WO1988002366A1 - 1,2,4-benzotriazine oxides as radiosensitizers and selective cytotoxic agents - Google Patents

1,2,4-benzotriazine oxides as radiosensitizers and selective cytotoxic agents Download PDF

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Publication number
WO1988002366A1
WO1988002366A1 PCT/US1987/001412 US8701412W WO8802366A1 WO 1988002366 A1 WO1988002366 A1 WO 1988002366A1 US 8701412 W US8701412 W US 8701412W WO 8802366 A1 WO8802366 A1 WO 8802366A1
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hydrocarbyl
amino
benzotriazine
hydroxy
independently
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PCT/US1987/001412
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English (en)
French (fr)
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William W. Lee
J. Martin Brown
Edward W. Grange
Abelardo P. Martinez
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Sri International
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Priority to GB8810634A priority Critical patent/GB2203151B/en
Priority to DE3790581A priority patent/DE3790581B4/de
Publication of WO1988002366A1 publication Critical patent/WO1988002366A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D253/00—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00
    • C07D253/08—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00 condensed with carbocyclic rings or ring systems
    • C07D253/10—Condensed 1,2,4-triazines; Hydrogenated condensed 1,2,4-triazines
    • 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
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/0038—Radiosensitizing, i.e. administration of pharmaceutical agents that enhance the effect of radiotherapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention relates to cytotoxic agents and radiotherapy effective against hypoxic cells. Specifically, the invention relates to selectively killing tumor cells and to sensitizing tumor cells to radiation using 1,2,4-benzotriazine oxides.
  • Hypoxic cell radiosensitizers are compounds that selectively increase the sensitivity of hypoxic cells to destructive radiation. Cytotoxins which have enhanced activity under hypoxic conditions also provide a means for selective destruction of cells under low oxygen pressure. This specificity for hypoxic cells is important because it is tumors that are typically characterized by such cells. Virtually all tumors which are present as solid masses contain these cells, while normal cells generally have an adequate supply of oxygen. Accordingly, anti-tumor agents can be made selective for tumors by virtue of high activity under hypoxic conditions, and radiation can be employed more effectively in the presence of these ⁇ ensitizers.
  • a group of compounds which has not previously been suggested for use in either selectively killing hypoxic cells or in radiosensitizing such cells is 3-amino-1,2,4-benzotriazine 1,4-di-N-oxide and related compounds.
  • Related US patents 3.980,779; 3,868,371; and 4,001,410 disclose the preparation of a group of these compounds and their use as anti-microbial agents, particularly by addition of these materials to livestock fodder.
  • US patents 3,991,189 and 3,957,799 disclose derivatives of these compounds bearing substituents on the nitrogen of the 3-amino group. These compounds also have anti-microbial activity.
  • the present invention provides additional compounds which specifically radiosensitize hypoxic cells in vitro and which, furthermore, are directly cytotoxic to hypoxic cells both in vitro and in vivo. Therefore, administration of these compounds prior to or following radiation treatment of tumors selectively kills the hypoxic (tumor) cells which survive the radiation dose. Both the ability of these compounds to radiosensitize hypoxic cells in vitro and especially their ability to selectively kill hypoxic cells directly are unexpected properties of these compounds.
  • the invention provides a valuable addition to the group of compounds currently available as selective radrosensitizers and selective cytotoxic agents for hypoxic tumor cells. Some of the compounds useful in this regard are known compounds, others are novel.
  • One aspect of the invention is a method of radiosensitizing or selectively killing hypoxic tumor cells with a compound of the formula:
