JPH03503888A - How to protect from chemotherapy side effects - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] How to protect from chemotherapy side effects Chemotherapy is the most useful therapy available to medicine today in the fight against cancer. It is one of the treatments. Among the known chemotherapeutic agents, strong alkylating agents, antibiotics Platinum-containing compounds have found widespread use in the treatment of various cancers. Ru.

However, the anti-cancer effects of these chemotherapeutic agents are limited by the fact that the drugs are non-cancerous in the patient's system. limited by the influence it can have on the sexual part. For example, doxol Bicine and its derivatives can cause cardiotoxicity and bone marrow toxicity. Might Platinum-containing compounds such as the mycin family and carpoplatin may May cause bone marrow toxicity. As a result of these side effects, the amount of chemotherapy administered and the frequency is at a level that is below the appropriate level for treatment of the cancer the patient is suffering from. limited to.

Doxorubicin (also sold under the name ADRT AMYCI N) derivatives, such as hydrochloride derivatives), currently have a dosage of about 25 per 11 IIt of patient surface area. ~1001119 is administered in chemotherapy approximately once every 3 to 4 weeks. Ru. The dosage is usually about 60x9/y''.

The frequency and amount of the drug administered will depend on the cardiotoxicity and myelotoxicity associated with its administration. Limited due to side effects.

Another group of anti-tumor antibiotics is the mitomycin family, which includes koreba, mitomycin, and mitomycin. Mycin A1 Mitomycin B1 Mitomycin C and N-methyl mitomycin Contains SynC (porphyromycin). For example, mitomycin C is currently Currently, about 5 to 30 m9/x", usually about 10 m9/x" every 4 to 6 weeks. It has been administered approximately once. The frequency and amount administered will depend on the administration of mitomycin. limited due to associated bone marrow toxicity.

Second generation analogues of cisplatin log), carboplaten [both Bristol-Meyers (Bristol- Myers) is about 200 to 800πy/x”, usually about 400*9 /y,” is administered approximately once every 3 to 4 weeks. Frequency and amount of administration The present invention provides protection for patients against cardiotoxicity and/or bone marrow toxicity. A sufficient amount of S-2-(3-aminopropylamino)ethyl dihydrogenthiophosphate ( and pharmaceutically acceptable derivatives thereof). address the undesirable side effects of chemotherapeutic agents without significant damage to their therapeutic properties. protect the patient against

S-2-(3-aminopropylamino)ethyl dihydrogen thiophosphate has the structural formula.

NHl(CH,), NH(CH,)tsPO, H2. The present invention Not only S-2-(3-aminopropylamino)ethyl thiophosphate, but also its Also regarding pharmaceutically acceptable derivatives such as alkali metal salts and hydrates. be. S-2-(3-aminopropylamino)ethyl dihydrogen thiophosphate and its Derivatives of are disclosed in Piper et al., U.S. Pat. It can be prepared according to the method shown, the description of which is incorporated herein by reference. I will post it.

The above cardiotoxicity and myelotoxicity risks are due to dihydrogen thiophosphate S-2-(3-amino significantly by administration of propylamino)ethyl or its pharmaceutically useful derivatives. Decrease. Amount of S-2-(3-aminopropylamino)ethyl dihydrogen thiophosphate ranges from about 300 to 1,000o/1, preferably about 740 m9/x2 This is the medication. S-2-(3-aminopropylamino)ethyl dihydrogen thiophosphate or a derivative thereof, in conjunction with the administration of the chemotherapeutic agent or, more preferably, the administration of the chemotherapeutic agent. should be administered before administration. Particularly preferably 15 to 30 minutes of administration of chemotherapeutic agent. It is an intravenous infusion of a buffered aqueous solution. Oral administration is also preferred.

As an example, S-2-(3-aminopropylamino)ethyl dihydrogenthiophosphate is It can be stored frozen at low temperatures, for example -70'C. Intravenous (1, V,) The body solution is 5% dextrose in Ringer's lactate with a pH of approximately 7.2-7.4. buffered solution. This solution is 5% dextrose in Ringer's lactate. Prepared by adding 20cc of 44.9+Eq Sodium Bicarbonate to IQ. can be done. 9.3 cc of this solution was added to dihydrogen thiophosphoric acid S-2-(3-amino propylamino)ethyl 5001119 to the vial containing 5Q rn9/cc dihydrogen thiophosphoric acid S-2-(3-aminopropylamine) A solution containing chill can be prepared. Add additional buffering solution before administration. It can be added to make a total volume of 50cc, and a volumetric pump (volumetri Administer the resulting solution to the patient over approximately 15 minutes using a pump. I can do it.

