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was“ i’? ii,®$§,8l2 ?atenteti May id, 1953 2 and 3,089,812 THERAPEUTIQ CGMPOSH'E'EGN?» FQR THE PUTEN gIAéI‘lQN ()F BAREETURATES AND ANALGE ROOC~< >~NHCOCHzGHOHr 1C Arthur Ernest Wilder Smith, 18 Chemin ties Lilas Blames, Geneva, Switzerland No Drawing. Filed Jan. 29, 1962, Ser. No. 169,590 (Ilaims priority, application "Great Britain Feb. 7, 1961 11 Claims. (Ci. 167-52) (IV) (in which R, R1 and R2 represent alkyl groups having from 1 to 5 carbon ‘atoms, X represents a group ROO¥C-—, a hydrogen atom or a halogen atom and Y is a halogen atom or a hydrogen atom) and/ or non-toxic salts thereof. This invention is concerned with improvements in or relating to therapeutic compositions more particularly compositions containing one or more pharmacologically active barbituratesv or- morphinic analgesics. This application is a eontinuation-in-part of my appli cation Serial No. 764,756, ?led October 2, 1958, now Suitable non-toxic salts of both morphinic analgesics and the potentiating compound include particularly addi tion salts with acids which are physiologically compatible at the dosages employed, examples of such acids being abandoned. As is known, pharmacologically active barbiturates and hydrochloric, hydrobromic, sulphuric, citric, tartaric, manifests'itself by- increasing the sopori?c and/or anti N-(?-pyrrolidino)butyryl-p-amino benzoic acid ethyl acetic, fumaric, and maleic acids. morphinic analgesics suffer from a number of disadvan , In the above general Formulae I and IV R is preferably tages which limit their use in therapeutics. Thus, there 20 a methyl, ethyl, n-propyl or n-butyl group. In general may be an inconveniently long latent period ‘after admin Formula I R1 and R2 are preferably both ethyl groups. istration of a barbiturate before it takes e?ect and the The substituted butyric acid anilides of Formulae l to sedation produced may not be of the required depth or IV can be readily prepared by reacting the appropriately length. The toxicity of some barbiturates is marked and substituted crotonic acid anilide with an amine R1R2NH, seriously limits the dose which can be administered. 25 such method being described, for example, in my US. Morphinic analgesics alsoin-general possess marked toxic Patent 2,801,247 and in my British Patent No. 801,405. properties, which limits the dose which can be used. As speci?c preferred examples of compounds of general I have now found, however, that compounds of the Formulae I—IV which we have found to be particularly , general formulae set out below markedly potentiate the suitable for potentiation of the action of barbiturates may pharmacological activity of barbiturates and of morphinio 30 be mentioned the following: analgesics. In the case of barbiturates this potentiation epileptic etfect of barbiturates and also in some cases by ester shortening the latent period ‘which elapses after the ad N—(l3-pyrrolidin0)-butyryl-p-amino benzoic acid methyl ministration of the barbiturate before it takes effect. The compounds mentioned also in general lower the acute toxicity of barbiturates and render the therapeutic indices more favourable. In the case of morphinic analgesics N-(?-piperidino)-butyryl-p-arnino benzoic acid ethyl ester N-(?-piperidino)-butyryl-p-amino benzoic acid n-butyl the ratio of analgesic action to toxicity and respiratory depression is increased thereby enabling more powerful ester ester 40 B-Pyrrolidino-butyric acid anihde ?-Pyrrolidino-butyric acid (2 : 4-d-ichloro ) —anilide analgesic action to be safely achieved. It is thus possible to formulate barbiturate and mor ,B-Pyrrolidino-butyric acid (4-chloro)-am'lide phinic analgesic compositions containing compounds of the general Formulae I-IV which compositions have a far lower rate of toxicity to pharmacological action than The barbiturate or barbiturates to be included in the compositions according to the invention may be any de sired barbiturate such as phenobarbitone, hexobarbitone, the barbiturates and morphinic analgesics themselves, thus enabling the barbiturates and morphinic analgesics to be secobarbitone, pentobarbitone and butobarbitone. By