U.S. patent application number 15/492398 was filed with the patent office on 2017-11-09 for thyroid hormone receptor agonist and use thereof.
The applicant listed for this patent is Metabasis Therapeutics, Inc.. Invention is credited to Serge Henri Boyer, Mark Erion, Hongjian Jiang.
Application Number | 20170319604 15/492398 |
Document ID | / |
Family ID | 60116377 |
Filed Date | 2017-11-09 |
United States Patent
Application |
20170319604 |
Kind Code |
A1 |
Erion; Mark ; et
al. |
November 9, 2017 |
THYROID HORMONE RECEPTOR AGONIST AND USE THEREOF
Abstract
A thyroid hormone receptor agonist and its use in the treatment
of a disease associated thyroid hormone receptor beta are
described. The compound can be effective in lowering cholesterol
with minimum or no adverse effects on the heart or thyroid hormone
axis.
Inventors: |
Erion; Mark; (Mountainside,
NJ) ; Jiang; Hongjian; (Shanghai, CN) ; Boyer;
Serge Henri; (San Diego, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Metabasis Therapeutics, Inc. |
San Diego |
CA |
US |
|
|
Family ID: |
60116377 |
Appl. No.: |
15/492398 |
Filed: |
April 20, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
62326392 |
Apr 22, 2016 |
|
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|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/661 20130101;
A61P 5/06 20180101; A61P 9/00 20180101; C07F 9/4006 20130101; A61P
9/12 20180101; A61P 1/16 20180101; A61P 3/06 20180101; A61P 35/00
20180101; A61P 5/14 20180101; C07F 9/09 20130101; A61P 3/10
20180101; C07F 9/092 20130101; A61P 3/00 20180101; A61P 9/10
20180101; A61P 3/04 20180101; C07F 9/40 20130101; A61K 45/06
20130101 |
International
Class: |
A61K 31/661 20060101
A61K031/661; C07F 9/09 20060101 C07F009/09 |
Claims
1. A compound having a structure: ##STR00004## or a
pharmaceutically acceptable salt thereof
2. A pharmaceutical composition comprising the compound of claim 1
and a pharmaceutically acceptable excipient.
3. A method for the treatment of a disease that is associated with
thyroid hormone receptor .beta., comprising administering an
effective amount of the compound of claim 1 to a subject in need
thereof.
4. The method of claim 3, wherein the disease is selected from the
group consisting of obesity, hyperlipidemia, hypercholesterolemia
and diabetes, non-alcoholic fatty liver disease, NASH (nonalcoholic
steatohepatitis), atherosclerosis, cardiovascular diseases,
hypothyroidism, and thyroid cancer.
5. A method of agonizing thyroid hormone receptor .beta.,
comprising contacting the thyroid hormone receptor .beta. with an
effective amount of the compound of claim 1 to a subject in need
thereof.
6. A method for lowering cholesterol levels comprising
administering an effective amount of the compound of claim 1 to a
subject in need thereof.
7. A method for lowering triglyceride levels comprising
administering an effective amount of the compound of claim 1 to a
subject in need thereof.
8. A method of preventing or treating a metabolic disease
comprising administering to a subject in need thereof a
pharmaceutically effective amount of the compound of claim 1.
9. The method of claim 8, wherein the metabolic disease is selected
from the group consisting of obesity, hypercholesterolemia,
hyperlipidemia, atherosclerosis, coronary heart disease, and
hypertension.
10. The method of claim 3, further comprising administering an
additional therapeutic agent.
11. The method of claim 3, wherein the compound has a plasma
half-life of less than 6 hours.
12. The method of claim 3, wherein the LDL level of the subject is
reduced by at least 10% post administration compared to
pre-administration level.
13. The method of claim 3, wherein the LDL level of the subject is
reduced by at least 20% post administration compared to
pre-administration level.
14. The method of claim 3, wherein the triglyceride level of the
subject is reduced by at least 10% post administration compared to
pre-administration level.
15. The method of claim 3, wherein the triglyceride level of the
subject is reduced by at least 20% post administration compared to
pre-administration level.
16. The method of claim 3, wherein the level of total T4 in the
subject has a change of less than 50% post administration compared
to pre-administration level.
17. The method of claim 3, wherein the level of total T3 in the
subject has a change of less than 50% post administration compared
to pre-administration levels.
18. The method of claim 3, wherein the level of thyroid-stimulating
hormone (THS) in the subject has a change of less than 50% post
administration compared to pre-administration level.
19. The method of claim 3, wherein the compound is administered
parenterally.
20. The method of claim 3, wherein the compound is administered
orally.
Description
INCORPORATION BY REFERENCE TO ANY PRIORITY APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional
Application No. 62/326,392, entitled Thyroid Hormone Receptor
Agonist and Use Thereof, filed Apr. 22, 2016, the disclosure of
which is incorporated herein by reference in its entirety.
BACKGROUND
Field
[0002] The instant invention relates to a thyroid hormone analog
and its use for treating metabolic diseases such as obesity, NASH,
hypercholesterolemia and hyperlipidemia with low adverse
effects.
Description of the Related Art
[0003] The thyroid hormones (THs) play a critical role in growth,
development, metabolism, and homeostasis. They are produced by the
thyroid gland as thyroxine (T4) and 3,5,3'-triiodo-L-thyronine
(T3). T4 is the major secreted form in humans and is enzymatically
deiodinated by deiodinases to the more active form, T3, in
peripheral tissues. THs exert their action by interacting with
thyroid hormone receptors (TRs), which belong to the nuclear
hormone receptor superfamily, and regulate the transcription of
target genes.
[0004] TRs are expressed in most tissues and exist as two isoforms
(TR.alpha. and TR.beta.). Tissue distribution studies, mouse
knockout studies, and evaluation of patients with resistance to
thyroid hormone (RTH) syndrome have established that TR.alpha. is
the predominant isoform in the heart and regulates most cardiac
functions, while the TR.beta. isoform predominates in the liver and
the pituitary and regulates cholesterol metabolism and thyroid
stimulating hormone (TSH) production, respectively. In recognition
of the potential benefits associated with modulation of TRs,
numerous approaches have been pursued to identify a suitable TR
agonist to lower plasma cholesterol levels. However, these benefits
were offset by deleterious cardiovascular side effects
(tachycardia, arrhythmia) as well as effects on the thyroid hormone
axis, muscle metabolism and bone loss.
SUMMARY
[0005] Some embodiments provide a compound having a structure:
##STR00001##
[0006] or a pharmaceutically acceptable salt thereof
[0007] Other embodiments provide a method for the treatment of a
disease that is associated with thyroid hormone receptor .beta.,
comprising administering an effective amount of the compound to a
subject in need thereof.
[0008] Still other embodiments provide a method of agonizing
thyroid hormone receptor .beta., comprising contacting the thyroid
hormone receptor .beta. with an effective amount of the compound to
a subject in need thereof.
BRIEF DESCRIPTION OF THE DRAWINGS
[0009] FIG. 1 shows the total plasma cholesterol levels
(mean.+-.SEM) in male, cholesterol-fed Sprague Dawley rats
(n=6/group) at baseline and at 24 hours after administration of
vehicle or Compound I.
[0010] FIG. 2 shows the percentage change in in total plasma
cholesterol (TPC) levels from baseline values at 24 hours after
administration of Compound I to male, cholesterol-fed Sprague
Dawley rats (n=6/group).
[0011] FIG. 3 shows the ED.sub.50 value, defined as the dose that
elicits a half-maximal reduction in total plasma cholesterol (TPC)
levels from baseline, of Compound I.
[0012] FIG. 4 shows the effect of once-daily oral administration of
Compound I on total plasma cholesterol (TPC) levels in beagle dogs
expressed as change in levels, mg/dL, from baseline.
[0013] FIG. 5 shows the effect of once-daily oral administration of
Compound I on total plasma cholesterol (TPC) levels in beagle dogs
(n=4/group) expressed as % change from baseline.
[0014] FIG. 6 shows the tT4 levels in serum after once-daily oral
administration of Compound I to beagle dogs for 14 days.
[0015] FIG. 7 shows the fT4 levels in serum after once-daily oral
administration of Compound I to beagle dogs for 14 days.
[0016] FIG. 8 shows the tT3 levels in serum after once-daily oral
administration of Compound I to beagle dogs for 14 days.
[0017] FIG. 9 shows the fT3 levels in serum after once-daily oral
administration of Compound I to beagle dogs for 14 days.
[0018] FIG. 10 shows the TSH serum levels after once-daily oral
administration of Compound I to beagle dogs for 14 days.
[0019] FIGS. 11a and 11b show the effects of Compound I on fT3 and
fT4 levels in human serum.
[0020] FIGS. 12a and 12b show the effects of Compound I on fT3 and
fT4 levels in monkey serum.
[0021] FIGS. 13a and 13b show the effects of Compound I on fT3 and
fT4 levels in dog serum.
[0022] FIGS. 14a and 14b show the effects of Compound I on fT3 and
fT4 levels in rat serum.
[0023] FIG. 15 shows the oral efficacy of Compound I or Compound
MB07811 in a comparative study.
[0024] FIGS. 16a and 16b shows the average tT4 levels in the animal
serum when treated with compound I or compound MB07811 at various
doses.
[0025] FIGS. 17a and 17b shows the serum Thyroid stimulating
hormone (TSH) levels when treated with compound I or compound
MB07811 at various doses.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
[0026] Some embodiments relate to compound 1 or a pharmaceutically
acceptable salt thereof.
##STR00002##
[0027] Compound I may exist in one or more crystalline or amorphous
forms. Unless otherwise indicated, all such forms are included in
the scope of Compound I, including any polymorphic forms. In
addition, Compound I may form solvates with water (i.e., hydrates)
or common organic solvents. Unless otherwise indicated, such
solvates are included in the scope of Compound I.
[0028] Isotopes may be present in Compound I. Each chemical element
as represented in a compound structure may include any isotope of
said element. For example, in a compound structure a hydrogen atom
may be explicitly disclosed or understood to be present in the
compound. At any position of the compound that a hydrogen atom may
be present, the hydrogen atom can be any isotope of hydrogen,
including but not limited to hydrogen-1 (protium) and hydrogen-2
(deuterium). Thus, reference herein to a compound encompasses all
potential isotopic forms unless the context clearly dictates
otherwise.
[0029] Some embodiments relate to a method of treating metabolic
diseases such as obesity, NASH, hypercholesterolemia and
hyperlipidemia with low adverse effects, comprising administering
an effective amount of Compound I or a pharmaceutically acceptable
salt thereof to a subject in need thereof
[0030] Many previously studied thyroid hormone receptor agonists
have been reported to show deleterious cardiovascular side effects
(tachycardia, arrhythmia) as well as effects on the thyroid hormone
axis. Erion, M. D., Proc Natl Acad Sci, (2007) vol 104 (39) p.
15490-15495. One leading thyroid hormone receptor agonist,
(2R,4S)-4-(3-chlorophenyl)-2-[(3,5-dimethyl-4-(4'-hydroxy-3'-isopropylben-
zyl)phenoxy)methyl]-2-oxido-[1,3,2]-dioxaphosphonane (MB07811), has
been reported to be effective in reducing the cholesterol level and
also show reduced effects on the cardiac function. Erion, M. D.,
Proc Natl Acad Sci, (2007) vol 104 (39) p. 15490-15495. However,
MB07811 still shows significant effects on the thyroid hormone
axis.
[0031] It has been discovered that Compound I described herein not
only is effective in lowering the cholesterol, triglyceride, and
lipid levels in a subject but also has minimum or no adverse
cardiovascular effects (tachycardia, arrhythmia) and adverse
effects on the thyroid hormone axis. Compound I also has a short
active plasma half-life and rapid clearance. In addition, Compound
I has shown selective activation of TRI3 and minimum or no effects
on T3, T4, and thyroid-stimulating hormone (TSH). Therefore,
Compound I has an increased therapeutic index (TI) and surprisingly
better safety profile than MB07811.
Definitions
[0032] The term "agent" includes any substance, molecule, element,
compound, entity, or a combination thereof. It includes, but is not
limited to, e.g., protein, polypeptide, peptide or mimetic, small
organic molecule, polysaccharide, polynucleotide, and the like. It
can be a natural product, a synthetic compound, or a chemical
compound, or a combination of two or more substances.
[0033] The term "mammal" is used in its usual biological sense.
Thus, it specifically includes humans, cattle, horses, dogs, cats,
rats and mice but also includes many other species.
[0034] The term "pharmaceutically acceptable carrier" or
"pharmaceutically acceptable excipient" includes any and all
solvents, dispersion media, coatings, antibacterial and antifungal
agents, isotonic and absorption delaying agents and the like. The
use of such media and agents for pharmaceutically active substances
is well known in the art. Except insofar as any conventional media
or agent is incompatible with the active ingredient, its use in the
therapeutic compositions is contemplated. Supplementary active
ingredients can also be incorporated into the compositions. In
addition, various adjuvants such as are commonly used in the art
may be included. These and other such compounds are described in
the literature, e.g., in the Merck Index, Merck & Company,
Rahway, N.J. Considerations for the inclusion of various components
in pharmaceutical compositions are described, e.g., in Gilman et
al. (Eds.) (1990); Goodman and Gilman's: The Pharmacological Basis
of Therapeutics, 8th Ed., Pergamon Press.
[0035] The term "pharmaceutically acceptable salt" refers to salts
that retain the biological effectiveness and properties of the
compounds with which they are associated and, which are not
biologically or otherwise undesirable. In many cases, the compounds
herein are capable of forming acid and/or base salts by virtue of
the presence of amino and/or carboxyl groups or groups similar
thereto. Pharmaceutically acceptable acid addition salts can be
formed with inorganic acids and organic acids. Inorganic acids from
which salts can be derived include, for example, hydrochloric acid,
hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and
the like. Organic acids from which salts can be derived include,
for example, acetic acid, propionic acid, glycolic acid, pyruvic
acid, oxalic acid, maleic acid, malonic acid, succinic acid,
fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic
acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,
p-toluenesulfonic acid, salicylic acid, and the like.
Pharmaceutically acceptable base addition salts can be formed with
inorganic and organic bases. Inorganic bases from which salts can
be derived include, for example, sodium, potassium, lithium,
ammonium, calcium, magnesium, iron, zinc, copper, manganese,
aluminum, and the like; particularly preferred are the ammonium,
potassium, sodium, calcium and magnesium salts. Organic bases from
which salts can be derived include, for example, primary,
secondary, and tertiary amines, substituted amines including
naturally occurring substituted amines, cyclic amines, basic ion
exchange resins, and the like, specifically such as isopropylamine,
trimethylamine, diethylamine, triethylamine, tripropylamine, and
ethanolamine. Many such salts are known in the art, as described in
WO 87/05297, Johnston et al., published Sep. 11, 1987 (incorporated
by reference herein in its entirety).
[0036] "Solvate" refers to the compound formed by the interaction
of a solvent and a compound described herein, or salt thereof.
Suitable solvates are pharmaceutically acceptable solvates
including hydrates.
