Title of Invention

HALOGENATED BENZAMIDE DERIVATIVES

Abstract A halogenated benzamide derivative characterized by greater specificity for viral pathogens and less disruptive to beneficial gut microflora, according to formula (III): in which R1 is a halogen atom, and R2 -R6 are independently hydrogen, hydroxyl, C1-C4 alkyl, -C1-C4 alkoxy, acyloxy, nitro, halogen, -C(O)R7 where R7 is -C1-C4 alkyl, or aromatic including salts and hydrates of these compounds.
Full Text

FIELD OF THE INVENTION
The invention relates to halogenated benzamide
derivatives, and more specifically, benzamide derivatives
characterized by greater specificity for viral pathogens and
less disruptive to beneficial gut microflora.
BACKGROUND TO THE INVENTION
(2-(acetolyloxy)-N-(5-nitro-2-thiazolyl) benzamide, the
compound of formula (I), also referred to as nitrothiazole,
nitazoxanide, or NTZ, is known for use in the treatment and
prevention of parasitic infections, bacterial infections,
fungal infections, diarrhea and other intestinal troubles
(U.S. Patent Nos. 3,950,351, 4,315,018 and 5,578,621)
including treatment of trematodes (U.S. Patent No.
5,856,348). The preparation of NTZ is disclosed in U.S.
Patent No. 3,950,351. Improved pharmaceutical compositions
for delivery of NTZ are disclosed in U.S. Patent Nos.
6,117,894 and 5,968,961.

It has been postulated that, in anaerobic bacteria and
protozoa, NTZ exhibits a mode of action based upon reduction
2

of its nitro group by nitroreductases, and particularly
pyruvate ferredoxin oxidoreductase (PFOR) dependent electron
transfer reactions that are essential for anaerobic energy
metabolism. Nothing is currently known regarding the
possible mode of action of NTZ for helminthes, however, the
enzymes of anaerobic electron transport are considered as
potential targets, with the 5-nitro group implicated in this
mechanism.
Compounds according to formula (II), in which one of Ri_
5 is -OH and the remainder of R1-5 being H, are known to
exhibit antiviral activity, and are known for treatment of
human viral diseases such as those caused by human
cytomegalovirus, varicella zoster, Epstein Barr virus, HSV-
I and HSV-II (U.S. Patent Nos. 5,886,013 and 6,020,353).

While potent, these compounds are not selective for
only viral pathogens. They are described as having
excellent efficacy against parasites, bacteria and fungus.
In practice, this is associated with a problem. Namely, in
humans and many animals, the gut contains beneficial
populations of microflora, principally comprised of
anaerobic bacteria. Oral administration of broad spectrum
compounds such as those of Formula (II) kills the bacterial
3

gut flora, which may lead to secondary complications
including diarrhea requiring further treatment.
Accordingly, there is a need for therapeutic compounds
that are more selective for viral pathogens. Most
preferably, these compounds should possess antiviral
activity, but be substantially devoid of antibacterial and
antiparasite activity, at least to the extent of avoiding
deleterious effects upon the beneficial gut microflora when
administered orally.
This need, and more, is achieved by the present
invention, as will become clear to one of ordinary skill
upon reading the following disclosure and examples.
SUMMARY OF THE INVENTION
The present invention relates to antiviral benzamide
derivatives that are more selective for viral pathogens, and
accordingly cause reduced deleterious effects upon
beneficial gut microflora when administered orally.
In a first aspect, the invention is surprisingly made
by replacing the nitro substituent, which has until now been
believed to be the key to the activity of NTZ, with a
halogen atom. This substitution may be made in any of the
known therapeutically effective 2-benzamido-5nitro-thizaoles
(wherein the benzene ring may be variously substituted).
Surprisingly, the novel halogenated compounds retain their
antiviral properties, but they lack activity against the
bacterial gut microflora when administered orally.

