JPH04504859A - Extended-release (tight-binding) dopamine, serotonin or norepinephrine reuptake inhibitors as cocaine, amphetamine and phencyclidine antagonists - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Extended release (strong) cocaine, amphetamine and phencyfridine antagonist Fixed binding) dopamine, serotonin or norepinephrine reuptake inhibitor invention background Abuse of cocaine, amphetamines, phencyfridine (PCP) and similar drugs is a significant public health problem in the United States. These highly addictive The drug initially produces euphoria. Users often become psychotic or violent. He then becomes depressed and desperate. If the above drug is administered by injection If used, the user is often exposed to viral infections, such as AIDS and hepatitis. . Safe and effective means of counteracting drug abuse are needed. Disclosed herein The present invention provides a means for inhibiting the acute effects of such drugs. euphoric drug Reduce or limit the "high" effect of drug administration treatment methods that neutralize cocaine addiction and prevent drug use during and after treatment. You can prevent it from going backwards. 1-(2-[bis(4-fluoroph phenyl)methoxy]ethyl]-4-[3-phenylpropylcopiperazine (GB R12909) and similar drugs have been shown to act as cocaine antagonists. ing.

GBR12909 and analogs can be used to treat Parkinson's disease, peripheral hypertrophy and hyperprolactin Patented as a dopamine agonist for the treatment of tinemia [European patent application] Application No. 243903 (International Classification C07D295108, November 4, 1987) . However, GBR12909 and its analogs as cocaine antagonists The method of the invention used was hitherto unknown.

Clinically effective antidepressant drugs are used to treat cocaine craving. deer However, the efficacy of this treatment modality is disputed. Just 1 week of antidepressant medication It is known that a decrease in desire can be observed after a period of time. has been used so far Antidepressant drugs include desibramine, imibrine, and macindol.

These treatments for treating abuse are similar because they take similar amounts of time to take effect. The effectiveness of these drugs is thought to be related to their effectiveness as antidepressants. Ru. This treatment of craving shows that GBR12909 inhibits the acute effects of cocaine and This is different from the present invention because the effect occurs immediately after administration of the drug. Machine Doll is G Like BR12909, it inhibits dopamine reuptake, but The anti-appetitive effects of chlorine are a neurotransmitter that is more closely associated with affective disorders than dopamine. It probably exhibits strong inhibitory properties for the reuptake of certain norepinephrine.

Another drug, anticonvulsant carbamazepine, is an effective treatment for cocaine craving. This has been reported in open clinical trials involving small numbers of patients. Its mechanism of action is It is thought to involve the suppression of heightened emotions. I mentioned above about antidepressants. However, this therapeutic strategy is different from the use of GBR12909 as a cocaine antagonist. Ru.

Summary of the invention Although drug treatments for cocaine craving are effective, the acute effects of cocaine There are currently no useful drugs that would inhibit the effect. We are GBR12 1-(2-(bis(4-fluorophenyl)methoxy), known as 909 [Ethyl)-4-(1-phenylpropylcopiperazine] is used in animal models of cocaine abuse. discovered that it acts as a cocaine antagonist in humans. we are dopami G that binds tightly to the DA reuptake complex and gradually dissociates from the complex. Properties of BR12909 are the intrinsic mechanisms associated with its cocaine antagonist activity I believe.

For the treatment of cocaine, amphetamine and PCP abuse in humans, as described above. The administration of compounds that act through similar mechanisms is heretofore unknown. won. For the purposes of the present invention, we will reincorporate the term "tight coupling". Robust, either as a result of non-covalent bonds that resist coalescence or as a result of covalent bond formation Even drugs that bind to Ill! Expand I. Inhibition of DA reuptake by cocaine, PC thought to be the primary neurochemical mechanism associated with P and amphetamine addiction. However, these drugs also reduce serotonin and norepinephrine. to interact with reuptake carriers. These drugs also increase serotonin or Because it binds tightly (reversibly or irreversibly) to the Pinephrine reuptake carrier, it is therapeutic. Also within the scope of the present invention is the treatment of addiction to the above-mentioned drugs, in which the drug acts on the DA uptake complex. be.

