CN111548313A - Guanidine compounds as medicine for preventing and treating chronic pain - Google Patents

Guanidine compounds as medicine for preventing and treating chronic pain Download PDF

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CN111548313A
CN111548313A CN201911266613.9A CN201911266613A CN111548313A CN 111548313 A CN111548313 A CN 111548313A CN 201911266613 A CN201911266613 A CN 201911266613A CN 111548313 A CN111548313 A CN 111548313A
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阳怀宇
蒋若天
张乾森
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Shaoxing Zeroin Biomedicines Co ltd
East China Normal University
West China Hospital of Sichuan University
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East China Normal University
West China Hospital of Sichuan University
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Abstract

The invention relates to a guanidine compound shown as a general formula (I), a pharmaceutically acceptable salt thereof, a prodrug thereof, a solvate thereof, a deuteride or a stereoisomer thereof for preventing and treating chronic pain diseases, wherein R is1、R2、R3、R4、R5、Ar1、Ar2P and q are defined as in the specification; the invention also relates to a preparation method of the compound, a pharmaceutical composition and a pharmaceutical preparation containing the compound, and application of the compound in preparing medicaments for preventing or treating neuropathic pains such as herpes zoster pain, trigeminal neuralgia and migraine, pain symptoms such as acute and chronic inflammatory pains including pancreatitis and arthritis pain, and diseases such as sleep disorder caused by pain and other factors in mammals.

Description

Guanidine compounds as medicine for preventing and treating chronic pain
Technical Field
The invention relates to the field of medicinal chemistry, and relates to a guanidine compound of a medicament for preventing and treating chronic pain, a pharmaceutically acceptable salt, a prodrug, a solvate, a deutero-compound or a stereoisomer thereof, a preparation method of the compound, a pharmaceutical composition and a pharmaceutical preparation containing the compound, and application of the compound in preparing the medicament for preventing and treating chronic pain.
Background
Persistent and repeatedly intractable chronic pain makes patients suffer long-term affliction, even produces malignant emotional reactions such as anxiety, depression and the like. Only chronic pain patients in China exceed 3 million people, and the speed of more than ten million people per year is increased. At present, the clinical medication for treating pain mainly takes opioid analgesics, non-steroidal anti-inflammatory drugs, anticonvulsants, depressive drugs and other drugs. Opioids have good analgesic effect, however, these drugs have strong toxic side effects and bring great harm, for example, the number of deaths caused by drug abuse due to addiction exceeds that of traffic accidents in the United states. The non-steroidal anti-inflammatory drug has weak and poor curative effect and has strong side effects on gastrointestinal tract and cardiovascular aspect. The anticonvulsant pregabalin is a first-line medicine for treating neuropathic pain and herpes zoster, but the treatment effect is not ideal, and only half of patients who take the medicine are partially relieved. In addition, effective treatment of cancer pain is a key factor for improving the quality of life of cancer patients, but the existing drugs have poor effect on cancer pain, and new analgesic drugs are needed. Exploring new targets and new mechanisms for resisting pain, and developing new drugs with better analgesic effect and small toxic and side effects is urgent and trending for treating pain at present.
The two-hole potassium channel (K2P channel) is a new type of potassium channel superfamily discovered in recent years, and 15 members have been discovered. According to the coding gene sequence and functional characteristics, the 15 members are divided into six subfamilies, namely a TWIK subfamily, a TREK subfamily, a TASK subfamily, a TALK subfamily, a THIK subfamily and a TRESK subfamily. The structures of K2P channels such as TREK-1, TRAAK and TASK-3 are reported successively. It is widely believed that K2P channels are highly expressed on neurons [17], and that K2P channels play a key role in the stabilization of neuronal resting membrane potentials, since they can open at resting potentials, mediating background potassium ion leakage currents. Because of their key role in regulating cellular excitability, they are thought to play an important role in pain signaling. The existing gene knockout and knockdown experiments also support that K2P channels such as TASK-3 and the like are potential analgesic drug targets. The TASK-3 channel is highly expressed in peripheral DRG and in areas such as the granular cell layer of the central cerebral cortex and cerebellum. Early studies suggest that general anesthesia drugs such as halothane and isoflurane can excite the TASK-3 channel, the sensitivity of a mouse knocked out from the TASK-3 gene to the anesthesia drugs is reduced, and the mouse knocked out from the TASK-3 gene shows abnormal sleep and wake transition, so that the TASK-3 is highly concerned as an important molecular action target spot participating in general anesthesia mechanism and consciousness transition. In cerebellar granule cells, TASK-3 maintains the resting membrane potential of cells, thereby regulating the high-frequency emission of action potential. The TASK-3 channel is highly sensitive to extracellular pH change, and the function of the TASK-3 is obviously inhibited in an acidic environment. Most painful pathologies (including arthritis, nerve injury and surgery) are accompanied by acidification of the damaged tissue and inflammatory reactions, which necessitate significant inhibition of the physiological function of TASK-3 on the damaged tissue. The literature suggests that: under inflammatory pain, the mRNA expression level of TASK-3 was significantly reduced and the reduction in expression level was associated with spontaneous pain behavior. In addition, the results of the breast cancer gene screening conducted by Langford et al found the association of breast pain with a mutation in the KCNK9 gene (encoding the TASK-3 channel). Recently, Morenilla-Palao et al found that cold receptor TRPM8 channel positive DRG neurons highly express TASK-3 at the same time, and inhibition of TASK-3 causes TRPM8 positive neurons to lower the cellular excitability threshold caused by temperature change, suggesting that TRPM8 or TASK-3 synergize and induce cold. More importantly, the study showed that TASK-3 knockout mice exhibit cold pain sensitivity. These studies suggest that TASK-3 is involved in the perception of cold and heat in peripheral tissues. Linden et al found that in a mouse hot plate experiment, the analgesic effect of an exogenously synthesized cannabinoid analgesic drug, cannabinoid receptor CB1/CB2 agonist WIN55212-2, was significantly reduced in TASK-3 knockout mice, strongly suggesting that TASK-3 participates in cannabinoid analgesia. In addition, TASK-3 can be used as a clinical treatment target for improving sleep disorder. Studies have shown that TASK-3 knockout mice exhibit increased nocturnal behavior compared to wild-type mice (Anni-Maija Linden, he juournal OF pharmacologyang EXPERIMENTAL thermousage, 2007), slower progression OF THE transition from awake to sleep state, shorter sleep cycles in THE sleep phase and more fragmented REM theta oscillations (Daniel s.j.pang, PNAS,2009, kensukeyoshida, PNAS, 2018). Therefore, TASK-3 is activated or can be used as a therapeutic strategy for improving sleep.
In conclusion, through a series of molecular docking and screening, a novel compound with better TASK-3 agonistic activity is discovered to be used for treating pain symptoms such as acute and chronic inflammatory pain including but not limited to herpes zoster pain, trigeminal neuralgia, migraine and other neuropathic pain, pancreatitis, arthritis pain and the like, and sleep disorder caused by pain and other factors.
Disclosure of Invention
In order to meet clinical requirements, the invention provides guanidine compounds with better TASK-3 agonistic activity, and the specific technical scheme is as follows:
a compound represented by the general formula (I), a pharmaceutically acceptable salt thereof, a prodrug thereof, a solvate thereof, a deuteride thereof, or a stereoisomer thereof:
Figure BDA0002313026580000021
wherein X is selected from S, O or NH;
Ar1selected from benzene ring, naphthalene ring, benzo 5-7 membered heterocyclic group, benzo 3-8 membered cycloalkyl or 3-14 membered heterocyclic ring;
Ar2selected from benzene ring, naphthalene ring, benzo 5-7 membered heterocyclic group, benzo 3-8 membered cycloalkyl or 3-14 membered heterocyclic ring;
R1，R6selected from H, C substituted or unsubstituted by 1 to 3Q 11-10Alkyl, C substituted or unsubstituted by 1 to 3Q 12-10Alkenyl, C substituted or unsubstituted by 1 to 3Q 12-10Alkynyl, halogen, -COOR ', -NR ' R ', -OR ', -COR ', -CONR ', -O, -SR ', -SO3R′，-SO2NR′R″，-SOR′，-SO2R′，-NO2，-OCF3,-CF3,-C2F5，-C3F7Or — CN, 3-8 membered heterocycloalkyl substituted or unsubstituted with 1-3 of Q1, 1-3 of Q1 substituted or unsubstituted phenyl rings;
R2，R3，R4，R5selected from H, C substituted or unsubstituted by 1 to 3Q 11-10Alkyl, substituted or not by 1-3Q 1Substituted C2-10Alkenyl, C substituted or unsubstituted by 1 to 3Q 12-10Alkynyl, halogen, -COOR ', -NR ' R ', -OR ', -COR ', -CONR ', -O, -SR ', -SO3R′，-SO2NR′R″，-SOR′，-SO2R′，-NO2，-OCF3,-CF3,-C2F5，-C3F7Or — CN, 3-8 membered heterocycloalkyl substituted or unsubstituted with 1-3 of Q1, 1-3 of Q1 substituted or unsubstituted phenyl rings;
wherein said substituent Q1 is selected from the group consisting of C1-C8 linear OR branched hydrocarbyl, halogen, C3-C6 cycloalkane, C3-C6 cycloalkane (C1-C6) alkyl, C1-C8 linear OR branched alkoxy, -COOR ', -NR' R ', -OR', -COR ', -CONR' R ', -O, -SR', C1-C4 haloalkyl, amino, mercapto, cyano, nitro, hydroxy, trifluoromethyl, trifluoromethoxy, substituted OR unsubstituted with 1-3Q 2: an aromatic heterocyclic ring containing one to two oxygen or nitrogen, a heteroaryl (C1-C6) alkyl group containing one to two oxygen or nitrogen, a (C6-C12) fused heterocyclic (C1-C6) alkyl group containing one to two oxygen or nitrogen, a C5-C12 aryl (C1-C6) alkyl group, a phenoxy group, a benzyloxycarbonyl group,
wherein the substituent Q2 is selected from halogen, oxo, C1-C8 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, amino, mercapto, cyano, nitro, hydroxy, trifluoromethyl, trifluoromethoxy, phenyl or phenoxy, which is substituted or unsubstituted with 1 to 3Q 3,
wherein the substituent Q3 is selected from halogen, C1-C4 haloalkyl, amino, mercapto, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, wherein R ', R' are independently selected from: h, phenyl substituted or unsubstituted by 1 to 3Q 4, benzyl substituted or unsubstituted by 1 to 3Q 4, C1-10 alkyl substituted or unsubstituted by 1 to 3Q 4, C2-10 alkenyl substituted or unsubstituted by 1 to 3Q 4, C2-10 alkynyl substituted or unsubstituted by 1 to 3Q 4; alternatively, the radicals R 'and R' are joined together to form a 4-to 7-membered ring,
wherein said substituent Q4 is selected from the group consisting of halogen, -COOR ', -NR' R ', -OR', -COR ', -CONR' R ', -O, -SR', -SO3R′，-SO2NR′R″，-SOR′，-SO2R′，-NO2，-OCF3,-CF3,-C2F5，-C3F7Or a group of-CN groups,
m is 0,1 or 2; n is 0,1 or 2, and m + n is more than or equal to 1;
p is selected from 0,1,2,3,4 or 5, and when p is 2,3,4 or 5, R is1May be the same or different;
q is selected from 0,1,2,3,4 or 5, and when q is 2,3,4 or 5, R is6May be the same or different.
A compound represented by the general formula (II), a pharmaceutically acceptable salt thereof, a prodrug thereof, a solvate thereof, a deuteride thereof, or a stereoisomer thereof:
Figure BDA0002313026580000041
wherein R is1，R6，Ar1，Ar2X, p, q, m, n are defined as stated in claim 1.
A compound represented by the general formula (III), a pharmaceutically acceptable salt thereof, a prodrug thereof, a solvate thereof, a deuteride thereof, or a stereoisomer thereof:
Figure BDA0002313026580000042
wherein R is1，R6，Ar1，Ar2P, q, m, n are as defined in claim 1.
A compound represented by the general formula (IV), a pharmaceutically acceptable salt thereof, a prodrug thereof, a solvate thereof, a deuteride thereof, or a stereoisomer thereof:
Figure BDA0002313026580000043
wherein R is4’，R5' is selected from H, C substituted or unsubstituted by 1 to 3Q 11-10Alkyl, C substituted or unsubstituted by 1 to 3Q 12-10Alkenyl, C substituted or unsubstituted by 1 to 3Q 12-10Alkynyl, halogen, -COOR ', -NR ' R ', -OR ', -COR ', -CONR ', -O, -SR ', -SO3R′，-SO2NR′R″，-SOR′，-SO2R′，-NO2，-OCF3,-CF3,-C2F5，-C3F7Or — CN, 3-8 membered heterocycloalkyl substituted or unsubstituted with 1-3 of Q1;
R1，R6，Ar1，Ar2q1, p, Q, m, n are defined as stated in claim 1.
