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US3255190A - Amine salts of pyrrolidone carboxylic acid - Google Patents

Amine salts of pyrrolidone carboxylic acid Download PDF

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US3255190A
US3255190A US113649A US11364961A US3255190A US 3255190 A US3255190 A US 3255190A US 113649 A US113649 A US 113649A US 11364961 A US11364961 A US 11364961A US 3255190 A US3255190 A US 3255190A
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carboxylic acid
pyrrolidone carboxylic
solution
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pyrrolidone
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Robert H Broh-Kahn
Halpern Alfred
Ernest J Sasmor
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LAB FOR PHARMACEUTICAL DEV Inc
LABORATORIES FOR PHARMACEUTICAL DEVELOPMENT Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/273—2-Pyrrolidones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
    • C07D207/277—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D207/28—2-Pyrrolidone-5- carboxylic acids; Functional derivatives thereof, e.g. esters, nitriles

Definitions

  • This invention relates to novel therapeutic compounds derived from pyrrolidone carboxylic acid and an organic amine, which exert a beneficial effect in the treatment of the alcoholic patient, the elderly chronically ill patient with deteriorated mental function, and the patient with generalized psychologic depression arising from a multiplicity of causes, chiefly associated with anxiety-tension.
  • this invention relates to the amine salts of pyrrolidone carboxylic acid, as for example, choline pyrrolidone carboxylate, betaine pyrrolidone carboxylate, morpholine pyrrolidone carboxylate, methenarnine pyrrolidone carboxylate, and piperazine pyrrolidone carboxylate, their method of manufacture, therapeutic compositions comprising the said compounds and a pharmaceutically acceptable carrier and a method of obtaining an elevated blood level of glutamic acid by the administration of these compounds.
  • pentylenetetrazole a potent convulsive compound, which was intended to produce a beneficial eifect through stimulation of the central nervous system. It was soon found that this drug must be used at its toxic level and the frequency with which convulsions were produced soon led to the discarding of this preparation for routine usage. When pentylenetetrazole was used at lower and safer dosages, the beneficial effects which have been described for it were not observed.
  • the administration of the large amounts of the sodium salt of glutamic acid may result in disturbances of the acid-base balance of the blood, as well as affecting water retention, particularly in patients with cardiac disease.
  • the use of special solubilizing agents has. similarly failed in this connection.
  • Pyrrolidone carboxylic acid is pyrogenetically derived from glutamic acid by loss of Water.
  • the resultant compound is capable of exerting a similar physiologic elfect as glutamic acid, either by entering into the same enzyme reactions or by being converted into glutamic acid at the cellular level. 7
  • the products of the present invention are stabilized so that the hydration of pyrrolidone carboxylic acid to glutamic acid in the presence of physiologic fluids is virtually eliminated and the compound is capable of exerting its salutory, pharmacodynamic action at the cellular level. This is established by the transfer across the blood-brain barrier. This further establishes the improved absorption and physiologic utilization of pyrrolidone carboxylic acid in contrast to the older glutamic acid.
  • the amine salts of pyrrolidone carboxylic acid are obtained through the inter-reaction between the appropriate amine and pyrrolidone carboxylic acid. Since pyrrolidone carboxylic acid has a high degradation rate, the freshly prepared acid is neutralized with the selected amine in an inert medium. When conducting this reaction, it is preferred that an excess of pyrrolidone carboxylic acid is present until the pH break-point is reached, after which a slight excess of the amine is desired. The excess of amine present during the latter phases of the reaction is from 0.1 to 0.5 percent.
  • the freshly prepared pyrrolidone carboxylic acid is dissolved in an inert medium, as for example, butyl alcohol, and to this is added, in small increments, a solution of the selected amine, dissolved in the same solvent.
  • the pH of the solution is determined after each increment is added. When the pH break-point is reached, the concentration of amine is increased slightly to maintain the described excesses.
  • the resultant compound may be used for further manufacturing steps of the final dosage form; or it may be isolated and purified.
  • An outstanding advantage of these compounds is their increased solubility in aqueous or physiologic fluids,
  • the unit dosage range of concentration of active material for the tablet may be as high as 0.75 gram of active substance. However, it will be found preferable to utilize a smaller concentration and 500 mgms. of active ingredient per tablet is an optimal concentration.
  • the granulated mix prior to the addition of a lubricant, may be utilized for the preparation of capsules, or, the
  • AClt0line pyrrolidone carboxylic acid is a semi-solid compound at room temperature.
  • the amine salts of pyrrolidone carboxylic acid in therapy may be administered orally as a solution, tablet capsule or powder or parenterally by intramuscular or intravenous injection.
  • the daily dosage range is from 1 gram to 15 grams per day depending upon the individual patient needs.
  • the particular dosage-form used may then be administered to provide the total daily dosage selected for the particular patient.
  • these agents may be administered intravenously by the continuous slow-drip technique or by multiple injections either intravenously or intramuscularly.
  • a preferred technique is by slow intravenous drip.
  • the active ingredient previously dissolved in water-for-injection, under an aseptic technique and sterilized, is added to the intravenous drip solution so that thetotal daily dose is provided in a slow, continuous manner.
  • Still another desirable pharmacologic property is observed when these compounds are administered to an agitated patient in that it facilitates the tranquilization of the patient without the super-imposition of noxious side reactions, such as addiction, as with opiate and barbiturates or nausea and vomiting and convulsions.
  • the amine salts of pyrrolidone carboxylic acid may be formulated into tablets by mixing the selected compound with a diluent in a ratio of 1 part active compound to from 0.25 to 9 parts of diluent.