Examples of these known 2-benzamido-5nitro-thizaol.es,
which are analogues of the compounds of the present
invention differing only in that in accordance with the
present invention the nitro group is removed and replaced
with a halogen atom, are extensively set forth in the above
referenced U.S. Patents, and U.S. Patent Nos. 5,886,013 in
particular, their disclosure being incorporated herein by
reference.
The present invention further provides (5-halo-2-
thiazolyl) benzamide compounds according to formula (III):

in which
Ri is a halogen atom, preferably F, Cl, Br, or I, more
preferably Br or Cl, most preferably Br, and
R2 -R6 are independently hydrogen, hydroxyl, C1-C4 alkyl,
-C1-C4 alkoxy, acyloxy (preferably acetoxy or propionoxy),
nitro, halogen, -C(0)R-7 where R7 is -C1-C4 alkyl, or aromatic
5

(preferably unsubstituted or substituted phenyl or benzyl),
including salts and hydrates of these compounds.
Preferably, one of R2 -R6 is hydroxyl.
Preferably at least one of R2 -R6 are other than
hydrogen, and more preferably at least two of R2 -R6 are
other than hydrogen.
Two adjacent R2 -R6 may together form a benzyl ring.
Preferably, R2 -R6 include no more than one acyloxy and
no more than one halogen.
The present invention further provides antiviral
compounds according to formula (IV):

in which Rx is a halogen atom, R8 is -C(0)Rio, where R10 is -
C1-C4 alkyl, and R9 is -C1-C4 alkyl or -C1-C4 alkoxy, including
salts and hydrates of these compounds.
The invention further provides antiviral pharmaceutical
compositions comprising a compound of Formula (III) or (IV)
and a pharmaceutically acceptable carrier.

Finally, the invention provides a method of treating or
preventing a viral infection in an animal or human subject,
the method comprising administering to said subject at least
one dose of the pharmaceutical composition comprising an
effective amount of the antiviral compound according to
Formula (III) or (IV) and a pharmaceutically acceptable
carrier.
DETAILED DESCRIPTION
Compounds of the present invention include those
according to formula (III):

III)
in which
R1 is a halogen atom, preferably F, Cl, Br, or I, more
preferably Br or Cl, most preferably Br, and
R2 -R6 are independently hydrogen, hydroxyl, C1-C4 alkyl,
-C1-C4 alkoxy, acyloxy (preferably acetoxy or propionoxy),
nitro, halogen, -C(O)R7 where R7 is -C1-C4 alkyl, or aromatic
(preferably phenyl or benzyl, which may be further
substitued) , including salts and hydrates of these
compounds.

Preferably, one of R2 -R6 is hydroxyl.
Preferably at least one of R2 -R6 are other than
hydrogen, and more preferably at least two of R2 -R6 are
other than hydrogen.
Two adjacent R2 -R6 may together form a benzyl ring.
Preferably, R2 -R6 include no more than one acyloxy and
no more than one halogen. Compounds according to the
present invention are illustrated by the following non-
limitina list:





Preferred examples of compounds within Formula (III)
include:
2-(acetolyloxy)-3-methyl-N-(5-bromo-2-thiazolyl)benzamide
(RM4803);
2-(hydroxy)-3-methyl-N-(5-bromo-2-thiazolyl)benzamide
(RM4819);
2-(acetolyloxy)-N-(5-bromo-2-thiazolyl)benzamide (RM4820);
2-(acetolyloxy)-5-methoxy-N-(5-bromo-2-thiazolyl)benzamide
(RM4821); and
2-(acetolyloxy)-5-methoxy-N-(5-bromo-2-thiazolyl)benzamide
(RM4822).
10

It has further been discovered that compounds with a
hydroxyl subsitutent in the ortho position of the benzene
ring have good efficacy. Thus, from among the above
illustrative compounds, the following compounds are
preferred: RM-4819, RM-4826, RM-4827, RM -RM-4831, RM-4832, RM-
4833, RM-4834, RM-4835, RM-4836, RM-4838, RM-4839, RM-4840.
Compounds according to the invention preferably include
those of formula (IV):

wherein:
R1 is halogen, preferably F, Cl, Br, or I, more
preferably Br or Cl, most preferably Br,
R8 is -C(0)R10, in which R10 is -C1-C4 alkyl. R1O
includes methyl, ethyl, propyl and butyl, including isomers
thereof. Methyl is preferred, whereby the benzamide
substituent is acetolyloxy, and
R9 is -C1-C4 alkyl or -C1-C4 alkoxy. Methyl and methoxy are
preferred. Methyl is most preferred.
11

