Note: Descriptions are shown in the official language in which they were submitted.
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UROTENSIN-II RECEPTOR ANTAGONISTS
FIELD OF THE INVENTION
The present invention relates to sulfonamides, pharmaceutical compositions
containing them and their use as urotensin II antagonists
BACKGROUND OF THE INVENTION
The integrated control of cardiovascular homeostasis is achieved through a
combination of both direct neuronal control and systemic neurohormonal
activation.
Although the resultant release of both contractile and relaxant factors is
normally under
stringent regulation, an aberration in this status quo can result in
cardiohemodynamic
dysfunction with pathological consequences.
The principal mammalian vasoactive factors that comprise this neurohumoral
axis,
namely angiotensin-II, endothelia-1, norepinephrine, all function via an
interaction with
specific G-protein coupled receptors (GPCR). Urotensin-II, represents a novel
member of
this neurohumoral axis.
In the fish, this peptide has significant hemodynamic and endocrine actions in
diverse end-organ systems and tissues:
~ smooth muscle contraction
both vascular and non-vascular in origin including smooth muscle preparations
from
the gastrointestinal tract, respiratory, and genitourinary tract. Both pressor
and
depressor activity has been described upon systemic administration of
exogenous
peptide
~ osmoregulation:
effects which include the modulation of transepithelial ion (Na+, Cl-)
transport.
Although a diuretic effect has been described, such an effect is postulated to
be
secondary to direct renovascular effects (elevated GFR)
~ metabolism:
urotensin-II influences prolactin secretion and exhibits a lipolytic effect in
fish
(activating triacylglycerol lipase resulting in the mobilization of non-
esterified free
fatty acids)
(Pearson, et. al. Proc. Natl. Acad. Sci. (U.S.A.) 1980, 77, 5021; Conlon, et.
al. J.
Exp. Zool. 1996, 275, 226.)
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In studies with human Urotensin-II it was found that it:
~ was an extremely potent and efficacious vasoconstrictor
~ exhibited sustained contractile activity that was extremely resistant to
wash out
~ had detrimental effects on cardiac performance (myocardial contractility)
Human Urotensin-II was assessed for contractile activity in the rat-isolated
aorta and
was shown to be the most potent contractile agonist identified to date. Based
on the in vitro
pharmacology and in vivo hemodynamic profile of human Urotensin-II it plays a
pathological
role in cardiovascular diseases characterized by excessive or abnormal
vasoconstriction and
myocardial dysfunction. (Ames et. al. Nature 1999, 401, 282)
Compounds that antagonize the Urotensin-II receptor may be useful in the
treatment
of congestive heart failure, stroke, ischemic heart disease (angina,
myocardial ischemia),
cardiac arrhythmia, hypertension (essential and pulmonary), COPD, restenosis,
asthma,
(Hay DWP, Luttmann MA, Douglas SA: 2000, Br J Pharmacol: volume 131, pages 10-
12)
neurogenic inflammation and metabolic vasculopathies all of which are
characterized by
abnormal vasoconstriction and/or myocardial dysfunction. Since U-II and GPR14
are both
expressed within the mammalian CNS (Ames et. al. Nature 1999, 40~, 282), they
also may
be useful in the treatment of addiction, schizophrenia, impulsivity, anxiety,
stress,
depression, and neuromuscular function. Functional U-II receptors are
expressed in
rhabdomyosarcomas cell lines and therefore may have oncological indications.
Urotensin
may also be implicated in various metabolic diseases such as diabetes (Ames
et. al. Nature
1999, 401, 282, Nothacker et al., Nature Cell Biology 1: 383-385, 1999)
SUMMARY OF THE INVENTION
In one aspect this invention provides for sulfonamides and pharmaceutical
compositions containing them.
In a second aspect, this invention provides for the use of sulfonamides as
antagonists of urotensin II, and as inhibitors of urotensin II.
In another aspect, this invention provides for the use of sulfonamides for
treating
conditions associated with urotensin II imbalance.
In yet another aspect, this invention provides for the use of sulfonamides for
the
treatment of congestive heart failure, stroke, ischemic heart disease (angina,
myocardial
ischemia), cardiac arrhythmia, hypertension (essential and pulmonary), COPD,
restenosis,
asthma, neurogenic inflammation and metabolic vasculopathies, addiction,
schizophrenia,
impulsivity, anxiety, stress, depression, neuromuscular function, and
diabetes.
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The urotensin antagonist may be administered alone or in conjunction with one
or
more other therapeutic agents, said agents being selected from the group
consisting of
endothelin receptor antagonists, angiotensin converting enzyme (ACE)
inhibitors,
vasopeptidase inhibitors, diuretics, digoxin, and dual non-selective ~i-
adrenoceptor and al-
adrenoceptor antagonists.
Other aspects and advantages of the present invention are described further in
the
following detailed description of the preferred embodiments thereof.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides for compounds of Formula(I):
O
II H
R1-S-N ~ X~NR3R
O
R2 Formula (I)
wherein:
RI is phenyl, benzothiophenyl, thienyl, furyl, pyrrolyl, pyridinyl,
benzthiadiazoyl,
benzoxadiazoyl, quinolinyl, or naphthyl, all of which may be substituted or
unsubstituted by
one, two, three, four or five of the following: halogen, methoxy, OH, NO~,
YCF3, C 1 _4
alkyl, C~p_4)alkylCOZC~p_4)alkyl, cyano, cycloC~ 1 _4)alkylenedioxy, or
dimethylamino;
R2 is halogen, CN or methyl;
R3 and R4 are independently hydrogen, C1-6 alkyl or benzyl; or with the
nitrogen form a
pyrrolidine or piperidine ring;
X is O or CH2;
Y is a bond or O;
provided the compound of Formula (I) is not 5-Chloro-3-methyl-
benzo[b]thiophene-2-
sulfonic acid [3-(2-dimethylamino-ethoxy)-4-iodo-phenyl]-amide;
or a pharmaceutically acceptable salt thereof.
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When used herein, the term "alkyl" includes all straight chain and branched
isomers.
Representative examples thereof include methyl, ethyl, n-propyl, iso-propyl, n-
butyl, sec-
butyl, iso-butyl, t-butyl, n-pentyl and n-hexyl.
When used herein, the terms fialogen' and 'halo' include fluorine, chlorine,
bromine
and iodine and fluoro, chloro, bromo and iodo, respectively.
The compounds of the present invention may contain one or more asymmetric
carbon atoms and may exist in racemic and optically active form. All of these
compounds
and their diastereoisomers are contemplated to be within the scope of the
present invention.
Preferably R1 is phenyl, thienyl, pyridinyl, benzthiadiazoyl, benzoxadiazoyl,
or naphthyl,
all of which may be substituted or unsubstituted by one, two, or three of the
following:
halogen, methoxy, N02, YCF3, or C 1 _4 alkyl.
Preferably R2 is halogen.
Preferably R3 is alkyl; more preferably R3 is methyl or ethyl.
Preferably R4 is alkyl; more preferably R4 is methyl or ethyl.
Preferably X is O.
Preferably Y is a bond.
