WO2018097291A1 - コカイン依存症の治療または再発予防薬 - Google Patents
コカイン依存症の治療または再発予防薬 Download PDFInfo
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- WO2018097291A1 WO2018097291A1 PCT/JP2017/042425 JP2017042425W WO2018097291A1 WO 2018097291 A1 WO2018097291 A1 WO 2018097291A1 JP 2017042425 W JP2017042425 W JP 2017042425W WO 2018097291 A1 WO2018097291 A1 WO 2018097291A1
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- 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
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
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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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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- 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
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
- A61P25/36—Opioid-abuse
Definitions
- the present invention relates to a treatment for cocaine dependence or a preventive agent for recurrence containing a NOP receptor agonist as an active ingredient.
- NOP receptor is known as one of opioid receptors.
- NOP nociceptin orphanin FQ peptide
- ORL1 opioid receptor-like 1 receptor
- DOP ⁇
- KOP ⁇
- MOP ⁇
- the other opioid receptors have about 60% amino acid sequence homology with other opioid receptors, but the non-selective opioid receptor antagonist naloxone does not bind (see Non-Patent Document 2). It is clearly different from the body.
- N / OFQ Endogenous ligands for the NOP receptor were identified in succession by research groups in France and Switzerland in 1995, with nociceptin (see Non-Patent Document 3) and orphanin FQ (see Non-Patent Document 4), respectively. Named (hereinafter also referred to as N / OFQ). N / OFQ and NOP receptors are widely distributed in the central nervous system (see Non-Patent Document 5 and Non-Patent Document 6) and are involved in many physiological functions such as pain, learning memory, feeding, and reward. (Refer nonpatent literature 7).
- Non-Patent Document 8 As methods for evaluating the strength of drug dependence, a self-administration method and a conditioned place preference (CPP) method (see Non-Patent Document 8) are known. So far, N / OFQ or low molecular NOP receptor agonists have been alcohol (see Non-Patent Document 9, Non-Patent Document 10, Non-Patent Document 11, Non-Patent Document 12, and Patent Document 13) and opioids (Non-Patent Document 14, It has been confirmed by the self-administration method and the CPP method that the enhancement effect of Non-Patent Document 15 and Non-Patent Document 17), that is, the desire to repeatedly take a drug (also referred to as a reward effect) is suppressed.
- a drug also referred to as a reward effect
- Non-patent Documents 16 and 17 Non-patent document 18, Non-patent document 19 and Non-patent document 20).
- Non-Patent Document 21 As a NOP receptor agonist used for treatment of cocaine dependence or prevention of recurrence, a molecule having high selectivity of NOP receptor with respect to MOP receptor is desirable.
- SCH221510 which has the highest NOP receptor selectivity for the MOP receptor, is opioid self-administration in rats. Is inhibited by intracerebral administration, but is not suppressed by peripheral (subcutaneous) administration (see Non-patent Document 14), and is considered to have low brain migration (see Non-Patent Document 21), and is a cocaine dependence model Its effectiveness as a NOP receptor agonist was insufficient.
- Non-patent Document 22 it is a low molecular NOP receptor agonist with high receptor selectivity and excellent brain migration, and side effects such as sleepiness based on the central inhibitory action of the NOP receptor agonist. It is desirable to develop compounds that show efficacy at low doses that do not show). However, there have been no reports of low molecular weight compounds that have shown efficacy in cocaine dependence models with high clinical predictability, such as cocaine self-administration models in primates (see Non-Patent Document 21).
- the present inventor finds a compound having high NOP receptor selectivity and a low molecular NOP receptor agonist that excels in brain entry and that is effective at low doses that do not exhibit side effects such as sleepiness. Therefore, it has been intensively studied and (R) -2- ⁇ 3- [1- (5-methyl-1,2,3,4-tetrahydronaphthalen-1-yl) is a NOP receptor agonist having the following structure: Piperidin-4-yl] -2,3-dihydro-2-oxo-benzimidazol-1-yl ⁇ -N-methylacetamide (hereinafter also referred to as Compound A) or a pharmaceutically acceptable salt thereof, As a result of evaluating the efficacy in a rat cocaine dependence model, it was found that Compound A or a pharmaceutically acceptable salt thereof has a therapeutic effect on cocaine dependence and an effect of preventing recurrence, thereby completing the present invention.
- the present invention is as follows.
- a pharmaceutical composition for treating or preventing relapse of cocaine comprising oxo-benzimidazol-1-yl ⁇ -N-methylacetamide or a pharmaceutically acceptable salt thereof.
