FIELD OF THE INVENTION
The present invention relates t hr, concentrated under reduced pressure, and the
residue partitioned between ethyl aceta te and water. The organic layer is washed with IN
hydrochloric acid (4 times, 20 mL/mmo!), then the combined aqueous phases extracted
with ethyl acetate (twice, 20 mL/mmol). The combined organic layers are finally washed
with water and saturated aqueous sodium chloride, dried over sodium sulfate and
concentrated under reduced pressure. The residue may be subjected to silica gel
chromatography or crystallization if ni cessary or desired.
\ ]

The compounds of EXAMPLES 1-86 arc prepared essentially as described in this
general procedure.

EXAMPLE
# Produc t Mass Spectral Data
(m/e)
1 Af-[2,4-dichlorobenzoyl]-- -bromophenylsulfonamide MS(ES): 408 [M-H]"
2 iV-[2,4-dichlorobenzoyl]-:»-chlorophenylsulfonamide MS(ES): 362 [M-H]'
3 N-[2,4-dichl< >robenzoyl]-4-
methoxypher ylsulfonamide MS(ES): 360 [M-H]"
4 iV-[2,4-dibromobenzoyl]^^-methylphenylsulfonamide ESMS: 434 (M++1)
5 iV-[2,4-dibromi >benzoyl]-4-tert-
butylpheny sulfonamide ESIMS: 476 (M++l)
6 iV-[2,4-dibromobenzoyl]-t-chlorophenylsulfonamide ESMS: 454,456(M++1)
7 iV-[2-bromo-4-< hlorobenzoyl]-4-
methylphen /lsulfonamide ESMS: 388,390^+1)
8 iV-[2-bromo-4-< hlorobenzoyl]-4-
chlorophen; 'lsulfonamide ESIMS: 408,410(M++l)
9 N-[2,4-dichlorobimzoyl]-3-chloro-4-
fluorophen? lsulfonamide ESIMS: 380(M+-2),
382CM+), 384(M++2)
10 iV-[2-chloro-4- nitrobenzoyl]-4-
chlorophen /lsulfonamide ESMS: 373(M+-2),
375CM+), 377(M++2)
11 iV-[2-chloro-4-bromobeiizoyl]-phenylsulfonamide ESMS: 372(M+-2),
374(M+)
12 iV-[2-methyl-4-bromobenzoyl]-phenylsulfonamide ESMS: 352(M+-2),
354(M+)
13 N-[2-chloro-4-nitrobeizoyl]-phenylsulfonamide ESIMS:339(M+-l),
341(M++1)
14
i iV-[2-chloro-4-)romobenzoyl]-4-
bromophen ylsulfonamide ESMS: 450(M+-3).
452(M+-1), 454(M++0
15 /V-[2-chloro-4 nitrobenzoyl]-4-
bromopher ylsulfonamide ESMS:417(M+-2),
419(M+)

16 7Y-[2-chloro-4-bomobenzoyl]-4-
fluoropheny sulfonamide ES1MS: 390(M+-2);
392(M+)
17 iV-[2-chloro-4-b omobenzoyl]-3-
chloropheny i sulfonamide ESIMS: 406(M'"-3),
408(M+-1),410(M++1)
18 N-[2-chloro-4-b omobenzoyl]-4-
methoxyphen ylsulfonamide ESMS: 402(M+-2),
404(Nf), 406(M++2)
19 iV-[2-methyl-4-b romobenzoyl]-4-
methoxyphen ^sulfonamide ESMS: 382CM+-2),
384(M+)
20 AT-[2-chloro-4-i titrobenzoyl]-4-
methoxyphen ^sulfonamide ESMS: 369(^-1),
371(M+)
21 A/-[2-chloro-4-n trobenzoyl]-3,4- .
dichlorophen ^sulfonamide ESIMS: 407(M+-2),
409(M+),411(M++2)
22 iV-[2-methyl-4-c hlorobenzoyl]-3-
chlorophen) [sulfonamide ESMS: 342(M-1),
344(JVr-l),346(M"-l)
23 iV-[2-methyl-4-c hiorobenzoyl]-4-
methylphem lsulfonamide ES Negative Ion MS
[M-H]" ions observed:
m/z 342(35C1,35C1), m/z
344(35Cl,37Cl)andm/z
346 (37C1, 37C1).
24 N-[ 2,4-dichlo:obenzoyl]-3,4-
dibromopher ylsulfonamide ES Negative Ion MS
[M-H]" ions observed:
m/z 322 (35C1) and m/z
324 (37C1).
25 N-[2,4-dichlhenylsulfonamide ESIMS m/e 473.8,
475.9, and 477.9 (MM;
79Br,79Br;79Br,81Br;
81Br, 81Br)
32 7V-[2-bromo-4-chlorobenz3yl]-3-methoxycarbonyl-4-
methoxypher ylsulfonamide ESIMS m/e 459.9,
461.9,463.9 (M+-l;
79Br,35Cl;81Br,35Cl;
81Br,37Cl)
33 7V-[2-bromo-4-ch]orobenzoyl]-4-terr-
butylpheny sulfonamide ESIMS m/e 428.2,
430.2, and 432.2;
(MM;79Br,35Cl;81Br,
35Cl;81Br,37Cl
1
34 N- [2,4-dibromobenzoy tJ~3-methoxycarbonyl-4-
methoxyphei ylsulfonamide ESIMS m/e 503.9, 506.0
and 508.0;
(MM;7yBr,79Br;81Br,
79Br; slBr, slBr)
i
i
L Ar-[2-methyI-4-broirobenzoyl]-3-chloro-4-
fluorophen; lsulfonamide ESIMS m/e 404.0,
406.0, 408.0(MM;79Br,
35Cl;81Br,35Cl;8,Br,
37C1)