The compound of claim 1, a pharmaceutically acceptable salt thereof, a prodrug thereof, a solvate thereof, a deuteride thereof, or a stereoisomer thereof, having a structure represented by the following general formula (v):
Figure BDA0002313026580000044
r7, R8 is selected from H, C1-10 alkyl substituted OR unsubstituted by 1-3Q 1, C2-10 alkenyl substituted OR unsubstituted by 1-3Q 1, C2-10 alkynyl substituted OR unsubstituted by 1-3Q 1, halogen, -COOR ', -NR' R ', -OR', -COR ', -CONR', O, -SR ', -SO 3R', -SO2NR 'R', -SOR ', -SO 2R', -NO2, -OCF3, -CF3, -C2F5, -C3F7 OR-CN, 3-8 membered heterocycloalkyl substituted OR unsubstituted by 1-3Q 1, 1-3Q 1 substituted OR unsubstituted benzene rings;
the compound of claim 1, a pharmaceutically acceptable salt thereof, a prodrug thereof, a solvate thereof, a deuteride, or a stereoisomer thereof, having the structure of the following general formula (VI):
Figure BDA0002313026580000051
r9, R10 is selected from H, C1-10 alkyl substituted OR unsubstituted by 1-3Q 1, C2-10 alkenyl substituted OR unsubstituted by 1-3Q 1, C2-10 alkynyl substituted OR unsubstituted by 1-3Q 1, halogen, -COOR ', -NR' R ', -OR', -COR ', -CONR', O, -SR ', -SO 3R', -SO2NR 'R', -SOR ', -SO 2R', -NO2, -OCF3, -CF3, -C2F5, -C3F7 OR-CN, 3-8 membered heterocycloalkyl substituted OR unsubstituted by 1-3Q 1, 1-3Q 1 substituted OR unsubstituted benzene rings;
the invention aims to provide a novel guanidine compound;
the invention also relates to the use of said compounds for the preparation of a medicament for the prevention and treatment of chronic pain, and to compositions containing said compounds;
the invention also aims to provide a pharmaceutical composition, a health-care product composition or a food composition containing the guanidine compound.
Another object of the present invention is to provide a process for producing a guanidine compound.
It is another object of the present invention to provide a method for preventing or treating chronic pain disorders.
Detailed Description
The "halogen" as referred to herein means a fluorine atom, a chlorine atom, a bromine atom, an iodine atom or the like. Fluorine atom and chlorine atom are preferred.
The term "halo" as used herein means that any atom in the group which can be substituted is substituted by halogen, and can be perhalogenated, i.e., the halogen atom is substituted at all positions in the group which can be substituted.
Said "C" of the present invention1-10Alkyl "means a straight or branched chain alkyl group having 1 to 10 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 1, 2-dimethylpropyl, and the like. Preferably C1-7Alkyl radical, C1-3An alkyl group. Said "C" of the present invention1-3Alkyl "refers to the above examples containing 1 to 3 carbon atoms.
Said "C" of the present invention2-6Alkenyl "means a straight-chain or branched or cyclic alkenyl group having 2 to 6 carbon atoms containing a double bond, such as vinyl, 1-propenylAlkenyl, 2-propenyl, 1-methylethenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 3-methyl-1-butenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 2-methyl-3-butenyl, 2-methyl-2-butenyl, 2-methyl-pentenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, 1-dimethyl-2-propenyl, 1, 2-dimethyl-1-propenyl, 1, 2-dimethyl-2-propenyl, 1-ethyl-1-propenyl, 1-ethyl-2-propenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 3-methyl-1-pentenyl, 4-methyl-1-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-methyl-1-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 1-methyl-hexenyl, 1-hexenyl, 2-methyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1-dimethyl-2-butenyl, 1-dimethyl-3-butenyl, 1, 2-dimethyl-1-butenyl, 1, 2-dimethyl-2-butenyl, 1, 2-dimethyl-3-butenyl, 1-methyl-3-pentenyl, 3-methyl-3-pentenyl, 3-methyl-pentenyl, 4-methyl-pentenyl, 1-dimethyl-2-butenyl, 1,1, 3-dimethyl-1-butenyl, 1, 3-dimethyl-2-butenyl, 2-dimethyl-3-butenyl, 2, 3-dimethyl-1-butenyl, 2, 3-dimethyl-2-butenyl, 2, 3-dimethyl-3-butenyl, 3-dimethyl-1-butenyl, 3-dimethyl-2-butenyl, 1-ethyl-1-butenyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 2-ethyl-1-butenyl, 2-ethyl-2-butenyl, 2-methyl-3-butenyl, 2-methyl-2-butenyl, 2-methyl-butenyl, 2-ethyl-3-butenyl, 1, 2-trimethyl-2-propenyl, 1-ethyl-1-methyl-2-propenyl, 1-ethyl-2-methyl-1-propenyl, 1-ethyl-2-methyl-2-propenyl, 1, 3-butadienyl, 1, 3-pentadienyl, 1, 4-pentadienyl, 2, 4-pentadienyl, 1, 4-hexadienyl, 2, 4-hexadienyl, cyclopentenyl, 1, 3-cyclopentadienyl, cyclohexenyl, 1, 4-cyclohexadienyl and the like. The double bond may optionally be cis and trans.
Said "C" of the present invention2-6Alkynyl "refers to a straight or branched chain alkynyl group of 2-6 carbon atoms containing a triple bond, such as acetyleneA group selected from the group consisting of 1-propynyl group, 2-butynyl group, 3-butynyl group, 1-methyl-2-propynyl group, 2-pentynyl group, 3-pentynyl group, 4-pentynyl group, 1-methyl-2-butynyl group, 1-methyl-3-butynyl group, 2-methyl-3-butynyl group, 1-dimethyl-2-propynyl group, 1-ethyl-2-propynyl group, 2-hexynyl group, 3-hexynyl group, 4-hexynyl group, 5-hexynyl group, 1-methyl-2-pentynyl group, 4-methyl-2-pentynyl group, 1-methyl-3-pentynyl group, 2-methyl-3-pentynyl group, and the like, 1-methyl-4-pentynyl, 2-methyl-4-pentynyl, 3-methyl-4-pentynyl, 1-dimethyl-2-butynyl, 1-dimethyl-3-butynyl, 1, 2-dimethyl-3-butynyl, 2-dimethyl-3-butynyl, 1-ethyl-2-butynyl, 1-ethyl-3-butynyl, 2-ethyl-3-butynyl, 1-ethyl-1-methyl-2-propynyl and the like.
Said "C" of the present invention1-6Alkoxy "means" C1-6Alkyl "a group bonded to another structure through an oxygen atom, such as methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, 1-dimethylethoxy, pentyloxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1-dimethylpropyloxy, 1, 2-dimethylpropyloxy, 2-dimethylpropyloxy, 1-ethylpropyloxy, hexyloxy, 1-methylpentyloxy, 2-methylpentyloxy, 3-methylpentyloxy, 4-methylpentyloxy, 1-dimethylbutyloxy, 1, 2-dimethylbutyloxy, 1, 3-dimethylbutyloxy, 2-dimethylbutyloxy, 1-methylpropyloxy, 1-dimethylbutyloxy, 2-dimethylbutyloxy, 1-methylpropyloxy, 1-dimethylbutyloxy, 1-methylpropyloxy, 2, 3-dimethylbutyloxy, 3-dimethylbutyloxy, 1-ethylbutoxy, 2-ethylbutoxy, 1, 2-trimethylpropoxy, 1,2, 2-trimethylpropoxy, 1-ethyl-1-methylpropyloxy and 1-ethyl-2-methylpropyloxy. The term "C1-3The "alkoxy group" refers to a specific example containing 1 to 3 carbon atoms among the above examples.
Said "C" of the present invention1-6Alkylcarbonyl "refers to the term" C1-6Alkyl "a group attached to another structure through a carbonyl group, such as methylcarbonyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl, isobutylcarbonyl, tert-butylcarbonyl, sec-butylcarbonyl, pentylcarbonyl, neopentylcarbonyl, hexylcarbonyl, and the like.
Said "C" of the present invention1-6Alkoxycarbonyl "is the term" C1-6Alkoxy "a group bonded to another structure through a carbonyl group, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, sec-butoxycarbonyl, pentyloxycarbonyl, neopentyloxycarbonyl, hexyloxycarbonyl, etc.
The "3-to 14-membered cycloalkyl" as used herein means a cyclic alkyl group derived from an alkane moiety of 3 to 14 carbon atoms by removing one hydrogen atom, and includes a 3-to 8-membered monocyclic cycloalkyl group, a 6-to 14-membered fused cycloalkyl group, a 7-to 12-membered bridged cyclic group and a 7-to 12-membered spiro cyclic group. Preferably C3-8Cycloalkyl radical, C3-6Cycloalkyl and C5-6A cycloalkyl group. The term "C3-8Cycloalkyl group "," C3-6Cycloalkyl group "," C5-6Cycloalkyl "is a specific example containing 3 to 8, 3 to 6, and 5 to 6 carbon atoms in the following examples, respectively.
3-8 membered monocyclic cycloalkyl groups, including 3-8 membered saturated monocyclic cycloalkyl groups and 3-8 membered partially saturated monocyclic cycloalkyl groups. 3-8 membered saturated monocyclic cycloalkyl, meaning that the monocyclic ring is fully saturated carbocyclic, examples of which include, but are not limited to: cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, methylcyclopropane, dimethylcyclopropane, methylcyclobutane, dimethylcyclobutane, methylcyclopentane, dimethylcyclopentane, methylcyclohexane, dimethylcyclohexane, etc. 3-8 membered partially saturated monocyclic cycloalkyl, meaning that the monocyclic ring is a partially saturated carbocyclic ring, examples of which include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, 1, 4-cyclohexadienyl, cycloheptenyl, 1, 4-cycloheptadienyl, cyclooctenyl, 1, 5-cyclooctadienyl, and the like;
"C" according to the invention3-8Cycloalkoxy "refers to the term" C3-8Cycloalkyl "a group attached to another structure through an oxygen atom, such as cyclopropyloxy, cyclobutyloxy, 1-methylcyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, cyclooctyloxy, and the like.
The "6-14 membered aryl" as referred to herein means a cyclic aromatic group having 6-14 membered carbon atoms as ring atoms, and includes 6-8 membered monocyclic aryl and 8-14 membered fused ring aryl. The 6-8 membered monocyclic aryl group means an all unsaturated aryl group such as phenyl, cyclooctatetraenyl and the like. The 8-to 14-membered fused ring aryl group means a cyclic group formed by two or more cyclic structures sharing two adjacent carbon atoms with each other and having at least one ring being an all unsaturated aromatic ring, and includes 8-to 14-membered all unsaturated fused ring aryl, naphthyl, anthryl, phenanthryl and the like, and also includes 8-to 14-membered partially saturated fused ring aryl groups such as benzo 3-to 8-membered saturated monocyclic cycloalkyl, benzo 3-to 8-membered partially saturated monocyclic cycloalkyl, and specific examples thereof are 2, 3-dihydro-1H-indenyl, 1,2,3, 4-tetrahydronaphthyl, 1, 4-dihydronaphthyl and the like. Preferably 6-to 10-membered aryl, more preferably benzene or a benzo 3-to 8-membered saturated monocyclic cycloalkyl, a benzo 3-to 8-membered partially saturated monocyclic cycloalkyl. The term "6-to 10-membered aryl" refers to a specific example of the above-mentioned "aryl" having 6 to 10 ring atoms.
The "5-to 14-membered heteroaryl" includes one or more heteroatoms in addition to carbon atoms in the ring, including but not limited to oxygen, nitrogen, and sulfur atoms. Heteroaryl groups may be bonded through carbon or a heterocyclic atom. Including 5-8 membered monocyclic heteroaryl and 8-14 membered fused heterocyclic aryl. 5-8 membered monocyclic heteroaryl groups include, but are not limited to, pyrrolyl, imidazolyl, pyrazolyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, pyridyl, furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2, 3-thiadiazolyl, 1,2, 4-thiadiazolyl, 1,3, 4-thiadiazolyl, 1,2, 3-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,2, 3-triazinyl, 1,2, 4-triazinyl, tetrazolyl, oxadiazolyl, 2H-1, 2-oxazinyl, 4H-1, 2-oxazinyl, 6H-1, 2-oxazinyl, 2H-1, 3-oxazinyl, 4H-1, 3-oxazinyl, 6H-1, 3-oxazinyl, 2H-1, 4-oxazinyl, 4H-1, 4-oxazinyl, isooxazinyl, pyridazinyl, pyrimidinyl, pyrazinyl and the like; 8-14 membered fused heterocyclic aryl groups include, but are not limited to, benzofuranyl, isobenzofuranyl, benzothienyl, indolyl, isoindolyl, quinolinyl, isoquinolinyl, indolizinyl, indazolyl, phthalazinyl, quinoxalinyl, quinazolinyl, benzodiazinyl, benzisoxazolyl, benzoxazinyl, benzimidazolyl, pyridopyridyl, pyrazolo [3,4-b ] pyridyl, purinyl, acridinyl, xanthenyl, and the like.
The term "3-14 membered heterocyclic group" as used herein means a 3-14 membered cyclic group containing one or more heteroatoms, wherein the "heteroatom" means N, S, O, SO and/or SO2And the like. Including saturated, partially saturated, unsaturated having 1-4 substituents selected from N, S, O, SO and/or SO2And saturated, partially saturated, unsaturated, 5-14 membered heteromonocyclic group. Also included are the heteroaryl groups mentioned above and their dihydro and tetrahydro analogs. 5-14 membered diheterocyclyl includes saturated, partially saturated, unsaturated having 1-4 substituents selected from N, S, O, SO and/or SO2Fused, spiro, bridged rings of heteroatoms of (a). Preferred is a 3-to 8-membered heterocyclic group, and further preferred is a saturated, partially saturated, unsaturated 3-to 8-membered heteromonocyclic group. More preferred is a 5-8-membered, 5-7-membered, 5-6-membered heterocyclic group, and further preferred is a saturated, partially saturated, unsaturated 5-8-membered, 5-7-membered, 5-6-membered heteromonocyclic group.