GBR12909 is known to be a high affinity blocker of DA reuptake. Show The data showed that GBR12909 was strongly implicated in the DA reuptake complex after in vivo administration. and is thought to be closely related to the stimulant and addictive effects of cocaine. bioassay used to counteract the effects of cocaine, which increases ECDA levels. Indicates that it can be used. The data shown are for cocaine, amphetamine and P To counteract the acute effects of CP, these drugs or other tightly bound sustained-release agents Alternatively, we support the use of irreversible DA reuptake blockers. In addition, Seroto Inhibition of norepinephrine reuptake by cocaine, amphetamines and P Am, which contributes to the addictive effects of CP, is a tightly bound reversible substance that cannot be abused by humans. Or the irreversible ligand will prove to be an effective antagonist. many kinds Although several drugs are known for use as DA reuptake blockers, tight binding Antagonizing irreversible or sustained-release biological amine reuptake blockers that affect drug habits The concept of use as substances provides novel and useful uses for these medical compounds .

Table 1 Detailed description of the invention Cocaine antagonists have an effective amount determined by the following formula 1: Formula l (In the formula, each of RI and Rt is independently hydride, halo, cyano, carboxy syl, nitro, hydroxyl, alkoxyl, amino, alkylamino, alkyl ruthio, mercapto, haloalkyl, and linear or or a branched alkyl group, and R8 is selected from hydride, halo, cyano, carbohydride, boxyl, nitro, hydroxyl, alkoxyl, haloalkyl, amino, alkaline Kylamino, alkylthio, mercapto, and lines containing 1 to about 10 carbon atoms or branched alkyl groups and designated C1 and C, Atomic bonds from atoms can be single bonds (alkyl), double bonds (alkenyl), or triple bonds. Substituted 1-(2 -(diphenylmethoxy)ethylcopiperazine compounds or their pharmaceutical acceptance Provided by treatment with sex salts.

A preferred class of compounds of formula 1 is where each of R1 and R3 is independently , hydride, halo, alkyl, haloalkyl, cyano, hydroxyl or alkyl selected from coxyl, R1 is hydride, halo, alkyl, haloalkyl, hydride Selected from Roxy, Alkoxy or Cyano and labeled C1 and C1. The atomic bond from the carbon atom is a single bond (alkyl) or double bond (alkenyl). ).

The term hydride refers to compounds that are bonded to a carbon atom or bonded to a nitrogen atom, for example. means a single hydrogen atom (H) capable of forming a primary or secondary amino group. “Al The term ``kyl'' may be used alone or with other terms, such as ``haloalkyl''. When used in “alkylamino” or “alkylamino”, the term “alkyl” Contains linear or branched groups having from 1 to about 10 atoms. Preferred alkyl groups are carbon atom It is a "lower alkyl" group having 1 to about 5 molecules. The term "haloalkyl" one or more of the alkyl carbon atoms preferably from fluorine, chlorine and bromine Includes groups substituted with one or more selected halogen atoms. r halo The term "alkyl" includes monohaloalkyl, dihaloalkyl and polyhaloalkyl. Particularly included are alkyl groups. Examples of polyhaloalkyl are trifluoromethyl, 2, 2.2-trifluoroethyl and perfluoroethyl. "Alkenyl" The term is commonly referred to by those skilled in the art as a carbon-carbon double bond that develops a SP" hybridization. includes the electronic configuration between two atoms.

The term "alkynyl" is defined by those skilled in the art as a carbon-carbon triplet with an SP hybridization. It involves the electronic configuration between two atoms called a bond. The term "alkoxy" The term refers to linear or branched oxy-containing radicals of from 1 to about 10 carbon atoms, such as methoxy Contains groups. An alkoxy group has one or more halo atoms, e.g. fluorine, chlorine. or may be further substituted with bromine to provide a haloalkoxy group. "Alkylami The term noj includes linear or branched nitrogen-containing groups, where the nitrogen atom has 1 carbon atom optionally substituted with from 1 to about 10 1 to 3 alkyl groups, such as N- Includes methylamino and N,N-dimethylamino.

