United States Patent (19) 11 4,138,484 Fuxe 45 Feb. 6, 1979

(54) METHOD FOR TREATING (56) References Cited SCHIZOPHRENIA AND METHOD AND COMPOSITION FOR POTENTIATING PUBLICATIONS NEUROLEPTIC DRUGS Gordon, Medicinal Chemistry, Psychopharmacological Chemistry 11, (1967), p. 271. 75 Inventor: Kjell Fuxe, Sollentuna, Sweden Benson & Shiele-Tranquilizing & 73) Assignee: Nelson Research & Development Drugs (1962), pp. 82, 83, 23 & 24. Company, Irvine, Calif. Chem. Abstr., vol. 72 (1970), p. 119, 694f. (21) Appl. No.: 818,534 Primary Examiner-Stanley J. Friedman 22 Filed: Jul. 25, 1977 Attorney, Agent, or Firm-Martin A. Voet 57 ABSTRACT Related U.S. Application Data A method for treating schizophrenia and a method and 60 Continuation of Ser. No. 714,707, Aug. 16, 1976, composition for potentiating the beneficial effects and abandoned, which is a division of Ser. No. 596,571, Jul. reducing the side effects of neuroleptic drugs. Schizo 16, 1975, Pat. No. 3,978,216, which is a phrenia is treated with a GABA-like compound such as continuation-in-part of Ser. No. 475,856, Jun. 3, 1974, Lioresal. Neuroleptic drugs are potentiated by coad Pat. No. 3,947,579. ministering to a schizophrenic a neuroleptic drug and a 51) Int. C.2 ...... A61K 3.1/54; A61K 31/335 GABA-like drug such as Lioresal. 52 U.S. C...... 424/247; 424/279 58 Field of Search ...... 424/262, 279, 247 1 Claim, No Drawings 4,138,484 1. 2 METHOED FOR TREATING SCHIZOPHERENA DETALED DESCRIPTION OF THE AND METHOD AND COMPOSITION FOR INVENTION POTENTIATING NEUROLEPTC DRUGS Compounds having the foregoing structural formula 5 such as, for example, 3-(4-chlorophenyl)-y- RELATIONSHIP TO PRIORAPPLICATION aminobutyric acid and pharmaceutically acceptable This is a Continuation of application Ser, No. salts thereof and pharmaceutical compositions thereof 714,707, filed Aug. 16, 1976, now abandoned, which in and their manner of making is described in U.S. Pat. No. turn was a division of application Ser. No. 596,571, filed 3,471,548 and relevant portions thereof are hereby in 10 corporated by this reference, y-hydroxybutyrolactone, July 16, 1975, now U.S. Pat. No. 3,978,216 which in y-hydroxybutyrate and aminooxyacetic acid, 5-ethyl-5- turn was a Continuation-in-Part of application Ser. No. phenyl-2-pyrrolidone, 1-hydroxy-3-amino-2-pyrroli 475,856, filed June 3, 1974, now U.S. Pat. No. 3,947,579. done are also known to those of skill in the art. BACKGROUND OF THE INVENTION The amount of GABA-like or gabergic compound 15 which may be used in the present invention ranges from Background of the Prior Art about 0.1 to about 100 mg/kg and preferably from about U.S. Pat. No. 3,471,548 describes compounds having 0.1 to about 10 mg/kg and preferably about 0.1 to 1.5 the structural formula mg/kg per day. The term "gabergic' compound herein refers to com 20 pounds which are related pharmacologically to y gh- NH2 aminobutyric acid, known as GABA. Typical examples CH-CH-COOH of GABA-like or gabergic compound include y hydroxybutyrolactone, y-hydroxybutyrate, aminooxya cetic acid, 5-ethyl-5-phenyl-2-pyrrolidone, 1-hydroxy wherein R is chloro, bromo, fluoro or fluoromethyl. 25 3-amino-2-pyrrolidone, and 6-(4-chlorophenyl) -y- The compounds are known to cross the blood brain aminobutyric acid. When used herein, the term "gaber barrier and are known to have proper gic compound” refers to any gabergic compound, such ties and to be useful in the treatment in man of spasticity as, but not limited to, the foregoing gabergic com of spinal origin. pounds. Neuroleptic drugs are used to treat schizophrenia. 