Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
  • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
  • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
  • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
  • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• the present invention relates to ⁇ , ⁇ , ⁇ -trifluorothymidine (FTD) and thymidine phosphorylase inhibitor
• the present invention relates to an anticancer agent that is used in combination with (TPI) and has a cancer therapeutic effect enhanced.
• a, a, a-Trifluorothymidine is a nucleic acid derivative in which the methyl group at the 5-position of thymidine synthesized by Heidelberger et al. Is substituted with a trifluoromethyl group.
• FTD is phosphorylated by intracellular thymidine kinase, which has no effect on RNA, unlike fluorarosinole (FU) antitumor agents that are widely used in clinical practice, and monophosphorylated trifluorothymidine monophosphate (F TMP) is formed.
• F TMP monophosphorylated trifluorothymidine monophosphate
• Non-patent Documents 3 and 4 Inhibits DNA synthesis by binding to synthase (TS) (Non-patent Documents 3 and 4).
• TS inhibition synthase
• Non-Patent Documents 5-7 Since FTD is incorporated into DNA, the antitumor effect of FTD can be differentiated from FU antitumor agents, and is considered to be a clinically useful antitumor homologous IJ that overcomes the above problems. .
• FTD is a force for which clinical trials were attempted in the 1970s.
• Intravenous administration causes degradation of FTD by thymidine phosphorylase (TP) in vivo and the resulting half-life of blood FTD is very short, about 12 minutes. A point was pointed out (Non-patent Document 8).
• intravenous administration every 3 hours shows a tumor reduction effect in some patients.
• problems such as hematological toxicity and gastrointestinal toxicity were observed, and even patients with tumor shrinkage did not necessarily contribute to survival. (Non-Patent Document 9).
• the applicant should be able to administer orally to maintain the blood concentration of FTD and improve its versatility. It is a thymidine phosphorylase inhibitor (TPI) for inhibiting the degradation of FTD.
• TPI thymidine phosphorylase inhibitor
• Black mouth 6_ (1— (2-Iminopyrrolidinyl) methyl) uracil hydrochloride (see the structural formula below) was found, and a cancer drug containing FTD and the TPI in a molar ratio of 1: 0. TAS 102) was developed (Patent Document 1, Non-Patent Document 10).
• This combination drug is a phase I clinical trial conducted in the USA, started once a day by oral administration, blood FTD concentration is maintained, and the combination drug should be an orally administrable drug confirmed. However, the clinical cancer treatment effect of this combination drug was not satisfactory.
• Non-Patent Document 1 J. Am. Chem. So, 84: 3597-3598, 1962
• Non-Patent Document 2 J. Med. Chem., 7: 1—5, 1964
• Non-Patent Document 3 Biochemistry, 33: 15086-15094, 1994
• Non-Patent Document 4 ⁇ 1 Pharmacol., 1: 14—30, 1965
• Non-Patent Document 5 J. Clin. Oncol., 12: 2640-2647, 1994
• Non-Patent Document 6 J. Clin. Oncol., 14: 176-182, 1996
• Non-Patent Document 7 J. Clin. Oncol., 21: 815— 819, 2003
• Non-Patent Document 8 Cancer Res., 32: 247-253, 1972
• Non-Patent Document 9 Cancer Chemother. Rep., 55: 205—208, 1971
• Patent Literature 10 international Journal of Oncology 25: 571-578, 2004 Patent Literature 1: Patent No. 3088757 Disclosure of the invention
• an object of the present invention is to provide a more effective cancer therapeutic agent.
• the present inventor changed the administration schedule of the combination drug and performed divided oral administration to humans 2 to 4 times a day.
• 100 mg / m 2 It was found that a remarkable anticancer effect was observed at a low dose of 20 to 80 mg / m 2 per day. Was completed.
• the present invention relates to FTD and 5-chloro-6- (1- (2-iminopyrrolidinyl) methyl) uracil hydrochloride (hereinafter referred to as TPI-1) in a molar ratio of 1: 0.5.
• a composition for treating cancer (TAS-102) containing 20 to 80 mg / m 2 / day as an FTD equivalent divided into 2 to 4 doses per day for oral administration Is to provide.
• the present invention provides a molar ratio of ⁇ , ⁇ , ⁇ -trifluorothymidine (FTD) and 5-chloro-6- (1- (2-iminopyrrolidinyl) methyl) uracil hydrochloride at a molar ratio of 1: Provided for use in the manufacture of a therapeutic drug for cancer for oral administration by dividing the dose of 20-80 mg / m 2 / day of the composition contained in To do.
• FTD fluorothymidine
• 5-chloro-6- (1- (2-iminopyrrolidinyl) methyl) uracil hydrochloride at a molar ratio of 1: Provided for use in the manufacture of a therapeutic drug for cancer for oral administration by dividing the dose of 20-80 mg / m 2 / day of the composition contained in To do.
