0.72mmol), then displacing nitrogen three times, reacting at room temperature for 2 hours, adding water (20mL) and ethyl acetate (30mL) to the reaction system, separating, extracting the aqueous phase with ethyl acetate (20mL × 3), combining the organic phases, drying over anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to obtain a residue, and purifying the residue by column chromatography (methanol: dichloromethane ═ 0-100%) to obtain 1(10mg) yield: 10 percent.
MS-ESI calculated value [ M +1 ]]+508, found 508.
1H NMR(400MHz,DMSO-d6)δ10.79(s,1H),8.13(s,1H),7.89(s,1H),7.43(d,J＝9.6Hz,1H),7.35(d,J＝8.9Hz,1H),7.22(s,1H),6.99(d,J＝8.1Hz,1H),6.38(d,J＝9.4Hz,1H),3.77(s,3H).
Example 2
Figure BDA0002865208870000161
First step of
Compound 2a (200mg, 1.56mmol) was dissolved in toluene (5mL), and potassium hydroxide (263mg, 4.68mmol) and benzyl alcohol (336mg, 3.12mmol) were added to the reaction system, followed by replacement of nitrogen three times, and then the temperature was raised to 120 ℃ for reaction overnight. After the system was cooled to room temperature, water (50mL) was added to the reaction system, and extraction was performed with ethyl acetate (50mL × 3), and after organic phases were combined, the mixture was washed with saturated brine (50mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (ethyl acetate: petroleum ether ═ 0 to 100%) to obtain compound 2b (212mg) in yield: 58 percent.
MS-ESI calculated value [ M +1 ]]+201, measured value: 201.
second step of
After 1h (600mg, 1.45mmol) was dissolved in N, N-dimethylformamide (10mL), 2b (300mg, 1.45mmol), 2- (7-benzotriazole oxide) -N, N' -tetramethyluronium hexafluorophosphate (827mg, 2.17mmol), N-diisopropylethylamine (562mg, 4.35mmol) were added thereto, followed by nitrogen substitution three times, and reaction at room temperature for 2 hours, water (60mL) and ethyl acetate (60mL) were added to the reaction system, liquid separation was performed, the aqueous phase was extracted with ethyl acetate (20mL × 3), organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (methanol: dichloromethane ═ 0 to 100%) to obtain 2c (350mg), yield: and 43 percent.
MS-ESI calculated value [ M +1 ]]+598, found 598.
The third step
2c (300mg, 0.50mmol) was dissolved in tetrahydrofuran (15mL), and then 10% wet palladium on carbon (30mg) was added to replace hydrogen (15psi) three times, followed by reaction at room temperature for 2 hours. The reaction solution was filtered through celite, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (methanol: dichloromethane 0-100%) to give 2(150mg) in yield: 59 percent.
MS-ESI calculated value [ M +1 ]]+508, found 508.
1H NMR(400MHz,DMSO-d6)δ11.38(s,1H),11.05(s,1H),8.14(s,1H),7.35(dd,J＝16.1,8.0Hz,2H),7.23(s,1H),7.00(d,J＝8.5Hz,1H),6.66(s,1H),6.29(d,J＝7.0Hz,1H),3.77(s,3H).
Example 3
Figure BDA0002865208870000171
First step of
1f (300mg, 1.17mmol), 3a (148mg, 1.17mmol) were dissolved in N, N-dimethylformamide (10mL), cesium carbonate (767mg, 2.35mmol) was slowly added at 0 ℃, nitrogen gas was replaced at 0 ℃ and the mixture was stirred at room temperature for 2 hours, the reaction system was diluted with water (30mL), and extracted with ethyl acetate (50mL × 3), the organic phases were combined, washed with saturated brine (20mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (ethyl acetate: petroleum ether ═ 0 to 100%) to give compound 3b (380mg) in yield: 90 percent.
1H NMR(400MHz,CDCl3)δ7.85(s,1H),7.04–6.90(m,3H),4.48–4.41(m,2H),2.20(s,3H),1.42–1.36(m,3H).
Second step of
3b (380mg, 1.05mmol) was dissolved in tetrahydrofuran (5mL), and a 1N aqueous solution (5mL) of sodium hydroxide was added thereto, followed by stirring at room temperature for 2 hours while replacing nitrogen. The reaction mixture was adjusted to pH about 1 by addition of 6N dilute hydrochloric acid, diluted with water (40mL), extracted with ethyl acetate (30mL x3), the organic phases were combined, washed with saturated brine (50mL x1), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give crude 3c (250mg), yield: 95 percent.