Preferred Compounds are:
N-[4-Iodo-3-(2-dimethylamino-ethoxy)-phenyl]-3,4-dimethoxy-benzenesulfonamide;
4-Bromo-N-[4-iodo-3-(2-dimethylamino-ethoxy)-phenyl]-benzenesulfonamide;
N-[4-Methyl-3-(2-dimethylamino-ethoxy)-phenyl]-3,4-dimethoxy-
benzenesulfonamide;
N-[4-Iodo-3-(2-dimethylamino-ethoxy)-phenyl]-3-methoxy-benzenesulfonamide;
N-[4-Bromo-3-(2-dimethylamino-ethoxy)-phenyl]-3,4-dimethoxy-
benzenesulfonamide;
N-[4-Chloro-3-(2-dimethylamino-ethoxy)-phenyl]-3,4-dimethoxy-
benzenesulfonamide;
4,5-Dibromo-N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-2-
thiophenesulfonamide;
3,4-Dibromo-N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-benzenesulfonamide;
2,4,6-Trichloro-N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-
benzenesulfonamide;
2,6-Dichloro-N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-4-trifluoromethyl-
benzenesulfonamide;
2-Bromo-N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-4,5-dimethoxy-
benzenesulfonamide;
4-Bromo-N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-benzenesulfonamide;
4-Iodo-N-[4-iodo-3-(2-dimethylamino-ethoxy)-phenyl]-benzenesulfonamide;
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3,5-Dichloro-N-[4-iodo-3-(2-dimethylamino-ethoxy)-phenyl]-benzenesulfonamide;
2,3-Dichloro-N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-
benzenesulfonamide;
3-Chloro-4-fluoro-N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-
benzenesulfonamide;
3-Chloro-4-methyl-N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-
benzenesulfonamide;
2,5-Dimethyl-4-chloro-N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-
benzenesulfonamide;
2-Chloro-4-trifluoromethyl-N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-
benzenesulfonamide;
2,4-Dichloro-6-methyl-N-[4-iodo-3-(2-dimethylamino-ethoxy)-phenyl]-
benzenesulfonamide;
3-Methoxy-N-[4-iodo-3-(2-dimethylamino-ethoxy)-phenyl]-benzenesulfonamide;
2,5-Dimethoxy-N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-
benzenesulfonamide;
2,5-Dimethoxy-N-[4-bromo-3-(2-dimethylamino-ethoxy)-phenyl]-
benzenesulfonamide;
3-Nitro-N-[4-iodo-3-(2-dimethylamino-ethoxy)-phenyl]-benzenesulfonamide;
2-Nitro-4-methoxy-N-[4-iodo-3-(2-dimethylamino-ethoxy)-phenyl]-
benzenesulfonamide;
3-Nitro-4-methyl-N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-
benzenesulfonamide;
2-Ethyl-4-bromo-N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-
benzenesulfonamide;
3,4-Dichlorophenyl-N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-
benzenesulfonamide;
2,4,6-Trimethyl-N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-
benzenesulfonamide;
4-Chloro-N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-2-
naphthalenesulfonamide;
5-Chloro-N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-2-
thiophenesulfonamide;
2,5-Dichloro-N-[4-iodo-3-(2-dimethylamino-ethoxy)-phenyl]-3-
thiophenesulfonamide;
5-Bromo-N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-2-thiophenesulfonamide;
4,5-Dichloro-N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-2-
thiophenesulfonamide;
5-( { [ 1-(4-Chloro-phenyl)-methanoyl]-amino } methyl)-N-[4-chloro-3-(2-
dimethylamino-
ethoxy)-phenyl]-2-thiophenesulfonamide;
N-[4-Iodo-3-(2-dimethylamino-ethoxy)-phenyl]-benzo[1,2,5]-4-
thiadiazolesulfonamide;
2,4-Dichloro-N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-
benzenesulfonamide;
2-Methyl-4-bromo-N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-
benzenesulfonamide;
2,6-Dimethyl-4-bromo-N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-
benzenesulfonamide;
3-Methoxy-4-bromo-N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-
benzenesulfonamide;
2,4-Dichloro-5-methyl-N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-
benzenesulfonamide;
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3-Nitro-4-chloro-N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-
benzenesulfonamide;
2-Nitro-4-trifluoromethyl-N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-
benzenesulfonamide;
5-Chloro-N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-1-
naphthalenesulfonamide;
4-Bromo-5-chloro-N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-2-
thiophenesulfonamide;
3-Bromo-5-chloro-N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-2-
thiophenesulfonamide;
4-Nitro-5-chloro-N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-2-
thiophenesulfonamide;
4,5-Dichloro-N-[4-iodo-3-(2-dimethylamino-ethoxy)-phenyl]-2-
thiophenesulfonamide;
7-Chloro-N-[4-iodo-3-(2-dimethylamino-ethoxy)-phenyl]-benzo[ 1,2,5]oxadiazole-
4-
sulfonamide;
5-Bromo-6-chloro-N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-3-
pyridinesulfonamide;
2,4-Dibromo-5-methoxy-N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-
benzenesulfonamide;
2-Methyl-4,5-dimethoxy-N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-
benzenesulfonamide;
2,6-Dimethyl-4-bromo-N-[4-chloro-3-(2-diethylamino-ethoxy)-phenyl]-
benzenesulfonamide;
3,4-Dimethoxy-N-[4-chloro-3-(2-methylamino-ethoxy)-phenyl]-benzenesulfonamide;
2-Bromo-4,5-dimethoxy-N-[4-chloro-3-(2-methylamino-ethoxy)-phenyl]-
benzenesulfonamide;
5-Chloro-N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-2-
naphthalenesulfonamide;
2,6-Dichloro-4-trifluoromethoxy-N-[4-chloro-3-(2-diethylamino-ethoxy)-phenyl]-
benzenesulfonamide;
4,5-Dibromo-N-[4-chloro-3-(2-diethylamino-ethoxy)-phenyl]-2-
thiophenesulfonamide;
2-Bromo-4,5-dimethoxy-N-[4-chloro-3-(2-diethylamino-ethoxy)-pheny1]-
benzenesulfonamide;
3,4-Dimethoxy-N-[4-chloro-3-(3-dimethylamino-propyl)-phenyl]-
benzenesulfonamide;
3,4-Dimethoxy-N-[4-chloro-3-(2-diethylamino-ethoxy)-phenyl]-
benzenesulfonamide;
2-Chloro-4,5-dimethoxy-N-[4-chloro-3-(2-diethylamino-ethoxy)-phenyl]-
benzenesulfonamide; and
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2-Chloro-4,5-dimethoxy-N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-
benzenesulfonamide.
