WO1997006178A1 - Pyrimidine nucleosides - Google Patents

Pyrimidine nucleosides Download PDF

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Publication number
WO1997006178A1
WO1997006178A1 PCT/EP1996/003259 EP9603259W WO9706178A1 WO 1997006178 A1 WO1997006178 A1 WO 1997006178A1 EP 9603259 W EP9603259 W EP 9603259W WO 9706178 A1 WO9706178 A1 WO 9706178A1
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Prior art keywords
dideoxy
fluoro
lower alkyl
arabinofuranosyl
carboxamido
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PCT/EP1996/003259
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French (fr)
Inventor
Robert Wilson Lambert
Joseph Armstrong Martin
John Herbert Merrett
Kevin Edward Burdon Parkes
Gareth John Thomas
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F. Hoffmann-La Roche Ag
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Priority claimed from GBGB9515978.6A external-priority patent/GB9515978D0/en
Application filed by F. Hoffmann-La Roche Ag filed Critical F. Hoffmann-La Roche Ag
Priority to AU67868/96A priority Critical patent/AU6786896A/en
Publication of WO1997006178A1 publication Critical patent/WO1997006178A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals

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  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
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  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
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Abstract

Pyrimidine nucleoside derivatives of formula (I), wherein R1 to R8 each individually represent hydrogen, halogen, cyano, lower alkyl, halo-lower alkyl, lower alkoxy, lower cycloalkyl or aryl; or R?1 and R2¿ together or R?2 and R3¿ together or R?3 and R4¿ together represent a fused benzene ring; R9 represents hydrogen or lower alkyl; R10 represents hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl-lower alkyl, lower cycloalkyl-lower alkyl, acyl, 2-pyrrolidinylcarbonyl or a group of the formula -C(O)-CH(R12)-NH2; R11 represents halogen, lower alkyl, halo-lower alkyl or lower cycloalkyl; R12 represents hydrogen, lower alkyl, aryl-lower alkyl, lower alkylthio-lower alkyl, amino-lower alkyl or (4-imidazolyl)-lower alkyl; W represents CH¿2?, C(O) or C(S); X represents CH2 or O; Y represents hydrogen, fluorine or hydroxy; Z represents C(R?13)(R14¿), O, S, SO, SO¿2?, Si(R?15)(R16¿) or N(R?17); R13 and R14¿ each represent hydrogen, lower alkyl, halo-lower alkyl, aryl or aryl-lower alkyl or R?13 and R14¿ together represent lower alkylene; R?15 and R16¿ each represent lower alkyl; and R17 represents lower alkyl, and pharmaceutically acceptable salts of those compounds of formula (I) which are basic inhibit viral thymidine kinase and are useful as antiviral agents.

Description

Pyrimidine nucleosides
The present invention is concerned with pyrimidine nucleoside derivatives and a process for their manufacture. The invention is also concerned with pharmaceutical preparations based on these pyrimidine nucleoside derivatives and the production of said preparations.
The pyrimidine nucleoside derivatives provided by the present invention are compounds of the general formula
Figure imgf000003_0001
wherein R1 to R8 each individually represent hydrogen, halogen, cyano, lower alkyl, halo-lower alkyl, lower alkoxy, lower cycloalkyl or aryl; or R1 and R2 together or R2 and R3 together or R3 and R4 together represent a fused benzene ring;
R9 represents hydrogen or lower alkyl; R10 represents hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl-lower alkyl, lower cycloalkyl- lower alkyl, acyl, 2-pyrrolidinylcarbonyl or a group of the formula -C(0)-CH(R12)-NH ; RU represents halogen, lower alkyl, halo-lower alkyl or lower cycloalkyl;
R12 represents hydrogen, lower alkyl, aryl-lower alkyl, lower alkylthio-lower alkyl, amino-lower alkyl or (4-imidazolyl)-lower alkyl; W represents CH2, C(O) or C(S);
X represents CH2 or O; Y represents hydrogen, fluorine or hydroxy;
Z represents C(R 3)(R14), 0, S, SO, S02, Si(Ri 5)(Rl6) or
N(R17); and R 1 3 and R14 each represent hydrogen, lower alkyl, halo-lower alkyl, aryl or aryl-lower alkyl or R1 3 and R1 4 together represent lower alkylene;
R1 5 and R1 6 each represent lower alkyl; and
R 7 represents lower alkyl. and pharmaceutically acceptable acid addition salts of those compounds of formula I which are basic.
The aforementioned compounds and salts possess valuable pharmacological properties. In particular, they inhibit viral thymidine kinase and can accordingly be used in the treatment and prophylaxis of viral infections, especially those caused by herpes simplex virus (HSV).
Compounds of formula I belong, in part, to a class of 5'- carbocyclyl- or heterocyclyl-carboxamido substituted pyrimidine nucleosides disclosed in European Patent No. 0 257 378. However, this patent makes no mention of the particular carbocyclyl and heterocyclyl groups described in the present Application, which confer an unexpected advantage to the present compounds by way of an increase in activity.
As used in this Specification, the term "lower" means that the group qualified thereby contains a maximum of 7, preferably a maximum of 4, carbon atoms and can be a straight-chain or branched-chain group. Methyl, ethyl, n-propyl, isopropyl, n-butyl, sec. butyl, tert. butyl, n-pentyl, n-hexyl and the like are examples of alkyl groups, chloromethyl, difluoromethyl, trifiuoromethyl, pentafluoroethyl and the like are examples of halo-lower alkyl groups, aminomethyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl and the like are examples of amino-lower alkyl groups and methylthiomethyl, 2-ethylthioethyl and the like are examples of lower alkylthio-lower alkyl groups. The term "lower alkoxy" means a lower alkyl group as defined hereinbefore which is attached via an oxygen atom, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec. butoxy, tert. butoxy, n-pentyloxy, n- hexyloxy and the like. Allyl is an example of a lower alkenyl group and propargyl is an example of a lower alkynyl group. A lower cycloalkyl group can be, for example, cyclopropyl, cyclo¬ butyl, cyclopentyl or cyclohexyl. Cyclopropylmethyl, cyclohexyl- methyl and 2-cyclopentylethyl are examples of a lower cyclo- alkyl-lower alkyl group. The term "aryl" means phenyl or naphthyl which may be unsubstituted or substituted by one or more halo, lower alkyl, lower alkoxy, lower alkylthio, nitro, trifiuoromethyl or similar inert substituents, such as phenyl, 4-chlorophenyl, 4- fluorophenyl, p-tolyl, 4-methoxyphenyl, 3,4-dichlorophenyl and the like. The term "aryl-lower alkyl" means a lower alkyl group as defined earlier in which one or more hydrogen atoms has/have been replaced by an aryl group as defined earlier, such as benzyl, 4-fluorobenzyl, 2-phenyl-ethyl and the like. The term "lower alkylene" means an alkylene group containing at least 2 carbon atoms, e.g. ethylene, propylene and the like, with C(R1 3)(R1 4) in the former case forming a spirocyclopropane ring. An acyl group can be derived from an aliphatic carboxylic acid, preferably an alkanoic acid containing up to 20 carbon atoms, such as formic acid, acetic acid, propionic acid, decanoic acid, palmitic acid, stearic acid etc., or from an aromatic carboxylic acid, such as benzoic acid or a substituted benzoic acid, e.g. p-chlorobenzoic acid, 3.4,5-trimethoxybenzoic acid and the like. The term "halogen" means fluorine, chlorine, bromine or iodine unless specifically indicated to the contrary.
It will be appreciated that the compounds of formula I can exist as optically pure enantiomers or diastereoisomers or as mixtures of such enantiomers or diastereoisomers and that the invention includes within its scope not only the individual enantiomers and diastereoisomers, but also the respective mixtures. Preferred compounds of formula I are those in which R1 , R2, R3 and R4 each represent hydrogen; or two of R1 , R2, R3 and R4 represent hydrogen and the remaining two represent halogen, expecially chlorine or fluorine; or three of R1 , R2, R3 and R4 represent hydrogen and the remaining one represents halogen, especially fluorine of chlorine, lower alkyl, especially methyl, halo-lower alkyl, especially trifiuoromethyl, lower alkoxy, especially methoxy, lower cycloalkyl, especially cyclohexyl, or aryl, especially phenyl; or R1 and R2 together or R3 and R4 togther represent a fuzed benzene ring. Preferably, R5, R6 R7 and R8 each represent hydrogen; or two of R5, R6, R7 and R8 represent hydrogen and the remaining two represent halogen, especially fluorine or chlorine; or three of R5, R6, R7 and R8 represent hydrogen and the remaining one represents halogen, especially fluorine or chlorine, or lower alkyl especially methyl. R9 preferably represents hydrogen or methyl. R 0 preferably represents hydrogen, lower alkyl, especially ethyl, lower alkenyl, especially allyl, lower alkynyl, especially propargyl, or a group of the formula -C(0)-CH(R12)-NH2, especially where R12 represents lower alkyl, lower alkylthio-lower alkyl or amino-lower alkyl, particularly isopropyl, methylthiomethyl or 4-aminobutyl. When R 1 2 represents (4-imidazolyl)-lower alkyl, this is preferably (4- imidazolyl)methyl, i.e. histidyl. Preferably, R 1 represents halogen, especially iodine, or lower alkyl, especially ethyl. W preferably represents C(O) or C(S); X preferably represents O; Y preferably represents hydrogen or fluorine; and Z preferably represents O or SO2.
Examples of especially preferred compounds of formula I are:
2',5'-dideoxy-5-ethyl-5'-[(9-xanthenyl)-carboxamido]- uridine;
1 -[2,5-dideoxy-2-fluoro-5-[(9-xanthenyl)-carboxamido]-β- D-arabinofuranosyl]-5-ethyluracil;
1 -[5-[(2-chloro-9(RS)-xanthenyl)-carboxamido]-2,5- dideoxy-2-fluoro-β-D-arabinofuranosyl]-5-ethy I uracil;
1 -[5-[(4-chloro-9(RS)-xanthenyl)-carboxamido]-2,5- dideoxy-2-fluoro-β-D-arabinofuranosyl]-5-ethyluracil;
1-[2,5-dideoxy-2-fluoro-5-[(4,5-difluoro-9-xanthenyl)- carboxamido]-β-D-arabinofuranosyl]-5-ethyluracil;
1-[2,5-dideoxy-2-fluoro-5-[(9-thioxanthenyl)- carboxamido]-β-D-arabinofuranosyl]-5-ethyluracil S,S-dioxide;
1-[2,5-dideoxy-2-fluoro-5-[(4-fluoro-9(RS)-thioxanth- enyl)-carboxamido]-β-D-arabinofuranosyl]-5-ethyluracil S,S- dioxide;
1 -[2, 5-dideoxy-2-fluoro-5-[N-[[4-(trif luoromethyl) -9- (RS)-xanthenyl]-carbonyl]-N-methylamino]-β-D-arabino- fu ran osy I] -5 -ethyl uracil;
1 -[5-[N-[ (4, 5-di chloro- 9-xan the ny I) -carbonyl]- N- methyl- ami no]-2,5-dideoxy-2-fluoro-β-D-arabin of uranosyl]-5- ethyluracil; and 1-[2,5-dideoxy-2-fluoro-5-[N-[4-(trifluoromethyl)-9-(RS)- xantheny I]- carbonyl]- N -methy lamino]-3-0-(L-valyl)-β-D -arabi n o- furanosyl]-5-ethyluracil.
Other interesting compounds of formula I are:
1-[5-Deoxy-5-[(9-xanthenyl)-carboxamido]-β-D-arabino- f u ran osy I] -5-e thy I uracil;
1-[2,5-dideoxy-2-fluoro-5-[(4-methy!-9(RS)-xanthenyl)- carboxamido]-β-D-arabinofu ran osyl]-5-ethy I uracil; 1-[2,5-dideoxy-2-fluoro-5-[(4-cyclohexyl-9(RS)- xanthenyl)-carboxamido]-β-D-arabinofuranosyl]-5-ethyluracil;
1-[2,5-dideoxy-2-fluoro-5-[(4-phenyl-9(RS)-xanthenyl)- carboxamido]-β-D-arabinofuranosyl]-5-ethy I uracil;
5'-[(1-chloro-9(RS)-xanthenyl)-carboxamido]-2',5'- dideoxy-5-ethyluridine;
5'-[(3-chloro-9(RS)-xanthenyl)-carboxamido]-2',5'- dideoxy-5-ethyl uri dine;
1-[5-[(2,7-dichloro-9-xanthenyl)-carboxamido]-2,5- dideoxy-2-fluoro-β-D-arabinofuranosyl]-5-ethyl uracil; 1-[5-[(2,3-dichloro-9(RS)-xanthenyl)-carboxamido]-2,5- dideoxy-2-fluoro-β-D-arabinofuranosyl]-5-ethyl uracil;
1-[5-[(2,4,5.7-tetrachloro-9-xanthenyl)-carboxamido]-2,5- dideoxy-2-fluoro-β-D-arabinofuranosyl]-5-ethyluracil; 1 -[2 ,5-dideoxy-2-fluoro-5-[(2,7-difl uoro-9-xanthenyl)- carboxamido]-β-D-arabinofuranosyl]-5-ethyluracil;
1 -[2,5-dideoxy-2-fluoro-5-[(4,5-difl uoro-9-xanthenyl)- carboxamido]-β-D-arabinofuranosyl]-5-ethyl uracil; 1 -[2,5-dideoxy-2-fluoro-5-[[(4-(trifl uoromethyl)-9 ( RS)- xanthenyl]-carboxamido]-β-D-arabinofuranosyl]-5-ethyluracil ;
1 -[2,5-dideoxy-2-fluoro-5-[(4-methoxy-9(RS)-xanthenyl)- carboxamido]-β-D-arabinofuranosyl]-5-ethyluracil;
5,-[(12H-benzo[a]xanthen-12(RS)-yl)-carboxamido]-2'I5'- dideoxy-5-ethyluridine;
1 -[5-[(benzo[c]xanthen-7(RS)-yl)-carboxamido]-2,5- dideoxy-2-fluoro-β-D-arabinofuranosyl]-5-ethyluracil ;
2' ,5'-dideoxy-5'-[(9, 1 0-dihydro-9-anthracenyl)-carbox- amido]-5-ethy I u ridine; 2' ,5'-dideoxy-5-ethyl-5'-[(9-thioxanthenyl)-carboxamido]- uridine;
1 -[2,5-dideoxy-2-fluoro-5-[(9-thioxanthenyl)- carboxamido]-β-D-arabinofuranosyl]-5-ethyluracil;
5'-[(2-chloro-9(RS)-thioxanthenyl)-carboxamido]-2',5'- dideoxy-5-ethyluridine;
1 -[5-[(4-chloro-9(RS)-thioxanthenyl)-carboxamido]-2,5- dideoxy-2-fluoro-β-D-arabinofuranosyl]-5-ethy I uracil ;
1 -[2,5-dideoxy-2-fluoro-5-f(4-fluoro-9(RS)-thioxan- thenyl)-carboxamido]-β-D-arabinofuranosyl]-5-ethyluracil; 1 -[2, 5-dideoxy-2-fluoro-5-[(4, 5-difl uoro-9-thioxan- theny I )-carboxamido]-β-D-arabinofuranosyl]-5-ethyl uracil;
1 -[2, 5-dideoxy-2-fl uoro-5-[(4,5-difl uoro-9-thioxanth- enyl)-carboxamido]-β-D-arabinofuranosyl]-5-ethy luracil S-oxide;
2' ,5'-dideoxy-5-ethyl-5'-[(9-thioxanthenyl)-carboxamido]- uridine S-oxide;
1 -[5-[(4-chloro-9(RS)-thioxanthenyl)-carboxamido]-2,5- dideoxy-2-fluoro-β-D-arabinofuranosyl]-5-ethyluracil S,S- dioxide;
2\5'-dideoxy-5-ethyl-5,-[(1 0-methyl-9-acridanyl)- carboxamido]-uridine;
5-ethyl-1 -[3(S)-hydroxy-4(R)-[(9-xanthenyl)-carboxamido- methyl]-1 (R)-cyclopentyl]uracil;
1 -[3(R)-[(2,7-dichloro-9-xanthenyl)-carboxamidomethyl]- 4(S)-hydroxy-1 (R)-cyclopentyl]-5-ethyluracil ;
5-ethyl-1 -[3(S)-hydroxy-4(R)-[(9-thioxanthenyl)- carboxamidomethyl]-1 (R)-cyclopentyl]-uracil;
5-ethyl-1 -[3(S)-hydroxy-4(R)-[(9-thioxanthenyl)- carboxamidomethyl]-1 (R)-cyclopentyl]-uracil S,S-dioxide;
2\5'-dideoxy-5-ethyl-5'-[(9-xanthenyl)-thiocarboxamido]- uridine;
1 -[2 , 5-dideoxy-2-fluoro-5-[(9-xanthenyl)-thiocarbox- amido]-β-D-arabinofuranosyl]-5-ethyluracil; 1 -[2,5-dideoxy-2-fluoro-5-[(9-xanthenyl)-methylami no]-β-
D-arabinofuranosyl]-5-ethyluracil ;
1 -[2,5-dideoxy-2-fluoro-5-[N-methyl-N-(9-xanthenyl- carbonyl)-amino]-β-D-arabinofuranosyl]-5-ethy I uracil ;
1 -[2,5-dideoxy-2-fluoro-5-[N-(4-phenyl-9(RS)-xanthenyl- carbonyl)-N -methy lamino]-β-D-arabinofuranosyl]-5-ethyl uracil ;
1 -[2,5-dideoxy-2-fluoro-5-[N-methyl-N-[(4,5-dimethyl-9- xanthenyl)-carbonyl]amino]-β-D-arabinofuranosyl]-5-ethyluracil;
1 -[2, 5-dideoxy-2-fl uoro-5-[N-methyl-N-(9-thioxanthenyl- carbonyl)-amino]-β-D-arabinofuranosyl]-5-ethylu racil ; 1 -[2 , 5-dideoxy-2-fluoro-5-[N-methyl-N-(9-thioxanthenyl- carbonyl)-amino]-β-D-arabinofuranosyl]-5-ethyluracil S,S- dioxide;
1 -[2,5-dideoxy-3-0-ethyl-2-fluoro-5-[(9-thioxanthenyl)- carboxami do] -β-D-arabinofuranosyl]-5-ethyl uracil; 1 -[2, 5-d ideoxy-3-0-ethyl-2-fl uoro-5-[(9-thioxanthenyl)- carboxam id o]-β-D-arabinofuranosyl]-5-ethyl uracil S,S-dioxide;
1 -[3-0- (cyclohexy lmethy l)-2,5-dideoxy-2-f I uoro-5-[(9- thioxanthenyl)-carboxamido]-β-D-arabinofuranosyl]-5- ethyluracil ; 1 -[3-0- (cyclohexy I methy l)-2, 5-dideoxy-2-f luoro-5-[(9- thioxanthenyl)-carboxamido]-β-D-arabinofuranosyl]-5-ethyluracil S,S-dioxide;
1 -[3-0-allyl-2, 5-dideoxy-2-fl uoro-5-[(9-thioxanthenyl)- carboxamido]-β-D-arabinofuranosyl]-5-ethyluracil; 1 -[3-0-allyl-2,5-dideoxy-2-fl uoro-5-[(9-thioxanthenyl)- carboxamido]-β-D-arabinofuranosyl]-5-ethyluracil S,S-dioxide;
1 -[2,5-dideoxy-2-fluoro-3-0-propargyl-5-[(9- thioxanthenyl)-carboxamido]-β-D-arabinofuranosyl]-5-ethyluracil; 1 -[2,5-dideoxy-2-fluoro-3-0-propargyl-5-[(9-thioxan- thenyl)-carboxami do]- β-D-arabinofuranosy l]-5-ethyl uracil S,S- dioxide;
3'-0-benzyl-2' ,5'-dideoxy-5-ethyl-5'-[(9-xanthenyl)- carboxamido]-uridine;
1 -(2,5-dideoxy-2-fl uoro-3-0-(4-fluorobenzyl)-5-[(9- xanthenyl)-carboxamido]-β-D-arabinofuranosyl)-5-ethyluracil;
2' ,5'-dideoxy-5-ethyl-3'-0-palm itoyl-5'-[(9-xanthenyl)- carboxamido]-uridine; 2' ,5'-dideoxy-5-ethyl-3'-0-(3,4,5-trimethoxybenzoyl)-5'-
[(9-xanthenyl)-carboxamido]-uridine;
2' ,5'-dideoxy-5-ethyl-3'-0-(L-methionyl)-5,-[(9- xanthenyl)-carboxamido]-uridine;
2' ,5'-dideoxy-5-ethyl-3'-0-(L-lysyl)-5'-[(9-xanthenyl)- carboxamido]uridine;
5'-deoxy-5'-[(9-xanthenyl)-carboxamido]-thymidine;
5-cyclopropyl-2' ,5'-dideoxy-5'-[(9-xanthenyl)-carbox- amido]-uridine;
2', 5'-dideoxy-5- (pentaf luoroethyl)-5'-[(9-xanthenyl)- carboxamido]-uridine;
1 -[2,5-dideoxy-2-fluoro-5-[(9-th ioxanthenyl)- carboxamido]-β-D-arabinofuranosyl]-5-iodouracil;
1 -[2 ,5-dideoxy-2-fluoro-5-[(9-thioxanthenyl)- carboxamido]-β-D-arabinofuranosyl]-5-iodouracil S,S-dioxide; 1 -[2,5-dideoxy-2-fluoro-5-[(9-xanthenyl)-carboxamido]-β-
L-arabinofu ran osy l]-5-ethy I uracil ;
1 -[5-[(2,7-dichloro-9-xanthenyl)-carboxamido]-2,5- dideoxy-2-fluoro-β-L-arabinofuranosyl]-5-ethylu racil ;
1 -[2,5-dideoxy-2-fluoro-5-[(9-thioxanthenyl- carboxamido]-β-L-arabinofuranosyl]-5-ethyluracil; and
1 -[2,5-dideoxy-2-fluoro-5-[(9-thioxanthenyl)- carboxamido]-β-L-arabinofuranosyl]-5-ethy luracil S,S-dioxide.
