EP0409845A1 - Method for protection from chemotherapeutic side effects - Google Patents
Method for protection from chemotherapeutic side effectsInfo
- Publication number
- EP0409845A1 EP0409845A1 EP89902904A EP89902904A EP0409845A1 EP 0409845 A1 EP0409845 A1 EP 0409845A1 EP 89902904 A EP89902904 A EP 89902904A EP 89902904 A EP89902904 A EP 89902904A EP 0409845 A1 EP0409845 A1 EP 0409845A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- derivative
- aminopropylamino
- ethyl dihydrogen
- dihydrogen phosphorothioate
- patient
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
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
- A61K31/66—Phosphorus compounds
-
- 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
- A61P39/00—General protective or antinoxious agents
- A61P39/02—Antidotes
-
- 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
- Chemotherapy is one of the most useful treatments available to present day medicine in the struggle against cancer.
- chemotherapeutic agents powerful alkylating agents, antibiotics and platinum-containing compounds have found wide use through the treatment of a variety of cancers.
- doxorubicin and its derivatives can cause cardiac toxicity and bone marrow toxicity.
- the mitomycin family and platinum-containing compounds such as carboplatin can cause bone marrow toxicity in a patient.
- the amount and frequency of chemotherapeutic agent administration may be limited to levels which are below the optimum level for treatment of the cancer from which the patient suffers.
- Doxorubicin (and derivatives such as the hydrochloride derivative, sold under the name ADRIAMYCIN) presently is administered in chemotherapy about once every 3 to 4 weeks in an amount of about 25 to 100 mg/m 2 patient surface area.
- the dosage is commonly about 60 mg/m 2 .
- the frequency and amount of the agent administered is limited because of the cardiotoxic and bone marrow toxic side effects associated with its administration.
- mitomycin family which includes mitomycin A, mitomycin B, mitomycin C and N-methyl mitomycin C (porfiromycin).
- Mitomycin C for example, is presently administered about once every 4 to 6 weeks in amounts of about 5 to 30 mg/m 2 , usually about 10 mg/m 2 .
- the frequency and amount administered is limited due to the bone marrow toxicity associated with administration of the mitomycins.
- Carboplatin a second generation analog of cisplatin (both from Bristol-Myers), is administered about once every 3 to 4 weeks in amounts of about 200-800 mg/m 2 , normally about 400 mg/m 2 .
- the frequency and amount administered is limited due to the bone marrow toxicity associated with carboplatin administration.
- This invention protects a patient against the undesired side effects of the chemotherapeutic agents without significant damage to the beneficial therapeutic properties of the chemotherapeutic agents through the administration of S -2 - ( 3 -aminopr opylamino) ethyl dihydrogen phosphorothioate (and pharmaceutically acceptable derivatives thereof) in an amount sufficient to protect the patient against the cardiac toxicity and/or bone marrow toxicity discussed above.
- S-2-(3-aminopropylamino) ethyl dihydrogen phosphorothioate has the structural formula:
- S-2-(3- aminopropylamino) ethyl dihydrogen phosphorothioate but also to pharmaceutically acceptable derivatives such as alkali metal salts and hydrates thereof.
- S-2-(3- aminopropylamino) ethyl dihydrogen phosphorothioate and its derivatives may be prepared in accordance with the methods disclosed in U.S. Patent No. 3,892,824 to Piper et al., the disclosure of which is incorporated herein by reference.
- S-2-(3-aminopropylamino) ethyl dihydrogen phosphorothioate or a pharmaceutically useful derivatives thereof The amount of S-2-(3-aminopropylamino) ethyl dihydrogen phosphorothioate can be from about 300 to 1,000 mg/m 2 , with a dosage of about 740 mg/m 2 being preferred.
- the S -2 -(3-aminopropylamino) ethyl dihydrogen phosphorothioate or its derivative should be administered either with, or more preferably, before administration of the chemotherapeutic agent. Particularly preferred is drip intravenous infusion in a buffered aqueous solution 15 to 30 minutes before administration of the chemotherapeutic agent. Oral administration is also desirable.
- the S-2-(3-aminopropylamino) ethyl dihydrogen phosphorothioate can be stored frozen at low temperatures, e.g., -70°C.
- the I.V. carrier solution may be a buffered solution of 5% dextrose in Ringers lactate, having a pH of about 7.2 to 7.4. This solution can be made by adding 20 cc of 44.9 mEq sodium bicarbonate to 1 liter of 5% dextrose in Ringers lactate.
