U.S. patent application number 10/946376 was filed with the patent office on 2005-03-10 for phenyl naphthol ligands for thyroid hormone receptor.
Invention is credited to Hangeland, Jon J..
Application Number | 20050054727 10/946376 |
Document ID | / |
Family ID | 27807704 |
Filed Date | 2005-03-10 |
United States Patent
Application |
20050054727 |
Kind Code |
A1 |
Hangeland, Jon J. |
March 10, 2005 |
Phenyl naphthol ligands for thyroid hormone receptor
Abstract
New thyroid receptor ligands are provided which have the general
formula I 1 wherein R.sub.1 is halogen, trifluoromethyl,
substituted or unsubstituted aryl, substituted or unsubstituted
C.sub.1-6 alkyl, or substituted or unsubstituted C.sub.3-7
cycloalkyl; R.sub.2 and R.sub.3 are each independently hydrogen,
halogen, substituted or unsubstituted C.sub.1-4 alkyl, or
substituted or unsubstituted C.sub.3-6 cycloalkyl, wherein at least
one of R.sub.2 and R.sub.3 is other than hydrogen; R.sub.4 is a
carboxylic acid selected from the group consisting of
(CH.sub.2).sub.nCOOH, (CH).sub.2COOH, NHCO(CH.sub.2).sub.nCOOH,
CONH(CH.sub.2).sub.nCOOH and NH(CH.sub.2).sub.mCOOH; n is an
integer from 0 to 4; and m is an integer from 1 to 4. In addition,
a method is provided for preventing, inhibiting or treating a
disease associated with metabolism dysfunction or which is
dependent upon the expression of a T.sub.3 regulated gene, wherein
a compound as described above is administered in a therapeutically
effective amount.
Inventors: |
Hangeland, Jon J.;
(Morrisville, PA) |
Correspondence
Address: |
STEPHEN B. DAVIS
BRISTOL-MYERS SQUIBB COMPANY
PATENT DEPARTMENT
P O BOX 4000
PRINCETON
NJ
08543-4000
US
|
Family ID: |
27807704 |
Appl. No.: |
10/946376 |
Filed: |
September 21, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10946376 |
Sep 21, 2004 |
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10313864 |
Dec 6, 2002 |
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6831102 |
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60337760 |
Dec 7, 2001 |
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Current U.S.
Class: |
514/567 ;
514/569; 562/450; 562/490 |
Current CPC
Class: |
A61K 2300/00 20130101;
A61K 2300/00 20130101; A61K 45/06 20130101; C07C 233/25 20130101;
A61K 31/195 20130101; A61K 31/198 20130101; A61K 31/198 20130101;
C07C 233/56 20130101; C07C 229/18 20130101; A61K 31/195 20130101;
C07C 59/56 20130101 |
Class at
Publication: |
514/567 ;
514/569; 562/450; 562/490 |
International
Class: |
A61K 031/195; C07C
063/36; A61K 031/192; C07C 233/75 |
Claims
1-12. (cancelled)
13. A method for preventing, inhibiting or treating a disease
associated with metabolism dysfunction, or which is dependent on
the expression of a T.sub.3 regulated gene, which comprises
administering to a mammalian patient in need of treatment a
therapeutically effective amount of a compound of formula I
34wherein R.sub.1 is selected from the group consisting of halogen,
trifluoromethyl, aryl, C.sub.1-6 alkyl and C.sub.3-7 cycloalkyl,
wherein the aryl group may optionally be substituted with one or
more substituent selected from the group consisting of hydrogen,
halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl,
trifluoromethyl, trifluoromethoxy, alkynyl, hydroxy, amino, nitro,
cyano, aryl, cycloalkyl, heteroaryl, carboxyl or an alkyl ester
thereof, and carboxamide; the C.sub.1-6 alkyl group may optionally
be substituted with one or more substituent selected from the group
consisting of alkyl, alkenyl, alkynyl, aryl, cycloalkyl,
heteroaryl, hydroxy, cyano, nitro, amino, halogen, carboxyl or an
alkyl ester thereof, and carboxamide; the C.sub.3-7 cycloalkyl
group may optionally be substituted with one or more substituent
selected from the group consisting of hydrogen, halogen, alkyl,
haloalkyl, alkoxy, haloalkoxy, alkenyl, trifluoromethyl,
trifluoromethoxy, alkynyl, hydroxy, amino, nitro, cyano, aryl,
cycloalkyl, heteroaryl, carboxyl or an alkyl ester thereof, and
carboxamide; R.sub.2 and R.sub.3 are each independently selected
from the group consisting of hydrogen, halogen, C.sub.1-4 alkyl and
C.sub.3-6 cycloalkyl, wherein at least one of R.sub.2 and R.sub.3
is other than hydrogen, and wherein the C.sub.1-6 alkyl group may
optionally be substituted with one or more substituent selected
from the group consisting of alkyl, alkenyl, alkynyl, aryl,
cycloalkyl, heteroaryl, hydroxy, cyano, nitro, amino, halogen,
carboxyl or an alkyl ester thereof, and carboxamide; the C.sub.3-7
cycloalkyl group may optionally be substituted with one or more
substituent selected from the group consisting of hydrogen,
halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl,
trifluoromethyl, trifluoromethoxy, alkynyl, hydroxy, amino, nitro,
cyano, aryl, cycloalkyl, heteroaryl, carboxyl or an alkyl ester
thereof, and carboxaide; R.sub.4 is selected from the group
consisting of (CH.sub.2).sub.nCOOH, (CH).sub.2COOH,
NHCO(CH.sub.2).sub.nCOOH, CONH(CH.sub.2)COOH and
NH(CH.sub.2).sub.mCOOH, or esters thereof; n is an integer from 0
to 4; and m is an integer from 1 to 4, including all stereoisomers
thereof, prodrug esters thereof, and pharmaceutically acceptable
salts thereof.
14. A method for treating or delaying the progression or onset of
obesity, hypercholesterolemia, atherosclerosis, depression,
osteoporosis, hypothyroidism, subclinical hyperthyroidism,
non-toxic goiter, reduced bone mass, density or growth, eating
disorders, reduced cognitive function, thyroid cancer, glaucoma,
cardiac arrhythmia, congestive heart failure or a skin disorder or
disease, which comprises administering to a mammalian patient in
need of treatment a therapeutically effective amount of a compound
of formula I 35wherein R.sub.1 is selected from the group
consisting of halogen, trifluoromethyl, aryl, C.sub.1-6 alkyl and
C.sub.3-7 cycloalkyl, wherein the aryl group may optionally be
substituted with one or more substituent selected from the group
consisting of hydrogen, halogen, alkyl, haloalkyl, alkoxy,
haloalkoxy, alkenyl, trifluoromethyl, trifluoromethoxy, alkynyl,
hydroxy, amino, nitro, cyano, aryl, cycloalkyl, heteroaryl,
carboxyl or an alkyl ester thereof, and carboxamide; the C.sub.1-6
alkyl group may optionally be substituted with one or more
substituent selected from the group consisting of alkyl, alkenyl,
alkynyl, aryl, cycloalkyl, heteroaryl, hydroxy, cyano, nitro,
amino, halogen, carboxyl or an alkyl ester thereof, and
carboxamide; the C.sub.3-7 cycloalkyl group may optionally be
substituted with one or more substituent selected from the group
consisting of hydrogen, halogen, alkyl, haloalkyl, alkoxy,
haloalkoxy, alkenyl, trifluoromethyl, trifluoromethoxy, alkynyl,
hydroxy, amino, nitro, cyano, aryl, cycloalkyl, heteroaryl,
carboxyl or an alkyl ester thereof, and carboxamide; R.sub.2 and
R.sub.3 are each independently selected from the group consisting
of hydrogen, halogen, C.sub.1-4 alkyl and C.sub.3-6 cycloalkyl,
wherein at least one of R.sub.2 and R.sub.3 is other than hydrogen,
and wherein the C.sub.1-6 alkyl group may optionally be substituted
with one or more substituent selected from the group consisting of
alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, hydroxy,
cyano, nitro, amino, halogen, carboxyl or an alkyl ester thereof,
and carboxamide; the C.sub.3-7 cycloalkyl group may optionally be
substituted with one or more substituent selected from the group
consisting of hydrogen, halogen, alkyl, haloalkyl, alkoxy,
haloalkoxy, alkenyl, trifluoromethyl, trifluoromethoxy, alkynyl,
hydroxy, amino, nitro, cyano, aryl, cycloalkyl, heteroaryl,
carboxyl or an alkyl ester thereof, and carboxaide; R.sub.4 is
selected from the group consisting of (CH.sub.2).sub.nCOOH,
(CH).sub.2COOH, NHCO(CH.sub.2).sub.nCOOH, CONH(CH.sub.2).sub.nCOOH
and NH(CH.sub.2).sub.mCOOH, or esters thereof; n is an integer from
0 to 4; and m is an integer from 1 to 4. including all
stereoisomers thereof, prodrug esters thereof, and pharmaceutically
acceptable salts thereof.
15. The method according to claim 14 wherein the skin disorder or
disease is dermal atrophy, keloids, stria, cellulite, roughened
skin, actinic skin damage, lichen planus, ichtyosis, acne,
psoriasis, Dernier's disease, eczema, atopic dermatitis, chloracne,
pityriasis or skin scarring.
16. A method according to claim 14 further comprising
administering, concurrently or sequentially, a therapeutically
effective amount of at least one additional therapeutic agent
selected from the group consisting of other compounds of formula I,
anti-diabetic agents, anti-osteoporosis agents, anti-obesity
agents, growth promoting agents, anti-inflammatory agents,
anti-anxiety agents, anti-depressants, anti-hypertensive agents,
cardiac glycosides, cholesterol/lipid lowering agents, appetite
suppressants, bone resorption inhibitors, thyroid mimetics,
anabolic agents, anti-tumor agents and retinoids.
