TW201226406A - A pharmaceutical composition for treating cancer - Google Patents

Abstract

Disclosed herein is a new use of a pyrrolidone derivative, particularly, the use of the pyrrolidone derivative for treating a subject suffering from a cancer. A pharmaceutical composition for treating cancer is provided accordingly. The pharmaceutical composition includes a pyrrolidone derivative, a salt or a solvate thereof; and a pharmaceutically acceptable carrier. The pharmaceutical composition may further include a chemo therapeutic agent.

Description

201226406 VI. Description of the Invention: TECHNICAL FIELD OF THE INVENTION The present disclosure is broadly related to the field of pharmacy. DETAILED DESCRIPTION This disclosure relates to a pharmaceutical composition that can be used to treat cancer. [Prior Art]

In advanced countries, cancer ranks first in the list of causes of death _ cancer diagnosis and treatment have been continuously improving, but most of the current (four) = 4 methods still have side effects or limited efficacy. Since the tumors and metastasis involve many sequences of cancer, the treatment of cancer is quite complicated, and some of them have not been known until now. Chemotherapy is still the case for many types of cancer (eg, the main method of blood therapy, and the second second spring therapy method for relapsed tumors. Most of the currently used anticancer drugs are 丨 molecular compounds' need In the form of parenteral (Pars injection) or a large number of injections: (b coffee-tiGn) to the patient, during the treatment period, the patient must receive the hospital's treatment, resulting in high cost of medical care. Therefore, the relevant field needs The development of 'can be taken orally|(4) effective anticancer drugs can reduce the cost of treatment for cancer care. 3 The present invention proposes the use of drugs for treating cognitive diseases, and some drugs for treating cognitive diseases. Mainly belong to 2 heart ketone family members ^ 'Because of the function that can help cognitive learning (_-) 'early known as "Cong; music" used to treat such things as (four) Haimo's disease (four) retreat = These drugs also have neuroprotective effects, in particular, protection = ? ^.^^i^(antiepi,eptic agent), 201226406 The inventors of the present invention have unexpectedly discovered such conventional 2-pyrrolidone family compounds, which are used alone. Suppressive The effect of tumor growth, if combined with the conventional chemotherapeutic agent, the anti-cancer effect is better. In addition, because most of the 2-pyrrolidone family compounds have been developed into therapeutic drugs, the drug-free safety concerns and the drugs developed by them have been developed. The form includes an oral formulation such as a tablet or syrup. Therefore, such a 2-pyrrolidone family compound will be a novel anticancer drug with market potential for the next generation. [Disclosed] The present disclosure features a method for treating a patient A novel pharmaceutical formulation for an individual having a cancer-related disease. Thus, a first object of the present disclosure is to provide a novel pharmaceutical composition comprising a pharmaceutically effective amount of a pyrrolidone derivative and a salt or a solvate thereof; An acceptable carrier. According to a particular embodiment of the present disclosure, the pyronone derivative is a compound selected from the group consisting of 2-° ratios of sulphonone, including aloacetam, aniracetam ), brivaracetam, cebaracetam, colacetacetam, diraceracem, Doiiracetam, imuracetam, molracetam, noopept, piracetam, oxiracetam, pula Pramiracetam, nefiracetam, nebracetam, fasoracetam, levetiracetam, dupracetam, ilaxi Etiracetam and any combination thereof. In a particular instance, this. The ketone derivative of each hospital is piracetam. In another example, this. The specific ketone derivative of 17 is levetiracetam. According to another specific embodiment of the present disclosure, the present invention is for treating a problem 201226406