[0037] "Subject" as used herein, means a human or a non-human
mammal, e.g., a dog, a cat, a mouse, a rat, a cow, a sheep, a pig,
a goat, a non-human primate or a bird, e.g., a chicken, as well as
any other vertebrate or invertebrate.
[0038] A therapeutic effect relieves, to some extent, one or more
of the symptoms of a disease or disorder, and includes curing the
disease or disorder. "Curing" means that the symptoms of active
disease are eliminated. However, certain long-term or permanent
effects of the disease may exist even after a cure is obtained
(such as extensive tissue damage).
[0039] "Treat," "treatment," or "treating," as used herein refers
to administering a pharmaceutical composition for prophylactic
and/or therapeutic purposes. The term "prophylactic treatment"
refers to treating a patient who does not yet have the relevant
disease or disorder, but who is susceptible to, or otherwise at
risk of, a particular disease or disorder, whereby the treatment
reduces the likelihood that the patient will develop the disease or
disorder. The term "therapeutic treatment" refers to administering
treatment to a patient already having a disease or disorder.
Administration and Pharmaceutical Compositions
[0040] Administration of the compounds disclosed herein or the
pharmaceutically acceptable salts thereof can be via any of the
accepted modes of administration for agents that serve similar
utilities including, but not limited to, orally, subcutaneously,
intravenously, intranasally, topically, transdermally,
intraperitoneally, intramuscularly, intrapulmonarilly, vaginally,
rectally, or intraocularly. Oral and parenteral administrations are
customary in treating the indications that are the subject of the
preferred embodiments.
[0041] The compounds useful as described above can be formulated
into pharmaceutical compositions for use in treatment of these
conditions. Standard pharmaceutical formulation techniques are
used, such as those disclosed in Remington's The Science and
Practice of Pharmacy, 21st Ed., Lippincott Williams & Wilkins
(2005), incorporated herein by reference in its entirety.
Accordingly, some embodiments include pharmaceutical compositions
comprising: (a) a safe and therapeutically effective amount of a
compound described herein, or pharmaceutically acceptable salts
thereof; and (b) a pharmaceutically acceptable carrier, diluent,
excipient or combination thereof
[0042] The term "pharmaceutically acceptable carrier" or
"pharmaceutically acceptable excipient" includes any and all
solvents, dispersion media, coatings, antibacterial and antifungal
agents, isotonic and absorption delaying agents and the like. The
use of such media and agents for pharmaceutically active substances
is well known in the art. Except insofar as any conventional media
or agent is incompatible with the active ingredient, its use in the
therapeutic compositions is contemplated. In addition, various
adjuvants such as are commonly used in the art may be included.
Considerations for the inclusion of various components in
pharmaceutical compositions are described, e.g., in Gilman et al.
(Eds.) (1990); Goodman and Gilman's: The Pharmacological Basis of
Therapeutics, 8th Ed., Pergamon Press, which is incorporated herein
by reference in its entirety.
[0043] 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; polyols such as
propylene glycol, glycerine, sorbitol, mannitol, and polyethylene
glycol; alginic acid; emulsifiers, such as the TWEENS; wetting
agents, such as sodium lauryl sulfate; coloring agents; flavoring
agents; tableting agents, stabilizers; antioxidants; preservatives;
pyrogen-free water; isotonic saline; and phosphate buffer
solutions.
[0044] 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.
[0045] The compositions described herein are preferably provided in
unit dosage form. As used herein, a "unit dosage form" is a
composition containing an amount of a compound that is suitable for
administration to an animal, preferably mammal subject, in a single
dose, according to good medical practice. The preparation of a
single or unit dosage form however, does not imply that the dosage
form is administered once per day or once per course of therapy.
Such dosage forms are contemplated to be administered once, twice,
thrice or more per day and may be administered as infusion over a
period of time (e.g., from about 30 minutes to about 2-6 hours), or
administered as a continuous infusion, and may be given more than
once during a course of therapy, though a single administration is
not specifically excluded. The skilled artisan will recognize that
the formulation does not specifically contemplate the entire course
of therapy and such decisions are left for those skilled in the art
of treatment rather than formulation.
[0046] The compositions useful as described above may be in any of
a variety of suitable forms for a variety of routes for
administration, for example, for oral, nasal, rectal, topical
(including transdermal), ocular, intracerebral, intracranial,
intrathecal, intra-arterial, intravenous, intramuscular, or other
parental routes of administration. The skilled artisan will
appreciate that oral and nasal compositions include compositions
that are administered by inhalation, and made using available
methodologies. Depending upon the particular route of
administration desired, a variety of pharmaceutically-acceptable
carriers well-known in the art may be used.
Pharmaceutically-acceptable carriers include, for example, solid or
liquid fillers, diluents, hydrotropies, surface-active agents, and
encapsulating substances. Optional pharmaceutically-active
materials may be included, which do not substantially interfere
with the activity of the compound. The amount of carrier employed
in conjunction with the compound is sufficient to provide a
practical quantity of material for administration per unit dose of
the compound. Techniques and compositions for making dosage forms
useful in the methods described herein are described in the
following references, all incorporated by reference herein: Modern
Pharmaceutics, 4th Ed., Chapters 9 and 10 (Banker & Rhodes,
editors, 2002); Lieberman et al., Pharmaceutical Dosage Forms:
Tablets (1989); and Ansel, Introduction to Pharmaceutical Dosage
Forms 8th Edition (2004).
[0047] Various oral dosage forms can be used, including such solid
forms as tablets, capsules, granules and bulk powders. Tablets can
be compressed, tablet triturates, enteric-coated, sugar-coated,
film-coated, or multiple-compressed, containing suitable binders,
lubricants, diluents, disintegrating agents, coloring agents,
flavoring agents, flow-inducing agents, and melting agents. Liquid
oral dosage forms include aqueous solutions, emulsions,
suspensions, solutions and/or suspensions reconstituted from
non-effervescent granules, and effervescent preparations
reconstituted from effervescent granules, containing suitable
solvents, preservatives, emulsifying agents, suspending agents,
diluents, sweeteners, melting agents, coloring agents and flavoring
agents.
[0048] The pharmaceutically-acceptable carriers suitable for the
preparation of unit dosage forms for peroral administration is
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, and can be readily made by a person skilled
in the art.
[0049] 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. Typical components of
carriers for syrups, elixirs, emulsions and suspensions include
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.
[0050] Such compositions may also be coated by conventional
methods, typically with pH or time-dependent coatings, such that
the subject compound is released in the gastrointestinal tract in
the vicinity of the desired topical application, or 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.
[0051] Compositions described herein may optionally include other
drug actives.
[0052] Other compositions useful for attaining systemic delivery of
the subject compounds include sublingual, buccal and nasal 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.
[0053] A liquid composition, which is formulated for topical
ophthalmic use, is formulated such that it can be administered
topically to the eye. The comfort may be maximized as much as
possible, although sometimes formulation considerations (e.g. drug
stability) may necessitate less than optimal comfort. In the case
that comfort cannot be maximized, the liquid may be formulated such
that the liquid is tolerable to the patient for topical ophthalmic
use. Additionally, an ophthalmically acceptable liquid may either
be packaged for single use, or contain a preservative to prevent
contamination over multiple uses.
[0054] For ophthalmic application, solutions or medicaments are
often prepared using a physiological saline solution as a major
vehicle. Ophthalmic solutions may preferably be maintained at a
comfortable pH with an appropriate buffer system. The formulations
may also contain conventional, pharmaceutically acceptable
preservatives, stabilizers and surfactants.
[0055] Preservatives that may be used in the pharmaceutical
compositions disclosed herein include, but are not limited to,
benzalkonium chloride, PHMB, chlorobutanol, thimerosal,
phenylmercuric, acetate and phenylmercuric nitrate. A useful
surfactant is, for example, Tween 80. Likewise, various useful
vehicles may be used in the ophthalmic preparations disclosed
herein. These vehicles include, but are not limited to, polyvinyl
alcohol, povidone, hydroxypropyl methyl cellulose, poloxamers,
carboxymethyl cellulose, hydroxyethyl cellulose and purified
water.
[0056] Tonicity adjustors may be added as needed or convenient.
They include, but are not limited to, salts, particularly sodium
chloride, potassium chloride, mannitol and glycerin, or any other
suitable ophthalmically acceptable tonicity adjustor.
[0057] Various buffers and means for adjusting pH may be used so
long as the resulting preparation is ophthalmically acceptable. For
many compositions, the pH will be between 4 and 9. Accordingly,
buffers include acetate buffers, citrate buffers, phosphate buffers
and borate buffers. Acids or bases may be used to adjust the pH of
these formulations as needed.
[0058] Ophthalmically acceptable antioxidants include, but are not
limited to, sodium metabisulfite, sodium thiosulfate,
acetylcysteine, butylated hydroxyanisole and butylated
hydroxytoluene.
[0059] Other excipient components, which may be included in the
ophthalmic preparations, are chelating agents. A useful chelating
agent is edetate disodium, although other chelating agents may also
be used in place or in conjunction with it.
[0060] For topical use, creams, ointments, gels, solutions or
suspensions, etc., containing the compound disclosed herein are
employed. Topical formulations may generally be comprised of a
pharmaceutical carrier, co-solvent, emulsifier, penetration
enhancer, preservative system, and emollient.
[0061] For intravenous administration, the compounds and
compositions described herein may be dissolved or dispersed in a
pharmaceutically acceptable diluent, such as a saline or dextrose
solution. Suitable excipients may be included to achieve the
desired pH, including but not limited to NaOH, sodium carbonate,
sodium acetate, HCl, and citric acid. In various embodiments, the
pH of the final composition ranges from 2 to 8, or preferably from
4 to 7. Antioxidant excipients may include sodium bisulfite,
acetone sodium bisulfite, sodium formaldehyde, sulfoxylate,
thiourea, and EDTA. Other non-limiting examples of suitable
excipients found in the final intravenous composition may include
sodium or potassium phosphates, citric acid, tartaric acid,
gelatin, and carbohydrates such as dextrose, mannitol, and dextran.
Further acceptable excipients are described in Powell, et al.,
Compendium of Excipients for Parenteral Formulations, PDA J Pharm
Sci and Tech 1998, 52 238-311 and Nema et al., Excipients and Their
Role in Approved Injectable Products: Current Usage and Future
Directions, PDA J Pharm Sci and Tech 2011, 65 287-332, both of
which are incorporated herein by reference in their entirety.
Antimicrobial agents may also be included to achieve a
bacteriostatic or fungistatic solution, including but not limited
to phenylmercuric nitrate, thimerosal, benzethonium chloride,
benzalkonium chloride, phenol, cresol, and chlorobutanol.
[0062] The compositions for intravenous administration may be
provided to caregivers in the form of one more solids that are
reconstituted with a suitable diluent such as sterile water, saline
or dextrose in water shortly prior to administration. In other
embodiments, the compositions are provided in solution ready to
administer parenterally. In still other embodiments, the
compositions are provided in a solution that is further diluted
prior to administration. In embodiments that include administering
a combination of a compound described herein and another agent, the
combination may be provided to caregivers as a mixture, or the
caregivers may mix the two agents prior to administration, or the
two agents may be administered separately.
[0063] The actual unit dose of the active compounds described
herein depends on the specific compound, and on the condition to be
treated; the selection of the appropriate dose is well within the
knowledge of the skilled artisan. In some embodiments, the dose may
be from about 0.25 mg/kg to about 120 mg/kg or more of body weight,
from about 0.5 mg/kg or less to about 70 mg/kg, from about 1.0
mg/kg to about 50 mg/kg of body weight, or from about 1.5 mg/kg to
about 10 mg/kg of body weight. In some embodiments, the dose may be
less than 100 mg/kg, 90 mg/kg, 80 mg/kg, 70 mg/kg, 60 mg/kg, 50
mg/kg, 40 mg/kg, 30 mg/kg, 25 mg/kg, 20 mg/kg, 10 mg/kg, 7.5 mg/kg,
5 mg/kg, 4 mg/kg, 2.5 mg/kg, or 1 mg/kg of body weight. Thus, for
administration to a 70 kg person, the dosage range would be from
about 17 mg to about 8000 mg, from about 35 mg or less to about
7000 mg or more, from about 70 mg to about 6000 mg, from about 100
mg to about 5000 mg, or from about 200 mg to about 3000 mg.
Method of Treatment
[0064] Some embodiments relate to a method for the treatment of a
disease associated with thyroid hormone receptor .beta., comprising
administering an effective amount of the compound described herein
to a subject in need thereof
[0065] In some embodiments, the disease is selected from the group
consisting of obesity, hyperlipidemia, hypercholesterolemia and
diabetes, and NASH (nonalcoholic steatohepatitis), atherosclerosis,
cardiovascular diseases, hypothyroidism, and thyroid cancer.
[0066] Some embodiments relate to a method of agonizing thyroid
hormone receptor .beta., comprising contacting the thyroid hormone
receptor .beta. with an effective amount of the compound described
herein.
[0067] Some embodiments relate to a method for lowering cholesterol
levels comprising administering an effective amount of the compound
described herein to a subject in need thereof
[0068] Some embodiments relate to a method for lowering
triglyceride levels comprising administering an effective amount of
the compound described herein to a subject in need thereof.
[0069] In some embodiments, the method described herein can include
an additional therapeutic agent.
[0070] In some embodiments, the level of total T4 in the subject
has a change of less than 50%, 20%, 10%, 5%, 1%, or 0.5% post
administration compared to pre-administration levels. In some
embodiments, the level of free T4 in the subject has a change of
less than 50%, 20%, 10%, 5%, 1%, or 0.5% post administration
compared to pre-administration levels. In some embodiments, the
level of free T4 in the subject has a change in the range of about
0.5%-5%, 0.5%-10%, 0.5%-20%, 0.5%-30%, 0.5%-40%, 0.5%-50%,
0.5%-60%, 0.5%-70%, 0.5%-80%, 1%-5%, 1%-8%, 1%-10%, 1%-15%, 1%-20%,
1%-30%,1%-40%, 1%-50%, 1%-60%, 2%-4%, 2%-5%, 2%-8%, 2%-10%, 2%-15%,
2%-20%, 2%-30%,2%-40%, 2%-50%, 2%-60%, 3%-4%, 3%-5%, 3%-8%, 3%-10%,
3%-15%, 3%-20%, 3%-30%, 3%-40%, 3%-50%, 4%-5%, 4%-8%, 4%-10%,
4%-15%, 4%-20%, 4%-30%, 4%-40%, 4%-50%, 5%-8%, 5%-10%, 5%-15%,
5%-20%, 5%-30%, 5%-40%, 5%-50%, 5%-60%, 4%-8%, 10%-15%, 10%-20%,
10%-30%, 10%-40%, 10%-50%, 10%-60%, 15%-20%, 15%-30%, 15%-40%,
15%-50%, 15%-60%, 20%-30%, 20%-40%, 20%-50%, or 20%-60% post
administration compared to pre-administration level.
