WO2023011599A1 - Promédicament de persulfure d'hydrogène et son utilisation pharmaceutique - Google Patents

Promédicament de persulfure d'hydrogène et son utilisation pharmaceutique Download PDF

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WO2023011599A1
WO2023011599A1 PCT/CN2022/110332 CN2022110332W WO2023011599A1 WO 2023011599 A1 WO2023011599 A1 WO 2023011599A1 CN 2022110332 W CN2022110332 W CN 2022110332W WO 2023011599 A1 WO2023011599 A1 WO 2023011599A1
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drugs
prodrug
compound
alkyl
hsp
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柯博文
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四川大学
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/095—Sulfur, selenium, or tellurium compounds, e.g. thiols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C321/00—Thiols, sulfides, hydropolysulfides or polysulfides
    • C07C321/12—Sulfides, hydropolysulfides, or polysulfides having thio groups bound to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/10—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C323/11—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/12—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention belongs to the field of pharmacy, and in particular relates to a hydrogen persulfide prodrug and its pharmaceutical use.
  • Hydrogen sulfide is the third gas signal molecule besides nitric oxide (NO) and carbon monoxide (CO). Studies have found that H 2 S has a wide range of physiological and pathological effects and medicinal prospects. Indications such as gastrointestinal mucosal ulceration caused by body anti-inflammatory drugs, anti-oxidation, delaying cell aging, anti-cancer, immune regulation, artificial dormancy, etc. have very good application prospects.
  • Esterase is a kind of prodrug activator ubiquitous in biological environment, therefore, H 2 S prodrug triggered by esterase has a very bright prospect in clinical medicine.
  • Wang's research group (Zheng Y, Yu B, Ji K, et al. Esterase-sensitive prodrugs with tunable release rates and direct generation of hydrogen sulfide[J].
  • Hydrogen persulfide (H 2 S 2 ) is an endogenous signaling molecule.
  • H 2 S 2 has similar physiological effects to H 2 S, and in some indications, H 2 S 2 has stronger pharmacodynamic effects than H 2 S (Yu, B.; Yuan, Z .; Yang, X.; Wang, B. (2020).
  • Prodrugs of Persulfides, Sulfur Dioxide, and Carbon Disulfide Important Tools for Studying Sulfur Signaling at Various Oxidation States. Antioxid. Redox. Signal.
  • H 2 S 2 has stronger analgesic effect and higher safety than H 2 S (Yu, B., Kang, T.; Xu, Y., Liu, Y.; Ma, Y. ; Ke, B. Prodrugs of Persulfide and Sulfide: Is There a Pharmacological Difference between the Two in the Context of Rapid Exchanges among Various Sulfur Species In Vivo? Angew. Chem. Int. Ed. 2022, 61, e202201668). Therefore, H 2 S 2 probably has a better prospect of drug development than H 2 S.
  • H 2 S 2 and other polysulfides also exhibit higher biological activities than H 2 S in other aspects, such as scavenging peroxides and oxidative free radicals (Reactive cysteine persulfides and S-polythiolation regulate oxidative stress and redox signaling.Proc.Natl.Acad.Sci.USA2014,111(21),7606-7611.) and activate ion channels for the treatment of cardiovascular diseases (Polysulfides are possible H2S-derived signaling molecules in rat brain. FASEB J. 2013, 27(6), 2451-7).
  • H 2 S 2 has stronger activity than H 2 S in analgesia, peroxide removal, and cardiovascular diseases, and H 2 S 2 has better safety than H 2 S. Therefore, H 2 S 2 probably has a better prospect of drug development than H 2 S.
  • H 2 S 2 is an extremely unstable molecule, it needs to be made into a prodrug form before it can be used in clinical practice.
  • An ideal H 2 S 2 prodrug needs to have the following characteristics: stability, controllable release, controllable release rate, and non-toxic or less toxic by-products after release.
  • H 2 S 2 prodrugs there are few reports on H 2 S 2 prodrugs.
  • the literature reports a H 2 S 2 prodrug BW-HP-301, which can release H 2 S under the action of esterase 2 gas.
  • the by-product generated after the H 2 S 2 prodrug releases the H 2 S 2 gas is not an endogenous substance, which may cause toxic and side effects to the human body.