A pharmaceutical composition of an individual of cancer further comprises a chemotherapeutic agent. The chemotherapeutic agent may be selected from the group consisting of paclitaxel 'irinotecan HC1', octitaxopel (docitaxel), doxorubicin, daunorubicin, and epirubicin. ), I urinary secret. Fluorouracil, melphalan, cis-platin, carb〇platin, cyclophosphamide, mitomycin, methotrexate ), mitoxantrone, vinblastine, vincristine, ifosfamide, teniposide, etoposide, filament chain Bleomycin, leucovorin, cytarabine, dactinomycin, interferon alpha, strept0Z0Cin, hydrogenation Prednisolone or procarbazine HC丨. In one example, 5 Xuan Chemotherapy is anti-cancer (irin〇tecan HC1). Thus, a second object of the present disclosure is to provide a method for treating an individual suffering from cancer. The method comprises administering to the individual suffering from cancer the pharmaceutical composition of the invention described above. The pharmaceutical composition comprises a pharmaceutically effective amount of a pyrrolidone derivative, and salts or solvates thereof; and a pharmaceutically acceptable carrier. Applied in a consistent example. The ratio of each ketone derivative is β biracetam (pjracej; am). In another example, it is applied. The ketone derivative of each hospital is levetiracetam. According to a particular embodiment of the present disclosure, a cancer suitable for treatment with a pharmaceutical composition of the present invention is selected from any one of the following: human leukemia, muscle tumor, bone cancer, lymphoma, melanoma, ovarian cancer, skin cancer, testicular cancer , gastric cancer, pancreatic cancer, kidney cancer, breast cancer, prostate cancer, rectal cancer, head and neck cancer, brain cancer, esophageal cancer 'bladder cancer' adrenal cortical cancer, lung cancer, bronchial cancer, endometrial cancer, cervical cancer or Liver cancer. In one example, the cancer is rectal cancer. 201226406 In another specific embodiment, the method for treating the body of the cancer further comprises administering the chemotherapy of the method of the present invention before, simultaneously or at the same time as: administering the pharmaceutical composition of the present invention. The drug is selected from the group consisting of 1 cedarol, anticancer, isopropyloxy^^ 本 本, 杉, doxorubicin, danzimycin, acetonide, fluorouridine. Ding, sarcoma*, 封私山# 素顺铂, 妷platinum, cyclophosphamide, lysin, thiomethyl-folate, ketone, Dingnong, 匕, 匕, Changchun, Changchun, Changchun Alkali, Yin-Fluoride, Oedoside, Scorpion Etoposide, Round Wire Bond, > Visiting - Lord.贱贱京,甲醯tetrahydrofolate, stellate, 囷素素 D,α·interferon, 铋苽杜# Bu — ”. Saskatchewan, gasified prednisone or methyl acetate

year. In a consistent example, the chemotherapy is administered to the individual simultaneously with the pyrrolidone derivative. Wang Wei-cho's detailed description and attached patents will be able to better understand these and other characteristics of this article. The above summary and the following detailed description are merely illustrative, and are not intended to limit the scope of the disclosure. [Embodiment] The following is a novel use of a pyrrolidone compound, particularly a novel use of such a compound for treating cancer. - This case 'X Yue people use a unique drug screening platform' to identify a new group of conventional pyrrole derivatives, especially for the treatment of cancer. Therefore, such a compound having tumor growth inhibiting which is identified by the present invention can be developed into a lower-generation anticancer drug. According to this month, ☆, this kind of conventionally known tumor inhibiting tumor growth includes the following compounds: 201226406

N-[2-(3-mercapto-2,5-dimercaptopyrrol-1-yl)ethyl]acetamidamine (N-[2-(3-formyl-2,5-dimethylpyrrol-l-) Yl)ethyl]acetamide), commonly known as aniracetam

L-[(4-methoxybenzyl)]-2- 0 is 0 0 ( _ (l-[(4-methoxybenzoyl)]-2-pyrrolidinone), commonly known as aloacetam (aloracetam);

(2S)-2-[(4/?)-2.oxo-4-propylindole-1-yl]butanamine ((25)-2-[(4/?)-2-〇 Father 〇-4-propylpyrrolidin-l'y|] butanamide), commonly known as boisacetam (brivaracetam); 201226406

4-[2_[4-(4-Phenylphenyl)-2.oxo. Than a bite -1 -yl]acetamidine]-[2-[4-[4-(4-chlorophenyl)-2-oxopyrrolidin-l-yl]acetyl]piperazin-2-one), commonly known as Cebatacetam;

N-[2-(3-Dimethyl-5,6,7,8-tetrahydrofuro[2,3-b]quinolin-4-yl)-2-(2-oxopyrrolidin-1-yl) Acetamine (A/-(2,3-dimethyl-5,6,7,8-tetrahydrofuro[2,3-b] quinolin-4-yl)-2-(2-oxopyrrolidin-l-yl)acetamide ), commonly known as colacetacetam;

Η (RS )-3,6,7,78-113 It [1,5-a] ((RS )-3,6,7,7a-tetrahydro-lH-pyrrolo[l,5-a]imidazole-2 , 5-dione), commonly known as Dilla 8 201226406 Seantan (dimiracetam);

2-(2-oxo-3-phenyl-3H-indol-l-yl)acetamide, commonly known as 2-(2-oxo-3-phenyl-3H-indol-l-yl)acetamide Lacidine (doliracetam);

Ν, Ν'-bis[(2-oxopyrrolidin-1-yl)methylurea (N,l\T-bis[(2-oxopyrro丨ia_in-l-yi)methyi]urea), commonly known as Yingla Sitan (imuracetam);

2·[4-(4-methoxybenzyl)piperazin-1-yl]-1-morpholin-4-ylethanone (2-[4-(4-methoxybenzoyl)piperazin-l-yl]- L-morpholin-4-ylethanone), commonly known as molracetam;

