MXPA99000255A - Treatment regimen for the administration of phenylacetilglutamine, phenylacetilisoglutamine and / or fen acetate - Google Patents

Abstract

The present invention relates to a method for the treatment of neoplastic disease, including cancer, which comprises administering a pharmaceutical composition, the pharmaceutical composition comprising a highly concentrated aqueous solution of phenylacetylglutamine and phenylacetylisoglutamine in a ratio of 4: 1, at a rate of infusion of 100 ml / hour at 400m / hour. In a further embodiment, a method for the treatment of neoplastic disease, including cancer, comprising administering a pharmaceutical composition, the pharmaceutical composition comprising a highly concentrated aqueous solution of phenyl acetate (phenylacetylglutamine or phenylacetylisoglutamine) is also described herein. ratio of 4: 1, at an infusion rate of 100 me / hours at 400 mi / hour. Also described herein are the pharmaceutical compositions used in the above methods

Description

REGIME OF TREATMENT FOR THE ADMINISTRATION OF PHENYLACYLGLUTAMINE. FEN ILAC ETI LISOGLUTAM I N A AND / OR PHENYL ACETATE BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates generally to the field of treatment of neoplastic disease. More particularly, it relates to the intravenous administration of highly concentrated solutions of phenylacetylglutamine and phenylacetylisoglutamine or phenylacetylglutamine and phenyl acetate, or salts or derivatives thereof, at high infusion rates and high dose levels. 2. Description of Related Art The search for growth factors and growth inhibitors during the last thirty years indicates the possible existence of a defense system of the human body complementary to the immune system. This defense system of inducers and regulators of oncogene expression differentiation and tumor suppressor gene can be termed as a "biochemical defense system" or "BDS". Since the main purpose of the immune system is to protect the body against external invasion, the main purpose of BDS is to protect the body against defective cells. Neoplastic diseases of being Human (cancer, malignant and benign tumors) are examples of diseases that can be combated by BDS. A class of compounds that provide BDS components are naturally occurring amino acid analogs and carboxylic acids. Although not bound by theory, the mechanism of defense against cancer through naturally occurring amino acid analogs can be the induction of differentiation, conjugation of glutamine to inhibit the growth of cancer cells, down-regulation of oncogenes such as ras, or over-regulation of detoxification genes such as GSTP1 and GSTM1 and tumor suppressor genes such as p53, retinoblastoma gene and neurofibromatosis type 1 gene, possibly reducing methylation of hypermethylated genes. Without considering the detailed mechanism of action, naturally occurring amino acid analogs are known to induce abnormal cells to undergo terminal differentiation and die through programmed cell death. Unlike the necrosis associated with chemotherapy or radiation therapy, the dead cells are gradually eliminated and replaced by normal cells, leading to organ healing and function reconstruction. The study of naturally occurring amino acid analogs as potential anticancer agents, hereinafter generally referred to as "antinoplastons", began in 1967 with the observation of significant deficiencies in the peptide content in the serum of cancer patients. During the 1980s, the isolation of fractions of antineoplaston from human urine and the use of these fractions in the treatment of human cancer were taught by Burzynski, patent of E.U.A. 4,470,970, the entire specification of which is incorporated herein by reference. Among the established compositions for cancer treatments are: (a) 3-phenylacetylamino-2,6-piperidinedione, and (b) a mixture of sodium acetate-phenyl and phenylacetylglutamine in a ratio of 4: 1 by mass. The composition (b) can be referred to hereafter as "antineoplaston AS2-1" or simply "AS2-1". It was discovered that 3-phenylacetylamino-2,6-piperidinedione is hydrolyzed during the treatment with sodium hydroxide after dissolution and neutralization to phenylacetylglutamine and phenylacetylisoglutamine in a ratio of 4: 1. The formulations of the above compositions were preparative and had a successful pre-clinical activity. The 3-phenylacetylamino-2,6-piperidinedione had a cytostatic effect on the cultured human breast cancer cell line, MDA-MB-231. The dose-dependent inhibition of cell line curves growth KMCH-1, KYN-1 and KIM-1; Rat Nb2 lymphoma; and human colon adenocarcinoma, was also observed after administration of 3-phenylacetylamino-2,6-piperidinedione. In vivo experiments were performed where 3-phenylacetylamino-2,6-piperidinedione or A10 was administered to mice implanted with S180 cells or R-27 human breast cancer cells. In the S180 experiment, the levels of cAMP in livers and tumors of treated mice were significantly elevated relative to the control mice after administration of 3-phenylacetylamino-2,6-piperindione. In the R-27 experiment, an inhibition of 3H-TdR consumption and an inhibition of the growth curve after an injection of A10 were observed. AS2-1 or phenylacetic acid produced a dose-dependent growth inhibition in the breast carcinoma cell line HBL-100 and Ki-1, and also promoted phenotypic differentiation or reversion in human promyelocytic leukemia cell lines HL-60 , chronic lymphocytic leukemia, neuroblastoma, murine fibrosarcoma V7T, PC3 hormonally refractory prostate adenocarcioma, astrocytoma, medulloblastoma, malignant melanoma and ovarian carcinoma. AS2-1 or phenylacetic acid caused adipocyte conversion to cultured premalignant mesenchymal C3H 10T1 / 2 cells and improved hemoglobin production in K562 erythroleukemia cells. In addition, and in distinction to standard chemotherapeutic current agents such as 5-aza-2-deoxycytidine, acetic acid did not cause tumor progression in C3H 10T1 / 2 cells. Pre-clinical toxicology studies determined that LD50 for A10 in mice was 10.33 g / kg / day. The autopsy of the animals that died revealed a general congestion of the viscera, pulmonary edema, and hemorrhagic changes in the alveoli. At autopsy, the surviving test animals were identical to the control animals. Chronic toxicity studies do not They revealed negative effects after 180 days. The LD5o for AS2-1 in mice was 2.83 g / kg / day. The autopsy of the animals that died revealed a generalized congestion of the viscera, pulmonary edema, and hemorrhagic changes in the alveoli, as well as Tardieu spots and congestion of the thymus. Chronic toxicity studies using up to 1.11 g / kg / day showed no negative effects after 365 days. It was observed that A10 and AS2-1 are non-mutagenic through the Ames method, and it was observed that A10 is non-teratogenic in rat fetuses. A notable point with respect to toxicological studies is that phenylacetylglutamine, a component of AS2-1 and also a breakdown product of 3-phenylacetylamino-2,6-piperidinedione, is not normally found in mice but is usually found in humans . This suggests that humans may exhibit a greater tolerance to both A10 and AS2 / 1 than mice, and thus higher doses of both compositions may be possible for humans. This suggestion is exact as will be shown later. In human toxicity studies in Phase I clinical trials, intravenous administration of A10 at doses up to 2.21 g / kg / day was associated with minimal side effects, including febrile reaction, muscle and joint pain, muscle contraction in the throat, abdominal pain of short duration, and individual incidences of nausea, vertigo and headache (Drugs Exptl Clin Res 1986, 12 Suppl 1, 47-55). Oral administration of AS2-1 at doses up to 238 mg / kg / day was associated with a moderate temporary reduction in the white blood cell count in one patient. Injection of AS2-1 at doses of up to 160 mg / kg / day was associated with minimal side effects, including mild nausea and vomiting, allergic skin reaction, moderate elevation of blood pressure, febrile reaction, moderate reduction in blood count. white blood cells (in each patient) and moderate electrolyte imbalance in three patients. Clinical experiments determined that 3-phenylacetylamino-2,6-piperidinedione, A10 and AS2-1 were effective in the treatment of cancer. Burzynski et al. (Drugs Exptl. Clin. Res. 12 Suppl 1, 25-35 (1986)) reported that an intravenous solution of antineoplaston AS2.1 (100 mg / ml of active ingredients) was injected into patients at doses of not more than 0.16. g / kg / day. Of 21 cases of neoplastic disease, six complete remissions, two partial remissions, seven stabilizations and six cases of progressive disease were observed. Phase II clinical trials were conducted, where patients with astrocytomas were infused with A10 (100 mg / ml) at dose levels of 0.5 to 1.3 g / kg / day or with AS2-1 (100 mg / ml) at levels of doses from 0.2 to 0.5 g / kg / day for 67 to 706 days (in: Recent Advances in Chemotherapy, Adam, D., ed., Munich: Futuramed, 1992). Of 20 patients, four experienced complete responses, two experienced partial responses, ten they experienced stabilizations and four experienced progressive disease. In Samid, patent of E.U.A. 5,605,930 (all the content of which is incorporated herein by reference), phenyl sodium acetate was used only in the treatment of cancer in humans, and was administered in doses no greater than 0.3 g / kg / day. However, a number of disadvantages were noted for the low concentrations, flow regimes and dose of intravenous solutions. First, Burzynski et al., (Drugs Expt. Clin. Res. 12 Suppl 1, 11-16 (1986)) reported a complete colony reduction of tumor cell lines HBL-100 and Ki No.1 with 5.0 mg / ml either phenylacetic acid or antineoplaston AS2-1. Similarly, cytostasis was observed for the human breast carcinoma cell line MDA-MB-231 using concentrations of 3-phenylacetylamino-2,6-piperidinedione of 2.0 mg / ml and AS2-1 of 3.0 mg / ml. However, 3-phenylacetylamino-2,6-piperidinedione is poorly soluble in water, and when administered orally to rats, the peak level in plasma is about 0.2 mg / ml, about 10 times less than the observed cytostatic concentration in tissue culture experiments. Under typical administration regimens of antineoplaston AS2-1, peak plasma levels of phenylacetic acid with approximately 0.43 mg / ml, approximately 7 times less than the cytostatic concentration observed in tissue culture experiments. Also, both 3-phenylacetylamino-2,6-piperidinedione, its hydrolysis products and AS2-1 are quickly cleared in vivo. Also, during the consumption of antineoplastons by the tumor tissue, a concentration gradient is formed between the outside of the tumor tissue, at which the concentration of antineoplaston will be equal to the concentration in the plasma, and a point or points in the interior of the tumor tissue, to which the concentration of antineoplaston will be at a minimum, and may be zero. The relatively low plasma concentrations of anti-cancer agents, therefore, will lead to some internal portion of the tumor tissue by avoiding the consumption of the anti-cancer agent and remaining in its cancerous state. Secondly, the administration of a solution comprising the hydrolysis products of 3-phenylacetylamino-2,6-piperidinedione at low infusion rates of 2.5 ml / h at 84 ml / h frequently results in the elevation in product levels of waste in the plasma. An illustrative waste product thus raised in uric acid. This elevation interferes with the treatment requiring either a reduction in dose or an interruption in treatment to administer additional drugs, for example, Allopurinol, to reduce the level of the waste product, for example, uric acid. Therefore, it is desirable to have intravenous formulations of pharmaceutical compositions of amino acid analogues with anti-cancer activity, wherein the intravenous formulations provide high concentrations of the active ingredient or ingredients in the plasma in order to fully penetrate tumors with effective amounts of the active ingredient or ingredients. It is also desirable that such intravenous formulations do not lead to high levels of waste products in the plasma.

