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Home , Benzylmorphine, Clonitazene, Dimepheptanol, Furethidine, Morpheridine, Nicocodeine

United States Patent (19) (11) 4,126,684 w Robson et al. 45 Nov. 21,9 1978

(54) 4-AMINO-3-p-HALOPHENYLBUTYRIC . (56) References Cited ACDS AND THER DERVATIVES USED IN THE CONTROL OF NARCOTCABUSE U.S. PATENT DOCUMENTS 3,47,548 - 10/1969. Kererle et al...... 424/319 (75) Inventors: Ronald D. Robson, Mendham; 3,773,955 1 1/ 1973 Pachter et al...... 424/10 E. Selens. North Brunswick, OTHER PUBLICATIONS Oth ONJ. Cutting et al, Br. J. Pharmac, (1975), 54, 171-179. 73) Assignee: Ciba-Geigy Corporation, Ardsley, Eye Ek Reference, (PDR), 25th Ed., (1971), pp. 1449-143U. . . ' N.Y. Physicians Desk Reference, (PDR), 26th Ed., (1972), (Isordil with Phenobarbital), pp. 758-759. 21 Appl. No.: 748,591 Brodie-New Zealand Medical Journal, 22, 157, Aug. (22) Filed: Dec. 8, 1976 27, 1975. Primary Examiner-Leonard Schenkman Related U.S. Application Data Attorney, p Agent,p or Firm-Theodoreirm O. Groeger 63 Continuation-in-part of Ser. No. 656,996, Feb. 11, 1976, 57 ABSTRACT abandoned. 4-Amino-3-p-halophenylbutyric acids, acyl derivatives, esters and/or salts thereof reduce liability, 51) Int. Cl...... A61K 31/55; A61K 31/195 particularly that of , or the withdrawal symp 52 U.S. C...... 424/254; 424/260; toms observed after interruption of prolonged use of 424/263; 424/266; 424/267; 424/309; 424/319; addicting agents, especially of narcotics. 424/330 58) Field of Search ...... 424/260, 309, 319, 254 7 Claims, No Drawings 4,126,684 1 2 tracts, powdered , granulated opium, raw opium, 4-AMINO-3-p-HALOPHENYLBUTYRIC ACIDS tincture of opium, , , , AND THER DERVATIVES USED IN THE , , racemethorphan, racemor CONTROL OF NARCOTICABUSE phan or , or their salts. Also for those narcotics, often illegally abused, a CROSS-REFERENCE TO RELATED withdrawal-cure may be beneficial in conjunction with APPLICATION said 4-amino-3-p-halophenylbutyric acids or said deriv This is a continuation-in-part of application Ser. No. atives thereof. Such narcotics are, for example, acetor 656,996, filed Feb. 11, 1976 (now abandoned). phine, , , allylpro 10 dine, alphracetylmethadol, alphameprodine, alphame BACKGROUND OF THE INVENTION thadol, , , betacetylme 4-Amino-3-p-halophenylbutyric acids and suitable thadol, betameprodine, , betaprodine, derivatives thereof are disclosed in U.S. Pat. Nos. , methylbromide, codeine-N-oxide, 3,471,548 and 3,634,428 and one member thereof, i.e. , , , dex baclofen 4-amino-3-p-chlorophenylbutyric acid or 3- 15 trorphan, , , dihydro (aminomethyl)-p-chlorohydrocinnamic acid respec , , , dimethyl tively, is the active ingredient of the thiamubutene, , , LIORESAL (R). Moreover, non-spasmolytic doses of , , , etor baclofen were described in Brit. J. Pharmacol. 54, 171 phine, , , , hydromor (1975) as enhancing the action of morphine. 20 phinol, , , levomora Surprisingly it was found that said 4-amino-3-p-halo mide, , , me phenylbutyric acids and derivatives thereof, especially thyldihydromorphine, , morphine methyl baclofen, do not necessarily enhance the other effects of bromide, morphine methylsulfonate, morphine-N- morphine, in particular the drug seeking behavior and oxide, myrophin, , , physical dependence liability. They actually depress the 25 , , , nor symptoms of withdrawal of addicting agents, particu morphine, , , phenampro larly of narcotics, such as morphine, and reduce the mide, , , , phol craving for said agents, particularly for morphine ad codine, , , , racemora ministration. Therefore, combinations of addicting mide, or , or suitable salts agents, e.g. narcotics, especially with said 4-amino-3-p- 30 thereof. halophenylbutyric acids, or derivatives thereof, should Other addicting agents are, for example, barbiturates, be administered, in order to prevent future addiction, or such as allobarbital, amylbarbital, butabarbital, hexobar to ameliorate the withdrawal symptoms in the addicted. bital, mephobarbital, metharbital, methohexital, pento SUMMARY OF THE INVENTION 35 barbital, phenobarbital, phenethylbarbital, secobarbital, The present invention concerns and has for its object talbutal or thiopental; as well as glutethimide, metha the provision of: (1) a pharmaceutical composition com qualone, chloral or . prising: (A) an effective amount of an addicting agent, The 4-amino-3-p-halophenylbutyric acids, or said (B) an effective amount of a 4-amino-3-p-halophenyl derivatives, correspond to the formula butyric acid, a suitable acyl derivative, ester or salt thereof, which neither enhances an analgesic agent, nor impairs muscle coordination and (C) a pharmaceutical H-NH-r