Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
  • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
  • C07D407/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • 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
  • C07D307/56—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 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
  • C07D307/62—Three oxygen atoms, e.g. ascorbic acid

Definitions

• the present invention relates condensation products between enediol ketolactones and 2-haloethyl isocyanates and pharmaceutically acceptable salts thereof as antitumor agents and possible analgesic agents, and more particularly, to condensation products of 5,6-0-isoalkylidene ascorbic acid derivatives with 2-haloethyl isocyanates and pharmaceutically acceptable salts thereof as novel antitumor agents and possibly analgesic agents.
• the invention also includes pharmaceutical compositions containing these compounds and methods of using them.
• antitumor agents derived from ascorbic acid includes condensation products between underivatized ascorbic acid and strongly electrophilic conjugated aldehydes, such as glyoxal, methyl glyoxal, phenyl glyoxal, and a number of olefinic aldehydes, such as acrolein and crotonic, maleic, and fumaric aldehydes (Fodor, et al, U. S. Patent No. 4,238,500).
• aldehydes such as glyoxal, methyl glyoxal, phenyl glyoxal
• olefinic aldehydes such as acrolein and crotonic, maleic, and fumaric aldehydes
• Ascorbic acid was originally intended as a carrier for methyl glyoxal, which was subsequently to be released in vivo as the active antitumor agent. Free ascorbic acid has also been proposed as a prophylactic treatment for bladder carcinoma (Schlegel, Ann. N.Y. Acad. Sci., 432 (1975) .
• antitttmor agents presently employed in clinical use consist of either complex natural products, cytotoxic antibiotics, nitrosoureas, and other alkylating or mutagenic agents.
• BCNU bis -(2 chloroethyl)-N-nitrosourea
• BCNU bis -(2 chloroethyl)-N-nitrosourea
• the immediate precursor of these metabolites viz. the 2-chloroethyl carbonium ion
• the alkylating agent accounts for the mutagenicity and much of the toxicity associated with the use of BCNU and other nitrosoureas.
• the second major product resulting from the hydrolysis of BCNU in vivo is 2-chloroethyl isocyanate, which may account for the.carcinostatic effectiveness of BCNU.
• the carbamoylated products In vivo resulting from the reaction of 2-chloroethyl isocyanate with a number of enzymes may be the possible mode of action.
• the study of possible "carriers" of 2-chloroethyl isocyanate may, therefore, result in an antitumor agent of practica utility which would not involve the release of a mutagenic alkylating agent.
• R is an alkyl group containing no nucleophilic substituents, e.g., such as amino, hydroxyl, or sulfhydryl groups but may comprise lower alkyl ethers, lower alkyl esters, or carbonate esters or carboxylic acids or amides, preferably ketal or acetals of the formula:
• R 2 and R 3 are lower alkyl groups containing 1 to 3 carbons or H, preferably a protected ascorbic acid derivative which may be a 5,6-0-isoalkylidene ascorbic acid derivative, and more preferably the 5,6-0-isopropylidene derivative of ascorbic acid:
• Ha1. is an electron-withdrawing group, such as a halogen, preferably C1, Br, or I, and more preferably C1.
• the preferred solvents for the reaction are any solvent in which the final products show solubility with dipolor, aprotic solvents being preferred, such as lower aliphatic ketones, e.g., acetone, DMSO (dimethyl sulfoxide), DMF (dimethyl formamide), and HMPA (hexamethyl phosphoramide), along with other similar solven acetone being most preferred.
• aprotic solvents such as lower aliphatic ketones, e.g., acetone, DMSO (dimethyl sulfoxide), DMF (dimethyl formamide), and HMPA (hexamethyl phosphoramide), along with other similar solven acetone being most preferred.
• Reactants (1 part 5,6-0-isoalkylidene ascorbic acid to 2 to 10 parts of isocyanate, preferably 3 to 6 parts isocyanate) are combined in a small amount of solvent (1 part reactants to 1 to 100 parts of solvent) and reflexed under anlydrous conditions, preferably under an inert atmosphere, such as nitrogen or argon. While a large amount of material reacts within a 3 hour period, longer reaction times (up to 72 hours) depending on the solvent, are preferred. Reaction temperatures may range from less than 0° to 150°C, with 30° to 100°C being preferred.
• the produ does not contain two carbamate linkages, and may, in fact, be a tricyclic compound in the case of the reaction between 5,6-0-isopropylidene ascorbic acid and 2-chloroethyl isocyanate (Scorbethane).
• an object of the present invention to provide novel compounds having antitumor activity in humans and mammals. It is another object of the invention to provide condensation products of enediol ketolactones, notable ascorbic acid derivatives with the nucleophilic 5,6-0-positions protected by suitable protecting groups, and 2-haloethyl isocyanates having antitumor activity. Still another object of the invention is to provide novel effective antitumor agents at low dosages without the in vivo formation of mutagenic alkylating agents.
• Yet another object of this invention is to provide novel compounds having analgesic activity.
• Ascorbic acid was converted to the 5,6-0-isopropylidene ascorbic acid derivative employing the method of Solomon(Experie tia 19: 619 (1963)).