  • X is OH, OR, NH 2 , NHR or NR 2 where each R is independently an alkyl of 1-4 carbon atoms, an amide, or a morpholino moiety and may further be substituted with hydroxy. alkoxy, amino, or halogeno substituents; wherein n is O or 1; and
  • Y 1 and Y 2 are independently either H, halogeno, hydrocarbyl (1-14C) including cyclic and unsaturated hydrocarbyl. optionally substituted with 1 or 2 substituents selected from the group consisting of halogeno. hydroxy. epoxy, alkoxy. alkylthio, amino (including morpholino), acyloxy. acylamido and their thio analogs, alkylsulfonyl, alkylphosphonyl. carboxy, alkoxycarbonyl. carbamyl or alkylcarbamyl, and wherein the hydrocarbyl can optionally be interrupted by a single ether (-O-) linkage, or wherein Y 1 and Y 2 are independently either NHR'. O(CO)R'. NH(CO)R'. O(SO)R', or O(POR)R' in which R' is a hydrocarbyl optionally substituted as defined above.
  • novel compounds encompassed by Formula 1 are already known in the art as being useful for other purposes; other compounds are novel.
  • the novel compounds encompassed by the present invention and which may be prepared by methods disclosed herein include compounds represented by the formula above, in the following three classes: I. X is OH, OR, or NR 2 with R as defined above, n is 0 or 1. and Y 1 and Y 2 are as defined above; II. X is NH 2 or NHR with R as defined above, n is 0, and Y 1 and Y 2 are as defined above; III. 3 is NH 2 , n is 1. and Y 1 and Y 2 are as defined above but not halogeno. saturated alkyl
  • Figures 1A. 1B and 1C show the selective cytotoxicity of 3-amino-1,2,4-benzotriazine 1,4-dioxide for hypoxic cells derived from hamster, mouse and human tissues.
  • Figure 2 shows the in vivo efficacy of
  • Figure 3 shows the killing of tumor cells in vivo by 3-amino-1,2,4-benzotriazine 1,4-dioxide when the tumor has been made hypoxic by the intraperitoneal administration of the antihypertensive drug hydralazine.
  • the compounds useful in radiosensitizing hypoxic tumor cells as described herein are derivatives of 1,2,4-benzotriazine oxide.
  • the hydrocarbyl group represented by Y 1 or Y 2 may contain 1-14 carbon atoms, may be saturated or unsaturated. cyclic or acyclic, and may optionally be interrupted by a single ether linkage.
  • the unsubstituted form of Y 1 or Y 2 can be, for example. methyl, ethyl, n-propyl. s-butyl, n-hexyl. 2-methyl-n- pentyl. 2-ethoxyethyl. 3-(n-propoxy)-n-propyl, 4-methoxybutyl, cyclohexyl, tetrahydrofurfuryl, furfuryl. cyclohexenyl. 3-(n-decyloxy)-n-propyl. 4-methyloctyl. 4.7-dimethyloctyl. and the like.
  • the hydrocarbyl may be substituted with one or two substituents as follows:
  • the halogeno substituents are fluoro, chloro. bromo. or iodo.
  • the alkoxy substituents represented by OR' may contain 1 to 4 carbon atoms, and include, for example, methoxy, n-propoxy, and t-butoxy.
  • the amino substituent may be NH 2 . NHR or NR 2 . where each R is independently an alkyl of 1-4 carbons or a morpholino moiety. R may optionally be substituted with 1-2 hydroxy. alkoxy. amino, or halogeno substituents.
  • the acyloxy and acylamido groups are represented by R'COO- and R'CONH-.
  • R' contains 1-4 carbons, and their thio analogs are represented by R'CSO- and R'CSNH-.
  • Alkyl sulfonyl and alkyl phosphonyl are. respectively.
  • Carboxy is the group -C(O)OH; alkoxycarbonyl is -C(O)OR'; carbamyl is -C(O)NH 2 ; and alkylcarbamyl is -C(O)NHR'.
  • the compounds may also be prepared and used as the pharmaceutically acceptable salts formed from inorganic bases, such as sodium, potassium, or calcium hydroxide, or from organic bases.
  • inorganic bases such as sodium, potassium, or calcium hydroxide
  • organic bases such as caffeine, ethylamine, and lysine.
  • salts are those with inorganic acids such as hydrochloric, hydrobromic or phosphoric acids or organic acids such as acetic acid, pyruvic acid, succinic acid, mandelic acid, p-toluene sulfonic acid, and so forth. (Amino substituents on the hydrocarbyl side chain can also, of course, be converted to salts.)
  • the 1,2,4-benzotriazine may be used as the mono- or dioxide. Either the 1-nitrogen of the triazino ring may be oxidized, or both the 1- and 4-nitrogens may be oxidized.
