CN111214469B - Compound for preventing and treating chronic pain and application thereof - Google Patents
Compound for preventing and treating chronic pain and application thereof Download PDFInfo
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- CN111214469B CN111214469B CN201811416098.3A CN201811416098A CN111214469B CN 111214469 B CN111214469 B CN 111214469B CN 201811416098 A CN201811416098 A CN 201811416098A CN 111214469 B CN111214469 B CN 111214469B
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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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/428—Thiazoles condensed with carbocyclic rings
-
- 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
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- 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
- A61P25/06—Antimigraine agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pain & Pain Management (AREA)
- Engineering & Computer Science (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a benzothiazole compound for preventing and treating chronic pain and application thereof. Specifically, the invention provides a compound of formula I or a pharmaceutically acceptable salt thereof, which has a significant chronic pain effect and can be used for preventing and/or treating chronic pain. The invention also provides the use of a compound of formula I in the treatment of chronic pain.
Description
Technical Field
The invention relates to the field of medicinal chemistry, in particular to a compound for preventing and treating chronic pain and application thereof.
Background
Persistent and repeatedly intractable chronic pain makes patients suffer long-term affliction, even produces malignant emotional reactions such as anxiety, pain 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, pain-relieving 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.
Disclosure of Invention
The invention aims to provide a compound for preventing and treating chronic pain and application thereof.
In a first aspect of the present invention there is provided the use of a compound of formula I (CLT3001a), or a pharmaceutically acceptable salt thereof, for the manufacture of a pharmaceutical composition or formulation for the prevention and/or treatment of chronic pain, in another preferred embodiment said compound of formula I is compound CLT3001a, both of which are the same compound.
In another preferred embodiment, the prevention and/or treatment of chronic pain includes diabetic pain, cancer pain, herpes zoster pain, trigeminal neuralgia, migraine pain, or chronic pain caused by inflammation such as arthritis, or a combination thereof.
In another preferred embodiment, the compound of formula I is administered in a dose of 0.1-50mg/kg, preferably 1-5 mg/kg.
In another preferred embodiment, the compound of formula I is administered at a dose of 50mg/kg or less without adverse effects.
In another preferred embodiment, the pharmaceutical composition further comprises other active ingredients for treating pain.
In another preferred embodiment, the pharmaceutical composition comprises 0.001-99 wt%, preferably 0.1-90 wt%, more preferably
1-80 wt% of a compound of formula I or a pharmaceutically acceptable salt thereof, based on the total weight of the composition.
In another preferred embodiment, the dosage form of the pharmaceutical composition is an oral dosage form or an injection.
In another preferred example, the oral dosage form comprises tablets, capsules, films, granules and the like, and also comprises sustained-release or non-sustained-release dosage forms.
In a second aspect of the invention, there is provided a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof
In another preferred embodiment, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.
In another preferred embodiment, the total amount of said compound of formula I or a pharmaceutically acceptable salt thereof is 0.001-99 wt%, preferably 0.1-90 wt%, more preferably 1-80 wt% of the composition.
In another preferred embodiment, the pharmaceutical composition is for use in the prevention and/or treatment of pain.
In a third aspect of the invention, there is provided a method of preventing and/or treating pain, the method comprising: administering to a subject in need thereof a compound of formula I as described in claim 1 or a pharmaceutically acceptable salt thereof.
In another preferred embodiment, the subject includes humans and non-human mammals (e.g., rodents and primates).
In another preferred embodiment, the subject is a human, and the compound of formula I is administered at a dose of 1-20 mg/kg, preferably 5 mg/kg.
In another preferred embodiment, the frequency of application is 1-4 times per day, preferably 1 time per day.
In another preferred embodiment, the application period is 2 weeks to 5 years, preferably 2 months to 1 year.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.
Drawings
Figure 1 shows the structural formula of compound CLT3001 a.
Figure 2 shows that CLT3001a concentration dose-dependently inhibited acute pain caused by malicious thermal stimuli in normal mice, and the analgesic effect of CLT3001a at medium dose was not significantly different from that of morphine at medium dose.
Fig. 3 shows analgesic effect of compound CLT3001a on spontaneous pain in mice induced by day 12 of model creation in a mouse neuropathological pain model (retained nerve injury (SNI) model).
