JPH0672098B2 - Sustained-release (tight-binding) dopamine, serotonin or norepinephrine reuptake inhibitors as cocaine, amphetamine and phencyclidine antagonists - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION Cocaine, amphetamine, phencyclidine (PCP).
And abuse of similar drugs is a significant public health problem in the United States. These highly addictive drugs initially cause euphoria. Often the employer becomes psychotic, violent, and desperately depressed. When the drug is administered by injection, its users are often exposed to viral infections such as AIDS and hepatitis. Safe and effective means of neutralizing drug abuse are needed. The invention disclosed herein provides a means for inhibiting the acute effects of the above agents. Treatment methods neutralize cocaine addiction and prevent it from reverting to drug use during and after treatment by reducing or limiting the "high" effect of euphoric drug administration. You can 1- [2- [bis (4-fluorophenyl) methoxy] ethyl] -4-
[3-Phenylpropyl] piperazine (GBR12909) and similar drugs have been shown to act as cocaine antagonists.

GBR12909 and analogues have been patented as dopamine agonists for the treatment of Parkinson's disease, peripheral hypertrophy and hyperprolactinemia [European Patent Application No. 243903 [International Classification C07D295 / 08, November 4, 1987]] . However, the method of the present invention using GBR12909 and its analogs as a cocaine antagonist has heretofore been unknown.

Clinically effective antidepressant drugs are used to treat cocaine cravings. However, the efficacy of this treatment regime is controversial. It is known that a decrease in desire can be observed as little as one week after administration of antidepressant drugs. The antidepressant drugs used to date include desipramine, imiprein and mazindol. The effectiveness of these agents for treating abuse is believed to be related to their effectiveness as antidepressants, as the time required to achieve an effect is similar. This treatment of desire differs from the present invention because GBR12909 inhibits the acute effects of cocaine, and that effect occurs shortly after drug administration. Although mazindol, like GBR12909, inhibits dopamine reuptake, its anti-craving properties strongly inhibit reuptake of norepinephrine, a neurotransmitter more associated with affective disorders than dopamine. Probably indicates.

Another agent, the anticonvulsant carbamazepine, is reported to be an effective therapeutic agent for cocaine craving in open clinical trials involving a small number of patients. Its mechanism of action is thought to involve suppression of emotional heightening. As described above for antidepressant drugs, this therapeutic strategy differs from the use of GBR12909 as a cocaine antagonist.

SUMMARY OF THE INVENTION Although drug treatment of cocaine cravings is effective,
There is currently no useful drug that would effectively inhibit the acute effects of cocaine. We are known as GBR12909 1- [2- [bis (4-fluorophenyl)
It was discovered that methoxy] ethyl] -4- [3-phenylpropyl] piperazine acts as a cocaine antagonist in an animal model of cocaine abuse. We believe that the property of GBR12909 to tightly bind to and slowly dissociate from the dopamine (DA) reuptake complex is an intrinsic mechanism associated with its cocaine antagonist activity.

The administration of the above compounds or compounds acting via a similar mechanism for the treatment of cocaine, amphetamine and PCP abuse in humans has heretofore been unknown.
For the purposes of this invention, we extend the term "tight binding" to agents that bind tightly to the reuptake complex either as a result of strong non-covalent binding or the formation of covalent bonds. Spread. Inhibition of DA reuptake is cocaine, PCP
And although believed to be the major neurochemical mechanism associated with amphetamine addiction, these agents also interact with reuptake carriers for serotonin and norepinephrine. Since these agents also bind tightly (reversibly or irreversibly) to the serotonin or norepinephrine reuptake carriers, the treatment of the addiction of the above agents, where the treatment acts on the DA uptake complex, is also a subject of the present invention. It is within the range.

GBR12909 is known to be a DA reuptake high affinity blocker. The data presented show that GBR12909 binds tightly to the DA reuptake complex after in vivo administration and is closely related to the euphoric and addictive effects of cocaine, an effect of cocaine that enhances ECDA levels. It can be used to neutralize. The data presented support the use of these agents or other tight-binding sustained-release or irreversible DA reuptake blockers to neutralize the acute effects of cocaine, amphetamine and PCP. Furthermore, inhibition of serotonin or norepinephrine reuptake is associated with cocaine, amphetamine and PCP.
To the extent that it contributes to its addictive effects, a tight binding reversible or irreversible ligand that is not abused by humans would prove to be an effective antagonist. Various drugs are DA
Although known for use as reuptake blockers, the concept of using tight-binding, irreversible or sustained-release biological amine reuptake blockers as antagonists acting on drug habits is the concept of these medical compounds. To provide new and useful uses of.

