EP0057700A1 - Dérivés de nitroso-urées possédant une activité antitumorale et compositions pharmaceutiques les contenant - Google Patents

Dérivés de nitroso-urées possédant une activité antitumorale et compositions pharmaceutiques les contenant

Info

Publication number
EP0057700A1
EP0057700A1 EP81902235A EP81902235A EP0057700A1 EP 0057700 A1 EP0057700 A1 EP 0057700A1 EP 81902235 A EP81902235 A EP 81902235A EP 81902235 A EP81902235 A EP 81902235A EP 0057700 A1 EP0057700 A1 EP 0057700A1
Authority
EP
European Patent Office
Prior art keywords
compounds
groups
compound according
activity
derivatives
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.)
Ceased
Application number
EP81902235A
Other languages
German (de)
English (en)
Other versions
EP0057700A4 (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 EP0057700A1 publication Critical patent/EP0057700A1/fr
Publication of EP0057700A4 publication Critical patent/EP0057700A4/fr
Ceased 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 to novel nitrosourea derivatives and pharmaceutically acceptable salts thereof useful for their antitumor and anticoagulant activity.
  • the invention also includes pharmaceutical compositions containing these compounds and methods of using them.
  • MeCCNU has been found to possess the highest degree of activity against most tumor systems, especially solid tumor systems. Numerous studies have been directed toward the metabolic products produced in vivo and in vitro in aqueous media, which consist mainly of 2-chloroethanol, vinyl chloride, acetaldehyde, and dichloroethane from the nitr ⁇ sated side of the molecule. (T. P . Johnston et al, J. Med. Chem., 18: 634 (1975)). It is also known that the N-nitr ⁇ so-N-alkyl ureido portion of the molecule alkylates DNA (de ⁇ xyribonucleic acid) in vivo and in vitro (Frei et al, Biochem. J., 174: 1031
  • the structure of the active site of transglutaminase has been found to contain the pentapeptide sequence --Tyr-Gly- Gln-Cys-Trp - and has the shape of a pocket 5 x 5 Angstroms in dimension (Folk et al, J. Biol. Chem. , 241: 5253 (1960)).
  • Gamma-glutamyl transpeptidase may be expected to have a somewhat similar active site structure.
  • a superior inhibitor ⁇ f transglutaminase and related enzymes would have, in view of the shape and size indicated above, hydrophobic moieties directed away from, but in proximity to, the pocket at the active site.
  • the substrate may have groups which aid hydrogen bonding to the active site tyrosine hydroxyl group.
  • Other compounds designed previously by the inventor of the present application U.S. Patent Application S.N. 68,470 using this approach have been shown to be successful antitumor agents and anticoagulants.
  • BCNU contains a chloro group which may hydrogen bond to the active-site tyrosine hydroxyl group
  • CCNU and MeCCNU are known to be hydroxylated in the liver to derivatives which may contribute to its binding to the active site in a similar manner. This hydroxylation, however, lowers lipid solubility and hinders crossing ⁇ f the blood brain barrier.
  • the mechanism of inhibition of the isocynate is via the alkyl thiocarbamate ester formation at the single sulfhydryl group at the active site of the enzyme (Gross et al, J . Biol. Chem., 250: 7693 (1975) ) :
  • R represents an alkyl group
  • nitrosourea derivatives release the following cycloalkyl isocyanates:
  • R is a group capable ⁇ f hydrogen bonding to the active site tyrosyl group of the enzyme, preferably a halogen, carboxyl, or hydroxyl group, or a derivative thereof, and more preferably a chloro or hydroxyl group .
  • the cycloalkyl ring may be further substituted with 1 or more preferably 1 or 2 alkyl groups, preferably methyl groups, or 1 or more preferably 1 or 2 hydroxyl groups.
  • novel compounds which possess the structural criteria necessary to selectively inhibit transglutaminase and similar glutamyl cycle enzymes and therefore be of potential significance as antitumor as well as anticoagulant agents are defined by the
  • n 4 to 7
  • hai is chlorine or flourine
  • R is a group capable of hydrogen bonding to the active site tyrosyl group of the enzyme, preferably a halogen, carboxyl, or hydroxyl group, or a derivative thereof, and more preferably a chloro or hydroxyl group.
  • the resulting 5 to 8 carbon ring may be substituted with one or more, preferably 1 or 2 lower alkyl groups, preferably methyl groups to enhance selectivity, or certain hydrophilic groups, such as hydroxyl groups, to enhance solubility, or other groups, which are widely described in the art.
  • Yet another object of this invention is to provide novel nitrosourea derivatives which have anticoagulant activity.
  • 1-Aminomethyl-1-cyclohexanol hydrochloride (16.6 g, 0.1 mol) was stirred with 13.9 ml (0.1 mol) of triethylamine in 75 ml of anhydrous diethyl ether and cooled to less than 5o.
  • 2-Chloroethyl isocyanate (10.5 g, 0.1 mol) was dissolved in 25 ml of ether and added in small portions with stirring while maintaining a temperature of less than 5o. After 2 hr.
  • reaction mixture was filtered and the residue was washed with two 20 ml portions of ether and suspended in 20 ml of water, filtered, resuspended in 20 ml of water, refiltered, and dried in vacua over CaCl 2 /KOH.
  • the yield of the urea was 19.5 g (83%) as a white powder, MP 109-110°.
  • Example 1 The above compound was made using, the procedure in Example 1 replacing the hydroxy-starting material with the corresponding chloro-compound. Yields were similar with approximately 35% of the isomer present.
  • Other compounds according to the present invention such as methyl or hydroxyl substituted cycloalkyl derivatives may be synthesized according to the procedure described in Example 1 by using an appropriately substituted 1-aminomethyl-1-cycloalkanol hydrochloride which may be synthesized by known procedures.
  • Antitumor screening data were obtained through the National Cancer Institute, Drug Evaluation Branch, National Institutes of Health, Bethesda, MD. Screening data for MeCCNU was generated simultaneously for comparison purposes.
  • L-1210 lymphoid leukemia tumors, (10 5 cells) were implanted in CDF 1 mice in accordance with NIH Protocols.
  • the results reported in Table I are single dose responses with survival being evaluated 5 8ays after i.p. injection of Neostatin (six days after implantation) .
  • the compound was inj ected 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 specif iced on individual protocols .
  • Table II contains comparison data for MeCCNU, the most potent agent against this tumor system in use at the present time.
  • Table III compares the results obtained using a different tumor system (P-1534 leukemia). I.p. injections were made daily for 5 days. Survival was measured on day 5, and "cures" were determined 45 days after implantations.
  • Neostatin was found to have activity paralleling that of MeCCNU in the L-1210 system with lower toxicity at high doses as measured in terms of weight loss. Since L-1210 leukemia responds well to a number of nitrosoureas, the additional, less responsive tumor system (P-1534) was employed for further testing. Using this system, Neostatin is seen to be far superior to MeCCNU at similar dose levels.
  • 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 pharmaceutical 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.
  • Neostatin 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) , resulting in a solution slightly acidic in pH. Intravenous administration may be continued for a period of up to about two hours.
  • the nitrosoureas may be administered parenterally or orally at dosages of about 0.5-3 mg/kg.
  • parenteral routes of administration may be accomplished using any formulation known in the art that allows for the emulsification, dissolution and suspension of relatively water-insoluble drugs or other compounds prior to parenteral administration.
  • Neostatin When given in unit dosage forms orally, compounds such as Neostatin 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)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Furan Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

