Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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5-(2-IMIDAZOLINYLAMINO)BENZIMIDAZOLE COMPOUNDS
USEFUL AS ALPHA-2 ADRENOCEPTOR AGONISTS
TECHNICAL FIELD
The subject invention relates to 5-(2-imidazolinylamino)benzimidazole
compounds. The compounds have been found to be alpha-2 adrenoceptor
agonists and are useful for treatment of disorders modulated by alpha-2
adrenoceptors.
BACKGROUND OF THE INVENTION
Therapeutic indications of alpha-2 adrenoceptor agonists have been
discussed in the literature: Ruffolo, R.R., A.J. Nichols, J.M. Stadel, & J.P.
Hieble, "Pharmacologic and Therapeutic Applications of Alpha-2 Adrenoceptor
Subtypes", Annual Review of Pharmacoloay & Toxicoloay Vol. 32 (1993) pp.
243-279.
Information regarding alpha adrenergic receptors, agonists and
antagonists, in general, and regarding compounds related in structure to those
of this invention are disclosed in the following references: Timmermans,
P.B.M.W.M., A.T. Chiu & M.J.M.C. Thoolen, "12.1 a-Adrenergic Receptors",
Comprehensive Medicinal Chemistry, Vol. 3, Membranes & Receptors, P. G.
Sammes & J. B. Taylor, eds., Pergamon Press (1990), pp. 133-185;
Timmermans, P.B.M.W.M. & P.A. van Zwieten, "a-Adrenoceptor Agonists and
Antagonists", Drugs of the Future, Vol. 9, No. 1, (January, 1984), pp. 41-55;
Megens, A.A.H.P., J.E. Leysen, F.H.L. Awouters & C.J.E. Niemegeers, "Further
Validation of in vivo and in vitro Pharmacological Procedures for Assessing
the
a1 and a2-Selectivity of Test Compounds: (2) a-Adrenoceptor Agonists",
European Journal of Pharmacology, Vol. 129 (1986), pp. 57-64; Timmermans,
P.B.M.W.M., A. de Jonge, M.J.M.C. Thoolen, B. Wilffert, H. Batink & P.A.
van Zwieten, "Quantitative Relationships between a-Adrenergic Activity and
Binding Affinity of a-Adrenoceptor Agonists and Antagonists", Journal of
Medicinal Chemistry, Vol. 27 (1984) pp. 495-503; van Meel, J.C.A., A. de
Jonge,
P.B.M.W.M. Timmermans & P.A. van Zwieten, "Selectivity of Some Alpha
Adrenoceptor Agonists for Peripheral Alpha-1 and Alpha-2 Adrenoceptors in the
Normotensive Rat", The Journal of Pharmacology and Experimental
Therapeutics, Vol. 219, No. 3 (1981), pp. 760-767; Chapieo, C.B., J.C. Doxey,
P.L. Myers, M. Myers, C.F.C. Smith & M. R. Stillings, "Effect of 1,4-Dioxanyl
Substitution on the Adrenergic Activity of Some Standard a-Adrenoreceptor
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Agents", European Journal of Medicinal Chemistry, Vol. 24 (1989), pp. 619-622;
Chapfeo, C.B., R.C.M. Butler, D.C. England, P.L. Myers, A.G. Roach, C.F.C.
Smith, M.R. Stillings & I.F. Tulloch, "Heteroaromatic Analogues of the a2-
Adrenoreceptor Partial Agonist Clonidine", Journal of Medicinal Chemistry,
Vol.
32 (1989), pp. 1627-1630; Clare, K.A., M.C. Scrutton & N.T. Thompson, "Effects
of a2-Adrenoceptor Agonists and of Related Compounds on Aggregation of, and
on Adenylate Cyclase Activity in, Human Platelets", British Journal of
Pharmacology, Vol. 82 (1984), pp. 467-476; U.S. Patent No. 3,890,319 issued to
Danielewicz, Snarey 8~ Thomas on June 17, 1975; and U.S. Patent No.
5,091,528 issued to Gluchowski on February 25, 1992.
PCT Publication WO 96/04270, Synaptic Pharmaceutical Corporation,
February 15, 1996 discloses benzimidazoles said to be useful as analgesics,
anethetics, or sedatives. Any compounds disclosed, which may be related in
structure to those of this invention do not provide the activity or
specificity
desirable when treating disorders modulated by alpha-2 adrenoceptors. For
example, sedative and anesthetic activity would be considered an undesirable
side effect for a compound used to treat the maladies described that are
modulated by the activity of peripheral alpha-2 adrenoceptors. For example,
many compounds found to be effective nasal decongestants are frequently
found to have undesirable side effects, such as causing hypertension and
insomnia at systemically effective doses. In addition, it is common for other
classes of drugs, such as antihistamines, such as diphenhydramine to produce
drowsiness (i.e. mild sedation). There is a need for new drugs which provide
relief from nasal congestion without causing these undesirable side effects.
This need relates to all disorders modulated by alpha adrenoceptors. The
invention meets this need by providing selective alpha 2 agonists, without the
undesired side effects.
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OBJECTS OF THE INVENTION
It is an object of the invention to provide compounds and compositions
useful in treating disorders modulated by alpha-2 adrenoceptors.
It is an object of this invention to provide novel compounds having
substantial activity in preventing or treating nasal congestion, otitis media,
and
sinusitis, without undesired side effects.
It is also an object of this invention to provide novel compounds for
treating cough, chronic obstructive pulmonary disease (COPD) and/or asthma.
It is also an object of this invention to provide novel compounds for
treating diseases and disorders associated with sympathetic nervous system
activity, including benign prostatic hypertrophy, cardiovascular disorders
comprising myocardial ischemia, cardiac reperfusion injury, angina, cardiac
arrhythmia, heart failure and hypertension.
It is also an object of this invention to provide novel compounds for
treating ocular disorders, such as ocular hypertension, glaucoma, hyperemia,
conjunctivitis and uveitis.
It is also an object of this invention to provide novel compounds for
treating gastrointestinal disorders, such as diarrhea, irritable bowel
syndrome,
hyperchlorhydria (hyperacidity) and peptic ulcer (ulcer).
It is also an object of this invention to provide novel compounds for
treating migraine.
It is also an object of this invention to provide novel compounds for
treating pain, substance abuse and/or withdrawal.
It is a still further object of this invention to provide such compounds
which have good activity from peroral, parenteral, intranasal andlor topical
dosing.
SUMMARY OF THE INVENTION
This invention relates to compounds having the following structure:
The subject invention relates compounds having the following structure:
R~ NH
N N
R
I~
N ~ R2
Ra R3
Formula I
wherein
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(a) R1 is hydrogen, C1-Cg alkanyl or alkenyl, cyclopropyl or halo;
{b) R2 is halo or C1-C3 alkanyl or alkenyl
(c) R3 is hydrogen; C1-C3 alkanyl, alkenyl or alkynyl; cyclopropyl,
cycloalkenyl; C1-Cg alkylthio or alkoxy; hydroxy; thio; nitro; cyano;
amino; C1-C3 alkylamino or C1-C3 dialkylamino and halo;
(d) R4 is hydrogen or C1-C3 alkanyi; and
(e) R5 is selected from hydrogen and methyl;
and enantiomers, optical isomers, stereoisomers, diastereomers, tautomers,
addition salts, biohydrolyzable amides and esters, and pharmaceutical
compositions containing such novel compounds, and the use of such
compounds for preventing or treating disorders modulated by alpha-2
adrenoceptors.
DETAILED DESCRIPTION OF THE INVENTION
As used herein, "alkanyl" means a saturated hydrocarbon substituent,
straight or branched chain, unsubstituted or substituted. Preferred alkanyi
includes methyl and ethyl.
As used herein, "alkenyl" means a hydrocarbon substituent with one
double bond, straight or branched chain, unsubstituted or substituted.
As used herein, "alkylthio" means a substituent having the structure Q-S-,
where Q is alkanyl or alkenyl.
As used herein, "alkoxy" means a substituent having the structure Q-O-,
where Q is alkanyl or alkenyl.
As used herein, "alkylamino" means a substituent having the structure
Q-NH-, where Q is alkanyi or alkenyl.
As used herein, "dialkylamino" means a substituent having the structure
Q1-N(Q2}-, where each Q is independently~alkanyl or alkenyl.
"Halo", "halogen", or "halide" is a chloro, bromo, fluoro or iodo.
A "pharmaceutically-acceptable salt" is a cationic salt formed at any
acidic (e.g., carboxyl} group, or an anionic salt formed at any basic (e.g.,
amino) group. Many such salts are known in the art, as described in World
Patent Publication 87105297, Johnston et al., published September 11, 1987,
incorporated by reference herein. Preferred cationic salts include the alkali
metal salts (such as sodium and potassium), alkaline earth metal salts (such
as magnesium and calcium) and organic salts. Preferred anionic salts
include halides, sulfonates, carboxylates, phosphates, and the like. Clearly
contemplated in such salts are addition salts that may provide an optical
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center, where once there was none. For example, a chiral tartrate salt may
be prepared from the compounds of the invention, and this definition
includes such chiraf salts.
The compounds of the invention are sufficiently basic to form acid-
addition salts. The compounds are useful both in the free base form and the
form of acid-addition salts, and both forms are within the purview of the
invention. The acid-addition salts are in some cases a more convenient form
for
use. In practice, the use of the salt form inherently amounts to the use of
the
base form of the active. Acids used to prepare acid-addition salts include
preferably those which produce, when combined with the free base, medicinally
acceptable salts. These salts have anions that are relatively innocuous to the
animal organism, such as a mammal, in medicinal doses of the salts so that the
beneficial property inherent in the free base are not vitiated by any side
effects
ascribable to the acid's anions.