  • H 2 S 2 prodrugs that do not produce toxic by-products after releasing H 2 S 2 .
  • the object of the present invention is to provide a H 2 S 2 prodrug that does not produce toxic by-products and its pharmaceutical use.
  • the present invention provides a compound represented by formula I, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a solvate thereof, or a deuterated compound thereof:
  • R 1 and R 2 are each independently selected from the following groups that are unsubstituted or substituted by one or more R a : C 1-25 alkyl, C 1-25 alkoxy, C 2-20 alkenyl, C 2-20 alkynyl, C 2-10 dienyl, C 2-10 di -alkynyl, L 2 COR b ;
  • Ring A is selected from 5-6 membered aryl, 5-6-membered heteroaryl, 3-8-membered saturated cycloalkyl, 3-8-membered saturated heterocyclic group;
  • L1 is selected from none or C1-5 alkylene ;
  • L 2 is selected from none or C 1 ⁇ 5 alkylene;
  • R a is selected from halogen, carboxyl, hydroxyl, amino, C 1 ⁇ 8 alkyl;
  • R b is selected from C 1 ⁇ 8 alkyl, hydroxyl;
  • R 3 , R 4 , R 5 , and R 6 are each independently selected from hydrogen, C 1-8 alkyl, C 1-8 alkoxy, phenyl, Carboxyl; L 3 is selected from none or C 2 ⁇ 5 alkenylene; B ring is selected from 5 ⁇ 6 membered aryl, 5 ⁇ 6 membered heteroaryl, 3 ⁇ 8 membered saturated cycloalkyl, 3 ⁇ 8 membered saturated heteroaryl ring group;
  • R1 and R3 are connected to form a ring
  • R2 and R4 are connected to form a ring.
  • R 1 and R 2 are each independently selected from the following groups that are unsubstituted or substituted by one or more R a : C 1-25 alkyl, C 1-25 alkoxy, C 2-20 alkenyl, C 2-20 alkynyl, C 2-10 dienyl, C 2-10 di -alkynyl, L 2 COR b ;
  • L 1 is selected from none or C 1 ⁇ 5 alkylene
  • L 2 is selected from none or C 1 ⁇ 5 alkylene
  • R a is selected from halogen, carboxyl, hydroxyl, amino, C 1 ⁇ 5 alkyl
  • R b is selected from C 1 ⁇ 5 alkyl, hydroxyl
  • R 3 , R 4 , R 5 , and R 6 are each independently selected from hydrogen, C 1-5 alkyl, C 1-5 alkoxy, phenyl, Carboxyl; L 3 is selected from none or C 2 ⁇ 5 alkenylene.
  • R 3 , R 4 , R 5 , and R 6 are each independently selected from hydrogen, C 1-3 alkyl, phenyl,
  • the structure of the compound is one of the following structures:
  • R 1 and R 2 are each independently selected from the following groups that are unsubstituted or substituted by one or more R a : C 1-25 alkyl, C 1-25 alkoxy, C 2-20 alkenyl, C 2-20 alkynyl, C 2-10 dienyl, C 2-10 di -alkynyl, L 2 COR b ;
  • L 1 is selected from none or C 1 ⁇ 5 alkylene
  • L 2 is selected from none or C 1 ⁇ 5 alkylene
  • R a is selected from halogen, carboxyl, hydroxyl, amino, C 1-5 alkyl
  • R b is selected from C 1-5 alkyl and hydroxyl.
  • R 1 and R 2 are the same;
  • R 1 is selected from the following groups that are unsubstituted or substituted by one or more R a : C 1 ⁇ 23 alkyl, C 1 ⁇ 23 alkoxy, C 2-17 alkenyl, C 2-17 alkynyl, C 2-5 dienyl, C 2-5 di -alkynyl, L 2 COR b ;
  • L 1 is selected from none or C 1 ⁇ 3 alkylene
  • L 2 is selected from none or C 1 ⁇ 3 alkylene
  • R a is selected from halogen, carboxyl, hydroxyl, amino, C 1-4 alkyl
  • R b is selected from C 1-4 alkyl and hydroxyl.
  • the compound is selected from:
  • n is selected from an integer of 1-20, preferably an integer of 1-7.