The term "3-to 8-membered heterocyclyl" as used herein means a compound containing 3 to 8 ring atoms (at least one heteroatom selected from N, S, O, SO and/or SO)2) The monocyclic heterocyclic group of (1) includes a 3-8-membered unsaturated monocyclic heterocyclic group, a 3-8-membered partially saturated monocyclic heterocyclic group and a 3-8-membered saturated monocyclic heterocyclic group. 3-8 membered unsaturated heteromonocyclic group and 3-8 membered partially saturated heteromonocyclic group, which means 3-8 membered heterocyclic group in which unsaturated bond exists in ring, preferably 5-7 membered unsaturated heteromonocyclic group and 5-7 membered partially saturated heteromonocyclic group, specific examples include, but are not limited to, including, but not limited to, for example, the following groups: azetidine, 1, 2-diazacyclobutene, pyrrole, 4, 5-dihydropyrrole, 2, 5-dihydropyrrole, imidazole, 4, 5-dihydroimidazole, pyrazole, 4, 5-dihydropyrazole, 1,2, 3-triazole, 1,2, 4-triazole, pyridine, 2-pyridone, 4-pyridone, pyridazine, pyrimidine, pyrazine, 1,2, 3-triazine, 1,2, 4-triazine, azepane, 1, 2-diazepane, 1, 3-diazepane, 1, 4-diazepane, azacyclooctatetraene, 1, 4-dihydro-1, 4-diazacyclooctatriene, 1, 2-dithiocyclobutene, furan, 4, 5-dihydrofuran, 2, 5-dihydrofuran, Thiophene, 2, 5-dihydrothiophene, 4, 5-dihydrothiophene, 1, 2-dithiolene, 1, 3-dithiolaneAlkenes, 2H-pyrans, 2H-pyran-2-ones, 3, 4-dihydro-2H-pyrans, 4H-pyran-4-ones, 1, 4-dioxadienes, 1, 4-dithiines, 1, 4-oxathiahexadienes, oxepines, thieepines, 1, 4-dioxaoctatrienes, oxazoles, 4, 5-dihydrooxazoles, 2, 3-dihydrooxazoles, isoxazoles, 4, 5-dihydroisoxazoles, 2, 3-dihydroisoxazoles, 1,2, 3-oxadiazoles, 1,2, 5-oxadiazoles, thiazoles, 4, 5-dihydrothiazoles, 2, 3-dihydrothiazoles, isothiazoles, 1,2, 3-thiadiazoles, 2H-1, 2-oxazine, 4H-1, 2-oxazine, 6H-1, 2-oxazine, 2H-1, 3-oxazine, 4H-1, 3-oxazine, 5, 6-dihydro-4H-1, 3-oxazine, 6H-1, 3-oxazine, 2H-1, 4-oxazine, 4H-1, 4-oxazine, 2H-1, 3-thiazine, 4H-1, 3-thiazine, 5, 6-dihydro-4H-1, 3-thiazine, 6H-1, 3-thiazine, 2H-1, 4-thiazine, 4H-1, 4-thiazine group, and the like. Among them, preferred are azetidine, 1, 2-diazacyclobutene, pyrrole, dihydropyrrole, imidazole, 4, 5-dihydroimidazole, pyrazole, 4, 5-dihydropyrazole, pyridine, 2-pyridone, 4-pyridone, pyridazine, pyrimidine, pyrazine, azepane, 1, 2-dithiacyclobutene, furan, thiophene, 2, 5-dihydrothiophene, 1, 2-dithiacyclopentene, 2H-pyran-2-one, 3, 4-dihydro-2H-pyran, 4H-pyran-4-one, 1, 4-dioxadiene, 1, 4-dithiadiene, 1, 4-oxathiadiene, oxepine, 1, 4-dioxacyclooctatriene, Oxazole, 4, 5-dihydrooxazole, isoxazole, 4, 5-dihydroisoxazole, 2, 3-dihydroisoxazole, 1,2, 3-oxadiazole, 1,2, 5-oxadiazole, thiazole, 4, 5-dihydrothiazole, isothiazole, 1,2, 3-thiadiazole, 2H-1, 2-oxazine, 4H-1, 2-oxazine, 6H-1, 2-oxazine, 2H-1, 3-oxazine, 4H-1, 3-oxazine, 5, 6-dihydro-4H-1, 3-oxazine, 6H-1, 3-oxazine, 2H-1, 4-oxazine, 4H-1, 4-oxazine, 2H-1, 3-thiazine, 4H-1, 3-thiazine, 2H-1, 3-oxazine, 2H-1, 3-thiazine, 2H-1, 3-oxa, 5, 6-dihydro-4H-1, 3-thiazine, 6H-1, 3-thiazine, 2H-1, 4-thiazine, 4H-1, 4-thiazine, morpholine, 1,3, 4-thiadiazole group. More preferred are pyrrole, dihydropyrrole, imidazole, 4, 5-dihydroimidazole, pyrazole, 4, 5-dihydropyrazole, pyridine, pyridazine, pyrimidine, pyrazine, furan, thiophene, 2, 5-dihydrothiophene, 2H-pyran-2-one, 3, 4-dihydro-2H-pyran, 4H-pyran-4-one, 1, 4-dioxadiene, 1, 4-dithiine, 1, 4-oxathiiraneDiene, oxazole, 4, 5-dihydrooxazole, isoxazole, 4, 5-dihydroisoxazole, 2, 3-dihydroisoxazole, 1,2, 3-oxadiazole, 1,2, 5-oxadiazole, thiazole, 4, 5-dihydrothiazole, isothiazole, 1,2, 3-thiadiazole, 1,2, 4-thiadiazole, 1,3, 4-thiadiazole group, and the like; 3-8 membered saturated heteromonocyclic group means a heteroatom-containing cyclic group having all saturated bonds, preferably 5-7 membered saturated heteromonocyclic group, specific examples include but are not limited to: aziridine, azetidine, 1, 2-diazetidine, pyrrolidine, imidazolidine, pyrazolidine, hydropyridone, piperidine, piperazine, ethylene oxide, thietane, oxetane, 1, 2-dioxetane, thietane, tetrahydrofuran, tetrahydrothiophene, 1, 3-dioxolane, 1, 3-dithiolane, tetrahydropyran, 1, 4-dioxane, 1, 3-oxathiane, oxazolidine, morpholine groups, and the like; among them, aziridine, azetidine, pyrrolidine, imidazolidine, pyrazolidine, hydropyridone, piperidine, piperazine, ethylene oxide, tetrahydrofuran, tetrahydrothiophene, 1, 3-dioxolane, 1, 3-dithiolane, tetrahydropyran, 1, 4-dioxane, 1, 3-oxathiane, oxazolidine, morpholine group and the like are preferable.
The terms 3-8 membered heterocyclic group, 5-7 membered heterocyclic group, 5-6 membered heterocyclic group mean specific examples in which the number of ring atoms in the above-mentioned "3-14 membered heterocyclic group" is 3-8, 5-7, 5-6 membered.
The term "3-to 8-membered" as used herein means 3,4,5,6,7, 8-membered, preferably 5-to 8-membered. Further preferably 5 to 7 membered. Even more preferably 5-6 membered. The 5-8 yuan means 5,6,7 and 8 yuan, and the 5-7 yuan means 5,6 and 7 yuan.
The "5-to 7-membered heterocyclic group" according to the present invention includes, but is not limited to, for example, aziridine, azetidine, 1, 2-diazetidine, pyrrolidine, imidazolidine, pyrazolidine, hydropyridone, piperidine, piperazine, ethylene oxide, thietane, oxetane, 1, 2-dioxetane, thietane, tetrahydrofuran, tetrahydrothiophene, 1, 3-dioxolane, 1, 3-dithiolane, tetrahydropyran, 1, 4-dioxane, 1, 3-oxathiane, oxazolidine, morpholine group and the like; among them, preferred are aziridine, azetidine, pyrrolidine, imidazolidine, pyrazolidine, hydropyridone, piperidine, piperazine, ethylene oxide, tetrahydrofuran, tetrahydrothiophene, 1, 3-dioxolane, 1, 3-dithiolane, tetrahydropyran, 1, 4-dioxane, 1, 3-oxathiane, oxazolidine, morpholine groups and the like;
the term "halo (C)1-6Alkyl) group "means the above-mentioned C substituted by the same or different 1 to 6 of the above-mentioned halogen atoms1-6Alkyl groups such as trifluoromethyl, pentafluoroethyl, or the like.
The term "C1-4The acyl group "means a straight or branched acyl group having 1 to 4 carbon atoms, such as formyl, acetyl, propionyl, butyryl, isobutyryl, or the like.
The term "aryl" refers to a monocyclic to tricyclic aromatic hydrocarbon group, such as phenyl, naphthyl, or the like.
The term "aralkyl" refers to C substituted with an aryl group as described above1-6An alkyl group.
The term "aromatic heterocyclic ring containing one to two oxygen or nitrogen atoms" means a furan ring, pyridine ring, pyrimidine ring, pyrrole ring, pyrazine ring, pyridazine ring, triazine ring, or the like.
The term "C3-C6Heterocycloalkyl "refers to a pyrrole ring, a piperidine ring, a morpholine ring, a piperazine ring, or similar groups.
The term "C5-C12Aryl "refers to benzyl, phenethyl, naphthylmethylene, or similar groups
Particularly preferred compounds include:
Figure BDA0002313026580000101
Figure BDA0002313026580000111
Figure BDA0002313026580000121
Figure BDA0002313026580000131
Figure BDA0002313026580000141
the present invention also provides a pharmaceutical composition for treating or preventing an analgesic disease, comprising: (a) a prophylactically or therapeutically effective amount of an active ingredient of the invention of formula (I); and (b) a pharmaceutically acceptable carrier, excipient or sustained release agent.
In the present invention, the term "comprising" means that various ingredients can be used together in the mixture or composition of the present invention. Thus, the terms "consisting essentially of and" consisting of are encompassed by the term "comprising.
In the present invention, a "pharmaceutically acceptable" component is a substance that is suitable for use in humans and/or animals without undue adverse side effects (such as toxicity, irritation, and allergic response) commensurate with a reasonable benefit/risk ratio.
In the present invention, the "pharmaceutically acceptable carrier" is a pharmaceutically acceptable solvent, suspending agent or excipient for delivering the active substance of the present invention or a physiologically acceptable salt thereof to animals or humans. The carrier may be a liquid or a solid.
In the present invention, the pharmaceutical composition comprises a safe and effective amount (e.g., 0.001 to 99.9 parts by weight, more preferably 0.01 to 99 parts by weight, and still more preferably 0.1 to 90 parts by weight) of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier or excipient, wherein the total weight of the composition is 100 parts by weight.
Alternatively, the pharmaceutical composition of the present invention comprises 0.001 to 99.9 wt%, preferably 0.01 to 99 wt%, more preferably 0.1 to 90 wt% of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier or excipient, wherein the total weight of the composition is 100% by weight.
In another preferred embodiment, the preferred ratio of the compound of formula (I) to the pharmaceutically acceptable carrier, excipient or sustained release agent is such that the total weight of the active ingredient of formula (I) is more than 65%, and the remainder is 0.5-40%, or more preferably 1-20%, or most preferably 1-10%.
The pharmaceutical composition of the present invention can be prepared in various forms, and the unit dose thereof contains 0.05mg to 500mg, preferably 0.5mg to 200mg, more preferably 0.1mg to 100mg of the compound of formula (I), enantiomer, racemate, pharmaceutically acceptable salt or mixture thereof.
When the pharmaceutical composition contains an additional pharmaceutical active ingredient for treating or preventing chronic pain diseases, the amount of the active ingredient can be generally the conventional amount in the prior art or less.
The pharmaceutical compositions of the present invention may be in a variety of forms such as tablets, capsules, powders, syrups, solutions, suspensions, aerosols, and the like, wherein the compound of formula (I) may be present in a suitable solid or liquid carrier or diluent. The pharmaceutical compositions of the present invention may also be stored in a suitable injection or drip sterilization device. The pharmaceutical composition may also comprise flavoring agent, etc.
The compound of formula (I) or the pharmaceutical composition comprising the compound of formula (I) of the present invention can be clinically administered to mammals (including humans) through oral, nasal, dermal, pulmonary or gastrointestinal routes of administration. The preferred route of administration is oral. The preferred daily dosage is 0.5mg-200mg/kg body weight, administered once or in portions. Regardless of the method of administration, the optimal dosage for an individual will depend on the particular treatment. Usually starting with a small dose and gradually increasing the dose until the most suitable dose is found.
The effective dose of the active ingredient employed may vary with the compound employed, the mode of administration and the severity of the condition being treated. However, in general, satisfactory results are obtained when the compounds of the invention are administered at a dose of about 1 to 300mg/kg animal body weight per day, preferably 1 to 3 divided doses per day, or in sustained release form. For most large mammals, the total daily dose is from about 5 to about 1000mg, preferably from about 10 to about 500 mg. A dosage form suitable for oral administration comprising about 1-200mg of the active compound in intimate admixture with a solid or liquid pharmaceutically acceptable carrier. This dosage regimen may be adjusted to provide the best therapeutic response. For example, divided doses may be administered several times per day, or the dose may be proportionally reduced, as may be required by the urgency of the condition being treated.
