WO1992019108A1 - Treatment of alcohol withdrawal symptoms - Google Patents

Abstract

This invention is directed to a method for treating alcohol abstinence (withdrawal) syndrome in mammals using compounds of formula (I). The preferred compound is 5-aminocarbonyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine.

Description

TREATMENT OF ALCOHOL WITHDRAWAL SYMPTOMS

FIELD OF THE INVENTION

This invention relates to the field of clinical neurology and psychiatry. It relates specifically to compounds, compositions and methods for the treatment of patients experiencing the alcohol abstinence (withdrawal) syndrome characterized by tremulousness, hallucinations, seizures, confusion, and psychomotor and autonomic hyperactivity occurring after a period of relative or absolute abstinence from alcohol.

BACKGROUND OF THE INVENTION

A wide variety of drugs are effective in controlling alcohol withdrawal symptoms including benzodiazepines, barbiturates, phenothiazines and paraldehyde. However, all of the presently used pharmacotherapies have the disadvantage of causing sedation or impairment of motor performance at clinically effective doses. The present invention overcomes these problems in that it is highly effective in reducing or eliminating the symptoms of alcohol withdrawal, including tremulousness and seizures, but does not produce sedation or an impairment of motor performance at effective doses. In addition, the compounds of the present invention may not be addictive, a common problem with presently available therapies.

SUMMARY OF THE INVENTION

The treatment of the alcohol abstinence (withdrawal) syndrome in accordance with the present invention is conducted with compounds of the general class as shown in Formula I:

These compounds are 5-aminocarbonyl-10,11-dihydro-5H- dibenzo[a,d]cyclohepten-5,10-imines. Modifications of these compounds may be employed which involve changes in the aromatic substituents on either or both aromatic rings and/or changes in the substituents on the aminocarbonyl nitrogen and/or substitutions on the amino nitrogen.

In Formula I, each of R₁ and R₂ is independently selected from hydrido, linear or branched alkyl groups of from one to about twenty carbon atoms, alkenyl groups from two to about twenty carbon atoms, alkynyl groups from two to about twenty carbon atoms, cycloalkyl groups of three to about eight carbon atoms, cycloalkenyl groups from three to about eight carbon atoms, or R₁ and R₂ may be taken together to form an N-containing cyclic structure having two to about eight carbon atoms, any of the said groups being optionally substituted with one or more substituents selected from alkyl, haloalkyl, hydroxyalkyl, alkenyl, oxo, hydroxyl, alkoxy, thio, alkoxyalkyl, amino, halo, cyano or mercapto. R₃ and R₄ are independently selected from hydrido, halo, linear or branched alkyl groups of from one to about ten carbon atoms, alkenyl groups from two to about ten carbon atoms, alkynyl groups from two to about ten carbon atoms, hydroxyl, amino, alkylamino, alkoxy, cyano, nitro, haloalkyl and mercapto, and R₅ is selected from hydrido, linear or branched alkyl groups of from one to about ten carbon atoms, alkenyl groups from two to about ten carbon atoms, alkynyl groups from two to about ten carbon atoms, hydroxyl, phenyl, haloalkyl, aminoalkyl, 1-phenylmethyl, 2-phenylethyl and alkoxy, or R₁and R₅ taken together may form a cyclic structure containing two nitrogen atoms possessing from two to about six carbon atoms. Any of these groups may be optionally substituted by alkyl, oxo, thio, alkoxy, hydroxy, amino, alkylamino. phenyl, haloalkyl and thio. Pharmaceutically acceptable salts of these compounds may be employed.

BRIEF DESCRIPTION OF THE DRAWING

The present invention will become more fully understood from the detailed description herein and the accompanying drawing which is given by way of illustration only, and thus, is not limitative of the present invention, and wherein:

Figure 1 is a graph showing the effects of ADCI (Compound of Formula II) on the severity of ethanol withdrawal seizures.

DETAILED DESCRIPTION OF THE INVENTION

Each of the Compounds herein encompassed by Formula I is useful in the present inventive methods, however, a preferred class of compounds within Formula I are those wherein each of R₁ and R₂ is independently selected from hydrido, alkyl, alkenyl, alkoxy or phenyl; wherein each of R₃ and R₄ is independently selected from hydrido, alkyl, alkenyi, halo, haloalkyl, hydroxy, alkoxy, nitro, cyano, thio, mercapto, amino, or alkylamino, and wherein R₅ is selected from hydrido, alkyl, alkenyl, haloalkyl, hydroxy, alkoxy, phenyl and aminoalkyl.