30 Neuroleptic drugs which may be used in the present invention include derivatives such as Examples of common neuroleptic drugs include pheno , promozine, trifiupromozine, aceto thiazines such as chloropromazine; butyrophenones phenazine, butaperozine, corphenazine, , such as and others such as pimocide and periphenazine, prochlorperozine, , trifluo . Side effects of neuroleptic drugs include 35 , mepazine, , piperacetozine, sedation and tardive dyskinesias. The latter side effect is theoridazine, chlorprothizine, thiothixine, benzocta particularly important because it results in involuntary mine, cidorepin, clomacran, , clothiapine, muscle movements especially of the face and mouth clothixamide, clozapine, dimeprozan, , lova which become irreversible. The onset of this side effect pine, perlapine and pinovepin; rauwolfia derivatives is directly related to the amounts of and length of time including deserpidine, metaserpate, rescinnamine, reser which a neuroleptic drug is used in treatment. pine, bezquinamide, oxypertine, tetrabenazine, indo pine, indriline, methopholine, millipertine, , SUMMARY OF THE INVENTION solypertine, and solertine; There has now been discovered a method for treating derivatives including , piperilate, azacy schizophrenia and a method and composition for poten clonal, captodiamine, , cyprolidol, hexan tiating the beneficial effects and for reducing the side drol and pimizide; and butyrophenone derivatives in effects of neuroleptic drugs. cluding haloanisone, haloperidol, ozaperone, benpe The foregoing results are obtained by administering ridal, carperone, droperidal, , meperone, to a schizophrenic an effective amount of a gabergic , , seperidol, and tri compound or by coadministering to a schizophrenic a 50 fluperidol. When used herein, the term "neuroleptic neuroleptic drug and a potentiating amount of a gaber drugs' refers to any neuroleptic drug such as, but not gic compound such as y-hydroxybutyrolactone, y limited to, the foregoing neuroleptic drugs. hydroxybutyrate, aminooxyacetic acid, 5-ethyl-5-phe While Applicant does not necessarily rely on the nyl-2-pyrrolidone, 1-hydroxy-3-amino-2-pyrrolidone, following theory of action as to why the gabergic com 55 pounds are useful in the treatment of schizophrenia and or a compound having the structural formula to potentiate the effects of neuroleptic drugs, Applicant believes that known neuroleptic drugs act by blocking (H-NH, receptor activity in the brain. However, CH-CH-COOH whenever the activity is blocked, compensatory mechanisms are initiated by the central nervous systems to restore normal dopamine receptor activity. The compensatory mechanisms act by block wherein R is halogen or trifluoromethyl and salts ing the normal inhibitory y-aminobutyric acid (GABA) thereof. activity of dopamine cell bodies, thus tending to in The present invention further relates to a composi 65 crease dopamine neuron activity. Applicant believes the tion comprising a neuroleptic drug and a potentiating gabergic compounds selectively interfere with the com amount of a gabergic compound together with a suit pensatory mechanisms controlling activity in the meso able pharmaceutical carrier. limbic dopamine neurons by increasing GABA receptor 4,138,484 3 4. activity in the medial dopamine cell bodies of the mid agents, for example, sodium carboxymethyl cellulose, brain, which innervate the limbic forebrain and thereby methylcellulose, hydroxypropylmethylcellulose, so potentiate the effect of neuroleptic drugs by blocking dium alginate, polyvinylpyrrolidone, gum tragacanth the the increase of limbic dopamine turnover otherwise and gum acacia; dispersing or wetting agents may be a caused by the neuroleptic drug. In this manner, the naturally-occurring phosphatide, for example , gabergic compound can be used to potentiate the bene or condensation products of an alkylene oxide with ficial effects of neuroleptic drugs, since their antipsy fatty acids, for example, polyoxyethylene stearate, or chotic effect is believed to be due to blockade of limbic condensation products of ethylene oxide with long dopamine receptors and themselves have therapeutic chain aliphatic , for example, heptadecae benefit in the treatment of schizophrenia. Applicant O thyleneoxycetanol, or condensation products of ethyl further believes that extrapyramidal side effects, e.g., ene oxide with partial esters derived from fatty acids tardive dyskinesia and parkinsonianlike side effects, are and a hexitol, for example polyoxyethylene sorbitol mediated through the blockade of neostriatal dopamine monooleate, or condensation product of ethylene oxide receptors. Thus, when coadministered with the forego with partial esters derived from fatty acids and hexitol ing neuroleptic drugs, the gabergic compounds de 15 anhydrides, for example polyoxyethylene sorbitan scribed herein allow the use of lower doses of neurolep monoleate. The said aqueous suspensions may also con tic drugs to obtain the same effect as ob tain one or more preservatives, for example, ethyl, or tained with higher doses of neuroleptic drug without n-propyl, p-hydroxy benzoate, one or more coloring the gabergic compounds. At the same time, neostriatal agents, one or more flavoring agents and one of more dopamine receptor blockade is reduced and thus extra 20 pyramidal side effects are likewise reduced or elimi sweetening agents, such as sucrose, saccharin, or so nated. As a result of the foregoing, the dose of neurolep dium or calcium cyclamate. tics now given may be decreased by a factor of 2-20 Dispersible powders and granules suitable for prepa times (about 5-50% of usual dose) when co-adminis ration of an aqueous suspension by the addition of water tered with an effective amount of one of the gabergic 25 provide the active ingredient in admixture with a dis compounds of the present invention. persing or wetting agent, suspending agent and one or For purposes of this invention, the term "co-adminis more preservatives. Suitable dispersing or wetting tered' means the administration of a neuroleptic drug agents and suspending agents are exemplified by those and a gabergic compound as described herein to a pa already mentioned above. Additional excipients, for tient during a course of treatment. example, sweetening, flavoring and coloring agents, For purposes of this disclosure, the phrase "treatment may also be present. of schizophrenia” means the temporary alleviation of at Syrups and elixirs may be formulated with sweeten least some of the signs or symptoms of schizophrenia. ing agents, for example, glycerol, sorbitol or sucrose. The pharmaceutical compositions may be in a form Such formulations may also contain a demulcent, a suitable for oral use, for example, as tablets, aqueous or 35 preservative and flavoring and coloring agents. The oily suspensions, dispersible powders or granules, emul pharmaceutical compositions may be in the form of a sions, hard or soft capsules, or syrups or elixirs. Compo sterile, injectable preparation, for example as a sterile, sitions intended for oral use may be prepared according injectable aqueous suspension. This suspension may be to any method known to the art for the manufacture of formulated according to the known art using those pharmaceutical compositions and such compositions 40 suitable dispersing or wetting agents and suspending may contain one or more agents selected from the agents which have been mentioned above. The sterile group consisting of sweetening agents, flavoring agents, injectable preparation may also be a sterile injectable coloring agents and preserving agents in order to pro solution or suspension in a non-toxic parenterally vide a pharmaceutically elegant and palatable prepara acceptable diluent or solvent, for example, as a solution tion. Tablets contain the active ingredient in admixture 45 in 1,3-butane diol. with non-toxic pharmaceutically acceptable excipients The pharmaceutical compositions may be tableted or which are suitable for manufacture of tablets. These otherwise