Examples of compounds within Formula (IV) include:
2-(acetolyloxy)-3-methyl-N-(5-bromo-2-thiazolyl)benzamide
(RM4803);
2-(acetolyloxy)-3-methyl-N-(5-chloro-2-thiazolyl)benzamide
(RM4804); and
2-(acetolyloxy)-3-methoxy-N-(5-bromo-2-thiazolyl)benzamide
(RM4806).
The compositions of the present invention may be
formulated as solid or liquid dosage forms, or as pastes or
ointments, and may optionally contain further active
-ingredients.
The pharmaceutical compositions of the present
invention comprise a pharmaceutically acceptable carrier,
which is not particularly limited, and includes a wide range
of carriers known to those of ordinary skill in the art, and
including wetting or dispersing agents (U.S. Patent
5,578,621), starch derivatives (U.S. Patent 5,578,621),
excipients, and the like. Tablet embodiments may optionally
comprise a coating of a substance that constitutes an
enteric coating, i.e. a coating that substantially insoluble
in gastric secretion but substantially soluble in intestinal
fluids.
Pharmaceutical compositions comprising compounds
according to Formula (III) or (IV) are preferably formulated
for oral administration and are optionally in the form of a
liquid, for example an emulsion or a solution or a
suspension in water or oil such as arachis oil, or other
liquid. Formulations of non-aqueous micellar solutions may
be prepared according to the method disclosed in U.S. Patent
5,169,846. Alternatively, tablets can be manufactured, for
12

example, by performing the following steps: wet granulation;
drying; and compression. Film coating is generally
performed with organic solvents.
The term "selective antiviral" as used herein means
that, at dosages effective for the prevention or treatment
of a viral disease, the activity is more antiviral than
antibacterial, antifungal, or antiparasite, and gut flora of
the subject is not disrupted to levels expected with broad
spectrum antibiotics.
The preferred antiviral - treatment or prophylactic
dosages of the compounds of the present invention may depend
upon the weight of the subject, and may be inferred by one
of ordinary skill without undue experimentation by reference
to the following examples, which are set forth for purposes
of illustration and are not intended to be limiting.
EXAMPLE 1: TESTING AGAINST VIRUSES
METHODS
Non-hepatic viruses
Cell cultures and Treatments. HEp-2 laryngeal carcinoma
cells, monkey kidney 37RC, MA104 and VERO cells, canine
Madin-Darby kidney (MDCK) and mammary adenocarcinoma (A72)
cells, were grown at 37°C in a 5% C02 atmosphere in RPMI
medium (Gibco-Invitrogen, Carlsbad, CA) , supplemented with
10% fetal calf serum (FCS), 2 mM glutamine and antibiotics.
Compounds dissolved in DMSO stock solution (50 mg/ml) were
diluted in culture medium and added to infected cells
immediately after the 1 hour adsorption period. Compounds
were maintained in the medium for the duration of the
experiment. Controls received equal amounts of DMSO
13

diluent. Each concentration of each compound was tested in
duplicate and each experiment was repeated twice.
Virus infection and titration. The following viruses were
utilized: Influenza A: strain Puertorico (PR8);
Paramyxovirus (Parainfluenza): Sendai virus (SV);
Rhabdovirus: Vesicular Stomatitis Virus (VSV); Rotavirus:
Simian Rotavirus SA-11 (SA-11); Herpes Simplex virus type 1:
strain Fl (HSV-1); Coronavirus: canine coronavirus strain S-
378 (CCoV). Confluent cell monolayers were infected with
Influenza A virus (MDCK cells) or parainfluenza SV (37RC
cells) for 1 h at 37°C at a multiplicity of infection
(m.o.i.) of 5 HAU (Hemagglutinating Units)/105 cells.
Alternatively, confluent cell monolayers were infected with
HSV-1 (HEp-2 cells), VSV (MA104 cells), CCoV (A72 cells) or
Rotavirus SA-11 (MA104 cells) for 1 h at 37°C at a m.o.i. of
5 PFU (Plaque Forming Units)/105 cells for HSV-1, VSV and
CCoV and 1 PFU/105 cells for SA-11. After the adsorption
period, the viral inoculum was removed and cell monolayers
were washed three times with phosphate-buffer saline (PBS).
Cells were maintained at 37 °C in appropriate culture medium
containing 2% FCS in the presence of the test compound or
control diluent. Virus yield was determined 24 hours post
infection (p.i.) by hemagglutinin titration (WSN, PR8, SV
and SA-11) or CPE50% assay (VSV, HSV-1, and CCoV), according
to standard procedures (Amici, C, Belardo, G., Rossi, A. &
Santoro, M.G. Activation of IKB kinasa by Herpes Simplex
virus type 1. A novel target for anti-herpetic therapy. J.
Biol. Chem. 276, 28759-28766 (2001) and Bernasconi, D.,
Amici, C, La Frazia, S., Ianaro, A. & Santoro, M.G. The IKB
kinase is a key factor in triggering Influenza A virus -
induced inflammatory cytochine production in airway
epithelial cells. J. Biol. Chem. 280, 24127-24134 (2005)).
14