  • the diluent to be used may be lactose, sucrose, corn starch or potato starch. After thorough mixing, the whole is wetted with a granulating solution, as for example, 5% gelatin solution, 2% tragacanth solution or 1% acacia solution, and the wetted mass passed through a No. 16 coarse sieve. The granulated mass is then dried and mixed with a lubricant, as forexample, magnesium stearate. The amount of lubricant required depends upon the total mass and generally a range of from 0.1 to 0.25 gram will be sufficient. After thorough mixing, the granulation is then compounded into tablets by compression.
  • the amount of active ingredient which is utilized for each unit dose ranges from 0.1 gram to 1.0 gram.
  • the active ingredient may also be dispensed in the form of a powder or granulation.
  • the active ingredient is mixed directly with a diluent in a ratio of from 1 part active ingredient to 1 part diluent, to 1 part active ingredient to 14 parts diluent.
  • Diluents such as sucrose, lactose, mannitol, corn starch, potato starch, and mixtures of these may be utilized.
  • the mixture is then wetted with a pharmaceutically acceptable granulating solution, such as 5% gelatin solution, 2% tragacanth solution, or 1% acacia solution, and the mass passed through a coarse sieve with a No. 8 screen.
  • a pharmaceutically acceptable granulating solution such as 5% gelatin solution, 2% tragacanth solution, or 1% acacia solution
  • the granules are mixed with suitable coloring and flavoring, as for example, volatile oils and artificial sweeteners, and the entire mass regranulated through a No. 8 screen.
  • suitable coloring and flavoring as for example, volatile oils and artificial sweeteners
  • the powder or granules are dispensed so that an individual unit dose (a teaspoonful or a tablespoonful), contains from 0.5 gram to 3 grams of the active ingredient.
  • a particular therapeutic advantage of the amine salts of pyrrolidone carboxylic acid is their dramatically increased solubility in aqueous media. This property facilitates the utilization of the compound in liquid dose-form.
  • a pharmaceutically acceptable carrier such as water, s mple syrup, alcohol, glycerine, propylene glycol or combinations of these, a liquid preparation is obtained, which permits the convenient administration of the daily dosage of the active material, to the patient.
  • the liquid dose-forms are particularly advantageous for administration of the active compound for those patients who cannot swallow tablets or capsules.
  • the range in concentration of the active material in the liquid dose-form is adjusted so that the individual unit dose (teaspoonful or tablespoonful) will contain from 1 gram to 5 grams of the active compound. Suitable flavoring and coloring may be added, if desired, to the liquid preparations.
  • concentrate of the active compound in water-for-inection is prepared so that each cc. contains at least 1 gram of the active substance. This concentrate may then be diluted further with water-for-injection for direct intravenous or intramuscular administration or added to the continuous intravenous infusion drip, to provide a daily dose by parenteral administration.
  • the aqueous concentration is of particular advantage in administering the products of the present invention to those patients who are being fed intravenously and who require the special, beneficial pharmacodynamic effects afiorded by these compounds.
  • Example 1 Pyrrolidone carboxylic acid is prepared by autoclaving a suspension of glutamic acid inan equal weight of water for 3 to '5 hours at 135 C. to 140 C., after which time, the warm solution is decolorized with activated charcoal; filtered and cooled. Pyrrolidone carboxylic acid precipitates as a white solid which is separated from the mother liquor by filtration. The compound may be re-crystallized from butyl alcohol or acetone and dried if desired.- The dried pyrrolidone carboxylic acid melts at 160 C.
  • the pH of the solution is then carefully controlled, so that it never rises above pH 7.
  • the mixture is allowed to cool to room temperature and the solvent removed under reduced pressure (0.2 mm. Hg).
  • the residue may be further purified by dissolving in acetone and recovering the compound.
  • the resultant compound is semi-solid, has a molecular weight of 232.3 and contains 44.86 percent choline and 55.4 percent of pyrrolidone carboxylic acid.
  • Choline pyrrolidone carboxylate analyzes in good agreement with its theoretical values for carbon, hydrogen and nitrogen.
  • the compound is very soluble in water, alcohol, propylene glycol, glycerine and sorbitol; slightly soluble in acetone and insoluble in chloroform.
  • Example 2 In place of the choline bicarbonate used in Example I above, 'may be substituted a stoichiometric equivalent quantity of betaine bicarbonate morpholine bicarbonate, piperazine bicarbonate or menthenamine bicarbonate. The remainder of the steps are the same and the compound resulting will be the respective salt of pyrrolidone carboxylic acid of selected amine bicarbonate used, having the following properties:
  • Example 3 One mol of freshly prepared pyrrolidone carboxylic acid is dissolved in one liter of isopropyl alcohol and to it is added a solution of onemol of betaine dissolved in one-half liter of isopropyl alcohol. When all of the betaine has been added, the solvent is removed by distillation and the residue recovered. The residue is betaine Betaine pyrrolidone carboxylate is a white crystalline solid melting at 128 C. to 130 C., and is very soluble in water, slightly soluble in allcohol and acetone and insoluble in chloroform. It analyzes in good agreement with its calculated theoretical values for percent carbon, hydrogen and nitrogen.
  • Example 4 In place of betaine used in Example 3, may be substituted a stoichiometric equivalent quantity of choline, methenamine, morpholine or piperazine. The remainder of the steps being the same as described.
  • the respective amine salts of pyrrolidone carboxylic acid are obtained, which have identical properties to those described in Example 2 above.