[0071] In some embodiments, the level of total T3 in the subject
has a change of less than 50%, 20%, 10%, 5%, 1%, or 0.5% post
administration compared to pre-administration levels. In some
embodiments, the level of free T3 in the subject has a change of
less than 50%, 20%, 10%, 5%, 1%, or 0.5% post administration
compared to pre-administration levels. In some embodiments, the
level of free T3 in the subject has a change in the range of about
0.5%-5%, 0.5%-10%, 0.5%-20%, 0.5%-30%, 0.5%-40%, 0.5%-50%,
0.5%-60%, 0.5%-70%, 0.5%-80%, 1%-5%, 1%-8%, 1%-10%, 1%-15%, 1%-20%,
1%-30%,1%-40%, 1%-50%, 1%-60%, 2%-4%, 2%-5%, 2%-8%, 2%-10%, 2%-15%,
2%-20%, 2%-30%,2%-40%, 2%-50%, 2%-60%, 3%-4%, 3%-5%, 3%-8%, 3%-10%,
3%-15%, 3%-20%, 3%-30%, 3%-40%, 3%-50%, 4%-5%, 4%-8%, 4%-10%,
4%-15%, 4%-20%, 4%-30%, 4%-40%, 4%-50%, 5%-8%, 5%-10%, 5%-15%,
5%-20%, 5%-30%, 5%-40%, 5%-50%, 5%-60%, 4%-8%, 10%-15%, 10%-20%,
10%-30%, 10%-40%, 10%-50%, 10%-60%, 15%-20%, 15%-30%, 15%-40%,
15%-50%, 15%-60%, 20%-30%, 20%-40%, 20%-50%, or 20%-60% post
administration compared to pre-administration level.
[0072] In some embodiments, the level of thyroid-stimulating
hormone (THS) in the subject has a change of less than 50%, 20%,
10%, 5%, 1%, or 0.5% post administration compared to
pre-administration levels. In some embodiments, the level of THS in
the subject has a change in the range of about 0.5%-5%, 0.5%-10%,
0.5%-20%, 0.5%-30%, 0.5%-40%, 0.5%-50%, 0.5%-60%, 0.5%-70%,
0.5%-80%, 1%-5%, 1%-8%, 1%-10%, 1%-15%, 1%-20%, 1%-30%,1%-40%,
1%-50%, 1%-60%, 2%-4%, 2%-5%, 2%-8%, 2%-10%, 2%-15%, 2%-20%,
2%-30%,2%-40%, 2%-50%, 2%-60%, 3%-4%, 3%-5%, 3%-8%, 3%-10%, 3%-15%,
3%-20%, 3%-30%, 3%-40%, 3%-50%, 4%-5%, 4%-8%, 4%-10%, 4%-15%,
4%-20%, 4%-30%, 4%-40%, 4%-50%, 5%-8%, 5%-10%, 5%-15%, 5%-20%,
5%-30%, 5%-40%, 5%-50%, 5%-60%, 4%-8%, 10%-15%, 10%-20%, 10%-30%,
10%-40%, 10%-50%, 10%-60%, 15%-20%, 15%-30%, 15%-40%, 15%-50%,
15%-60%, 20%-30%, 20%-40%, 20%-50%, or 20%-60% post administration
compared to pre-administration level.
[0073] Also provided are methods of reducing fat content in the
liver or of preventing or treating steatosis, NA.SH or NAFLD in a
subject in need thereof, the method comprising administering to the
subject an effective amount of the compound described herein.
[0074] Some embodiments relate to a method for modulating
cholesterol levels, for treating obesity, hypercholesterolemia,
hyperlipidemia, hypertriglyderidemia, and other metabolic diseases.
In some embodiments, the metabolic disease is obesity, NASH,
hypercholesterolemia, or hyperlipidemia. Some embodiments relate to
a method for treating impaired glucose tolerance, insulin
resistance, arteriosclerosis, atherosclerosis, coronary heart
disease, heart failure, or diabetes. Some embodiments relate to the
liver specific delivery of thyroid receptor ligands and the use of
these compounds for the prevention and treatment of diseases
responsive to modulation of T3-responsive genes in the liver. Some
embodiments relate to treatment of hypothyroidism. The method
described herein for treating the various listed diseases can be
achieved using the compound described herein without affecting
thyroid function, thyroid production of circulating iodinated
thyronines such as T3 and T4, and/or the ratio of T3 to T4.
[0075] In one embodiment, the compound described herein can have a
high therapeutic index for a use disclosed herein. Examples of said
use disclosed herein includes but is not limited to reducing lipid
levels, increasing the ratio of HDL to LDL or apoAI to LDL,
reducing weight or preventing weight gain, maintaining or improving
glycemic control, lowering blood glucose levels, increasing
mitochondrial biogenesis, increasing expression of PGC-1, A
activated protein kinase or nuclear respiratory factor, inhibiting
hepatic gluconeogenesis or for the treatment or prevention of a
disease or disorder selected from the group consisting of
atherosclerosis, hypercholesterolemia, obesity, NASH, NAFLD,
insulin resistance, diabetes, metabolic syndrome X, impaired
glucose tolerance, hyperlipidemia, coronary heart disease, thyroid
disease, thyroid cancer, depression, glaucoma, cardiac arrhythmias,
heart failure, and osteoporosis. Examples wherein the property or
function is a cardiac property/function include but is not limited
to cardiac hypertrophy (heart weight to body weight ratio), heart
rate, and various hemodynamic parameters, including systolic and
diastolic arterial pressure, end systolic left ventricular pressure
and maximal speeds of contraction and relaxation.
[0076] Compound I can have a higher therapeutic index (TI) than the
compound MB07811 when used in the treatment methods described
herein. In some embodiments, compound I can have a TI that is at
least abut 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40 , 50, 60, 70, 80,
90, 100, 150, 200 times greater than compound MB07811. In some
embodiments, compound I can have a TI that is in the range of about
2-200, 2-100, 2-50, 2-25, 2-10, 5-200, 5-100, 5-50, 5-10, 10-200,
10-100, 10-50, 10-25, 20-100, 20-50, or 50-100 times greater than
compound MB07811.
[0077] In some embodiments, the compound described herein has a
plasma half-life of less than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,
12, 14, 16, 18, 20, or 25 hours. In some embodiments, the compound
described herein has a plasma half-life of greater than about 1, 2,
3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, or 25 hours. In some
embodiments, the compound described herein has a plasma half-life
in the range of about 1-25, 1-20, 1-18, 1-15, 1-10, 1-8, 1-6, 1-4,
1-2, 2-20, 2-15, 2-10, 2-8, 2-6, 2-4, 3-20, 3-15, 3-10, 3-9, 3-6,
3-5, 4-20, 4-18, 4-15, 4-10, 4-8, 4-6, 5-20, 5-15, 5-10, 5-8, 5-6,
6-20, 6-15, 6-10, 6-8, 8-20, 8-15, 8-10, 10-20, 10-15, 12-20,
12-15, or 15-20 hours.
[0078] In some embodiments, the LDL level of the subject is reduced
by at least 10% or 20% post administration compared to
pre-administration level. In some embodiments, the LDL level of the
subject is reduced by at least about 2%, 5%, 10%, 15%, 18%, 20%,
25%, 28%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 70%, 80%, 90%, or 95%
post administration compared to pre-administration level. In some
embodiments, the LDL level of the subject is reduced in the range
of about 2%-90%, 5%-10%, 5%-20%, 5%-30%, 5%-40%, 5%-50%, 5%-60%,
5%-70%, 5%-80%, 5%-90%, 10%-20%, 10%-30%,10%-40%, 10%-50%, 10%-60%,
10%-70%, 10%-80%, 10%-90%, 20%-30%,20%-40%, 20%-50%, 20%-60%,
20%-70%, 20%-80%, 20%-90%, 30%-40%, 30%-50%, 30%-60%, 30%-70%,
30%-80%, 30%-90%, 40%-50%, 40%-60%, 40%-70%, 40%-80%, 40%-90%,
50%-60%, 50%-70%, 50%-80%, 50%-90%, 60%-70%, 60%-80%, 60%-90% post
administration compared to pre-administration level.
[0079] In some embodiments, the triglyceride level of the subject
is reduced by at least 10% or 20% post administration compared to
pre-administration level. In some embodiments, the triglyceride
level of the subject is reduced by at least about 2%, 5%, 10%, 15%,
18%, 20%, 25%, 28%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 70%, 80%,
90%, or 95% post administration compared to pre-administration
level. In some embodiments, the triglyceride level of the subject
is reduced in the range of about 2%-90%, 5%-10%, 5%-20%, 5%-30%,
5%-40%, 5%-50%, 5%-60%, 5%-70%, 5%-80%, 5%-90%, 10%-20%,
10%-30%,10%-40%, 10%-50%, 10%-60%, 10%-70%, 10%-80%, 10%-90%,
20%-30%,20%-40%, 20%-50%, 20%-60%, 20%-70%, 20%-80%, 20%-90%,
30%-40%, 30%-50%, 30%-60%, 30%-70%, 30%-80%, 30%-90%, 40%-50%,
40%-60%, 40%-70%, 40%-80%, 40%-90%, 50%-60%, 50%-70%, 50%-80%,
50%-90%, 60%-70%, 60%-80%, 60%-90% post administration compared to
pre-administration level.
[0080] In some embodiments, the ratio of the HDL and LDL can be
increased by at least about at least about 2%, 5%, 10%, 15%, 18%,
20%, 25%, 28%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 70%, 80%, 90%, or
95% post administration compared to pre-administration level. In
some embodiments, the ratio of the HDL and LDL can be increased by
a range of about 2%-90%, 5%-10%, 5%-20%, 5%-30%, 5%-40%, 5%-50%,
5%-60%, 5%-70%, 5%-80%, 5%-90%, 10%-20%, 10%-30%,10%-40%, 10%-50%,
10%-60%, 10%-70%, 10%-80%, 10%-90%, 20%-30%,20%-40%, 20%-50%,
20%-60%, 20%-70%, 20%-80%, 20%-90%, 30%-40%, 30%-50%, 30%-60%,
30%-70%, 30%-80%, 30%-90%, 40%-50%, 40%-60%, 40%-70%, 40%-80%,
40%-90%, 50%-60%, 50%-70%, 50%-80%, 50%-90%, 60%-70%, 60%-80%,
60%-90% post administration compared to pre-administration
level.
[0081] In some embodiments, the compound can be administered
parenterally. In some embodiments, the compound can be administered
orally. In some embodiments, the compound can be administered
intravenously or intramuscularly.
[0082] In some embodiments, the subject is a human. In some
embodiments, the subject is a mammal.
[0083] Further embodiments include administering a combination of
compounds to a subject in need thereof. A combination can include a
compound, composition, pharmaceutical composition described herein
with an additional medicament.
[0084] Some embodiments include co-administering a compound,
composition, and/or pharmaceutical composition described herein,
with an additional medicament. By "co-administration," it is meant
that the two or more agents may be found in the patient's
bloodstream at the same time, regardless of when or how they are
actually administered. In one embodiment, the agents are
administered simultaneously. In one such embodiment, administration
in combination is accomplished by combining the agents in a single
dosage form. In another embodiment, the agents are administered
sequentially. In one embodiment the agents are administered through
the same route, such as orally. In another embodiment, the agents
are administered through different routes, such as one being
administered orally and another being administered i. v.
[0085] Moreover, the compound described herein can be administered
in combination with other pharmaceutical agents that are used to
lower serum cholesterol such as a cholesterol biosynthesis
inhibitor or a cholesterol absorption inhibitor, especially a
HMG-CoA reductase inhibitor, or a HMG-CoA synthase inhibitor, or a
HMG-CoA reductase or synthase gene expression inhibitor, a
cholesteryl ester transfer protein (CETP) inhibitor (e.g.,
torcetrapib), a bile acid sequesterant (e.g., cholestyramine
(Questran.RTM.), colesevelam and colestipol (Colestid.RTM.)), or a
bile acid reabsorption inhibitor (see, for example, U.S. Pat. No.
6,245,744, U.S. Pat. No. 6,221,897, U.S. Pat. No. 6,277,831, EP
0683 773, EP 0683 774, all of which are incorporated herein by
reference), a cholesterol absorption inhibitor as described (e.g.,
ezetimibe, tiqueside, pamaqueside or see, e.g., in WO 0250027,
which is incorporated herein by reference), a PPARalpha agonist, a
mixed PPAR alpha/gamma agonist such as, for example, AZ 242
(Tesaglitazar,
(S)-3-(442-(4-methanesulfony-loxyphenyl)ethoxy]phenyl)-2-ethoxypropionic
acid), BMS 298585
(N-[(4-methoxyphenoxy)carbonyl]-N-[[4-[2-(5-methyl-2-phenyl-4-oxazolyl)et-
hoxy]phenyl]methyl]glycine) or as described in WO 99/62872, WO
99/62871, WO 01/40171, WO 01/40169, W096/38428, WO 01/81327, WO
01/21602, WO 03/020269, WO 00/64888 or WO 00/64876, all of which
are incorporated herein by reference; a MTP inhibitor such as, for
example, implitapide, a fibrate, an ACAT inhibitors (e.g.,
avasimibe), an angiotensin II receptor antagonist, a squalene
synthetase inhibitor, a squalene epoxidase inhibitor, a squalene
cyclase inhibitor, combined squalene epoxidase/squalene cyclase
inhibitor, a lipoprotein lipase inhibitor, an ATP citrate lyase
inhibitor, lipoprotein(a) antagonist, an antioxidant or niacin
(e.g., slow release niacin). The compound described herein may also
be administered in combination with a naturally occurring compound
that act to lower plasma cholesterol levels. Such naturally
occurring compounds are commonly called nutraceuticals and include,
for example, garlic extract and niacin.
[0086] In one aspect, the HMG-CoA reductase inhibitor is from a
class of therapeutics commonly called statins. Examples of HMG-CoA
reductase inhibitors that may be used include but are not limited
to lovastatin (MEVACOR; see U.S. Pat. Nos. 4,231,938; 4,294,926;
4,319,039), simvastatin (ZOCOR; see U.S. Pat. Nos. 4,444,784;
4,450,171, 4,820,850; 4,916,239, all of which are incorporated
herein by reference), pravastatin (PRAVACHOL; see U.S. Pat. Nos.
4,346,227; 4,537,859; 4,410,629; 5,030,447 and 5,180,589, all of
which are incorporated herein by reference), lactones of
pravastatin (see U.S. Pat. No. 4,448,979, which is incorporated
herein by reference), fluvastatin (LESCOL; see U.S. Pat. Nos.
5,354,772; 4,911,165; 4,739,073; 4,929,437; 5,189,164; 5,118,853;
5,290,946; 5,356,896, all of which are incorporated herein by
reference), lactones of fluvastatin, atorvastatin (LIPITOR; see
U.S. Pat. Nos. 5,273,995; 4,681,893; 5,489,691; 5,342,952, all of
which are incorporated herein by reference), lactones of
atorvastatin, cerivastatin (also known as rivastatin and BAYCHOL;
see U.S. Pat. No. 5,177,080, and European Application No.