  • the present invention also provides a H 2 S 2 prodrug, the H 2 S 2 prodrug is the above-mentioned compound, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a solvate thereof,
  • the preparation prepared by adding the active ingredient or its deuterated compound with pharmaceutically acceptable auxiliary materials.
  • the present invention also provides the use of the above compounds, or pharmaceutically acceptable salts, or stereoisomers, or solvates, or deuterated compounds thereof in the preparation of H 2 S 2 prodrugs.
  • H 2 S 2 prodrug is an esterase-activated H 2 S 2 prodrug.
  • the H 2 S 2 prodrug is an analgesic drug, an anesthetic drug, an anti-inflammatory drug, a drug for treating neurodegenerative diseases, a vasodilator drug, a drug for treating gastrointestinal mucosal ulceration, an antioxidant drug, and a cell Drugs for aging, anticancer drugs, immunomodulatory drugs, drugs for artificially inducing hibernation, drugs for regulating intestinal flora and increasing the proportion of intestinal probiotics, drugs for treating congestive heart failure or chronic heart failure, treating myocardial infarction and myocardial infarction Drugs for infarction, drugs for arthritis, drugs for oligoasthenospermia, drugs for anti-apoptosis, drugs for fibrinolysis, drugs for anti-platelet activation and aggregation, drugs for promoting angiogenesis, drugs for regulating or inhibiting metabolism, Drugs to inhibit atherosclerosis, drugs to promote bone tissue growth and repair, drugs to promote wound healing, drugs to protect muscle function from ischemia
  • the minimum and maximum carbon atom content in a hydrocarbon group is indicated by a prefix, for example, the prefix C a-b alkyl means any alkyl group containing "a" to "b" carbon atoms.
  • a C 1-25 alkyl group refers to a linear or branched chain alkyl group containing 1-25 carbon atoms.
  • Alkenyl means an aliphatic hydrocarbon group having one carbon-carbon double bond.
  • the alkenyl group may be straight chain or branched. When the number of carbon atoms is limited before the alkenyl group, for example, “C 2-20 alkenyl” refers to a straight-chain or branched alkenyl group having 2-20 carbon atoms.
  • Alkynyl means an aliphatic hydrocarbon group having one carbon-carbon triple bond.
  • the alkynyl group may be straight or branched.
  • C 2-20 alkynyl refers to a straight-chain or branched alkynyl group having 2-20 carbon atoms.
  • Dienyl refers to an aliphatic hydrocarbon group having two carbon-carbon double bonds.
  • the dienyl group may be straight chain or branched.
  • C 2-10 dienyl group refers to a straight-chain or branched dienyl group having 2-10 carbon atoms.
  • Dialkynyl means an aliphatic hydrocarbon group having two carbon-carbon triple bonds.
  • the diacetylenyl group can be straight chain or branched.
  • C 2-10 diynyl group refers to a straight-chain or branched-chain diynyl group with 2-10 carbon atoms.
  • Aryl refers to an all-carbon monocyclic or fused polycyclic (ie, rings sharing adjacent pairs of carbon atoms) group having a conjugated pi-electron system, eg, phenyl and naphthyl.
  • the aryl ring can be fused to other cyclic groups (including saturated and unsaturated rings), but cannot contain heteroatoms such as nitrogen, oxygen, or sulfur, and the point of connection to the parent must be in a conjugated ⁇ -electron system on the carbon atoms in the ring.
  • Aryl groups can be substituted or unsubstituted.
  • Heteroaryl refers to a heteroaromatic group containing one to more heteroatoms.
  • the heteroatoms referred to herein include oxygen, sulfur and nitrogen.
  • the heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring bonded to the parent structure is a heteroaryl ring.
  • Heteroaryl groups can be optionally substituted or unsubstituted.
  • Cycloalkyl refers to a saturated or unsaturated cyclic hydrocarbon substituent; the cyclic hydrocarbon may be monocyclic or polycyclic.
  • saturated cycloalkyl refers to saturated cycloalkyl, for example: 3-8 membered saturated cycloalkyl.
  • Heterocyclyl refers to a saturated or unsaturated cyclic hydrocarbon substituent; the cyclic hydrocarbon can be monocyclic or polycyclic, and carries at least one ring heteroatom (including but not limited to O, S or N).
