EP0265506A1 - A prodrug form of 5-fluorouracil and a method of treatment of cancer - Google Patents

A prodrug form of 5-fluorouracil and a method of treatment of cancer

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Publication number
EP0265506A1
EP0265506A1 EP19870903272 EP87903272A EP0265506A1 EP 0265506 A1 EP0265506 A1 EP 0265506A1 EP 19870903272 EP19870903272 EP 19870903272 EP 87903272 A EP87903272 A EP 87903272A EP 0265506 A1 EP0265506 A1 EP 0265506A1
Authority
EP
European Patent Office
Prior art keywords
fluorouracil
prodrug
group
hydrogen
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.)
Withdrawn
Application number
EP19870903272
Other languages
German (de)
French (fr)
Inventor
Hans Bundgaard
Anders Buur
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.)
Farmaceutisk Laboratorium Ferring AS
Original Assignee
Farmaceutisk Laboratorium Ferring AS
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Filing date
Publication date
Application filed by Farmaceutisk Laboratorium Ferring AS filed Critical Farmaceutisk Laboratorium Ferring AS
Publication of EP0265506A1 publication Critical patent/EP0265506A1/en
Withdrawn legal-status Critical Current

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Classifications

    • 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.A prodrug form of 5-fluorouracil selected from the group consisting of 1-alkoxycarbonyl, 3-acyl, 1-acyloxyalkyl and 3-acyloxyalkyl derivatives optionally substituted with 5-fluorouracil, has: a) a separation coefficient between octanol and a aqueous buffer solution (pH 7.4) greater than 0.5; b) a solubility in water at a pH of 7.4 greater than 0.05 M (at 20 ° C); c) a susceptibility to undergo rapid enzymatic cleavage in vivo in order to regenerate quantifiable quantities of 5-fluorouracil with the simultaneous release of a non-toxic profraction; and d) a stability in aqueous solution such that no significant degradation occurs before absorption through the rectal biomembrane. Said prodrug form has improved bioadaptability during rectal administration. Said compounds are extremely useful in the treatment of cancer and can be administered both orally and rectally.

