Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
  • C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
  • C07F15/0086—Platinum compounds
  • C07F15/0093—Platinum compounds without a metal-carbon linkage
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
  • C07F9/02—Phosphorus compounds
  • C07F9/28—Phosphorus compounds with one or more P—C bonds
  • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
  • C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
  • C07F9/3808—Acyclic saturated acids which can have further substituents on alkyl

Definitions

• N-phosphonacetyl-L-aspartato (1,2-diaminocyclohexane) platinum(II) or alkali metal salt thereof has shown antitumor activity in animals such as activity against murine leukemia L1210. Additionally, this agent is used against B-16 and Colon 38 tumors and also Ehrlich ascites tumor. It is effective in dosages of 5-60 mg/kg of body weight and is potentiated in a treatment with cyclophosphamide (CY) (50 mg/kg of body weight) to which may be added hydroxyurea (HU) (1000-1500 mg/kg of body weight).
• CY cyclophosphamide
• HU hydroxyurea
• the preferred ratio of the present compound to cisplatin is about 10:1 with a range of about 10:1 to 1:10 in mg/kg of body weight.
• the formula on the left hand side it may be varied as monodentate, such as cisplatin containing a single amine group proceeding from the ring, or bidentate, such as the present compound.
• the saturated cyclo ring may be C 4 or C 5 -C 7 in addition to the present cyclohexane.
• aromatic may be substituted or unsubstituted.
• Heterocyclic where Y N, O, or S or any other donor atom.
• the present platinum compound may be prepared reacting the known L-aspartic acid, N-(phosphonacetyl-) disodium salt (PALA; NSC-224131), with dinitrato (1,2-diaminocyclohexane) platinum (II) (NSC-239851).
• PAA N-(phosphonacetyl-) disodium salt
• II dinitrato (1,2-diaminocyclohexane) platinum
• N-phosphonacetyl-L-aspartato (1 ,2-diaminocyclohexane)platinum (II) may be combined in multiple drug regimen with substantially improved yield cures over the parent compounds,
• the compound denoted Pt-268 may be combined in a dual regimen with, cyclophospha-mide (CY), hydroxyurea (HU), and cisplatin.
• NSC numbers in this application are the official numbers made public by the National Cancer Institute and the following numbers are particularly utilized.
• NSC-224131 N-(phosphonacetyl-)disodium salt (PALA)
• NSC-314926 N-phosphbnacatyl-L-aspartato(1,2- diaminocyclohexaneLplatinum(II), Na (Pt-268)
• NSC-328Q05 N-phosphonacetyl-L-aspartato(1,2- diaminocyclohexanelplatinum(II) (acid form) DESCRIPTION OF THE DRAWINGS
• Fig. 1 shows the effect of N-phosphonacetyl-L-aspartato (1,2-diaminocyclohexane) platinum(II) [Pt-268] on life spans of mice bearing L1210 leukemia.
• Mice received 10 6 L1210 cells on Day 0 via intraperitoneal route.
• Pt-268 was given intraperitoneally on Day 1 only in 5% glucose solution.
• Fig. 2 shows the effect of Pt-268 on life spans of mice bearing L1210 leukemia.
• Mice received 10 L1210 cells on Day 0 via intraperitoneal route.
• Pt-268 was given intraperitoneally on Days 1, 5, and 9 in 5% glucose solution.
• Numbers adjacent to symbols number of >60-day survivors in each group of 10 animals.
• Control survival time 203 hours.
• Fig. 4 shows the effect of pt-268 when used in combination with cisplatin (NSC-119875). Mice were given an inoculum of 10 L1210 cells. One group received Pt-268 on Day 3; another group received cisplatin on Days 3, 4, 5, and 6; and a third group received the two drugs in combination on the same schedule . This third group of animals showed an increased median life span of 25 days over the control group with a cure rate ( > 50-day survivors) of 50% .
• step (a) recites the conventional preparation of cisplatin (NSC-194814) and in steps (b) and (c) 1.38 grams (4.6 mmoles) of PALA [N-(phosphonacetyl-)disodium salt] was added to 1.6 grams (3.7 mmoles) of dinitrato (1,2-diaminocyclohexa platinum(II) (NSC-239851). These reactants were initially dissolved in a minimum of distilled water prior to mixing. The reaction mixture was stirred overnight at room temperature with a flow of filtered air to facilitate evaporation. The solid material was collected and dissolved in 20 ml of distilled water.