17. A method of treating or delaying the progression or onset of a
skin disorder or disease which comprises administering to a
mammalian patient in need of treatment a therapeutically effective
amount of a compound of formula I 36wherein R.sub.1 is selected
from the group consisting of halogen, trifluoromethyl, aryl,
C.sub.1-6 alkyl and C.sub.3-7 cycloalkyl, wherein the aryl group
may optionally be substituted with one or more substituent selected
from the group consisting of hydrogen, halogen, alkyl, haloalkyl,
alkoxy, haloalkoxy, alkenyl, trifluoromethyl, trifluoromethoxy,
alkynyl, hydroxy, amino, nitro, cyano, aryl, cycloalkyl,
heteroaryl, carboxyl or an alkyl ester thereof, and carboxamide;
the C.sub.1-6 alkyl group may optionally be substituted with one or
more substituent selected from the group consisting of alkyl,
alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, hydroxy, cyano,
nitro, amino, halogen, carboxyl or an alkyl ester thereof, and
carboxamide; the C.sub.3-7 cycloalkyl group may optionally be
substituted with one or more substituent selected from the group
consisting of hydrogen, halogen, alkyl, haloalkyl, alkoxy,
haloalkoxy, alkenyl, trifluoromethyl, trifluoromethoxy, alkynyl,
hydroxy, amino, nitro, cyano, aryl, cycloalkyl, heteroaryl,
carboxyl or an alkyl ester thereof, and carboxamide; R.sub.2 and
R.sub.3 are each independently selected from the group consisting
of hydrogen, halogen, C.sub.1-4 alkyl and C.sub.3-6 cycloalkyl,
wherein at least one of R.sub.2 and R.sub.3 is other than hydrogen,
and wherein the C.sub.1-6 alkyl group may optionally be substituted
with one or more substituent selected from the group consisting of
alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, hydroxy,
cyano, nitro, amino, halogen, carboxyl or an alkyl ester thereof,
and carboxamide; the C.sub.3-7 cycloalkyl group may optionally be
substituted with one or more substituent selected from the group
consisting of hydrogen, halogen, alkyl, haloalkyl, alkoxy,
haloalkoxy, alkenyl, trifluoromethyl, trifluoromethoxy, alkynyl,
hydroxy, amino, nitro, cyano, aryl, cycloalkyl, heteroaryl,
carboxyl or an alkyl ester thereof, and carboxaide; R.sub.4 is
selected from the group consisting of (CH.sub.2).sub.nCOOH,
(CH).sub.2COOH, NHCO(CH.sub.2).sub.nCOOH, CONH(CH.sub.2).sub.nCOOH
and NH(CH.sub.2).sub.mCOOH, or esters thereof; n is an integer from
0 to 4; and m is an integer from 1 to 4, including all
stereoisomers thereof, prodrug esters thereof, and pharmaceutically
acceptable salts thereof, in combination with a retinoid or a
vitamin D analog.
18. A method for treating or delaying the progression or onset of
obesity which comprises administering to mammalian patient in need
of treatment a therapeutically effective amount of a compound of
formula I 37wherein R.sub.1 is selected from the group consisting
of halogen, trifluoromethyl, aryl, C.sub.1-6 alkyl and C.sub.3-7
cycloalkyl, wherein the aryl group may optionally be substituted
with one or more substituent selected from the group consisting of
hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl,
trifluoromethyl, trifluoromethoxy, alkynyl, hydroxy, amino, nitro,
cyano, aryl, cycloalkyl, heteroaryl, carboxyl or an alkyl ester
thereof, and carboxamide; the C.sub.1-6 alkyl group may optionally
be substituted with one or more substituent selected from the group
consisting of alkyl, alkenyl, alkynyl, aryl, cycloalkyl,
heteroaryl, hydroxy, cyano, nitro, amino, halogen, carboxyl or an
alkyl ester thereof, and carboxamide; the C.sub.3-7 cycloalkyl
group may optionally be substituted with one or more substituent
selected from the group consisting of hydrogen, halogen, alkyl,
haloalkyl, alkoxy, haloalkoxy, alkenyl, trifluoromethyl,
trifluoromethoxy, alkynyl, hydroxy, amino, nitro, cyano, aryl,
cycloalkyl, heteroaryl, carboxyl or an alkyl ester thereof, and
carboxamide; R.sub.2 and R.sub.3 are each independently selected
from the group consisting of hydrogen, halogen, C.sub.1-4 and
C.sub.3-6 cycloalkyl, wherein at least one of R.sub.2 and R.sub.3
is other than hydrogen, and wherein the C.sub.1-6 alkyl group may
optionally be substituted with one or more substituent selected
from the group consisting of alkyl, alkenyl, alkynyl, aryl,
cycloalkyl, heteroaryl, hydroxy, cyano, nitro, amino, halogen,
carboxyl or an alkyl ester thereof, and carboxamide; the C.sub.3-7
cycloalkyl group may optionally be substituted with one or more
substituent selected from the group consisting of hydrogen,
halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl,
trifluoromethyl, trifluoromethoxy, alkynyl, hydroxy, amino, nitro,
cyano, aryl, cycloalkyl, heteroaryl, carboxyl or an alkyl ester
thereof, and carboxaide; R.sub.4 is selected from the group
consisting of (CH.sub.2).sub.nCOOH, (CH).sub.2COOH,
NHCO(CH.sub.2).sub.nCOOH, CONH(CH.sub.2).sub.nCOOH and
NH(CH.sub.2).sub.mCOOH, or esters thereof; n is an integer from 0
to 4; and m is an integer from 1 to 4, including all stereoisomers
thereof, prodrug esters thereof, and pharmaceutically acceptable
salts thereof.
19. A method according to claim 18 further comprising
administering, concurrently or sequentially, a therapeutically
effective amount of at least one additional therapeutic agent
selected from the group consisting of an anti-obesity agent and an
appetite suppressant.
20. A method according to claim 18 wherein said anti-obesity agent
is selected from the group consisting of aP2 inhibitors, PPAR gamma
antagonists, PPAR delta agonists, beta 3 adrenergic agonists,
lipase inhibitors, serotonin reuptake inhibitors, other thyroid
receptor beta agents and anorectic agents.
21. Cancelled
Description
CROSS REFERENCE TO RELATED APPLICATION
[0001] This application is a divisional application of Ser. No.
10/313,864 filed Dec. 6, 2002 which claims priority to 60/337,760
filed Dec. 7, 2001.
FIELD OF THE INVENTION
[0002] The present invention relates to novel phenyl naphthol
compounds which are thyroid receptor ligands and are preferably
selective for the thyroid hormone receptor .beta.. Further, the
present invention relates to methods for using such compounds and
to pharmaceutical compositions containing such compounds.
BACKGROUND OF THE INVENTION
[0003] While the extensive role of thyroid hormones in regulating
metabolism in humans is well recognized, the discovery and
development of new specific drugs for improving the treatment of
hyperthyroidism and hypothyroidism has been slow. This has also
limited the development of thyroid agonists and antagonists for
treatment of other important clinical indications, such as
hypercholesterolemia, obesity and cardiac arrhythmias.
[0004] Thyroid hormones affect the metabolism of virtually every
cell of the body. At normal levels, these hormones maintain body
weight, metabolic rate, body temperature and mood, and influence
blood levels of serum low density lipoprotein (LDL). Thus, in
hypothyroidism there is weight gain, high levels of LDL
cholesterol, and depression. In hyperthyroidism, these hormones
lead to weight loss, hypermetabolism, lowering of serum LDL levels,
cardiac arrhythmias, heart failure, muscle weakness, bone loss in
postmenopausal women, and anxiety.
[0005] Thyroid hormones are currently used primarily as replacement
therapy for patients with hypothyroidism. Therapy with L-thyroxine
returns metabolic functions to normal and can easily be monitored
with routine serum measurements of levels of thyroid-stimulating
hormone (TSH), thyroxine (3,5,3',5'-tetraiodo-L-thyronine, or
T.sub.4) and triiodothyronine (3,5,3'-triiodo-L-thyronine, or
T.sub.3). However, replacement therapy, particularly in older
individuals, may be restricted by certain detrimental effects from
thyroid hormones.
[0006] In addition, some effects of thyroid hormones may be
therapeutically useful in non-thyroid disorders if adverse effects
can be minimized or eliminated. These potentially useful influences
include weight reduction, lowering of serum LDL levels,
amelioration of depression and stimulation of bone formation. Prior
attempts to utilize thyroid hormones pharmacologically to treat
these disorders have been limited by manifestations of
hyperthyroidism, and in particular by cardiovascular toxicity.
[0007] Development of specific and selective thyroid hormone
receptor ligands, particularly agonists of the thyroid hormone
receptor could lead to specific therapies for these common
disorders, while avoiding the cardiovascular and other toxicity of
native thyroid hormones. Tissue-selective thyroid hormone agonists
may be obtained by selective tissue uptake or extrusion, topical or
local delivery, targeting to cells through other ligands attached
to the agonist and targeting receptor subtypes. Thyroid hormone
receptor agonists that interact selectively with the .beta.-form of
the thyroid hormone receptor offers an especially attractive method
for avoiding cardio-toxicity.
[0008] Thyroid hormone receptors (TRs) are, like other nuclear
receptors, single polypeptide chains. The various receptor forms
appear to be products of two different genes .alpha. and .beta..
Further isoform differences are due to the fact that differential
RNA processing results in at least two isoforms from each gene. The
TR.alpha..sub.1, TR.beta..sub.1 and TR.beta..sub.2 isoforms bind
thyroid hormone and act as ligand-regulated transcription factors.
In adults, the TR.beta..sub.1, isoform is the most prevalent form
in most tissues, especially in the liver and muscle. The
TR.alpha..sub.2 isoform is prevalent in the pituitary and other
parts of the central nervous system, does not bind thyroid
hormones, and acts in many contexts as a transcriptional repressor.
The TR.alpha..sub.1 isoform is also widely distributed, although
its levels are generally lower than those of the TR.beta..sub.1
isoform. Whereas many mutations in the TR.beta. gene have been
found and lead to the syndrome of generalized resistance to thyroid
hormone, mutations leading to impaired TR.alpha. function have not
been found.
[0009] A growing body of data suggests that many or most effects of
thyroid hormones on the heart, and in particular, on the heart rate
and rhythm, are mediated through the .alpha.-form of the
TR.alpha..sub.1 isoform, whereas most actions of the hormone such
as on the liver, muscle and other tissues, are mediated more
through the .beta.-forms of the receptor. Thus, a
TR.beta.-selective agonist might not elicit the cardiac rhythm and
rate influences of the hormones, but would elicit many other
actions of the hormones. Applicants believe that the .alpha.-form
of the receptor is primarily associated with heart rate function
for the following reasons:
[0010] 1) tachycardia is very common in the syndrome of generalized
resistance to thyroid hormone in which there are defective
TR.beta.-forms, and high circulating levels of T.sub.4 and
T.sub.3;
[0011] 2) there was a tachycardia in the only described patient
with a double deletion of the TR.beta. gene (Takeda et al, J. Clin.
Endrocrinol. & Metab. 1992, Vol. 74, p. 49);
[0012] 3) a double knockout TR.alpha. gene (but not .beta.-gene) in
mice resulted in a slower mouse heart rate, as compared to control
mice; and
[0013] 4) western blot analysis of human myocardial TRs show
presence of the TR.alpha..sub.1, TR.alpha..sub.2 and TR.beta..sub.2
proteins, but not TR.beta..sub.1.
[0014] If these indications are correct, then it may be possible
that a TR.beta.-selective agonist could be used to mimic a number
of thyroid hormone actions, while having a lesser effect on the
heart. Such a compound may be used for: (1) replacement therapy in
elderly subjects with hypothyroidism who are at risk for
cardiovascular complications; (2) replacement therapy in elderly
subjects with subclinical hypothyroidism who are at risk for
cardiovascular complications; (3) obesity; (4) hypercholesterolemia
due to elevations of plasma LDL levels; (5) depression; and, (6)
osteoporosis in combination with a bone resorption inhibitor.
