U.S. patent application number 16/595633 was filed with the patent office on 2020-02-13 for boron containing small molecules as anti-inflammatory agents.
This patent application is currently assigned to Anacor Pharmaceuticals, Inc.. The applicant listed for this patent is Anacor Pharmaceuticals, Inc.. Invention is credited to Tsutomo Akama, Stephen J. Baker, Carolyn Bellinger-Kawahara, Yvonne Freund, Vincent S. Hernandez, Kirk R. Maples, Jacob J. Plattner, Virginia Sanders, Yong-Kang Zhang, Huchen Zhou.
Application Number | 20200046745 16/595633 |
Document ID | / |
Family ID | 38372267 |
Filed Date | 2020-02-13 |
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United States Patent
Application |
20200046745 |
Kind Code |
A1 |
Baker; Stephen J. ; et
al. |
February 13, 2020 |
BORON CONTAINING SMALL MOLECULES AS ANTI-INFLAMMATORY AGENTS
Abstract
Methods of treating anti-inflammatory conditions through the use
of boron-containing small molecules are disclosed.
Inventors: |
Baker; Stephen J.;
(Collegeville, PA) ; Sanders; Virginia; (San
Francisco, CA) ; Akama; Tsutomo; (Tokyo, JP) ;
Bellinger-Kawahara; Carolyn; (West Linn, OR) ;
Freund; Yvonne; (Los Altos, CA) ; Maples; Kirk
R.; (San Jose, CA) ; Plattner; Jacob J.;
(Berkeley, CA) ; Zhang; Yong-Kang; (San Jose,
CA) ; Zhou; Huchen; (Shanghai, CN) ;
Hernandez; Vincent S.; (Watsonville, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Anacor Pharmaceuticals, Inc. |
New York |
NY |
US |
|
|
Assignee: |
Anacor Pharmaceuticals,
Inc.
New York
NY
|
Family ID: |
38372267 |
Appl. No.: |
16/595633 |
Filed: |
October 8, 2019 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
Y02A 50/30 20180101;
A61P 13/12 20180101; A61P 19/00 20180101; A61P 29/00 20180101; A61P
3/10 20180101; A61P 21/04 20180101; A61P 31/14 20180101; A61P 43/00
20180101; A61P 7/00 20180101; A61P 9/14 20180101; A61P 25/08
20180101; A61P 31/18 20180101; A61P 11/02 20180101; A61P 25/24
20180101; A61P 27/02 20180101; A61P 33/06 20180101; A61P 1/16
20180101; A61P 9/12 20180101; A61P 25/22 20180101; A61P 33/02
20180101; A61P 25/18 20180101; A61P 25/16 20180101; A61P 25/02
20180101; A61P 3/00 20180101; A61P 3/04 20180101; A61P 19/08
20180101; A61P 27/06 20180101; A61P 3/06 20180101; A61P 31/12
20180101; A61P 37/06 20180101; A61P 7/04 20180101; A61P 7/06
20180101; A61P 9/08 20180101; A61P 35/02 20180101; A61P 37/02
20180101; A61P 39/02 20180101; A61P 17/02 20180101; A61P 31/08
20180101; A61P 31/16 20180101; A61P 37/00 20180101; A61P 15/00
20180101; A61P 9/04 20180101; A61P 25/00 20180101; A61P 25/06
20180101; A61P 25/28 20180101; A61P 1/00 20180101; A61P 1/18
20180101; A61P 9/00 20180101; A61P 9/02 20180101; A61P 17/06
20180101; A61P 19/02 20180101; A61P 37/08 20180101; A61P 1/04
20180101; A61P 11/00 20180101; A61P 27/14 20180101; A61P 31/00
20180101; C07F 5/027 20130101; A61P 9/10 20180101; A61P 25/30
20180101; Y02A 50/411 20180101; A61P 1/14 20180101; A61P 11/06
20180101; A61P 19/06 20180101; A61P 25/14 20180101; A61P 35/00
20180101; A61P 7/02 20180101; A61P 21/00 20180101; A61P 17/00
20180101; A61P 1/12 20180101; A61P 17/16 20180101; A61P 7/08
20180101; A61P 17/10 20180101; A61P 19/10 20180101; A61K 31/69
20130101; A61P 1/02 20180101 |
International
Class: |
A61K 31/69 20060101
A61K031/69; C07F 5/02 20060101 C07F005/02 |
Claims
1-39. (canceled)
40. A method of treating or preventing diabetes in a human
comprising administering to the human in need of such treatment a
therapeutically effective amount of a compound of structure
##STR00127## or a pharmaceutically acceptable salt thereof.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 14/688,581, filed Apr. 16, 2015, which is a
continuation of U.S. patent application Ser. No. 13/954,770, filed
Jul. 30, 2013, now U.S. Pat. No. 9,029,353 issued May 12, 2015,
which is a continuation of U.S. patent application Ser. No.