More preferred compounds are:
N-[4-Chloro-3-(2-dimethylamino-ethoxy)-phenyl]-3,4-dimethoxy-
benzenesulfonamide;
4,5-Dibromo-N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-2-
thiophenesulfonamide;
3,4-Dibromo-N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-benzenesulfonamide;
2,4,6-Trichloro-N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-
benzenesulfonamide;
2,6-Dichloro-N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-4-trifluoromethyl-
benzenesulfonamide;
N-[4-Iodo-3-(2-dimethylamino-ethoxy)-phenyl]-3,4-dimethoxy-benzenesulfonamide;
2-Bromo-N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-4,5-dimethoxy-
benzenesulfonamide;
2,4-Dichloro-N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-
benzenesulfonamide;
2-Methyl-4-bromo-N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-
benzenesulfonamide;
2,6-Dimethyl-4-bromo-N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-
benzenesulfonamide;
3-Methoxy-4-bromo-N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-
benzenesulfonamide;
2,4-Dichloro-5-methyl-N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-
benzenesulfonamide;
3-Nitro-4-chloro-N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-
benzenesulfonamide;
2-Nitro-4-trifluoromethyl-N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-
benzenesulfonamide;
4-Chlorophenyl-N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-
benzenesulfonamide;
5-Chloro-N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-1-
naphthalenesulfonamide;
4-Bromo-5-chloro-N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-2-
thiophenesulfonamide;
3-Bromo-5-chloro-N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-2-
thiophenesulfonamide;
4-Nitro-5-chloro-N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-2-
thiophenesulfonamide;
4,5-Dichloro-N-[4-iodo-3-(2-dimethylamino-ethoxy)-phenyl]-2-
thiophenesulfonamide;
7-Chloro-N-[4-iodo-3-(2-dimethylamino-ethoxy)-phenyl]-benzo[1,2,5]oxadiazole-4-
sulfonamide;
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5-Bromo-6-chloro-N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-3-
pyridinesulfonamide;
2,4-Dibromo-5-methoxy-N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-
benzenesulfonamide;
2-Methyl-4,5-dimethoxy-N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-
benzenesulfonamide;
2,6-Dichloro-4-trifluoromethoxy-N-[4-chloro-3-(2-diethylamino-ethoxy)-phenyl]-
benzenesulfonamide;
4,5-Dibromo-N-[4-chloro-3-(2-diethylamino-ethoxy)-phenyl]-2-
thiophenesulfonamide;
2-Bromo-4,5-dimethoxy-N-[4-chloro-3-(2-diethylamino-ethoxy)-phenyl]-
benzenesulfonamide;
3,4-Dimethoxy-N-[4-chloro-3-(3-dimethylamino-propyl)-phenyl]-
benzenesulfonamide;
3,4-Dimethoxy-N-[4-chloro-3-(2-diethylamino-ethoxy)-phenyl]-
benzenesulfonamide;
2-Chloro-4,5-dimethoxy-N-[4-chloro-3-(2-diethylamino-ethoxy)-phenyl]-
benzenesulfonamide; and
2-Chloro-4,5-dimethoxy-N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-
benzenesulfonamide.
Compounds of Formula (I) were prepared as outlined in Scheme 1.
Scheme 1
BOCNH ~ OH H2N ~ O~NR R
3 4
b
/ R2 / R2
1 2
O H
R '~~/N I \ O~NR R
O /
R2
3
Conditions: a) C1CH2CH2NR3R4-hydrochloride, potassium carbonate, water/1,2-
dimethoxyethane, reflux; b) HCI; c) R1S02C1, CHCI~, ambient temperature. (R1,
R3 and
R4 as defined above)
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For example, phenol 1 was alkylated with various dialkylaminoethyl chlorides
and
the resulting ethers deprotected to provide the anilines 2. Subsequent
sulfonylation of the
anilines furnished the target compounds 3.
With appropriate manipulation, including the use of alternative nitrogen
protecting
group(s), the synthesis of the remaining compounds of Formula (I) was
accomplished by
methods analogous to those above and to those described in the Experimental
section.
In order to use a compound of the Formula (I) or a pharmaceutically acceptable
salt
thereof for the treatment of humans and other mammals it is normally
formulated in
accordance with standard pharmaceutical practice as a pharmaceutical
composition.
Compounds of Formula (I) and their pharmaceutically acceptable salts may be
administered in a standard manner for the treatment of the indicated diseases,
for example
orally, parenterally, sub-lingually, transdermally, rectally, via inhalation
or via buccal
administration.
Compounds of Formula (I) and their pharmaceutically acceptable salts which are
active when given orally can be formulated as syrups, tablets, capsules and
lozenges. A
syrup formulation will generally consist of a suspension or solution of the
compound or salt
in a liquid carrier for example, ethanol, peanut oil, olive oil, glycerine or
water with a
flavoring or coloring agent. Where the composition is in the form of a tablet,
any
pharmaceutical carrier routinely used for preparing solid formulations may be
used.
Examples of such carriers include magnesium stearate, terra alba, talc,
gelatin, agar, pectin,
acacia, stearic acid, starch, lactose and sucrose. Where the composition is in
the form of a
capsule, any routine encapsulation is suitable, for example using the
aforementioned
carriers in a hard gelatin capsule shell. Where the composition is in the form
of a soft
gelatin shell capsule any pharmaceutical Garner routinely used for preparing
dispersions or
suspensions may be considered, for example aqueous gums, celluloses, silicates
or oils and
are incorporated in a soft gelatin capsule shell.
Typical parenteral compositions consist of a solution or suspension of the
compound or salt in a sterile aqueous or non-aqueous carrier optionally
containing a
parenterally acceptable oil, for example polyethylene glycol,
polyvinylpyrrolidone, lecithin,
arachis oil, or sesame oil.
Typical compositions for inhalation are in the form of a solution, suspension
or
emulsion that may be administered as a dry powder or in the form of an aerosol
using a
conventional propellant such as dichlorodifluoromethane or
trichlorofluoromethane.
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A typical suppository formulation comprises a compound of Formula (1) or a
pharmaceutically acceptable salt thereof which is active when administered in
this way,
with a binding and/or lubricating agent, for example polymeric glycols,
gelatins, cocoa-
butter or other low melting vegetable waxes or fats or their synthetic
analogues.
Typical transdermal formulations comprise a conventional aqueous or non-
aqueous
vehicle, for example a cream, ointment, lotion or paste or are in the form of
a medicated
plaster, patch or membrane.
Preferably the composition is in unit dosage form, for example a tablet,
capsule or
metered aerosol dose, so that the patient may administer to themselves a
single dose.
Each dosage unit for oral administration contains suitably from 0.1 mg to 500
mg/Kg, and preferably from 1 mg to 100 mg/Kg, and each dosage unit for
parenteral
administration contains suitably from 0.1 mg to 100 mg, of a compound of
Formula (I) or a
pharmaceutically acceptable salt thereof calculated as the free acid. Each
dosage unit for
intranasal administration contains suitably 1-400 mg and preferably 10 to 200
mg per
person. A topical formulation contains suitably 0.01 to 1.0% of a compound of
Formula
(I).
The daily dosage regimen for oral administration is suitably about 0.01 mg/Kg
to
40 mg/Kg, of a compound of Formula (I) or a pharmaceutically acceptable salt
thereof
calculated as the free acid. The daily dosage regimen for parenteral
administration is
suitably about 0.001 mg/Kg to 40 mg/Kg, of a compound of the Formula (I) or a
pharmaceutically acceptable salt thereof calculated as the free acid. The
daily dosage
regimen for intranasal administration and oral inhalation is suitably about 10
to about 500
mg/person. The active ingredient may be administered from I to 6 times a day,
sufficient
to exhibit the desired activity.
These sulphonamide analogs may be used for the treatment of congestive heart
failure, stroke, ischemic heart disease (angina, myocardial ischemia), cardiac
arrhythmia,
hypertension (essential and pulmonary), COPD, restenosis, asthma, neurogenic
inflammation and metabolic vasculopathies, addiction, schizophrenia,
impulsivity, anxiety,
stress, depression, neuromuscular function, and diabetes.
The urotensin antagonist may be administered alone or in conjunction with one
or
more other therapeutic agents, said agents being selected from the group
consisting of
endothelin receptor antagonists, angiotensin converting enzyme (ACE)
inhibitors,
vasopeptidase inhibitors, diuretics, digoxin, and dual non-selective (3-
adrenoceptor and ocl-
adrenoceptor antagonists.
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No unacceptable toxicological effects are expected when compounds of the
invention are administered in accordance with the present invention.