• the present compound has been tested alone and in combination with cyclophosphamide and hydroxyurea. It is believed that there is a substantial advantage synergistically in the combination of Pt-268 and cyclophosphamide although the advantage as with hydroxyurea was minimal. In the ternary system with Pt-268 plus cyclophosphamide plus hydroxyurea, there is a substantial synergistic advantage over the binary system with cyclophosphamide and the results of this multiple therapy are set out in Fig. 3.
• the PALA group apparently dissociates or leaves from the Pt-268 complex rather slowly.
• Pt-268 is dissolved in 0.9% NaCl solution
• displacement of the PALA with chlorides as evidenced by the appearance of an insoluble precipitate of dichloro (1,2-diaminocyclohexane) platinum(II) (NSC-194814)
• the intact Pt-268 complex may be transported into or otherwise gain access into the tumor cell.
• Glacial acetic acid Ammonia A 2-mg sample was either very slightly soluble or insoluble in each of the following solvents: ethanol dimethylformamide acetone dimethylsulfoxide tetrahydrofuran cyclopentanone t-butanol heptane
• Ultraviolet (uv) spectrum The uv spectrum of platinum-PALA complex at 10 -4 molar concentration has a prominent peak at 200 nm with a shoulder at 240 nm. The 200 nm peak decreases with time while the 240 nm peak becomes more prominent. The spectrum stabilizes within 10 hours. PALA also exhibits the characteristic end absorption with a peak at 278 nm in 1% aqueous solution.
• the N-phosphonacetyl-L-aspartato (1,2-diamino chclohexane)platinum(II) complex (Pt-268; NSC-314926) was dissolved in 5% glucose and tested for its activity in the L1210 leukemia in mice.
• LD 50 was determined in tumored BDF 1 mice and was found to be 180 mg/kg.
• the BDF 1 mice received 10 6 L1210 leukemia cells by I.P. injection on Day 0 and were divided into groups of 10, including a control group of 40 mice. The treated groups were treated on Day 1 only at different dose levels from 10 mg/kg to 200 mg/kg or treated on Days 1,
• Fig. 1 shows the dose-response curve for Day 1 only treatment.
• Fig. 2 summarizes the results obtained from a dose schedule in which Pt-268 was administered on
• N-phosphonacetyl-L-aspartate (PALA; NSC-224131) as received from the National Cancer Insti- tute had a purity of 87 ⁇ 2% and consisted of 64% disodium salt and 26% trisodium salt. The remainder was water and ethanol. Therefore, the stoichiometry was adjusted so that 2.5 grams (8.36 mmoles) of the PALA would be added to 3.55 grams (8.2 moles) of dinitrato (1, 3-diaminocyclohexane)platinum (II) (NSC-239851).
• PALA N-phosphonacetyl-L-aspartate
• NSC-268252 The synthesis of NSC-268252 is described in Schwartz et al., Cancer Treatment Report, 61:1519-1525, 1977.
• the solutions were allowed to react with the resins and were then filtered from the resins, combined, and the mixture was transferred to the flask of a vacuum flash evaporator. Upon removal of all the water, the product was dissolved in ⁇ 30 ml of water, filtered, and 400 ml of absolute ethanol was added to precipitate the white product. Yield of NSC-328005 was approximately 30% of the theoretical value.
• the final reaction can be depicted thus:
• NSC-328005 can also be used as the starting material for producing the alkali metal salt form. This is done by titrating with a known amount of alkali metal base such as sodium bicarbonate.
• mice bearing the Ehrlich ascites carcinoma.
• Mice received an intraperitoneal inoculation of 10 7 tumor cells on Day 0; treatment was by the intraperitoneal route on Day 1 only.
• NSC-3.14926 [N-phosphonacetyl-L-aspartato (1,2-diaminocyclohexane) platinum(II)] was dissolved in 5% dextrose solution. There were 10 mice per group.

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• 1980
  • 1980-06-09 US US06/155,531 patent/US4284579A/en not_active Expired - Lifetime
  • 1980-06-23 JP JP50188580A patent/JPS56500849A/ja active Pending
  • 1980-06-23 WO PCT/US1980/000777 patent/WO1981000256A1/en not_active Ceased
  • 1980-07-14 IL IL60575A patent/IL60575A/xx unknown
  • 1980-07-15 DE DE8080104102T patent/DE3069356D1/de not_active Expired
  • 1980-07-15 EP EP80104102A patent/EP0026813B1/en not_active Expired
  • 1980-07-17 CA CA000356429A patent/CA1151663A/en not_active Expired
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