WO1987006581A1 - Forme promedicamenteuse de 5-fluorouracile et procede de traitement du cancer - Google Patents

Forme promedicamenteuse de 5-fluorouracile et procede de traitement du cancer Download PDF

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Publication number
WO1987006581A1
WO1987006581A1 PCT/DK1987/000046 DK8700046W WO8706581A1 WO 1987006581 A1 WO1987006581 A1 WO 1987006581A1 DK 8700046 W DK8700046 W DK 8700046W WO 8706581 A1 WO8706581 A1 WO 8706581A1
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WO
WIPO (PCT)
Prior art keywords
fluorouracil
prodrug
group
hydrogen
derivatives
Prior art date
Application number
PCT/DK1987/000046
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English (en)
Inventor
Hans Bundgaard
Anders Buur
Original Assignee
Farmaceutisk Laboratorium Ferring A/S
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 Farmaceutisk Laboratorium Ferring A/S filed Critical Farmaceutisk Laboratorium Ferring A/S
Publication of WO1987006581A1 publication Critical patent/WO1987006581A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
    • C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/553—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms with halogen atoms or nitro radicals directly attached to ring carbon atoms, e.g. fluorouracil

Definitions

  • the present application concerns a prodrug for 5-fluoro ⁇ uracil and a composition and a method of treatment of cancer by administration of such a prodrug.
  • 5-fluorouracil is a widely used antitumor agent.
  • its clinical use is largely restricted to parenteral, in particular intravenous, administration.
  • Following oral administration it shows an incomplete and highly variable bioavailability which makes oral administration an unsuitable and unreliable mode of therapy, cf. e.g. N. Christophidis et al.
  • the rectal route of administration is of even less value than the oral one, since 5-fluorouracil shows negligible absorption following rectal administration to humans, cf. N. Christo ⁇ phidis, op. cit.
  • the object of the present invention is to provide such improved forms.
  • the invention is based on the surprising finding that a selected group of 1-alkoxycarbonyl , 3-acyl, 1-acyloxy ⁇ alkyl and 3-acyloxyalkyl derivatives of 5-fluorouracil showing the following characteristics are absorbed to a significant extent when administered rectally in rabbits: a) a partition coefficient between octanol and aqueous buffer (pH 7.4) greater than 0.5,
  • R 1 is selected from hydrogen, alkoxycarbonyl -C"-0R3
  • R is selected from hydrogen, acyl R CO- and acyloxy ⁇ alkyl as defined for R , wherein R is a straight or branched C- j -C ⁇ alkyl group, each group R and R is a straight or branched C.-C ⁇ alkyl group or each group R , R and R is a C,-C,- alkyl substituted by a group -OR*, -C00R', -0-C0-R', -CONR- 'R' ' or -NR ⁇ R' ' 1 , wherein each of the groups R' , R 1 ' and R 1 ' ' is hydrogen or C.-C. alkyl, and R is hydrogen, a straight or branched C.-C ⁇ alkyl group or a phenyl
  • R is hydrogen
  • Preferred compounds at present are l-butoxycarbonyl-5- fluorouracil , 3-propionyl-5-fluorouracil , 1-butyryl- oxymethyl-5-fluorouracil and l-(3-pentyloxycarbonyl)-5- fluorouracil .
  • the object of this patent is to provide 5-fluorouracil derivatives having a similar anti-tumor activity but a lower toxicity.
  • the anti-tumor activity was investigated by oral administration in mice. It is shown that a number
  • 25 of the derivatives exhibits an anti-tumor activity similar or superior to 5-fluorouracil. No reference is given to the use of prodrug forms of 5-fluorouracil nor is the absorption mechanism discussed.
  • JP-A-55-129272 discloses 5-FU-derivatives with 1- and 3-acyl substituents, e.g. 3-propionyl-5-FU, having improved carcinostatic activity. Their administration route is not mentioned.
  • p_A-55-108857 discloses an improved process for prepar ⁇ ing 5-fluorouracil derivatives in high yield, e.g. 1-, 3-acyl and 1 , 3-diacyl-5-fluorouracil derivatives with antitumor activity. However, the administration route is not given.
  • JP-A-54-122281 discloses carcinostatic 3-acyloxyalkyl-5- fluorouracil derivatives. The activity is tested by oral and intraperitoneal administration in mice and are superior to the activity of the corresponding 1- position substituent and 1 , 3-disubstituent . None of the preferred compounds of the present application are mentioned.
  • JP-A-54-55582 discloses l-C,-C 6 alkoxycarbonyl-5-fluoro ⁇ uracil compounds having antitumor activity and lower toxicity than 5-FU.
  • the preferred compound is N,-ethoxy- carbonyl-5-FU.
  • Other specifically mentioned compounds are the N,-methoxycarbony1-, N, -n-propoxycarbonyl- and N, -sec.butoxycarbonyl-5-FU. None of the preferred com ⁇ pounds according to the present invention are mentioned.