201226406 Ο V° 〇 ο Ν 醯 醯-L-脯 ammonia-glycine vinegar (N_pheny|acety|-L-pr〇|y|g|ycineethyl ester) ‘commonly known as Noahbit (N〇〇pept};

2-oxo-1-α is a kind of 2-〇x〇-l-pyrr〇lidineacetamide, commonly known as. Piracetam (piracetam);

(brother S)-2-(4-hydroxy-2-oxopyrrolidin-1-yl)acetamide ((/?5)-2-(4-hydroxy-2-oxopyrrolidin-l-yl)acetamide) > Commonly known as oxiracetam; 10 201226406

N-[2-(diisopropylamino)ethyl]-2-(2-oxo.pyrrolidin-1-yl)acetamidamine (N-[2-(diisopropylamino)ethyl]-2-( 2-oxopyrrolidin-l-yl)acetamide), commonly known as pramiracetam;

〇Λ % Ν-(2,6-dimethylphenyl)-2-(2-oxo.pyrrolidin-1-yl)acetamidamine ((N-(2,6-dimethylphenyl)-2- (2-oxopynOlidin-l-yl)acetamide), commonly known as nefiracetam;

(RS)-4-(aminomethyl)-1-phenyl-. Bis(r)-2-oxo ((RS)-4-(aminomethyl)-1 -benzyl-pyrrolidin-2-one), commonly known as nebracetam; 201226406 〇

(5R)-5-(six gas α ratio sigma-1 -syl) α ratio _ 2-嗣((5R)-5-(piperidine-1 -carbonyl) pyrrolidin-2-one), commonly known as Fasoracetam

(S)-2-(2-oxopyrrolidin-1-yl)butanamide ((5)-2-(2-oxopyrrolidin-1 -yl)butanamide), commonly known as levetiracetam;

(2-(2-oxopyrrolidin-1-yl)-N'-[2-(2-ketopyrrolidin-1-yl)ethenyl]acetate (2-(2-oxopyrrolidin-1 - Yl)-N'-[2-(2-oxopyrrolidin-1 -yl)acetyl]acetohydrazide), commonly known as dupracetam; and 12 201226406

(RS)-2-(2-oxopyrrolidinyl)butanamide (RS(RS)-2-(2-oxopyrrolidin-l-yl)butanamide), commonly known as etiracetam. These compounds are commercially available or can be synthesized by conventional methods. Thus, in accordance with an embodiment of the present disclosure, a method for treating an individual suffering from cancer is provided. The method comprises administering to the individual a pharmaceutical derivative of any one of the above pyrrolidone derivatives, or a combination, salt or solvate thereof. In one example, the s-xanthene ketone derivative is piracetam. In another example, the acetophenone derivative is levetiracetam. In this paper, the words 'inhibiting tumors', 'anti-cancer' and/or 'anti-tumor' can be used for cross-production, and can inhibit the growth of tumor cells and/or cancer cells (gr〇wth) and proliferation. ) also includes killing tumor cells and/or cancer cells. The term "treatment" means applying the compound to a body to cure (aure or relieve), alter 'remedy', improve "mehofate" or affect ( Affected by the disease, the symptoms of the disease, or the predisposition to disease. The term "a therapeutically effective amount" is intended to mean the administration of a therapeutically effective compound to a subject. The measure of efficacy can be objective (measured by some test or sign) or subjective (the subject gives the child > the description of the fruit and feeling). The effective dose of the above compound may range from about 丨mg & kg/day to about 500 mg/kg/day, preferably from 1 〇mg/kg/day to 13 201226406, about 400 mg/kg/day, more preferably It is from 50 mg/kg/day to about 250 mg/kg/day. The effective dose will also vary with the route of administration and the other agents that may be used in combination. In one example, the effective dose is about 100 mg/kg/day; in another example, the effective dose is about 250 mg/kg/day.

The term "salt" refers to a salt formed by the reaction of a base (such as a pyrrolidone derivative of the present disclosure) with an acid (including an organic or inorganic acid), examples of which include hydrochloric acid, hydrobromic acid Hydrohydric acid, peroxyacid, methyl acid, sulfuric acid, nitric acid, acid, propionic acid, glycolic acid, pyruvic acid, malonic acid, succinic acid, maleic acid (maleic acid), fumaric acid, tartaric acid, citric acid, benzoic acid, carbonic acid, cinnamic acid, methanesulfonic acid Acid), ethanesulfonic acid, hydroxyethanesulfonic acid, benezenesulfonic acid, p-toluene sulfonic acid, cyclohexyl ruthenium ( Cycohexanesulfamic acid), salicyclic acid, p-aminosalicyclic acid, 2-phenoxybenzoic acid and 2-acetoxybenzoic acid (2 -acetoxybenzoic acid). In a preferred embodiment, the salt is levetiracetan gasification hydrogen. In another preferred embodiment, the salt is. Piracetam hydrogenates hydrogen. The term "solvate" as used herein refers to a complex formed by the reaction of a compound (e.g., a pyrrolidone derivative in the present disclosure) with a solvent molecule (e.g., water, ethanol, etc.) in the vicinity thereof. In one example, the pyrrolidone derivative is a levetiracetam hydrate. The pharmaceutically acceptable salts of the compounds of the invention comprise a pharmaceutically acceptable inorganic acid and an organic acid base. Suitable acid salts are, for example, acetate, adipate, alginate, aspartate, benzoate 14 201226406