Examples of appropriate acid-addition salts include, but at not limited to
hydrochloride, hydrobromide, hydroiodiode, sulfate, hydrogensulfate, acetate,
trifluoroacetate, nitrate, maleate, citrate, fumarate, formate, stearate,
succinate,
mallate, malonate, adipate, glutarate, lactate, propionate, butyrate,
tartrate,
methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, dodecyl
sulfate, cyclohexanesulfamate, and the like. However, other appropriate
medicinally acceptable salts within the scope of the invention are those
derived
from other mineral acids and organic acids. The acid-addition salts of the
basic
compounds are prepared by several methods. For example the free base can
be dissolved in an aqueous alcohol solution containing the appropriate acid
and
the salt is isolated by evaporation of the solution. Alternatively, they may
be
prepared by reacting the free base with an acid in an organic solvent so that
the
salt separates directly. Where separation of the salt is difficult, it can be
precipitated with a second organic solvent, or can be obtained by
concentration
of the solution.
Although medicinally acceptable salts of the basic compounds are
preferred, all acid-addition salts are within the scope of the present
invention.
All acid-addition salts are useful as sources of the free base form, even if
the
particular salt per se is desired only as an intermediate product. For
example,
when the salt is formed only for purposes of purification or identification,
or when
it is used as an intermediate in preparing a medicinally acceptable salt by
ion
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exchange procedures, these salts are clearly contemplated to be a part of this
invention.
"Biohydroiyzable amide" refers to an amide of the compound of the
invention that is readily converted in vivo by a mammal subject to yield an
active compound of the invention.
A "biohydrolyzable ester" refers to an ester of the compound of the
invention that is readily converted by a mammal subject to yield an active
compound of the invention.
"Optical isomer", "stereoisomer", "enantiomer," "diastereomer," as
referred to herein have the standard art recognized meanings (Cf., Hawleys
Condensed Chemical Dictionary, 11th Ed.). Of course, an addition salt may
provide an optical center, where once there was none. For example, a chiral
tartrate salt may be prepared from the compounds of the invention, and this
definition includes such chiral salts. It will be apparent to the skilled
artisan
that disclosure of the racemic mixture alone discloses any enantiomers
therein. Thus by one disclosure, more than one compound is taught.
As used herein "animal" includes "mammals" which includes
"humans".
The skilled artisan will appreciate that tautomeric forms will exist in
certain
compounds of the invention. Thus, in this description the disclosure of one
tautomeric form discloses each and alt of the tautomers. For example, when the
2-iminoimidazolidinyl form of the molecule is shown, it is understood to
include
the 2-imidazolinylamino form of that molecule although not specifically
depicted.
The illustration of specific protected forms and other derivatives of the
Formula (I) compounds is not intended to be limiting. The application of
other useful protecting groups, salt forms, etc. is within the ability of the
skilled artisan.
Compounds
This invention includes compounds of the structure of formula I.
Preferred compounds include:
R~ NH
N N
R
N ~ R2
R4 R3
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Example R R R R R
1 methyl methyl H H H
2 methyl methyl H methyl H
3 ethyl methyl H H H
Methods of making the compounds of the invention
The compounds of this invention are synthesized the procedures
disclosed in U. S. Patent 5,478,858 and U.S. Patent 5,541,210, incorporated
herein by reference.ln addition, imidazolinylamino groups are conveniently
prepared from nitro and amino compounds via the following example synthetic
sequence:
H O N
N Abs. EtOH N ~ K2CO3 ~ ~-SCH3
~S + CH31 = ~ ~SCH3 + CI OCH3 - N
30 - 35 oC N 30 - 35 oC ~OCFi3
H H O
CN
~-S~H
N ~ NHZ N N ~ N~ NH HOAc
~OCH3
HN ~ O HN ~ HNJ
AcOH, Reflux
As with all other starting materials, the above starting nitro and amino
compounds are known, obtained via known methodologies, or are commercially
available. For example, substituents may be incorporated at the 2- position
for
example, by treating a 1,2 phenyl diamine with a acyl halide or the like in
the
presence of a dehydrating agent.
It will be apparent to the skilled artisan that the reactions illustrated
above
are known reactions. Furthermore, it is within the purview of the skilled
artisan
to vary these reactions to prepare compounds within the scope of the claims.
It is recognized that the skilled artisan in the art of organic chemistry can
readily carry out manipulations without further direction, that is, it is well
within
a the scope and practice of the skilled artisan to carry out these
manipulations.
These include reduction of carbonyl compounds to their corresponding alcohols,
oxidations, acylations, aromatic substitutions, both electrophilic and
nucleophilic,
etherifications, esterifications and saponifications and the like. These
manipulations are discussed in standard texts such as March, Advanced
Organic Chemistry (Wiley), Carey and Sundberg, Advanced Organic Chemistry
(2 vol.) and Trost and Fleming Comprehensive Or aq nic Synthesis (6 vol.). The
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skilled artisan will readily appreciate that certain reactions are best
carried out
when other functionality is masked or protected in the molecule, thus avoiding
any undesirable side reactions and/or increasing the yield of the reaction.
Often
the skilled artisan utilizes protecting groups to accomplish such increased
yields
or to avoid the undesired reactions. These reactions are found in the
literature
and are also well within the scope of the skilled artisan. Examples of many of
these manipulations are found, for example, in T. Greene, Protecting Groups in
Organic Synthesis.
The following non-limiting example provide details for the synthesis of the
compounds of the invention:
Preparation of 4,6-dimethyl-5-(2-imidazolinylamino)benzimidazole
CH3 CH3 CH3
02N / NOz
/ KN03 02N / N~ NaN3
H3C ~ CI Hzs04 H3C \ CI H3C ~ Na
CH3 CH3
~ o°i° Pd/c OZN / N\ Hz, ~ o°i° Pa/c H2N / N\
HC02H \ ~ N~ MeOH \ ~ N
H3C H3C
CH3 CH3
SCN S NH N
_DPT / ~ ~ ethylenediamine
DMAP H C \ NH NH3C ~ NH
3
H2N
CH3
NH' /N / N\
Hg(OAc) ~'2
~NH ~ NH
H3C
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5-Chloro-2,4-dinitro-m-xylene. To a 250 mL round bottom flask is added conc.
sulfuric acid. This is then cooled to OoC and 10 g of neat 5-chloro-m-xylene
is
added. With vigorous stirring, 14.35 g of solid potassium nitrate is added
slowly
over 30 minutes. Upon completion of addition, the reaction mixture is warmed
to
room temperature and stirred for 2 hours, afterwhich a solid forms. The solid
is
isolated via suction filtration and recrystallized from ethanol/water to give
rise to
9.5 g of 5-chloro-2,4-dinitro-m-xylene as an off-white solid. This material is
purified further via flash column chromatography on silica gel (95:5
hexane:ethyl
acetate) to give rise to 6.2 g of 5-chloro-2,4-dinitro-m-xylene as a white
crystalline solid.
5-Azido-2,4-dinitro-m-xylene. To a 100 mL round bottom flask are added 10
mL of N,N-dimethylformamide, 707 mg of 5-chloro-2,4-dinitro-m-xylene, and 219
mg of sodium azide. The resulting mixture is heated at 80oC for 45 minutes
then cooled to room temperature and poured into ice/water and extracted with
ethyl acetate (3 x 50 mL). The combined organics are dried over magnesium
sulfate, filtered, and concentrated via rotary evaporation to provide 650 mg
of 5-
azido-2,4-dinitro-m-xylene as a yellow/brown solid.
4,6-dimethyl-5-nitrobenzimidazole. To a 100 mL round bottom flask are
added 20 mL of 80% formic acid, 650 mg of 5-azido-2, 4-dinitro-m-xylene and
100 mg of 10% palladium-on-carbon. This mixture is heated to 80oC for 30
minutes, cooled to room temperature, and filtered through a plug of silica gel
(elution with water). The filtrate is then made basic (~ pH 10) with the
addition of
28% ammonium hydroxide, then extracted with ethyl acetate (3 x 100 mL). The
combined organics are dried over magnesium sulfate, filtered, and concentrated
to give rise to 410 mg of 4,6-dimethyl-5-nitrobenzimidazole as a yellow oil.
5-Amino-4,6-dimethylbenzimidazole. A heterogeneous mixture of 410 mg of
4,6-dimethyl-5-nitrobenzimidazole and 50 mg of 10% palladium-on-carbon in 25
mL of methanol is treated with hydrogen (1 atm, balloon) for 16 hours. The
resulting mixture is filtered through Celite and concentrated via rotary
evaporation to give rise to a yellow residue. This residue is purified via
flash
chromatography on silica gel (95:5 methylene chloride:methanol) to give rise
to
265 mg of 5-amino-4,6-dimethylbenzimidazole as a white solid.
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4,6-Dimethyl-5-isothiocyanatobenzimidazole. To a 100 mL round bottom
flask are added 265 mg of 5-amino-4,6-dimethylbenzimidazole, 20 mL of
tetrahydrofuran, 584 mg of di-2-pyridylthionocarbonate (DPT), and 20 mg of 4-
dimethylaminopyridine (DMAP). The resulting reaction mixture is stirred at
room
temperature for 2 hours. One gram of silica gel is added to the reaction
mixture
and the resulting slurry is concentrated in vacuo. The resulting solid is
added at
the top of a silica gel column and eluted with 50:50 hexane:ethyl acetate to
provide 250 mg of slightly impure 4,6-dimethyl-5-isothiocyanatobenzimidazole
as an off-white solid. The product is used in the next step without further
purification.
