CN118388466A - Amide derivatives as sodium channel modulators and uses thereof - Google Patents
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Abstract
本发明涉及用作钠通道调节剂的式I所示的酰胺衍生物或其药学上可接受的盐、立体异构体、氘取代的衍生物、水合物、溶剂化物或溶剂复合物。本发明还提供了包含本发明所述酰胺衍生物的药学上可接受的组合物，以及使用该酰胺衍生物或组合物在治疗包括疼痛、多发性硬化症、病理性咳嗽等钠通道相关疾病上的应用。 The present invention relates to an amide derivative shown in formula I or a pharmaceutically acceptable salt, stereoisomer, deuterium-substituted derivative, hydrate, solvate or solvent complex thereof used as a sodium channel modulator. The present invention also provides a pharmaceutically acceptable composition comprising the amide derivative of the present invention, and the use of the amide derivative or the composition in treating sodium channel-related diseases including pain, multiple sclerosis, pathological cough, etc.
Description
Technical Field
The invention relates to the technical field of biological medicine, in particular to an amide derivative used as a sodium channel regulator or pharmaceutically acceptable salt, stereoisomer, deuterium-substituted derivative, hydrate, solvate or solvent complex thereof, and application thereof in the aspect of treating sodium channel related diseases.
Background
Pain is a sensation produced when the human body is subjected to various nociceptive stimuli, is a complex physiological and psychological activity, is also a defensive mechanism for protecting the body from injury, and is one of the most common symptoms in clinic. The international society of pain (InternationalAssociation forthe Study ofPain, IASP) classifies pain as nociceptive pain (caused by the activation of corresponding pain receptors by inflamed or damaged tissues, and also as somatic and visceral), neuropathic pain (caused by damage or disease to the nervous system, and as peripheral and central), psychogenic pain (described by the elucidation of pain with aversive and unpleasant sensations and exaggerated language and behaviors due to the affliction of psychological factors, psychological conflicts, mood disorders, or psychological diseases). Among them, neuropathic pain generally includes pain caused by systemic metabolic injury (post-herpetic neuralgia, diabetic neuralgia and drug-induced neuralgia) and pain caused by discrete nerve injury (post-amputation pain, post-operative nerve injury pain, etc.).
Voltage-gated sodium channels are distributed mainly in the nervous system, excitable cells (e.g., neurons), and play an important biophysical role in the transmission of pain-related signals. They transmit electrical signals by the generation and propagation of Action Potentials (APs) in the Periphery (PNS) IN THE PERIPHERAL and the central nervous system (central nervous systems, CNS). Humans have a total of 9 sodium ion channels, nav1.1 to Nav1.9, respectively, each formed from an alpha subunit and one or more beta subunits. Despite high structural and sequence similarity, nav channels of different subtypes not only have specific tissue distributions, but also have different voltage dependencies and kinetics of activation, inactivation and recovery, etc. (Xiaoshuang H,Xueqin J,Gaoxingyu H,et al.Proceedings of the National Academy of Sciences of the United States of America,2022,119(30);Eleonora S,PeterW,RaafiaM,et al.Cardiovascularresearch,2014,104(2):355-63). studies, which suggest that mutations, changes in expression or inappropriate regulation of these channels can lead to electrical instability of cell membranes and abnormal spontaneous activity observed under pathological conditions, etc (Chahine M,ChatelierA,Babich O,et al.CNS&Neurological Disorders-Drug Targets,2008,7(2):144-158).
Nav1.8 is a tetrodotoxin (TTX) insensitive sodium channel encoded by SCN10A, expressed predominantly in sensory neurons, located in the 3p21-22 region of the human chromosome, encoding predominantly the alpha subunit. Research shows that Nav1.8 plays an important role in neuropathic and chronic inflammatory pain, such as regulating malondialdehyde (one of important factors of diabetes pain) and tumor necrosis factor alpha (tumornecrosis factor α, TNF- α) and other (Huang Q,ChenY,GongN,et al.Metabolism,2016,65(4):463-474;He XH,ZangY,Chen X,et al.Pain.2010Nov;151(2):266-279.).Nav1.8 blockers are expected to become an ideal therapeutic drug for neuropathic and inflammatory pain of a new generation.
Some of the currently known nav1.8 blockers lack isoform selectivity and because not all nav1.8 positive neurons are nociceptive neurons, some nav1.8 blockers act in non-nociceptive neurons, limiting the therapeutic efficacy and safety of such blockers. Based on this, there is a need to develop an effective and highly selective inhibition of NaV 1.8.
Disclosure of Invention
In order to solve the technical problems, the invention provides an amide derivative used as a sodium channel regulator or pharmaceutically acceptable salts, stereoisomers, deuterium substituted derivatives, hydrates, solvates or solvent complexes thereof, has the characteristics of high selectivity, good pharmacokinetic properties, high bioavailability, low side effects and the like, and has good application prospects in the aspect of treating sodium channel related diseases.
The invention provides the following technical scheme:
The first aspect of the present invention provides an amide derivative represented by formula I or a pharmaceutically acceptable salt, stereoisomer, deuterium-substituted derivative, hydrate, solvate or solvent complex thereof:
Wherein,
A is selected from aryl or heteroaryl comprising one or more heteroatoms in N, O, S;
G 1、G2、G3 is independently selected from hydrogen, deuterium, halogen, carboxyl, ester, amide, sulfonamide, tetrazole, methyltetrazole, acyl sulfonamide, imide, N-hydroxyimide, or G 1 and/or G 2 form a ring with the imide to which tetrahydrofuran and pyridine are attached;
R is selected from C1-C10 alkyl, halogen and/or deuterium substituted C1-C10 alkyl, C3-C10 cycloalkyl, halogen and/or deuterium substituted C3-C10 cycloalkyl;
y 1、Y2、Y3、Y4 is independently selected from hydrogen, deuterium, halogen;
when X is O, NH or S, R 1 is selected from C1-C10 alkyl, halogen and/or deuterium substituted C1-C10 alkyl, C3-C10 cycloalkyl, halogen and/or deuterium substituted C3-C10 cycloalkyl;
When X is N, R 1 X is selected from C3-C7 carbon heterocycles, C1-C6 dialkylamines, C5-C10 fused heterocycles;
When X is C, R 1 X is selected from the group consisting of C2-C3 alkynyl, C2-C3 alkenyl, C3-C4 cycloalkyl, C5-C6 aryl, C5-C6 heteroaryl.
