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WO2003097023A1 - Utilisation du transmetteur de l'inhibiteur de l'acide $g(g)-aminobutyrique (gaba) dans la preparation d'analgesiques - Google Patents

Utilisation du transmetteur de l'inhibiteur de l'acide $g(g)-aminobutyrique (gaba) dans la preparation d'analgesiques Download PDF

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Publication number
WO2003097023A1
WO2003097023A1 PCT/CN2002/000846 CN0200846W WO03097023A1 WO 2003097023 A1 WO2003097023 A1 WO 2003097023A1 CN 0200846 W CN0200846 W CN 0200846W WO 03097023 A1 WO03097023 A1 WO 03097023A1
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Prior art keywords
acid
ethyl
analgesic
piperidinecarboxylic
gaba
Prior art date
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PCT/CN2002/000846
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English (en)
Chinese (zh)
Inventor
Lihe Guo
Jiahua Hu
Na Yang
Yinghua Ma
Jian Fei
Original Assignee
Shanghai Institutes For Biological Sciences, Cas
Shanghai Celstar Institute Of Biotechnology Co. Ltd.
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Application filed by Shanghai Institutes For Biological Sciences, Cas, Shanghai Celstar Institute Of Biotechnology Co. Ltd. filed Critical Shanghai Institutes For Biological Sciences, Cas
Priority to AU2002367951A priority Critical patent/AU2002367951A1/en
Publication of WO2003097023A1 publication Critical patent/WO2003097023A1/fr

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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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • 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
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/401—Proline; Derivatives thereof, e.g. captopril
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • 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