• a 10g quantity of L-ascorbic acid (0.054 mol) was added to 100 ml of anhydrous acetone and cooled on an ice bath.
• Anhydrous HCl was passed through the suspension with vigorous stirring for 0.5 hr.
• Hexane (80ml) was added and the mixture was stirred and allowed to settle. The liquid was decan ed, and the solid was washed repeatedly with 100 ml volumes of acetone :hexane, 4:7, until all the HCl was removed.
• the remaining solid (11.3g, 91%) had a MP of 220° (lit. 222°) and it pres ence was confirmed by IR and NMR.
• Other 5 , 6 - 0 - isoalkyliden ascorbic acids may be synthes ized us ing this procedure .
• Scorbethane the 2-chloroethyl isocyanate adduct of isopropylidene ascorbic acid, was prepared by suspending 2.16g (0.01 mol) of the isopropylidene derivative in 10 ml of anhydrous ace tone, and the reaction vessel was flooded with nitrogen. 2- chloroethyl isocyanate (4.4g, 0.04 mol) was added and the mixture was refluxed for 65 hours. The solvent was removed in vacuo an the compound was dried in vacuo for 48 hours over KOH. NMR analysis showed a singlet (6H) at 1.3 ppm, a multiplet (9H) at 3.7 ppm, and a multiplet (4H) at 4.1 ppm. IR showed peaks at
• Antitumor screening data were obtained through the National Cancer Institute, Drug Evaluation Branch, National Institutes of Health, Bethesda, Maryland.
• L-1210 lymphoid leukemia tumors (10 cells) were implanted in CDF 1 mice in accordance with NIH Protocols.
• the results reported in Tables 1 and 2 are single dose responses with survival being evaluated five days after i.p. injection of Scorbethane (six days after implantation).
• the compound was injected as a suspension in 10% EtOH, 10% emulphor, and 80% saline.
• Log kill data indicates the number of tumor cells killed, and 30 -day survivors are termed "cured".
• the degree of antitumor activity is expressed as a ratio of treated animals over control animals using NCI test evaluation numbers, as specified in individual protocols.
• Table I shows the remarkable effectiveness of Scorbethane, the adduct found from the reaction of 5,6-0-isopropylidine ascorbic acid and 2-chloroethyl isopropylidene ascorbic acid and 2-chloroethyl isocyanate, against L-1210 lymphocytic leukemia, with results comparable to those observed from MeCCNU.
• MeCCNU (1-cyclohexyl-3-(2-chloroethyl)-3-nitrosourea) is currently the most effective against L-1210 leukemia and many solid tumor systems.
• T/C 184% at 47 mg/kg for L-1210), which has been widely studied in these tumor systems in the art.
• Table II shows the effectiveness of Scorbethane vs. the P-1534 leukemia model. This model shows a higher degree of resistance to nitrosoureas than many other leukemia models. Again, activty approximates the activity of MeCCNU, exceeding that of BNCU, without in vivo production of an alkylating species.
• nitrosoureas of the invention can be formulated into a form suitable for administration by methods well known in the art.
• they can be admixed with pharmaceutically acceptable carriers or diluents such as ethanol, lactose, starch, magnesium stearate, tragacanth, gelatin and sodium carboxymethylcellulose, and the resulting mixture or solution may be processed by conventional procedures to pharmaceutical dosage unit forms such as capsules, tablets, powders, pills, ampoules, suppositories and the like.
• the compounds of the invention may be administered orally or parenterally.
• the drug may be given intravenously by first dissolving the compound to be administered in 0.5-10 ml of ethanol and adding 50-90% water thereto. Further dilution may be made with physiological saline solution or 5% dextrose (USP) with or without the inclusion of an emulsifying agent. Intravenous administration may be continued for a period of up to several hours.
• 5 ,6-0-substituted ascorbic acid derivatives and similar compounds can be injected intravenously at dosages of about 0.1-10 mg/kg.
• parenteral routes of administration may be accomplished using any formulation known in the art that allows for the emulsification, dissolution or suspension of relatively water-insoluble drugs or other compounds prior to parenteral administration.
• the compounds When given in unit dosage forms orally, the compounds are active when provided in a gelatin capsule or tablet combined with pharmaceutically acceptable binders, fillers or other additives as known in the art.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Furan Compounds (AREA)
• Plural Heterocyclic Compounds (AREA)

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• 1981
  • 1981-08-14 JP JP50279881A patent/JPS57501581A/ja active Pending
  • 1981-08-14 WO PCT/US1981/001088 patent/WO1982000644A1/en not_active Application Discontinuation
  • 1981-08-14 EP EP19810902235 patent/EP0057700A4/en not_active Ceased
  • 1981-08-14 JP JP56502797A patent/JPS57501580A/ja active Pending
  • 1981-08-14 EP EP19810902234 patent/EP0057699A4/en not_active Withdrawn
  • 1981-08-14 WO PCT/US1981/001089 patent/WO1982000642A1/en not_active Application Discontinuation
  • 1981-08-14 HU HU813004A patent/HU185969B/hu unknown
• 1982
  • 1982-04-14 DK DK167282A patent/DK167282A/da active IP Right Grant
  • 1982-04-14 NO NO821221A patent/NO821221L/no unknown
  • 1982-04-14 NO NO821220A patent/NO821220L/no unknown
  • 1982-04-14 DK DK167182A patent/DK167182A/da active IP Right Grant

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