EP-491226A), lactones of cerivastatin, rosuvastatin (Crestor; see
U.S. Pat. Nos. 5,260,440 and RE37314, and European Patent No.
EP521471, all of which are incorporated herein by reference),
lactones of rosuvastatin, itavastatin, nisvastatin, visastatin,
atavastatin, bervastatin, compactin, dihydrocompactin, dalvastatin,
fluindostatin, pitivastatin, mevastatin (see U.S. Pat. No.
3,983,140, which is incorporated herein by reference), and
velostatin (also referred to as synvinolin). Other examples of
HMG-CoA reductase inhibitors are described in U.S. Pat. Nos.
5,217,992; 5,196,440; 5,189,180; 5,166,364; 5,157,134; 5,110,940;
5,106,992; 5,099,035; 5,081,136; 5,049,696; 5,049,577; 5,025,017;
5,011,947; 5,010,105; 4,970,221; 4,940,800; 4,866,058; 4,686,237;
4,647,576; European Application Nos. 0142146A2 and 0221025A1; and
PCT Application Nos. WO 86/03488 and WO 86/07054, all of which are
incorporated herein by reference. Also included are
pharmaceutically acceptable forms of the above. All of the above
references are incorporated herein by reference.
[0087] Non-limiting examples of suitable bile acid sequestrants
include cholestyramine (a styrene-divinylbenzene copolymer
containing quaternary ammonium cationic groups capable of binding
bile acids, such as QUESTRAN or QUESTRAN LIGHT cholestyramine which
are available from Bristol-Myers Squibb), colestipol (a copolymer
of diethylenetriamine and 1-chloro-2,3-epoxypropane, such as
COLESTID tablets which are available from Pharmacia), colesevelam
hydrochloride (such as WelChol Tablets (poly(allylamine
hydrochloride) cross-linked with epichlorohydrin and alkylated with
1-bromodecane and (6-bromohexyl)-trimethylammonium bromide) which
are available from Sankyo), water soluble derivatives such as
3,3-ioene, N-(cycloalkyl)alkylamines and poliglusam, insoluble
quaternized polystyrenes, saponins and mixtures thereof. Other
useful bile acid sequestrants are disclosed in PCT Patent
Applications Nos. WO 97/11345 and WO 98/57652, and U.S. Pat. Nos.
3,692,895 and 5,703,188 which are incorporated herein by reference.
Suitable inorganic cholesterol sequestrants include bismuth
salicylate plus montmorillonite clay, aluminum hydroxide and
calcium carbonate antacids.
[0088] In the above description, a fibrate base compound is a
medicament for inhibiting synthesis and secretion of triglycerides
in the liver and activating lipoprotein lipase, thereby lowering
the triglyceride level in the blood. Examples include bezafibrate,
beclobrate, binifibrate, ciprofibrate, clinofibrate, clofibrate,
clofibric acid, ethofibrate, fenofibrate, gemfibrozil, nicofibrate,
pirifibrate, ronifibrate, simfibrate and theofibrate. Such an ACAT
inhibitor includes, for example: a compound having the general
formula (I) disclosed in WO 92/09561 [preferably FR-129169, of
which the chemical name is
N-(1,2-diphenylethyl)-2-(2-octyloxyphenyl)acetamide]; a compound
having the general formula (I) including a pharmacologically
acceptable salt/co-crystal, ester or prodrug thereof disclosed in
the Japanese Patent Publication (Kohyo) Hei 8-510256 (WO 94/26702,
U.S. Pat. No. 5,491,172) {preferably CI-1011, of which the chemical
name is
2,6-diisopropylphenyl-N-[(2,4,6-tr-iisopropylphenyl)acetyl]sulfamate,
and CI-1011 described herein including a pharmacologically
acceptable salt/co-crystal, ester or prodrug thereof; a compound
having the general formula (I) including a pharmacologically
acceptable salt/co-crystal, ester or prodrug thereof disclosed in
EP 421-441 (U.S. Pat. No. 5,120,738) {preferably F-1394, of which
the chemical name is (1S,2S)-2-[3-(2,2-dimet-hylpropyl)-3
-nonylureido]cyclohexan-1-yl 3-[(4R)-N-(2,2,5,5-tetramethyl-1,-3
-dioxane-4-carbonyl)amino]propionate, and F-1394 including a
pharmacologically acceptable salt/co-crystal, ester or prodrug
thereof}; a compound including a pharmacologically acceptable
salt/co-crystal, ester or prodrug thereof disclosed in the Japanese
Patent Publication (Kohyo) 2000-500771 (WO 97/19918, U.S. Pat. No.
5,990,173, all of which are incorporated herein by reference)
{preferably F-12511, of which the chemical name is
(S)-2',3',5'-trimethyl-4'-hydroxy-.alpha.-dodecylthio-.alpha.-phenylaceta-
-nilide, and F-12511 including a pharmacologically acceptable
salt/co-crystal, ester or prodrug thereof]; a compound having the
general formula (I) including a pharmacologically acceptable
salt/co-crystal, ester or prodrug thereof disclosed in the Japanese
Patent Publication (Kokai) Hei 10-195037 (EP 790240, U.S. Pat. No.
5,849,732, all of which are incorporated herein by reference)
[preferably T-2591, of which the chemical name is
1-(3-t-butyl-2-hydroxy-5-methoxyphenyl)-3-(2-cyclohexylethyl)-3-(4-diethy-
laminophenyl)urea, and T-2591 including a pharmacologically
acceptable salt/co-crystal, ester or prodrug thereof.]; a compound
having the general formula (I) including a pharmacologically
acceptable salt/co-crystal, ester or prodrug thereof disclosed in
WO 96/26948 [preferably FCE-28654, of which the chemical name is
1-(2,6-diisopropylphenyl)-3-[(4R,5R)-4,5
-di-methyl-2-(4-phosphonophenyl)-1,3-dioxolan-2-ylmethyl]urea,
including a pharmacologically acceptable salt/co-crystal, ester or
prodrug thereof }; a compound having the general formula (I) or a
pharmacologically acceptable salt thereof disclosed in the
specification of WO 98/54153 (EP 987254), which is incorporated
herein by reference {preferably K-10085, of which the chemical name
is
N42,4-bis(methylthio)-6-methyl-3-pyridyl]-2-[4-[2-(oxazolo[4,5-b]pyridine-
-2-ylthio)ethyl]piperazin-1-yl]acetamide, including a
pharmacologically acceptable salt/co-crystal, ester or prodrug
thereof.}; a compound having the general formula (I) disclosed in
WO 92/09572 (EP 559898, U.S. Pat. No. 5,475,130, all of which are
incorporated herein by reference) [preferably HL-004, of which the
chemical name is
N-(2,6-diisopropylphenyl)-2-tetradecylthioacetamide.]; a compound
having the general formula (I) including a pharmacologically
acceptable salt/co-crystal, ester or prodrug thereof disclosed in
the Japanese Patent Publication (Kokai) Hei 7-82232 (EP 718281,
which is incorporated herein by reference) {preferably NTE-122, of
which the chemical name is
trans-1,4-bis[1-cyclohexyl-3-(4-dimethylaminophenyl)urei-domethyl]cyclohe-
xane, and NTE-122 includes pharmacologically acceptable salts of
NTE-122.}; a compound including a pharmacologically acceptable
salt/co-crystal, ester or prodrug thereof disclosed in the Japanese
Patent Publication (Kohyo) Hei 10-510512 (WO 96/10559, which is
incorporated herein by reference) {preferably FR-186054, of which
the chemical name is 1-benzyl-1-[3-(pyrazol-3
-yl)benzyl]-3-[2,4-bis(methylthio)-6-methylpyridi-n-3-yl]urea, and
FR-186054 including a pharmacologically acceptable salt/co-crystal,
ester or prodrug thereof.}; a compound having the general formula
(I) including a pharmacologically acceptable salt/co-crystal, ester
or prodrug thereof disclosed in WO 96/09287 (EP 0782986, U.S. Pat.
No. 5,990,150, all of which are incorporated herein by reference)
[preferably
N-(1-pentyl-4,6-dimethylindolin-7-yl)-2,2-dime-thylpropaneamide,
and including a pharmacologically acceptable salt/co-crystal, ester
or prodrug thereof.]; and a compound having the general formula (I)
including a pharmacologically acceptable salt/co-crystal, ester or
prodrug thereof disclosed in WO 97/12860 EP 0866059, U.S. Pat. No.
6,063,806, all of which are incorporated herein by reference)
[preferably
N-(1-octyl-5-carboxymethyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanea-
mide, including a pharmacologically acceptable salt/co-crystal,
ester or prodrug thereof.]. The ACAT inhibitor preferably is a
compound selected from the group consisting of FR-129169, CI-1011,
F-1394, F-12511, T-2591, FCE-28654, K-10085, HL-004, NTE-122,
FR-186054,
N-(1-octyl-5-carboxymethyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanea-
mide (hereinafter referred as compound A), and
N-(1-pentyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropan-eamide
(hereinafter referred as compound B), including a pharmacologically
acceptable salt/co-crystal, ester or prodrug thereof. The ACAT
inhibitor more preferably is a compound selected from the group
consisting of CI-1011, F-12511,
N-(1-octyl-5-carboxymethyl-4,6-dime-thylindolin-7-yl)-2,2-dimethylpropane-
amide (compound A), and
N-(1-pentyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropaneamide
(compound B), including a pharmacologically acceptable
salt/co-crystal, ester or prodrug thereof; most preferred is
N-(1-octyl-5-carboxymethyl-4,6-dimethylindolin-7-yl)-2,2-ditnethylpropane-
a-mide (compound A).
[0089] An angiotensin II receptor antagonist includes, for example,
a biphenyl tetrazole compound or biphenylcarboxylic acid derivative
such as: a compound having the general formula (I) including a
pharmacologically acceptable salt/co-crystal, ester or prodrug
thereof disclosed in the Japanese Patent Publication (Kokai) Sho
63-23868 (U.S. Pat. No. 5,138,069) {preferably losartan, of which
the chemical name is
2-butyl-4-chloro-1-[2'-(1H-tetrazol-5-yl)biphe-nyl-4-ylmethyl]-1H-imidazo-
l-5-methanol, and losartan including a pharmacologically acceptable
salt/co-crystal, ester or prodrug thereof}; a compound having the
general formula (I) including a pharmacologically acceptable
salt/co-crystal, ester or prodrug thereof disclosed in the Japanese
Patent Publication (Kohyo) Hei 4-506222 (WO 91/14679, which is
incorporated herein by reference) {preferably irbesartan, of which
the chemical name is
2-N-butyl-4-spirocyclopentane-1-[2'-(1H-tetrazol-5-yl)bi-phenyl-4-ylmethy-
l]-2-imidazoline-5-one, and irbesartan including a
pharmacologically acceptable salt/co-crystal, ester or prodrug
thereof.}; a compound having the general formula (I), an ester
thereof, including a pharmacologically acceptable salt/co-crystal,
ester or prodrug thereof disclosed in the Japanese Patent
Publication (Kokai) Hei 4-235149 (EP 433983, which is incorporated
herein by reference) {preferably valsartan, of which the chemical
name is
(S)-N-valeryl-N-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]valine,
and valsartan including a pharmacologically acceptable
salt/co-crystal, ester or prodrug thereof.}; a carboxylic acid
derivative having the general formula (I), including a
pharmacologically acceptable salt/co-crystal, ester or prodrug
thereof disclosed in the Japanese Patent Publication (Kokai) Hei
4-364171 (U.S. Pat. No. 5,196,444) {preferably candesartan, of
which the chemical name is 1-(cyclohexyloxycarbonyloxy)ethyl
2-ethoxy-1-[2'-(1H-etrazol-5-yl)biphen-yl-4-ylmethyl]-1H-benzimidazole-7--
carboxylate, and candesartan including a pharmacologically
acceptable salt/co-crystal, ester or prodrug thereof (TCV-116 or
the like), including a pharmacologically acceptable
salt/co-crystal, ester or prodrug thereof.}; a carboxylic acid
derivative having the general formula (I), including a
pharmacologically acceptable salt/co-crystal, ester or prodrug
thereof disclosed in the Japanese Patent Publication (Kokai) Hei
5-78328 (U.S. Pat. No. 5,616,599, which is incorporated herein by
reference) {preferably olmesartan, of which the chemical name is (5
-methyl-2-oxo-1,3-dioxolen-4-yl)methyl
4-(1-hydroxy-1-methylethyl)-2-pr-opyl-1-[2'-(1H-tetrazol-5-yl)biphenyl-4--
ylmethyl]imidazole-5-carboxylate, and olmesartan includes
carboxylic acid derivatives thereof, pharmacologically acceptable
esters of the carboxylic acid derivatives (CS-866 or the like),
including a pharmacologically acceptable salt/co-crystal, ester or
prodrug thereof}; and a compound having the general formula (I),
including a pharmacologically acceptable salt/co-crystal, ester or
prodrug thereof disclosed in the Japanese Patent Publication
(Kokai) Hei 4-346978 (U.S. Pat. No. 5,591,762, EP 502,314, which
are incorporated herein by reference) {preferably telmisartan, of
which the chemical name is
4'-[[2-n-propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl]-
-methyl]biphenyl-2-carboxylate, including a pharmacologically
acceptable salt/co-crystal, ester or prodrug thereof}. The
angiotensin II receptor antagonist preferably is losartan,
irbesartan, valsartan, candesartan, olmesartan, or telmisartan;
more preferred is losartan or olmesartan; and most preferred is
olmesartan.
[0090] In addition to being useful in treating or preventing
certain diseases and disorders, combination therapy with the
compound described herein may be useful in reducing the dosage of
the second drug or agent (e.g., atorvastatin).
[0091] In addition, the compound described herein can be used in
combination with an apolipoprotein B secretion inhibitor and/or
microsomal triglyceride transfer protein (MTP) inhibitor. Some
apolipoprotein B secretion inhibitors and/or MTP inhibitors are
disclosed in U.S. Pat. No. 5,919,795, which is incorporated herein
by reference.
[0092] Any HMG-CoA reductase inhibitor may be employed as an
additional compound in the combination therapy aspect described
herein. The term HMG-CoA reductase inhibitor refers to a compound
that inhibits the biotransformation of
hydroxymethylglutaryl-coenzyme A to mevalonic acid as catalyzed by
the enzyme HMG-CoA reductase. Such inhibition may be determined
readily by one of skill in the art according to standard assays
(e.g., Methods of Enzymology, 71: 455-509 (1981); and the
references cited therein, which is incorporated herein by
reference). A variety of these compounds are described and
referenced below. U.S. Pat. No. 4,231,938, which is incorporated
herein by reference discloses certain compounds isolated after
cultivation of a microorganism belonging to the genus Aspergillus,
such as lovastatin. Also U.S. Pat. No. 4,444,784 discloses
synthetic derivatives of the aforementioned compounds, such as
simvastatin. Additionally, U.S. Pat. No. 4,739,073, which is
incorporated herein by reference, discloses certain substituted
indoles, such as fluvastatin. Further, U.S. Pat. No. 4,346,227,
which is incorporated herein by reference, discloses ML-236B
derivatives, such as pravastatin. In addition, EP 491,226 teaches
certain pyridyldihydroxyheptenoic acids, such as rivastatin. Also,
U.S. Pat. No. 4,647,576, which is incorporated herein by reference,
discloses certain
6-[2-(substituted-pyrrol-1-yl)-alkyl]-pyran-2-ones such as
atorvastatin. Other HMG-CoA reductase inhibitors will be known to
those skilled in the art. Examples of currently or previously
marketed products containing HMG-CoA reductase inhibitors include
cerivastatin Na, rosuvastatin Ca, fluvastatin, atorvastatin,
lovastatin, pravastatin Na and simvastatin.