EXAMPLE 85
N-[2-chloro-4-bromobenzoyl]-4-chlorophenylsulfonamide
An 8 mL reaction vial is cha ged with 2-chloro-4-bromobenzoic acid (0.39 mmol,
1.5 eq) and 2.0 mL of dichloromethane. A stock solution (4.0 mL) containing 4-
chlorophenylsulfonamide (0.26 mmol, 1 eq) and N,N-[dimethyl]-4-aminopyridine (48 mg,
0.39 mmol, 1.5 eq) in dichlorometh me is added, followed by 0.261 g carbodiimide
polystyrene resin (2.0 mmol/g, 0.52 mmol, 2.0 eq, Novabiochem) and the vial is capped
and rotated. After 72 hr, 0.77 g sulohonated polystyrene resin (MP-TsOH) is added (1.53
mmol/g, 1.17 mmol, Argonaut). After about 18 hr the reaction mixture is filtered and
concentrated under a stream of nitrogen. The residue is subjected to reverse phase HPLC;
CombiPrep column, YMC ODS-A 20X50 mm column with 5 micron, C18, 120
Angstrom pore size, gradient: 5% o 95% CH3CN/O.O1 HCI aqueous solution. Fractions
containing product are combined and concentrated under reduced pressure to provide the
title compound.
ESIMS: m/e = 408(M++1), 406(m+-1), 410(M++3).

The compounds of Examples 86 -107 are prepared essentially as described in
Example 85.

EXAMPLE
# Product Mass Spectral Data
(m/e)
86 iV-[2,4-dichlor< >benzoyl]-4-
methylphenylsul fonamide ESIMS: 342(M+-1),
344(^+1)
87 AT-[2,4-dichlor< »benzoyl]-4-
methylthiophenylsulfonamide ESIMS: 374CM+-1),
376(M++1)
88 iV-[2,4-dichlorobsnzoyl]-4-tert-
butylphenylsi ilfonamide ESIMS: 384(MM),
386(^+1)
89 JV-[2,4-dichlorobentoyl]-3-chloro-4-
methylphenyl lulfonamide ESIMS: 378(M++1),
376(M+-1), 380(M++3)
90 iV-[2-methyl-4-cb lorobenzoyV]-3-
bromophenyl! ;ulfonamide ESIMS: 388(^+1),
386(MM), 390(^+3)
91 N-[2,4-dichlor obenzoyl]-4-
fluorophenylt ulfonamide ESIMS: 346(M+-1),
348(M++1)
92 iV-[2,4-dichlorc benzoyl]-3,4-
dichloropheny isulfonamide ESIMS: 398(M++1),
396^-1), 400(M++3)
93 iV-[2-methyl-4-cllorobenzoyl]-4-
chlorophenylsu fonamide ESIMS: 342(M+-1),
344(M++1)
94 Af-[2,4-dichlorobt snzoyl]-4-bromo
phenylsulfo namide ESIMS: 408(M+1), 406
(M-l), 410(M+3)
95 iV-[2,4-dichk» obenzoyl]-4-
methylsulfonyloxyphenylsulfonamide ESIMS: 422 (M-2), 424
(M), 426 (M+2)
96 iV-[2,4-dichlo obenzoyl]-4-
trifluoromethoxyp henylsulfonamide ESIMS: 412 (M-2), 414
(M), 416 (M+2)
i
t
97
i
i A'-[2,4-dichloroben2 3y]]-4-methoxy-3,5-
dimethylphen /Isulfonamide ESIMS: 368 (M-2), 370
(M), 372 (M+2)

N-[2,4-dichlorobenzoyl]-4-(l-methylsulfanylo-phen-4-yl)phenylsulfonamide
Step A: Procedure for activation of the resin
The Rink amide resin (CA Novabiochem, 0.53 mmol/g) was suspended in a 30%
solution of pyridine in DMF and stirrec at room temperature for 3 hours. The mixture was
filtered and the resin was washed twice with DMF and then, alternatively with CB2CI2
and MeOH. The activated resin having a free amino group was dried and used without
further purification.