4,6-Dimethyl-5-{2-imidazolinylamino)benzimidazole. A solution of 250 mg of
impure 4,6-dimethyl-5-isothiocyanatobenzimidazole in 5 mL of methylene
chloride is added dropwise to a solution of 370 mg of ethylenediamine in 5 mL
of
methylene chloride. The resulting solution is stirred at room temperature for
15
minutes then concentrated via rotary evaporation to give rise to N-(4,6-
dimethylbenzimidazol-5-yl}-N'-2-aminoethylthiourea as an off-white solid. This
solid is dissolved in 10 mL of methanol and to this solution is added 13 mg of
mercuric acetate. The resulting reaction mixture is stirred at room
temperature
for 1 hour, filtered through a pad of silica gel and concentrated to give rise
to an
off-white solid. This residue is purified by flash column chromatography on
silica
gel (70:30:0.5 methylene chloride:methanol:ammonium hydroxide) to give rise to
14 mg of 4, 6-dimethyl-5-(2-imidazolinylamino)benzimidazole as a white solid.
Using the methodologies outlined and exemplified above the preferred
compounds, described earlier, are made.
Compositions
Another aspect of this invention is compositions which comprise a safe
and effective amount of a subject compound, or a pharmaceutically-acceptable
salt thereof, and a pharmaceutically-acceptable carrier.
As used herein, "safe and effective amount" means an amount of the
subject compound sufficient to significantly induce a positive modification in
the
condition to be treated, but low enough to avoid serious side effects (at a
reasonable benefit/risk ratio), within the scope of sound medical judgment. A
safe and effective amount of the subject compound will vary with the age and
physical condition of the patient being treated, the severity of the
condition, the
duration of the treatment, the nature of concurrent therapy, the particular
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pharmaceutically-acceptable carrier utilized, and like factors within the
knowledge and expertise of the attending physician.
Preparing a dosage form is within the purview of the skilled artisan.
Examples are provided for the skilled artisan, but are non-limiting, and it is
contemplated that the skilled artisan can prepare variations of the
compositions
claimed.
Compositions of this invention preferably comprise from about 0.0001
to about 99% by weight of the subject compound, more preferably from about
0.01 % to about 90% of the compound of the invention. Depending upon the
route of administration and attendant bioavailability, solubility or
dissolution
characteristics of the dosage form, the dosage form has preferably from about
10% to about 50%, also preferably from about 5% to about 10%, also preferably
from about 1 % to about 5%, and also preferably from about 0.01 % to about 1
of the subject compound. The frequency of dosing of the subject compound is
dependent upon the pharmacokinetic properties of each specific agent (for
example, biological half-life) and can be determined by the skilled artisan.
In addition to the subject compound, the compositions of this invention
contain a pharmaceutically-acceptable carrier. The term "pharmaceutically-
acceptable carrier", as used herein, means one or more compatible solid or
liquid filler diluents or encapsulating substances which are suitable for
administration to a mammal. The term "compatible", as used herein, means that
the components of the composition are capable of being commingled with the
subject compound, and with each other, in a manner such that there is no
interaction which would substantially reduce the pharmaceutical efficacy of
the
composition under ordinary use situations. Preferably when liquid dose forms
are used, the compounds of the invention are soluble in the components of the
composition. Pharmaceutically-acceptable carriers must, of course, be of
sufficiently high purity and sufficiently low toxicity to render them suitable
for
administration to the mammal being treated.
Some examples of substances which can serve as pharmaceutically-
acceptable carriers or components thereof are sugars, such as lactose, glucose
and sucrose; starches, such as corn starch and potato starch; cellulose and
its
derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and
methyl
cellulose; powdered tragacanth; malt; gelatin; talc; solid lubricants, such as
stearic acid and magnesium stearate; calcium sulfate; vegetable oils, such as
peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil of
theobroma;
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polyols such as propylene glycol, glycerine, sorbitol, mannitol, and
polyethylene
glycol; alginic acid; emulsifiers, such as the Tweens~; wetting agents, such
sodium lauryl sulfate; coloring agents; flavoring agents; tableting agents,
stabilizers; antioxidants; preservatives; pyrogen-free water; isotonic saline;
and
phosphate buffer solutions.The choice of a pharmaceutically-acceptable carrier
to be used in conjunction with the subject compound is basically determined by
the way the compound is to be administered. If the subject compound is to be
injected, the preferred pharmaceutically-acceptable carrier is sterile,
physiological saline, with a blood-compatible suspending agent, the pH of
which
has been adjusted to about 7.4.
If the preferred mode of administering the subject compound is perorally,
the preferred unit dosage form is therefore tablets, capsules, lozenges,
chewable tablets, and the like. Such unit dosage forms comprise a safe and
effective amount of the subject compound, which is preferably from about 0.01
mg to about 350 mg, more preferably from about 0.1 mg to about 35 mg, based
on a 70 kg person. The pharmaceutically-acceptable carrier suitable for the
preparation of unit dosage forms for peroral administration are well-known in
the
art. Tablets typically comprise conventional pharmaceutically-compatible
adjuvants as inert diluents, such as calcium carbonate, sodium carbonate,
mannitol, lactose and cellulose; binders such as starch, gelatin and sucrose;
disintegrants such as starch, alginic acid and croscarmelose; lubricants such
as
magnesium stearate, stearic acid and talc. Glidants such as silicon dioxide
can
be used to improve flow characteristics of the powder mixture. Coloring
agents,
such as the FD&C dyes, can be added for appearance. Sweeteners and
flavoring agents, such as aspartame, saccharin, menthol, peppermint, and fruit
flavors, are useful adjuvants for chewable tablets. Capsules typically
comprise
one or more solid diluents disclosed above. The selection of carrier
components
depends on secondary considerations like taste, cost, and shelf stability,
which
are not critical for the purposes of this invention, and can be readily made
by a
person skilled in the art.
Peroral compositions also include liquid solutions, emulsions,
suspensions, and the like. The pharmaceutically-acceptable carriers suitable
for
preparation of such compositions are well known in the art. Such liquid oral
compositions preferably comprise from about 0.001 % to about 5% of the subject
compound, more preferably from about 0.01 % to about 0.5%. Typical
components of carriers for syrups, elixirs, emulsions and suspensions include
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ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose,
sorbitol
and water. For a suspension, typical suspending agents include methyl
cellulose, sodium carboxymethyl cellulose, Avicel~ RC-591, tragacanth and
sodium alginate; typical wetting agents include lecithin and polysorbate 80;
and
typical preservatives include methyl paraben and sodium benzoate. Peroral
liquid compositions may also contain one or more components such as
sweeteners, flavoring agents and colorants disclosed above.
Other compositions useful for attaining systemic delivery of the subject
compounds include sublingual and buccal dosage forms. Such compositions
typically comprise one or more of soluble filler substances such as sucrose,
sorbitol and mannitol; and binders such as acacia, microcrystalline cellulose,
carboxymethyl cellulose and hydroxypropyl methyl cellulose. Glidants,
lubricants, sweeteners, colorants, antioxidants and flavoring agents disclosed
above may also be included.
Compositions can also be used to deliver the compound to the site where
activity is desired: intranasal doses for nasal decongestion, inhalants for
asthma,
and eye drops, gels and creams for ocular disorders.
Preferred compositions of this invention include solutions or emulsions,
preferably aqueous solutions or emulsions comprising a safe and effective
amount of a subject compound intended for topical intranasal administration.
Such compositions preferably comprise from about 0.001 % to about 25% of a
subject compound, more preferably from about 0.01 % to about 10%. Similar
compositions are preferred for systemic delivery of subject compounds by the
intranasal route. Compositions intended to deliver the compound systemically
by intranasal dosing preferably comprise similar amounts of a subject compound
as are determined to be safe and effective by peroral or parenteral
administration. Such compositions used for intranasal dosing also typically
include safe and effective amounts of preservatives, such as benzalkonium
chloride and thimerosal and the like; chelating agents, such as edetate sodium
and others; buffers such as phosphate, citrate and acetate; tonicity agents
such
as sodium chloride, potassium chloride, glycerin, mannitol and others;
antioxidants such as ascorbic acid, acetylcystine, sodium metabisulfate and
others; aromatic agents; viscosity adjustors, such as polymers, including
cellulose and derivatives thereof, and polyvinyl alcohol and acids and bases
to
adjust the pH of these aqueous compositions as needed. The compositions may
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14
also comprise local anesthetics or other actives. These compositions can be
used as sprays, mists, drops, and the like.
Other preferred compositions of this invention include aqueous solutions,
suspensions, and dry powders comprising a safe and effective amount of a
subject compound intended for atomization and inhalation administration. Such
compositions preferably comprise from about 0.1 % to about 50% of a subject
compound, more preferably from about 1 % to about 20%; of course, the amount
can be altered to fit the circumstance of the patient contemplated and the
package. Such compositions are typically contained in a container with
attached
atomizing means. Such compositions also typically include propellants such as
chlorofluorocarbons 12/11 and 12/114, and more environmentally friendly
fluorocarbons, or other nontoxic volatiles; solvents such as water, glycerol
and
ethanol, these include cosolvents as needed to solvate or suspend the active;
stabilizers such as ascorbic acid, sodium metabisulfite; preservatives such as
cetylpyridinium chloride and benzalkonium chloride; tonicity adjustors such as
sodium chloride; buffers; and flavoring agents such as sodium saccharin. Such
compositions are useful for treating respiratory disorders, such as asthma and
the like.
Other preferred compositions of this invention include aqueous solutions
comprising a safe and effective amount of a subject compound intended for
topical intraocular administration. Such compositions preferably comprise from
about 0.0001 % to about 5% of a subject compound, more preferably from about
0.01 % to about 0.5%. Such compositions also typically include one or more of
preservatives, such as benzalkonium chloride, thimerosal, phenylmercuric
acetate; vehicles, such as poloxamers, modified celluloses, povidone and
purified water; tonicity adjustors, such as sodium chloride, mannitol and
glycerin;
buffers such as acetate, citrate, phosphate and borate; antioxidants such as
sodium metabisulfite, butylated hydroxy toluene and acetyl cysteine; acids and
bases may be used to adjust the pH of these formulations as needed.