  • Specific particularly preferred compounds which are useful in the radiosensitization and cytotoxic procedures of the invention include 3-hydroxy-1,2,4-benzotriazine 1-oxide; 3-hydroxy-1,2,4-benzotriazine 1.4-dioxide; 3-amino-1,2,4-benzotriazine 1-oxide; 3-amino-1,2,4-benzotriazine 1,4-di-oxide; 6(7)-aethoxy-3-hydroxy-1,2,4-benzotriazine 1-oxide; (7)-methoxy-3-hydroxy-1,2,4-benzotriazine 1,4-dioxide; (7)-methoxy-3-amino-1,2,4-benzotriazine 1-oxide; (7)-methoxy-3-amino-1,2,4-benzotriazine 1-oxide; (7)-methoxy-3-amino-1,2,4-benzotriazine 1,4-dioxide; (7)-ethoxy-3-hydroxy-1,2,4-
  • 1,2,4-benzotriazine 1,4-dioxide 6(7)-[1-(2-hydroxy-3-morpholino)propoxy]-3-amino-1,2,4- benzotriazine 1-oxide; 6(7)-[1-(2-hydroxy-3-morpholino)propoxy]-3-amino-1,2,4- benzotriazine 1.4-dioxide; 6(7)-[3-amino-n-propoxy]-3-hydroxy-1,2,4- benzotriazine 1-oxide; 6(7)-[3-amino-n-propoxy]-3-hydroxy-1,2,4- benzotriazine 1.4-dioxide; 6(7)-[3-amino-n-propoxy3-3-amino-1,2,4- benzotriazine 1-oxide; 6(7)-[3-amino-n-propoxy]-3-amino-1,2,4- benzotriazine 1.4-dioxide; 6(7)-[2,3-epoxypropoxy]
  • each R is independently an alkyl of 1-4 carbon atoms, an amide, or a morpholino moiety and may further be substituted with hydroxy, alkoxy, amino. or halogeno substituents.
  • n is 0 or 1.
  • Y 1 and Y 2 are independently either H, halogeno, hydrocarbyl (1-14C) including cyclic and unsaturated hydrocarbyl. optionally substituted with 1 or 2 substituents selected from the group consisting of halogeno. hydroxy. epoxy, alkoxy, alkylthio. amino
  • acyloxy. acylamido and their thio analogs alkylsulfonyl. alkylphosphonyl. carboxy. alkoxycarbonyl. carbamyl or alkylcarbamyl, and wherein the hydrocarbyl can optionally be interrupted by a single ether (-O-) linkage, or wherein Y 1 and Y 2 are independently either NHR'. O(CO)R' . NH(CO)R'. O(SO)R' or O(POR)R' in which R' is a hydrocarbyl optionally substituted as defined above; II.
  • X is NH 2 or NHR with R as defined above, n is 0. and Y 1 and Y 2 are as defined in I; III.
  • X is NH 2 , n is 1. and Y 1 and
  • Y 2 are independently either H, hydrocarbyl (7-14C; saturated or unsaturated), unsaturated hydrocarbyl
  • hydrocarbyl substituent being either unsubstituted or substituted with halogen, hydroxy, epoxy, alkoxy, alkylthio. amino (including morpholino). acyloxy. acylamido and their thio analogs, alkylsulfonyl or alkylphosphonyl. and wherein the hydrocarbyl can optionally be interrupted by a single ether (-O-) linkage, or wherein Y 1 and Y 2 are independently either NHR'. O(CO)R', NH(CO)R', O(SO)R', or O(POR)R' in which R' is a hydrocarbyl optionally substituted as defined above.
  • the benzofuroxan starting material is not symmetric with respect to its own 5 and 6 positions (which are the 6 and 7 positions of the resulting 3-amino benzotriazine oxide). Therefore, a mixture of the 6- and 7-substituted materials may result. If desired, this mixture can be separated using conventional means into individual components having a substituent in either the 6 or 7 position.
  • the dioxide may also be prepared from the parent monoxide by peracid oxidation (see Robbins et al, J Chem Soc 3186 (1975) and Mason et al. J Chem Soc B 911 (1970)).
  • the monoxide may be prepared by: (1) cyclization of a 1-nitro-2-aminobenzene compound using H 2 NCN; (2) oxidation of the parent compound given by the structure
  • 3-amino-1,2,4-benzotriazines may be prepared either by cyclization of a parent compound (see Scheme I and Arndt, Chem. Ber. 3522 (1913)) or by reduction of the monoxide or dioxide as above.
  • the 3-hydroxy-1,2,4-benzotriazine oxides may be prepared using peroxide and and tungsten oxide (Scheme II). a novel synthetic procedure for making the 3-hydroxy-1,4-dioxide compound, or concentrated sulfuric acid and sodium nitrate (Scheme III).
  • the oxidized benzotriazines of the invention may be used to radiosensitize or selectively kill hypoxic tumor cells in warm-blooded animal hosts.
  • a way in which they may be used is in conjunction with agents known to selectively create hypoxia in tumors.