Figure 4 shows that compound CLT3001a is resistant to cold pain sensitivity (cold hyperalgesia) in chronic pain at 14 days of molding.
Figure 5 shows the efficacy of compound CLT3001a on triggered mechanical hyperalgesia (mechanical allodynia) resistance at day 16 of molding.
FIG. 6 shows The analgesic effect of compound CLT3001a on anti-thermal hyperalgesia (heat hyperalgesia) in chronic pain induced within 2-3 days of molding in a model of inflammatory pain in mice injected with CFA (The complete free's adjivant) from The plantar left foot. (One-way ANOVA with LSD post-hoc tests: <0.05, p <0.05 compared with Vehicle group)
Detailed Description
The present inventors have made extensive and intensive studies and, for the first time, have unexpectedly found a compound for preventing and/or treating chronic pain and use thereof. Experiments show that the compound has a remarkable anti-chronic pain effect and can be used for preventing and/or treating chronic pain. On the basis of this, the present invention has been completed.
Specifically, the invention carries out a large amount of drug design and screening aiming at a novel anti-chronic pain target point, and pharmacodynamic tests are carried out through experimental animal models, and the compound CLT3001a is found to have obvious anti-pain effect, and the analgesic efficacy of CLT3001a is similar to that of a positive control drug morphine in resisting pain generated by malicious thermal stimulation.
The invention selects Balb/c mice or Sprague-Dawley rats to carry out four behavioural pharmacodynamic experiments for evaluating acute and chronic pains, and uses CLT3001a with different doses in an intraperitoneal or intravenous injection administration mode, and the result shows that the compound has obvious chronic pain resisting effect, and the effect of the compound is similar to that of positive control medicament morphine, so the compound can be used for preparing the medicament for treating chronic pains.
Compounds of the invention
As used herein, the terms "compound of the invention", "compound of formula I", "compound CLT3001 a", or "CLT 3001 a" are used interchangeably to refer to a compound of formula I, or a pharmaceutically acceptable salt thereof.
In the present invention, pharmaceutically acceptable salts of the compounds of formula I are also included. The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention with an acid or base that is suitable for use as a pharmaceutical. Pharmaceutically acceptable salts include inorganic or organic salts.
Compositions and methods of administration
The present invention provides a pharmaceutical composition for the prevention and/or treatment of pain comprising a compound of formula I as described above or a pharmaceutically acceptable salt thereof.
The pharmaceutical composition of the present invention can be used for preventing and/or treating pain. Other pain treatments, such as fluoxetine, may also be used concurrently with the pharmaceutical formulation of the present invention.
The pharmaceutical composition of the invention contains a safe and effective amount of the compound of the invention and a pharmaceutically acceptable carrier or excipient. Such vectors include (but are not limited to): saline, buffer, dextrose, water, glycerol, ethanol, powders, and combinations thereof. The pharmaceutical preparation should be compatible with the mode of administration.
The pharmaceutical composition of the present invention can be prepared in the form of an injection, for example, by a conventional method using physiological saline or an aqueous solution containing glucose and other adjuvants. Pharmaceutical compositions, such as tablets and capsules, can be prepared by conventional methods. Pharmaceutical compositions such as injections, solutions, tablets and capsules are preferably manufactured under sterile conditions. The pharmaceutical combination of the present invention may also be formulated as a powder for inhalation by nebulization. The amount of active ingredient administered is a therapeutically effective amount, for example, from about 1 microgram/kg body weight to about 50mg/kg body weight, from about 5 microgram/kg body weight to about 10mg/kg body weight, from about 10 microgram/kg body weight to about 5mg/kg body weight per day. In addition, the compounds of the present invention may also be used with other therapeutic agents.
For the pharmaceutical compositions of the present invention, administration to a subject in need thereof (e.g., human and non-human mammals) can be by conventional means. Representative modes of administration include (but are not limited to): oral administration, injection, aerosol inhalation, etc. In the case of pharmaceutical compositions, a safe and effective amount of the drug is administered to the mammal, wherein the safe and effective amount is generally at least about 10 micrograms/kg body weight, and in most cases does not exceed about 50mg/kg body weight, preferably the dose is from about 10 micrograms/kg body weight to about 20mg/kg body weight. Of course, the particular dosage will depend upon such factors as the route of administration, the health of the patient, and the like, and is within the skill of the skilled practitioner.