- Cocaine dependence is a disease selected from the group consisting of cocaine abuse, psychological and physical symptoms resulting from use of cocaine, and re-intake (recurrence), as described in (2) or (3) above Method of treatment.
- Cocaine dependence is a disease selected from the group consisting of cocaine abuse, psychological and physical symptoms resulting from use of cocaine, and re-intake (relapse), as described in (4) or (5) above Recurrence prevention method.
- the pharmaceutical composition according to the above (1) or (6) or the above (2) to (5) or (7) to (8), wherein the cocaine dependence is a withdrawal symptom after discontinuation of cocaine use The treatment method or recurrence prevention method according to any one of the above.
- Cocaine dependence is a disease selected from the group consisting of cocaine abuse, psychiatric and physical symptoms resulting from use of cocaine, and reuptake (relapse), as described in (10) or (11) above use.
- the compound A which is an active ingredient of the present invention or a pharmaceutically acceptable salt thereof can be used as an effective therapeutic agent or a preventive agent for recurrence of cocaine dependence.
- Compound A or a pharmaceutically acceptable salt thereof also treats cocaine abuse, psychiatric and physical symptoms resulting from use of cocaine (including withdrawal symptoms after cessation of cocaine use), and reuptake (relapse) It can be used as a drug or a preventive drug.
- the left figure shows the results of the food acquisition test before the cocaine self-administration test (Food 1), the central figure shows the results of the cocaine self-administration test (Cocaine), and the right figure shows the results of the food acquisition test after the cocaine self-administration test (Food 2). Yes.
- the vertical axis shows the number of rewards (coin self-injection or pellet) (Reinforcers)
- the horizontal axis shows the dose of Compound A (Dose of Compound A (mg / kg, im))
- Sal is The physiological saline administration group as a control is shown.
- Compound A decreased the number of cocaine rewards at a dose that did not affect the number of food acquisitions.
- the dotted line indicates the width of the average value of the number of lever presses in each group on the last day of the erasing process (extinction phase) (the day before reinstatement test).
- Compound A significantly suppressed stress-induced cocaine seeking behavior at a dose of 3 mg / kg (* ⁇ 0.05 vs solvent treatment group).
- Compound A of the present invention can be produced by the method described in Example 10 of Patent Document 1.
- Compound A of the present invention or a pharmaceutically acceptable salt thereof is an isotope (eg, 2 H, 3 H, 13 C, 14 C, 15 N, 18 F, 32 P, 35 S, 125 I etc.) Includes labeled compounds and deuterium converters.
- the pharmaceutically acceptable salt of Compound A of the present invention includes acid addition salts with inorganic acids and organic acids or salts with inorganic bases. Specifically, acid addition salts with inorganic acids and organic acids such as hydrochloric acid, oxalic acid, maleic acid and fumaric acid, and salts with inorganic bases such as sodium, potassium, calcium and magnesium are included.
- the present invention also includes racemic mixtures of Compound A or their corresponding enantiomers.
- patient in the present specification is an individual to be treated or prevented from recurrence with Compound A or a pharmaceutically acceptable salt thereof, preferably a human.
- the term “cocaine addiction” is a broad concept that includes cocaine abuse, psychiatric and physical symptoms resulting from cocaine use (eg, withdrawal symptoms after cocaine use is discontinued), and reuptake (relapse). It is used in.
- symptoms included in the term “psychiatric symptoms” in the present specification include, but are not limited to, weakness, loss of appetite, anxiety, depression, withdrawal symptoms after discontinuation of cocaine use, and the like.
- symptoms included in the term “physical symptom” in the present specification are not limited, but dilated pupils, increased blood pressure, convulsions, sleep disorders, extreme neurosis, hallucinations, delusions, and cocaine use discontinuation The later withdrawal symptoms can be mentioned.
- the present invention can prevent recurrence due to craving for cocaine that is triggered not only by cocaine dependence but also by various stresses after the use of cocaine is stopped.
- stress is not limited, but includes mental stress (eg, loneliness, anxiety, alienation, fatigue, harassment, etc.) and physical stress (eg, noise, illness, pain, injury, Lack of sleep, overwork, etc.).
- a medicament containing the compound A of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient can be administered either orally or parenterally.
- the dosage form include tablets, capsules, granules, powders, injections, buccal tablets, coating agents, ointments and suppositories. These can be formulated with a pharmaceutically acceptable carrier, if necessary, using a widely used technique.
- a pharmaceutically acceptable carrier a carrier conventionally used in the art may be used.