Other preferred compositions of this invention useful for peroral
administration include solids, such as tablets and capsules, and liquids, such
as
solutions, suspensions and emulsions (preferably in soft gelatin capsules),
comprising a safe and effective amount of a subject compound. Such
compositions preferably comprise from about 0.01 mg to about 350 mg per
dose, more preferably from about 0.1 mg to about 35 mg per dose. Such
compositions can be coated by conventional methods, typically with pH or time-
r r
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dependent coatings, such that the subject compound is released in the
gastrointestinal tract at various times to extend the desired action. Such
dosage
forms typically include, but are not limited to, one or more of cellulose
acetate
phthalate, polyvinylacetate phthalate, hydroxypropyl methyl cellulose
phthalate,
ethyl cellulose, Eudragit~ coatings, waxes and shellac.
Any of the compositions of this invention may optionally include other
drug actives. Non-limiting examples of drug actives which may be incorporated
in these compositions, include:
Antihistamines, including;
Hydroxyzine, preferably at a dosage range of from about 25 to about 400 mg;
Doxylamine, preferably at a dosage range of from about 3 to about 75 mg;
Pyrilamine, preferably at a dosage range of from about 6.25 to about 200 mg;
Chlorpheniramine, preferably at a dosage range of from about 1 to about 24 mg;
Phenindamine, preferably at a dosage range of from about 6.25 to about 150
mg; Dexchlorpheniramine, preferably at a dosage range of from about 0.5 to
about 12 mg; Dexbrompheniramine, preferably at a dosage range of from about
0.5 to about 12 mg; Clemastine, preferably at a dosage range of from about 1
to
about 9 mg; Diphenhydramine, preferably at a dosage range of from about 6.25
to about 300 mg; Azefastine, preferably at a dosage range of from about 140 to
about 1,680 ~g (when dosed intranasally); 1 to about 8 mg (when dosed orally);
Acrivastine, preferably at a dosage range of from about 1 to about 24 mg;
Levocarbastine (which can be dosed as an intranasal or ocular medicament),
preferably at a dosage range of from about 100 to about 800 mg; Mequitazine,
preferably at a dosage range of from about 5 to about 20 mg; Astemizole,
preferably at a dosage range of from about 5 to about 20 mg; Ebastine,
preferably at a dosage range of from about 5 to about 20 mg; Loratadine,
preferably at a dosage range of from about 5 to about 40 mg; Cetirizine,
preferably at a dosage range of from about 5 to about 20 mg; Terfenadine,
preferably at a dosage range of from about 30 to about 480 mg; Terfenadine
metabolites; Promethazine, preferably at a dosage range of from about 6.25 to
about 50 mg; Dimenhydrinate, preferably at a dosage range of from about 12.5
to about 400 mg; Meclizine, preferably at a dosage range of from about 6.25 to
about 50 mg; Tripelennamine, preferably at a dosage range of from about 6.25
to about 300 mg; Carbinoxamine, preferably at a dosage range of from about
0.5 to about 16 mg; Cyproheptadine, preferably at a dosage range of from about
2 to about 20 mg; Azatadine, preferably at a dosage range of from about 0.25
to
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16
about 2 mg; Brompheniramine, preferably at a dosage range of from about 1 to
about 24 mg; Triprolidine, preferably at a dosage range of from about 0.25 to
about 10 mg; Cyclizine, preferably at a dosage range of from about 12.5 to
about 200 mg; Thonzylamine, preferably at a dosage range of from about 12.5
to about 600 mg; Pheniramine, preferably at a dosage range of from about 3 to
about 75 mg; Cyclizine, preferably at a dosage range of from about 12.5 to
about 200 mg and others;
Antitussives, including:
Codeine, preferably at a dosage range of from about 2.5 to about 120 mg;
Hydrocodone, preferably at a dosage range of from about 2.5 to about 40 mg;
Dextromethorphan, preferably at a dosage range of from about 2.5 to about 120
mg; Noscapine, preferably at a dosage range of from about 3 to about 180 mg;
Benzonatate, preferably at a dosage range of from about 100 to about 600 mg;
Diphenhydramine, preferably at a dosage range of from about 12.5 to about 150
mg; Chfophedianol, preferably at a dosage range of from about 12.5 to about
100 mg; Clobutinol, preferably at a dosage range of from about 20 to about 240
mg; Fominoben, preferably at a dosage range of from about 80 to about 480
mg; Glaucine; Phoicodine, preferably at a dosage range of from about 1 to
about 40 mg; Zipeprol, preferably at a dosage range of from about 75 to about
300 mg; Hydromorphone, preferably at a dosage range of from about 0.5 to
about 8 mg; Carbetapentane, preferably at a dosage range of from about 15 to
about 240 mg; Caramiphen, preferably at a dosage range of from about 10 to
about 100 mg; Levopropoxyphene, preferably at a dosage range of from about
25 to about 200 mg and others;
Antiinflammatories, preferably Non-Steroidal Anti-inflammatories. (NSAIDS)
including:
Ibuprofen, preferably at a dosage range of from about 50 to about 3,200 mg;
Naproxen, preferably at a dosage range of from about 62.5 to about 1,500 mg;
Sodium naproxen, preferably at a dosage range of from about 110 to about
1,650 mg; Ketoprofen, preferably at a dosage range of from about 25 to about
300 mg; Indoprofen, preferably at a dosage range of from about 25 to about 200
mg; Indomethacin, preferably at a dosage range of from about 25 to about 200
mg; Sulindac, preferably at a dosage range of from about 75 to about 400 mg;
Diflunisal, preferably at a dosage range of from about 125 to about 1,500 mg;
Ketorolac, preferably at a dosage range of from about 10 to about 120 mg;
Piroxicam, preferably at a dosage range of from about 10 to about 40 mg;
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Aspirin, preferably at a dosage range of from about 80 to about 4,000 mg;
Meclofenamate, preferably at a dosage range of from about 25 to about 400 mg;
Benzydamine, preferably at a dosage range of from about 25 to about 200 mg;
Carprofen, preferably at a dosage range of from about 75 to about 300 mg;
Diclofenac, preferably at a dosage range of from about 25 to about 200 mg;
Etodolac, preferably at a dosage range of from about 200 to about 1,200 mg;
Fenbufen, preferably at a dosage range of from about 300 to about 900 mg;
Fenoprofen, preferably at a dosage range of from about 200 to about 3,200 mg;
Flurbiprofen, preferably at a dosage range of from about 50 to about 300 mg;
Mefenamic acid, preferably at a dosage range of from about 250 to about 1,500
mg; Nabumetone, preferably at a dosage range of from about 250 to about
2,000 mg; Phenylbutazone, preferably at a dosage range of from about 100 to
about 400 mg; Pirprofen, preferably at a dosage range of from about 100 to
about 800 mg; Tolmetin, preferably at a dosage range of from about 200 to
about 1,800 mg and others;
Analgesics, including:
Acetaminophen, preferably at a dosage range of from about 80 to about 4,000
mg; and others:
Expectorants/Mucolytics, including;
Guaifenesin, preferably at a dosage range of from about 50 to about 2,400 mg;
N-Acetylcysteine, preferably at a dosage range of from about 100 to about 600
mg; Ambroxol, preferably at a dosage range of from about 15 to about 120 mg;
Bromhexine, preferably at a dosage range of from about 4 to about 64 mg;
Terpin hydrate, preferably at a dosage range of from about 100 to about 1,200
mg; Potassium iodide, preferably at a dosage range of from about 50 to about
250 mg and others;
Anticholinergics e.g., Atropinics), preferably intranasally or
orall~administered
antichoiinergics, including;
Ipratroprium (preferably intranasally}, preferably at a dosage range of from
about 42 to about 252 fig; Atropine sulfate (preferably oral), preferably at a
dosage range of from about 10 to about 1,000 fig; Belladonna (preferably as an
extract), preferably at a dosage range of from about 15 to about 45 mg
equivalents; Scopolamine, preferably at a dosage range of from about 400 to
about 3,200 ~.g; Scopolamine methobromide, preferably at a dosage range of
from about 2.5 to about 20 mg; Homatropine methobromide, preferably at a
dosage range of from about 2.5 to about 40 mg; Hyoscyamine (preferably oral),
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18
preferably at a dosage range of from about 125 to about 1,000 pg;
Isopropramide (preferably oral), preferably at a dosage range of from about 5
to
about 20 mg; Orphenadrine (preferably oral), preferably at a dosage range of
from about 50 to about 400 mg; Benzalkonium chloride (preferably intranasally)
preferably a 0.005 to about 0.1 % solution and others;
Mast Cell Stabilizers, preferably intranasally, or orally administered mast
cell
stabilizers, including;
Cromalyn, preferably at a dosage range of from about 10 to about 60 mg;
Nedocromil, preferably at a dosage range of from about 10 to about 60 mg;
Oxatamide, preferably at a dosage range of from about 15 to about 120 mg;
Ketotifen, preferably at a dosage range of from about 1 to about 4 mg;
Lodoxamide, preferably at a dosage range of from about 100 to about 3,000 ~.g
and others;
Leukotriene Antagonists, including Zileuton and others;
Met~lxanthines, including;
Caffeine, preferably at a dosage range of from about 65 to about 600 mg;
Theophylline, preferably at a dosage range of from about 25 to about 1,200 mg;
Enprofylline; Pentoxifyliine, preferably at a dosage range of from about 400
to
about 3,600 mg; Aminophylline, preferably at a dosage range of from about 50
to about 800 mg; Dyphylline, preferably at a dosage range of from about 200 to
about 1,600 mg and others;
Antioxidants or radical inhibitors, including;
Ascorbic acid, preferably at a dosage range of from about 50 to about 10,000
mg; Tocopherol, preferably at a dosage range of from about 50 to about 2,000
mg; Ethanol, preferably at a dosage range of from about 500 to about 10,000
mg and others;
Steroids, preferably intranasally administered steroids, including:
Beclomethasone, preferably at a dosage range of from about 84 to about 336 p
g; Fluticasone, preferably at a dosage range of from about 50 to about 400
fig;
Budesonide, preferably at a dosage range of from about 64 to about 256 p,g;
Mometasone, preferably at a dosage range of from about 50 to about 300 mg;
Triamcinolone, preferably at a dosage range of from about 110 to about 440 pg;
Dexamethasone, preferably at a dosage range of from about 168 to about 1,008
fig; Flunisolide, preferably at a dosage range of from about 50 to about 300
fig;
Prednisone (preferably oral), preferably at a dosage range of from about 5 to
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19
about 60 mg; Hydrocortisone (preferably oral), preferably at a dosage range of
from about 20 to about 300 mg and others;
Bronchodilators, preferably for inhalation, including;
Albuterol, preferably at a dosage range of from about 90 to about 1,080 fig; 2
to
about 16 mg (if dosed orally); Epinephrine, preferably at a dosage range of
from
about 220 to about 1,320 fig; Ephedrine, preferably at a dosage range of from
about 15 to about 240 mg (if dosed orally); 250 to about 1,000 ~g (if dosed
intranasally); Metaproterenol, preferably at a dosage range of from about 65
to
about 780 ~g or 10 to about 80 mg if dosed orally; Terbutaline, preferably at
a
dosage range of from about 200 to about 2,400 fig; 2.5 to about 20 mg (if
dosed
orally); Isoetharine, preferably at a dosage range of from about 340 to about
1,360 ~.g; Pirbuterol, preferably at a dosage range of from about 200 to about
2,400 fig; Bitolterol, preferably at a dosage range of from about 370 to about
2,220 fig; Fenoterol, preferably at a dosage range of from about 100 to about
1,200 fig; 2.5 to about 20 mg (if dosed orally); Rimeterol, preferably at a
dosage
range of from about 200 to about 1,600 fig; Ipratroprium, preferably at a
dosage
range of from about 18 to about 216 ~g (inhalation) and others; and
Antivirals, including;
Amantadine, preferably at a dosage range of from about 50 to about 200 mg;
Rimantadine, preferably at a dosage range of from about 50 to about 200 mg;
Enviroxime; Nonoxinols, preferably at a dosage range of from about 2 to about
20 mg (preferably an intranasal form); Acyclovir, preferably at a dosage range
of
from about 200 to about 2,000 mg (oral); 1 to about 10 mg (preferably an
intranasal form); Alpha-Interferon, preferably at a dosage range of from about
3
to about 36 MIU; Beta-Interferon, preferably at a dosage range of from about 3
to about 36 MIU and others;
Ocular Druq actives: acetylcholinesterase inhibitors, e.g., echothiophate from
about 0.03% to about 0.25% in topical solution and others; and
Gastrointestinal actives: antidiarrheals, e.g., loperamide from about 0.1 mg
to
about 1.0 mg per dose, and bismuth subsalicylate from about 25 mg to about
300 mg per dose and others.