formulated so that for every 100 parts by excipients may be, for example, inert diluents, for exam weight of the composition there are present between 5 ple calcium carbonate, sodium carbonate, lactose, cal and 95 parts by weight of the active ingredients and cium phosphate or sodium phosphate; granulating and 50 preferably between 25 and 85 parts by weight of the disintegrating agents, for example, maize starch, or active ingredients. The dosage unit form will generally alginic acid; binding agents, for example starch, gelatine contain between about 10 mg and about 500 mg of the or acacia, and lubricating agents, for example magne active ingredients. A preferred dosage rate for oral sium stearate or stearic acid. The tablets may be un administration is of the order of 1-1000 mg daily, op coated or they may be coated by known techniques to 55 tionally in divided doses. delay disintegration and absorption in the gastrointesti From this foregoing formulation discussion, it is ap nal tract and thereby provide a sustained action over a parent that the compositions of this invention can be longer period. administered orally or parenterally. The term "paren Formulations for oral use may also be presented as teral” as used herein includes subcutaneous injection, hard gelatine capsules wherein the active ingredient is intravenous, intramuscular, or intrasternal injection or mixed with an inert solid diluent, for example, calcium infusion techniques. carbonate, calcium phosphate or kaolin, or as soft gela This invention is further demonstrated by the follow tine capsules wherein the active ingredient is mixed ing examples in which all parts are by weight. with an oil medium, for example, arachis oil, liquid EXAMPLE paraffin or olive oil. 65 Aqueous suspensions contain the active ingredients in The effect of 3-(4-chlorophenyl)-y-aminobutyric admixture with excipients suitable for the manufacture acid Lioresal) on the -induced increase in do of aqueous suspensions. Such excipients are suspending pamine fluorescence disappearance from the neostria 4,138,484 5 6 tum and subcortical limbic areas of rats after treatment peridol is significantly counteracted by pre-treatment with a-methyltyrosine methyl ester. with 3-(4-chlorophenyl)-y-aminobutyric acid. Dopamine neuron nerve endings can be made to It can thus also be stated that Lioresal can counteract fluoresce strongly as a result of the presence of stored the pimozide increase in dopamine turnover also in the dopamine. These stores of dopamine are not static; there limbic cortex. This is important, since thought processes is a continual release, reuptake, degradation and de are usually linked to cortical regions and therefore these novo synthesis at the nerve ending. limbic dopamine receptors may be particularly in a-methyltyrosine methyl ester is an inhibitor of dopa volved in the control of the abnormal thought processes mine synthesis. Fluorescence microscopy shows that found in schizophrenia. a-methyltyrosine methyl ester depletes dopamine O stores. Therefore, a-methyltyrosine methyl ester may EXAMPLE I be used to determine dopamine turnover in the nerve Effect of y-OH-butyrolactone on the pimozide endings since turnover is directly proportional to the induced increase in DA fluorescence disappearance rate of dopamine depletion. found after treatment with a-methyl methyl When dopamine receptors are blocked by drugs such 15 ester in rats (6-9). as pimozide and haloperidol, the dynamic state of dopa The method in Example I was followed. Pimozide mine at and in the nerve endings increase. This appears was given i.p. in a dose of 1 mg/kg 2 hrs before a as an increased disappearance of fluorescence after ad methyltyrosine methyl ester (H44/68) (250 mg/kg, i.p., ministration of a-methyltyrosine methyl ester. This 2hr). y-OH-Butyrolactone was given i.p. 15 min. before increase results