DETAILED DESCRIPTION OF THE INVENTION A chemical cocaine antagonist is an effective amount of the following formula: (Wherein each of R ₁ and R ₂ is independently hydride, halo, cyano, carboxyl, nitro, hydroxyl, alkoxyl, amino, alkylamino, alkylthio,
Selected from mercapto, haloalkyl, and linear or branched alkyl groups of 1 to about 20 carbon atoms, and
R ₃ is hydride, halo, cyano, carboxyl, nitro,
Hydroxyl, alkoxyl, haloalkyl, amino,
Atomic bonds from carbon atoms selected from alkylamino, alkylthio, mercapto, and linear or branched alkyl groups of 1 to about 10 carbon atoms, and designated as C ₇ and C ₈ are single bonds (alkyl), dialkyl By treatment with a compound of the substituted 1- [2- (diphenylmethoxy) ethyl] piperazines represented by a heavy bond (alkenyl) or triple bond (alkynyl)) or a pharmaceutically acceptable salt thereof. Supplied.

Preferred classes of compounds of formula 1 are those in which R ₁ and
Each of R ₂ is independently selected from hydride, halo, alkyl, haloalkyl, cyano, hydroxyl or alkoxyl, R ₃ is selected from hydride, halo, alkyl, haloalkyl, hydroxy, alkoxy or cyano,
And the atomic bonds from the carbon atoms designated C ₇ and C ₈ are selected from either single bonds (alkyl) or double bonds (alkenyl).

The term hydride is, for example, attached to a carbon atom or
Or, it means a single hydrogen atom (H) which can be bonded to a nitrogen atom to form a primary or secondary amino group. "Alkyl"
When the term is used alone or in other terms such as "haloalkyl" or "alkylamino", the term "alkyl" includes linear or branched radicals having one to about ten carbon atoms. Preferred alkyl groups are "lower alkyl" groups having 1 to about 5 carbon atoms. The term "haloalkyl" includes groups in which one or more of the alkyl carbon atoms has been replaced with one or more halogen atoms, preferably selected from fluorine, chlorine and bromine. The term "haloalkyl" specifically includes monohaloalkyl, dihaloalkyl and polyhaloalkyl groups. Examples of polyhaloalkyl are trifluoromethyl, 2,2,2-trifluoroethyl and perfluoroethyl. The term "alkenyl", by those skilled in the art, carbon having SP ² hybrid - including electronic configuration between two atoms called a carbon double bond.
The term "alkynyl" includes electronic configurations between two atoms, referred to by those of ordinary skill in the art as carbon-carbon triple bonds with SP hybridization. The term "alkoxy" includes linear or branched oxy-containing groups having 1 to about 10 carbon atoms, such as methoxy groups. Alkoxy groups may be further substituted with one or more halo atoms such as fluorine, chlorine or bromine to provide haloalkoxy groups. The term "alkylamino" includes linear or branched nitrogen-containing groups in which the nitrogen atom is 1 to 3 carbon atoms of 1 to 3.
Optionally substituted with one alkyl group, including, for example, N-methylamino and N, N-dimethylamino.

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

Included within the family of compounds represented by Formula 1 are tautomers, isomers such as diastereomers of the above compounds, and pharmaceutically acceptable salts thereof. Examples of acids that can be used to form pharmaceutically acceptable acid addition salts include inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid and organic acids such as maleic acid, succinic acid and citric acid. .

Table 1 summarizes 12 very interesting compounds within the scope of Formula 1.

BIOLOGICAL EVALUATION To fulfill the purpose of the present invention, which provides a means of suppressing the physiological "elevation" normally experienced after administration of cocaine, amphetamines, phencyclidine and similar drugs, the compounds of the present invention are readily active ingredients. A hydrolyzable substituent,
For example, it may be used in the form of a drug precursor having an amine, an amide, a carboxyl, a benzyl group and other substituents known in the pharmaceutical industry attached thereto.

Cocaine, a major drug of abuse, is thought to exert its effect primarily by inhibiting reuptake of biological amines. Although cocaine inhibits norepinephrine and serotonin reuptake, its property of inhibiting dopamine (DA) reuptake is believed to be the major neurochemical mechanism associated with its addictive and euphoric properties . The role of inhibition of serotonin and norepinephrine reuptake has not been fully elucidated.