Specific examples of alkyl groups are methyl, ethyl, propyl, isopropyl, n-butyl , isobutyl, tert-butyl, ni-butyl, neopentyl and n-pentyl. Ru.

Included within the family of compounds of formula 1 are the tautomerisms of the above compounds. isomers such as diastereomers, and pharmaceutically acceptable salts thereof. pharmaceutical Examples of acids that can be used to form acceptable acid addition salts are hydrochloric acid, sulfuric acid and Inorganic acids such as phosphoric acid and organic acids such as maleic acid, succinic acid, and citric acid. Includes acids.

Table 1 summarizes 12 specific compounds within Formula 1 of great interest.

biological evaluation Usually after administration of cocaine, amphetamines, phencyfridine and similar drugs. In order to fulfill the purpose of the present invention, which is to provide a means of reducing the physiological "high" experienced by , the compounds of the invention contain substituents that are readily hydrolyzable to the active ingredient, such as amines, amines, etc. Attaching mido, carboxyl, benzyl groups and other substituents known in the pharmaceutical industry It can be used in the form of a drug precursor.

Cocaine, a major drug of abuse, works primarily by inhibiting the reuptake of biological amines. It is believed that this effect is shown in Cocaine is norepinephrine and serotonin Although it inhibits the reuptake of nin, it inhibits the reuptake of dopamine (DA). The property is thought to be the primary neurochemical mechanism associated with its addictive and euphoric properties. It is being

The role of inhibition of serotonin and norepinephrine reuptake is well defined. It has not been.

Various aspects of the data support the DA hypothesis: 1) as a neurochemical mediator of reward; Role of the dopaminergic system = 2) Efficacy of cocaine-like drugs to inhibit DA reuptake and their interrelationship with their efficacy as self-administered drugs in animals. however However, not all DA reuptake inhibitors are abused by humans. in a test tube Machindol and Nomifu are more effective DA reuptake inhibitors than Caine. Ensin is not abused and is a clinically active depressant in humans. moreover, Treatment of Parkinson's disease and extracorporeal side effects caused by administration of antipsychotics Benztropine, which is a widely described drug, is effective and not abused. A reuptake complex. To clarify these differences, we DA reuptake blockers that are abused are called “type 1” and those that are not abused are called “type 2.” Name it. We treat cocaine, amphetamines, amphetamine-like drugs, and Type 1 drugs include phencyfridine and phencyflidine-like drugs.

1! The reason why reuptake blockers are abused and type 2 reuptake blockers are not is currently Although not well understood at this time, the scientific literature suggests that the interaction with the DA reuptake complex is provides sufficient support for the assumption that interactions are important. Therefore, dissociating intracellular DA In order to must be communicated. Similarly, cocaine has amphetamine-like dissociative properties. Although not well established, it also depends on dopaminergic neurons. In order to be transmitted into the end, it would have to interact with the reuptake complex. cormorant. To the extent that the psychotic hallucinogenic effects of PCP are due to inhibition of DA reuptake, DA Interaction with the reuptake complex may play a role in the action of this drug.

Although inhibition of DA reuptake in vitro does not predict abuse propensity in humans, Available data indicate that drugs that increase extracellular levels of DA (ECDA) in vivo Suggests that it shows efficacy. For example, cocaine, PCP, and amphetamines for ECDACD as measured by in vivo microdialysis techniques. This results in a large increase in In contrast, drugs such as nomifensine and benztropine Type 2 DA reuptake blockers further reduce ECDACD production, leading to erratic increases. It is reported that this occurs.

When ECDA, which does not specify the mechanism of action, is defined as the dependent variable, type 1 and type 2 DA recurrence Uptake inhibitors are shown to be completely and manually actuated, respectively. 1st base drug produces a large increase in ECDA, and type 2 drugs reduce ECDA to lower levels. Ru. A direct prediction of this hypothesis is that 8 inhibition of the reuptake complex by type 2 DA reuptake blockers It decreases the effects of cocaine and has a role in humans as an antagonist of type 1 drugs. There is a possibility that it is for use. However, humans find it easier to self-administer type 1 drugs. , overcome inhibition, and increase the risk of peripheral side effects e.g. cardiac arrhythmia. , competitive antagonists would have limited use. On the other hand, tightly bonded Administration of a released type 2 reuptake inhibitor results in a non-binding period during which it remains bound to the reuptake complex. Overcoming (non-competitive) inhibition will occur.