(benzoate), benzenesulfonate, butyrate, citrate, camphorate, camphorsulfonate 'ethyl sulfonate' ), formate, fumarate, glucosinolate, heptanoate, hexanoate, hydrochloride, hydrogen Hydrobromide, 2-hydroxyethanesulfonate 'lactate, maleate, maleate, methanesulfonate , 2-naphthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, 3-phenylpropionate 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, succinate Succinate), sulfate [tartrate], thiocyanate (Thiocyanate), Yue benzenesulfonate (as tosylate) and undecanoate (undecan〇ate). Alternatively, pharmaceutically unacceptable acids, such as ethanedicarboxylic acid, can be used to prepare the salts of the intermediates to obtain the compounds of the invention and their pharmaceutically acceptable acid salts. Salts obtained from appropriate tests include metal (such as sodium), soil (such as town), salt and N (alkyl) / salts. The present invention also contemplates a nitrogen-containing quaternary ammonium salt of any of the compounds disclosed herein to provide a water soluble, oil soluble or dispersible product. According to another specific embodiment, the method of the present invention further comprises administering a chemotherapeutic agent to the individual prior to, concurrently with, or subsequent to administration of the pyrrolidone derivative described above to the individual, and the amount of the chemotherapeutic agent is about applied. The amount of the pyrrolidone derivative is from 1/6 to 丨/4. In one example, the pyrrolidone derivative chemotherapeutic agent is administered to the individual simultaneously. Chemotherapeutic agents suitable for use in the methods of the invention include, but are not limited to, paclitaxel 15 201226406 (paclitaxel), anti-cancer (irin〇tecan HCl), isopropylidene paclitaxel (docitaxel), doxorubicin (doxorubicin), Daunorubicin, epirubicin, fluorouracil, melphalan, cis-platin, carboplatin, cyclophosphamide, Mitomycin, methotrexate, mitoxantrone, vinblastine, vincristine, ifosfamide, teniposide ), etoposide, bleomycin, leucov〇rin, cytarabine, dactinomycin, alpha-interferon (interferon alpha), streptozocin, prednisolone and procarbazine HC1. In a consistent example, the chemotherapeutic agent is irinotecan HC1. A cancer suitable for treatment by the method of the present invention is selected from the group consisting of leukemia, muscle tumor, bone cancer, lymphoma, melanoma, ovarian cancer, skin cancer, testicular cancer, gastric cancer, smear cancer, kidney cancer, breast cancer, Prostate cancer, rectal cancer, head> cancer of the member, brain cancer, esophageal cancer, bladder cancer, adrenocortical carcinoma, lung cancer, bronchial cancer, endometrial cancer, cervical cancer or liver cancer. In one example, a cancer suitable for treatment by the methods of the invention is rectal cancer. Individuals suitable for treatment by the methods of the invention are mammals such as humans; primates such as monkeys, orangutans; poultry such as cattle, sheep, horses, pigs, chickens, ducks, geese, and the like, such as dogs and cats. Class of pets. Another aspect of the present invention is to provide a pharmaceutical composition for treating an individual suffering from cancer. The pharmaceutical composition comprises a pharmaceutically effective amount of the above. a ratio of 11 ketone derivatives, salts or solvates thereof; and a pharmaceutically acceptable carrier. The pyrrolidone derivative is selected from the group consisting of 2-pyrrolidone family compounds 'including Alo 16 201226406 atheacetam, anisracetam, brivaracetam, cebaracetam 'Kuraxi Coluracetam, dimisracetam, doliracetam, imuracetam, molracetam, noopept, piracetam ), oxiracetam, pramiracetam, nefiracetam, nebracetam, fasoracetam, levetiracetam , Duraracetam (dUpracetam), etiracetam, and any combination thereof. In a specific example, the pyrrolidone derivative