Various sources of data support the DA hypothesis: 1) The role of the dopaminergic system as a neurochemical mediator of rewards; 2) DA
Correlation between the efficacy of cocaine-like agents that inhibit reuptake and their efficacy as self-administered agents in animals. However, not all DA reuptake inhibitors are abused by humans. The more effective DA reuptake inhibitors mazindol and nomifensine in vitro than cocaine are not abused and are clinically effective depressants in humans. In addition, benztropine, a widely described drug for the treatment of Parkinson's disease and the treatment of extrapyramidal side effects caused by the administration of antipsychotics, is an effective, non-abuse DA reuptake inhibitor. To clarify these differences, we have defined “type 1” DA reuptake blockers that are abused by humans and “2” those that are not abused.
Type ". We include cocaine, amphetamines, amphetamine-like agents, and phencyclidine and phencyclidine-like agents in type 1 agents.

Although the reasons why type 1 reuptake blockers are abused and type 2 reuptake blockers are not abused are not fully understood at this time, the scientific literature indicates that interaction with the DA reuptake complex is important. Fully supports the assumption that Therefore, in order to dissociate intracellular DA, amphetamine must be transduced into the dopaminergic nerve terminals via the reuptake complex. Similarly, if cocaine has amphetamine-like dissociative properties, it is not well established, but it must also interact with the reuptake complex to be transduced into dopaminergic nerve terminals. Will not be. To the extent that the psychotic hallucinogenic effects of PCP are due to inhibition of DA reuptake, its interaction with the DA 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, the available data suggest that agents that enhance in vivo extracellular levels of DA (ECDA) may be efficacious. For example, cocaine, PCP, and amphetamine all produce large increases in ECDA levels as measured by the technique of in vivo microdialysis. On the other hand, 2 such as nomifensine and benztropine
Type DA reuptake blockers have been reported to further reduce ECDA levels, producing an inconsistent increase.

If ECDA that does not specify the mechanism of action is defined as the dependent variable, 1
It is shown that type-II and type-2 DA reuptake inhibitors are full and semi-agonists, respectively. Type 1 drugs cause a large increase in ECDA, and type 2 drugs lower ECDA levels. A direct prediction of this hypothesis is that occupancy of the reuptake complex by type 2 DA reuptake blockers reduces the action of cocaine,
And it may be useful in humans as an antagonist of type 1 drug. However, competitive antagonists will have limited use as humans make self-management of type 1 drugs easier, overcome inhibitions and increase the risk of peripheral side effects such as cardiac arrhythmias. On the other hand, administration of a tight-binding sustained-release type 2 reuptake inhibitor is non-overcomerable (non-competitive) over the time it remains bound to the reuptake complex.
Will result in inhibition).

GBR12909 is a preferred compound and is an effective, sustained release DA reuptake inhibitor that does not result in a large increase in ECDA as described below: (1) Administration of GBR12909 to rats [ ³ H] cocaine and [ ³ H] GBR12935 1- [2- (diphenylmethoxy) ethyl] -4- (3-phenylpropyl) bind to DA reuptake complex assayed with in vitro striated membrane A dose-dependent piperazine dose-dependent inhibition of washing resistance occurs, showing strong binding.

(2) Administration of GBR12909 to rats neutralizes the efficacy of cocaine to increase ECDA levels in vivo.

Example 1: Rats were injected with a dose of GBR12909 (ip). Those
Killed 60 minutes later. The tail was excised and frozen at -70 ° C. Membranes were prepared on the day of assay. Ice-cool the tail in a short time 5
Homogenized with Polytron in 5.2 mM sodium phosphate buffer (pH 7.4). The homogenate was centrifuged, the pellet resuspended in ice-cold buffer and then centrifuged again. The pellet was then resuspended in ice-cold 25 mM sodium phosphate buffer (pH 7.4) for [ ³ H] cocaine binding assay. The results shown in Figure 1 showed a dose-dependent pseudo-irreversible inhibition of [ ³ H] cocaine binding.