SUMMARY OF THE INVENTION
[0015] In accordance with the illustrative embodiments and
demonstrating features of the present invention, compounds are
provided which are thyroid receptor ligands, and have the general
formula I 2
[0016] wherein;
[0017] R.sub.1 is halogen, trifluoromethyl, substituted or
unsubstituted aryl, substituted or unsubstituted C.sub.1-6 alkyl,
or substituted or unsubstituted C.sub.3-7 cycloalkyl;
[0018] R.sub.2 and R.sub.3 are each independently hydrogen,
halogen, substituted or unsubstituted C.sub.1-4 alkyl, or
substituted or unsubstituted C.sub.3-6 cycloalkyl, wherein at least
one of R.sub.2 and R.sub.3 is other than hydrogen;
[0019] R.sub.4 is a carboxylic acid, or an ester thereof, selected
from the group consisting of (CH.sub.2).sub.nCOOH, (CH).sub.2COOH,
NHCO(CH.sub.2).sub.nCOOH, CONH(CH.sub.2).sub.nCOOH and
NH(CH.sub.2).sub.mCOOH;
[0020] n is an integer from 0 to 4; and
[0021] m is an integer from 1 to 4,
[0022] including all prodrug-esters, stereoisomers and
pharmaceutically acceptable salts of formula I.
[0023] The compounds of formula I are thyroid hormone receptor
ligands, and include compounds which are, for example, selective
agonists, partial agonists, antagonists or partial antagonists of
the thyroid receptor. Preferably the compounds of formula I possess
activity as agonists of the thyroid receptor, preferably selective
agonists of the thyroid receptor-beta, and may be used in the
treatment of diseases or disorders associated with thyroid receptor
activity. In particular, the compounds of formula I may be used in
the treatment of diseases or disorders associated with metabolism
dysfunction or which are dependent upon the expression of a T.sub.3
regulated gene, such as obesity, hypercholesterolemia,
atherosclerosis, cardiac arrhythmias, depression, osteoporosis,
hypothyroidism, goiter, thyroid cancer, glaucoma, skin disorders or
diseases and congestive heart failure.
[0024] The present invention provides for compounds of formula I,
pharmaceutical compositions employing such compounds and for
methods of using such compounds. In particular, the present
invention provides for a pharmaceutical composition comprising a
therapeutically effective amount of a compound of formula I, alone
or in combination with a pharmaceutically acceptable carrier.
[0025] Further, in accordance with the present invention, a method
is provided for preventing, inhibiting or treating the progression
or onset of diseases or disorders associated with the thyroid
receptor, particularly, the thyroid receptor-beta, such as the
diseases or disorders defined above and hereinafter, wherein a
therapeutically effective amount of a compound of formula I is
administered to a mammalian, i.e., human, patient in need of
treatment.
[0026] The compounds of the invention can be used alone, in
combination with other compounds of the present invention, or in
combination with one or more other agent(s) active in the
therapeutic areas described herein.
[0027] In addition, a method is provided for preventing, inhibiting
or treating the diseases as defined above and hereinafter, wherein
a therapeutically effective amount of a combination of a compound
of formula I and another type of therapeutic agent, is administered
to a mammalian species in need of treatment.
[0028] Preferably, compounds of this invention include embodiments
of formula I wherein:
[0029] R.sub.1 is selected from the group consisting of halogen,
substituted or unsubstituted C.sub.1-3 alkyl and substituted or
unsubstituted aryl;
[0030] R.sub.2 and R.sub.3 are each independently hydrogen or
chloro, wherein at least one of R.sub.2 and R.sub.3 is chloro;
[0031] R.sub.4 is selected from the group consisting of
NHCO(CH.sub.2).sub.nCOOH, NH(CH.sub.2).sub.mCOOH, CONHCH.sub.2COOH
and CH.sub.2COOH;
[0032] n is an integer from 0 to 1; and
[0033] m is an integer from 1 to 2.
[0034] Particularly preferred embodiments include compounds of
formula I wherein:
[0035] R.sub.1 is bromo or substituted or unsubstituted C.sub.1-3
alkyl;
[0036] R.sub.2 and R.sub.3 are chloro;
[0037] R.sub.4 is NHCO(CH.sub.2).sub.nCOOH or
NH(CH.sub.2).sub.mCOOH;
[0038] n is an integer from 0 to 1; and
[0039] m is an integer from 1 to 2.
[0040] Specific examples of the preferred compounds of the
invention have the structures: 3
[0041] or an alkyl ester thereof.
[0042] Particularly preferred are compounds of the invention having
the structures: 4
[0043] or alkyl esters thereof, such as the methyl or ethyl
ester.
DETAILED DESCRIPTION OF THE INVENTION
[0044] The following definitions apply to the terms as used
throughout this specification, unless otherwise limited in specific
instances.
[0045] The term "thyroid receptor ligand" as used herein is
intended to cover any moiety which binds to a thyroid receptor. The
ligand may act as an agonist, an antagonist, a partial agonist or a
partial antagonist. Another term for "thyroid receptor ligand" is
"thyromimetic".
[0046] Unless otherwise indicated, the term "alkyl" as employed
herein alone or as part of another group includes both straight and
branched chain hydrocarbons, containing 1 to 12 carbons in the
normal chain, preferably 1 to 6 carbons, such as methyl, ethyl,
propyl, isopropyl, butyl, t-butyl, or isobutyl, pentyl, hexyl,
isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl,
nonyl, decyl, undecyl, dodecyl. "Substituted alkyl" includes an
alkyl group optionally substituted with one or more functional
groups which are commonly attached to such chains, such as, alkyl,
alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, hydroxy, cyano,
nitro, amino, halogen, carboxyl or alkyl ester thereof and/or
carboxamide, substituted or unsubstituted.
[0047] The term "aryl" as employed herein alone or as part of
another group refers to monocyclic and bicyclic aromatic groups
containing 6 to 10 carbons in the ring portion (such as phenyl or
naphthyl including l-naphthyl and 2-naphthyl). "Substituted aryl"
includes an aryl group optionally substituted through available
carbon atoms with one or more groups selected from hydrogen,
halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl,
trifluoromethyl, trifluoromethoxy, alkynyl, hydroxy, amino, nitro,
cyano and/or any of the alkyl substituents set out herein.
[0048] The term "halogen" as used herein alone or as part of
another group refers to chlorine, bromine, iodine and fluorine,
with chlorine or bromine being preferred.
[0049] The term "cycloalkyl" as used herein includes saturated or
partially saturated (containing one or more double bonds) cyclic
hydrocarbon groups containing 3 to 7 carbon atoms, such as
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. "Substituted
cycloalkyl" includes a cycloalkyl group optionally substituted with
one or more substituents, such as those described for alkyl and/or
aryl.
[0050] The compounds of formula I can be present as salts, which
are also within the scope of this invention. Pharmaceutically
acceptable (i.e., non-toxic, physiologically acceptable) salts are
preferred. If the compounds of formula I have, for example, at
least one basic center, they can form acid addition salts. These
are formed, for example, with strong inorganic acids, such as
mineral acids, for example sulfuric acid, phosphoric acid or a
hydrohalic acid, with strong organic carboxylic acids, such as
alkanecarboxylic acids of 1 to 4 carbon atoms that may be
unsubstituted or substituted, for example acetic acid, such as
saturated or unsaturated dicarboxylic acids, for example oxalic,
malonic, succinic, maleic, fumaric, phthalic or terephthalic acid,
such as hydroxycarboxylic acids, for example ascorbic, glycolic,
lactic, malic, tartaric or citric acid, such as amino acids, (for
example aspartic or glutamic acid or lysine or arginine), or
benzoic acid, or with organic sulfonic acids, such as
(C.sub.1-C.sub.4) alkyl or arylsulfonic acids which are
unsubstituted or substituted, for example by halogen, for example
methanesulfonic acid or p-toluenesulfonic acid. Corresponding acid
addition salts can also be formed having, if desired, an
additionally present basic center. If the compounds of formula I
have at least one acid group, (i.e., COOH) they can form salts with
bases. Suitable salts with bases are, for example, metal salts,
such as alkali metal or alkaline earth metal salts, for example
sodium, potassium or magnesium salts, or salts with ammonia or an
organic amine, such as morpholine, thiomorpholine, piperidine,
pyrrolidine, a mono, di or tri-lower alkylamine, for example ethyl,
tertbutyl, diethyl, diisopropyl, triethyl, tributyl or
dimethyl-propylamine, or a mono, di or trihydroxy lower alkylamine,
for example mono, di or triethanolamine. Corresponding internal
salts may furthermore be formed. Salts which are unsuitable for
pharmaceutical uses but which can be employed, for example, for the
isolation or purification of free compounds of formula I, or their
pharmaceutically acceptable salts, are also included.
[0051] Preferred salts of the compounds of formula I, which contain
a basic group, include monohydrochloride, hydrogensulfate,
methanesulfonate, phosphate or nitrate.
[0052] Salts of the compounds of formula I, which contain an acid
group, preferably include sodium, potassium and magnesium salts and
pharmaceutically acceptable organic amines.
[0053] The compounds of formula I may also have prodrug forms. Any
compound that will be converted in vivo to provide the bioactive
agent (i.e., the compound of formula I) is a prodrug within the
scope and spirit of the invention.
[0054] Various forms of prodrugs are well known in the art. A
comprehensive description of prodrugs and prodrug derivatives are
in:
[0055] a.) The Practice of Medicinal Chemistry, Camille G. Wermuth
et al., Ch 31, (Academic Press, 1996);
[0056] b.) Design of Prodrugs, edited by H. Bundgaard, (Elsevier,
1985); and
[0057] c.) A Textbook of Drug Design and Development, P.
Krogsgaard-Larson and H. Bundgaard, eds. Ch 5, pg. 113-191 (Harwood
Academic Publishers, 1991).
[0058] Said references are incorporated herein by reference.
[0059] Embodiments of prodrugs suitable for use in the present
invention include alkyl esters, such as ethyl ester, or
acyloxyalkyl esters, such as pivaloyloxymethyl (POM).
[0060] An administration of a therapeutic agent of the invention
includes administration of a therapeutically effective amount of
the agent of the invention. The term "therapeutically effective
amount" as used herein refers to an amount of a therapeutic agent
to treat or prevent a condition treatable by administration of a
composition of the invention. That amount is the amount sufficient
to exhibit a detectable therapeutic or preventative or ameliorative
effect. The effect may include, for example, treatment or
prevention of the conditions listed herein. The precise effective
amount for a subject will depend upon the subject's size and
health, the nature and extent of the condition being treated,
recommendations of the treating physician, and the therapeutics or
combination of therapeutics selected for administration. Thus, it
is not useful to specify an exact effective amount in advance.
[0061] All stereoisomers of the compounds of the instant invention
are contemplated, either in admixture or in pure or substantially
pure form. The compounds of the present invention can have
asymmetric centers at any of the carbon atoms, including any one of
the R substituents. Consequently, compounds of formula I can exist
in astereometric forms or in mixtures thereof. The below described
processes can utilize racemates, enantiomers or diasteromers as
starting materials. When diastereomeric products are prepared, they
can be separated by any known conventional method. For example,
they can be separated by chromatographic or fractional
crystallization.