[0093] Any HMG-CoA synthase inhibitor may be used as an additional
compound in the combination therapy. The term HMG-CoA synthase
inhibitor refers to a compound that inhibits the biosynthesis of
hydroxymethylglutaryl-coenzyme A from acetyl-coenzyme A and
acetoacetyl-coenzyme A, catalyzed by the enzyme HMG-CoA synthase.
Such inhibition may be determined readily by one of skill in the
art according to standard assays (e.g., Methods of Enzymology 35:
155-160 (1975); and Methods of Enzymology, 110: 19-26 (1985); and
the references cited therein). A variety of these compounds are
described and referenced below. U.S. Pat. No. 5,120,729 discloses
certain beta-lactam derivatives. U.S. Pat. No. 5,064,856 discloses
certain spiro-lactone derivatives prepared by culturing the
microorganism MF5253. U.S. Pat. No. 4,847,271 discloses certain
oxetane compounds such as
11-(3-hydroxymethyl-4-oxo-2-oxetayl)-3,5,7-trimethyl-2,4-undecadienoic
acid derivatives, all of which are incorporated herein by
reference. Other HMG-CoA synthase inhibitors known to those skilled
in the art can also be used in the methods, compositions and kits
described herein.
[0094] Any compound that decreases HMG-CoA reductase gene
expression may be used as an additional compound in the combination
therapy described herein. These agents may be HMG-CoA reductase
transcription inhibitors that block the transcription of DNA or
translation inhibitors that prevent translation of mRNA coding for
HMG-CoA reductase into protein. Such inhibitors may either affect
transcription or translation directly, or may be biotransformed
into compounds that have the aforementioned attributes by one or
more enzymes in the cholesterol biosynthetic cascade or may lead to
the accumulation of an isoprene metabolite that has the
aforementioned activities. Such regulation is readily determined by
those skilled in the art according to standard assays (Methods of
Enzymology, 110: 9-19 (1985)). Several such compounds are described
and referenced below; however, other inhibitors of HMG-CoA
reductase gene expression will be known to those skilled in the
art, for example, U.S. Pat. No. 5,041,432, which is incorporated
herein by reference, discloses certain 15-substituted lanosterol
derivatives that are inhibitors of HMG-CoA reductase gene
expression. Other oxygenated sterols that suppress the biosynthesis
of HMG-CoA reductase are discussed by E. I. Mercer (Prog. Lip.
Res., 32:357-416 (1993)), which is incorporated herein by
reference.
[0095] Any compound having activity as a CETP inhibitor can serve
as the second compound in the combination therapy aspect. The term
CETP inhibitor refers to compounds that inhibit the cholesteryl
ester transfer protein (CETP) mediated transport of various
cholesteryl esters and triglycerides from HDL to LDL and VLDL. A
variety of these compounds are described and referenced below;
however, other CETP inhibitors will be known to those skilled in
the art. U.S. Pat. No. 5,512,548 discloses certain polypeptide
derivatives having activity as CETP inhibitors, while certain
CETP-inhibitory rosenonolactone derivatives and
phosphate-containing analogs of cholesteryl ester are disclosed in
J. Antibiot., 49(8): 815-816 (1996), and Bioorg. Med. Chem. Lett.,
6:1951-1954 (1996), respectively, which are incorporated herein by
reference.
[0096] Any ACAT inhibitor can serve as an additional compound in
the combination therapy. The term ACAT inhibitor refers to a
compound that inhibits the intracellular esterification of dietary
cholesterol by the enzyme acyl CoA: cholesterol acyltransferase.
Such inhibition may be determined readily by one of skill in the
art according to standard assays, such as the method of Heider et
al. described in Journal of Lipid Research, 24:1127 (1983). A
variety of these compounds are described and referenced below;
however, other ACAT inhibitors will be known to those skilled in
the art. U.S. Pat. No. 5,510,379 discloses certain
carboxysulfonates, while WO 96/26948 and WO 96/10559 both disclose
urea derivatives having ACAT inhibitory activity, which are
incorporated herein by reference.
[0097] Any compound having activity as a squalene synthetase
inhibitor can serve as an additional compound in the combination
therapy. The term squalene synthetase inhibitor refers to compounds
that inhibit the condensation of two molecules of
famesylpyrophosphate to form squalene, a reaction that is catalyzed
by the enzyme squalene synthetase. Such inhibition is readily
determined by those skilled in the art according to standard
methodology (Methods of Enzymology 15:393-454 (1969); and Methods
of Enzymology 110: 359-373 (1985); and references cited therein,
which are incorporated herein by reference). A summary of squalene
synthetase inhibitors has been complied in Curr. Op. Ther Patents,
861-4, (1993). EP 0 567 026 A1 discloses certain 4,1-benzoxazepine
derivatives as squalene synthetase inhibitors and their use in the
treatment of hypercholesterolemia and as fungicides. EP 0 645 378
A1 discloses certain seven- or eight-membered heterocycles as
squalene synthetase inhibitors and their use in the treatment and
prevention hypercholesterolemia and fungal infections. EP 0 645 377
A1 discloses certain benzoxazepine derivatives as squalene
synthetase inhibitors useful for the treatment of
hypercholesterolemia or coronary sclerosis. EP 0 611 749 A1
discloses certain substituted amic acid derivatives useful for the
treatment of arteriosclerosis. EP 0 705 607 A2 discloses certain
condensed seven- or eight-membered heterocyclic compounds useful as
antihypertriglyceridemic agents. WO 96/09827 discloses certain
combinations of cholesterol absorption inhibitors and cholesterol
biosynthesis inhibitors including benzoxazepine derivatives and
benzothiazepine derivatives. EP 0 701 725 A1 discloses a process
for preparing certain optically-active compounds, including
benzoxazepine derivatives, having plasma cholesterol and
triglyceride lowering activities. All of the cited references are
incorporated herein by reference.
[0098] Other compounds that are currently or previously marketed
for hyperlipidemia, including hypercholesterolemia, and which are
intended to help prevent or treat atherosclerosis, include bile
acid sequestrants, such as colestipol HCl and cholestyramine; and
fibric acid derivatives, such as clofibrate, fenofibrate, and
gemfibrozil. These compounds can also be used in combination with
the compound described herein.
[0099] It is also contemplated that the compound described herein
can be administered with a lipase inhibitor and/or a glucosidase
inhibitor, which are typically used in the treatment of conditions
resulting from the presence of excess triglycerides, free fatty
acids, cholesterol, cholesterol esters or glucose including, inter
alia, obesity, hyperlipidemia, hyperlipoproteinemia, Syndrome X,
and the like.
[0100] In a combination with the compound described herein, any
lipase inhibitor or glucosidase inhibitor may be employed. In one
aspect lipase inhibitors comprise gastric or pancreatic lipase
inhibitors. In a further aspect glucosidase inhibitors comprise
amylase inhibitors. Examples of glucosidase inhibitors are those
inhibitors selected from the group consisting of acarbose,
adiposine, voglibose, miglitol, emiglitate, camiglibose,
tendamistate, trestatin, pradimicin-Q and salbostatin. Examples of
amylase inhibitors include tendamistat and the various cyclic
peptides related thereto disclosed in U.S. Pat. No. 4,451,455,
AI-3688 and the various cyclic polypeptides related thereto
disclosed in U.S. Pat. No. 4,623,714, and trestatin, consisting of
a mixture of trestatin A, trestatin B and trestatin C and the
various trehalose-containing aminosugars related thereto disclosed
in U.S. Pat. No. 4,273,765, all of which are incorporated herein by
reference.
[0101] A lipase inhibitor is a compound that inhibits the metabolic
cleavage of dietary triglycerides into free fatty acids and
monoglycerides. Under normal physiological conditions, lipolysis
occurs via a two-step process that involves acylation of an
activated serine moiety of the lipase enzyme. This leads to the
production of a fatty acid-lipase hemiacetal intermediate, which is
then cleaved to release a diglyceride. Following further
deacylation, the lipase-fatty acid intermediate is cleaved,
resulting in free lipase, a monoglyceride and a fatty acid. The
resultant free fatty acids and monoglycerides are incorporated into
bile acid phospholipid micelles, which are subsequently absorbed at
the level of the brush border of the small intestine. The micelles
eventually enter the peripheral circulation as chylomicrons.
Accordingly, compounds, including lipase inhibitors that
selectively limit or inhibit the absorption of ingested fat
precursors are useful in the treatment of conditions including
obesity, hyperlipidemia, hyperlipoproteinemia, Syndrome X, and the
like.
[0102] Pancreatic lipase mediates the metabolic cleavage of fatty
acids from triglycerides at the 1- and 3-carbon positions. The
primary site of the metabolism of ingested fats is in the duodenum
and proximal jejunum by pancreatic lipase, which is usually
secreted in vast excess of the amounts necessary for the breakdown
of fats in the upper small intestine. Because pancreatic lipase is
the primary enzyme required for the absorption of dietary
triglycerides, inhibitors have utility in the treatment of obesity
and the other related conditions.
[0103] Gastric lipase is an immunologically distinct lipase that is
responsible for approximately 10 to 40% of the digestion of dietary
fats. Gastric lipase is secreted in response to mechanical
stimulation, ingestion of food, the presence of a fatty meal or by
sympathetic agents. Gastric lipolysis of ingested fats is of
physiological importance in the provision of fatty acids needed to
trigger pancreatic lipase activity in the intestine and is also of
importance for fat absorption in a variety of physiological and
pathological conditions associated with pancreatic insufficiency.
See, for example, C. K Abrams, et al., Gastroenterology 92: 125
(1987), which is incorporated herein by reference.
[0104] A variety of lipase inhibitors are known to one of ordinary
skill in the art. In some embodiments, lipase inhibitors are those
inhibitors that are selected from the group consisting of
lipstatin, tetrahydrolipstatin (orlistat), FL-386, WAY-121898,
Bay-N-3176, valilactone, esterastin, ebelactone A, ebelactone B and
RHC 80267.
[0105] The pancreatic lipase inhibitors lipstatin, 2S, 3S, SS,
7Z,1OZ)-5-[(S)-2-formamido-4-methyl-valeryloxy]-2-hexyl-3-hydroxy-7,1
(t-hexadecan oic acid lactone, and tetrahydrolipostatin (orlistat),
2S, 3S,
55)-5-[(S)-2-formamido-4-methyl-valeryloxy]-2-hexyl-3-hydroxy-hexadec-
anoic acid lactone, and the variously substituted N-formylleucine
derivatives and stereoisomers thereof, are disclosed in U.S. Pat.
No. 4,598,089, which is incorporated herein by reference.
[0106] The pancreatic lipase inhibitor FL-386,
1-[4-(2-methylpropyl)cyclohexyl]-2-[(phenylsulfonyl)oxy]-ethanone,
and the variously substituted sulfonate derivatives related
thereto, are disclosed in U.S. Pat. No. 4,452,813, which is
incorporated herein by reference.
[0107] The pancreatic lipase inhibitor WAY-121898,
4-phenoxyphenyl-4-methylpiperidin-1-yl-carboxylate, and the various
carbamate esters and pharmaceutically acceptable salts related
thereto, are disclosed in U.S. Pat. Nos. 5,512,565; 5,391,571 and
5,602,151, all of which are incorporated herein by reference.
[0108] The lipase inhibitor Bay-N-3176,
N-3-trifluoromethylphenyl-N`-3-chloro-4-trifluoromethylphenylurea,
and the various urea derivatives 65 related thereto, are disclosed
in U.S. Pat. No. 4,405,644, which is incorporated herein by
reference.
[0109] The pancreatic lipase inhibitor valilactone, and a process
for the preparation thereof by the microbial cultivation of
Actinomycetes strain MG147CF.sub.2, are disclosed in Kitahara, et
al., J. Antibiotics, 40(11): 1647-50 (1987), which is incorporated
herein by reference.
[0110] The lipase inhibitor esteracin, and certain processes for
the preparation thereof by the microbial cultivation of
Streptomyces strain ATCC 31336, are disclosed in U.S. Pat. Nos.
4,189,438 and 4,242,453, all of which are incorporated herein by
reference.
[0111] The pancreatic lipase inhibitors ebelactone A and ebelactone
B, and a process for the preparation thereof by the microbial
cultivation of Actinomycetes strain MG7-G1, are disclosed in
Umezawa, et al., J. Antibiotics, 33, 1594-1596 (1980). The use of
ebelactones A and B in the suppression of monoglyceride formation
is disclosed in Japanese Kokai 08-143457, published Jun. 4, 1996,
which is incorporated herein by reference.
[0112] The lipase inhibitor RHC 80267,
cyclo-O,O'-[(1,6-hexanediyl)-bis-(iminocarbonyl)]dioxime, and the
various bis(iminocarbonyl)dioximes related thereto may be prepared
as described in Petersen et al., Liebig's Annalen, 562: 205-29
(1949), which is incorporated herein by reference.
[0113] The ability of RHC 80267 to inhibit the activity of
myocardial lipoprotein lipase is disclosed in Carroll et al.,
Lipids, 27 305-7 (1992) and Chuang et al., J. Mol. Cell. Cardiol.,
22: 1009-16 (1990), all of which are incorporated herein by
reference.
[0114] In another embodiment, the compound described herein can be
used in combination with an additional anti-obesity agent. The
additional anti-obesity agent in one aspect is selected from the
group consisting of a 3-adrenergic receptor agonist, a
cholecystokinin-A agonist, a monoamine reuptake inhibitor, a
sympathomimetic agent, a serotoninergic agent, a dopamine agonist,
a melanocyte-stimulating hormone receptor agonist or mimetic, a
melanocyte-stimulating hormone receptor analog, a cannabinoid
receptor antagonist, a melanin concentrating hormone antagonist,
leptin, a leptin analog, a leptin receptor agonist, a galanin
antagonist, a lipase inhibitor, a bombesin agonist, a
neuropeptide-Y antagonist, a thyromimetic agent,
dehydroepiandrosterone or an analog thereof, a glucocorticoid
receptor agonist or antagonist, an orexin receptor antagonist, a
urocortin binding protein antagonist, a glucagon-like peptide-1
receptor agonist, and a ciliary neurotrophic factor.