  • Example 5 In place of the butyl alcohol. and isopropyl alcohol used in Examples 1 through 4, may be substituted any liquid alcohol of the class ROH, wherein R is a straight or branched alkyl chain of from 1 to 6 carbons.
  • Water may be used to replace the alcohols used as a solvent in Examples 1 through 4, either wholly or in part.
  • water When water is used to dilute the alcohols used as a solvent it may be utilized in concentration of from one percent to 99 percent by weight.
  • the final reaction product need not be isolated but the evaporation of the water may be carried to the point Where the concentration of active compound per cc. is that desired to be used in therapy.
  • the flavoring and other components desired for the final formulation may be added to the solution of the selected amine salt of the pyrrolidone carboxylic acid.
  • Morpholine pyrrolidone carboxylate obtained in this way compares in every respect with that obtained as a result of Examples 2 and 4.
  • Example 6 When it is desired to administer the amine salts of pyrrolidone carboxylic acid in therapy of humans and animals, these may be administered tablets, capsules,
  • powders, granules or liquid-dose forms for oral administration or parenterally by intravenous or intramuscular injection or by slow continuous intravenous drip infusion.
  • the range of daily dosage is from 1 gram to 15 grams per day, depending upon the individual patients needs.
  • the particular dosage-form used may then be administered to provide the daily dosage selected for the particular patient.
  • Tablets are prepared by mixing the selected amine salt of pyrrolidone carboxylic acid with a diluent in a ratio of 1 part active compound to from 0.25 to 9 parts of diluent.
  • the diluent to be used may be lactose, sucrose, corn starch and potato starch. After thorough mixing, the whole is wetted with a granulating solution, as for example, 5 percent gelatin solution, 2 percent tragacanth solution or 1 percent acacia solution and the wetted mass passed through a No. 16 coarse sieve. The granulated mass is then dried and mixed with a lubricant, such as magnesium stearate, in the amount of from 0.1 to 0.25 gram, dependent upon the size of the batch.
  • a lubricant such as magnesium stearate
  • the unit dosage concentration of active material for a tablet may be as high as 0.75 gram of active substance, although itwill be found preferable to utilize a smaller concentration as for example, 500 mg. of active ingredient per tablet.
  • the granulation-mix prior to the addition of a lubricant as prepared above may be utilized for the preparation of capsules, or the pure active ingredient may be filled directly into the capsule.
  • the amount of active ingredient which is utilized for each unit dose may range from 0.1.gram to 1.0 gram.
  • the active ingredient in the form of a powder When it is desired to dispense the active ingredient in the form of a powder, it is mixed directly with a diluent such as sucrose, lactose, mannitol, corn starch, potato starch or mixtures of these, in a ratio of from 1 part active ingredient and 1 part diluent to 1 part active ingredient and 14 parts diluent.
  • a diluent such as sucrose, lactose, mannitol, corn starch, potato starch or mixtures of these, in a ratio of from 1 part active ingredient and 1 part diluent to 1 part active ingredient and 14 parts diluent.
  • the concentration of active ingredient is adjusted so that each unit dose of the powder, as for example, a teaspoonful or tablespoonful, will contain from 0.5 to 5 grams of the active substance.
  • Each unit dose of the powder may be taken with milk, fruit juice or any other suitable liquid.
  • a preliminary mix of the active ingredient and a diluent is formulated.
  • the ratio of the active ingredient to the diluent is from 1 part active ingredient to one to fourteen parts diluent.
  • Such substances as sucrose, lactose, mannitol, corn starch, potato starch or mixtures of these, may be utilized as diluents.
  • the preliminary mix is then granulated with a granulating solution such as 5 percent gelatin solution, 2 percent tragacanth solution, 1 percent acacia solution and the wetted mass passed through a No. 8 coarse sieve.
  • the primary granulation After the primary granulation has been dried, it is mixed with suitable coloring and flavoring and the granulating process repeated, utilizing either water or 40 percent (by weight) alcohol-water solution. After passing. through a coarse No. 8 sieve, the granules are dried.
  • the range in concentration of active substance per unit dose of the granules is from 0.5 to 5 grams of active ingredient.
  • Liquid dose forms suitable for either oral or parenteral administration, are prepared by the simple dissolution of i the active compound in a pharmaceutically acceptable carrier.
  • a liquid-preparation suitable for oral administration results, which permits the convenient administration of the daily dosage requirements.
  • the range in concentration of the active material in the liquid dosage form is adjusted so that the individual unit dose (teaspoonful r tablespoonful) will continue from 1 gram to grams of the active compound.
  • the active ingredient is dissolved directly into the selected vehicle and suitable flavoring and coloring may be added if desired.
  • suitable flavoring and coloring When water is used as the solvent for the synthesis of the active compound, then the reaction product need not be isolated, if a liquid dose form is intended. In this instance, the reaction mixture is concentrated under reduced pressure so that a range of from 1 gram to 5 grams per unit dose (teaspoonful or tablespoonful) results. The addition of suitable flavoring and coloring is then added to this mixture.
  • water-for-injection is utilized as a solvent and the formulation is prepared under aseptic conditions.
  • the active ingredient is selected and dissolved in the water-for-injection and the solution is filtered through a bacterial filter.
  • the filtered solution is then filled into ampules and sterilized by autoclaving or any other suitable technique as for example, Tyndalization.
  • the concentration of active ingredient per cc. of injectable solution ranges from 0.1 to 5.0 grams.
  • a concentrated solution is desired for addition to the continuous intravenous drip infusion, it will be found preferable to adjust the amount of active ingredient in the concentrate so that each cc. of solution contains at least one gram of active substance.