The Rink amide resin (0.53 n mol/g) was suspended in a 1:1 mixture CH2CI2/THF
and Bt3N (4 eq), 4-iodophenylsulfona mide (3 eq) and DMAP (catalytic amount). The
solution was stirred overnight at room temperature. The mixture was filtered and the resin
was washed alternatively with CH2C 2 and MeOH. The 4-iodophenylsulfonamide Rink
resin was dried under vacuum.
The corresponding 4-iodophenylsulfonamide Rink resin (0.26 mmol, 0.53
mmol/g), Methylsulfanyl-phenyl bor )nic acid (2 eq), potassium carbonate (6 eq) and the
Palladium acetate (0.5 eq) were mixed together and suspended in 7 mL of a mixture
dioxane/water 6:1. This mixture was heated in an Argovant® QUEST® 210 at 100°C for
24 hours. Then, the resin was washed twice with 5 mL of a mixture dioxane/water 6:1 and
then six times with CH2CI2 (7 mL) f ollowed each time by MeOH (7 mL).
3 mL of a 95% aqueous solu ion of trifluoroacetic acid were added to the resin
previously dissolved in 3 mL of CH2Cl2-The mixture was stirred for 30 min at room
temperature, filtered as described above. The 4'-methylsulfanyl-biphenyl-4-sulfonamide
was employed without further purification.
To a stirred solution of 2,4-Dichloro-benzoic acid (1.25 eq) in dry CH2CI2 (10
mL/mmol), 4'-Methylsulfanyl-biphenyl-4-sulfonamide (1.0 eq) was added in one portion
followed by EDC (1.25 or 1.5 eq) and finally, DMAP (1.2 equiv). The mixture was
vigorously stirred under nitrogen for 16 hours, then evaporated in vacuo and the residue
partitioned between EtOAc and water. The organic layer was washed with IN HCl (4
times, 20 mL/mmol), then the aqueous phase was extracted with EtOAc (twice, 20
mL/mmol). The combined organic ayers were finally washed with water and brine, dried
over Na2SO4 and concentrated in vacuo. The crude product was purify by silica gel
chromatography using the appropriate eluent afford the title compound.
ES1-MS (M+-H) 450.9870 / 450.0.
EXAMPLE 109
N-[2,4-dichlorobenzoyl]-4-3' -acetyl-biphenylsulfonamide
A suspension of 4-iodophc nylsulfonamide Rink resin (0.26 mmol, 0.53 mmol/g),
3-acctylphenyl boronic acid (2 eq) and 2,4-dichloro-benzoic acid (1.25 eq); were used
essentially as described in Exampl 5 108 to prepare the title compound.
ES1-MS (M+-H) 447.0099 / 446.0.

EXAMPLE 110
N-[2,4-dichlo:obenzoyl]phenylsulfonamide
To a mixture of phenylsulfonamide (0.16 mol; 25.12 g) and potassium carbonate
(0.2 mol; 27.6 g) in 500 mL dioxane s added dropwise 2,4-dichiorobenzoyl chloride
(0.13 mole; 18.0 mL). The mixture is warmed to reflux under nitrogen for 16 hr. The
reaction is then diluted with water (500 mL), neutralized to pH 5 with concentrated
hydrochloric acid, and extracted 3 times with ethyl acetate. The combined ethyl acetate
layers are washed with saturated aqueous sodium chloride, dried over sodium sulfate and
concentrated under reduced pressure to a white solid. The solid residue is subjected to
silica gel chromatography, eluting w ith dichloromethane containing from 0-5% methanol.
Fractions containing the product are combined and concentrated under reduced pressure
to provide the title compound.
MS(ES): m/e = 329.9 (M++1), 327 9 (MM).
EXAMPLE 111
N-[2,4-dichlorobenzoyl]-4-chlorophenylsulfonamide
A mixture of 4-chlorophenylsulfonamide (0.1 mol; 19.0 g) and 2,4-
dichlorobenzoyl chloride (0.12 mo ; 16.8 mL); the title compound was prepared
essentially as described in Example 110.
MS(ES): m/e = 363.9 (M+)
EA: Calculated for C13H8Cl3NO3,S: Theory: C, 42.82; H, 2.21; N, 3.84. Found: C,
42.56; H, 2.14; N, 3.76.
EXAMPLE 112
iV-[2-chloro-4~bremobenzoyl]-4-chlorophenylsulfonamide
To a reaction mixture of A -chlorophenylsulfonamide (15.6 g, 81.4 mmol), CD1
(15.82 g, 97.7 mmol) and ethyl acetate (300 mL) at room temperature is added a slurry of
2-chloro-4-bromobenzoic acid ('. ,3.0 g, 97.7 mmol) in ethyl acetate (100.0 mL) over a
period of 15.0 min (note: gas evc lution is observed which can be controlled by the rate of
addition of the slurry; reaction mixture goes into solution by the end of" addition of the
slurry; reaction can be monitorec by HPLC or TLC with 1:1 ethyl acetate/heptane eluent.
The reaction is then stirred at room temperature for 30 min and then heated at 60°C for 90

