WO2006013833A1 - Nouvel agent anxiolytique - Google Patents

Nouvel agent anxiolytique Download PDF

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Publication number
WO2006013833A1
WO2006013833A1 PCT/JP2005/014060 JP2005014060W WO2006013833A1 WO 2006013833 A1 WO2006013833 A1 WO 2006013833A1 JP 2005014060 W JP2005014060 W JP 2005014060W WO 2006013833 A1 WO2006013833 A1 WO 2006013833A1
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Prior art keywords
general formula
pmp
anxiolytic
sigma
phenol
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English (en)
Japanese (ja)
Inventor
Masaaki Yoshikawa
Shuzhang Yang
Jun Hiratake
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Kyoto University NUC
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Kyoto University NUC
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by 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
    • A61P25/22—Anxiolytics

Definitions

  • the present invention relates to an anxiolytic agent characterized by containing 4- (1-piperidylmethyl) phenol or a derivative having a biological activity equivalent thereto as an active ingredient.
  • the present invention further relates to a method of using 4- (1-piperidylmethyl) phenol or a derivative having biological activity equivalent thereto as an anxiolytic agent.
  • Benzodiazepine derivatives are classified into long-term, intermediate, and short-term types based on the duration of action associated with metabolic rate.
  • Long-term representative drugs include chlordiazepoxide, diazepam, metazebam, prazepam, chlorazepate, cloxazolamoxaxazolam.
  • Intermediate type representative drugs include oxazepam, and short-time representative drugs include triazolam, bromazepam, fluzazepam and lorazepam.
  • chenodiazepine derivatives Other than benzodiazepine derivatives, chenodiazepine derivatives, strong rubamate derivatives, diphenylmethane derivatives and the like are also used as anxiolytic agents.
  • Representative drugs of chenodiazepine derivatives include clothiazepam and etizolam, representative drugs of strength rubamate derivatives include mepronomate, and diphenylmethane derivatives include hydroxyzine.
  • Currently used anti-anxiety agents are described in various pharmacology textbooks, and examples include “New Pharmacology” by Chikako Tanaka and Takashi Kato, edited by Nanedo.
  • the sigma (sigma) receptor is a receptor found as a receptor for drugs such as SKF10,047 and 1,3-di-0-tolyguanidine (DTG).
  • the sigma receptors are independent of opioid receptors because the forces ⁇ , ⁇ , and ⁇ receptors that were originally classified as opioid receptors are blocked by naloxone in common, but only ⁇ receptors are not blocked. It has come to be considered a receptacle.
  • Neuropeptide Y is an endogenous substance that exhibits a weak affinity for sigma receptors, and corticosterone, dehydroepandrosterone (DHEA), etc. have been reported as non-peptides. The true endogenous ligand and second messenger are still unknown.
  • sigma receptors are involved in a variety of physiological functions, and the ligands of sigma receptors are glucose utilization, neuroprotective action, antipsychotic action, antidepressant action, anti-unsafe action, Dementia, anticonvulsant, drug-dependent antagonism, antitussive, antitussive, anti-inflammatory, tear protein release, and central urinary reflex suppression. Therefore, not only the above-mentioned schizophrenia treatments but also sigma receptor ligands have been developed as drugs for various diseases! A review by Nabeshima et al. (Toshitaka Nabeshima, Japanese Pharmacology Reported in a magazine (1999) 114 pl3-23).
  • an object of the present invention is to provide a novel anxiolytic agent that acts via a sigma receptor.
  • PMP 4- (1-piperidylmethyl) phenol (4- (l-pip erydylmethyl) phenol: hereinafter abbreviated as PMP) is a sigma receptor, particularly sigma-1 It was found to have affinity for the receptor. Furthermore, when the pharmacological action of PMP was further examined, it was found that it exhibits an anxiolytic action in mice. The anxiolytic effect of PMP appeared at low doses and was effective after oral administration. Although PMP itself is a known substance, there have been no examples of anti-anxiety activity reported so far.
  • PMP selectively binds to sigma-1 receptor among sigma receptors, and therefore the action of PMP is expressed through sigma-1 receptor. Data indicating this will be described in detail in the following examples. PMP sigma - 1 selectivity for the receptor even in the presence of PMP in Kogu 10- 4 molar concentration, dopamine D1 receptor, dopamine D2 receptor, the histamine HI receptor, histamine H2 receptor, serotonin receptor There is also an in vitro binding assay finding that it does not substantially affect the binding of their ligands to.
  • the terms “sigma receptor”, “sigma-1 receptor”, and “sigma-2 receptor” in the present specification should be interpreted as meanings commonly used in this technical field. is there.
  • the present invention provides an anxiolytic agent characterized by containing 4- (1-piperidylmethyl) phenol (PMP) or a derivative having biological activity equivalent thereto as an active ingredient. is there. Furthermore, the present invention provides a method of using 4- (1-piperidylmethyl) phenol (PMP) or a derivative having biological activity equivalent thereto as an anxiolytic agent.