Description

A prodrug form of 5-fluorouracil and a method of treatment of cancer
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. However, 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. "Fluorouracil Therapy in Patients with Carcinoma of the Large Bowel: A Pharmacokinetic Comparison of Various Rates and Routes of Administration", Clinical Pharmacgkinetics 3: 330 - 336 (1978). 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.
Thus, it is quite obvious that a serious need exists for improved forms of 5-fluorouracil which would be devoid of these drawbacks in terms of oral and rectal delivery that to date have characterized the drug.
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,
b) a solubility in water at pH 7.4 greater than 0.05 (at 20°C),
c) a susceptibility to undergo rapid enzymatic cleavage in vivo to regenerate 5- luorouraciJ in quantitative amounts with the simultaneous release of a non- toxic pro-moiety, and
d) a stability in aqueous solution to such an extent that no significant degradation occurs before the occurrence of absorption across the rectal biomembrane.
Accordingly, these compounds are highly useful as prodrugs for 5-fluorouracil.
A particular group of compounds showing these character¬ istics have the general formula
0
II
wherein 0 R 1 is selected from hydrogen, alkoxycarbonyl -C"-0R3
0
4 " and acyloxyalkyl R -C-0-CH-
R6
2 5 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' , R1 ' and R1 ' ' is hydrogen or C.-C. alkyl, and R is hydrogen, a straight or branched C.-Cς alkyl group or a phenyl
1 group, with the proviso that one of the groups R and
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 very poor ability of 5-fluorouracil to be absorbed rectally can most probably be attributed to its low lipophilicity combined with a relatively low water- solubility of the compound. It was thought that by bio- reversible derivatization it may be possible to obtain prodrug forms showing improved bioavailability following rectal administration as a result of increased lipo¬ philicity and water-solubility. In addition to these properties, successful prodrug derivatives should be capable of reverting to 5-fluorouracil when absorbed into the bloodstream of warm-blooded animals, e.g. humans, or when reaching the site of therapeutic activity of the parent drug. A useful prodrug should furthermore possess an adequate stability in vitro so that pharma¬ ceutically useful dosage forms such as suppositories with a suitable shelf-life can be prepared.
Several types of possible 5-fluorouracil prodrugs have been described, cf. Anders Buur and Hans Bundgaard "Prodrug of 5-fluorouracil. I. Hydrolysis kinetics and physicochemical properties of various N-acyl derivatives
of 5-fluorouracil", International Journal of Pharma¬ ceutics, 1 (1984) 349-364; Anders Buur and Hans Bundgaard "Prodrugs of 5-fluorouracil. II. Hydrolysis kinetics, bioactivation, solubility and lipophilicity of N-alkoxy- carbonyl derivatives of 5-fluorouracil", Arch. Pharm. Chem., Sci.ed. 1984, _12., 37-44; Anders Buur and Hans Bundgaard "Prodrugs of 5-fluorouracil. III. Hydrolysis kinetics in aqueous solution and biological media, lipo¬ philicity and solubility of various 1-carbamoyl deriva¬
10 tives of 5-fluorouracil", International Journal of Pharmaceutics, b_ (1985) 209-222; Anders Buur, Hans Bundgaard and Erik Falch "Prodrugs of 5-fluorouracil. IV. Hydrolysis kinetics, bioactivation and physicochemical properties of various N-acyloxymethyl derivatives of
15 5-fluorouracil", International Journal of Pharmaceutics, 24 (1985) 43-60.
A number of compounds comprised by the above formula is known from GB Patent Specification No. 1,542,053.
20 Based on the recognized high toxicity of 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.
30 JP-A-53-2483 discloses carcinostatic 1-aryloxycarbonyl , 1-aralkyloxycarbonyl and l-alkoxycarbonyl-5-FU compounds, e.g. 1-n-hexyloxycarbonyl- and l-n-octyloxycarbonyl-5-FU, but none of the preferred compounds according to the present invention are mentioned. The compounds are given
35 intraperitoneally or orally. 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,-C6alkoxycarbonyl-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 -COoCH-R, wherein R is a lower alkyl group, R is 2 a
0
II a halogen atom or the group -0C-R ' , wherein R' is straight chain, branched or cyclic alkyl. The compounds are given orally or by injection.