excipient, and, (2) a method for reducing either the CH-CH-COOR" addiction liability of an addicting agent, or the with drawal symptoms caused by it, which consists in admin 45 istering to a mammal in need of said agent, or suffering wherein R is halo, e.g. fluoro, chloro or bromo, or the from withdrawal symptoms caused by the lack of it, pseudohalogen trifluoromethyl, R' is hydrogen, lower enterally or parenterally either a composition according alkanoyl or phenyl-lower alkanoyl, e.g. acetyl, propio to item one, or (3) a pharmaceutical composition com nyl, butyryl, benzoyl or phenylacetyl, and R" is hydro prising an amount of the compounds according to item 50 gen, lower alkyl or phenyl-lower alkyl, e.g. methyl, (B) which neither enhances an analgesic agent, nor ethyl, propyl, butyl or benzyl, as well as salts said acids impairs muscle coordination, in conjunction with the or esters with therapeutically acceptable acids or bases. excipient according to item (C). Said new compositions The analgesically effective amounts of said narcotics, and methods are valuable therapeutic regimens, for i.e. the useful doses thereof, are well known in the art example in surgery, or in the prevention of abuse of 55 and the analgesically non-enhancing amounts of said addicting agents, particularly of abuse, and in 4-amino-3-p-halophenylbutyric acids, or said deriva the management of the chronically ill. tives thereof, can easily be determined in classical tests, e.g. those illustrated by said Vol. 54 of Brit. J. Phar DESCRIPTION OF THE PREFERRED macol. In general, such doses are advantageously be EMBODIMENTS tween about 0.01 and 5 mg/kg/day, preferably between The addicting agents most suitable for the composi about 0.1 and 1 mg/kg/day, or a single dosage unit tions claimed herein are preferably narcotics, such as between about 1 and 10 mg/day. those commonly prescribed for pain and discomfort, The newly discovered activity of said 4-amino-3-p- e.g. alphaprodine, , , codeine, halophenylbutyric acids and their derivatives can be , , , fenta 65 demonstrated in relevant tests, using preferably mam nyl, , , , mals, e.g. rodents, as test objects. Thus, for example, , , , , baclofen, a representative member of said aminoacids, , morphine, opium extracts, opium fluid ex causes at p.o. doses down to about 2.5 mg/kg/day an

4,126,684 3 4. impressive, dose-related reduction in both qualitative pensions, and suppositories are advantageously solidis. and quantitative measures of mouse jumping. (Arch, int, fied fatty emulsions or suspensions. They may be steril Pharmacodyn. 190, p. 213, 1971). In this test, mice are ized and/or contain adjuvants, such as preserving, stabi injected subcutaneously with 20 mg/kg morphine sul lizing, wetting or emulsifying agents, solution promot fate, in form of an about 0.2% aqueous solution, seven ers, salts for regulating the osmotic pressure and/or times over a 2-day period. Two hours after the last dose buffers. Said pharmaceutical compositions may also a similar solution of 100 mg/kg is injected contain other therapeutically valuable substances. They intraperitoneally, which causes all mice to jump. In are prepared according to conventional mixing, granu addition to a quantal measure, the total of individual lating or coating methods respectively, and contain jumping episodes is recorded and the influence of test O about 1 to 90%, preferably about 2 to 50% of the active substances on this behavior is determined by administer ingredient by weight. ing them one hour prior to the naloxone challenge. In The following examples are intended to illustrate the separate tests other muscle relaxants, e.g. methocar invention and are not to be construed as being limita bimol, fail to cause jumping protection at p.o. doses as tions thereon. high as 600 mg/kg/day, indicating that the effect of 15 baclofen is not due to its muscle relaxant action. Simi EXAMPLE1 larly, p.o. doses, down to about 2.5 mg/kg/day, of ba Preparation of 1,000 tablets each containing 2.5 mg of clofen markedly attenuate the aberrant behavior in the active ingredients: duced by naloxone challenge of heavily morphine sul fate dosed rats (10 x 38.75 mg/kg/2.5 days). Similarly, 20 subcutaneous doses down to 1 mg/kg/day of baclofen Formula: Levorphanol tartrate markedly attenuated the abstinence syndrome of mor Baclofen phine addicted rhesus monkeys, which were already in Lactose 1 1 Corn starch withdrawal by withholding the normal maintenance Polyethylene glycol 6000 doses of morphine. This was again accomplished with 25 Talcum powder out any signs of muscle relaxation due to baclofen and Magnesium stearate was therefore below the muscle