Cell toxicity. Cell viability was determined by the 3-(4,5-
dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT)
to MTT formazan conversion assay (Sigma-Aldrich, St Louis,
MO) . For MTT assay, reduced MTT (formazan) was extracted
from cells by adding 100 ul of acidic isopropanol
containing 10% Triton X-100, and formazan absorbance was
measured in an ELISA microplate reader at two different
wavelengths (540 and 690 nm).
Hepatitis B virus
Anti-Hepatitis B Virus (HBV) analyses and an assessment of
cytotoxicity were performed in a 9-day assay in the
chronically-producing HBV human hepatoblastoma cell line,
2.2.15, as previously described (Korba, B.E. & Gerin, J.L.
Use of a standardized cell culture assay to assess
activities of nucleosides analogues against hepatitis B
virus replication. Antivir. Res. 19, 55-70 (1992)).
Hepatitis C virus
Anti-Hepatitis C Virus (HCV) analyses and an assessment of
cytotoxicity were performed in a 3-day assay in the HCV
replicon-containing human hepatoblastoma cell line, AVA5
(Okuse, C, Rinaudo, J.A., Farrar, K., Wells, F. & Korba,
B.E. Enhancement of antiviral activity against hepatitis C
virus in vitro by interferon combination therapy. Antivir.
Res. 65, 23-34 (2005)) as previously described (Blight,
K.J., Kolykhalov, A.A. & Rice, CM. Efficient initiation of
HCV RNA replication in cell culture. Science 290, 1972-1974
(2000)).
15

RESULTS OF TESTING AGAINST VIRUSES
Table 1. Activity of RM-4803 and RM-4819 against viruses in
cell culture.
EC50 (uM)/SI
Virus RM4819 RM4803 Cell
Culture
Rotavirus: Simian rotavirus 0.3/>500 0.06/>2500 MA104
SA-11
Influenza A: PR8 strain 9.6/>17 2.8/>50 MDCK
Paramyxovirus: Sendai virus 1.3/>125 1.1/>125 37RC
Coronavirus: canine 4.9/>33 4.2/13 A72
coronavirus strain S-378
Rhabdovirus: Vesicular 1.6/>100 2.8/>50 MA104
stomatitis virus
Herpes Simplex type 1: 0.6/>250 5.6/3 HEp-2
strain Fl
EC50 - drug concentration at which a 2-fold depression of
viral DNA or RNA (relative to the average levels in
untreated cultures) was observed. CC50 = drug concentration
at which a 2-fold depression of reduced MTT was observed
relative to average levels in untreated cultures. SI
(selectivity index) = CC50/EC50.
Table 2. Activity of other compounds against paramyxovirus:
sendai virus in cell culture.
Paramyxovirus: Sendai virus
Compound EC50 (μM) SI
RM-4820 0.34 35
RM-4821 0.36 >50
RM-4822 0.36 7
EC50 = drug concentration at which a 2-fold depression of
viral RNA (relative to the average levels in untreated
cultures) was observed. CC50 = drug concentration at which a
2-fold depression of reduced MTT was observed relative to
16