Further interesting compounds of formula I are:
5'-[(2-Chloro-9(RS)-xanthenyl)-carboxamido]-2',5'- dideoxy-5-ethyl uridine,
1 -[5-[N-[(4-methoxy-9(RS)-xanthenyl)-carbonyl]-N- methylamino]-2,5-dideoxy-2-fluoro-β-D-arabinofuranosyl]-5- ethyluracil,
1-[5-[(4,5-dichloro-9-xanthenyl)-carboxamido]-2,5- dideoxy-2-fluoro-β-D-arabinofuranosyl]-5-ethyluracil, 1 -[2, 5-dideoxy-2-fluoro-5-[(9,10-di hydro-9, 9-di methyl -9- silaanthracen-10-yl)-carboxamido]-β-D-arabinofuranosyl]-5- ethyluracil,
1 -(2, 5-dideoxy-2-f I uoro-5-[(9,1 O-di hydro- 10,10-di methy I- 9-anth race ny I )-carboxam ido] -β-D-arabinofuranosy I] -5- ethyluracil,
1 -[5-[[10,10-bis (trif luo romethyl)-9,10-di hydro-9-anth ra¬ ce ny I] -carboxamido]-2,5-dideoxy- β-D-arabinofuranosy I] -5-ethy I- uracil,
1-[5-[[10,10-bis (trif I uoromethyl)-9,10-dihydro-9-anthra- cenyl]-carboxamido]-2,5-dideoxy-2-fluoro-β-D- arabinofuranosyl]-5-ethyl uracil and
1-(2,5-dideoxy-2-fluoro-5-[[spiro[anthracene-9(10H),1'- cyclopropan]-10-yl]-carboxamido]-β-D-arabinofuranosyl]-5- ethyluracil.
According to the process provided by the present invention, the compounds of formula I hereinbefore and pharmaceutically acceptable acid addition salts of those compounds of formula I which are basic are manufactured by:
a) for the manufacture of a compound of formula I in which R10 represents hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl-lower alkyl or lower cycloalkyl-lower alkyl, W represents C(O) and Z represents C(R13)(R14)_ o, S, Si(Rl5)(Rl6) or N(R17), reacting an amine of the general formula
OD
Figure imgf000011_0001
wherein R9' R 1 , X and Y have the significance given earlier and R1 0a represents hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl-lower alkyl or lower cycloalkyl-lower alkyl , with an acid of the general formula
Figure imgf000012_0001
wherein R1 to R8 have the significance given earlier and Z1 represents C(R13)(R14), O, S, Si(Rl 5)(Rl 6) 0r N(R17) , or a reactive derivative thereof, or
b) for the manufacture of a compound of formula I in which R1 0 represents hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl-lower alkyl or lower cycloalkyl-lower alkyl, W represents C(S) and Z represents C(R13)(R14), O, S, Si(Ri 5)(Ri 6) or N(R17), reacting an amine of formula (II) hereinbefore with a carbodithioate of the general formula
(IV)
Figure imgf000012_0002
wherein R1 to R8 and Z1 have the significance given earlier and R1 8 represents lower alkyl, o r
c) for the manufacture of a compound of formula I in which R1 0 represents hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl-lower alkyl or lower cycloalkyl-lower alkyl, W represents CH2 and Z represents C(R1 3)(R1 4), O, S, S-(R15)(R16) or N(R17), reductively alkylating an amine of formula (II) hereinbefore with an aldehyde of the general formula
Figure imgf000013_0001
wherein R1 to R8 and Z1 have the significance given earlier, o r
d) for the manufacture of a compound of formula I in which Z represents SO or S02, appropriately oxidizing a compound of formula I in which Z represents S, or
e) for the manufacture of a compound of formula I in which R1 ° represents acyl, acylating a compound of formula I in which R1 0 represents hydrogen, or
f ) for the manufacture of a compound of formula I in which R1 0 represents -C(0)-CH(R12)-NH2, reacting a compound of formula I in which R1 0 represents hydrogen with a protected amino acid of the general formula
HOOC-C(R12a)-NHRl9 (V I) wherein R1 a has any of the values accorded to R 2 hereinbefore but any amino group present is protected, and R1 9 represents an amino protecting group, and cleaving off the protecting group(s) present in the reaction product, and
g) if desired, converting a basic compound of formula I obtained into a pharmaceutically acceptable acid addition salt.
Embodiment a) of the process in accordance with the invention can be carried out according to known methods. Thus, for example, an amine of formula II can be reacted with an acid of formula III in the presence of a condensation agent, e.g. 1 ,3- dicyclohexylcarbodiimide and 1 -hydroxybenzotriazole, ethyl dimethylaminopropyl carbodiimide or the like, in an inert organic solvent, e.g. an acid amide, e.g. dimethylformamide, a halogenated hydrocarbon, e.g. dichloromethane, a nitrile, e.g. acetonitrile, or an ether, e.g. tetrahydrofuran, at about 0 deg.C to room temp- erature. Alternatively, the acid of formula I can be used in the form of a reactive derivative such as an ester, acid anhydride, mixed anhydride or especially acid halide, especially acid chloride. The reaction of such a reactive acid derivative with an amine of formula II can be conveniently carried out in an inert organic solvent, for example an ether such as diethyl ether, tetrahydrofuran or dioxan, an optionally chlorinated hydrocarbon such as dichloromethane, chloroform, benzene, chlorobenzene or toluene, or the like, and in the presence of an acid-binding agent at about 0°C to room temperature. The acid-binding agent may be an inorganic base, especially an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide, or an organic base, especially a tertiary amine such as triethylamine or pyridine.
The reaction of an amine of formula II with a carbodithioate of formula IV, especially one in which R1 8 represents methyl, in accordance with embodiment b) of the process can also be carried out according to generally known methods. Thus, for example, the reaction can be conveniently carried out in an inert organic solvent, for example a cyclic ether such as dioxan, tetrahydro¬ furan or the like, and in the presence of a base, especially an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide, at about 0°C to room temperature.
Known procedures may be used for the reductive alkylation of an amine of formula II with an aldehyde of formula V in accordance with embodiment c) of the process. For example, the reaction may be suitably carried out in an inert organic solvent, expediently an alkanol such as methanol, in the presence of an alkali metal cyanoborohydride, especially sodium cyanoboro¬ hydride, and under acidic conditions, achieved, for example, by the addition of hydrochloric acid, at about room temperature.
The oxidation of a compound of formula I in which Z represents S in accordance with embodiment d) of the process can be carried out in a known manner, with the nature of the product obtained (Z = SO or SO2) depending on the type and amount of oxidizing agent used.
For example, the oxidation can be carried out using an organic peracid such as peracetic acid, perbenzoic acid, m- chloroperbenzoic acid, perphthalic acid or the like in an inert organic solvent, especially a halogenated hydrocarbon such as dichloromethane or chloroform, which may be used in conjunction with a lower alkanol such as methanol, at about 0°C to room temperature. Use of equivalent amounts of compound of formula I (Z = S) and peracid gives a compound of formula I in which Z represents SO, while use of two equivalents or more of peracid gives a compound of formula I in which Z represents SO2.
Alternatively, the oxidation can be performed using hydrogen peroxide in the presence of an alkali metal tungstate, preferably sodium tungstate, in an inert aqueous solvent, preferably an aqueous alkanol, especially aqueous methanol, containing a small amount of an acid, preferably an alkanoic acid, especially acetic acid, at an elevated temperature, preferably 60-90°C, especially about 80°C. This procedure normally yields a mixture of compounds of formula I in which Z represents SO and SO2, with the latter predominating. The mixture may be separated into the individual components in a conventional manner, for example by chromatography.
Further, the oxidation can be carried out using an alkali metal persulphate, e.g. potassium peroxymonosulphate (Caro's acid), preferably Oxone® (potassium peroxymonosulphate complex with potassium hydrogen sulphate and potassium sulphate), in an inert aqueous solvent, preferably an aqueous alkanol, especially aqueous methanol, at about room temperature. This procedure usually yields a compound of formula I in which Z represents SO2.
The acylation in accordance with embodiment e) of the process can also be carried out according to methods known per se, for example using an appropriate reactive acid derivative such as a halide, especially the chloride, anhydride or activated ester. Suitably, the acylation is carried out in a tertiary organic base such as pyridine, 4-dimethylaminopyridine or the like at about 0°C to room temperature.
The reaction of a compound of formula I in which R1 0 represents hydrogen with a protected amino acid of formula VI in accordance with embodiment f) of the process can be carried out in a manner known per se using reagents, solvents and protecting groups which will be well known to a person skilled in the art. In a preferred embodiment, the protected amino acid of formula VI carries benzyloxycarbonyl or tert-butoxycarbonyl as the protecting group(s) and the reaction is carried out in an inert organic solvent, preferably an acid amide such as dimethyl¬ formamide, in the presence of a condensation agent, preferably ethyl dimethylaminopropyl carbodiimide, at about 0°C to room temperature. The subsequent cleavage of the protecting group(s) from the reaction product is also carried out in a manner known per se, for example by hydrogenolysis in the case of benzyloxy¬ carbonyl, treatment with hydrogen chloride in the case of tert- butoxycarbonyl, and the like. Basic compounds of formula I can be converted into pharma¬ ceutically acceptable acid addition salts in accordance with embodiment g) of the process by treatment with an appropriate inorganic or organic acid according to procedures which are known per se. Examples of such acids are hydrohalic acids, e.g. hydrochloric acid and hydrobromic acid, sulphuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, citric acid, fumaric acid, malic acid, maleic acid, succinic acid, tartaric acid, methanesulphonic acid, benzene-sulphonic acid, toluenesulphonic o acid, and the like.
The starting materials of formulae ll, III, IV and V herein¬ before, insofar as they are not known compounds, can be prepared in analogy to the known compounds or as described in the 5 following Examples or in analogy thereto.
As will be evident from the foregoing, the compounds of formula I and pharmaceutically acceptable acid addition salts of those compounds which are basic are useful as antiviral agents. 0
The pharmacological activity of the compounds and salts provided by the invention can be demonstrated on the basis of the following test procedure for the inhibition of HSV-1 and HSV-2 thymidine kinase (TK): 5
In this test procedure, the assay mixture contains 50 mmol Tris HCl, pH 8, 5 mmol magnesium chloride, 5 mmol ATP, 0.3 μmol 3H-thymidine (50 Ci/mmol), suitably diluted enzyme preparation and various concentrations of test compounds in a 0 total volume of 100 μl. Assays are incubated at 37°C for 30 minutes and the reaction is terminated by immersion in a boiling water bath for 2 minutes. 85 μl aliquots from each assay are then dried on to DEAE-cellulose paper discs and the unphosphorylated 3H-thymidine is removed by washing in 4 mmol ammonium 5 formate. The radioactivity remaining bound to the discs is then measured by scintillation spectrophotometry. The degree of inhibition at each concentration of test compound is expressed as a percentage of the control reaction (100%) after subtracting a measured blank value which represents the amount of radio¬ activity bound to the disc from a reaction containing heat- inactivated enzymes. The IC50 value, namely the concentration of test compound which inhibits enzyme activity by 50%, is then calculated.
The results obtained in the foregoing test using representative compounds of formula I are given in the following Table:
Table
Activity against Activity against
Compound HSV-1 TK HSV-2 TK
IC50 (nmol) IC50 (nmol)
A 4.2 0.34
B 1 .6 0.1 3
C 2.1 0.17
D 0.76 0.14
E 1 .3 0.23
F 0.78 0.1 1
G 0.36 0.081
H 4.1 0.48
I 1 .9 0.28
J 1 7 1 .6
K 28 5.2
Compound A: 2'.5'-Dideoxy-5-ethyl-5'-[(9-xanthenyl)- carboxamido]-uridine.
Compound B: 1 -[2,5-Dideoxy-2-fluoro-5-[(9-xanthenyl)- carboxamido]-β-D-arabinofuranosyl]-5- ethyluracil.
Compound C: 1 -[5-[(2-Chloro-9(RS)-xanthenyl)-carboxamido]-
2,5-dideoxy-2-fluoro-β-D-arabinofuranosyl]-5- ethyluracil.
Compound D: 1 -[5-[(4-Chloro-9(RS)-xanthenyl)-carboxamido]- 2,5-dideoxy-2-fluoro-β-D-arabinofu ranosyl]-5- ethyluracil.
Compound E: 1 -[2,5-Dideoxy-2-fl uoro-5-[(4, 5-difl uoro-9- xanthenyl)-carboxamido]-β-D-arabinofuranosyl]- 5-ethylu raci l .
Compound F 1 -[2, 5-Dideoxy-2-fluoro-5-[(9-thioxanthenyl)- carboxamido]-β-D-arabinofuranosyl]-5-ethyl- uracil S,S-dioxide.
Compound G: 1 -[2,5-Dideoxy-2-fl uoro-5-[(4-f luoro-9( RS)- thioxanthenyl)-carboxamido]-β-D- arabinofu ran osy l]-5-ethyl uracil S,S-dioxide.
Compound H: 1 -[2, 5-Dideoxy-2-fl uoro-5-[N -[[4- (trifl uoro- methyl)-9-(RS)-xanthenyl]-carbonyl]-N-methyl- amino]-β-D-arabinofuranosyl]-5-ethyl uracil . Compound I: 1 -[5-[N-[(4,5-Dichloro-9-xanthenyl)-carbonyl]- N -methy lamino]-2,5-dideoxy-2-f luo ro-β-D - a rabin of u ran osy I] -5-ethy I uracil .
Compound J: 1 -[2 , 5-Dideoxy-2-f I uoro-5-[N -[4-(trif luo ro¬ methyl) -9-(RS)-xantheny I] -carbonyl]- N-methyl - amino]-3-0-(L-valyl)-β-D-arabinofuranosyl]-5- ethyluracil .
Compound K: 2'5'-Dideoxy-5-ethyl-5'-(9-fl uorenylcarbox- amido)-uridine (known from EP-A-0 257 378).
The compounds of formula I and pharmaceutically acceptable acid addition salts of those compounds which are basic can be used as medicaments, e.g. in the form of pharma¬ ceutical preparations. The pharmaceutical preparations can be administered orally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions. The administration can, however, also be effected rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions.
The compounds of formula I and their aforementioned salts can be processed with pharmaceutically inert, organic or inorganic carriers for the production of pharmaceutical preparations. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts and the like can be used, for example, as such carriers for tablets, coated tablets, dragees and hard gelatine capsules. Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like; depending on the nature of the active ingredient no carriers are, however, usually required in the case of soft gelatine capsules. Suitable carriers for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose and the like. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.
The pharmaceutical preparations can also contain preserv¬ atives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
Medicaments containing a compound of formula I or a pharmaceutically acceptable acid addition salt of a basic compound of formula I and a compatible pharmaceutical carrier are also an object of the present invention, as is a process for the production of such medicaments which comprises bringing one or more of said compounds or salts and, if desired, one or more other therapeutically valuable substances into a galenical adminis¬ tration form together with a compatible pharmaceutical carrier.
As mentioned earlier, the compounds of formula I and pharmaceutically acceptable acid addition salts of those compounds which are basic can be used in accordance with the invention as therapeutically active substances, especially as antiviral agents. The dosage can vary within wide limits and will, of course, be fitted to the individual requirements in each particular case. In general, in the case of administration to adults a daily dosage of about 1 mg to 1000 mg, preferably about 5 mg to 500 mg, should be appropriate. The daily dosage may be administered as a single dose or in divided doses. Finally, the use of compounds of formula I and pharma¬ ceutically acceptable acid addition salts of those compounds which are basic for the production of medicaments, especially of antiviral medicaments, is also an object of the invention.
The following Examples illustrate the present invention in more detail, but are not intended to limit its scope in any manner.
Example 1 o
A solution of 0.226 g of xanthene-9-carboxylic acid in 10 ml of dimethylformamide was stirred and cooled to 0°C . 0.135 g of 1 -hydroxybenzotriazole and 0.206 g of 1 ,3-dicyclo- hexylcarbodiimide were added and the mixture was stirred at 0°C 5 for 10 minutes. 0.255 g of 5'-amino-2',5'-dideoxy-5-ethyluridine was added and the mixture was left to warm to room temperature and stirred for 20 hours. The mixture was filtered and the filtrate was evaporated. The residue was suspended in ethyl acetate and the suspension was filtered to give 0.380 g of crude 0 product as a cream coloured solid. This solid was crystallized from 15 ml of hot 2-methoxyethanol to give 0.224 g of 2', 5'- dideoxy-5-ethyl-5'-[(9-xanthenyl)-carboxamido]-uridine as a white solid of melting point 271 -273°C .
5 Example 2
Reaction of xanthene-9-carboxylic acid with 1 -(5-amino- 2,5-dideoxy-2-fluoro-β-D-arabinofuranosyl)-5-ethyluracil in a manner analogous to that described in Example 1 gave 1 -[2,5- 0 dideoxy-2-fluoro-5-[(9-xanthenyl)-carboxamido]-β-D-arabino- furanosyl]-5-ethyluracil as a white solid of melting point 263- 265°C.
