EP0057699A1 - Derives d'acide 5,6-o-isoalkylidene ascorbique - Google Patents

Derives d'acide 5,6-o-isoalkylidene ascorbique

Info

Publication number
EP0057699A1
EP0057699A1 EP81902234A EP81902234A EP0057699A1 EP 0057699 A1 EP0057699 A1 EP 0057699A1 EP 81902234 A EP81902234 A EP 81902234A EP 81902234 A EP81902234 A EP 81902234A EP 0057699 A1 EP0057699 A1 EP 0057699A1
Authority
EP
European Patent Office
Prior art keywords
ascorbic acid
tumor
alkyl group
composition according
enediol
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Withdrawn
Application number
EP81902234A
Other languages
German (de)
English (en)
Other versions
EP0057699A4 (fr
Inventor
Andrew Welebir
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
NATIONAL FOUNDATION FOR CANCER RESEARCH, INC.
Original Assignee
NATIONAL FOUNDATION FOR CANCER RESEARCH Inc
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by NATIONAL FOUNDATION FOR CANCER RESEARCH Inc filed Critical NATIONAL FOUNDATION FOR CANCER RESEARCH Inc
Publication of EP0057699A1 publication Critical patent/EP0057699A1/fr
Publication of EP0057699A4 publication Critical patent/EP0057699A4/fr
Withdrawn legal-status Critical Current

Links

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.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Nouveaux produits de condensation entre des cetolactones d'enediol tel que de l'acide 5,6-0-isopropylidene ascorbique et des isocyanates de 2-chloroethyle presentant une puissante activite anti-tumorale probablement sans la liberation d'agents d'alkylation in vivo. Bien que les structures des produits ne puissent pas etre facilement tirees au clair, il apparait que leur activite est superieure a celle du BCNU (bis(2-chloroethyle)-N-nitrosouree) et parallele a celle de la nitrosouree NeCCNU(1-(4-trans-methylcyclohexyle)-3-(2-chlorotethyle)-3-nitrosouree), qui est toxique et tres efficace. Les composes preferes sont des produits de condensation selon la formule (FORMULE) ou R2 et R3 representent un groupe alkyle inferieur contenant de 1 a 3 atomes de carbone ou H et hal-CH2-CH2-N=C=O (B) ou hal represente I, Br ou Cl.
EP19810902234 1980-08-14 1981-08-14 Derives d'acide 5,6-o-isoalkylidene ascorbique. Withdrawn EP0057699A4 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US17794080A 1980-08-14 1980-08-14
US177940 1980-08-14

Publications (2)

Publication Number Publication Date
EP0057699A1 true EP0057699A1 (fr) 1982-08-18
EP0057699A4 EP0057699A4 (fr) 1982-11-08

Family

ID=22650546

Family Applications (2)

Application Number Title Priority Date Filing Date
EP19810902234 Withdrawn EP0057699A4 (fr) 1980-08-14 1981-08-14 Derives d'acide 5,6-o-isoalkylidene ascorbique.
EP19810902235 Ceased EP0057700A4 (fr) 1980-08-14 1981-08-14 Dérivés de nitroso-urées possédant une activité antitumorale et compositions pharmaceutiques les contenant.

Family Applications After (1)

Application Number Title Priority Date Filing Date
EP19810902235 Ceased EP0057700A4 (fr) 1980-08-14 1981-08-14 Dérivés de nitroso-urées possédant une activité antitumorale et compositions pharmaceutiques les contenant.

Country Status (6)

Country Link
EP (2) EP0057699A4 (fr)
JP (2) JPS57501580A (fr)
DK (2) DK167282A (fr)
HU (1) HU185969B (fr)
NO (2) NO821221L (fr)
WO (2) WO1982000642A1 (fr)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS60130582A (ja) * 1983-12-19 1985-07-12 Takeda Chem Ind Ltd 食品用酸化防止剤，アスコルビン酸誘導体およびその製造法
JPS60139619A (ja) * 1983-12-27 1985-07-24 Mutsuyuki Kochi Ｏ−ベンジリデン−アスコルビン酸又はその塩よりなる抗腫瘍剤
US5405412A (en) * 1994-04-13 1995-04-11 The Procter & Gamble Company Bleaching compounds comprising N-acyl caprolactam and alkanoyloxybenzene sulfonate bleach activators

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2539483A (en) * 1945-03-28 1951-01-30 Simon L Ruskin Urea ascorbate and complexes containing the same and process for their manufacture
US3074998A (en) * 1959-12-10 1963-01-22 Shell Oil Co Enol carbamates
CH495980A (de) * 1967-02-25 1970-09-15 Bayer Ag Verfahren zur Herstellung von Benzodioxan-N-methylcarbamaten
DE2346305A1 (de) * 1973-09-14 1975-04-03 Basf Ag Neue carbamate und ihre verwendung als arzneimittel
US4111958A (en) * 1977-06-03 1978-09-05 Pfizer Inc. Ascorbic acid synthesis
US4148921A (en) * 1977-07-13 1979-04-10 Suami T Antitumor agents
NL7904249A (nl) * 1978-06-20 1979-12-27 Cancer Res Nat Found Nieuwe cyclische acetalen met cytostatische, bloed- drukverlagende en pijnstillende werking, werkwijze ter bereiding van deze verbindingen alsmede farmaceu- tische preparaten die een dergelijke verbinding bevat- ten.
JPS554324A (en) * 1978-06-26 1980-01-12 Kaken Pharmaceut Co Ltd Novel glycopyranosidoamine derivative, its preparation, and antitumor agent comprising it as active constituent
JP2811964B2 (ja) * 1990-12-20 1998-10-15 富士通株式会社 接続相手指定方式

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO8200644A1 *

Also Published As

Publication number Publication date
NO821220L (no) 1982-04-14
HU185969B (en) 1985-04-28
JPS57501581A (fr) 1982-09-02
JPS57501580A (fr) 1982-09-02
WO1982000642A1 (fr) 1982-03-04
EP0057700A4 (fr) 1982-11-17
NO821221L (no) 1982-04-14
EP0057699A4 (fr) 1982-11-08
EP0057700A1 (fr) 1982-08-18
DK167182A (da) 1982-04-14
DK167282A (da) 1982-04-14
WO1982000644A1 (fr) 1982-03-04

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Legal Events

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PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

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Effective date: 19820419

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Designated state(s): AT CH DE FR GB LI LU NL SE

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Owner name: NATIONAL FOUNDATION FOR CANCER RESEARCH, INC.

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Effective date: 19850124

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Inventor name: WELEBIR, ANDREW