JPH09221423A - Agent for suppressing drug dependence - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a drug dependence suppressing agent containing a compound having activity to inhibit a specific enzymatic action as an active component and effective for suppressing or mitigating the development of drug dependence caused by the repetitive administration of various dependent drugs such as morphine. SOLUTION: A compound active to inhibit the enzymatic activity of phosphodiesterase, especially a compound having a specific enzyme inhibiting activity on phosphodiesterase IV is used as an active component. The suppressing agent is especially preferably the one suppressing the development of withdrawal symptom exhibiting the formation of drug dependency. The active component compound is especially preferably 4-[3-(cyclopentyloxy or cyclopropylmethoxy)-4-lower alkoxyphenyl]-2-pyrrolidinone of formula (R<1> is a 1-4C alkyl; R<2> is cyclopentyl or cyclopropylmethyl), etc. The content of the active component in the suppressing agent is 0.001-95wt.%, preferably about 0.01-90wt.%.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel drug dependence formation inhibitor, and more particularly to a compound used for suppressing drug dependence formation and having an activity of inhibiting the enzymatic action of phosphodiesterase (PDE) as an active ingredient. As a drug dependence inhibitor.

In particular, the drug dependence formation inhibitor of the present invention is a withdrawal symptom which shows drug dependence formation induced by continuous administration of a narcotic drug such as morphine, that is, continuous injection.
alsyndrome; also referred to as withdrawal symptoms). Here, the expression of withdrawal symptoms refers to the formation of physical dependence classified as one of drug dependence formation,
By stopping or reducing the dose after continuous administration of the drug, it means that a morbid state with clear physical symptoms appears in the process of the drug disappearing below a certain level of the drug concentration in the body.

[0003]

2. Description of the Related Art Morphine is known as a typical example of a drug capable of inducing drug dependence formation by continuous administration. Morphine has long been a medically useful drug as a narcotic analgesic, and it selectively exerts a strong analgesic effect by selectively blocking the pain afferents, and acts on the cerebral cortex to increase the threshold of pain sensation. To raise. It also acts on the limbic system and affects emotional responses. As an analgesic, morphine still has no alternative drug and is highly effective against almost all pain. In particular, it is used for post-operative pain, end-stage cancer pain, myocardial infarction pain, and dyspnea associated with acute pulmonary edema or acute left ventricular failure, and the symptoms are dramatically improved.

However, the continuous administration of morphine causes a phenomenon of drug dependence formation, and therefore, it is treated as a "narcotic" according to the regulations. Drug dependence has three aspects: psychological dependence with a strengthening effect, physical dependence that causes pathological physical symptoms upon withdrawal, and development of tolerance, but morphine depends on these three aspects. Are known to cause (Kob of "Science" 242, 715-723 (1988)).
See Bloom's paper).

Generally, during the formation of physical dependence by morphine, withdrawal symptoms appear about 8 to 20 hours after the administration of morphine is stopped. Symptoms of withdrawal include sympathetic hyperexcitability such as sweating, tearing, rhinorrhea, increased blood pressure, tachycardia, and parasympathetic hyperexcitability such as vomiting, diarrhea, and abdominal pain. . In addition, manifestations of psychotic symptoms such as anxiety, irritability, and insomnia are also recognized. In this case, the degree of withdrawal is said to be proportional to the dose administered. In addition, morphine addicts often take antisocial behavior to obtain morphine because of the above-mentioned distress and fear of withdrawal, and often cause crimes and other social problems.
On the other hand, tolerance means that the effect of a drug is diminished by continuous administration, and in morphine, diminished analgesic effect is also a clinical problem requiring treatment of pain.

As described above, morphine is a clinically useful drug, but the problem of the expression of drug-dependent formation by morphine has not yet been solved.

In addition to the above-mentioned morphine, drugs capable of inducing drug dependence formation include barbiturate anesthetics,
LSD-25 (a hallucinogen), cocaine, cannabis, amphetamines, cannabinates, and benzodiazepine compounds (sedatives, hypnotics, anxiolytics) are known.