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.
Other compounds having the above formula I are known from J. Me . Chem. 1980, b_, 1324-1329 and from US patent No. 4,267,326 and the corresponding Danish patent no. 142,413. The objects are again to provide anti-tumor 5-fluorouracil derivatives with low toxicity and high activity. The compounds are administered by injection or orally. The rectal route is not mentioned.
A number of 5-fluorouracil derivatives have now been studied with a view to investigate their absorption characteristics and potential usefulness as prodrugs, as further explained below. As shown below, it was found that several of the compounds do not possess the desirable properties and do not show any significant rectal absorp¬ tion.
Of particular interest is 1-n-butoxycarbonyl 5-fluoro¬ uracil, which exhibits particularly favourable charac¬ teristics in terms of the present invention. As seen from GB patent No. 1,542,053 this compound only shows poor anti-tumor activities, and it has further been characterized as unsuitable for the use as a drug in Chem. Pharm. Bull. 21> 1985, 2832, where it is stated that l-alkoxycarbonyl-5-fluorouracils are unstable in water and therefore not suitable for use as drugs.
Despite the vast number of 5-fluorouracil derivatives described in the literature which are potential candidates for a prodrug with improved delivery characteristics, it could not be foreseen that the above-mentioned four criteria as to the partition coefficient, water solubility, cleavage and stability were critical in terms of ensuring an adequate bioavailability , especially upon rectal administration.
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.
Synthesis of 5-fluorouracil derivatives
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. 2Λ , 1985, 43-60).
The synthesis is further illustrated in the following examples .
The derivatives had spectroscopic properties (UV and H NMR) and elemental analysis (C, H, N) in agreement with their structures. The melting points of the compounds are given in Table 1.
EXAMPLE 1
Preparation of 1-(butoxycarbonyl )-5-fluorouracil
A solution of pyridine (3.65 g; 44.3 mmol) in aceto- nitrile (50 ml) was added dropwise to a 'solution of 5-fluorouracil (3.25 g; 25 mmol) and n-butyl chloro- formate (4.2 g; 30 mmol) in acetonitrile (20 ml) at -3 - 0°C. After stirring for 30 min. at -3 - 0°C, the reaction mixture was stirred for 3 h at room temperature (20 - 25°C) and then concentrated in vacuo. The residue was diluted with water (50 ml) and extracted with ethyl acetate (2 x 50 ml). The combined extracts were dried over anhydrous sodium sulphate and evaporated in vacuo. The residue obtained was recrystallized from ethyl acetate to give 4.7 g (83,°_), m.p. 102-104°C.
EXAMPLE 2
Preparation of 1- (butyryloxymethyl )-5-fluorouracil
Potassium carbonate (690 mg; 5 mmol) was added to a solution of 5-fluorouracil (652 mg; 5 mmol) in 10 ml of dimethyl sulfoxide. Then a solution of chloromethyl butyrate (341 mg; 2.5 mmol) in 5 ml of dimethyl sulf- oxide was added dropwise. The reaction mixture was stirred at 80°C for 3 h, cooled and poured onto 15 g of ice. The mixture was acidified with hydrochloric acid and extracted with three 10 ml portions of chloroform. .The combined chloroform extracts were washed with 20 ml of water, dried over magnesium sulphate, and evaporated under reduced pressure. The residue was dissolved in toluene and transferred onto a column containing 50 g of silica gel ("Silica oelm" 63-100 ,urn). The sample was eluted with toluene mixed with increasing amounts of ethyl acetate (10-15 % ) . The eluate fractions containing pure title compound were pooled and evaporated in vacuo. Recrystallization of the residue from ether-petroleum ether gave 291 mg (51?ό yield): m.p. 92-93°C.
EXAMPLE 3
Preparation of 3-propionyl-5-fluorouracil
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?ό), m.p. 128-129°C.
To a stirred mixture of l-acetyl-5-fluorouracil (0.02 mol), 6 ml of dioxane and triethylamine (0.022 mol), cooled in an ice bath, was added propionylchloride (0.022 mol) dropwise over 30 min. The mixture was stirred for
1.5 h at room temperature. The precipitated triethylamine hydrochloride was filtered off and the filtrate evaporated in vacuo. The residue solidified on addition of ether and was recrystallized from ether to give l-acetyl-3- propionyl-5-fluorouracil , m.p. 87-89°C.
10