  • the route of administration may be either oral or par- enteral, and powder, granule, tablet, capsule, injection, suppository, ointment and the like may be mentioned as the dosage forms. Thus no special criteria with regard to rectal administration are given, and as shown below a number of the disclosed compounds have an insufficient bioavailability following rectal administration.
  • JP-A-59-219268 discloses carcinostatic 1-subs ituted- 5-fluorouracil compounds with lower toxicity, but also lower carcinostatic effect than 5-FU.
  • the 1-substituent R is -CO o CH-R, wherein R is a lower alkyl group, R is 2 a
  • JP-A-56-147774 discloses carcinostatic 1 , 3-di-acyloxy- 2-propoxycarbonyl-5-fluorouracil compounds with low toxicity and good absorbability. The compounds are tested orally.
  • C.A., 83_, 13681q and C.A., 91_, 4922w disclose rectal administration of 5-fluorouracil and 1-(2-tetrahydro- furyl)-5-fluorouracil.
  • C.A., 9jS, 210437f discloses 1-aryloxymethyl derivatives _ of 5-fluorouracil against L1210 leukemia by i.p. injection and oral administration showing that such compounds are more active than 5-fluorouracil.
  • the rectal admini ⁇ stration is not mentioned.
  • the compounds of the invention are used for the treatment of cancer by a method according to the invention, charac ⁇ terized in administration of an effective amount of the prodrug of the invention.
  • 1-Alkoxycarbonyl derivatives of 5-fluorouracil may be prepared by reacting 5-fluorouracil with the appropriate alkyl or phenyl chloroformate in a mixture of aceto- nitrile and pyridine as described in GB Patent No. 1,542,053.
  • 3-Acyl derivatives of 5-fluorouracil may be prepared as described by Buur and Bundgaard (Int. J. Pharm. 21 , 1984, 349-364) and N-acyloxymethyl derivatives as described by Buur et al. (Int. J. Pharm. 2 ⁇ , 1985, 43-60).
  • l-Acetyl-5-fluorouracil was prepared by refluxing a solution of 5-fluorouracil (3.9 g; 0.03 mol) in acetic anhydride (15 ml) and pyridine (0.15 ml) for 40 min. The mixture was then evaporated in vacuo and the residue recrystallized from toluene (4.6 g; 90? ⁇ ), m.p. 128-129°C.
  • the aliquot withdrawn was de- proteinized with ethanol or trichloroacetic acid and after centrifugation, the clear supernatant was injected on HPLC.
  • an aqueous solution of 5-fluorouracil was given by intravenous injection in the marginal ear vein.
  • the enemas were prepared by dis ⁇ solving or slurrying the compounds in water containing 0.5? ⁇ methyl cellulose and adjusting the pH to 7.4 with
  • the plasma samples obtained after centrifugation 35 were immediately analyzed for 5-fluorouracil by HPLC as follows. Plasma samples of 2007,ul were mixed with 250 r,ul of a
  • Fig. 1 shows plots of plasma 5-fluorouracil concentration versus time following rectal administration to rabbits of compounds 5 and 1 and of compound 1 given intravenous ⁇ ly.
  • the absolute bioavailabilities for the various com ⁇ pounds were determined by comparing the area under the plasma concentration-time curves for these compounds with the area under the plasma "concentration-time curve for 5-fluorouracil given intravenously.
  • the results obtained for compounds 1 to 15 are given in Table 3.
  • the plasma samples were also analyzed for intact 5-fluoro ⁇ uracil derivatives but with the exception of 3-benzoyl- 5-fluorouracil no measurable concentra ions were observed. This demonstrates that these compounds possess the ability to be converted back to the parent drug in vi o .
  • partition coefficients are generally being considered to be primary factors influencing the gastrointestinal or rectal absorption of drugs. For rectal absorption no general relationships between these factors and extent of absorption are, however, known.
  • the prodrugs according to the invention 35 may be formulated as medicaments for rectal administration by admixture with suitable pharmaceutically acceptable carriers.
  • the prodrugs may thus be administered e.g. as suppositories, enemas, ointments or capsules.
  • 5-Fluorouracil and l-butoxycarbonyl-5-fluorouracil were each given orally to two rabbits (cross-over design) in equivalent doses (9 mg 5-fluorouracil equiva ⁇ lents/kg).
  • no intact compound 5 was detected in the plasma samples.
  • the results of the experiment clearly show that the 5-fluorouracil prodrug exhibits a greatly enhanced bioavailability as compared with 5-fluorouracil per se.
  • the present prodrugs can be administered in doses cor ⁇ responding to those commonly used for parenteral admini- stration of 5-fluorouracil, usually from about 1 to 25 mg/kg body weight.
  • 5-fluorouracil 1 280- 284 l-methoxycarbonyl-5-FU 2 159- 160 l-ethoxycarbonyl-5-FU 3 126- 128 l-isopropoxycarbonyl-5-FU 4 178- 179 l-butoxycarbonyl-5-FU 5 102- 104 l-isobutoxycarbonyl-5-FU 6 131- 133 l-hexyloxycarbonyl-5-FU 7 67- 68 l-cyclohexyloxycarbonyl-5-FU 8 146- 147 l-phenyloxycarbonyl-5-FU 9 203- 204 l-benzyloxycarbonyl-5-FU 10 188- 190