COMPENDIUM OF THE INVENTION The present invention relates to a method for the treatment of neoplastic disease, including cancer, which comprises administering a pharmaceutical composition to a patient, the pharmaceutical composition comprising a phenylacetylglutamine compound of the formula I and a phenylacetylisoglutamine compound of the formula III. The compound of the formula I is present in a weight ratio of 4: 1 for a phenylacetylisoglutamine compound of the formula III. Formula I is represented by the structure: wherein R and Ri are independently selected from the group consisting of H, lower alkoxy (C? _6) or lower alkyl (C? _6); R2 is selected from the group consisting of aryl (C6.?2) and substituted aryl; M is hydrogen, a salt-forming cation, such as sodium, potassium, or ammonium, diethanolamine, cyclohexylamine, a naturally-occurring amino acid with a molecular weight of less than 500 kD, lower alkyl (d6), cycloalkyl or aryl (C6_) ?2); n is 0-5. Preferably, M is hydrogen or sodium; n is 0; R is selected from the group consisting of H and C3H7; R, is selected from the group consisting of H, CH3, CH3-O-C2H5 and C3H7; and R2 is aryl selected from the group consisting of Formula II: Formula II wherein X is halogen, lower alkyl (C, .β), lower alkoxy (Ci-β), cycloalkyl, cycloalkoxy, aryl (C6-? 2), substituted aryl or hydroxy and n is 0, 1, 2, 3 or 4 Most preferably, R2 is phenyl or is selected from the group of formula II, wherein X is selected from Cl, F, or OH. Most preferably, R2 is phenyl or phenyl chloride. In addition, the compound of the formula I can be used as a racemic mixture or as separate optical isomers or any combination thereof. Formula III is represented by the structure: wherein R and Ri are independently selected from the group consisting of H, lower alkoxy (C? _6) or lower alkyl (C? _6); R2 is selected from the group consisting of aryl (C6.?2) and substituted aryl; M is hydrogen, a salt-forming cation, such as sodium, potassium, or ammonium, diethanolamine, cyclohexylamine, a naturally-occurring amino acid with a molecular weight less than 500 kD, lower alkyl (d6), cycloalkyl or aryl (C6) -?2); and n is 0-5. Preferably, M is hydrogen or sodium; n is 0; R is selected from the group consisting of H and C3H7; R *, is selected from the group consisting of H, CH3, CH3-O-C2H5 and C3H7; and R2 is an aryl (C6.12) or a substituted aryl selected from the group consisting of formula II, wherein X is halogen, lower (C1-6) alkyl, lower alkoxy (d.6), cycloalkyl, cycloalkoxy, aryl (C6.?2), substituted aryl or hydroxy and n is 0, 1, 2, 3, or 4. Most preferably, R2 is phenyl or substituted aryl of formula II, wherein X is selected from Cl, F, or OH. Most preferably, R2 is phenyl or phenyl chloride. Also, the compound of the formula III can be used as a racemic mixture or as separate optical isomers or any compound thereof. In the composition, the combined concentration of the phenylacetylglutamine compound of the formula I and the compound of phenylacetylisoglutamine of formula III in an aqueous solution is from about 200 mg / ml to about 350 mg / ml, and the composition is administered at an infusion rate of 2.5 ml / h at 400 ml / h, preferably 100 ml / h 400 ml / h. In a further embodiment, the present invention relates to a method for the treatment of a neoplastic disease, including cancer, comprising administering a pharmaceutical composition, the pharmaceutical composition comprising a phenylacetic acid compound of the formula IV: Formula IV wherein R and R are independently selected from the group consisting of H, lower alkoxy (d.6) or lower alkyl (d.6); R2 is selected from the group consisting of (C6.12) aryl and substituted aryl; M is hydrogen, a salt-forming cation, such as sodium, potassium, or ammonium, diethanolamine, cyclohexylamine, a naturally-occurring amino acid with a molecular weight less than 500 kD, lower alkyl (d6), cycloalkyl, or aryl ( C6-? 2); and n is 0-5. Preferably, M is hydrogen or sodium; n is 0; R is selected from the group consisting of H and C3H7; R < is selected from the group consisting of H, CH3, CH3-O-C2H5 and C3H7; and R2 is an aryl selected from the group consisting of Formula II, wherein X is halogen, lower alkyl (de), lower alkoxy (d.6), cycloalkyl, cycloalkoxy, aryl (C6.12), substituted aryl or hydroxy and n is 0, 1, 2, 3, or 4. Most preferably, R2 is phenyl or substituted aryl selected from the group consisting of formula II, wherein X is selected from Cl, F or OH. Very preferably, R2 is phenyl or phenyl chloride. In another embodiment, the compound of formula IV is present in a weight ratio of 4: 1 for a compound of formula I, typically in aqueous solution. In the composition, the combined concentration of the compound of the formula I and the compound of the formula IV is from about 70 mg / ml to about 150 mg / ml, and the composition is administered at an infusion rate of 2.5 ml / hr. ml / h, preferably 100 ml / h at 400 ml / h. In still another embodiment, the present invention relates to a pharmaceutical composition comprising a compound of formula IV in a ratio of 4: 1 for a compound of formula III, wherein the combined concentration of the compound of formula IV and the compound of the formula III is from about 200 mg / ml to about 350 mg / ml, and the composition is administered at an infusion rate of 2.5 ml / h at about 400 ml / h, preferably from 100 ml / h at 400 ml / h.