the peutic compositions comprising at least one pharmaco logically-active compound chosen from the group com By the expression “morphinic analgesic” as used herein I mean morphine itself and analgesics structurally and/or prising barbiturates and morphinic analgesics together pharmacologically related thereto including particularly with one or more compounds of the ‘following (general but not exclusively naturally occurring substances. Analgesics related to morphine include, for example term “pharmacologically active” when used herein in rela tion to barbiturates is meant barbituric acid and related administered in a lower dose toobtain the same pharma compounds which have a sopori?c and/ or antiepileptic cological e?ect. ‘According to the invention, therefore, I provide thera 50 effect. "formulae: pethidine, codeine, dihydrocodeine, oxymorphone, oxy codone, dipipanone, dextromoramide, leverphanol, hydro morphone, hydrocodone, methadone, phenazocine, pro R0 0 o-Qnno o emotions N (19 Y (II) X-QNHCOCHMFICH; Y f \i 1 poxyphene, piminodine and anileridine. 60 The compositions according to the invention may be formulated together with a pharmaceutical carrier or ex cipient in any convenient form suitable for administration orally, parenterally or in the form of a suppository. Thus, the compositions may be formulated in a form suitable for oral administration either in a solid or liquid form. A particularly suitable solid formulation is as tablets containing the desired barbiturate or morphinic analgesic together with the potentiation compound in an inert tablet base. N In liquid ‘form the compositions may be made up as a syrup or like preparation, which (III) may if desired contain surface active and/ or ?avouring 3,089,812 3 4 agents, the latter serving to mask any undesirable taste of the active components. For parenteral administration the compositions can, the following representative formulations are given by way of illustration only: Tablets for example, be made up in liquid form in pyrogen-free water, the active components preferably in such cases being presented in a water soluble form. Surface active agents may be added if desired. In such formulations, the potentiating compounds can be present as their Water soluble salts for example as hy drochlorides, citrates or tartrates, whilst the barbiturates may for example be present as their alkali-metal salts if these are soluble; the morphinic analgesics may be present as their acid addition salts. Mgs. (l) Phenobarbitone ________________________ __ 45 IS-Pyrrolidino butyric acid anilide _________ __ 75 Tablet base to 200 mgs. (2) Butobarbitone _________________________ __ 30 ?-Pyrrolidino butyric acid anilide _________ __ 50 Tablet base to 150 mgs. (3) Butobarbitone _________________________ __. 40 N-(B-pyrrolidino)-butyryl-p-amino benzoic acid ethyl ester ____________________________ _- The proportion of the potentiating compounds to the barbiturates or morphinic analgesics present in compo 15 sitions according to the invention can vary Within wide limits. In the case of barbiturates, in general, the ratio of po tentiating compound to barbiturate should be at least 0.75 and preferably at least 1.5, advantageously 1.5-3.0 20 parts by weight, of potentiating compound to 1 part by Weight of barbiturate. In the case of morphinic analgesics, the proportion of the potentiating compounds to the morphinic analgesic is generally in the ratio of 10 to 50 parts by weight of 25 60 Tablet base to 200 mgs. (4) 'Phenobarbitone ________________________ __ 30 N- (,B-pyrrolidino ) -butyryl-p-amino-benzoic acid ethyl ester ____________________________ __ 50 Tablet base to 150 mgs. In the above tablet formulations the mentioned bar biturate can be replaced by hexobarbitone, secobarbitone or pentobarbitone and the potentiating compound by N (?-piperidino)-butyryl-p-amino benzoic acid ethyl ester. (5) Dihydrocodeine acid tar trate _______________ __ 10-15 mg., e.g. 10 mg. potentiating compound to 1 part by Weight of morphinic analgesic. Preferably the ratio is about 15-3021. Where the compositions according to the invention ?