mm or until no gas evolution is observed. The reaction is cooled to 40°C, and 1,8-
diazabicyclo[5.4.0]undec-7-ene is (14 63 mL) added (all at once). The reaction
temperature goes from 40°C to 45°C. The mixture is stirred until it reaches room
temperature before quenching with deionized water (400 mL). The top organic layer is
separated, washed with IN HC1 (300 0 mL), dried with anhydrous MgSO4, filtered and
the cake washed with ethyl acetate (20.0 mL). The filtrate is concentrated to 50.0 g of
syrupy solution, then heptane (250.0 mL) is added with vigorous stirring. With heating, a
white slurry is formed and is refluxe i and then allowed to equilibrate to room
temperature. The white precipitate is filtered and the cake is washed with heptane (20.0
mL). The precipitate is dried in a house vacuum at 55°C for 18 hr. (mass = 29.12 g,
87.4% wt yield).
A mixture of 19.17 g of the product and 1:2 ethyl acetate/heptane (150.0 mL) is
heated at reflux for 30 min, and the a cooled to room temperature. The off white
precipitate is filtered and then the < ake is washed with heptane (50.0 mL). The
precipitate is dried in a house vacuum at 50°C for 18 hr. (mass = 14.93 g; 78%
recovery).
ESIMS: m/e = 408(M++1), 406(M+-1), 410(M++3).
EXAMPLE 113
N-[2-chloro-4-bromobenzoyl]-4-chlorophenylsulfonamide
sodium salt
To a solution of N-[2-chloro-4-bromobenzoyl]-4-chlorophenylsulfonamide (5.2 g,
12.72 mmol) and tert-butyl meth yl ether (88.0 mL) at room temperature is added sodium
methoxide (0.69 g, 12.72 mmol] all at once. The reaction is then stirred for 5 hr, after
which heptane (88.0 mL) is added followed by vigorous stirring for 60 min. A white
precipitate is formed, filtered of f under a positive nitrogen pressure, and the cake
subsequently washed with heptane (2 x 44.0 mL). The cake is dried to semi-dryness,
followed by drying in a house vacuum oven at 130°C for 18 hr (mass = 4.4 g, 80% wt.
Yield; 1H nmr (DMSO d6) 7.8- 7.85 (m,lH), 7.81-7.82 (m, 1H), 7.58-7.59 (d, 1H, J = 1.76
Hz), 7.51-7.52 (m, 1H), 7.48-7 49 (m, 1H), 7.44-7.45 (d, 1H, J = 1.76) 7.37-7.4 (d, 1H).

EXAMPLE 114
N-[3-chloro-4-fluorophenylsulfonyl]-3-fluoro-4-methylbenzamidine
Add 3-fluoro-4-methylbenzan ictine hydrochloride (0.025 g, 0.133 mmol) in THF
(0.5 mL) to 3-chloro-4-fluorophenyl sulfonylchloride (0.0304 g, 0.133 mmol) followed by
iV-methylmorpholine (0.2 mL). The reaction mixture was concentrated and
chromatographed using reverse phase chromatography (gradient of 5-95% (0.1% TFA in
CH3CN)in (0.1%TFA in H2O). A white solid (16.4 mg, 36%) was isolated. ES
Positive Ion MS [M+H] ions observed: m/z 345 (35CI) and m/z 347 (37C1).
EXAMPLE 115
N-[3-chloro-4-fluorophenylsulfonyl]-4-chlorobenzamidine
4-chlorobenzamidine hydroc hloride (0.025 g, 0.133 mmol) and 3-ehloro-4-
fluorophenyl sulfonylchloride (0.03 34 g, 0.133 mmol); were used essentially as described
in Example 114 to prepare the title compound. ES Positive Ion MS [M+H]+ ions
observed: m/z 347 (35C1,35C1), m/z.A9 (35C1,37C1) and m/z 351 (37C1,37C1).
EXAMPLE 116
N-[3-chIoro-4-tluorophenylsulfonyl]-3-chloro-4-fluorobenzamidine
A mixture of 3-chloro-4-fl lorobenzamidine hydrochloride (0.025 g, 0.133 mmol)
and 3-chloro-4-lluorophenyl sulfonylchloride (0.0304 g, 0.133 mmol); the title compound
is prepared essentially as describe 1 in Example 115. ES Positive Ion MS [M+H]+ ions
observed: m/z 365 (35C1,35C1), m/z 367 (35C1,37C1) and m/z 369 (37C1,37C1).
EXAMPLE 117
N-[2,4-dichlorobenzoyl]-4-hydroxyphenylsulfonamide
4-Methoxy-phenyl-4-sulf onamide (0.0608 g, 0.132 mmol) is dissolved in THF
(1.25 mL) and treated with tetrabutylammonium fluoride (1.0 N/THF; 200 \iL, 2.0 mmol)
at room temperature with stirring for 18 hr. The reaction mixture is diluted with EtOAc
(10 mL) and washed with satura;ed aq. NH4CI (1 ml.), H2O (2 x 1 mL), and brine (1 mL).
The organic phase is dried MgSO4, filtered, and concentrated by rotary evaporation.
(Lyopholized from H2O/MeOH to obtain a glassy solid, 20 mg (0.058 mmol, 58%).