The substance is piracetam. In another example, the pyrrolidone derivative is levetiracetam. According to a particular mode of the invention, the pharmaceutical composition may further comprise a chemotherapeutic agent. The chemotherapeutic agent may be selected from the group consisting of paclitaxel, anticancer, isopropyloxetrol, aphthyl, danubimycin, azadirachtin, and fluoropenic. Ding, sarcoma, shunming, carboplatin, cycloheximide, mitomycin, aminomethyl folate, silk _, periwinkle test, vincristine, indoflurane, podophyllotoxin, sneaky Ethidium, streptomycin, formazan tetrahydrofolate, serotonin, actin fel D, alpha-interferon, streptozotocin, prednisolone or guanidinium hydrochloride. In one example, the chemotherapeutic agent is irinotecan HC1. The dosage of the pharmaceutical composition disclosed herein may be affected by a number of factors, including the activity of the drug used, 'the age, weight, overall health, sex, diet, time of administration of the composition, route of administration, frequency of administration, The rate of drug excretion, whether there is a combination of drugs, the progress and severity of cancer, the location and condition of cancer, and the treatment and judgment of doctors on cancer. "Pharmaceutically acceptable carrier" means a carrier or adjuvant that can be administered to a subject together with a compound of the invention (i.e., a pyrrolidone derivative), and when a sufficient therapeutic agent is administered 17 201226406 to deliver a therapeutic dose of a compound The carrier or adjuvant does not destroy the pharmaceutical activity of the compounds of the invention and is not toxic.

Pharmaceutically acceptable carriers, adjuvants or vehicles which may be used in the pharmaceutical compositions of the invention include, but are not limited to, ion exchangers, alumina, aurinum stearate, pebbles Lecithin, self-emulsifying drug delivery systems (SEDDS) such as da-tocopherol polyethylene glycol 1000 succinate, used in pharmaceutical dosages Surfactants, such as Tweens or similar polymeric carrier media, plasma proteins (eg, plasma albumin), buffers (eg, citrate, glycine, sorbic acid, sorbic acid) Potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (eg protamine sulfate, disodium hydrogen sulfate) Hydrogen phosphate), potassium hydrogen phosphate, sodium vapor, zinc salt, colloidal silica Magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, methyl ether Sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, and wool fat Cyclodextrins such as α-, β- and γ-cyclodextrin or their chemically modified derivatives, such as hydroxyalkylcyclodextrins, contain 2- and 3-hydroxyoxypropyl groups. -β-cyclodextrin or other soluble derivative. The pharmaceutical composition of the invention may be applied orally, parenterally, by inhalation spray, topical surface application 18 201226406