13/453,682, filed Apr. 23, 2012, now U.S. Pat. No. 8,501,712 issued
on Aug. 6, 2013, which is a continuation of U.S. patent application
Ser. No. 11/676,120, filed Feb. 16, 2007, now U.S. Pat. No.
8,168,614 issued on May 1, 2012, which claims priority to U.S.
Provisional Patent Application No. 60/823,888 filed on Aug. 29,
2006 and U.S. Provisional Patent Application No. 60/774,532 filed
on Feb. 16, 2006. All applications to which priority is claimed are
hereby incorporated by reference in their entirety for all
purposes.
BACKGROUND FOR THE INVENTION
[0002] Irregular inflammation is a major component of a wide range
of human diseases. People suffering from degenerative disorders
often exhibit excess levels of pro-inflammatory regulators in their
blood. One type of such pro-inflammatory regulators are cytokines
including IL-1.alpha., .beta., IL-2, IL-3, IL-6, IL-7, IL-9, IL-12,
IL-17, IL-18, IL-23, TNF-.alpha., LT, LIP, Oncostatin, and
IFNc1.alpha., .beta., .gamma..
[0003] A non-limiting list of common medical problems that are
directly caused by inflammatory cytokines include: arthritis where
inflammatory cytokines can lead to lesions in the synovial membrane
and destruction of joint cartilage and bone: kidney failure where
inflammatory cytokines restrict circulation and damage nephrons:
lupus where inflammatory cytokines exacerbate immune complex
deposition and damage; asthma where inflammatory cytokines close
the airway; psoriasis where inflammatory cytokines induce
dermatitis: pancreatitis where inflammatory cytokines induce
pancreatic cell injury; allergy where inflammatory cytokines induce
vasopermeability and congestion: fibrosis where inflammatory
cytokines attack traumatized tissue; surgical complications where
inflammatory cytokines prevent healing; anemia where inflammatory
cytokines attack erythropoietin production; and fibromyalgia where
inflammatory cytokines are elevated in fibromyalgia patients.
[0004] Other diseases associated with chronic inflammation include
cancer; heart attack where chronic inflammation contributes to
coronary atherosclerosis; Alzheimer's disease where chronic
inflammation destroys brain cells; congestive heart failure where
chronic inflammation causes heart muscle wasting; stroke where
chronic inflammation promotes thrombo-embolic events; and aortic
valve stenosis where chronic inflammation damages heart valves.
Arteriosclerosis, osteoporosis, Parkinson's disease, infection,
inflammatory bowel disease including Crohn's disease and ulcerative
colitis as well as multiple sclerosis (a typical autoimmune
inflammatory-related disease) are also related to inflammation
(Bebo, B. F., Jr., J Neurosci Res, 45: 340-348, (1996); Mennicken,
F., Trends Pharmacol Sci, 20: 73-78, (1999); Watanabe, T. Int J
Cardiol, 66 Suppl 1: S45-53; discussion S55, (1998); Sullivan, G.
W., J Leukoc Biol, 67: 591-602, (2000); Franceschi, C., Ann N Y
Acad Sci, 908: 244-254, (2000); Rogers, J, Ann N Y Acad Sci, 924:
132-135, (2000); Li, Y. J., Hum Mol Genet, 12: 3259-3267, (2003);
Maccarrone, M., Curr Drug Targets Inflamm Allergy, 1: 53-63,
(2002); Lindsberg, P. J., Stroke, 34: 2518-2532, (2003); DeGraba,
T. J., Adv Neurol, 92: 29-42, (2003); Ito, H., Curr Drug Targets
Inflamm Allergy, 2: 125-130, (2003); von der Thusen, J. H.,
Pharmacol Rev, 55: 133-166, (2003); Schmidt, M. I., Clin Chem Lab
Med, 41: 1120-1130, (2003); Virdis, A., Curr Opin Nephrol
Hypertens, 12: 181-187, (2003); Tracy, R. P., Int J Clin Pract,
Suppl 10-17, (2003); Haugeberg, G., Curr Opin Rheumatol, 15:
469-475, (2003); Tanaka, Y., J Bone Miner Metab, 21: 61-66, (2003);
Williams, J. D., Clin Exp Dermatol, 27: 585-590, (2002)). Some
diseases in advanced stages can be life threatening. Several
methodologies are available for the treatment of such inflammatory
diseases; the results, however, are generally unsatisfactory as
evidenced by a lack of efficacy and drug related side effects
associated therewith.