  • “Saturated heterocyclic group” refers to a saturated heterocyclic group, for example: 3-8 membered saturated heterocyclic group.
  • the experimental results show that the compound provided by the invention can exert an effective analgesic effect in vivo on the pain model induced by glacial acetic acid and the inflammatory pain model induced by complete Freund's adjuvant.
  • the compound KB-HSP-101 of the present invention achieved similar analgesic effect at a lower dose, indicating that the compound KB-HSP-101 of the present invention has better analgesic effect in vivo than the reference compound 301. It is proved that the compound of the present invention has a good application prospect in the preparation of analgesic and anesthetic drugs.
  • the experimental results show that the compound provided by the invention can exert an effective analgesic effect in vivo on compressive neuropathic pain models and neuropathic pain induced by chemotherapeutic drugs.
  • H 2 S 2 has similar physiological effects to H 2 S, and in some indications, H 2 S 2 has stronger pharmacodynamic effects than H 2 S; in addition, compared with H 2 S prodrugs Compared with H 2 S 2 prodrug, the toxicity is lower and the safety is higher.
  • the H2S2 prodrug provided by the invention has the physiological activity of hydrogen sulfide and hydrogen persulfide, and has low toxicity.
  • H2S2 prodrugs have the potential to treat the following diseases: neurodegenerative diseases (such as Alzheimer 's disease), anti-inflammation, vasodilation, treatment of alcohol or NSAID-induced Indications such as gastrointestinal mucosal ulceration, anti-oxidation, anti-aging, anti-cancer, immune regulation and other drugs.
  • neurodegenerative diseases such as Alzheimer 's disease
  • anti-inflammation such as Alzheimer 's disease
  • vasodilation vasodilation
  • Treatment of alcohol or NSAID-induced Indications such as gastrointestinal mucosal ulceration, anti-oxidation, anti-aging, anti-cancer, immune regulation and other drugs.
  • the H2S2 prodrug provided by the present invention can also be used to prepare artificially induced hibernation, regulate intestinal flora and increase the proportion of intestinal probiotics, treat congestive heart failure or chronic heart failure, and treat myocardial choking and myocardial infarction , treatment of arthritis, treatment of oligoasthenospermia, anti-apoptosis, fibrinolytic activity, anti-platelet activation and aggregation, promote angiogenesis, regulate or inhibit metabolism, inhibit atherosclerosis, promote bone tissue growth and repair bone tissue , promote wound healing, protect muscle function from ischemia-reperfusion injury, relieve diabetes, treat chronic kidney injury, and treat lung injury; it can also be used to prepare neutralized heavy metal ions as heavy metal ion antidotes (relevant literature information: 10.1073 /pnas.2017225118,10.1016/bs.mie.2014.11.021,10.1007/978-3-319-18144-8,10.3164/jcbn.20
  • the H 2 S 2 prodrug provided by the present invention can also be used to prepare and treat neurodegenerative diseases (such as Alzheimer's disease), anti-inflammation, vasodilation, and treatment of alcohol or non- Indications such as gastrointestinal mucosal ulceration caused by steroidal anti-inflammatory drugs, anti-oxidation, anti-aging, anti-cancer, immune regulation and other drugs.
  • neurodegenerative diseases such as Alzheimer's disease
  • anti-inflammation such as Alzheimer's disease
  • vasodilation vasodilation
  • alcohol or non- Indications such as gastrointestinal mucosal ulceration caused by steroidal anti-inflammatory drugs, anti-oxidation, anti-aging, anti-cancer, immune regulation and other drugs.
  • the H2S2 prodrug provided by the present invention can also be used to prepare artificially induced hibernation, regulate intestinal flora and increase the proportion of intestinal probiotics, treat congestive heart failure or chronic heart failure, and treat myocardial choking and myocardial infarction , treatment of arthritis, treatment of oligoasthenospermia, anti-apoptosis, fibrinolytic activity, anti-platelet activation and aggregation, promote angiogenesis, regulate or inhibit metabolism, inhibit atherosclerosis, promote bone tissue growth and repair bone tissue , promote wound healing, protect muscle function from ischemia-reperfusion injury, relieve diabetes, treat chronic kidney injury, and treat lung injury; H 2 S 2 prodrugs provided by the invention can also be used to prepare neutralized heavy metal ions as Heavy metal ion antidote.