The biological activity of the compounds of Formula (I) are demonstrated by
the
following tests:
Radioligand binding:
HEK-293 cell membranes containing stable cloned human and rat GPR-14 (20
ug/assay) were incubated with 200 pM [125I] h-U-II (200 Ci/mmol-' in the
presence of
increasing concentrations of test compounds in DMSO (0.1 nM to 10 uM), in a
final
incubation volume of 200 u1 (20 mM Tris-HCI, 5 mM MgCl2). Incubation was done
for 30
minutes at room temperature followed by filtration GF/B filters with Brandel
cell harvester.
1251 labeled U-II binding was quantitated by gamma counting. Nonspecific
binding was
defined by 1251 U-II binding in the presence of 100 nM of unlabeled human U-
II. Analysis
of the data was performed by nonlinear least square fitting.
Ca2+-mobilization:
A microtitre plate based Ca'+-mobilization FLIPR assay (Molecular Devices,
Sunnyvale,
CA) was used for the functional identification of the ligand activating HEK-
293 cells
expressing (stable) recombinant GPR-14. The day following transfection, cells
were plated
in a poly-D-lysine coated 96 well black/clear plates. After I 8-24 hours the
media was
aspirated and Fluo 3AM-loaded cells were exposed to various concentrations (
10 nM to 30
uM) of test compounds followed by h-U-II. After initiation of the assay,
fluorescence was
read every second for one minute and then every 3 seconds for the following
one minute.
The inhibitory concentration at 50% (IC50)was calculated for various test
compounds.
Inositol phosphates assays:
HEK-293-GPR14 cells in TI50 flask were prelabeled overnight with 1 uCi myo-
[3H] inositol per ml of inositol free Dulbecco's modified Eagel's medium.
After labeling, the
cells were washed twice with Dulbecco's phosphate-buffered saline (DPBS) and
then
incubated in DPBS containing 10 mM LiCI for 10 min at 37°C. The
experiment was
initiated by the addition of increasing concentrations of h-U-II ( 1 pM to 1
~tM ) in the
absence and presence of three different concentrations (0.3, 1 and 10 uM) of
test compounds
and the incubation continued for an additional 5 min at 37°C after
which the reaction was
terminated by the addition of 10% (final concentration) trichloroacetic acid
and
centrifugation. The supernatants were neutralized with 100u1 of 1M Trizma base
and the
inositol phosphates were separated on AG 1-X8 columns (0.8 ml packed, 100-200
mesh) in
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CA 02394603 2002-06-17
WO 01/45694 PCT/IJS00/34574
formate phase. Inositol monophosphate was eluted with 8 ml of 200 mM ammonium
formate. Combined inositol di and tris phosphate was eluted with 4m1 of 1M
ammonium
formate/ 0.1 M formic acid. Eluted fractions were counted in beta
scintillation counter.
Based on shift from the control curve KB was calculated.
Activity for the compounds of this invention range from (radioligand binding
assay): Ki = 50 nM - 10000 nM (example 8 Ki = 1300 nM)
The following Examples are illustrative but not limiting embodiments of the
present
mvenrion.
Example 1
N-f4-Chloro-3-(2-dimethylamino-ethoxy)phenyll-3,4-dimethoxy-benzenesulfonamide
0
,N ~ O~N/
CI
a). 2-Chloro-5-aminophenol
2-Chloro-5-nitroanisole (310 g, 1.7 mol) was taken up in a mixture of 48% HBr
(I .5 L) and
AcOH ( 1.2 L) and heated at reflux for 3 days. The dark solution was allowed
to cool to
room temperature, poured into ice water ( 10 L), and let stand for 3 h. The
resultant dull
yellow solid was filtered, washed with water, and dried in vacuo (230 g, 79%):
mp I 15-
117°C.
b). 2-Chloro-5-aminophenol
A solution of 2-chloro-5-nitrophenol (25 g, 0.14 mol) in ethyl acetate ( 150
mL) was treated
with 5% Pt/C (250mg) and the mixture shaken under a hydrogen atmosphere (30
psi) for 4h.
The mixture was filtered through Celite° and the residue washed well
with hot ethyl acetate.
The filtrate was treated with activated charcoal and re-filtered as above.
Evaporation of the
ethyl acetate gave a solid (19.8 g, 98%).
c). 4-Chloro-3-hydroxyphenylcarbamic acid tert-butyl ester
To a solution of 2-chloro-5-aminophenol (20 g, 0.14 mol) in THF (150 mL) was
added a
solution of di-tert-butyl dicarbonate (33 g, 0.15 mol) in THF (150 mL). The
reaction was
heated at reflux for 6 h, at which time it was allowed to cool to room
temperature. The
solvent was removed in vacuo and the residue diluted with ether (500 mL) and
washed with
I M citric acid (2 x 300 mL). The aqueous washings were extracted with ether
(300 mL)
and the combined organics washed with brine (300 mL), dried (MgSO,~), and
concentrated.
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WO 01/45694 PCT/US00/34574
The resultant brown solid was triturated with hexanes and dried in vacuo to
give 33 g (97%)
of the title compound: mp 103-106 °C.
d). 3-[2-(N,N-Dimethylamino)ethoxyJ-4-chloroaniline
To a solution of 4-chloro-3-hydroxyphenylcarbamic acid ten-butyl ester (140
mg, 0.57
mmol) in 4:1 DME/water (5 mL) was added dimethylaminoethyl chloride
hydrochloride (90
mg, 0.63 mmol) and K~C03 (320 mg, 2.3 mmol). The reaction mixture was heated
at reflux
for 16 h, at which time it was allowed to cool to room temperature. The DME
was removed
in vacuo and the residue treated with 6 N HCl (2 mL). The resultant mixture
was stirred at
room temperature for 2 h, at which time it was diluted with water (5 mL) and
washed with
EtOAc (5 mL). The aqueous layer was basified with solid KZC03 and extracted
with EtOAc
(2 x 10 mL). The EtOAc layers were washed with brine (10 mL), dried (MgS04),
and
concentrated to give 60 mg (50%) of the title compound.
e). N-[4-Chloro-3-(2-dimethylamino-ethoxy)phenylJ-3,4-dimethoxy-
benzenesulfonamide
3-[2-(N,N-Dimethylamino)ethoxyJ-4-chloroaniline (l.OOg, 4.66 mmol) was
dissolved in 15
mL CHCl3. A solution of 3,4-dimethoxybenzenesulfonyl chloride (l.lOg, 4.66
mmol) in 14
mL CHC13 was added and the solution was allowed to stir overnight. Diethyl
ether was
added to the cloudy white mixture and the white product (1.978, 94%) was
filtered and
dried. Recrystallisation from hot methanol gave sparkling white crystals which
were
filtered and dried: mp 228-229°C; MS (ES+) m/e 415 [M+HJ+
The compounds of Examples 2 - 6 were prepared by using the general procedures)
of
Example 1 above with appropriate substitution of reactants:
Example 2
4,5-Dibromo-thiophene-2-sulfonic acid f4-chloro-3-(2-dimethylamino-ethoxy)-
phenyll-
amide.
~s~N
N
Br \ ~ y ~ / C
Br
Prepared from 4,5-dibromo-thiophene-2-sulfonyl chloride and 3-[2-(N,N-
dimethylamino)ethoxy]-4-chloroaniline. MS (ES+) m/e 517 [M+HJ+.
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Example 3
3,4-Dibromo-N-f 4-chloro-3-(2-dimethylamino-ethoxy~phenyll-benzenesulfonamide.
o~ /
Br ~ S~ ~ N
O
CI
Br
Prepared from 3,4-dibromobenzenesulfonyl chloride and 3-[2-(N,N-
dimethylamino)ethoxy]-4-chloroaniline. MS (ES+) m/e 511 [M+H]+.