  • the concentrate is then added directly to the infusing liquid for administration by slow continuous intravenous drip.
  • Example 7 When it is desired to utilize the amine salts of pyrrolidone carboxylic acid to treat the depressed mental state of the geriatric patient, it will be found desirable to administer a total daily dosage of from 1 gram to 15 grams of the selected active compound in a convenient close form, as for example, capsules, tablets, powders, granules, or liquids by the oral route, or by injection of a parenteral solution, either intramuscularly or intraveneously.
  • the total daily dosage of the chosen compound may be divided into from one to six individual doses, to be administered at a frequency consistent with the patients needs.
  • Example 8 In order to efiect a normalization of the elevated level of serum gamma-globulin fraction of the blood of the alcoholic patient, choline pyrrolidone carboxylate or betaine pyrrolidone carboxylate may be administered in a total daily dosage of from 1 gram to 15 grams.
  • the total daily dosage may be divided into from 1 to 6 unit doses of a liquid, tablet, capsule, powder or granules, to be administered by the oral route, or injected intravenously or intramuscularly or by slow continuous intravenous drip.
  • Example 9 When it is desired to achieve a psychotonic effect, then the selected amine salt of pyrrolidone carboxylic acid may be administered as a liquid, tablet, capsule, powder or granule by the oral route, or as an intravenous or intramuscular injection by the parenteral route in a total daily dosage of from 1 to 15 grams.
  • the active ingredient is shown to traverse the blood-brain barrier to achieve an augmentation of cerebro-cellular functioning.
  • NICHOLAS S. RIZZO Primary Examiner.

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Description

United States Patent 3,255,190 AMINE SALTS 0F PYRRQLIDONE CARBOXYLIC Ailil) Robert H. Broh-Kahn, Hastings on Hudson, Alfred Halpern, Lake Success, and Ernest J. Sasmor, Yonkers, N.Y., assignors to Laboratories for Pharmaceutical Development, Inc., Yonkers, N.Y., a corporation of New York No Drawing. Filed May 31, 1961, Ser. No. 113,649
6 Claims. (Cl. 260-2472) This invention relates to novel therapeutic compounds derived from pyrrolidone carboxylic acid and an organic amine, which exert a beneficial effect in the treatment of the alcoholic patient, the elderly chronically ill patient with deteriorated mental function, and the patient with generalized psychologic depression arising from a multiplicity of causes, chiefly associated with anxiety-tension. In particular, this invention relates to the amine salts of pyrrolidone carboxylic acid, as for example, choline pyrrolidone carboxylate, betaine pyrrolidone carboxylate, morpholine pyrrolidone carboxylate, methenarnine pyrrolidone carboxylate, and piperazine pyrrolidone carboxylate, their method of manufacture, therapeutic compositions comprising the said compounds and a pharmaceutically acceptable carrier and a method of obtaining an elevated blood level of glutamic acid by the administration of these compounds.
Although medical advances have led to an appreciable increase in the average life-span, paradoxically this has resulted in an increased number of problems pertaining to care of the aged. It is known that the mental status tends to deteriorate more rapidly than does the physical condition and with an increased number of individuals living longer, psychologic deterioration is observed more frequently than before. The many problems arising in the course of everyday living in modern society, all too frequently induce a state of psychologic disorientation, re
sulting in apathy and depression. Consequently, more and more aged individuals are being channeled into specialized institutions for the care which they require and the treatment of these individuals has created a most pressing problem for modem-day medicine.
In the past very little benefit could be provided to these individuals and recently much interest has been given to the problem of devising new therapeutic modalities which would enhance mental functioning of these patients so as to restore them as useful, creative members of society.
Among the modalities studied was pentylenetetrazole, a potent convulsive compound, which was intended to produce a beneficial eifect through stimulation of the central nervous system. It was soon found that this drug must be used at its toxic level and the frequency with which convulsions were produced soon led to the discarding of this preparation for routine usage. When pentylenetetrazole was used at lower and safer dosages, the beneficial effects which have been described for it were not observed.
The use of sympathomimetic stimulants, such as amphetamine and related compounds, is not desirable because of the concurrent state of agitation which is produced by these compounds. Furthermore, the generalized stimulation of the overall sympathetic nervous system is undesirable for therapy intended for long periods of time in patients who are prone to debilitating diseases. Recent years have witnessed a new approach to the support of failing functioning of the brain cell through the use of essential metabolites, thereby supporting the deteriorating systems at a cellular level. Glutamic acid is such an essential metabolite which has been found to exert a beneficial elfect on the mental functioning of the patient. It has been shown that glutamic acid is found in high concentration in brain tissue with approximately times greater amounts present than are other amino acids essential to normalized functioning of the brain cell. Clinical study of glutamic acid has revealed that it is capable of exerting a beneficial psychotonic effect, if administered in large quantity and for prolonged periods of time. This necessity for elevated levels of dosage administration results from its insolubility in tissue fluids and consequent limited absorption. Furthermore, even after absorption into the blood stream, glutamic acid does not penetrate across the blood-brain barrier, which is necessary if it is to exert a beneficial effect on cerebrocellular metabolism.
These inherent limitations of glutamic acid therapy have led to many attempts at their correction but with little success. Among the means used to improve the absorption rate of glutamic acid is the conversion of the acid to the sodium salt, but it was soon demonstrated that this did little to effect passage across the blood-brain barrier.
Furthermore, the administration of the large amounts of the sodium salt of glutamic acid may result in disturbances of the acid-base balance of the blood, as well as affecting water retention, particularly in patients with cardiac disease. The use of special solubilizing agents has. similarly failed in this connection.