Of course, clearly contemplated and included in the description above are
the acid or base addition salts, esters, metabolites, stereoisomers and
enantiomers of these preferred combination actives, as well as their analogues
of these actives that are safe and effective. It is also recognized that an
active
may be useful for more than one of the above uses, and these uses are clearly
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contemplated as well. This overlap is recognized in the art and adjusting
dosages and the like to fit the indication is well within the purview of the
skilled
medical practitioner.
Methods of use
Without being bound by theory, it is contemplated that the primary
mechanism by which alpha-2 agonists provide efficacy is by intervening in the
biological cascade responsible for disorders) and/or manifestations) thereof.
It
may be that there is no deficit in alpha-2 adrenoceptor activity: such
activity may
be normal. However, administration of an alpha-2 agonist may be a useful way
of rectifying a disorder, condition or manifestation thereof.
Thus as used herein, the terms "disease," "disorder" and "condition" are
used interchangeably to refer to maladies related to or modulated by alpha-2
adrenoceptor activity.
As used herein, a disorder described by the terms "modulated by alpha-2
adrenoceptors," or "modulated by alpha-2 adrenoceptor activity" refers to a
disorder, condition or disease where alpha-2 adrenoceptor activity is an
effective
means of alleviating the disorder or one or more of the biological
manifestations
of the disease or disorder; or interferes with one or more points in the
biological
cascade either leading to the disorder or responsible for the underlying
disorder;
or alleviates one or more symptoms of the disorder. Thus, disorders subject to
"modulation" include those for which:
~ The lack of alpha-2 activity is a "cause" of the disorder or one or more of
the
biological manifestations, whether the activity was altered genetically, by
infection, by irritation, by internal stimulus or by some other cause;
~ The disease or disorder or the observable manifestation or manifestations of
the disease or disorder are alleviated by alpha-2 activity. The lack of alpha-
2
activity need not be causally related to the disease or disorder or the
observable manifestations thereof;
~ Alpha-2 activity interferes with part of the biochemical or cellular cascade
that
results in or relates to the disease or disorder. In this respect, the alpha-2
activity alters the cascade, and thus controls the disease, condition or
disorder.
The compounds of this invention are particularly useful for the treatment
of nasal congestion associated with allergies, colds, and other nasal
disorders,
as well as the sequelae of congestion of the mucous membranes (for example,
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21 -
sinusitis and otitis media). At effective doses, it has been found that
undesired
side effects can be avoided.
While not limited to a particular mechanism of action, the subject
compounds are believed to provide advantages in the treatment of nasal
decongestion over related compounds through their ability to interact with
alpha-
2 adrenoceptors. The subject compounds have been found to be alpha-2
adrenoceptor agonists which cause constriction of peripheral vascular beds in
the nasal turbinates.
Alpha-2 adrenoceptors are distributed both inside and outside of the
central nervous system. Thus, though not essential for activity or efficacy,
certain disorders preferably are treated with compounds that act on alpha-2
adrenoceptors in only one of these regions. Compounds of this invention vary
in
their ability to penetrate into the central nervous system and, thus, to
produce
effects mediated through central alpha-2 adrenoceptors. Thus, for example, a
compound which displays a higher degree of central nervous system activity is
preferred for central nervous system indications over other compounds as
described below. However, even for compounds that exhibit primarily peripheral
activity, central nervous system actions can be evoked by an increase in the
dose of the compound. Further specificity of action of these compounds can be
achieved by delivering the agent to the region where activity is desired (for
example, topical administration to the eye, nasal mucosa or respiratory
tract).
Compounds preferred for, but not limited to, the treatment of certain
cardiovascular disorders, pain, substance abuse and/or withdrawal, ulcer and
hyperacidity include those compounds that are centrally acting. By centrally
acting what is meant is that they have some action on the alpha-2
adrenoceptors in the central nervous system in addition to their action at
peripheral alpha-2 adrenoceptors.
Compounds preferred for, but not limited to, the treatment of respiratory
disorders, ocular disorders, migraine, certain cardiovascular disorders, and
certain other gastrointestinal disorders are peripherally acting. By
peripherally
acting, what is meant is that these compounds act primarily on alpha-2
adrenoceptors in the periphery, rather than those in the central nervous
system.
Methods are available in the art to determine which compounds are primarily
peripherally acting and which are primarily centrally acting.
Thus, compounds of the subject invention are also useful for the
treatment of ocular disorders such as ocular hypertension, glaucoma,
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22
hyperemia, conjunctivitis, and uveitis. The compounds are administered either
perorally, or topically as drops, sprays, mists, gels or creams directly to
the
surface of the mammalian eye.
The compounds of this invention are also useful for controlling
gastrointestinal disorders, such as diarrhea, irritable bowel syndrome,
hyperchlorhydria and peptic ulcer.
The compounds of this invention are also useful for diseases and
disorders associated with sympathetic nervous system activity, including
hypertension, myocardial ischemia, cardiac reperfusion injury, angina, cardiac
arrhythmia, heart failure and benign prostatic hypertrophy. Due to their
sympatholytic effect, compounds are also useful as an adjunct to anesthesia
during surgical procedures.
The compounds of this invention are also useful for relieving pain
associated with various disorders. The compounds are administered perorally,
parenterally, and/or by direct injection into the cerebrospinal fluid.
The compounds of this invention are also useful for the prophylactic or
acute treatment of migraine. The compounds are administered perorally,
parenterally or intranasally.
The compounds of this invention are also useful for treatment of
substance abuse, in particular abuse of alcohol and opiates, and alleviating
the
abstinence syndromes evoked by withdrawal of these substances.
The compounds of this invention are also useful for other diseases and
disorders where vasoconstriction, particularly of veins, would provide a
benefit,
including septic or cardiogenic shock, elevated intracranial pressure,
hemmorhoids, venous insufficiency, varicose veins, and menopausal flushing.
The compounds of this invention are also useful for neurologic diseases
and disorders, including spasticity, epilepsy, attention deficit hyperactive
disorder, Tourette's syndrome, and cognitive disorders.
The pharmacological activity and selectivity of these compounds can be
determined using published test procedures. The alpha-2 selectivity of the
compounds is determined by measuring receptor binding affinities and in vitro
functional potencies in a variety of tissues known to possess alpha-2 and/or
alpha-1 receptors. (See, e.g., The Apha-2 Adrenergic Receptors, L.E. Limbird,
ed., Humana Press, Clifton, NJ.) The following in vivo assays are typically
conducted in rodents or other species. Central nervous system activity is
determined by measuring locomotor activity as an index of sedation. (See,
e.g.,
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23
Spyraki, C. & H. Fibiger, "Clonidine-induced Sedation in Rats: Evidence for
Mediation by Postsynaptic Alpha-2 Adrenoreceptors", Journal of Neural
Transmission, Vol. 54 (1982), pp. 153-163). Nasal decongestant activity is
measured using rhinomanometry as an estimate of nasal airway resistance.