Inflammatory Bowel Disease
[0005] Inflammatory bowel disease (IBD) comprises Crohn's disease
(CD) and ulcerative colitis (UC), both of which are idiopathic
chronic diseases occurring with an increasing frequency in many
parts of the world. In the United States, more than 600,000 are
affected every year. IBD can involve either small bowel, large
bowel, or both. CD can involve any part of the gastrointestinal
tract, but most frequently involves the distal small bowel and
colon. It either spares the rectum, or causes inflammation or
infection with drainage around the rectum. UC usually causes ulcers
in the lower part of the large intestine, often starting at the
rectum. Symptoms vary but may include diarrhea, fever, and pain.
Patients with prolonged UC are at an increased risk of developing
colon cancer. There is currently no satisfactory treatment, as the
cause for IBD remains unclear although infectious and immunologic
mechanisms have been proposed. IBD treatments aim at controlling
inflammatory symptoms, conventionally using corticosteroids,
aminosalicylates and standard immunosuppressive agents such as
azathioprine (6-mercaptopurine), methotrexate and ciclosporine. Of
these, the only disease-modifying therapies are the
immunosuppressive agents azathioprine and methotrexate, both of
which have a slow onset of action and only a moderate efficacy.
Long-term therapy may cause liver damage (fibrosis or cirrhosis)
and bone marrow suppression. Also patients often become refractory
to such treatment. Other therapeutic regimes merely address
symptoms (Rutgeerts, P. A, J Gastroenterol Hepatol. 17 Suppl:
S176-185 (2002); Rutgeerts, P., Aliment Pharmacol Ther. 17: 185-192
(2003)).
Psoriasis
[0006] Psoriasis is one of the most common immune-mediated chronic
skin diseases that comes in different forms and varied levels of
severity, affecting approximately 2% of the population or more than
4.5 million people in the United States of which 1.5 million are
considered to have a moderate to severe form of the disease. Ten to
thirty percent of patients with psoriasis also develop a form of
arthritis-psoriatic arthritis, which damages the bone and
connective tissue around the joints. Psoriasis appears as patches
of raised red skin covered by a flaky white buildup. It may also
have a pimple-ish (pustular psoriasis) or burned (erythrodermic)
appearance. Psoriasis may also cause intense itching and burning.
Patients suffer psychologically as well as physically. Several
modalities are currently available for treatment of psoriasis,
including topical treatment, phototherapy, and systemic
applications. However, they are generally considered to be only
disease suppressive and disease modifying; none of them are
curative. Moreover, many treatments are either cosmetically
undesirable, inconvenient for long-term use, or associated with
significant toxicity.
[0007] With increased understanding of the biological properties of
psoriasis over the past two decades, biologic therapies targeting
the activity of T lymphocytes and cytokines responsible for the
inflammatory nature of this disease have become available.
Currently, drugs prescribed for psoriasis include TNF-.alpha.
inhibitors initially used for rheumatoid arthritis (RA) treatment,
ENBREL.RTM. (etanercept), REMICADE.RTM. (infliximab) and
HUMIRA.RTM. (adalimumab), and T-cell inhibitor AMEVIVE.RTM.
(alefacept) from Biogen approved in 2002 and RAPTIVA.RTM.
(efalizumab) from Genentech/Xoma approved in 2003 (Weinberg, J. M.,
J Drugs Dermatol, 1: 303-310, (2002)). AMEVIVE ALEFACEPT.RTM. is an
immunoglobulin fusion protein composed of the first extracellular
domain of human LFA-3 fused to the hinge, C(H)2 and C(H)3 domains
of human IgG(1). It inhibits T cell proliferation through NK cells
(Cooper, J. C., Eur J Immunol, 33: 666-675, (2003)). RAPTIVA.RTM.
is also known as anti-CD11a, a humanized monoclonal antibody which
targets the T cell adhesion molecule, leukocyte function-associated
antigen-1 (LFA-1). Prevention of LFA-1 binding to its ligand
(ICAM-1, intercellular adhesion molecule-1) inhibits lymphocyte
activation and migration, resulting in a decreased lymphocyte
infiltration, thereby limiting the cascade of events eventually
leading to the signs and symptoms of psoriasis (Cather, J. C.,
Expert Opin Biol Ther, 3: 361-370, (2003)). Potential side effects
for current TNF-.alpha. inhibitors of the prior art, however, are
severe, including development of lymphoma (Brown, S. L., Arthritis
Rheum, 46: 3151-3158, (2002)), worsening congestive heart failure,
resulting in a serious infection and sepsis, and exacerbations of
multiple sclerosis and central nervous system problems (Weisman, M.
H., J Rheumatol Suppl, 65: 33-38, (2002); Antoni, C., Clin Exp
Rheumatol, 20: S152-157, (2002)). While side effects of the T-cell
inhibitor of AMEVIVE.RTM./RAPTIVA.RTM. may be more tolerable in
psoriasis treatment, RAPTIVA.RTM. is an immunosuppressive agent.