Example 3 5
Reaction of xanthene-9-carboxylic acid with 1 -(5-amino-5- deoxy-β-D-arabinofuranosyl)-5-ethyluracil in a manner analogous to that described in Example 1 gave 1 -[5-deoxy-5-[(9-xanthenyl)- carboxamido]-β-D-arabinofuranosyl]-5-ethyluracil as a white solid of melting point 265-275°C .
The 1 -(5-amino-5-deoxy-β-D-arabinofuranosyl)-5- ethyluracil used as the starting material was prepared as foll ows :
(A) A mixture of 2.72 g of 1 -(β-D-arabinofuranosyl)-5- ethyluracil, 3.75 g of triphenylphosphine and 1 .47 g of lithium o azide in 50 ml of anhydrous dimethylformamide was stirred under nitrogen and 4.975 g of carbon tetrabromide were added. The mixture was stirred at room temperature ovemight and the solvent was then evaporated. The residue was taken up in dichloromethane/methanol (9:1 , v/v) and applied to a silica gel 5 column which was eluted with the same solvent mixture.
Appropriate fractions were combined and evaporated and the residue was crystallized from hot ethanol to give 0.809 g of 1 - (5-azido-5-deoxy-β-D-arabinofuranosyl)-5-ethyluracil as a white solid of melting point 215-225°C (dec.) which was used 0 directly in the next step.
(B) A solution of 1.546 g of 1 -(5-azido-5-deoxy-β-D-arabino- furanosyl)-5-ethyluracil in 750 ml of ethanol was hydrogenated over 0.50 g of 10% palladium on carbon catalyst for 5.5 hours. 5 The mixture was filtered and the filtrate was evaporated to give 1 .235 g of 1 -(5-amino-5-deoxy-β-D-arabinofuranosyl)-5- ethyluracil as a pale grey gum.
Example 4 0
220 mg of 4-methylxanthene-9(RS)-carboxylic acid were suspended in a mixture of 10 ml of toluene and one drop of dimethylformamide. 1.0 ml of oxalyl chloride was added and the mixture was stirred for 30 minutes. The solvents were 5 evaporated, the residue was dissolved in 10 ml of diethyl ether and the resulting solution was added to a solution of 250 mg of 1 (5-amino-2,5-dideoxy-2-fluoro-β-D-arabinofuranosyl)-5- ethyluracil in a mixture of 0.92 ml of 1 M sodium hydroxide solution and 10 ml of water. The mixture was shaken vigorously for 10 minutes and then filtered. The solid was washed with water and diethyl ether and was then crystallized from hot methanol to give 120 mg of 1 -[2,5-dideoxy-2-fluoro-5-[(4- methyl-9(RS)-xanthenyl)-carboxamido]-β-D-arabinofuranosyl]-5- ethyluracil as a white solid of melting point 251 -253°C .
Example 5
Conversion of 4-cyclohexylxanthene-9(RS)-carboxylic acid into the corresponding acid chloride followed by reaction with 1 - (5-amino-2, 5-dideoxy-2-fluoro-β-D-arabinofu ranosyl)-5-ethyl- uracil in a manner analogous to that described in Example 4 gave 1 -[2,5-dideoxy-2-fl uoro-5-[(4-cyclohexyl-9(RS)-xanthenyl)- carboxamido]-β-D-arabinofuranosyl]-5-ethyluracil as a white solid of melting point 202-203°C .
The 4-cyclohexylxanthene-9(RS)-carboxylic acid used as starting material was prepared as follows:
(A) 0.40 g of a 60% dispersion of sodium hydride in mineral oil was added to a solution of 2.16 g of 2-(2-propenyl)-6-cyclo- hexylphenol in 100 ml of toluene. After the evolution of hydrogen had ceased 2.96 g of 3,6-dichloropyrazine were added and the mixture was heated under reflux for 2 hours. After cooling to room temperature the mixture was washed with water and the separated organic phase was evaporated to give 2.65 g of 3- chloro-6-[2-(2-propenyl)-6-cyclohexylphenoxy]-pyrazine as a white solid.
(B) 2.2 g of 3-chloro-6-[2-(2-propenyl)-6-cyclohexylphenoxy]- pyrazine were dissolved in 10 ml of N,N-diethylaniline and the mixture was heated to 250°C for 2 hours. After cooling to room temperature the mixture was poured into 30 ml of 2M hydro- chloric acid and then extraction was carried out with 30 ml of ethyl acetate. The organic solution was washed with water and evaporated. The residue was chromatographed on a silica gel column using dichloromethane for the elution to give 1.43 g of 4- cyclohexylxanthene as a pale yellow oil which crystallized on standing.
(C) A solution of 1.32 g of 4-cyclohexylxanthene in 20 ml of tetrahydrofuran was added dropwise to a mixture of 2.8 ml of 2M lithium diisopropylamide in hexane and 5 ml of tetrahydrofuran at -70°C. The mixture was stirred and dry carbon dioxide was bubbled through for 1 hour at -70°C. The mixture was left to warm to room temperature and 5 ml of water were added cautiously. The resulting mixture was diluted with a further 30 ml of water and extracted with 30 ml of ethyl acetate. The organic solution was evaporated and the residue was chromato¬ graphed on a silica gel column using methanol/dichloromethane (5:95, v/v) to give 0.85 g of 4-cyclohexyixanthene-9(RS)- carboxylic acid as a white solid.
Example 6
Conversion of 4-phenylxanthene-9(RS)-carboxylic acid into the corresponding acid chloride followed by reaction with 1 -(5- amino-2,5-d ideoxy-2-f I uoro- β-D-arabinofu ranosy I) -5-ethy lu racil in a manner analogous to that described in Example 4 gave 1 -[2,5- dideoxy-2-fluoro-5-[(4-phenyl-9(RS)-xanthenyl)-carboxamido]- β-D-arabinofuranosyl]-5-ethyluracil as a white foam, mass spectrum (FAB) m/e 558 [M + H]+.
The 4-phenylxanthene-9(RS)-carboxylic acid used as the starting material was prepared by carboxylating 4- phenylxanthene in a manner analogous to that described in Example 5 (C).
Example 7
Reaction of 1 -chloroxanthene-9(RS)-carboxylic acid with 5'-amino-2',5'-dideoxy-5-ethyluridine in a manner analogous to that described in Example 1 gave 5'-[(1 -chloro-9(RS)-xanthenyl)- carboxamido]-2',5'-dideoxy-5-ethyluridine as a cream coloured solid of melting point 237-241 °C . The 1 -chloroxanthene-9(RS)-carboxylic acid used as the starting material was prepared as follows:
(A) A solution of 0.390 g of 1 -chloroxanthone in 5 ml of tetrahydrofuran was cooled to -5°C and 3.5 ml of a 1 M solution of borane in tetrahydrofuran was added. The cooling bath was removed and the mixture was stirred for 1 hour. The mixture was then cooled to -5°C and a further 3.5 ml of 1 M solution of borane in tetrahydrofuran was added. The mixture was left to warm to room temperature and was stirred overnight. It was then cooled to -5°C and a further 3.5 ml of 1 M solution of borane in tetra¬ hydrofuran was added. The mixture was left to warm to room temperature over a period of 3 hours and was then stirred at 28°C overnight. The mixture was then cooled to 0°C and the excess reagent was destroyed by the careful addition of acetone. The solvents were evaporated and the residue was partitioned between 50 ml of diethyl ether and 25 ml of water. The organic solution was washed with 25 ml of water, dried and evaporated. The crude product was taken up in 10 ml of hot diethyl ether and filtered to remove a small amount of insoluble material. The filtrate was diluted with 50 ml of diethyl ether and the solution was washed with two 25 ml portions of water and dried. The solvent was evaporated to give 0.329 g of 1 -chloroxanthene as a white solid of melting point 88-90°C .
(B) Carboxylation of 1 -chloroxanthene in a manner analogous to that described in Example 5 (C) gave 1 -chloroxanthene-9(RS)- carboxylic acid as a solid of melting point 170-195°C .
Example 8
Reaction of 2-chloroxanthene-9(RS)-carboxylic acid with 1 (5-amino-2,5-dideoxy-2-fluoro-β-D-arabinofuranosyl)-5-ethyl- uracil in a manner analogous to that described in Example 1 gave 1 -[5-[(2-chloro-9(RS)-xanthenyl)carboxamido]-2,5-dideoxy-2- fluoro-β-D-arabinofuranosyl]-5-ethyluracil as a cream coloured solid of melting point 185-197°C (dec). The 2-chloroxanthene-9(RS)-carboxylic acid used as starting material was prepared by carboxylating 2-chloro- xanthene in a manner analogous to that described in Example 5 (C).
Example 9
Reaction of 2-chloroxanthene-9(RS)-carboxylic acid with 5'-amino-2',5'-dideoxy-5-ethyluridine in a manner analogous to that described in Example 1 gave 5'-[(2-chloro-9(RS)-xanthenyl)- carboxamido]-2',5'-dideoxy-5-ethyluridine as a cream solid of melting point 225-230° (dec).
The mixture of diastereomers obtained was subjected to preparative high pressure liquid chromatography (hplc) to give the pure diastereomers. The faster running diastereomer was obtained as a white solid of melting point 225-230°C and the slower running diastereomer was obtained as a white hygroscopic solid; mass spectrum (FAB) m/e 498 [M + H]+.
Example 10
Reaction of 3-chloroxanthene-9(RS)-carboxylic acid with 5'-amino-2',5'-dideoxy-5-ethyluridine in a manner analogous to that described in Example 1 gave 5'-[(3-chloro-9(RS)-xanthenyl)- carboxamido]-2',5'-dideoxy-5-ethyluridine as a white solid of melting point 220-230°C (dec).
The 3-chloroxanthene-9(RS)-carboxylic acid used as the starting material was prepared in a manner analogous to that described in Example 7 (A) and (B) by reducing 3-chloroxanthone to give 3-chloroxanthene as a cream coloured solid of melting point 109-1 1 1 °C followed by carboxylation to give 3-chloro- xanthene-9(RS)-carboxylic as a solid; mass spectrum (El) m/e 260, 262 [M]+. Example 11
Reaction of 4-chloroxanthene-9(RS)-carboxylic acid with 1 - (5-amino-2,5-dideoxy-2-fluoro-β-D-arabinof u ranosyl) -5-ethyl- uracil in a manner analogous to that described in Example 1 gave
1 -[5-[(4-chloro-9(RS)-xanthenyl)-carboxamido]-2,5-dideoxy-2- fluoro-β-D-arabinofuranosyl]-5-ethyluracil as a white solid of melting point 235-237°C (dec).
The 4-chloroxanthene-9(RS)-carboxylic acid used as the starting material was prepared by carboxylating 4- chloroxanthene in a manner analogous to that described in Example 5 (C).
Example 12
Reaction of 2,7-dichloroxanthene-9-carboxylic acid with 1 - (5-amino-2,5-dideoxy-2-fluoro-β-D-arabinofu ranosyl)-5-ethyl- uracil in a manner analogous to that described in Example 1 gave 1 -[5-[(2,7-dichloro-9-xanthenyl)-carboxamido]-2,5-dideoxy-2- fluoro-β-D-arabinofuranosyl]-5-ethyluracil as a lemon solid of melting point 244-251 °C (dec).
The 2,7-dichloroxanthene-9-carboxylic acid used as the starting material was obtained as a solid of melting point 240- 255°C (dec.) by carboxylating 2,7-dichloroxanthene in a manner analogous to that described in Example 5 (C).
Example 13
Reaction of 2,3-dichloroxanthene-9(RS)-carboxylic acid with 1 -(5-amino-2,5-dideoxy-2-fluoro-β-D-arabinof u ranosyl)-5- ethyluracil in a manner analogous to that described in Example 1 gave 1 -[5-[(2,3-dichloro-9(RS)-xanthenyl)-carboxamido]-2,5- dideoxy-2-fluoro-β-D-arabinofuranosyl]-5-ethyluracil as a lemon coloured solid of melting point 190-200°C (dec). The 2,3-dichloroxanthene-9(RS)-carboxylic acid used as the starting material was prepared by carboxylating 2,3-dichloro- xanthene in a manner analogous to that described in Example 5 (C).
Example 14
Reaction of 2,4,5,7-tetrachloroxanthene-9-carboxylic acid with 1 -(5-amino-2,5-dideoxy-2-fluoro-β-D-arabi nof u ranosyI)-5- ethyluracil in a manner analogous to that described in Example 1 gave 1 -[5-[(2,4,5,7-tetrachloro-9-xanthenyl)-carboxamido]-2,5- dideoxy-2-fluoro-β-D-arabinofuranosyl]-5-ethyluracil as a fawn solid of melting point 241 -249°C (dec).
The 2,4,5,7-tetrachloroxanthene-9-carboxylic acid used as the starting material was prepared as follows:
(A) 2.038 g of sodium were added in portions to a stirred solution of 10.0 g of 2,3,5-trichlorobenzoic acid and 7.23 g of 2,4-dichlorophenol in 50 ml of methanol. 50 mg of copper powder were added and the methanol was removed by evaporation. The residue was heated to 220°C for 10 minutes and then left to cool to room temperature. The resulting solid mass was broken up and 60 ml of concentrated sulphuric acid were added dropwise. The mixture was heated to 100°C for 15 minutes and subsequently left to cool and poured on to 500 g of ice. The mixture was stirred at 0°C for 30 minutes and the crude product was collected by filtration, washed with water and then suspended in 50 ml of acetone and stirred at 25°C for 1 hour. The product was collected by filtration to give 0.669 g of 2,4,5.7-tetrachloroxanthone as a grey solid of melting point 205-210°C (dec.)
(B) 2,4,5,7-Tetrachloroxanthone was reduced in a manner analogous to that described in Example 7 (A) to give 2,4,5,7- tetrachloroxanthene as a solid of melting point 208-213°C. This was then carboxylated in a manner analogous to that described in Example 5 (C) to give 2,4,5, 7-tetrachloroxanthene-9-carboxylic acid as a solid of melting point 235-240°C . Example 15
Reaction of 2,7-difluoroxanthene-9-carboxylic acid with 1 - (5-amino-2, 5-dideoxy-2-fluoro-β-D-arabinofu ranosyl)-5-ethyl- uracil in a manner analogous to that described in Example 1 gave 1 -[2,5-dideoxy-2-fluoro-5-[(2,7-difluoro-9-xanthenyl) -carbox- amido]-β-D-arabinofuranosyl]-5-ethyluracil as a lemon coloured solid of melting point 210-215°C .
The 2,7-difluoroxanthene-9-carboxylic acid used as the starting material was prepared in a manner analogous to that described in Example 7 (A) and (B) by reducing 2,7-difluoro- xanthone to 2,7-difluoroxanthene followed by carboxylation to give 2,7-difluoroxanthene-9-carboxylic acid as a lemon coloured solid; mass spectrum (El) m/e 260,262 [M]+.
Example 16
Reaction of 4,5-difluoroxanthene-9-carboxylic acid with 1 - (5-ami no-2, 5-dideoxy-2-fluoro-β-D-arabinofu ranosyl)-5-ethyl- uracil in a manner analogous to that described in Example 1 gave 1 -[2 ,5-dideoxy-2-fluoro-5-[(4,5-difl uoro-9-xanthenyl)-carbox- amido]-β-D-arabinofuranosyl]-5-ethyluracil as a white solid of melting point above 220°C.
The 4,5-difluoroxanthene-9-carboxylic acid used as the starting material was prepared as follows:
(A) 4.40 g of potassium carbonate and 1.70 g of copper (II) oxide were added to a solution of 3.70 g of methyl 2,3-difluorobenzoate and 2.10 g of 2-fluorophenol in 45 ml of pyridine. The mixture was stirred and refluxed under argon for 36 hours and then cooled to room temperature and poured on to a stirred mixture of 150 ml of ice-water and 60 ml of diethyl ether. The mixture was filtered and the layers were separated. The aqueous solution was extracted with two further 60 ml portions of diethyl ether and the combined extracts were washed in succession with four 50 ml portions of 1 M hydrochloric acid, 50 ml of water, two 50 ml portions of saturated sodium hydrogen carbonate solution, and 50 ml of saturated sodium chloride solution and then dried over anhydrous magnesium sulphate and evaporated. The crude product was purified by distillation to give 2.00 g of methyl 3-fluoro-2- (2-fluorophenoxy)benzoate as a pale yellow syrup which crystallized on standing; mass spectrum (El) m/e 264 [M]+.
(B) A solution of 1 .92 g of 3-fluoro-2-(2-fluorophenoxy)- benzoate and 0.853 g of sodium hydroxide in a mixture of 26 ml of ethanol and 6.6 ml of water was refluxed for 30 minutes. The ethanol was evaporated, the residue was taken up in 100 ml of water and the solution was washed with two 75 ml portions of diethyl ether. The aqueous solution was acidified to pH 1 using concentrated hydrochloric acid and extracted with three 75 ml portions of dichloromethane. The combined extracts were washed with 85 ml of saturated sodium chloride solution, dried over anhydrous sodium sulphate and evaporated to give 1.65 g of 3- fluoro-2-(2-fluorophenoxy)benzoic acid as a pink solid of melting point 1 10-1 12°C .
(C) 3-Fluoro-2-(2-fluorophenoxy)-benzoic acid was treated with concentrated sulphuric acid in a manner analogous to that described in Example 14 (A) to give 4,5-difluoro-9-xanthone which was reduced to 4,5-difluoro-9-xanthene in a manner analogous to that described in Example 7 (A). The latter was carboxylated in a manner analogous to that described in Example 5 (C) to give 4,5-difluoroxanthene-9-carboxylic acid.
Example 17
Reaction of 4-trifluoromethylxanthene-9(RS)-carboxylic acid with 1 -(5-amino-2,5-dideoxy-2-fluoro-β-D-arabinofuran- osyl)-5-ethy!uracil in a manner analogous to that described in Example 1 gave 1 -[2,5-dideoxy-2-fluoro-5-[[(4-(trifluoro- methyl)-9(RS)-xanthenyl]-carboxamido]-β-D-arabinofuranosyl]- 5-ethyluracil as a cream coloured solid of melting point 202- 209°C. The 4-trifluoromethylxanthene-9(RS)-carboxylic acid used as the starting material was obtained as a solid of melting point 1 50-1 52°C by carboxylating 4-trifluoromethylxanthene in a manner analogous to that described in Example 5 (C).
Example 18
Conversion of 4-methoxyxanthene-9'(RS)-carboxylic acid into the corresponding acid chloride followed by reaction with 1 - (5-ami no-2,5-dideoxy-2-fl uoro-β-D-arabi nof u ranosyl)-5-ethyl- uracil in a manner analogous to that described in Example 4 gave 1 -[2,5-dideoxy-2-fluoro-5-[(4-methoxy-9(RS)-xanthenyl)- carboxamido]-β-D-arabinofuranosyl]-5-ethyluracil as a white solid of melting point 225-226°C .
The 4-methoxyxanthene-9(RS)-carboxylic acid used as the starting material was prepared by carboxylating 4-methoxy- xanthene in a manner analogous to that described in Example 5 (C).
Example 19
Conversion of 12H-benzo[a]xanthene-12(RS)-carboxylic acid into the corresponding acid chloride followed by reaction with 5'- amino-2',5'-dideoxy-5-ethyluridine in a manner analogous to that described in Example 4 gave 5'-[(12H-benzo[a]xanthene-12(RS)- yl)-carboxamido]-2',5'-dideoxy-5-ethyluridine as a white solid of melting point 252-255°C .
The 12H-benzo[a]xanthene-12(RS)-carboxylic acid used as the starting material was obtained as a white solid of melting point 225-235°C by carboxylating 12H-benzo[a]xanthene in a manner analogous to that described in Example 5 (C).