relaxant dose of ba Purified water clofen in this species. In another test suitably trained rats have an opportu Procedure: nity to intravenously inject themselves with morphine 30 All the powders are passed through a screen with by pressing a lever activating the delivery-mechanism openings of 0.6 mm. Then the drug substance, lactose, for aqueous morphine sulfate via an indwelling cannula. talcum, magnesium stearate and half of the starch are : Presumably the injection is perceived pleasurable, rats mixed in a suitable mixer. The other half of the starch is soon become addicted and, on deprivation, extreme suspended in 40 ml of water and the suspension added to withdrawal symptoms are manifested. Baclofen, at p.o. 35 the boiling solution of the polyethylene glycol in 150 ml doses allow as 1.25 mg/kg/day during 5 day periods, of water. The paste formed is added to the powders : causes a distinct reduction in the amount of self-admin which are granulated, if necessary, with an additional istered morphine sulfate, as well as a suppression of amount of water. The granulate is dried overnight at: withdrawal symptoms in addicted animals, hitherto 35, broken on a screen with 1.2 mm openings and come only achieved by administration of a morphine substi 40 pressed into tablets using concave punches with 6.4 mm tute, such as methadone. diameter, uppers bisected. The new method for reducing the addiction liability In the analogous manner tablets" are prepared, con of narcotics, or their withdrawal effects, comprises taining instead of levorphanol tartrate either 2.5 mg of preferably the enteral, e.g. oral or anal administration of methadone hydrochloride or 5 mg of oxycodone hydro said compositions, advantageously in the form of a sin 45 chloride. gle dosage unit three times per day. Also parenteral, e.g. intramuscular or intravenous, administration may be EXAMPLE 2 chosen, or mixed regimens, e.g. intravenous administra Preparation of 1,000 chewable tablets each contain tion of any known narcotic composition, followed by ing 30 and 2.5 mg. of the active ingredients: the oral administration of a spasmolytically ineffective 50 amount of any known composition of said 4-amino-3-p- halophenylbutyric acids or their derivatives, e.g. LI Formula: Codeine phosphate ORESAL (R). Baclofen The pharmaceutical excipient, mentioned under item (C) is preferably such for enteral administration, e.g. for 55 Lactose Talcum tablets, capsules or suppositories, comprising the active Glycine t ingredients together with (a) diluents, e.g. lactose, dex Stearic acid trose, sucrose, mannitol, sorbitol, cellulose and/or gly Saccharin cine, (b) iubricants, e.g. silica, talcum, stearic acid, its 5% Aqueous gelatin solution magnesium or calcium salt and/or polyethyleneglycol, 60 for tablets also (c) binders, e.g. magnesium aluminum Procedure: silicate, starch paste, gelatin, tragacanth, methylcellu All the powders are passed through a screen with lose, sodium carboxymethylcellulose and/or polyvinyl 0.25 mm openings. The mannitol and lactose are pyrrolidone, if desired, (d) disintegrants, e.g. starches, blended, granulated with the gelatin solution, the wet, agar, alginic acid or its sodium salt, enzymes of the 65 mass passed through a screen with 2 mm openings, binders or effervescent mixtures and/or (e) absorbents, dried at 50 and passed through a screen with 1.7 mm colorants, flavors and sweeteners. Injectable composi openings. The drug substance, glycine and saccharin, tions are preferably aqueous isotonic solutions or sus are throughly blended, the mannitol-lactose granula

------Hamil 4,126,684 5. 6. tion, stearic acid and talcum added, the whole mixed symptoms caused by the lack of it, enterally or parenter until homogeneous and compressed into tablets using. ally a composition-comprising: (A) an addicting amount concave punches with 10.3 mm diameter, uppers bi of a member selected from the group consisting of a sected.Analogously prepared tablets contain 50 ing of pen barbiturate and a narcotic agent, (B) a compound of the tazocine lactate or 50 mg of meperidine hydrochloride s formula instead of the codeine phosphate. EXAMPLE 3 H-NH-r Preparation of 1,000 tablets each containing 100 and 5 CH-CH-COOR" mg of the active ingredients: 10