Nitroso-urees nouvelles et hautement efficaces utiles dans le traitement de tumeurs chez les mammiferes. Le degre eleve de selective des composes est attribue au positionnement de certains groupes electronegatifs sur le carbone (Beta) sur l'extremite non nitrosee de la molecule. Par hypothese, ceci pourrait influencer favorablement la liaison de l'hydrogene sur certains sites presentant une activite enzymatiques, en eliminant ainsi de maniere plus selective le maintien enzymatique de proteines, masquant les antigenes des surfaces des cellules tumorales, ce qui a son tour empeche la destruction par le systeme immunitaire normal du tissu neoplastique. L'activite de ces composes apparait en outre comme etant superieure a celle du MeCCNU(1-(4-trans-methylcyclohexyle)-3-(2-chloroethyle)-3-nitroso-uree), un compose tres actif utilise couramment dans la chimiotherapie du cancer. Les composes selon la formule generale suivante sont decrits: (FORMULE) ainsi que les sels derives pharmaceutiquement acceptables, ou hal represente du chlore ou du fluor; R est un groupe hydroxy, halogene, acide carboxylique ou des derives de ceux-ci; n varie entre 4 et 7, le groupe cycycloalkyle pouvant etre facultativement substitue avec un ou plusieurs groupes methyle ou groupes hydroxyle.
EP19810902235 1980-08-14 1981-08-14 Dérivés de nitroso-urées possédant une activité antitumorale et compositions pharmaceutiques les contenant. Ceased EP0057700A4 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US17794080A 1980-08-14 1980-08-14
US177940 2002-06-21

Publications (2)

Publication Number Publication Date
EP0057700A1 true EP0057700A1 (fr) 1982-08-18
EP0057700A4 EP0057700A4 (fr) 1982-11-17

Family

ID=22650546

Family Applications (2)

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.
EP19810902234 Withdrawn EP0057699A4 (fr) 1980-08-14 1981-08-14 Derives d'acide 5,6-o-isoalkylidene ascorbique.

Family Applications After (1)

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.

Country Status (6)

Country Link
EP (2) EP0057700A4 (fr)
JP (2) JPS57501580A (fr)
DK (2) DK167182A (fr)
HU (1) HU185969B (fr)
NO (2) NO821221L (fr)
WO (2) WO1982000644A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5405412A (en) * 1994-04-13 1995-04-11 The Procter & Gamble Company Bleaching compounds comprising N-acyl caprolactam and alkanoyloxybenzene sulfonate bleach activators

Families Citing this family (4)

* 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
RU2192413C1 (ru) * 2001-03-12 2002-11-10 Государственный научный центр Российской Федерации "НИОПИК" Способ получения 1-(2-хлорэтил)-3-циклогексил-1-нитрозомочевины
CN117486761B (zh) * 2023-10-31 2025-08-12 南方医科大学 一种含芳基的氯乙基亚硝基脲类化合物及其制备方法和应用

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 WO8200642A1 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5405412A (en) * 1994-04-13 1995-04-11 The Procter & Gamble Company Bleaching compounds comprising N-acyl caprolactam and alkanoyloxybenzene sulfonate bleach activators

Also Published As

Publication number Publication date
EP0057699A1 (fr) 1982-08-18
WO1982000644A1 (fr) 1982-03-04
WO1982000642A1 (fr) 1982-03-04
JPS57501581A (fr) 1982-09-02
NO821220L (no) 1982-04-14
HU185969B (en) 1985-04-28
EP0057700A4 (fr) 1982-11-17
JPS57501580A (fr) 1982-09-02
DK167182A (da) 1982-04-14
EP0057699A4 (fr) 1982-11-08
NO821221L (no) 1982-04-14
DK167282A (da) 1982-04-14

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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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Inventor name: WELEBIR, ANDREW