While not wishing to be bound to one particular theory of protection, dihydrogen thiophosphate S-2-(3-aminopropylamino)ethyl competes with chemotherapeutic agents to destroy normal cells. but not to tumors. That is, dihydrogen thiophosphoric acid S -2-(3-aminopropylamino)ethyl is taken up by normal cells, but , not taken up by tumor cells. Therefore, it binds to chemotherapeutic agents and Protect normal tissue by inactivating therapeutic agents. Dihydrogen thiophosphoric acid S- 2-(3-ami/propylamino)ethyl is not taken up by cancer tissue , leaving the cancerous tissue open to attack by chemotherapeutic agents.

leukocytes and granulocytes during the stagnation phase and throughout the stagnation period (or until recovery). time), significant improvement is expected. This allows carpoplatin and Safe administration of routine and high clinical dosing of tomycin I can do it. Significant reduction in myocardial damage caused by doxorubicin Cumulative clinical doses can also be safely administered.

Example Dihydrogen thiophosphate S-2-(3-aminopropylamino)ethyl-hydrate H ,N(CH,),NHCH,CH,SPO,H,・H,048% hydrobromic acid (2 00x 2-(3-amino/propylamino)ethanol (25.0g, 0°2 12 mol) is distilled until 35 λQ of distillate is recovered. the solution is refluxed to periodically collect further distillate. Removed during 7 distillation periods The total amount of distillate was 160. wff or 48% hydrobromic acid initial 80% of the volume, and the continuous boiling time is about 48 hours. Then, under reduced pressure, meth The remaining solution is evaporated to dryness with the help of a few drops of Kol.

Thoroughly triturate the crystalline residue with acetone and remove the acetone. Wash on the funnel using After pressing the product as dry as possible on the funnel, slightly Dissolve in excess boiling methanol and filter the solution. Add acetone to the filtrate colorless crystalline pure N(2-bromoethyl)-1,3-propanediamide. 58.0 Get a score of 9 (80%). Melting point 205-206°C by water bath (15-20°C) Trisodium thiophosphate was added to externally cooled water (38 ml) with vigorous stirring. Lium (6.93 g, 38.5 mmol) is added slowly in small portions.

N-(2-bromoethyl)-'1,3-propanediamine was added to the resulting suspension. Add trihydrobromide (13,39,38,8 mmol!J mole). After a few minutes, completely The N,N-dimethylform Add Lumamide (19xQ).

The solution was stirred at approximately 20 °C for 90 min, then poured into methanol (250xQ) and Refrigerate the mixture at 4°C overnight. Collect the white precipitate that forms and drain it on the funnel. Press dry as much as possible. Dissolve the damp solid in 40 m of water and pour the solution into Filter. The product is reprecipitated by addition of methanol (250jIQ). Applicable After refrigerating the mixture for approximately 1 hour, the product was collected and diluted first with methanol on a funnel. Wash and finally with ether. The white solid was dried under vacuum at room temperature and then Expose to laboratory environmental conditions for 5 hours, bottle under nitrogen, and store in the refrigerator. . S-2-(3-aminopropylamino)ethyl dihydrogen thiophosphate -hydrate, The yield with a melting point of 160-161°C (decomposition) is 8. l5y (91%). elemental analysis (C, H,, N!O, PS-H, ○): Theoretical value 20-25,86; H-7,38 ; N-12,07° Measured value: C-25°83; H-7,27; N-11, 81゜Nosburachi 739 1P (19) 1 (16 ) 11 (14) 1 (20) (21) (Q2) 2/6 28 (20), (17) 1 13 (13) (19) (21) (22) I/620 (19) (16) 2 (1,5) (19) (20) (22) 4/6 dihydrogen thiophosphoric acid S -2-(3-aminopropylami/)ethyl 300 1P (19) (19) (19) (20) (21) (21) 6/6) 30 02)=S-2-(3-aminopropylamino)ethyl dihydrogen thiyphosphate 1) 39　]) IP　　(19)　(17)　　12(13)2　(1 5) (19) (23) l/6 approximately 182) 300 2) iP, Cisblatin (Cisbratin) 30 minutes before 1) 28 (20) (18) (15) (1 8) (19) (21) 6/6 (2 with naked eye) 300 Measurement) 1) 20 (19) (17) (17) l (+9) (20) (Q1) 5/6 (Cisbratin) i21) 6/6 Cisplatin was prepared (dissolved) in saline.

S-2-(3-aminopropylamino)ethyl trihydrogenthiophosphate was prepared in saline. prepared (dissolved).

Although the detailed description of the present invention has been described above, the present invention is not limited thereto. Defined by the claims below.