Immunosuppressive agents have the potential to increase the risk of
infection, reactivate latent, chronic infections or increase the
risk of cancer development.
[0008] Although many advances have been made in the understanding
of the biological properties of psoriasis over the past two decades
and an unconventional treatment for psoriasis has become available
as described above, much of the suffering it produces is still not
adequately addressed. A survey of over 40,000 American patients
with psoriasis performed by the National Psoriasis Foundation in
1998 showed 79% of the younger patients felt frustrated by the
ineffectiveness of their treatment. Of those with severe disease,
32% felt their treatment was not aggressive enough (Mendonca, C.
O., Pharmacol Ther, 99: 133-147, (2003); Schon, M. P., J Invest
Dermatol, 112: 405-410, (1999)).
Rheumatoid Arthritis
[0009] Rheumatoid arthritis (RA) represents another example of
troublesome inflammatory disorders. It is a common chronic
inflammatory-related disease characterized by chronic inflammation
in the membrane lining (the synovium) of the joints and/or other
internal organs. The inflammatory cells can also invade and damage
bone and cartilage. The joint involved can lose its shape and
alignment, resulting in loss of movement. Patients with RA have
pain, stiffness, warmth, redness and swelling in the joint, and
other systemic symptoms like fever, fatigue, and anemia.
Approximately 1% of the population or 2.1 million in the U.S. are
currently affected, of which more are women (1.5 million) than men
(0.6 million). The pathology of RA is not fully understood although
the cascade of improper immunological reactions has been postulated
as a mechanism. Conventional treatment is unfortunately inefficient
in RA (Bessis, N., J Gene Med, 4: 581-591, (2002)) (29). The
disease does not respond completely to symptomatic medications
including corticosteroids and non-steroidal anti-inflammatory drugs
(NSAIDs) used since the 1950s. Also, these medications carry a risk
of serious adverse effects. The therapeutic effects of the
disease-modifying antirheumatic drugs (DMARDs) such as Methotrexate
(MTX) are often inconsistent and short-lived.
[0010] A new class of biologic DMARDs (disease-modifying
antirheumatic drugs) for the treatment of RA has recently been
developed based on an understanding of the role of cytokines,
TNF-.alpha. and IL-1, in the inflammatory process. The FDA has
approved several such DMARDs including ENBREL.RTM. (etanercept)
from Immunex/Amgen Inc. in 1998, REMICADE.RTM. (infliximab) from
Centocor/Johnson & Johnson, HUMIRA.RTM. (adalimumab) from
Abbott Laboratories Inc. in 2002, and KINERET.RTM. (anakinra) from
Amgen in 2001. ENBREL.RTM. is a soluble TNF receptor (TNFR)
recombinant protein. REMICADE.RTM. is a humanized mouse (chimeric)
anti-TNF-.alpha. monoclonal antibody. HUMIRA.RTM. is a fully human
anti-TNF monoclonal antibody created using phage display technology
resulting in an antibody with human-derived heavy and light chain
variable regions and human IgG1:k constant regions. All these 3
protein-based drugs target and bind to TNF-.alpha. to block the
effects of TNF-.alpha.. KINERET.RTM. is a recombinant IL-1 receptor
antagonist, which is similar to native human IL-1Ra, except for the
addition of a single methionine residue at its amino terminus.
KINERET.RTM. blocks the biologic activity of IL-1 by competitively
inhibiting IL-1 binding to the IL-1 type I receptor (IL-1RI) and
consequently reducing the pro-inflammatory effects of IL-1.
[0011] The treatment with these biologic DMARDs relieves symptoms,
inhibits the progression of structural damage, and improves
physical function in patients with moderate to severe active RA.
The three marketed TNF-.alpha. blocking agents have similar
efficacy when combined with MTX, a widely used DMARD, in the
treatment of patients with RA (Hochberg, M. C., Ann Rheum Dis, 62
Suppl 2: ii13-16, (2003)). While providing significant efficacy and
a good overall safety profile in the short and medium term in many
patients with RA, these biologic treatments may create serious
problems and long-term side effects, such as in the liver, and
still need to be evaluated. There has been a disturbing association
between the use of both of ENBREL.RTM. or REMICADE.RTM. and the
development of lymphoma, (S. L., Arthritis Rheum, 46: 3151-3158,
(2002)). As described above, several reports have shown that
patients treated with ENBREL.RTM. or REMICADE.RTM. worsen their
congestive heart failure and develop serious infection and sepsis,
and increase exacerbations of multiple sclerosis and other central
nervous system problems (Antoni, C., Clin Exp Rheumatol, 20:
S152-157, (2002); Mendonca, C. O., Pharmacol Ther, 99: 133-147,
(2003)).