These flow rates are even higher than any previously reported for anti-cancer agents. The high flow velocity is beneficial for the treatment of cancer since it allows to reach concentrations, in the blood, of the agents antineoplaston A10 assets approximately as much as twice as much with conventional lower infusion rates. The high flow rates allow to reach concentrations in the blood, which are comparable with those that show activity against cancer in tissue culture, and also allow superior penetration of the tumor tissue. The high flow rates, therefore, are more effective than the higher infusion rates in the treatment of cancer.

DESCRIPTION OF ILLUSTRATIVE MODALITIES As used herein, the term "antineoplaston A10" is defined as a mixture of the sodium salts of phenylacetylglutamine and phenylacetylisoglutamine in a ratio of 4: 1. As used herein, the terms "antineoplaston" AS2-1"and" AS2-1"are defined as a mixture of the sodium salts of phenylacetic acid and phenylacetylglutamine in a ratio of 4: 1. As used herein, the term" patient "includes patients humans and The invention will be described in terms of preferred embodiments known at the time of filing this application, which represent the best mode currently contemplated for making and using the pharmaceutical compositions of the present invention in the methods of the present invention.

A. Preparation of Pharmaceutical Compositions The pharmaceutical compositions of the present invention comprise, in one embodiment, a compound of Formula I: Formula I wherein R and Ri are independently selected from the group consisting of H, lower alkoxy (d-e) or lower alkyl (C 1-6); R2 is selected from the group consisting of aryl (C6.?2) and substituted aryl; M is hydrogen, a salt-forming cation, such as sodium, potassium, or ammonium, diethanolamine, cyclohexylamine, a naturally occurring amino acid with a molecular weight less than 500 kD, alkyl (d.6), cycloalkyl or aryl (C6-) ?2); n is 0-5. Preferably, M is hydrogen or sodium; n is 0; R is selected from the group consisting of H and C3H7; R < is selected from the group consisting of H, CH3, CH3-O-C2H5 and C3H7; and R2 is an aryl (C6-? 2) selected from the group consisting of Formula II: Formula II T ^ xn wherein X is halogen, lower alkyl (d.6), lower alkoxy (de), cycloalkyl, cycloalkoxy, aryl (C6-? 2), substituted aryl or hydroxy and n is 0, 1, 2, 3 or 4. Most preferably , R2 is phenyl or substituted aryl selected from the group of formula II, wherein X is selected from Cl, F, or OH. Most preferably, R2 is phenyl or phenyl chloride. The compound of the formula I is present in a ratio of 4: 1 by mass for a compound of the formula III: Formula III wherein R and R are independently selected from the group consisting of H, lower alkoxy (d-e) or lower alkyl (C 1-6); R2 is selected from the group consisting of aryl (C6.i2) and substituted aryl; M is hydrogen, a salt-forming cation, such as sodium, potassium, or ammonium, diethanolamine, cyclohexylamine, a naturally occurring amino acid with a molecular weight less than 500 kD, alkyl (d e). cycloalkyl or aryl (C6.12); and n is 0-5. Preferably, M is hydrogen or sodium; n is 0; R is selected from the group consisting of H and C3H7; Ri is selected from the group consisting of H, CH 3, CH 3 -O-C 2 H 5 and C 3 H 7; and R2 is an aryl selected from the group consisting of Formula II, wherein X is halogen, lower alkyl (C e e), lower alkoxy (d.6), cycloalkyl, cycloalkoxy, aryl (C6.?2), substituted aryl or hydroxy and n is 0, 1, 2, 3 , or 4. Most preferably, R2 is phenyl or substituted aryl of formula II, wherein X is selected from Cl, F, or OH. Most preferably, R2 is phenyl or phenyl chloride. In the composition, the combined concentration of the compound of the formula I and the compound of the formula III is from about 200 mg / ml to about 350 mg / ml. Typically, a racemic mixture of each compound will be used; however, separate optical isomers can also be used. In a second embodiment, the pharmaceutical compositions of the present invention comprise an aqueous solution of a compound of formula IV: Formula IV wherein R and R are independently selected from the group consisting of H, lower alkoxy (d-ß) or lower alkyl (C? .ei); R2 is selected from the group consisting of (C6.12) aryl and substituted aryl; M is hydrogen, a salt-forming cation, such as sodium, potassium, or ammonium, diethanolamine, cyclohexylamine, an amino acid of existence natural with a molecular weight of less than 500 kD, (C1-6) alkyl, cycloalkyl, or aryl (C6-? 2); and n is 0-5. Preferably, M is hydrogen or sodium; n is 0; R is selected from the group consisting of H and C3H7; R * is selected from the group consisting of H, CH3, CH3-O-C2H5 and C3H7; and R2 is an aryl selected from the group consisting of formula II, wherein X is halogen, lower alkyl (d.6), lower alkoxy (de), cycloalkyl, cycloalkoxy, aryl (C6 *? 2), substituted aryl or hydroxy and n is 0, 1, 2, 3, or 4. Most preferably, R2 is phenyl or substituted aryl selected from the group consisting of formula II, wherein X is selected from Cl, F or OH. Most preferably, R2 is phenyl or phenyl chloride. The compound of the formula IV is present in a ratio of 4: 1 by mass for a compound of the formula I, and in the composition, the combined concentration of the compound of the formula I and the compound of the formula IV is about 70. mg / ml to approximately 150 mg / ml. In yet another embodiment of the invention, the compound of the formula IV is present in a ratio of 4: 1 by mass for a compound of the formula III, and in the composition, the combined concentration of the compound of the formula IV and the compounds of formula III is from about 70 mg / ml to about 150 mg / ml. Preferred compounds are, of the formula I, phenylacetylglutamine and sodium phenylacetylglutamine and the optical isomers L thereof; of the formula III, phenylacetylisoglutamine and sodium phenylacetylisoglutamine; and of formula IV, phenylacetic acid and phenyl sodium acetate. Phenylacetylglutamine can be isolated from the fluids of the human body, for example, urine, or can be synthesized by techniques known in the art, for example, the treatment of phenylacetic acid with N, N'-disuccinimidyl carbonate in acetonitrile followed by the reaction of L-glutamine in the presence of NaHCO3 in a 1: 1 mixture of acetonitrile / water. Phenylacetylglutamine can also be synthesized through the reaction of phenylacetyl chloride with L-glutamine in the presence of NaHCO3 in an aqueous solution. Still another method of synthesis that can be used is the treatment of 3-phenylacetylamino-2,6-piperidinedione with sodium hydroxide. Phenylacetylisoglutamine can be synthesized through the reaction of phenylacetyl chloride with L-glutamine to produce phenylacetylglutamine, with subsequent heating under vacuum at 160 ° C to produce 3-phenylacetylamino-2,6-piperidinedione, which can then be treated with sodium hydroxide. Also, phenylacetylisoglutamine can be prepared through the treatment of phenylacetic acid with N, N'-disuccinimide carbonate in acetonitrile followed by reaction with L-isoglutamine in the presence of NaHCO 3 in a 1: 1 mixture of acetonitrile / water. However, the second synthesis requires L-isoglutamine, which is expensive, so that the first synthesis route is preferred for reasons of economy.