  • agents known to selectively create hypoxia in tumors include the use of antihypertensive drugs such as hydraIazine. or agents which affect the amount of oxygen carried by the blood. While these compounds will typically be used in cancer therapy of human patients, they may be used to kill hypoxic tumor cells in other warm blooded animal species such as other primates, farm animals such as cattle, and sports animals and pets such as horses, dogs, and cats.
  • carcinomas and sarcomas include carcinomas such as epithelial cell, acidic cell, alveolar cell, basal cell, basal squamous cell, cervical, renal, liver, Hurthle, Lucke. mucinous and Walker, and sarcomas such as Abernathy's, alveolar soft part, angiolithic. botyroid. encephaloid. endoraetria stroma.
  • the compounds may be administered to patients orally or parenterally (intravenously, subcutaneously. intramuscularly, intraspinally, intraperitoneally. and the like).
  • parenterally When administered parenterally the compounds will normally be formulated in a unit dosage injectable form (solution, suspension, emulsion) with a pharmaceutically acceptable vehicle.
  • a pharmaceutically acceptable vehicle are typically nontoxic and nontherapeutic. Examples of such vehicles are water, aqueous vehicles such as saline. Ringer's solution, dextrose solution, and Hank's solution and nonaqueous vehicles such as fixed oils (e.g., corn, cottonseed, peanut, and sesame), ethyl oleate. and isopropyl myristate.
  • Sterile saline is a preferred vehicle and the compounds are sufficiently water soluble to provide a solution for all foreseeable needs.
  • the vehicle may contain minor amounts of additives such as substances that enhance solubility, isotonicity, and chemical stability, e.g., antioxidants, buffers, and preservatives.
  • additives such as substances that enhance solubility, isotonicity, and chemical stability, e.g., antioxidants, buffers, and preservatives.
  • the compounds When administered orally (or rectally) the compounds will usually be formulated into a unit dosage form such as a tablet, capsule, suppository or cachet.
  • Such formulations typically include a solid, semisolid or liquid carrier or diluent.
  • Exemplary diluents and vehicles are lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, mineral oil, cocoa butter, oil of theobroma, aginates. tragacanth, gelatin, syrup, methylcellulose, polyoxyethylene sorbitan monolaurate, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, and magnesium stearate.
  • the amount of compound admini ⁇ tered to the subject is sufficient to radiosensitize or to produce cytotoxicity in the malignant neoplasm to be treated but below that which may elicit toxic effects. This amount will depend upon the type of tumor, the species of the subject being treated, the indication dosage intended and the weight or body surface of the subject.
  • the radiation may be administered to humans in a variety of different fractionation regimes, i.e., the total radiation dose is given in portions over a period of several days to several weeks. These are most likely to vary from daily (i.e., five times per week) doses for up to six weeks, to once weekly doses for four to six weeks.
  • An individual dose of the benzotriazine will be given before or after each radiation treatment and is likely to be in the range of 0.01 to 20 mmol/kg and usually in the range of 0.1 to 2 mmol/kg.
  • the compounds of the invention can be administered alone, with radiation or other cancer cytotoxic agents, with vasoactive drugs (e.g., hydralazine), or, with procedures which reduce the amount of available oxygen carried by the blood such as anemia or drugs which increase the binding of oxygen to hemoglobin, all of which can enhance selectively the degree of hypoxia in the tumor.
  • vasoactive drugs e.g., hydralazine
  • 5-(1-decyl)-benzofuroxan A combined mixture of 4-(1-decyl)-2-nitroaniline (77g, 0.28 mole), 5.25% NaOCl in H 2 O (476g, 0.34 mole). 85% KOH (20.3g, 0.31 mole). Bn 4 NHSO 4 (4.7g. 0.014 mole), and CH 2 Cl 2 (2.28 1) was stirred rapidly for 6h and diluted with
  • the compounds of the invention were tested in vivo for activity by the assay of Brown. J.M., Radiation Res (1975) 64:633-47. incorporated herein by reference.
  • SCCVII carcinomas in female C3H mice veighing 20-25 g were used. These mice were bred under specific pathogen-free conditions and were 3-4 months old at the beginning of each experiment.