1H NMR(400MHz,DMSO-d6)δ8.02(s,1H),7.32–7.18(m,2H),7.11(dd,J＝8.4,3.1Hz,1H),2.15(s,3H).
The third step
3c (100mg, 0.28mmol) was dissolved in anhydrous dichloromethane (5mL), two drops of N, N-dimethylformamide were added, oxalyl chloride (107mg, 0.83mmol) was further added, the mixture was replaced with nitrogen three times, and after stirring at room temperature for 2 hours, the organic solvent was removed by concentration under reduced pressure. Then dissolved in anhydrous dichloromethane (5mL), the compound 3c (56mg, 0.45mmol) and triethylamine (151mg, 1.51mmol) were added to the reaction system, warmed to room temperature, stirred for reaction for 2 hours, concentrated under reduced pressure to give a residue, which was purified by column chromatography (methanol: dichloromethane ═ 0-100%) to give 3e (70mg) in yield: 53 percent.
MS-ESI calculated value [ M +1 ]]+440, found value 440.
The fourth step
3e (70mg, 0.16mmol) was dissolved in acetic acid (10mL) and a hydrobromic acid acetic acid solution (3mL), followed by nitrogen substitution three times, stirring at 100 ℃ for 2 hours, and then concentration under reduced pressure to give a residue, which was purified by column chromatography (methanol: dichloromethane ═ 0-100%) to give compound 3(56mg), yield: 82 percent.
MS-ESI calculated value [ M +1 ]]+426, found value 426.
1H NMR(400MHz,DMSO-d6)δ11.40(s,1H),11.09(s,1H),8.14(s,1H),7.37(d,J＝7.2Hz,1H),7.30–7.24(m,2H),7.14–7.12(m,1H),6.69(d,J＝2.0Hz,1H),6.33–6.31(m,1H),2.19(s,3H).
Example 4
Figure BDA0002865208870000191
First step of
Compound 4a (100mg, 0.44mmol) was dissolved in dichloromethane (10mL), followed by the addition of oxalyl chloride (113mg, 0.88mmol) and a catalytic amount of N, N-dimethylformamide. After three times replacement with nitrogen and stirring at room temperature for 2 hours, concentration under reduced pressure gave a residue, which was then dissolved in dichloromethane (20mL), triethylamine (133mg, 1.32mmol) and compound 3d (82mg, 0.66mmol) were added, after three times replacement with nitrogen and stirring at room temperature for 12 hours, water (20mL) and dichloromethane (30mL) were added for liquid separation, the aqueous phase was further extracted with dichloromethane (30mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (ethyl acetate: petroleum ether ═ 0-100%) to give 4b (90mg), yield: 62 percent.
Second step of
Compound 4b (90mg, 0.27mmol) and 3a (34mg, 0.27mmol) were dissolved in N, N-dimethylformamide (10mL), and cesium carbonate (877mg, 2.69mmol) was added under ice bath. After the replacement with nitrogen gas three times, the reaction system was further stirred for 1.5 hours in an ice bath, warmed to room temperature, added with water (20mL) and ethyl acetate (30mL), separated, the aqueous phase was extracted with ethyl acetate (30mL × 3), the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (petroleum ether: ethyl acetate ═ 0-100%) to give 4c (70mg), yield: 62 percent.
The third step
4c (70mg, 0.16mmol) was dissolved in acetic acid (10mL) and a hydrobromic acid acetic acid solution (3mL), followed by nitrogen substitution three times, stirring at 100 ℃ for 2 hours, and then concentrated under reduced pressure to give a residue, which was purified by column chromatography (methanol: dichloromethane ═ 0 to 100%) to give compound 4(50mg), yield: 77 percent
MS-ESI calculated value [ M +1 ]]+408, found value 408.
1H NMR(400MHz,DMSO-d6)δ11.32(s,1H),10.78(s,1H),8.90(s,1H),7.33–7.27(m,3H),7.18–7.16(m,1H),6.96(s,1H),6.78(s,1H),6.37(d,J＝5.6Hz,1H),2.12(s,3H).
Example 5
Figure BDA0002865208870000201
First step of
Compound 5a (500mg, 2.72mmol) was dissolved in dichloromethane (20mL) and thionyl chloride (6.42g, 54.40mmol) was added under ice bath. Stirring at room temperature for 1 hour, cooling to 0 ℃, adding ammonia (1mL), adding water (30mL) to quench the reaction solution, adding ethyl acetate (50mL), separating, extracting the aqueous phase with ethyl acetate (30mL x3), combining the organic phases, washing with saturated brine (100mL x1), drying with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain crude product 5b (200mg), yield: 40 percent.