from a compensatory response to the 20 H44/68 in a dose of 300 mg/kg. The results of the study decreased stimulation of the nerve cells normally re showed that y-hydroxybutyrolactone selectively coun ceiving the dopamine stimulation. teracted the pimozide-induced increases in dopamine a-methyltyrosine methyl ester (H44/68), an inhibitor turnover in the limbic system. of dopamine synthesis, was given to male Sprague Thus, the foregoing Example II shows that y-hydrox Dawley rats i.p. in a dose of 250 mg/kg 4 hrs before 25 ybutyrolactone also potentiates the antipsychotic action killing. 3-(4-chlorophenyl)-y-aminobutyric acid (Li of neuroleptic drugs and at the same time reduces ex oresal) was given i.p. in a dose of 10, 20 or 25 mg/kg 15 trapyramidal-like side effects of neuroleptic drugs by minutes before H 44/68. Pimozide was given i.p. in a enabling a lowering of the dosage of the neuroleptic dose of 1 mg/kg 2 hours before H44/68, and haloperi given. The study also showed that y-hydroxybutyrolac dol in a dose of 5 mg/kg 1 hour before H 44/68. The 30 tone would also be useful alone in the treatment of dopamine levels were determined by measuring histo schizophrenia. chemical fluorescence. The fluorescence intensity re flects the amount of dopamine present. The fluores EXAMPLE III cence intensity was semi-quantitatively estimated on Effect of Lioresal and aminooxyacetic acid (AOAA) coded slides. 3 = strong;2 = moderate; 1 = weak; = 35 on the pimozide-induced increase in dopamine fluores very weak. Number of animals is shown within paren cence disappearance found after treatment with 3 thesis. Table 1 below tabulates the data obtained. methyl tyrosine methyl ester in rats (9-10). The method of Example I was followed, pimozide (1 Table 1 mg/kg i.p. was given 2 hrs before a-methyl tyrosine Fluorescence intensity 40 methyl ester (250 mg/kg, i.p. 2 hr before filling). Li Treatment Neostriatum Limbic forebrain oresal (5 mg/kg, i.p.) was given 15 min. before a-methyl No drug treatment 3 (4) 3 (4) H44/68 0.5(1) 1(2) 1.5(2) 0.5(2) 1(2) 5(1) tyrosine methyl ester, as was aminooxyacetic acid (25 Pimozide -- H44/68 O(7) 05(1) O(7) 05(5) mg/kg, i.p.). Pimozide -- Lioresal 1.5(2) 2(2) 1.5(4) 20 (20) + H44/68 The results of the study showed that aminooxyacetic 0(2) 0.5(4) 45 acid selectively counteracted the pimozide-induced Pimozide -- Lioresal 1 (2) 1.5(3) 1(1) 1.5(6) 204) increase in dopamine turnover in the limbic system (10) + H44/68 0(3) 0.5(3) . (nuc. accumbens, tuberculum olfactorium). Haloperidol + H44/68 0.5(1) 1(6) 93(2) S. Thus, the foregoing Example III also shows that Haloperidol + Lioresal 1(4) 1.5(2) 2(1) 206) 2.5(2) (10) + H44/68 aminooxyacetic acid potentiates the antipsychotic ac Lioresal (25) + H44/68 1(1) 1.5(3) 1(1) 1.5(1) 202) 50 tion of neuroleptic drugs and at the same time lowers Lioresal (10) -- H44/68 1.5(2) 2(1) i.5(1) 201) 2.5(1) extrapyramidal side effects by enabling a lowering of the dosage of the neuroleptic given. The study also Statistical significance according to Tukey's Quick test: shows that aminooxyacetic acid would also be useful alone in the treatment of schizophrenia. 55 EXAMPLE IV d-e: p < 0.001 g-h:h; p < 0.001 Effect of 5-ethyl-5-phenyl-pyrrolidone (EEP) on the dif: p < 0.001 a-methyl tyrosine methyl ester induced dopamine fluo rescence disappearance in the nuc, caudatus, nuc. ac The foregoing Example I shows that the dopamine cumbens and tuberculum olfactorium of rats. turnover at the nerve endings is increased by pimozide The method of Example I was followed. EPP was and haloperidol. This increase is antagonized by S-(4- given i.p. in a dose of 50 mg/kg 15 min. before a-methyl chlorophenyl)-y-aminobutyric acid in the limbic for tyrosine methyl ester (H44/68) (250 mg/kg, i.p. 2 hr brain (nuc. accumbens, tuberculum olfactorium). Thus, before killing). The specific DA flourescense is given in as seen from the foregoing table, the increased disap 65 arbitrary fluorescence units. A Leitz microspectrofluo pearance (i.e. decrease in amount) of dopamine fluores rometer was used. The number of animals used is shown cence from the limbic forebrain but not from the neo within parenthesis. The data is reported as a mean striatum seen after introduction of pimozide and halo s.e.m. in Table 2 below. 4,138,484 7 8 Table 2 Dopamine fluorescence Tuberculum C. C. Treatment olfactorium % accumbens % caudatus %