Topically, rectal, nasally, buccally, vaginally, subdermally, transmucosally, or implanted reservoir to enter the body Preferably, it is introduced into the body via oral or parenteral. The pharmaceutical compositions of the present invention may comprise any conventional non-toxic and pharmaceutically acceptable carrier, adjuvant or vehicle. In some instances, a pharmaceutically acceptable acid or buffer may be used to adjust the acidity of the formulation to increase the stability of the formulation compound or its delivery profile. The term "parenteral" as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular (intraarticular). ), intraarterial, intrasynovial, intrasternal, intrathecal 'intralesional', intraperitoneal (intraperitoneally) and intracranial (intraperito) Intracranial) injection or infusion technique. The pharmaceutical compositions can be prepared in a sterile, injectable form, such as a sterile injectable aqueous solution or an oily suspension. The suspension may be formulated with a suspending agent according to known techniques using conventional dispersing or wetting agents (e.g., Tween 80). The sterile injectable form can also be a sterile injectable solution or can be suspended in a non-toxic, non-orally acceptable diluent or solvent, such as 1,3-butanediol. Acceptable media and > granules can be hexitol (mannit®), water >Ringer's solution and isotonic pressure gasified sodium solution. In addition, sterile, fixed oils are conventionally used as a solvent or suspending medium. For this purpose, any type of fixed oil can be used to synthesize monoglyceride or diglyceride. Fatty acids such as oleic acid and its glyceride derivatives can be used in the preparation of injectables, as they are pharmaceutically acceptable natural oils such as olive oil or castor oil, especially its ethoxylates. Polyoxyethylated form. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, or a methicone (carboxyl hyI cenuj) commonly used in pharmaceutical formulations (eg, emulsions and/or suspensions 19 201226406). 〇se) and similar dispersants. Other commonly used surfactants such as Tween or Qiu and/or other emulsifiers or bioavailable enhancers' are commonly used to make pharmaceutically acceptable solids, liquids or other dosage forms that can be used as a formulation. The pharmaceutical composition of the present invention is preferably administered in an orally acceptable dosage of 'including' but not limited to (four) capsules, money, suspensions of emulsions and waters, dispersions and liquids. In the case of an oral key, a commonly used carrier comprises lactose and corn powder. Also "injectable lubricants, such as magnesium stearate. In the case of oral capsules, useful thin-boiled release agents include lactose and dried corn powder. When oral suspensions and / or emulsions of water, = composition Suspended or dissolved in an oil phase combined with an emulsifier and a domain dispersing agent. If necessary, some sweeteners and/or flavors may be added. The pharmaceutical composition of the present invention may also be formulated as a suppository for rectal administration to an individual. The composition can be prepared by mixing the compound of the present invention with a suitable non-irritating excipient. The excipient must be solid at room temperature, but liquid at the rectal temperature = in the rectum. Dissolve the compound that releases the active agent. Examples of the bismuth agent include <not limited to cocoa butter, bee sacrifice and polyethylene glycol (called 丨丨 咖 咖 (3) (4). ^ When the required treatment involves topical surface application (topica丨) The method is to use a pharmaceutical composition suitable for topical application. When the pharmaceutical composition for topical application is applied to the skin, the formula should be $suitable. Ointment contains suspension or dissolution An active compound which is dissolved in a suitable carrier. A carrier suitable for the application of the compound of the invention in a topical surface application, including but not limited to, liquid petroleum, white petroleum, polyethylene glycerol, polyoxyethylene polyoxypropylene ^化:物' emulsifying wax and water. In addition, the formulation of the pharmaceutical composition may also be emulsion (丨〇d〇n) or ritual (cream) s containing suspension or dissolution in a suitable carrier and a suitable spoon to emulsify A compound which is active in sputum. Suitable carriers include, but are not limited to, sorbitan monostearate, polysorbate 6 〇, f "20 201226406 ten /, alcohol S0 butterfly, sixteen Alcohol, 2-oxyldodecanol, benzyl alcohol and water. The composition of the invention may also be applied in the lower intestinal tract in the form of an enteric suppository or enema. The application method also includes transdemal patches. The pharmaceutical composition formulation of the present invention also comprises a nasal spray (nasal aeros) or an inhalant (inhalati〇n). The composition can be formulated according to known pharmaceutical formulations. system Aqueous salt solution, using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance its bioavailability, halothanes, and / or other known solubilizers or dispersants. φ Anticancer drugs described herein The daily dosage standard is from about 1 mg/kg/day to about 500 mg/kg/day, preferably from about 1 mg/kg/day to about 4 (9) mg/kg/day, more preferably about 5 〇. From mg/kg/day to about 25 mg/kg/day, it is useful in unilateral treatment or in combination with other therapies for the prevention and treatment of cancer. Under typical conditions, the pharmaceutical composition of the present invention can be administered about 1 - 6 per day. The second (ie 丨〇 - 1 〇〇〇 mg / dose) 'either is applied by continuous injection. This mode of administration can be used in chronic or acute treatment. The amount of active ingredient which may be combined with the carrier materials to produce a single dosage will vary depending on the subject to be treated and the method of administration. A typical preparation will comprise from 5% to 95% by weight of active compound or 鸠-(by weight) of active compound. When the pharmaceutical composition of the present invention contains the above. In addition to the pyrrolidone derivative, there are 4 or more additional agents that can treat or prevent cancer. The dose of biroxan derivatives and additional therapeutic agents is approximately 1 / 6 ‘ 1 /4 of the dose used for unilateral therapy. Additional therapeutic agents can be administered separately from the compounds of the invention as multiple agents! 1 therapy - part. Alternatively, the agents may be in a single dosage form, or may be combined with the compounds of the invention in an early dosage composition. It is to be noted that, unless otherwise stated, the singular expression "21" ("a", "an") or (the, the) refers to its plural in the scope of the article and the accompanying claims. form. The embodiments and proper nouns are used to illustrate the summary of the invention and are not intended to limit the scope of the disclosure. The disclosure of the present disclosure also covers other embodiments that are not specifically described by those skilled in the art after reading this disclosure. Unless otherwise defined, all the professional and scientific terms used in the text have the same meaning as those familiar to the skilled artisan. In addition, any methods and materials similar or equivalent to those described may be employed in the methods of the invention. The preferred embodiment of the method φ and materials described herein are for demonstration purposes only. All references cited in this application are hereby incorporated by reference in their entirety in their entirety in the extent of the disclosure of the disclosure of the disclosure. Moreover, the documents discussed herein merely disclose prior art techniques of the present application. And there is no document showing that the present invention has been disclosed in the prior art. SUMMARY OF THE INVENTION The actual data obtained will differ from the data disclosed herein in the context of the present specification due to individual implementation conditions. The following examples are presented to illustrate the specific aspects of the disclosure and to assist those skilled in the art to understand and practice the disclosure. However, the scope of the disclosure is not limited to these embodiments. EXAMPLES Example 1 In vivo anticancer activity evaluation of levetiracetam The in vivo anticancer activity of the experimental drug was evaluated in NOD SCID cancer mice. 5 to 1 〇 Zhou Dazhi's NOD SCID mouse was purchased from the National Taiwan University Animal Center (Taipei, Taiwan). Human rectal adenoma cells HT29 were provided by Huang Shiming, a member of the National Defense Medical College (Taipei Taiwan). Each of the 5 NOD SCID mice was grouped into 5 groups. First, 1 X 108 HT29 cells were suspended in HμΐHBSS buffer (GIBCO Cat 22 201226406