As a therapeutic method for drug-dependent patients with stimulants and heroin, α-methyl-p-tyrosine and fusaric acid (5-butylpicolinic), which are considered to act as neurotransmission inhibitors of dopaminergic nerve tracts,
acid) has been reported to alleviate the patient's thirst for ingestion of the drug ("Handbook for Psychopharmaceuticals", Second Edition, 112 pages, published by Nankodo 1989). However, no compound has yet been reported to have the effect of directly suppressing or reducing drug dependence formation.

[0009]

SUMMARY OF THE INVENTION An object of the present invention is to provide a novel drug capable of suppressing or reducing drug dependence formation caused by continuous drug administration of various addictive drugs such as morphine.

On the other hand, the analgesic effect of morphine and the phenomenon of drug dependence formation by continuous administration are observed in experimental animals such as mice as in humans, and the mechanism thereof has been studied for many years. . According to these studies, morphine acts on opioid receptors in the brain and affects adenylyl cyclase activity, and a single dose of morphine produces intracellular cAMP (cyclic adenosine-3 ′,
It is said to decrease the amount of 5'-monophosphate) and increase the amount of cAMP when withdrawal symptoms occur (“Pro
c. Nat. Acad. Sci. USA "72, No. 3, 3092-3096 (1
975) Sharma et al. `` Dual regulation of adenylate
cyclase accounts for narcotic dependence and tole
rance ”), but the mechanism of the fluctuation of the amount of cAMP is still unclear.

Theophylline (Theofyl), a non-selective PDE inhibitor, is used in animals that have undergone drug-dependent formation by morphine.
line) or cAMP enhances resistance to morphine and drug-dependent formation by morphine,
A possible involvement of cAMP in tolerance and dependence formation has been reported ("Life Sciences", Vol. 16, 1895-1900 (1975), Ho et al., "Effect of cyclic nucleotides and pho
sphodiesterase inhibition on morphine tolerance an
d physical dependence ''). On the other hand, when a methylxanthine derivative, which is a PDE inhibitor having an adenosine antagonistic action, is administered to an animal in which drug dependence formation is caused by morphine, the withdrawal symptom is enhanced. The possible involvement of sexual adenosine has also been suggested (“Clin. Exp. Pharmacol. Physio
L. Suppl. "18, p. 55 (1991)).

In general, the mechanisms that regulate the level of cAMP in cells in the brain are adenylyl cyclase, which is a cAMP synthase, and an enzyme that decomposes cyclic nucleotides such as cAMP, as its main action factors. There is PDE. PDE has at least five subtypes (I, II, III, IV, due to its enzyme activity regulator and substrate specificity).
V) PDE is known to exist. PDE I, P
DE II and PDE III hydrolyze cAMP and cGMP (cyclic guanosine-3 ', 5'-monophosphate) to approximately the same degree (non-selectively), while PDE IV has a selective inhibitory activity against cAMP. It is known that PDE V is highly selective for cGMP.

Rolipram: (±) -4
-[3- (Cyclopentyloxy) -4-methoxyphenyl] -2-pyrrolidinone) is a compound that inhibits the enzyme activity of PDE, that is, one of PDE inhibitors, and in particular, the selectivity of the enzyme inhibitory activity against PDE IV. It is known to be effective as a therapeutic agent for dementia due to cerebrovascular disorder (see US Pat. No. 5,059,612, European Patent Application Publication No. 0 432 856 and Japanese Patent Application Laid-Open No. 3-181418).

Another object of the present invention is useful for suppressing or reducing drug dependence formation induced by continuous administration of drugs, particularly drug dependence formation by various drugs capable of causing physical dependence formation and PDE. Another object of the present invention is to provide a novel drug dependence inhibitor or reducer containing a compound having an enzyme-inhibiting activity against the above as an active ingredient.

[0015]

[Means for Solving the Problems] This time, the present inventors noted that the fluctuation of the cAMP amount in the brain occurred during the formation of drug dependence by continuous injection of morphine as described above.
Focusing on the enzyme inhibitory action of rolipram, which is an inhibitor of PDE that decomposes MP, and the locomotive force of rolipram in the brain, when rolipram is concurrently administered and used concurrently with continuous administration of morphine, drug dependence formation by morphine, particularly It is expected that the formation of physical dependence, which is represented by the occurrence of withdrawal symptoms, can be suppressed or reduced. Based on this expectation, repeated animal experiments in which rolipram was continuously administered concurrently with morphine were repeated in mice to which morphine was continuously administered, and withdrawal symptoms induced by continuous administration of morphine and morphine A series of studies were conducted to examine the relationship between the concurrently administered rolipram and the inhibitory effect on withdrawal symptoms. As a result, it was found that the parallel administration of rolipram can suppress the body-dependent formation of mice by morphine and can suppress or delay the development of resistance to morphine (diminished analgesic effect).