(See, e.g., Salem, S. & E. Clemente, "A New Experimental Method for
Evaluating Drugs in the Nasal Cavity", Archives of Otolar~g_oloay, Vol. 96
(1972), pp. 524-529). Antiglaucoma activity is determined by measuring
intraocular pressure. (See, e.g., Potter, D., "Adrenergic Pharmacology of
Aqueous Human Dynamics", Pharmacological Reviews, Vol. 13 (1981 ), pp. 133-
153). Antidiarrheal activity is determined by measuring the ability of the
compounds to inhibit prostaglandin-induced diarrhea. (See, e.g., Thollander,
M.,
P. Hellstrom & T. Svensson, "Suppression of Castor Oil-Induced Diarrhea by
Alpha-2 Adrenoceptor Agonists", Alimentary Pharmacology and Therapeutics,
Vol. 5 (1991 ), pp. 255-262). Efficacy in treating irritable bowel syndrome is
determined by measuring the ability of compounds to reduce the stress-induced
increase in fecal output. (See, e.g., Barone, F., J. Deegan, W. Price, P.
Fowler,
J. Fondacaro & H. Ormsbee III, "Cold-restraint stress increases rat fecal
pellet
output and colonic transit", American Journal of Physiology, Vol. 258 (1990),
pp.
6329-G337). Antiulcer and reduction of hyperchlorhydria efficacy is determined
by measuring the reduction in gastric acid secretion produced by these
compounds (See, e.g., Tazi-Saad, K., J. Chariot, M. Del Tacca & C. Roze,
"Effect of a2-adrenoceptor agonists on gastric pepsin and acid secretion in
the
rat", British Journal of Pharmacoloay, Vol. 106 (1992), pp. 790-796).
Antiasthma
activity is determined by measuring the effect of the compound on
bronchoconstriction associated with pulmonary challenges such as inhaled
antigens. (See, e.g., Chang, J. J. Musser 8~ J. Hand, "Effects of a Novel
Leukotriene D4 Antagonist with 5-Lipoxygenase and Cyclooxygenase inhibitory
Activity, Wy-45,911, on Leukotriene-D4- and Antigen-Induced
Bronchoconstriction in Guinea Pig", International Archives of Allergy and
Applied
Immunoloay, Vol. 86 (1988), pp. 48-54; and Delehunt, J., A. Perruchound, L.
Yerger, B. Marchette, J. Stevenson & W. Abraham, "The Role of Slow-Reacting
Substance of Anaphylaxis in the Late Bronchial Response After Antigen
Challenge in Allergic Sheep", American Reviews of Respiratory Disease, Vol.
130 (1984), pp. 748-754). Activity in cough is determined by measuring the
number and latency of the cough response to respiratory challenges such as
inhaled citric acid. (See, e.g., Callaway, J. & R. King, "Effects of Inhaled
a2-
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24
Adrenoceptor and GABAg Receptor Agonists on Citric Acid-Induced Cough and
Tidal Volume Changes in Guinea Pigs", European Journal of Pharmacology,
Vol. 220 (1992), pp. 187-195). The sympatholytic activity of these compounds
is
determined by measuring the reduction of plasma catecholamines (See, e.g., R.
Urban, B. Szabo & K. Starke "Involvement of peripheral presynaptic inhibition
in
the reduction of sympathetic tone by moxonidine, rilmenidine and UK 14,304",
European Journal of Pharmacology, Vol. 282 (1995), pp. 29-37) or the reduction
in renal sympathetic nerve activity (See, e.g., Feng, Q., S. Carlsson, P.
Thoren &
T. Hedner, "Effects of clonidine on renal sympathetic nerve activity,
natriuresis
and diuresis in chronic congestive heart failure rats", Journal of
Pharmacoloay
and Exeerimental Therapeutics, Vol. 261 (1992), pp. 1129-1135), providing the
basis for their benefit in heart failure and benign prostatic hypertrophy. The
hypotensive effect of these compounds is measure directly as a reduction in
mean blood pressure (See, e.g., Timmermans, P. & P. Van Zwieten, "Central
and peripheral a-adrenergic effects of some imidazolidines", European Journal
of Pharmacoloay, Vol. 45 (1977), pp. 229-236). Clinical studies have
demonstrated the beneficial effect of alpha-2 agonists in the prevention of
myocardial ischemia during surgery (See, e.g., Talke, P., J. Li, U. Jain, J.
Leung,
K. Drasner, M. Hollenberg & D. Mangano, "Effects of Perioperative
Dexmedetomidine Infusion in Patients Undergoing Vascular Surgery",
Anesthesioloay, Vol. 82 (1995), pp. 620-633) and in the prevention of angina
(See, e.g., Wright, R.A., P. Decroly, T. Kharkevitch & M. Oiiver, "Exercise
Tolerance in Angina is Improved by Mivazerol--an a2-Adrenoceptor Agonist",
Cardiovascular Drugis and Therapy, Vol. 7 (1993), pp. 929-934). The efficacy
of
these compounds in cardiac reperfusion injury is demonstrated by measuring
the reduction of cardiac necrosis and neutrophil infiltration (See, e.g.,
Weyrich,
A., X. Ma, & A. Lefer, "The Role of L-Arginine in Ameliorating Reperfusion
Injury
After Myocardial Ischemia in the Cat", Circulation, Vol. 86 (1992), pp. 279-
288).
The cardiac antiarrhythmic effect of these compounds is demonstrated by
measuring the inhibition of ouabain induced arrhythmias (See, e.g., Thomas, G.
& P. Stephen, "Effects of Two Imidazolines (ST-91 and ST-93) on the Cardiac
Arrhythmias and Lethality Induced by Ouabain in Guinea-Pig", Asia-Pacific
Journal of Pharmacoloay, Vol. 8 (1993), pp.109-113; and Samson, R., J. Cai, E.
Shibata, J. Martins & H. Lee, "Electrophysiological effects of a2-adrenergic
stimulation in canine cardiac Purkinje fibers", American Journal of
Physiology,
Vol. 268 (1995), pp. H2024-H2035). The vasoconstrictor activity of these
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compounds is demonstrated by measuring the contractile properties on isolated
arteries and veins in vitro (See, e.g., Flavahan, N., T. Rimeie, J. Cooke & M.
Vanhoutte, "Characterization of Postjunctional Alpha-1 and Alpha-2
Adrenoceptors Activated by Exogenous or Nerve-Released Norepinephrine in
the Canine Saphenous Vein", Journal of Pharmacology and Experimental
Therapeutics, Vol. 230 (1984), pp. 699-705). The effectiveness of these
compounds at reducing intracranial pressure is demonstrated by measurement
of this property in a canine model of subarachnoid hemorrhage (See, e.g.,
McCormick, J., P. McCormick, J. Zabramski & R. Spetzier, "intracranial
pressure
reduction by a central alpha-2 adrenoreceptor agonist after subarachnoid
hemorrhage", NeurosurgerY, Vol. 32 (1993), pp. 974-979). The inhibition of
menopausal flushing is demonstrated by measuring the reduction of facial blood
flow in the rat (See, e.g., Escott, K., D. Beattie, H. Connor & S. Brain, "The
modulation of the increase in rat facial skin blood flow observed after
trigeminal
ganglion stimulation", European Journal of Pharmacoloay, Vol. 284 (1995), pp.
69-76) as demonstrated for alpha-2 adrenergic agonists on cutaneous blood
flow in the tail (See, e.g., Redfern, W., M. MacLean, R. Clague & J. McGrath,
"The role of alpha-2 adrenoceptors in the vasculature of the rat tail",
British
Journal of Pharmacology, Vol. 114 (1995), pp. 1724-1730). The antinociceptive
and pain reducing properties of these compounds is demonstrated by measuring
the increase in pain threshold in the rodent writhing and hot plate
antinociceptive
models (See, e.g., Millan, M., K. Bervoets, J. Rivet, R. Widdowson, A.
Renouard, S, Le Marouille-Girardon & A. Gobert, "Multiple Alpha-2 Adrenergic
Receptor Subtypes. II. Evidence for a Role of Rat Alpha-2A Adrenergic
Receptors in the Control of Nociception, Motor Behavior and Hippocampal
Synthesis of Noradrenaline", Journal of Pharmacology and Experimental
Therapeutics, Vol. 270 (1994), pp. 958-972). The antimigraine effect of these
compounds is demonstrated by measuring the reduction of dural neurogenic
inflammation to trigeminal ganglion stimulation in the rat (See, e.g.,
Matsubara,
T., M. Moskowitz & Z. Huang, "UK-14,304, R(-)-alpha-methyl-histamine and
SMS 201-995 block plasma protein leakage within dura mater by prejunctional
mechanisms", European Journal of Pharmacoloay, Vol. 224 (1992}, pp. 145-
150). The ability of these compounds to suppress opiate withdrawal is
demonstrated by measuring the suppression of enhanced sympathetic nerve
activity (See, e.g., Franz, D., D. Hare & K. McCloskey, "Spinal sympathetic
neurons: possible sites of opiate-withdrawal suppression by clonidine",
Science,
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26
Vol. 215 (1982), pp. 1643-1645). Antiepileptic activity of these compounds is
demonstrated by measuring the inhibition of the kindling response (See, e.g.,
Shouse, M., M. Bier, J. Langer, O. Alcalde, M. Richkind & R. Szymusiak, "The
a2-agonist clonidine suppresses seizures, whereas the alpha-2 antagonist
idazoxan promotes seizures--a microinfusion study in amygdala-kindled
kittens",
Brain Research, Vol. 648 (1994), pp. 352-356). The effectiveness of other
alpha-2 agonists in the management of neurologic disorders has been
demonstrated, including attention-deficit hyperactive disorder and Tourette's
syndrome (See, e.g., Chappell P., M. Riddle, L. Scahill, K. Lynch, R. Schultz,
A.