Pyrrolidone carboxylic acid is pyrogenetically derived from glutamic acid by loss of Water. The resultant compound is capable of exerting a similar physiologic elfect as glutamic acid, either by entering into the same enzyme reactions or by being converted into glutamic acid at the cellular level. 7
However, unless pyrrolidone carboxylic acid is protected, it is rapidly converted to glutamic acid by hydration and the compound now assumes all of the inherent limitations of the older glutamic acid.
In contrast to this, the products of the present invention are stabilized so that the hydration of pyrrolidone carboxylic acid to glutamic acid in the presence of physiologic fluids is virtually eliminated and the compound is capable of exerting its salutory, pharmacodynamic action at the cellular level. This is established by the transfer across the blood-brain barrier. This further establishes the improved absorption and physiologic utilization of pyrrolidone carboxylic acid in contrast to the older glutamic acid.
Furthermore, through the administration of the amine salts of pyrrolidone carboxylic acid, a more convenient therapy is available, since the compound does not have the disagreeable taste of glutamic acid and may be administered less frequently and in smaller dosage regimens.
The amine salts of pyrrolidone carboxylic acid are obtained through the inter-reaction between the appropriate amine and pyrrolidone carboxylic acid. Since pyrrolidone carboxylic acid has a high degradation rate, the freshly prepared acid is neutralized with the selected amine in an inert medium. When conducting this reaction, it is preferred that an excess of pyrrolidone carboxylic acid is present until the pH break-point is reached, after which a slight excess of the amine is desired. The excess of amine present during the latter phases of the reaction is from 0.1 to 0.5 percent.
In carrying out the reaction, the freshly prepared pyrrolidone carboxylic acid is dissolved in an inert medium, as for example, butyl alcohol, and to this is added, in small increments, a solution of the selected amine, dissolved in the same solvent. The pH of the solution is determined after each increment is added. When the pH break-point is reached, the concentration of amine is increased slightly to maintain the described excesses.
After the reaction has been completed, the resultant compound may be used for further manufacturing steps of the final dosage form; or it may be isolated and purified. An outstanding advantage of these compounds is their increased solubility in aqueous or physiologic fluids,
The unit dosage range of concentration of active material for the tablet, may be as high as 0.75 gram of active substance. However, it will be found preferable to utilize a smaller concentration and 500 mgms. of active ingredient per tablet is an optimal concentration.
The granulated mix, prior to the addition of a lubricant, may be utilized for the preparation of capsules, or, the
TABLE I.PHYSICAL-CHEMICAL PROPERTIES OF THE AMINE SALTS OF PYRROLIDONE CARBOXYLIC ACID Elemental Analysis Amine salt Enipiric M.W. M.P., 0. Percent Percent Percent formula Carbon Hydrogen Nitrogen Thry. Fnd. Thry. Fnd. Thry. Fnd.
Betnine CmHnNzO5 245. 3 128-130 48. 97 48. 83 6. 99 7.02 11. 42 11. 31 Choline (31011 232. 3 A 51. 70 49.12 8. 68 7.14 12.06 11. 01 Mcthemmine C1iH1sN O 268. 3 204 (dec.) 49. 24 49. 31 6.76 6. 66 26.11 26. 23 Morpholine CnHN:Oi 215. 2 105-106 50. 22 50. 81 7. 02 T. 12 13. 02 13. 26 Piperazine CQI'I15N303 214. 2 181-183 50. 45 51.01 7. 53 7. 8G 19. 62 19. 41
Thry.=thcory; Fnd.=found.
AClt0line pyrrolidone carboxylic acid is a semi-solid compound at room temperature.
When it is desired to utilize the amine salts of pyrrolidone carboxylic acid in therapy, they may be administered orally as a solution, tablet capsule or powder or parenterally by intramuscular or intravenous injection. When oral administration is utilized, the daily dosage range is from 1 gram to 15 grams per day depending upon the individual patient needs. The particular dosage-form used may then be administered to provide the total daily dosage selected for the particular patient. When these agents are intended for parenteral administration, they may be administered intravenously by the continuous slow-drip technique or by multiple injections either intravenously or intramuscularly. A preferred technique is by slow intravenous drip. The active ingredient, previously dissolved in water-for-injection, under an aseptic technique and sterilized, is added to the intravenous drip solution so that thetotal daily dose is provided in a slow, continuous manner.
Both routes of administration have been found useful in treating psychologic depression associated with senility and also to support the failing cerebral function. These techniques have also proven of value in treating the alcoholic patient and beneficial effects have been demonstrated by a decrease in the serum gamma-globulin fraction of blood of the alcoholic patient. It is well known that in alcoholics, disturbances of the gamma-globulin fraction of the blood are common, due to disturbed liver function. Thus, by the administration of choline pyrrolidone carboxylate, or betaine pyrrolidone carboxylate, or mixtures of these, a prompt return to normal level of the serum gamma-globulin fraction of the alcoholic patient is observed, at the same time that cerebral cellular function is augmented.
Still another desirable pharmacologic property is observed when these compounds are administered to an agitated patient in that it facilitates the tranquilization of the patient without the super-imposition of noxious side reactions, such as addiction, as with opiate and barbiturates or nausea and vomiting and convulsions.