From another series of animal experiments, like rolipram, a compound having an enzyme-inhibiting activity on PDE and having intracerebral transfer is administered concurrently with various addictive drugs. In some cases, it could be expected that drug dependence formation caused by continuous administration of addictive drugs could generally be suppressed or reduced.

Therefore, the gist of the present invention is that P
Provided is a drug dependence formation inhibitor, which comprises a compound having an enzyme inhibitory activity against DE as an active ingredient.

The active ingredient used in the inhibitor of the present invention is preferably a compound having a specific enzyme inhibitory activity against PDE IV. The compound used as an active ingredient in the present invention is required to have the ability to enter the brain so that it can cross the blood-brain barrier.

The inhibitor of the present invention is particularly useful for suppressing the development of withdrawal symptoms among the phenomena showing drug dependence formation. The compound used as the active ingredient in the present invention is (±)-
4- [3- (cyclopentyloxy) -4-methoxyphenyl] -2-pyrrolidinone, a compound known by the general name rolipram, or 4- [3-cyclopropylmethoxy) -4-methoxyphenyl] -2-pyrrolidinone Preferably, there are the following general formula (I) including rolipram: (In the formula, R ¹ is a lower alkyl group having 1 to 4 carbon atoms,
R ² can be 4- [3- (cyclopentyloxy or cyclopropylmethoxy) -4-loweralkoxyphenyl] -2-pyrrolidinone represented by a cyclopentyl group or a cyclopropylmethyl group.

Further, P which can be used as an active ingredient in the present invention
Compounds having DE inhibitory activity are propentofylline [Propen
tofylline ； Merck Index 11th edition code number 782
3, chemical name is 3,7-dihydro-3-methyl-1-
(5-oxohexyl) -7-propyl-1H-purine-
2,6-dione], Denbufylline; chemical name is 7- (2-oxopropyl) -1,3-di-n-
Butylxanthine], Ro 20-1724 [Journal of Medi
cinal Chmeistry, Vol. 34, No. 1, pp. 291-298 (1991)], Vinpocetine (Merck Index 11th edition code number 9894, chemical name is everamenine-14-carboxylic acid ethyl ester), and IBMX ( The chemical name may be 3-isobutyl-1-methylxanthine).

The drug dependence formation-inhibiting agent of the present invention containing the above-mentioned active ingredient compound is prepared in various dosage forms as a pharmaceutical composition containing a solid or liquid carrier commonly used in medicine mixed with the active ingredient. it can. It can also be formulated in the form of a mixture with morphine or other addictive drug.

The dose of the drug dependence inhibitor of the present invention to an adult, in the case of oral administration, is in the range of 0.001 to 1000 mg, calculated as the active ingredient compound per day.

The active ingredient compound having PDE inhibitory activity used in the inhibitor of the present invention can be formulated into a pharmaceutical composition by a conventional method in the technical field of formulation. The dosage form for oral administration is not particularly limited, but may be tablets, granules, powders, capsules and the like. That is, an excipient, and if necessary, a binder, a disintegrating agent, a lubricant, a coloring agent and the like are added to the active ingredient, and then tablets, coated tablets, granules, powders, capsules and the like are prepared by a conventional method. It can be formulated. Further, the parenteral administration of the inhibitor of the present invention can be carried out as an injection in the form of a solution or suspension in which the active ingredient compound is dissolved.