  • PMP has an anxiolytic action via a sigma receptor. Therefore, according to the present invention, an anxiolytic agent characterized by containing PMP or a derivative having a biological activity equivalent thereto as an active ingredient, and a derivative having a biological activity equivalent to PMP or an equivalent agent. Given how to use. Since PMP according to the present invention is effective at a low dose and can be administered orally, it may be an excellent drug for treating anxiety. It is also possible to search for anxiolytic effects using PMP as a lead compound.
  • FIG. 1 is a graph showing the results of testing the anxiolytic activity of mice administered intraventricularly with PMP in an elevated plus maze.
  • FIG. 2 is a graph showing the results of testing an anxiolytic activity of mice administered orally with PMP in an elevated plus maze.
  • FIG. 3 is a graph showing the results of testing the anxiolytic activity of mice administered orally with diazebam in the elevated plus maze.
  • FIG. 4 is a graph showing the results of examining the effect of BMY14802 on anxiolytic activity in mice administered with PMP.
  • FIG. 5 is a graph showing the results of examining the effects of antisense-oligooxynucleotide and mismatch-oligooxynucleotide on the anxiolytic activity of mice administered with PMP.
  • the present invention is directed to induction of PMP or equivalent biological activity.
  • An anxiolytic agent characterized by containing the body as an active ingredient and a method of using PMP or a derivative having a biological activity equivalent thereto as an anxiolytic agent are provided.
  • PMP may be a new treatment for anxiety that can replace benzodiazepine derivatives.
  • a derivative having a biological activity equivalent to that of PMP means a compound having a partly modified chemical structure of PMP and having an anxiolytic action equivalent to that of PMP.
  • the term “equivalent” mentioned here means qualitative identity or similarity such as anxiolytic activity, and does not mean quantitative identity or similarity. Examples of such derivatives include compounds represented by any one of the following general formula 1, general formula 2 and general formula 3.
  • R, R, R, and R are each independently H (hydrogen), OH (hydroxyl), CH (methyl
  • the compound represented by general formula 1 is PMP.
  • the derivatives having biological activity equivalent to PMP in the present invention are not limited to those compounds, but other derivatives may be used as long as they are derivatives of PMP having biological activity equivalent to PMP. Compounds are also within the scope of the present invention.
  • the route of administration of PMP used in the present invention is not particularly limited, and oral administration, parenteral administration, and rectal administration can be used orally or parenterally.
  • PMP method dosages of administration, the condition of the patient, varies depending on the age or the like, in the case of oral administration, usually 0.1 ⁇ ⁇ / 13 ⁇ 4 ⁇ 1000 / ⁇ g / kg per day, preferably 1 mu g / kg to 100 g / kg.
  • PMP is usually administered in the form of a preparation prepared by mixing with a pharmaceutically acceptable pharmaceutical carrier. Used as such carriers are substances that are commonly used in the pharmaceutical field and do not react with PMP.
  • parenteral administration with an injection it can be administered by various means such as intraventricular injection, intravenous injection, intramuscular injection, subcutaneous injection, and intradermal injection.
  • substances that can be used as such carriers include lactose, glucose, mannitol, dextrin, cyclodextrin, starch, sucrose, magnesium metasilicate aluminate, synthetic aluminum silicate, carboxymethylcellulose.
  • the dosage form to be administered is not particularly limited.
  • the possible dosage forms include tablets, capsules, granules, powders, syrups, suspensions, suppositories, ointments, creams, gels. , Patches, inhalants, injections and the like. These preparations are prepared according to a conventional method.
  • the liquid preparation may be dissolved or suspended in water or other appropriate solvent at the time of use. Tablets and granules may be coated by a known method. In the case of an injection, it is prepared by dissolving PMP in water, but if necessary, it may be dissolved in physiological saline or glucose solution, and a buffer or preservative may be added.
  • These preparations may contain PMP in a proportion of 0.01% to 100% by weight, preferably 1 to 90% by weight. These formulations may also contain other therapeutically valuable ingredients.
  • the active ingredient and excipient components such as lactose, starch, crystalline cellulose, calcium lactate, anhydrous caustic acid, etc. are mixed into a powder, and further, If necessary, add a binder such as sucrose, hydroxypropylcellulose, or polybulurpyrrolidone, a disintegrant such as carboxymethylcellulose or carboxymethylcellulose calcium, and wet or dry granulate to form granules.
  • these powders and granules can be tableted as they are or with the addition of lubricants such as magnesium stearate and talc.
  • These granules or tablets are coated with an enteric solvent base such as hydroxypropyl methylcellulose phthalate or methyl methacrylate polymer and coated with an enteric solvent preparation, or with ethyl cellulose, carnauba wax, hardened oil, etc. It can also be made into a pharmaceutical preparation.