In No. 14065), 1 χ 1 〇 6 HT29 cells were implanted into the small gas peritoneal cavity by intraperitoneal inoculation. Five days after inoculation, each group of cancer mice received different treatments. The first group was the control group, the second group was the experimental group, the first group received 100 μΐ of HBSS buffer, and the second group received 40. Mg/Kg/day anti-cancer (IRO), third group received 4〇mg/Kg/day IRO and 100mg/Kg/day of levetiracetam, and group 4 received 40mg/Kg/ IRO of the day and 250 mg/kg/day of levetiracetam, and the fifth group received l〇〇mg/Kg/day of levetiracetam. Anti-cancer (IRO) was administered to the experimental animals by intravenous injection, and levetiracetam was administered to the experimental animals by intraperitoneal injection (twice a day). These mice were observed daily and their survival ratio was recorded until all the mice died. In addition, the heart, liver, lung and tumor tissues of each dead mouse were collected, and the expression of the cancer indicator protein was analyzed by Western blotting method, including carcinoembryonic antigen (CEA) and proliferating cell nuclear antigen. (Proliferating Cell Nuclear Antigen, PCNA), and the expression of tubulin (tubilin). The results are provided in Figure 1. Figure 1 shows the survival curves of the above six groups of cancer mice, in which the treated cancer mice were treated with anticancer, levetiracetam or a combination of levetiracetam and anticancer drugs. In the treated mice, the life of the experimental group was extended about 2 times compared to the control group mice not receiving the drug treatment. The life expectancy of mice that have not received drug treatment is about 40 days, and the cancer rats treated with levetiracetam alone can be extended to about 90 days; as for the combination treatment of levetiracetam and anticancer In mice, the life span is extended from about 40 days to about 85-95 days. Example 2 «Evaluation of anti-cancer activity of siracetam in vivo 2.1 In vitro use of piracetam alone to inhibit cancer cell growth 23 201226406 The cancer mice used in this experiment are the same as in Example 1, and are roughly based on The experimental mice were grouped by the method of Example 1. When starting the test, first! x 1 〇 8 ΗΤ 29 cells were suspended in 200 μM of HBSS buffer (GIBC 〇 CatN 〇 14 〇 65) and 2 x 107 HT29 cells were implanted into the shoulder of the experimental mice. One day after vaccination, each group of cancer mice received different treatments, the first group was the control group, the second group and the second group were the continuous test group; the first group received 1 〇〇μ丨 of HBSS buffer, the first group The second group received 20 mg/kg/day of amil〇ride and the third group received lg/kg/day of piracetam. Both amiloride and piracetam were administered as experimental animals by intraperitoneal injection. The mice were observed daily and their tumor size was recorded. After 35 days of implantation of the tumor cells, all the experimental mice were sacrificed, and the heart, liver, lung and tumor tissues of each dead mouse were collected and weighed and immunostained. Method of staining. Figure 2 shows the acceptance of amiloride or compared to the control group (injection buffer only). The trend of tumor volume in vitro in mice treated with diracacetam. It can be seen that in mice treated with buffer solution, the tumor volume in the body is longer with the implantation time, and the tumor volume is larger; however, if administered with 20 mg/kg/day of amHoride (amHoride) Or lg/Kg/day of piracetam, the tumor volume in these mice is significantly inhibited, showing that piracetam alone, that is, has the ability to inhibit tumor cell proliferation. 2.2 In vivo combined use of piracetam and doxorubicin (dX) to inhibit cancer cell growth