  • the SCVII tumor was grown intradermally in the flank from an inoculation of 2 x 10 5 tumor cells taken from the 2nd-8th in vitro passage of the tumor cells after removal from the previous in vivo tumor. Two tumors per mouse were implanted, and were used as subject tumors when they reached a volume of approximately 100 ml. At this point the tumors contained approximately 20% hypoxic cells.
  • test compound was tested at a fixed injected dose of either 5 mmol/kg or 2/3 of the LD 50 (whichever is lower). Suitable controls of test compound-injected but nonirradiated and saline-injected and irradiated mice were also included. A fixed radiation dose of 20 Gy was applied at variable intervals of 2 hr after to 3 hr before injection of the drug. By using these intervals, the results give an indication of both the optimum irradiation time and the extent of extra cell killing compared to radiation alone. The results of such time-course experiments using 3-amino-1,2,4-benzotriazine 1,4-dioxide are shown in Figure 2.
  • Irradiation of the SCCVII tumors was done by irradiating nonanaesthetized tumor-bearing mice in a Plexiglas box. Irradiation condition ⁇ were 250 kVp X-rays. 15 mA. FSC 33 cm. added filtration of 0.35 mm Cu. half value layer 1.3 mm Cu. and a dose rate of 317 rad/min.
  • the amount of cell killing was judged by survival rate of dissected and cultured tumor cells as follows.
  • the tumor-bearing mice were killed 24 hr after irradiation, and tumors were dissected from the skin. cut into several pieces, and made into a fine brei by high speed chopping with a razor blade attached to a jigsaw.
  • the brei was added to 30 ml of Hank's buffered salt solution (HBSS) containing 0.02% DNase, 0.05% promase, and 0.02% collagenase. The suspension was stirred for 30 min at 37oC. filtered, and centrifuged at 1.600 rmp for 10 min at 4oC.
  • HBSS Hank's buffered salt solution
  • the cell pellet was resuspended in complete Waymouth's medium plus 15% fetal calf serum (FCS) and an aliquot mixed with trypan blueand counted with the use of a hemacytometer. Suitable dilutions of this serum plated into 60- or 100-mm polystyrene petri dishes (Lux Scientific Corp) in 5 or 15 ml of medium. After incubation for 13 days, the colonies were fixed and stained, and those containing 50 cells or more were counted. The dilution yielding an average count of 25-100 colonies in a 60 mm dish was used in calculation of results.
  • FCS fetal calf serum
  • Cytotoxicity tests were carried out using 3-amino-1,2,4-benzotriazine 1,4-dioxide and a variety of aerobic and hypoxic cells in culture (human, mouse, and hamster). The cells in spinner flasks were gassed for one hour at 37oC with either air or nitrogen containing 5% CO 2 prior to adding the specified amounts of the drug.
  • Figures 1A, 1B and 1C show the results for cell survival of mouse, hamster and human cells at various concentrations of 3-araino-1,2,4-benzotriazine 1,4-dioxide. It was found that only 1 to 2% of the drug concentration under aerobic conditions was required to get equal cell killing under hypoxia. This ratio of selective hypoxic toxicity (50-100) is higher than that for any compound so far reported in the literature.
  • LD 50 is determined in BALB/c female mice
  • LD 50 values at 1, 2, 5, and 60 days are determined by administering graded doses of the drug dissolved in physiological saline immediately prior to injection.
  • Example 12 Enhanced Tumor Cell Toxicity Using HydraIazine
  • Hydralazine is an antihypertensive drug which acts by relaxing the smooth muscle around blood vessels. This has the effect of preferentially shunting blood flow into normal tissues and away from tumors, which process produces immediate hypoxia in the tumors. If 3-amino-1,2,4-benzotriazine 1,4-dioxide is given in conjunction with this agent, there is a massive increase in tumor cell killing. In this experiment, neither hydralazine nor the aforementioned benzotriazine compound produced any significant cell killing in the SCCVII tumor, whereas the combination of the two reduced survival by a factor of 10 (i.e., only 1 cell in every 1000 was left viable). The experimental procedures are the same as described in Example 8, and the results are shown in Figure 3.