The term hydrido denotes a single hydrogen atom (H) which may be attached, for example, to a carbon atom or to a nitrogen atom to form a primary or secondary amino group. Where the term "alkyl" is used, either alone or within other terms such as "haloalkyl" or "alkylamino" the term "alkyl" embraces linear or branched radicals having one to about ten carbon atoms. Preferred alkyl radicals are "lower alkyl" radicals having from one to about five carbon atoms. The term "cycloalkyl" embraces radicals having from three to about ten carbon atoms, such as cyclopropyl and cyclobutyl. The term "haloalkyl" embraces radicals wherein one or more of the alkyl carbon atoms is substituted with one or more halogen atoms, preferably selected from fluoro, chloro and bromo.

Specifically embraced by the term "haloalkyl" are monohaloalkyl, dihaloalkyl and polyhaloalkyl groups. Examples of a polyhaloalkyl are trifluoromethyl, 2,2,2-trifluoroethyl and perfluoroethyl. The term "alkenyl" embraces linear or branched radicals having from two to about ten carbon atoms and containing at least one double bond. The term "alkynyl" embraces linear or branched radicals having from two to about ten carbon atoms containing at least one carbon-carbon triple bond. The term "alkoxy" embraces linear or branched oxy-containing radicals having alkyl portions of from one to about ten carbon atoms, such as the methoxy group. The alkoxy radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo to provide haloalkoxy groups. The term "alkylamino" embraces linear or branched nitrogen-containing radicals where the nitrogen atom may be substituted with from one to three alkyl radicals of from one to about ten carbon atoms, such as 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. Typical alkenyl groups may have one unsaturated double bond, such as allyl or may have a plurality of double bonds.

Included within the family of compounds of Formula I are the tautomeric forms of the described compounds, isomeric forms such as diastereomers, and the pharmaceutically acceptable salts thereof. Examples of acids which may be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, sulphuric acid and phosphoric acid and such organic acids as maleic acid, succinic acid and citric acid.

A preferred compound is the following compound of Formula II (shown as compound No. 1 in Table 1):

The prototype compound II is a low affinity antagonist of N-methyl-D-aspartate type excitatory amino acid receptors that possess anticonvulsant activity in a wide variety of animal seizure models (M.A. Rogawski, et al., Epilepsia 31:620, 1990). Compound II has been demonstrated to produce a dose-dependent reduction in the severity of seizures occurring upon ethanol withdrawal in mice that were chronically exposed to ethanol. Full activity was obtained at 3 mg/kg, i.p. Compound II also has been shown to suppress whole body tremors in withdrawing mice. Even at doses that were much higher than those required to suppress or eliminate the withdrawal syndrome (56 mg/kg, i.p.), the drug failed to produce an impairment in motor performance as determined with the rotarod test. No tolerance to the effects of Compound II was apparent even when it was administered repeatedly during the course of the withdrawal period. In similar experiments, the N-methyl-D-aspartate antagonist MK-801 also reduced the severity of ethanol withdrawal seizures, but caused significant motor impairment at effective doses. Other antagonists of the NMDA receptor-channel complex, the benzodiazepine diazepam, and the barbiturate pentobarbital were either ineffective or caused significant motor impairment at effective doses.

Based upon pharmacological test results obtained by the present inventors with this novel prototype Compound II, it appears that the compounds of the present invention possess a much higher therapeutic index than do similar compounds such as MK-801. This broad therapeutic index allows one to administer the compounds described herein to patients in need thereof in doses which can control alcohol abstinence syndrome without producing unwanted toxic effects, such as motor impairment or the like.