Purified by preparative HPLC.) mp 155- 157°C; ESI-MS m/e 344.0 (M+ - H); 1H NMR
(d6-DMSO) 7.90 (d, 2 H); 7.68 (s, 1 H); 7.44 (s, 2II); 6.90 (d, 2H); 3.43 (br s, 3 tl).
EXAMPLE 118
N-[2,4-dichlorobcnzoyl -4-(thien-3-yI)-phenylsulfonamide
To a solution of N-(2,4-dichlorc benzoyl)~4-iodo-phenylsulfonamide (0.10 mmol)
in toluene/ethanol 20/1 (3 mL) is addec 3-thiopheneboronic acid (0.18 mmol, 0.18 mL,
1.0M solution in DMF) and tetrakis-(tr phenylphosphine) palladium (0) (10 mol%). Then
2M aqueous Na2CO3 is added (0.3 mL and the stirred mixture is heated to 100°C
overnight (17 hr)(Buchi Syncore system). The reaction mixture is concentrated (Genevac
apparatus), then water is added (2.5 mL) and ethyl acetate (5 mL). The phases are
separated and the aqueous layer is extracted with ethyl acetate (3x5 mL). This process is
automatically carried out using a Tecs n system. The solvents are evaporated and the
corresponding crude product is purified by HPLC to give the title compound.
ESI-MS m/e 410.96 / 410.0 [M+-H]
The compounds of EXAMPLES 119-130 are prepared essentially as described in
the procedure for EXAMPLE 118.



All of the compounds concerned are orally available and are normally
administered orally, and so oral administration is preferred. However, oral administration
is not the only route or even the only preferred route. For example, transdermal
administration may be very desirable for patients who are forgetful or petulant about
taking oral medicine, and the i ltravenous route may be preferred as a matter of
convenience or to avoid poten ial complications related to oral administration.
Compounds of Formula II ma / also be administered by the percutaneous, intramuscular,
intranasal or intrarectal route n particular circumstances. The route of administration
may be varied in any way, lin ited by the physical properties of the drugs, the convenience
of the patient and the caregiver, and other relevant circumstances (Remington's
Pharmaceutical Sciences, 18th Edition, Mack Publishing Co. (1990)).

The pharmaceutical compositic ns are prepared in a manner, well known in the
pharmaceutical art. The carrier or excibient may be a solid, semi-solid, or liquid material
that can serve as a vehicle or medium for the active ingredient. Suitable carriers or
excipients are well known in the art. The pharmaceutical composition may be adapted for
oral, inhalation, parenteral, or topical use and may be administered to the patient in the
form of tablets, capsules, aerosols, inhalants, suppositories, solutions, suspensions, or the
like.
The compounds of the present invention may be administered orally, for example,
with an inert diluent for capsules or compressed into tablets. For the purpose of oral
therapeutic administration, the compounds may be incorporated with excipients and used
in the form of tablets, troches, capsufes, elixirs, suspensions, syrups, wafers, chewing
gums and the like. These preparatic ns should contain at. least 4% of the compound of the
present invention, the active ingredient, but may be varied depending upon the particular
form and may conveniently be between 4% to about 70% of the weight of the unit. The
amount of the compound present in compositions is such that a suitable dosage will be
obtained. Preferred compositions and preparations of the present invention may be
determined by methods well known to the skilled artisan.
The tablets, pills, capsules, troches, and the like may also contain one or more of
the following adjuvants: binders such as povidone, hydroxypropyl cellulose,
microcrystalline cellulose, or gelatin, excipients or diluents such as: starch, lactose,
microcrystalline cellulose or dicalcium phosphate; disintegrating agents such as:
croscarmellose, crospovidone, sodium starch glycolate, corn starch and the like; lubricants
such as: magnesium stearate, steric acid, talc or hydrogenated vegetable oil; glidants such
as colloidal silicon dioxide; wetting agents such as: sodium lauryl sulfate and polysorbate
80 (CAS No.9005-65-6); and sweetening agents such as: sucrose, aspartame or saccharin
may be added or a flavoring agent such as: peppermint, methyl salicylate or orange
flavoring. When the dosage unit form is a capsule, it may contain, in addition to materials
of the above type, a liquid carrier such as polyethylene glycol or a fatty oil. Other dosage
unit forms may contain other va ious materials that modify the physical form of the
dosage unit, for example, as coatings. Thus, tablets or pills may be coated with sugar,
hydroxypropyl methylcellulose polymethacrylates, or other coating agents. Syrups may
contain, in addition to the present compounds, sucrose as a sweetening agent and certain