The compounds or pharmaceutically acceptable salts thereof and compositions thereof can be administered orally, as well as intravenously, intramuscularly or subcutaneously. Preferred pharmaceutical compositions are solid compositions, especially tablets and solid-filled or liquid-filled capsules, from the standpoint of ease of preparation and administration. Oral administration of the pharmaceutical composition is preferred.
The solid support comprises: starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose and kaolin, and liquid carriers include: sterile water, polyethylene glycols, non-ionic surfactants and edible oils (such as corn, peanut and sesame oils) as are appropriate to the nature of the active ingredient and the particular mode of administration desired. Adjuvants commonly used in the preparation of pharmaceutical compositions may also advantageously be included, for example flavouring agents, colouring agents, preservatives and antioxidants such as vitamin E, vitamin C, BHT and BHA.
The active compounds or pharmaceutically acceptable salts thereof and compositions thereof may also be administered parenterally or intraperitoneally. Solutions or suspensions of these active compounds (as the free base or pharmaceutically acceptable salt) may also be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquids, polyethylene glycols and mixtures thereof in oils. Under normal conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
The pharmaceutical forms suitable for injection include: sterile aqueous solutions or dispersions and sterile powders (for the extemporaneous preparation of sterile injectable solutions or dispersions). In all cases, these forms must be sterile and must be fluid to facilitate the syringe to expel the fluid. Must be stable under the conditions of manufacture and storage and must be resistant to the contaminating effects of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, alcohols (for example, glycerol, propylene glycol and liquid polyethylene glycols), suitable mixtures thereof and vegetable oils.
The compound shown in the formula (I) or the pharmaceutically acceptable salt and the composition thereof can also be combined with other active ingredients or medicines for treating or preventing chronic pain diseases. When two or more drugs are administered in combination, the effect is generally superior to that when the two drugs are administered separately.
The pharmaceutically acceptable salt of any one of the above compounds of the invention refers to a pharmaceutically acceptable salt, which includes (but is not limited to): (1) salts with the following inorganic acids: such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid; (2) salts with organic acids such as acetic acid, oxalic acid, succinic acid, tartaric acid, methanesulfonic acid, maleic acid, or arginine. Other salts include those formed with alkali or alkaline earth metals (e.g., sodium, potassium, calcium or magnesium), in the form of esters, carbamates, or other conventional "prodrugs".
The compounds of the invention in free form can be converted to the corresponding compounds in salt form and vice versa. The compounds of the invention in free form or in salt form and/or solvate form can be converted into the corresponding compounds in non-solvate form, in free form or in salt form; and vice versa.
The term "solvate" is used herein to describe a molecular complex comprising a compound of the invention and a stoichiometric amount (stoichiometric amount) of one or more molecules of a pharmaceutically acceptable solvent, such as ethanol. When the solvent is water, the term "hydrate" is used.
Prodrugs, such as esters, and the like, of the compounds to which the present invention relates are also part of the present invention. By "prodrug" is meant a compound that can be converted in vivo by metabolic means (e.g., by hydrolysis, reduction or oxidation) to the compound of formula (I). For example, ester prodrugs of compounds of formula (I) may be converted in vivo to the parent molecule by hydrolysis. Examples of ester prodrugs are those described in f.j.leinweber, drug metab.res, 1987, 18, 379. As used herein, reference to the meaning of the compounds of formula (I) also includes prodrug forms.
The present invention relates to "stereoisomers" of compounds of formula (I), which contain one or more asymmetric centers and thus may be present as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. The compounds of the present invention have asymmetric centers that each independently produce two optical isomers, and the scope of the present invention includes all possible optical isomers and diastereomeric mixtures and pure or partially pure compounds. The present invention includes all stereoisomeric forms of these compounds. The compounds of formula (I) according to the invention or their pharmaceutically acceptable salts may exist as one optical isomer due to the presence of an asymmetric carbon atom, and therefore the invention also includes these optical isomers and mixtures thereof. The structures described herein are also intended to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational) forms of the structures described; for example, R and S configurations, Z and E double bond isomers, and Z and E conformational isomers with respect to each asymmetric center. Thus, single stereochemical isomers as well as mixtures of enantiomers, diastereomers and geometric isomers (or conformers) of the compounds of the present invention are within the scope of the present invention. Unless otherwise specified, all tautomeric forms of the compounds of the invention are within the scope of the invention.
The present invention relates to the "deuterons" of the compounds of formula (I), the structures of the compounds of the invention also including compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the structure of the present invention but including hydrogen replaced with deuterium or tritium or carbon replaced with enriched or carbon are within the scope of the present invention. Such compounds may be used, for example, as analytical tools, probes in biological assays, or therapeutic agents of the invention. In some embodiments, one or more deuterium atoms are included in formula (I).
The amide-based compound of the present invention has 1 or more chiral centers. The synthesis is racemic, and the desired enantiomerically pure compound can be obtained by chiral resolution: chromatography with a chiral stationary phase (like high pressure preparative liquid phase, supercritical fluid chromatography) can be used. Chiral fillers include, but are not limited to: chiralcel OJ-H, ChiralpakAD-H, Chiralpak IA, and Chiralpak AS-H.
The compound, the pharmaceutically acceptable salt, the prodrug, the solvate, the deuteron or the stereoisomer of the compound are used for preventing or treating diseases such as chronic pain and the like of mammals through the TASK-3 function.
The present invention further claims a pharmaceutical composition comprising any of the compounds described above, a pharmaceutically acceptable salt thereof, a deutero-compound thereof, or a stereoisomer thereof, wherein the composition further comprises a drug selected from one or more of the following: including salicylic acids (aspirin), anilines (acetaminophen), pyrazolones, indoleacetic acids, fenamic acids, propionic acids, oxicams, and the like.
Compared with the closest prior art, the compound of the invention has the following advantages:
(1) the guanidine compound has better activation activity of TASK-3;
(2) the guanidine compound is safe and effective for oral administration.
(3) The compound has low toxicity and side effect and large safety window;
(4) the compound of the invention has simple preparation process, good physical and chemical properties, stable quality and easy large-scale industrial production.
4. Detailed description of the preferred embodiments
The invention will be further illustrated by the following examples. These examples are intended to illustrate the invention, but not to limit it in any way. All parameters and the remaining descriptions in the examples are based on quality, unless otherwise specified. The experimental procedures, in which specific conditions are not specified in the examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers.
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. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention.
Example 1(E) -2- (4-hydroxy-6- ((p-benzylthio) methyl) pyrimidin-2-yl) -1- (naphthalen-1-yl) guanidine
Figure BDA0002313026580000181
Step 1:
Figure BDA0002313026580000182
4-Methylthiophenol (4.26g, 34.3mmol) was dissolved in acetone (50mL) and K was added at room temperature2CO3(12.0g, 86.8mmol) and 4-chloro-3-oxobutanoate (4.70g,28.6mmol), and stirred at room temperature for 3 hours. TLC spot plate detection till the reaction is finished. The reaction solution was poured into ice water, extracted 3 times with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and spin-dried on a column to give the desired product as a yellow oil (6.52g, yield 90%).
Step 2:
Figure BDA0002313026580000183
1-aminonaphthalene (1.43g,10mmol), dicyandiamide (0.84g,10mmol) and 37% concentrated hydrochloric acid (1mL) were dissolved in dioxane (20mL), refluxed for 16h, cooled to room temperature after TLC detection, and the solid was precipitated and collected by filtration. The solid was redissolved in saturated sodium bicarbonate solution, the solid was collected by filtration, and the filter cake was washed three times with water and dried to give the desired product as a yellow solid (1.86g, yield 82%).
And step 3:
Figure BDA0002313026580000191
the product of step 1 (1.60g,6.34mmol) and the product of step 2 (1.00g,4.40mmol) were dissolved in absolute ethanol (10mL) and refluxed overnight. The precipitated solid was filtered while hot, washed with ethanol 3 times, and dried to give the objective product (820mg, yield 45%).
LCMS:416.2[M+1]+；
1HNMR:(DMSOd6,400MHz):2.20(s,3H),3.89(s,2H),5.65(s,1H),7.04(d,J＝8.0Hz,2H),7.19(d,J＝8.0Hz,2H),7.49-7.59(m,3H),7.74(br,1H),7.80(d,J＝8.4Hz,1H),7.95-7.97(m,1H),8.03-8.05(m,1H),10.03(br,1H),11.14(br,1H).
Example 2(E) -1- (4-tert-butylphenyl) -2- (4-hydroxy-6- ((p-benzylthio) methyl) pyrimidin-2-yl) Guanidine (guanidine)
Figure BDA0002313026580000192
Step 1:
Figure BDA0002313026580000193
4-tert-butylaniline (3.00g,20.1mmol), dicyandiamide (1.68g,20mmol), 37% concentrated hydrochloric acid (2mL) was dissolved in dioxane (20mL), refluxed for 10h, TLC checked for completion, and the solid was collected by concentration and the crude product (3.12 g) was used in the next step without purification.
Step 2:
Figure BDA0002313026580000194
the crude product from step 1 (1.10g), ethyl 3-oxo-4- (p-tollylthio) butanoate (1.00g,4.0mmol), sodium bicarbonate (200mg,2.38mmol) was dissolved in absolute ethanol (30mL), refluxed overnight, cooled, and the solid collected by filtration was purified using the preparative liquid phase to afford the desired product (416mg, 25%).
LCMS:422.2[M+1]+；
1HNMR(400MHz,DMSO_d6)(s,1H),9.06(s,1H),7.52(d,J＝8.4Hz,2H),7.27(t,J＝8.0Hz,4H),7.12(d,J＝8.0Hz,2H),5.67(s,1H),3.93(s,2H),2.26(s,3H),1.27(s,9H).
Examples 3 to 13: the following compounds were synthesized according to example 1
Figure BDA0002313026580000201
Figure BDA0002313026580000211
Figure BDA0002313026580000221
Example 14:(E) -1- (2, 3-dihydroxybenzo [ b ]][1,4]-dioxy-6-yl) -2- (4-hydroxy-6- ((4- Propylphenylthio) methyl) pyrimidin-2-yl) guanidines
Figure BDA0002313026580000222
The synthetic route is as follows:
Figure BDA0002313026580000223
step 1:
Figure BDA0002313026580000224
propylbenzene (10.0g, 83.20mmol) was dissolved in DCM (100ml) under nitrogen, cooled in an ice bath, chlorosulfonic acid (27.7ml, 416.7mmol) in DCM (30ml) was added dropwise at 0 deg.C, reaction was completed at 0 deg.C for 2.0h, and TLC monitored (starting material was reacted and new spots were generated). The reaction was quenched into ice water, extracted with DCM, the organic phases combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography on crude silica gel to give a colourless oil (19.0g, crude) which was used directly in the next step.
Step 2:
Figure BDA0002313026580000231
concentrated sulfuric acid (28.7ml) was added dropwise to ice water (160ml) and the mixture was cooled to 0 ℃ in an ice bath, B003-1(16.0g, crude product) was added dropwise, zinc powder (26.2g, 400.7mmol) was added dropwise after the addition, the mixture was reacted at 0 ℃ for 1.0h and slowly warmed to room temperature overnight, and TLC showed the completion of the reaction. The reaction was filtered, the filtrate was extracted with MTBE, the organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated to give colorless oil B003-2(4.0g, crude) which was used directly in the next step.
Step 3-4: compound 14 was synthesized according to the procedure of example 2, steps 1 and 3.
LCMS:452.2[M+1]+；
1H NMR(400MHz,DMSO_d6)11.26(br,1H),9.37(br,1H),7.26–6.95(m,7H),6.75(d,J＝8.4HZ，1H),5.66(s,1H),4.21(br,4H),3.90(br,2H),1.54(br,2H),0.86(br.3H).
Examples 15 to 16: the following compounds were prepared according to the procedure of example 5
Figure BDA0002313026580000232
Figure BDA0002313026580000241
Example 17:(E) -1- (2, 3-dihydroxybenzo [ b ]][1,4]-dioxy-6-yl) -2- (4-hydroxy-6- ((3- Methylbenzylthio) methyl) pyrimidin-2-yl) guanidines
Figure BDA0002313026580000242
The synthetic route is as follows:
Figure BDA0002313026580000243
step 1:
Figure BDA0002313026580000244
3-methylbenzyl bromide (5.0g, 27.02mmol) and CH3COSK (3.7g, 32.40mmol) were dissolved in CH3CN (60ml), stirred overnight at room temperature and TLC indicated complete reaction. The reaction mixture was extracted with water and ethyl acetate, and the organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated to give (6.5g, crude) which was used directly in the next step.
Step 2:
Figure BDA0002313026580000245
b004-1(6.5g, crude) was dissolved in a mixed solvent of EtOH (100ML) and H2O (10ML), cooled in an ice bath, NaOH solid (5.77g, 144.3mmol) was added in portions, the temperature was slowly raised to room temperature after the addition was complete, stirring was carried out for 2 hours, and TLC showed the reaction to be complete. The reaction mixture was extracted with water and ethyl acetate, and the organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography on a crude silica gel (2.5g, 67% yield over two steps).
Step 3-4: compound 17 was synthesized following the procedure of example 2, steps 1 and 3.