Further, A is selected from phenyl, pyridine, thiazole, furan, oxazole, isoxazole, quinoline.
Further, in the formula I,Selected from one of the following structures:
further, R is preferably trifluoromethyl.
Further, the C5-C10 fused heterocycle is preferably one of the following structures:
further, the amide derivative has a structure shown in formula Ia:
Wherein,
G 1、G2、G3 is independently selected from hydrogen, deuterium, halogen, carboxyl, ester, amide, sulfonamide, tetrazole, methyltetrazole, acyl sulfonamide, imide, N-hydroxyimide, or G 1 and/or G 2 form a ring with the imide to which tetrahydrofuran and pyridine are attached;
y 1、Y2、Y3、Y4 is independently selected from hydrogen, deuterium, halogen;
when X is O, NH or S, R 1 is selected from C1-C10 alkyl, halogen and/or deuterium substituted C1-C10 alkyl, C3-C10 cycloalkyl, halogen and/or deuterium substituted C3-C10 cycloalkyl;
When X is N, R 1 X is selected from C3-C7 carbon heterocycles, C1-C6 dialkylamines, C5-C10 fused heterocycles;
When X is C, R 1 X is selected from the group consisting of C2-C3 alkynyl, C2-C3 alkenyl, C3-C4 cycloalkyl, C5-C6 aryl, C5-C6 heteroaryl.
Further, the amide derivative has the structure:
Wherein,
Q is N or CH;
g 1、G2、G3 is independently selected from hydrogen, deuterium, halogen, carboxyl, ester, amide, sulfonamide, tetrazole, methyltetrazole, acyl sulfonamide, imide, N-hydroxyimide;
y 1、Y2、Y3、Y4 is independently selected from hydrogen, deuterium, halogen;
when X is O, NH or S, R 1 is selected from C1-C10 alkyl, halogen and/or deuterium substituted C1-C10 alkyl, C3-C10 cycloalkyl, halogen and/or deuterium substituted C3-C10 cycloalkyl;
When X is N, R 1 X is selected from C3-C7 carbon heterocycles, C1-C6 dialkylamines, C5-C10 fused heterocycles;
When X is C, R 1 X is selected from the group consisting of C2-C3 alkynyl, C2-C3 alkenyl, C3-C4 cycloalkyl, C5-C6 aryl, C5-C6 heteroaryl.
Further, the amide derivative has a structure as shown in formula Id-If:
Wherein,
G 1、G2、G3 is independently selected from hydrogen, deuterium, halogen, carboxyl, ester, amide, sulfonamide, tetrazole, methyltetrazole, acyl sulfonamide, imide, N-hydroxyimide, or G 1 and/or G 2 form a ring with the imide to which tetrahydrofuran and pyridine are attached;
y 1、Y2、Y3、Y4 is independently selected from hydrogen, deuterium, halogen;
when X is O, NH or S, R 1 is selected from C1-C10 alkyl, halogen and/or deuterium substituted C1-C10 alkyl, C3-C10 cycloalkyl, halogen and/or deuterium substituted C3-C10 cycloalkyl;
When X is N, R 1 X is selected from C3-C7 carbon heterocycles, C1-C6 dialkylamines, C5-C10 fused heterocycles;
When X is C, R 1 X is selected from the group consisting of C2-C3 alkynyl, C2-C3 alkenyl, C3-C4 cycloalkyl, C5-C6 aryl, C5-C6 heteroaryl.
Further, the amide derivative has the structure shown in formulas Ig and Ih:
Wherein,
Q is N or CH;
M is O, S or N;
G 1 is selected from hydrogen, deuterium, halogen, carboxyl, ester, amide, sulfonamide, tetrazole, methyltetrazole, acyl sulfonamide, imide, N-hydroxyimide, or G 1 forms a ring with imide attached to tetrahydrofuran and pyridine;
y 1、Y2、Y3、Y4 is independently selected from hydrogen, deuterium, halogen;
when X is O, NH or S, R 1 is selected from C1-C10 alkyl, halogen and/or deuterium substituted C1-C10 alkyl, C3-C10 cycloalkyl, halogen and/or deuterium substituted C3-C10 cycloalkyl;
When X is N, R 1 X is selected from C3-C7 carbon heterocycles, C1-C6 dialkylamines, C5-C10 fused heterocycles;
When X is C, R 1 X is selected from the group consisting of C2-C3 alkynyl, C2-C3 alkenyl, C3-C4 cycloalkyl, C5-C6 aryl, C5-C6 heteroaryl.
Further, the amide derivative has the structure shown in formulas Ii and Ij:
Wherein,
Q is N or CH;
M is O, S or N;
G 1 is selected from hydrogen, deuterium, halogen, carboxyl, ester, amide, sulfonamide, tetrazole, methyltetrazole, acyl sulfonamide, imide, N-hydroxyimide, or G 1 forms a ring with imide attached to tetrahydrofuran and pyridine;
y 1、Y2、Y3、Y4 is independently selected from hydrogen, deuterium, halogen;
when X is O, NH or S, R 1 is selected from C1-C10 alkyl, halogen and/or deuterium substituted C1-C10 alkyl, C3-C10 cycloalkyl, halogen and/or deuterium substituted C3-C10 cycloalkyl;
When X is N, R 1 X is selected from C3-C7 carbon heterocycles, C1-C6 dialkylamines, C5-C10 fused heterocycles;
When X is C, R 1 X is selected from the group consisting of C2-C3 alkynyl, C2-C3 alkenyl, C3-C4 cycloalkyl, C5-C6 aryl, C5-C6 heteroaryl.