preservatives, dyes and colorings and. flavors. Materials used in preparing these various
compositions should be pharmaceuty cally pure and non-toxic in the amounts used.
Injections for parenteral adrr frustration include sterile aqueous or non-aqueous
solutions, suspensions and emulsions. Aqueous solutions and suspensions may include
distilled water for injection or phys ological salt solution. Non-aqueous solutions and
suspensions may include propylene glycol, polyethylene glycol, vegetable oil such as
olive oil, alcohol such as ethanol or polysorbate 80. Injections may comprise additional
ingredients other than inert diluents e.g. preserving agents, wetting agents, emulsifying
agents, dispersing agents, stabilizing agents (such as lactose), assisting agents such as
agents to assist dissolution (e.g. g utamic acid or aspartic acid). They may be sterilized
for example, by filtration through a bacteria-retaining filter, by incorporation of sterilizing
agents in the compositions or by rradiation. They may also be manufactured in the form
of sterile solid compositions whi :h may be dissolved in sterile water or some other sterile
diluent(s) for injection immedial ely before use.
The compounds of Formula II are generally effective over a wide dosage
range. For example, dosages pe r day normally fall within the range of about 10 to
about 300 mg/kg of body weight. In some instances dosage levels below the lower
limit of the aforesaid range may be more than adequate, while in other cases still
larger doses may be employed without causing any harmful side effect, and therefore
the above dosage range is not intended to limit the scope of the invention in any way.
It will be understood that the amount of the compound actually administered will be
determined by a physician, in he light of the relevant circumstances, including the
condition to be treated, the chosen route of administration, the actual compound or
compounds administered, the age, weight, and response of the individual patient, and
the severity of the patient's s> mptoms.
Inhibition of HUVEC Prolife ration
Human umbilical vein endothelial cells (HUVEC; BioWhittaker/Clonetics,
Walkersville, MD) were mai ntained in endothelial cell growth medium (EGM) containing
basal medium (EBM) with bovine brain extract, human epidermal growth factor,
hydrocortisone, gentamicin, amphotericin B and 2% fetal bovine serum. For the assay,
HUVEC (5 x 103) in EBM (200 µl) with 0.5% fetal bovine serum were added to wells in a

96-well cell culture plate and incubaced at 37°C for 24 hr in humidified 5% carbon
dioxide/air. The test compounds were serially diluted in dimethyl sulfoxide (DMSO) in
concentrations from 0.0013 to 40 µvl and added to the wells in 20 µl. Then human
vascular endothelial growth factor VEGF) (20 ng/mL in wells; R&D Systems,
Minneapolis, MN) prepared from a stock solution of 100 µ,g/mL in phosphate buffered
normal saline containing 0.1 % bovine serum albumin,, was added to the wells. The
HUVBC were incubated at 37°C for 72 hr in humidified 5% carbon dioxide/air. WSX-1
cell proliferation reagent (20 µl; Foehringer Mannheim, Indianapolis, IN) was added to
the wells and the plates returned to the incubator for 1 hr. The absorbance of each well at
440 nra was measured. The growth fraction was determined from the absorbance of
treated wells with and without VEGF divided by the absorbance obtained from control
wells set to zero and 1.0. The exemplified compounds were tested in this assay and all
exhibited an IC50 < 1.0 µM.
Rat Corneal Micropocket Assa'
Fisher 344 female rats ( 145-155 grams; Taconic, Inc., Germantown, NY) were
anesthesized with acepromazine (2.5 mg/kg, ip) 20 minutes prior to initiation of 2-3%
isoflurane/oxygen inhalation. The body temperature was maintained with a circulating
hot water pad. The surgery was performed using an ophthalmic operating microscope
(OMS.75 Operating Microscope, TopCon Corporation, Japan). A scalpel blade (#15) was
vsed to make a vertical half-tldckness linear corneal incision just lateral to the center of
the eye. The tip of the scalpe blade was used to gently undermine the superior corneal
layer of the cornea nearest to the limbus. A pocket was formed in the cornea using blunt
dissection with corneal scissors (Roboz, Rockville, MD). Nitrocellulose filters (0.45 µn,
Millipore, Bedford, MA) were cut into small disks using a 20 gauge needle punch. The
disks were soaked in 2 µ1 of ouman VEGF solution (0.82 vg/µl; R&D Systems) or human
basic fibroblast growth factor (0.20 µg/µl; R&D Systems) for 10 minutes on ice. Using
forceps, the disks impregnated with the angiogenic factor (VEGF or bFGF) were inserted
into the corneal pocket so th at the disk is firmly covered with corneal epithelium. The
animals were treated with th e compound of Example 110 (160 mg/kg) administered orally
by gavage in phosphate buftered saline once per day on days 1 through 10 post
implantation of the disks. The eyes were photographed on days 7 and 14 post

