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• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
  • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
• • 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
  • A61K31/16—Amides, e.g. hydroxamic acids
  • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
• • 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
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
  • C07D213/81—Amides; Imides
  • C07D213/82—Amides; Imides in position 3
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
  • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
  • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical

Definitions

• the invention is in the field of radiotherapy. Specifically, it relates to sensitizing tumor cells to radiation using substituted benzamides .
• Hypoxic tumor cell radiosensitizers are compounds that selectively increase the sensitivity of hypoxic cells in tumors to radiation. This specificity for hypoxic cells is important because it is tumors that are typically characterized by such cells. All tumors which are present as solid masses contain these cells, while normal cells generally have an adequate supply of oxygen. The effects of radiation are enhanced by the presence of oxygen, and it is established that as the dose of radiation is increased, the effectiveness of the radiation in destroying target cells is enhanced most dramatically when oxygen is present.
• the present invention provides a new group of radiosensitizers that do not contain oxidized nitrogen-- the substituted benzamides and nicotinamides and their thio analogs.
• it is important to distinguish the ability to sensitize hypoxic cells selectively, for instance, by enhancing their oxygen supply from another mechanism commonly encountered for "sensitizing" cells -- inhibiting the enzyme poly ( ADP-ribose)polymerase, which is believed to be essential in the repair of irradiated cells after radiation.
• This repair mechanism is operative in both hypoxic tumor cells and in normal cells.
• administration of "radiosensitizers" which exert their effects by this mechanism does not accomplish the desired purpose of selectively sensitizing the target tumor cells.
• PLDR potential lethal damage repair
• the m-aminobenzamide was added either during or after irradiation, and was found to sensitize these cells to the lethal effects of radiation. These cells are not hypoxic, since they are maintained in culture.
• the Miyakoshi et al results showed that the greatest enhancement ratio was obtained when cells were first treated with X-rays, then at increased temperature in the presence of m-aminobenzamide, followed by prolonged treatment with m-aminobenzamide.
• both benzamide and nicotinamide derivatives and their thio analogs have been shown to have selective radiosensitizing activity in vivo. This effect has been shown to be due to enhancement of oxygen supply and to exhibit a time dependence which corresponds to direct radiosensitization. Therefore, administration of these compounds prior to radiation is sensitizing selectively for hypoxic (tumor) cells. This is an unexpected property even for those compounds which are known to inhibit poly (ADP-ribose) polymerase.
• the invention provides a valuable addition to the repertoire of compounds available as selective radiosensitizers 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 hypoxic tumor cells in a warm blooded animal comprising administering a compound of the formula:
• X is O or S
• Y is H, Me, OMe , OEt, acetoxy or acetamido
• Z is OR, SR or NHR in which R is H, hydrocarbyl (1-6C) including cyclic and unsaturated hydrocarbyl, optionally substituted with 1 or 2 substituents selected from the group consisting of halo, hydroxy, epoxy, alkoxy, alkylthio, amino including morpholino, acyloxy and acylamido and their thio analogs, alkysulfonyl or alkyl phosphonyl, carboxy or alkoxy carbonyl, or carbamyl or alkylcarbamyl, and in which R can optionally be interrupted by a single ether (-O-) linkage; or Z is O(CO)R, NH(CO)R, O(SO)R, or O(POR)R in which R is as above defined.
• Z may be H .
• Certain compounds of formulas 1 and 2 wherein Z is in the 3-position, and wherein Z is OR, SR, or NHR in which R is substituted or interrupted with -O-, or wherein Z is O(CO)R, NH(CO)R, O(SO)R or O(POR)R in which R is substituted or interrupted with -O-, are novel. Therefore, in another aspect, the invention is directed to these compounds per se.
• Figure 1 shows the radiosensitizing effect of 3-hydroxybenzamide as compared to MIS.
• Figure 2 shows similar results for 3-(2-hydroxyethoxy) benzamide.
• Figure 3 and 4 show the dependence of the radiosensitizing effect of several nicotinamide derivatives on time of injection.
• the Compounds useful in radiosensitizing hypoxic tumor cells as described herein are. derivatives of benzamide or nicotinamide or the thio analogs thereof.
• the Benzamide Derivatives The benzene ring of the benzamide or thiobenzamide of formula 1 may be substituted with one or two additional substituents.