The amine salts of pyrrolidone carboxylic acid may be formulated into tablets by mixing the selected compound with a diluent in a ratio of 1 part active compound to from 0.25 to 9 parts of diluent. The diluent to be used may be lactose, sucrose, corn starch or potato starch. After thorough mixing, the whole is wetted with a granulating solution, as for example, 5% gelatin solution, 2% tragacanth solution or 1% acacia solution, and the wetted mass passed through a No. 16 coarse sieve. The granulated mass is then dried and mixed with a lubricant, as forexample, magnesium stearate. The amount of lubricant required depends upon the total mass and generally a range of from 0.1 to 0.25 gram will be sufficient. After thorough mixing, the granulation is then compounded into tablets by compression.
pure active ingredient may be filled directly into the capsule. In the preparation of capsules, the amount of active ingredient which is utilized for each unit dose ranges from 0.1 gram to 1.0 gram.
The active ingredient may also be dispensed in the form of a powder or granulation. When the powder is utilized, the active ingredient is mixed directly with a diluent in a ratio of from 1 part active ingredient to 1 part diluent, to 1 part active ingredient to 14 parts diluent. Diluents such as sucrose, lactose, mannitol, corn starch, potato starch, and mixtures of these may be utilized.
In order to prepare granules, the mixture is then wetted with a pharmaceutically acceptable granulating solution, such as 5% gelatin solution, 2% tragacanth solution, or 1% acacia solution, and the mass passed through a coarse sieve with a No. 8 screen.
After the primary granulation, the granules are mixed with suitable coloring and flavoring, as for example, volatile oils and artificial sweeteners, and the entire mass regranulated through a No. 8 screen. The powder or granules are dispensed so that an individual unit dose (a teaspoonful or a tablespoonful), contains from 0.5 gram to 3 grams of the active ingredient.
A particular therapeutic advantage of the amine salts of pyrrolidone carboxylic acid is their dramatically increased solubility in aqueous media. This property facilitates the utilization of the compound in liquid dose-form. Thus, by the simple dissolution of the active ingredient in a pharmaceutically acceptable carrier, such as water, s mple syrup, alcohol, glycerine, propylene glycol or combinations of these, a liquid preparation is obtained, which permits the convenient administration of the daily dosage of the active material, to the patient. Furthermore, the liquid dose-forms are particularly advantageous for administration of the active compound for those patients who cannot swallow tablets or capsules. The range in concentration of the active material in the liquid dose-form is adjusted so that the individual unit dose (teaspoonful or tablespoonful) will contain from 1 gram to 5 grams of the active compound. Suitable flavoring and coloring may be added, if desired, to the liquid preparations. concentrate of the active compound in water-for-inection is prepared so that each cc. contains at least 1 gram of the active substance. This concentrate may then be diluted further with water-for-injection for direct intravenous or intramuscular administration or added to the continuous intravenous infusion drip, to provide a daily dose by parenteral administration. The aqueous concentration is of particular advantage in administering the products of the present invention to those patients who are being fed intravenously and who require the special, beneficial pharmacodynamic effects afiorded by these compounds.
Example 1 Pyrrolidone carboxylic acid is prepared by autoclaving a suspension of glutamic acid inan equal weight of water for 3 to '5 hours at 135 C. to 140 C., after which time, the warm solution is decolorized with activated charcoal; filtered and cooled. Pyrrolidone carboxylic acid precipitates as a white solid which is separated from the mother liquor by filtration. The compound may be re-crystallized from butyl alcohol or acetone and dried if desired.- The dried pyrrolidone carboxylic acid melts at 160 C.
In a three-neck, round-bottom glass boiling flask, fitted with a reflux condenser, a stirrer and a dropping funnel, is placed a solution of one mol of freshly prepared pyrrolidone carboxylic acid, dissolved in one liter of n-butyl alcohol. The stirring is started and the solution heated to a temperature of about 80 C. and one mol of a 33% aqueous solution of choline bicarbonate is added, dropwise. There is an immediate ebullition of carbon dioxide gas as the reaction takes place. When about three-fourths of the quantity of choline bicarbonate has been introduced into the reaction mixture, the pH of the solution is determined and plotted against concentration of amine added. The pH of the solution is then carefully controlled, so that it never rises above pH 7. After all of the choline bicarbonate has been added, the mixture is allowed to cool to room temperature and the solvent removed under reduced pressure (0.2 mm. Hg). The residue may be further purified by dissolving in acetone and recovering the compound. The resultant compound is semi-solid, has a molecular weight of 232.3 and contains 44.86 percent choline and 55.4 percent of pyrrolidone carboxylic acid. Choline pyrrolidone carboxylate analyzes in good agreement with its theoretical values for carbon, hydrogen and nitrogen.
Theory: Percent carbon, 51.70; percent hydrogen, 8.68; percent nitrogen, 12.06. Found: Percent carbon, 49.12; percent hydrogen, 7.14; percent nitrogen, 11.01.
The compound is very soluble in water, alcohol, propylene glycol, glycerine and sorbitol; slightly soluble in acetone and insoluble in chloroform.
Example 2 In place of the choline bicarbonate used in Example I above, 'may be substituted a stoichiometric equivalent quantity of betaine bicarbonate morpholine bicarbonate, piperazine bicarbonate or menthenamine bicarbonate. The remainder of the steps are the same and the compound resulting will be the respective salt of pyrrolidone carboxylic acid of selected amine bicarbonate used, having the following properties:
pyrrolidone carboxylate.
6 Example 3 One mol of freshly prepared pyrrolidone carboxylic acid is dissolved in one liter of isopropyl alcohol and to it is added a solution of onemol of betaine dissolved in one-half liter of isopropyl alcohol. When all of the betaine has been added, the solvent is removed by distillation and the residue recovered. The residue is betaine Betaine pyrrolidone carboxylate is a white crystalline solid melting at 128 C. to 130 C., and is very soluble in water, slightly soluble in allcohol and acetone and insoluble in chloroform. It analyzes in good agreement with its calculated theoretical values for percent carbon, hydrogen and nitrogen.