LCMS:438.2[M+1]+；
1HNMR(400MHz,DMSO_d6)11.20(br,1H)，9.27(br,1H),7.19(t,J＝7.2Hz,1H),7.10-6.99(m,5H),6.77(d,J＝8.8Hz,1H),5.66(s,1H),4.22-4.21(m,4H),3.69(s,2H),3.38(s,2H),2.28(s,3H).
Example 18:(E) -1- (2, 3-dihydroxybenzo [ b ]][1,4]-dioxy-6-yl) -2- (4- (((4-ethoxy) ethyl ether) Methyl) phenyl) thio) methyl) -6-hydroxypyrimidin-2-yl) guanidine
Figure BDA0002313026580000251
The synthetic route is as follows:
Figure BDA0002313026580000252
step 1:
Figure BDA0002313026580000253
1-bromo-4- (ethoxymethyl) benzene (2.6g, 12.1mmol) was dissolved in tetrahydrofuran (30mL), cooled to-60 deg.C, n-butyllithium (2.5M/L,5.8mL,14.5mmol) was added dropwise, stirring was continued at-60 deg.C for 1 hour, sulfuryl chloride (3.4g, 25.2mmol) was added dropwise, stirring was continued at-60 deg.C for 2 hours, and sampling was performed to analyze completion of the reaction. The reaction solution was added with saturated brine, extracted with ethyl acetate, the organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to silica gel column chromatography to obtain a crude product (1.1g, yield 39%).
Step 2:
Figure BDA0002313026580000261
the above intermediate (1.1g, 4.7mmol) was dissolved in toluene (40mL), triphenylphosphine (3.6g, 13.7mmol) was added at room temperature, the temperature was raised to 110 ℃ for reaction for 8 hours, and a sample was taken to analyze completion of the reaction. The reaction mixture was concentrated, and the crude product was subjected to silica gel column chromatography (690mg, yield 87%).
Step 3-4: compound 18 was synthesized following the procedure of example 2, steps 1 and 3.
LCMS:468.2[M+1]+
1HNMR(400MHz,DMSO_d6)7.31(d,J＝8.0Hz,2H),7.22(d,J＝8.0Hz,2H),7.01-6.94(m,2H),6.74(d,J＝8.4Hz,1H),5.66(s,1H),4.38(s,2H),4.23-4.18(m,4H),3.93(s,2H),3.44(q,J＝7.2Hz,2H),1.22(t,J＝7.2Hz,3H).
Example 19:(E) -1- (2, 3-dihydroxybenzo [ b ]][1,4]-dioxy-6-yl) -2- (4-hydroxy-6- ((p-hydroxy) Tolyloxy) methyl) pyrimidin-2-yl) guanidine
Figure BDA0002313026580000262
The synthetic route is as follows:
Figure BDA0002313026580000263
step 1:
Figure BDA0002313026580000264
potassium hydroxide solid (2.1g, 37.4mmol) was dissolved in DMSO (30ml), p-cresol (2.0g, 18.5mmol) was added, stirred at room temperature for 15 min, methyl 4-chloroacetoacetate (2.8g, 18.6mmol) was added dropwise, reacted overnight at room temperature, and no separation of starting material from product was evident by TLC. Quenching the reaction solution by using 2M diluted hydrochloric acid, extracting by using ethyl acetate, combining organic phases, washing by using water, washing by using saturated salt solution, drying by using anhydrous sodium sulfate, concentrating, and carrying out chromatography and purification on a crude silica gel column to obtain (1.1g, crude product), wherein the purity of the product is 50% by using HNMR.
Step 2:
Figure BDA0002313026580000271
the (1.1g, 50% pure crude) and biguanide-based intermediate (500mg, 2.12mmol) from the previous step were dissolved in anhydrous ethanol (20ml), warmed to 90 ℃ for 8 hours, the reaction solution was filtered to precipitate a solid while hot, washed and dried to give a crude product (purity 90%), and pre-TLC purified to give the product (13mg, yield 2%).
LCMS:408.1[M+1]+
1H NMR(400HZ,DMSO_d6)11.20(br,1H),9.08(br,1H),7.09-6.84(m,7H),5.70(s,1H),4.78(s,2H),4.20(s,4H),2.21(s,3H)
Example 20:(E) -2- (4-amino-6- ((p-benzylthio) methyl) pyrimidin-2-yl) -1- (2, 3-dihydroxy Radical benzo [ b][1,4]-dioxy-6-yl) guanidine
Figure BDA0002313026580000272
The synthetic route is as follows:
Figure BDA0002313026580000273
step 1:
Figure BDA0002313026580000274
the above intermediate (600mg, 1.41mmol) was dissolved in POCl3(6ml), heated to reflux and the reaction was followed by TLC to completion. The reaction solution was concentrated to remove the solvent, the pH was adjusted to neutral with saturated aqueous sodium bicarbonate solution, a solid precipitated, filtered, and the filter cake was washed and dried to give (570mg, crude) which was used directly in the next step.
MS:441.2[M+1]+
Step 2:
Figure BDA0002313026580000281
the above intermediate (570mg, crude) was dissolved in DMF (10ml), potassium carbonate (469mg, 3.39mmol) and p-methoxybenzylamine (310mg, 2.26mmol) were added at room temperature, and the reaction was heated to 90 ℃ for 2 hours and LCMS showed completion. The reaction was cooled to room temperature, water was added and a solid precipitated, filtered, and the filter cake washed and dried to give the product (580mg, crude) which was used directly in the next step.
LCMS:543.2[M+1]+
And step 3:
Figure BDA0002313026580000282
the above intermediate (580mg, crude) was dissolved in TFA (5ml) and heated at reflux overnight, with LCMS showing half of the reaction and TFA (5ml) supplemented, at reflux overnight, with LCMS showing substantial completion of the reaction. The reaction was concentrated to remove TFA, dissolved in an appropriate amount of methanol, adjusted to neutral pH with saturated aqueous sodium bicarbonate solution, to precipitate a solid, filtered to give a crude product, and purified by pre-HPLC to give the product (105 mg).
LCMS:423.1[M+1]+.
1H NMR(400HZ,DMSO_d6)7.25(d,J＝8.1Hz,2H),7.23(d,J＝8.0Hz,2H),6.96-6.93(m,2H),6.82(dd,J＝2.8，8.4Hz,1H),6.12(br,1H),4.27(s,4H),4.04(s,2H),2.25(s,3H).
Example 21:(E) -2- (4-hydroxy-6- ((p-benzylthio) methyl) pyrimidin-2-yl) -1- (8-methoxy-l Naphthalen-1-yl) guanidines
Figure BDA0002313026580000283
The synthetic route is as follows:
Figure BDA0002313026580000291
step 1:
Figure BDA0002313026580000292
1, 8-diaminonaphthalene (8.0g, 50.57mmol) was dissolved in ethanol (30ml), and a saturated aqueous solution of sodium bisulfite (50ml) was added, and the mixture was refluxed overnight at elevated temperature; the reaction mixture was cooled to room temperature, and 6M aqueous potassium hydroxide (50ml) was added thereto, followed by reflux at elevated temperature for 2 hours. The reaction was cooled to room temperature, the pH was adjusted to 5-6 with 4N HCl, extracted with ethyl acetate, the organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated to give (7.90g, crude) and directly put into the next step.
Step 2:
Figure BDA0002313026580000293
the above intermediate (7.90g, crude) was dissolved in ethanol (60ml) and (Boc) was added2(11.0g, 50.40mmol), reaction overnight at room temperature, and completion of the reaction by TLC. The reaction mixture was extracted with water and ethyl acetate, the organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography on a crude silica gel to give the desired product (5.20g, 40% yield in two steps).
And step 3:
Figure BDA0002313026580000294
the above intermediate (5.20g, 20.05mmol) and potassium carbonate (5.50g, 39.79mmol) were dissolved in acetonitrile (50ml), methyl iodide (2.5ml, 40.16mmol) was added at room temperature, the reaction was warmed to 60 ℃ overnight, and the reaction was complete by TLC. The reaction solution was cooled to room temperature, extracted with ethyl acetate, the organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give the desired product (5.08g, crude product).
And 4, step 4:
Figure BDA0002313026580000301
the above intermediate (5.08g, crude) was dissolved in dichloromethane (20ml), added TFA (7ml), and reacted at room temperature for 2 hours with TLC check of completion. The reaction mixture was extracted with water and ethyl acetate, the organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography on crude silica gel column to give a visual inspection of the product (1.90g, 55% yield over two steps).
And 5-6: compound 21 was synthesized according to the procedure of example 2, steps 1 and 3.
LCMS：446.1[M+1]+
1HNMR(400MHz,DMSO_d6)11.17(br,1H),10.50(br,1H),8.18(br,1H),7.61(d,J＝8.0Hz,1H),7.49(d,J＝8.4Hz,1H),7.41(q,J＝8.0Hz,2H),7.23(d,J＝7.6Hz,2H),7.07(d,J＝7.6Hz,2H),7.01(d,J＝7.6Hz,1H),5.68(s,1H),3.96(s,3H),3.92(s,2H),2.23(s,3H)
Example 22:(E) -1- (3, 4-dihydroxy-2-hydro-benzo [ b ]][1,4]-oxazin-6-yl) -2- (4-hydroxy-6- ((p-benzylthio) methyl) pyrimidin-2-yl) guanidines
Figure BDA0002313026580000302
The synthetic route is as follows:
Figure BDA0002313026580000303
step 1:
Figure BDA0002313026580000311
dissolving benzomorpholine (10.0g, 74.0mmol) in acetic anhydride (100ml) under nitrogen protection, cooling in ice bath, and adding 65% HNO dropwise3(17.6g, 181.6 mmol) nitric acid was added dropwise to 40m at 0 deg.CI acetic anhydride), the reaction is finished by dripping, the reaction is carried out for 0.5h at the temperature of 0 ℃, and the reaction is completely shown by TLC. Adding saturated sodium carbonate aqueous solution into the reaction solution to adjust the reaction solution to be alkaline, extracting by ethyl acetate, combining organic phases, washing by water, washing by saturated salt solution, drying by anhydrous sodium sulfate, and concentrating to obtain a yellow solid (13.5g, crude product) which is a mixture substituted by nitro at two different positions.
Step 2:
Figure BDA0002313026580000312
the above intermediate (13.5g, crude) was dissolved in ethanol (100ml), concentrated hydrochloric acid (100ml) was added at room temperature, the temperature was raised to 60 ℃ and the reaction was carried out for 4.0h, as indicated by TLC (the starting material was reacted to completion, giving two new spots). The reaction mixture was made alkaline with saturated aqueous sodium carbonate, extracted with ethyl acetate, the organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and purified by TLC to give a yellow solid (1.85g, 14%, 2 step yield) and a yellow by-product (5.21g, 39%).
And step 3:
Figure BDA0002313026580000313
the above intermediate (2.39g, 13.26mmol) and pyridine (1.15g, 14.54mmol) were dissolved in DCM (30ml), cooled in an ice bath, TFAA (3.06g, 14.57mmol, 2.0ml DCM dilution) was added dropwise at 0 deg.C, and reaction was carried out at room temperature for 2.0h after dropping, and TLC showed (the starting material was reacted to generate a new spot). The reaction was extracted with water and DCM, the organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated to give a yellow solid (3.57g, crude).
And 4, step 4:
Figure BDA0002313026580000314
the above intermediate (2.0g, crude) was dissolved in EA (20ml), 10% Pd-C (200mg) was added, hydrogen was substituted 3 times, the reaction was carried out overnight at room temperature, and TLC showed completion of the reaction. The reaction was filtered through celite and the filtrate was concentrated to give the product (1.51g, crude).
And 5:
Figure BDA0002313026580000321
dicyandiamide (840mg, 9.99mmol) and the above intermediate (2.33g, crude product) were dissolved in absolute ethanol (20ml), and sodium methoxide (1.0g, 18.51mmol) was added thereto at room temperature, followed by heating and refluxing for reaction overnight. Cooling the reaction solution to room temperature, separating out solid, filtering, washing and drying filter cake to obtain target product 2.0g, crude product)
Step 6:
Figure BDA0002313026580000322
intermediate 1(492mg,2.0mmol) and intermediate 2(544mg,2.0mmol) were dissolved in Dioxane (10ml), and a 4M LHCl/Dioxane solution (0.5ml) was added thereto at room temperature, and the reaction was allowed to proceed overnight at 105 ℃. The reaction solution was solid-precipitated, hot-filtered, washed and dried to give the product (812mg, crude).
And 7:
Figure BDA0002313026580000323
the above intermediate (812mg, crude) was dissolved in ethanol (5ml) and water (5ml), potassium carbonate (1.0g,7.23mmol) was added, and the reaction was stirred at room temperature overnight. The reaction solution was precipitated as a solid, filtered, washed, and dried to obtain the objective product (300mg, yield in two steps: 36%).
LCMS:423.2[M+1]+.
1H NMR(400HZ,DMSO_d6):10.87(br,1H),9.20(br,1H),7.23(d,J＝8.0Hz,2H),7.09(d,J＝8.0Hz,2H),7.01(br,1H),6.53(d,J＝7.6Hz,1H),6.40(dd,J＝2.4,8.4Hz,1H),5.64(s,2H),4.08(t,J＝4.4Hz,2H),3.55(s,2H),3.27(br,2H),2.24(s,3H).