Example 4
2,4,6-Trichloro-N-f 4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-
benzenesulfonamide.
CI
~ SiN \ O\/~ /
/ I \O I /
\ CI
CI CI
Prepared from 2,4,6-trichlorobenzenesulfonyl chloride and 3-[2-(N,N-
dimethylamino)ethoxy]-4-chloroaniline. MS (ES+) m/e 457 [M+H]+
Example 5
2 6-Dichloro-N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyll-4-trifluoromethyl-
benzenesulfonamide.
c1
~ SiN ~ O~N/
F / CI
CI
F
F
Prepared from 2,6-Dichloro-4-trifluoromethylbenzenesulfonyl chloride and 3-[2-
(N,N-
dimethylamino)ethoxy]-4-chloroaniline. MS (ES+) m/e 491 [M+H]+
Example 6
N-f 3-(2-Dimethylamino-ethoxy)-4-iodo-phenyll-3,4-dimethoxy-
benzenesulfonamide.
\O
O H
O \ I \S~N \ O\/\N/
/
o I /
I
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WO 01/45694 PCT/US00/34574
a). N-[3-(2-Dimethylamino-ethoxy)-4-iodo-phenyl]-acetamide
2-Iodo-5-acetamidophenol (2.15 g, 7.76 mmol) was dissolved in 1,2-
dimethoxyethane (30 mL). 2-Dimethylaminoethyl chloride hydrochloride ( 1 eq,
7.76 mmol,
1.12 g) was added, followed by a solution of potassium carbonate (4 eq, 31.0
mmol, 4.30 g)
in water (8 mL). The solution was heated to reflux, stirring at this
temperature for 22 hours.
The 1,2-dimethoxyethane was evaporated in vacuo and the residue was acidified
to pH 1
using 3N hydrochloric acid. The mixture was washed 2 x ethyl acetate, and the
aqueous
portion basified to pH 11 using solid potassium carbonate. It was extracted 2
x ethyl
acetate, dried over magnesium sulfate, filtered, and concentrated to afford
the product ( 1.53
g, 57%) as a rust-colored oil.
MS (ES+) m/e 349 [M+H]+
b). 3-(2-Dimethylamino-ethoxy)-4-iodo-phenylamine
To a solurion of the compound of Example 1 (a) ( 1.52 g, 4.39 mmol) in ethanol
(22 mL) was
added 10% aqueous sodium hydroxide solution (29 mL). The mixture was heated to
reflux
and allowed to stir at this temperature for 16 hours. It was cooled to room
temperature and
concentrated in vacuo. The residue was extracted 2 x ethyl acetate, dried over
magnesium
sulfate, filtered, and concentrated to furnish the product (1.13 g, 84%) as a
rust-colored oil
which solidified upon standing.
MS (ES+) m/e 307 [M+H]+
c). N-[3-(2-Dimethylamino-ethoxy)-4-iodo-phenyl]-3,4-dimethoxy-
benzenesulfonamide
To a solution of the compound of Example 1 (b) (0.25 g, 0.81 mmol) in N,N-
dimethylformamide (4 mL) was added 3,4-dimethoxybenzenesulfonyl chloride ( 1
eq, 0.81
mmol, 0.19 g). The pale orange solution was allowed to stir at room
temperature for 23
hours. The crude product was purified via Gilson HPLC purification (10-90%
acetonitrile/water over 5 minutes) and lyophilized overnight. The resulting
hydochloride
salt was azeotroped 1 x methanol and 1 x methylene chloride to furnish the
product (0.16 g,
35%) as a fluffy white solid. MS (ES+) m/e 507 (M+H)+
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WO 01/45694 PCT/US00/34574
Example 7
2-Bromo-N-f4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-4,5-dimethox~
benzenesulfonamide
N ~ ~ O~ /
O OSO
/ CI
/O ~ Br
\ ~ / i
a). 2-Bromo-4,5-dimethoxy-benzenesulfonyl chloride.
To a cooled (0 °C) solution of 4-bromoveratrole ( 15 mL, 100 mmol) in
methylene chloride
( 100 mL) was added dropwise over 30 minutes chlorosulfonic acid (26 mL, 400
mmol).
The resultant solution was allowed to warm to ambient temperature, maintained
at this
temperature for 3 hours, and then partitioned into a 1:1 methylene
chloride/ice water
mixture (500 mL). The organic layer was washed with water (2 x 200 mL) and
brine (200
mL), dried (magnesium sulfate), and concentrated to give 2-bromo-4,5-
dimethoxybenzenesulfonyl chloride (25 g, 78% yield) as a grey solid.
b).2-Bromo-N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-4,5-dimethoxy-
benzenesulfonamide.
Prepared from 2-bromo-4,5-dimethoxy-benzenesulfonyl chloride and 3-[2-(N,N-
dimethylamino)ethoxy]-4-chloroaniline using the general procedure of Example
1E above.
MS (ES+) m/e 494 [M+H]+
MS
(ES+)
Example Compound m/e
[M+H]
a, i ~ N
I 4-Bromo-N-[4-iodo-3-(2-dimethylamino-
'
, ~ 525
,
8 ethoxy)-phenyl]-benzenesulfonamide
5-Chloro-3-methyl-N-[4-methyl-3-(2-
i i
dimethylamino-ethoxy)-phenyl]-2- 439
benzothiophenesulfonamide
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CA 02394603 2002-06-17
WO 01/45694 PCT/US00/34574
O H
\\,N O
N-[4-Methyl-3-(2-dibenzylamino-ethoxy)-493
phenyl]-2-thiophenesulfonamide
o ~ ~ S ~ ~ N-[4-Methyl-3-(2-dimethylamino-ethoxy)-
~ ~./~~~
395
phenyl]-3,4-dimethoxy-benzenesulfonamide
11
/
I O H
~\SiN \ O~N/
o I , I 2,6-Dichloro-N-[4-iodo-3-(2-dimethylamino-
515
ethoxy)-phenyl]-benzenesulfonamide
12
N
0
( ~o I ~ N-[4-Iodo-3-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-
I 533
3,4-dimethoxy-benzenesulfonamide
13
\N~
\
O p H
N-[4-Iodo-3-(2-dimethylamino-ethoxy)-phenyl]-507
I \
~~'N
I
/
' 2,5-dimethoxy-benzenesulfonamide
,o
14
~N~
H
I ~s~ N j N-[4-Iodo-3-(2-dimethylamino-ethoxy)-phenyl]-477
I
3-methoxy-benzenesulfonamide
,o
O~ 4
/
~ I O N
N 3,4-Dichloro-N-[
\ -iodo-3-(2-dimethylamino-
C.