Further, in the above structural formula, R 1 X is preferably one of the following structures:
further, the amide derivative is preferably one of the compounds represented by the following structures:
In a second aspect, the present invention provides the use of an amide derivative according to the first aspect or a pharmaceutically acceptable salt, stereoisomer, deuterium-substituted derivative, hydrate, solvate or solvent complex thereof for the manufacture of a medicament for the treatment, alleviation or prevention of a sodium channel modulation-related disorder.
Further, the sodium channel is Nav 1.8.
Further, the diseases include pain, multiple sclerosis, pathological cough, but are not limited to the above listed disease categories.
Further, the drug is administered alone or in combination with other therapeutic agents.
Further, the medicament is administered orally, parenterally, intravenously or transdermally.
In a third aspect the present invention provides a pharmaceutical composition comprising an amide derivative according to the first aspect or a pharmaceutically acceptable salt, stereoisomer, deuterium-substituted derivative, hydrate, solvate or solvent complex thereof, and a pharmaceutically acceptable carrier or excipient.
In a fourth aspect, the present invention provides the use of a pharmaceutical composition according to the third aspect for the manufacture of a medicament for the treatment, alleviation or prevention of a sodium channel modulation-related disorder.
Further, the sodium channel is Nav 1.8.
Further, the diseases include pain, multiple sclerosis, pathological cough, but are not limited to the above listed disease categories; the pain includes acute pain, chronic pain; the acute pain includes but is not limited to surgical pain, bone pain, toothache, and the chronic pain includes but is not limited to diabetic neuralgia and herpetic neuralgia.
Further, the drug is administered alone or in combination with other therapeutic agents.
Further, the medicament is administered orally, parenterally, intravenously or transdermally.
As used herein, the following definitions and terms shall apply unless otherwise indicated.
"R" and "S" are terms describing isomers and are descriptors of stereochemical configuration of asymmetrically substituted carbon atoms. The designation of asymmetrically substituted carbon atoms as "R" or "S" is accomplished by the application of the Cahn-Ingold-Prelog priority rules, which are well known to those skilled in the art and are described in International Union of pure chemistry and applied chemistry (lUPAC) organic chemistry naming rules, section E, stereochemistry.
The term "aryl" refers to a monocyclic, bicyclic or tricyclic ring system having a total of 5 to 14 ring carbon atoms, wherein at least one ring in the system is aromatic, and wherein each ring in the system contains 3 to 7 ring carbon atoms. The term "heteroaryl" refers to a monocyclic, bicyclic or tricyclic ring system having a total of 5 to 14 ring carbon atoms, wherein at least one ring in the system is aromatic, wherein at least one ring in the system contains one or more heteroatoms, such as N, O, S, and each ring contains 3 to 7 ring members, such as pyridine, thiazole, furan, oxazole, isoxazole, quinoline, and the like.
In the present invention, the term "halogen" refers to F, cl, br or I.
The term "ester" refers to-COOR wherein R is an alkyl or other non-hydrogen group.
The term "Ci-Cj" means that the moiety has i-j carbon atoms. For example, "C1-C10 alkyl" means that the alkyl unit has any number of carbon atoms between 1 and 10.
As used herein, "alkyl" refers to a straight-chain, branched-chain, fully saturated alkane group. In certain embodiments, the alkyl groups contain 1 to 10 carbon atoms. Non-limiting examples of exemplary alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-heptyl, n-octyl, and the like. In addition, the term "cycloalkyl" refers to a monocyclic or bicyclic saturated carbocycle, each ring having 3 to 10 carbon atoms.
The term "substituted" refers to the replacement of a hydrogen group in a given structure with a particular substituent group, unless otherwise indicated, the optionally substituted group may have a substituent at each of the substituent positions of the group, and where more than one position in any given structure may be substituted with more than one substituent selected from the specified group, the substituents at each position may be the same or different. In some embodiments, three hydrogens in the methyl group are each substituted with F to form-CF 3, or three hydrogens are substituted with two F and one deuterium to form-CF 2 D.
The term "carbon heterocycle" as used herein is a single ring containing at least one heteroatom in the ring, including but not limited to N, O, S, which may be saturated or contain one or more unsaturated bonds.
The term "dialkylamine" is R-NH-R 1, R and R 1 are the same or different alkyl groups.
The term "fused heterocycle" includes at least two rings, with the rings being co-extensive, and at least one ring containing one or more heteroatoms.
The term "alkynyl" refers to a carbon chain containing at least one carbon-carbon triple bond, which may be straight or branched, or a combination thereof, and the above-mentioned C2-C3 alkynyl groups include ethynyl, propynyl; the term "alkenyl" refers to a carbon chain containing at least one carbon-carbon double bond, which may be straight or branched, or a combination thereof, and the above-mentioned C2-C3 alkenyl groups include ethenyl, propenyl, 2-methyl-1-propenyl, and the like.
Optical isomers, diastereomers, geometric isomers and tautomers: some compounds of formula I may contain one or more ring systems and thus cis and trans isomers may be present. The present invention is intended to encompass all such cis and trans isomers. Containing olefinic double bonds, unless specified otherwise, is meant to include both E and Z geometric isomers.
Any enantiomer of a compound of formula I may be obtained by stereospecific synthesis using optically pure starting materials or reagents of known configuration.