Compounds of Formula I may be prepared in accordance with the following general procedures:

With reference to the foregoing scheme, the known and/or readily accessible racemic or optically active C₃-unsubstituted-10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5,10-imines are converted into their N-tertbutylformamidine derivatives. This is conveniently accomplished by reaction with a commercially available reagent, N'-tert-butyl-N,N-dimethylformamidine at elevated temperatures (110ºC.) in the presence of an acid catalyst, generally ammonium sulfate. Secondly, the N-tert-butylformamidine derivatives in an anhydrous ethereal solvent at room temperature or at 5ºC. are treated with sec-butyl lithium followed by ethyl chloroformate. This results in the formation of the C₅-substituted ethyl ester. The next step in the chemical sequence is the removal of the tert-butylformamidine moiety from the nitrogen atom of the parent ring system. This is achieved by heating in ethanolic sulfuric acid, and gives rise to 5-ethoxycarbonyl-10,11-dihydro-5H-dibenzo(a,d]cyclohepten-5,10-imines. The final step in the chemical synthesis is the replacement of ester functionality with an amide group. This is accomplished by warming the ester in methanol with the appropriate amine derivative. The presence of a catalytic amount of sodium cyanide facilitates this reaction. If N-substitution is desired, the secondary amine is allowed to react with the appropriate alkyl halide in the presence of a suitable base (e.g. triethylamine).

Example: Preparation of 5-Aminocarbonyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine.

A mixture of 10,11-dihydro-5H-dibenzo(a,d]cyclohepten-5,10-imine (5.18 g, 25.0 mmol), N'-tert-butyl-N,-N-dimethyl-formamidine (12.84 g, 100.0 mmol) and a few crystals of ammonium sulfate in anhydrous toluene was warmed under reflux for 6 days. Evaporation of the solvent and purification of the crude product by column chromatography employing 7% triethylamine in hexane as the eluent afforded the N-tert-butyl-formamidinyl-10,11- dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (6.98 g, 24.1 mmol, 96%): mp 63-64º.

A solution of this material (5.80 g, 20.0 mmol) in anhydrous ethyl ether (150 ml) under an atmosphere of nitrogen was treated at 5ºC. with a 1.25 M solution of sec-butyllithium in cylohexane (20.0 ml, 25 mmol). The deep red colored solution of the anion was allowed to stir at this temperature for 40 minutes, then was treated with ethyl chloroformate (2.40 ml, 25.0 mmol). The solution color immediately changed to pale yellow, and gas chromatographic analysis of the reaction mixture demonstrated the complete consumption of the starting material. The reaction mixture was treated with ethanol (100 ml) and H₂SO₄ (0.56 ml, 10.0 mmol), and the ether was evaporated under reduced pressure. The ethanolic solution was warmed under reflux for 4 h, then was diluted with 0.5 N HCl (100 ml) and extracted with Et₂O (3 × 100). The aqueous part was made alkaline by the addition of 1 N NaOH, and extracted with Et₂O (3 × 100). The combined organic part was washed once with H₂O (100 ml), then dried over K₂CO₃ and concentrated to dryness affording

5-ethoxycarbonyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten5,10-imine (3.37g, 12.1 mmol, 60%). The hydrogen chloride salt was formed by passing a stream of anhydrous HCl gas through an ethereal solution of the secondary amine:

mp 229 - 230ºC.

A solution of the preceding amino ester (0.53 g, 1.90 mmol) and sodium cyanide (10 mg) in anhydrous methanol (40 ml) which had been previously saturated at 5ºC. with ammonia gas was warmed to 60ºC in a sealed tube for 40 h. After cooling to 5ºC, the solid which had formed was filtered, washed with H₂0, and air-dried affording 5-aminocarbonyl-10,11-dihydro-5H-dibenzo[a,dlcyclohepten-5,10-imine (0.25 g, 1.0 mmol). The filtrate was extracted with CH₂Cl₂ (3 × 50), the organic pool was dried (K₂CO₃) and evaporated under reduced pressure, affording an additional quantity of the title compound (0.19 g, 0.76 mmol). Recrystallization of the combined samples from ethanol then gave the analytically pure material (0.37 g, 1.5 mmol, 78%). mp 235 - 236ºC.

Table I sets forth a list of 20 specific compounds of most interest within Formula I. The preparation of compound 1 in Table I is described in detail in the previous example. Compounds 2 through 20 may likewise be prepared in accordance with the above-described general synthesis procedures.

BIOLOGICAL EVALUATION

Subjects Male C57BL mice (20-24 g) were obtained from the National Cancer Institute (Frederick, MD). The mice were housed individually in cages (29×18×13 cm) with wood bedding. Lighting was on a 12 h light cycle (on at 7:00 am), and temperature and humidity of the room housing the mice were maintained within NIH guidelines (HHS, 1985).