I
/ ~ 515
ethoxy)-phenyl]-benzenesulfonamide
16
N-[4-Iodo-3-(2-dimethylamino-ethoxy)-phenyl]-
O , 477
~ 4-methoxy-benzenesulfonamide
17
_17_
CA 02394603 2002-06-17
WO 01/45694 PCT/US00/34574
i
0
o ' I O H ' -[4-Bromo-3-(2-dimethylamino-ethoxy)-
N 60
o i / ~i
phenyl]-3,4-dimethoxy-benzenesulfonamide
18
CI 5-Chloro-3-methyl-N-[4-iodo-3-(3-
\ ~ S Q H
'
~ dimethylamino-propyl)-phenyl]-2-S49
/
19 benzothiophenesulfonamide
O H
~SiN ' OWN/
~ S ~ ~ / , ,S-Dichloro-N-[4-iodo-3-(2-dimethylamino-
~
521
I ethoxy)-phenyl]-2-thiophenesulfonamide
20
O H
\SiN ' O~N/
,S-Dichloro-N-[4-chloro-3-(2-dimethylamino-
429
I ethoxy)-phenyl]-2-thiophenesulfonamide
21
O H
~ ~ \o N ~ / 4-Iodo-N-[4-iodo-3-(2-dimethylamino-ethoxy)-
~~~/ 73
phenyl]-benzenesulfonamide
22
O H
\SiN ' O~N/
CI
,S-Dichloro-N-[4-iodo-3-(2-dimethylamino-
S1S
I ethoxy)-phenyl]-benzenesulfonamide
23
F
F 4-Trifluoromethyl-N-[4-chloro-3-(2-
F '
I O H
~ ' ~i/ imethylamino-ethoxy)-phenyl]- 23
0
GI
24 benzenesulfonamide
O H
\\ ~N O~
I
N-[4-iodo-3-(2-dimethylamino-ethoxy)-phenyl]-
~N SOS
"
-s benzo-2,1,3-thiadiazole-4-sulfonamide
2S
/
I
~~= ~~'N' N-[4-chloro-3-(2-dimethylamino-ethoxy)-
~~ ~ 413
~
~
/
I
S-N
phenyl]-benzo-2,1,3-thiadiazole-4-sulfonamide
26
O H
' i ' So t , N-[4-Cyano-3-(2-dimethylamino-ethoxy)-
~i
' '
' 406
N
phenyl]-3,4-dimethoxy-benzenesulfonamide
27
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WO 01/45694 PCT/US00/34574
5-Chloro-3-methyl-N-[4-cyano-3-(2-
N
I
~
I \
~
\
dimethylamino-ethoxy)-phenyl]-2-450
28 benzothiophenesulfonamide
i
t
-[4-Iodo-3-(2-dimethylamino-ethoxy)-phenyl]-
o y 493
4-hydroxy-3-methoxy-benzenesulfonamide
29
5-Chloro-3-methyl-N-[4-chloro-3-(2-
\ /5 I ~~~~ 515/51
i ~ ~N~ ] 2_
~ diiso ro lamino-ethox - h n 1
-
a
)
~ Y
P pY Y
P
6
30 benzothiophenesulfonamide
\N~
~5 N ~ ~ 3-Chloro-N-[4-chloro-3-(2-dimethylamino-
407
~ ethoxy)-phenyl]-4-fluoro-benzenesulfonamide
31
~N~
2,4-Dichloro-N-[4-chloro-3-(2-dimethylamino-
' 423
~ ethoxy)-phenyl]-benzenesulfonamide
32
~N~
'
~
2,3-Dichloro-N-[4-chloro-3-(2-dimethylamino-
,s/N ~ 423
0
ethoxy)-phenyl]-benzenesulfonamide
33
~N~
5-Chloro-N-[4-chloro-3-(2-dimethylamino-
395
~ s ~ c~ ethoxy)-phenyl]-2-thiophenesulfonamide
ci
34
~N~
~~ N O
2,4-Dichloro-N-[4-chloro-3-(2-dimethylamino-
37
~ ethoxy)-phenyl]-5-methyl-benzenesulfonamide
35
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WO 01/45694 PCT/US00/34574
4-Bromo-N-[4-chloro-3-(2-dimethylamino-
447
' ethoxy)-phenyl]-2-methyl-benzenesulfonamide
36
~N~
I ~S N ~ c N-[4-Chloro-3-(2-dimethylamino-ethoxy)-414
o I
\
l
phenyl]-4-methyl-3-nitro-benzenesulfonamide
o~~o
37
~N~
CI o S N ~ O
3-Chloro-N-[4-chloro-3-(2-dimethylamino-
I 03
~
I ethoxy)-phenyl]-4-methyl-benzenesulfonamide
38
\ ~S N \ ~
N
S-Chloro-N-[4-chloro-3-(2-dimethylamino-
439
ethoxy)-phenyl]-1-naphthalenesulfonamide
39
~N~
di
h
l
i
4
hl
3
2
no-
met
y
am
-c
oro-
-(
-
5-Chloro-N-[
henyl]-2-methoxy- 419
ethox
)-
y
p
i a
c1 benzenesulfonamide
40
~N~
5-Bromo-N-[4-chloro-3-(2-dimethylamino-
I 439
s ethoxy)-phenyl]-2-thiophenesulfonamide
~ c1
41
\N~
~
. ,, N 4-Chloro-N-[4-chloro-3-(2-dimethylamino-
o ~N \ 5 434
~ \
0
~ ethoxy)-phenyl]-3-nitro-benzenesulfonamide
42
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WO 01/45694 PCT/US00/34574
~N'
4-Chloro-N-[4-chloro-3-(2-dimethylamino-
OS N
ethoxy)-phenyl]-2,5-dimethyl- 417
p
benzenesulfonamide
43
o-N
N-[4-chloro-3-(2-dimethylamino-ethoxy)-
431
phenyl]-benzo[1,2,5]oxadiazole-4-sulfonamide
44
~N~
5-Bromo-6-chloro-N-[4-chloro-3-(2-
~S N ~ O
"\ ~ I ~ dimethylamino-ethoxy)-phenyl]-3-468
I
pyridinesulfonamide
45
~N'
3-Bromo-5-chloro-N-[4-chloro-3-(2-
a~ o
~
\
o dimethylamino-ethoxy)-phenyl]-2-473
thiophenesulfonamide
46
~N~
4-Bromo-N-[4-chloro-3-(2-dimethylamino-
. 461
I
~
'
a ~ ethoxy)-phenyl]-2-ethyl-benzenesulfonamide
~
47
~N~
2-Chloro-N-[4-chloro-3-(2-dimethylamino-
~5 N ~ O
ethoxy)-phenyl]-4-trifluoromethyl-457
benzenesulfonamide
48
o
W S~NH
amino-
~ 4-Bromo-N-[4-chloro-3-(2-dimeth
~ I I y 433
~N~ ethoxy)-phenyl]-benzenesulfonamide
49
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WO 01/45694 PCT/US00/34574
00
's
~ ~NH
i ~ I I N-[4-Chloro-3-(2-dimethylamino-ethoxy)- 415
°~N~ phenyl]-2,5-dimethoxy-benzenesulfonamide
of
O H
~ , ~~i/ N-[4-Iodo-3-(2-dimethylamino-ethoxy)-phenyl]-
' 491
3-nitro-benzenesulfonamide
51
of o N I j obi/
n 2,5-Dichloro-N-[4-iodo-3-(2-dimethylamino-
I~
514
o~ ethoxy)-phenyl]-benzenesulfonamide
52
O H
\\,N O~ /
I o I , i 2,5-Dichloro-N-[4-iodo-3-(2-dimethylamino- 520
5 CI
ethoxy)-phenyl]-3-thiophenesulfonamide
53
N \ O~N/
I 2,4-Dichloro-N-[4-iodo-3-(2-dimethylamino- 528
ethoxy)-phenyl]-6-methyl-benzenesulfonamide
54
' ' t ~°N ~ / G~~' S-Chloro-N-[4-chloro-3-(2-dimethylamino-
439
ethoxy)-phenyl]-2-naphthalenesulfonamide
2,4-Dichloro-6-methyl-N-[4-iodo-3-(2-
o ~ i i i
dimethylamino-ethoxy)-phenyl]- 529
benzenesulfonamide
56
s1°: o
i o I ~ ~~~~ 3-Methoxy-N-[4-iodo-3-(2-dimethylamino- 477
ethoxy)-phenyl]-benzenesulfonamide
57
I ° " 2,5-Dimethoxy-N-[4-bromo-3-(2-
\ S.N \ O~N/
dimethylamino-ethoxy)-phenyl]- 460
benzenesulfonamide
58
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2-Nitro-4-methoxy-N-[4-iodo-3-(2-
O I Nv0-
I R
~~.N O
~ i ~ dimethylamino-ethoxy)-phenyl]- 522
59 benzenesulfonamide
" 2,4,6-Trimethyl-N-[4-chloro-3-(2-
\ N O
~n ~ N
dimethylamino-ethoxy)-phenyl]- 397
60 benzenesulfonamide
I ~
N
,
O N-[4-Iodo-3-(2-dimethylamino-ethoxy)phenyl]-
I
~;
I ~ 505
benzo [ 1,2,5]-4-thiadiazolesulfonamide
61
~N \ O~N~ 2-Methyl-4-bromo-N-[4-chloro-3-(2-
\a I
I
I
I dimethylamino-ethoxy)-phenyl]- 447
a,
62 benzenesulfonamide
~ ~N~ 2,6-Dimethyl-4-bromo-N-[4-chloro-3-(2-
I\ o I, I
in 62
-ethox
)-
hen
l]-
di
th
l
a,
y
p
y
me
y
am
o
63 benzenesulfonamide
I ,N \ .~.N~ 3-Methoxy-4-bromo-N-[4-chloro-3-(2-
I~ o II I
dimethylamino-ethoxy)-phenyl]- 464
64 benzenesulfonamide
\ ..