average levels in untreated cultures. SI (selectivity index)
= CC50/EC50.
Table 3. Activity of compounds against HBV replication in
2.2.15 cell culture.
Extracellular Intracellular Selectiv
Virion DNA HBV R.I. ity
Index
Compoun EC50 EC90 EC50 EC90 CC50 Viri R.
_d (μM) (μM) (μM) (μM) (uM) on I.
Lamivud 0.058±0 0.164+0 0.172±0 0.660±0 2229±7 1295 33
ine .006 .015 .020 .068 6 9 77
RM4803 6.3 ± 15 12 + 50 ± >67 >2
0.7 ± 1.1 1.5 5.5 >1000s 0
RM4819 3.5 ± 9.0 7.6 ± 22 ± >4
0.5 ± 0.8 (L_9 2.6 >1000§ >111 6
Values presented (± standard deviations [S.D.]) were
calculated by linear regression analysis using data combined
from all treated cultures. S.D. were calculated using the
standard error of regression generated from linear
regression analyses (QuattroPro™) . EC50, EC90 = drug
concentration at which a 2-fold, or a 10-fold depression of
HBV DNA (relative to the average levels in untreated
cultures), respectively, was observed. CC50 = drug
concentration at which a 2-fold depression of neutral red
dye uptake (relative to the average levels in untreated
cultures) was observed. The ECg0 values were used for the
calculation of the Selectivity Indexes [S.I.] since at least
a 3-fold depression of HBV levels is typically required to
achieve statistical significance in this assay system. HBV
R.I. = intracellular HBV DNA replication intermediates.
17

§ No significant cytotoxic effects were observed up to the
highest indicated concentration.
Table 4. Activity of compounds against hepatitis C virus
replication in AVA5 cell culture.
Compound CC50 (μM) EC50 (μM) EC90 (μM) Selectivity
Index
∞ - >10,000*s 2.2 ± 8.5 ± >4,545
Interferon 0.2* 0.6*
Ribavirin 61 ± 2.9 94 ± 10 >100s 0.6
RM4803 282 ±21 37 ± 2.7 98 ± 9.3 7.6
RM4819 164 ± 18 8.9 ± 0.7 79 ± 8.2 18
Values presented (± standard deviations [S.D.]) were
calculated by linear regression analysis using data combined
from all treated cultures. S.D. were calculated using the
standard error of regression generated from the linear
regression analyses (QuattroPro™) . EC50, EC90 = drug
concentration at which a 2-fold, or a 10-fold depression of
HCV RNA (relative to the average levels in untreated
cultures), respectively, was observed. CC50 = drug
concentration at which a 2-fold depression of neutral red
dye uptake was observed relative to the average levels in
untreated cultures. Selectivity index = CC50/EC50.
* Values for interferon are expressed as "IU/ml."
§ No significant cytotoxic or antiviral effects were
observed up to the highest indicated concentration.
18

EXAMPLE 2: TESTING AGAINST ANAEROBIC BACTERIA
Methods. Recent clinical anaerobic isolates (2000 to date)
comprised 40 B.fragilis group, 26 Prevotella/Porphyromonas,
28 fusobacteria, 16 anaerobic Gram positive cocci, 14
anaerobic Gram-positive non-sporeforming rods and 18
clostridia. CLSI agar dilution MIC methodology with enriched
Brucella blood agar and inocula of 1 x 105 cfu/spot was used.
Plates were incubated in an anaerobic glove box at 35°C for
48 h.

Results. MIC50 /MIC90 values (μg/ml) were as follows:
Drug B. fragil-is gp(40) Prev/Porphy (26) Fusobact-eria(28) Gram+cocci(16) Gram+rods(14) Clostrid-ia(18) All(142)
Nitazox-anide 2/4 4/8 1/4 0.5/2 16/>32 0.5/4 2/4
Tizoxanide 2/4 2/16 0.5/2 0.5/1 8/>32 0.25/2 2/4
RM 4803 >32/>32 >32/>32 >32/>32 >32/>32 >32/>32 >32/>32 >32/>32
RM 4819 >32/>32 >32/>32 >32/>32 >32/>32 >32/>32 >32/>32 >32/>32
Amoxicillin-clavulanicacid 1/ 4 0.06/0.5 0.5/4 0.125/0.5 0.25/1.0 0.125/1.0 0.5/2.0
Clinda-mycin 2/>32 32 0.125/8.0
Metronid-azole 1/ 2 0.5/2 0.25/0.25 0.5/1.0 >16/>16 0.25/2 1.0/2.0
Results showed that nitazoxanide, tizoxanide, potent
against all anaerobic bacteria groups except for Gram-
positive anaerobic rods including lactobacilli (which are
in reality mostly microaerophils). By contrast, RM 4803 and
RM 4819 were without significant activity.
19