- 9.3 cc of the solution can be added to a vial containing 500 mg of S-2-(3-aminopropylamino) ethyl dihydrogen phosphorothioate to produce a solution containing 50 mg/cc of S-2-(3-aminopropylamino) ethyl dihydrogen phosphorothioate.
- further buffered solution can be added for a total volume of 50 cc, and the resulting solution can be administered to a patient over a period of about 15 minutes, using a volumetric pump.
- S-2-(3-aminopropylamino) ethyl dihydrogen phosphorothioate binds to normal cells in competition with the chemotherapeutic agent, but not to tumors.
- S-2-(3-aminopropylamino) ethyl dihydrogen phosphorothioate may be taken up by normal cells, but not tumor cells. It thereby protects the normal tissues by then binding with and inactivating the chemotherapeutic agents.
- S-2-(3-aminopropylamino) ethyl dihydrogen phosphorothioate is not taken up by cancerous tissues, it leaves them open to attack by the chemotherapeutic agents. Significant improvement is expected in white blood cell and granulocyte nadirs, as well as duration of nadirs (or time to recovery). This will allow for the safer administration of conventional dosages of carboplatin and mitomycins and for the safer administration of higher clinical dosages. A significant reduction in the damage to cardiac muscle by doxorubicin will also allow for safer administration of higher cumulative clinical doses.
- a solution of 2-(3-aminopropylamino)ethanol (25.0 g. 0.212 mole) in 48 percent hydrobromic acid (200 ml) is distilled until 35 ml of distillate has been collected.
- the solution is refluxed and periodically, more distillate is collected.
- the total volume of distillate removed in 7 distillation periods is 160 ml. or 80 percent of the original volume of 48 percent hydrobromic acid and the time of continuous boiling is approximately 48 hours.
- the residual solution is then evaporated to dryness under reduced pressure with the aid of several added portions of methanol.
- the crystalline residue is thoroughly triturated with acetone, collected, and washed on the funnel with acetone.
- Trisodium phosphorothioate (6.93 g, 38.5 mmoles) is gradually added in small portions with vigorous stirring to water (38 ml) cooled externally by means of a water bath (15o-20°C.).
- N-(2- bromoethyl)-1.3-propanediamine dihydrobromide (13.3 g, 38.8 mmoles).
- N,N-dimethylformamide (19 ml) is added with continued external cooling at 15°-20oC.
- the solution has been stirred at about 20oC for 90 minutes, it is poured into methanol (250 ml), and the mixture is refrigerated at 4oC overnight.
- the white precipitate that formed is collected and pressed as dry as possible on the funnel.
- the damp solid is dissolved in water (40 ml), and the solution is filtered.
- Addition of methanol (250 ml) reprecipitates the product.
- the product is collected and washed on the funnel, first with methanol and finally with ether.
- the white solid is dried in vacuo at room temperature, then exposed to ambient conditions of the laboratory for 5 hours, and bottled under nitrogen and stored in a freezer.
- the yield of S-2-(3-aminopropylamino) ethyl dihydrogen phosphorothioate monohydrate, mp 160°-161°C. dec. is 8.15 g (91%).
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Toxicology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
Le S-2-(3-aminopropylamino)éthyl dihydrogéno-phosphorothiotate et des dérivés pharmaceutiquement acceptables de ce composé sont utilisés pour protéger un patient soumis à un traitement chimiothérapique contre les effets secondaires toxiques pour le coeur et pour la moelle osseuse, associés à l'administration d'agents chimiothérapiques.S-2- (3-aminopropylamino) ethyl dihydrogenophosphorothiotate and pharmaceutically acceptable derivatives of this compound are used to protect a patient undergoing chemotherapy against toxic side effects for the heart and bone marrow, associated with administration of chemotherapeutic agents.