l-Acetyl-3-propionyl-5-fluorouracil (600 mg) was dissolved in ethanol (25 ml) and 2 ml of 1 M hydrochloric acid was added. Upon standing for 3 h at room temperature the N, -deacetylation was completed. Sodium hydroxide (1M, 2 ml) was added and the mixture evaporated in vacuo. The residue was extracted with chloroform (2 x 25 ml). The extracts were evaporated in vacuo and the residue recrystallized from chloroform-petroleum ether to give the title compound, m.p. 128-130°C.
10
EXAMPLE 4
Prepration of 2-(3-pentyloxycarbonyl)-5-fluorouracil
15 A solution of pyridine (0.70 g; 8.8 mmol) in acetonitrile (10 ml) was added dropwise to a solution of 5-fluorouracil (0.65 g; 5.0 mmol) and 3-pentyl chloroformate (0.90 g; 6.0 mmol) in acetonitrile (50 ml) at -3 - 0°C. After stirring for 30 min. at -3 - 0DC, the reaction mixture
20 was stirred for 5 h at room temperature (20 - 25°C) and then concentrated in vacuo. The residue was diluted with water (30 ml) and extracted with methylene chloride (2 x 30 ml). The combined extracts were dried over an¬ hydrous sodium sulphate and evaporated in vacuo. The
25 residue obtained was recrystallized from ether-pe roleum ether to give 0.85 g 870?_, m.p. 98 - 100°C.
In-vitro cleavage of 5-fluorouracil derivatives
30 Reaction Conditions; Solutions of various derivatives of 5-fluorouracil in aqueous buffer solutions or 80?ό human plasma solutions (pH 7.4) were kept at 37°C. The initial concentration of the derivatives was in the range 0.02-0.1 mg/ml. At various times an aliquot of
35 the solutions was withdrawn and analyzed by HPLC for remaining derivative as well as for 5-fluorouracil. 1 1
For the plasma solutions the aliquot withdrawn was de- proteinized with ethanol or trichloroacetic acid and after centrifugation, the clear supernatant was injected on HPLC.
Analytical method: An HPLC method was used for the de¬ termination of 5-fluorouracil and its derivatives. In this method a reversed-phase "Lichrosorb (^R) RP-8" column
(250 x 4 mm) was eluted at ambient temperature with mixtures of methanol (5-60% v/v) and 0.01 M acetate buffer pH 5.0. The composition of the eluant was adjusted for each compound in order to provide an appropriate retention time. The flow rate was 0.8-1.2 ml/ iπ. and the column effluent was monitored spectrophotometri- cally at 266 n . Quantitation of the compounds was done by measurement of peak heights in relation to those of standards chromatographed under the same conditions.
A complete conversion of all the derivatives to 5-fluoro- uracil was found to take place in aqueous buffer solutions at pH 1-13 as well as in 80?_ human plasma solutions. In all cases, the cleavage of the derivatives displayed strict first-order kinetics at constant pH.
The half-times of 5-fluorouracil formation from various derivatives at physiological conditions of pH and tem¬ perature are given in Table 2. It can be seen that in the presence of human plasma the rate of degradation is strongly accelerated, thus showing the susceptibility of the derivatives to undergo conversion into the parent active compound at conditions similar to those prevailing in vivo.
12
Water-solubility and lipophilicity of 5-fluorouracil and its derivatives
The apparent partition coefficients (P) for 5-fluoro¬ uracil and the derivatives listed in table 1 were measured using the widely used octanol-aqueous buffer system as described by Buur and Bundgaard I (1984) op. cit. The values found for P and the water-solubilities are listed in Table 3. The results obtained clearly show
10 that the physico-chemical properties of the various derivatives differ greatly.
Bioavailability of 5-fluorouracil and its derivatives following rectal administration
15
Male albino rabbits weighing 1.8-2.1 kg were fasted for 24 h prior to drug administration. The rabbits re¬ ceived 9.0 mg/kg fluorouracil or the equivalent amount (on a molar basis) of its derivatives rectally in the
20 form of an enema. Furthermore, 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?ό methyl cellulose and adjusting the pH to 7.4 with
25 phosphate buffer, the total buffer concentration being 0.005 M. The enemas (= 2 ml) were administered about 5 cm from the anus using a rectal polyethylene tube. During the experiments the rabbits were kept in restrain¬ ing boxes and it was controlled that there was no leakage
30 from the anus.