Ethanol Administration Animals were given a measured amount of liquid diet containing 7% (v/v) ethanol and vitamin supplement as their sole nutrient source (Ritzmann and Tabakoff, 1976). Every 24 h, the amount of diet consumed was measured and replaced with fresh ethanol- containing diet. Every 12 h the drinking tubes were checked for easy passage of the liquid diet. The mice were rated for signs of gross behavioral intoxication each morning. An intoxication rating of 0 indicated normal behavior. A rating of 1 corresponded to abnormal gait and decreased activity. A rating of 2 corresponded to a pronounced decrease in activity and staggering when prodded. Finally, a rating of 3 indicated a loss of righting reflex. The same investigator rated all mice without knowledge of how much diet the animals had consumed. The mice were exposed to ethanol in this manner for a total of 7 days.

Pair-fed control mice were given the same volume of liquid diet (with sucrose substituted in isocaloric quantities for ethanol) as the ethanol mice had consumed the previous day.

Seizure Severity All ethanol exposed mice were counterbalanced into the various treatment groups on the basis of the intoxication ratings gathered over the course of the chronic ethanol treatment. Handling-induced withdrawal seizures were rated on a scale of 0 to 4 modified from a scale described previously (Ritzmann and Tabakoff, 1976). Briefly, the mice were picked up by the tail and rated as follows: 0 corresponded to little or no reaction; 1 corresponded to a mild reaction, usually limited to a slight jerkiness upon handling; 2 corresponded to an initial jerkiness escalating into a clonic-tonic seizure; 3 corresponded to either a spontaneous seizure, or an instantaneous clonic-tonic seizure upon being handled; 4 corresponded to death as the result of a seizure.

Two investigators, blind to the drug conditions, rated the mice for seizure severity at 2 h intervals for the first 6 h of withdrawal (2, 4, and 6 h into withdrawal), then every hour until 11 h of withdrawal had passed (7th, 8th, 9th, 10th, and 11th h of withdrawal) and a final observation was made at 24 h.

For the administration of ADCI, MK-801 (Research Biochemicals Inc.) and carbamazepine (Sigma Chemical Co.) the mice were given an intraperitoneal (ip) injection of each unit dose ( 1 ml/100 g body weight) 3 times during the course of withdrawal: at 0, 3 and 7 h into withdrawal.

Table 2 shows the effect of ADCI, MK-801 or carbamazepine on the severity of ethanol withdrawal seizures. The results are reported as the median seizure severity for each group at various times over the course of withdrawal, with the interquartile ranges indicated in parentheses. The unit doses shown in the table were given 3 times during withdrawal (i.e., following the ratings at 0, 4, and 7 hours).

An asterisk in Table 2 indicates a group seizure score that was significantly lower than the saline treated group (Wilcoxen rank t-test, p<0.05).

A pound mark indicates a group score that was significantly greater than the saline treated group (Wilcoxen rank t-test, p<0.05). A graphic representation of the data on the mean seizure severity scores for the saline and ADCI treated groups in Table 2 is presented in Figure 1.

Table 3 shows a comparison of the therapeutic index between ADCI and other drugs commonly used for treatment of alcohol withdrawal and further demonstrates the benefits of ADCI over the other compounds tested. The higher the therapeutic index, the more likely to produce a therapeutic effect without causing unacceptable side affects such as motor impairment. In Table 3 the therapeutic index for each test compound was derived by dividing the dose of the test compound producing significant impairment of motor function by the dose which produces approximately 90% decrease in seizure scores over the initial 24 hour period after ethanol withdrawal. The motor impairment was measured as described by Grant, et al. Eur. J. Pharmacol, Vol. 176, pp.289-296 (1990).

*Doses of carbamazepine up to 150 mg/kg and of pentobarbital up to 56 mg/kg in 8 hours were used. PHARMACEUTICAL FORMULATIONS

The administration of compounds within the scope of

Formula I to humans can be by any technique capable of introducing the compounds into the bloodstream of a human patient, including oral administration, and by intravenous, intramuscular and subcutaneous injections.

Compounds indicated by prophylactic therapy will preferably be administered in a daily dose generally in the range of 0.5 mg to 100 mg per kilogram of body weight per day. A more preferred dosage will be in the range of 1.0 to 50 mg per kilogram of body weight for a mammal including a human. A suitable dose can be administered in suitable subdoses per day.

