JP2000186041A - Pain therapeutic agent - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain pain therapeutic agent exerting excellent analgesic activity against acute and chronic pains by including dioxoimidazolyl nitrotetrahydroquinoxalinyl acetic acid as an active ingredient. SOLUTION: This pain therapeutic agent is obtained by including (A) 2,3- dioxo-7-(1H-imidazol-1-yl)-6-nitro-(1,2,3,4-tetrahydro-1-quinoxalinyl) acetic acid as an active ingredient. The component A is preferably administrated at a daily dose of 1-1000 mg per a conventional adult. Further, by including (B) an activating agent for a benzodiazepine-GABA receptor complex, preferably a benzodiazepine derivative (e.g. midazolam) as an active ingredient in addition to the component A, the pain therapeutic agent which exerts a synergistic analgesic effect particularly on acute pain and gives a reduced adverse drug reaction is obtained. Furthermore, the dose of the component B is 0.05-0.3 mg/kg/hour and, when the component B is used in combination with the component A, the above doses can be respectively decreased to 1/3-1/4.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to an AMPA receptor antagonist, 2,3-dioxo-7- (1H-imidazol-1-yl) -6-nitro-1,2,3,4-tetrahydro- The present invention relates to a novel agent for treating pain comprising 1-quinoxalinyl) acetic acid or a salt thereof as an active ingredient, and a pharmaceutical composition of the compound and at least one activator of a benzodiazepine-GABA receptor complex.

[0002]

BACKGROUND OF THE INVENTION Excessive activation of glutamate receptors is
It is thought to play an important role in pain response through the spinal cord. Glutamate receptors involved in nociception are mainly N-methyl-D-aspartate (NMDA) receptors and α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors. is there. Fast excitatory transmission by non-noxious and acute noxious inputs occurs via AMPA receptors. NMDA receptors, on the other hand, are particularly involved in nociceptive responses to strong and persistent stimuli that cause hyperalgesia in neuropathic pain (J. Neurosci. 12: 3025-3041, 1992). So far,
NMDA and AMPA receptor antagonists have shown antinociceptive effects in various animal models (Tran
ds in Pharmacological Sciences 11: 307-309, 199
0). Hitherto, NMDA receptor antagonists have received a strong clinical interest not only as a therapeutic agent for pain but also as a therapeutic agent for neurodegenerative diseases (Drugs 44: 279-292, 199).
2). However, since NMDA receptor antagonists cause serious side effects and have limited efficacy, interest has shifted to drugs having an effect on non-NMDA receptors, particularly AMPA receptors (J. Med. Chem. 37: 46
7-475, 1994). However, early AMPA receptor antagonists such as NBQX (2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo (f) quinoxaline) have not reached clinical application due to low water solubility and nephrotoxicity. (J. Cereb. Blood Flow Metab. 14: 251-261, 199
Four). One of the AMPA receptor antagonists disclosed in WO 96/10023, [2,3-dioxo-7- (1H-imidazol-1-yl) -6-nitro-1,2,3,4-tetrahydro- 1-quinoxalinyl) acetic acid] (hereinafter referred to as compound A) has been shown to have potent and selective AMPA binding activity and high water solubility. However,
The analgesic effect in acute and chronic pain, and the effect in combination with other agents such as an activator of a benzodiazepine-GABA receptor complex, have not been confirmed so far.

[0003]

DISCLOSURE OF THE INVENTION An object of the present invention is to provide a compound having compound A as an active ingredient, which is a powerful agent for treating pain, especially an agent for suppressing acute and chronic pain, and compound A which is useful as an agent for treating pain.
And a benzodiazepine-GABA receptor complex activator.