[0115] In an additional aspect the anti-obesity agents comprise
those compounds selected from the group consisting of sibutramine,
fenfluramine, dexfenfluramine, bromocriptine, phentermine,
ephedrine, leptin, phenylpropanolamine pseudoephedrine,
{4-[2-(2-[6-aminopyridin-3
-yl]-2(R)-hydroxyethylamino)ethoxy]phenyl}acetic acid,
{4-[2-(2-[6-aminopyridin-3-yl]-2(R)-hydroxyethylamino)ethoxy]phenyl}benzo-
ic acid,
{4-[2-(2-[6-aminopyridin-3-yl]-2(R)-hydroxyethylamino)ethoxy]phen-
yl}propionic acid, and
{4-[2-(2-[6-aminopyridin-3-yl]-2(R)-hydroxyethylamino)ethoxy]phenoxy
acetic acid.
[0116] In some embodiments, the prevention or treatment of diabetes
can include impaired glucose tolerance, insulin resistance, insulin
dependent diabetes mellitus (Type I) and non-insulin dependent
diabetes mellitus (NIDDM or Type II). Also included in the
prevention or treatment of diabetes are the diabetic complications,
such as neuropathy, nephropathy, retinopathy or cataracts.
[0117] In one aspect the type of diabetes to be treated by the
compound described herein is non-insulin dependent diabetes
mellitus, also known as Type II diabetes or NIDDM.
[0118] Diabetes can be treated by administering to a patient having
diabetes (Type I or Type II), insulin resistance, impaired glucose
tolerance, or any of the diabetic complications such as neuropathy,
nephropathy, retinopathy or cataracts, a therapeutically effective
amount of the compound described herein. It is also contemplated
that diabetes be treated by administering the compound described
herein along with other agents that can be used to prevent or treat
diabetes.
[0119] Representative agents that can be used to treat diabetes in
combination with the compound described herein include insulin and
insulin analogs (e.g., LysPro insulin); GLP-1 (7-37)
(insulinotropin) and GLP-1 (7-36)-NH.sub.2. Agents that enhance
insulin secretion, e.g., eblorpropamide, glibenclamide,
tolbutamide, tolazamide, acetohexamide, glypizide, glimepiride,
repaglinide, nateglinide, meglitinide; biguanides: metformin,
phenformin, buformin; A2-antagonists and imidazolines: midaglizole,
isaglidole, deriglidole, idazoxan, efaroxan, fluparoxan; other
insulin secretagogues linogliride, A-4166; glitazones: ciglitazone,
pioglitazone, englitazone, troglitazone, darglitazone, BR149653;
fatty acid oxidation inhibitors: clomoxir, etomoxir; a-glucosidase
inhibitors: acarbose, miglitol, emiglitate, voglibose, MDL25,637,
camiglibose, MDL-73,945; .sup..about.3-agonists: BRL 35135, BRL
37344, RO 16-8714, ICI D7114, CL 316,243; phosphodiesterase
inhibitors: -386,398; lipid-lowering agents benfluorex; antiobesity
agents: fenfiuramine; vanadate and vanadium complexes (e.g.,
bis(cysteinamide N-octyl) oxovanadium) and peroxovanadium
complexes; amylin antagonists; glucagon antagonists;
gluconeogenesis inhibitors; somatostatin analogs; antilipolytic
agents: nicotinic acid, acipimox, WAG 994. Also contemplated to be
used in combination with the compound described herein are
pramlintide (symlin.TM.), AC 2993 and nateglinide. Any agent or
combination of agents can be administered as described above.
[0120] In addition, the compound described herein can be used in
combination with one or more aldose reductase inhibitors, DPPIV
inhibitor, glycogen phosphorylase inhibitors, sorbitol
dehydrogenase inhibitors, NHE-1 inhibitors and/or glucocorticoid
receptor antagonists.
[0121] Any compound having activity as a
fructose-1,6-bisphosphatase (FBPase) inhibitor can serve as the
second compound in the combination therapy (e.g.,
2-Amino-5-isobutyl-4-{2-[5-(N,N'-bis((S)-1-ethoxycarbonyl)ethyl)phosphona-
mido]furanyl}thiazoles). FBPase is a key regulatory enzyme in
gluconeogenesis, the metabolic pathway by which the liver
synthesizes glucose from 3-carbon precursors. The term FBPase
inhibitor refers to compounds that inhibit FBPase enzyme activity
and thereby block the conversion of fructose-1,6-bisphosphate, the
substrate of the enzyme, to fructose 6-phosphate. FBPase inhibition
can be determined directly at the enzyme level by those skilled in
the art according to standard methodology (e.g., Gidh-Jain M, Zhang
Y, van Poele P D et al., J Biol Chem. 1994, 269(44): 27732-8, which
is incorporated herein by reference). Alternatively, FBPase
inhibition can be assessed according to standard methodology by
measuring the inhibition of glucose production by isolated
hepatocytes or in a perfused liver, or by measuring blood glucose
lowering in normal or diabetic animals (e.g., Vincent M F, Erion M
D, Gruber H E, Van den Berghe, Diabetologia. 1996, 39(10):1148-55;
Vincent M F, Marangos P J, Gruber H E, Van den Berghe G, Diabetes
1991 40(10):1259-66, all of which are incorporated herein by
reference). In some cases, in vivo metabolic activation of a
compound may be required to generate the FBPase inhibitor. This
class of compounds may be inactive in the enzyme inhibition screen,
may or may not be active in hepatocytes, but is active in vivo as
evidenced by glucose lowering in the normal, fasted rat and/or in
animal models of diabetes.
[0122] A variety of FBPase inhibitors are described and referenced
below; however, other FBPase inhibitors will be known to those
skilled in the art. Gruber et al. U.S. Pat. No. 5,658,889 described
the use of inhibitors of the AMP site of FBPase to treat diabetes;
WO 98/39344 and U.S. Pat. No. 6,284,748 describe purine inhibitors;
WO 98/39343 and U.S. Pat. No. 6,110,903 describe benzothiazole
inhibitors to treat diabetes; WO 98/39342 and U.S. Pat. No.
6,054,587 describe indole inhibitors to treat diabetes; and WO
00/14095 and U.S. Pat. No. 6,489,476 describe heteroaromatic
phosphonate inhibitors to treat diabetes. Other FBPase inhibitors
are described in Wright S W, Carlo A A, Carty M D et al., J Med
Chem. 2002 45(18):3865-77 and WO 99/47549, all of which are
incorporated herein by reference.
[0123] The compound described herein can also be used in
combination with sulfonylureas such as arnaryl, alyburide,
glucotrol, chlorpropamide, diabinese, tolazamide, tolinase,
acetohexamide, glipizide, tolbutamide, orinase, glimepiride,
DiaBeta, micronase, glibenclamide, and gliclazide.
[0124] The compound described herein can also be used in
combination with antihypertensive agents. Any anti-hypertensive
agent can be used as the second agent in such combinations.
Examples of presently marketed products containing antihypertensive
agents include calcium channel blockers, such as Cardizem, Adalat,
Calan, Cardene, Covera, Dilacor, DynaCirc, Procardia XL, Sular,
Tiazac, Vascor, Verelan, Isoptin, Ninotop, Norvasc, and Plendil;
angiotensin converting enzyme (ACE) inhibitors, such as Accupril,
Altace, Captopril, Lotensin, Mavik, Monopril, Prinivil, Univasc,
Vasotec and Zestril.
[0125] Examples of compounds that may be used in combination with
the compound described herein to prevent or treat osteoporosis
include: anti-resorptive agents including progestins,
polyphosphonates, bisphosphonate(s), estrogen agonists/antagonists,
estrogen, estrogen/progestin combinations, Premarin, estrone,
estriol or 17.alpha.- or 17.beta.-ethynyl estradiol); progestins
including algestone acetophenide, altrenogest, amadinone acetate,
anagestone acetate, chlormadinone acetate, cingestol, clogestone
acetate, clomegestone acetate, dehnadinone acetate, desogestrel,
dimethisterone, dydrogesterone, ethynerone, ethynodiol diacetate,
etonogestrel, fluorogestone acetate, gestaclone, gestodene,
gestonorone caproate, gestrinone, haloprogesterone,
hydroxyprogesterone caproate, levonorgestrel, lynestrenol,
medrogestone, medroxyprogesterone acetate, melengestrol acetate,
methynodiol diacetate, norethindrone, norethindrone acetate,
norethynodrel, norgestimate, norgestomet, norgestrel, oxogestone
phenpropionate, progesterone, quingestanol acetate, quingestrone,
and tigestol; and bone resorption inhibiting polyphosphonates
including polyphosphonates such as of the type disclosed in U.S.
Pat. No. 3,683,080, the disclosure of which is incorporated herein
by reference. Examples of polyphosphonates include geminal
diphosphonates (also referred to as bis-phosphonates), tiludronate
disodium, ibandronic acid, alendronate, resindronate zoledronic
acid, 6-amino-1-hydroxy-hexylidene-bisphosphonic acid and
1-hydroxy-3 (methylpentylamino)-propylidene-bisphosphonic acid.
Salts, co-crystals and esters of the polyphosphonates are likewise
included. Specific examples include ethane-1-hydroxy
1,1-diphosphonic acid, methane diphosphonic acid,
pentane-1-hydroxy-1,1-diphosphonic acid, methane dichloro
diphosphonic acid, methane hydroxy diphosphonic acid,
ethane-1-amino-1,1-diphosphonic acid,
ethane-2-amino-1,1-diphosphonic acid, propane-3
-amino-1-hydroxy-1,1-diphosphonic acid,
propane-N,N-dimethyl-3-amino-1-hydroxy-1,1-diphosphonic acid,
propane-3,3-dimethyl-3-amino-1-hydroxy-1,1-diphosphonic acid,
phenyl amino methane diphosphonic acid, N,N-dimethylamino methane
diphosphonic acid, N(2-hydroxyethyl)amino methane diphosphonic
acid, butane-4-amino-1-hydroxy-1,1-diphosphonic acid,
pentane-5-amino-1-hydroxy-1,1-diphosphonic acid, and
hexane-6-amino-1-hydroxy-1,1-diphosphonic acid.
[0126] Estrogen agonist/antagonist include
3-(4-(1,2-diphenyl-but-1-enyl)-phenyl)-acrylic acidr, tamoxifen:
(ethanamine, 2-(4-(1,2-diphenyl-1-butenyl)phenoxy)-N,N-dimethyl,
(Z)-2-, 2-hydroxy-1,2,3-propanetricarboxylate(1:1)) and related
compounds which are disclosed in U.S. Pat. No. 4,536,516, the
disclosure of which is incorporated herein by reference, 4-hydroxy
tamoxifen, which is disclosed in U.S. Pat. No. 4,623,660, the
disclosure of which is incorporated herein by reference,
raloxifene: (methanone,
(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl)(4-(2-(1-piperidinyl)eth-
-oxy)phenyl)-hydrochloride) which is disclosed in U.S. Pat. No.
4,418,068, the disclosure of which is incorporated herein by
reference, toremifene: (ethanamine,
2-(4-(4-chloro-1,2-diphenyl-1-butenyl)phenoxy)-N,N-dimethyl-, (Z)-,
2-hydroxy-1,2,3-propanetricarboxylate (1:1) which is disclosed in
U.S. Pat. No. 4,996,225, the disclosure of which is incorporated
herein by reference, centchroman: 1-(2-((4-(-methoxy-2,2,
dimethyl-3-phenyl-chrornan-4-yl)-phenoxy)-ethyl)-p-pyrrolidine,
which is disclosed in U.S. Pat. No. 3,822,287, the disclosure of
which is incorporated herein by reference, levormeloxifene,
idoxifene:
(E)-1-2-(4-(1-(4-iodo-phenyl)-2-phenyl-but-1-enyl)-phenoxy)-ethyl)-pyrro--
lidinone, which is disclosed in U.S. Pat. No. 4,839,155, the
disclosure of which is incorporated herein by reference,
2-(4-methoxy-phenyl)-3-[4-(2-piperidin-1-yl-ethoxy)-phenoxy]-benzo[b]thio-
-phen-6-ol which is disclosed in U.S. Pat. No. 5,488,058, the
disclosure of which is incorporated herein by reference,
6-(4-hydroxy-phenyl)-5-(4-(2-piperidin-1-yl-ethoxy)-benzyl)-naphthalen-2--
ol, which is disclosed in U.S. Pat. No. 5,484,795, the disclosure
of which is incorporated herein by reference,
(4-(2-(2-aza-bicyclo[2.2.1]hept-2-yl)-ethoxy)-phenyl)-(6-hydroxy-2-(4-hyd-
-roxy-phenyl)-benzo [b]thiophen-3 -yl)-methanone which is
disclosed, along with methods of preparation, in PCT publication
no. WO 95/10513 assigned to Pfizer Inc, TSE-424 (Wyeth-Ayerst
Laboratories) and arazoxifene,
cis-6-(4-fluoro-phenyl)-5-(4-(2-piperidin-1-yl-ethoxy)-phenyl)-5,6,-7,8-t-
etrahydro-naphthalene-2-ol;
(-)-cis-6-phenyl-5-(4-(2-pyrrolidin-1-yl-ethoxy)-phenyl)-5,6,7,8-te-trahy-
dro-naphthalene-2-ol (also known as lasofoxifene);
cis-6-phenyl-5-(4-(2-pyrrolidin-1-yl-ethoxy)-phenyl)-5,6,7,8-tetrah-ydro--
naphthalene-2-ol;
cis-1-(6'-pyrrolodinoethoxy-3'-pyridyl)-2-phenyl-6-hydroxy-1,2,3,4-tetrah-
ydronaphthalene;
1-(4'-pyrrolidinoethoxyphenyl)-2-(4''-fluorophenyl)-6-hydroxy-1,2,3,-4-te-
trahydroisoquinoline;
cis-6-(4-hydroxyphenyl)-5-(4-(2-piperidin-1-yl-ethoxy)-phenyl)-5,6,-7,8-t-
etrahydro-naphthalene-2-ol;
1-(4'-pyrrolidinolethoxyphenyl)-2-phenyl-6-hydroxy-1,2,3,4-tetrahyd-roiso-
quinoline, 2-phenyl-3-aroyl-benzoth-iophene and
2-phenyl-3-aroylbenzothiophene-1-oxide.
[0127] Other anti-osteoporosis agents, which can be used as the
second agent in combination with the compound described herein,
include, for example, the following: parathyroid hormone (PTH) (a
bone anabolic agent); parathyroid hormone (PTH) secretagogues (see,
e.g., U.S. Pat. No. 6,132,774), particularly calcium receptor
antagonists; calcitonin; and vitamin D and vitamin D analogs.
Further anti-osteoporosis agents includes a selective androgen
receptor modulator (SARM). Examples of suitable SARMs include
compounds such as cyproterone acetate, chlormadinone, flutamide,
hydroxyflutamide, bicalutamide, nilutamide, spironolactone,
4-(trifluoromethyl)-2(1H)-pyrrolidino[3,2-g]quinoline derivatives,
1,2-dihydropyridino[5,6-g]quinoline derivatives and
piperidino[3,2-g]quinolinone derivatives. Other examples include
cypterone, also known as
(1b,2b)-6-chloro-1,2-dihydro-17-hydroxy-3'-H-cyclopropa[1,2]pregna-1,4,6--
triene-3,20-dione is disclosed in U.S. Pat. No. 3,234,093.