• the present invention relates to a molar ratio of 1: 0 to 5: 1 black _ 6 _ (1- (2-iminopyrrolidinyl) methyl) uracil hydrochloride.
• a method for treating cancer characterized by orally administering the composition comprising 5 in 20 to 80 mg / m 2 Z daily dose divided into 2 to 4 doses per day as an FTD equivalent It is.
• the cancer therapeutic agent of the present invention even though the total daily dose is lower than in the case of once-daily administration, a better cancer therapeutic effect can be obtained.
• FIG. 1 A diagram comparing the therapeutic effects on gastrointestinal cancer when TAS-102 preparation containing FTD and TPI-1 was administered orally three times a day and once a day. Yes (PD: progression, SD: stable, MR: slight effect, PR: partial response).
• the vertical axis represents individual patients, and the horizontal axis Indicates a single number.
• the treatment course is 5 days per week, 2 days off for 2 weeks, 2 weeks off for a total of 4 weeks. The patient's health status, side effect status, etc. can be gradually increased as necessary.
• FIG. 2 Comparison of therapeutic effects in breast cancer when TAS-102 preparation containing FTD and TPI-1 was orally administered twice a day (PD: progression, SD: stable, MR: slight effect) , PR: partial response).
• the vertical axis represents individual patients, and the horizontal axis represents the number of treatment courses. The treatment course is the same as above.
• the composition of the present invention is a composition containing FTD and TPI-1 at a molar ratio of 1: 0.5.
• FTD is ⁇ , ⁇ , ⁇ -trifluorothymidine, which is phosphorylated by intracellular thymidine kinase to form F ⁇ , which binds to thymidine synthase.
• PI-1 is an agent that prevents inactivation due to FTD degradation by inhibiting thymidine phosphorylase, an FTD degradation enzyme.
• the composition is an orally administrable composition, it may be one preparation containing both FTD and TPI-1, and a preparation containing FTD and a preparation containing TPI-1. It may be a combination with.
• these preparations include tablets, coated tablets, pills, powders, granules, capsules, solutions, suspensions, emulsions and the like.
• These preparations can be formulated by a conventional formulation method commonly known in this field using a pharmaceutically acceptable carrier or the like.
• the preparation can be appropriately divided and packaged so that the dose of 20 to 80 mg / m 2 / day is divided into 2 to 4 times a day.
• the packaging method is not particularly limited as long as it is a conventional packaging method generally known in this field.
• a tablet can be packaged in moisture and oxygen protective packaging materials.
• a carrier for example, lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, kylic acid, etc .; water, ethanol, propanol , Corn starch, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, potassium phosphate, Binders such as polybulurpyrrolidone; dry starch, sodium alginate, agar powder, laminaran powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, monoglyceride stearate, tempun, lactose, etc.
• lactose sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, kylic acid, etc .
• water, ethanol, propanol Corn starch
• Disintegrants such as sucrose, stearic acid, cocoa butter, hydrogenated oil
• absorption promoters such as quaternary ammonium base and sodium lauryl sulfate
• humectants such as glycerin and starch
• starch lactose and kaolin
• Adsorbents such as bentonite and colloidal carboxylic acid
• lubricants such as purified talc, stearate, boric acid powder and polyethylene glycol can be used.
• the tablets can be made into tablets with ordinary coatings as necessary, such as sugar-coated tablets, gelatin-encapsulated tablets, enteric-coated tablets, film-coated tablets, double tablets, multilayer tablets and the like.
• excipients such as glucose, lactose, starch, cacao butter, hydrogenated vegetable oil, kaolin, talc; gum arabic powder, tragacanth powder, gelatin, ethanol, etc.
• Binders Disintegrants such as laminaran and agar can be used.
• Capsules are prepared according to a conventional method, and the above ingredients are mixed with various carriers exemplified above and filled into hard gelatin capsules, soft capsules and the like.
• a liquid preparation, a syrup, an elixir or the like can be produced by a conventional method using a corrigent, a buffer, a stabilizer, a corrigent and the like.
• the corrigent include sucrose, orange peel, citrate, and tartaric acid
• examples of the buffer include sodium taenoate
• examples of the stabilizer include tragacanth, gum arabic, and gelatin.
• each of the above-mentioned preparations may be blended with a coloring agent, a preservative, a fragrance, a flavoring agent, a sweetening agent, and other pharmaceuticals as necessary.
• the composition is orally administered in a dose of 20 to 80 mg / m 2 Z as FTD equivalent divided into 2 to 4 times a day. More preferred daily dosage is at 25 to 75 mg / m 2 / day as FTD equivalent amount, further 30 ⁇ 75mg / m 2 / day preferably particularly 50 ⁇ 70mgZm 2 / day preferably les.