Second step of
Compound 5b (200mg, 1.10mmol), iron powder (200mg, 6.60mmol) and ammonium chloride (200mg, 2.20mmol) were dissolved in a mixed solution of ethanol (20mL) and water (4mL), and the reaction system was heated to 90 ℃ under nitrogen and stirred for 8 hours. Cooling to room temperature, concentrating the reaction solution under reduced pressure to obtain a residue, adding the residue to a mixed solvent of water (10mL) and ethyl acetate (50mL), separating the liquids, extracting the aqueous phase with ethyl acetate (30mL × 3), combining the organic phases, washing with a saturated brine (100mL × 1), drying over anhydrous sodium sulfate, filtering, concentrating under reduced pressure to obtain a residue, and purifying the residue by column chromatography (methanol: dichloromethane ═ 0 to 100%) to obtain compound 5c (80mg) in yield: 48 percent.
The third step
Compound 5c (50mg, 0.33mmol), 1h (136mg, 0.33mmol) and 2- (7-benzotriazol oxide) -N, N' -tetramethyluronium hexafluorophosphate (163mg, 0.43mmol) were dissolved in N, N-dimethylformamide (10mL), N-diisopropylethylenediamine (126mg, 0.99mmol) was added, the reaction mixture was stirred at room temperature for 2 hours, water (50mL) and ethyl acetate (50mL) were added to the reaction mixture, liquid separation was performed, the aqueous phase was extracted with ethyl acetate (30mL × 3), the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and purified by column chromatography (methanol: dichloromethane 0 to 100%) under reduced pressure to give compound 5(14mg), yield: 8 percent.
MS-ESI calculated value [ M +1 ]]+551, measured value 551.
1H NMR(400MHz,DMSO-d6)δ11.99(s,1H),8.82(s,1H),8.60(s,1H),8.20(s,1H),7.42(d,J＝8.5,1H),7.21(s,1H),6.97(d,J＝8.4,1H),3.76(s,3H).
Example 6
Figure BDA0002865208870000211
Figure BDA0002865208870000221
First step of
After 2(50mg, 0.10mmol) was dissolved in tetrahydrofuran (2mL), 60% sodium hydride (10mg, 0.30mmol) was added thereto in an ice bath, and the mixture was allowed to warm to room temperature naturally for 30 minutes, followed by addition of methanol (0.5mL) and stirring at room temperature for 1 hour. Filtration through celite, concentration of the filtrate under reduced pressure to give a residue, and purification of the residue by column chromatography (methanol: dichloromethane ═ 0 to 100%) to give compound 6(38mg) in yield: 74 percent.
MS-ESI calculated value [ M +1 ]]+520, found 520.
1H NMR(400MHz,DMSO-d6)δ11.36(s,1H),11.04(s,1H),7.89(s,1H),7.34–7.32(m,2H),7.22(s,1H),6.99–6.98(m,1H),6.74(s,1H),6.34(d,J＝7.2Hz,1H),3.91(s,3H),3.78(s,3H).
Example 7
Figure BDA0002865208870000222
First step of
Potassium hydroxide (159mg, 2.80mmol) was added to a solution of compound 7a (300mg, 2.30mmol) and benzyl alcohol (249mg, 2.30mmol) in toluene (10mL), and the reaction was allowed to warm to 100 ℃ for 16 hours. The reaction solution was concentrated under reduced pressure to give a residue, and the residue was added to water (10mL) and dichloromethane (20mL), liquid-separated, aqueous phase was extracted with dichloromethane (20mL × 3), organic phases were combined and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (methanol: dichloromethane ═ 0 to 100%) to give compound 7b (320mg), yield: and 64 percent.
1H NMR(400MHz,CDCl3)δ7.41(d,J＝7.0,2H),7.36(d,J＝8.0,2H),7.34–7.29(m,1H),5.84(s,1H),5.75(d,J＝1.4,1H),5.26(s,2H),4.24(s,2H).
Second step of
To a solution of compound 7b (50mg, 0.23mmol) in tetrahydrofuran (5mL) was added 10% wet palladium on carbon (5 mg). The reaction system was stirred at room temperature for 1 hour while replacing hydrogen. Filtration over celite and concentration of the filtrate under reduced pressure afforded crude 7c (22mg), yield: 75 percent.
