Prodrugs

Details Prodrugs Prodrugs

1999-02-12

2002-10-01

Wilson, James O. (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C514S046000, C514S049000, C514S050000, C536S027140, C536S028200, C536S028500, C536S028520, C536S028540, C536S028550

Reexamination Certificate

active

06458772

ABSTRACT:

TECHNICAL FIELD
This invention relates to the field of prodrugs, that is novel derivatives of otherwise known and proven drugs which release that drug in active or pro-active form in vivo. The enzymatic and/or chemical cleavage of the compounds of the present invention occurs in such a manner that the parent drug is released and the moiety or moieties split off remain non-toxic or are metabolized so that non-toxic or acceptable amounts of metabolic products are produced. The present compounds thus modify the in vivo availability of the parent compound compared to what would be the case if the parent compound was to be administered itself. For instance the prodrugs of the invention may give higher bioavailabities, varied bioavailability kinetics or bioavailabilities with a decreased interpersonal spread.
A first aspect of the invention relates to the field of nucleoside analogues, such as antivirals including inhibitors of retroviral reverse transcriptase and the DNA polymerase of Hepatitis B Virus (HBV). The invention provides novel compounds with favourable pharmaceutical parameters, methods for their preparation, pharmaceutical compositions comprising these compounds and methods employing then for the inhibition of viral and neoplastic diseases including HBV and HIV.
BACKGROUND TO THE INVENTION
International patent application no. WO 88/00050 describes the antiretroviral and anti-HBV activity of a series of 3′-fluorinated nucleosides, including the compounds 2′, 3′-dideoxy, 3′-fluoroguanosine (LG) and 3′-fluorothymidine FLT). The latter compound underwent clinical evaluation as an anti-mECV agent and although its antiviral activity and pharmacokinetics were good, it showed unexpected toxicity (Flexner et al, J Inf Dis 170(6) 1394-403 (1994)). The former compound FLG is very active in vitro however the present inventors have detected that its bioavailability is so poor—around 4%—that the in vivo utility of the compound has thus far been limited to intraperitoneally or subcutaneously administered animal models. U.S. Pat. No. 4,963,662 discloses generically a series of 3′-fluorinated nucleosides and corresponding triphosphates and specifically describes the preparation of the 5′-O-palmitoyl derivative of FLT, without reporting any improvement in bioavailability. International patent application WO 93 13778 describes FLG derivatives modified at the 6-position of the base, in particular with n-propoxy, cyclobutoxy, cyclopropylamino, piperidino or pyrrolidino. International patent application no. 93 14103 describes FLG derivatives where the oxygen at the guanine 6-position is replaced with amino, ether, halo or sulphonate.
BRIEF DESCRIPTION OF THE INVENTION
In accordance with one aspect of the invention there are provided compounds of the formula I
wherein:
R
1
is selected from
hydroxy, amino or carboxy; optionally having esterified/amide bonded thereon a C
4
-C
22
saturated or unsaturated, optionally substituted fatty acid or alcohol or an aliphatic L-amino acid;
R
2
is the residue of an aliphatic L-amino acid;
L
1
is a trifunctional linker group;
L
2
is absent or a difunctional linker group,
and pharmaceutically acceptable salts thereof.
The invention further provides pharmaceutical compositions comprising the compounds and salts of formula I and pharmaceutically acceptable carriers or diluents therefor. Additional aspects of the invention provide methods for the inhibition of HBV and retroviruses such as HIV, comprising bringing a compound or salt of the formula I into contact with a retrovirus or HBV, for example by administering an effective amount of the compound or salt to an individual afflicted with a retrovirus or HBV. The invention also extends to the use of the compounds or salts of formula I in therapy, for example in the preparation of a medicament for the treatment of retroviral or HBV infections.
In treating conditions caused by retroviruses such as HIV, or HBV, the compounds or salts of formula I are preferably administered in an amount of 50 to 1 500 mg once, twice or three times per day, especially 100 to 700 mg twice or thrice daily. It is desirable to achieve serum levels of the active metabolite of 0.01 to 100 &mgr;g/ml, especially 0.1 to 5 &mgr;g/ml.
Where R
1
is a fatty acid residue, it preferably has in total an even number of carbon atoms, advantageously decanoyl (C
10
), lauryl (C
12
), myristoyl (C
14
), palmitoyl (C
16
), stearoyl (C
18
), eicosanoyl (C
20
) or behenoyl (C
22
). The fatty acid preferably has in total 10 to 22, and more preferably 16 to 20 carbon atoms, especially 18. The fatty acid may be unsaturated and have one to three double bonds, especially one double bond. Unsaturated fatty acids preferably belong to the n-3 or n-6 series. Convenient unsaturated R
1
groups include those derived from the monounsaturated acids myristoleic, myristelaidic, palmitoleic, palmitelaidic, n6-octadecenoic, oleic, elaidic, gandoic, erucic, brassidic acids or multiply unsaturated fatty acids such as linoleic, &ggr;-linolenic, arachidonic acid and &agr;-linolenic acid. Preferably, however, R1 as a fatty acid is saturated as these compounds tend to have superior stability and shelf life.
R
1
as fatty alcohol residue preferably corresponds to one of the above described fatty acids. Alternatively the fatty alcohol may comprise residues of shorter alcohols, such as methanol ethanol or propanol.
R
1
as a saturated or unsaturated fatty acid or alcohol may optionally be substituted with up to five similar or different substituents independently selected from the group consisting of hydroxy, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, C
1
-C
6
alkoxy C
1
-C
6
alkyl, C
1
-C
6
alkanoyl, amino, halo, cyano, azido, oxo, mercapto and nitro, and the like.
Suitable aliphatic amino acids for R
2
and, if present R
1
, include L-alanine, L-leucine, L-isoleucine and most preferably L-valine. For ease of synthesis it is preferred that both R
2
and R
1
are residues of aliphatic amino acids, preferably the same residue.
The expression trifunctional in the context of the first linker group L
1
means that the linker has at least three functional groups, including at least two functional groups derived from respective hydroxy, amine or carboxyl groups, the amine and hydroxy function(s) being available for esterification/amide bonding with the carboxy functions of R
1
and R
2
whereas a carboxy function(s) on the linker is available for amide bonding with the free &agr;-amine function of R
2,
or R
1
as the case may be, or esterification with R
1
as a fatty alcohol. Where R
1
itself defines an hydroxy, amide or carboxy group, the hydroxy group being presently favoured of the three, one of said functions on the trifunctional linker simply comprises this hydroxy, amide or carboxy group.
The trifunctional linker further comprises a third functional group for linkage with either the optional second linker group L
2
illustrated in more detail below, or the hydroxy group at the 5′ position of the mother nucleoside, such as 2′,3′-dideoxy-3′-fluoroguanosine. Appropriate third functional groups will depend on the nature of the cooperating function on optional linker group L
2
, if present, and may include amino, hydoxy, carbonyl, sulfonyl, phosphoryl, phosphonyl, carbamoyl and the like. If L
2
is absent, this third functional group or, first linker L
1
will typically comprise a carboxyl function which can esterify with the 5′-O group of the nucleoside analogue.
Preferably the functional groups on the trifunctional linker which cooperate with R
1
and R
2
are hydroxyl functions and the linkage is an ester linkage with the carboxyl functions of an R
1
fatty acid, if present, and R
2
. A further preferred embodiment comprises a free hydroxy group as R
1
and an hydroxyl function on the linker esterified to the carboxy function of R
2
. An alternative embodiment comprises an (optionally protected) carboxyl group as R
1
and an hydroxyl function on the linker esterified to a carboxy function on R
2
.
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