2-Nitro-4-trifluoromethyl-N-[4-chloro-3-(2-
F ~ ~ ~' n 68
l]-
di
th
l
i
th
)
h
F y
me
y
am
no-e
oxy
-p
e
F
65 benzenesulfonamide
~.N \ OfNi 4-Bromo-5-chloro-N-[4-chloro-3-(2-
i
I ' dimethylamino-ethoxy)-phenyl]-2-474
66 thiophenesulfonamide
.N \ ~.N~ 4-Nitro-5-chloro-N-[4-chloro-3-(2-
o, . a I
I
0
s dimethylamino-ethoxy)-phenyl]-2-440
'
67 thiophenesulfonamide
O H
,~o N I , ~I~ 4,5-Dichloro-N-[4-iodo-3-(2-dimethylamino-
Y5 ' 21
ethoxy)-phenyl]-2-thiophenesulfonamide
68
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I 2,4-Dibromo-5-methoxy-N-[4-chloro-3-(2-
I / O
~ I dimethylamino-ethoxy)-phenyl]- 543
benzenesulfonamide
69
-" ~ ~N/ 2-Methyl-4,5-dimethoxy-N-[4-chloro-3-(2-
I
O I ~
a dimethylamino-ethoxy)-phenyl]- 429
I ~
O~
70 benzenesulfonamide
O H
~S.N ~ OfN/
I
I
, 5-Chloro-N-[4-iodo-3-(2-dimethylamino-
531
' ethoxy)-phenyl]-2-naphthalenesulfonamide
71
4-Trifluoromethyl-N-[4-iodo-3-(2-
I % o I / I
'
F dimethylamino-ethoxy)-phenyl]- 515
F
F
72 benzenesulfonamide
-N ~ O~N~ 2,6-Dimethyl-4-bromo-N-[4-chloro-3-(2-
I
I , diethylamino-ethoxy)-phenyl]- 490
~ ~ J
73 benzenesulfonamide
,N O /
I , 3,4-Dimethoxy-N-[4-chloro-3-(2-methylamino-
~H
401
ethoxy)-phenyl]-benzenesulfonamide
74
,N ~ O~ 2-Bromo-4,5-dimethoxy-N-[4-chloro-3-(2-
/
N
n ~ H
o I ~ B, ~ ~ methylamino-ethoxy)-phenyl]- 480
75 benzenesulfonamide
O H
~S.N ~ OfN/
i -Chloro-N-[4-chloro-3-(2-dimethylamino-
39
ethoxy)-phenyl]-2-naphthalenesulfonamide
76
2,6-Dichloro-4-trifluoromethoxy-N-[4-chloro-3-
F I ~ ~~ ' (2-diethylamino-ethoxy)-phenyl]-519
F F
77 benzenesulfonamide
4,5-Dibromo-N-[4-chloro-3-(2-diethylamino-
547
ethoxy)-phenyl]-2-thiophenesulfonamide
78
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",N ~ O~N~ 2-Bromo-4,5-dimethoxy-N-[4-chloro-3-(2-
J
I
o diethylamino-ethoxy)-phenyl]- 522
~ e, '
79 benzenesulfonamide
I ~N ~ Ni 3,4-Dimethoxy-N-[4-chloro-3-(3-
I
~
' ' dimethylamino-propyl)-phenyl]- 413
80 benzenesulfonamide
oN
I I ~ ~g N I 3,4-Dimethoxy-N-[4-chloro-3-(2-diethylamino-443
, ~ ~
0
ethoxy)-phenyl]-benzenesulfonamide
81
I ,N ~ O~N~ 2-Chloro-4,5-dimethoxy-N-[4-chloro-3-(2-
I
I ' ' J
o diethylamino-ethoxy)-phenyl]- 477
~ y
82 benzenesulfonamide
,N ~ O~N~ 2-Chloro-4,5-dimethoxy-N-[4-chloro-3-(2-
I
,
o I ~ c~ ' dimethylamino-ethoxy)-phenyl]- 449
83 benzenesulfonamide
CI ~i H ~ N~ 2,6-Dichloro-N-[4-chloro-3-(3-diethylamino-
~~ ~ L
~
c~
F F propyl)-phenyl]-4- 516
~ ~
g4 trifluoromethylbenzenesulfonamide
o ~i.