GBR12909 is a preferred compound and has an EC An effective, sustained release DA reuptake inhibitor that does not produce large increases in DA: (1) Administration of GBR12909 to rats resulted in DA assayed on in vitro muscled membranes. Binds to the reuptake complex (“H) Koi” J and U (“H) GBRI 2 935 1-(2-(diphenylmethoxy)ethyl)-4-(3-phenylp It produces a dose-dependent inhibition of wash resistance of piperazine and exhibits tight binding.

(2) Administration of GBRI 2909 to rats increases ECDACD production in vivo. neutralizes the effects of cocaine.

Example 1: Rats were injected (ip) with a dose of GBR12909.

They were killed after 60 minutes. Tails were excised and frozen at -70°C. assay The membrane was prepared on the day of. Briefly soak the tail in water-cooled 55.2 mM sodium phosphate buffer ( Homogenized with Polytron in pH 7.4). Centrifuge the homogenate; The pellet was resuspended in water-cold buffer and then centrifuged again. Next, [1H ] For covalent binding assays, pellets were placed in a water-cold 25mM sodium phosphate solution. Resuspended in buffer solution (pH 7.4). The results shown in Figure 1 are [3H] showed dose-dependent pseudo-irreversible inhibition of kine binding.

Example 2: Rats were injected (ip) with a dose of GBR12909.

They were killed after 60 minutes. Tails were excised and frozen at -70°C. assay The membrane was prepared on the same day. Briefly cool the tail in water-cooled 55.2 mM sodium phosphate buffer. (pH 7.4) and homogenized with polytron. Centrifuge the homogenate , the pellet was resuspended in water-cold buffer and then centrifuged again. next,(" H) For GBRI2935 (2nM) binding assay, the pellet was placed in water-cold buffer. (pH 7.4). The results shown in Figure 2 are (“H)GBR1 Represents a dose-dependent pseudo-irreversible inhibition of 2935 binding and a sustained effect of the DA reuptake complex. Indicates occupancy. Additional experiments showed that wash resistance inhibition was primarily due to (“H)GBRI 2935 binding. This was shown to be due to a decrease in the number of joint sites. Other experiments have shown that this effect lasts for 6 times. It was shown to be retained even after membrane washing by heart isolation.

The results of Experiments 1 and 2 showed that GBR12909 was firmly attached to the DA reuptake complex in vivo. , supporting the hypothesis that it remains occupied in vitro. child These results indicate that once GBR12909 binds to the DA reuptake complex, it is extremely unstable. This is consistent with reports in the literature of gradual dissociation.

Example 3: Rats were anesthetized with chloryl hydrate and placed in a microdialysis machine. GBR Injection of 25 mg/kg of 12909 is stable but low for ECDACD. (approximately 200%). Cocaine (0, 1, 1, 0 and 10.0mM) administration via the probe results in an additional increase in BCDA levels and returned to baseline within 20 minutes. For ECDACD caused by cocaine The increase in is defined as the difference: ECDA (+cocaine) - ECDA (-cocaine). weighed. GBR12909 (25 mg/kg and 1 00 mg/kg) is shown in Figure 3. The result is higher for ECDACD. showed a very marked reduction in the potency of cocaine. Furthermore, the GBR12 used A high dose of 909 (25 mg/kg) completely eliminated over 70% of the reuptake binding sites. A slight increase was observed for ECDACD, although it was sufficient to occupy It was just that.

Administration of a compound within formula 1 to humans may lead to the compound in the blood of a human patient. It can be performed by any technique including oral administration, intravenous, intramuscular and subcutaneous injection.

The compounds required for prophylactic treatment are preferably administered at a dosage of 0.000 mg/kg body weight per day. It will generally be administered in the range of 1 mg to 100 mg daily. more preferable A suitable dosage will be within the range of 1.0 to 50 mg per kilogram of body weight. suitable dosage may be administered in appropriate divided doses per day.