EXAMPLE 3 - ANTIVIRAL ACTIVITY
Compounds within Formula (IV) of the present invention
exhibit potent antiviral activity, as shown in Table 5.
EC50 (μg/mL) values for 2-(acetolyloxy)-3-methyl-N-(5-
bromo-2-thiazolyl)benzamide (RM4803), 2-(acetolyloxy)-3-
methyl-N-(5-chloro-2-thiazolyl)benzamide (RM4804), and 2-
(acetolyloxy)-3-methoxy-N-(5-bromo-2-thiazolyl)benzamide
(RM4806) , on Human Rhinovirus Type 39 (HRV-39), and H3N2
influenza virus, type A, using a multiple cycle CPE
inhibition assay on OH-I Hela and Madin Darby Canine Kidney
(MDCK) cell monolayers, respectively, were measured by
microscopic and spectrophotometric methods. Pirodavir and
Oseltamivir were included as positive controls.
Table 5. Activity of RM-4803, RM-4804 and RM-4806 against
viruses in cell monolayer

Human Rhinovirus Type Influenza A Virus
39 MDCK
Compound OH-Hela 0% EMEM + Hepes +
2% McCoys + Hepes Trypsin
Buffer Microscopic
Microscopic Spectrophotometer
Spectrophotometer
Ri = Br
R4 = methyl 0.06 0.03 0.45 0.18
R3 = methyl
(RM 4803)
Ri = Cl
R4 = methyl 0.57 0.32 0.93 0.57
R3 = methyl
(RM 4804)
Ri = Br
R4 = methyl 5.0 4.0 0.46 0.57
R3 =
methoxy
(RM 4806)
Pirodavir 0.007 0.004" NA NA
Oseltamivir NA NA 0.13-0.17 0.08-0.36
20

EXAMPLE 4 - SELECTIVE ANTI-VIRAL ACTIVITY
The above identified compounds according to Formula
(IV) were tested by conventional means against Trichomis
vaginalis, Giardia Intestinalis, and Trypanosoma brucei.
2-(acetolyloxy)-3-methyl-N-(5-bromo-2-thiazolyl)benzamide
(RM4803), 2-(acetolyloxy)-3-methyl-N-(5-chloro-2-
thiazolyl)benzamide (RM4804), and 2-(acetolyloxy)-3-methoxy-
N-(5-bromo-2-thiazolyl)benzamide (RM4806) each failed to
exhibit antiparasite activitity against Trichomonas
vaginalis, Giardia intestinalis, or Trypanosoma brucei at
concentrations of at least 50 μg/mL.
Accordingly, it has been demonstrated that in
accordance with the present invention, novel compounds can
be provided which are generally characterized by selective
antiviral activity.
As an additional benefit, it has been discovered that
the above halogen-substituted benzamide compounds are
effective against intracellular protozoa including
Cryptosporidium spp., Neospora spp. and Sarcocystis neurona
(RM-4820, RM-4821 and RM-4822).
With respect to the above description, it is to be realized
that the optimum formulations and methods of the invention
are deemed readily apparent and obvious to one skilled in
the art, and all equivalent relationships to those described
in the specification are intended to be encompassed by the
present invention.
21

Therefore, the foregoing is considered as illustrative
only of the principles of the invention. Further, since
numerous modifications and changes will readily occur to
those skilled in the art, it is not desired to limit the
invention to the exact construction and operation shown and
described, and accordingly, all suitable modifications and
equivalents may be resorted to, falling within the scope of
the invention.
Certain references, patents and other printed
publications have been referred to herein: the teachings and
scope of each of said publications are hereby incorporated
in their respect entireties by reference.
Now that the invention has been described:
22