Arnsten, J. Leckman & D. Cohen, "Guanfacine treatment of comorbid attention-
deficit hyperactivity disorder and Tourette's syndrome: preliminary clinical
experience", Journal of American Academy of Child and Adolescent Psychiatry,
Vol. 34 (1995), pp. 1140-1146), cognitive disorders (See, e.g., Coull, J.,
"Pharmacological manipulations of the a2-noradrenergic system. Effects on
cognition", Drubs and Aaing, Vol. 5 (1994), pp. 116-126), and spasticity (See,
e.g., Eyssette, M., F. Rohmer, G. Serratrice, J. Waiter 8~ D. Boisson,
"Multicenter, double-blind trial of a novel antispastic agent, tizanidine, in
spasticity associated with multiple sclerosis", Current Medical Research &
Opinion, Vol. 10 (1988), pp. 699-708).
Another aspect of this invention involves methods for preventing or
treating nasal congestion by administering a safe and effective amount of a
subject compound to a mammal experiencing or at risk of experiencing nasal
congestion. Such nasal congestion may be associated with human diseases or
disorders which include, but are not limited to, seasonal allergic rhinitis,
acute
upper respiratory viral infections, sinusitis, perennial rhinitis, and
vasomotor
rhinitis. In addition, other disorders can be generally associated with mucous
membrane congestion (for example, otitis media and sinusitis.) Each
administration of a dose of the subject compound preferably administers a dose
within the range of from about 0.0001 mg/kg to about 5 mg/kg of a compound,
more preferably from about 0.001 mg/kg to about 0.5 mg/kg. Peroral
administration of such doses is preferred. The frequency of administration of
a
subject compound according to this invention is preferably from about once to
about six times daily, more preferably from about once to about 4 times daily.
Such doses and frequencies are also preferred for treating other respiratory
conditions, such as, cough, chronic obstructive pulmonary disease (COPD) and
asthma. Such doses and frequencies are also preferred for treating conditions
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that are associated with mucous membrane congestion (for example, sinusitis
and otitis media).
Another aspect of this invention involves methods for preventing or
treating glaucoma by administering a safe and effective amount of a subject
compound to a mammal experiencing or at risk of experiencing glaucoma. If
administered systemically, each administration of a dose of the subject
compound preferably administers a dose within the range of from about 0.0001
mg/kg to about 5 mg/kg of a compound, more preferably from about
0.001 mg/kg to about 0.5 mg/kg. If intraocular dosing is used then preferably
one administers a typical volume (for example, 1 or 2 drops) of a liquid
composition, comprising from about 0.0001 % to about 5% of a subject
compound, more preferably from about 0.01 % to about 0.5% of the compound.
Determination of the exact dosage and regimen is within the purview of the
skilled artisan. Intraocular administration of such doses is preferred. The
frequency of administration of a subject compound according to this invention
is
preferably from about once to about six times daily, more preferably from
about
once to about 4 times daily.
Another aspect of this invention involves methods for preventing or
treating gastrointestinal disorders, such as diarrhea, irritable bowel
syndrome,
and peptic ulcer by administering a safe and effective amount of a subject
compound to a mammal experiencing or at risk of experiencing gastrointestinal
disorders. Each administration of a dose of the subject compound preferably
administers a dose within the range of from about 0.0001 mg/kg to about
mg/kg of a compound, more preferably from about 0.001 mg/kg to about
0.5 mg/kg. Peroral administration of such doses is preferred. The frequency of
administration of a subject compound according to this invention is preferably
from about once to about six times daily, more preferably from about once to
about 4 times daily.
Another aspect of this invention involves methods for preventing or
treating migraine, by administering a safe and effective amount of a subject
compound to a mammal experiencing or at risk of experiencing migraine. Each
administration of a dose of the subject compound preferably administers a dose
within the range of from about 0.0001 mg/kg to about 5 mglkg of a compound,
more preferably from about 0.001 mglkg to about 0.5 mg/kg. Peroral, parenteral
or intranasal administration of such doses is preferred. The frequency of
peroral
administration of a subject compound according to this invention is preferably
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from about once to about six times daily, more preferably from about once to
about 4 times daily. The frequency of parenteral dosing of a subject compound
according to this invention is preferably from about once to about six times
daily,
more preferably from about once to about 4 times daily or by infusion to the
desired effect. The frequency of intranasal dosing of a subject compound
according to this invention is preferably from about once to about six times
daily,
more preferably from about once to about 4 times daily.
Another aspect of this invention involves methods for preventing or
treating disorders related to sympathetic nervous system activity, such as
hypertension, myocardial ischemia, cardiac reperfusion injury, angina, cardiac
arrhythmia, and benign prostatic hypertrophy, by administering a safe and
effective amount of a subject compound to a mammal experiencing or at risk of
experiencing these diseases or disorders. Each administration of a dose of the
subject compound preferably administers a dose within the range of from about
0.0001 mg/kg to about 5 mg/kg of a compound, more preferably from about
0.001 mg/kg to about 0.5 mg/kg. Peroral and parenteral administration of such
doses are preferred. The frequency of peroral administration of a subject
compound according to this invention is preferably from about once to about
six
times daily, more preferably from about once to about 4 times daily. The
frequency of parenteral dosing of a subject compound according to this
invention is preferably from about once to about six times daily, more
preferably
from about once to about 4 times daily or by infusion to the desired effect.
Another aspect of this invention involves methods for preventing or
treating pain, by administering a safe and effective amount of a subject
compound to a mammal experiencing or at risk of experiencing pain. Each
administration of a dose of the subject compound preferably administers a dose
within the range of from about 0.0001 mg/kg to about 5 mglkg of a compound,
more preferably from about 0.001 mg/kg to about 0.5 mg/kg. Peroral or
parenteral administration of such doses is preferred. The frequency of peroral
administration of a subject compound according to this invention is preferably
from about once to about six times daily, more preferably from about once to
about 4 times daily. The frequency of parenteral dosing of a subject compound
according to this invention is preferably from about once to about six times
daily,
more preferably from about once to about 4 times daily or by infusion to the
desired effect.
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Another aspect of this invention involves methods for preventing or
treating substance abuse and the abstinence syndrome resulting from
withdrawal of these substances, such as alcohol and opiates, by administering
a
safe and effective amount of a subject compound to a mammal experiencing or
at risk of experiencing substance abuse or withdrawal symptoms. Each
administration of a dose of the subject compound preferably administers a dose
within the range of from about 0.0001 mg/kg to about 5 mg/kg of a compound,
more preferably from about 0.001 mg/kg to about 0.5 mg/kg. Peroral
administration of such doses is preferred. The frequency of administration of
a
subject compound according to this invention is preferably from about once to
about six times daily, more preferably from about once to about 4 times daily.
Composition and Method Examples
The following non-limiting examples illustrate the compositions and
methods of use of this invention.
Example A
Oral Tablet Composition
Ingredient Amount per tablet (mg)
Subject Compound 3 20.0
Microcrystalline cellulose (Avicel PH 102~) 80.0
Dicalcium phosphate 96.0
Pyrogenic silica (Cab-O-Sil~) 1.0
Magnesium stearate 3-00
Total = 200.0 mg
One tablet is swallowed by a patient with nasal congestion. The congestion is
substantially diminished.
Other compounds having a structure according to Formula I are used with
substantially similar results.
Example B
Chewable Tablet Composition
Ingredient Amount aer tablet (mq~
Subject Compound 1 15.0
Mannitol 255.6
Microcrystalline cellulose (Avicel PH 101 ~) 100.8
Dextrinized sucrose (Di-Pac~) 199.5
Imitation orange flavor 4.2
Sodium saccharin 1.2
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Stearic acid 15.0
Magnesium stearate 3.0
FD&C Yellow #6 dye 3.0
Pyrogenic silica (Cab-O-Sil~) 2-77
Total = 600.0 mg
One tablet is chewed and swallowed
by a patient with nasal congestion.
The
congestion is substantially reduced.
Other compounds having a structure
according to Formula I are used
with
substantially similar results.
Example C
Sublingual Tablet Composition
Ingredient Amount per tablet (mq~
Subject Compound 2 2.00
Mannitol 2.00
Microcrystalline cellulose (Avicel 29.00
PH 101 ~)
Mint flavorants 0.25
Sodium saccharin 0.08
Total = 33.33 mg
One tablet is placed under the tongue
of a patient with nasal congestion
and
allowed to dissolve. The congestionand substantially diminished.
is rapidly
Other compounds having a structure cording to Formula I are
ac used with
substantially similar results.
Example D
Intranasal Solution Composition
ingredient Composition j% wlv)
Subject Compound 3 0.20
Benzalkonium chloride 0.02
Thimerosal 0.002
d-Sorbitol 5.00
Glycine 0.35
Aromatics 0.075
Purified water q.s.
Total = 100.00
One-tenth of a mL of the composition
is sprayed from a pump actuator
into each
nostril of a patient with nasal The congestion is substantially
congestion.
diminished.
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Other compounds having a structure according to Formula I are used with
substantially similar results.
Example E
intranasal Gel Comeosition
Ingredient Composition (% w/v)
Subject Compound 1 0.10
Benzalkonium chloride 0.02
Thimerosal 0.002
Hydroxypropyl methyfcellulose 1.00
(Metolose 65SH4000~)
Aromatics 0.06
Sodium chloride (0.65%) q.s.
Total = 100.00
One-fifth of a mL of the composition is applied as drops from a dropper into
each
nostril of a patient with nasal congestion. The congestion is substantially
reduced.
Other compounds having a structure according to Formula I are used with
substantially similar results.
Example F
Inhalation Aerosol Composition
Inaredient Composition (% w/v~
Subject Compound 2 5.0
Alcohol 33.0
Ascorbic acid 0.1
Menthol 0.1
Sodium Saccharin 0.2
Propellant (F12, F114) g.s.
Total = 100.0
Two-puffs of the aerosol composition is inhaled from a metered-dose inhaler by
a patient with asthma. The asthmatic condition is effectively relieved.