Formula: wherein R is fluoro, chloro, bromo or the pseudohalo Meperidine hydrochloride 100 gen trifluoromethyl, R' is hydrogen, lower alkanoyl or Baclofen 15 phenyl-lower alkanoyl, and R" is hydrogen, lower alkyl Lactose 2.4. Corn starch or phenyl-lower alkyl, or a salt of said acids or esters Polyethylene glycol 6000 with therapeutically acceptable acids or bases, in an Talcum powder Magnesium stearate effective but non-muscle relaxing amount of between Purified water about 0.1 and 1 mg/kg/day and (C) a pharmaceutical 20 excipient. Procedure: 2. A method as claimed in claim 1, wherein the nar All the powders are passed through a screen with cotic agent is a member selected from the group consist openings of 0.6 mm. Then the drug substance, lactose, ing of alphaprodine, anileridine, bezitramide, codeine, talcum, magnesium stearate and half of the starch are dihydrocodeine, diphenoxylate, ethylmorphine, fenta mixed in a suitable mixer. The other half of the starch is 25 nyl, hydrocodone, hydromorphone, isomethadone, suspended in 65 ml of water and the suspension added to levomethorphan, levorphanol, metazocine, methadone, the boiling solution of the polyethylene glycol in 260 ml metopon, morphine, opium extracts, opium fluid ex of water. The paste formed is added to the powders tracts, powdered opium, granulated opium, raw opium, which are granulated, if necessary, with an additional tincture of opium, oxycodone, oxymorphone, pethidine, amount of water. The granulate is dried overnight at 30 phenazocine, piminodine, racemethorphan, racemor 35, broken on a screen with 1.2 mm openings and com phan, thebaine, and a therapeutically acceptable salt pressed into tablets using concave punches with 10.3 thereof. mm diameter, uppers bisected. 3. A method as claimed in claim 1, wherein the nar cotic agent is a member selected from the group consist EXAMPLE 4 35 ing of , acetyldihydrocodeine, acetylme Preparation of an intramuscular solution containing thadol, , alphracetylmethadol, alphamepro 10 mg and 5 mg of the active ingredients per vial. dine, , benzethidine, benzylmorphine, , betameprodine, betamethadol, beta Formula: , clonitazene, codeine methylbromide, codeine Morphine sulfate N-oxide, cyprenorphine, desomorphine, dextromora Baclofen mide, , diampromide, diethylthiambutene, Chlorobutanol Methylcellulose 100 cps. , dimenoxadol, dimepheptanol, dime Polysorbate 80 thylthiamubutene, dioxaphetyl butyrate, dipipanone, Sodium chloride 1 Sodium carboxymethylcellulose 70 45 drotebanol, ethylmethylthiambutene, etonitazene, etor Water for injection i phine, etoxeridine, furethidine, heroin, hydromor phinol, hydroxypethidine, ketobemidone, levomora Procedure: mide, levophenacylmorphan, methyldesorphine, me The chlorobutanol is dissolved in 12 lit of water at 90 thyldihydromorphine, morpheridine, morphine methyl while stirring, followed by sodium carboxymethylcel 50 bromide, morphine methylsulfonate, morphine-N- lulose and methylcellulose. After dissolution agitation is oxide, myrophin, nicocodeine, nicomorphine, continued for 15 minutes, the solution cooled to 10' for noracymethadol, norlevorphanol, normethadone, nor 12 hours and the polysorbate is added. Morphine sul morphine, norpipanone, phenadoxone, phenampro fate, baclofen and sodium chloride are dissolved in 500 mide, phenomorphan, phenoperidine, piritramide, phol ml of water each, if necessary with warming. All solu 55 codine, proheptazine, properidine, propiram, racemora tions are combined, the volume of the solution is made mide, thebacon, trimeperidine, and a therapeutically up to 17 lt with water and the whole is filtered through acceptable salt thereof. a sintered glass filter. The filtrate is steam sterilized in 2 4. A method as claimed in claim 1, wherein the nar lt bottles at 100 for 3 hours and 15 minutes and the cotic agent is a member selected from the group consist contents filled into 2 ml sterile vials. ing of codeine phosphate, levorphanol tartrate, meperi Analogously a solution is prepared, containing 50 mg dine hydrochloride, methadone hydrochloride, mor meperidine hydrochloride instead of the morphine sul phine sulfate, oxycodone hydrochloride and pentazo fate, per vial. cine lactate. We claim: 5. A method as claimed in claim 1, wherein the barbi 1. A method for reducing either the addiction liability. 65 turate is a member selected from the group consisting of of an addicting agent, or the withdrawal symptoms allobarbital, amylbarbital, butabarbital, hexobarbital, caused by it, which consists in administering to a mam mephobarbital, metharbital, methohexital, pentobarbi mal in need of said agent, or suffering from withdrawal tal, phenobarbital, phenethylbarbital, secobarbital, tal 4,126,684 amino-3-phalophenylbutyric acid compound is ba-. butal, thiopental, and a therapeutically acceptable salt clofen. * . . . . 7. A method as claimed in claim 6, wherein the dos thereof, . . . . age unit contains between about 1 and 10 mg of ba-. 5 clofen. 6. A method as claimed in claim 1, wherein the 4

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