[0004]

Means for Solving the Problems The present inventors have developed a strong A
Compound A having MPA receptor antagonism and high water solubility
Did not show any side effects at the effective dose, and showed high analgesic effect on acute and chronic pain, and the combined administration of Compound A and the activator of benzodiazepine-GABA receptor complex was more than the theoretical value derived from single administration. It was confirmed that a low dose is effective for acute pain, and that side effects can be further reduced as compared with the case of administration of Compound A alone. Thereby, it was found that Compound A was useful as a therapeutic agent for pain. That is, pain treatment containing 2,3-dioxo-7- (1H-imidazol-1-yl) -6-nitro-1,2,3,4-tetrahydro-1-quinoxalinyl) acetic acid or a salt thereof as an active ingredient. The present invention relates to an agent, preferably an agent for treating pain which is effective for preventing or treating acute pain, or an agent for treating pain which is effective for preventing or treating chronic pain. Another object of the present invention is to provide 2,3-dioxo-7- (1H-imidazol-1-yl) -6-nitro-1,2,3,4-tetrahydro-1-quinoxalinyl) acetic acid or a salt thereof with benzodiazepine -A composition comprising an activator of a GABA receptor complex as an active ingredient, preferably a pain therapy agent, particularly a pain therapy agent effective for prevention or treatment of acute pain, more preferably a benzodiazepine-GABA receptor complex It relates to a therapeutic agent for pain, wherein the activating agent of the body is a benzodiazepine derivative, most preferably to a therapeutic agent for pain, wherein the benzodiazepine derivative is midazolam.

[0005]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be further described.
It is as follows. The therapeutic agent for pain means a drug used for preventing or treating pain, and includes a painkiller, an anesthetic, and a drug used for pain management before and after surgery. Pain is an unpleasant sensation or an emotional experience associated with an actual or potential tissue disorder, or a state expressed using words such as a disorder (Classification of Chronic Pain, 2 ^nd
Edition, IASP Task Force on Taxonomy, edited by
H. Merskey and N. Bogdug, IASP Press, Seattle, 199
4, p209). The definition of acute pain is (Halpe
rn, 1984, Advances in Pain Research and Therapy, V
ol 7, Ed. C. Bendetii et al, page 47,
(Not limited to this), types of unpleasant sensations, perceptions, emotional experiences involving autonomous (reflex) reactions, and types of mental and behavioral reactions caused by injuries and acute illnesses. Tissue injury causes a series of noxious stimuli that are converted by nociceptors into action potentials transmitted to the spinal cord,
The stimulus is transmitted to the upper nervous system. Examples of acute pain include toothache, postoperative pain, obstetric pain, neuralgia, myalgia and the like. Examples of acute pain that can be prevented or treated by the present compounds include toothache, postoperative pain, obstetrical pain, neuralgia, and myalgia. In particular, the compounds of the present application can be administered before surgery to reduce acute pain associated with dental surgery and surgical operations including labor. Another preferred embodiment is a pain suppressant capable of administering an effective amount of Compound A or a salt thereof to a patient before dental surgery, for example, tooth extraction. At present, there are virtually no analgesics that can be administered before surgery to effectively control pain. Therefore, it is particularly surprising that Compound A is effective in preoperative administration. The definition of chronic pain is defined in, but not limited to, Halpern, ibid, 1984, as persistent pain beyond the normal course of acute illness, or beyond the normal course of wound healing. Chronic pain is a typical result of persistent dysfunction of the nociceptive pain system. Examples of chronic pain include trigeminal neuralgia, post-rash neuralgia (a form of chronic pain associated with skin changes that occur in the skin following acute herpes), diabetic neuralgia, burning pain, phantom limb pain, and osteoarthritis , Rheumatism, pain associated with cancer and the like. Benzodiazepine-
The substance that activates the GABA receptor complex (BGC) is a compound that binds to a receptor on BGC and can release the Cl ⁻ channel bound to BGC. These substances include benzodiazepine derivatives and G
ABA _A receptor agonists are included. Preferred are benzodiazepine derivatives. Examples of benzodiazepine derivatives include, but are not limited to, diazepam, flunitrazepam, midazolam, and the like. Preferably, it is midazolam. Compound A of the present invention can further form hydrates, solvates with ethanol, etc., optical isomers, and polymorphs. The method for producing the compound of the present invention comprises:
These are disclosed in the disclosed patents. For example, compound A is disclosed in WO 96/10023 and diazepam is disclosed in US 3,371,085. Flunitrazepam is disclosed in US 3,116,203. Midazolam is disclosed in US 4,280,957. Pharmaceutical preparations comprising Compound A or a salt thereof, and optionally one or more of the above-mentioned drugs or salts thereof, as a single agent or an active ingredient of a concomitant drug, may contain carriers, excipients, and the like usually used for the dosage form. Manufactured with other additives. Carriers and excipients used in pharmaceutical preparations are solids such as lactose, magnesium, stearic acid, starch, talc, gelatin, gums, pectin, gum arabic, olive oil, liquids such as cocoa butter and ethylene glycol. You may. Other commonly used carriers and excipients can also be used. This compound is mainly used for parenteral administration (subcutaneous administration, intramuscular administration, intravenous administration, etc.), transdermal administration, intrathecal administration, epidural, intraarticular, and topical administration.
Alternatively, if possible, it can be administered in various dosage forms such as oral administration.