  • Figure 1 is the nuclear magnetic spectrum of compound 3.
  • Figure 2 is the H NMR spectrum of compound KB-HPS-101.
  • Figure 3 is the carbon NMR spectrum of compound KB-HPS-101.
  • Fig. 4 is the verification experiment result of compound KB-HPS-101 releasing H 2 S 2 under the action of esterase.
  • Fig. 5 is a schematic diagram of the mechanism of the compound of the present invention releasing H 2 S 2 under the action of esterase.
  • Figure 6 shows the results of the mouse writhing experiment.
  • Fig. 7 is a broken line graph of the analgesic time-effect of the experimental mice in each group within 4 hours after the intervention of different drugs.
  • Figure 8 is a histogram of the area under the curve of the analgesic effect of the experimental mice in each group within 4 hours after the intervention of different drugs.
  • Figure 9 is a schematic diagram of the construction process of the mouse CCI model.
  • Figure 11 shows the change of the cold stimulation pain threshold of the hydrogen persulfide prodrug KB-HSP-1 in the mouse CCI model.
  • Figure 12 is a schematic diagram of the construction process of the mouse PTX model.
  • Figure 13 shows the change of the cold stimulation pain threshold of the hydrogen persulfide prodrug KB-HSP-1 in the mouse PTX model.
  • the experimental method is to observe and record the withdrawal, licking, enough cumulative time.
  • Fig. 14 is the change of mechanical stimulation pain threshold of hydrogen persulfide prodrug KB-HSP-1 in mouse PTX model.
  • Figure 15 shows the analgesic effect of the hydrogen persulfide prodrug of the present invention in the formalin inflammatory pain model.
  • the raw materials and equipment used in the present invention are known products obtained by purchasing commercially available products.
  • PE is the abbreviation of petroleum ether
  • EA is the abbreviation of ethyl acetate
  • DCM is the abbreviation of dichloromethane
  • MeCN is the abbreviation of acetonitrile
  • NIS is the abbreviation of N-iodosuccinimide
  • DMF is Abbreviation for N,N-dimethylformamide.
  • Embodiment 1 synthetic target compound KB-HSPs
  • R 1 and R 3 correspond to the substituents in the structure of the target product in Table 1.
  • step 1
  • Intermediate M3 (1eq.) and KSAc (1eq.) were mixed and dissolved in acetone (the mass volume ratio of intermediate M3 and acetone was controlled to be 1:10g/mL), and the reaction was stirred at room temperature for 12h. After the reaction, the solid impurities were removed by filtration, the liquid was concentrated under reduced pressure to remove the organic solvent, and the crude product was separated and purified by silica gel column chromatography to obtain intermediate M4.
  • Table 1 Structure, molecular formula and high-resolution mass spectrometry characterization results of the target product KB-HSPs
  • Embodiment 2 Synthesis of target compound KB-HPS-101
  • the target compound KB-HPS-101 (namely, the target compound KB-HSP-1) can be prepared not only according to the method of Example 1, but also according to the method of this example.
  • the specific route and operation are as follows:
  • reaction solution was diluted with Na 2 S 2 O 3 aqueous solution (5wt.%, 100 mL), then extracted with DCM (50 mL ⁇ 3), the combined organic layer was dried with Na 2 SO 4 , filtered, and the filtrate was concentrated in vacuo , to obtain a crude product, which was purified by preparative high-performance liquid chromatography (Pre-HPLC) to obtain a light yellow oily product KB-HPS-101 (50 mg).
  • Pre-HPLC preparative high-performance liquid chromatography
  • the esterase used in this experiment was porcine liver esterase, which was purchased from Sigma.
  • H 2 S 2 fluorescent probe DSP-3 was used to detect the release of H 2 S 2 .
  • the above results show that the KB-HSPs of the present invention can release H 2 S 2 under the action of esterase, and can be used as H 2 S 2 prodrugs.
  • the KB-HSPs of the present invention have obvious advantages as H 2 S 2 prodrugs, and they have good stability in PBS, and will not degrade and release H 2 S 2 in the absence of esterase, and besides releasing H 2 S 2 , the rest
  • the by-products are endogenous substances produced during metabolism in the human body, with high safety.