The main advantages of the invention include:
(a) the compound CLT3001a has good analgesic effect on various chronic pains caused by different injury mechanisms.
(b) Compound CLT3001a has rapid onset of action
(c) The compound CLT3001a has low concentration of onset and small administration dose
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are by weight
Test drug
The test drugs used in the examples include: CLT3001a and pregabalin (Pregabaline). Wherein CLT3001a is synthesized by conventional method, and pregabalin is commercially available.
Test drug configuration
In the CLT3001a example, two doses were set, respectively: 5mg/kg and 10mg/kg
Compound CLT3001a was dissolved according to the following procedure: (1) injection volume 5% DMSO primary solution; (2) after complete dissolution, TWEEN80 was added at 5% of the injection volume to aid dissolution; (3) the injection volume is diluted to the final volume with 90% sterile saline. Operating according to the sequence, carrying out vortex for 30s at each step, and then carrying out ultrasonic assisted dissolution for 5-10 min, and using the traditional Chinese medicine preparation.
Morphine: the dosage is 3 mg/kg; dissolved in physiological saline.
Solvent control group: 10% DMSO + 5% Tween-80 + 85% physiological saline
Data analysis
All data analysis was done using the ss 22(for mac) data processing software. And (4) carrying out multiple comparisons on the check result by using a single-factor analysis of variance and adopting an LSD method. Data are expressed as Mean ± sem. One asterisk is marked when p < 0.05; two asterisks are marked when p < 0.01.
Grouping animals
60 male 8-week-old Balb/c mice, randomized into 2 groups:
balb/c Mice (SPF grade, Inbred-infected Mice) or Sprague-Dawley rats (SPF grade, Inbred-infected Mice) are internationally common laboratory Mice purchased from the Goodds-driven center.
Example 1
Mouse tail flick experiment (tail immerge)
In the tail flick experiment of the mouse, the tail of the mouse is immersed in water at 52 ℃, and the pain tolerance of the mouse is judged by calculating the time latency for the mouse to raise the tail because the mouse feels pain caused by malignant thermal stimulation. The experimental result shows that the CLT3001a concentration-dependent can effectively relieve the pain of the mice caused by the malignant thermal stimulation, and the analgesic efficacy of the CLT3001a and morphine in the medium dose is not obviously different.
Example 2
Evaluation experiment of spontaneous pain in mice
Mouse Spontaneous pain evaluation experiment (Spontaneous pain test)
The neuropathic pain mouse shows spontaneous behaviors of paw withdrawal, paw licking and the like, image data of the mouse in a quiet state within 5min are recorded by a camera, and the number of times of rapidly lifting the paw is counted to serve as an index for evaluating spontaneous pain. As shown in fig. 3, 12 days after the model of neuropathic pain in mice (retained nerve injure (SNI) model), the mice showed marked frequent spontaneous paw-pinching, licking, etc. behaviors, while the CLT3001a or the control solvent was intraperitoneally injected. As a result, it was found that 30min after CLT3001a (5mg/kg) injection, the number of spontaneous paw-locking times was significantly reduced, suggesting that the spontaneous pain symptoms of neuropathic pain could be improved.
Example 3
Mouse cold plate experiment
Cold plate experiment (Cold plate test) for evaluating mice's tolerance response to malicious Cold stimuli. The cold plate was a borate glass plate (6 mm thick). (1) The mouse adapts to the environment in a single compartment, the size of the compartment is 4 'multiplied by 11', and the adjacent part is black and opaque; (2) preparation of cold stimulant: breaking dry ice stored at-80 ℃ into powder, cutting the head end of a BD brand injector of 3mL, filling the powder dry ice into the modified injector and compacting, and trimming the open head end into a smooth surface with the diameter of 1 cm; (3) the mice are tested in a quiet state rather than a sleeping state, and the hind feet of the mice are required to be in direct contact with the glass plate, so that gaps are avoided; withdrawing the syringe pintle to make the dry ice higher than the tail end of the syringe and slightly pressing the dry ice below the glass plate; (4) recording the latent period of the paw-contracting by using a stopwatch, wherein the time interval of two continuous tests is more than or equal to 7min, and the serial test interval of two time points is more than or equal to 15 min; (5) 3 consecutive measurements were used as a base control value, the hind paw was measured 1-2 times per time point, given the time constraints of the experimental phase; (6) to reduce freezing injury, the maximum paw withdrawal latency was 30 seconds, i.e., no paw withdrawal response within 30 seconds, and this time was recorded as the cutoff value. As shown in figure 4, after the SNI model is established for 13 days, CLT3001a (5mg/kg) can remarkably relieve the cold pain sensitivity symptoms of the mice after intravenous injection, and the duration is about 1.5 hours after the injection.