• the substituent of formula Z is preferably in the 3 position; substituent Y preferentially in position 4. However, if substituent Z is in the 4 position, embodiments wherein Y is in position 3 are preferred. Especially preferred are those embodiments wherein X is 0 and those wherein Y is H--i.e., the compound of formula 1 is a monosubstituted benzamide.
• the hydrocarbyl group represented by R may contain 1-6 carbon atoms, may be saturated or unsaturated, cyclic or acyclic, and may optionally be interrupted by a single ether linkage.
• the unsubstituted form of R 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, and the like.
• R may be substituted with one or two substituents as follows:
• the halo 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
• each R' is independently an alkyl of 1-4 carbons or a morpholino.
• R' may optionally be substituted with 1-2 hydroxy, alkoxy, amino, or halo substituents.
• the acyloxy and acylamido groups are represented by R ' COO- and R'CONH-, respectively, where R' contains 1-4 carbons, and their athio analogs are represented by R'CSO- and R'CSNH-.
• Alkyl sulfonyl and alkyl phosphonyl are, respectively, R'SO 2 and R'P(OR')O- wherein each R' is independently as above defined.
• Carboxy is the group -C(O)OH; alkoxycarbonyl is -C(O)OR'; carbamyl is -C(O)NH 2 ; and alkylcarbamyl is -C(O)NHR' .
• a particularly preferred subset of benzamide compounds useful in the method of the invention are, in general, those wherein Y is H, Z is in the 3 position, and Z is either hydroxy or contains 4 carbons or less. Where Z is OH, of course, the compounds may also be prepared and used as the pharmaceutically acceptable salts. These salts include those formed from inorganic bases, such as sodium, potassium, or calcium hydroxide, and those formed from organic bases, such as caffeine, ethylamine, and lysine.
• the preferred embodiments of Z are generally those as set forth above for the benzamide derivatives. Particularly preferred rsre those embodiments wherein X is O and Z is H, OH, or NH 2 , or wherein Z contains 4 carbons or less, Those embodiments wherein Z is OH may, of course, be prepared and used as the salts.
• Particularly preferred compounds also include: 5-hydroxynicotinamide and its pharmaceutically acceptable salts: 5-methoxynicotinamide; 5-ethoxynicotinamide;
• Certain of the compounds of formula 1 are available as the benzoic acid analogs. These can be converted to the compounds of the invention by converting the carboxylic acid group to the corresponding amide.
• 3-hydroxybenzoic acid can be converted to the corresponding 3-hydroxybenzamide by conventional reactions including treatment with SOCl 2 , followed by reaction with ammonia.
• the reaction is carried out in the presence of base such as sodium or potassium carbonate in a suitable solvent, preferably an aprotic polar solvent such as dimethylformamide (DMF) .
• a suitable solvent preferably an aprotic polar solvent such as dimethylformamide (DMF) .
• the reaction can be carried out at approximately room to elevated temperature. Work-up and purification of products are carried out by conventional means.
• R may be obtained as an epoxide substituted alkyl, and the corresponding dihydroxy or alkoxy, hydroxy derivative prepared by hydrolysis.
• the thioamide analogs of the invention are prepared by substituting for the benzamide derivative in the reactions set forth above the corresponding thiobenzamide derivatives. These can be obtained from the benzamide derivatives by standard means. In one preferred method the benzamide compound is treated with P 2 S 5 in dioxane, substantially as described in
• the 5- substituted nicotinamide derivatives may be prepared using similar reactions.
• 5-bromonicotinamide may be readily prepared from the corresponding 5-bromonicotinic acid.
• the 5-bromo substituent may be replaced by either a hydroxyl or an amino group, which groups may then be subsequently alkylated or acylated using the appropriate halides.
• the general reaction for preparation for the nicotinamide derivatives which are alkoxy or acyloxy substituted is as follow:s:
• the general conditions of reaction and necessity for protection in the case of certain embodiments of R is as set forth previously for the benzamide derivatives.
• the compounds of the invention wherein the 5- position is substituted by an amino or acylamino group are prepared analogously using the corresponding 5-aminonicotinamide.
• the thio analogs of the nicotinamide derivatives may be prepared as set forth above for the benzamide derivatives.
• the compounds of the invention may be prepared directly from 5-bromonicotinarnide by nucleophilic substitution at the 5- position. The reaction is typically carried out in the presence of a base, such as, for example, carbo.nates or phosphates.