Phenylacetic acid can be isolated from fluids of the human body, for example, urine, or can be synthesized by techniques known in the art, such as refluxing benzyl cyanide with dilute sulfuric or hydrochloric acid. Other compounds of formulas I, III and IV can be synthesized by techniques known in the art. For example, the acid addition salts can be generated from the free base forms of the compounds through the reaction of the latter with an equivalent of a pharmaceutically acceptable, non-toxic, suitable acid, followed by the evaporation of the solvent used for the reaction and recrystallization of the salt, if required. The free base can be recovered from the acid addition salt by reaction of the salt with a solution of water of the salt with a suitable base such as sodium carbonate, sodium hydroxide, and the like. "Pharmaceutically acceptable salts" means salts having the biological activity of the parent compound and lacking toxic activity at the selected level of administration. Again, the determination that if a salt is pharmaceutically acceptable can be achieved through methods known to those skilled in the art. The pharmaceutically acceptable salts of phenylacetylglutamine, phenylacetylisoglutamine and phenylacetic acid include, but are not limited to, inorganic, potassium and ammonium sodium salts, and organic salts of diethanolamine, cyclohexylamine and amino acid. Preferably, the salt is a sodium salt.

Suitable acids for forming acid addition salts of the compounds of the present invention include, but are not limited to, acetic, benzoic, benzenesulfonic, tartaric, hydrobromic, hydrochloric, citric, fumaric, glucuronic, glutamic, lactic, malic, maleic acids. , methanesulfonic, pamico, salicylic, stearic, succinic, sulfuric and tartaric. The class of acids suitable for the formation of pharmaceutically acceptable, non-toxic salts is well known to practitioners of the pharmaceutical formulating art. (See, for example, Stephen N. Berge, et al., J. Pharm. Sciences, 66: 1-19 (1977)). The compounds of the present invention can also exist in the different stereoisomeric forms by virtue of the presence of one or more asymmetric centers in the compound. The present invention contemplates all stereoisomeric forms of the compounds as well as mixtures thereof, including racemic mixtures. Individual stereoisomers can be obtained, if desired, by methods known in the art such as, for example, the separation of stereoisomers in chiral chromatographic columns. In addition, the compounds of the present invention can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like. In general, solvated forms are considered equivalent to unsolvated forms for the purposes of the present invention.

The precursors of phenylacetylglutamine, phenylacetylisoglutamine and phenylacetic acid can be used in the compositions herein. The precursors of phenylacetylglutamine, phenylacetylisoglutamine and phenylacetic acid are hereby defined as compounds that can be metabolized to produce phenylacetylglutamine, phenylacetylisoglutamine and phenylacetic acid in humans. The pharmaceutically acceptable precursors of phenylacetylglutamine, phenylacetylisoglutamine and phenylacetic acid are precursors lacking toxic activity at the selected administration level, either per se or as any metabolic intermediate between the precursor and the final compound. The determination that whether the phenylacetylglutamine, phenylacetylisoglutamine and phenylacetic acid precursors are pharmaceutically acceptable through the application of methods known to those skilled in the art. A preferred precursor of phenylacetylglutamine and phenylacetylisoglutamine is 3-phenylacetylamino-2,6-piperdinedione. A preferred precursor of phenylacetic acid for use in the present invention is phenyl butyrate, the structure of which is as follows: Phenyl butyrate For compounds of formulas I, III and IV, purification after synthesis may be required. Any known techniques can be used to purify the desired compound from other compounds and impurities, for example, HPLC and crystallization from water, among others. The compounds can be quantified by any known method. To prepare a pharmaceutical composition of antineoplaston A10, an aqueous solution of sodium phenylacetylglutamine and sodium phenylacetylisoglutamine in a ratio of 4: 1 is prepared, so that the concentration of phenylacetylglutamine in the solution is between 160 mg / ml and 280. mg / ml, and preferably between 230 mg / ml and 250 mg / ml; and the concentration of the phenylacetylisoglutamine in the solution is between 40 mg / ml and 70 mg / ml, and preferably between 55 mg / ml and 65 mg / ml. The preparation of the solution can be carried out using any technique known to those skilled in the art. It should be noted that the solution will become sterile, and the pH will be adjusted to a value at or near the plasma pH which is 7.4, for example, 7.0. The active ingredients can be prepared as any compound of the formulas I and III before the preparation of the solution, if desired. To prepare an antineoplaston pharmaceutical composition AS2-1 according to the present invention, an aqueous solution of sodium phenyl acetate and sodium phenylacetylglutamine is prepared in a ratio of 4: 1 by mass, so that the concentration of the phenyl is between 56 mg / ml and 120 mg / ml, and preferably between 62 mg / ml and 66 mg / ml; and the concentration of phenylacetylglutamine is between 14 mg / ml and 30 mg / ml, and preferably 15 mg / ml and 17 mg / ml. The preparation of the solution can be carried out using any technique known to those skilled in the art. It should be noted that the solution is going to be sterile, and the pH will be adjusted to a value at or near the physiological pH which is 7.4, for example, 7.0. The active ingredients can be prepared as any compounds of the formulas IV and I before the preparation of the solution, if said use is desired. Both for the antineoplaston A10 and for the antineoplaston AS2-1, the concentrations of active ingredients used are even higher than those used through any aqueous solution composition previously reported, known as anti-cancer agents. Optionally, all compositions according to the present invention may include other agents, such as pH, glucose, other sugars, preservatives, etc., suitable for use in pharmaceutical compositions prepared for intravenous administration, as is known in the art. .