Although the compound of formula 1 may be administered alone in any acute protective state, The active compound is normally administered in a pharmaceutically acceptable formulation. Such preparations are activated and one or more pharmaceutically acceptable carriers or diluents. So Other therapeutic agents may be present in the formulation. A pharmaceutically acceptable carrier or diluent is Provides a suitable vehicle for delivery of active compounds without undesirable side effects . Delivery of the active compound in such formulations can be by various routes, e.g. oral, nasal, By buccal or sublingual administration, or parenterally, e.g. subcutaneously, intramuscularly, intravenously or It can also be done through the sarcastic route. Delivery of active compounds is made by controlled dissociation in subcutaneous implants It may also be done by using an agent.

Formulations for oral administration include a binder such as gelatin or hydroxypropyl methane. The active compounds dispersed in the cellulose are combined with one or more lubricants, preservatives, It may be in the form of capsules containing surface-active or dispersing agents. like that Capsules or tablets contain the active compound in hydroxypropyl methylcellulose. A controlled dissociation formulation may be included as may be provided in the configuration.

Preparations for parenteral administration are aqueous or non-aqueous isotonic sterile injection solutions or suspensions. It may be in the form of The use of these solutions or suspensions in formulations for oral administration sterile powder with one or more carriers or diluents mentioned in It can be prepared from granules.

Although the invention has been described with respect to particular embodiments, the details of those embodiments are It should not be construed as limiting. various iso-individuals, “changes and Changes may be made without departing from the spirit or scope of the invention, and such It is understood that equivalent embodiments are part of the invention. Dose in mammals is 0 ．． 1-100 mg/kg and 0.1 per day for adult primates. A dosage of 1 to 1 g is a preferred dosage range.

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Claims (1)