Example 20
Conversion of 7H-benzo[c]xanthene-7(RS)-carboxylic acid into the corresponding acid chloride followed by reaction with 1 - (5-amino-2,5-dideoxy-2-fluoro-β-D-arabinofu ranosyl)-5-ethyl- uracil in a manner analogous to that described in Example 4 gave 1 -[5-[(benzo[c]xanthen-7(RS)-yl)-carboxamido]-2,5-dideoxy-2- fluoro-β-D-arabinofuranosyl]-5-ethyluracil as a white solid of melting point 255-259°C .
The 7H-benzo[a]xanthene-7(RS)-carboxylic acid used as starting material was prepared by carboxylating 7H-benzo[c]- xanthene in a manner analogous to that described in Example 5 (C).
Example 21
Reaction of 9,10-dihydro-9-anthracenecarboxylic acid with 5'-amino-2',5'-dideoxy-5-ethyluridine in a manner analogous to that described in Example 1 gave 2',5'-dideoxy-5'-[(9,10-dihydro- 9-anthracenyl)-carboxamido]-5-ethyluridine as a fawn solid of melting point 222-225°C (dec).
Example 22
Reaction of 9-thioxanthenecarboxylic acid with 5'-amino- 2',5'-dideoxy-5-ethyluridine in a manner analogous to that described in Example 1 gave 2',5'-dideoxy-5-ethyl-5'-[(9- thioxanthenyl)-carboxamido]-uridine as a fawn solid of melting point 206-210°C (dec).
Example 23
Reaction of 9-thioxanthenecarboxylic acid with 1 -(5- ami no-2,5-dideoxy-2-f luoro- β-D-arabinofu ranosyl)-5-ethy luraci l in a manner analogous to that described in Example 1 gave 1 -[2,5- dideoxy-2-fluoro-5-[(9-thioxanthenyl)carboxamido]-β-D-arabino- furanosyl]-5-ethyluracil as a white solid of melting point 210- 213°C. Example 24
Reaction of 2-chlorothioxanthene-9(RS)-carboxylic acid with 5'-amino-2',5'-dideoxy-5-ethyluridine in a manner analogous to that described in Example 1 gave 5'-[(2-chloro- 9(RS)-thioxanthenyl)-carboxamido]-2' ,5'-dideoxy-5-ethyluridine as a white solid of melting point 197-202°C .
Example 25
Reaction of 4-chlorothioxanthene-9(RS)-carboxylic acid with 1 -(5-amino-2,5-dideoxy-2-fluoro-β-D-arabi nof u ran osyl)-5- ethyluracil in a manner analogous to that described in Example 1 gave 1 -[5-[(4-chloro-9(RS)-thioxanthenyl)-carboxamido]-2,5- dideoxy-2-fluoro-β-D-arabinofuranosyl]-5-ethyluracil as a pale pink solid of melting point 155-160°C .
The 4-chlorothioxanthene-9(RS)-carboxylic acid used as the starting material was prepared by reducing 4-chlorothioxanthone in a manner analogous to that described in Example 7 (A) to 4- chlorothioxanthene and subsequent carboxylating the latter in a manner analogous to that described in Example 5 (C).
Example 26
Reaction of 4-fluorothioxanthene-9(RS)-carboxylic acid with 1 -(5-amino-2,5-dideoxy-2-fluoro-β-D-arabinofuranosyl)-5- ethyluracil in a manner analogous to that described in Example 1 gave 1 -[2,5-dideoxy-2-fluoro-5-[(4-fluoro-9(RS)-thioxanthenyl)- carboxamido]-β-D-arabinofuranosyl]-5-ethyluracil as a buff solid of melting point 1 12-1 16°C .
The 4-fluorothioxanthene-9(RS)-carboxylic acid used as the starting material was prepared as follows:
(A) 9.64 g of lithium hydroxide were added to a mixture of 12.8 g of 2-fluorothiophenol and 17.22 g of 2-chlorobenzoic acid in 45 ml of tetralin. The mixture was stirred at 190°C for 18 hours in a flask fitted with a condenser and a Dean-Stark trap. The mixture was left to cool and was then poured into 50 ml of water. The aqueous solution was diluted with a further 150 ml of water and then acidified to pH 2 with concentrated hydrochloric acid. The resulting precipitate was collected, washed with water and dried to give 22.0 g of 2-(2-fluorothiophenoxy)-benzoic acid as an off-white solid which was used in the next step without further purification.
(B) A mixture of 1 .0 g of 2-(2-fiuorothiophenoxy)-benzoic acid and 10 ml of concentrated sulphuric acid was heated to 100°C for 15 minutes. The mixture was then cautiously poured on to 100 g of ice and extracted with four 20 ml portions of dichloromethane. The combined organic extracts were washed with four 20 ml portions of saturated aqueous sodium hydrogen carbonate solution and two 30 ml portions of water, dried over anhydrous sodium sulphate and evaporated to give 0.960 g of 4-fluorothioxanthone as an off-white solid.
(C) 4-Fluorothioxanthone was reduced in a manner analogous to that described in Example 7 (A) to give 4-fluorothioxanthene as an off-white solid of melting point 164-166°C. This solid was then carboxylated in a manner analogous to that described in Example 5 (C).
Example 27
Reaction of 4,5-difluorothioxanthene-9-carboxylic acid with 1 -(5-amino-2,5-dideoxy-2-fluoro-β-D-arabinofu ranosyl)-5- ethyluracil in a manner analogous to that described in Example 1 gave 1 -[2,5-dideoxy-2-fluoro-5-[(4,5-difluoro-9-thioxanthenyl)- carboxamido]-β-D-arabinofuranosyl]-5-ethyluracil as a white solid of melting point 105-1 10°C .
The 4,5-difluorothioxanthene-9-carboxylic acid used as the starting material was prepared as follows: Reaction of 2,3-difluorobenzoic acid with 2-fluorothio- phenol in a manner analogous to that described in Example 28 (A) followed by cyclization of the product in concentrated sulphuric acid in a manner analogous to that described in Example 28 (B) gave 4,5-difluoroxanthone. This was reduced in a manner analogous to that described in Example 7 (A) to 4,5-fluorothio- xanthene which was then carboxylated in a manner analogous to that described in Example 5 (C).
o Example 28
0.164 g of 3-chloroperoxybenzoic acid was added to a solution of 0.100 g of 1 -[2,5-dideoxy-2-fluoro-5-[(4,5-difluoro- 9-th ioxantheny I )carboxam ido] -β-D-arabinofuranosy I] -5-ethy I- 5 uracil in 20 ml of dichloromethane and the mixture was stirred ovemight at room temperature. The solution was washed with five 20 ml portions of saturated aqueous sodium hydrogen carbonate solution and three 33 ml portions of water, dried over anhydrous sodium sulphate and evaporated to give 0.100 g of 1 - 0 [2, 5-dideoxy-2-fluoro-5-[(4, 5-difluoro-9-thioxanthenyl)- carboxamido]-β-D-arabinofuranosyl]-5-ethyluracil S-oxide as a mixture of (R) and (S) oxides in the form of a white solid of melting point 155-160°C .
5 Example 29
0.025 ml of a solution of 14 mg of sodium tungstate dihydrate in a mixture of 4 ml of water and one drop of acetic acid was added to a stirred solution of 96 mg of 2',5'-dideoxy-5- 0 ethyl-5'-[(9-thioxanthenyl)-carboxamido]-uridine in 10 ml of ethanol. 0.1 ml of 30% hydrogen peroxide was added and the mixture was stirred at 80°C for 4 hours. A further 0.1 ml of the sodium tungstate solution described above and a further 0.4 ml of 30% hydrogen peroxide were added and the mixture was stirred at 5 80°C for a further 1.5 hours and then left to cool to room temperature ovemight. One drop of 2M ammonium hydroxide solution and three drops of 5% sodium metabisulphite solution were added and the solvents were evaporated. The residue was partitioned between 5 ml of dichloromethane and 5 ml of water. The organic solution was dried and evaporated and the residue was chromatographed on a silica gel column using dichloro¬ methane/methanol (9:1 , v/v) for the elution to give 45 mg of 2\5'-dideoxy-5-ethyl-5'-[(9-thioxanthenyl)-carboxamido]- uridine S,S-dioxide as a fawn solid of melting point 165°C (dec). Further elution of the column gave the diastereomers of 2', 5'- dideoxy-5-ethyl-5'-[(9-th ioxantheny l)-carboxamido]-uridine S- oxide as a fawn solid, mass spectrum (FAB) m/e 496 [M + H]+, and as a fawn gum, mass spectrum (FAB) m/e 496 [M + H]+.
Example 30
A mixture of 0.263 g of 3-chloroperoxybenzoic acid and
0.150 g of 1 -[2,5-dideoxy-2-fluoro-5-[(9-thioxanthenyl)- carboxamido]-β-D-arabinofuranosyl]-5-ethyluracil in a mixture of 70 ml of dichloromethane and ten drops of methanol was stirred at room temperature for 18 hours. The solvents were evaporated and the residue was partitioned between 50 ml of dichloro¬ methane and 75 ml of saturated aqueous sodium hydrogen carbonate solution. The organic solution was washed with a further 75 ml of saturated aqueous sodium hydrogen carbonate solution and two 30 ml portions of saturated sodium chloride solution, dried over anhydrous sodium sulphate and evaporated to give 0.123 g of 1 -[2,5-dideoxy-2-fluoro-5-[(9-thioxanthenyl)- carboxamido]-β-D-arabinofuranosyl]-5-ethyluracil S,S-dioxide as a white solid of melting point 142-145°C .
Example 31
Oxidation of 1 -[5-[(4-chloro-9(RS)-thioxanthenyl)-carbox- amido]-2,5-dideoxy-2-fluoro-β-D-arabinofuranosyl]-5-ethyl- uracil with 3-chloroperoxybenzoic acid in a manner analogous to that described in Example 30 gave 1 -[5-[(4-chloro-9(RS)-thioxan- thenyl)-carboxamido]-2,5-dideoxy-2-fluoro-β-D-arabinofurano- syl]-5-ethyluracil S,S-dioxide as an off-white solid of melting point 95°C. Example 32
Oxidation of 1 -[2,5-dideoxy-2-fluoro-5-[(4-fluoro-9(RS)- thioxanthenyl)carboxamido]-β-D-arabinofuranosyl]-5-ethyluracil with 3-chloroperoxybenzoic acid in a manner analogous to that described in Example 32 gave 1 -[2,5-dideoxy-2-fluoro-5-[(4- fluoro-9(RS)-thioxanthenyl)-carboxamido]-β-D-arabino- furanosyl]-5-ethyluracil S,S-dioxide as a white solid of melting point 142-145°C .
Example 33
Reaction of 10-methylacridane-9-carboxylic acid with 5'- amino-2',5'-dideoxy-5-ethyluridine in a manner analogous to that described in Example 1 gave 2',5'-dideoxy-5-ethyl-5'-[(10- methyl-9-acridanyl)-carboxamido]-uridine as a cream coloured solid of melting point 241 -243°C (dec).
Example 34
Reaction of xanthene-9-carboxylic acid with 1 -[3(R)- (aminomethyl)-4(S)-hydroxy-1 (R)-cyclopentyl]-5-ethyluracil in a manner analogous to that described in Example 1 gave 5-ethyl-1 - [3(S)-hydroxy-4(R)-[(9-xanthenyl)-carboxamidomethyl]-1 (R)- cyclopentyl]uracil as a white solid of melting point 207-208°C .
The 1 -[3(R)-(aminomethyl)-4(S)-hydroxy-1 (R)-cyclopentyl]- 5-ethyluracil used as the starting material was prepared as follows:
(A) 0.406 g of a 60% suspension of sodium hydride in mineral oil were added in portions to a stirred suspension of 5.01 g of 5- ethyluracil in 50 ml of dimethylformamide. The mixture was stirred at room temperature for 1 hour and then a solution of 9.26 g of 3(S)-benzyloxy-2(R)-(benzyloxymethyl)-(1 S,5R)-6- oxabicyclo[3.1 .0]hexane in 35 ml of dimethylformamide was added. The mixture was heated to 145°C for 41 hours and then cooled and the solvent was evaporated. The residue was partitioned between 150 ml of ethyl acetate and 150 ml of water and the organic solution was washed with 100 ml of water, dried over anhydrous sodium sulphate and evaporated. The crude product was chromatographed on a silica gel column using initially ethyl acetate/hexane (1 :1 , v/v) and then ethyl acetate for the elution to give 7.52 g of 1 -[4(S)-benzyloxy-3(R)-(benzyl- oxymethyl)-2(S)-hydroxy-1 (S)-cyclopentyl]-5-ethyluracil as a colourless gum. o
(B) A solution of 2.994 g of 1 -[4(S)-benzyloxy-3(R)-(benzyloxy- methyl)-2(S)-hydroxy-1 (S)-cyclopentyl]-5-ethyluracil in 31 ml of dichloromethane was stirred under nitrogen and cooled to 0°C . 0.812 g of 4-dimethylaminopyridine was added, followed by 5 1.039 g of phenyl chlorothionoformate. The mixture was left to warm to room temperature and was then stirred for 21 hours. The solvent was evaporated and the residue was extracted with 450 ml of ethyl acetate. The ethyl acetate solution was filtered to remove a small amount of solid material and was then 0 evaporated to give 4.18 g of 1 -[4(S)-benzyloxy-3(R)-(benzyloxy- methyl)-2(S)-(phenoxythiocarbonyloxy)-1 (S)-cyclopentyl]-5- ethyluracil as a gum which was used without further purification in the next step. A sample chromatographed on a silica gel column using ethyl acetate/hexane (2:3, v/v) for the elution gave 5 the pure product as a white solid of melting point 131 -133°C .
(C) 4.18 g of 1 -[4(S)-benzyloxy-3(R)-(benzyloxymethyl)-2(S)- (phenoxythiocarbonyloxy)-l (S)-cyclopentyl]-5-ethyluracil were dissolved in 50 ml of toluene and the solution was stirred at room 0 temperature for 30 minutes while gassing with nitrogen. 2.4 ml of tri-n-butyltin hydride and 0.190 g of azoisobutyronitrile were added and the mixture was heated to 80°C for 1 hour and then left to stand at room temperature ovemight. The solvent was evaporated and the residue was chromatographed on a silica gel 5 column using ethyl acetate/hexane (1 :1 , v/v) for the elution to give 1 .91 g of 1 -[3(S)-benzyloxy-4(R)-(benzyloxymethyl)-1 (R)- cyclopentyl]-5-ethyluracil as a colourless gum; mass spectrum (FAB) m/e 435 [M + H]+. (D) A solution of 1.90 g of 1 -[3(S)-benzyloxy-4(R)-(benzyloxy- methyl)-1 (R)-cyclopentyl]-5-ethyluracil in a mixture of 85 ml of methanol and 4.4 ml of 2M hydrochloric acid was hydrogenated over 1 .4 g of 10% palladium on carbon catalyst for 40 minutes. The catalyst was removed by filtration and the solvent was evaporated to give 1 .1 g of 5-ethyl-1 -[3(S)-hydroxy-4(R)- (hydroxymethyl)-1 (R)-cyclopentyl]uracil as a white foam; mass spectrum (FAB) m/e 255 [M + H]+.
(E) A solution of 0.680 g of 5-ethyl-1 -[3(S)-hydroxy-4(R)- (hydroxymethyl)-1 (R)-cyclopentyl]-uracil in 8.5 ml of pyridine was stirred under nitrogen and 0.213 ml of methanesulphonyl chloride was added. The mixture was stored at 0°C for 18 hours and the solvent was then evaporated. The crude product was chromatographed on a column of silica gel using dichloromethane for the elution to give 0.510 g of 5-ethyl-1 -[3(S)-hydroxy-4(R)- (methanesulphonyloxymethyl)-1 (R)-cyclopentyl]-uracil as a colourless oil, nmr spectrum (CD3OD, 250 MHz) δ 1.12 (3H, t), 1.70 (1 H, m), 1 .90 (1 H, m), 2.12-2.35 (6H, m), 3.12 (3H, s), 4.19-4.40 (3H, m), 5.00 (1 H, m), 7.40 (1 H, s).
(F) 0.300 g of sodium azide was added to a solution of 0.510 g of 5-ethyl-1 -[3(S)-hydroxy-4(R)-(methanesulphonyloxymethyl)- 1 (R)-cyclopentyl]-uracil in 12 ml of dimethylformamide and the mixture was then stirred at 100°C for 18 hours. The solvent was evaporated and the crude product was chromatographed on a silica gel column using methanol/dichloromethane (1 :10, v/v) for the elution to give 0.360 g of 1 -[4(R)-(azidomethyl)-3(S)-hydroxy- 1 (R)-cyclopentyl]-5-ethyluracil as a colourless oil; mass spectrum (FAB) m/e 280 [M = H]+.
(G) A solution of 0.360 g of 1 -[4(R)-(azidomethyl)-3(S)- hydroxy-1 (R)-cyclopentyl]-5-ethyluracil in 15 ml of ethanol was hydrogenated over 0.040 g of 10% palladium on carbon catalyst for 3 hours. The catalyst was removed by filtration and the solvent was evaporated to give 0.320 g of 1 -[4(R)-(aminomethyl)- 3(S)-hydroxy-1 (R)-cyclopentyl]-5-ethyluracil as a white foam; mass spectrum (FAB) m/e 254 [M + H]+.
Example 35
Reaction of 2,7-dichloroxanthene-9-carboxylic acid with 1 -
[3(R)-(aminomethyl)-4(S)-hydroxy-1 (R)-cyclopentyl]-5-ethyl- uracil in a manner analogous to that described in Example 1 gave 1 -[3(R)-[[(2,7-dichloro-9-xanthenyl)-carboxamido]-methyl]-4(S)- hydroxy-1 (R)-cyclopentyl]-5-ethyluracil as an off-white solid of melting point 195-200°C .
Example 36
Reaction of thioxanthene-9-carboxylic acid with 1 -[3(R)- (aminomethyl)-4(S)-hydroxy-1 (R)-cyclopentyl]-5-ethyluracil in a manner analogous to that described in Example 1 gave 5-ethyl-1 -
[3(S)-hydroxy-4(R)-[(9-thioxanthenyl)-carboxamidomethyl]-1 (R)- cyclopentyl]-uracil as a white solid of melting point 153°C (dec).
Example 37
Oxidation of 5-ethyl-1 -[3(S)-hydroxy-4(R)-[(9-thioxan- thenyl)-carboxamidomethyl]-1 (R)-cyclopentyl]uracil with 3- chloroperoxybenzoic acid in a manner analogous to that described in Example 30 gave 5-ethyl-1 -[3(S)-hydroxy-4(R)-[(9-thioxan- thenyl)-carboxamidomethyl]-1 (R)-cyclopentyl]-uracil S,S-dioxide as a white solid; mass spectrum (FAB) m/e 510 [M = H]+.
Example 38
A solution of 432 mg of methyl xanthene-9-carbodithioate in 5 ml of dioxan was added over a period of 1 hour to a solution of 405 mg of 5'-amino-2',5'-dideoxyuridine in a mixture of 12.9 ml of 0.25M aqueous sodium hydroxide and 6 ml of dioxan. After completion of the addition a further 6 ml of dioxan was added to bring the mixture to homogeneity and stirring was continued for 72 hours. The dioxan was evaporated under reduced pressure and the residue was diluted to 60 ml with water and washed with diethyl ether. During the washing a fine precipitate formed; this was collected and recrystallized from methanol to give 80 mg of 2',5'-dideoxy-5-ethyl-5'-[(9-xanthenyl)thiocarbox- amido]uridine as a white solid of melting point 225°C (dec).