[0062] The compounds of formula I of the invention can be prepared
as shown in the following reaction schemes and description thereof,
as well as by relevant published literature procedures that may be
used by one skilled in the art. Exemplary reagents and procedures
for these reactions appear hereinafter and in the working Examples.
Protection and deprotection in the Schemes below may be carried out
by procedures generally known in the art. For example, see T. W.
Greene & P. G. M. Wuts, "Protecting Groups in Organic
Synthesis", 3.sup.rd Edition, (Wiley, 1999), incorporated herein by
reference. 5
[0063] Scheme 1 depicts a general reaction sequence used in the
synthesis of Examples 1-16 to produce the compounds of formula I.
Boronic acid, indicated by the compound of formula 1a
(R.dbd.R'.dbd.H) or its pinacol ester
(R.dbd.R'.dbd.C(CH.sub.3).sub.2C(CH.sub.3).sub.2) can be reacted
with a compound of formula 2 using conditions commonly employed for
a Suzuki reaction (T. R. Hoye, M. Chen, J. Org. Chem., 61,
7940-7942, 1996; T. R. Hoye, L. Mi, Tetrahedron Lett., 37,
3097-3098, 1996; U. Anton, C. Goeltner, K. Muellen, Chem. Ber.,
125, 2325-2330, 1992; U. Anton, M. Adam, M. Wagner, Q.-L. Zhou, K.
Muellen, Chem. Ber., 126, 517-521, 1993; W.-C. Shieh, J. A.
Carlson, J. Org. Chem., 57, 379-381, 1992; Y. Nakano, D. Imai,
Synthesis, 12, 1425-1428, 1997; S. Kumar, J. Org. Chem., 62,
8535-8539, 1997; C. G. Blettner et al., J. Org. Chem., 64,
3885-3890, 1999). The B group in formulas 2 and 3 represent a
functional group commonly present in reagents used in combination
with boronic acids or their esters for the formation of a
carbon-carbon bond, namely I, Br, or OSO.sub.2CF.sub.3. The A group
in formulas 2 and 3 represents, in separate examples, nitro
(NO.sub.2), the ester of a carboxylic acid (COOR, R.dbd.Me or Et),
the ester of acetic acid (CH.sub.2COOR, R.dbd.Me or Et) or other
groups compatible with the reaction conditions. A suitable A group
is chosen to allow further chemical modification and elaboration to
provide the R.sub.4 groups defined for the compounds of formula I.
For example, when A is nitro, the nitro group can be reduced to an
amino group and subsequently acylated or alkylated. Further,
installation of lipophilic groups at R.sub.1 for the compound of
formula I was accomplished by electrophilic substitution using, for
example, elemental bromine or acetic anhydride. However, synthesis
of the compounds of formula I is not limited by the examples, such
that chemical modification of group A or B, or installation of any
of the R groups of formula I, may be accomplished by any other
suitable means known to those skilled in the art. 6
[0064] Scheme 2 is a detailed reaction scheme utilized for the
synthesis of Examples 1-5 and 7-9 hereinafter. Synthesis of the
core phenyl naphthyl system was carried out in four steps from
naphthol of formula 4 (naphthol 4 is a known compound and is
synthesized from commercially available 6-methoxy-tetralone; see T.
Kasturi, T. Arunachalam, Can. J. Chem., 46, 3625-3629, 1968) and
2,6-dichloro-4-nitrophenol 7. Thus, naphthol 4 is reacted with
trifluoromethyl sulfonic acid anhydride in dichloromethane at
-40.degree. C. to provide the compound of formula 5. The pinacol
boronate ester of formula 6 is formed by the reaction of the
compound of formula 5 with bis(pinacolato)diborane in the presence
of a 1,1'-[bis(diphenylphosphino)ferrocene]-dichloropalladium(II)
and potassium acetate using established procedures, such as those
described in T. Ishiyama, M. Murata, N. Miyaura, J. Org. Chem., 60,
7508-7510, 1995; M. Murata, S. Watanabe, Y. Masuda, J. Org. Chem.,
62, 6458-6459, 1997; J. Frahn, A.-D. Schleuter, Synthesis, 11,
1301-1304, 1997; S. R. Piettre, S. Baltzer, Tetrahedron Lett., 38,
1197-1200, 1997. Triflate of formula 8 is independently prepared by
the reaction of phenol 7 with trifluoromethyl sulfonic acid
anhydride in dichloro-methane at -40.degree. C. Intermediate 9 was
prepared by carbon-carbon bond formation between intermediate 6 and
8, carried out under conditions commonly employed for a Suzuki
reaction; specifically, in dimethoxy-ethane:water (3:1) with sodium
carbonate as base and tetrakis(triphenylphosphine) palladium(0) as
catalyst. Installation of bromine at R.sub.1 was accomplished by
reacting intermediate 9 with elemental bromine in dichloromethane
to yield intermediate 10. The nitro group of intermediate 10 was
reduced using iron(0) in aqueous acetic acid. For Example 1, the
amino group of intermediate 11 was acylated with ethyl
3-chloro-3-oxopropanoate in the presence of triethylamine in
dichloromethane to form R.sub.4 as indicated. The intermediate
ester was treated first with boron tribromide in dicholoromethane
at 0.degree. C. to demethylate the naphthol followed by hydrolysis
of the ester with aqueous sodium hydroxide in methanol. This
general three step procedure, acylation or alkylation followed by
removal of the methyl group with boron tribromide and hydrolysis of
the ester at R.sub.4, was applied during the synthesis of Examples
2-5 hereinafter.
[0065] Examples 7-9 hereinafter were synthesized by further
modification at R.sub.1 by reacting intermediate bromide 12
separately with phenyl boronic acid in the presence of sodium
carbonate and tetrakis(triphenylphosphine)-palladium(0) or methyl
boronic acid (T. Harada et al., Synlett, 3, 283-284, 1995) in the
presence of tribasic potassium phosphate and
1,1'-[(bis(diphenyl-phosphino)-ferrocene]dichloro- palladium(II).
The intermediates so obtained were subjected to boron tribromide
and sodium hydroxide as described for Example 1 hereinafter. 7
[0066] Scheme 3 shows the route taken for the synthsis of Example 5
hereinafter. Installation of the iso-propyl group at R.sub.1 of
intermediate 9 from Scheme 2 was carried out in three steps.
Intermediate 9 was reacted with acetic anhydride in the presence of
boron trifluoride dimethylsulfide complex in dichloromethane.
Intermediate 13 was reacted with Nysted reagent (L. Nysted, U.S.
Pat. No. 3,865,848; S. Matsubara, M. Sugihara, K. Utimoto, Synlett,
3, 131-315, 1998; G. S. Bisacchi, J. E. Sundeen, PCT Int. App. WO
9809964 A1 19980312) in the presence of titanium tetrachloride in
dichloromethane to yield an olefin 14. Reduction of the nitro group
was carried out as described in the explanation of Scheme 2, to
give aniline 15. Reduction of the double bond of compound 15 was
carried out under an atmosphere of hydrogen using platinum oxide as
a catalyst to give intermediate 16. Intermediate 16 was further
modified at R.sub.4 using the procedures described in Scheme 2 for
Example 1-5 and 7-9.
[0067] By suitable application of the procedures described above,
Examples 10-15 hereinafter may be constructed. In these examples,
the ester of a carboxylic acid is further modified by hydrolysis of
the ester with, for example, aqueous sodium hydroxide in methanol,
or by hydrolysis followed by amide coupling using, for example,
1-[3-(dimethylamino)propyl]-3-ethyl- carbodiimide hydrochloride,
1-hydroxy-7-azabenzotriazole and a base such as triethylamine in a
suitable solvent. These chemical transformations are well
established in the literature.
[0068] Utilities & Combinations
[0069] A. Utilities
[0070] The compounds of the present invention are thyroid receptor
ligands, and include compounds which are, for example, selective
agonists, partial agonists, antagonists or partial antagonists of
the thyroid receptor. Preferably compounds of the present invention
possess activity as agonists of the thyroid receptor, preferably
selective agonists of the thyroid receptor-beta, and may be used in
the treatment of diseases or disorders associated with thyroid
receptor activity. In particular, compounds of the present
invention may be used in the treatment of diseases or disorders
associated with metabolism dysfunction or which are dependent upon
the expression of a T.sub.3 regulated gene.
[0071] Accordingly, the compounds of the present invention can be
administered to mammals, preferably humans, for the treatment of a
variety of conditions and disorders, including, but not limited to
hypothyroidism; subclinical hyperthyroidism; non-toxic goiter;
atherosclerosis; thyroid hormone replacement therapy (e.g., in the
elderly); malignant tumor cells containing the thyroid receptor;
papillary or follicular cancer; maintenance of muscle strength and
function (e.g., in the elderly); reversal or prevention of frailty
or age-related functional decline ("ARFD") in the elderly (e.g.,
sarcopenia); treatment of catabolic side effects of
glucocorticoids; prevention and/or treatment of reduced bone mass,
density or growth (e.g., osteoporosis and osteopenia); treatment of
chronic fatigue syndrome (CFS); accelerating healing of complicated
fractures, e.g. distraction osteogenesis; in joint replacement;
eating disorders (e.g., anorexia); treatment of obesity and growth
retardation associated with obesity; treatment of depression,
nervousness, irritability and stress; treatment of reduced mental
energy and low self-esteem (e.g., motivation/assertiveness);
improvement of cognitive function (e.g., the treatment of dementia,
including Alzheimer's disease and short term memory loss);
treatment of catabolism in connection with pulmonary dysfunction
and ventilator dependency; treatment of cardiac dysfunction (e.g.,
associated with valvular disease, myocardial infarction, cardiac
hypertrophy or congestive heart failure); lowering blood pressure;
protection against ventricular dysfunction or prevention of
reperfusion events; treatment of hyperinsulinemia; stimulation of
osteoblasts, bone remodeling and cartilage growth; regulation of
food intake; treatment of insulin resistance, including NIDDM, in
mammals (e.g., humans); treatment of insulin resistance in the
heart; treatment of congestive heart failure; treatment of
musculoskeletal impairment (e.g., in the elderly); improvement of
the overall pulmonary function; skin disorders or diseases, such as
glucocorticoid induced dermal atrophy, including restoration of
dermal atrophy induced by topical glucocorticoids, and the
prevention of dermal atrophy induced by topical glucocorticoids
(such as the simultaneous treatment with topical glucocorticoid or
a pharmacological product including both glucocorticoid and a
compound of the invention), the restoration/prevention of dermal
atrophy induced by systemic treatment with glucocorticoids,
restoration/prevention of atrophy in the respiratory system induced
by local treatment with glucocorticoids, UV-induced dermal atrophy,
dermal atrophy induced by aging (wrinkles, etc.), wound healing,
keloids, stria, cellulite, roughened skin, actinic skin damage,
lichen planus; ichtyosis, acne, psoriasis, Dernier's disease,
eczema, atopic dermatitis, chloracne, pityriasis and skin
scarring.
[0072] The term treatment is also intended to include prophylactic
treatment.