[Claims] 1. The following formula 1: ▲There are mathematical formulas, chemical formulas, tables, etc.▼Formula 1 (in the formula, each of R1 and R2 is independent) , hydride, halo, cyano, carboxyl, nitro, hydroxyl, alkoxy syl, amino, monoalkylamino, dialkylamino, alkylthio, merca but, haloalkyl, and linear or branched alkyl of 1 to about 20 carbon atoms. and R3 is selected from the group consisting of hydride, halo, cyano, carboxyl, nito. B, hydroxyl, alkoxyl, amino, alkylamino, alkylthio, metal lucapto, and linear or branched alkyl groups having from 1 to about 10 carbon atoms. The atomic bonds from the carbon atoms chosen and labeled C7 and C8 are single bonds ( either a double bond (alkenyl) or a triple bond (alkynyl) Desire-inhibiting effective amount of a compound represented by (selected from) or a pharmaceutically acceptable salt thereof To reduce cocaine addiction and the acute effects of cocaine in mammals, How to treat and control. 2. In the formula, each of R1 and R2 is independently hydride, halo, alkyl, halo selected from alkyl, cyano, hydroxyl or alkoxyl, and R3 is hydrogen Lido, halo, alkyl, alkenyl, halo, haloalkyl, hydroxyl, alkyl Select from koxy, nitro, cyano, thio, mercapto, amino, alkylamino and the atomic bonds from the carbon atoms labeled C7 and C8 form single bonds (a (alkyl), dimeric bond (alkenyl) or triple bond (alkynyl) The method according to claim 1, wherein the method is selected from: 8. wherein each of R1 and R2 is independently selected from hydride or halo , R■ was selected from hydride or halo and designated C7 and C8 The atomic bond from the carbon atom is a single bond (alkyl) or a double bond (alkenyl). 3. The method according to claim 2, wherein the method is selected from: 4. 1-[2-[bis(4-fluoro) having the chemical formula corresponding to compound 1 in Table 1. lophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine 2. The method according to claim 1, wherein the method uses a pharmaceutically acceptable salt thereof. 5. Mammals with cocaine addiction, acute effects of cocaine, or craving for cocaine a therapeutically effective amount of the compound and a pharmaceutically acceptable carrier or diluent. treating with a pharmaceutical composition, said compound having the following formula 1: ▲There are mathematical formulas, chemical formulas, tables, etc.▼Formula 1 (in the formula, each of R1 and R2 is independent) , hydride, halo, cyano, carboxyl, nitro, hydroxyl, alkoxy syl, amino, monoalkylamino, dialkylamino, alkylthio, merca but, haloalkyl, and linear or branched alkyl of 1 to about 20 carbon atoms. and R2 is selected from the group consisting of hydride, halo, cyano, carboxyl, nito. B, hydroxyl, alkoxyl, amino, alkylamino, alkylthio, metal lucapto, and linear or branched alkyl groups having from 1 to about 10 carbon atoms. The atomic bonds from the carbon atoms chosen and labeled C7 and C8 are single bonds ( either a double bond (alkenyl) or a triple bond (alkynyl) or a pharmaceutically acceptable salt thereof; Cocaine addiction, acute effects of cocaine and coca in selected mammals How to treat and control in-cravings. 6. In the formula, each of R1 and R2 is independently hydride, halo, alkyl, halo selected from alkyl, cyano, hydroxyl or alkoxyl, and R■ is hydrogen Lido, halo, alkyl, alkenyl, halo, haloalkyl, hydroxyl, alkyl Select from koxy, nitro, cyano, thio, mercapto, amino, alkylamino and the atomic bonds from the carbon atoms labeled C7 and C8 form single bonds (a (alkyl), double bond (alkenyl) or triple bond (alkynyl) 6. The method according to claim 5, wherein the method is selected from: 7. wherein each of R1 and R2 is independently selected from hydride or halo , R■ was selected from hydride or halo and designated C7 and C8 The atomic bond from the carbon atom is a single bond (alkyl) or a double bond (alkenyl). 7. The method according to claim 6, wherein the method is selected from: 8. 1-[2-[bis(4-fluoro) having the chemical formula corresponding to compound 1 in Table 1. lophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine or a pharmaceutically acceptable salt thereof. 9. 2. The method according to claim 1, wherein said compound is administered orally, intravenously, intramuscularly or subcutaneously. Law. 10. 6. The compound according to claim 5, wherein said compound is administered orally, intravenously, intramuscularly or subcutaneously. Method. 11. The following formula 1: ▲There are mathematical formulas, chemical formulas, tables, etc.▼Formula 1 (in the formula, each of R1 and R2 is independent) , hydride, halo, cyano, carboxyl, nitro, hydroxyl, alkoxy syl, amino, monoalkylamino, dialkylamino, alkylthio, merca but, haloalkyl, and linear or branched alkyl of 1 to about 20 carbon atoms. and R■ is selected from the group consisting of hydride, halo, cyano, carboxyl, nito. B, hydroxyl, alkoxyl, amino, alkylamino, alkylthio, metal lucapto, and linear or branched alkyl groups having from 1 to about 10 carbon atoms. The atomic bonds from the carbon atoms chosen and labeled C7 and C8 are single bonds ( either a double bond (alkenyl) or a triple bond (alkynyl) ) or a pharmaceutically acceptable salt thereof to a mammal. Methods used to treat and control cocaine addiction and the acute effects of cocaine . 12. In the formula, each of R1 and R2 independently represents hydride, halo, alkyl, halo selected from loalkyl, cyano, hydroxyl or alkoxyl, R■ is hydrogen Dolide, halo, alkyl, alkenyl, halo, haloalkyl, hydroxyl, a Select from lukoxy, nitro, cyano, thio, mercabuto, amino, alkylamino. The atomic bonds from the carbon atoms selected and labeled C7 and C8 are single bonds ( either a double bond (alkenyl) or a triple bond (alkynyl) 12. The method of use according to claim 11, wherein the method is selected from: 13. wherein each of R1 and R2 is independently selected from hydride or halo. and R■ is selected from hydride or halo, and are denoted C7 and C8. The atomic bond from the carbon atom is a single bond (alkyl) or double bond (alkenyl) 13. The method of use according to claim 12, wherein the method is selected from any of the following. 14. 1-[2-[bis(4-fluor) with the chemical formula corresponding to compound 1 in Table 1. Orophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine or a pharmaceutically acceptable salt thereof.