Description
Claims
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US15910488A | 1988-02-23 | 1988-02-23 | |
US159104 | 1988-02-23 |
Publications (2)
Publication Number | Publication Date |
---|---|
EP0409845A1 true EP0409845A1 (en) | 1991-01-30 |
EP0409845A4 EP0409845A4 (en) | 1991-07-03 |
Family
ID=22571099
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP19890902904 Withdrawn EP0409845A4 (en) | 1988-02-23 | 1989-02-21 | Method for protection from chemotherapeutic side effects |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP0409845A4 (en) |
JP (1) | JPH03503888A (en) |
AU (1) | AU636107B2 (en) |
CA (1) | CA1336506C (en) |
WO (1) | WO1989007942A1 (en) |
Families Citing this family (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE3827974A1 (en) * | 1988-08-18 | 1990-02-22 | Boehringer Mannheim Gmbh | COMBINATION PREPARATIONS OF PROTEINKINASE-C INHIBITORS WITH LIPIDS, LIPID ANALOGS, CYTOSTATICA OR INHIBITORS OF PHOSPHOLIPASES |
US5567686A (en) * | 1992-03-13 | 1996-10-22 | Arch Development Corporation | Method for protection against genotoxic mutagenesis |
US6051563A (en) * | 1997-02-12 | 2000-04-18 | U.S. Bioscience, Inc. | Methods for the administration of amifostine and related compounds |
US6573253B2 (en) | 1997-02-12 | 2003-06-03 | Medimmune Oncology Inc. | Methods for the administration of amifostine and related compounds |
US6239119B1 (en) | 1998-04-27 | 2001-05-29 | Medimmune Oncology, Inc. | Topical administration of amifostine and related compounds |
US6489312B1 (en) | 1999-06-15 | 2002-12-03 | Medimmune Oncology, Inc. | Pharmaceutical formulations comprising aminoalkyl phosphorothioates |
US7053072B2 (en) | 2001-05-11 | 2006-05-30 | Medimmune Oncology, Inc. | Methods for the administration of amifostine and related compounds |
CN102260288B (en) * | 2010-06-08 | 2014-02-26 | 成都大有得药业有限公司 | Synthesis method of 3-amino-propyl aminoethyl thiophosphate trihydrate |
RU2450791C1 (en) * | 2010-10-18 | 2012-05-20 | Федеральное государственное учреждение "Ростовский научно-исследовательский онкологический институт Федерального агентства по высокотехнологичной медицинской помощи" | Method for determining cardiotoxic complications in patients with chronic lymphatic leukemia |
CN104230984B (en) * | 2013-06-08 | 2017-02-08 | 国药集团国瑞药业有限公司 | Preparation method for trihydrate 3-amino propyl aminoethyl thiophosphoric acid |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4656034A (en) * | 1985-05-20 | 1987-04-07 | Survival Technology, Inc. | Absorption enhancing agents |
-
1989
- 1989-02-21 AU AU31940/89A patent/AU636107B2/en not_active Expired
- 1989-02-21 WO PCT/US1989/000624 patent/WO1989007942A1/en not_active Application Discontinuation
- 1989-02-21 EP EP19890902904 patent/EP0409845A4/en not_active Withdrawn
- 1989-02-21 JP JP1502696A patent/JPH03503888A/en active Pending
- 1989-02-23 CA CA000591907A patent/CA1336506C/en not_active Expired - Lifetime
Non-Patent Citations (5)
Title |
---|
American Association for Cancer Research Proceedings, Vol. 22, March 1981, page 271, Abstract No. 1075, Washington, DC, US; T.L. PHILLIPS et al.: "Differential protection against cytotoxic chemotherapeutic effects on bone marrow CFUs, intestinal crypt cells, EMT6 tumor", whole article. * |
Drugs of the Future, Vol. 14, No. 11, November 1989, pages 1105-1107; whole article. * |
J. Pharmacobio.-Dynamics, Vol. 3, No. 7, July 1980, page s-21; M. ONODA et al.: "Effect of various kinds of drugs in vitro on the proliferation of leukopoietic stem cells (CFU-C)", whole article. * |
Proceedings of the 9th Annual Conference of the IEEE Engineering in Medicine and Biology Society, Boston, 13th-16th November 1987, pages 1443-1445, New York, US; M.-A. RIX-MONTEL: "Radioprotective effects of thiophosphates", whole article. * |
See also references of WO8907942A1 * |
Also Published As
Publication number | Publication date |
---|---|
WO1989007942A1 (en) | 1989-09-08 |
JPH03503888A (en) | 1991-08-29 |
AU636107B2 (en) | 1993-04-22 |
CA1336506C (en) | 1995-08-01 |
EP0409845A4 (en) | 1991-07-03 |
AU3194089A (en) | 1989-09-22 |
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Legal Events
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Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN |
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18D | Application deemed to be withdrawn |
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