The methyl xanthene-9-carbodithioate used as the starting material was prepared as follows:
A mixture of 1.98 g of xanthene-9-carboxylic acid and 5.01 g of 2,4-bis(methylthio)-1 ,3-dithia-2,4-diphosphetane-2,4- disulphide in 100 ml of dry dimethoxyethane was refluxed under argon for 1 1 hours. Concentration under reduced pressure gave a green-brown oil which was purified by chromatography on silica gel using hexane for the elution followed by crystallization from hexane to give 526 mg of methyl xanthene-9-carbodithioate as a solid of melting point 102-103°C .
Example 39
Reaction of 9-xanthenecarbodithioate with 1 -(5-amino-2,5- dideoxy-2-fluoro-β-D-arabinofuranosyl)-5-ethyluracil in a manner analogous to that described in Example 40 gave 1 -[2,5- dideoxy-2-fluoro-5-[(9-xanthenyl)-thiocarboxamido]-β- D - arabinofuranosyl]-5-ethyluracil as a white solid of melting point 228-230°C .
Example 40
A solution of 0.30 g of 1 -(5-amino-2,5-dideoxy-2-fluoro-β- D-arabinofuranosyl)-5-ethyluracil in 2 ml of methanol was adjusted to pH 6 using one drop of a saturated solution of hydrogen chloride in methanol. 0.041 g of xanthene-9-carbox- aldehyde and 0.25 g of 3A molecular sieves were added, followed by 0.033 g of sodium cyanoborohydride, and the mixture was stirred at room temperature for 3 days. 15 ml of methanol were then added and the mixture was filtered. The filtrate was evaporated and the residue was dissolved in 50 ml of 5% citric acid solution. The solution was adjusted to pH 7 using 2M sodium hydroxide solution and extracted with four 20 ml portions of ethyl acetate. The combined extracts were dried over anhydrous sodium sulphate and evaporated. The resulting gum was triturated with diethyl ether to give 0.015 g of 1 -[2,5-dideoxy-2- fluoro-5-[(9-xanthenyl)-methylamino]-β-D-arabinofu ranosyl]-5- ethyluracil as a white solid of melting point 201 -203°C .
Example 41
o Conversion of xanthene-9-carboxylic acid into the corresponding acid chloride followed by reaction with 1 -(2,5- dideoxy-2-fluoro-5-[N-methylamino-β-D-arabinofuranosyl)-5- ethyluracil in a manner analogous to that described in Example 4 gave 1 -[2,5-dideoxy-2-fluoro-5-[N-methyl-N-(9-xanthenyl- 5 carbonyl)-amino]-β-D-arabinofuranosyl]-5-ethyluracil as a cream coloured solid of melting point 186-190°C (dec).
The 1 -(2,5-dideoxy-2-fluoro-5-[N-methylamino-β- D - arabinofuranosyl)-5-ethyluracil used as starting material was 0 prepared as follows:
(A) A solution of 2.74 g of 1 -(2-deoxy-2-fluoro-β-D-arabino- furanosyl)-5-ethyluracil in 60 ml of pyridine was cooled to 0°C and 0.78 ml of methanesulphonyl chloride were added. The 5 mixture was stirred at 0°C for 30 minutes and then stored at 4°C for 22 hours. The solvent was removed by evaporation and the residue was chromatographed on a silica gel column using dichloromethane/methanol (9:1 , v/v) for the elution to give 2.451 g of 1 -(2-deoxy-2-fluoro-5-0-methanesulphonyl-β- D- 0 arabinofuranosyl)-5-ethyluracil as a white solid of melting point
188-1 90°C .
(B) A mixture of 2.44 g of 1 -(2-deoxy-2-fluoro-5-0-methane- sulphonyl-β-D-arabinofuranosyl)-5-ethyluracil and 1.79 ml of N- 5 methylbenzylamine in 20 ml of dimethylformamide was stirred at 100°C for 89 hours. The solvent was removed by evaporation and the residue was chromatographed on a silica gel column using dichloromethane/methanol (9:1 , v/v) for the elution. The thus- obtained product was triturated with diethyl ether to give 1.64 g of 1 -(5-N-benzyl-N-methylamino-2,5-dideoxy-2-fluoro-β- D - arabinofuranosyl)-5-ethyluracil as a white solid of melting point 148-151 °C.
(C) A solution of 0.840 g of 1 -(5-N-benzyl-N-methylamino-2,5- dideoxy-2-fluoro-β-D-arabinofuranosyl)-5-ethyluracil in 80 ml of ethanol was hydrogenated over 0.150 g of 10% palladium on carbon catalyst for 4 hours. The catalyst was removed by filtration and the filtrate was evaporated to give 0.405 g of 1 - (2,5-dideoxy-2-fluoro-5-[N-methylamino-β-D-arabinofu ranosyl)- 5-ethyluracil as a colourless gum.
Example 42
Conversion of 4-phenylxanthene-9(RS)-carboxylic acid into the corresponding acid chloride followed by reaction with 1 -(2,5- dideoxy-2-fluoro-5-[N-methylamino-β-D-arabi nofuranosyl)-5- ethyluracil in a manner analogous to that described in Example 4 gave 1 -[2,5-dideoxy-2-fluoro-5-[N-(4-phenyl-9(RS)-xanthenyl- carbonyl)-N-methylamino]-β-D-arabinofuranosyl]-5-ethyl uracil as a white foam; mass spectrum (FAB) m/e 572 [M = H]+.
Example 43
Reaction of 1 -(2,5-dideoxy-3-0-tert.-butyldimethylsilyl-2- fl uoro-5-N-methylamino-β-D-arabinofuranosyl)-5-ethyl uraci l with 4-trifluoromethylxanthene-9(RS)-carboxyiic acid in a manner analogous to that described in Example 1 followed by removal of the tert. -butyldimethylsilyl protecting group by treatment with triethylamine trihydrofluoride gave 1 -[2,5- dideoxy-2-fluoro-5-[N-[[4-(trifluoromethyl)-9-( RS)-xanthenyl]- carbonyl]-N-methylamino]-β-D-arabinofuranosyl]-5-ethyluracil as a fawn solid of melting point 115-140°C (effervescence).
The 1 -(2,5-dideoxy-3-0-tert-butyldimethylsilyl-2-fluoro- 5-N-methylamino-β-D-arabinofuranosyl)-5-ethyluracil used as starting material was prepared as follows: (A) A mixture of 1 .82 g of 1 -(5-N-benzyl-N-methylamino-2,5- dideoxy-2-fluoro-β-D-arabinofuranosyl)-5-ethyluracil, 1 .313 g of imidazole and 1 .453 g of tert-butylchlorodimethylsilane in 25 ml of dimethylformamide was stirred at 25°C for 18 hours. 75 ml of water were added and the mixture was extracted with three 75 ml portions of diethyl ether. The combined extracts were washed with three 50 ml portions of saturated aqueous sodium hydrogen carbonate solution, dried and evaporated to give 2.693 g of 1 -(5-N-benzyl-N-methylamino-3-0-tert-butyldimethylsilyl- 2,5-dideoxy-2-fluoro-β-D-arabinofuranosyl)-5-ethyluracil as a white solid of melting point 80-100°C .
(B) A solution of 0.491 g of 1 -(5-N-benzyl-N-methylamino-3- 0-tert-butyldi methyl6ilyl-2 ,5-dideoxy-2-fl uoro-β- D-a rabi no- furanosyl)-5-ethyluracil in 20 ml of ethanol was hydrogenated over 0.200 g of 10% palladium on carbon catalyst for 4 hours. The catalyst was removed by filtration and the filtrate was evaporated to give 1 -(2,5-dideoxy-3-0-tert-butyldimethylsilyl- 2-f I uoro-5-N -methy lam ino-β-D-arabinofu ran osy I) -5-ethy I uracil as a gum which was used without further purification in the next step.
Example 44
The mixture of diastereomers prepared in the first paragraph of Example 43 was subjected to preparative hplc to give the pure diastereomers. The faster running diastereomer was obtained as a white solid, mass spectrum (FAB) m/e 564 [M + H]+, and the slower running diastereomer was obtained as a white solid, mass spectrum (FAB) m/e 564 [M + H]+.
Example 45
Conversion of 4,5-dimethylxanthene-9-carboxylic acid into the corresponding acid chloride followed by reaction with 1 -(2,5- dideoxy-2-fluoro-5-[N-methylamino-β-D-arabinofuranosyl)-5- ethyluracil in a manner analogous to that described in Example 4 gave 1 -[2,5-dideoxy-2-fluoro-5-[N-methyl-N-[(4,5-dimethyl-9- xanthe ny I ) -carbonyl] -ami no]- β-D-arabin of uranosyl]-5-ethy I u racil as a white solid of melting point 198-200°C .
Example 46
Conversion of 4,5-dichloroxanthene-9-carboxylic acid into the corresponding acid chloride followed by reaction with 1 -(2,5- dideoxy-2-fluoro-5-[N-methylamino-β-D-arabinofuranosyl)-5- ethyluracil in a manner analogous to that described in Example 4 gave 1 -[5-[N-[(4,5-dichloro-9-xanthenyl)-carbonyl]-N-methyl- amino]-2,5-dideoxy-2-fluoro-βD-arabinofu ranosyl]-5-ethyluracil as a white solid of melting point 182-187°C .
The 4,5-dichloroxanthene-9-carboxylic acid used as the starting material was prepared as follows:
(A) A solution of 10.00 g of 2,3-dichlorobenzoic acid and 8.00 g of 2-chlorophenol in a mixture of 95 ml of dry dioxan and 48 ml of dry dimethyl sulphoxide was stirred under nitrogen and 4.60 g of a
60% dispersion of sodium hydride in mineral oil were added in portions over a period of 20 minutes. The mixture was stirred for a further 30 minutes at room temperature and then 2.5 ml of tris- [2-(2-methoxyethoxy)-ethyl]amine and 0.527 g of cuprous chloride were added. The mixture was stirred at 105°C for
12 hours. The solvents were evaporated and the residue was taken up in 500 ml of 0.1 M sodium hydroxide solution and the mixture was filtered. The filtrate was acidified to pH 1 with concentrated hydrochloric acid and the resulting white precipitate was collected by filtration, washed with water and dried. This material was taken up in a mixture of 150 ml of concentrated sulphuric acid and 16 ml of water and the mixture was stirred at 80°C for 10 minutes. It was then left to cool to room temperature and poured into 1200 ml of a mixture of ice and water. The resulting suspension was extracted with two 600 ml portions of diethyl ether and the combined extracts were washed with 1000 ml of 0.1 M sodium hydroxide solution dried over anhydrous magnesium sulphate and the solvent was evaporated to give 3.575 g of 4,5-dichloroxanthone as a white solid of melting point 184-185°C .
The 4,5-dichloroxanthone obtained was reduced in a manner analogous to that described in Example 7 (A) to give 4,5-dichloro- xanthene as a white solid of melting point 85-86°C. This was carboxylated in a manner analogous to that described in Example 5 (C) to give 4,5-dichloroxanthene-9-carboxylic acid.
Example 47
Conversion of thioxanthene-9-carboxylic acid into the corresponding acid chloride followed by reaction with 1 -(2,5- dideoxy-2-fluoro-5-[N-methylamino-β-D-arabinofuranosyl)-5- ethyluracil in a manner analogous to that described in Example 4 gave 1 - [2, 5-d i deoxy-2-f I uoro-5-[N- methy I-N -(9-th ioxantheny I - carbonyl)-amino]-β-D-arabinofuranosyl]-5-ethyluracil as a buff solid of melting point 120-123°C (foaming).
Example 48
Oxidation of 1 -[2,5-dideoxy-2-fluoro-5-[N-methyl-N-(9- thioxanthenylcarbonyl)-amino]-β-D-arabinofuranosyl]-5-ethyl- uracil with 3-chloroperoxybenzoic acid in a manner analogous to that described in Example 30 gave 1 -[2,5-dideoxy-2-fluoro-5-[N- methyl-N-(9-thioxanthenylcarbonyl)-amino]-β-D-arabino- furanosyl]-5-ethyluracil S,S-dioxide as a white solid of melting point 130-135°C (foaming).
Example 49
Reaction of thioxanthene-9-carboxylic acid with 1 -(5- amino-2,5-dideoxy-3-0-ethyl-2-fluoro-β-D-arabinofu ranosyl)-5- ethyluracil in a manner analogous to that described in Example 1 gave 1 -[2,5-dideoxy-3-0-ethyl-2-fluoro-5-[(9-thioxanthenyl)- carboxamido]-β-D-arabinofuranosyl]-5-ethyluracil as a white solid of melting point 90-102°C . Example 50
Oxidation of 1 -[2,5-dideoxy-3-0-ethyl-2-fluoro-5-[(9- thioxanthenyl)-carboxamido]-β-D-arabinofuranosyl]-5-ethyl uracil with 3-chloroperoxybenzoic acid in a manner analogous to that described in Example 30 gave 1 -[2,5-dideoxy-3-0-ethyl-2- fluoro-5-[(9-thioxanthenyl)-carboxamido]-β-D-arabinofu ranosyl]- 5-ethyluracil S,S-dioxide as a white solid of melting point 187- 194°C.
Example 51
Reaction of thioxanthene-9-carboxylic acid with 1 -(5- amino-3-0-cyclohexyl methyl-2,5-dideoxy-2-fluoro-β-D-arabi no- furanosyl)-5-ethyluracil in a manner analogous to that described in Example 1 gave 1 -[3-0-(cyclohexylmethyl)-2,5-dideoxy-2- fluoro-5-[(9-thioxanthenyl)-carboxamido]-β-D-arabinofu ranosyl]- 5-ethyluracil as a white foam; mass spectrum (FAB) m/e 594 [M + H]+.
The 1 -(5-amino-3-0-cyclohexylmethyl-2,5-dideoxy-2- fluoro-β-D-arabinofuranosyl)-5-ethyluracil used as the starting material was prepared as follows:
(A) A solution of 3.0 g of 1 -(5-azido-2,5-dideoxy-2-fluoro-β-
D-arabinofuranosyl)-5-ethyluracil in 15 ml of tetrahydrofuran was added dropwise to a stirred and cooled suspension of 1 .2 g of a 60% dispersion of sodium hydride in mineral oil in 15 ml of tetrahydrofuran. The mixture was left to warm up to room temperature and was stirred for a further hour. 2.63 g of 1 -
(bromomethyl)cyclohexene and 0.15 g of sodium iodide were added and the mixture was heated to 60°C for 65 hours. The mixture was left to cool to room temperature and 10 ml of 2M hydro¬ chloric acid were added dropwise. The mixture was diluted with a further 40 ml of 2M hydrochloric acid and extracted with three 40 ml portions of ethyl acetate. The combined extracts were washed with 50 ml of saturated sodium chloride solution, dried over anhydrous magnesium sulphate and evaporated. The residue was chromatographed on a silica gel column using ethyl acetate/ hexane (1 :2, v/v) for the elution to give 2.03 g of 1 -[5-azido-3-0- (1 -cyclohexenylmethyl)-2,5-dideoxy-2-fluoro-β-D-arabino- furanosyl)-5-ethyluracil; mass spectrum (FAB) m/e 394 [M + H]+.
(B) A solution of 0.77 g of 1 -[5-azido-3-0-(1 -cyclohexenyl¬ methyl)^, 5-dideoxy-2-f luo ro-β-D-arabinofuranosy I) -5-ethy I- uracil in 41 ml of ethanol was hydrogenated over 0.16 g of 10% palladium on carbon catalyst for 20 hours. The catalyst was o removed by filtration and the solvent was evaporated to give 0.65 g of 1 -(5-amino-3-0-cyclohexylmethyl-2,5-dideoxy-2- fluoro-β-D-arabinofuranosyl)-5-ethyluracil; mass spectrum (FAB) m/e 370 [M + H]+.
5 Example 52
Oxidation of 1 -[3-0-(cyclohexylmethy!)-2,5-dideoxy-2- fluoro-5-[(9-thioxanthenyl)-carboxamido]-β-D-arabinofuranosyl]- 5-ethyluracil with 3-chloroperoxybenzoic acid in a manner 0 analogous to that described in Example 30 gave 1 -[3-0-(cyclo- hexyl methy l)-2,5-dideoxy-2-fluoro-5-[(9-thioxanthenyl)- carboxamido]-β-D-arabinofuranosyl]-5-ethyluracil S,S-dioxide as a white solid of melting point 195-197°C .
5 Example 53
Reaction of thioxanthene-9-carboxylic acid with 1 -(3-0- allyl-5-amino-2,5-dideoxy-2-fluoro-β-D-arabinofu ranosyl)-5- ethyluracil in a manner analogous to that described in Example 1 0 gave 1 -[3-0-allyl-2,5-dideoxy-2-fluoro-5-[(9-thioxanthenyl)- carboxamido]-β-D-arabinofuranosyl]-5-ethyluracil as a white solid of melting point 112-1 18°C .
The 1 -(3-0-allyl-5-amino-2,5-dideoxy-2-fluoro-β- D - 5 arabinofuranosyl)-5-ethyluracil used as the staring material was prepared as follows: (A) Reaction of 1 -(5-azido-2,5-dideoxy-2-fluoro-β- D - arabinofuranosyl)-5-ethyluracil with allyl bromide in a manner analogous to that described in Example 53 (A) gave 1 -[3-O-allyl- 5-azido-2,5-dideoxy-2-fluoro-β-D-arabi nofu ranosyl)-5- ethyl u raci l .
(B) A solution of 1 .0 g of 1 -[3-0-allyl-5-azido-2,5-dideoxy-2- fluoro-β-D-arabinofuranosyl)-5-ethyluracil in 20 ml of pyridine was stirred under nitrogen at 0°C and 0.81 g of triphenylphosphine was added. The mixture was left to warm to room temperature and stirred for 17 hours. 20 ml of a saturated solution of ammonia in methanol were added and the mixture was stirred for a further 24 hours. The solvents were evaporated and the residue was partitioned between 25 ml of ethyl acetate and 20 ml of water. The aqueous layer was saturated with sodium chloride and extracted with two 10 ml portions of ethyl acetate. The combined organic extracts were washed with three 15 ml portions of 2M hydrochloric acid and the combined aqueous solutions were made alkaline by the careful addition of 1 M sodium carbonate solution and then extracted with five 10 ml portions of ethyl acetate. The combined ethyl acetate extracts were dried over anhydrous magnesium sulphate and evaporated to give 0.46 g of 1 -(3-0-allyl-5-amino-2,5-dideoxy-2-fluoro-β-D-arabi n o- f u ran osy I) -5-ethy I uracil .
Example 54
Oxidation of 1 -[3-0-allyl-2,5-dideoxy-2-fluoro-5-[(9- thioxanthenyl)carboxamido]-β-D-arabinofuranosyl]-5-ethyluracil with 3-chloroperoxybenzoic acid in a manner analogous to that described in Example 30 gave 1 -[3-0-allyl-2,5-dideoxy-2-fluoro- 5- [(9-th ioxantheny I )-carboxamido]-β-D-arabin of uranosyl]-5- ethyluracil S,S-dioxide as a white solid of melting point 193- 195°C. Example 55
Reaction of thioxanthene-9-carboxylic acid with 1 -(5- amino-2,5-dideoxy-2-fluoro-3-0-propargyl-β-D-arabino- furanosyl)-5-ethyluracil in a manner analogous to that described in Example 1 gave 1 -[2,5-dideoxy-2-fluoro-3-0-propargyl-5-[(9- thioxanthenyl)-carboxamido]-β-D-arabinofuranosyl]-5-ethyl uracil as a white solid; mass spectrum (FAB) m/e 536 [M + H]+.