[0006] Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Aqueous solutions and suspensions include, for example, distilled water for injection and physiological saline. Examples of water-insoluble solutions and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and polysorbate 80 (trade name).
Etc. Such compositions may further include preservatives, wetting agents,
Auxiliaries such as emulsifiers, dispersants, stabilizers (eg, lactose), and solubilizers (eg, megluminic acid) may be included. These are sterilized by, for example, filtration through a bacteria retaining filter, blending of a bactericide or irradiation. In addition, these can be used by preparing a sterile solid composition and dissolving it in sterile water or a sterile injection solvent before use. The dose of Compound A is appropriately determined depending on the individual case in consideration of the symptoms, age of the subject to be administered, gender, etc., but is usually 1 to 1000 mg per adult day, preferably about 50 to 200 mg per day. . 1 to 1000 mg per adult daily
It may be administered in two or four divided doses. For intravenous or continuous intravenous administration, one dose per day
It may be administered from 24 hours to 24 hours. As indicated above, the dosage depends on various conditions. If effective, doses lower than the above ranges can be used. Typical doses of benzodiazepine derivatives range from 0.05 mg / kg to 0.3 mg / kg per hour. In the case of co-administration or composition, the dose of each compound can be reduced from 1/3 to 1/4 of that of a single agent. The present invention is more specifically illustrated by the following examples.

[0007]

EXAMPLES The analgesic effect of single administration of Compound A was confirmed by two nociceptive tests using acute heat stimulus and formalin stimulus to induce progressive pain. The rats used had an intrathecal catheter indwelled. The combined therapy of Compound A was compared with the effect of Compound A alone by using a pain test by acute heat stimulation. Midazolam, a benzodiazepine derivative, was used as a concomitant drug. The NMDA receptor antagonist AP-5 was similarly examined.

[Drugs and Methods Used] Preparation of Animals for Intrathecal Administration This study protocol was approved by the University of Harbor California Los Angeles Medical Center Research and Education Institute. Yaksh and Rudy (Physiol Behav 17: 1
031-1036, 1976), the rats were implanted with a lumbar intrathecal catheter. Spra under 2% halothane anesthesia
gue-Dawley rat (280-300g BK Universal, Fremon
The incision of the atlanto-occipital periosteum at (t, CA) was made, and an 8.5 cm polyethylene catheter (PE-10; Clay Adams. Parsippany, NJ) was inserted toward the tail and reached the thoracolumbar surface of the spinal cord. The outside of the catheter was placed subcutaneously at the top of the head, and the tip was closed with a 28G stainless steel wire. On the 5th postoperative day, only rats showing no abnormalities in motor function and behavior were used for the pain test. [Drugs and Administration] 10 mg of Compound A was dissolved in 0.97 ml of distilled water, and adjusted to pH 7.3-7.5 with 30 μl of 1N sodium hydroxide. 0.3 μg (0.86 nMol), 1 μg (2.86 nMol), 3 μg (8.59 nMol
l), 10 μg (28.63 nMol), 30 μg (85.89 nMol) / 10 μl were adjusted using physiological saline, and injected intrathecally. After drug administration, all the drug remaining in the catheter was injected with 10 μl of physiological saline. (Dead space of catheter;
7 ± 0.4μl, mean ± standard error). A micro-injector syringe was used for all administrations. Eight rats in each administration group were randomly selected and used. The control group received 10 μl of physiological saline.