Example 2: Rats were injected with a dose of GBR12909 (ip). Those
Killed 60 minutes later. The tail was excised and frozen at -70 ° C. Membranes were prepared on the day of assay. Ice-cool the tail in a short time 5
Homogenized with Polytron in 5.2 mM sodium phosphate buffer (pH 7.4). The homogenate was centrifuged, the pellet resuspended in ice-cold buffer and then centrifuged again. The pellet was then resuspended in ice-cold buffer (pH 7.4) for the [ ³ H] GBR12935 (2 nM) binding assay. The results shown in FIG. 2 represent a dose-dependent pseudo-irreversible inhibition of [ ³ H] GBR12935 binding, indicating a persistent occupancy of the DA reuptake complex. Additional experiments are mainly for cleaning resistance inhibition [
³ H] GBR12935 It was shown to be due to a decrease in the number of binding sites. Other experiments have shown that this effect is retained even after 6 membrane washes by centrifugation. The results of experiments 1 and 2 support the hypothesis that GBR12909 is tightly bound in vivo to the DA reuptake complex, so that it continues to occupy in vitro. These results show that GBR12909
Consistent with reports in the literature that once bound to the DA reuptake complex they dissociate very slowly.

Example 3: Rats were anesthetized with chloryl hydrate and placed in a microdialysis machine. Injecting 25 mg / kg of GBR12909 resulted in ECDA
It produced a stable but low increase in levels (about 200%). Cocaine (0.1, 1.0 and 10.0 mM) administered via the probe produced an additional increase in ECDA levels, returning to pretreatment baseline within 20 minutes. Differences in ECDA levels caused by cocaine differ: ECDA (+ cocaine)
Quantified as -ECDA (-Cocaine). The effect of GBR12909 (25 mg / kg and 100 mg / kg) on the effect of cocaine is shown in FIG. The results showed a very pronounced reduction in the efficacy of cocaine increasing ECDA levels. Furthermore, although the high dose of GBR12909 used (25 mg / kg) was sufficient to completely occupy more than 70% of the reuptake binding sites, only a slight increase in ECDA levels was observed. .

Administration of a compound within the scope of Formula 1 to a human can be by any technique that can bring the compound into the blood of a human patient, oral administration, intravenous, intramuscular, subcutaneous injection, and the like.

The compounds required for prophylactic treatment will preferably be generally administered daily in the range of 0.1 mg to 100 mg per kilogram of body weight daily. A more preferred dosage will be in the range 1.0 to 50 mg per kilogram body weight. The appropriate dose may be administered in appropriate divided doses per day.

Although the compound of Formula 1 may be administered alone in any acute protective condition, the active compound will normally be administered in a pharmaceutically acceptable formulation. Such formulations may consist of the active compound and one or more pharmaceutically acceptable carriers or diluents. Other therapeutic agents may be present in the formulation. Pharmaceutically acceptable carriers or diluents provide suitable vehicles for the delivery of active compounds without undesired side effects. Delivery of the active compounds in such formulations may be by various routes, such as oral, nasal, buccal or sublingual, or by parenteral administration, such as subcutaneous, intramuscular, intravenous or intradermal routes. Delivery of the active compound may be by the use of controlled dissociation formulations in subcutaneous implants.

Formulations for oral administration may be in the form of capsules containing a binder such as an active compound dispersed in gelatin or hydroxypropylmethylcellulose together with one or more lubricants, preservatives, surface active or dispersing agents. . Such capsules or tablets may contain a controlled release formulation as may be provided in the placement of the active compound in hydroxypropylmethyl cellulose.

Formulations for parenteral administration may be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions or suspensions may be prepared from sterile powders or granules having one or more of the carriers or diluents mentioned for use in the formulation for oral administration.

Although the invention has been described with respect to particular embodiments,
The details of these embodiments should not be construed as limiting. Various equivalents, changes and modifications may be made without departing from the spirit or scope of the invention,
And such equivalent embodiments are understood to be part of the present invention. The dose in mammals is 0.1-100 mg / kg, and for adult primates a dose range of 0.1 to 1 g per day is the preferred dose range.

Front Page Continuation (72) Inventor Rice, Kenner Sea. Maryland 20817, Bethesda, Kirkdale Road 9007 (72) Inventor Greig, Niger Hamilton, Maryland 20906, Silver Spring, Long Green Drive 14415 (72) Inventor Raid, Audrey Alice United States, Maryland 20814, Bethesda, 714 Es, Pooks Hill Road 5225 (72) Inventor Akune, Hyacinth Charles Kai United States, Maryland 20708, Laurel, 12, Attleboro Court 13502 (72) Invention Melle, Andre Maryland, USA 20895, Kensington, Ferndale Street 3304 (72) Inventor Sir Kerff, Andrew USA, Connecticut 06405, Branford, Foxbridge VILLAGE LOAD 6 (56) REFERENCE JP-A-62-273969 (JP, A) US Patent 4935429 (US, A)