- a bulking agent such as lactose, sucrose, corn starch, potassium phosphate, sorbit, glycine, mannitol, and crystalline cellulose
- a lubricant stearin
- Magnesium acid, talc, polyethylene glycol, and silica binders (syrup, gum arabic, gelatin, sorbit, tragacanth, polyvinyl pyrrolidone, hydroxypropyl cellulose, polyvinyl alcohol, polyethylene glycol, etc.), disintegrants (potato starch, low Degree of substitution hydroxypropylcellulose, and crosslinked carboxymethylcellulose), coating agents or coating agents (such as ethylcellulose and hydroxypropylmethylcellulose), and ointment bases (petroleum, And paraffin, etc.), and the like.
- the medicament of the present invention is an oral preparation such as a tablet, capsule, granule, powder, etc., a bulking agent, a lubricant, a binder, a disintegrant, a coating agent, a film agent, etc. are used as necessary.
- the medicament of the present invention is an ointment, it can be prepared using a widely used base.
- the compound A of the present invention is particularly suitable as an oral preparation because of its good brain migration.
- the dose (ie, effective amount) of Compound A, which is an active ingredient of the present invention, or a pharmaceutically acceptable salt thereof can be appropriately selected depending on symptoms, patient age, body weight, dosage form, etc. If so, 0.01 to 30 mg, preferably 0.1 to 3 mg per day can be administered in a single dose or divided into several doses.
- NOP receptor agonists are known to have side effects such as drowsiness based on the central inhibitory action due to the characteristics of their mechanism of action (Non-patent Document 22), so that they can be used safely and effectively.
- the dose setting is extremely important for this purpose. That is, administration at a dose that is 1/3 to 1/3 of the dose at which a central inhibitory effect is observed in experimental animals is desirable.
- the dose of Compound A in humans is estimated to be 0.1 to 3 mg, and it is considered preferable to use within this dose range.
- the strength of drug dependence can be examined using the strengthening effect (reward effect) as an index, and there is a self-administration method as a non-clinical method for measuring the strengthening effect.
- the self-administration method when the lever is pressed, the strength of dependence can be examined using the lever pressing behavior as an index under the condition that the drug is automatically administered intravenously from the infusion pump.
- the self-administration method is the most reliable method for evaluating the strengthening effect of a drug, but has a drawback that it takes a long time for self-administration training.
- a conditioned place preference (CPP) method has been devised as a method for overcoming this drawback and evaluating drug dependence in a relatively short period of time (see Non-Patent Document 8).
- the CPP method is a method for predicting the strengthening effect using place preference as an index, and is not a system for directly evaluating the strengthening effect.
- the CPP method conditioned the place preference by addictive drugs, ie, the effect on CPP acquisition, the effect on the expression of CPP after the place preference acquisition, and the once acquired place preference It is possible to evaluate the effect on reinstatement, which later restores place preference due to stress load.
- the self-administration method since training takes a long time, the effect on acquisition is not evaluated, but the drug search by the effect on drug intake behavior after acquisition of self-administration, stress load after self-administration elimination, etc. It is possible to evaluate the effects on behavior.
- Non-Patent Document 9 Non-Patent Document 10, Non-Patent Document 11, Non-Patent Document 12, and Patent Document 13
- opioids Non-Patent Document 14
- Table 1 summarizes the previous reports on the effects of NOP receptor agonists on the evaluation system for alcoholism. Note that the description such as “9)” in the table indicates the number of the non-patent document in which each experimental result is described (the same applies to Table 2).
- the effectiveness of NOP receptor agonists for alcoholism is suggested by the results of several low molecular weight compounds.
- Non-Patent Document 17 When N / OFQ was administered into the cerebral ventricles of mice, the acquisition of CPP by cocaine (see Non-Patent Document 17) and the expression of CPP (see Non-Patent Document 18) were blocked.
- the low molecular NOP receptor agonist Ro65-6570 (see Non-patent Document 18 and Non-patent Document 19) did not affect CPP acquisition and CPP expression by cocaine.
- AT-202 which is a small molecule NOP receptor agonist, did not affect CPP acquisition, but suppressed CPP recurrence due to stress.
- Table 2 summarizes the reports of the effects of NOP receptor agonists on the above evaluation system for cocaine dependence.
- the low molecular weight NOP receptor agonists reported so far in the evaluation system (CPP acquisition, CPP expression) in which the endogenous agonist N / OFQ is effective are not effective. It is possible that the selectivity was insufficient. That is, it is possible that both Ro65-6570 and AT-202 have not only the NOP receptor but also the agonist activity for the MOP receptor, and the deviation from the NOP receptor agonist activity was insufficient. . Therefore, there is a possibility that the effect of NOP receptor agonist activity was attenuated or disappeared due to the dependency expression based on MOP receptor agonist activity.
