CN-121991042-A - N- (hydroxyalkyl pyridyl) tetrahydrofuran sodium channel regulator and its medical application

Abstract

The invention provides N- (hydroxyalkyl pyridyl) tetrahydrofuran carboxamides, prodrugs, oxides, salts, metal complexes or stereochemical isomers and pharmaceutical compositions containing the same, their use as Nav inhibitors and their use in the manufacture of medicaments for the treatment and/or alleviation of pain and pain related diseases. The compound provided by the invention has the advantages of high metabolic stability, high oral absorption, better bioavailability, better activity, higher selectivity, better pharmacokinetic property, quicker onset of action, low heart side effect and the like.

Inventors

• ZHU XIAOYUN
• JIANG WEIPING

Assignees

• 嘉兴安帝康生物科技有限公司

Dates

Publication Date

20260508

Application Date

20241101

Claims (6)

1. 1. An N- (hydroxyalkyl pyridinyl) tetrahydrofurancarboxamide compound of formula (I), a stereoisomer, a hydrate, a solvate, a polymorph, an active metabolite, a pharmaceutically acceptable salt or a prodrug thereof: Wherein: R1, R 2 、R 3 and R are the same or different and are each independently selected from the group consisting of a hydrogen atom, a deuterium atom, a halogen, a hydroxyl group, a cyano group, an amino group, an amide group, a nitro group, an alkyl group, a deuterated alkyl group, an alkylthio group, an alkyl sulfoxide group, an alkenyl group, an alkynyl group, an alkoxy group, a deuteroalkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group, -O- (heterocyclic group), -O- (cycloalkyl), - (OCH 2 CH 2 ) n -OH、-(OCH 2 CH 2 ) n -OCH 3 ; wherein each of the cycloalkyl group, the heterocyclic group, the aryl group and the heteroaryl group is independently optionally substituted with 1 or more R 5 ; n is selected from 1, 2, 3,4, 5, 6; Or R1 and R 2 and the atoms connected with the R 2 form a substituted or unsubstituted 3-10 membered cycloalkyl group or R1 and R 2 and the atoms connected with the R 2 form a substituted or unsubstituted 3-10 membered heterocyclic group, or R 3 and R and the atoms connected with the R form a substituted or unsubstituted 3-10 membered cycloalkyl group or R 3 and the atoms connected with the R form a substituted or unsubstituted 3-10 membered heterocyclic group, wherein each of the substituted 3-10 membered cycloalkyl group and the substituted 3-10 membered heterocyclic group is independently optionally substituted by 1 or more R 5 ; Each R 5 is the same or different and is each independently selected from the group consisting of halogen, hydroxy, cyano, oxo, amino, amido, alkyl, deuterated alkyl, alkenyl, alkynyl, alkoxy, deuterated alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; r 6 is independently selected from the group consisting of a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a cycloalkyl group; R 7 is independently selected from the group consisting of hydrogen, hydroxy, amino, amido, alkyl, deuterated alkyl, alkoxy, deuterated alkoxy, alkylamino, deuterated alkylamino, cycloalkylamino, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, haloacetamido.
2. 2. The N- (hydroxyalkyl pyridinyl) tetrahydrofurancarboxamide compound, stereoisomer, hydrate, solvate, polymorph, active metabolite thereof, pharmaceutically acceptable salt thereof or a prodrug thereof according to claim 1, wherein the compound is represented by any of the following structural formulas:
3. 3. A pharmaceutical composition comprising: (i) An effective amount of the tetrahydrofurancarboxamide compound according to claim 1 or 2, a stereoisomer, a hydrate, a solvate, a polymorph, an active metabolite, a pharmaceutically acceptable salt or a prodrug thereof, and (Ii) Pharmaceutically acceptable excipients.
4. 4. Use of a tetrahydrofurancarboxamide compound according to claim 1 or 2, a stereoisomer, a hydrate, a solvate, a polymorph, an active metabolite, a pharmaceutically acceptable salt thereof or a prodrug thereof or a pharmaceutical composition according to claim 3 for the manufacture of a medicament for the treatment, prevention or alleviation of a voltage-gated sodium channel related disorder.
5. 5. The use according to claim 4, wherein the voltage-gated sodium channel related diseases include chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, primary pain, multiple sclerosis, charpy-Chart's disease, incontinence and arrhythmia.
6. 6. The use of claim 5, wherein the neuropathic pain comprises one or more of post-herpetic neuralgia, diabetic neuralgia, painful HIV-associated sensory neuropathy, trigeminal neuralgia, oral burn syndrome, post-amputation pain, phantom pain, painful neuroma, traumatic neuroma, morton neuroma, nerve crush injury, spinal stenosis, carpal tunnel syndrome, radicular pain, sciatica, nerve avulsion injury, brachial plexus avulsion injury, complex regional pain syndrome, drug therapy-induced neuralgia, cancer chemotherapy-induced neuralgia, antiretroviral therapy-induced neuralgia, spinal cord injury post-pain, primary small fiber neuropathy, primary sensory neuropathy, trigeminal autonomic headache; the musculoskeletal pain comprises one or more of osteoarthritis pain, back pain, cold pain, burn pain and toothache; the inflammatory pain includes rheumatoid arthritis pain and/or vulvodynia; the primary pain includes fibromyalgia.