[0073] In addition, the conditions, diseases, and maladies
collectively referenced to as "Syndrome X" or Metabolic Syndrome as
detailed in Johannsson J. Clin. Endocrinol. Metab., 82, 727-34
(1997), may be treated employing the compounds of the
invention.
[0074] B. Combinations
[0075] The present invention includes within its scope
pharmaceutical compositions comprising, as an active ingredient, a
therapeutically effective amount of at least one of the compounds
of formula I, alone or in combination with a pharmaceutical carrier
or diluent. Optionally, compounds of the present invention can be
used alone, in combination with other compounds of the invention,
or in combination with one or more other therapeutic agent(s),
e.g., an antidiabetic agent or other pharmaceutically active
material.
[0076] The compounds of the present invention may employed in
combination with other modulators and/or ligands of the thyroid
receptor or other suitable therapeutic agents useful in the
treatment of the aforementioned disorders including: anti-diabetic
agents; anti-osteoporosis agents; anti-obesity agents; growth
promoting agents (including growth hormone secretagogues);
anti-inflammatory agents; anti-anxiety agents; anti-depressants;
anti-hypertensive agents; cardiac glycosides; cholesterol/lipid
lowering agents; appetite suppressants; bone resorption inhibitors;
thyroid mimetics (including other thyroid receptor agonists);
anabolic agents; and anti-tumor agents.
[0077] Examples of suitable anti-diabetic agents for use in
combination with the compounds of the present invention include
biguanides (e.g., metformin or phenformin), glucosidase inhibitors
(e.g,. acarbose or miglitol), insulins (including insulin
secretagogues or insulin sensitizers), meglitinides (e.g.,
repaglinide), sulfonylureas (e.g., glimepiride, glyburide,
gliclazide, chlorpropamide and glipizide), biguanide/glyburide
combinations (e.g., Glucovance.RTM.), thiazolidinediones (e.g.,
troglitazone, rosiglitazone and pioglitazone), PPAR-alpha agonists,
PPAR-gamma agonists, PPAR alpha/gamma dual agonists, SGLT2
inhibitors, glycogen phosphorylase inhibitors, inhibitors of fatty
acid binding protein (aP2), glucagon-like peptide-1 (GLP-1), and
dipeptidyl peptidase IV (DP4) inhibitors.
[0078] Examples of suitable anti-osteoporosis agents for use in
combination with the compounds of the present invention include
alendronate, risedronate, PTH, PTH fragment, raloxifene,
calcitonin, RANK ligand antagonists, calcium sensing receptor
antagonists, TRAP inhibitors, selective estrogen receptor
modulators (SERM) and AP-1 inhibitors.
[0079] Examples of suitable anti-obesity agents for use in
combination with the compounds of the present invention include aP2
inhibitors, PPAR gamma antagonists, PPAR delta agonists, beta 3
adrenergic agonists, such as AJ9677 (Takeda/Dainippon), L750355
(Merck), or CP331648 (Pfizer) or other known beta 3 agonists as
disclosed in U.S. Pat. Nos. 5,541,204, 5,770,615, 5,491,134,
5,776,983 and 5,488,064, a lipase inhibitor, such as orlistat or
ATL-962 (Alizyme), a serotonin (and dopamine) reuptake inhibitor,
such as sibutramine, topiramate (Johnson & Johnson) or axokine
(Regeneron), other thyroid receptor beta drugs, such as a thyroid
receptor ligand as disclosed in WO 97/21993 (U. Cal SF), WO
99/00353 (KaroBio) and GB98/284425 (KaroBio), and/or an anorectic
agent, such as dexamphetamine, phentermine, phenylpropanolamine or
mazindol.
[0080] The compounds of the present invention may be combined with
growth promoting agents, such as, but not limited to, TRH,
diethylstilbesterol, theophylline, enkephalins, E series
prostaglandins, compounds disclosed in U.S. Pat. No. 3,239,345,
e.g., zeranol, and compounds disclosed in U.S. Pat. No. 4,036,979,
e.g., sulbenox or peptides disclosed in U.S. Pat. No.
4,411,890.
[0081] The compounds of the invention may also be used in
combination with growth hormone secretagogues such as GHRP-6,
GHRP-1 (as described in U.S. Pat. No. 4,411,890 and publications WO
89/07110 and WO 89/07111), GHRP-2 (as described in WO 93/04081),
NN703 (Novo Nordisk), LY444711 (Lilly), MK-677 (Merck), CP424391
(Pfizer) and B-HT920, or with growth hormone releasing factor and
its analogs or growth hormone and its analogs or somatomedins
including IGF-1 and IGF-2, or with alpha-adrenergic agonists, such
as clonidine or serotinin 5-HT.sub.D agonists, such as sumatriptan,
or agents which inhibit somatostatin or its release, such as
physostigmine and pyridostigmine. A still further use of the
disclosed compounds of the invention is in combination with
parathyroid hormone, PTH(1-34) or bisphosphonates, such as MK-217
(alendronate).
[0082] A still further use of the compounds of the invention is in
combination with estrogen, testosterone, a selective estrogen
receptor modulator, such as tamoxifen or raloxifene, or other
androgen receptor modulators, such as those disclosed in Edwards,
J. P. et al., Bio. Med. Chem. Let., 9, 1003-1008 (1999) and Hamann,
L. G. et al., J. Med. Chem., 42, 210-212 (1999).
[0083] A further use of the compounds of this invention is in
combination with steriodal or non-steroidal progesterone receptor
agonists ("PRA"), such as levonorgestrel, medroxyprogesterone
acetate (MPA).
[0084] Examples of suitable anti-inflammatory agents for use in
combination with the compounds of the present invention include
prednisone, dexamethasone, Enbrel.RTM., cyclooxygenase inhibitors
(i.e., COX-1 and/or COX-2 inhibitors such as NSAIDs, aspirin,
indomethacin, ibuprofen, piroxicam, Naproxen.RTM., Celebrex.RTM.,
Vioxx.RTM.), CTLA4-Ig agonists/antagonists, CD40 ligand
antagonists, IMPDH inhibitors, such as mycophenolate
(CellCept.RTM.), integrin antagonists, alpha-4 beta-7 integrin
antagonists, cell adhesion inhibitors, interferon gamma
antagonists, ICAM-1, tumor necrosis factor (TNF) antagonists (e.g.,
infliximab, OR1384), prostaglandin synthesis inhibitors,
budesonide, clofazimine, CNI-1493, CD4 antagonists (e.g.,
priliximab), p38 mitogen-activated protein kinase inhibitors,
protein tyrosine kinase (PTK) inhibitors, IKK inhibitors, and
therapies for the treatment of irritable bowel syndrome (e.g.,
Zelmac.RTM. and Maxi-K.RTM. openers such as those disclosed in U.S.
Pat. No. 6,184,231 B1).
[0085] Example of suitable anti-anxiety agents for use in
combination with the compounds of the present invention include
diazepam, lorazepam, buspirone, oxazepam, and hydroxyzine
pamoate.
[0086] Examples of suitable anti-depressants for use in combination
with the compounds of the present invention include citalopram,
fluoxetine, nefazodone, sertraline, and paroxetine.
[0087] For the treatment of skin disorders or diseases as described
above, the compounds of the present invention may be used alone or
optionally in combination with a retinoid, such as tretinoin, or a
vitamin D analog.
[0088] Examples of suitable anti-hypertensive agents for use in
combination with the compounds of the present invention include
beta adrenergic blockers, calcium channel blockers (L-type and
T-type; e.g. diltiazem, verapamil, nifedipine, amlodipine and
mybefradil), diuretics (e.g., chlorothiazide, hydrochlorothiazide,
flumethiazide, hydroflumethiazide, bendroflumethiazide,
methylchlorothiazide, trichloromethiazide, polythiazide,
benzthiazide, ethacrynic acid tricrynafen, chlorthalidone,
furosemide, musolimine, bumetanide, triamtrenene, amiloride,
spironolactone), renin inhibitors, ACE inhibitors (e.g., captopril,
zofenopril, fosinopril, enalapril, ceranopril, cilazopril,
delapril, pentopril, quinapril, ramipril, lisinopril), AT-1
receptor antagonists (e.g., losartan, irbesartan, valsartan), ET
receptor antagonists (e.g., sitaxsentan, atrsentan and compounds
disclosed in U.S. Pat. Nos. 5,612,359 and 6,043,265), Dual ET/AII
antagonist (e.g., compounds disclosed in WO 00/01389), neutral
endopeptidase (NEP) inhibitors, vasopepsidase inhibitors (dual
NEP-ACE inhibitors) (e.g., omapatrilat and gemopatrilat), and
nitrates.
[0089] Examples of suitable cardiac glycosides for use in
combination with the compounds of the present invention include
digitalis and ouabain.
[0090] Examples of suitable cholesterol/lipid lowering agents for
use in combination with the compounds of the present invention
include HMG-CoA reductase inhibitors, squalene synthetase
inhibitors, fibrates, bile acid sequestrants, ACAT inhibitors, MTP
inhibitors, lipooxygenase inhibitors, an ileal Na.sup.+/bile acid
cotransporter inhibitor, cholesterol absorption inhibitors, and
cholesterol ester transfer protein inhibitors (e.g.,
CP-529414).
[0091] MTP inhibitors which may be employed herein in combination
with one or more compounds of formula I include MTP inhibitors as
disclosed in U.S. Pat. No. 5,595,872, U.S. Pat. No. 5,739,135, U.S.
Pat. No. 5,712,279, U.S. Pat. No. 5,760,246, U.S. Pat. No.
5,827,875, U.S. Pat. No. 5,885,983 and U.S. Pat. No. 5,962,440 all
incorporated herein by reference.
[0092] A preferred MTP inhibitor is
[0093]
9-[4-[4-[[2-(2,2,2-Trifluoroethoxy)benzoyl]amino]-1-piperidinyl]but-
yl]-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide 8
[0094] The HMG CoA reductase inhibitors which may be employed in
combination with one or more compounds of formula I include
mevastatin and related compounds as disclosed in U.S. Pat. No.
3,983,140, lovastatin (mevinolin) and related compounds as
disclosed in U.S. Pat. No. 4,231,938, pravastatin and related
compounds such as disclosed in U.S. Pat. No. 4,346,227, simvastatin
and related compounds as disclosed in U.S. Pat. Nos. 4,448,784 and
4,450,171. Further HMG CoA reductase inhibitors which may be
employed herein include fluvastatin, disclosed in U.S. Pat. No.
5,354,772, cerivastatin disclosed in U.S. Pat. Nos. 5,006,530 and
5,177,080, atorvastatin disclosed in U.S. Pat. Nos. 4,681,893,
5,273,995, 5,385,929 and 5,686,104, pyrazole analogs of
mevalonolactone derivatives as disclosed in U.S. Pat. No.