- Non-Patent Document 21 the compound having the highest NOP receptor selectivity for the MOP receptor is SCH221510 (see Non-Patent Document 21).
- opioid self-administration in rats is suppressed by intracerebral administration, it is not suppressed by peripheral (subcutaneous) administration (see Non-Patent Document 14), and thus it is considered that the ability to enter the brain is low (see Non-Patent Document 21). .
- Example 1 Effect of Compound A on central cocaine self-administration and effects on central inhibitory action (method)
- Four rhesus monkeys were used in the experiment. Each monkey is individually placed in a stainless steel chamber (64 x 64 x 79 cm), and if the monkey touches the reaction key on the operant panel (28 x 28 cm) installed on the wall in front of the chamber, 1 g of banana is rewarded Training was carried out under conditions where the food pellets of the taste could be received. Under the condition of FR30 (30 times touching the reaction key will give you a reward for one feed), after training until the monkey is stable and rewarded, place the cocaine administration catheter into the monkey's vein An indwelling operation was performed. After the monkey recovered from the operation, a cocaine self-administration model was created by training in the condition that cocaine was intravenously injected as a reward when the reaction key on the operant panel was touched.
- Compound A was evaluated according to the experimental protocol shown in FIG. That is, Compound A or physiological saline as a control was administered intramuscularly 15 minutes before the start, and then a 120 minute session was performed. In the 120-minute session, if you touch the operant panel's reaction key, the 100-minute drug component (100 min Drug Component) in which cocaine is infused intravenously as a reward. A time-out component (5 min TO) that can't get any rewards, and a bait component (5 min Food Component (Food 1, Food 2) for 5 minutes starting and ending 5 minutes when you touch the operant panel reaction key )).
- the red LED lamp of the reaction key was turned on during the bait component, the green LED lamp of the reaction key was turned on during the drug component, and the yellow LED lamp of the reaction key was turned on during the timeout component.
- a condition was set in which the next reward could not be obtained unless a certain period of time had passed, that is, a timeout was set.
- the timeout was 10 seconds for the bait component and 60 seconds for the drug component.
- the yellow LED lamp of the reaction key was turned on. Both the bait and drug components were tested at FR30 conditions.
- Example 2 Effect of Compound A at different doses of cocaine in monkey cocaine self-administration (method)
- the effect of Compound A on cocaine self-administration was examined under conditions using various doses of cocaine (0.001 to 0.1 mg / kg / infusion).
- Compound A dose in Example 1 was either 0.1 mg / kg (1 case) or 0.32 mg / kg (3 cases), which was the dose that did not affect the food acquisition number of food component 1 (Food 1). Was used.
- Example 3 Effect of Compound A (Method) on Stress-Induced Cocaine Search Behavior in Rats
- 12 male Long-Evans hooded rats per group were used.
- Cocaine self-administration training was started after a recovery period of 5 days or more after the catheter was placed in the external jugular vein of the rat in advance.
- a chamber with two levers on the wall and a foot shock grid on the floor was used. Rats are placed in the chamber once a day (2 hours / session) and when the rat presses the active lever (right lever) once (FR1), the cocaine solution (0.2 ml / 6 seconds, cocaine 0.5 mg / kg) is intravenous Self-administration was obtained under the conditions of infusion. As shown in FIG.
- Compound A not only becomes an effective therapeutic drug for cocaine addiction, but can also be a preventive drug for preventing recurrence due to stress of cocaine addiction.
- the medicament of the present invention can be used as a therapeutic agent for cocaine dependence or a preventive agent for recurrence.