Description

N- (hydroxyalkyl pyridyl) tetrahydrofuran sodium channel regulator and its medical application Technical Field The present invention provides an N- (hydroxyalkyl pyridyl) tetrahydrofuran carboxamide derivative, prodrug, oxide, salt, metal complex or stereochemical isomer and a pharmaceutical composition containing the same. In particular to an N- (hydroxyalkyl pyridyl) tetrahydrofuran carboxamide compound shown in a general formula (I), a preparation method thereof, a pharmaceutical composition containing the compound, application of the compound as a Nav inhibitor and application of the compound in preparing medicines for treating and/or relieving pain and pain related diseases. Technical Field Pain is a complex physiological activity, which can be used as an alert signal to alert the body to potential hazards and to provide an essential protective effect on the body's normal vital activities. Meanwhile, after the pain is caused to be glaring and disappeared, the intense or lasting pain can cause disorder of physiological functions, and the life quality of a living body is seriously affected. Statistics show that about one fifth of the world's people suffer from moderate to severe chronic pain. Pain originates from nociceptors of the peripheral nervous system. This is a free nerve ending, widely distributed in the skin, muscle, joint and visceral tissues throughout the body, which converts the perceived thermal, mechanical or chemical stimulation into nerve impulses (action potentials) and is transmitted via afferent nerve fibers to its cytoplasmic portion located in the dorsal root ganglion (dorsal root ganglia, DRG), ultimately to the higher nerve center, causing pain sensation. The generation and conduction of action potentials in neurons in turn depends on voltage-gated sodium channels (voltage-gated sodium channels, nav) on the cell membrane. When the cell membrane depolarizes, sodium ion channels activate, the channels open, causing sodium ion influx, further depolarizing the cell membrane, resulting in the generation of action potentials. Thus, inhibition of aberrant sodium channel activity contributes to the treatment, relief of pain. Nav forms a subfamily of the voltage-gated ion channel superfamily and includes 9 isoforms, designated Nav1.1-Nav1.9. Tissue localization was different for the nine isoforms. The functional behavior of the nine isoforms are similar but different in their details of voltage dependence and kinetic behavior. Nav1.4 is the primary sodium channel of skeletal muscle, and nav1.5 is the primary sodium channel of cardiomyocytes. Nav1.1, 1.2, 1.3 and 1.6 are neuronal channels found in the central and peripheral nervous system. Nav1.1, nav1.2, nav1.3 are mainly distributed in CNS area and are related to CNS diseases such as epilepsy, local anesthesia, etc., nav1.4 is mainly distributed in skeletal muscle, inhibitor thereof is used as myotonic local anesthetic, nav1.5 is mainly distributed in cardiac muscle cells, inhibitor thereof is used for treating arrhythmia, nav1.6 is related to dyskinesia, and at present, targets related to pain are mainly Nav1.7, nav1.8 and Nav1.9. Among them, nav1.7 inhibitors are most widely used in the pain field, but no related clinical test has been successful so far, and Nav1.9 has less research, and its action mechanism in pain is not completely clear. Nav1.8 is TTX-R type, and the coding gene is SCN10A, which is mainly existed in trigeminal ganglion neuron and DRG neuron, and has electrophysiological characteristics of slow inactivation and rapid recovery. In neurons expressing nav1.8, the rise in action potential is mainly composed of nav1.8 current. In some models of neuropathic pain, nerve damage results in elevated levels of Nav1.8 expression in axons and neuronal cell bodies (Sleeper A. J. Neurosci.2000,20, 7279-7289). The use of Nav1.8 antisense oligonucleotides significantly reduced pain while reducing Nav1.8 expression (Yoshimura N., et al J. Neurosci.2001,21, 8690-8696). The human Nav1.8 gene causes peripheral neuralgia after the mutation of functional gain. According to a series of animal experiments and human genetic evidence, the selective inhibition of Nav1.8 can be used for treating various pain types such as inflammatory pain, neuropathic pain, postoperative pain, cancer pain and the like, and becomes a novel analgesic therapy. Nav inhibitors used clinically have a narrow therapeutic window and limited application range due to their lack of subtype selectivity and their ability to inhibit sodium ion channels expressed in the heart and central nervous system. Nav1.8 is distributed mainly in the peripheral nervous system, so selective inhibition of Nav1.8 can effectively reduce side effects. Therefore, it is necessary to develop Nav1.8 inhibitors with higher activity, better selectivity, better solubility, better pharmacokinetic properties, faster onset of action, longer lasting analgesic effect, and less toxic and side effects of the