The 1 -(5-amino-2,5-dideoxy-2-fluoro-3-0-propargyl-β- D - arabinofuranosyl)-5-ethyluracil used as the starting material was prepared as follows:
Reaction of 1 -(5-azido-2,5-dideoxy-2-fluoro-β-D-arabino- furanosyl)-5-ethyluracil with propargyl bromide in a manner analogous to that described in Example 53 (A) gave 1 -(5-amino- 2,5-dideoxy-2-fluoro-3-0-propargyl-β-D-arabinofuranosyl)-5- ethyluracil as a solid of melting point 100.5-101 °C .
Reduction of 1 -(5-amino-2,5-dideoxy-2-fluoro-3-0- propargyl-β-D-arabinofuranosyl)-5-ethyluracil using triphenyl¬ phosphine in a manner analogous to that described in Example 55 (B) gave 1 -(5-amino-2,5-dideoxy-2-fluoro-3-0-propargyl-β- D- arabi nofu ran osyl)-5-ethyl uracil .
Example 56
Oxidation of 1 -[2,5-dideoxy-2-fluoro-3-0-propargyl-5-[(9- thioxanthenyl)-carboxamido]-β-D-arabinofuranosyl]-5-ethyl uracil with 3-chloroperoxybenzoic acid in a manner analogous to that described in Example 30 gave 1 -[2,5-dideoxy-2-fluoro-3-0- propargyl-5-[(9-thioxanthenyl)-carboxamido]-β-D-arabino- furanosyl]-5-ethyluracil S,S-dioxide as a white solid of melting point 108-1 12°C . Example 57
Conversion of xanthene-9-carboxylic acid into the corresponding acid chloride followed by reaction with 5-amino- 3-0-benzyl-2,5-dideoxy-5-ethyluridine in a manner analogous to that described in Example 4 gave 3'-0-benzyl-2',5'-dideoxy-5- ethyl-5'-[(9-xanthenyl)-carboxamido]-uridine as a white solid of melting point 228-238°C .
Example 58
Conversion of xanthene-9-carboxylic acid into the corresponding acid chloride followed by reaction with 1 -(5- ami no-2 ,5-dideoxy-2-f luoro-3-0-(4-fluorobenzyi)-β- D - arabinofuranosyl)-5-ethyluracil in a manner analogous to that described in Example 4 gave 1 -(2,5-dideoxy-2-fluoro-3-0-(4- fluorobenzyl)-5-[(9-xanthenyl)-carboxamido]-β-D-arabi no- furanosyl)-5-ethyluracil as a white solid of melting point 198- 199°C.
The 1 -(5-amino-2,5-dideoxy-2-fluoro-3-0-(4-fluoro- benzyl)-β-D-arabinofuranosyl)-5-ethyluracil used as the starting material was prepared as follows:
(A) Reaction of 1 -(5-azido-2,5-dideoxy-2-fluoro-β-D-arabi no- furanosyl)-5-ethyluracil with 4-fluorobenzyl bromide in a manner analogous to that described in Example 51 (A) gave 1 -[5-azido- 2,5-dideoxy-2-fluoro-3-0-(4-fluorobenzyl)-β-D-arabi no- furanosyl)-5-ethyluracil as a solid of melting point 132-133°C .
(B) A solution of 1 .60 g of 1 -[5-azido-2,5-dideoxy-2-fluoro-3- 0-(4-fluorobenzyl)-β-D-arabinofuranosyl)-5-ethyluracil in 100 ml of ethanol was hydrogenated over 0.40 g of 10% palladium on calcium carbonate catalyst for 4 hours. The catalyst was removed by filtration and the solvent was evaporated. The crude product was triturated with diethyl ether to give 1.10 g of 1 -(5- amino-2 ,5-dideoxy-2-fluoro-3-0-(4-fluorobenzyl)-β-D-arabi no- furanosyl)-5-ethyluracil as a hygroscopic solid of melting point o u 91 -99°C .
Example 59
A solution of 116 mg of 2',5'-dideoxy-5-ethyl-5'-[(9- xanthenyl)-carboxamido]-uridine in 5 ml of pyridine was cooled to -15°C and 70 mg of palmitoyl chloride were added. The mixture was stirred at 0°C for 2 hours and then left to stand at room temperature for 18 hours. The solvent was evaporated and the residue was partitioned between 25 ml of dichloromethane and 25 ml of water. The aqueous solution was extracted with a further 25 ml of dichloromethane and the combined extracts were washed with saturated sodium chloride solution, dried and evaporated. The crude product was purified by repeated recrystallization from hot methanol followed by chromatography on a silica gel column using dichloromethane/methanol (9:1 , v/v) for the elution to give 16 mg of 2',5'-dideoxy-5-ethyl-3'-0- palmitoyl-5'-[(9-xanthenyl)-carboxamido]-uridine as a fawn solid of melting point 140-145°C .
Example 60
Reaction of 2',5'-dideoxy-5-ethyl-5'-[(9-xanthenyl)- carboxamido]-uridine with 3,4,5-trimethoxybenzoyl chloride in a manner analogous to that described in Example 59 gave 2',5'- dideoxy-5-ethyl-3'-0-(3,4,5-tri methoxybenzoyl)-5'-[(9- xanthenyl)-carboxamido]-uridine as a white solid of melting point 245-247°C (dec).
Example 61
(A) A solution of 0.150 g of 1 -[2,5-dideoxy-2-fluoro-5-[N-[[4- (trifluoromethyl)-9-(RS)-xanthenyl]-carbonyl]-N-methylamino]- β-D-arabinofuranosyl]-5-ethyluracil in 10 ml of dimethyl- formamide was stirred at 0°C and 0.134 g of N-benzyloxy- carbonyl-L-valine, 0.066 g of 4-dimethylaminopyridine and 0.104 g of 1 -(3-dimethylaminopropyl)-3-ethylcarbodiimide hydro¬ chloride were added. The mixture was stirred at 0°C for 1 hour and then left to warm to room temperature and stirred for 2 days. The solvent was evaporated and the residue was chromatographed on silica gel column using dichloromethane/methanol (95:5, v/v) for the elution to give 0.214 g of 1 -[3-0-(N-benzyloxycarbonyl-L- valy I )-2, 5-di deoxy-2-f I uoro-5-[N -[4- (trif l uoromethyl )-9-(RS) - xantheny I] -carbonyl]- N-methyl ami no]-β-D-arabinofuranosy I] -5- ethyluracil as a white solid; mass spectrum (FAB) m/e 797 [M + H]+
(B) A solution of 0.199 g of 1 -[3-0-(N-benzyloxycarbonyl-L- valyl)-2, 5-d ideoxy-2-fl uoro-5-[N-[4- (trif l uoromethyl)-9- ( RS)- xanthenyl]-carbony I]- N-methyl ami no]-β-D-arabinofuranosyl] -5- ethyluracil in 25 ml of ethanol was hydrogenated over 0.150 g of 10% palladium on carbon catalyst for 3.5 hours. The catalyst was removed by filtration and the filtrate was evaporated. The residue was triturated with 20 ml of diethyl ether to give 0.155 g of 1 -[2,5-dideoxy-2-fl uoro-5-[N-[4-(trifluoromethyl)-9-(RS)- xanthenyl]-carbonyl]-N-methylamino]-3-0-(L-valyl)-β-D-arabino- furanosyl]-5-ethyluracil hydrochloride as a white solid of melting point 144-150°C .
Example 62
(A) 3'-0-(N-tert-Butoxycarbonyl-L-methionyl)-2' ,5'-dideoxy- 5-ethy!-5'-[(9-xanthenyl)-carboxamido]-uridine was prepared as a white solid of melting point 186-187°C by coupling 2', 5'- dideoxy-5-ethyl-5'-[(9-xanthenyl)-carboxamido]-uridine with N-tert butoxycarbonyl-L-methionine in a manner analogous to that described in Example 61 (A).
(B) A solution of 0.160 g of 3'-0-(N-tert-butoxycarbonyl-L- methionyl)-2' ,5'-dideoxy-5-ethyl-5'-[(9-xanthenyl)- carboxamido]uridine in 5 ml of a saturated solution of hydrogen chloride in ethyl acetate was held at 25°C for 1.5 hours. The solvent was evaporated and the residue was triturated with diethyl ether to give 0.079 g of 2',5'-dideoxy-5-ethyl-3'-0-(L- methionyl)-5'-[(9-xanthenyl)-carboxamido]-uridine hydrochloride as a white solid of melting point 150°C (dec). Example 63
Reaction of 2',5'-dideoxy-5-ethyl-5'-[(9-xanthenyl)carbox- amido]uridine with Nα,Nε-bis-benzyloxycarbonyl-(L)-lysine in analogy to Example 61 (A) followed by hydrogenolysis in a manner analogous to that described in Example 63 (B) gave 2',5'-dideoxy- 5-ethyl-3'-0-(L-lysyl)-5'-[(9-xanthenyl)-carboxamido]-u ridine hydrochloride as a white solid of melting point 185-230°C (dec).
Example 64
Reaction of xanthene-9-carboxylic acid with 5'-amino-5'- deoxythymidine in a manner analogous to that described in Example 1 gave 5'-deoxy-5'-[(9-xanthenyl)-carboxamido]- thymidine as a white solid of melting point 268-269°C .
Example 65
Conversion of xanthene-9-carboxylic acid into the corresponding acid chloride and reaction with 5'-amino-5- cyclopropyl-2',5'-dideoxyuridine in a manner analogous to that described in Example 4 gave 5-cyclopropyl-2',5'-dideoxy-5'-[(9- xanthenyl)-carboxamido]-uridine as a white solid of melting point
2670C.
The 5'-amino-5-cyclopropyl-2',5'-dideoxyuridine used as the starting material was prepared as follows:
(A) A mixture of 0.340 g of 5-cyclopropyl-2'-deoxyuridine, 0.332 g of triphenylphosphine, and 0.412 g of sodium azide in 20 ml of dimethylformamide was stirred at room temperature and 0.421 g of carbon tetrabromide was added. The mixture was stirred at room temperature for 20 hours and then 5 ml of methanol were added, with stirring being continued for
30 minutes. The solvents were evaporated and the crude product was chromatographed on a silica gel column using methanol/ O O dichloromethane (1 :9, v/v) for the elution to give 0.088 g of 5'- azido-5-cyclopropyl-2',5'-dideoxyuridine as a colourless oil which was used without further purification in the next step.
(B) A solution of 0.080 g of 5'-azido-5-cyclopropyl-2',5'- dideoxyuridine in 100 ml of ethanol was hydrogenated over 0.020 g of 10% palladium on charcoal catalyst for 4 hours. The catalyst was removed by filtration and the solvent was evaporated to give 0.070 g of 5'-amino-5-cyclopropyl-2',5'- o dideoxyuridine as a colourless oil; mass spectrum (FAB) m/e
268 [M + H]+.
Example 66
5 Reaction of xanthene-9-carboxylic acid with 5'-amino-
2',5'-dideoxy-5-(pentafluoroethyl)-uridine in a manner analogous to that described in Example 1 gave 2',5'-dideoxy-5-(penta- fluoroethyl)-5'-[(9-xanthenyl)-carboxamido]-uridine as a white solid; mass spectrum (FAB) m/e 554 [M + H]+. 0
The 5'-amino-2',5'-dideoxy-5-(pentafluoroethyl)-uridine used as the starting material was prepared by reacting 2'-deoxy- 5-(pentafluoroethyl)-uridine with methanesulphonyl chloride followed by treatment with sodium azide and then hydrogenation 5 in a manner analogous to that described in Example 34 (E), (F) and
(G).
Example 67
0 Reaction of thioxanthene-9-carboxylic acid with 1 -(5- amino-2,5-dideoxy-2-fluoro-β-D-arabinofuranosyl)-5-iodouracil in a manner analogous to that described in Example 1 gave 1 -[2,5- dideoxy-2-fluoro-5-[(9-thioxanthenyl)-carboxamido]-β- D - arabinofuranosyl]-5-iodouracil as a pale lemon coloured solid; 5 mass spectrum (FAB) m/e 596 [M + H]+. Example 68
Oxidation of 1 -[2,5-dideoxy-2-fluoro-5-[(9-thioxanthenyl)- carboxamido]-β-D-arabinofuranosyl]-5-iodouracil with 3- chloroperoxybenzoic acid in a manner analogous to that described in Example 30 gave 1 -[2,5-dideoxy-2-fluoro-5-[(9-thioxan- thenyl)-carboxamido]-β-D-arabinofuranosyl]-5-iodouracil S,S- dioxide as a buff solid, mass spectrum (FAB) m/e 628 [M + H]+.
Example 69
Reaction of xanthene-9-carboxylic acid with 1 -(5-amino- 2,5-dideoxy-2-fluoro-β-L-arabinofuranosyl)-5-ethyluracil in a manner analogous to that described in Example 1 gave 1 -[2,5- dideoxy-2-fluoro-5-[(9-xanthenyl)-carboxamido]-β-L-arabino- furanosyl]-5-ethyluracil as a white solid of melting point 243- 246°C.
The 1 -(5-amino-2,5-dideoxy-2-fluoro-β-L-arabi no- furanosyl)-5-ethyluracil used as the starting material was prepared as follows:
(A) A solution of 24.06 g 1 -0-acetyl-2,3,5-tri-0-benzoyl-β-L- ribofuranose in 105 ml of a 0.5M solution of hydrogen bromide in dichloromethane was stirred at 0°C for 1.5 hours. 36 ml of water were added and the mixture was stirred at room temperature for 4 hours. The organic phase was separated and washed with water, saturated aqueous sodium hydrogen carbonate and water, dried over anhydrous magnesium sulphate and evaporated. The residue was taken up in 32 ml of dichloromethane and 36 ml of heptane were added. The thus-precipitated product was collected by filtration to give 11 .495 g of 1 ,3,5-tri-O-benzoyl-α-L-ribo- furanose as a white solid of melting point 139-140°C .
(B) A solution of 16.88 g of 1 ,3,5-tri-O-benzoyl-α-L-ribo- furanose in 128 ml of dichloromethane was stirred under argon at -70°C and 9.865 g of sulphuryl chloride were added dropwise. The mixture was left to warm to room temperature over a period of 1 hour and was then cooled to 0°C and treated with a solution of 24.847 g of imidazole in 90 ml of dichloromethane. The mixture was then stirred at room temperature for 1.5 hours and washed with three portions of water, dried over anhydrous magnesium sulphate and evaporated. The crude product was crystallized from 100 ml of hot isopropanol to give 18.108 g of 2-0-(1 -imidazolyl- sulphonyl)-1 ,3,5-tri-O-benzoyl-α-L-ribofuranose as a white solid.
(C) A solution of 17.592 g of 2-0-(1 -imidazolylsulphonyl)-
1 ,3,5-tri-O-benzoyl-α-L-ribofuranose in 100 ml of triethylamine trihydrofluoride was stirred at 80°C for 12.5 hours and then left to stand at room temperature overnight. The mixture was poured on to a mixture of ice and water and extracted with dichloro- methane. The extracts were washed with water, dried over anhydrous magnesium sulphate and evaporated. The residue was crystallized from hot ethanol to give 10.502 g of 1 ,3,5-tri-O- benzoyl-2-fluoro-α-L-arabinofuranose as an off-white solid.
(D) 13.18 ml of a 30% solution of hydrogen bromide in acetic acid were added to a solution of 10.486 g of 1 ,3,5-tri-O-benzoyl- 2-fluoro-α-L-arabinofuranose in 48 ml of dichloromethane. The mixture was stirred at room temperature for 18 hours and was then diluted with further dichloromethane. The resulting solution washed with two portions of water, saturated aqueous sodium hydrogen carbonate solution and water, dried over anhydrous magnesium sulphate and evaporated to give 9.758 g of 3,5-di-O- benzoyl-1 -bromo-2-fluoro-α-L-arabinofuranose as a yellow oil which was used without further purification in the next step.
(E) A suspension of 1.006 g of 5-ethyluracil and 2 mg of ammonium sulphate in 4.68 ml of hexamethyldisilazane was stirred and refluxed under nitrogen for 3.5 hours. The solvent was evaporated and the residue was taken up in 19.5 ml of chloroform. A solution of 2.75 g of 3,5-di-0-benzoyl-1 -bromo-2-fluoro-α- L- arabinofuranose in 13 ml of chloroform was added and the mixture was stirred and refluxed for 3 days. The mixture was cooled to room temperature and diluted with dichloromethane. The resulting solution was washed with saturated aqueous sodium hydrogen carbonate solution and then with water, dried over anhydrous magnesium sulphate and evaporated. The residue was crystallized from a hot mixture of ethyl acetate and hexane to give 2.065 g of 1 -(3,5-di-0-benzoyl-2-deoxy-2-fluoro-β- L- arabinofuranosyl)-5-ethyluracil as a white solid of melting point 149-150°C .
(F) A suspension of 1 .877 g of 1 -(3,5-di-0-benzoyl-2-deoxy-2- fluoro-β-L-arabinofuranosyl)-5-ethyluracil in a mixture of 36 ml of methanol and 18 ml of triethylamine was stirred at room temperature for 22 hours. The solvents were evaporated and the crude product was chromatographed on a silica gel column using dichloromethane, then dichloromethane/methanol (95:5, v/v) and finally dichloromethane/methanol (9:1 , v/v) for the elution. The product was crystallized from hot acetonitrile to give 0.064 g of 1 -(2-deoxy-2-fluoro-β-L-arabinofuranosyl)-5-ethyluracil as a white solid of melting point 166-167.5°C .
(G) Reaction of 1 -(2-deoxy-2-fluoro-β-L-arabinof uranosyl)-5- ethyluracil with methanesulphonyl chloride, subsequent treat¬ ment with sodium azide and then hydrogenation in a manner analogous to that described in Example 34 (E), (F) and (G) gave 1 - (5-amino-2,5-dideoxy-2-fl uoro-β-L-arabinofu ranosyl)-5- ethyluracil as a colourless gum.
Example 70
Reaction of 2,7-dichloroxanthene-9-carboxylic acid with 1 - (5-amino-2,5-dideoxy-2-fl uoro-β-L-arabinofu ranosyl)-5-ethyl- uracil in a manner analogous to that described in Example 1 gave 1 -[5-[(2,7-dichloro-9-xanthenyl)carboxamido]-2,5-dideoxy-2- fluoro-β-L-arabinofuranosyl]-5-ethyluracil as a white solid of melting point 240-245°C . Example 71
Reaction of 9-thioxanthenecarboxylic acid with 1 -(5- amino-2,5-dideoxy-2-f I uoro-β-L-arabinofuranosyl)-5-ethy lu racil in a manner analogous to that described in Example 1 gave 1 -[2,5- dideoxy-2-fluoro-5-[(9-thioxanthenyJ,-carboxamido]-β-L-arabino- furanosyl]-5-ethyluracil as a white solid of melting point 180- 190°C (foaming).
Example 72
Oxidation of 1 -[2,5-dideoxy-2-fluoro-5-[(9-thioxanthenyl)- carboxamido]-β-L-arabinofuranosyl]-5-ethyluracil with 3- chloroperoxybenzoic acid in a manner analogous to that described in Example 30 gave 1 -[2,5-dideoxy-2-fluoro-5-[(9-thioxanth- enyl)-carboxamido]-β-L-arabinofuranosyl]-5-ethyluracil S,S- dioxide as a white solid of melting point 125-131 °C (foaming).