After administration, blood samples were taken from the ear vein at appropriate times in heparinized test tubes. 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
0.1 M ZnSO. solution. After centrifugation for 2 min. at 10,000 rpm 20 ,ul of the clear supernatant was chrorna- tographed on a "Lichrosorb ^ RP-18" (5 ,urn particles) column (250 x 4 mm), using 0.01 M acetate buffer of pH 5.0 as mobile phase. The flow rate was 1.2 ml/min and the eluate was monitored at 266 nm. Quantitation of 5-fluorouracil which showed a retention time of 4.2 min. was done by measuring the peak heights in relation to those of standards (solutions of 5-fluorouracil in rabbit blood) chromatographed under the same conditions.
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 .
No detectable absorption (< 2% ) of 5-fluorouracil was observed which corresponds to previous findings in a rectal absorption study in man (Christophidis et al., op. cit.). The absorption behaviour of the various 5- fluorouracil derivatives is seen to vary widely. Thus, whereas the derivatives 5, 6, 11 and 14 are absorbed to an extent of 50-100.0 the compounds 8, 9, 10 and 13 show no or only a very slight absorption. Water-solubility and lipophilicity (as expressed in terms of octanol-buffer
14
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.
An analysis of the absorption behaviour of the various compounds (Table 3) disclosed no direct relationship between bioavailability an'd lipophilicity or between
10 bioavailability and aqueous solubility. However, a closer examination of the data revealed a proportionality between bioavailability and aqueous solubility provided that a certain lipophilicity is possessed. The requirements to lipophilicity and aqueous solubility can be defined
15 as follows:
In order to provide a bioavailability of at least 50?ό following rectal administration a 5-fluorouracil prodrug should possess:
20 a) a partition coefficient between octanol and aqueous buffer (pH 7.4) greater than 0.5,
b) a solubility in water at pH 7.4 greater than 25 0.05M as determined at 20°C.
The above studies thus demonstrate that by selecting 5-fluorouracil derivatives with those physico-chemical characteristics as prodrugs it is feasible to obtain
30 an efficient absorption of 5-fluorouracil after rectal administration, in sharp contrast to the behaviour of 5-fluorouracil per se.
Consequently 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.
Bioavailability after oral administration
5-Fluorouracil and l-butoxycarbonyl-5-fluorouracil (com¬ pound 5) were each given orally to two rabbits (cross-over design) in equivalent doses (9 mg 5-fluorouracil equiva¬ lents/kg). The extent of absorption, determined as de- scribed above, was 9?ό for 5-fluorouracil and 57?ό for l-butoxycarbonyl-5-fluorouracil . As was the case for rectal absorption 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.
T ABLE 1
Melting points of 5-fluorouracil and various 5-fluorouracil derivatives
Compound No m.p. ( °C)
5-fluorouracil (5-FU) 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
3-propionyl-5-FU 11 113- 114
3-benzoyl-5-FU 12 172- 174
3-nicotinoyl-5-FU 13 161-•162 l-butyryloxymethyl-5-FU 14 92-■93 l-(3-pentyloxycarbonyl)-5-FU 15 98- 100
Compounds 5, 6, 11, 14 and 15 are prodrugs of the invention. The other compounds are given by way of examples. TABLE 2
Half-lives of hydrolysis of various 5-fluorouracil prodrugs at 37°C
1/2
Compound 80?ό human Buffer, Buffer plasma, pH 7 pH 7.4 pH 4.0 (min) (min) (h)
2 2 190 7.2
3 2 550 19.3
4 3 975 42
5 3 550 26.3
6 2 550 20.6
7 2 550 -
8 5 910 45
9 <0.5 18 18 min
10 0.8 ' 150 4.4
11 20 50 9.6
12 110 2880 130
13 15 220 6.1
14 140 8400 >200
15 10 _ 82
TABEL 3
Physico-chemical properties of various derivatives of 5-fluorouracil and bioavailability following rectal administration to rabbits
Compound a) -c)
PK, ,b) log P (mq/ml)' (M) Bioavailability
1 8.0 0.11 -0.96 13.9 0.11 0
2 6.8 0.04 -1.38 116.5 0.62 44
3 6.9 0.16 -0.79 •28.8 0.14 49
4 6.8 0.32 -0.50 23.5 0.11 25
5 6.8 1.55 0.19 29.5 0.13 101
6 6.9 1.78 0.25 12.5 0.054 50
7 6.8 219 1.34 7.5 0.029 17
8 6.8 5.25 0.72 4.6 0.012 9
9 Λ/6.8 0.87 -0.06 4.5 0.018 0
10 1^6.8 3.02 0.48 0.4 0.0015 0
11 7.2 0.62 -0.21 ' 90.5 0.48 93
12 6.9 1.45 0.16 5.4 0.023 29
13 1.6; 6.4 0.08 -1.10 29.7 0.13 3
14 7.2 1.15 0.06 24.6 0.11 62
15 6.8 4.00 0.60 14.9 0.061 - a) At 37°C. b) P is the partition coefficient between octanol and aqueous buffer of pH 7.4 (at 22°C c) S is the solubility in aqueous buffer of pH 7.4 (at 22°C)