implantation of the disks. For photography, the animals were treated with atropine sulfate
(AmTech Group, Inc., Phoenix Scier tific, Inc., St. Joseph, MO) topically for mydriasis
and anesthetized with 2-3% isoflurane/oxygen. The eyes were photographed using the
ophthalmic microscope and the images were saved using Image Pro-Plus software. The
images were analyzed by converting the area of interest to high contrast black and white
reversed image and counting the bnght pixels as a determination of the vascular area. The
data are images from at least 6 eyes. The compound of Example 110 was a very effective
inhibitor of VEGF-induced neoangiogenesis, but was not an effective inhibitor of bFGF-
induced neoangiogenesis.
HCT116 Colon Cajnginoma Cell Growth Inhibition
Human HCT116 colon carcinoma ceils were grown monolayer culture in RPMI
1640 medium supplemented with 10% fetal bovine serum and 1% penicillin-streptomycin
(GibcoBRL, Grand Island, NY). HCT116 cells in exponential growth phase were
exposed to various coneentratiot s of the test compounds at 37°C for 72 hr in 5% carbon
dioxide/air. After exposure to the agent, the cells were washed with 0.9% phosphate
buffered saline. Growth inhibition was determined using WST-1 cell proliferation reagent
as described above. The results are expressed as the growth fraction of treated cells
compared with control cultures. Representative compounds of the present invention were
tested for efficacy against the human colon HCT116 tumor cells. The data from these
experiments are summarized in TABLE I.

Conventional Murine Tumor andHnman Tumor Xenograft Assays
Inhibition of tumors transplanted into mice is an accepted procedure for studying
the efficacy of antitumor agents (Corbett, et al., In vivo Methods for Screening and
Preclinical Testing; Use of roden solid tumors for drug discovery In: Anticancer Drug
Development Guide; Preclinical Screening, Clinical Trials, and Approval, B. Teichcr
(ed), Humana Press Inc., Totowa, NJ, Chapter 5, pages 75-99 (1997); (Corbett, et al., Int
J. Pharmacog., 33, Supplement, 102-122 (1995)). Murine tumors or human xenographs
were implanted essentially as described by Corbett in In vivo Methods for Screening and
Preclinical Testing; Use of rode at solid tumors for drug discovery. Briefly, the murine
tumor or human xenograph was implanted subcutaneously using either 12-gauge trocar
implants or counted number of cells. The location for the trocar insertion is midway
between the axillary and inguir at region along the side of the mouse. The trocar is
slipped approximately 3/4 of a I inch subcutaneously up toward the axilla before
discharging the tumor fragment, and pinching the skin as the trocar is removed.
Alternatively, human tumor cells prepared from a brie of donor tumors (5 x 106 cells)
were implanted subcutaneousl y in a hind-leg of a male or female nude mouse (Charles
River). Either a test compoun i in vehicle or vehicle alone was administered by
intravenous bolus injection (iv), intraperitoneal injection (ip), or oral gavage (po). Each
treatment group, as well as a group of untreated control animals, consisted of five animals
per group in each experiment. Subcutaneous tumor response was monitored by tumor
volume measurement pcrforrr ed twice each week over the course of the experiment (60-
i 20 days). Body weights were taken as a general measure of toxicity. The subcutaneous
tumor data were analyzed by ietermining the median tumor weight for each treatment
group over the course of the experiment and calculating the tumor growth delay as the

difference in days for the treatment versus the control tumors to reach a volume of either
500 or 1000 mm3.
The compound of Example 1 0 was tested against a variety of murine and human
tumors substantially as described surra. The data from these tests are summarized in
TABLES n-XIII. The parameters measured in each experiment are summarized in the
following paragraphs.
Tumor Weight(mg) = (a x b ')/2 where a =tumor length (mm) and b = tumor width
(mm).
Tumor Growth Delay = T - C where T is the median time (days) required for the
treatment group tumors to each a predetermined size, and C is the median time
(days) for the control group tumors to reach the same size. Tumor-free survivors
are excluded from this caleulation, and are tabulated separately (Tumor Free).
Log Kill = Tumor Growth Delay
(3.32)(Td)
where Tumor Growth Delay is as previously defined and Td is tumor volume
doubling time (days), estimated from the best fit straight line from a log-linear
growth plot of the contrc 1 group of tumors in exponential growth (100-800 mg
range)
%T/C mass - The treatr lent and control groups are measured when the control
group tumors reach app oximately 700 to 1200 mg in size (median group). The
median tumor weight o ' each group is determined (including zeros). The T/C
value in percent is an ir dication of antitumor effectiveness. A T/C < 42% is
considered significant antitumor activity. A T/C < 10% is considered to indicate
highly significant antitu mor activity.
Body weight Loss Nadir - A body weight loss nadir (mean of group) of greater
than 20% or drug deaths greater than 20% are considered to indicate an
excessively toxic dosa ge in single course trials.