4,613,610, indene analogs of mevalonolactone derivatives, as
disclosed in PCT application WO 86/03488,
6-[2-(substituted-pyrrol-1-yl)-alkyl)pyran-2-one- s and derivatives
thereof, as disclosed in U.S. Pat. No. 4,647,576, Searle's SC-45355
(a 3-substituted pentanedioic acid derivative) dichloroacetate,
imidazole analogs of mevalonolactone, as disclosed in PCT
application WO 86/07054, 3-carboxy-2-hydroxy-propane-phosphonic
acid derivatives, as disclosed in French Patent No. 2,596,393,
2,3-disubstituted pyrrole, furan and thiophene derivatives, as
disclosed in European Patent Application No. 0221025, naphthyl
analogs of mevalonolactone, as disclosed in U.S. Pat. No.
4,686,237, octahydronaphthalenes, such as disclosed in U.S. Pat.
No. 4,499,289, keto analogs of mevinolin (lovastatin), as disclosed
in European Patent Application No.0,142,146 A2, as well as other
known HMG CoA reductase inhibitors.
[0095] The squalene synthetase inhibitors which may be used in
combination with the compounds of the present invention include,
but are not limited to, .alpha.-phosphono-sulfonates disclosed in
U.S. Pat. No. 5,712,396, those disclosed by Biller et al, J. Med.
Chem., 1988, Vol. 31, No. 10, pp 1869-1871, including isoprenoid
(phosphinylmethyl)phosphonates, terpenoid pyrophosphates disclosed
by P. Ortiz de Montellano et al, J. Med. Chem., 1977, 20, 243-249,
the farnesyl diphosphate analog A and presqualene pyrophosphate
(PSQ-PP) analogs as disclosed by Corey and Volante, J. Am. Chem.
Soc., 1976, 98, 1291-1293, phosphinylphosphonates reported by
McClard, R. W. et al, J.A.C.S., 1987, 109, 5544 and cyclopropanes
reported by Capson, T. L., PhD dissertation, June, 1987, Dept. Med.
Chem. U of Utah, Abstract, Table of Contents, pp 16, 17, 40-43,
48-51, as well as other squalene synthetase inhibitors as disclosed
in U.S. Pat. No. 4,871,721 and 4,924,024 and in Biller, S. A.,
Neuenschwander, K., Ponpipom, M. M., and Poulter, C. D., Current
Pharmaceutical Design, 2, 1-40 (1996).
[0096] Bile acid sequestrants which may be used in combination with
the compounds of the present invention include cholestyramine,
colestipol and DEAE-Sephadex (Secholex.RTM., Policexide.RTM.), as
well as lipostabil (Rhone-Poulenc), Eisai E-5050 (an N-substituted
ethanolamine derivative), imanixil (HOE-402), tetrahydrolipstatin
(THL), istigmastanylphos-phorylch- oline (SPC, Roche),
aminocyclodextrin (Tanabe Seiyoku), Ajinomoto AJ-814 (azulene
derivative), melinamide (Sumitomo), Sandoz 58-035, American
Cyanamid CL-277,082 and CL-283,546 (disubstituted urea
derivatives), nicotinic acid, acipimox, acifran, neomycin,
p-aminosalicylic acid, aspirin, poly(diallylmethylamine)
derivatives such as disclosed in U.S. Pat. No. 4,759,923,
quaternary amine poly(diallyldimethylammonium chloride) and ionenes
such as disclosed in U.S. Pat. No. 4,027,009, and other known serum
cholesterol lowering agents.
[0097] ACAT inhibitors suitable for use in combination with
compounds of the invention include ACAT inhibitors as described in,
Drugs of the Future 24, 9-15 (1999), (Avasimibe); "The ACAT
inhibitor, C1-1011 is effective in the prevention and regression of
aortic fatty streak area in hamsters", Nicolosi et al,
Atherosclerosis (Shannon, Irel). (1998), 137(1), 77-85; "The
pharmacological profile of FCE 27677: a novel ACAT inhibitor with
potent hypolipidemic activity mediated by selective suppression of
the hepatic secretion of ApoB100-containing lipoprotein", Ghiselli,
Giancarlo, Cardiovasc. Drug Rev. (1998), 16(1), 16-30; "RP 73163: a
bioavailable alkylsulfinyl-diphenylimidazole ACAT inhibitor",
Smith, C., et al, Bioorg. Med. Chem. Lett. (1996), 6(1), 47-50;
"ACAT inhibitors: physiologic mechanisms for hypolipidemic and
anti-atherosclerotic activities in experimental animals", Krause et
al, Editor(s): Ruffolo, Robert R., Jr.; Hollinger, Mannfred A.,
Inflammation: Mediators Pathways (1995), 173-98, Publisher: CRC,
Boca Raton, Fla.; "ACAT inhibitors: potential anti-atherosclerotic
agents", Sliskovic et al, Curr. Med. Chem. (1994), 1(3), 204-25;
"Inhibitors of acyl-CoA:cholesterol O-acyl transferase (ACAT) as
hypocholesterolemic agents. 6. The first water-soluble ACAT
inhibitor with lipid-regulating activity. Inhibitors of
acyl-CoA:cholesterol acyltransferase (ACAT). 7. Development of a
series of substituted N-phenyl-N'-[(1-phenylcyclopentyl)-
methyl]ureas with enhanced hypocholesterolemic activity", Stout et
al, Chemtracts: Org. Chem. (1995), 8(6), 359-62.
[0098] Examples of suitable cholesterol absorption inhibitor for
use in combination with the compounds of the invention include
SCH48461 (Schering-Plough), as well as those disclosed in
Atherosclerosis 115, 45-63 (1995) and J. Med. Chem. 41, 973
(1998).
[0099] Examples of suitable ileal Na.sup.+/bile acid cotransporter
inhibitors for use in combination with the compounds of the
invention include compounds as disclosed in Drugs of the Future,
24, 425-430 (1999).
[0100] Examples of suitable thyroid mimetics for use in combination
with the compounds of the present invention include thyrotropin,
polythyroid, KB-130015, and dronedarone.
[0101] Examples of suitable anabolic agents for use in combination
with the compounds of the present invention include testosterone,
TRH diethylstilbesterol, estrogens, .beta.-agonists, theophylline,
anabolic steroids, dehydroepiandrosterone, enkephalins, E-series
prostagladins, retinoic acid and compounds as disclosed in U.S.
Pat. No. 3,239,345, e.g., Zeranol.RTM.; U.S. Pat. No. 4,036,979,
e.g., Sulbenox.RTM. or peptides as disclosed in U.S. Pat. No.
4,411,890.
[0102] The aforementioned patents and patent applications are
incorporated herein by reference.
[0103] The above other therapeutic agents, when employed in
combination with the compounds of the present invention, may be
used, for example, in those amounts indicated in the Physicians'
Desk Reference (PDR) or as otherwise determined by one of ordinary
skill in the art.
[0104] Where the compounds of the invention are utilized in
combination with one or more other therapeutic agent(s), either
concurrently or sequentially, the following combination ratios and
dosage ranges are preferred:
[0105] When combined with a hypolypidemic agent, an antidepressant,
a bone resorption inhibitor and/or an appetite suppressant, the
compounds of formula I may be employed in a weight ratio to the
additional agent within the range from about 500:1 to about
0.005:1, preferably from about 300:1 to about 0.01:1.
[0106] Where the antidiabetic agent is a biguanide, the compounds
of formula I may be employed in a weight ratio to biguanide within
the range from about 0.01:1 to about 100:1, preferably from about
0.5:1 to about 2:1.
[0107] The compounds of formula I may be employed in a weight ratio
to a glucosidase inhibitor within the range from about 0.01:1 to
about 100:1, preferably from about 0.5:1 to about 50:1.
[0108] The compounds of formula I may be employed in a weight ratio
to a sulfonylurea in the range from about 0.01:1 to about 100:1,
preferably from about 0.2:1 to about 10:1.
[0109] The compounds of formula I may be employed in a weight ratio
to a thiazolidinedione in an amount within the range from about
0.01:1 to about 100:1, preferably from about 0.5:1 to about
5:1.
[0110] The thiazolidinedione may be employed in amounts within the
range from about 0.01 to about 2000 mg/day, which may optionally be
administered in single or divided doses of one to four times per
day.
[0111] Further, where the sulfonylurea and thiazolidinedione are to
be administered orally in an amount of less than about 150 mg,
these additional agents may be incorporated into a combined single
tablet with a therapeutically effective amount of the compounds of
formula I.
[0112] Metformin, or salt thereof, may be employed with the
compounds of formula I in amounts within the range from about 500
to about 2000 mg per day, which may be administered in single or
divided doses one to four times daily.
[0113] The compounds of formula I may be employed in a weight ratio
to a PPAR-alpha agonist, a PPAR-gamma agonist, a PPAR-alpha/gamma
dual agonist, an SGLT2 inhibitor and/or an aP2 inhibitor within the
range from about 0.01:1 to about 100:1, preferably from about 0.5:1
to about 5:1.
[0114] An MTP inhibitor may be administered orally with the
compounds of formula I in an amount within the range of from about
0.01 mg/kg to about 100 mg/kg and preferably from about 0.1 mg/kg
to about 75 mg/kg, one to four times daily.
[0115] A preferred oral dosage form, such as tablets or capsules,
may contain the MTP inhibitor in an amount of from about 1 to about
500 mg, preferably from about 2 to about 400 mg, and more
preferably from about 5 to about 250 mg, administered on a regimen
of one to four times daily.
[0116] For parenteral administration, the MTP inhibitor may be
employed in an amount within the range of from about 0.005 mg/kg to
about 10 mg/kg and preferably from about 0.005 mg/kg to about 8
mg/kg, administered on a regimen of one to four times daily.
[0117] A HMG CoA reductase inhibitor may be administered orally
with the compounds of formula I within the range of from about 1 to
2000 mg, and preferably from about 4 to about 200 mg.
[0118] A preferred oral dosage form, such as tablets or capsules,
will contain the HMG CoA reductase inhibitor in an amount from
about 0.1 to about 100 mg, preferably from about 5 to about 80 mg,
and more preferably from about 10 to about 40 mg.
[0119] A squalene synthetase inhibitor may be administered with the
compounds of formula I within the range of from about 10 mg to
about 2000 mg and preferably from about 25 mg to about 200 mg.
[0120] A preferred oral dosage form, such as tablets or capsules,
will contain the squalene synthetase inhibitor in an amount of from
about 10 to about 500 mg, preferably from about 25 to about 200
mg.
[0121] The compounds of the formula I can be administered for any
of the uses described herein by any suitable means, for example,
orally, such as in the form of tablets, capsules, granules or
powders; sublingually; bucally; parenterally, such as by
subcutaneous, intravenous, intramuscular, or intrasternal injection
or infusion techniques (e.g., as sterile injectable aqueous or
non-aqueous solutions or suspensions); nasally, including
administration to the nasal membranes, such as by inhalation spray;
topically, such as in the form of a cream or ointment; or rectally
such as in the form of suppositories; in dosage unit formulations
containing non-toxic, pharmaceutically acceptable vehicles or
diluents. The present compounds can, for example, be administered
in a form suitable for immediate release or extended release.