We Claim
1. A compound according to formula (III):

in:
in which
R1 is a halogen atom, and
R2 -R6 are independently hydrogen, hydroxyl, C1-C4
alkyl, -C1-C4 alkoxy, acyloxy, nitro, halogen, -C(O)R7
where R7 is -C1-C4 alkyl, or aromatic including salts
and hydrates of these compounds.
2. A compound as in claim 1, wherein at least one of
R2 -R6 is other than hydrogen.
3. A compound as in claim 1, wherein at least one of
R2 -R6 is hydroxyl.
4. A compound as in claim 3, wherein said at least
one hydroxyl is in the ortho position.
5. A compound as in claim 3, wherein the remainder of
R2 -R6 are hydrogen.
6. A compound as in claim 1, wherein at least two of
R2 -R6 are other than hydrogen.
23

7. A compound as in claim 1, wherein one of R2 -R6 is
hydroxyl, and the remainder of R2 -R6 are
independently hydrogen, C1-C4 alkyl, -C1-C4 alkoxy,
acyloxy (preferably acetoxy or propionoxy), nitro,
halogen, -C(O)R7 where R7 is -C1-C4 alkyl, or
aromatic, including salts and hydrates of these
compounds.
8. A compound as in claim 1, wherein one of R2 -R6 is
hydroxyl, and at least one of R2 -R6 is C1-C4 alkyl,
-C1-C4 alkoxy, acyloxy, nitro, halogen, -C(O)R7
where R7 is -C1-C4 alkyl, or aromatic, including
salts and hydrates of these compounds.
9. A compound as in claim 1, wherein said acyloxy is
acetoxy or propionoxy, and wherein said aromatic
is phenyl or benzyl, which may be further
substituted.
10. A compound as in claim 1, wherein R1 is Br or Cl.
11. A compound as in claim 1, wherein R2 -Re include no
more than one acyloxy and no more than one
halogen.
12. A compound as in claim 1, wherein two adjacent R2 -R6 together form a benzyl ring.
13. A compound as in claim 1, wherein one of R2 -R6 is
hydroxyl, and the remainder of R2 -R6 are
independently hydrogen, C1-C4 alkyl, -C1-C4 alkoxy,
24

acyloxy, or -C(O)R7 where R7 is -C1-C4 alkyl,
including salts and hydrates of these compounds.
14. A compound as in claim 1, selected from the group
consisting of
2-(acetolyloxy)-3-methyl-N-(5-bromo-2-
thiazolyDbenzamide (RM4803);
2-(hydroxy)-3-methyl-N-(5-bromo-2-
thiazolyl)benzamide (RM4819);
2-(acetolyloxy)-N-(5-bromo-2-thiazolyl)benzamide
(RM4820);
2-(acetolyloxy)-5-methoxy-N-(5-bromo-2-
thiazolyl)benzamide (RM4821); and
2-(acetolyloxy)-5-methoxy-N-(5-bromo-2-
thiazolyl)benzamide (RM4822).
15. A compound according to formula (IV):


O-R

wherein:
R1 is halogen,
R8 is -C(0)R10, in which R10 is -C1-C4 alkyl, and
R9 is -C1-C4 alkyl or -C1-C4 alkoxy.
25

16. A compound as in claim 14, wherein R1 is Cl or Br.
17. A compound as in claim 14, wherein R8 is -C(O)Ri0,
in which R10 is methyl, ethyl, propyl or butyl,
including isomers thereof.
18. A compound as in claim 14, wherein R9 is methyl or
methoxy.
19. A compound as in claim 14, selected from the group
consisting of:
2-(acetolyloxy)-3-methyl-N-(5-bromo-2-
thiazolyl)benzamide (RM4803);
2-(acetolyloxy)-3-methyl-N-(5-chloro-2-
thiazolyl)benzamide (RM4804); and
2-(acetolyloxy)-3-methoxy-N-(5-bromo-2-
thiazolyl)benzamide (RM4806).
20. A pharmaceutical composition comprising as active
agent a compound according to formula (III):

an;
26

in which
R1 is a halogen atom, and
R2 -R6 are independently hydrogen, hydroxyl, C1-C4
alkyl, -C1-C4 alkoxy, acyloxy, nitro, halogen, -C(O)R7
where R7 is -C1-C4 alkyl, or aromatic including salts
and hydrates of these compounds.
21. A method for treating viral infections, comprising
administering to a subject in need of treatment an
effective amount of a pharmaceutical composition
comprising as active agent a compound according to
formula (III) :



in which
R1 is a halogen atom, and
R2 -R6 are independently hydrogen, hydroxyl, C1-C4
alkyl, -C1-C4 alkoxy, acyloxy, nitro, halogen, -C(O)R7
where R7 is -C1-C4 alkyl, or aromatic including salts
and hydrates of these compounds.