Multiple Sclerosis
[0012] Multiple Sclerosis (MS) is an autoimmune disease diagnosed
in 350,000 to 500,000 people in the United States. Multiple areas
of inflammation and loss of myelin in the brain and spinal cord
signify the disease. Patients with MS exhibit varied degrees of
neurological impairment depending on the location and extent of the
loss of the myelin. Common symptoms of MS include fatigue,
weakness, spasticity, balance problems, bladder and bowel problems,
numbness, vision loss, tremors and depression. Current treatment of
MS only alleviates symptoms or delays the progression of
disability, and several new treatments for MS including stem cell
transplantation and gene therapy are conservatory (Fassas, A.,
Blood Rev, 17: 233-240, (2003); Furlan, R., Curr Pharm Des, 9:
2002-2008, (2003)). While anti-TNF antibodies have shown protective
effects in experimental autoimmune encephalomyelitis (EAE), they
aggravate the disease in MS patients, suggesting that inhibition of
TNF-.alpha. alone is not sufficient (Ghezzi, P.,
Neuroimmunomodulation, 9: 178-182, (2001)).
Neurodegenerative Disorders
[0013] Alzheimer's disease (AD) and Parkinson's disease (PK) are
the two most common neurodegenerative disorders. AD seriously
affects a person's ability to carry out daily activities. It
involves the parts of the brain that control thought, memory, and
language. About 4 million Americans, usually after age 60, are
estimated to suffer from AD.
[0014] PK is a progressive disorder of the central nervous system
affecting over 1.5 million people in the United States. Clinically,
the disease is characterized by a decrease in spontaneous
movements, gait difficulty, postural instability, rigidity and
tremor. PK is caused by the degeneration of the pigmented neurons
in the substantia nigra of the brain, resulting in decreased
dopamine availability. The causes of these neurodegenerative
disorders are unknown and there is currently no cure for the
disease.
[0015] Thus, novel approaches for the treatment of the above and
other inflammatory-related diseases are needed. Although
inflammatory-related disease mechanisms remain unclear and often
vary from each other, dysfunction of the immune system caused by
deregulation of cytokines has been demonstrated to play an
important role in the initiation and progression of inflammation
(Schon, M. P., J Invest Dermatol, 112: 405-410, (1999); Andreakos,
E. T., Cytokine Growth Factor Rev, 13: 299-313, (2002); Najarian,
D. J., J Am Acad Dermatol, 48: 805-821, (2003)).
[0016] Cytokines can be generally classified into 3 types:
pro-inflammatory (IL-1.alpha., .beta., IL-2, IL-3, IL-6, IL-7,
IL-9, IL-12, IL-17, IL-18, IL-23, TNF-.alpha., LT, LIF, Oncostatin,
and IFNc1.alpha., .beta., .gamma.); anti-inflammatory (IL-4, IL-10,
IL-11, W-13 and TGF-.beta.); and chemokines (IL-8, Gro-.alpha.,
MIP-1, MCP-1, ENA-78, and RANTES).
[0017] In many inflammatory conditions, pro-inflammatory cytokines,
especially TNF-.alpha., IL-1.beta., and IL-6, as well as
anti-inflammatory cytokine IL-10 appear to play an important role
in the pathogenesis of various inflammatory-related diseases and
therefore may serve as potential therapeutic targets. For example,
elevated levels of some pro-inflammatory cytokines (TNF-.alpha.,
IFN.gamma., IL-1, IL-2, IL-6 and IL-12) and chemokines (IL-8, MCP-1
and RANTES) have been observed in several inflammatory-related
diseases such as CD, psoriasis, RA, Grave's disease and Hashimoto's
thyroiditis (Andreakos, E. T., Cytokine Growth Factor Rev, 13:
299-313, (2002)), which parallels an increase in soluble TNF
receptors, IL-1 receptor antagonists and the anti-inflammatory
cytokine IL-10 (Noguchi, M., Gut, 43: 203-209, (1998); Autschbach,
F., Am J Pathol, 153: 121-130, (1998)). IL-10 has been shown to
suppress elevated pro-inflammatory cytokine production both in
vitro in LPMC cultures and in vivo in patients (Schreiber, S.,
Gastroenterology, 108: 1434-1444, (1995)). Positive response of CD
patients treated with IL-10 demonstrates that there might also be
an imbalance between the production of pro-inflammatory and
anti-inflammatory cytokines in CD.