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Claims (28)

[Claims] (1) Chemotherapy involving administration of doxorubicin or its pharmaceutically acceptable derivatives Doxorpicin or its derivatives should be used to A method for protecting against undesirable cardiotoxic side effects, the method comprising: dihydrogenthiophosphate S-2-(3-aminopropylene) in an amount sufficient to protect the patient against ropylamino)ethyl or a pharmaceutically acceptable derivative thereof is administered to the patient. A protection method characterized by: (2) S-2-(3-aminopropylamino)ethyl dihydrogen thiophosphate or its The method according to claim (1), wherein the derivative is administered intravenously. (3) Approximately 15 to 30 minutes before administration of doxorubicin or its derivatives, Administration of S-2-(3-aminopropylamino)ethyl olinate or its derivatives The method according to claim (2). (4) S-2-(3-aminopropylamino)ethyl dihydrogen thiophosphate or its The dose of the derivative is approximately 300 to 1.000 mg/m2 of patient surface area. The method described in claim (2). (5) S-2-(3-aminopropylamino)ethyl dihydrogen thiophosphate or its The method of claim 4, wherein the dose of the derivative is about 740 mg/m2. (6) S-2-(3-aminopropylamino)ethyl dihydrogen thiophosphate or its according to claim 2, wherein the derivative is administered via intravenous infusion in a buffered aqueous solution. the method of. (7) Chemotherapy involving the administration of doxorpicin or its pharmaceutically acceptable derivatives Doxorpicin or its derivatives should be used to A method for protecting against undesirable myelotoxic side effects, the method comprising: dihydrogenthiophosphate S-2-(3-aminopropylene) in an amount sufficient to protect the patient against ropylamino)ethyl or a pharmaceutically acceptable derivative thereof is administered to the patient. A protection method characterized by: (8) S-2-(3-aminopropylamino)ethyl dihydrogen thiophosphate or its The method according to claim 7, wherein the derivative is administered intravenously. (9) Approximately 15 to 30 minutes before administration of doxorubicin or its derivatives, Administration of S-2-(3-aminopropylamino)ethyl olinate or its derivatives The method according to claim (8). (10) S-2-(3-aminopropylamino)ethyl dihydrogen thiophosphate or The dose of the derivative is approximately 300-1,000 mg/m2 of patient surface area. The method according to claim (8). (11) S-2-(3-aminopropylamino)ethyl dihydrogen thiophosphate or 11. The method of claim 10, wherein the dose of the derivative is about 740 mg/m2. (12) S-2-(3-aminopropylamino)ethyl dihydrogen thiophosphate or Claim 8, wherein the derivative is administered via intravenous infusion in a buffered aqueous solution. How to put it on. (13) Chemistry involving administration of mitomycin or a pharmaceutically acceptable derivative thereof Patients receiving therapy should not be given the benefit of mitomycin or its derivatives. A method for protecting against undesirable myelotoxic side effects, the method comprising: dihydrothiophosphate S-2-(3-amino) in an amount sufficient to protect the patient against propylamino)ethyl or a pharmaceutically acceptable derivative thereof to the patient. A protection method characterized by: (14) The method according to claim (13), wherein the mitomycin is mitomycin A. (15) The method according to claim (13), wherein the mitomycin is mitomycin B. (16) The method according to claim (13), wherein the mitomycin is mitomycin C. (17) Claim (13), wherein the mitomycin is N-methylmitomycin C. How to put it on. (18) S-2-(3-aminopropylamino)ethyl dihydrogen thiophosphate or 14. The method according to claim 13, wherein the derivative is administered intravenously. (19) Approximately 15 to 30 minutes before administration of mitomycin or its derivative, dihydrogen Administration of S-2-(3-aminopropylamino)ethyl thiophosphate or its derivatives The method according to claim (18), which provides: (20) S-2-(3-aminopropylamino)ethyl dihydrogen thiophosphate or The dose of the derivative is approximately 300-1,000 mg/m2 of patient surface area. The method according to claim (18). (21) S-2-(3-aminopropylamino)ethyl dihydrogen thiophosphate or 21. The method of claim 20, wherein the dose of the derivative is about 740 mg/m2. (22) S-2-(3-aminopropylamino)ethyl dihydrogen thiophosphate or Claim (18) wherein the derivative is administered via intravenous infusion in a buffered aqueous solution. Method described. (23) Chemistry involving administration of carboplatin or a pharmaceutically acceptable derivative thereof Patients receiving therapy should not be given the benefit of carboplatin or its derivatives. A method for protecting against undesirable myelotoxic side effects, the method comprising: Dihydrogen thiophosphate S-2-(3-amino) in an amount sufficient to protect the patient against propylamino)ethyl or a pharmaceutically acceptable derivative thereof to the patient. A protection method characterized by: (24) S-2-(3-aminopropylamino)ethyl dihydrogen thiophosphate or 24. The method according to claim 23, wherein the derivative is administered intravenously. (25) Approximately 15 to 30 minutes before administration of carboplatin or its derivative, dihydrogen Administration of S-2-(3-aminopropylamino)ethyl thiophosphate or its derivatives The method according to claim (24), which provides: (26) S-2-(3-aminopropylamino)ethyl dihydrothiophosphate or The dose of the derivative is approximately 300-1,000 mg/m2 of patient surface area. The method according to claim (24). (27) S-2-(3-aminopropylamino)ethyl dihydrogen thiophosphate or 27. The method of claim 26, wherein the dose of the derivative is about 740 mg/m2. (28) S-2-(3-aminopropylamino)ethyl dihydrogen thiophosphate or Claim (24), wherein the derivative is administered via intravenous infusion in a buffered aqueous solution. Method described.