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Abstract
Description
(1)(R)-2-{3-[1-(5-メチル-1,2,3,4-テトラヒドロナフタレン-1-イル)ピペリジン-4-イル]-2,3-ジヒドロ-2-オキソ-ベンズイミダゾール-1-イル}-N-メチルアセタミドまたはその医薬上許容される塩を含むコカイン依存症の治療または再発予防用医薬組成物。
(2)(R)-2-{3-[1-(5-メチル-1,2,3,4-テトラヒドロナフタレン-1-イル)ピペリジン-4-イル]-2,3-ジヒドロ-2-オキソ-ベンズイミダゾール-1-イル}-N-メチルアセタミドまたはその医薬上許容される塩を治療を必要とする患者に投与することを含む、コカイン依存症の治療方法。
(3)(R)-2-{3-[1-(5-メチル-1,2,3,4-テトラヒドロナフタレン-1-イル)ピペリジン-4-イル]-2,3-ジヒドロ-2-オキソ-ベンズイミダゾール-1-イル}-N-メチルアセタミドまたはその医薬上許容される塩の投与量が1日あたり0.01~30mgである前記(2)に記載のコカイン依存症の治療方法。
(4)(R)-2-{3-[1-(5-メチル-1,2,3,4-テトラヒドロナフタレン-1-イル)ピペリジン-4-イル]-2,3-ジヒドロ-2-オキソ-ベンズイミダゾール-1-イル}-N-メチルアセタミドまたはその医薬上許容される塩を治療を必要とする患者に投与することを含む、コカイン依存症の再発予防方法。
(5)(R)-2-{3-[1-(5-メチル-1,2,3,4-テトラヒドロナフタレン-1-イル)ピペリジン-4-イル]-2,3-ジヒドロ-2-オキソ-ベンズイミダゾール-1-イル}-N-メチルアセタミドまたはその医薬上許容される塩の投与量が1日あたり0.01~30mgである前記(4)に記載のコカイン依存症の再発予防方法。
(6)コカイン依存症が、コカイン乱用、コカインの使用に起因する精神症状および身体症状、ならびに再摂取(再発)よりなる群から選択される疾患である前記(1)に記載の医薬組成物。
(7)コカイン依存症が、コカイン乱用、コカインの使用に起因する精神症状および身体症状、ならびに再摂取(再発)よりなる群から選択される疾患である前記(2)または(3)に記載の治療方法。
(8)コカイン依存症が、コカイン乱用、コカインの使用に起因する精神症状および身体症状、ならびに再摂取(再発)よりなる群から選択される疾患である前記(4)または(5)に記載の再発予防方法。
(9)コカイン依存症が、コカイン使用中止後の離脱症状である、前記(1)もしくは(6)に記載の医薬組成物または前記(2)~(5)もしくは(7)~(8)のいずれか1つに記載の治療方法もしくは再発予防方法。
(10)コカイン依存症の治療または再発予防用医薬組成物の製造のための(R)-2-{3-[1-(5-メチル-1,2,3,4-テトラヒドロナフタレン-1-イル)ピペリジン-4-イル]-2,3-ジヒドロ-2-オキソ-ベンズイミダゾール-1-イル}-N-メチルアセタミドまたはその医薬上許容される塩の使用。
(11)コカイン依存症の治療または再発予防のための(R)-2-{3-[1-(5-メチル-1,2,3,4-テトラヒドロナフタレン-1-イル)ピペリジン-4-イル]-2,3-ジヒドロ-2-オキソ-ベンズイミダゾール-1-イル}-N-メチルアセタミドまたはその医薬上許容される塩の使用。
(12)コカイン依存症が、コカイン乱用、コカインの使用に起因する精神症状および身体症状、ならびに再摂取(再発)よりなる群から選択される疾患である前記(10)または(11)に記載の使用。
(13)コカイン依存症の治療または再発予防のための(R)-2-{3-[1-(5-メチル-1,2,3,4-テトラヒドロナフタレン-1-イル)ピペリジン-4-イル]-2,3-ジヒドロ-2-オキソ-ベンズイミダゾール-1-イル}-N-メチルアセタミドまたはその医薬上許容される塩。
(14)コカイン依存症が、コカイン乱用、コカインの使用に起因する精神症状および身体症状、ならびに再摂取(再発)よりなる群から選択される疾患である前記(13)に記載の治療または再発予防のための(R)-2-{3-[1-(5-メチル-1,2,3,4-テトラヒドロナフタレン-1-イル)ピペリジン-4-イル]-2,3-ジヒドロ-2-オキソ-ベンズイミダゾール-1-イル}-N-メチルアセタミドまたはその医薬上許容される塩。
(15)コカイン依存症が、コカイン使用中止後の離脱症状である、前記(10)~(12)のいずれか1つに記載の使用または前記(13)もしくは(14)に記載の治療または再発予防のための(R)-2-{3-[1-(5-メチル-1,2,3,4-テトラヒドロナフタレン-1-イル)ピペリジン-4-イル]-2,3-ジヒドロ-2-オキソ-ベンズイミダゾール-1-イル}-N-メチルアセタミドまたはその医薬上許容される塩。
本発明の化合物Aは、特許文献1の実施例10に記載の方法によって製造することができる。