[0018] In summary, the approach of treating inflammatory-related
diseases has undergone an evolutionary change in recent years in
part as a consequence of growing concerns of the severity of these
diseases and in part due to considerable progress in the
understanding of the important role of cytokines in their
immuno-pathogenesis. The majority of the efforts have been focused
on targeting TNF-.alpha. and IL-1 (Baugh, J. A., Curr Opin Drug
Discov Devel, 4: 635-650, (2001)), and several products
(TNF-.alpha. inhibitors: infliximab, a monoclonal anti-TNF-.alpha.
antibody; and etanercept, the p75 TNF-.alpha. receptor) are
currently marketed or in clinical trials for the treatment of RA,
psoriasis and IBD as mentioned above. Several other drug candidates
or strategies targeting IL-1 (Gabay, C., Curr Opin Investig Drugs,
4: 593-597, (2003)), IL-6 or IL-10 are under development (Gabay,
C., Curr Opin Investig Drugs, 4: 593-597, (2003); Palladino, M. A.,
Nat Rev Drug Discov, 2: 736-746, (2003); Girolomoni, G., Curr Opin
Investig Drugs, 3: 1590-1595, (2002)). These biological treatments
provide significant efficacy in the short and medium term in many
patients with RA (Elliott, M. J., Lancet, 344: 1125-1127, (1994);
Moreland, L. W., N Engl J Med, 3377: 141-147, (1997); Campion, G.
V., Arthritis Rheum, 39: 1092-1101, (1996); Feldmann, M., Nat
Immunol, 2: 771-773, (2001)). Although these drugs are well
tolerated and have a good overall safety profile, there remains a
need in the art for additional drugs which can inhibit
pro-inflammatory cytokines or stimulate anti-inflammatory
cytokines.
[0019] Based on this concept, we examined several types of small
molecules to test their ability in the regulation of multiple
cytokines and explored their potential clinical applications for
the treatment of a variety of inflammatory-related diseases.
SUMMARY OF THE INVENTION
[0020] In a first aspect, the invention provides a method of
treating or preventing an inflammatory-related disease in a human
or an animal, said method comprising administering to the human or
the animal a therapeutically effective amount of a compound
described herein. In an exemplary embodiment, the compound is a
member selected from C1-C100. In an exemplary embodiment, the
compound has a structure according to Formula I:
##STR00001##
wherein B is boron. R.sup.1a is a member selected from a negative
charge, a salt counterion, H, cyano, substituted or unsubstituted
alkyl, substituted or unsubstituted heteroalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, and
substituted or unsubstituted heteroaryl. M is a member selected
from oxygen, sulfur and NR.sup.2a. R.sup.2a is a member selected
from H, substituted or unsubstituted alkyl, substituted or
unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted heterocycloalkyl, substituted or
unsubstituted aryl, and substituted or unsubstituted heteroaryl. J
is a member selected from (CR.sup.3aR.sup.4a).sub.n1 and CR.sup.5a,
R.sup.3a, R.sup.4a, and R.sup.5a are members independently selected
from H, cyano, substituted or unsubstituted alkyl, substituted or
unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted heterocycloalkyl, substituted or
unsubstituted aryl, and substituted or unsubstituted heteroaryl.
The index n1 is an integer selected from 0 to 2. W is a member
selected from C.dbd.O (carbonyl), (CR.sup.6aR.sup.7a).sub.m1 and
CR.sup.8a, R.sup.6a, R.sup.7a, and R.sup.8a are members
independently selected from H, cyano, substituted or unsubstituted
alkyl, substituted or unsubstituted heteroalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, and
substituted or unsubstituted heteroaryl. The index m1 is an integer
selected from 0 and 1. A is a member selected from CR.sup.9a and N.
D is a member selected from CR.sup.10a and N. E is a member
selected from CR.sup.11a and N. G is a member selected from
CR.sup.12a and N. R.sup.9a, R.sup.10a, R.sup.11a and R.sup.12a are
members independently selected from H, OR*, NR*R**, SR*, --S(O)R*,
--S(O).sub.2R*, --S(O).sub.2NR*R**, --C(O)R*, --C(O)OR*,
--C(O)NR*R**, nitro, halogen, cyano, substituted or unsubstituted
alkyl, substituted or unsubstituted heteroalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, and
substituted or unsubstituted heteroaryl. Each R* and R** are
members independently selected from H, nitro, halogen, cyano,
substituted or unsubstituted alkyl, substituted or unsubstituted
heteroalkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocycloalkyl, substituted or unsubstituted
aryl, and substituted or unsubstituted heteroaryl. The combination
of nitrogens (A+D+E+G) is an integer selected from 0 to 3. A member
selected from R.sup.3a, R.sup.4a and R.sup.5a and a member selected
from R.sup.6a, R.sup.7a and R.sup.8a, together with the atoms to
which they are attached, are optionally joined to form a 4 to 7
membered ring. R.sup.3a and R.sup.4a, together with the atoms to
which they are attached, are optionally joined to form a 4 to 7
membered ring. R.sup.6a and R.sup.7a, together with the atoms to
which they are attached, are optionally joined to form a 4 to 7
membered ring. R.sup.9a and R.sup.10a, together with the atoms to
which they are attached, are optionally joined to form a 4 to 7
membered ring. R.sup.10a and R.sup.11a together with the atoms to
which they are attached, are optionally joined to form a 4 to 7
membered ring. R.sup.11a and R.sup.12a, together with the atoms to
which they are attached, are optionally joined to form a 4 to 7
membered ring.