Definitions

  • the invention relates to the field of biomedicine, and in particular to the application of a ⁇ -aminobutyric acid (GABA) transporter inhibitor in the preparation of analgesics.
  • GABA ⁇ -aminobutyric acid
  • Pain is a common condition that can be divided into mild, moderate and severe pain.
  • non-opiates are generally used for the treatment of mild pain
  • weak opioids are used for moderate pain
  • strong opioids are used for severe pain.
  • analgesics can be mainly divided into: (1) acting on peripheral pain receptors, which are weak analgesics; (2) acting on GABA receptors and enhancing the function of GABAergic nerves. Good sedative effect; (3) Inhibition of prostaglandin biosynthesis, mainly antipyretic and analgesics, such as aspirin; (4) Blocking of dopamine receptors in the brain, such as cranitonin; (5) Activation of opioid receptors, Such as morphine, pethidine.
  • opioids have the best analgesic effect, but their side effects are large (nausea, vomiting, constipation, drowsiness, dizziness, respiratory depression, etc.), and they are tolerant and addictive, so they should be used with caution. Because many diseases can cause pain, especially in the advanced stage of cancer, it can cause severe pain. Therefore, finding, designing and synthesizing high-efficiency, low-toxicity, intolerance and non-addiction analgesics have been pursued by drug research for a long time. aims.
  • GABA is the most important inhibitory neurotransmitter in the mammalian central nervous system.
  • the biological function of GABA transporters is to stop the transmission of neurosuppressive information by taking up GABA neurotransmitters in the synaptic cleft, and then to regulate the transmission of neural signals.
  • Strength and timeliness in order to achieve coordination and unity between complex neural network signals.
  • Compounds with specific inhibitory functions have been reported, mainly 3-piperidinecarboxylic acid and tetrahydronicotinic acid and many derivatives with these two compounds as the mother core.
  • GABA transporters such as high ⁇ -proline, tetrahydropyridyl isoxazol, pentaazaisoxazole and its derivatives, etc.
  • GABA transporters such as high ⁇ -proline, tetrahydropyridyl isoxazol, pentaazaisoxazole and its derivatives, etc.
  • GABA transporter inhibitors have been reported in the clinical treatment of epilepsy, and it is mentioned that tiagabine may be used for pain treatment, and this drug has small side effects and is safe for long-term use (Genton p., Et al., Epilepsia, 2001, 42 (Suppl.3): 42-45; Meldrum BS, et al., Epilepsia, 1999, 40 (Suppl.9): S2-S6).
  • Patent WO 9415618 (1994) also mentions that some abnormal conditions (such as epilepsy, myoclonus, chronic pain) are related to the overexpression or underexpression of GABA transporters.
  • the present invention finds a class of compounds that target the ⁇ -aminobutyric acid transporter as having good analgesic effects.
  • the present invention provides the use of a ⁇ -aminobutyric acid transporter inhibitor in the preparation of analgesic drugs.
  • the present invention finds that such compounds having an inhibitory function have a good effect on analgesia.
  • the mechanism of action of these compounds is to inhibit the function of the GABA transporter, increase the GABA concentration in the synaptic space, and eventually lead to the enhancement of the inhibitory GABAergic nerve function, thereby achieving analgesic effect. This can be confirmed by the following experiments.
  • ⁇ -aminobutyric acid transporter inhibitors include all compounds that reduce the function of ⁇ -aminobutyric acid transporter uptake (transport), such as the known compounds mentioned above, 3-piperidinecarboxylic acid, tetrahydronicotinic acid, and high ⁇ -proline , Tetrahydropyridyl isoxazol, pentahydroazaisoxazol, and their derivatives, etc. See FIG. 1 for a diagram of an exemplary compound structure (the above derivatives are not limited to these exemplary compounds). These compounds can be synthesized according to the methods reported in the aforementioned literatures or purchased from the market.
  • the hair One of the competitive inhibitors ethyl 3-piperidinecarboxylic acid (a derivative of 3-piperidinecarboxylic acid) and one non-competitive inhibitor, N- (diphenyliminoethanolyl) -tetrahydrogen, were selected.
  • Niacin NO-711, a derivative of tetrahydronicotinic acid
  • Heat-induced pain tail-flicking
  • formalin-induced inflammatory pain paw licking
  • acetic acid-induced visceral pain test were used to test mice for both 3-piperidinecarboxylic acid ethyl ester and NO-711 For the response, use saline as a control.
  • the analgesic application of ⁇ -aminobutyric acid transporter inhibitors can give effective doses of GABA transporter inhibitor drugs to patients with pain to achieve the purpose of treating pain.
  • These pains include painful diseases caused by various reasons such as thermal irritation, inflammation, internal organ damage, cancer, and the like.
  • Clinical administration can be by oral or injection. Oral medicines can be made into tablets, capsules, powders, solutions and other dosage forms according to conventional methods. The injection can be intramuscular, subcutaneous or intravenous.
  • ⁇ -aminobutyric acid transporter inhibitors in the treatment of pain depends on the nature and extent of the disease and the patient's treatment. Ultimately, it is up to the prescriber to decide how many doses to give to the patient. The clinically used dose is 0.1-2 mg per kilogram of body weight per day. GABA transporter inhibitor.
  • the drug may also include pharmacologically acceptable carriers, solvents, fillers, buffers and stabilizers, etc. substance.
  • pharmacologically acceptable is meant a non-toxic substance that does not affect the biological activity of a GABA transporter inhibitor. The choice of carrier and other substances depends on the different route of administration.
  • the invention discloses that the GABA transporter inhibitor has analgesic effect, and opens up a new application field for the GABA transporter inhibitor.
  • the inhibitor includes all compounds that inhibit the analgesic effect of the GABA transporter.
  • these compounds also have significant advantages: experiments have shown that they are small non-opioid molecules, are not tolerant, can avoid increasing doses, are not addictive, and can be avoided Subsequent withdrawal treatment after medication. Therefore, these compounds have clinical application value for the treatment of pain, and ⁇ -aminobutyric acid transporter inhibitors can be used to prepare analgesics.
  • Figure 1 illustrates compounds that inhibit GABA transporters.
  • 1-3-piperidinecarboxylic acid (piperidine-3 -carboxylic acid, nipecotic acid, C 6 H n N0 2 ), 2-tetrahydronicotinic acid (l, 2,5,6-tetrahydro-pyridine-3-carboxylic acid, guvacine, C 6 H 9 N0 2 ), 3 ⁇ 3-neoacetic acid ethyl ester (piperidine-3-carboxylic acid ethyl ester, ethyl nipecotate, C 8 H 15 N0 2 ), 4-n- (diphenylimine Ethyl alcohol) -tetrahydronicotinic acid (1- [2- [[((diphenyl) imino] oxy] ethyl] -3- (l, 2 5 5,6-te1xahydropyridin-l-yl) carboxylic acid, NO-711 , C 21 H 22