  • Experimental example 2 utilize mouse writhing test to test the analgesic effect of the compound of the present invention on the pain model caused by glacial acetic acid
  • compound 301 is the reference (Yu, B.; Zheng, Y.; Yuan, Z.; Li, S.; Zhu, H.; De La Cruz, L.K.; Zhang, J.; Ji, K.; Wang , S.; Wang, B. (2018). Toward Direct Protein S-Persulfidation: A Prodrug Approach That Directly Delivers Hydrogen Persulfide. J.Am.Chem.Soc.140(1):30-33) reported method prepared of:
  • mice were randomly divided into KB-HSPs group (injection of drug is KB-HSPs), 301 group (injection of drug is 301) and model group (injection of blank solvent, denoted as Vehicle group).
  • injection of drug is KB-HSPs
  • 301 group injection of drug is 301
  • model group injection of blank solvent, denoted as Vehicle group.
  • the KB-HSPs group when the injected drug is compound KB ⁇ HPS ⁇ 101 (ie compound KB ⁇ HSP ⁇ 1), it is recorded as 101 group.
  • Grouping process inject 0.2mL KB-HSP solution s or 301 solution or blank solvent into the abdominal cavity of the experimental animals respectively, and inject 0.6% glacial acetic acid solution into the different side abdominal cavity according to the dose of 0.1mL/10g after 5 minutes, and record the first writhing time immediately ( time from the injection of glacial acetic acid), and the number of writhing times within the 5-20 min period after the injection of glacial acetic acid was recorded.
  • Judging criteria for writhing Abdominal concave, trunk and limbs stretched, buttocks raised are a complete writhing response.
  • Pain inhibition rate [the number of writhing times in the model group - the number of writhing times in the drug-administered group]/the number of writhing times in the model group
  • mice in the Vehicle group was 28.13 ⁇ 7.57 times
  • the number of writhing times of the mice in the 301 group (30mg/kg) was 2.88 ⁇ 3.36 times
  • that of the mice in the 101 group (7mg/kg) ) mice writhing times was 11.63 ⁇ 7.01 times
  • 101 group (14mg/kg) mice writhing times were 4.5 ⁇ 3.12 times
  • 101 group (28mg/kg) mice writhing times were 2.50 ⁇ 3.16 times.
  • the pain inhibition rate of administering the reference compound 301 (30mg/kg) was 89.78 ⁇ 11.93%; the pain inhibition rate of administering the compound KB-HSP-101 of the present invention (7mg/kg) was 58.67 ⁇ 24.92%, and the administration of the compound KB-HSP of the present invention was 58.67 ⁇ 24.92%.
  • -101 (14mg/kg) pain inhibition rate was 84.00 ⁇ 14.08%, and the pain inhibition rate of the compound KB-HSP-101 (28mg/kg) of the present invention was 91.13 ⁇ 11.24%.
  • the compound KB-HSP-101 of the present invention can significantly reduce the number of writhing times in mice, significantly delay the time for the first writhing in mice, and has good analgesic effect. Moreover, compared with the reference compound 301, the compound KB-HSP-101 of the present invention achieved similar analgesic effects at a lower dose, indicating that the compound KB-HSP-101 of the present invention has better analgesic effects in vivo than the reference compound 301.
  • the average number of writhing times and the average first writhing time of the mice after administration of each KB-HSPs at an equimolar amount of 59 ⁇ mmol/kg were further compared.
  • the dosage of 59 ⁇ mmol/kg KB-HSP-101 is the above-mentioned dosage of 14 mg/kg KB-HSP-101.
  • Table 5 The results are shown in Table 5.
  • the KB-HSPs provided by the present invention can all exert effective analgesic effects in vivo, wherein, KB-HSP-1, KB-HSP-2, KB-HSP-3, KB ⁇ HSP ⁇ 4, KB ⁇ HSP ⁇ 5, KB ⁇ HSP ⁇ 6, KB ⁇ HSP ⁇ 7, KB ⁇ HSP ⁇ 8, KB ⁇ HSP ⁇ 14, KB ⁇ HSP ⁇ 15, KB ⁇ HSP ⁇ 19, KB ⁇ HSP
  • the analgesic effect of ⁇ 21 was better, and the pain suppression rate reached over 70%.