-Pyrrolidino-butyric acid anilide hydrochloride 1 __ 200-300 mg., e.g. 200 mg. Tablet base to 500 mg. contain more than one barbiturate the action of the bar biturates may well be synergistic. In this case the total 30 (6) Levorphenol tartrate _______________ __mg__ 1.5 ?-Pyrrolidino-butyric acid anilide acid male dose of barbiturates given may Well be less, than if only ate ______________________________ __mg__ 300 one barbiturate is given, and in such cases the concen Tablet base to 500 mg. tration of potentiating compound can be reduced accord (7) Pethidine hydrochloride ____________ __mg__ ingly. ate ______________________________ __mg.... 300 morphinic analgesic together with ?~pyrrolidino butyric acid anilide or a non-toxic salt thereof. 25 ?-Pyrrolidino-butyric acid anilide acid male Preferred analgesic compositions include at least one 35 Tablet base to 500 mg. Preferred salts 1This constituent may be replaced by the acid malcate include the acid fumarate (M.P. 168° C.) and, in par ticular, the hydrochloride (M.P. 141-2“ C.) and the acid maleate (M.P. 125—7° C.). The following table gives by way of example only fac (300-325 mg). Capsules M gs_ (l) Pentobarbitone sodium __________________ __ tors by which ?-pyrroldino butyric acid anilide potentiates 25 N-(B-piperidino)-butyryl-p-amino-benzoic ethyl the action of various morphinic analgesics as determined ester hydrochloride _____________________ __ experimentally in rats. 50 Orally acceptable liquid base to 150 mgs. In each case the ?-pyrrolidinoebutyric acid anilide was (2) Butobarbitone sodium __________________ __ given in a ?xed dose of 50 mg./kg. body weight intra peritoneally. The values given for potentiation are those by which the original dose of the drug may be reduced to obtain equi-analgesia when the drug is given in com bination with ?-pyrrolidino-butyric acid anilide. N-(?-pyrrolidino)-butyryl-p-amino benzoic acid ethyl ester ____________________________ __ Morphine hydrochlorlde__ Codeine phosphate ______ ._ Dihydrocodeine acid tartr Pethidine hydrochloride- .. _ (+)-Propoxyphene hydrochlor1de__-._ Sodium aspirin ________________________________________ __ 60 Liquid ‘base to 200 mgs. lnjectable Preparations 50 TABLE Drug 40 Potentiation 55 Factor (1) Morphine hydrochloride ____________ "mg..- 5 ,8-pyrrolidino-butyric acid anilide acid maleate1 .. 200-300 mg., e.ig. 200mg. Water for injection _________________ __ml__ 5 (2) Methadone hydrochloride __________ __mg__ 5 ,B-Pyrrolidino-butyric acid anilide acid male eate _____________________________ __mg__ 300 race-vimosuca Water for injection _________________ __ml__ (3) 'Pethidine hydrochloride ____________ __mg.._. 60 5 25 ?-Pyrrolidino-butyric ‘acid anilide acid male ate mg 300 Water for injection _________________ .._ml__ 5 1This constituent may be replaced by the hydrochloride (230 mg.). Norm-These ?gures were obtained by using the rat tail pressure method of assessing analgesia (modi?ed 65 (4) A preparation suitable for intravenous injection from the method of Green and Young, Brit. J. Pharma can be made by dissolving 50 mgs. of phenobarbitone sodium and 70 mgs. of N-(?-pyrrolidino)-butyryl~p col. (1951), 6, 572). amino benzoic acid ethyl ester hydrochloride in pyrogen 30 groups (approx) of rats were used, each group con free water. The phenobarbitone sodium may be replaced taining 10 animals. A mean value was found for each rat by recording the response to ?ve rapid and consecu 70 by any other suitable water-soluble barbiturate and any tive pressures on the tail. The ten means thus obtained were used to calculate the group mean response for both untreated animals and those which receive an injection other suitable water-soluble potentiating compound may be used. Suppositories of the analgesic. 