Theory: Percent carbon, 48.97; percent hydrogen, 6.99; percent nitrogen, 11.42. Found: Percent carbon, 48.83; percent hydrogen, 7.02; percent nitrogen, 11.31.
Example 4 In place of betaine used in Example 3, may be substituted a stoichiometric equivalent quantity of choline, methenamine, morpholine or piperazine. The remainder of the steps being the same as described. The respective amine salts of pyrrolidone carboxylic acid are obtained, which have identical properties to those described in Example 2 above.
Example 5 In place of the butyl alcohol. and isopropyl alcohol used in Examples 1 through 4, may be substituted any liquid alcohol of the class ROH, wherein R is a straight or branched alkyl chain of from 1 to 6 carbons.
Water may be used to replace the alcohols used as a solvent in Examples 1 through 4, either wholly or in part. When water is used to dilute the alcohols used as a solvent it may be utilized in concentration of from one percent to 99 percent by weight. When water is used as a solvent, the final reaction product need not be isolated but the evaporation of the water may be carried to the point Where the concentration of active compound per cc. is that desired to be used in therapy. In this instance the flavoring and other components desired for the final formulation may be added to the solution of the selected amine salt of the pyrrolidone carboxylic acid.
When'a liquid amine, such as morpholine is used as the reactant, no solvent is necessary. A huge excess, as for example, a 5 molar excess is used, and the additional liquid amine serves as its own solvent. In this instance the pyrrolidone carboxylic acid is added to the amine and when all of the acid has been added, the excess solvent is removed by distillation and the desired compound isolated, and re-crystallized from butyl alcohol or Elemental Analysis Amine salt Empirie M.W. M.P., 0. Percent Percent Percent formula Carbon Hydrogen Nitrogen Thry. Fnd. Thry. Fnd. Thi'y. Fnd.
Betaine CmHnNzOs--- 245.3 128-130 48.97 48.83 6.99 7.02 11.42 11.31 Choline ommuoinu u 232. A 51.70 49.12 8. 68 7.14 12.06 11.01 Methenamine n ,8 503--- 268.3 204 (dee) 49.24 49.31 6.76 6.66 26.11 26.23 Morpholine Gammon--. 215.2 106-106 50.22 50.81 7.02 7.12 13.02 13.20 Piperazine CQHNN3O3 214.2 181-183 60.45 51.01 7.53 7.86 19.62 19.41
The appropriate amine carbonate may be used in place acetone. Morpholine pyrrolidone carboxylate obtained in this way compares in every respect with that obtained as a result of Examples 2 and 4.
Example 6 When it is desired to administer the amine salts of pyrrolidone carboxylic acid in therapy of humans and animals, these may be administered tablets, capsules,
powders, granules or liquid-dose forms for oral administration or parenterally by intravenous or intramuscular injection or by slow continuous intravenous drip infusion. The range of daily dosage is from 1 gram to 15 grams per day, depending upon the individual patients needs. The particular dosage-form used may then be administered to provide the daily dosage selected for the particular patient.
Tablets are prepared by mixing the selected amine salt of pyrrolidone carboxylic acid with a diluent in a ratio of 1 part active compound to from 0.25 to 9 parts of diluent. The diluent to be used may be lactose, sucrose, corn starch and potato starch. After thorough mixing, the whole is wetted with a granulating solution, as for example, 5 percent gelatin solution, 2 percent tragacanth solution or 1 percent acacia solution and the wetted mass passed through a No. 16 coarse sieve. The granulated mass is then dried and mixed with a lubricant, such as magnesium stearate, in the amount of from 0.1 to 0.25 gram, dependent upon the size of the batch. After thorough mixing, the granulation is compressed into tablets of the proper size and shape. The unit dosage concentration of active material for a tablet may be as high as 0.75 gram of active substance, although itwill be found preferable to utilize a smaller concentration as for example, 500 mg. of active ingredient per tablet.
The granulation-mix prior to the addition of a lubricant as prepared above, may be utilized for the preparation of capsules, or the pure active ingredient may be filled directly into the capsule. In the preparation of capsules, the amount of active ingredient which is utilized for each unit dose may range from 0.1.gram to 1.0 gram.
When it is desired to dispense the active ingredient in the form of a powder, it is mixed directly with a diluent such as sucrose, lactose, mannitol, corn starch, potato starch or mixtures of these, in a ratio of from 1 part active ingredient and 1 part diluent to 1 part active ingredient and 14 parts diluent. The concentration of active ingredient is adjusted so that each unit dose of the powder, as for example, a teaspoonful or tablespoonful, will contain from 0.5 to 5 grams of the active substance. Each unit dose of the powder may be taken with milk, fruit juice or any other suitable liquid.
In order to prepare granules, a preliminary mix of the active ingredient and a diluent, is formulated. The ratio of the active ingredient to the diluent is from 1 part active ingredient to one to fourteen parts diluent. Such substances as sucrose, lactose, mannitol, corn starch, potato starch or mixtures of these, may be utilized as diluents. The preliminary mix is then granulated with a granulating solution such as 5 percent gelatin solution, 2 percent tragacanth solution, 1 percent acacia solution and the wetted mass passed through a No. 8 coarse sieve. After the primary granulation has been dried, it is mixed with suitable coloring and flavoring and the granulating process repeated, utilizing either water or 40 percent (by weight) alcohol-water solution. After passing. through a coarse No. 8 sieve, the granules are dried. The range in concentration of active substance per unit dose of the granules (teaspoonful or tablespoonful) is from 0.5 to 5 grams of active ingredient.