Example 23:(E) -1- (3, 4-dihydroxy-2-hydro-benzo [ b ]][1,4]-oxazin-7-yl) -2- (4-hydroxy-6- ((p-benzylthio) methyl) pyrimidin-2-yl) guanidines
Figure BDA0002313026580000331
The synthetic route is as follows:
Figure BDA0002313026580000332
steps 1-4 operating Steps reference example 22
1H NMR(400HZ,DMSO_d6)11.10(br,1H),9.60(br,1H),7.92(br,1H),7.17(d,J＝8.4Hz,2H),7.04(d,J＝8.0Hz,2H),6.69-6.60(m,2H),6.47(d,J＝8.4Hz,1H),5.65(s,1H),5.58(s,1H),4.06(t,J＝4.4Hz,2H),3.83(s,2H),3.20(br,2H),2.19(s,3H).
LCMS：423.1[M+1]+
Example 24:(E) -2- (4-hydroxy-6- ((p-benzylthio) methyl) pyrimidin-2-yl) -1- (4-methyl-3, 4-dihydroxy-2-hydro-benzo [ b ]][1,4]-oxazin-6-yl) -guanidine
Figure BDA0002313026580000333
The synthetic route is as follows:
Figure BDA0002313026580000341
step 1:
Figure BDA0002313026580000342
under the protection of nitrogen, the intermediate (1.3g, 7.22mmol) is dissolved in DMF (15ml), the temperature is reduced to 0 ℃ in an ice bath, 60% NaH (320mg, 8.00mmol) is added in batches, the reaction is carried out for 20min at the temperature of 0 ℃, methyl iodide (1.13g, 7.96mmol,1.0ml DMF) is added dropwise, the reaction is carried out for 0.5h at the temperature of 0 ℃, and TLC shows (the raw materials are reacted to generate new points). The reaction solution was quenched with water and a solid precipitated, stirred for 20min, filtered, and the filter cake washed and dried to give a yellow solid (1.20g, crude) which was used directly in the next step.
Step 2:
Figure BDA0002313026580000343
the above intermediate (1.20g, crude) was dissolved in EA (30ml), Pd/C (400mg) was added, hydrogen was substituted 3 times, and the reaction was carried out at room temperature for 3.0h, as indicated by TLC (completion of the reaction of the starting material). The reaction was filtered through celite and the filtrate was concentrated to give a brown oil (1.05g, crude) which was used directly in the next step.
And step 3:
Figure BDA0002313026580000344
intermediate 1(544mg, 2.0mmol) and intermediate 2(328mg, crude) were dissolved in 4-dioxane (10ml), 4M/L hydrochloric acid, 4-dioxane solution (0.5ml) was slowly added at room temperature, heated to 105 ℃ and reacted overnight with LCMS indicating completion of the reaction. The reaction solution was precipitated as a solid, filtered hot, washed and dried to obtain 482mg of a product to be observed visually, yield 55%).
1H NMR(400HZ,DMSO_d6)10.86(br,1H),9.60(br,1H),7.22(d,J＝8.0Hz,2H),7.08(d,J＝8.4Hz,2H),6.69-6.56(m,3H),5.61(s,1H),4.18(t,J＝4.0Hz,2H),3.87(s,2H),3.21(t,J＝4.0Hz,2H),2.81(s,3H),2.23(s,3H).
LCMS:437.2[M+1]+.
Example 25:(E) -2- (4-hydroxy-6- ((p-benzylthio) methyl) pyrimidin-2-yl) -1- (4-methyl-3, 4-dihydroxy-2-hydro-benzo [ b ]][1,4]-oxazin-7-yl) -guanidine
Figure BDA0002313026580000351
The synthetic route is as follows:
Figure BDA0002313026580000352
steps 1-3 operating Steps reference example 24
1H NMR(400HZ,DMSO_d6)11.17(br,1H),9.70(br,1H),7.23(d,J＝8.4Hz,2H),7.09(d,J＝8.0Hz,2H),6.85(d,J＝8.0Hz,1H),6.73(br,1H),6.64(d,J＝8.4Hz,1H),5.65(s,1H),4.23(t,J＝4.4Hz,2H),3.89(s,2H),3.20(t,J＝4.0Hz,2H),2.81(s,3H),2.24(s,3H).
LCMS:437.2[M+1]+.
Example 26(E) -2- (4-hydroxy-6- ((p-benzylthio) methyl) pyrimidin-2-yl) -1- (naphthalen-2-yl) guanidine
Figure BDA0002313026580000353
The synthetic route is as follows:
the method comprises the following steps: synthesis of 1- (diaminoethylene) -2- (naphthalen-2-yl) guanidine hydrochloride
2-naphthylamine (1.0g, 6.99mmol) was dispersed in 1, 4-dioxane (25mL), dicyandiamide (560mg, 6.67mmol) and hydrochloric acid (12M, 0.55mL, 6.60mmol) were added at room temperature, nitrogen was substituted, the temperature was raised to 100 ℃ and the reaction was allowed to complete overnight with stirring. The reaction solution was cooled to room temperature, filtered, the filter cake washed with dioxane, concentrated to give a crude product, added to 20mL ethanol, warmed to 60 ℃ and stirred for 30 minutes, filtered, the filter cake washed with ethanol, dried to give an off-white solid (1.0g, crude product) which was used directly in the next step.
Step two: (E) synthesis of (E) -2- (4-hydroxy-6- ((p-tolylthio) methyl) pyrimidin-2-yl) -1- (naphthalen-2-yl) guanidine
The intermediate (500mg, crude, 1.20mmol in theory) from the previous step was dispersed in ethanol (15mL) and added at room temperature
Figure BDA0002313026580000361
(550mg, 2.31mmol) and sodium bicarbonate (370mg, 4.40 mmol). After the addition, the temperature was raised to 100 ℃ and stirred overnight. The reaction solution was filtered while hot, the filter cake was washed with water and methanol, then dissolved in methanol, heated to 60 ℃ and stirred for 30 minutes, filtered while hot, the filter cake was salified with dilute hydrochloric acid (1M, 2.4mL, 2.4mmol), and pre-HPLC purified to give SYY-B019 as a white solid (129mg, 9% yield over two steps).1H NMR(400MHz,DMSO-d6):12.15(brs,1H),10.61(brs,1H),7.96-7.92(m,4H),7.56-7.47(m,3H),7.28(d,J＝8.0Hz,2H),7.13(d,J＝7.6Hz,2H),5.82(brs,2H),4.01(s,2H),2.26(s,3H).LCMS:m/z＝416.37[M+H]+
Examples 27 to 45: the following compounds were prepared according to the procedure for example 26
Figure BDA0002313026580000362
Figure BDA0002313026580000371
Figure BDA0002313026580000381
Example 46(E) -2- (4-hydroxy-6- ((p-tolylthio) methyl) pyrimidin-2-yl) -1- (quinolin-7-yl) guanidine
Figure BDA0002313026580000382
The synthetic route is as follows:
the method comprises the following steps: synthesis of 1- (diaminomethyl) -2- (quinolin-7-yl) guanidine hydrochloride
7-aminoquinoline (1.0g, 6.94mmol) was dispersed in 1, 4-dioxane (25mL), dicyandiamide (555mg, 6.60mmol) and concentrated hydrochloric acid (0.55mL, 6.6mmol) were added at room temperature, replaced with nitrogen, and the mixture was heated to 100 ℃ and stirred overnight. The reaction solution was filtered while hot, the filter cake was washed with 1, 4-dioxane for several times and concentrated to give a crude product, which was added to 20mL of ethanol, warmed to 60 ℃ and stirred for 30 minutes, filtered, the filter cake was washed with ethanol and concentrated to give a brown solid (850mg, crude product) which was used directly in the next step. Step two: (E) synthesis of (E) -2- (4-hydroxy-6- ((p-tolylthio) methyl) pyrimidin-2-yl) -1- (quinolin-7-yl) guanidine
The intermediate (850mg, crude) from the above step was dispersed in absolute ethanol (15mL) and added at room temperature
Figure BDA0002313026580000383
(935mg, 3.9mmol) and sodium bicarbonate (630mg, 7.5mmol), warmed to 100 ℃ and stirred overnight. Filtering the hot reaction solution, washing the filter cake with water and methanol, dissolving in methanol, heating to 60 deg.C, stirring for 30 min, and hot filteringFiltration, cake dissolution in DMSO and methanol, pre-HPLC purification gave SYY-B028 as a yellow solid (121mg, 4% yield over two steps).1H NMR(400MHz,DMSO-d6):10.50(s,1H),9.08(d,J＝5.2Hz,1H),8.86(s,2H),8.17(d,J＝8.0Hz,1H),8.09(d,J＝9.2Hz,1H),7.97(brs,1H),7.79-7.75(m,1H),7.65(brs,1H),7.30(d,J＝8.0Hz,2H),7.23(d,J＝8.0Hz,1H),7.14-7.07(m,2H),5.38(s,1H),4.15(s,1H),3.89(s,1H),3.78(s,2H),2.25(s,3H).LCMS:m/z＝415.1[M-H]-
Examples 47 to 50: the following compounds were prepared according to the procedure for example 46
Figure BDA0002313026580000391
Example 51(E) -2- (4-hydroxy-6- ((p-tolylthio) methyl) pyrimidin-2-yl) -1- (5,6,7, 8-tetrahydronaphthalen-2-yl) guanidine
Figure BDA0002313026580000392
The synthetic route is as follows:
step 1: synthesis of 1- (diaminomethyl) -2- (5,6,7, 8-tetrahydronaphthalen-1-yl) guanidine hydrochloride
N25,6,7, 8-tetrahydronaphthalen-1-amine (500mg, 3.40mmol), dicyandiamide (272mg, 3.24mmol) and hydrochloric acid (0.29mL,3.48mmol, 12N) were dispersed into 1, 4-dioxane (10mL) under protection, warmed to 95 ℃ and stirred for 12 hours, TLC showed the starting material was essentially complete. The reaction was cooled to room temperature, filtered, and the filter cake was washed with 1, 4-dioxane and dried to give a grey solid (800mg, crude) which was used directly in the next step.
Step 2: (E) synthesis of (E) -2- (4-hydroxy-6- ((p-tolylthio) methyl) pyrimidin-2-yl) -1- (5,6,7, 8-tetrahydronaphthalen-2-yl) guanidine
Under the protection of nitrogen, the intermediate (500mg, crude product),
Figure BDA0002313026580000401
(467mg, 1.96mmol) and NaHCO3(314mg, 3.74mmol) was dispersed in absolute ethanol (10mL), warmed to 85 deg.C and stirred for 12 hours, TLC indicatedThe raw materials are basically completely reacted. The reaction was cooled to room temperature, filtered, and the filter cake was washed with an appropriate amount of water and methanol, respectively, and dried to give a gray solid (300mg, 36% yield over two steps).1H NMR(400MHz,DMSO-d6):11.19(s,1H),9.07(s,1H),7.28-7.24(m,3H),7.21-7.19(m,1H),7.14-7.10(m,2H),6.94(d,J＝8.4Hz,1H),5.66(s,1H),3.90(s,2H),2.68(d,J＝26.8Hz,4H),2.25(s,3H),1.72-1.69(m,4H).LC-MS:m/z＝420.2[M+H]+
Examples 52 to 60: the following compounds are according to example 51
Figure BDA0002313026580000402
Figure BDA0002313026580000411
Example 61(E) -1 (-chromanone-6-yl) -2- (4-hydroxy-6- ((p-tolylthio) methyl) pyrimidin-2-yl) guanidine
Figure BDA0002313026580000412
The synthetic route is as follows:
the method comprises the following steps: synthesis of 3, 4-dihydro-1H-benzopyran
Under the protection of nitrogen, 2, 3-dihydrobenzopyran-4-one (10.0g,67.49mmol) is dissolved in anhydrous tetrahydrofuran (120mL), anhydrous aluminum trichloride (31.5g,236.2mmol) and lithium aluminum hydride (4.35g,114.6mmol) are slowly added in batches under the cooling of ice bath, after the addition is finished, the stirring is continued for 0.5h under the ice bath, and the temperature is increased to 40 ℃ and the stirring is continued for 2 h. Cooling the reaction solution to room temperature, slowly adding water (4.5mL) to quench the reaction, continuously adding saturated ammonium chloride aqueous solution (20mL), water (50mL) and anhydrous sodium sulfate (20g), stirring for 0.5h, filtering, washing filter cake with ethyl acetate, combining organic phases, washing with saturated salt solution (50mL 2), drying with anhydrous sodium sulfate, concentrating, and performing silica gel column chromatography on the crude product to obtain colorless oily substance
Figure BDA0002313026580000421
(7.5g, yield 83%).1H NMR(400MHz,CDCl3):7.03-7.01(m,2H),6.77-6.89(m,2H),4.18-4.21(t,J＝4.8Hz,2H),2.78-2.82(t,J＝6.4Hz,2H),1.99-2.06(m,2H)
Step two: synthesis of 6-nitro-3, 4-dihydro-1H-benzopyran
Cooling with ice salt bath, mixing
Figure BDA0002313026580000422
(7.50g,55.90mmol) was slowly added to HNO3(63%, 13 mL). After the addition, the mixture was stirred at-10 ℃ for 1 hour. Slowly pouring the reaction solution into ice water (20mL), adjusting the pH value of the reaction solution to be alkalescent by using sodium hydroxide aqueous solution (1N), extracting the mixture by using DCM (50mL & gt2), combining organic phases, washing the organic phases by using saturated salt water (40mL & gt2), drying the organic phases by using anhydrous sodium sulfate, concentrating the organic phases, and performing silica gel column chromatography on a crude product to obtain a yellow solid
Figure BDA0002313026580000423
(2.1g, yield 21%).1H NMR(400MHz,CDCl3):7.96-7.99(m,2H),6.83-6.85(m,2H),4.27-4.30(t,J＝5.2Hz,2H),2.84-2.87(t,J＝6.4Hz,2H),2.02-2.08(m,2H).