  • an enteric solvent base such as hydroxypropyl methylcellulose phthalate or methyl methacrylate polymer
  • enteric solvent preparation or with ethyl cellulose, carnauba wax, hardened oil, etc. It can also be made into a pharmaceutical preparation.
  • To produce capsules add powder or granules. Strength for filling hard capsules
  • the active ingredient can be coated as it is or dissolved in glycerin, polyethylene glycol, sesame oil, olive oil, etc., and then coated with a gelatin film to make soft capsules.
  • an active ingredient and a sweetener such as sucrose, sorbitol and glycerin are dissolved in water, and a transparent syrup, further essential oil, ethanol and the like are added to form an elixir. It can also be used as an emulsion or suspension by adding coconut, gum arabic, tragacanth, polysorbate 80, sodium carboxymethylcellulose, etc.
  • a transparent syrup, further essential oil, ethanol and the like are added to form an elixir. It can also be used as an emulsion or suspension by adding coconut, gum arabic, tragacanth, polysorbate 80, sodium carboxymethylcellulose, etc.
  • These liquid preparations may contain a corrigent, a coloring agent, a preservative and the like as desired.
  • the active ingredient is adjusted to a pH adjusting agent such as hydrochloric acid, sodium hydroxide, lactose, lactic acid, sodium, sodium monohydrogen phosphate, sodium dihydrogen phosphate as necessary.
  • a pH adjusting agent such as hydrochloric acid, sodium hydroxide, lactose, lactic acid, sodium, sodium monohydrogen phosphate, sodium dihydrogen phosphate as necessary.
  • Dissolve in distilled water for injection together with isotonic agents such as sodium and glucose add aseptic filtration to fill ampoules, add mannitol, dextrin, cyclodextrin, gelatin, etc. It may be a dissolved injection.
  • an emulsion for injection can be prepared by emulsifying in water an active ingredient containing reticin, polysorbate 80, polyoxyethylene hydrogenated castor oil and the like.
  • the active ingredient is moistened with a suppository base material such as cacao butter, fatty acid tri-, di- and monoglycerides, polyethylene glycol, etc., dissolved, poured into a mold, and cooled.
  • a suppository base material such as cacao butter, fatty acid tri-, di- and monoglycerides, polyethylene glycol, etc.
  • the active ingredient may be dissolved in polyethylene glycol, soybean oil, etc. and then covered with a gelatin film.
  • the active ingredient is mixed with white petrolatum, beeswax, liquid paraffin, polyethylene glycol, etc., and if necessary, moisturized and kneaded to form an ointment, mouth gin, acrylic After kneading with a pressure-sensitive adhesive such as an acid alkyl ester polymer, it is spread on a non-woven fabric such as polyalkyl to form a tape.
  • a pressure-sensitive adhesive such as an acid alkyl ester polymer
  • PMP was shown to have an anxiolytic effect on mice.
  • animals to which PMP is administered are not limited to mice, but a wide range of animals including rodents, non-human primates, animals raised as pets, animals raised as livestock
  • PMP can be administered as an anxiolytic agent.
  • Preferred examples of such animals include mice, rats, Guinea pigs; non-human primates such as monkeys, chimpanzees, gorillas; animals raised as pets include dogs, cats; animals raised as domestic animals include horsetails, horses, eagle birds, and hidges Yes, but not limited to those animals.
  • the term “animal” is intended to exclude humans.
  • PMP can be administered to human anxiety patients to treat anxiety, and the mode of administering PMP to humans is also within the scope of the present invention.
  • sigma receptor activity is required by administering an effective amount of a compound represented by any one of the following general formula 1, general formula 2 and general formula 3 to a subject.
  • Methods for activating sigma receptors in the subject are also within the scope of the present invention.
  • the compounds represented by the following general formula 1, general formula 2, and general formula 3 are preferably R, R, R, and R.
  • a subject requiring sigma receptor activity requires, for example, sigma receptor activity in order to ameliorate a disorder of a disease or pathological condition involving sigma receptor activity.
  • a subject having a disease or pathological condition involving receptor activity is suffering from a disease or pathological condition involving abnormal sigma receptor activity, such as anxiety, for example. It means an organism which is a subject to which an effective amount of a compound represented by any one of general formula 2 and general formula 3 is administered.
  • General formula 1
  • PMP was synthesized according to the method described by P. Jacob et al. In J. Chromatogr. B, 1995, 664, 449-457. Piperidine (1.7 g, 20 mmol) and p-hydroxybenzaldehyde (1.22 g, 10 mmol) were dissolved in 48 ml of methanol. Add acetic acid to adjust pH to 6.0, NaBH C
  • the reaction was initiated by adding N (471.3 mg, 7.5 mmol). The mixture was stirred at room temperature for 70 hours. Methanol was evaporated, and the remaining oil was dissolved in 30 ml of water and acidified to pH 1.0 with diluted HC1.