In addition, the compounds of formula I may also include a range of stable isotopically-labeled analogues. For example, one or more protons in the compound of formula I may be substituted with deuterium atoms, thereby providing deuterated analogs with improved pharmacological activity.
By "pharmaceutically acceptable salt" is meant an acid or base salt of a compound of the invention, which salt has the desired pharmacological activity and is neither biologically nor otherwise desirable. Salts may be formed with acids including, but not limited to, acetic acid, adipic acid, benzoic acid, citric acid, camphoric acid, camphorsulfonic acid, bisphosphonates, dodecyl sulfate, ethane sulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrobromide hydrochloride, hydroiodide, 2-hydroxyethane sulfonate, lactate, maleate, oxalate.
By means of the technical scheme, the invention has at least the following advantages:
The invention provides a novel amide derivative which can be used as a sodium channel regulator, has high inhibition activity and high selectivity on Nav.18, has small influence on other sodium channels, and can reduce side effects of heart and central nervous system, thereby improving the treatment effect and safety on Nav.18-mediated related diseases, and being beneficial to expanding the clinical application range of medicaments. In addition, the amide derivatives provided by the invention have better pharmacokinetic properties, so that the medicine can be effectively absorbed and distributed to a target part, and proper concentration is kept in a body, so that a continuous treatment effect is realized; and the bioavailability is high, and the medicine can reach and act on target neurons in a sufficient quantity, so that the treatment effect is enhanced. Therefore, the novel amide derivatives have good application prospect in preparing medicaments for treating, relieving or preventing sodium channel regulation related diseases.
Detailed Description
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used herein in the description of the invention is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. The term "and/or" as used herein includes any and all combinations of one or more of the associated listed items. The term "comprising" or "comprises" as used herein means that it may include or comprise other components in addition to the components described. The term "comprising" or "comprising" as used herein may also be replaced by "being" or "consisting of" closed.
The present invention will be further described with reference to examples, which are not intended to be limiting, so that those skilled in the art will better understand the present invention and practice it.
Example 1
This example relates to the preparation of compound I-1, 1F1 (4- ((2 r,3s,4s,5 r) -3- (2- (difluoromethoxy-d) -3, 4-difluorophenyl) -4, 5-dimethyl-5- (trifluoromethyl) tetrahydrofuran-2-carboxamido) pyridine carboxamide), 1F2 (4- ((2 s,3r,4r,5 s) -3- (2- (difluoromethoxy-d) -3, 4-difluorophenyl) -4, 5-dimethyl-5- (trifluoromethyl) tetrahydrofuran-2-carboxamido) pyridine carboxamide) as follows:
The preparation process comprises the following steps:
(1) Compound 1a (prepared as disclosed in patent application "WO2021113627," instruction example 14) (500 mg,1.5 mmol) was dissolved in 10mL of tetrahydrofuran, naH (588 mg,14.7 mmol) was added, stirred at room temperature for 30 minutes, deuterium water (1.47 g,73.5 mmol) was added, after stirring for 30 minutes, bromofluoromethylphosphonic acid diethyl ester (785 mg,2.9 mmol) was added, reacted at room temperature for 1 hour, the reaction solution was extracted with ethyl acetate, the combined organic layers were washed with aqueous sodium chloride, dried over anhydrous sodium sulfate and evaporated to give crude product, and 1b (400 mg) was purified by silica gel column chromatography.
(2) To a mixture of compound 1b (1.0 g,2.8 mmol) in dichloromethane (20 mL) at 0deg.C was added oxalyl chloride (1.1 mL,14.0 mmol) and two drops of DMF, stirred at room temperature for 1 hour, the solvent was removed from the mixture under reduced pressure, then it was added to methyl 4-aminopicolinate (640 mg,4.2 mmol), triethylamine (850 mg,8.4 mmol) and DMAP (20 mg,0.1 mmol) in dichloromethane (6 mL), stirred at room temperature for 4 hours, the solvent was removed from the mixture under reduced pressure, and the crude mixture was purified by silica gel column chromatography to give 1c (1.1 g, yield: 79.7%).
Characterization data for compound 1c are as follows:
LCMS:526.1[M+H]，
1H NMR(400MHz,DMSO-d6)δ10.76(s,1H),8.58(d,J＝5.5Hz,1H),8.37(d,J＝2.1Hz,1H),7.86(dd,J＝5.5,2.2Hz,1H),7.47(dd,J＝9.8,7.8Hz,1H),7.34(dd,J＝8.5,5.9Hz,1H),5.17(d,J＝10.2Hz,1H),4.28(dd,J＝10.2,7.6Hz,1H),4.03(q,J＝7.1Hz,2H),3.87(s,3H),1.60(s,3H),0.81–0.69(m,3H).
(3) Compound 1c (200 mg,0.38 mmol) was added to 8mL of methanolic ammonia solution (7M) at ambient temperature and stirred overnight. Subsequently, the reaction mixture was concentrated in vacuo to give the objective compound I-1 (170 mg, yield: 89.5%).
(4) Resolution of compound I-1 (230 mg) by chiral column gave compound 1F1 (81 mg, yield: 35.2%), 1F2 (84 mg, yield: 36.4%); chiral resolution conditions:
Instrument: water 150PREPARATIVE SFC (SFC-26);
chromatographic column: CHIRALPAKAY, 250X 30mm I.D.,10 μm;
Mobile phase a: supercritical CO 2, mobile phase B: ethanol, gradient ratio: a: b=3:1, flow rate: 120mL/min.
Characterization data for compound 1F1 are as follows:
LCMS:511.1[M+H]，
1H NMR(400MHz,DMSO-d6)δ10.74(s,1H),8.50(d,J＝5.5Hz,1H),8.29(d,J＝2.1Hz,1H),8.09(d,J＝2.8Hz,1H),7.84(dd,J＝5.5,2.2Hz,1H),7.65(d,J＝2.8Hz,1H),7.57–7.39(m,1H),7.43–7.24(m,1H),5.17(d,J＝10.2Hz,1H),4.28(dd,J＝10.2,7.6Hz,1H),2.76(t,J＝7.5Hz,1H),1.60(s,3H),0.76(d,J＝7.3Hz,3H).