Other compounds having a structure according to Formula I are used with
substantially similar results.
Example G
Topical Ophthalmic Composition
Ingiredient Composition (% w/v~
Subject Compound 3 0.10
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Ben2alkonium chloride 0.01
EDTA 0.05
Hydroxyethylcellulose (Natrosol 0.50
M~)
Sodium metabisulfite 0.10
Sodium chloride (0.9%) .cLs.
Total = 100.0
One-tenth of a mL of the composition is administered directly into each eye of
a
patient with glaucoma. The intraocular pressure is substantially reduced.
Other compounds having a structure according to Formula I are used with
substantially similar results.
Example H
Oral Liquid Comp osition
Ingredient Amount/15 mL Dose
Subject Compound 2 15 mg
Chlorpheniramine maleate 4 mg
Propylene glycol 1.8 g
Ethanol (95%) 1.5 mL
Methanol 12.5 mg
Eucalyptus oil 7.55 mg
Flavorants 0.05 mL
Sucrose 7.65 g
Carboxymethylcellulose (CMC) 7.5 mg
Microcrystalline cellulose and 187.5 mg
Sodium CMC (Avicel RC 591 ~)
Polysorbate 80 3.0 mg
Glycerin 300 mg
Sorbitol 300 mg
FD&C Red #40 dye 3 mg
Sodium saccharin 22.5 mg
Sodium phosphate monobasic 44 mg
Sodium citrate monohydrate 28 mg
Purified Water .cps.
Total = 15 mL
One 15 mL dose of the liquid composition is swallowed by a patient with nasal
congestion and runny nose due to allergic rhinitis. The congestion and runny
nose are effectively reduced.
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Other compounds having a structure
according to Formula I are used
with
substantially similar results.
Example J
Oral Liquid Comp osition
Ingredient Amount/15 mL Dose
Subject Compound 2 30 mg
Sucrose 8.16 g
Glycerin 300 mg
Sorbitol 300 mg
Methylparaben 19.5 mg
Propylparaben 4.5 mg
Menthol 22.5 mg
Eucalyptus oil 7.5 mg
Fiavorants 0.07 mL
FD&C Red #40 dye 3.0 mg
Sodium saccharin 30 mg
Purified water g.s.
Total = 15 mL
One 15 mL dose of the alcohol-free
liquid medication is swallowed
by a patient
with nasal congestion. The congestion
is substantially diminished.
Other compounds having a structure
according to Formula I are used
with
substantially similar results.
Example K
Oral Tablet Comp osition
Ingredient Amountper tablet ~ma)
Subject Compound 1 4
Microcrystalline cellulose, NF 130
Starch 1500, NF 100
Magnesium stearate, USP 2
Total = 236 mg
One tablet is swallowed by a patientmigraine. The pain and
with aura of
migraine is substantially diminished.
Other compounds having a structure
according to Formula I are used
with
substantially similar results.
Example L
Oral Tablet Composition
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Ingredient Amount eer tablet~mg)
Subject Compound 2 12
Hydroxypropyl methylcellulose, USP 12
Magnesium stearate, USP 2
Lactose anhydrous, USP 200
Total= 226 mg
For the relief of pain. Adults 12 one tablet every twelve
and over take hours.
Other compounds having a structure
according to Formula I are used
with
substantially similar results.
Example M
Oral Caplet Comp osition
Ingredient Amount per tablet (mq~
Naproxen sodium anhydrous, USP 220
Subject Compound 3 6
Hydroxypropyl methylcellulose, USP 6
Magnesium stearate, USP 2
Povidone K-30, USP 10
Talc, USP 12
Microcrystalline cellulose, NF 44
Total= 300 mg
For relief of symptoms associated e common cold, sinusitis,
with th or flu
including nasal congestion, headache,body aches, and pains.
fever, Adults 12
and over take two caplets every
twelve hours.
Other compounds having a structure
according to Formula I are used
with
substantially similar results.
Example N
Oral Tablet Composition
Ingredient Amount per tablet (mct)
Subject Compound 3 6
Hydroxypropyl methylcellulose, USP 6
Silicon dioxide, colloidal, NF 30
Pregelatinized starch, NF 50
Magnesium stearate, USP 4
Total= 96 mg
For treatment of benign prostatic hypertrophy. Take one tablet per day.
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Other compounds having a structure according to Formula I are used with
substantially similar results.
Example O
Oral Tablet Composition
Ingredient Amount per caplet ma)
Subject Compound 2 6
Hydroxypropyl methylcellulose, USP 6
Magnesium stearate, USP 2
Povidone K-30, USP 10
Talc, USP 12
Microcrystalline cellulose, NF 44
Total= 80 mg
For the use in the treatment of alcoholism or opiate addiction. Adults 12 and
over take two caplets every twelve hours.
Other compounds having a structure according to Formula I are used with
substantially similar results.
Example P
Oral Tablet Composition
Ingredient Amount aer tablet~mq~
Subject Compound 1 6
Hydroxypropyl methylcellulose, USP 12
Magnesium stearate, USP 2
Povidone K-30, USP 10
Talc, USP 12
Microcrystalline cellulose, NF 44
Total= 86 mg
For the treatment of ulcer and hyperacidity. Take two tablets as appropriate.
Other compounds having a structure according to Formula 1 are used with
substantially similar results.
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Example Q
Oral Tablet Composition
Ingredient Amount per tablet (mg,~
Comeonent Amount
Subject Compound 2 10 mg/ml carrier
Carrier:
Sodium citrate buffer with (percent
by weight of carrier):
Lecithin 0.48%
Carboxymethylcellulose 0.53
Povidone 0.50
Methyl paraben 0.11
Propyl paraben 0.011
For the reduction of cardiac reperfusion
injury.
Other compounds having a structure
according to Formula I are used
with
substantiaNy similar results.
Example R
Oral Liquid Comp osition
Ingredient Amount/fl oz Dose !m~)
Acetaminophen, USP 1000
Doxylamine succinate, USP 12.5
Dextromethorphan hydrobromide, USP 30
Subject Compound 2 6
Dow XYS-40010.00 resin 3
High fructose corn syrup 16000
Polyethylene glycol, NF 3000
Propylene glycol, USP 3000
Alcohol, USP 2500
Sodium citrate dihydrate, USP 150
Citric acid, anhydrous, USP 50
Saccharin sodium, USP 20
Flavor 3.5
Purified water, USP 3500
Total= 29275 mg/fl oz
For the relief of minor aches, pains,
headache, muscular aches, sore
throat
pain, and fever associated with Relieves nasal congestion,
a cold or flu. cough
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due to minor throat and bronchial irritations, runny nose, and sneezing
associated with the common cold. Adults 12 and over take one fluid ounce
every six hours.
Other compounds having a structure
according to Formula I are used
with
substantially similar results.
Example S
Oral Liquid Comp osition
Ingredient Amount/fl oz Dose (mg)
Naproxen sodium anhydrous, USP 220
Doxylamine succinate, USP 12.5
Dextromethorphan hydrobromide, 30
USP
Subject Compound 1 6
Dow XYS-40010.00 resin 3
High fructose corn syrup 16000
Polyethylene glycol, NF 3000
Propylene glycol, USP 3000
Alcohol, USP 2500
Sodium citrate dehydrate, USP 150
Citric acid, anhydrous, USP 50
Saccharin sodium, USP 20
Flavor 3.5
Purified water, USP 3800
Total= 28795 mg/fl oz
For the relief of minor aches, che, muscular aches, sore
pains, heada throat
pain, and fever associated with Relieves nasal congestion,
a cold or flu. cough
due to minor throat and bronchial
irritations, runny nose, and sneezing
associated with the common cold.
Adults 12 and over take one fluid
ounce
every six hours.
Other compounds having a structure according to Formula I are used with
substantially similar results.
COMPOSITION EXAMPLE T
A composition for parenteral administration, according to this invention, is
made comprising:
Component Amount
Subject Compound I 10 mg/ml carrier
Carrier:
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Sodium citrate buffer with (percent
by weight of carrier):
Lecithin 0.48%
Carboxymethylcellulose 0.53
Povidone 0.50
Methyl paraben 0.11
Propyl paraben 0.011
The above ingredients are mixed, forming a solution. Approximately
2.0 ml of the solution is administered, intravenously, to a human subject
suffering from septic or cardiogenic shock. The symptoms subside.
Other compounds having a structure according to Formula I are used with
substantially similar results.
Example U
Oral Tablet Composition
IncLredient Amount per tablet (mg)
Subject Compound 3 10
Hydroxypropyl methylceliulose, USP 12
Magnesium stearate, USP 2
Povidone K-30, USP 10
Talc, USP 12
Microcrystalline cellulose, NF 44
Total= 90 mg
For the treatment of cardiac arrhythmia. Take as prescribed.
Other compounds having a structure according to Formula ! are used with
substantially similar results.
Example V
Oral Tablet Composition
Inqredient Amount per tablet (mg,~
Subject Compound 1 4
Microcrystalline cellulose, NF 130
Starch 1500, NF 100
Magnesium stearate, USP 2
Total = 236 mg
For the treatment of congestive heart failure. Take as prescribed.
Other compounds having a structure according to Formula I are used with
substantially similar results.
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Modification of the preceding embodiments is within the scope of the
skilled artisan in formulation, given the guidance of the specification in
light of
the state of the art.
Other examples of combination actives are contemplated. Examples of
medicaments which can be combined with the primary active are included in
U.S. Patent No. 4,552,899 to Sunshine, et al., hereby incorporated by
reference.
All other references referred to throughout this specification are hereby
incorporated by reference.
While particular embodiments of this invention have been described, it will
be obvious to those skilled in the art that various changes and modifications
of
this invention can be made without departing from the spirit and scope of the
invention. It is intended to cover, in the appended claims, all such
modifications
that are within the scope of this invention.