Liquid dose forms, suitable for either oral or parenteral administration, are prepared by the simple dissolution of i the active compound in a pharmaceutically acceptable carrier. Thus, by the simple dissolution of the selected amine sale of pyrrolidone carboxylic acid in water, simple syrup, alcohol, glycerine, propylene glycol, sorbitol, or combinations of these, a liquid-preparation suitable for oral administration results, which permits the convenient administration of the daily dosage requirements. The range in concentration of the active material in the liquid dosage form is adjusted so that the individual unit dose (teaspoonful r tablespoonful) will continue from 1 gram to grams of the active compound. In the preparation of the liquid dose form the active ingredient is dissolved directly into the selected vehicle and suitable flavoring and coloring may be added if desired. When water is used as the solvent for the synthesis of the active compound, then the reaction product need not be isolated, if a liquid dose form is intended. In this instance, the reaction mixture is concentrated under reduced pressure so that a range of from 1 gram to 5 grams per unit dose (teaspoonful or tablespoonful) results. The addition of suitable flavoring and coloring is then added to this mixture.
When it is intended to utilize the liquid dose form by parenteral means, then water-for-injection is utilized as a solvent and the formulation is prepared under aseptic conditions. The active ingredient is selected and dissolved in the water-for-injection and the solution is filtered through a bacterial filter. The filtered solution is then filled into ampules and sterilized by autoclaving or any other suitable technique as for example, Tyndalization. The concentration of active ingredient per cc. of injectable solution ranges from 0.1 to 5.0 grams. When a concentrated solution is desired for addition to the continuous intravenous drip infusion, it will be found preferable to adjust the amount of active ingredient in the concentrate so that each cc. of solution contains at least one gram of active substance. The concentrate is then added directly to the infusing liquid for administration by slow continuous intravenous drip.
Example 7 When it is desired to utilize the amine salts of pyrrolidone carboxylic acid to treat the depressed mental state of the geriatric patient, it will be found desirable to administer a total daily dosage of from 1 gram to 15 grams of the selected active compound in a convenient close form, as for example, capsules, tablets, powders, granules, or liquids by the oral route, or by injection of a parenteral solution, either intramuscularly or intraveneously. The total daily dosage of the chosen compound may be divided into from one to six individual doses, to be administered at a frequency consistent with the patients needs.
Example 8 In order to efiect a normalization of the elevated level of serum gamma-globulin fraction of the blood of the alcoholic patient, choline pyrrolidone carboxylate or betaine pyrrolidone carboxylate may be administered in a total daily dosage of from 1 gram to 15 grams. The total daily dosage may be divided into from 1 to 6 unit doses of a liquid, tablet, capsule, powder or granules, to be administered by the oral route, or injected intravenously or intramuscularly or by slow continuous intravenous drip.
Example 9 When it is desired to achieve a psychotonic effect, then the selected amine salt of pyrrolidone carboxylic acid may be administered as a liquid, tablet, capsule, powder or granule by the oral route, or as an intravenous or intramuscular injection by the parenteral route in a total daily dosage of from 1 to 15 grams. The active ingredient is shown to traverse the blood-brain barrier to achieve an augmentation of cerebro-cellular functioning.
What is claimed is:
1. A compound selected from the group consisting of betaine pyrrolidone carboxylate, choline pyrrolidone carboxylate, methenamine pyrrolidone carboxylate, morpholine pyrrolidone carboxylate, and piperazine pyrrolidon carboxylate. 1
2. Betaine pyrrolidone carboxylate.
3. Choline pyrrolidone carboxylate.
4. Methenamine pyrrolidone carboxylate.
5. Morpholine pyrrolidone carboxylate.
6. Piperazine pyrrolidone carboxylate.
(References on following page) References Cited by the Examiner UNITED STATES PATENTS Connstein 260268 Ledrut 260285 Henderson 16755 Sprague et a1. 16755 Fox 260247.2
Cusic 260247.2 Blackett et a1. 260251.5 10 Skel1y 260-326.3
10 3,002,978 10/ 1961 Bocher 260326.3 3,013,058 12/1961 Richter 260247.2 3,019,226 1/ 1962 Bernstein et a1. 260268 FOREIGN PATENTS No. 51M 2/1961 France. No. 121M 3/1961 France.
N0.M1134 3/1962 France.
NICHOLAS S. RIZZO, Primary Examiner.
IRVING MARCUS, WALTER MODANCE, Examiners.

Claims (2)

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF BETAINE PYRROLIDONE CARBOXYLATE, CHOLINE PYRROLIDONE CARBOXYLATE, METHENAMINE PYRROLIDONE CARBOXYLATE, MORPHOLINE PYRROLIDONE CARBOXYLATE, AND PIPERAZINE PYRROLIDONE CARBOXYLATE.
5. MORPHOLINE PYRROLIDONE CARBOXYLATE.
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US3345264A (en) * 1960-06-03 1967-10-03 Bocher Dominique Methods of suppressing anxiety employing sodium and iron salts of pyrrolidone carboxylic acid
US4097490A (en) * 1975-09-25 1978-06-27 Merck & Co., Inc. Pyroglutamic acid salts of t-butylamino-2,3-dihydroxypropane

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US4097490A (en) * 1975-09-25 1978-06-27 Merck & Co., Inc. Pyroglutamic acid salts of t-butylamino-2,3-dihydroxypropane

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