Chiral HPLC analysis results: the retention time was 1.970 minutes, the purity was 100% (chromatographic column: CHIRALPAK AY,150×4.6mm i.d.,3 μm, mobile phase a: supercritical CO 2, mobile phase B: ethanol, gradient ratio: b=5-40%, flow rate: 2.5 mL/min).
Characterization data for compound 1F2 are as follows:
LCMS:511.1[M+H]；
Chiral HPLC analysis results: the retention time was 2.317 minutes, the purity was 98.5% (column: CHIRALPAK AY,150×4.6mm i.d.,3 μm, mobile phase a: supercritical CO 2, mobile phase B: ethanol, gradient ratio: b=5-40%, flow rate: 2.5 mL/min).
Example 2
This example relates to the reaction of compound I-2, 2F1 (4- ((2 r,3s,4s,5 r) -3- (2- (difluoromethoxy-d) -5-fluorophenyl) -4, 5-dimethyl-5- (trifluoromethyl) tetrahydrofuran-2-carboxamide) 2F2 (4- ((2 s,3r,4r,5 s) -3- (2- (difluoromethoxy-d) -5-fluorophenyl) -4, 5-dimethyl-5- (trifluoromethyl) tetrahydrofuran-2-carboxamide) pyridine carboxamide), 2F3 (4- ((2 s,3r,4s,5 r) -3- (2- (difluoromethoxy-d) -5-fluorophenyl) -4, 5-dimethyl-5- (trifluoromethyl) tetrahydrofuran-2-carboxamide) 2F4 (4- ((2 r,3s,4r,5 s) -3- (2- (difluoromethoxy-d) -5-fluorophenyl) -4, 5-dimethyl-5- (trifluoromethyl) tetrahydrofuran-2-carboxamide) pyridine carboxamide) as follows:
The preparation process comprises the following steps:
(1) To a mixture of compound 2a (25 g,0.17 mol) in tetrahydrofuran (1L) were added triethylamine (52.6 g,0.52 mol) and 4-acetamidobenzenesulfonyl azide 2b (50 g,0.20 mol), the mixture was stirred at room temperature for 4 hours, the solvent was removed under reduced pressure, petroleum ether (500 mL) was then added, stirring was carried out for 30 minutes, the filtrate was collected by filtration and the solvent was removed under reduced pressure, and the crude mixture was purified by silica gel column chromatography to give ethyl 2-diazonium-3-oxopentanoate 2c (27 g, yield ：91.5％),1HNMR(400MHz,CHCl3-d)δ4.29(q,J＝7.1Hz,2H),2.86(q,J＝7.4Hz,2H),1.32(t,J＝7.1Hz,3H),1.13(t,J＝7.3Hz,3H).
(2) To a mixture of compound 2c (25 g,0.15 mol) and triethylamine (29.7 g,0.29 mol) in dichloromethane (300 mL), trimethylsilyl triflate (49 g,0.22 mol) was added at 0 degrees celsius after three nitrogen substitutions, stirred for 30 minutes at 0 degrees celsius, diluted with petroleum ether (500 mL), quenched with saturated sodium bicarbonate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and evaporated to give a crude mixture which was directly used in the next reaction. Titanium tetrachloride (25 g,0.13 mol) was slowly added to a mixture of trifluoroacetone (19.8 g,0.18 mol) in methylene chloride (300 mL) at-78℃and then the above-obtained crude mixture was further added to react for 3 hours at-78℃and quenched with water, methylene chloride (300 mL. Times.2) was extracted, the combined organic layers were washed with aqueous NaCl solution, dried over anhydrous Na 2SO4 and evaporated to give a crude mixture, and the crude mixture was purified by silica gel column chromatography to give ethyl (4R, 5S) -2-diazonium-6, 6-trifluoro-5-hydroxy-4, 5-dimethyl-3-oxohexanoate (2 d,10g, yield) ：24.1％),1H NMR(400MHz,CHCl3-d)δ4.33(q,J＝7.1Hz,2H),4.13(q,J＝7.0Hz,1H),3.99(s,1H),1.42(d,J＝1.2Hz,3H),1.35(t,J＝7.1Hz,3H),1.30(dd,J＝7.0,1.5Hz,3H).
(3) To a mixture of rhodium acetate dimer (157 mg,0.35 mmol) in toluene (100 mL) at 100deg.C was added compound 2d (10 g,35.5 mmol), stirred for 1 hour, and the mixture was depressurized to remove the solvent to give ethyl (4R, 5R) -4, 5-dimethyl-3-oxo-5- (trifluoromethyl) tetrahydrofuran-2-carboxylate (2 e,9g, yield) ：100％),1H NMR(400MHz,CHCl3-d)δ4.63(d,J＝1.5Hz,1H),4.26(t,J＝7.1Hz,2H),2.62(q,J＝7.2Hz,1H),2.36(s,3H),1.31(t,J＝7.1Hz,3H),1.25(dd,J＝7.3,1.9Hz,3H).
(4) To a mixture of compound 2e (9.5 g,37.4 mmol) in dichloromethane (100 mL), after three nitrogen substitutions, DIPEA (5.8 g,44.9 mol) and trifluoromethanesulfonic anhydride (10.5 g,37.4 mmol) were added at-78℃and kept at-78℃for 1 hour, the reaction was warmed to 0℃for 30 minutes, saturated sodium bicarbonate quench, dichloromethane (200 mL. Times.2) extraction, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and evaporated to give a crude mixture (2 f,14.4g, yield: 100%) which was directly used for the next reaction.