B. Administration of Pharmaceutical Compositions The pharmaceutical compositions of the present invention are administered intravenously. The methods of administration intravenous are widely known in the art. In the present invention, the intravenous infusion flow rate of antineoplaston A10 can be between 2.5 ml / hour and 400 ml / hour for administration to adults and minors. Preferably, the intravenous flow rate is 100 ml / hour at 400 ml / hour. Typical flow rates are 250 ml / hour for adults and 100-250 ml / hour for children, with flow rates generally higher for younger children. These flow rates are even higher than any known previously reported for anti-cancer agents. The high flow rates are beneficial for the treatment of cancer, since they allow to reach concentrations, in the blood, of the antineoplaston active agents A10 approximately twice the conventional lower infusion rates. High flow rates that reach concentrations in the blood that are comparable to those that show activity against cancer in the tissue culture also allow superior penetration of the tumor tissue. The high flow rates are, therefore, more effective than the lower infusion rates in the treatment of cancer. The high flow rate of the antineoplaston A10 infusion and the high concentration of antineoplaston A10 produce a diuretic effect. The diuretic effect is beneficial for the patient since it avoids the fluid overload of large volumes of infusion. The diuretic effect is also beneficial for the patient since it provides a mechanism for the elimination of waste products, which otherwise accumulate in the body. The antineoplaston composition A10 of the present invention can be administered at the high flow rate of the present invention one or more times a day, for example, from 4 to 12 times a day, for a period of between 15 minutes and 24 hours . A typical administration regimen is 6 to 8 infusions / day, each infusion approximately 90 minutes to 120 minutes duration. In the case of a hypersensitivity reaction (usually manifested as a skin rash) by patients with antineoplaston A10, a desensitization protocol can be followed. The total daily dose is administered in 96 injections (ie, every 15 minutes) at a flow rate of 1 ml / minute at 4 ml / minute (240 ml / hour). The daily dose level of antineoplaston A10 can be between 0.6 g / kg / day and 24 g / kg / day. Preferably, the daily dose level of antineoplaston A10 is between 5.0 g / kg / day and 12.0 g / kg / day. Typically, the daily dose level of antineoplaston A10 is approximately 8.0 g / kg / day. The present invention is also directed to intravenous infusion of antineoplaston AS2-1. The flow rate of the intravenous infusion of antineoplaston AS2-1 can be between 2.5 ml / hour and 400 ml / hour for administration to adults and can be between 25 ml / hour and 400 ml / hour for administration to minors. Preferably, the intravenous flow rate is 100 ml / hour at 400 ml / hour for adults and children. Typical flow rates are 250 ml / hour for adults and 100-250 ml / hour for children, with generally higher flow rates for younger children. These flow rates are even higher than any known previously reported for anti-cancer agents. The high flow rates are beneficial in the treatment of cancer since they allow to reach concentrations, in the blood, of the antineoplaston active agents AS2-1 approximately twice the conventional lower infusion rates. As described above, high flow rates that reach concentrations in the blood that are comparable to those that show anti-cancer activity in the tissue culture also allow superior penetration of the tumor tissue. The high flow rate of the antineoplaston infusion AS2-1 and the high concentration of antineoplaston AS2-1 produce a diuretic effect. The diuretic effect is beneficial to the patient as it prevents fluid overload of large volumes of infusion, and provides a mechanism for the elimination of waste products, which otherwise accumulate in the body, as described above. The antineoplaston composition AS2-1 of the present invention can be administered at the high flow rate of the present invention one or more times a day, for example, from 4 to 12 times a day, for a period of between 5 minutes and 24 hours. A Typical administration regimen is 6 to 8 infusions / day, each infusion approximately 10 minutes to 120 minutes duration.

In the case of a hypersensitivity reaction (usually manifested as a skin rash) by patients with antineoplaston AS2-1, a desensitization protocol can be followed. The total daily dose is administered in 96 injections (ie, every 15 minutes) at a flow rate of 1 ml / minute at 4 ml / minute (240 ml / hour). The daily dose level of antineoplaston AS2-1 can be between 2.6 g / kg / day. Preferably, the daily dose level of antineoplaston AS2-1 is between 0.2 g / kg / day and 0.9 g / kg / day. Typically, the daily dose level of antineoplaston A10 is approximately 0.4 g / kg / day. The treatment regimen described above is useful for the treatment of patients suffering from all types of neoplastic disease, including cancer, both hard tissue and soft tissue types, and malignant and benign tumors. In particular, neoplastic diseases that are advantageously susceptible to treatment using the described treatment regimen of this invention include adrenal gland carcinoma, bladder carcinoma, breast carcinoma, high grade glioma, glioblastoma multiforme, astrocytoma including anaplastic and astrocytoma. of low grade, brain stem glioma, primitive neuroectodermal tumors including medulloblastoma and pinealoblastoma, rhabdoid tumor of the central nervous system, mixed glioma, neurofibroma, schwannoma, visual pathway glioma, ependymoma, germ cell tumors, meningioma, carcinoma of the colon and rectum, carcinoma of the esophagus, primary and metastatic liver cancer, carcinoma of the head and neck, adenocarcinoma of the lung, undifferentiated cell carcinoma large lung, bronchial-alveolar carcinoma of the lung, squamous cell carcinoma of the lung, non-small cell carcinoma of the lung, non-Hodgkin lymphomas, chronic leukemias, mesothelioma, malignant melanoma, malignant fibrous histiocytoma, multiple myeloma, neuroblastoma, tumors neuroendocrine, carcinoma of the ovary, carcinoma of the pancreas, primitive neuroectodermal tumors outside the central nervous system, adenocarcinoma of the prostate, carcinoma of the kidney, sarcomas, carcinoma of the small intestine, carcinoma of the stomach, carcinoma of the uterus, carcinoma of the vulva, and carcinoma of an unknown primary. The following examples are included to demonstrate preferred embodiments of the invention. It should be appreciated by those skilled in the art that the techniques described in the examples that follow represent techniques discovered by the inventor to function well in the practice of the invention., and in this way can be considered to be preferred modes for their practice. However, those skilled in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific modalities, which are described and still obtain a similar or similar result without departing from the spirit and scope of the invention.

EXAMPLE 1 We treated 43 patients with primary malignant brain tumors with intravenous administration of antineoplaston A10 at an average dose of 7.9 g / kg / day and antineoplaston AS2-1 at an average dose of 0.39 g / kg / day. Of the 43 patients, 36 were evaluable, and 16 obtained complete or partial responses until the end of the therapy without serious side effects. Of the 43 patients, all but one were diagnosed with histologically confirmed primary brain tumors. The remaining patient presented a primary brain tumor in the brainstem, where the biopsy could not be performed with adequate safety. Fourteen patients were diagnosed with glioblastoma multiforma and six patients were diagnosed with anaplastic astrocytoma. The patients had an age on the scale of 2 to 71. Patients were selected for Karnofsky Performance Status from 40 to 100, with a possibility of life of more than two months, and an age of 1 year. Patients with liver failure, hypertension not adequately controlled, or those who are pregnant or breastfeeding were excluded. All patients previously underwent surgery or chemotherapy and / or radiation therapy with negative results.

The formulation of antineoplaston A10 was made as described above, with between 230 mg / ml and 250 ml / ml of phenylacetylglutamine and between 55 mg / ml and 65 mg / ml of phenylacetylisoglutamine and the pH was adjusted to 7.0. The formulation of antineoplaston AS2-1 was made as described above, with between 62 mg / ml and 66 mg / ml of phenyl-sodium acetate and between 15 mg / ml and 17 mg / ml of phenylacetylglutamine and the pH was adjusted to 7.0 Patients received intravenous injections of the antineoplastons through an individual lumen subclavicular catheter (Broviac, Groshong or equivalent). Patients received dose of gradual scale through multiple intermittent injections using a programmable portable dual channel Abbott Provider 6000 pump six times a day. Infusion rates for adults were 250 ml / hour and for people younger than 18, the infusion rates were 50-100 ml / hour, depending on the tolerance. The infusions were administered for periods ranging from 91 days to 3509 days, with an average treatment duration of 661 days. The average dose of antineoplaston A10 was 7.91 g / kg / day and the average dose of AS2-1 was 0.39 g / kg / day. The total dose of antineoplaston A10 was 551,865 kg and the maximum total dose of AS2-1 was 59,348 kg. Before starting treatment, the evaluable patients recovered completely from the surgery, if it was performed, or the chemotherapy was removed for at least 4 weeks (6 weeks if the chemotherapy consisted of nitrosoureas) and / or the therapy was removed. radiation for at least 6 weeks. A complete response was judged as a total disappearance of all tumors by contrast enhancement or imaging studies (MRl, etc.) for 4 weeks or more. A partial response was judged as a reduction of more than 50% in the sum of products of the largest perpendicular diameters of contrast enhancement tumors for at least 4 weeks without the appearance of new lesions. A stable disease state was judged as a change of less than 50% (either increase or decrease) in the sum of the products of the largest perpendicular diameters of contrast enhancement tumors for a minimum of 12 weeks. A progressive disease state was judged as an increase greater than 50% in the sum of the products of the larger perpendicular diameters of contrast enhancement tumors, or the appearance of new lesions. Of the 36 patients evaluated, 7 (19.5%) obtained complete answers. Nine patients (25%) obtained a partial response. Stable disease was observed in 12 patients (33.3%). Progressive disease developed in 8 patients (22.2%). A number of adverse drug experiences were observed during the experiment, including hypernatremia, hypochloremia, hyperchloremia, hypokalemia, skin urticaria, drowsiness, weakness, nausea and vomiting, headaches, poor pronunciation, confusion, hallucinations, fever and fluid retention. The majority of the adverse drug experiences were moderate and did not significantly interrupt the treatment program. For example, there were 23 cases of hypernatremia no more than 150 mEq / L, 12 cases no greater than 160 mEq / L, and two cases no greater than 170 mEq / L. Hypochloremia was identified in six cases and hyperchloremia in two cases. There were seven cases of hypokalemia no more than 2.8 mEq / L. The dose limiting factor for antineoplaston A10 appeared to be the volume of intravenous fluid, and for AS2-1 the dose limiting factor is increased drowsiness and weakness. Of the 16 patients classified with complete or partial responses, 13 remained alive, as 8 patients classified as stable disease, progressive disease and not evaluable. Most of the surviving patients are now alive, for more than four years, since the diagnosis of pathology, and two patients, one with oligodendroglioma and the other with low-grade astrocytoma, survived approximately 12 years from the diagnosis of the pathology. Therefore, the treatment of cancer through intravenous administration of highly concentrated aqueous solutions of antineoplaston A10 and antineoplaston AS2-1 at high flow rates and at high daily doses according to the present invention resulted in a partial or complete response in almost 50% of patients evaluated with adverse drug experiences minimum.