The active compound is usually administered in a pharmaceutically acceptable formulation, although in some acute-care situations a compound of Formula I may be administered alone. Such formulations may comprise the active compound with one or more pharmaceutically acceptable carriers or diluents. Other therapeutic agents may also be present in the formulation. A pharmaceutically acceptable carrier or diluent provides an appropriate vehicle for delivery of the active compound without undesirable side effects. Delivery of the active compound 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 also be through the use of controlled release formulations in subcutaneous implants.

Formulations for oral administration may be in the form of capsules containing the active compound dispersed in a binder such as gelatin or hydroxypropylmethyl cellulose, together with one or more of a lubricant, preservative, surface active or dispersing agent. Such capsules or tablets may contain controlled release formulations as may be provided in a disposition of active compound in hydroxypropylmethyl cellulose.

Formulations for parental 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 formulations for oral administration.

Although this invention has been described with respect to specific embodiments, the details of these embodiments are not to be construed as limitations. Various equivalents, changes and modifications may be made without departing from the spirit or scope of this invention, and it is understood that such equivalent embodiments are part of this invention.

Claims

CLAIMS :

1. A method for treating alcohol withdrawal symptoms in mammals which comprises administering to a mammal in need of such treatment an effective amount of a compound of the formula:

wherein each of R₁ and R₂ is independently selected from hydrido, linear or branched alkyl groups of from 1 to about 20 carbon atoms, alkenyl groups of from 2 to about 20 carbon atoms, alkynyl groups of from 2 to about 20 carbon atoms, cycloalkyl groups of from 3 to about 8 carbon atoms, or cycloalkenyl groups of from 3 to about 8 carbon atoms, and wherein R₁ and R₂ may be taken together to form an N-containing cyclic structure having 2 to about 8 carbon atoms, any of the said groups being optionally substituted with one or more substituents selected from alkyl, haloalkyl, hydroxyalkyl, alkenyl, oxo, hydroxyl, alkoxy, thio, alkoxyalkyl, amino, halo, cyano or mercapto, and wherein R₃ and R₄ is independently selected from hydrido, halo, linear or branched alkyl groups of from 1 to about 10 carbon atoms, alkenyl groups of from 2 to about 10 carbon atoms, or alkynyl groups of from 2 to about 10 carbon atoms, hydroxyl, amino, alkylamino, alkoxy, cyano, nitro, haloalkyl and mercapto, and wherein R₅ is selected from hydrido, linear or branched alkyl groups of from 1 to about 10 carbon atoms, alkenyl groups of from 2 to about 10 carbon atoms, or alkynyl groups of from 2 to about 10 carbon atoms, hydroxyl, phenyl, haloalkyl, aminoalkyl, 1-phenylmethyl, 2-phenylethyl and alkoxy, and wherein R₁ and R₅ taken together form a cyclic structure containing two nitrogen atoms having from 2 to about 6 carbon atoms, any of the said groups being optionally substituted by alkyl, oxo, thio, alkoxy, hydroxy, amino, alkylamino, phenyl, haloalkyl and thio; or a pharmaceutically acceptable salt thereof.

2. The method of claim 1, wherein each of R₁ and R₂ is independently selected from hydrido, alkyl, alkenyl, alkoxy and phenyl; wherein each of R₃ and R₄ is independently selected from hydrido, alkyl, alkenyl, halo, haloalkyl, hydroxy, alkoxy, nitro, cyano, thio, mercapto, amino and alkylamino, and wherein R₅ is selected from hydrido, alkyl, alkenyl, haloalkyl, hydroxy, alkoxy, phenyl and aminoalkyl.

3. The method of claim 1, wherein each of R₁ and R₂ is independently selected from hydrido, alkyl, alkenyl and phenyl; wherein each of R₃ and R₄ is independently selected from hydrido, alkyl, halo, haloalkyl, hydroxy, alkoxy, nitro, amino and alkylamino, and wherein R₅ is selected from hydrido, alkyl, alkenyl, haloalkyl, hydroxy, alkoxy, phenyl and aminoalkyl.

4. The method of claim 1, wherein said compound is 5-aminocarbonyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine.

5. The method of claim 1, wherein said compound is administered in an amount of about 0.5 mg/kg to 100 mg/kg of body weight per day.

6. The method of claim 1, wherein said compound is administered in an amount of about 1 mg/kg to 50 mg/kg of body weight per day.

7. The method of claim 1, wherein said mammal is a human and said compound is administered in an amount of about 1 mg/kg to 50 mg/kg of body weight per day.

8. The method of claim 7, wherein said compound is

5-aminocarbonyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine.