Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-04-12
2001-04-24
Higel, Floyd D. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S414000, C514S417000, C546S105000, C548S462000, C548S463000, C548S474000, C548S480000, C548S479000
Reexamination Certificate
active
06221877
ABSTRACT:
BACKGROUND OF THE INVENTION
FIELD OF THE INVENTION
This invention pertains to novel heterocyclic derivatives that are useful for treating parasitic protozoa infections in mammals, in particular bovine trichomoniasis and giardiasis.
RELATED DISCLOSURES
Parasitic protozoa infections in mammals are widespread and difficult to prevent or remedy effectively. For example,
Tritrichomonas foetus
is an anaerobic protozoan parasite that causes bovine trichomoniasis in cattle; it is prevalent in cattle herds throughout much of the world, and causes a substantial loss in beef production.
Gardia lamblia
is an example of a water-borne zoonotic protozoan parasite; it is also found worldwide, and infection leads to severe diarrhea and growth retardation in humans.
It has been observed that parasitic protozoa lack a de novo purine nucleotide synthetic pathway (Wang,
Trends Biochem. Sci.
7:354-356 (1982)). Instead, they utilize purine salvage pathways to convert the host organism's purine bases and nucleosides to the corresponding nucleotides (Wang,
J. Med. Chem.
27:1-9 (1984)). Purine phosphoribosyltransferases (PRTs) are a class of enzymes that catalyze the reaction of a purine with &agr;-D-S-phosphoribosyl-1-pyrophosphate (PRPP) to produce nucleotide monophosphates via nucleophilic displacement of pyrophosphate. Inhibiting PRTs could represent an efficient approach to antiparasite chemotherapy if these enzymes provide the primary means of purine salvage for the parasite (Wang,
Parasitology
114:S31-S44 (1997)).
Tritrichomonas foetus,
an anaerobic flagellated protozoan that causes urogenital trichomoniasis in cattle, relies primarily on a single enzyme, hypoxanthine-guanine-xanthine phosphoribosyltransferase (HGXPRT) to replenish its purine nucleotide pool (Wang, et al.,
Mol. Biochem. Parasitol.
8:325-337 (1983)). Similarly,
G. lamblia
relies upon the guanine phosphoribosyltransferase enzyme (GPRT) for supplying its guanine nucleotide pool.
It is apparent that inhibition of the purine salvage pathways of the parasitic protozoa would be an effective way to block the ability of the parasites to survive in the host. However, it is important that any compounds capable of such an inhibiting effect should not interfere with the host hypoxanthine-guanine phosphoribosyltransferase (HGPRT). For example, in humans defects in HGPRT are known to be responsible for gouty arthritis and a number of central nervous system disorders.
To assist in the identification of compounds that selectively inhibit purine salvage pathways, both enzymes (HGXPRT from
T. foetus
and GPRT from
G. lamblia
) were purified to homogeneity and partially characterized (Beck, et al.,
Mol. Biochem. Parasitol.
60:187-194 (1993); Aldritt, et al.,
J. Biol. Chem.
261:8528-8533 (1986)). The genes encoding the two enzymes were cloned, sequenced and expressed in transformed
Escherichia coli
to produce large quantities of recombinant enzyme proteins in their native state (Chin, et al.,
Mol. Biochem. Parasitol.
63:221-230 (1994); Sommer, et al.,
Mol. Biochem. Parasitol.
78:185-193 (1996)). The purified recombinant
T. foetus
HGXPRT was crystallized and the crystal structure was determined by X-ray crystallography (Somoza, et al.,
Biochemistry
35:7032-7040 (1996)). The X-ray structure of this enzyme is a useful tool in the search for novel scaffolds that could be used to design new selective inhibitors of HGXPRT. Computer modeling of the active site in the enzyme molecule was initiated in the laboratory of Professor Irwin Kuntz to identify chemical compounds that conform to the dimensions of (and complement the chemistry of) the pocket and thus inhibit the enzyme function.
A group of heterocyclic compounds have been identified that conform to the dimensions of the pocket and complement its chemistry, and inhibit the purine salvage pathways of the parasites without affecting the mammalian HGPRT, and are described in Wang, et al, U.S. Ser. No. 09/118,451 and Somoza, et al.,
Biochemistry
37(16): 5344-5348 (1998). However, in spite of these advances in the field, there continues to remain a need for HGXPRT inhibitors having better potency and improved affinity and selectivity.
Rapid growth in the field of parasite structural biology, spurred by recent advances in parasite biology and biochemistry, is becoming increasingly important in the process of drug discovery for parasitic infections (Hunter,
Parasitology
114:S17-S29(1997)). A combination of rational target selection with molecular modeling tools, aided by new combinatorial chemistry technologies, has become a method of choice for designing potent and selective ligands for a number of targets in parasites (Gutteridge,
Parasitology
114:S145-S151 (1997); Haque, et al.,
J. Med. Chem.
42:1428-1440 (1999)). This technology, and continued efforts to use the X-ray structure of the
T. foetus
HGXPRT-guanosine 5′-monophosphate complex, have now provided a novel group of heterocyclic compounds that bind tightly to the purine pocket of HGXPRT and are selective submicromolar inhibitors of
T. foetus
HGXPRT.
SUMMARY OF THE INVENTION
The present invention relates to compounds of Formula I:
wherein: R
1
is selected from the group consisting of:
and a fused three-membered aryl or heteroaryl group; R
2
, R
3
and R
4
are independently selected from the group consisting of H, lower alkyl and halo; X is selected from the group consisting of —CH
2
—O— and —O—CH
2
—; R
5
is aryl; R
6
, R
7
and R
8
are independently selected from the group consisting of H and lower alkyl; R
9
is lower alkyl and R
10
is a cyclic aliphatic ring, or R
9
and R
10
can be taken together to form a cyclic aliphatic ring; Y is selected from the group consisting of NH and O; and the pharmaceutically acceptable salts thereof.
One aspect of the invention relates to a method of treating parasitic protozoa infections in mammals, which method comprises administering to a mammal in need of such treatment a therapeutically effective amount of a compound of Formula I.
Yet another aspect of the invention pertains to a pharmaceutical composition containing a therapeutically effective amount of a compound of Formula I in a pharmaceutically acceptable carrier.
DETAILED DESCRIPTION OF THE INVENTION
The invention relates to a family of substituted 4-phthalimidocarboxanilide compounds. These compounds inhibit growth of
T. foetus
parasite culture by selectively interfering with parasite purine salvage as inhibitors of the parasite's HGXPRT competitive with the purine substrate. Accordingly, this family of compounds is useful for treating disease states that are caused by parasitic protozoa. In particular, these compounds are useful for treating disease states in mammals by inhibiting hypoxanthine-guanine-xanthine phosphoribosyltransferase or guanine phosphoribosyltransferase in the purine salvage pathways of the parasitic protozoa responsible for the disease state.
The compounds of the invention have the Formula I:
wherein: R
1
is selected from the group consisting of:
and a fused three-membered aryl or heteroaryl group; R
2
, R
3
and R
4
are independently selected from the group consisting of H, lower alkyl and halo; X is selected from the group consisting of —CH
2
—O— and —O—CH
2
—; R
5
is aryl; R
6
, R
7
and R
8
are independently selected from the group consisting of H and lower alkyl; and R
9
is lower alkyl and R
10
is a cyclic aliphatic ring, or R
9
and R
10
can be taken together to form a cyclic aliphatic ring; Y is selected from the group consisting of NH and O; and the pharmaceutically acceptable salts thereof.
The compounds of Formula I can be easily produced from inexpensive starting materials, an important feature of any potential anti-parasitic agent. The invention also contemplates varying the anilide portion of these inhibitors in a solid phase format in response to emerging resistance, which is another feature that could potentially enable rapid access to newly improved inhibitors with increased efficacy against the resistant strains. The compounds of the invent
Aronov Alex M.
Kuntz Irwin D.
Munagala Narsimha R.
Ortiz de Montellano Paul R.
Wang Ching C.
Godward LLP Cooley
Higel Floyd D.
Regents of the University of California
Wright Sonya N.
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