EXAMPLE 2 A Phase II clinical study of antineoplaston A10 and AS2-1 was conducted in twelve patients with high-grade glioma. Seven patients were diagnosed with glioblastoma multiforme, four patients were diagnosed with anaplastic astrocytoma and one patient was diagnosed with brainstem glioma with multiple metastases. Patients received continuous antineoplaston infusions A10 and AS2-1 from 41 to 713 days. The dose levels of antineoplaston A10 were from 0.9 g / kg / day to 1.7 g / kg / day, and the dose levels of AS2-1 were from 0.2 g / kg / day to 0.8 g / kg / day. Adverse drug experiences of moderate nature and sporadic occurrence were observed in five patients in the experiment. Two patients exhibited a moderate, temporary reduction in the white blood cell count and one patient exhibited a temporary reduction in the red blood cell count and hemoglobin. Two patients had hypokalemia and hypoglycemia, one patient had increased fluid retention, and one patient had abdominal cramps and nausea during treatment. A complete response was observed in two patients, and a partial response was observed in two patients. Four patients experienced stabilization, and four patients experienced progressive disease.

EXAMPLE 3 A Phase II study of antineoplaston A10 and AS2-1 was conducted in 11 patients with tumors in the brain. The dose levels of antineoplaston A10 were 3.9 g / kg / day to 12.9 g / kg / day, and the dose levels of AS2-1 were 0.20 g / kg / day to 0.40 g / kg / day. Eight patients were evaluable. The partial response was observed in five patients after finishing the treatment. The patients suffered from tumors in the brain. Injections of antineoplaston A10 and AS2-1, 6 x day were administered at 250 ml / hour using a subclavicular catheter and a dual channel infusion pump as described in Example 1. The duration of the treatment varied from 44 days to 480 days , with an average treatment duration of 195 days. The dose levels of antineoplaston A10 were 3.9 g / kg / day to 12.9 g / kg / day with an average dose of 7.2 g / kg / day. The dose levels of AS2-1 were from 0.20 g / kg / day to 0.40 g / kg / day, with an average dose of 0.29 g / kg / day. The maximum total dose of antineoplaston A10 was 381,738 kg and the maximum total dose of AS2-1 was 9,702 kg. Of the eight patients evaluated in the study, a partial response was observed for five patients, stable disease was observed in two patients, and one patient developed progressive disease. Several possible adverse experiences with the drug were identified, consisting of hypernatremia, hypochloremia, creatinine elevated, allergy, drowsiness, weakness, fever and arthralgia. The experiences adverse to the drug were moderate and did not present a significant impact on the continuation of the treatment; specifically, there were two cases of hypernatremia no greater than 150 mEq / l and four cases no greater than 160 mEq / l. One case of hypochloremia was identified at 82 mEq / L, as well as three cases of hypokalemia no greater than 2.5 mEq / L. Therefore, the treatment of cancer through intravenous administration of highly concentrated aqueous solutions of antineoplaston A10 and antineoplaston AS2-1 at high flow rates and at high daily doses according to the present invention resulted in a partial or complete response in 62.5% of patients evaluated with minimal adverse drug experiences.

EXAMPLE 4 A Phase II study of antineoplaston A10 and AS2-1 was conducted in 15 patients with brainstem glioma. Antineoplaston dose levels A10 varied from 5.27 g / kg / day to 16.06 g / kg / day, and dose levels of AS2-1 ranged from 0.20 g / kg / day to 0.57 g / kg / day. A complete response was observed in two patients and two other patients obtained a partial response. Fifteen patients with brainstem gliomas were accumulated in the study, of which 14 were evaluated. The patients received injections of antineoplaston A10 and AS2-1, 6 x day as described in Example 1. The dose levels of antineoplaston A10 varied from 5.27 g / kg / day to 16.06 g / kg / day, with an average dose of 9.47 g / kg / day. The dose levels of AS2-1 ranged from 0.20 g / kg / day to 0.57 g / kg / day, with an average dose of 0.37 g / kg / day. The maximum total dose of antineoplaston A10 was 311.985 kg and AS2-1 was 9.912 kg. Of the 14 patients evaluated, a complete response was observed in two patients and two other patients obtained a partial response, according to the definitions given in Example 1. Stable disease was observed in five patients and five patients developed progressive disease. Several adverse experiences per drug were identified, possibly related to antineoplaston treatment A10 and AS2-1. These consisted of hypernatremia, hypokalemia, allergic skin urticaria, elevated transaminases, drowsiness, weakness, dyspnea, nausea and vomiting, diarrhea, fever, and arthralgia. There were eight cases of hypernatremia no greater than 150 mEq / l, three cases no greater than 165 mEq / l, and one case of 189 mEq / l. Hypokalemia not less than 2.5 mEq / l was identified in two cases. The adverse drug experiences were moderate and did not have a significant impact on the continuation of the treatment. Therefore, the treatment of cancer through intravenous administration of highly concentrated aqueous solutions of antineoplaston A10 and antineoplaston AS2-1 to High flow rates and high daily doses according to the present invention resulted in a partial or complete response in almost 30% of the patients evaluated with minimal adverse drug experiences.

EXAMPLE 4 A Phase II study of antineoplaston A10 and AS2-1 was conducted in 12 adult patients with mixed glioma. Nine patients were evaluated. Antineoplaston dose levels A10 were 3.5 g / kg / day at 12.1 g / kg / day, and dose levels of AS2-1 ranged from 0.24 g / kg / day to 0.40 g / kg / day. Of nine patients evaluated, complete responses were determined in three patients and one patient had a partial response. Patients received antineoplaston A10 injections and AS2-1 as described in Example 1. The duration of treatment varied from 32 days to 615 days, with an average treatment duration of 191 days. The dose levels of antineoplaston A10 were 3.5 g / kg / day at 12.1 g / kg / day, with an average dose level of 7.6 g / kg / day. The dose levels of AS2-1 were 0.24 g / kg / day at 0.40 g / kg / day, with an average dose level of 0.33 g / kg / day. The maximum total dose of antineoplaston A10 was 192,907 kg and for AS2-1 it was 11,189 kg. Of the twelve patients, nine were evaluable. Of these nine, complete responses were determined in three patients and a The patient obtained a partial response, according to the definitions given in Example 1. Stable disease was observed in two patients, and three patients developed progressive disease. Several adverse drug experiences were found possibly related to antineoplaston treatment A10 and AS2-1. These consisted of hypernatremia, hypokalemia, diarrhea and nausea. There were eight cases of hypernatremia no greater than 150 mEq / L, three cases no greater than 160 mEq / L. Hyperchloremia of 111 mEq / L and hypokalemia not less than 3.1 mEq / L were identified in one case. Adverse drug experiences were moderate and had no significant impact on the continuation of antineoplaston administration.