The third step
To a solution of compound 7c (22mg, 0.17mmol), 1h (70mg, 0.17mmol) in pyridine (5mL) at 0 deg.C was added phosphorus oxychloride (77mg, 0.50mmol), then warmed to room temperature and stirred for 1 h. After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a residue, and the residue was purified by column chromatography (methanol: dichloromethane ═ 0 to 100%) to obtain compound 7(3mg) in yield: 4 percent.
MS-ESI calculated value [ M +1 ]]+526, measured value 526.
1H NMR(400MHz,CD3OD)δ8.01(s,1H),7.32(d,J＝8.8,1H),7.08(s,1H),6.95–6.89(m,1H),6.83(s,1H),6.75(s,1H),3.80(s,3H).
Example 8
Figure BDA0002865208870000231
Figure BDA0002865208870000241
First step of
Compound 8a (173mg, 1.00mmol) was dissolved in medium ethanol (4mL) and water (1mL), and iron powder (280mg, 5.00mmol) and ammonium chloride (535mg, 10.00mmol) were added, followed by replacement of nitrogen gas and reaction at 80 ℃ for 2 hours. Cooled to room temperature, filtered through celite, the filtrate extracted with ethyl acetate (50mL x3), the organic phases combined, washed with saturated brine (20mL x1), dried over anhydrous sodium sulfate, concentrated under reduced pressure and dried to give crude 8b (140mg), yield: 98 percent.
Second step of
Compound 8b (140mg, 0.98mmol) and benzyl alcohol (216mg, 2.00mmol) were dissolved in toluene (10mL), followed by addition of potassium hydroxide (168mg, 3.00mmol), stirring at 120 ℃ under replacement of nitrogen for 16 hours, addition of water (30mL) to the reaction system, extraction with ethyl acetate (50mL × 3), organic phase combination, washing with saturated brine (20mL × 1), drying over anhydrous sodium sulfate, filtration, concentration under reduced pressure to give a residue, and purification of the residue by column chromatography (methanol: dichloromethane ═ 0 to 100%) gave compound 8c (20mg) in yield: 10 percent.
MS-ESI calculated value [ M +1 ]]+215, found: 215.
the third step
After 8c (20mg, 0.09mmol) was dissolved in N, N-dimethylformamide (2mL), 1h (37mg, 0.09mmol), 2- (7-benzotriazole oxide) -N, N' -tetramethyluronium hexafluorophosphate (76mg, 0.20mmol), N-diisopropylethylamine (32mg, 0.25mol) were added, then nitrogen substitution was carried out three times, stirring was carried out at room temperature for 2 hours, water (20mL) and ethyl acetate (30mL) were added, liquid separation was carried out, the aqueous phase was extracted with ethyl acetate (20mL × 3), organic phase was combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (methanol: dichloromethane ═ 0 to 100%) to give compound 8d (15mg) in yield: 27 percent.
MS-ESI calculated value [ M +1 ]]+612, found: 612.
the fourth step
After 8d (15mg, 0.02mmol) was dissolved in tetrahydrofuran (3mL), 10% wet palladium on carbon (5mg) was added, the mixture was replaced three times under hydrogen, stirred at room temperature for 1 hour, filtered through celite, the filtrate was concentrated under reduced pressure to give a residue, and the residue was purified by column chromatography (methanol: dichloromethane 0-100%) to give compound 8(4mg) in yield: 33 percent.
MS-ESI calculated value [ M +1 ]]+522, found: 522.
1H NMR(400MHz,CD3OD)δ8.00(s,1H),7.32(d,J＝8.8Hz,1H),7.09(s,1H),6.94(d,J＝8.8Hz,1H),6.76(s,1H),6.45(s,1H),3.80(s,3H),2.27(s,3H).
example 9
Figure BDA0002865208870000251
First step of
Compound 9a (500mg, 2.90mmol) was dissolved in a mixed solvent of ethanol (4mL) and water (1mL), followed by addition of iron powder (812mg, 14.50mmol) and ammonium chloride (1552mg, 29.00 mmol). After replacing with nitrogen three times, heating to 80 ℃ and stirring for 2 hours, the reaction solution was filtered through celite, the filtrate was concentrated under reduced pressure to give a residue, the residue was added to water (50mL), and extracted with ethyl acetate (50mL x3), the organic phases were combined, washed with saturated brine (50mL x1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude 9b (380mg), yield: 92 percent.