(5) To a mixture of compound 2f (3.7 g,9.5 mmol) in toluene (40 mL) was added (5-fluoro-2-methoxyphenyl) boronic acid 2g (1.8 g,10.5 mmol), tetrakis triphenylphosphine palladium (0.553 g,0.4 mmol) and potassium phosphate (6.1 g,28 mmol), after three nitrogen substitutions at 100 degrees celsius for 2 hours, quenched with water, extracted with ethyl acetate (300 mL x 2), the combined organic layers were washed with aqueous NaCl solution, dried over anhydrous Na 2SO4 and evaporated to give a crude mixture which was purified by silica gel column chromatography for 2h (1.6 g, yield ：46.3％),LCMS:362.9[M+H];1H NMR(400MHz,CHCl3-d)δ7.03–6.95(m,1H),6.91–6.85(m,1H),6.83–6.78(m,1H),4.20–4.06(m,2H),3.77(s,3H),1.68(s,3H),1.11(t,J＝7.1Hz,3H),1.08–1.02(m,3H).
(6) To a mixture of compound 2h (1.6 g,4.0 mmol) in dichloromethane (15 mL) at 0deg.C, nitrogen displacement was followed by addition of 1M boron tribromide (6.6 mL,6 mmol), stirring for 2h, saturated sodium bicarbonate quenching, extraction of dichloromethane (50 ml×2), washing the combined organic layers with aqueous NaCl solution, drying over anhydrous Na2SO4 and evaporation to give a crude mixture which was then dissolved in dichloromethane (50 mL), adding trifluoroacetic acid (1 g,8.0 mmol), stirring at 50deg.C for 16 h, waiting for natural cooling to room temperature, saturated sodium bicarbonate quenching, extraction of dichloromethane (30 ml×2), washing the combined organic layers with aqueous NaCl solution, drying over anhydrous Na 2SO4 and evaporation, addition of petroleum ether (200 mL), stirring for 30min, filtration and collection of solids to give compound 2i (1.2 g, yield) ：95％),LCMS:302.6[M+H];1H NMR(400MHz,DMSO-d6)δ7.60(dd,J＝9.0,3.0Hz,1H),7.54(dd,J＝9.1,4.6Hz,1H),7.39(td,J＝8.8,3.0Hz,1H),1.64(s,3H),1.45(dt,J＝6.6,2.0Hz,3H).
(7) To a mixture of compound 2i (6.5 g,19.34 mmol) in methanol (65 mL) was added palladium on carbon hydroxide (1.5 g), and after three hydrogen substitutions, the hydrogen pressure in the pressurizing device was brought to 10psi, stirred at room temperature for 16 hours, and the crude compound 2j (3.1 g, yield: 42.8%) was obtained by filtration with celite, which was directly used in the next reaction.
(8) To a mixture of compound 2j (1.3 g,3.8 mmol) in tetrahydrofuran (13 mL) was added sodium tert-butoxide (1.48 g,15 mmol) at 0 degrees celsius, stirred for 30 minutes at room temperature, adjusted to pH 1-2 with 2M hydrochloric acid in ice bath, quenched with water, extracted with ethyl acetate (200 x 2), the combined organic layers were washed with aqueous NaCl, dried over anhydrous Na 2SO4 and evaporated to give crude compound 2k (1.7 g) which was used directly in the next reaction.
(9) Compound 2k (1.7 g,5.2 mmol) was dissolved in 25mL of tetrahydrofuran solution, naH (1.26 g,52 mmol) was added, stirred at room temperature for 30 minutes, deuterium water (5.2 g,260 mmol) was added, after stirring for 30 minutes, bromofluoromethylphosphonic acid diethyl ester (2.8 g,10.4 mmol) was added, reacted at room temperature for 1 hour, the reaction solution was extracted with ethyl acetate, the combined organic layers were washed with aqueous sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to give a crude product, which was purified by silica gel column chromatography to give 2l (1.4 g) which was directly used for the next reaction ,LCMS:374.1[M+H];1HNMR(400MHz,DMSO-d6)δ7.34(dd,J＝10.0,2.9Hz,1H),7.26–7.13(m,2H),4.80(d,J＝10.1Hz,1H),4.03(dd,J＝10.2,7.3Hz,1H),2.66(t,J＝7.4Hz,1H),1.50(s,3H),0.78–0.62(m,3H).
(10) To a mixture of 2l (1.4 g,3.7 mmol) of the compound in dichloromethane (20 mL) at 0℃were added oxalyl chloride (2.3 g,18.7 mmol) and two drops of DMF, stirred at room temperature for 1 hour, the solvent was removed from the mixture under reduced pressure, then it was added to methyl 4-aminopicolinate (855 mg,5.6 mmol), triethylamine (1.13 g,11.2 mmol) and DMAP (23 mg,0.1 mmol) in dichloromethane (6 mL), stirred at room temperature for 4 hours, the solvent was removed from the mixture under reduced pressure, and the crude mixture was purified by silica gel column chromatography to give 2m (1.0 g, yield: 53.3%).
(11) Compound 2M (600 mg,1.1 mmol) was added to 17mL of methanolic ammonia solution (7M) at ambient temperature and stirred overnight. Subsequently, the reaction mixture was concentrated in vacuo to give the objective compound I-2 (300 mg, yield ：55.5％),LCMS:508.1[M+H];1H NMR(400MHz,DMSO-d6)δ8.58(d,J＝5.5Hz,1H),8.39(d,J＝2.1Hz,1H),7.87(dd,J＝5.4,2.2Hz,1H),7.39(dd,J＝9.9,2.8Hz,1H),7.31–7.20(m,2H),5.76(s,1H),5.20(d,J＝10.1Hz,1H),4.27(dd,J＝10.1,7.5Hz,1H),3.91–3.82(m,4H),1.61(s,3H),0.80–0.69(m,3H).