• a general reaction scheme for the preparation of the compounds of the invention from 5-bromonicotinamide is set forth below:
• the corresponding carboxylic acid derivative of the bromo-substituted pyridine can be used as the substrate and subsequently converted to amide.
• the substituted benzamides and nicotinamides and thio analogs of the invention may be used to radiosensitize hypoxic tumor cells in warm-blooded animal hosts. While these radiosensitizers will typically be used in radiotherapy of human patients, they may be used to radiosensitize 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. Hypoxia is believed to be associated with all types of solid malignant neoplasms.
• the compounds of the invention may, therefore, be used to radiosensitize neoplastic epithelial cells, endothelial cells, connective tissue cells, bone cells, muscle cells, nerve cells, and brain cells.
• carcinomas and sarcomas that may be radiosensitized 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, anglolithic, botyroid, encephaloid, endometria stroma, Ewing's fascicular, giant cell, lymphatic, Jensen's, juxtocortical osteogenic, Kaposi's, medullary, and synovial.
• radiosensitizers may be administered to patients orally or parenterally (intravenously, subcutaneously, intramuscularly, intraspinally, intraperitoneally, and the like). It is likely, however, that the preferred route for human administration will be intravenous. When administered parenterally they will normally be formulated in a unit dosage injectable form (solution, suspension, emulsion) with a pharmaceutically acceptable vehicle. Such vehicles are typically nontoxic and nontherapeutic.
• Examples of such vehicles are water, aqueous vehicles such as saline, Ringer's solution, dextrose solution, and Hanks' solution and nonaqueous vehicles such as fixed oils (such as corn, cottonseed, peanut, and sesame), ethyl oleate, and isopropyl myristate.
• aqueous vehicles such as saline, Ringer's solution, dextrose solution, and Hanks' solution
• nonaqueous vehicles such as fixed oils (such as corn, cottonseed, peanut, and sesame), ethyl oleate, and isopropyl myristate.
• Sterile saline is a preferred vehicle and the compounds are sufficiently water soluble to be made up as 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.
• 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.
• 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 administered to the subject is sufficient to radiosensitize 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 benzamide, nicotinamide, or thio analog is given before 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 will ideally be administered at a time such that their peak concentration in the hypoxic cells occurs at a predictable time in relation to the time the tumor Is exposed to radiation. This time will depend upon the manner in which the compound is administered, the particular dosage form employed, the type of tumor, and the species of the patient. Intravenous administration will typically be done about 1/2 to about 1 hr prior to radiation exposure to provide maximum radiosensitization. Oral administration may require a somewhat longer lag because the compound must first pass through the gastrointestinal barrier.
• the subject compound was prepared using the general method of Example 3, except that 10.0 g (72.9 mmol) of 3-hydroxybenzamide was reacted with 29.0 g
• Example 9 Preparation of 3-aminoacetamidobenzamide A portion of 1,1'-carbonyldiimidazole (CDI) (813 mg , 5.01 mmol) was added to a stirred solution of Cbz-protected glycine (807 mg , 3.85 mmol) in THF (10 ml). The solution was stirred at 25°C for 1 hour and cooled to -10°C. Water (200 mg) was added, followed by 3-aminobenzamide (500 mg , 3.67 mmol). Stirring was continued at -10°C for 1/2 hour and then at 25°C for 16 hours, during which the intermediate protected aminoacetamidobenzamide precipitated.
• CDI 1,1'-carbonyldiimidazole
• the white solid was collected by filtration, combined with 5% PD/C (50 mg) in glacial HOAc (10 ml) and placed under hydrogen (40 psi) with agitation for 4 hours. The mixture was filtered, the filtrate evaporated in vacuum to dryness and recrystallized with ethyl ether/methanol to obtain 340 mg (48%) of the title compound, mp 139-140°C.
• the green residue was mixed with 40 ml MeOH, saturated with anhydrous HCl at room temperature, and allowed to stand 2 days in a stoppered flask, then evaporated to dryness.
• the residue was mixed in 125 ml CH 2 Cl 2 and treated with 7 g Na 2 CO 3 in 25 ml H 2 O and mixed thoroughly.
• the CH 2 Cl 2 solutions were decanted, dried over Na s SO 4 , and evaporated to afford 0.86 g .