2,6-Dichloro-N-[4-chloro-3-(3-dimethylamino-
propyl)-phenyl]-4- 488
g5 trifluoromethylbenzenesulfonamide
~N \ N/ 4,5-Dimethoxy-N-[4-chloro-3-(3-
0
dimethylamino-propyl)-phenyl]-2-491
86 bromobenzenesulfonamide
O H
~~,N
.5-Dimethoxy-N-[4-chloro-3-(3-diethylamino-
, 519
0 propyl)-phenyl]-2-bromobenzenesulfonamide
87
O H
~ ~o N I , 3,4-Dimethoxy-N-[4-chloro-3-(3-diethylamino-
~
I 440
~
propyl)-phenyl]benzenesulfonamide
88
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WO 01/45694 PCT/US00/34574
O H
\\,N
, ~ o I % ' ,5-Dimethoxy-N-[4-chloro-3-(3-diethylamino-
' 454
propyl)-phenyl]-2-methylbenzenesulfonamide
89
O H
~o N I % ' 4,5-Dimethoxy-N-[4-chloro-3-(3-diethylamino-
474
propyl)-phenyl]-2-chlorobenzenesulfonamide
90
O H
\o N I ~ ~i' N-[4-Chloro-3-(2-dimethylamino-ethoxy)-
~ ~ 371
H
phenylJ-4-hydroxybenzenesulfonamide
91
:S.N I ~ o~.N~ N-[4-Chloro-3-(2-dimethylamino-ethoxy)-
phenyl]-2,3,4,5,6-pentamethyl- 425
92 benzenesulfonamide
~ c~'so ~ ~ ~'N'2,4,5-Trichloro-N-[4-chloro-3-(2-
dimethylamino-ethoxy)-phenyl]- 457
93 benzenesulfonamide
~ so ~ ~ ~N' S-Bromo-N-[4-chloro-3-(2-dimethylamino-
ethoxy)-phenyl]-2-methoxy- 463
Br
benzenesulfonamide
94
a I c~'so ~ ~ 2,3,4-Trichloro-N-[4-chloro-3-(2-
~'N'
~
a dimethylamino-ethoxy)-phenyl]- 457
c~
95 benzenesulfonamide
~so ~ ~ ~'N' N-[4-Chloro-3-(2-dimethylamino-ethoxy)-
ci
phenyl]-2,3,5,6-tetramethyl- 41 I
96 benzenesulfonamide
.S.N I ~ o~.N, N-[4-Chloro-3-(2-dimethylamino-ethoxy)-
' ' ~ ' phenyl]-4-methoxy-2,3,6-trimethyl-427
97 benzenesulfonamide
~~SO ~ , ~N~ N-[4-Chloro-3-(2-dimethylamino-ethoxy)-
c' 383
phenyl]-4-ethyl-benzenesulfonamide
98
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WO 01/45694 PCT/LJS00/34574
Q.S.N I % pfN~
t h
l
i
h
, p1 y
am
no-et
oxy)-
N-[4-Chloro-3-(2-dimet
397
phenyl]-4-isopropyl-benzenesulfonanude
99
R.S.N ~ O~.N~
o ~ 4
~ hl
3
2
di
th
l
i
2
Chl
N
i , -c
~ c~ oro-
-(
-
me
y
am
no-
-
oro-
-[
N~ 414
ethoxy)-phenyl]-4-cyano-benzenesulfonamide
100
F~'so ~ ~ ~N' 2,5-Dibromo-N-[4-chloro-3-(2-dimethylamino-
~~
i F CI
ethoxy)-phenyl]-3,6-difluoro- 547
101 benzenesulfonamide
~' 2,4-Dichloro-N-[4-chloro-3-(2-dimethylamino-
~
cl 437
c1
ethoxy)-phenyl]-6-methyl-benzenesulfonamide
102
~Sb ~ , ~N~ N_[4-Chloro-3-(2-dimethylamino-ethoxy)-
a 373
phenyl]-3-fluoro-benzenesulfonamide
103
~so ~ % .~N~ 5-Bromo-N-[4-chloro-3-(2-dimethylamino-
F F I ethoxy)-phenyl]-2,4-difluoro- 469
104 benzenesulfonamide
a 'so ~ ~ ~'N' S-Chloro-N-[4-chloro-3-(2-dimethylamino-
ethoxy)-phenyl]-2,4-difluoro- 425
105 benzenesulfonamide
: .N O~
% S i
N
' a N_[4-Chloro-3-(2-dimethylamino-ethoxy)-
391
phenyl]-3,5-difluoro-benzenesulfonamide
106
4-Bromo-N-[chloro-(2-dimethylamino-ethoxy)-
O.
N
O
~
S. 1
~
~N
I
c1 phenyl]-2-trifluoromethoxy- 5
s~ 7
107 benzenesulfonamide
F S~N ~ ~ o~.N~ N-[4-Chloro-3-(2-dimethylamino-ethoxy)-
,
'o ~ ' phenyl]-3-fluoro-4-methoxy- 403
~ c1
108 benzenesulfonamide
~so ~ ~ ~'N' 2-Chloro-N-[4-chloro-3-(2-dimethylamino-
F~a c1 ethoxy)-phenyl]-4,5-difluoro- 425
109 benzenesulfonamide
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WO 01/45694 PCT/US00/34574
4-Butyl-N-[4-chloro-3-(2-dimethylamino-
411
110 ethoxy)-phenyl]-benzenesulfonamide
'so ~ ~ ~N' 4-Chloro-N-[4-chloro-3-(2-dimethylamino-
c' ethoxy)-phenyl]-2,5-difluoro- 425
111 benzenesulfonamide
3-{ 4-[4-Chloro-3-(2-dimethylamino-ethoxy)-
i
,
, phenylsulfamoyl]-phenyl }-propionic441
acid
112 methyl ester
~ ..N ~ o~.N. 4-[4-Chloro-3-(2-dimethylamino-ethoxy)-
~O~SO I
1
i
'
o phenylsulfamoyl]-2,5-dimethyl-furan-3-445
113 carboxylic acid ethyl ester
~so ~ ~ ~'N' 4-Bromo-N-[4-chloro-3-(2-dimethylamino-
cl
ethoxy)-phenyl]-2,5-difluoro- 469
114 benzenesulfonamide
~ ~ e' 7-Bromo-2,3-dihydro-benzo[1,4]dioxine-6-
C
~
S.N ~ O~.N~
~
o b sulfonic acid [4-chloro-3-(2-dimethylamino-491
~ c1 ~
115 ethoxy)-phenyl]-amide
" N-[4-Chloro-3-(2-diethylamino-ethoxy)-
i N ~ O~N
~
~~ ~ J
i
phenyl]-4,5-dimethoxy-2-methyl- 457
~
116 benzenesulfonamide
.~N~ 4-Bromo-2,5-dichloro-thiophene-3-sulfonic
a' acid
.~SO
/
I j
c~
a s c~ [4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-507
117 amide
' 3-Dimethylamino-naphthalene-1-sulfonic
'N I ~ O acid
N
O
,S.
~ l 448
fNi
]-
[4-chloro-3-(2-dimethylamino-ethoxy)-pheny
118 amide
EXAMPLE 119
Formulations for pharmaceutical use incorporating compounds of the present
invention can be prepared in various forms and with numerous excipients.
Examples of
such formulations are given below.
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Tablets/Ingredients Per Tablet
l.Active ingredient 40 mg
(Cpd of Form. I)
2.Corn Starch 20 mg
3.Alginic acid 20 mg
4.Sodium Alginate 20 mg
S.Mg stearate 1.3 m~
2.3 mg
Procedure for tablets:
Step 1: Blend ingredients No. l, No. 2, No. 3 and No. 4 in a suitable
mixer/blender.
Step 2: Add sufficient water portion-wise to the blend from Step 1 with
careful mixing after
each addition. Such additions of water and mixing until the mass is of a
consistency to
permit its conversion to wet granules.
Step 3: The wet mass is converted to granules by passing it through an
oscillating
granulator using a No. 8 mesh (2.38 mm) screen.
Step 4: The wet granules are then dried in an oven at 140°F
(60°C) until dry.
Step 5: The dry granules are lubricated with ingredient No. 5.
Step 6: The lubricated granules are compressed on a suitable tablet press.
Inhalant Formulation
A compound of Formula I, ( 1 mg to 100 mg) is aerosolized from a metered dose
inhaler to deliver the desired amount of drug per use.
Parenteral Formulation
A pharmaceutical composition for parenteral administration is prepared by
dissolving an appropriate amount of a compound of formula I in polyethylene
glycol with
heating. This solution is then diluted with water for injections Ph Eur. (to
100 ml). The
solution is then sterilized by filtration through a 0.22 micron membrane
filter and sealed in
sterile containers.
The above specification and Examples fully disclose how to make and use the
compounds of the present invention. However, the present invention is not
limited to the
particular embodiments described hereinabove, but includes all modifications
thereof within
the scope of the following claims. The various references to journals, patents
and other
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WO 01/45694 PCT/US00/34574
publications which are cited herein comprise the state of the art and are
incorporated herein
by reference as though fully set forth.
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