薬物の依存性の強さは強化効果(報酬効果)を指標に調べることができ、非臨床で強化効果を測定する方法としては自己投与法がある。自己投与法では、レバーを押すと薬物がインフュージョンポンプから自動で静脈内に投与される条件で、レバー押し行動を指標に依存性の強さを調べることができる。自己投与法は薬物の強化効果を評価する上で最も信頼性の高い方法であるが、自己投与の訓練に長期間を要するという欠点がある。この欠点を克服し、比較的短期間で薬物の依存性を評価する方法として、条件づけ場所嗜好性(conditioned place preference: CPP)法が考案され(非特許文献8参照)、主にマウスやラットを用いた依存性の評価系として汎用されている。しかしながら、CPP法は場所嗜好性を指標に強化効果を予測する方法であり、強化効果を直接評価する系ではない。CPP法では依存性薬物による場所嗜好性の条件づけ、すなわち、CPPの獲得(acquisition)に対する作用、場所嗜好性獲得後のCPPの発現(expression)に対する作用、ならびに一旦獲得した場所嗜好性を消去した後にストレス負荷等により場所嗜好性を復活させる再発(reinstatement)に対する作用の評価が可能である。一方、自己投与法の場合、訓練に長期間を要することから、獲得に対する作用の評価は行われないが、自己投与獲得後の薬物摂取行動に対する作用、自己投与消去後のストレス負荷等による薬物探索行動に対する作用の評価が可能である。
本発明の化合物Aまたはその医薬上許容される塩は、NOP受容体に対して高い親和性を有し、かつMOP受容体に対する親和性が低いため、NOP受容体選択性が高く、しかも脳内移行性に優れており、またNOP受容体作動薬の中枢抑制作用を示さない低用量でも高い効力を有する。
(方法)
実験には4頭のアカゲザルを用いた。サルを個別にステンレススチール製のチャンバー(64 x 64 x 79 cm)に入れ、サルがチャンバー前方の壁に設置してあるオペラントパネル(28 x 28 cm)の反応キーに触ると報酬として1gのバナナ味の餌ペレットが貰える条件での訓練を行った。FR30(反応キーに30回触れると1回の餌の報酬が得られる)の条件で、サルが安定して報酬を獲得するまで訓練を行った後、コカイン投与用のカテーテルをサルの静脈内に留置する手術を行った。サルが手術から回復した後、オペラントパネルの反応キーに触れると報酬としてコカインが静脈内注入される条件で訓練を行うことによりコカイン自己投与モデルを作製した。
その結果、図2の中央図に示すように、化合物Aは0.1、0.32、および0.56 mg/kgの用量において、用量依存的にコカインの自己投与の報酬数を減少させた。また、0.56 mg/kgの用量においては餌コンポーネント1(Food 1)の餌獲得数も減少させたことから、0.56 mg/kgは中枢抑制作用を示す用量であることが示唆されたが、化合物Aは餌コンポーネント1(Food 1)の餌獲得数に影響を及ぼさない用量(0.1および0.32 mg/kg)であってもコカイン自己投与を抑制することが明らかになった。すなわち、化合物Aは中枢抑制作用を示さない低用量でもコカイン依存症治療薬として有効であることが示された。さらに、化合物Aの0.56 mg/kgによる餌コンポーネント1(Food 1)における餌獲得数の減少は餌コンポーネント2(Food 2)では観察されなかったことから、化合物Aの中枢抑制作用は一過性であることが示唆された。
(方法)
実施例1と同様の方法で、化合物Aのコカイン自己投与に対する作用を、コカインの種々の用量(0.001~0.1 mg/kg/注入)を用いる条件下で検討した。化合物Aの用量は実施例1において、餌コンポーネント1(Food 1)の餌獲得数に影響を及ぼさなかった用量である0.1 mg/kg(1例)または0.32 mg/kg(3例)のいずれかを用いた。
その結果、図3に示すように、コカインの0.003、0.01、0.03、および0.1 mg/kg/注入の用量において、化合物Aの投与によりコカイン自己投与の報酬回数が顕著に減少することが、4例の平均データから示された。
また、コカイン依存症患者は十分な強化効果が得られるコカインの用量を自分で見つけることができるため、コカインの用量反応曲線(図3の○印のグラフ)を右方シフトさせる薬剤は治療薬としては意味をなさない。つまり、このような薬剤は低用量のコカインによる強化効果のみ抑制するが、高用量のコカインの強化効果を抑制しないため治療薬としては不十分である。一方、化合物Aは、図3の■印のグラフのように、低用量から高用量のいずれの用量のコカインの効果に対しても顕著な抑制作用を示したことから、優れたコカイン依存症治療薬となり得る薬理活性を有していることが示された。
(方法)
実験には1群12例の雄性Long-Evans hoodedラットを用いた。予めラットの外頚静脈内にコカイン投与用カテーテルの留置手術を行った後、5日以上の回復期間をおいてコカイン自己投与の訓練を開始した。訓練には壁面に2つのレバーが、床にフットショック用グリッドが設置されているチャンバーを用いた。ラットを1日1回(2時間/セッション)チャンバーに入れ、ラットがアクティブレバー(右レバー)を1回押すと(FR1)コカイン溶液(0.2 ml/6秒、コカイン0.5 mg/kg)が静脈内に注入される条件で自己投与を獲得させた。図4に示すように、訓練期間(training phase)において安定したレバー押し回数が観察された後、アクティブレバーを押してもコカインの報酬が得られない期間(extinction phase)を設けてレバー押し行動を消去させた。レバー押し行動が消去されたラットに15分間のフットショック(0.63 mA、0.5秒、40秒間隔)を負荷し、その後2時間/セッションのレバー押し回数を記録した(reinstatement test)。化合物Aまたはコントロールとしての溶媒はreinstatement testのセッション開始の30分前に経口投与した。
