Diketoacid-derivatives as inhibitors of polymerases

Details Diketoacid-derivatives as inhibitors of polymerases Diketoacid-derivatives as inhibitors of polymerases

2001-01-26

2002-12-10

Travers, Russell (Department: 1617)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Radical -xh acid, or anhydride, acid halide or salt thereof...

Reexamination Certificate

active

06492423

ABSTRACT:

TECHNICAL FIELD
The present invention relates to compounds useful as enzyme inhibitors, in particular as inhibitors of enzymes involved in the transfer of phosphoryl groups and, especially as inhibitors of polymerases. The invention further relates to pharmaceutical compositions containing such compounds, and to their use in the treatment of viral infections.
Polymerases are the enzymes which catalyse the formation of phosphodiester bonds in RNA and DNA. They play an essential role in viral replication and, therefore, are an important target in the fight against viral diseases such as human immunodeficiency virus (HIV), hepatitis, and poliomyelitis.
BACKGROUND ART
U.S. Pat. No. 5,475,109 describes dioxobutanoic acids substituted with piperidine or similar N-substituted saturated cycloalkyls as inhibitors of the cap-dependent endonuclease of influenza virus.
DISCLOSURE OF THE INVENTION
The present inventors have discovered that a range of diketoacids have utility as enzyme inhibitors and, in particular, as polymerase inhibitors and more particularly as inhibitors of hepatitis C NS5 RNA-dependent RNA polymerase, HBV DNA-dependent RNA polymerase and HIV DNA-dependent DNA polymerase. Their investigations indicate that these compounds may act by interfering with the binding of phosporyl groups at the active site of the enzyme and may, therefore, have broad application in inhibiting enzymes involved in the transfer of phosphoryl groups.
According to a first aspect of the present invention there is provided a compound of formula A shown below. This compound is suitable for therapeutic use, for instance as an enzyme inhibitor.
Optionally, the compound may be in the form of a pharmaceutically acceptable salt or ester, which can be hydrolysed in vivo to the corresponding diketoacid.
In formula A, the group R is an organic moiety which contains from 2 to 24, preferably 4 to 20, most preferably 6 to 17 carbon atoms in total. R includes an optionally substituted cyclic or heterocyclic group in which the atom directly bonded to the adjacent carbonyl in the diketoacid is part of the ring structure. Preferably, this atom is a carbon atom.
The ring which is thus bonded to the carbonyl group is preferably a 3 to 8 membered ring, particularly a 4 to 6 membered ring.
Thus, for example, R may be selected from:
(i) optionally substituted aromatic groups, especially those including six membered rings, such as phenyl and naphthyl;
(ii) optionally substituted heteroaryl groups especially those including five and six membered rings such as thiophene, pyrrole, furan, imidazole, pyridyl, pyrimidyl, and pyridazyl; the heteroaryl ring may, optionally be fused to another ring;
(iii) optionally substituted cycloalkyl groups, especially those including five or six membered rings such as cyclopentyl, cyclohexyl and adamantyl;
(iv) optionally substituted cycloalkenyl groups, especially those including five or six numbered rings such as cyclohexenyl, cyclopentenyl;
(v) optionally substituted cyclic heteroalkyl groups, especially those including five or six numbered rings such as piperidyl, pyrrolidyl, tetrahydrofuranyl, and tetrahydropyranyl; in this class 4-piperidyl rings substituted with an aryl group at carbon 4 and on acyl or sulfonyl substituent at N1 are preferred.
In the case of optional substitution, one or more substituents may be present and a wide variety of substituents are possible. Preferred optional substituents for all compounds of the present invention are set out in the following list:
(a)—OH;
(b)—SH;
(c)—halogen, such as fluorine, chlorine or bromine,
(d)—CO
2
H;
(e)—CN;
(f)—NO
2
;
(g)—NR
1
R
2
wherein each of R
1
and R
2
is selected from H and lower alkyl groups having 1 to 6 carbon atoms; or R
1
and R
2
together form a ring including 4 to 6 carbon atoms;
(h)—SO
2
NR
1
R
2
where R
1
and R
2
are as defined above;
(i)—CONH
2
, —NHCO
2
H, or —NHCOCOOH;
(j) an alkyl (or alkenyl or alkynyl group) group having 1 to 12 (2 to 12) carbon atoms, preferably 1 to 7 (2 to 7) carbon atoms optionally substituted by any one or more of the groups (a)-(i) above and/or optionally interrupted by a group selected from —O—, —S—, —NR
3
—,
—CO
2
—, —OCO—, —CONR
3
—, —NR
3
CONR
3
—, —SO
2
—, —NR
3
SO
2
—, and —SO
2
NR
3
—; where each R
3
independently is H or lower alkyl of 1 to 6 carbon atoms;
(k) an aryl or heteroaryl group having 2 to 10 carbon atoms optionally substituted with any one or more of groups (a) to (j) above;
(l) an aralkyl or heteroaralkyl group having 3 to 16 carbon atoms optionally substituted with any one or more of groups (a)-(j) above and/or in which the alkyl part of the group is optionally interrupted by a group selected from —O—, —S—, —NR
3
—,
—CO
2
—, —OCO—, —CONR
3
—, —NR
3
CONR
3
—, —SO
2
—, —NR
3
SO
2
—, and —SO
2
NR
3
—; where R
3
is as defined above;
(m)
where R
4
is an alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, or heteroaralkyl group as such groups are defined above at (j), (k) and (l);
(n)
where R
4
is as defined above;
(o) —OR
4
where R
4
is as defined above;
(p)
where R
4
is as defined above;
(q) —SO
2
R
4
where R
4
is as defined above;
(r) —NHR
4
or —N(R
4
)
2
where R
4
is as defined above;
(s) —NHSO
2
R
4
or —SO
2
NHR
4
, where R
4
is as defined above;
(t) —SR
4
and each of optional substituents (j) to (t) above may optionally itself be substituted by one or more groups selected from (j) to (t).
A preferred class of compounds of formula A is represented by formula E:
in which Ar is an optionally substituted aryl or heteroaryl group. Optional substituents may be selected from the list of preferred substituents set out above. Within this class of preferred compounds two especially preferred groups are set out below (formulas F and G)
R
5
, R
6
, R
7
and R
8
are, independently H or are selected from the optional substituents listed above and R
7
and R
8
taken together may form a 4 to 7, preferably 5 or 6 membered ring; and X is O, S, NH, or NR
4
where R
4
is as defined above.
In compounds of formula F, (which are optionally substituted phenyl diketoacids) ortho, meta and para substitution are possible.
In general, it is preferred that there is a single substituent, preferably at the position which is ortho- or meta- to the diketoacid group. Substitution at the meta-position is especially preferred. Where two substituents are present, then preferably the phenyldiketoacid is 2,5-substituted; 3,5-substitution is also possible, as is 2,4-substitution provided, in the latter case, that the substituent at the 4-position is relatively small (e.g. methyl). Disubstitution at the 2,3- and 2,6-positions is, in general, not preferred.
Preferred substituents, especially at the ortho and meta positions, are ether groups of formula (o) above (i.e. —OR
4
), hydroxyl, and —NHSO
2
R
4
. It is generally preferred that no more than one substituent be —OR
4
and/or —NHSO
2
R
4
.
Preferred examples of —OR
4
groups which may be found at the ortho and meta positions and particularly at the meta position include:
—OCH
2
Ar or, less preferably —O(CH
2
)
2
Ar where Ar is an optionally substituted aryl or heteroaryl group and is particularly preferably an optionally substituted phenyl group. Examples of preferred substituents on the aryl group, and especially on the phenyl ring include halogens, especially fluorine and chlorine, and electron-withdrawing groups such as —CN, —CO
2
H, and —CF
3
as well as ether and aryl groups;
—O—(CH
2
)
3
—CN; and
—O—(CH
2
)
3
—C≡CH.
Preferred sulfonamide groups which may be found at the ortho- and meta- positions, particularly at the meta-position are those of formula:
—NH—SO
2
—Ar, where Ar is an optionally substituted aryl or heteroaryl group, preferably an optionally substituted phenyl group. Preferred optional substituents for the aryl, preferably phenyl group, include: —CN; halogens, especially chlorine and fluorine, —CF
3
, lower (C
1-6
) alkyl (especially methyl), hydroxy-, ether, and —NO
2
groups.
For both the —OCH
2
Ar and —NHSO
2
Ar substituted compounds, another preferred example of Ar is naphthyl.
Other preferr

Affiliated with

Also associated with

Rating

Diketoacid-derivatives as inhibitors of polymerases does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Diketoacid-derivatives as inhibitors of polymerases, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Diketoacid-derivatives as inhibitors of polymerases will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2947260