[0021] In a second aspect, the invention provides a method of
treating or preventing an inflammatory-related disease in a human
or an animal, said method comprising administering to the human or
the animal a therapeutically effective amount of a compound having
a structure according to Formula II:
##STR00002##
wherein B is boron. R.sup.20, R.sup.21 and R.sup.22 are members
independently selected from a negative charge, a salt counterion,
H, substituted or unsubstituted alkyl, substituted or unsubstituted
heteroalkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocycloalkyl, substituted or unsubstituted
aryl, and substituted or unsubstituted heteroaryl. A is a member
selected from CR.sup.9a and N. D is a member selected from
CR.sup.10a and N. E is a member selected from CR.sup.11a and N. G
is a member selected from CR.sup.12a and N. R.sup.9a, R.sup.10a,
R.sup.11a and R.sup.12a are members independently selected from H,
OR*, NR*R**, SR*, --S(O)R*, --S(O).sub.2R*, --S(O).sub.2NR*R**,
--C(O)R*, --C(O)OR*, --C(O)NR*R**, nitro, halogen, cyano,
substituted or unsubstituted alkyl, substituted or unsubstituted
heteroalkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocycloalkyl, substituted or unsubstituted
aryl, and substituted or unsubstituted heteroaryl. Each R* and R**
are members independently selected from H, nitro, halogen, cyano,
substituted or unsubstituted alkyl, substituted or unsubstituted
heteroalkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocycloalkyl, substituted or unsubstituted
aryl, and substituted or unsubstituted heteroaryl. The combination
of nitrogens (A+D+E+G) is an integer selected from 0 to 3. A member
selected from R.sup.3a, R.sup.4a and R.sup.5a and a member selected
from R.sup.6a, R.sup.7a and R.sup.8a, together with the atoms to
which they are attached, are optionally joined to form a 4 to 7
membered ring. R.sup.3a and R.sup.4a, together with the atoms to
which they are attached, are optionally joined to form a 4 to 7
membered ring. R.sup.6a and R.sup.7a, together with the atoms to
which they are attached, are optionally joined to form a 4 to 7
membered ring. R.sup.9a and R.sup.10a, together with the atoms to
which they are attached, are optionally joined to form a 4 to 7
membered ring. R.sup.10a and R.sup.11a together with the atoms to
which they are attached, are optionally joined to form a 4 to 7
membered ring. R.sup.11a and R.sup.12a, together with the atoms to
which they are attached, are optionally joined to form a 4 to 7
membered ring.
[0022] The invention also provides additional methods of using the
compounds and pharmaceutical formulations of the compounds
described herein.
BRIEF DESCRIPTION OF THE DRAWINGS
[0023] FIG. 1A-FIG. 1B describe the degree to which the compounds
of the invention inhibited each of four cytokines: TNF-.alpha.,
IL-1.beta., IFN-.gamma., and IL-4.
[0024] FIG. 2A-FIG. 2K display exemplary compounds of the
invention.
[0025] FIG. 3A-FIG. 3H display exemplary compounds of the
invention.
DETAILED DESCRIPTION OF THE INVENTION
I. Definitions and Abbreviations
[0026] The abbreviations used herein generally have their
conventional meaning within the chemical and biological arts.
[0027] "Compound of the invention," as used herein refers to the
compounds discussed herein, pharmaceutically acceptable salts and
prodrugs of these compounds.
[0028] "Inhibiting" and "blocking," are used interchangeably herein
to refer to the partial or full blockade of the expression of a
pro-inflammatory cytokine by a method of the invention, which leads
to a decrease in the amount of the cytokine in the subject or
patient.
[0029] Where substituent groups are specified by their conventional
chemical formulae, written from left to right, they equally
encompass the chemically identical substituents, which would result
from writing the structure from right to left, e.g.,
--CH.sub.2O--is intended to also recite --OCH.sub.2--.
[0030] The term "poly" as used herein means at least 2. For
example, a polyvalent metal ion is a metal ion having a valency of
at least 2.
[0031] "Moiety" refers to the radical of a molecule that is
attached to another moiety.
[0032] The symbol , whether utilized as a bond or displayed
perpendicular to a bond, indicates the point at which the displayed
moiety is attached to the remainder of the molecule.