Example 73
Conversion of 4-methoxyxanthene-9(RS)-carboxylic acid into the corresponding acid chloride followed by reaction with 1 - (2, 5-dideoxy-2-f I uoro-5-[N -methylamino]- β- D-arabino- furanosyl)-5-ethyluracil in a manner analogous to that described in Example 4 gave 1 -[5-[N-[(4-methoxy-9(RS)-xanthenyl)- carbonyl]-N-methylamino]-2,5-dideoxy-2-fl uoro-β-D-arabino- furanosyl]-5-ethyluracil as a white solid of melting point 143- 145°C.
Example 74
Conversion of 4,5-dichloroxanthene-9-carboxylic acid into the corresponding acid chloride followed by reaction with 1 -(5- amino-2,5-dideoxy-2-f I uoro- β-D-arabinofuranosy I) -5-ethy lu racil in a manner analogous to that described in Example 4 gave 1 -[5-
[(4,5-dichloro-9-xanthenyl)-carboxamido]-2,5-dideoxy-2-fluoro- β-D-arabinofuranosyl]-5-ethyluracil as a white solid of melting point 263-265°C . Example 75
A solution of 20 mg of 9,10-dihydro-9,9-dimethyl-9- silaanthracene-10-carboxylic acid in 10 ml of dimethyl¬ formamide was stirred and cooled to 0°C. 1 1 mg of 3H-1 ,2,3- triazolo[4,5-b]pyridin-3-ol, 21 mg of 1 -(5-amino-2,5-dideoxy- 2-fluoro-β-D-arabinofuranosyl)-5-ethyluracil and 14 mg of 1 - ethyl-3-(3'-dimethylaminopropyl)-carbodiimide were added in o succession and the mixture was stirred at room temperature for
16 hours. The mixture was evaporated and the resulting orange gum was purified by flash chromatography on silica gel using 1 % methanol in dichloromethane for the elution. Product-containing fractions were combined, washed with sodium hydrogen carbonate 5 solution and evaporated to give 1 -[2,5-dideoxy-2-fluoro-5- [(9, 1 0-di hyd ro-9, 9-di methy l-9-silaanthracen- 1 0-yl)-carbox- amido]-beta-D-arabinofuranosyl]-5-ethyluracil as a white solid; mass spectrum (FAB) m/e 524 (M+H]+.
0 The 9,10-dihydro-9,9-dimethyl-9-silaanthracene-1 0- carboxylic acid used as the starting material was prepared as fol l ows:
A solution of 1 15 mg of 9, 10-dihydro-9,9-dimethyl-9- 5 silaanthracene in 5 ml of tetrahydrofuran was added to a solution of lithium tetramethylpiperidine, prepared in 5 ml of tetra¬ hydrofuran from 0.56 ml of 2,2,6,6-tetramethylpiperidine and 1.25 ml of 2.5M butyllithium in hexane at -70°C. The mixture was stirred at -70°C for 1 hour and then carbon dioxide was 0 bubbled through the mixture for 20 minutes, during which time the red colour was discharged. The mixture was left to warm to room temperature and was evaporated under reduced pressure. The oily residue was taken up in 1 M potassium hydroxide and the solution was washed with ethyl acetate, acidified with 5 concentrated hydrochloric acid and extracted with dichloro¬ methane. The extracts were combined, dried over magnesium sulphate and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel using dichloromethane for the elution to give 9,10-dihydro-9,9- dimethyl-9-silaanthracene-10-carboxylic acid which was used directly as the starting material in the process.
Example 76
Reaction of 9,10-dihydro-10,10-dimethyl-9-anthracene- carboxylic acid with 1 -(5-amino-2,5-dideoxy-2-fluoro-β- D - arabinofuranosyl)-5-ethyluracil in a manner analogous to that described in Example 1 gave 1 -[2,5-dideoxy-2-fluoro-5-[(9, 10- dihydro-1 0, 1 0-dimethyl-9-anth racenyl)-carboxamido]-β- D - arabinofuranosyl]-5-ethyluracil as a white solid of melting point 135°C.
The 9, 1 0-dihydro-1 0, 10-dimethyl-9-anthracenecarboxylic acid used as the starting material was prepared as follows:
(A) A solution of 10 g of 2-benzylbenzoic acid in 200 ml of anhydrous methanol was treated with 5.5 ml of thionyl chloride at below 5°C and then heated to reflux for 3 hours. After cooling to room temperature the mixture was evaporated to give 10.8 g of methyl 2-benzylbenzoate as a colourless syrup.
(B) A solution of 6.32 g of methyl 2-benzylbenzoate in 70 ml of diethyl ether was treated with 100 ml of a 1 .4M solution of methyllithium in diethyl ether at below 5°C and the mixture was then heated at reflux for 3 hours. After cooling to room temperature the mixture was poured into 1 I of 10% ammonium chloride solution. The separated organic phase was evaporated to give 5.84 g of 2-benzyl-α,α-dimethylbenzyl alcohol as a colourless oil.
(C) A mixture of 4.8 g of 2-benzyl-α,α-dimethylbenzyl alcohol in 25 ml of 70% sulphuric acid was heated at 100°C for 90 minutes. After cooling to room temperature the mixture was diluted with 500 ml of water and then extracted twice with 300 ml of ethyl acetate. The organic extracts were combined, washed with saturated sodium hydrogen carbonate solution and then evaporated to give 4.4 g of 9,9-dimethyI-9,10-dihydro- anthracene as a brown oil which crystallized on standing; mass spectrum (El) m/e 208 [M]+.
(D) A solution of 4.4 g of 9,9-dimethyl-9,10-dihydroanthracene in 50 ml of anhydrous tetrahydrofuran was added dropwise to a mixture of 13.75 ml of diisopropylamine and 44.40 ml of a 2.5M solution of butyllithium in hexane in 150 ml of anhydrous tetrahydrofuran at -70°C. The mixture was stirred and carbon dioxide was bubbled through for 10 minutes at -70°C. After warming to 0°C 50 ml of water were added cautiously. The resulting mixture was diluted with 300 ml of water and extracted twice with 400 ml of petroleum ether (40-60°C). The aqueous phase was acidified and extracted twice with 150 ml of dichloromethane. The combined organic extracts were then evaporated. The residue was triturated with hexane and filtered to give 2.7 g of 9,10-dihydro-10,10-dimethyI-9-anthracene- carboxylic acid as a white solid of melting point 180°C .
Example 77
Reaction of 10,10-bis(trifluoromethyl)-9, 1 0-dihydro-9- anthracenecarboxylic acid with 5'-amino-2',5'-dideoxy-5- ethyluridine in a manner analogous to that described in Example 1 gave 1 -[5-[[1 0, 1 0-bis(trifluoromethyl)-9, 1 0-dihydro-9- anth race nyl]-carboxamido]-2,5-dideoxy- β-D-arabinofuranosy I] -5- ethyluracil; mass spectrum (ESI) m/e 598 [M+H]+.
The 10, 10-bis(trifluoromethyl)-9, 10-dihydro-9-anthracene carboxylic acid used as the starting material was prepared as fol lows:
(A) A solution of 37.8 g of 4,4-dimethyl-2-phenyl-2-oxazoline in 700 ml of anhydrous diethyl ether was stirred under nitrogen and cooled to -70°C. 200 ml of a 1.3M solution of secbutyl- lithium in cyclohexane was added over a period of 20 minutes. After stirring at -70°C for 15 minutes and then at 0°C for 30 minutes hexafluoroacetone was passed into the mixture until 60 g has been absorbed. The mixture was stirred at 5°C for 2 hours and then at room temperature for 16 hours. The mixture was poured into 2 I of water and extracted three times with 500 ml of diethyl ether. The combined extracts were washed with 50 ml of brine and then dried over anhydrous magnesium sulphate, filtered and evaporated to give 71 g of a yellow syrup. The syrup was suspended in 620 ml of 6M hydrochloric acid and the mixture was stirred and boiled under reflux for 12 hours. After cooling the mixture was extracted three times with 500 ml of dichloromethane. The combined extracts were washed with
500 ml of 2M sodium hydroxide solution and 200 ml of brine, then dried over anhydrous magnesium sulphate and evaporated. The residue was purified by flash chromatography on silica gel using ethyl acetate/hexane (1 :9 v/v) for the elution to give 22 g of 1 , 1 -bis(trifluoromethyl)-2-benzofuran-3(1 H)-one as a pale yellow oil; mass spectrum (FAB) m/e 270 [M+H]+.
(B) 150 ml of a 0.77M solution of phenylmagnesium bromide in diethyl ether was prepared and cooled in ice while a solution containing 22 g of 1 , 1 -bis(trifluoromethyl)-2-benzofuran-3(1 H)- one in 70 ml of diethyl ether was added over a period of 15 minutes. The mixture was stirred at 5-10°C for 2 hours, then poured into 1 1 of 1 M hydrochloric acid and extracted three times with 300 ml of diethyl ether. The combined extracts were washed with 150 ml of brine, dried over anhydrous magnesium sulphate, filtered and evaporated. The residue was recrystallized from hexane to give 25.8 g of 3,3-bis(trifluoromethyl)-1 ,3- dihydro-1 -phenyl-1 -isobenzofuranol as a white solid of melting point 124-126°C .
(C) A mixture of 10 g of 3,3-bis(trifluoromethyl)-1 ,3-dihydro- 1 -phenyl-1 -isobenzofuranol and 100 g of polyphosphoric acid was heated at 300-350°C for 1 hour. The mixture was poured into 1 I of ice/water and extracted three times with 100 ml of diethyl ether. The combined extracts were washed with 100 ml of saturated sodium hydrogen carbonate solution and 100 ml of brine, then dried over anhydrous magnesium sulphate, filtered and evaporated. The residue was purified by flash chromatography on silica gel using ethyl acetate/hexane (1 :19, v/v) for the elution to give 7.1 g of 10,10-bis(trifluoromethyl)-9-(10H)-anthracenone as a white solid of melting poing 108-110°C .
(D) A solution of 5 g of 10,10-bis(trifluoromethyl)-9(10H)- anthracenone in 50 ml of anhydrous tetrahydrofuran was stirred under nitrogen and cooled in ice/salt while 82 ml of a 1 M solution of borane in tetrahydrofuran were added slowly. The solution was stirred in an ice bath for 1 hour then at room temperature for 3 days. 20 ml of acetone were added and the mixture was stirred for a further 1 hour and then diluted with 400 ml of 1 M hydrochloric acid. The combined extracts were washed with 100 ml of water, 200 ml of saturated sodium hydrogen carbonate and 100 ml of water, 200 ml of saturated sodium hydrogen carbonate and 100 ml of brine, then dried over anhydrous magnesium sulphate, filtered and evaporated. The residue was dissolved in a mixture of 250 ml of ethanol and 10 ml of glacial acetic acid then hydrogenated at room temperature and pressure in the presence of 0.6 g of 10% palladium on carbon for 24 hours. The catalyst was removed by filtration and the filtrate was evaporated. The residue was purified by flash chromatography on silica gel using hexane for the elution to give 4.5 g of 9,9-bis(trifluoromethyl)-9,1 0- dihydroanthracene as a white solid of melting point 125-127°C .
(E) Carboxylation of 5.5 g of 9,9-bis(trifluoromethyl)-9, 10- dihydroanthracene in a manner analogous to that described in Example 5(C) gave 6.0 g of 10,10-bis(trifluoromethyl)-9,10- dihydro-9-anthracenecarboxylic acid as a white solid of melting poing 219-223°C.
Example 78
Reaction of 1 0, 10-bis(trifluoromethyl)-9,10-dihydro-9- anthracenecarboxylic acid with 1 -(5-amino-2,5-dideoxy-2- fluoro-β-D-arabinofuranosyl)-5-ethyluracil in a manner analogous to that described in Example 1 gave 1 -[5-[[10,10- bis(trifluoromethyl)-9, 1 0-dihydro-9-anthracenyl]-carboxamido]- 2,5-dideoxy-1 -fluoro-β-D-arabinofuranosyl]-5-ethyluracil of melting point 109-1 15°C .
Example 79
Reaction of spiro[anthracene-9(10H),1 '-cyclopropane]-10- carboxylic acid with 1 -(5-amino-2,5-dideoxy-2-fluoro-β- D - arabinofuranosyl)-5-ethyluracil in a manner analogous to that described in Example 1 gave 1 -[2,5-dideoxy-2-fluoro-5- [[spiro[anthracene-9(1 0H), 1 '-cyclopropan]-1 0-yl]-carboxamido]- β-D-arabinofuranosyl]-5-ethyluracil of melting point 204°C; mass spectrum (ESI) m/e 506 [M+HJ+.
The spiro[anthracene-9(10H),1 '-cyclopropane]-10- carboxylic acid used as the starting material was prepared as follows :
(A) A solution of 10 g of anthrone in 50 ml of methanol was heated to reflux temperature and then treated with 0.25 ml of piperidine followed by 12.5 ml of 40% formaldehyde solution.
After cooling to toom temperature the mixture was filtered to give 9.7 g of 10-methylene-9(10H)-anthracenone as a yellow solid of melting point 142°C .
(B) A suspension of 7.8 g of 10-methylene-9(10H)-anthra- cenone in 15 ml of anhydrous methanol was stirred at 0°C. A solution of 3 g of diazomethane in 300 ml of diethyl ether was added and the mixture was stirred at room temperature for 48 hours. The mixture was filtered and the filtrate was evaporated to give 6.8 g of spiro[anthracene-9(10H),1 '- cyclopropan]-10-one as a yellow crystalline solid of melting point 147°C.
(C) A solution of 2 g of spiro[anthracene-9(10H),1 '-cyclo- propan]-10-one in 20 ml of anhydrous tetrahydrofuran was treated with 27 ml of a 1 M solution of borane in tetrahydrofuran. After stirring ovemight at room temperature 150 ml of 1 M hydrochloric acid were added and the mixture was extracted twice with 150 ml of diethyl ether. The combined organic extracts were washed with 100 ml of 1 M hydrochloric acid and evaporated to give 2.8 g of spiro[anthracene-9(10H),1 '- cyclopropane] as a colourless oil; mass spectrum (El) m/e 206 [M]+.
(D) A solution of 1 .4 g of spiro[anthracene-9(1 OH), 1 '-cyclo¬ propane] in 20 ml of anhydrous tetrahydrofuran was added dropwise to a mixture of 4.2 ml of diisopropylamine and 13.3 ml of a 2.5M solution of butyllithium in hexane in 40 ml of anhydrous tetrahydrofuran at -70°C. The mixture was stirred and carbon dioxide was bubbled through for 20 minutes at -70°C. After warming to 0°C 20 ml of water were added cautiously. The resulting mixture was diluted with 30 ml of water and extracted twice with 100 ml of petroleum ether (40-60°C). The aqueous phase was acidified and extracted twice with 150 ml of dichloromethane. The combined organic extracts were evaporated to give 1 .57 g of spiro[anthracene-9(10),1 '-cyclopropane]-10,10- dicarboxylic acid.
(E) A solution of 1 .28 g of spiro[anthracene-9(10H),1 '-cyclo- propane]-10,10-dicarboxylic acid in 80 ml of methanol was heated at reflux ovemight. After cooling to room temperature the mixture was evaporated. The residue was dissolved in 200 ml of dichloromethane and washed with 100 ml of water. Evaporation of the organic layer give 0.9 g of spiro[anthracene-9(10H),1 '- cyclopropane]-10-carboxylic acid as a yellow solid of melting point 184°C.
The following Example illustrates a pharmaceutical preparation containing a compound of formula I. Example A
Tablets containing the following ingredients may be produced in a conventional manner:
I ngredient Per tablet
Compound of formula I 100 mg
Lactose 70 mg Maize starch 70 mg
Polyvinylpyrrolidone 5 mg
Magnesium stearate 5 mg
Tablet weight 250 mg

Claims

Claims
Compounds of the general formula
Figure imgf000068_0001
wherein
R1 to R8 each individually represent hydrogen, halogen, cyano, lower alkyl, halo-lower alkyl, lower alkoxy, lower cycloalkyl or aryl; or R1 and R2 together or R2 and R3 together or R3 and R4 together represent a fused benzene ring; R9 represents hydrogen or lower alkyl;
R1 0 represents hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl-lower alkyl, lower cycloalkyl- lower alkyl, acyl, 2-pyrrolidinylcarbonyl or a group of the formula -C(0)-CH(R12)-NH2;
RU represents halogen, lower alkyl, halo-lower alkyl or lower cycloalkyl; R12 represents hydrogen, lower alkyl, aryl-lower alkyl, lower alkylthio-lower alkyl, amino-lower alkyl or (4-imidazolyl)-lower alkyl;
W represents CH2, C(O) or C(S);
X represents CH2 or O;
Y represents hydrogen, fluorine or hydroxy; z represents C(R13)(R14), O, S, SO, S0 , Si(Rl 5)(Ri6) or
N(R17); and R1 3 and R14 each represent hydrogen, lower alkyl, halo-lower alkyl, aryl or aryl-lower alkyl or R1 3 and R1 4 together represent lower alkylene; R15 and R1 6 each represent lower alkyl; and
R 7 represents lower alkyl, and pharmaceutically acceptable salts of those compounds of formula I which are basic.
2. Compounds according to claim 1 , wherein R1 2 represent hydrogen, lower alkyl, aryl-lower alkyl, lower alkylthio-lower alkyl, amino-lower alkyl or (4-imidazolyl)- methyl and Z represents C(R13)(R1 4) in which R1 3 and R1 4 each represent hydrogen, O, S, SO, SO2 or N(R17).
3. Compounds according to claim 1 or claim 2, wherein R1 , R2, R3 and R4 each represent hydrogen; or two of R1 , R2, R3 and R4 represent hydrogen and the remaining two represent halogen; or three of R1 , R2, R3 and R4 represent hydrogen and the remaining one represents halogen, lower alkyl, halo-lower alkyl, lower alkoxy, lower cycloalkyl or aryl; or R and R2 together or R3 and R4 together represent a fused benzene ring.
4. Compounds according to any one of claims 1 to 3, wherein R5, R6, R7 and R8 each represent hydrogen; or two of R5, R6, R7 and R8 represent hydrogen and the remaining two represent halogen; or three of R5, R6, R7 and R8 represent hydrogen and the remaining one represents halogen or lower alkyl.
5. Compounds according to any one of claims 1 to 4, wherein R9 represents hydrogen or methyl.
6. Compounds according to any one of claims 1 to 5, wherein R10 represents hydrogen, lower alkyl, lower alkenyl, lower alkynyl or a group of the formula -C(0)-CH(R12)-NH2.
7. Compounds according to claim 6, wherein R1 2 represents lower alkyl, lower alkylthio-lower alkyl or amino- lower alkyl.
8. Compounds according to any one of claims 1 to 7, wherein R1 1 represents halogen or lower alkyl.
9. Compounds according to any one of claims 1 to 8, wherein W represents C(O) or C(S).
10. Compounds according to any one of claims 1 to 9, wherein X represents O.
11. Compounds according to any one of claims 1 to 10, wherein Y represents hydrogen or fluorine.
12. Compounds according to any one of claims 1 to 11, wherein Z represents O or SO2.
13. 2',5'-Dideoxy-5-ethyl-5'-[(9-xanthenyl)- carboxamido]uridine.
14. 1 -[2,5-Dideoxy-2-fluoro-5-[(9-xanthenyl)-carbox- amido]-β-D-arabinofuranosyl]-5-ethy luracil.
15. 1-[5-[(2-Chloro-9(RS)-xanthenyl)-carboxamido]-2,5- dideoxy-2-fluoro-β-D-arabinofuranosyl]-5-ethyluracil.
16. 1-[5-[(4-Chloro-9(RS)-xanthenyl)-carboxamido]-2,5- dideoxy-2-fluoro-β-D-arabinofuranosyl]-5-ethyl uracil.