Chlormadinone, also known as
17-(acetyloxy)-6-chloropregna-4,6-diene-3,20-dione, in its acetate
form, acts as an anti-androgen and is disclosed in U.S. Pat. No.
3,485,852. Nilutamide, also known as
5,5-dimethyl-3-[4-nito-3-(trifluoromethyl)phenyl]-2,4-imidazolidinedione
and by the trade name Nilandron.RTM. is disclosed in U.S. Pat. No.
4,097,578. Flutamide, also known as
2-methyl-N-[4-nitro-3-(trifluoromethyl-1)phenyl]propanamide and the
trade name Eulexin.RTM. is disclosed in U.S. Pat. No. 3,847,988.
Bicalutamide, also known as
4'-cyano-a',a',a'-trifluo-ro-3-(4-fluorophenylsulfonyl)-2-hydroxy-2-methy-
lpropiono-m-toluidide and the trade name Casodex.RTM. is disclosed
in EP-100172. The enantiomers of biclutamide are discussed by
Tucker and Chesterton, J. Med. Chem. 1988, 31, 885-887.
Hydroxyflutamide, a known androgen receptor antagonist in most
tissues, has been suggested to function as a SARM for effects on
IL-6 production by osteoblasts as disclosed in Hofbauer et al. J.
Bone Miner. Res. 1999, 14, 1330-1337. Additional SARMs have been
disclosed in U.S. Pat. No. 6,017,924; WO 01/16108, WO 01/16133, WO
01/16139, WO 02/00617, WO 02/16310, U.S. Patent Application
Publication No. US 2002/0099096, U.S. Patent Application
Publication No. US 2003/0022868, WO 03/011302 and WO 03/011824. All
of the above references are hereby incorporated by reference
herein.
[0128] The following examples will further describe the present
invention, and are used for the purposes of illustration only, and
should not be considered as limiting.
EXAMPLES
Example 1
Preparation of Compound I
[0129] An eight-step synthesis of Compound I (five linear steps)
suitable for large scale has been developed. The synthesis scheme
is shown in Scheme 1 below.
##STR00003##
[0130] A 12 L flask was equipped with an overhead stirrer, heating
mantle, temperature probe, condenser with a nitrogen bubbler on the
outlet, and an addition funnel. The flask was charged with
paraformaldehyde (488 g, 16.3 mol), potassium carbonate (94 g, 0.7
mol), and 2-propanol (4.5 L). The mixture was heated to 50.degree.
C. then the heating mantle was turned off. Diisopropylphosphite
(Compound 1A, 2260 g, 13.6 mol) was added from the addition funnel
at a rate that would maintain the temperature at 50-60.degree. C.
for 2.5 h. The reaction progress was monitored by .sup.1HNMR. The
mixture was cooled to 35.degree. C. over 2 h then filtered through
Celite. The pad was washed with 2-propanol (2.times.200 mL). The
mixture was concentrated under reduced pressure. The colorless
residual oil (2950 g) was dissolved in dichloromethane (9 L). The
solution was washed with 1N HCl (1.35 L) and saturated aqueous
NaHCO.sub.3 (2.25 L), and dried over MgSO.sub.4 (1 kg). The mixture
was filtered through Celite and the pad washed with dichloromethane
(2.times.500 mL). The filtrate was concentrated under reduced
pressure, giving compound 1B as a colorless oil weighing 2836 g
(98% purity).
[0131] A 22 L, four-neck flask was equipped with an overhead
stirrer, cooling bath, temperature probe, 2 L addition funnel, and
a nitrogen bubbler. The flask was charged with Compound 1B (1408 g,
6.67 mol), triethylamine (1350 g, 13.34 mol), and dichloromethane
(4 L). The resulting solution was cooled to 5.degree. C. using an
ice/water bath. A solution of p-toluenesulfonyl chloride (1335 g,
7.0 mol) in dichloromethane (10 L) was added from the addition
funnel at a rate that would keep the temperature below 10.degree.
C. for 3 h. The mixture was stirred in an ice bath for 1.75 h, then
at ambient temperature (-20.degree. C.) for 15 h. The reaction
progress was monitored by .sup.1HNMR. The reaction mixture was
washed with 1N HCl (6 L) followed by saturated aqueous NaHCO.sub.3
(6 L). The organic layer was dried over MgSO.sub.4 (400 g) and
filtered. The filtrate was concentrated under reduced pressure to
give the tosylate Compound 1C as a yellow oil weighing 2111 g (90%
yield).
[0132] A 50 L, 4-neck flask was equipped with an overhead stirrer,
temperature probe, and cooling bath. The flask was charged with
3,5-dimethylphenol (Compound 1D, 2497 g, 20.5 mol), water (14 L),
and 50% (wt/wt) aqueous sodium hydroxide (1636 g, 20.5 mol). The
mixture was stirred 1.5h to complete dissolution. The mixture was
cooled to 4.degree. C. using an ice/water bath. Formaldehyde (1496
g, 18.5 mol) solution was added in one portion. The mixture was
stirred cold throughout the daytime and allowed to warm slowly
overnight. The reaction progress was monitored by HPLC. The
reaction mixture was diluted with dichloromethane (5 L) and ethyl
acetate (5 L). Concentrated HCl was added (1.5 L, 18.0 mol) over 30
minutes to pH 5. After stirring for 6 h, the solid was collected by
filtration. The filter cake was washed with water (1.2 L) and
dichloromethane (2 L). The beige solid was dried in a vacuum oven
(50.degree. C., -30 mmHg) to a constant weight, giving 1222 g (39%
yield) of the benzyl alcohol Compound 1E.
[0133] A 22 L, four-neck flask was equipped with an overhead
stirrer, temperature probe, heating mantle, and condenser with a
nitrogen bubbler on the outlet. The flask was charged with the
tosylate Compound 1C (2054 g, 5.45 mol), DMSO (2 L), the benzyl
alcohol Compound 1E (928 g, 5.62 mol), cesium carbonate (2841 g,
8.72 mol), and DMSO (2.5 L). The mixture was heated to 55.degree.
C. over 2h and maintained at 50-60.degree. C. for 6 h. The reaction
progress was monitored by HPLC. The reaction mixture was cooled to
20.degree. C. overnight then cooled to 5.degree. C. (ice/water
bath). Ethyl acetate (3.6 L) was added followed by slow addition of
1% (wt/vol) aqueous NaCl solution (7.2 L). The phases were
separated and the aqueous layer was extracted with ethyl acetate
(2.7 L). The combined organic layers were washed with brine
(2.times.2.7 L), dried over MgSO.sub.4 (500 g), and filtered,
rinsing with ethyl acetate (500 mL). The filtrate was concentrated
under reduced pressure, obtaining Compound 1F as a thick, dark
amber syrup weighing 1935 g.
[0134] A 500 mL round-bottom flask was charged with Compound 1F
(28.0 g, 84.8 mmol), dichloromethane (200 mL), and 2-benzylphenol
(31.23 g, 169.6 mmol). The solution was cooled to -1.degree. C.
using an ice/MeOH bath. Trifluoroacetic acid (18.9 mL, 254.4 mmol)
was added from an addition funnel over 1 minute. The reaction
progress was monitored by HPLC. The reaction mixture was poured
into water (200 mL) and the mixture was stirred for 5 minutes. The
phases were separated and the organic layer was washed with water
(200 mL). The organic layer was dried over MgSO.sub.4, filtered,
and concentrated to a thick, brown oil. Ether (200 mL) was added
and the mixture was stirred at ambient temperature
(.about.18.degree. C.). After 10 seconds, solids started to form
and the mixture thickened quickly. After stirring at room
temperature for 18 h, the solid was collected by filtration and
washed with ether (50 mL). The white solid was dried under high
vacuum giving 30.34 g of Compound 1G (72% yield).
[0135] A 250 mL round-bottom flask was charged with the diisopropyl
ester Compound 1G (29.33 g, 59.1 mmol), potassium iodide (31.38 g,
189.12 mmol), acetonitrile (120 mL), and chlorotrimethylsilane
(24.0 mL, 189.12 mmol). The resulting suspension was heated at
50.degree. C. The reaction progress was monitored by HPLC. The
mixture was cooled to 25.degree. C. Water (120 mL) was added, the
mixture was stirred 5 min, and the layers were separated. The
aqueous layer was extracted with ethyl acetate (60 mL). The
combined organic layers were washed with brine (60 mL), dried over
magnesium sulfate, filtered and concentrated to dryness to give a
thick oil Compound 1I. Upon standing, this material solidified to a
tan solid, which was ground into a fine powder and stirred
vigorously with 25 mL of water at 35-40.degree. C. for 30 minutes.
The tan solids were filtered, rinsed with a small portion of water
and dried on a lyophilizer overnight.
[0136] Sodium iodide (398.1 g, 2.49 mol) was added to acetone (850
mL) in a 2 L round-bottom flask at room temperature. After cooling
to room temperature, chloromethyl pivalate Compound 1J (250 g, 1.66
mol) was added in one portion and the reaction mixture became
turbid. The white slurry was stirred at room temperature overnight.
The salts were filtered off and rinsed with acetone (100 mL). The
combined brown filtrates were concentrated to dryness to give a
brown slurry which was taken up in ether (500 mL). The solids were
filtered off and rinsed with ether (100 mL). The combined filtrates
were concentrated to dryness to give crude iodomethyl pivalate
Compound 1K which was used without purification.
[0137] Diethylisopropylamine (19.5 mL, 118.2 mmol) was added to a
solution of crude phosphonic acid Compound 1I (59.1 mmol) in
acetonitrile at room temperature (300 mL). The orange turbid
mixture was heated at 40.degree. C. and crude iodomethyl pivalate
Compound 1K (28.6 g, 118.2 mmol) was added. The reaction was
monitored by HPLC. After 3.5 h, additional crude iodomethyl
pivalate Compound 1K (14.3 g, 59.1 mmol) and diethylisopropylamine
(9.75 mL, 59.1 mmol) were added. The reaction mixture was stirred
at 40.degree. C. overnight. A final aliquot of crude iodomethyl
pivalate Compound 1K (14.3 g, 59.1 mmol) and diethylisopropylamine
(9.75 mL, 59.1 mmol) were added. After stirring for an additional 2
h, the cooled reaction mixture was poured into a mixture of ethyl
acetate (150 mL) and water (300 mL). The layers were separated and
the organics were washed sequentially with water (150 mL), a
saturated solution of sodium bicarbonate (100 mL), and brine (100
mL) then dried (MgSO.sub.4), filtered and concentrated to dryness
to a brown oil. The residue was taken up in 1/1 acetone /hexanes
(400 mL) and filtered through a pad of silica. The pad was rinsed
with 1/1 acetone/hexanes (100 mL). The orange filtrate was
concentrated to dryness and the orange oil was taken up in acetone
(60 mL). Hexanes (300 mL) were added and the cloudy solution was
stirred at room temperature. After a few minutes, a solid appeared
and the mixture turned slowly into a thick slurry. After stirring
at room temperature overnight, the tan solid was collected by
filtration, rinsed with 1/6 acetone/hexanes (100 mL), air dried,
and then dried under high vacuum to give an off white solid
Compound I (24.06 g, 68.7% yield).
Example 2
Effects of Single Oral Doses on Plasma Cholesterol Levels
[0138] Compound I was tested to determine the cholesterol lowering
efficacy and potency of Compound I following oral administration of
single dose to a standard rodent model of hypercholesterolemia, the
cholesterol-fed Sprague Dawley rat.
[0139] Male Sprague Dawley rats were obtained from Harlan
(Livermore, Calif.) at a body weight of 250 g, caged 3 rats/cage,
and housed under a 12 h:12 h, light:dark cycle (lights on at 7 AM).
Pelleted 5001 chow containing 1.5% cholesterol and 0.5% cholic acid
(Harlan Teklad, Indianapolis, Ind.) was provided for 2 weeks prior
to the initiation of treatment. Food and water were provided ad
libitum.
[0140] Compound I was dissolved in 100% PEG-400. T3 was dissolved
in 100% PEG-400 (protocol 1) or in 100% PBS (protocol 2). All
formulations were prepared just prior to initiation of
treatment.
[0141] Male Sprague Dawley rats (.about.250 g) were fed a diet
containing 1.5% cholesterol and 0.5% cholic acid for 2 weeks prior
to the initiation of treatment. Compound I was administered as an
oral solution in PEG-400 and phosphate buffered saline,
respectively, at doses ranging from 0.3 to 100 mg/kg Compound I.
Thyroid hormone T3 (0.1 mg/kg) was evaluated as a positive
control.
[0142] A small blood sample was obtained from each rat by means of
a small incision in the tail vein prior to treatment. The blood
sample was collected in a tube containing lithium heparin. Animals
(6/group) were dosed by gavage according to the schedule shown in
the Table 1 below:
TABLE-US-00001 TABLE 1 Dosing schedule for Protocol 1 Dose Dose #
of Dose Solution Solution Route Compound animals concentration
(mg/ml) (mg/ml) PO Compound I 6 100 50 2 PO Compound I 6 30 15 2 PO
Compound I 6 10 5 2 PO Compound I 6 3 1.5 2 PO Compound I 6 1 0.5 2
PO Compound I 6 0.3 0.15 2 PO Vehicle (PEG-400) 6 NA NA 2 PO T3 6
0.1 0.1 1
[0143] At 24 hours after dose administration, a second blood sample
was taken as described above.
[0144] Analysis of plasma cholesterol: Plasma was prepared from the
blood samples by centrifugation in an Eppendorf Microfuge (14,000
rpm, 2 min, room temperature). Total plasma cholesterol was
measured using the Infinity cholesterol reagent (Thermo Electron
Corporation, Waltham, MA) and a standard curve prepared with a 300
mg/dL cholesterol standard. Plasma cholesterol levels were measured
at baseline and 24 hours after treatment using the Infinity
cholesterol reagent.
[0145] FIG. 1 shows the total plasma cholesterol levels
(mean.+-.SEM) in male, cholesterol-fed Sprague Dawley rats
(n=6/group) at baseline and at 24 hours after administration of
vehicle or Compound I. FIG. 2 shows the percentage change in in
total plasma cholesterol (TPC) levels from baseline values at 24
hours after administration of compound I to male, cholesterol-fed
Sprague Dawley rats (n=6/group). FIG. 3 shows the ED.sub.50 value,
defined as the dose that elicits a half-maximal reduction in total
plasma cholesterol (TPC) levels from baseline, of Compound I. As
shown in FIGS. 1 and 2, oral administration of Compound I resulted
in dose dependent reductions of plasma cholesterol levels up to
about 120 mg/dL (FIG. 1) or about 50% (FIG. 2) relative to baseline
levels. The reduction in cholesterol levels was similar at the two
highest doses, 30 and 100 mg/kg, indicating that the .about.120
mg/dL or .about.50% reductions observed at these doses was the
maximal response. In FIG. 3, the ED50 value for the cholesterol
lowering response was approximately 2 mg/kg. The magnitude of
cholesterol lowering at the two highest doses of Compound I was
comparable to that of T3 administered at a dose of 0.1 mg/kg (FIG.