Example 4
Rat Von Frey silk experiment
The Von Frey silk test was used to evaluate the tolerance response of mice to triggered mechanical pain. The stimulation force can be adjusted by adopting a Von Frey wire kit (capable of providing 0.008g-300g of stimulation force), selecting nylon wires with proper thickness according to actual conditions, adjusting the proper extension length, vertically stimulating the skin, and adjusting the stimulation force by adjusting the extension and replacing the nylon wires until the nylon wires are bent. Rats were subjected to mechanical stimulation, which resulted in withdrawal reflexes, recording the intensity of the stimulation force used when lifting the paw, and 3 consecutive measurements were averaged and used to assess the sensitivity of the rats to trigger mechanical pain. As shown in figure 5, a Von Frey wire experiment is performed after the rat SNI model is made for 16 days, and the sensitivity of the triggered mechanical pain of the rat is remarkably reduced 60 minutes after the CLT3001a (5mg/kg) is injected into the abdominal cavity, which indicates that the CLT3001a can effectively relieve the triggered mechanical pain sensitivity of the rat.
Example 5
Mouse heat radiation experiment
The bolometric assay (Hargreaves test) was used to evaluate the tolerance response of mice to malicious thermal stimuli. (1) Placing the mouse in a test room, and adapting to the environment for 1h multiplied by 3 d; (2) adapting in a grid box of resin glass for 30 min; (3) adjusting the energy of the radiation heat source to stabilize the basic value of the stimulation intensity within 8-11 s; (4) to avoid damage, the cutoff value was set to 20 s; (5) recording the latency time of the paw lifting, continuously measuring for 3 times, taking an average value, and setting the time interval of the two continuous tests to be 5 min. As shown in figure 6, the Balb/c mice become an inflammatory pain model after injecting CFA (20 mu l) into the plantar aspect of the left side for 48-72 hours, and the intraperitoneal injection of CLT3001a (5mg/kg) can remarkably prolong the paw withdrawal reaction time stimulated by heat radiation, which indicates that CLT3001a can remarkably relieve thermal hyperalgesia under inflammatory pain.
The results of the four behavioural pharmacodynamic experiments of acute and chronic pain are combined, and the CLT3001a has obvious effect of resisting chronic pain. All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.
Claims (9)
1. The use of a compound of formula I or a pharmaceutically acceptable salt thereof for the preparation of a pharmaceutical composition or formulation for the prevention and/or treatment of chronic pain,
2. the use according to claim 1, wherein the prevention and/or treatment of chronic pain comprises diabetic pain, cancer pain, herpes zoster pain, neuropathic pain or chronic pain caused by inflammation or a combination thereof.
3. The use according to claim 2, wherein the neuropathic pain is trigeminal neuralgia, migraine, and the chronic pain caused by inflammation is chronic pain caused by arthritis.
4. The use according to claim 1, wherein the pharmaceutical composition further comprises an additional active ingredient for the treatment of chronic pain.
5. The use according to claim 1, wherein the compound of formula I is administered in a dose of 0.1 to 50 mg/kg.
6. The use according to claim 1, wherein the compound of formula I is administered in a dose of 1-5 mg/kg.
7. The use according to claim 1, wherein the pharmaceutical composition comprises 0.001 to 99 wt% of the compound of formula I or a pharmaceutically acceptable salt thereof, based on the total weight of the composition.
8. The use according to claim 1, wherein the pharmaceutical composition is in the form of an oral dosage form or an injectable formulation.
9. The use as claimed in claim 8, wherein said oral dosage form comprises tablets, capsules, films, granules.
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