Immediate release or extended release can be achieved by the use of
suitable pharmaceutical compositions comprising the present
compounds, or, particularly in the case of extended release, by the
use of devices such as subcutaneous implants or osmotic pumps. The
present compounds can also be administered liposomally.
[0122] Exemplary compositions for oral administration include
suspensions which can contain, for example, microcrystalline
cellulose for imparting bulk, alginic acid or sodium alginate as a
suspending agent, methylcellulose as a viscosity enhancer, and
sweeteners or flavoring agents such as those known in the art; and
immediate release tablets which can contain, for example,
microcrystalline cellulose, dicalcium phosphate, starch, magnesium
stearate and/or lactose and/or other excipients, binders,
extenders, disintegrants, diluents and lubricants such as those
known in the art. The compounds of formula I can also be delivered
through the oral cavity by sublingual and/or buccal administration.
Molded tablets, compressed tablets or freeze-dried tablets are
exemplary forms which may be used. Exemplary compositions include
those formulating the present compound(s) with fast dissolving
diluents such as mannitol, lactose, sucrose and/or cyclodextrins.
Also included in such formulations may be high molecular weight
excipients such as celluloses (avicel) or polyethylene glycols
(PEG). Such formulations can also include an excipieht to aid
mucosal adhesion such as hydroxy propyl cellulose (HPC), hydroxy
propyl methyl cellulose (HPMC), sodium carboxy methyl cellulose
(SCMC), maleic anhydride copolymer (e.g., Gantrez), and agents to
control release such as polyacrylic copolymer (e.g. Carbopol 934).
Lubricants, glidants, flavors, coloring agents and stabilizers may
also be added for ease of fabrication and use.
[0123] Exemplary compositions for nasal aerosol or inhalation
administration include solutions in saline which can contain, for
example, benzyl alcohol or other suitable preservatives, absorption
promoters to enhance bioavailability, and/or other solubilizing or
dispersing agents such as those known in the art.
[0124] Exemplary compositions for parenteral administration include
injectable solutions or suspensions which can contain, for example,
suitable non-toxic, parenterally acceptable diluents or solvents,
such as mannitol, 1,3-butanediol, water, Ringer's solution, an
isotonic sodium chloride solution, or other suitable dispersing or
wetting and suspending agents, including synthetic mono- or
diglycerides, and fatty acids, including oleic acid, or
Cremaphor.
[0125] Exemplary compositions for rectal administration include
suppositories which can contain, for example, a suitable
non-irritating excipient, such as cocoa butter, synthetic glyceride
esters or polyethylene glycols, which are solid at ordinary
temperatures, but liquify and/or dissolve in the rectal cavity to
release the drug.
[0126] Exemplary compositions for topical administration include a
topical carrier such as Plastibase (mineral oil gelled with
polyethylene).
[0127] It will be understood that the specific dose level and
frequency of dosage for any particular subject can be varied and
will depend upon a variety of factors including the activity of the
specific compound employed, the metabolic stability and length of
action of that compound, the species, age, body weight, general
health, sex and diet of the subject, the mode and time of
administration, rate of excretion, drug combination, and severity
of the particular condition.
[0128] The following working Examples serve to better illustrate,
but not limit, some of the preferred embodiments of the present
invention.
EXAMPLE 1
[0129] 9
3-[3,5-dichloro-4-(5-bromo-6-hydroxynaphthyl)-phenyl]-3-amino-3-oxopropano-
ic acid
[0130] 10
[0131] 6-Methoxynaphth-1-ol (0.5 g, 2.8 mmol) and triethylamine
(313 mg, 3.1 mmol) were dissolved in anhyd dichloromethane (28 mL)
under a blanket of argon and cooled to -400.degree. C. Triflic
anhydride (891 mg, 3.1 mmol) was added dropwise. The reaction was
warmed to -10.degree. C. and stirred for an additional 1.5 h.
Additional triflic anhydride (291 mg, 0.3 mmol) was added to
complete the reaction. The reaction was quenched with water. The
layers were separated and the organic layer washed with water and
brine, dried over magnesium sulfate, filtered and dried in vacuo to
yield 877 mg (99%) of an oil which solidifies upon standing. 1H-NMR
is consistent with the proposed structure. 11
[0132] The triflate of Compound 1a (857 mg, 2.8 mmol),
bis-picolinatodi-borane (1.07 g, 4.2 mmol) and anhyd potassium
acetate (824 mg, 8.4 mmol) were placed in a one necked flask
equipped with an argon inlet. The solids were suspended in anhyd
DMSO (16 mL) and degassed by nitrogen sparge for 10 min.
PdCl.sub.2dppf dichloromethane (457 mg, 0.56 mmol) was added. The
reaction mixture was heated to 80.degree. C. for 4 hrs. After
cooling to room temperature, the reaction was diluted with ethyl
acetate and washed with half saturated brine (3.times.), followed
by brine (1.times.), than dried over anhyd magnesium sulfate,
filtered and evaporated in vacuo. The title compound (461 mg, 58%)
was obtained by flash chromatography (115 g silica gel, isocratic
elution with 5% ethyl acetate in hexanes). 1H-NMR and 13C-NMR are
consistent with the proposed structure. 12
[0133] 2,6-Dichloro-4-nitrophenol (626 mg, 3.0 mmol) and triethyl
amine (334 mg, 460 .mu.L, 3.3 mmol) were dissolved in anhyd
dichloromethane (30 mL). The solution was cooled to -40.degree. C.
Triflic anhydride (928 mg, 553 .mu.L, 3.3 mmol) was added dropwise
and the reaction was warmed to -10.degree. C. for 1.5 h. The
reaction was quenched with water and the layers separated. The
organic layer was washed with water and brine, dried over anhyd
magnesium sulfate, filtered and evaporated in vacuo to yield a
light tan solid (1.0 g, 99%). 1H-NMR was consistent with the
proposed structure. 13
[0134] 1,1,2,2,-tetramethylethyl 6-methoxynaphth-1-boronate ester
(300 mg, 1.01 mmol) and the triflate of 2,6-dichloro-4-nitrophenol
(721 mg, 2.12 mmol) were dissolved in 1,2-dimethoxyethane. (30 mL)
and degassed by nitrogen sparge for 10 min. Palladium
tetrakis(triphenyl-phosphine) (231 mg, 0.2 mmol) and an aqueous
solution of sodium carbonate (337 mg, 3.18 mmol) in 9 mL of water
were added to the flask and the reaction mixture was heated to
80.degree. C. for 30 min. The reaction was cooled to room
temperature and diluted with ethyl acetate, washed with water and
brine, dried over anhyd magnesium sulfate, filtered and evaporated
in vacuo. The product was isolated by flash chromatography (62 g
silica gel; isocratic elution with 10% ethyl acetate in hexanes) to
yield 254 mg (69%). 1H-NMR was consistent with the proposed
structure. 14
[0135] 1-(2',6'-dichloro-4'-nitrophenyl)-6-methoxynaphthylene (194
mg, 0.56 mmol) was dissolved in dichloromethane (4 mL) and treated
with bromine (98 mg, 0.61 mmol). The reaction was complete in 15
min. The reaction was washed with 5% aqueous sodium bisulfite,
saturated aqueous sodium bicarbonate and brine, dried over
magnesium sulfate, filtered and dried in vacuo to yield 212 mg
(88%). 1H-NMR was consistent with the proposed structure. 15
[0136]
5-bromo-1-(2',6'-dichloro-4'-nitrophenyl)-6-methoxy-naphthylene
(200 mg, 0.65 mmol) was suspended in acetic acid (40 mL) and water
(4 mL) and heated gently to dissolve. Iron powder (363 mg, 6.5
mmol) was added and the reaction stirred vigorously over night. The
reaction was diluted with ethyl acetate, filtered through a pad of
celite, washed with water and brine, dried over magnesium sulfate,
filtered and dried in vacuo to yield an off-white foam (200 mg,
99%). 1H-NMR was consistent with the proposed structure. 16
[0137] 5-bromo-1-(2,6-dichloro-4-aminophenyl)-6-methoxynaphthyl-ene
(200 mg, 0.65 mmol) and triethylamine (16 mg, 0.154 mmol) were
dissolved in anhyd dichloromethane (1.0 mL) and cooled to 0.degree.
C. Ethyl 3-chloro-3-oxopropanoate (20 mg, 0.13 mmol) was added and
the reaction was warmed to room temperature and stirred for 2 hrs.
The reaction mixture was diluted with ethyl acetate, washed with
water and brine, dried over magnesium sulfate, filtered and
evaporated in vacuo to yield 62 mg (99%) of an off white solid.
1H-NMR was consistent with the proposed structure.
[0138] The malonic ester formed by Compound lg (62 mg, 0.124 mmol)
was dissolved in anhyd dichloromethane (1.1 mL) under a blanket of
argon and cooled to -78.degree. C. Neat boron tribromide (310
mg,1.24 mmol) was added dropwise. The reaction was warmed to
0.degree. C. and stirred for ca. 30 min. The reaction was poured
into a mixture of saturated ammonium chloride and ethyl acetate.
The layers were separated and the organic extracts washed with
brine, dried over anhyd magnesium sulfate, filtered and evaporated
in vacuo. The crude demethylated product was dissolved in methanol
and treated with 1 N sodium hydroxide (0.75 mmol) and stirred at
room temperature for 1 hr. Methanol was removed in vacuo. The
residue was dissolved in water and acidified to pH 1 with 1 N
hydrochloric acid. The product was extracted into ethyl acetate.
The combined extracts were washed with brine, dried over anhyd
magnesium sulfate, filtered and evaporated in vacuo to give 38 mg
(83% yield) of the title compound of Example 1. 1H-NMR and mass
spec are consistent with the proposed structure.
EXAMPLE 2
[0139] 17
2-[3,5-dichloro-4-(5-bromo-6-hydroxynaphthyl)-phenyl]-2-amino-2-oxoacetic
acid
[0140] 18
[0141] Compound 1f (397 mg, 1.0 mmol) and triethyl amine (120 mg,
1.2 mmol) were dissolved in anhyd dichloromethane (5 mL) and cooled
to 0.degree. C. Ethyl chlorooxolate (163 mg, 1.2 mmol) was added
dropwise. The reaction was warmed to room temperature and stirred
overnight. The reaction was diluted with ethyl acetate and washed
with water and brine, dried over anhyd magnesium sulfate, filtered
and dried in vacuo. Flash chromatography (30 g silica gel, elute
with 15% ethyl acetate in hexanes) provided pure product (298 mg,
60%). 1H-NMR was consistent with the proposed structure.
[0142] The ester formed by Compound 2a (60 mg, 0.12 mmol) was
deprotected using the protocol described for Compound 1h yielding
25 mg, (55%) of the title compound of Example 2. 1H-NMR and mass
spec were consistent with the proposed structure of Example 2.