Activity Rating - the Activity Rating is derived from the Log Kill according to the
following table:

We Claim
A N- [benzoyl] -phenylsulfonair ide compound of formula (I)

where: X is O or NH ;
R1 is hydrogen, halo, C1-C4, alkyl, C1-C4 alkoxy, C1-C4 alkylthio, CF3, OCF3,
SCF3, (C1-C4 alkoxy) carbonyl, nitro, azido, O (SO2) CH3, N (CH3) 2, hydroxy,
phenyl, substituted phenyl,} yridinyl, thienyl, furyl, quinolinyl, or triazolyl;
R2 is hydrogen, halo, cyaro, CF3, C1-C6 alkyl, (C1-C4 alkoxy) carbonyl, C1-C4
alkoxy, phenyl, or quinoluy1:
R2a is hydrogen or C1-C4 all oxy;
R2b is hydrogen or C1-C6 alkyl provided that at least one of R2a and R2b is
hydrogen;
R3 is hydrogen, halo, C1-C6 alkyl, CF3, or nitro;
R3a is hydrogen, halo, or C1-C6 alkyl provided that when R3a is C1-C6 alkyl, R3 is
hydrogen and R4 is halo; and
R4 is halo, C1-C6 alkyl, or CF3 provided that only one of R3 and R4 may be C1-C6
alkyl and provided that v hen R4 is halo or C1-C6 alkyl only one of R3 and R3a is
hydrogen; or a pharmact utically acceptable base addition salt thereof, provided
that:
a) when R3 and R4 are loth chloro and R2 is hydrogen, R1 is bromo, iodo, C1-C4
alkoxy, C1-C4 alkylthio, CF3, OCF3, nitro, azido, O (SO2) CH3, N (CH3) 2,
hydroxy, phenyl, substituted phenyl, pyridinyl, thienyl, furyl, or triazolyl;
b) when R3 and R4 are both chloro and R1 is hydrogen, R2 is bromo, fluoro, CF3,
C1-C6 alkyl, C1-C4 alkoxy, phenyl, or quinolinyl.

The compound of claim 1, wherein R2, R2a, and R2b are hydrogen and R1 is
selected from the group consisting of hydrogen, halo, C1-C6 alkyl, C1-C4 alkoxy,
C1-C4 alkylthio, CF3, OCF3, S( T3, (C1-C4 alkoxy) carbonyl, nitro, azido, O (SO2)
CH3, N (CH3) 2, hydroxy, prenyl, substituted phenyl, pyridinyl, thienyl, furyl,
quinolinyl, and triazolyl.
The compound of claim 1 o • 2, wherein the compound is a pharmaceutically
acceptable base addition salt.
The compound of claim 3, wherein the pharmaceutically acceptable base addition
salt is a sodium salt.
The compound of claim 1 which is iV-[2-chloro-4-bromobenzoyl]-4-
chlorophenylsulfonamide or base addition salt therof.
The compound of claim 1 which is N- [2, 4- dichlorobenzoyl] phenylsulfonamide
or a base addition salt thereo f.
The compound of claim 5 01 6 wherein the base addition salt is a sodium salt.
A pharmaceutical formulation comprising a compound of Formula I as claimed in
claim 1:

R1 is hydrogen, halo, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 alkylthio, CF3, OCF3,
SCF3, (C1-C4 alkoxy) ca bonyl, nitro, azido, O(SO2)CH3, N (CH3) 2, hydroxy,
phenyl, substituted pheny , pyridinyl, thienyl, furyl, quinolinyl, or triazolyl;

R is hydrogen, halo, cyano, CF3, C1-C6 alkyl, (C1-C4 alkoxy) carbonyl, C1-C4
alkoxy, phenyl, or quinolinyl;
R2a is hydrogen or C1-C4 alkoxy
R2b is hydrogen or C1-C6 alkyl provided that at least one of R2a and R2b is
hydrogen;
R3 is hydrogen, halo, C1-C6 alkyl, CF3, or nitro; R3a is hydrogen, halo, or C1-C6
alkyl provided that when R3a is C1-C6 alkyl, R3 is hydrogen and R4 is halo; and
R4 is halo, C1-C6 alkyl, or CF3 provided that only one of R3 and R4 may be C1-C6
alkyl and provided that when R4 is halo or C1-C6 alkyl only one of R3and R3a is
hydrogen; or a pharmaceutially acceptable base addition salt thereof, and a
pharmaceutically acceptable ca rrier, diluent, or excipient.
N-[benzoyl]-phenylsulfonamice compound of formula (I)

where:
R1 is hydrogen, chloro, fluore, bromo, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylthio,
R is hydrogen, chloro, or brc mo
R3 is chloro, bromo, trifluoro methyl, or nitro; and
R4 chloro, bromo, trifluoromethyl, or C1-C4 alkyl, or a pharmaceutically
acceptable base addition salt thereof, provided that:
a) when R3 and R4 are ooth chloro and R2 is hydrogen, R1 is bromo, C1-C4
alkoxy, C1-C4 alkylth io, and
b) when R3 and R4 are both chloro and R1 is hydrogen, R2 is bromo.

The present invention provides antitumor compounds of the formula(I), and antitumor
methods.