  • Figure 2 shows the analgesic effect of ethyl 3-piperidinecarboxylate on heat-induced pain.
  • Figure 3 shows the analgesic effect of NO-711 on heat-induced pain.
  • Figure 4 shows the analgesic effect of ethyl 3-piperidinecarboxylate and NO-711 on formalin-induced foot inflammation and pain.
  • the results show that ethyl 3-piperidinecarboxylate (60mg / kg) and NO-711 (10mg / kg) can have analgesic effects on inflammatory pain.
  • Figure 5 shows the analgesic effect of ethyl 3-piperidinecarboxylate on acetic acid-induced visceral pain.
  • ethyl 3-piperidinecarboxylic acid (30 mg / kg, 60 mg kg) has a good visceral analgesic effect and a high dose
  • Ethyl 3-piperidinecarboxylate has better analgesic effect than low-dose ethyl 3-piperidinecarboxylic acid (n-8-9, ** indicates p ⁇ 0.01, ethyl 3-piperidinecarboxylic acid is normal to normal saline, one- way ANOVA evaluation significance).
  • Figure 6 shows the analgesic effect of NO-711 on visceral pain induced by acetic acid.
  • NO-711 5mg / kg, 10mg / kg
  • High-dose NO-711 is lower than low-dose NO-711 has a good analgesic effect.
  • n 8-9, ** indicates p ⁇ 0.01, NO-711 vs. saline, one-way ANOVA evaluation significance).
  • Figure 7 shows that ethyl 3-piperidinecarboxylate (90 mg / kg) was not tolerated after 4 and 8 days of continuous injection (a). However, morphine (8mg / kg) showed significant tolerance after 4 and 8 days of continuous injection (b).
  • dl the first day
  • d4 the fourth day
  • d8 the eighth day
  • n 8 * means p ⁇ 0.05
  • ** means p ⁇ 0.01
  • the fourth day and the eighth day to the first day, one-way ANOVA evaluation significance
  • Ethyl 3-piperidinecarboxylate was purchased from ACROS, and NO-711 was purchased from Sigma.
  • the animals used in the experiment were C57 BL / 6J mice.
  • mice There are 8-10 mice in each group.
  • the tail flick experiment uses 51.0 ° C hot water to soak the tail.
  • the experimental operation is as follows: (1) Wrap the mouse with a soft cloth, the tail is exposed, (2) immerse the 3/4 length of the tail in hot water, and record that the tail is immersed in heat The time interval from water to tail flick, (3) mice were given ethyl 3-piperidinecarboxylic acid 30mg / kg, 60mg / kg, NO-711 10mg / kg or the same volume of normal saline by intraperitoneal injection, (4) After the drug injection, test the tail-flick delay time at 5, 15, 30, 45, 60, 75, 90, 105, and 120 minutes, respectively, and repeat steps (1) and (2).
  • % MPE (delay time after administration-delay time before administration) I (12-delay time before administration).
  • One-way ANOVA was used to evaluate significance.
  • the experimental operation is as follows: (1) Place the mouse alone, record the time when the mouse licks or bites the left paw, record every 5 minutes, record three time periods, (2) subcutaneously inject the mouse ⁇ 5% of formalin, immediately record the length of time that the mouse licked or bite the injection site, every 5 minutes, (3) After recording the second time interval, that is, intraperitoneal injection of 60 mg / kg ethyl 3-piperidinecarboxylate, 10mg / kg NO-71 1 Or the same volume of normal saline, (4) Then record the time of licking or biting the paw of the mouse, every 5 minutes until the termination of the formalin injection 55 minutes.
  • One-way ANOVA was used to evaluate significance. There were 8 mice in each group.
  • mice showed no significant difference in pain response in stage I (0-10 minutes) after formalin injection, while stage II (10-55 minutes) was ethyl 3-piperidinecarboxylate and NO-711.
  • stage II 10-55 minutes
  • NO-711 Ethyl 3-piperidinecarboxylate
  • the animals injected with ethyl 3-piperidinecarboxylate and NO-711 had a significantly lower response to formalin-induced inflammation and pain than the animals injected with saline, and the analgesic effect of NO-711 Ethyl 3-piperidinecarboxylic acid is good ((a) and (b) in Figure 4; * means p ⁇ 0.05, ** means p ⁇ 0.01, ⁇ means p ⁇ 0.01) o
  • the experimental procedure is as follows: 30 mg / kg ethyl 3-piperidinecarboxylate, 60 mg / kg ethyl 3-piperidinecarboxylic acid, 5 mg / kg NO-71K 10 mg / kg NO-711 or the same volume of physiological saline ( (Control group), immediately return to the mouse cage; (2) Remove the mouse after 5 minutes, inject 0.6% acetic acid ( ⁇ ⁇ / g) into the abdominal cavity of the mouse, and immediately return to the mouse cage; (3) 5 Minutes of mouse writhing began to be recorded after 15 minutes, and continued for 15 minutes. The significance was evaluated by one-way ANOVA, with 8-9 mice per group.
  • mice injected with ethyl 3piperidinecarboxylate or NO-711 were significantly lower than that in the control group, and it was smaller after pretreatment with high-dose ethyl 3-piperidinecarboxylic acid or NO-711.
  • the response to visceral pain in mice was weaker than that in mice pretreated with low-dose ethyl 3-piperidinecarboxylate or NO-711 (see Figures 5 and 6, ** indicates p ⁇ 0.01).
  • mice were injected subcutaneously with 90 mg / kg ethyl 3-piperidinecarboxylate or 8 mg / kg morphine once a day for 8 days, respectively, and ethyl 3-piperidinecarboxylic acid was tested on days 1, 4, and 8 respectively. And analgesic effects of morphine. Methods The tail-flick experiment was used, and the operation was the same as above.
  • mice were injected subcutaneously with 60 mg / kg ethyl 3-piperidinecarboxylate or 10 mg / kg NO-711 on the 1st, 3rd, and 5th days. Enter the selected medicine-feeding chamber, isolate it for 20 minutes, and inject the same volume of physiological saline on day 2, 4, and 6 and place it in the selected saline-feeding chamber, and also isolate it for 20 minutes.
  • Test mice (after dosing) preference for drug-feeding chambers and saline-feeding chambers, that is, place the mice in the middle chamber on day 7, and record the mice in the left and right sides within the prescribed time (18 minutes) Time spent in the cab. Calculate the percentage of mouse drug chamber dwell time relative to both.
  • One-way ANOVA was used to evaluate significance. There are 8-10 mice in each group. Control experiments (saline and morphine) were performed as above.
  • mice in the morphine group had a significant preference for morphine-administered compartments ( Figure 6; * indicates p ⁇ 0.05).
  • the liquid is sealed in ampoules, sterilized, made into products, and protected from light.
  • Dissolve NO-711 1.5g, 2.5g, 5g in 1 liter of water, mix and dispense into 3mg / 2ml / piece, 5mg / 2ml / piece, 10mg / 2ml / piece injection solution in ampoules. Medium sealed, sterilized, made into products, protected from light.
  • each tablet weighs about 0.3 grams, each tablet contains NO-711 20mg.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Pain & Pain Management (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)