200_ mg. suppositories can be made by mixing suitable In order that the invention may be well understood 75 quantities of barbiturate and potentiating compound in a 3,089,812 the group consisting of phenobarbitone, hexobarbitone, suitable suppository base. A single 200 mg. suppository could have the following constitution: secobarbitone, pentobarbitone and butobarbitone and an e?ective amount of at least one compound potentiating Mgs. Butobarbitone _____________________________ __ 45 ,B-Pyrrolidino butyric acid anilide _____________ __ 70 the activity of the pharmacologically active compound, said potentiating compound being selected ‘from/the group consisting of: Suppository base to 200 mgs. I claim: 1. A therapeutic composition comprising at least one pharmacologically active compound selected from the 10 group consisting of barbiturates and morphinic analgesics and an e?ective amount of at least one compound po tentiating the activity of the pharmacologically active compound, said potentiating compound being selected from the group consisting of ROOC- 15 --NHOOCH2CHOH3 2 X-Q-NHCQoHZcHCHt Y i1 (I) | 20 XQ-NHOO onulnnons Y (Mi _: X—©—Nrto0om<|mom Y (W | N and (II) 25 | N -—-— 30 in which R, R1 and R2 are each alkyl radicals containing (III) from 1 to 5 carbon atoms, X is a member selected from and the group consisting of the group ROOC-, a hydrogen no 0 o-< 35 atom and a halogen atom and Y is a member selected >—NHC 0 omcaom N1 from the group consisting of a hydrogen atom and a halogen atom. 11. A therapeutic composition comprising at least one (1V) in which R, R1 and R2 are each alkyl radicals contain pharmacologically active morphinic analgesic selected 40 from the group consisting of pethidine, codeine, dihydro codeine, oxymorphone, oxycodone, dipipanone, dextro ing from 1 to 5 carbon atoms, X is a member selected from the group consisting of the group ROOC-—, a moramide, levorphanol, hydromorphone, hydrocodone, methadone, phenazocine, propoxyphene, piminodine and hydrogen atom and a halogen atom and Y is a mem— anileridine and an e?ective amount of at least one com ber selected from the group consisting of a hydrogen pound potentiating the activity of the pharmacologically 45 active compound, said potentiating compound being se atom and a halogen atom. 2. A composition as claimed in claim 1 in which said lected from the group consisting of potentiatinig compound is present in the form of its water soluble acid addition salt. 3. A composition as claimed in claim 1 in which the /N\ at pharmacologically active compound is a barbiturate and 50 from 0.75 to 3.0 parts by weight of said potentiating compound are present for each part by weight of barbi R1 X-— turate present. 4. A composition as claimed in claim 3 in which said potentiating compound is -/3~pyrrolidino butyric acid ani | 55 Y lide. 5. A composition as claimed in claim 3 in which said (I) NHOOOHQCHCH; N ii Z (11) potentiating compound is N-(B-pyrrolidino)-butyryl-p amino 'benzoic acid ethyl ester. 6. A composition as claimed in claim 1 in which the 60 pharmacologically active compound is a morphinic anal gesic and 10 to 50 parts by weight of potentiating com X-QNHQO ormlmom Y r1 N pound are present for each part by weight of morphinic __ (111) analgesic. 7. A composition as claimed in claim ‘6 in which 15 65 and to 30 parts ‘by weight of potentiating compound are pres ent for each part by weight of morphinic analgesic. 8. A composition as claimed in claim 6 in which the no 0 o-Qnnoomnonom N\ potentiating compound is ?-pyrrolidinobutyric acid ani 70 lide. 9. A composition as claimed in claim 8 in which the ?-pyrrolidino-butyric acid anilide is present in the form of its water-soluble acid addition salt. (W) in which R, R1 and R2 are each alkyl radicals containing from 1 to 5 carbon atoms, X is a member selected from the group consisting of the group ROOC—-, a hydrogen one pharmacologically active barbiturate selected from 75 ‘10. A therapeutic composition comprising at least 3,089,812 atom and a halogen atom and Y is a member selected from the group consisting of a hydrogen atom and a halogen atom. References Cited in the ?le of this patent UNITED STATES PATENTS 2,657,210 Clinton _____________ __ Oct. 27, 1953 2,793,155 Smith _______________ __ May 21, 1957 2,801,247 Smith _______________ -_ July 30, 1957 8 FOREIGN PATENTS 83,130 Netherlands _________ _.. Oct. 15, 1956 89,384 Norway _____________ __ Apr. 13, 1957 OTHER REFERENCES Beiler: Arch. Int. Pharmacodyn., November 1, 1956, CVIII, No. 2, pp. 129-134. A.M.A. Council on Drugs, New and Nonot?cial Drugs, 1958, pages 299-330.