MS-ESI calculated value [ M +1 ]]+143, found: 143.
second step of
Compound 9b (200mg, 1.41mmol) was dissolved in toluene (5mL), followed by the addition of potassium hydroxide (482mg, 282.00mmol) and benzyl alcohol (238mg, 4.23 mmol). After replacement with nitrogen three times, the reaction mixture was warmed to 120 ℃ and stirred overnight, water (50mL) was added, and extraction was performed with ethyl acetate (50mL × 3), and after organic phases were combined, the mixture was washed with saturated brine (50mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (ethyl acetate: petroleum ether ═ 0 to 100%) to obtain compound 9c (160mg) in yield: 53 percent.
MS-ESI calculated value [ M +1 ]]+215, found: 215.
the third step
After 9c (300mg, 0.75mmol) was dissolved in N, N-dimethylformamide (10mL), 1h (160mg, 0.75mmol), 2- (7-benzotriazole oxide) -N, N' -tetramethyluronium hexafluorophosphate (428mg, 1.13mmol), N-diisopropylethylamine (291mg, 2.25mmol) were added and then replaced with nitrogen three times, and after stirring at room temperature for 2 hours, water (60mL) and ethyl acetate (60mL) were added, liquid separation was performed, the aqueous phase was extracted with ethyl acetate (20mL × 3), organic phase was combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (methanol: dichloromethane ═ 0-100%) to give 9d (40mg) in yield: 10 percent.
MS-ESI calculated value [ M +1 ]]+612, found 612.
The fourth step
After 9d (40mg, 0.07mmol) was dissolved in tetrahydrofuran (2mL) and 10% wet palladium on carbon (10mg) was added to replace hydrogen, the reaction was stirred at room temperature for 2 hours. The reaction solution was filtered, dried and purified by column chromatography (methanol: dichloromethane ═ 0 to 100%) to give compound 9(13mg) in yield: 36 percent.
MS-ESI calculated value [ M +1 ]]+522, measured value 522.
1H NMR(400MHz,DMSO-d6)δ11.33(s,1H),10.12(s,1H),8.09(s,1H),7.36(d,J＝8.8Hz,1H),7.25(s,1H),7.21(s,1H),7.01(d,J＝8.0Hz,1H),6.87(s,1H),3.78(s,3H),1.94(s,3H).
Biological activity assay
The in vitro inhibition effect of the compound on Nav1.8 was tested on HEK293 cells stably expressing human Nav1.8 using a manual patch clamp assay. Test compounds were dissolved in DMSO to prepare 9mM stock solutions, which were dissolved in extracellular fluid at the desired concentration on the day of testing. The extracellular fluid component comprises (mM) NaCl, 137; KCl, 4; CaCl2,1.8；MgCl21, 1; HEPES, 10; glucose 10; pH 7.4(NaOH titration). Clamping cellsAt-80 mV, then depolarized to 10mV with a square wave lasting 10 milliseconds to give a NaV1.8 current. This procedure is repeated every 5 seconds. And detecting the maximum current caused by the square wave, perfusing a test compound (dissolved in extracellular fluid according to the required concentration) after the maximum current is stabilized, and calculating the blocking strength of the compound to Nav1.8 according to the current strength before and after the compound is perfused after the reaction is stabilized. Data collection and analysis was performed using pCLAMP10(Molecular Devices, Union City, Calif.), and current stabilization means that the current varies within a limited range with time. The test results are shown in the following Table-1.