EXAMPLE 3
[0143] 19
N-[3,5-dichloro-4-(5-bromo-6-hydroxynaphthyl)-phenyl]-glycine
[0144] 20
[0145] Compound 1f (50 mg, 0.126 mmol) was dissolved in anhyd
acetonitrile (1 mL) and treated with potassium carbonate (19 mg,
0.139 mmol) and ethyl bromoacetate (23 mg, 0.139 mmol). The
reaction was heated to 80.degree. C. for 2 h. Very little reaction
was evident. Additional ethyl bromoacetate (112 mg, 0.68 mmol) was
added. Heating was continued overnight. The reaction was diluted
with ethyl acetate and water. The layers were separated and the
organic layer was washed with water and brine, dried over anhyd
magnesium sulfate, filtered and evaporated in vacuo. The crude
product was carried onto the next step without further
purification.
[0146] The ester formed by Compound 3a (60 mg, 0.12 mmol) was
deprotected using the protocol described for compound 1 hr yielding
45 mg (55%) of the title Compound of Example 3. 1H-NMR and mass
spec were consistent with the proposed structure.
EXAMPLE 4
[0147] 21
3-[3,5-dichloro-4-(5-bromo-6-hydroxynaphthyl)-phenyl]-3-aminopropanoic
acid
[0148] 22
[0149] Compound 1f (45 mg, 0.113 mmol) was dissolved in acetic acid
(64 .mu.L). Methyl acrylate was added and the reaction mixture was
heated to 117.degree. C. Very little reaction had occurred in 1.5
hrs. Additional acetice acid (650 .mu.L) and methyl acrylate (490
mg, 5.6 mmol) were added. The reaction was heated at 117.degree. C.
overnight. The reaction was cooled to room temperature, diluted
with ethyl acetate, washed with water and brine, dried over anhyd
magnesium sulfate, filtered and evaporated to dryness. The crude
product mixture (55 mg) was carried onto the next step without
further purification.
[0150] The product from Compound 4a (55 mg) was deprotected using
the protocol described for Compound 1h. The title compound of
Example 4 (11 mg, 21%) was isolated by silica gel chromatography
(2.5 g silica gel, elute with 50% ethyl acetate in hexanes (100 mL)
followed by 50% ethyl acetate in hexanes containing 1% acetic
acid). 1H-NMR and mass spec were consistent with the proposed
structure.
EXAMPLE 5
[0151] 23
4-[3,5-dichloro-4-(5-bromo-6-hydroxynaphthyl)-phenyl]-4-amino-4-oxobutyric
acid
[0152] By appropriate application of the procedures described in
Example 4 above,
4-[3,5-dichloro-4-(5-bromo-6-hydroxynaphthyl)-phenyl]-4-amino-4-ox-
obutyric acid (17 mg, 31%) was synthesized from Compound 1f (40 mg,
0.112 mmol). 1H-NMR and mass spec were consistent with the proposed
structure.
EXAMPLE 6
[0153] 24
3-[3,5-dichloro-4-[5-(1-methylethyl)-6-hydroxynaphthyl]-phenyl]-3-amino-3--
oxopropanoic acid
[0154] 25
[0155] Compound 1d (282 mg, 0.81 mmol) and acetic anhydride (244
mg, 2.4 mmol) were dissolved in anhyd dichloromethane (10 mL).under
a blanket of argon and cooled to -78.degree. C. Boron trifluoride
dimethyl sulfide complex (311 mg, 2.4 mmol) was added dropwise. The
reaction was stirred at -78.degree. C. for 10 min then warmed to
room temperature for 6 hrs.
[0156] Compound 6a (243 mg, 77%) was isolated by silica gel
chromatography (30 g silica gel, elute with 5% ethyl acetate in
hexanes). 1H-NMR was consistent with the proposed structure. 26
[0157] Nysted reagent (927 .mu.L of a 20% w/w solution in THF, 216
mg, 0.47 mmol) was suspended in anhyd tetrahydrofuran (2 mL) and
cooled to -78.degree. C. A solution of the ketone from 6a (148 mg,
0.38 mmol) in anhyd dichloromethane (2 mL) was added over a period
of 10-15 min. Titanium tetrachloride (1.0 M in dichloromethane, 380
.mu.L, 0.38 mmol) was added dropwise. The reaction was stirred for
a further 0.5 hrs. at -78.degree. C., then warmed to room
temperature overnight. The reaction was diluted with ethyl acetate,
washed with saturated aqueous sodium bicarbonate and brine, dried
over anhyd magnesium sulfate, filtered and dried in vacuo. Compound
6b (40 mg, 27%) was isolated by silica gel chromatography (8 g
silica gel, elute with 2.5% ethyl acetate in hexanes). 1H-NMR was
consistent with the proposed structure. 27
[0158] Compound 6b (40 mg, 0.103 mmol), was dissolved in acetic
acid (3 mL) and water (0.3 mL). Iron powder (57 mg, 1.0 mmol) was
added and the reaction stirred vigorously for 1 h. The reaction was
filtered through a pad of celite. The celite was rinsed with ethyl
acetate three times. The combined organic layers were washed with
water, saturated aqueous sodium bicarbonate and brine, dried over
anhyd magnesium sulfate, filtered and evaporated in vacuo to yield
38 mg (99%) of product. 1H-NMR was consistent with the proposed
structure. 28
[0159] The olefin formed by Compound 6c (36 mg, 0.102 mmol) was
dissolved in ethanol (1 mL). Platinum (IV) oxide (25 mg) was added
and the reaction rapidly stirred under 1 atmosphere of hydrogen
gas. After 2 hrs., the reaction was filtered and dried in vacuo to
yield 36 mg (98%) of the title compound. 1H-NMR was consistent with
the proposed structure. 29
[0160] Compound 6d (37 mg, 0.102 mmol) and triethyl amine (12 mg,
0.122 mmol) were dissolved in anhyd dimethyl formamide and cooled
to 0.degree. C. Ethyl 3-chloro-3-oxoproprionate (18 mg, 0.122 mmol)
was added dropwise. The reaction was warmed to room temperature and
stirred overnight. Additional ethyl 3-chloro-3-oxorproprionate (7.5
mg, 0.05 mmol) was added. The reaction was complete after 2 h. The
solvent was evaporated in vacuo. The residue was dissolved in ethyl
acetate and washed with water and brine, dried over anhyd magnesium
sulfate, filtered and evaporated in vacuo to yield 45 mg of crude
product. Compound 6e (14 mg, 29%) was isolated by silica gel
chromatography (3 g silica gel, elute with 20% ethyl acetate in
hexanes). 1H-NMR was consistent with the proposed structure.
[0161] Compound 6e (14 mg, 0.03 mmol) was dissolved in anhyd
dichloromethane (300 .mu.L) and cooled to -78.degree. C. under a
blanket of argon. Boron tribromide (74 mg, 0.3 mmol) was added
dropwise. The reaction was stirred at -78.degree. C. for 15 min
then warmed to 0.degree. C. for 2 hrs. The excess boron tribromide
was quenched by pouring the reaction mixture into a flask
containing a rapidly stirring mixture of ethyl acetate and aqueous
ammonium chloride. The organic layer was separated and washed with
brine, dried over anhyd magnesium sulfate, filtered and evaporated
in vacuo. The residue was dissolved in methanol (1 mL) and treated
with 1 N sodium hydroxide (0.1 mL) at room temperature for 2 hrs.
The methanol was removed in vacuo. The residue was diluted with
water, acidified to a pH of 1 with 1 N hydrochloric acid and
extracted with ethyl acetate. The combined extracts were washed
with brine, dried over anhyd magnesium sulfate, filtered and
evaporated in vacuo to yield 10 mg (78%) of the title product of
Example 6 as a yellow glass. 1H-NMR and mass spec were consistent
with the proposed structure.
EXAMPLE 7
[0162] 30
N-[3,5-dichloro-4-(5-phenyl-6-hydroxynaphthyl)-phenyl]-glycine
[0163] 31
[0164] Compound 3a (26 mg, 0.054 mmol), phenylboronic acid (20 mg,
0.16 mmol) and sodium carbonate (18 mg, 0.16 mmol) were dissolved
in dimethoxyethane (300 .mu.L) and water (50 .mu.L). The solution
was degassed by nitrogen sparge for 10 min.
Tetrakis(triphenylphosphine) palladium (0) (18 mg, 0.015 mmol) was
added and the reaction mixture heated to 80.degree. C. for 4 h. The
reaction mixture was cooled to rt, diluted with water and extracted
with ethyl acetate. The combined extracts were washed with brine,
dried over anhyd sodium sulfate and evaporated in vacuo. Compound
7a (12 mg, 47%) was isolated by preparative thin layer
chromatography (elute with 40% ethyl acetate in hexanes). 1H-NMR
was consistent with the proposed structure.
[0165] The product from 7a (12 mg, 0.026 mmol)) was deprotected
using the protocol described for compound 1h. The title compound of
Example 7 (11 mg, 98%) was isolated by preparative high performance
reverse phase chromatography (YMC ODS 20.times.100 mm column;
buffer A=0.1% TFA in 10% methanol in water, buffer B=0.1% TFA in
90% methanol in water; gradient=50-100% B in 15 min). 1H-NMR and
mass spec were consistent with the proposed structure.
EXAMPLE 8
[0166] 32
N-[3,5-dichloro-4-(5-methyl-6-hydroxynaphthyl)-phenyl]-glycine
[0167] 33
[0168] Compound 3a (20 mg, 0.041 mmol), tribasic potassium
phoshphate (30 mg, 0.14 mmol), methylboronic acid (15 mg, 0.25
mmol) and
1,1'-bis[diphenylphosphino(ferrocene)]-dichloropalladium(II):dichlorometh-
ane 1:1 complex (16 mg, 0.02 mmol) were placed into a pressure tube
and dissolved in dioxane. The solution was degassed by nitrogen
sparge for 10 min. The tube was flushed with argon, sealed and
heated to 110.degree. C. overnight. The reaction was cooled to room
temperature, diluted with ethyl acetate, washed with water and
brine, dried over anhyd magnesium sulfate and dried in vacuo.
Compound 8a (10 mg, 58%) was isolated by preparative thin layer
chromatography (elute with 40% ethyl acetate in hexanes). 1H-NMR
was consistent with the proposed structure.
[0169] The product from 8a (10 mg, 0.024 mmol) was deprotected
using the protocol described for compound 1h. The title compound of
Example 8 (4.3 mg, 48%) was isolated by preparative high
performance reverse phase chromatography (YMC ODS 20.times.100 mm
column; buffer A=0.1% TFA in 10% methanol in water, buffer B=0.1%
TFA in 90% methanol in water; gradient=50-100% B in 15 min). 1H-NMR
and mass spec were consistent with the proposed structure.
EXAMPLES 9-15
[0170] By appropriate application of the procedures described
Examples 9-15 were prepared.
1 Example R.sub.1 R.sub.2 R.sub.3 R.sub.4 9 CH.sub.3 Cl Cl
NHCOCH.sub.2COOH 10 Br H Cl CONHCH.sub.2COOH 11 Ph H Cl
CONHCH.sub.2COOH 12 Br Cl Cl CH.sub.2COOH 13 Br Cl Cl NH.sub.2 14
Br H Cl CH.sub.2COOH 15 H Cl Cl CH.sub.2COOH
* * * * *