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Une forme promédicamenteuse de 5-fluorouracile choisi dans le groupe composé de dérivés 1-alkoxycarbonyle, 3-acyle, 1-acyloxyalkyle et 3-acyloxyalkyle éventuellement substitués de 5-fluorouracile, présente: a) un coefficient de séparation entre l'octanol et une solution tampon aqueuse (pH 7,4) supérieur à 0,5; b) une solubilité dans l'eau à un pH de 7,4 supérieure à 0,05 M (à 20°C); c) une susceptibilité à subir un clivage enzymatique rapide in vivo afin de régénérer des quantités quantifiables de 5-fluorouracile avec la libération simultanée d'une profraction non toxique; et d) une stabilité en solution aqueuse telle qu'aucune dégradation significative ne se produit avant absorption à travers la biomembrane rectale. Ladite forme promédicamenteuse présente une bioadaptabilité améliorée lors de l'administration rectale. Lesdits composés sont extrêmement utiles dans le traitement du cancer et peuvent être administrés aussi bien par voie orale que par voie rectale.
PCT/DK1987/000046 1986-04-30 1987-04-29 Forme promedicamenteuse de 5-fluorouracile et procede de traitement du cancer WO1987006581A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DK1974/86 1986-04-30
DK197486A DK197486A (da) 1986-04-30 1986-04-30 5-fluoruracilprodug

Publications (1)

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WO1987006581A1 true WO1987006581A1 (fr) 1987-11-05

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EP (1) EP0265506A1 (fr)
AU (1) AU7397587A (fr)
DK (1) DK197486A (fr)
WO (1) WO1987006581A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004043396A2 (fr) * 2002-11-09 2004-05-27 Nobex Corporation Promedicaments contenant du carbamate modifie et methodes de synthese de ces derniers
US20100240883A1 (en) * 2009-03-18 2010-09-23 Nian Wu Lipid-drug conjugates for drug delivery

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2814202A1 (de) * 1977-04-05 1978-10-12 Taiho Pharmaceutical Co Ltd Antikrebspraeparat
US4130648A (en) * 1976-12-24 1978-12-19 Eisai Co., Ltd. 5-Fluorouracil derivatives and antitumor preparations containing the same
GB1542053A (en) * 1976-09-03 1979-03-14 Ono Pharmaceutical Co 5-fluorouracil derivatives
US4267326A (en) * 1976-09-06 1981-05-12 Mitsui Toatsu Chemicals, Incorporated Uracil derivatives
EP0222155A1 (fr) * 1985-10-11 1987-05-20 TERUMO KABUSHIKI KAISHA trading as TERUMO CORPORATION Dérivés du fluoro-5 uracile