Claims (10)

[Claims] 1. The following equation 1: (Wherein each of R ₁ and R ₂ is independently hydrido, halo, cyano, carboxyl, nitro, hydroxyl, alkoxyl, amino, monoalkylamino, dialkylamino, alkylthio, mercapto, haloalkyl, and 1 carbon atoms. To about 20 linear or branched alkyl groups and R ₃ is hydride, halo, cyano,
Carboxyl, nitro, hydroxyl, alkoxyl,
Amino, alkylamino, alkylthio, mercapto,
And an atomic bond from a carbon atom selected from linear or branched alkyl groups having 1 to about 10 carbon atoms and labeled as C ₇ and C ₈ is a single bond (alkyl), double bond (alkenyl) or triple bond. A compound represented by a bond (alkenyl) or a pharmaceutically acceptable salt thereof for treating and controlling cocaine addiction in mammals and acute effects of cocaine. Composition. 2. wherein R ₁ and R ₂ are each independently selected from hydride, halo, alkyl, haloalkyl, cyano, hydroxyl or alkoxyl, and R ₃ is hydride, halo, alkyl, alkenyl, halo, Atomic bonds from carbon atoms selected from haloalkyl, hydroxyl, alkoxy, nitro, cyano, thio, mercapto, amino, alkylamino and labeled C ₇ and C ₈ are single bonds (alkyl), double bonds (alkenyl). ) Or triple bond (alkynyl). 3. wherein each of R ₁ and R ₂ is independently selected from hydride or halo, R ₃ is selected from hydride or halo, and from the carbon atoms designated C ₇ and C _8. The composition of claim 2 wherein the atomic bonds of are selected from either single bonds (alkyl) or double bonds (alkenyl). 4. 1- [2- [bis (4-fluorophenyl) methoxy] ethyl] -4- (3-phenylpropyl) piperazine having a chemical formula corresponding to the compound 1 in Table 1 or pharmaceutically acceptable thereof. The composition of claim 1 comprising a salt. 5. The following equation 1: (Wherein each of R ₁ and R ₂ is independently hydrido, halo, cyano, carboxyl, nitro, hydroxyl, alkoxyl, amino, monoalkylamino, dialkylamino, alkylthio, mercapto, haloalkyl, and 1 carbon atoms. To about 20 linear or branched alkyl groups and R ₃ is hydride, halo, cyano,
Carboxyl, nitro, hydroxyl, alkoxyl,
Amino, alkylamino, alkylthio, mercapto,
And an atomic bond from a carbon atom selected from linear or branched alkyl groups having 1 to about 10 carbon atoms and labeled as C ₇ and C ₈ is a single bond (alkyl), double bond (alkenyl) or triple bond. Cocaine addiction in mammals comprising a therapeutically effective amount of a family of compounds represented by a bond (selected from alkynyl) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent. , A pharmaceutical composition for treating and controlling the acute effects of cocaine and the desire for cocaine. 6. wherein R ₁ and R ₂ are each independently selected from hydride, halo, alkyl, haloalkyl, cyano, hydroxyl or alkoxyl, and R ₃ is hydride, halo, alkyl, alkenyl, halo, Atomic bonds from carbon atoms selected from haloalkyl, hydroxyl, alkoxy, nitro, cyano, thio, mercapto, amino, alkylamino and labeled C ₇ and C ₈ are single bonds (alkyl), double bonds (alkenyl). ) Or a triple bond (alkynyl). 7. In the formula, each of R ₁ and R ₂ is independently selected from hydride or halo, R ₃ is selected from hydride or halo, and from the carbon atoms designated C ₇ and C _8. 7. The pharmaceutical composition according to claim 6, wherein the atom bond of is selected from either a single bond (alkyl) or a double bond (alkenyl). 8. 1- [2- [bis (4-fluorophenyl) methoxy] ethyl] -4- (3-phenylpropyl) piperazine having a chemical formula corresponding to compound 1 in Table 1 or its pharmaceutically acceptable The pharmaceutical composition according to claim 5, comprising a salt. 9. The composition according to claim 1, which is administered orally, intravenously, intramuscularly or subcutaneously. 10. The pharmaceutical composition according to claim 5, which is administered orally, intravenously, intramuscularly or subcutaneously.