• the crystalline free base product was obtained by the acidification of a basic solution of 5-aminonicotinic acid (in NaOH) to pH 5.3 to afford 21 g (61.4% yield); mp 304-305°C dec (lit. 295-296°C dec; Urban , supra).
• reaction mixture was evaporated to dryness and the residue was mixed with 15 g NaHCO 3 and 25 ml MeOH, then chromatographed through a 150 cc SiO 2 (70-230 mesh) column packed in EtOAc and eluted with 20% MeOH/EtOAc to afford 1.81 g (81% yield) of 5-amino nicotinamide; IR(N) 3430m-s, 3100m-s, 1680s, 1630s,
• the sodium salt was prepared from the free acid.
• the salt is very water soluble and has an mp >300°C.
• the compounds of the invention are tested in vivo for radiosensitization activity by the assay of Brown, J.M., Radiation Res (1975) 64:633-47, incorporated herein by reference.
• EMT6 tumors in female BALB/c mice weighing 20-25 g are used. These mice are bred under specific pathogen-free conditions and are 3-4 months old at the beginning of each experiment.
• the EMT6 tumor is 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 since removal from the previous in vivo tumor. Two tumors per mouse are implanted, and are used as subject tumors when they reach a volume of approximately 100 ml.
• Test compounds are compared against MIS in this assay.
• the test compound is tested at a fixed injected dose of either 5 mmol/kg or 2/3 of the LD 50 (whichever is lower), MIS is injected into controls at the same dose. Additional suitable controls of test compound-injected but nonirradiated and saline-injected and irradiated mice are also included.
• a fixed radiation dose of 2,000 rad is applied at variable intervals of 5 min to 2 hr between injection and irradiation. Typically, irradiation is applied at 5, 10, 15, 20, 30, 45, 60, 90, and 120 min following intraperitoneal administration of both drugs.
• Irradiation of the EMT6 tumors is done by irradiating nonanesthetized tumor-bearing mice in a Plexiglas box. Irradiation conditions are 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.
• Radiosensitization activity is judged by survival rate of dissected and cultured tumor cells as follows:
• the tumor-bearing mice are killed immediately after irradiation, and tumors 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 is added to 30 ml of Hank's buffered salt solution (HBSS) containing 0.02% DNase, 0.05% promase, and 0.02% collagenase.
• HBSS Hank's buffered salt solution
• the suspension is stirred for 30 min at 37°C, filtered, and centrifuged at 1,600 rmp for 10 min at 4°C.
• the cell pellet is resuspended in complete Waymouth's medium plus 12-1/2% horse serum plus 2-12% fetal calf serum (FCS) and an aliquot mixed with trypan blue and 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 are fixed and stained, and those containing 50 cells or more are counted. The dilution yielding an average count of 25-100 colonies in a 60 mm dish is used in calculation of results. The more highly diluted the sample to achieve this result, the less successful the killing and the less sensitizing the test compound.
• FCS 2-12% fetal calf serum
• test compound is scored on the scale of 0 to 4 based on how it compares with MIS.
• the scoring system is:
• Cytotoxicity tests were also carried out on some of the compounds.
• the test procedure was as follows: Log-phase Chinese hamster ovary HA-1 cells were trypsinized (0.5% trypsin in Hank's buffered salt solution (HBSS)) and plated in 60 mm Permanox petri dishes in concentrations necessary to yield approximately 30 colonies after experimental treatment. The cells were allowed to attach overnight. Then the medium was removed from each dish and replaced with 2 ml of medium containing varying concentrations of the test compound. The petri dishes were then placed in nylon chamber fitted with gassing ports and, to achieve hypoxia, were gassed at room temperature with humidified N containing 5% CO 2 for 1 hr at a rate of 1 l/min. The cells are then exposed to 10 mM of the test compound for 1 hr at 22°C. The % cell survival is read after such treatment.
• HBSS Hank's buffered salt solution
• LD 50 is determined in BALB/c female mice
• LD 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.
• nicotinamide 3 3-(2-methoxyethylamino) nicotinamide 3
• each of the compounds of the invention tested gave a sensitizer enhancement ratio of 1.6 at a 1-2 mM concentration, which is comparable to that for MIS.
• these compounds were shown to have no radiosensitizing activity in normal cells.

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• 1986
  • 1986-04-30 WO PCT/US1986/000976 patent/WO1986006628A1/en active Application Filing
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