17. 1-[2,5-Dideoxy-2-fluoro-5-[(4,5-difluoro-9- xanthenyl)carboxam id o]-β-D-arabinofuranosyl]-5-ethyl uracil.
18. 1- [2, 5-Dideoxy-2-f I uoro-5-[(9-th ioxantheny I) - carboxam ido] -β-D-arabinofuranosyl]-5-ethyl uracil S,S-dioxide.
19. 1 -[2, 5-Dideoxy-2-f I uoro-5-[(4-fluoro-9(RS)-th io¬ xantheny I) -carboxam ido]-β-D-arabinofuranosy I] -5-ethy I uracil S,S-dioxide.
20. 1-[2,5-Dideoxy-2-fluoro-5-[N-[[4-(trifluoromethyl)- 9-(RS)-xanthenyl]-carbonyl]-N-methylamino]-β-D-arabino- furanosyl]-5-ethyl uracil.
21. 1-[5-[N-[(4,5-Dichloro-9-xanthenyl)-carbonyl]-N- met hy I am i n o] -2, 5-dideoxy-2-f I uoro- β-D-arabinofuranosy I] -5- ethyluracil.
22. 1-[2,5-dideoxy-2-fluoro-5-[N-[4-(trifluoromethyl)-9- (RS)-xanthenyl]-carbonyl]-N-methylamino]-3-0-(L-valyl)-β-D- a rabi nof u ran osy l]-5-ethy I uracil.
23. A compound according to claim 2 selected from:
1 -[5-deoxy-5-[(9 -xant he ny I) -carboxam ido] -β-D-a rabi n o- fu ran osy I] -5-ethy I uracil;
1-[2,5-dideoxy-2-fluoro-5-[(4-methyl-9(RS)-xanthenyl)- carboxamido]-β-D-arabinofuranosyl]-5-ethyluracil;
1-[2,5-dideoxy-2-fluoro-5-[(4-cyclohexyl-9(RS)- xan the ny I )-carboxam ido]- β-D-arabinofuranosy I] -5-ethy I uracil;
1-[2,5-dideoxy-2-fluoro-5-[(4-phenyl-9(RS)-xanthenyl)- carboxamido]-β-D-arabinofuranosyl]-5-ethyl uracil; 5'-[(1-chloro-9(RS)-xanthenyl)-carboxamido]-2',5'- dideoxy-5-ethyluridine;
5'-[(3-chloro-9(RS)-xanthenyl)-carboxamido]-2',5'- dideoxy-5-ethyluridine;
1-[5-[(2,7-dichloro-9-xanthenyl)-carboxamido]-2,5- dideoxy-2-fluoro-β-D-arabinofuranosyl]-5-ethyluracil;
1-[5-[(2,3-dichloro-9(RS)-xanthenyl)-carboxamido]-2,5- dideoxy-2-fluoro-β-D-arabinofuranosyl]-5-ethyl uracil;
1-[5-[(2,4,5,7-tetrachloro-9-xanthenyl)-carboxamido]-2,5- dideoxy-2-fluoro-β-D-arabinofuranosyl]-5-ethyluracil; 1-[2,5-dideoxy-2-fluoro-5-[(2,7-difluoro-9-xanthenyl)- ca rboxam i d o]-β-D-arabinofu ran osyl]-5-ethyl uracil;
1-[2,5-dideoxy-2-fluoro-5-[(4,5-difluoro-9-xanthenyl)- carboxami do] -β-D-arabinofuranosyl]-5-ethyl uracil;
1-[2,5-dideoxy-2-fluoro-5-[[(4-(trifluoromethyl)-9(RS)- xanthenyl]-carboxamido]-β-D-arabinofuranosyl]-5-ethyluracil;
1-[2,5-dideoxy-2-fluoro-5-[(4-methoxy-9(RS)-xanthenyl)- carboxami do] -β-D-arabinofuranosyl]-5-ethyl uracil;
5'-[(12H-benzo[a]xanthen-12(RS)-yl)-carboxamido]-2',5'- dideoxy-5-ethyl uri dine;
1-[5-[(benzo[c]xanthen-7(RS)-yl)-carboxamido]-2,5- dideoxy-2-fluoro-β-D-arabinofuranosyl]-5-ethy I uracil;
2',5'-dideoxy-5'-[(9,10-dihydro-9-anthracenyl)-carbox- amido]-5-ethyluridine;
2', 5'-d id eoxy-5-ethy I -5'-[(9-th ioxantheny I) -carboxam idoj- uridine;
1 -[2, 5-dideoxy-2-f luo ro-5-[(9-th ioxantheny I)- carboxamido]-β-D-arabinofuranosyl]-5-ethyl uracil; 5'-[(2-chloro-9(RS)-thioxanthenyl)-carboxamido]-2',5'- d ide oxy-5-ethyl uri dine;
1 -[5- [(4-chloro-9(RS)-th ioxantheny I) -carboxam ido] -2, 5- dideoxy-2-fluoro-β-D-arabinofuranosyl]-5-ethy I uracil;
1-[2,5-dideoxy-2-fluoro-5-[(4-fluoro-9(RS)-thioxan- thenyl)-carboxamido]-β-D-arabinofuranosyl]-5-ethyluracil;
1-[2,5-dideoxy-2-fluoro-5-[(4,5-difluoro-9-thioxan- thenyl)-carboxamido]-β-D-arabinofuranosyl]-5-ethyl uracil;
1-[2,5-dideoxy-2-fluoro-5-[(4,5-difluoro-9- thi oxantheny I) -carboxam ido]-β-D-arabin of u ran osy l]-5-ethy I uracil S-oxide;
2', 5'-dideoxy-5-e thy I -5' -[(9 -thi oxantheny I) -carboxam ido] - uridine S-oxide;
1 -[5-[(4-ch I oro-9(RS) -thi oxantheny I) -carboxam ido]-2, 5- dideoxy-2-fluoro-β-D-arabinofuranosyl]-5-ethyluracil S,S- dioxide;
2',5'-dideoxy-5-ethyl-5'-[(10-methyl-9-acridanyl)- carboxamido]uridine;
5-ethy I- 1 -[3(S)-hydroxy-4( R)-[(9-xantheny l)-carboxamido- methyl]-1(R)-cyclopentyl]uracil; 1-[3(R)-[(2,7-dichloro-9-xanthenyl)-carboxamidomethyl]-
4(S)-hydroxy-1(R)-cyclopentyl]5-ethyluracil;
5-ethy 1-1 -[3(S)-hydroxy-4(R)-[(9-thioxanthenyl)- carboxamidomethyl]-1(R)-cyclopentyl]-uracil;
5-ethyl-1-[3(S)-hydroxy-4(R)-[(9-thioxanthenyl)- carboxamidomethyl]-1(R)-cyclopentyl]-uracil S,S-dioxide;
2',5'-dideoxy-5-ethyl-5'-[(9-xanthenyl)-thiocarboxamido]- uridine;
1-[2,5-dideoxy-2-fluoro-5-[(9-xanthenyl)-thiocarbox- amido]-β-D-arabinofuranosyl]-5-ethyluracil;
1-[2,5-dideoxy-2-fluoro-5-[(9-xanthenyl)-methylamino]-β- D-arabinofuranosyl]-5-ethyl uracil;
1-[2,5-dideoxy-2-fluoro-5-[N-methyl-N-(9-xanthenyl- carbonyl)-amino]-β-D-arabinofuranosyl]-5-ethyluracil;
1-[2,5-dideoxy-2-fluoro-5-[N-(4-phenyl-9(RS)-xanthenyl- carbonyl)-N -methy lamino]-β-D-arabinofuranosyl]-5-ethyl uracil;
1-[2,5-dideoxy-2-fluoro-5-[N-methyl-N-[(4,5-dimethyl-9- xant he ny I )-carbony I] -ami no] -β-D-arabinofuranosy I] -5-ethy I uracil ; 1-[2,5-dideoxy-2-fluoro-5-[N-methyl-N-(9-thioxanthenyl- carbony I) -ami no] -β-D-arabinofuranosy I] -5-ethy I uracil;
1-[2,5-dideoxy-2-fluoro-5-[N-methyl-N-(9-thioxanthenyl- carbonyl) -am ino]-β-D-arabinofuranosyl]-5-ethyl uracil S,S- dioxide; 1-[2,5-dideoxy-3-0-ethyl-2-fluoro-5-[(9-thioxanthenyl)- carboxam ido] -β-D-arabinofuranosy I] -5-ethy I uracil;
1-[2,5-dideoxy-3-0-ethyl-2-fluoro-5-[(9-thioxanthenyl)- carboxamido]-β-D-arabinofuranosyl]-5-ethyluracil S,S-dioxide;
1- [3-0- (cyclohexy I methy I )-2, 5-d ideoxy-2-f I uoro-5-[(9- th ioxantheny I )-carboxam ido] -β-D-arabinofu ran osy l]-5- ethyluracil;
1 -[3-0- (cyclo hexyl methy I) -2, 5-d ide oxy-2-f luo ro-5-[(9- thioxanthenyl)-carboxamido]-β-D-arabinofuranosyl]-5-ethyl uracil S,S-dioxide; 1 -[3-O-ally I -2, 5-d id eoxy-2-f luo ro-5-[( 9-th ioxantheny I) - carboxamido]-β-D-arabinofuranosyl]-5-ethyl uracil;
1-[3-0-allyl-2,5-dideoxy-2-fluoro-5-[(9-thioxanthenyl)- carboxam ido]- β-D-arabinofu ranosyl]-5-ethyl uracil S,S-dioxide; 1 -[2, 5-dideoxy-2-f luo ro-3-O-propargy I -5 -[(9-th ioxantheny I)- carboxam i do]- β-D-arabinofu ranosyl]-5-ethy I uracil;
1- [2, 5-dideoxy-2-f luo ro-3-O-propargy I -5-[(9-th ioxan¬ theny I) -carboxam ido]-β-D-arabinofuranosyl]-5-ethyluracil S,S- dioxide;
3-0-benzyl-2,5-dideoxy-5-ethyl-5'-[(9-xanthenyl)- carboxamidoj-uridine;
1-(2,5-dideoxy-2-fluoro-3-0-(4-fluorobenzyl)-5-[(9- xanthenyl)-carboxamido]-β-D-arabinofuranosyl)-5-ethyluracil;
2',5'-dideoxy-5-ethyl-3'-0-palmitoyl-5'-[(9-xanthenyl)- carboxamido]-uridine;
2',5'-dideoxy-5-ethyl-3'-0-(3,4,5-trimethoxybenzoyl)-5'- [(9-xanthenyl)-carboxamido]-uridine;
2\5,-dideoxy-5-ethyl-3'-0-(L-methionyl)-5'-[(9- xanthenyl)-carboxamido]-uridine;
2',5'-dideoxy-5-ethyl-3'-0-(L-lysyl)-5'-[(9-xanthenyl)- carboxamido]-uridine;
5'-deoxy-5'-[(9-xanthenyl)-carboxamido]-thymidine;
5-cyclopropyl-2',5'-dideoxy-5'-[(9-xanthenyl)- carboxamidoj-uridine;
2',5'-dideoxy-5-(pentafluoroethyl)-5'-[(9-xanthenyl)- carboxamido]-uridine;
1 -[2, 5-dideoxy-2-f luo ro-5-[(9-th ioxantheny I)- carboxamido]-β-D-arabinofuranosyl]-5-iodouracil; 1-[2,5-dideoxy-2-fluoro-5-[(9-thioxanthenyl)- carboxam ido]- β-D-arabinofu ranosyl]-5-iodouracil S,S-dioxide;
1-[2,5-dideoxy-2-fluoro-5-[(9-xanthenyl)-carboxamido]-β- L-a rab in of u ran osy I] -5-ethy I uracil;
1 -[5-[(2,7-dich loro-9-xan the ny I) -carboxam ido] -2,5- dideoxy-2-fluoro-β-L-arabinofuranosyl]-5-ethyluracil;
1-[2,5-dideoxy-2-fluoro-5-[(9-thioxanthenyl)- carboxamido]-β-L-arabinofuranosyl]-5-ethyl uracil; and
1-[2,5-dideoxy-2-fluoro-5-[(9-thioxanthenyl)- carboxam ido]- β-L-arabinofuranosyl]-5-ethyl uracil S,S-dioxide.
24 A compound according to claim 1 selected from:
5'-[(2-Chloro-9(RS)-xanthenyl)-carboxamido]-2',5'- dideoxy-5-ethyl uridine, 1-[5-[N-[(4-methoxy-9(RS)-xanthenyl)-carbonyl]-N- methylamino]-2,5-dideoxy-2-fluoro-β-D-arabinofuranosyl]-5- ethyluracil,
1-[5-[(4,5-dichloro-9-xanthenyl)-carboxamido]-2,5- dideoxy-2-fluoro-β-D-arabinofuranosyl]-5-ethyluracil, 1-[2,5-dideoxy-2-fluoro-5-[(9,10-dihydro-9,9-dimethyl-9- silaanthracen-10-yl)-carboxamido]-β-D-arabinofuranosyl]-5- ethyluracil,
1-(2,5-dideoxy-2-fluoro-5-[(9,10-dihydro-10,10-dimethyl- 9-ant h race ny I) carboxam id o]-β-D-arabinofu ran osy I]-5-ethy I uracil ,
1 -[5-[[1 0 , 1 0-bis(trifluoromethyl)-9, 1 0-dihyd ro-9-anth ra¬ ce ny I] -carboxam ido]-2,5-dideoxy- β-D-arabinofu ranosy I] -5-ethy I- u racil , 1 -[5-[[1 0, 1 0-bis(trif I uoromethyl)-9, 1 0-dihyd ro-9-anth ra¬ ce nyl]-carboxamido]-2,5-dideoxy-2-fluoro-β-D- arabinofu ranosy l]-5-ethyl uracil and
1 -(2,5-dideoxy-2-fluoro-5-[[spiro[anthracene-9( 1 0H) , 1 '- cycl opropan]-1 0-y I] -carboxam id o]-β-D-arabinof u ranosy l]-5- ethyluracil.
25. A compound according to any one of claims 1 to 24 or a pharmaceutically acceptable acid addition salt of such a compound which is basic for use as a therapeutically active substance.
26. A compound according to any one of claims 1 to 24 or a pharmaceutically acceptable acid addition salt of such a compound which is basic for use as an antiviral agent.
27. A process for the manufacture of the compounds of formula I set forth in claim 1 and pharmaceutically acceptable acid addition salts of those compounds which are basic, which process comprises:
a) for the manufacture of a compound of formula I in which R1 0 represents hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl-lower alkyl or lower cycloalkyl-lower alkyl, W represents C(O) and Z represents C(R 3)(R14), O, S, Si(Rl5)(Rl 6) or N(R17), reacting an amine of the general formula
Figure imgf000075_0001
wherein R9, R1 1 , X and Y have the significance given in claim 1 and R1 0a represents hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl-lower alkyl or lower cycloalkyl-lower alkyl , with an acid of the general formula
Figure imgf000076_0001
wherein R1 to R8 have the significance given in claim 1 and
Z1 represents C(R13)(R14), O, S, Si(Ri5)(Ri 6) 0r N(R17) , or a reactive derivative thereof, or
b) for the manufacture of a compound of formula I in which R1 0 represents hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl-lower alkyl or lower cycloalkyl-lower alkyl, W represents C(S) and Z represents C(R13)(R14), 0, S, Si(Ri 5)(Ri 6) 0r N(R17), reacting an amine of formula (II) set forth earlier in this claim with a carbodithioate of the general formula
OV)
Figure imgf000076_0002
wherein R1 to R8 have the significance given in claim 1 , Z1 has the significance given earlier in this claim and R1 8 represents lower alkyl, o r
c) for the manufacture of a compound of formula I in which R1 0 represents hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl-lower alkyl or lower cycloalkyl-lower alkyl, W represents CH2 and Z represents C(R1 3)(R14), O, S, Si(R15)(Ri 6) 0r N(R17), reductively alkylating an amine of formula (II) set forth earlier in this claim with an aldehyde of the general formula
Figure imgf000077_0001
wherein R1 to R8 have the significance given in claim 1 and Z1 has the significance given earlier in this claim, o r
d) for the manufacture of a compound of formula I in which Z represents SO or SO2, appropriately oxidizing a compound of formula I in which Z represents S, or
e) for the manufacture of a compound of formula I in which R1 0 represents acyl, acylating a compound of formula I in which R1 0 represents hydrogen, or
f ) for the manufacture of a compound of formula I in which R1 0 represents -C(0)-CH(R12)-NH2, reacting a compound of formula I in which R1 0 represents hydrogen with a protected amino acid of the general formula HOOC-C(R1 a)-NHRi9 (V I)
wherein R1 2a has any of the values accorded to R12 in claim 1 but any amino group present is protected, and R1 9 represents an amino protecting group, and cleaving off the protecting group(s) present in the reaction product, and
o g) if desired, converting a basic compound of formula I obtained into a pharmaceutically acceptable acid addition salt.
28. A medicament, especially an antiviral medicament, containing a compound according to any one of claims 1 to 24 or a 5 pharmaceutically acceptable acid addition salt of such a compound which is basic and a compatible pharmaceutical carrier.
29. The use of a compound according to any one of claims 1 to 24 or a pharmaceutically acceptable acid addition salt of 0 such a compound which is basic for the production of antiviral medicaments.
30. The invention as hereinbefore described.
5
PCT/EP1996/003259 1995-08-04 1996-07-24 Pyrimidine nucleosides WO1997006178A1 (en)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006025920A3 (en) * 2004-06-19 2006-08-17 Human Biomolecular Res Inst Modulators of central nervous system neurotransmitters
JP2008094831A (en) * 2006-09-12 2008-04-24 Wako Pure Chem Ind Ltd New dideoxynucleoside derivative
CN102942552A (en) * 2012-10-29 2013-02-27 哈尔滨医科大学 3,11-disubstituted-14-aryl-14H-dibenzo[a,j]xanthene derivatives, preparation methods and uses thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0256400A2 (en) * 1986-08-12 1988-02-24 F. Hoffmann-La Roche Ag Pyrimidine derivatives, their preparation and medicaments containing these derivatives
EP0257378A1 (en) * 1986-08-18 1988-03-02 F. Hoffmann-La Roche Ag Pyrimidine derivatives, their preparation and medicaments containing these derivatives
EP0617046A1 (en) * 1993-03-18 1994-09-28 Nippon Chemiphar Co., Ltd. Nucleoside derivatives and antiherpes composition

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0256400A2 (en) * 1986-08-12 1988-02-24 F. Hoffmann-La Roche Ag Pyrimidine derivatives, their preparation and medicaments containing these derivatives
EP0257378A1 (en) * 1986-08-18 1988-03-02 F. Hoffmann-La Roche Ag Pyrimidine derivatives, their preparation and medicaments containing these derivatives
EP0617046A1 (en) * 1993-03-18 1994-09-28 Nippon Chemiphar Co., Ltd. Nucleoside derivatives and antiherpes composition

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006025920A3 (en) * 2004-06-19 2006-08-17 Human Biomolecular Res Inst Modulators of central nervous system neurotransmitters
JP2008094831A (en) * 2006-09-12 2008-04-24 Wako Pure Chem Ind Ltd New dideoxynucleoside derivative
CN102942552A (en) * 2012-10-29 2013-02-27 哈尔滨医科大学 3,11-disubstituted-14-aryl-14H-dibenzo[a,j]xanthene derivatives, preparation methods and uses thereof
CN102942552B (en) * 2012-10-29 2015-06-24 哈尔滨医科大学 3,11-disubstituted-14-aryl-14H-dibenzo[a,j]xanthene derivatives, preparation methods and uses thereof

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