A pharmaceutically acceptable carrier is selected as the above-mentioned solid or liquid carrier, and the type thereof depends on the administration route and administration method. For example, water, an animal or vegetable oil such as alcohol or soybean oil, mineral oil, sesame oil, or a synthetic oil is used as the liquid carrier. As the solid carrier, sugars such as maltose and sucrose, amino acids such as lysine, cellulose derivatives such as hydroxypropylmethyl cellulose, polysaccharides such as cyclodextrin, and organic acid salts such as magnesium stearate are used. When formulated as an injection, the liquid carrier can generally be physiological saline, various buffers, sugar solutions such as glucose, inositol, mannitol, and glycols such as ethylene glycol and polyethylene glycol. Inositol, mannitol, glucose, mannose, maltose, sucrose and other sugars, phenylalanine and other amino acids and other excipients are formulated as a lyophilized preparation, which is then injected into a suitable solvent for injection such as sterilization. It can be used by dissolving or suspending it in a liquid for intravenous administration such as water, physiological saline, glucose solution, electrolyte solution and amino acid. A suitable surfactant can be added as a solubilizer to aid in the dissolution of the active ingredient compound.

The content of the active ingredient in the formulated pharmaceutical composition of the inhibitor of the present invention varies depending on the formulation type, but is usually 0.001 to 95% by weight, preferably 0.01 to 90% by weight. For example, in the case of an injection solution, it is usually 0.01 to 5
It is preferable that the active ingredient compound is contained in a content of% by weight. In the case of oral administration, it is used in the form of tablets, capsules, powders, granules, dry syrups, liquids, syrups and the like together with the solid carrier or liquid carrier.
In the case of capsules, tablets, granules and powders, the content of the active ingredient compound is generally 0.01 to 95% by weight, preferably 0.02 to 90% by weight, and the balance is carrier.

Further, the dose of the active ingredient used in the present invention is generally determined according to the age, body weight, symptoms of the patient, therapeutic purpose and the like. However, the optimal dose can be administered continuously or intermittently within a range where the total dose does not exceed a certain amount in consideration of various situations such as the results of animal tests. The appropriate dose and frequency of administration under certain conditions are determined by the judgment of a specialist.

The active ingredient compound preferably used in the present invention is rolipram, and rolipram is cA.
It is a selective inhibitor of MP-specific PDE and is known to increase cAMP concentration in rat brain in animal experiments ["Journal of Medicinal Chemistry" 34.
Vol. 1, pp. 291-293 (1991)].

Next, the LD ₅₀ value when the acute toxicity of rolipram in the rat is tested is shown. Route of administration LD ₅₀ value Intraperitoneal Approx. 500 mg / kg Oral Approx. 1200 mg / kg As is clear from this, rolipram is a compound with extremely low toxicity.

[0029]

BEST MODE FOR CARRYING OUT THE INVENTION Next, the effects of the drug dependence inhibitor of the present invention will be described with reference to test examples. Test Example 1 This example is based on the document “J. Pharmacol. Exp. Ther.”, Vol. 72, 74-
According to the method of D'Amour, FE et al., P. 79 (published in 1941), the analgesic effect of morphine subcutaneously administered to mice was examined by the heat tail-flick reflection method.
It was evaluated by the pain response latency (seconds) measured in d) [expressed as (Tail-flick latency, seconds)], and also measured by the pain response latency (seconds). ,
Attenuation of the analgesic effect of morphine during and after continuous administration of morphine, that is, development of tolerance, and in comparison with this, occurred during and after continuous administration of morphine with parallel intraperitoneal administration of rolipram. 3 shows a test for evaluating the diminished analgesic effect of morphine.

In this test, first, a morphine solution was prepared by dissolving 10 mg of morphine hydrochloride in 10 ml of physiological saline.
Furthermore, several kinds of rolipram solutions were prepared by dissolving rolipram at various concentrations in physiological saline containing 2% dimethyl sulfoxide (DMSO). In addition, as an injection solution for a blank test, a first blank sample consisting of physiological saline and 2
A second blank sample consisting of saline containing% DMSO was prepared.

Group 1 male ddY mice (6 mice per group)
In addition, 0.1 ml of the first blank sample (saline solution) per 10 g of mouse body weight was twice a day (am and pm),
Subcutaneous injection was administered for 5 consecutive days, and the second blank sample (physiological saline containing 2% DMSO) was administered in the same volume as the first blank sample for 30 minutes. It was administered intraperitoneally every time (untreated control group).