  • the KB-HSPs provided by the present invention can all exert effective analgesic effects in vivo.
  • the compound KB-HSP-101 of the present invention achieved similar analgesic effect at a lower dose, indicating that the compound KB-HSP-101 of the present invention has better analgesic effect in vivo than the reference compound 301.
  • CFA Complete Freund's adjuvant
  • SIGMA SIGMA induced mouse hyperalgesia model of inflammatory pain. After injecting 20 ⁇ L of complete Freund's adjuvant into the left foot of the mouse, the animal's foot can show red and swollen state of inflammation, accompanied by local skin temperature rise. The pain threshold was recorded 24 hours after the modeling, and administered in groups, and the change of the pain threshold within 4 hours was measured.
  • KB-HSPs group 24 hours after modeling, each KB-HSPs was injected intraperitoneally at a dose of 14 mg/kg, 28 mg/kg or 30 mg/kg; wherein, when the injected drug was compound KB-HPS-101 (ie compound KB-HSP-1) When, it is recorded as 101 groups;
  • Group 301 24 hours after modeling, 301 was injected intraperitoneally, at a dose of 30 mg/kg;
  • Vehicle group 24 hours after modeling, a blank solvent was injected intraperitoneally;
  • Indomethacin group 24 hours after modeling, indomethacin was orally administered, at a dose of 10 mg/kg;
  • Normal group Normal mice were intraperitoneally injected with blank solvent.
  • Hind paw sensitivity to tactile allodynia to mechanically compressive stimuli was measured using an electronic Von Frey instrument (TIIC). After the mice have adapted to the transparent and closed environment laid by wire mesh, the mechanical threshold (PWT) of the animal's paw withdrawal to the electronic Von Frey is evaluated.
  • the weight range of the fiber is 0-800g, and the up and down method is used to measure The average value of three times, with an interval of at least 1 min each time.
  • Drug represents the administration group
  • AUC area under the curve
  • KB-HSP-101 has a similar analgesic effect to 301 (30mg/kg) at a low dose (14mg/kg);
  • the conventional treatment regimen of Mexin (10mg/kg, orally) and 301 (30mg/kg) have significantly better analgesic effects. It shows that the analgesic effect of the compound KB-HSP-101 of the present invention is better than that of the reference compound 301 in vivo.
  • the AUC of the mice after administration of each KB-HSPs at an equimolar amount of 120 ⁇ mmol/kg was further compared.
  • the dosage of 120 ⁇ mmol/kg KB-HSP-101 is the above-mentioned dosage of 28 mg/kg KB-HSP-101.
  • Table 6 It can be seen that the KB-HSPs provided by the present invention can all exert effective analgesic effects in vivo, wherein, KB-HSP-1 ⁇ KB-HSP-15, KB-HSP-17, KB ⁇ HSP ⁇ 21 ⁇ KB ⁇ HSP ⁇ 23 had better analgesic effect, and the analgesic rate was above 95%.
  • mice after administration of each KB-HSPs (equimolar amount: 120 ⁇ mmol/kg)
  • the analgesic rate in Table 6 is the maximum effective benefit of analgesia.
  • the KB-HSPs provided by the present invention can exert effective analgesic effect in vivo.
  • the compound KB-HSP-101 of the present invention achieved a similar analgesic effect at a lower dose, indicating that the compound KB-HSP-101 of the present invention has better analgesic effect in vivo than the reference compound 301.
  • the analgesic effects of the hydrogen persulfide prodrug of the present invention in the mouse CCI model (compressive neuropathic pain model) and the mouse PTX model (chemotherapy drug-induced neuropathic pain) were respectively tested.
  • Analgesic benefit% (administration group-model group)/(normal group-model group)*100%.