  • the solution was extracted with 20 ml of ethyl acetate and the aqueous layer was made alkaline with ammonia. A precipitate was formed. After centrifugation at 3000 g for 5 minutes, the precipitate was separated, redissolved in diluted HC1, and extracted twice with ethyl acetate. The precipitate was separated by making the aqueous layer alkaline. The final precipitate was purified by HPLC on a 5PE-MS column and separated at a flow rate of 3 ml / min with a linear acetonitrile gradient (0-60% / 30 min) containing 0.1% TFA. Purified PMP was analyzed by LC-Mass.
  • Non-selective sigma receptor binding was performed using the method of Weber E et al. (Weber E et al., Proc. Natl. Acad Sci USA, 1986) using [ 3 H] -DTG as a radioligand and by guinea pig brain. ; 83 (22): 8784-8788).
  • Sigma-1 binding was performed using [] -haloperidol as a radioligand with membranes also prepared with human Jurkat cell force (Ganapathy ME et al., J. Pharmacol. Exp. Ther 1999; 289 ( 1): 251-260).
  • the elevated plus maze (EPM) consists of two open arms (24x5x0.5) and two closed arms (24x5x13), which are connected to a central platform that is 50cm above the floor. .
  • EPM elevated plus maze
  • the mouse can safely walk because there is an enclosure around the close arm.
  • the surroundings of the open arm are open and surrounded, the mouse walking on the open arm feels anxiety that the high position force falls. Therefore, the more anxiety the mouse is in the open arm and the more times the mouse enters the open arm, the less the anxiety of the mouse, which becomes an index of anti-anxiety activity.
  • the test was started by placing a mouse on a central platform facing one of the open arms.
  • the cumulative time spent in the open arm, the number of times that it entered the open arm, and the number of times it entered the closed arm during the 5 minute test time were recorded.
  • the percentage of time spent in the open arm and the percentage of entry into the open arm are calculated as indicators of anxiety, and the total number of ingresses indicates mobile activity.
  • the data for which the elevated plus maze test ability has increased are expressed as the mean and SEM. Data were analyzed by one-way or two-way ANOVA, followed by Dunnett's test for multiple comparisons. The value of significant difference was set to 0.05.
  • the non-selective binding assembly IC was 200 nM.
  • the IC for sigma-1 binding is 791nM and the sigma-2 binding I
  • Fig. 1 shows the results of testing the anxiolytic activity after intraventricular (i.c.v) administration of PMP to mice in the elevated plus maze.
  • n 9-12, * represents P ⁇ 0.05, and ** represents P ⁇ 0.01.
  • Figure 1A is the percentage of time spent in the open arm
  • Figure 1B is the percentage that entered the open arm
  • Figure 1C is the sum that entered the open and closed arms.
  • PMP dose-dependent time spent in the open arm was prolonged (Figure 1A) and entry into the open arm increased ( Figure 1B).
  • the total number of ingresses did not change significantly (Fig. 1C). This result indicates that the administered PMP caused anxiety-reducing effects without affecting mobility.
  • the minimum effective dose was lOpmol per mouse.
  • Fig. 2 shows the results of testing the anxiolytic activity after oral administration of PMP to mice in the elevated plus maze.
  • n 10-15, * represents P ⁇ 0.05, ** represents P ⁇ 0.01, *** represents P ⁇ 0.001 .
  • PMP also increased the time and number of entries in the open arm ( Figures 2A and B), and did not significantly change the total number of entries ( Figure 2C). This suggests that an anxiolytic effect can be obtained by oral administration.
  • the minimum effective dose was 5 ⁇ g / kg.
  • FIG. 3 shows the anxiolytic effects of PMP (10 nmol / mouse: intracerebral administration) with and without pretreatment with BMY14802 (0.5 mg / kg).
  • n 14-16, * represents P ⁇ 0.05, ** represents P ⁇ 0.01, *** represents P ⁇ 0.001.
  • • 5 mg / kg BMY14802 had no significant effect on anxiety.
  • the migration activity did not change (Figure 4C), but both the percentage of time in the open arm and the percentage of entry decreased to the basal level ( Figures 4A and B). This shows that BMY14802, the sigma-1 antagonist, is blocking the anxiety-reducing effect of PMP.
  • antisense-oligode Pretreatment with oxynucleotides (10 ⁇ g / 4 ⁇ 1 / mouse: intracerebroventricular administration) resulted in acupuncture (lOnmol / mouse: intracerebroventricular administration) in both time percent and ingress percentage in the orb arm. The effect was reduced ( Figure 5A, B).
  • the anxiolytic effect of PMP occurred not only by administration to the central nerve but also by oral administration. Since PMP has a low molecular weight and an amphiphilic structure, PMP may be absorbed and transferred through the blood-brain barrier. The effect of PMP was quite strong, and it was effective at lOpmolZ mice for intraventricular administration and 5 / z g / kg for oral administration. Therefore, it is considered that PMP can be a highly effective anxiolytic agent. In order to obtain an anxiolytic effect by oral administration of positive concomitant and diazebam, a role, a concentration of the order of mg / kg was required. Considering this, the anxiolytic effect of PMP, which is effective at low doses, can be said to be quite strong.
  • PMP has an anxiolytic action via a sigma receptor, and has an advantage that it is effective at a low dose and can be administered orally. Therefore, the PMP of the present invention has the potential to be an excellent drug for treating anxiety. Furthermore, the present invention has opened the way to search for a superior anxiolytic action using PMP as a lead compound.