Step three: synthesis of 6-amino-3, 4-dihydro-1H-benzopyran
Figure BDA0002313026580000424
(2.0g,11.2mmol), reduced iron powder (3.1g,55.5mmol) and ammonium chloride (3.0g,56.1mmol) were added sequentially to ethanol/water (40mL/20mL), heated to 80 ℃ and stirred for 6 Europe, TLC indicated complete reaction of the starting materials. Filtering the hot reaction solution, washing the filter cake with ethyl acetate, separating the filtrate into layers, extracting and separating the layers, combining the organic phases, washing with saturated saline (40mL x 2), washing with water (40mL x 2), drying with anhydrous sodium sulfate, and concentrating to obtain a yellow solid
Figure BDA0002313026580000425
(1.5g, crude). LC-MS: m/z 150.2[ M + H ]]+
Step four: synthesis of 1- (diaminomethyl) -2- (dihydrobenzopyran-6-yl) guanidine hydrochloride
Under the protection of nitrogen, the mixture is subjected to
Figure BDA0002313026580000426
(400mg, crude), dicyandiamide (187mg,2.23mmol) and concentrated hydrochloric acid (12N,0.23mL,2.76mmol) were dispersed in 1, 4-dioxane (10mL) and heated to 95 ℃ with stirring for 16 h. Cooling the reaction liquid to room temperature, filtering, washing a filter cake by using 1, 4-dioxane, collecting and drying to obtain a dark gray solid
Figure BDA0002313026580000427
(680mg, crude). LC-MS: 234.2[ M + H ] M/z]+
Step five: under the protection of nitrogen, the mixture is subjected to
Figure BDA0002313026580000428
(680mg, crude),
Figure BDA0002313026580000429
(631mg,2.65mmol) and sodium bicarbonate (423mg, 5.04mmol) were added sequentially to absolute ethanol (10mL), heated to 85 deg.C and stirred overnight, TLC indicated complete reaction of starting material. The reaction was cooled to room temperature, concentrated to remove the solvent, diluted with water (40mL), extracted with ethyl acetate (20mL × 2), the organic phases combined, washed with water (20mL × 2), dried over anhydrous sodium sulfate, concentrated, slurried crude product (PE/EA ═ 5: 1, 20mL), filtered, the cake washed and dried, and pre-HPLC purified to give 100mg of off-white solid (HPLC 90%), and further pre-HPLC purified to give a pale yellow solid (60mg, three step 4.8%).1H NMR(400MHz,DMSO-d6):1.96(brs,1H),10.72(brs,1H),10.05(brs,1H),8.31(brs,2H),7.27-7.12(m,7H),6.81(s,1H),4.14(s,4H),2.76-2.74(m,2H),2.26(s,3H),1.93-1.90(m,2H).LC-MS:m/z＝422.2[M+H]+
Example 62 Synthesis by the method of reference example 61
Figure BDA0002313026580000431
Example 63(E) -1- (3, 4-dihydro-2H-benzo [ b ] [1,4] dioxolin-7-yl) -2- (4-hydroxy-6- ((p-tolylthio) methyl) pyrimidin-2-yl) guanidine
Figure BDA0002313026580000432
The synthetic route is as follows:
the method comprises the following steps: synthesis of 7-nitro-3, 4-dihydro-2H-1, 5-benzodioxepane
P-nitrophthaldiol (3.00g, 19.34mmol), 1, 3-dibromopropane (5.86g, 29.03mmol) and potassium carbonate (13.36g, 96.66mmol) were added sequentially to DMF (50mL), the reaction was warmed to 110 ℃ and stirred for 4h, TLC (PE: EA ═ 10:1) indicated that the starting material was reacted. Cooling the reaction liquid to room temperature, adding water (100mL), extracting with ethyl acetate, combining organic phases, washing with saturated salt water, drying with anhydrous sodium sulfate, concentrating, and purifying by crude silica gel column chromatography (PE: EA ═ 20:1) to obtain a light yellow solid
Figure BDA0002313026580000433
(2.86g, 76% yield).1H NMR(400MHz,CDCl3):7.83(d,J＝2.4Hz,1H),7.80(dd,J＝8.8,2.8Hz,1H),7.01(d,J＝8.8Hz,1H),4.38(t,J＝6.0Hz,2H),4.32(t,J＝6.0Hz,2H),2.24-2.32(m,2H).
Step two: synthesis of 7-amino-3, 4-dihydro-2H-1, 5-benzodioxepane
Figure BDA0002313026580000441
(1.00g, 5.12mmol), reduced iron powder (1.10g, 19.69mmol), and ammonium chloride (2.20g, 41.12mmol) were added to ethanol (20mL) and water (20mL) in this order, and the mixture was stirred under reflux for 4 hours, and TLC (PE: EA ═ 10:1) showed completion of the reaction. Filtering the reaction solution while the reaction solution is hot, washing with ethanol, concentrating, adding water (20mL), extracting with ethyl acetate, combining organic phases, washing with saturated salt water, drying with anhydrous sodium sulfate, filtering, concentrating, and purifying by using a crude silica gel column chromatography (PE: EA is 10: 1-5: 1) to obtain a light brown solid
Figure BDA0002313026580000442
(0.52g, yield 61%).1H NMR(400MHz,CDCl3):6.80(d,J＝8.4Hz,1H),6.35(d,J＝2.8Hz,1H),6.27(dd,J＝8.4,2.8Hz,1H),4.14(t,J＝5.6Hz,2H),4.08(t,J＝5.6Hz,2H),3.30(brs,2H),2.10-2.16(m,2H).
Step three: synthesis of 1- (diaminomethyl) -2- (3, 4-dihydro-2H-benzo [ b ] [1,4] dioxolin-7-yl) guanidine hydrochloride
Figure BDA0002313026580000443
(520mg, 3.15mmol), dicyandiamide (265mg, 3.15mmol) and concentrated hydrochloric acid (12N, 0.26mL, 3.12mmol) were sequentially added to 1, 4-dioxane (10mL), and the mixture was heated under reflux and stirred overnight. Cooling the reaction liquid to room temperature, filtering, washing a filter cake by using 1, 4-dioxane, and drying to obtain a reddish brown solid
Figure BDA0002313026580000444
(800mg, crude) was used directly in the next step. LCMS M/z 250.31[ M + H ]]+
Step four: (E) synthesis of (E) -1- (3, 4-dihydro-2H-benzo [ b ] [1,4] dioxolin-7-yl) -2- (4-hydroxy-6- ((p-tolylthio) methyl) pyrimidin-2-yl) guanidine
Figure BDA0002313026580000445
(800mg, crude),
Figure BDA0002313026580000446
(666mg, 2.79mmol) and sodium hydrogencarbonate (470mg, 5.59mmol) were successively added to anhydrous ethanol (10mL), and the mixture was stirred under reflux overnight. The reaction was filtered hot, the filter cake washed with water, methanol and dried to give a white solid (530mg, 93% pure), and 200mg of crude pre-HPLC was purified to give SYY-B027 as a light brown solid (130mg, 9% over two steps).1H NMR(400MHz,DMSO-d6):11.39(brs,2H),8.04(brs,2H),7.26–6.94(m,7H),5.72(brs,2H),4.13-3.96(m,6H),2.27(s,3H),2.10(s,2H).LCMS:m/z＝438.2[M+H]+.
Example 64
Figure BDA0002313026580000451
The synthetic route is as follows:
the method comprises the following steps: synthesis of 2-nitrodibenzo-p-dioxin
Dibenzo-p-dioxin (800mg, 4.34mmol) was dispersed in acetic acid (20mL), fuming nitric acid (328mg, 5.21mmol) was slowly dropped at room temperature, and after dropping, stirring was carried out at room temperature for 2 hours. Pouring the reaction solution into vigorously stirred water, extracting with ethyl acetate, mixing organic phases, washing with saturated salt water, drying with anhydrous sodium sulfate, concentrating, and purifying the crude product by silica gel column chromatography (pure PE) to obtain yellow solid
Figure BDA0002313026580000452
(500mg, yield 50%).
Step two: synthesis of 2-aminodibenzo-p-dioxin
Figure BDA0002313026580000453
(500mg, 2.18mmol) was dispersed in ethanol (10mL) and water (5mL), ammonium chloride (584mg, 10.92mmol) and reduced iron powder (611mg, 10.94mmol) were added, the temperature was raised to 80 ℃ and stirred for 30 minutes, and TLC showed complete conversion of the starting material. Filtering the hot reaction solution, washing the filter cake with ethyl acetate, concentrating the filtrate to remove ethanol, diluting with water, extracting with ethyl acetate, washing with organic phase saturated salt water, drying with anhydrous sodium sulfate, and concentrating to obtain dark yellow solid
Figure BDA0002313026580000454
(430mg, crude) was used directly in the next step.
Step three: synthesis of 1- (diaminomethyl) -2- (dibenzo [ b, e ] [1,4] dioxin-2-yl) guanidine hydrochloride
Figure BDA0002313026580000455
(420mg, 2.11mmol) was dispersed in 1, 4-dioxane (10mL), dicyandiamide (170mg, 2.02mmol) and hydrochloric acid (12M, 0.17mL, 2.04mmol) were added at room temperature, replaced with nitrogen, and the mixture was stirred overnight while the temperature was raised to 100 ℃. Cooling the reaction liquid to room temperature, filtering, washing the filter cake with 1, 4-dioxane for multiple times, drying to obtain a crude product, adding into 20mL ethanol, and heatingHeating to 60 deg.C, stirring for 30 min, filtering, washing filter cake with ethanol, and drying to obtain white solid
Figure BDA0002313026580000456
(500mg, crude) was used directly in the next step.
Step four: (e) synthesis of (E) -1- (dibenzo [ b, e ] [1,4] dioxo-2-yl) -2- (4-hydroxy-6- ((p-tolyl) methyl) pyrimidin-2-yl) guanidine
Figure BDA0002313026580000457
(500mg, crude) was dispersed in absolute ethanol (15mL) and added at room temperature
Figure BDA0002313026580000458
(450mg, 1.89mmol) and sodium bicarbonate (300mg, 3.57mmol), warmed to 100 ℃ and stirred overnight. The reaction was filtered hot, the filter cake washed with water and ethanol several times, salified with dilute hydrochloric acid (1N, 3.5mL, 3.5mmol) and purified by pre-HPLC to give a white solid (66mg, 10% yield in three steps).1H NMR(400MHz,DMSO-d6):12.01(brs，1H),10.21(brs,1H),8.21(brs,2H),7.28(d,J＝8.0Hz,2H),7.19-7.12(m,3H),6.99(s,6H),5.76(brs,1H),3.98(s,2H),2.26(s,3H).LC-MS:m/z＝472.2[M+H]+
Examples 65-66 Synthesis by reference to example 64
Figure BDA0002313026580000461
Example 67(E) -2- (4-hydroxy-6- ((p-tolylthio) methyl) pyrimidin-2-yl) -1- (5,6,7, 8-tetrahydronaphthalen-2-yl) guanidine hydrochloride
Figure BDA0002313026580000462
1mmol of the starting material from example 51 was dissolved in ethyl acetate, 1mL of a 1mol/L solution of hydrochloric acid in ethyl acetate was gradually added dropwise to precipitate a solid gradually, and the solid was collected by filtration to obtain the corresponding hydrochloride.
Examples 68-70 Synthesis according to example 67
Figure BDA0002313026580000463
Figure BDA0002313026580000471
The beneficial effects of the compounds of the present invention are further illustrated below by activity experiments, but this should not be understood as the only beneficial effects of the compounds of the present invention.
Example 26: method for testing activity of compound in TASK-3 channel
And (3) testing the sample:
the chemical names and preparation methods of the compounds of the invention are shown in the preparation examples of the compounds.
The experimental method comprises the following steps:
electrophysiological detection method of TASK-3 channel Activity of Compounds human TASK-3 gene sequence was cloned into pCDNA3 vector, HEK293 cells were inoculated in 35mM petri dishes and cultured, Polyjet was used for transfection until the cell density reached 30%, 0.3-3. mu.g of plasmid and 0.1. mu.g of EGFP fluorescent protein were co-transfected into HEK-293 cells. Cells were digested with 0.25% trypsin 6 to 24h after transfection and plated on 35mM dishes containing complete serum medium and cultured in a cell incubator for patch clamp recording. Whole cell patch clamp recording was performed at 23-25 ℃ using a HEKA EPC10 patch clamp amplifier, and the recording glass electrode was drawn from a borosilicate glass tube, and had a current resistance of 3-7M Ω. The standard electrode solution is 140KCl,2MgCl2,10EGTA,1CaCl2,10HEPES (mM), the pH value is adjusted to 7.3 by KOH, and the extracellular solution comprises: 150NaCl,5KCl,0.5CaCl2,1.2MgCl2,10HEPES (mM), pH 7.3 with NaOH, current signal filtering at 2kHz, and sampling frequency set at 10 kHz. Lower EC50 values indicate better activity.