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1542053A (en) * 1976-09-03 1979-03-14 Ono Pharmaceutical Co 5-fluorouracil derivatives
US4267326A (en) * 1976-09-06 1981-05-12 Mitsui Toatsu Chemicals, Incorporated Uracil derivatives
US4130648A (en) * 1976-12-24 1978-12-19 Eisai Co., Ltd. 5-Fluorouracil derivatives and antitumor preparations containing the same
DE2814202A1 (de) * 1977-04-05 1978-10-12 Taiho Pharmaceutical Co Ltd Antikrebspraeparat
EP0222155A1 (fr) * 1985-10-11 1987-05-20 TERUMO KABUSHIKI KAISHA trading as TERUMO CORPORATION Dérivés du fluoro-5 uracile

Non-Patent Citations (15)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, Vol 83 (1975), Abstract No 136 814q, Yakuzaigaku 1974, 34 (2), 47-53 (Japan) *
CHEMICAL ABSTRACTS, Vol. 105 (1986), Abstract No. 102428z, J. Pharm. Sci. 1986, 75 (5), 522-7 (Eng) *
CHEMICAL ABSTRACTS, Vol. 91 (1979), Abstract No. 49226w, Kyoto-Furitsu Ika Daigaku Zasshi 1979, 88 (3), 357-71 (Japan) *
CHEMICAL ABSTRACTS, Vol. 96 (1982), Abstract No. 210437f, J. Pharmacobio-Dyn. 1982, 5 (3), 208-12 (Eng.) *
CHEMICAL ABSTRACTS, Vol. 98 (1983), Abstract No. 22164g, Int. J. Pharm. 1982, 12 (2-3), 153-62 (Eng) *
International Journal of Pharmaceutics, Vol. 21, 194, ANDERS BUUR et al. "Prodrugs of 5-Fluorouracil. I. Hydrolysis Kinetics and Physicochemical Properties of Various N-Acylderivatives of K-Fluorouracil", pages 349-364. *
International Journal of Pharmaceutics, Vol. 24, 1985, ANDERS BUUR et al. "Prodrugs of 5-Fluorouracil, IV. Hydrolysis Kinetics, Bioactivation and Physicochemical Properties of Various N-Acyloxymethyl Derivatives of 5-Fluorouracil", pages 43-60. *
J. Med. Chem. 1980, 23, 1324-1329 (Tetsuji Kametani, Taiji Okada and Mitsuru Nakayama) *
PATENT ABSTRACTS OF JAPAN Abstract JP 53-2483 (Mitsui Toatsu Kagaku K.K.) publ. 11 January 1978. *
PATENT ABSTRACTS OF JAPAN Abstract of JP 54-122281 (Mitsui Toatsu Kagaku K.K.) publ. 21 September 1979 *
PATENT ABSTRACTS OF JAPAN Abstract of JP 54-55582 (Eisai K.K.) publ 2 May 1979 *
PATENT ABSTRACTS OF JAPAN Abstract of JP 55-108857 (Grelan Seiyaku K.K.) publ. 21 August 1980 *
PATENT ABSTRACTS OF JAPAN Abstract of JP 55-129272 (Grelan Seiyaku K.K.) publ. 6 October 1980 *
PATENT ABSTRACTS OF JAPAN Abstract of JP 56-147774 (Ajinomoto K.K.) publ 16 November 1981 *
PATENT ABSTRACTS OF JAPAN Abstract of JP 59-219268 (Kiyoutu Yakuhin Kogyo K.K.) publ 10 December 1984 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004043396A2 (fr) * 2002-11-09 2004-05-27 Nobex Corporation Promedicaments contenant du carbamate modifie et methodes de synthese de ces derniers
WO2004043396A3 (fr) * 2002-11-09 2004-08-12 Nobex Corp Promedicaments contenant du carbamate modifie et methodes de synthese de ces derniers
US20100240883A1 (en) * 2009-03-18 2010-09-23 Nian Wu Lipid-drug conjugates for drug delivery
WO2010107487A2 (fr) * 2009-03-18 2010-09-23 Wu Nian Conjugués lipide-médicament pour administration de médicaments
WO2010107487A3 (fr) * 2009-03-18 2011-11-10 Wu Nian Conjugués lipide-médicament pour administration de médicaments

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Publication number Publication date
EP0265506A1 (fr) 1988-05-04
DK197486D0 (da) 1986-04-30
DK197486A (da) 1987-10-31
AU7397587A (en) 1987-11-24

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