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Abstract

L'invention concerne un agent anxiolytique caractérisé en ce qu'il contient un ingrédient actif, le 4-(1-piperidylméthyle)phénol (PMP) ou un dérivé ayant la même activité biologique que celui mentionné; et une méthode pour utiliser un agent anxiolytique PMP ou un dérivé ayant la même activité biologique que celui mentionné. Le PMP est un agent anxiolytique capable d'agir à travers le récepteur sigma, et qui présente l'avantage d'être efficace, même en petite quantité, et qui peut être administré par voie orale. Le PMP a le potentiel de devenir un excellent médicament pour le traitement des troubles d'anxiété.
PCT/JP2005/014060 2004-08-02 2005-08-01 Nouvel agent anxiolytique Ceased WO2006013833A1 (fr)

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JP2004225745 2004-08-02

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009147831A1 (fr) * 2008-06-04 2009-12-10 株式会社Celest Procédé et composition pharmaceutique pour le traitement de troubles mentaux

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995000131A1 (fr) * 1993-06-23 1995-01-05 Cambridge Neuroscience, Incorporated Ligands du recepteur sigma et leur utilisation
JPH0789949A (ja) * 1993-07-28 1995-04-04 Santen Pharmaceut Co Ltd 新規１，４−（ジフェニルアルキル）ピペラジン誘導体

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995000131A1 (fr) * 1993-06-23 1995-01-05 Cambridge Neuroscience, Incorporated Ligands du recepteur sigma et leur utilisation
JPH0789949A (ja) * 1993-07-28 1995-04-04 Santen Pharmaceut Co Ltd 新規１，４−（ジフェニルアルキル）ピペラジン誘導体

Non-Patent Citations (2)

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Title
FOSTER A. ET AL.: "1,4-Dibenzylpiperazines possess anticocaine activity.", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 13, no. 4, 2003, pages 749 - 751, XP002991744 *
KLOUZ A. ET AL.: "[3H] as a novel and selective ligand for sigma 1 receptors in liver mitochondria and brain synaptosomes of the rat.", FEBS LETTERS, vol. 553, no. 1-2, 2003, pages 157 - 162, XP004463471 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009147831A1 (fr) * 2008-06-04 2009-12-10 株式会社Celest Procédé et composition pharmaceutique pour le traitement de troubles mentaux
JP5436419B2 (ja) * 2008-06-04 2014-03-05 Ｍｅｉｊｉ Ｓｅｉｋａファルマ株式会社 精神障害の治療方法および治療用医薬組成物

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