Inhibitory Activity of the Compounds of Table-1 on Nav1.8
Compound numbering IC50(nM)
Example 1 2.7
Example 2 1.2
TABLE-2 The% blockade of Nav1.8 channels at a concentration of 0.8nM of the compound
Figure BDA0002865208870000271
TABLE-3 percent blocking of Nav1.8 channel at 4nM concentration of compound
Figure BDA0002865208870000272
Figure BDA0002865208870000281
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. A compound of formula (I), and isomers, solvates or pharmaceutically acceptable salts thereof:
Figure FDA0002865208860000011
l is selected from the group consisting of: s (O)p，O，NR5CO or C (R)6)R7；
Cyc is selected from: 5-6 membered heteroaryl, the heteroatoms of which are independently selected from O, N or S (O)p；
R1Selected from the group consisting of: hydrogen, deuterium, ═ O, halogen, CHF2，CF3，CD3，OCF3，OCH3，OCD3Cyano, nitro, hydroxy, amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, 1 or 2 nonadjacent carbon atoms being replaced by O or NR5An alternative C1-C6 alkyl group, a substituted or unsubstituted C3-C6 cycloalkyl group, a substituted or unsubstituted C4-C6 heterocyclyl group, said heteroatoms independently selected from O, N or S (O)p(ii) a Or two adjacent R1And the atoms to which they are attached form a substituted or unsubstituted 5-6 membered carbocyclic or heterocyclic ring;
R2selected from the group consisting of: 0 to 4R1Substituted C3-C6 cycloalkyl, 0-4R1Substituted C4-C6 heterocyclyl, 0-4R1Substituted 6-10 membered aryl, 0-4R1Substituted 5-10 membered heteroaryl; wherein two adjacent R are1May form a 5-to 6-membered carbocyclic or heterocyclic ring together with the ring atoms to which they are attached;
R4selected from the group consisting of: hydrogen, deuterium, halogen, hydroxy, amino, cyano, substituted or unsubstituted C1-C4 alkyl, 1 or 2 non-adjacent carbon atoms being replaced by O or NR5An alternative C1-C4 alkyl group, a substituted or unsubstituted C3-C6 cycloalkyl group, a substituted or unsubstituted C4-C6 heterocyclyl group, said heteroatoms independently selected from O, N or S (O)p；
n is selected from the group consisting of: 0, 1,2,3 or 4;
p is selected from the group consisting of: 0, 1 or 2;
R5selected from the group consisting of: hydrogen, substituted or unsubstituted C1-C6 alkyl, C1-C6 alkyl wherein 1 or 2 non-adjacent carbon atoms are replaced by O or NH, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C4-C6 heterocyclyl, said heteroatoms being independently selected from O, N or S (O)p；
R6And R7Each independently selected from: hydrogen, substituted or unsubstituted C1-C4 alkyl, 1 or 2 non-adjacent carbon atoms being replaced by O or NR5An alternative C1-C4 alkyl group, a substituted or unsubstituted C3-C6 cycloalkyl group, a substituted or unsubstituted C4-C6 heterocyclyl group, said heteroatoms independently selected from O, N or S (O)p(ii) a Or R6And R7A carbocyclic ring having C3-C6 atoms or a heterocyclic ring having C4-C6 atoms attached thereto;
unless otherwise specified, "substituted" means substituted with one or more (e.g., 2,3, 4, etc.) substituents selected from the group consisting of: halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, halogenated C3-C8 cycloalkyl, oxo, -CN, hydroxy, amino, carboxy, amide, sulfonamide, sulfone; a group selected from the group consisting of unsubstituted or substituted with one or more substituents: a C6-C10 aryl group, a halogenated C6-C10 aryl group, a 5-10 membered heteroaryl group having 1-3 heteroatoms selected from N, S and O, a halogenated 5-10 membered heterocyclyl group having 1-3 heteroatoms selected from N, S and O, and said substituents are selected from the group consisting of: halogen, C1-C6 alkyl, C1-C6 alkoxy, ═ O.
2. The compound of claim 1, wherein R is4Selected from the group consisting of: hydrogen, halogen, hydroxy, substituted or unsubstituted C1-C4 alkyl.
3. The compound of any one of claims 1 or 2, wherein the compound of formula (I) has a structure as shown in formula (II):
Figure FDA0002865208860000021
wherein G is N or N+-O-。
4. A compound according to claims 1-3 wherein L is O.
5. The compound of claims 1-4, wherein the compound has the structure of formula (III):
Figure FDA0002865208860000031
6. the compound of claim 1, wherein said compound is selected from the group consisting of:
Figure FDA0002865208860000032
Figure FDA0002865208860000041
7. a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound, isomer, solvate or pharmaceutically acceptable salt or hydrate thereof according to claims 1 to 6.
8. The pharmaceutical composition of claim 7, wherein the pharmaceutical composition is for use in a method of treating, ameliorating or preventing a disease or disorder associated with sodium channel modulation; preferably, the disease or condition is pain.
9. Use of a compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt or hydrate thereof, for the preparation of a pharmaceutical composition for the treatment, alleviation or prevention of diseases associated with sodium channel modulation; preferably, the disease or condition is pain.
10. The use according to claim 9, wherein the pain or disease is selected from the group consisting of: chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, post-operative pain, visceral pain, multiple sclerosis, peroneal muscular atrophy (Charcot-Marie-Tooth syndrome), incontinence, pathological cough, or cardiac arrhythmia.
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