• the dose to the patient is determined by the body surface area (BSA) calculated from the height and weight of the patient.
• BSA body surface area
• a commonly used method is appropriately used depending on the race, sex, health condition, symptom, etc. of the patient.For example, the following formulas 1 to 5 are mentioned, and preferably the following 1 or 2 (a).
• BSA (m 2 ) 0.0003207 X height (cm) ⁇ 3 X body weight (grams) (. Communicating ⁇ ⁇ x x
• the body surface area of a cancer patient with a height of 175 cm and a weight of 70 kg is calculated using the above formula 1.
• the dose of 20 to 80 mg / m 2 Z as FTD-converted dose is orally administered in divided doses 2 to 4 times a day.
• the interval between administrations is preferably 6 hours or more.
• the administration schedule for one week may be administered every day, but it is preferable that the administration schedule is 5 days per week and 2 days off from the viewpoint of reducing the burden on the patient. In addition, it is preferable to administer 5 days per week for 2 weeks and then take 2 days off for 2 weeks.
• Cancers targeted by the cancer therapeutic agent of the present invention are not particularly limited, but for example, esophageal cancer, stomach cancer, liver cancer, gallbladder * bile duct cancer, knee cancer, colorectal cancer, head and neck cancer, lung cancer, Breast cancer, cervical cancer Ovarian cancer, bladder cancer, prostate cancer, testicular tumor, bone * soft tissue sarcoma, skin cancer, malignant lymphoma, leukemia, brain tumor, etc., preferably stomach cancer, knee cancer, breast cancer, colorectal cancer, head and neck Malignant solid cancers such as cancer, gallbladder 'bile duct cancer, lung cancer.
• an extremely excellent cancer therapeutic effect can be obtained in spite of a small dose compared with conventional once-daily administration. This is because the amount of FTD incorporated into the target site DNA increases by dividing the dose into 2-4 times a day. Furthermore, in the method of the present invention, side effects can be easily managed.
• Titanium oxide 0.50mg Hydroxypropinoremethinorescenellose 1. OOmg
• Tablets were prepared at the above blending ratio by a conventional method.
• Granules were prepared at the above blending ratio by a conventional method.
• Capsules were prepared at the above blending ratio by a conventional method.
• This study was conducted in patients with gastrointestinal cancer, where standard treatment is ineffective or untreated, and is a secondary phase II study conducted mainly for safety and for each cancer. Corresponds to the first clinical trial to determine the optimal dose (RD) that can be safely administered without causing effects. At that time, if the therapeutic effect on the tumor can be evaluated, We are going to evaluate.
• the therapeutic effect on the tumor can be measured according to the target lesion (CT and other slice widths) with reference to the RECIST evaluation method tiournal of the National Cancer Institute, 2000, Vol 92, No. 3, 205-216)
• the overall effect of lesions over size) and non-target lesions (all lesions other than the target lesions) was evaluated for the reduction effect on the tumor.
• PR partial response
• PD progression
• SD stable
• MR micro-effect
• Test 1 is the result of TAS-102 preparation (tablet) administered once a day at 100 mg / m 2 (FTD equivalent), administered 5 days per week for 2 days. Of the 6 cases, 2 cases (33%) were effective (stable without worsening the tumor).
• Study 2 the same preparation was divided into three doses of 70 mg / m 2 (FTD equivalent) per day, administered 5 days per week for 2 days, and 4 out of 6 cases (67%) was effective. That is, tumor progression stopped in 4 patients, no deterioration was observed, and tumor shrinkage was observed in 1 patient. Therefore, it was suggested that in the case of TAS-102 administration, the divided administration to patients with gastrointestinal cancer that is ineffective or has no treatment, is an effective administration method.
• Example 1 As in Example 1, a clinical vaginal test was performed on breast cancer patients.
• FTD-converted dose is orally administered twice at 60 mg / m 2 Z days (Study 3).
• the therapeutic effect of oral administration twice at 50 mg / mV day (Study 4) was examined.
• Study 3 is the result of TAS-102 preparation (tablet) administered twice a day at 60 mg / m 2 (FTD equivalent), 5 days per week, 2 days off, and 7 out of 7 cases Five Example (71%) was effective.
• Study 4 the same preparation was divided into 50 mgZm 2 (FTD equivalent) daily, divided into 2 doses, administered 5 days per week for 2 days, and 7 of 9 cases (78%) were effective.
• Met In other words, in most cases, the progression of the tumor ceased, and it did not worsen.
• SD continued for more than half a year in several cases, and in one case, SD continued for more than one year.

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