EC50(1 μ M-100 μ M) was characterized as A, EC50(0.01 μ M-1 μ M) was characterized as B
Figure BDA0002313026580000472
Figure BDA0002313026580000481
Experimental results show that the test compound has better agonistic activity on TASK-3. The compound has better clinical application potential in the field of treatment related to the TASK-3.

Claims (12)

1. A compound represented by the general formula (I), a pharmaceutically acceptable salt thereof, a prodrug thereof, a solvate thereof, a deuteride thereof, or a stereoisomer thereof:
Figure FDA0002313026570000011
wherein X is selected from S, O or NH;
Ar1selected from benzene ring, naphthalene ring, benzo 5-7 membered heterocyclic group, benzo 3-8 membered cycloalkyl or 3-14 membered heterocyclic ring;
Ar2selected from benzene ring, naphthalene ring, benzo 5-7 membered heterocyclic group, benzo 3-8 membered cycloalkyl or 3-14 membered heterocyclic ring;
r1, R6 is selected from H, C1-10 alkyl substituted OR unsubstituted by 1-3Q 1, C2-10 alkenyl substituted OR unsubstituted by 1-3Q 1, C2-10 alkynyl substituted OR unsubstituted by 1-3Q 1, halogen, -COOR ', -NR' R ', -OR', -COR ', -CONR', O, -SR ', -SO 3R', -SO2NR 'R', -SOR ', -SO 2R', -NO2, -OCF3, -CF3, -C2F5, -C3F7 OR-CN, 3-8 membered heterocycloalkyl substituted OR unsubstituted by 1-3Q 1, 1-3Q 1 substituted OR unsubstituted benzene rings;
R2，R3，R4，R5selected from H, C substituted or unsubstituted by 1 to 3Q 11-10Alkyl, C substituted or unsubstituted by 1 to 3Q 12-10Alkenyl, C substituted or unsubstituted by 1 to 3Q 12-10Alkynyl, halogen, -COOR ', -NR ' R ', -OR ', -COR ', -CONR ', -O, -SR ', -SO3R′，-SO2NR′R″，-SOR′，-SO2R′，-NO2，-OCF3,-CF3,-C2F5，-C3F7Or — CN, 3-8 membered heterocycloalkyl substituted or unsubstituted with 1-3 of Q1, 1-3 of Q1 substituted or unsubstituted phenyl rings;
wherein said substituent Q1 is selected from the group consisting of C1-C8 linear OR branched hydrocarbyl, halogen, C3-C6 cycloalkane, C3-C6 cycloalkane (C1-C6) alkyl, C1-C8 linear OR branched alkoxy, -COOR ', -NR' R ', -OR', -COR ', -CONR' R ', -O, -SR', C1-C4 haloalkyl, amino, mercapto, cyano, nitro, hydroxy, trifluoromethyl, trifluoromethoxy, substituted OR unsubstituted with 1-3Q 2: an aromatic heterocyclic ring containing one to two oxygen or nitrogen, a heteroaryl (C1-C6) alkyl group containing one to two oxygen or nitrogen, a (C6-C12) fused heterocyclic (C1-C6) alkyl group containing one to two oxygen or nitrogen, a C5-C12 aryl (C1-C6) alkyl group, a phenoxy group, a benzyloxycarbonyl group,
wherein the substituent Q2 is selected from halogen, oxo, C1-C8 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, amino, mercapto, cyano, nitro, hydroxy, trifluoromethyl, trifluoromethoxy, phenyl or phenoxy, which is substituted or unsubstituted with 1 to 3Q 3,
wherein the substituent Q3 is selected from halogen, C1-C4 haloalkyl, amino, mercapto, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, wherein R ', R' are independently selected from: h, phenyl substituted or unsubstituted by 1 to 3Q 4, benzyl substituted or unsubstituted by 1 to 3Q 4, C1-10 alkyl substituted or unsubstituted by 1 to 3Q 4, C2-10 alkenyl substituted or unsubstituted by 1 to 3Q 4, C2-10 alkynyl substituted or unsubstituted by 1 to 3Q 4; alternatively, the radicals R 'and R' are joined together to form a 4-to 7-membered ring,
wherein said substituent Q4 is selected from the group consisting of halogen, -COOR ', -NR' R ', -OR', -COR ', -CONR' R ', -O, -SR', -SO3R′，-SO2NR′R″，-SOR′，-SO2R′，-NO2，-OCF3,-CF3,-C2F5，-C3F7Or a group of-CN groups,
m is 0,1 or 2; n is 0,1 or 2, and m + n is more than or equal to 1;
p is selected from 0,1,2,3,4 or 5, and when p is 2,3,4 or 5, R is1May be the same or different;
q is selected from 0,1,2,3,4 or 5, and when q is 2,3,4 or 5, R is6May be the same or different.
2. The compound of claim 1, a pharmaceutically acceptable salt thereof, a prodrug thereof, a solvate thereof, a deuteride thereof, or a stereoisomer thereof, having the structure represented by the following general formula (II):
Figure FDA0002313026570000021
wherein R is1，R6，Ar1，Ar2X, p, q, m, n are defined as stated in claim 1.
3. The compound, a pharmaceutically acceptable salt thereof, a prodrug thereof, a solvate thereof, a deuteride thereof, or a stereoisomer thereof according to any one of claim 1 or claim 2, having the structure represented by the following general formula (III):
Figure FDA0002313026570000022
wherein R is1，R6，Ar1，Ar2P, q, m, n are as defined in claim 1.
4. The compound of claim 1, a pharmaceutically acceptable salt thereof, a prodrug thereof, a solvate thereof, a deuteride, or a stereoisomer thereof, having the structure shown in the following general formula (IV):
Figure FDA0002313026570000031
wherein R is4’，R5' is selected from H, C substituted or unsubstituted by 1 to 3Q 11-10Alkyl radicals, taken from 1 to 3Q 1Substituted or unsubstituted C2-10Alkenyl, C substituted or unsubstituted by 1 to 3Q 12-10Alkynyl, halogen, -COOR ', -NR ' R ', -OR ', -COR ', -CONR ', -O, -SR ', -SO3R′，-SO2NR′R″，-SOR′，-SO2R′，-NO2，-OCF3,-CF3,-C2F5，-C3F7Or — CN, 3-8 membered heterocycloalkyl substituted or unsubstituted with 1-3 of Q1;
R1，R6，Ar1，Ar2q1, p, Q, m, n are defined as stated in claim 1.
5. The compound of claim 1, a pharmaceutically acceptable salt thereof, a prodrug thereof, a solvate thereof, a deuteride thereof, or a stereoisomer thereof, having a structure represented by the following general formula (v):
Figure FDA0002313026570000032
r7, R8 is selected from H, C1-10 alkyl substituted OR unsubstituted by 1-3Q 1, C2-10 alkenyl substituted OR unsubstituted by 1-3Q 1, C2-10 alkynyl substituted OR unsubstituted by 1-3Q 1, halogen, -COOR ', -NR' R ', -OR', -COR ', -CONR', O, -SR ', -SO 3R', -SO2NR 'R', -SOR ', -SO 2R', -NO2, -OCF3, -CF3, -C2F5, -C3F7 OR-CN, 3-8 membered heterocycloalkyl substituted OR unsubstituted by 1-3Q 1, 1-3Q 1 substituted OR unsubstituted benzene rings.
6. The compound of claim 1, a pharmaceutically acceptable salt thereof, a prodrug thereof, a solvate thereof, a deuteride, or a stereoisomer thereof, having the structure of the following general formula (VI):
Figure FDA0002313026570000033
r9, R10 is selected from H, C1-10 alkyl substituted OR unsubstituted by 1-3Q 1, C2-10 alkenyl substituted OR unsubstituted by 1-3Q 1, C2-10 alkynyl substituted OR unsubstituted by 1-3Q 1, halogen, -COOR ', -NR' R ', -OR', -COR ', -CONR', O, -SR ', -SO 3R', -SO2NR 'R', -SOR ', -SO 2R', -NO2, -OCF3, -CF3, -C2F5, -C3F7 OR-CN, 3-8 membered heterocycloalkyl substituted OR unsubstituted by 1-3Q 1, 1-3Q 1 substituted OR unsubstituted benzene rings.
7. The compound of claim 1, a pharmaceutically acceptable salt thereof, a prodrug thereof, a solvate thereof, a deuteride, or a stereoisomer thereof:
Figure FDA0002313026570000041
Figure FDA0002313026570000051
Figure FDA0002313026570000061
Figure FDA0002313026570000071
8. the amine derivative according to any one of claims 1 to 5, wherein the salt is selected from (1) salts with inorganic acids: the inorganic acid is selected from hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid; (2) salts with organic acids selected from acetic acid, oxalic acid, succinic acid, tartaric acid, methanesulfonic acid, maleic acid or arginine, trifluoroacetic acid; (3) the other salts are selected from salts with alkali metals or alkaline earth metals.
9. A pharmaceutical composition comprising a compound of any one of claims 1-5, a pharmaceutically acceptable salt thereof, a prodrug thereof, a solvate thereof, a deuteride, or a stereoisomer thereof, and further comprising an additional pharmaceutically active ingredient.
10. The composition of claim 9, further comprising a drug selected from one or more of the group consisting of: salicylic acids, anilines, pyrazolones, indoleacetic acids, fenamic acids, propionic acids, and oxicams.
11. A pharmaceutical formulation comprising a compound as claimed in any one of claims 1 to 7, a pharmaceutically acceptable salt thereof, a prodrug thereof, a solvate thereof, a deuteron or a stereoisomer thereof, and one or more pharmaceutically acceptable carriers and/or diluents, in any pharmaceutically acceptable dosage form.
12. A compound as claimed in any one of claims 1 to 7, a pharmaceutically acceptable salt thereof, a prodrug thereof, a solvate thereof, a deuteron or a stereoisomer thereof for use in the prevention and/or treatment of pain symptoms including but not limited to neuropathic pain such as herpes zoster pain, trigeminal pain, migraine, pancreatitis, arthritic pain and other acute and chronic inflammatory pain and pain-induced sleep disorders by the action of TASK-3.
CN201911266613.9A 2019-02-11 2019-12-11 Guanidine compounds as medicine for preventing and treating chronic pain Pending CN111548313A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114075141A (en) * 2020-08-20 2022-02-22 上海致根医药科技有限公司 Opioid receptor 'bias' ligand, preparation method and application thereof in medicine

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995020950A1 (en) * 1994-02-03 1995-08-10 Cambridge Neuroscience, Inc. Therapeutic guanidines
CN1126434A (en) * 1993-05-27 1996-07-10 剑桥神经科学公司 Therapeutic substituted guanidines
CN1333767A (en) * 1999-01-19 2002-01-30 贝林格尔·英格海姆药物公司 Aromatic heterocyclic compounds as antiinflammatory agent
US20030153596A1 (en) * 2000-08-21 2003-08-14 Suh Young Ger Novel thiourea derivatives and the pharmaceutical compositions containing the same
CN101355939A (en) * 2005-10-06 2009-01-28 马萨诸塞大学 Composition and synthesis of new reagents for inhibition of HIV replication
CN101563318A (en) * 2006-12-20 2009-10-21 艾博特公司 N- (5, 6, 7, 8-tetrahydronaphthalen-1-yl) urea derivatives and related compounds as trpv1 vanilloid receptor antagonists for the treatment of pain
CN111067902A (en) * 2018-10-19 2020-04-28 绍兴从零医药科技有限公司 Compound for preventing and treating chronic pain and application thereof

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1126434A (en) * 1993-05-27 1996-07-10 剑桥神经科学公司 Therapeutic substituted guanidines
WO1995020950A1 (en) * 1994-02-03 1995-08-10 Cambridge Neuroscience, Inc. Therapeutic guanidines
CN1333767A (en) * 1999-01-19 2002-01-30 贝林格尔·英格海姆药物公司 Aromatic heterocyclic compounds as antiinflammatory agent
US20030153596A1 (en) * 2000-08-21 2003-08-14 Suh Young Ger Novel thiourea derivatives and the pharmaceutical compositions containing the same
CN101355939A (en) * 2005-10-06 2009-01-28 马萨诸塞大学 Composition and synthesis of new reagents for inhibition of HIV replication
CN101563318A (en) * 2006-12-20 2009-10-21 艾博特公司 N- (5, 6, 7, 8-tetrahydronaphthalen-1-yl) urea derivatives and related compounds as trpv1 vanilloid receptor antagonists for the treatment of pain
CN111067902A (en) * 2018-10-19 2020-04-28 绍兴从零医药科技有限公司 Compound for preventing and treating chronic pain and application thereof

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
N. LAXMA REDDY ET AL.: ""Synthesis and Pharmacological Evaluation of N,N"-Diarylguanidines as Potent Sodium Channel Blockers and Anticonvulsant Agents", 《J. MED. CHEM.》 *
PING LIAO ET AL.: "Selective Activation of TASK-3-containing K+ Channels Reveals Their Therapeutic Potentials in Analgesia", 《BIORXIV》 *
来源：CHEMICAL CATALOG SUPPLIER等提供的产品目录: "STN检索报告", 《数据库REGISTRY(在线)》 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114075141A (en) * 2020-08-20 2022-02-22 上海致根医药科技有限公司 Opioid receptor 'bias' ligand, preparation method and application thereof in medicine

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