No drug treatment 30.9(3) - 1.8 100 $25.93) 100 2551.33 100 H44/68 18.1 : 5 58 29.84 57 3.70.8 54 (5) (5) (5) EPP (50) + 28.7 - 1.6 93 37.1.2 71 1441.3 57 H44/68 (4) (5) (5)

-continued Mg. Stearic acid 6 EXAMPLE V 15 ChlorpromazineE. W :50 The effect of Lioresal, aminooxyacetic acid (AOAA) and 5-ethyl-5-phenyl-2-pyrrolidone (EPP) on the pimo Preparation of the tablets - The active ingredients zide induced increase of dopamine turnover in the dopa are homogeneously mixed with lactose and wheat mine terminal island of the entorhinal cortex. 20 starch and pressed through a 0.5 mm mesh sieve. Gela The method used in Example I was followed. Li tine is dissolved in 10 times its own weight of water; the oresal (10 mg/kg, i.p.), EPP (200 mg/kg, i.p.) and powder mixture is evenly moistened with this solution AOAA (25 mg/kg, i.p.) were administered 15 min. and and kneaded until a plastic mass has formed which is 2 hr. (AOAA) before the a-methyl tyrosine methyl then pressed through a 3 mm mesh sieve, dried at 45 C. ester (H44/68) injection (250 mg/kg, i.p. 1 hr before 25 and then sifted through a 1.5 mm mesh sieve. Arrow killing). Pimozide (1 mg/kg) was given i.p. 2 hrs before root, stearic acid, and talcum are finely sifted and the H44/68 injection. worked into the resulting mixture, and the paste is then The results of this study indicated that both EPP and made up in the usual manner into tablets of 9 mm diame AOAA, like Lioresal, counteracted the pimozide ter and 250 mg weight. induced increase in dopamine turnover in the entorhinal 30 cortex. These results indicated that AOAA and EPP EXAMPLE VII can selectively counteract the pimozide-induced in Example VI is repeated, except a number of tablet crease in dopamine turnover in the limbic system in formulations were prepared using one of the following cluding the important limbic cortical region. compounds in the place of 3-(4-chlorophenyl)-y- Thus, the foregoing study shows that gabergic drugs 35 aminobutyric acid: y-hydroxybutyrolactone, y-hydrox of the EPP type also can potentiate the antipsychotic ybutyrate, aminooxyacetic acid, 5-ethyl-5-phenyl-2- action of neuroleptic drugs, and also be active as such in pyrrollidone and 1-hydroxy-3-amino-2-pyrrollidone; and schizophrenia. At the same time, extrapyramidal side one of the following neuroleptic compounds in the effects of neuroleptic drugs are reduced by gabergic place of chlorpromazine: fluphenazine, clozapine, resp drugs since they enable a lowering of dosage of the erpine and haloperidol. neuroleptic drug given. What is claimed is: EXAMPLE VI 1. A method for potentiating the neuroleptic activity of a phenothiazine derivative having neuroleptic activ Tablets, each containing 60mg of the active combina ity comprising administering to a schizophrenic about tion can be prepared, for example, from the following 45 10 to about 50 percent of a conventional dosage amount ingredients: of a phenothiazine derivative selected from the group consisting of chlorpromazine and thoridazine and an Mg. amount equal to about 0.1 to about 50 mg/kg of a gaber gic compound selected from the group consisting of g-(4-chlorophenyl)-y-aminobutyric acid 40 50 Lactose 95 y-hydroxybutyrolactone, and a pharmaceutically ac Wheat starch 54 Gelatine 6 ceptable salt thereof. Arrowroot 24 sk

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