Claims

P A T E N T C L A I M S
1. A prodrug form of 5-fluorouracil selected from the group consisting of optionally substituted 1-alkoxy- carbonyl, 3-acyl, 1-acyloxyalkyl and 3-acyloxyalkyl derivatives of 5-fluorouracil having the following pro¬ perties:
a) a partition coefficient between octanol and aqueous buffer (pH 7.4) greater than 0.5,
b) a solubility in water at pH 7.4 greater than 0.05 M (at 20°C),
c) a susceptibility to undergo rapid enzymatic cleavage in vivo to regenerate 5-fluorouracil in quantitative amounts with the simultaneous release of a non- toxic pro-moiety, and
d) a stability in aqueous solution to such an extent that no significant degradation occurs before the occurrence of absorption across the rectal biomembrane.
2. A prodrug according to claim 1 comprising a compound of the general formula
0
II
wherein H>- 0
R,1 i•s selected from hydrogen, alkoxycarbonyl -C-0R 3
20
0 and acyloxyalkyl R4-C-0-CH-
R6
R 2 is selected from hydrogen, acyl R5CO- and acyloxy¬ alkyl as defined for R , wherein R is a straight or branched C,-C,- alkyl group, each group R 4 and R5 is a straight or branched C.-C, alkyl group or each group R 3, R4 and R5 is a C.-C,- alkyl substituted by a group -OR', -C00R1, -0-CO-R1, -C0NR' 'R*
10 or -NR^R11 ', wherein each of the groups R', R1 ' and
R'1' is hydrogen or C.-C. alkyl, and R is hydrogen, a straight or branched C.-C,. alkyl group or a phenyl group, with the proviso that one of the groups R 1 and
2 R is hydrogen.
15
3. A prodrug according to claim 2 wherein R is alkoxy-
2 carbonyl and R is hydrogen.
4. A prodrug according to claim 3 comprising 1-π-butoxy- 20 carbonyl-5-fluorouracil, l-isobutoxy-5-fluorouracil or l-(3-pentyloxycarbonyl)-5-fluorouracil.
5. A prodrug according to claim 2 comprising 3-propionyl- 5-fluorouracil .
25
6. A prodrug according to claim 2 comprising 1-butyryl- oxymethyl-5-fluorouracil.
7. Method of treatment of cancer in human beings,
30 characterized by administering an effective amount of a prodrug of claim 1 orally or rectally.
8. Method according to claim 7, characterized by administering an effective amount of 35 a prodrug of claim 2.
9. Method according to claim 8, characterized by administering an effective amount of a prodrug of claim 3.
10. Method according to claim 7, characterized by administering an effective amount of a prodrug of any of claims 4 to 6.
11. Composition for treating cancer adapted for rectal administration, characterized in that it comprises an effective amount of a prodrug compound of any of claims 1 to 6.
12. Use of a prodrug compound of any of claims 1 to 6 for preparing a medicament for rectal administra ion for treatment of cancer.
EP19870903272 1986-04-30 1987-04-29 A prodrug form of 5-fluorouracil and a method of treatment of cancer Withdrawn EP0265506A1 (en)

Applications Claiming Priority (2)

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DK197486A DK197486A (en) 1986-04-30 1986-04-30 5-FLUORURACIL PRODUCT
DK1974/86 1986-04-30

Publications (1)

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WO2004043396A2 (en) * 2002-11-09 2004-05-27 Nobex Corporation Modified carbamate-containing prodrugs and methods of synthesizing same
US20100240883A1 (en) * 2009-03-18 2010-09-23 Nian Wu Lipid-drug conjugates for drug delivery

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JPS6024789B2 (en) * 1976-09-03 1985-06-14 小野薬品工業株式会社 5-Fluorouracil derivative compound
JPS5331676A (en) * 1976-09-06 1978-03-25 Mitsui Toatsu Chem Inc Uracil derivatives and their preparation
JPS6052708B2 (en) * 1976-12-24 1985-11-20 エーザイ株式会社 5-Fluorouracil compounds and antitumor agents containing them
GB1570555A (en) * 1977-04-05 1980-07-02 Taiho Pharmaceutical Co Ltd Anti-cancer composition
JPS62174060A (en) * 1985-10-11 1987-07-30 Terumo Corp 5-fluorouracil derivative and drug preparation containing same

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Title
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