1).
[0146] Therefore, the single oral administration of Compound I to
cholesterol-fed rats resulted in dose-dependent reductions in
plasma cholesterol with ED.sub.50 values of about 2 mg/kg.
Example 3
Effects on Plasma Cholesterol Levels and Thyroid Function
Indicators
[0147] The effects of once-daily oral administration of Compound I
on plasma cholesterol levels and thyroid function indicators in
beagle dogs were evaluated for 14 days.
[0148] Male and female beagle dogs were purchased from Marshall
Farms (North Rose, N.Y.) at approximately 9-15 kg in body weight.
Animals were housed individually under a 12 hour lighting cycle (7
am-7 pm light) and controlled temperature (.about.22.degree. C.).
The dogs were fed twice-daily with Teklad 8563 chow (Harlan Teklad,
Madison, Wis.) and allowed water ad libitum.
[0149] Compound I was dissolved in 100% PEG-400. The formulation
was prepared just prior to initiation of treatment and stored at
4.degree. C. A fresh formulation was prepared for each 7 day
treatment period.
[0150] Twelve beagle dogs (9-15 kg) were randomized into 6 dosing
groups (1 male and 1 female/group) and gavaged once-daily with a
PEG-400 solution of Compound I at doses of 0.1, 0.3, 1, 3, or 10
mg/kg or with vehicle for 14 days. At the end of the treatment
cycle (Cycle 1), the dogs were washed out for 6 weeks and then
entered into a second 14-day treatment cycle. Cycle 2 employed the
same dosing paradigm as Cycle 1, but animals were randomized to
Cycle 2 in such a way that the combined dosing groups from the two
cycles each consisted of 4 different animals (2 males, 2 females).
Blood samples were collected at baseline and appropriate time
intervals thereafter and analyzed for total plasma cholesterol
levels, serum levels of total T4 (tT4), free T4 (fT4), total T3
(tT3), free T3 (fT3), thyroid stimulating hormone (TSH), and plasma
drug levels.
[0151] Plasma cholesterol: Total plasma cholesterol was measured
using an Infinity cholesterol reagent (Thermo Electron Corporation,
Waltham, Mass.) and with use of a standard curve prepared from a
300 mg/dL cholesterol standard. Average values.+-.the standard
error of the mean (SEM) were calculated for all treatment
groups.
[0152] Thyroid function tests (TFTs). Serum samples were shipped on
dry ice to the Diagnostic Center for Population and Animal Health
(Lansing, Mich.) and assayed for total T4 (tT4), free T4 (fT4),
total T3 (tT3), free T3 (fT3), and thyroid stimulating hormone
(TSH). Average values.+-.the standard error of the mean (SEM) were
calculated for all treatment groups.
[0153] Average values of total plasma cholesterol levels at
baseline in the various treatment groups ranged from 135.5 to 154.9
mg/dl. FIG. 4 shows the effect of once-daily oral administration of
Compound I on total plasma cholesterol (TPC) levels in beagle dogs
expressed as change in levels, mg/dL, from baseline. FIG. 5 shows
the effect of once-daily oral administration of Compound I on total
plasma cholesterol (TPC) levels in beagle dogs (n=4/group)
expressed as % change from baseline. As shown in FIGS. 4 and 5, the
once-daily administration of Compound I resulted in a progressive,
dose dependent reduction of total plasma cholesterol levels from
baseline, with an average reduction on Day 15 of about 20 mg/dL or
about 15% from baseline at the lowest dose evaluated (0.1
mg/kg/day), and of about 60 mg/dL or about 38% from baseline at the
highest dose evaluated (10 mg/kg/day).
[0154] FIG. 6 shows the tT4 levels in serum after once-daily oral
administration of Compound Ito beagle dogs for 14 days. In FIG. 6,
the reductions of 6.7-9.5% from baseline were observed on Day 15 in
the groups treated with doses of 0.1, 0.3, and 3 mg/kg/day of
Compound I. In the groups treated with 1 and 10 mg/kg/day of
Compound I, tT4 levels were reduced by about 29% and about 44%,
respectively on Day 15 relative to baseline. A small increase of
tT4 levels from baseline (about 5%) was observed in the vehicle
treated group on Day 15.
[0155] FIG. 7 shows the fT4 levels in serum after once-daily oral
administration of Compound I to beagle dogs for 14 days. In FIG. 7,
the reductions of about 13-32% from baseline were observed in the
Compound I treated groups on Day 15. However, the changes were not
dose dependent. Moreover, about 19% reduction in fT4 levels from
baseline was observed in the vehicle-treated group on Day 15.
[0156] FIG. 8 shows the tT3 levels in serum after once-daily oral
administration of Compound I to beagle dogs for 14 days. In FIG. 8,
reductions of about 8-15% were observed on Day 15 relative to
baseline in the treatment groups. However, the reductions were not
dose dependent. Moreover, about 13% reduction in tT3 levels from
baseline was observed in the vehicle-treated group on Day 15.
[0157] FIG. 9 shows the fT3 levels in serum after once-daily oral
administration of Compound I to beagle dogs for 14 days. In FIG. 9,
the reductions of about 8-20% from baseline were observed on Day 15
in the groups treated with doses up to and including 3 mg/kg/day of
compound I. In the group treated with 10 mg/kg/day of Compound I,
tT4 levels were reduced by .about.45% on Day 15 relative to
baseline values. About 4% reduction of fT3 levels from baseline was
observed in the vehicle-treated group on Day 15.
[0158] FIG. 10 shows TSH levels in serum after once-daily oral
administration of Compound I to beagle dogs for 14 days. In FIG.
10, no meaningful changes from baseline values were observed in any
of the treatment groups on Day 15. Administration of Compound I
(0.1 mg/kg/day to 10 mg/kg/day) did not show any effect on the TSH
level in the dog serum.
[0159] Therefore, the once-daily oral treatment of beagle dogs for
14 days with Compound I (0.1-10 mg/kg/day) reduced total plasma
cholesterol levels in a dose dependent manner by 15-38%. Serum TSH
levels were essentially unaffected by treatment with Compound I.
Other indicators of thyroid function in general did not undergo
major changes except in the highest dose group (10 mg/kg/day) at
which about 45% reductions in tT4 and fT3 were observed.
Example 4
Effect of Compound 1 on Free 3,5,3'-Triiodothyronine (fT3) and Free
3,5,3',5' Tetraiodothyronine (fT4) Levels
[0160] Compound I was tested to measure its ex vivo effects at
concentrations ranging from 0 to 100 .mu.M on the free
3,5,3'-triiodothyronine (fT3) and the free 3,5,3',5'
tetraiodothyronine (fT4) levels in human, monkey, dog, and rat
sera.
[0161] Stock solution of Compound I was prepared in 100% DMSO. The
test articles were combined with either human, monkey, dog or rat
serum in a microcentrifuge tube at concentrations of 1, 3, 10, 30,
and 100 .mu.M, and incubated at 37.degree. C. with agitation (800
rpm) using a Thermomixer R (Eppendorf, Inc.; Westbury, N.Y.) for 1
h. The DMSO concentration in the serum incubations was kept
constant at 1%. Following the serum incubations, fT3 and T4
quantification was accomplished using the GammaCoat.TM. FT3 and the
GammaCoat.TM. FT4 RIA kits, respectively. The kits were used
according to the manufacturer's recommendations. The T3 assay
specifications indicate 0.2% cross-reactivity with T4, while the T4
assay specifications indicate 0.5% cross-reactivity with T3. In
these RIA assays, a shaking water bath and a Wallac Wizard 1470
automatic gamma counter (Perkin Elmer, Inc.; Waltham, Mass.) were
used. At each concentration tested, a background signal was
subtracted from the data. This background signal was determined in
samples of the test articles in PBS in the absence of serum. All
assays were performed in duplicate.
[0162] FIGS. 11a and 11b shows the effects of Compound Ion fT3 and
fT4 levels in human serum. FIGS. 12a and 12b shows the effects of
Compound I on fT3 and fT4 levels in monkey serum. FIGS. 13a and 13b
shows the effects of Compound I on fT3 and fT4 levels in dog serum.
FIGS. 14a and 14b shows the effects of Compound I on fT3 and fT4
levels in rat serum. The solid and dotted straight lines indicate
the mean and standard deviation of fT3 or fT4 levels in untreated
serum samples containing 1% DMSO. Table 2 summarizes the highest
concentrations at which no increases in fT3 or fT4 levels were
observed after exposure of human, monkey, dog, or rat serum to
Compound I.
TABLE-US-00002 TABLE 2 Summary of the highest concentrations at
which no increases in fT3 or T4 levels were observed after exposure
of human, monkey, dog, or rat serum. Human Human Monkey Monkey Dog
Dog Rat Rat Test Serum Serum Serum Serum Serum Serum Serum Serum
Compound fT3 fT4 fT3 fT4 fT3 fT4 fT3 fT4 Compound I 30 .mu.M 100
.mu.M 30 .mu.M 100 .mu.M 100 .mu.M 100 .mu.M 100 .mu.M 100
.mu.M
[0163] As shown in the table, for the human serum, Compound I
showed no effect on fT3 when the concentration was less than 30
.mu.M, and Compound I showed no effect on fT4 when the
concentration was less than 100 .mu.M.
Example 5
Comparison of Compound I and Compound MB07811
[0164] Compound I was compared with Compound MB07811 with respect
to their efficacy in lowering cholesterol and their effects on the
total T4 (tT4) and thyroid stimulating hormone (TSH).
[0165] FIG. 15 shows the oral efficacy of Compound I and Compound
MB07811. In FIG. 15, the two compounds have shown similar oral
efficacy in reducing cholesterol level during the 14-day test.
[0166] Compound I and Compound MB07811 were tested to determine the
effects of oral administration of each compound once-daily for 14
days followed by alternate day dosing for 14 days on plasma
cholesterol levels and indicators of thyroid function in beagle
dogs.
[0167] Male and female Beagle dogs were purchased from Marshall
Farms (North Rose, N.Y.) at approximately 9-15 kg. Animals were
housed individually under a 12-hour lighting cycle (7 am-7 pm
light) and controlled temperature (.about.22.degree. C.). The dogs
were fed twice daily with Teklad 8563 chow (Harlan Teklad, Madison,
Wis.) and allowed water ad libitum.
[0168] MB07811 was administered as a suspension in 0.5% CMC/1%
Lutrol in deionized water. To prepare the vehicle, the required
amount of CMC was weighed and dissolved in deionized water using a
Waring blender. The required amount of Lutrol F68 was weighed and
slowly added to the Waring blender while mixing. The contents of
the blender were mixed until dissolved and stored refrigerated. To
prepare the dosing formulations, the required amount of MB07811 was
weighed into a beaker and the required volume of vehicle slowly
added to the beaker while stirring using a magnetic stir bar and
stir plate. The contents of the beaker were stirred until a fine
paste was obtained. Vehicle was added to the beaker while stirring
until a uniform MB07811 suspension was obtained. The formulation
was prepared fresh on a weekly basis and stored refrigerated.
[0169] Twelve beagle dogs (9-15 kg) were randomized into 6 dosing
groups (1 male and 1 female/group) and gavaged once-daily with a
0.5% CMC/1% Lutrol F68 suspension of MB07811 at doses of 0.1, 0.3,
1, 3, or 10 mg/day or with vehicle for 14 days. At the end of the
treatment cycle (Cycle 1), the dogs were washed out for 4 weeks and
then entered into a second 14-day treatment cycle. Cycle 2 employed
the same dosing paradigm as Cycle 1, but animals were randomized to
Cycle 2 in such a way that the combined dosing groups from the two
cycles consisted of 4 different animals (2 males, 2 females) each.
At the conclusion of Cycle 2, dosing was continued on alternate
days for an additional 14-day period (Cycle 2 Extension). Blood
samples were collected at baseline and appropriate time intervals
thereafter and analyzed for total plasma cholesterol levels, serum
levels of total T4 (tT4), free T4 (fT4), total T3 (tT3), free T3
(fT3), and thyroid stimulating hormone (TSH).
[0170] Compound I was dissolved in 100% PEG-400. The formulation
was prepared just prior to initiation of treatment and stored at
4.degree. C. A fresh formulation was prepared for each 7-day
treatment period.
[0171] Twelve beagle dogs (9-15 kg) were randomized into 6 dosing
groups (1 male and 1 female/group) and gavaged once-daily with a
PEG-400 solution of Compound I at doses of 0.1, 0.3, 1, 3, or 10
mg/kg or with vehicle for 14 days. At the end of the treatment
cycle (Cycle 1), the dogs were washed out for 6 weeks and then
entered into a second 14-day treatment cycle. Cycle 2 employed the
same dosing paradigm as Cycle 1, but animals were randomized to
Cycle 2 in such a way that the combined dosing groups from the two
cycles each consisted of 4 different animals (2 males, 2 females).
Blood samples were collected at baseline and appropriate time
intervals thereafter and analyzed for total plasma cholesterol
levels, serum levels of total T4 (tT4), free T4 (fT4), total T3
(tT3), free T3 (fT3), and thyroid stimulating hormone (TSH), and
for plasma drug levels
[0172] FIG. 16a and FIG. 16b show the average tT4 levels in the
animal serum when treated with compound MB07811 and compound I
respectively at various doses. Samples were collected at pre-dose
as baseline, at 8-day, and 15-day post administration. As shown in
FIGS. 16a and 16b, Compound I shows a reduced effect on T4 levels
at all five doses (0.1 mg/kg, 0.3 mg/kg, 1 mg/kg, 3 mg/kg, and 10
mg/kg) when compared with Compound I. FIG. 17a and FIG. 17b show
the serum TSH levels when treated with compound I and compound
MB07811 respectively at various doses. Samples were collected at
pre-dose as baseline, at 8-day, and 15-day post administration. As
shown in FIGS. 17a and 17b, Compound I shows no effect on the TSH
level at all five doses (0.1 mg/kg, 0.3 mg/kg, 1 mg/kg, 3 mg/kg,
and 10 mg/kg) when compared with compound MB07811.
[0173] Therefore, Compound I has similar cholesterol lowering
activity as Compound MB07811 but it has a much reduced effect on
the thyroid hormone axis (T4 and TSH) than Compound MB07811.
Example 5
Safety Study of Compound I
[0174] A pilot rat 28-day study was conducted using Compound I to
test its safety. Two doses were tested, 1 mg/kg per day and 5 mg/kg
per day. The control group was not injected with Compound I during
the study. The mice were sacrificed on day 29 and then analyzed for
clinical signs, BW, FC Clinical pathology (including TSH, T3, T4),
gross pathology, organ weights, histopathology, toxicokinetics.
[0175] At both dose levels, the study results showed that no deaths
or adverse effects on body weight, food consumption, hematology,
serum chemistry or urinalysis, or macroscopic or microscopic
pathology. There was also no evidence of cardiac or liver necrosis,
or TFT effects greater than Compound MB07811.
* * * * *