A halogenated benzamide derivative characterized by
greater specificity for viral pathogens and less disruptive
to beneficial gut microflora, according to formula (III):
in which
R1 is a halogen atom, and
R2 -R6 are independently hydrogen, hydroxyl,
C1-C4 alkyl,
-C1-C4 alkoxy, acyloxy, nitro, halogen, -C(O)R7 where R7 is -C1-C4 alkyl, or aromatic including salts and hydrates of
these compounds.

Documents:

01125-kolnp-2007-abstract.pdf

01125-kolnp-2007-claims.pdf

01125-kolnp-2007-correspondence others 1.1.pdf

01125-kolnp-2007-correspondence others.pdf

01125-kolnp-2007-description complete.pdf

01125-kolnp-2007-form 1 1.1.pdf

01125-kolnp-2007-form 1.pdf

01125-kolnp-2007-form 2.pdf

01125-kolnp-2007-form 3.pdf

01125-kolnp-2007-form 5.pdf

01125-kolnp-2007-gpa.pdf

01125-kolnp-2007-international publication.pdf

01125-kolnp-2007-international search report.pdf

01125-kolnp-2007-priority document.pdf

1125-KOLNP-2007-ABSTRACT 1.1.pdf

1125-KOLNP-2007-AMANDED CLAIMS.pdf

1125-KOLNP-2007-CANCELLED PAGES.pdf

1125-KOLNP-2007-CORRESPONDENCE 1.1.pdf

1125-KOLNP-2007-CORRESPONDENCE 1.2.pdf

1125-kolnp-2007-correspondence-1.3.pdf

1125-KOLNP-2007-CORRESPONDENCE.pdf

1125-KOLNP-2007-DESCRIPTION (COMPLETE) 1.1.pdf

1125-kolnp-2007-examination report.pdf

1125-KOLNP-2007-FORM 1.1.pdf

1125-kolnp-2007-form 18-1.1.pdf

1125-kolnp-2007-form 18.pdf

1125-KOLNP-2007-FORM 2.1.pdf

1125-kolnp-2007-form 3-1.2.pdf

1125-KOLNP-2007-FORM 3.1.1.pdf

1125-kolnp-2007-form 5.pdf

1125-KOLNP-2007-FORM-27.pdf

1125-kolnp-2007-granted-abstract.pdf

1125-kolnp-2007-granted-claims.pdf

1125-kolnp-2007-granted-description (complete).pdf

1125-kolnp-2007-granted-form 1.pdf

1125-kolnp-2007-granted-form 2.pdf

1125-kolnp-2007-granted-specification.pdf

1125-KOLNP-2007-OTHERS 1.1.pdf

1125-kolnp-2007-pa.pdf

1125-kolnp-2007-reply to examination report-1.1.pdf

1125-KOLNP-2007-REPLY TO EXAMINATION REPORT.pdf

abstract-01125-kolnp-2007.jpg


Patent Number 246133
Indian Patent Application Number 1125/KOLNP/2007
PG Journal Number 07/2011
Publication Date 18-Feb-2011
Grant Date 15-Feb-2011
Date of Filing 02-Apr-2007
Name of Patentee ROMARK LABORATORIES, L.C.
Applicant Address 3000 BAYPORT DRIVE, SUITE 200, TAMPA, FL
Inventors:
# Inventor's Name Inventor's Address
1 ROSSIGNOL, JEAN, FRANCOIS 510 PARK STREET, ST. PETERSBURG, FL 33710
PCT International Classification Number A61K 31/426
PCT International Application Number PCT/US2005/031868
PCT International Filing date 2005-09-06
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 60/608,354 2004-09-09 U.S.A.