The second group of male mice of the same ddY strain (10 per group)
Of the above morphine solution per 10 g of mouse body weight
0.1 ml was administered as a single morphine dose of 10 mg / kg twice a day (am and pm) by subcutaneous injection for 5 consecutive days, and a second blank sample (saline containing 2% DMSO was used). )
Was administered intraperitoneally every 30 minutes before morphine administration (10 mg / kg morphine alone administration group) in the same volume as the dose of morphine solution.

To a third group of mice of the same species (10 mice per group), the above morphine solution was administered once by subcutaneous injection twice a day for 5 consecutive days at a dose of 10 mg / kg of morphine. In addition, each time morphine was administered, 30 minutes before morphine administration, the above-mentioned rolipram solution was intraperitoneally administered at a dose of 0.01 mg / kg of rolipram (10 mg / kg morphine + 0.01 mg / kg rolipram combined administration group) ).

A fourth group (10 mice per group) of the same kind of mice was treated with the above morphine solution once, at a dose of 10 mg / kg of morphine.
Subcutaneous injection was given twice a day for 5 consecutive days, and each time morphine was administered, 30 minutes before morphine administration, the above-mentioned rolipram solution was intraperitoneally administered at a dose of 0.03 mg / kg of rolipram. (10 mg / kg morphine + 0.03 mg / kg rolipram combined administration group).

A fifth group of mice of the same species (10 mice per group) was subcutaneously injected once with a morphine solution at a dose of 10 mg / kg twice a day for 5 consecutive days as described above, and Each time the morphine was administered, the above-mentioned rolipram solution was intraperitoneally administered once at a dose of 0.1 mg / kg of rolipram 30 minutes before the administration of morphine (10 mg / kg morphine + 0.1 mg / kg rolipram combined administration group) . In the same manner, a morphine dose of 10 mg / kg and 0.3 mg / kg were given to a sixth group of mice of the same species (10 mice per group).
Morphine and rolipram were co-administered at a rolipram dose of mg / kg (10 mg / kg morphine + 0.3 mg / kg rolipram combined administration group). The 7th group of mice of the same species (10 mice per group)
Morphine and rolipram were co-administered with morphine at a dose of 10 mg / kg and rolipram at a dose of 1 mg / kg (10 mg / kg
kg morphine +1 mg / kg rolipram combined administration group).

The above-mentioned intraperitoneally administered rolipram solution is 0.1 mg per 10 g of mouse body weight.
It has a concentration of rolipram adjusted to give the above-mentioned prescribed dose of rolipram by injecting ml. The above-mentioned study day 0 before the administration of morphine and the first, third and fifth study days after the start of administration in the morning (11
60 minutes after the administration of morphine at 00:00), the mice in each group were subjected to the heat tremor reflex test method to measure the pain response latency (seconds), and the average value ± standard error at each measurement (SEM) was calculated.

Test 1 was performed when the analgesic effect of morphine was diminished by tolerance development in mice administered morphine.
Pain Response Latency Shown by Mice in the Single-Day Morphine-administered Group
It is customary to show significantly shorter pain response latencies (sec) compared to (sec). The test results obtained are summarized in Table 1 below.

[0038]

[Table 1] As is clear from the results of Table 1, the pain response latency (second) on the 0th day of the test was naturally no analgesic effect because morphine was not administered, and was in the range of 2.9 to 3.2 seconds. On the first day of the test, it is observed that the pain response latency (seconds) of each test mouse group receiving morphine administration is significantly prolonged due to the exertion of the analgesic effect of morphine. For prolongation of pain response latency by morphine administration (analgesic effect of morphine),
In the 1 mg / kg rolipram coadministration group (group 7), it was confirmed that rolipram had an analgesic-enhancing effect only on the 3rd day of the study, but on the other measurement days, morphine prolongs the pain response latency. In contrast, rolipram has little effect. In addition, at other combined doses of rolipram, no change was observed compared to the morphine alone administration group (Group 2). Therefore, it is recognized that the combined use of rolipram does not significantly enhance or attenuate the analgesic effect of morphine.