5 X 10 HT29 cells were suspended in 1 ml of hbsS buffer (GIBCO

In Cat No. 14065), 200 μ丨 (i.e., 1 x 6 6 n-butyl 29 cells) were then removed and implanted into the peritoneal cavity of the experimental mice. Four days after inoculation, each group of cancer rats received different treatments, the first group was the control group, the second group to the fourth group were the experimental group; the first group received 100 μΐ of HBSS buffer, and the second group received 1 Mg/Kg/day of adiponectin (DOX) and 丨00 μΐ of HBSS buffer, the third group of 1 mg/Kg/day [丨:] 24 201226406 of doxorubicin and 20 mg/Kg/day of Ami Lori, the fourth group received i mg/Kg/day of doxorubicin and 1 g/Kg/day of piracetam. Doxorubicin was administered to the experimental animals by intravenous injection, and amiloride and piracetam were administered to the experimental animals by intraperitoneal injection. These mice were observed daily and their survival ratio was recorded until all mice died. The results are shown in Figure 3. Figure 3 shows the survival curves of the above four groups of cancer mice. Compared with the control group (HBSS) that did not receive medical treatment, the combination of doxorubicin and amiloride did not significantly inhibit cancer cell growth. The effect of using the chemotherapeutic agent doxorubicin (DOX), which is used alone, can slightly improve the survival rate of mice, but the effect is not significant; instead, the combination of doxorubicin (D〇x) and In addition to significantly improving the survival rate of mice, piracetam can prolong the lifespan of mice. The life of untreated mice is about 42 days, and the combination of piracetam and doxorubicin is small. In rats, the life span is extended from about 42 days to about days. This result shows that in addition to its ability to inhibit the growth of cancer cells, piracetam has the function of acting as an adjuvant for U-chemotherapy, which can increase the effect of chemotherapy-inhibiting the growth of cancer cells. From the results of the above examples, it was confirmed that pyrrolidone derivatives, particularly piracetam and levetiracetam, have the effect of inhibiting the growth of tumor cells alone, if used together The chemotherapeutic agent (for example, anti-cancer or ruthenium doxorubicin) can further enhance the effect of inhibiting the growth of tumor cells. While the present invention has been described above by way of a preferred embodiment, it is not intended to limit the invention, and the present invention may be modified and modified without departing from the spirit and scope of the invention. Scope of protection: The scope defined by the patent scope shall prevail. & Application 25 201226406 Other Embodiments All of the features disclosed in the description of the specification can be used in any combination. Each of the features disclosed in the contents of the specification can be used for the same, equivalent or similar purpose. Other features are replaced. From the above description, those skilled in the art can easily determine the main features of the present invention, and can make various changes and refinements in various uses and situations without departing from the spirit and scope of the present disclosure. The scope of protection of the content shall be subject to the definition of patent scope as attached. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a survival curve of a cancer mouse according to an embodiment of the present invention; FIG. 2 is a diagram showing a tumor cell implanted in a mouse according to an embodiment of the present invention, and then respectively Figure: Changes in tumor volume over time after treatment with liquid, 2 〇 mg/kg/day of ami〇ride, g/Kg/day of piracetam; Fig. 3 is a survival curve of a cancer mouse according to an embodiment of the present invention. [Main component symbol description] 26

Claims (1)

201226406 VII. Patent Application Range: 1. A pharmaceutical composition for treating an individual suffering from cancer comprising a pharmaceutically effective amount of a pyrrolidone derivative and a salt or a solvate thereof; and a pharmaceutically acceptable carrier. 2. The pharmaceutical composition according to claim 1, wherein the pyrrolidone derivative is selected from the group consisting of aoracetam, anisracetam, brivaracetam, and ceibaacetam. ), colacetacetam, diraceracem, doliracetam, imuracetam, molracetam, noopept, pyridinium Piracetam (piracetam), oxiracetam, pramiracetam, nefiracetam, nebracetam, fasoracetam, leztra A group of substances consisting of levetiracetam, dupracetam, etiracetam, and any combination thereof. 3. The pharmaceutical composition according to claim 2, wherein the ratio of the ketone derivative is 0 piracetam. The pharmaceutical composition according to claim 2, wherein the pyrrolidone derivative is levetiracetam. 5. The pharmaceutical composition of claim 1 further comprising a chemotherapeutic agent. 6. The pharmaceutical composition according to claim 5, wherein the chemotherapeutic agent is paclitaxe, irinotecan HC1, docitaxel, doxorubicin, dan Doxorubicin (daunorubicin), Ai 27 201226406 Anhui (epirubicin), It urine 0 secret.定(^11〇1'〇1^(:丨1), melphalan, cis-platin, carboplatin, cyclophosphamide, mitomycin (mitomycin), aminomethyl folate (methotrexate), mitoxantrone, vinblastine, vincristine, ifosfamide, teniposide, sneaky Etoposide, bleomycin, leucovorin, cytarabine, dactinomycin, interferon alpha, bond Streptozocin, prednisolone or procarbazine HCl1. The pharmaceutical composition according to claim 6, wherein the chemotherapeutic agent is anticancer. The pharmaceutical composition according to claim 6, wherein the chemotherapeutic agent is doxorubicin. The pharmaceutical composition according to claim 1, wherein the cancer is human leukemia, muscle tumor, bone cancer, lymphoma, Melanoma, ovarian cancer, skin cancer, testicular cancer, gastric cancer 'pancreas 'Kidney cancer, breast cancer, prostate cancer, rectal cancer, head and neck cancer, brain cancer, esophageal cancer, bladder cancer, adrenal cortical cancer 'lung cancer' bronchial cancer, endometrial cancer, cervical cancer or liver cancer. 10.If requested The pharmaceutical composition according to Item 8, wherein the cancer is rectal cancer.