Summary of Toxicity Observations in Clinical Experiments The incidence of adverse drug experiences was analyzed from the data collected from 1,003 patients with various types of diseases introduced in 67 Phase II study protocols approved by the FDA. Some, but not all, of the Phase II protocols are described in detail in the previous Examples. Since in many cases patients who participated in the clinical studies had advanced cancer with short-lived experiences, it was usually difficult to identify whether the Side effects were due to the advanced stage of the diseases or to the antineoplaston treatment regimen. In any case, only 1.7% of patients experienced serious toxicity (Grade 3 or 4). In Phase II clinical trials of antineoplaston A10 and AS2-1, and also special exceptions, 0.3% of patients experienced Grade 4 toxicity, specifically individual cases of hypernatremia, thrombocytopenia and hyperbilirubinemia. 1.4% of patients experienced Grade 3 toxicity, specifically hypernatremia, hypocalcemia, hypokalemia, hypomagnesemia, elevated SGOT or elevated SGPT. Grade 2 toxicity was observed in 18.6% of patients, and included fever in the absence of infection (3.3%), hypokalemia (3.0%), hypernatremia (2.0%), hypochloremia (1.9%) and neurocortical symptoms such as confusion and drowsiness (1.5%). Between 0.5% and 0.9% of patients experienced allergy, hypomagnesemia, neuroaudition symptoms, vomiting, neurocerebellar symptoms such as vertigo and mispronunciation, nausea or hyperchloremia. Less than 0.5% of patients experienced reduced hemoglobin, hypocalcemia, increased SGPT, fluid retention, neuromotor weakness, or neurovission symptoms; Individual cases of chills, diarrhea, granulocytopenia, leukopenia, lymphocytopenia, headache, polyneuropathy and elevated SGOT were also observed. Grade 1 toxicity in the form of abnormalities of Laboratory and minor symptoms were experienced in the majority of patients, including hypernatremia (54.3%), hypokalemia (18.0%), allergy (14.2%), neurocortical symptoms (9.1%), neuromotor weakness (7.8%), vomiting (7.6%) ), hypochloremia (7.1%), nausea without vomiting (6.8%) and fever in the absence of infection (6.0%). Local toxicity was observed in 7.5% of the patients, very commonly as astralgia, as myalgia and erythema nodosum also observed. Additional Grade 1 toxicity was observed for between 1.0% and 5.0% of patients with hyperchloremia, headache, neurocerebellar symptoms, diarrhea, fluid retention, hypomagnesemia, neuroaudition symptoms, hyponatremia, and pulmonary dyspnea. Rare adverse drug experiences (less than 1.0%) included hypocalcemia, chills, constipation, neurovision symptoms, elevated SGOT and SGPT, hypertension, increased epidermalization, thrombocytopenia and individual cases of elevated alkaline phosphatase, bilirubin, creatinine or granulocytopenia, reduced hemoglobin and hypercalcemia. Almost all patients experienced increased diuresis (98.3%) and mild thirst, most likely experienced with the administration of large volumes of intravenous fluids. The high incidence of hypernatraemia is very likely explained by the consumption of antineoplastic compounds such as sodium salts, dehydration and malignant tumors, especially brain and liver tumors. The maximum doses administered were 25 g / kg / day of antineoplastons A10 and 2.59 g / kg / day of AS2-1. All compositions and methods described and claimed herein may be made and executed without undue experimentation in light of the present disclosure. Since the compositions and methods of this invention have been described in terms of preferred embodiments, it will be apparent to those skilled in the art that variations may be applied to the compositions and methods and to the steps or sequence of steps of the method described herein. without departing from the concept, spirit and scope of the invention. More specifically, it will be apparent that certain agents that are both chemically and physiologically related can be substituted for the agents described herein, while the same or similar results could be achieved. All of these substitutes and similar modifications apparent to those skilled in the art are intended to be within the spirit, scope and concept of the invention as defined in the appended claims.

REFERENCES The following references, to the extent that they provide an illustrative procedure or other details supplementary to those set forth herein, are specifically incorporated herein by reference. Burzynski, patent of E.U.A. 4,470,970 Burzynski et al. Drugs Exptl. Clin. Res. 12 Suppl. 1, 25-35 (1986) Burzynski et al. (Drugs Exptl. Clin. Res. 12 Suppl 1, 11-16 (1986)) Samid, patent of E.U.A. 5,605,930

Claims (22)