(12) Compound I-2 (400 mg) was purified by method 1: chiral column resolution (MG ii PREPARATIVE SFC (SFC-14), column: wheelk O1 (S, S), 250 x 30mm i.d.,10 μm, mobile phase a: supercritical CO2, mobile phase B: ethanol, gradient ratio: a: b=55:45, flow rate: 60 mL/min) to give compounds 2F1 (118 MG) and 2F2 (107 MG);
Compound I-2 (400 mg) was purified by method 2: chiral column resolution (MG IIPREPARATIVE SFC (SFC-13), column: cellulose-2, 250X 30mm I.D.,10 μm, mobile phase A: supercritical CO2, mobile phase B: isopropanol, gradient ratio: A: B=7:3, flow rate: 80 mL/min) gave compounds 2F3 (63 mg) and 2F4 (48 mg).
Characterization data for compound 2F1 are as follows:
LCMS:493.1[M+H]；
Chiral HPLC analysis results: retention time 0.899 min, purity 100% (column: whisk O1 (S, S), 250×4.6mm i.d.,5 μm, mobile phase a: supercritical CO 2, mobile phase B: ethanol, gradient ratio: b=40%, flow rate: 2.5 mL/min).
Characterization data for compound 2F2 are as follows:
LCMS:493.1[M+H]；
1H NMR(400MHz,DMSO-d6)δ10.67(s,1H),8.50(d,J＝5.5Hz,1H),8.30(d,J＝2.2Hz,1H),8.09(d,J＝2.8Hz,1H),7.85(dd,J＝5.5,2.2Hz,1H),7.64(d,J＝2.8Hz,1H),7.39(dd,J＝9.9,2.8Hz,1H),7.34–7.20(m,2H),5.19(d,J＝10.1Hz,1H),4.27(dd,J＝10.1,7.5Hz,1H),2.78(t,J＝7.5Hz,1H),1.61(s,3H),0.83–0.68(m,3H).
Chiral HPLC analysis results: retention time 1.368 min, purity 99.5% column: whelk O1 (S, S), 250X 4.6mm I.D.,5 μm, mobile phase A: supercritical CO 2, mobile phase B: ethanol, gradient ratio: b=40%, flow rate: 2.5 mL/min).
Characterization data for compound 2F3 are as follows:
LCMS:493.1[M+H]；
1H NMR(400MHz,DMSO-d6)δ10.36(s,1H),8.48(d,J＝5.6Hz,1H),8.24(d,J＝2.2Hz,1H),8.08(s,1H),7.63(s,2H),7.24(d,J＝6.4Hz,3H),4.66(d,J＝10.2Hz,1H),3.66(d,J＝10.7Hz,1H),2.91(dd,J＝12.4,6.5Hz,1H),1.46(s,3H),0.93(d,J＝6.8Hz,3H).
Chiral HPLC analysis results: the retention time was 2.965 minutes and the purity was 100% (column: cellulose-2, 150X 4.6mm I.D.,3 μm, mobile phase A: supercritical CO 2, mobile phase B: isopropanol, gradient ratio: B=5-40%, flow rate: 2.5 mL/min).
Characterization data for compound 2F4 are as follows:
LCMS:493.1[M+H]；
Chiral HPLC analysis results: the retention time was 3.302 minutes, the purity was 97.68% (column: cellulose-2, 150X 4.6mm I.D.,3 μm, mobile phase A: supercritical CO 2, mobile phase B: isopropanol, gradient ratio: B=5-40%, flow rate: 2.5 mL/min).
Test example 1
The compounds were tested for their inhibitory activity against Nav1.8 using the known Nav1.8 inhibitor A-803467 as a control, and are specifically as follows:
(1) The small slide with cells in the dish was placed in the perfusion cell of the micromanipulation station, and the tip of the glass electrode was found using a x 10 objective lens and placed in the center of the field of view. The electrode is moved down by the micromanipulator, and the coarse focusing spiral is adjusted at the same time, so that the electrode is gradually close to the cell, and the electrode is gradually close to the surface of the cell by fine shifting of the micromanipulator. Negative pressure is given to form a seal with a resistance higher than 1G between the electrode tip and the cell membrane.
(2) The instantaneous capacitance current Cfast is compensated in the voltage clamp mode. The slow capacitance current Cslow, cell membrane capacitance (Cm) and input membrane resistance (Ra) were compensated for under membrane potential clamping at-60 mV. After the cells are stable, the clamp voltage is changed to-80 mV for 200ms; the sampling frequency was set to 20kHz and the filtering frequency was 10kHz. The leakage current was detected at a depolarized membrane potential to-80 mV.
(3) The current stimulation method comprises the following steps: after cell clamping at-80 mV, a depolarization command voltage of 20ms was applied to-10 mV to open the channel. Stimulation was performed every 10 seconds. The instantaneous current peak at depolarization voltage is the magnitude of the nav1.8 sodium channel current.
(4) Test for inhibition of nav1.8 current: the Nav1.8 current measured in normal extracellular fluid was first used as a baseline for detection. After the Nav1.8 current has remained stable for at least 5 minutes, the solution containing the test compound is sequentially perfused around the cells from low to high concentrations. The last 5 nav1.8 current values were recorded after the current to be recorded had tended to stabilize and their average value was taken as their final current value at the specified concentration.
(5) Data analysis: the percent current suppression is calculated by the following formula:
Peak current inhibition ratio = [1- (peak current magnitude compound-peak current magnitude positive control)/(peak current magnitude blank control-peak current magnitude positive control) ]x100%;
The dose response curves were fitted by graphpadprism8.0 software and IC 50 values calculated.