  • model group 18.20 56.30 KB-HSP-1 42.92 65.15 KB-HSP-2 46.80 53.53 KB-HSP-3 41.70 59.23 KB-HSP-4 44.20 58.31 KB-HSP-5 43.80 46.92 KB-HSP-6 38.80 61.50 KB-HSP-7 45.20 48.97 KB-HSP-8 39.70 50.11 KB-HSP-9 40.20 41.69 KB-HSP-10 36.50 48.75 KB-HSP-11 39.60 52.16 KB-HSP-12 41.10 58.77 KB-HSP-13 44.00 64.24 KB-HSP-14 46.40 48.06 KB-HSP-15 39.30 54.67 KB-HSP-16 42.20 53.53 KB-HSP-17 41.70 49.43 KB-HSP-18 39.90 51.48 KB-HSP-19 40.80 57.18 KB-HSP-20 43.30 51.03 KB-
  • Analgesic benefit% (administration group-model group)/(normal group-model group)*100%.
  • mice were first given 0.2 mL of compound (28 mg/kg) by intraperitoneal injection, formalin solution was injected into the plantar 5 minutes later, and then a precise stopwatch was used to record the mice licking, shaking, Time to bite the right hind paw.
  • the present invention uses the sequential method to measure the median lethal dose (LD 50 ) of the compound without using the Bliss method, because the sequential method saves about 1/3 of the animals compared with the Bliss method, and the results measured by the two have no significant difference .
  • the dosage formula ratio between the groups of the mouse sequential method in this test is based on the literature (document Garfield, JM&Bukusoglu, C. Propofol and ethanol produce additive hypnotic and anesthetic effects in the mouse. Anesthesia and analgesia.83, 156-161 (1996).
  • mice When the test results of two adjacent mice appear (+) to (-) or (-) to (+), it is recorded as a crossing point, and the test is repeated until 5 crossings appear in the same direction for each test drug, and the test ends. After administration, mice were transferred to observation cages and observed for at least 1 h. During the whole experiment, the mice inhaled oxygen (2L/min) with open masks, and used a temperature-changing plate to prevent the mice from lowering their body temperature.
  • 2L/min 2L/min
  • ICR mouse tail vein bolus administration hydrogen persulfide prodrug
  • the present invention includes and is not limited to the compound in the above examples, or its salt, or its stereoisomer, or its solvate, or its prodrug.
  • Control the administration volume at 0.1-0.2mL, and control the administration time at 10 seconds. The state of the mice was observed after administration.
  • the present invention provides a hydrogen persulfide prodrug represented by formula I and its pharmaceutical use.
  • the hydrogen persulfide prodrug provided by the invention can release H 2 S 2 under the action of esterase; the hydrogen persulfide prodrug has good stability in PBS, and will not degrade and release H 2 S 2 without the presence of esterase.
  • the hydrogen sulfide prodrug releases H 2 S 2 under the action of esterase, and most of the other by-products are endogenous substances or FDA-approved drug excipients or food additives, which have high safety.
  • the hydrogen persulfide prodrug provided by the present invention can exert an effective analgesic effect in vivo, and the analgesic effect in vivo is better than that of the reference compound 301.
  • the hydrogen persulfide prodrug of the present invention has good clinical application prospects in the preparation of analgesic drugs.

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Abstract

L'invention concerne un promédicament de persulfure d'hydrogène et une utilisation pharmaceutique de celui-ci, appartenant au domaine des produits pharmaceutiques. La structure du promédicament de persulfure d'hydrogène est telle que représentée dans la formule I. Le promédicament de persulfure d'hydrogène selon l'invention peut libérer du H2S2 sous l'action d'une estérase. Le promédicament de persulfure d'hydrogène présente une bonne stabilité dans le PBS, et il ne dégradera pas et ne libèrera pas de H2S2 en l'absence de l'estérase. En plus de la libération de H2S2 sous l'action de l'estérase, la plupart des sous-produits restants du promédicament de persulfure d'hydrogène sont des substances endogènes ou des excipients de médicament ou encore des additifs alimentaires approuvés par la FDA, et ainsi ledit promédicament présente une sécurité élevée. Le promédicament de persulfure d'hydrogène selon l'invention peut exercer un effet analgésique efficace in vivo, et l'effet analgésique in vivo est meilleur que celui du composé de référence 301. Le promédicament de persulfure d'hydrogène présente de bonnes perspectives d'application clinique dans la préparation de médicaments analgésiques.
PCT/CN2022/110332 2021-08-05 2022-08-04 Promédicament de persulfure d'hydrogène et son utilisation pharmaceutique WO2023011599A1 (fr)

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