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PCT/US1987/001412 1986-09-25 1987-06-16 1,2,4-benzotriazine oxides as radiosensitizers and selective cytotoxic agents WO1988002366A1 (en)

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GB8810634A GB2203151B (en) 1986-09-25 1987-06-16 1,2,4-benzotriazine oxides as radiosensitisers and selective cytotoxic agents
DE3790581A DE3790581B4 (de) 1986-09-25 1987-06-16 Verfahren zur selektiven Vernichtung von hypoxischen Tumorzellen

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Cited By (8)

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WO1989008647A1 (en) * 1988-03-18 1989-09-21 Sri International 1,2,4-benzotriazine oxides as radiosensitizers and selective cytotoxic agents
GR890100167A (en) * 1989-03-17 1990-07-31 Stanford Res Inst Int Method for preparing 1,2,4-benzotriazine oxides
WO1991004028A1 (en) 1989-09-18 1991-04-04 Sri International 1,2,4-benzotriazine oxides as radiosensitizers and selective cytotoxic agents
US5175287A (en) * 1986-09-25 1992-12-29 S R I International Process for preparing 1,2,4-benzotriazine oxides
US5672702A (en) * 1995-12-04 1997-09-30 Sanofi Process for preparing 3 amino 1, 2, 4-benzotriazine dioxide
US6828321B2 (en) 1986-09-25 2004-12-07 Sri International 1,2,4-Benzotriazine oxides as radiosensitizers and selective cytotoxic agents
US10046022B2 (en) 2015-05-29 2018-08-14 Toagosei Co. Ltd. Synthetic peptide that increases radiosensitivity of tumor cells and use of same
US10981953B2 (en) 2013-12-26 2021-04-20 Toagosei Co, Ltd. Method for promoting expression of calreticulin, and synthetic peptide for use in method for promoting expression of calreticulin

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EP2800744A4 (en) * 2011-12-07 2015-06-03 Sri Internat Inc BENZOTRIAZINE OXIDE AS A MEDICAMENT AGAINST MYCOBACTERIUM TUBERCULOSIS

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FR2322140A1 (fr) * 1975-08-27 1977-03-25 Bayer Ag Nouvelles 3-alkoxy-benzo-1,2,4-triazines, leur procede de preparation et leur application comme fongicides et bactericides
EP0001090A2 (de) * 1977-09-10 1979-03-21 Bayer Ag Verwendung von 3-Halogen-benzotriazin-1-oxiden zur Bekämpfung von Pflanzenbakteriosen

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5175287A (en) * 1986-09-25 1992-12-29 S R I International Process for preparing 1,2,4-benzotriazine oxides
US6828321B2 (en) 1986-09-25 2004-12-07 Sri International 1,2,4-Benzotriazine oxides as radiosensitizers and selective cytotoxic agents
WO1989008647A1 (en) * 1988-03-18 1989-09-21 Sri International 1,2,4-benzotriazine oxides as radiosensitizers and selective cytotoxic agents
AU637572B2 (en) * 1988-03-18 1993-06-03 Sri International 1,2,4-benzotriazine oxides as radiosensitizers and selective cytotoxic agents
GR890100167A (en) * 1989-03-17 1990-07-31 Stanford Res Inst Int Method for preparing 1,2,4-benzotriazine oxides
WO1991004028A1 (en) 1989-09-18 1991-04-04 Sri International 1,2,4-benzotriazine oxides as radiosensitizers and selective cytotoxic agents
EP0478545A4 (en) * 1989-09-18 1992-08-05 Stanford Res Inst Int 1,2,4-benzotriazine oxides as radiosensitizers and selective cytotoxic agents
US5672702A (en) * 1995-12-04 1997-09-30 Sanofi Process for preparing 3 amino 1, 2, 4-benzotriazine dioxide
US10981953B2 (en) 2013-12-26 2021-04-20 Toagosei Co, Ltd. Method for promoting expression of calreticulin, and synthetic peptide for use in method for promoting expression of calreticulin
US10046022B2 (en) 2015-05-29 2018-08-14 Toagosei Co. Ltd. Synthetic peptide that increases radiosensitivity of tumor cells and use of same

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GB8810634D0 (en) 1988-07-06
GB2203151B (en) 1991-05-29
DE3790581B4 (de) 2004-12-23
CA1338445C (en) 1996-07-09
DE3790581T1 (enrdf_load_stackoverflow) 1988-08-25
GB2203151A (en) 1988-10-12
JPH01500826A (ja) 1989-03-23
JP2668232B2 (ja) 1997-10-27

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