The test results are shown in the following table:
TABLE 1
| Compounds of formula (I) | IC50(μM) |
| A-803467 | 1.572 |
| 1F1 | <0.0016 |
| 1F2 | 0.037 |
| 2F1 | 0.313 |
| 2F2 | >1 |
| 2F3 | >1 |
| 2F4 | >1 |
According to the inhibitory activity test result of Nav1.8, the novel amide derivatives provided by the invention have good inhibitory activity on Nav1.8, and the inhibitory activity of compounds 1F1, 1F2, 2F1 and the like on Nav1.8 is obviously better than that of A-803467. Wherein the IC 50 value of the compound 1F1 is less than 0.0016 mu M, and the compound shows extremely high inhibition activity on Nav1.8.
Test example 2
The compounds were tested for pharmacokinetic studies in rats using the known Nav1.8 inhibitor VX-548 as a control, as follows:
Experimental animals: SD male rats (purchased from SPF laboratory animal technologies limited), age: 6-8 weeks, body weight: 180-300 g.
The administration mode is as follows: intravenous (IV, 1 mg/kg); oral administration (PO, 10 mg/kg).
Blood collection time point: IV (0.083, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 10, 24 h); PO (0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 10, 24 h).
All blood samples were transferred to plastic microcentrifuge tubes containing anticoagulant, 4000g were centrifuged at 4℃for 5min, the supernatant was transferred to microcentrifuge tubes without anticoagulant, and the plasma was stored in a- (75.+ -.15) C freezer. LC-MS/MS analysis was performed after pretreatment.
Pharmacokinetic parameters were calculated using WinNonlin 8.3.1 software.
The test results are shown in table 2 below:
TABLE 2
In addition, as shown in table 2, the novel amide derivatives provided by the invention not only have high selectivity on Nav1.8, but also have the advantages of better pharmacokinetic property, high bioavailability and the like, and are beneficial to improving the treatment effect and safety on Nav.18-mediated related diseases and expanding the clinical application range of medicaments.
The above-described embodiments are merely preferred embodiments for fully explaining the present invention, and the scope of the present invention is not limited thereto. Equivalent substitutions and modifications will occur to those skilled in the art based on the present invention, and are intended to be within the scope of the present invention. The protection scope of the invention is subject to the claims.
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| AU2022285758A1 (en) * | 2021-06-04 | 2023-11-30 | Vertex Pharmaceuticals Incorporated | Substituted tetrahydrofuran analogs as modulators of sodium channels |
| CN117858875A (en) * | 2021-06-04 | 2024-04-09 | 沃泰克斯药物股份有限公司 | Hydroxyl and (halo)alkoxy substituted tetrahydrofurans as sodium channel modulators |
| WO2024041613A1 (en) * | 2022-08-24 | 2024-02-29 | 江苏恒瑞医药股份有限公司 | Heterocyclic compound, method for preparing same, and pharmaceutical use thereof |
| JP2025529931A (en) * | 2022-08-28 | 2025-09-09 | シャンハイ ホイルン ファーマシューティカル カンパニー リミテッド | Sodium channel modulators and their applications |
| WO2024217557A1 (en) * | 2023-04-19 | 2024-10-24 | 武汉人福创新药物研发中心有限公司 | Substituted tetrahydrofurans as nav1.8 inhibitors |
| CN120025321A (en) * | 2023-11-21 | 2025-05-23 | 武汉熙瑞医药科技有限公司 | A compound containing furan ring, its pharmaceutical composition and application thereof |
| CN118388466A (en) * | 2024-04-23 | 2024-07-26 | 安润医药科技（苏州）有限公司 | Amide derivatives as sodium channel modulators and uses thereof |
-
2024
- 2024-04-23 CN CN202410490663.XA patent/CN118388466A/en active Pending
-
2025
- 2025-04-01 CN CN202510398243.3A patent/CN120398854A/en active Pending
- 2025-04-08 WO PCT/CN2025/087765 patent/WO2025223193A1/en active Pending
Cited By (9)
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| WO2025092922A1 (en) * | 2023-11-02 | 2025-05-08 | Iongen Therapeutics Co., Ltd. | Compounds, compositions and methods thereof |
| WO2025108301A1 (en) * | 2023-11-21 | 2025-05-30 | 武汉熙瑞医药科技有限公司 | Furan ring-containing compound, pharmaceutical composition thereof, and use thereof |
| WO2025131100A1 (en) * | 2023-12-21 | 2025-06-26 | 武汉熙瑞医药科技有限公司 | Benzene ring-containing polycyclic compound, and pharmaceutical composition comprising same and use thereof |
| WO2025131099A1 (en) * | 2023-12-21 | 2025-06-26 | 武汉熙瑞医药科技有限公司 | Benzene ring-containing polycyclic compound, pharmaceutical composition comprising same, and use thereof |
| WO2025162194A1 (en) * | 2024-01-31 | 2025-08-07 | 上海汇伦医药股份有限公司 | Novel sodium channel modulator compound and use thereof |
| WO2025218764A1 (en) * | 2024-04-19 | 2025-10-23 | 广州市联瑞制药有限公司 | Compound as voltage-gated sodium channel inhibitor and use thereof |
| WO2025223193A1 (en) * | 2024-04-23 | 2025-10-30 | 安润医药科技（苏州）有限公司 | Amide derivative as sodium channel modulator and use thereof |
| WO2025252109A1 (en) * | 2024-06-04 | 2025-12-11 | 成都苑东生物制药股份有限公司 | Substituted tetrahydrofuran derivative, and preparation method therefor and use thereof |
| CN119285621A (en) * | 2024-12-13 | 2025-01-10 | 嘉兴安帝康生物科技有限公司 | Tetrahydrofuran carboxamide compounds as sodium channel modulators and their medical applications |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2025223193A1 (en) | 2025-10-30 |
| CN120398854A (en) | 2025-08-01 |
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