Abstract

L'invention concerne l'utilisation du transmetteur de l'inhibiteur de l'acide η-aminobutyrique (GABA) dans la préparation d'analgésiques. Cet inhibiteur comprend l'ensemble des composés qui ont un effet inhibiteur sur le transmetteur de GABA ainsi qu'un effet analgésique, tels que l'acide 3-carboxylique, la guvacine, l'homo-β-proline, 4,5,6,7-tétrahydro-4H-isoxazolo-[4,5-C]-pyridin-3-ol(THPO), 4,5,6,7-tétrahydro-4H-isoxazolo-[4,5-C]azépine-3-ol(THAO) et leurs dérivés. Les résultats de l'expérience indiquent que ces composés, qui possèdent un effet inhibiteur sur le transmetteur de GABA, possèdent également un effet analgésique et ne posent pas de problèmes de tolérance ou de dépendance. De plus, ces composés ont une valeur clinique en terme d'analgésiques et sont utilisés pour fabriquer des analgésiques.
PCT/CN2002/000846 2002-05-21 2002-11-26 Utilisation du transmetteur de l'inhibiteur de l'acide $g(g)-aminobutyrique (gaba) dans la preparation d'analgesiques WO2003097023A1 (fr)

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AU2002367951A AU2002367951A1 (en) 2002-05-21 2002-11-26 THE USE OF THE INHIBITOR TRANSMITTER OF Gamma-AMINOBUTYRIC ACID (GABA) IN THE MANUFACTURE OF ANALGESIC

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CN02111772A CN1382441A (zh) 2002-05-21 2002-05-21 γ－氨基丁酸转运蛋白抑制剂在制备镇痛药物中的应用
CN02111772.1 2002-05-21

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Cited By (1)

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WO2014192698A1 (fr) * 2013-05-27 2014-12-04 国立大学法人岡山大学 Agent thérapeutique à visée antalgique

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101711862B (zh) * 2008-10-08 2012-07-18 中国科学院上海生命科学研究院 一种炎症性疾病相关的药物靶点及其应用
CN102399275A (zh) * 2011-11-21 2012-04-04 中国科学院微生物研究所 一种γ-氨基丁酸转运蛋白及其编码基因与应用

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EP0066456A1 (fr) * 1981-05-26 1982-12-08 Smithkline Beckman Corporation Acides carboxyliques azahétérocycliques N-substitués et leurs esters
US5010090A (en) * 1985-06-26 1991-04-23 Novo Nordisk A/S. N-(butenyl substituted) azaheterocyclic carboxylic acids
US4931450A (en) * 1986-01-07 1990-06-05 Novo Industri A/S Amino acid derivatives
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014192698A1 (fr) * 2013-05-27 2014-12-04 国立大学法人岡山大学 Agent thérapeutique à visée antalgique
JPWO2014192698A1 (ja) * 2013-05-27 2017-02-23 国立大学法人 岡山大学 疼痛治療薬

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