その結果、図5に示すように、化合物Aの3 mg/kgの投与により、フットショックストレスによって誘発されるコカイン探索行動が有意に抑制された。この結果により、化合物Aはストレスによるコカイン摂取欲求を抑制すること、すなわち、ストレスによるコカイン依存の再発を予防する効果を有することが示された。
Claims (15)
- (R)-2-{3-[1-(5-メチル-1,2,3,4-テトラヒドロナフタレン-1-イル)ピペリジン-4-イル]-2,3-ジヒドロ-2-オキソ-ベンズイミダゾール-1-イル}-N-メチルアセタミドまたはその医薬上許容される塩を含むコカイン依存症の治療または再発予防用医薬組成物。
- (R)-2-{3-[1-(5-メチル-1,2,3,4-テトラヒドロナフタレン-1-イル)ピペリジン-4-イル]-2,3-ジヒドロ-2-オキソ-ベンズイミダゾール-1-イル}-N-メチルアセタミドまたはその医薬上許容される塩を治療を必要とする患者に投与することを含む、コカイン依存症の治療方法。
- (R)-2-{3-[1-(5-メチル-1,2,3,4-テトラヒドロナフタレン-1-イル)ピペリジン-4-イル]-2,3-ジヒドロ-2-オキソ-ベンズイミダゾール-1-イル}-N-メチルアセタミドまたはその医薬上許容される塩の投与量が1日あたり0.01~30mgである請求項2に記載のコカイン依存症の治療方法。
- (R)-2-{3-[1-(5-メチル-1,2,3,4-テトラヒドロナフタレン-1-イル)ピペリジン-4-イル]-2,3-ジヒドロ-2-オキソ-ベンズイミダゾール-1-イル}-N-メチルアセタミドまたはその医薬上許容される塩を治療を必要とする患者に投与することを含む、コカイン依存症の再発予防方法。
- (R)-2-{3-[1-(5-メチル-1,2,3,4-テトラヒドロナフタレン-1-イル)ピペリジン-4-イル]-2,3-ジヒドロ-2-オキソ-ベンズイミダゾール-1-イル}-N-メチルアセタミドまたはその医薬上許容される塩の投与量が1日あたり0.01~30mgである請求項4に記載のコカイン依存症の再発予防方法。
- コカイン依存症が、コカイン乱用、コカインの使用に起因する精神症状および身体症状、ならびに再摂取(再発)よりなる群から選択される疾患である請求項1に記載の医薬組成物。
- コカイン依存症が、コカイン乱用、コカインの使用に起因する精神症状および身体症状、ならびに再摂取(再発)よりなる群から選択される疾患である請求項2または3に記載の治療方法。
- コカイン依存症が、コカイン乱用、コカインの使用に起因する精神症状および身体症状、ならびに再摂取(再発)よりなる群から選択される疾患である請求項4または5に記載の再発予防方法。
- コカイン依存症が、コカイン使用中止後の離脱症状である、請求項1もしくは6に記載の医薬組成物または請求項2~5もしくは7~8のいずれか1項に記載の治療方法もしくは再発予防方法。
- コカイン依存症の治療または再発予防用医薬組成物の製造のための(R)-2-{3-[1-(5-メチル-1,2,3,4-テトラヒドロナフタレン-1-イル)ピペリジン-4-イル]-2,3-ジヒドロ-2-オキソ-ベンズイミダゾール-1-イル}-N-メチルアセタミドまたはその医薬上許容される塩の使用。
- コカイン依存症の治療または再発予防のための(R)-2-{3-[1-(5-メチル-1,2,3,4-テトラヒドロナフタレン-1-イル)ピペリジン-4-イル]-2,3-ジヒドロ-2-オキソ-ベンズイミダゾール-1-イル}-N-メチルアセタミドまたはその医薬上許容される塩の使用。
- コカイン依存症が、コカイン乱用、コカインの使用に起因する精神症状および身体症状、ならびに再摂取(再発)よりなる群から選択される疾患である請求項10または11に記載の使用。
- コカイン依存症の治療または再発予防のための(R)-2-{3-[1-(5-メチル-1,2,3,4-テトラヒドロナフタレン-1-イル)ピペリジン-4-イル]-2,3-ジヒドロ-2-オキソ-ベンズイミダゾール-1-イル}-N-メチルアセタミドまたはその医薬上許容される塩。
- コカイン依存症が、コカイン乱用、コカインの使用に起因する精神症状および身体症状、ならびに再摂取(再発)よりなる群から選択される疾患である請求項13に記載の治療または再発予防のための(R)-2-{3-[1-(5-メチル-1,2,3,4-テトラヒドロナフタレン-1-イル)ピペリジン-4-イル]-2,3-ジヒドロ-2-オキソ-ベンズイミダゾール-1-イル}-N-メチルアセタミドまたはその医薬上許容される塩。
- コカイン依存症が、コカイン使用中止後の離脱症状である、請求項10~12のいずれか1項に記載の使用または請求項13もしくは14に記載の治療または再発予防のための(R)-2-{3-[1-(5-メチル-1,2,3,4-テトラヒドロナフタレン-1-イル)ピペリジン-4-イル]-2,3-ジヒドロ-2-オキソ-ベンズイミダゾール-1-イル}-N-メチルアセタミドまたはその医薬上許容される塩。