On the other hand, in the group administered with morphine alone, the pain response latency on the 5th day of the test was markedly shorter than that on the 1st day of the test, and the analgesic effect of morphine was attenuated by continuous injection, that is, tolerance. Is recognized. On the other hand, in each test group of morphine + 1 mg / kg rolipram combined administration, the difference in the pain response latency length on the 5th day of the study compared to the 1st day of the study was found in the case of the morphine alone administration group. Significantly smaller than the difference given. Therefore, the combined administration of 1 mg / kg of rolipram diminishes the analgesic effect of continuous administration of morphine,
That is, it is recognized that it has the effect of delaying or suppressing the development of resistance.

Test Example 2 This test is based on the literature "Neuropharmacology", Vol. 33, pages 189-192 (1
1994) and the method of Majeed, NH et al.
ience '' 251, pp. 85-87 (published 1991).
According to the method of o, KA et al., a test for evaluating the expression of withdrawal symptoms induced by continuous injection of morphine is shown. Known as a completely competitive antagonist to morphine, naloxone is a drug that induces withdrawal symptoms immediately when given to chronic morphine addicts ("Modern Pharmacology", pp. 106-107,
Edited by Sumiko Fujino et al., Kodansha Scientific, published in 1988). First, a naloxane solution in which 5 mg of naloxane was dissolved in 10 ml of physiological saline was prepared. 120 minutes after morphine was re-administered to the mice of each test group tested in Test Example 1 on the 6th day of the test, the above-mentioned naloxane solution was intraperitoneally administered at a naloxane dose of 5 mg / kg. did. The concentration of naloxane in the solution was adjusted so that the administration amount of the naloxane solution was 0.1 ml per 10 g of mouse body weight.

Changes in the number of jumping behaviors (jumping), standing behaviors (rearing) and forelimb tremor (forepaw tremor) of the mice were observed for 15 minutes after the administration of naloxane, as behaviors that are indicators of morphine withdrawal symptoms in the mice. Observed and recorded. The test results obtained are summarized in Table 2 below.

[0042]

[Table 2] As is clear from the results in Table 2, as compared with the 10 mg / kg morphine alone administration group, 10 mg / kg morphine and 0.01 mg / kg to 1
In the test group that was co-administered with rolipram (mg / kg), the number of jumping, standing, and forelimb tremor behaviors was significantly small. Therefore, concomitant administration of rolipram concurrently with continuous morphine administration It was observed that the frequency of withdrawal symptoms that occurred after continuous injection of sucrose was clearly suppressed.

From the above experimental results using mice in Test Examples 1 and 2, rolipram was administered in parallel with morphine to prevent the withdrawal symptoms occurring during continuous morphine administration without diminishing the analgesic effect of morphine. It became clear that the expression was suppressed. Therefore, it was confirmed that rolipram has an effect of suppressing the drug dependence formation by continuous morphine injection.

[0044]

EFFECT OF THE INVENTION PD used as an active ingredient in the present invention
A compound having an E inhibitory activity is effective for suppressing drug dependence formation that occurs during continuous administration of an addictive drug, for example, for use in combination with morphine to suppress physical dependence formation and development of tolerance that occur during continuous injection of morphine.

Claims (7)

[Claims] 1. A drug dependence formation inhibitor comprising a compound having an enzyme inhibitory activity against phosphodiesterase as an active ingredient. 2. The inhibitor according to claim 1, wherein a compound having a specific enzyme inhibitory activity against phosphodiesterase IV is the active ingredient. 3. The inhibitor according to claim 1, which suppresses the occurrence of withdrawal symptoms showing drug dependence formation. 4. 4- [3- (cyclopentyloxy) -4 having enzyme inhibitory activity against phosphodiesterase
The inhibitor according to claim 1, wherein -lower alkoxyphenyl] -2-pyrrolidinone is an active ingredient. 5. 4- [3- (Cyclopentyloxy)-
The inhibitor according to claim 1, wherein 4-methoxyphenyl] -2-pyrrolidinone, that is, rolipram, is an active ingredient. 6. The inhibitor according to claim 1, wherein rolipram is an active ingredient, and suppresses the occurrence of withdrawal symptoms showing drug dependence formation induced by continuous administration of narcotic analgesics. 7. The inhibitor according to claim 1, wherein rolipram is an active ingredient, and suppresses development of withdrawal symptoms and development of resistance showing drug dependence formation induced by continuous administration of morphine.