1. CLAIMS 1. - A pharmaceutical composition comprising a compound of Formula I: where R and R < are independently selected from the group consisting of H, lower alkoxy (d-β) and lower alkyl (d_6); R2 is selected from Formula II: wherein X is halogen, lower alkyl (C1 6), lower alkoxy (d.e), cycloalkyl, cycloalkoxy, aryl (C6-? 2), substituted aryl or hydroxy and n is 0, 1, 2, 3 or 4; M is hydrogen, a salt-forming cation, C e) alkyl, cycloalkyl, or aryl (C6-? 2); and n is 0-5; and a compound of Formula III: wherein R and R are independently selected from the group consisting of H, lower alkoxy (d e) and lower alkyl (d_6); R2 is selected from Formula II.
2. 2. The pharmaceutical composition according to claim 1, wherein in the compound of Formula I, M is hydrogen or sodium; n is 0; R is H or C3H7; R < It is selected from the group consisting of H, CH 3, CH 3 -O-, C 2 H 5 and C 3 H 7; R2 is selected from Formula II, wherein X is Cl, F or OH, and wherein in the compound of Formula III, M is hydrogen or sodium; n is 0; R is selected from the group consisting of H and C3H7; Ri is selected from the group consisting of H, CH 3, CH 3 -O-, C 2 H 5 and C 3 H 7; R2 is selected from Formula II, wherein X is Cl, F, or OH.
3. 3. The pharmaceutical composition according to claim 1, wherein the compound of the Formula I is phenylacetylglutamine or pharmaceutically acceptable salts thereof, and the compound of the Formula III is phenylacetylisoglutamine or pharmaceutically acceptable salts thereof.
4. 4. The pharmaceutical composition according to claim 3, characterized in that it also comprises sufficient water to form an aqueous solution of phenylacetylglutamine and phenylacetylisoglutamine, wherein the combined concentration of phenylacetylglutamine and phenylacetylisoglutamine is from about 200 mg / ml to about 350 mg / ml.
5. 5. The pharmaceutical composition according to claim 4, wherein the combined concentration is about 300 mg / ml.
6. 6. The pharmaceutical composition according to claim 1, wherein the compound of Formula I is present in a ratio of about 4: 1 by weight for the compound of Formula III.
7. 7. A pharmaceutical composition comprising a compound of Formula IV: R wherein R and R are independently selected from the group consisting of H, lower alkoxy (C 1-6) and lower alkyl (C 1-6); R2 is selected from Formula II: n wherein X is halogen, lower alkyl (C1 6), lower alkoxy (C1-6), cycloalkyl, cycloalkoxy, aryl (C6-? 2), substituted aryl or hydroxy and n is O, 1, 2, 3 or 4; M is hydrogen, a salt-forming cation, alkyl (d.6), cycloalkyl, or aryl (C6-? 2); and n is 0-5; and a compound of Formula I: wherein R and R (are independently selected from the group consisting of H, lower alkoxy (de) and lower alkyl (d_6); R 2 is selected from Formula II, wherein R and R (are independently selected from the group consisting of H, lower alkoxy (d-β) and lower alkyl (d.6): R 2 is selected from Formula II, wherein the compound of Formula IV and the compound of Formula I are present in a ratio of about 4: 1 by weight, and sufficient water to form an aqueous solution of the compound of the formula IV and the compound of the formula I, wherein the combined concentration of the compound of the formula IV and the compound of the formula I is about 70 mg / ml at approximately 150 mg / ml 8. The pharmaceutical composition according to claim 7, wherein in the compound of Formula IV, M is hydrogen or sodium; n is 0; R is H or C3Hr; R- is selected from the group consisting of H, CH 3, CH 3 -O-, C 2 H 5 and C 3 H 7; R2 is selected from Formula II, wherein X is Cl, F or OH; and wherein in the compound of formula I, M is hydrogen or sodium; n is 0; R is H or C3H7; R-, is selected from the group consisting of H, CH 3, CH 3 -O-, C 2 H 5 and C 3 H 7; R2 is selected from Formula II, wherein X is Cl, F or OH. 9. The pharmaceutical composition according to claim 7, wherein in the compound of Formula IV is phenylacetic acid or pharmaceutically acceptable salts thereof, and the compound of Formula I is phenylacetylglutamine or pharmaceutically acceptable salts thereof. 10. The pharmaceutical composition according to claim 9, wherein the combined concentration is about 80 mg / ml. 11. A pharmaceutical composition comprising a compound of Formula IV: wherein R and R are independently selected from the group consisting of H, lower alkoxy (d.6) and lower alkyl (d.6); R2 is selected from Formula II: n wherein X is halogen, lower alkyl (d.6), lower alkoxy (d.6), cycloalkyl, cycloalkoxy, aryl (C6-? 2), substituted aryl or hydroxy and n is 0, 1, 2, 3 or 4; M is hydrogen, a salt-forming cation, alkyl (d.6), cycloalkyl, or aryl (C6-? 2); and n is 0-5; and a compound of Formula III: wherein R and R (are independently selected from the group consisting of H, lower alkoxy (d.6) and lower alkyl (d.6); R2 is selected from Formula II 12.- The pharmaceutical composition according to Claim 11, wherein in the compound of Formula IV, M is hydrogen or sodium, n is 0, R is H or C3H7, RT is selected from the group consisting of H, CH3, CH3-O-, C2H5 and C3H7; R2 is selected from Formula II, wherein X is Cl, F or OH, and wherein in the compound of Formula III, M is hydrogen or sodium, n is 0, R is H or C3H7, R is selected from group consisting of H, CH3, CH3-O-, C2H5 and C3H7; R2 is selected from Formula II, wherein X is Cl, F, or OH. 13 -. 13 - The pharmaceutical composition according to claim 11, wherein in the compound of Formula IV is phenylacetic acid or pharmaceutically acceptable salts thereof, and the compound of Formula III is phenylacetylisoglutamine or pharmaceutically acceptable salts thereof. 14. The pharmaceutical composition according to claim 13, wherein the combined concentration is about 80 mg / ml. 15. The pharmaceutical composition according to claim 11, wherein the compound of Formula IV and the compound of Formula III are present in a ratio of 4: 1 by weight. 16. The pharmaceutical composition according to claim 11, characterized in that it also comprises sufficient water to form an aqueous solution of the compound of the formula IV and the compound of the formula III, wherein the combined concentration of the compound of the formula IV and the compound of Formula III is from about 70 mg / ml to about 150 mg / ml. 17. A pharmaceutical composition comprising a compound of Formula I: wherein R and R are independently selected from the group consisting of H, lower alkoxy (d.6) and lower alkyl (d.6); R2 is selected from Formula II: n wherein X is halogen, lower alkyl (d.6), lower alkoxy (C1-6), cycloalkyl, cycloalkoxy, aryl (C6-? 2), substituted aryl or hydroxy and n is 0, 1, 2, 3 or 4; M is hydrogen, a salt-forming cation, alkyl (C? .6), cycloalkyl, or aryl (C6-? 2); and n is 0-5; said compound of the Formula I being a racemic mixture, optical isomer L or R, or mixtures thereof; and a pharmaceutically acceptable diluent. 18. The pharmaceutical composition according to claim 17, wherein in the compound of Formula II, M is hydrogen or sodium; n is 0; R is H or C3H7; R < is selected from the group consisting of H, CH 3, CH 3 -O-, C 2 H 5 and C 3 H 7; R2 is selected from the Formula II, wherein X is Cl, F or OH. 19. The pharmaceutical composition according to claim 17, wherein in the compound of Formula I is phenylacetylglutamine or its pharmaceutically acceptable salts. 20. The pharmaceutical composition according to claim 17, characterized in that it also comprises sufficient water to form an aqueous solution of the phenylacetylglutamine in a concentration ranging from about 200 mg / ml to about 350 mg / ml. 21. A pharmaceutical composition comprising a compound of Formula III: wherein R and R are independently selected from the group consisting of H, lower alkoxy (d.6) and lower alkyl (C? β); R2 is selected from Formula II: wherein X is halogen, lower alkyl (d-6), lower alkoxy (d.6), cycloalkyl, cycloalkoxy, aryl (C6-? 2), substituted aryl or hydroxy and n is 0, 1, 2, 3 or 4; M is hydrogen, a salt-forming cation, alkyl (d.6), cycloalkyl, or aryl (C6-? 2); and n is 0-5; said compound of the Formula I being a racemic mixture, optical isomer L or R, or mixtures thereof; and a pharmaceutically acceptable diluent. 22. - The pharmaceutical composition according to claim 21, wherein in the compound of Formula III, M is hydrogen or sodium; n is 0; R is selected from the group consisting of H and C3H7; R- is selected from the group consisting of H, CH 3, CH 3 -O-C 2 H 5 and C 3 H 7; R2 is selected from Formula II, wherein X is Cl, F or OH. 23. The pharmaceutical composition according to claim 21, wherein in the compound of Formula III is phenylacetylisoglutamine or pharmaceutically acceptable salts thereof. 24. The pharmaceutical composition according to claim 21, characterized in that it also comprises enough water to form an aqueous solution of the phenylacetylisoglutamine in a concentration ranging from about 200 mg / ml to about 350 mg / ml. 25. A pharmaceutical composition comprising an aqueous solution of a compound of Formula IV: wherein R and Ri are independently selected from the group consisting of H, lower alkoxy (d-β) and lower alkyl (d.6); R2 is select from Formula II: n wherein X is halogen, lower alkyl (C6-6), lower alkoxy (C1.6), cycloalkyl, cycloalkoxy, aryl (C6.12), substituted aryl or hydroxy and n is 0, 1, 2, 3 or 4; M is hydrogen, a salt-forming cation, alkyl (d.6), cycloalkyl, or aryl (C6-? 2); and n is 0-5; and wherein the concentration of the compound of Formula IV is from about 70 mg / ml to about 150 mg / ml. 26. The pharmaceutical composition according to claim 25, wherein the compound of the Formula IV is phenylacetic acid or its pharmaceutically acceptable salts. 27. The pharmaceutical composition according to claim 25, wherein the compound of Formula IV is a precursor compound. 28. The pharmaceutical composition according to claim 27, wherein the precursor compound of Formula IV is phenylbutyric acid or its pharmaceutically acceptable salts.