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CA3044950A CA3044950A1 (en) | 2016-11-28 | 2017-11-27 | Drug for treating cocaine addiction or preventing recurrence of same |
JP2018553001A JPWO2018097291A1 (ja) | 2016-11-28 | 2017-11-27 | コカイン依存症の治療または再発予防薬 |
AU2017364801A AU2017364801A1 (en) | 2016-11-28 | 2017-11-27 | Drug for treating cocaine addiction or preventing recurrence of same |
RU2019120099A RU2019120099A (ru) | 2016-11-28 | 2017-11-27 | Лекарственное средство для лечения кокаиновой наркозависимости или предотвращения ее рецидива |
MX2019006084A MX2019006084A (es) | 2016-11-28 | 2017-11-27 | Farmaco para tratar la adiccion a la cocaina o prevenir la recurrencia de la misma. |
US16/464,178 US11058674B2 (en) | 2016-11-28 | 2017-11-27 | Drug for treating cocaine addiction or preventing recurrence of same |
CN201780073113.6A CN110139650A (zh) | 2016-11-28 | 2017-11-27 | 可卡因依赖症的治疗或防复发药 |
BR112019010719A BR112019010719A2 (pt) | 2016-11-28 | 2017-11-27 | composição farmacêutica para tratar a dependência de cocaína ou prevenir a recaída da dependência de cocaína, métodos para tratar a dependência e para prevenir a recaída da dependência de cocaína de cocaína, uso de (r)-2-{3-[1-(5-metil-1,2,3,4-tetra-hidronaftalen-1-il)piperidina-4-il]-2,3-di-hidro-2-oxo-benzimidazol-1-il}-n-metilacetamida ou um sal farmaceuticamente aceitável do mesmo, e, (r)-2-{3-[1-(5-metil-1,2,3,4-tetra-hidronaftalen-1-il)piperidina-4-il]-2,3-di-hidro-2-oxo-benzimidazol-1-il}-n-metilacetamida ou um sal farmaceuticamente aceitável do mesmo. |
KR1020197018656A KR20190092464A (ko) | 2016-11-28 | 2017-11-27 | 코카인 의존증의 치료 또는 재발 예방약 |
IL266866A IL266866A (en) | 2016-11-28 | 2019-05-26 | A drug to treat cocaine addiction or prevent its relapse |
PH12019501165A PH12019501165A1 (en) | 2016-11-28 | 2019-05-27 | Drug for treating cocaine addiction or preventing recurrence of same |
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RU2019120099A (ru) | 2020-12-30 |
IL266866A (en) | 2019-08-29 |
US11058674B2 (en) | 2021-07-13 |
EP3545955A4 (en) | 2020-07-29 |
MX2019006084A (es) | 2019-11-12 |
US20200289492A1 (en) | 2020-09-17 |
EP3545955A1 (en) | 2019-10-02 |
CA3044950A1 (en) | 2018-05-31 |
KR20190092464A (ko) | 2019-08-07 |
BR112019010719A2 (pt) | 2019-10-01 |
JPWO2018097291A1 (ja) | 2019-10-17 |
PH12019501165A1 (en) | 2019-10-28 |
AU2017364801A1 (en) | 2019-06-20 |
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