[Data analysis and statistics] The response latency of the tail flick measurement was converted to% MPE (maximum response effect) according to the following equation. % MPE = [(reaction latency after administration−reaction latency before administration) /
(Cut-off time-reaction latency before administration)] × 100 (cut-off time was 14 seconds; see Example 1) ED ₅₀ (50% effective dose) was calculated using a computer program as a dose expressing 50% MPE. Calculated. Differences between treatment groups were determined by two-way analysis of variance followed by Newman-Keuls tes.
t was compared. The number of animals that developed side effects was Chi-squ
We compared using are test. A P value of 0.05 or less was considered statistically significant. Example 1 Compound A in acute pain model (tail flick test)
Effect of Tail Flick Test Rats were placed in clear plastic cylindrical cages and their tails were extended along a groove provided rearward. A high-intensity ray (Tail Flick) is placed 2-3 cm from the tip of the tail.
Analgesia Meter 0570-001L, Columbus Instruments In
ternational Co, Ltd., Columbus, Ohio, US
A.) was irradiated to give a noxious stimulus. The time from the start of the thermal stimulation to the jump of the tail was measured and defined as the reaction latency. Thermal stimulation was limited to a maximum of 14 seconds (cutoff time) even in the absence of a response to prevent tissue damage. Reaction times were measured before dosing, 5, 10, 15, 30, 60, 90, and 120 minutes after drug administration, and at hourly intervals (up to 360 minutes) until the reaction time returned to baseline. Results The baseline (before drug administration) response latency of the tail flick test was 3.1 ± 0.1 seconds (mean ± standard error). Intrathecal administration of compound A prolonged tail flick response latency in a dose-dependent manner (FIG. 1). ED ₅₀ is 1.0 μg (95% confidence interval (CI):
0.37-2.76 μg).

Example 2 Effect of Compound A in Rats with Acute and Chronic Pain Model Formalin test Rats were intrathecally administered with Compound A, and anesthetized with 3% halothane 10 minutes later. After confirming, it was taken out of the anesthesia box. 50 μl of 5% formalin was subcutaneously administered to the instep of the right hind limb with a 30G needle, and the rats were placed in a plexiglass chamber and observed for 60 minutes. 1-2 minutes after administration,
After the 5th and 6th minutes, and after the 10th minute, every 5 minutes
The pain response was quantified by measuring the frequency of linche) and the shaking of the injected foot. The animals were then sacrificed by administering a lethal dose of halothane. Pain response due to formalin stimulation is described in J. Pharmacol. Exp. Ther. 263: 136-
146, 1992 and expressed biphasically. ： Phase1
(0-6 minutes after formalin administration), Phase 2 (approximately 1
(After 0 min) Results In both Phase 1 (1-6 min) and phase 2 (10-60 min), the number of flinches decreased as the intrathecal dose of Compound A increased. E in phase 1
D ₅₀ values are 0.24μg (95% CI: 0.08-0.75μg) , phase
The ED ₅₀ value in 2 was 0.21 μg (95% CI: 0.06-0.73 μg).

Example 3 Effect of Combination Therapy of Compound A and Midazolam on Rat Acute Pain Model Midazolam (1-100 μg), AP-5 (2-amino-5-phosphonovalerate, NMDA antagonist) (1-30)
μg) and 10 μl of compound A (0.3-30 μg) were administered intrathecally either alone or in combination. Controls received saline similarly. After the administration, the tail flick reaction of the rat was measured over time according to Example 1. The interaction of midazolam with AP-5 or Compound A at ED ₅₀ values was examined using isobolographic analysis (LifeSci, 46: 947-961, 1989). To
The tal dose fraction value (the ratio of the measured ED ₅₀ value to the theoretical value when used together) was calculated using the following formula (J. Phar
macol. Exp. Ther. 247: 603-608, 1998). [Singly amount of ED ₅₀ of ED ₅₀ / drug 1 combination of drug 1]
+ [ED ₅₀ of combined amount of drug 2 / E of single amount of drug 2
D ₅₀ ] Side effects such as abnormal behavior and movement disorders were also examined. RESULTS Midazolam, AP-5 and Compound A withdraw the tail
(tail withdrawal) The response latency increased in a dose-dependent manner, and the ED _{50 for} single agent administration was 1.6 ± 0.3 μg (mean ± standard error), 5.5 ± 0.2 μg and 1.0 ± 0.2 μg, respectively. .
Midazolam and AP-5 or results compound in combination with A, is effective at a lower dose than the theoretical value predicted from ED ₅₀ values of monotherapy, total dose fraction value is midazolam + AP-5 In 0.27, the midazolam + Compound A 0.
30 (FIGS. 3 (a) and 3 (b)). In addition, the side effects were reduced when used in combination as compared with the case of single agent administration. Data are shown as mean ± SEM. A: each drug alone ED ₅₀ B: theoretical value of the combination at ED ₅₀ C: measured value of the combination at ED ₅₀

[0012]

According to the present invention, compound A has an excellent analgesic effect on acute and chronic pain. In addition, the combined use of compound A and a benzodiazepine-GABA receptor activator has a synergistic analgesic effect on acute pain and can reduce side effects. Therefore, Compound A is useful as an analgesic for acute and chronic pain.

[Brief description of the drawings]

[Fig. 1] In the Tail flick test (acute pain model), tail flicking (tail fl
FIG. 2 is a graph showing the maximum response effect of ick) over time after administration.

FIG. 2 shows the number of flinches per minute in each administration group of Compound A in the Formalin test (acute and chronic pain models) over time after administration.

FIG. 3 shows the ED ₅₀ value of a single agent in a combination experiment of (a) AP-5 + midazolam and (b) Compound A + midazolam, a theoretical value of the ED ₅₀ value in combination with the ED ₅₀ derived therefrom, and the ED value in combination.
_It shows ₅₀ measured values.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) // C07D 403/04 C07D 403/04

Claims (7)

[Claims] 1. An active ingredient comprising 2,3-dioxo-7- (1H-imidazol-1-yl) -6-nitro-1,2,3,4-tetrahydro-1-quinoxalinyl) acetic acid or a salt thereof. Pain treatment agent. 2. An agent for treating pain which is effective for the prevention or treatment of acute pain, comprising the compound of claim 1 as an active ingredient. [3] a therapeutic agent for pain which is effective for preventing or treating chronic pain, comprising the compound of [1] as an active ingredient; (4) 2,3-dioxo-7- (1H-imidazol-1-yl) -6-nitro-1,2,3,4-tetrahydro-1-quinoxalinyl) acetic acid or a salt thereof and at least one benzodiazepine -A composition containing an activator of a GABA receptor complex as an active ingredient. (5) 2,3-dioxo-7- (1H-imidazol-1-yl) -6-nitro-1,2,3,4-tetrahydro-1-quinoxalinyl) acetic acid or a salt thereof, and at least one kind thereof. A therapeutic agent for pain, comprising an activator of a benzodiazepine-GABA receptor complex as an active ingredient. 6. The therapeutic agent for pain according to claim 5, wherein the activator of the benzodiazepine-GABA receptor complex is a benzodiazepine derivative. 7. The method according to claim 6, wherein the benzodiazepine derivative is midazolam.