[0033] The term "alkyl," by itself or as part of another
substituent, means, unless otherwise stated, a straight or branched
chain, or cyclic hydrocarbon radical, or combination thereof, which
may be fully saturated, mono- or polyunsaturated and can include
di- and multivalent radicals, having the number of carbon atoms
designated (i.e. C.sub.1-C.sub.10 means one to ten carbons).
Examples of saturated hydrocarbon radicals include, but are not
limited to, groups such as methyl, ethyl, n-propyl, isopropyl,
n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl,
(cyclohexyl)methyl, cyclopropylmethyl, homologs and isomers of, for
example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. An
unsaturated alkyl group is one having one or more double bonds or
triple bonds. Examples of unsaturated alkyl groups include, but are
not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl,
2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1-
and 3-propynyl, 3-butynyl, and the higher homologs and isomers. The
term "alkyl," unless otherwise noted, is also meant to include
those derivatives of alkyl defined in more detail below, such as
"heteroalkyl." Alkyl groups that are limited to hydrocarbon groups
are termed "homoalkyl".
[0034] The term "alkylene" by itself or as part of another
substituent means a divalent radical derived from an alkane, as
exemplified, but not limited, by
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--, and further includes those
groups described below as "heteroalkylene." Typically, an alkyl (or
alkylene) group will have from 1 to 24 carbon atoms, with those
groups having 10 or fewer carbon atoms being preferred in the
present invention. A "lower alkyl" or "lower alkylene" is a shorter
chain alkyl or alkylene group, generally having eight or fewer
carbon atoms.
[0035] The terms "alkoxy," "alkylamino" and "alkylthio" (or
thioalkoxy) are used in their conventional sense, and refer to
those alkyl groups attached to the remainder of the molecule via an
oxygen atom, an amino group, or a sulfur atom, respectively.
[0036] The term "heteroalkyl," by itself or in combination with
another term, means, unless otherwise stated, a stable straight or
branched chain, or cyclic hydrocarbon radical, or combinations
thereof, consisting of the stated number of carbon atoms and at
least one heteroatom. In an exemplary embodiment, the heteroatoms
can be selected from the group consisting of B, O, N and S, and
wherein the nitrogen and sulfur atoms may optionally be oxidized
and the nitrogen heteroatom may optionally be quatemized. The
heteroatom(s) B, O, N and S may be placed at any interior position
of the heteroalkyl group or at the position at which the alkyl
group is attached to the remainder of the molecule. Examples
include, but are not limited to, --CH.sub.2--CH.sub.2--O--CH.sub.3,
--CH.sub.2--CH.sub.2--NH--CH.sub.3,
--CH.sub.2--CH.sub.2--N(CH.sub.3)--CH.sub.3,
--CH.sub.2--S--CH.sub.2--CH.sub.3, --CH.sub.2--CH.sub.2,
--S(O)--CH.sub.3, --CH.sub.2--CH.sub.2--S(O).sub.2--CH.sub.3,
--CH.dbd.CH--O--CH.sub.3, --CH.sub.2--CH.dbd.N--OCH.sub.3, and
--CH.dbd.CH--N(CH.sub.3)--CH.sub.3. Up to two heteroatoms may be
consecutive, such as, for example, --CH.sub.2--NH--OCH.sub.3.
Similarly, the term "heteroalkylene" by itself or as part of
another substituent means a divalent radical derived from
heteroalkyl, as exemplified, but not limited by,
--CH.sub.2--CH.sub.2--S--CH.sub.2--CH.sub.2-- and
--CH.sub.2--S--CH.sub.2--CH.sub.2--NH--CH.sub.2--. For
heteroalkylene groups, heteroatoms can also occupy either or both
of the chain termini (e.g., alkyleneoxy, alkylenedioxy,
alkyleneamino, alkylenediamino, and the like). Still further, for
alkylene and heteroalkylene linking groups, no orientation of the
linking group is implied by the direction in which the formula of
the linking group is written. For example, the formula
--C(O).sub.2R'-- represents both --C(O).sub.2R'-- and
--R'C(O).sub.2--.
[0037] The terms "cycloalkyl" and "heterocycloalkyl", by themselves
or in combination with other terms, represent, unless otherwise
stated, cyclic versions of "alkyl" and "heteroalkyl", respectively.
Additionally, for heterocycloalkyl, a heteroatom can occupy the
position at which the heterocycle is attached to the remainder of
the molecule. Examples of cycloalkyl include, but are not limited
to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl,
cycloheptyl, and the like. Examples of heterocycloalkyl include,
but are not limited to, 1-(1,2,5,6-tetrahydropyridyl),
1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl,
3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl,
tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl,
2-piperazinyl, and the like.
[0038] The terms "halo" or "halogen," by themselves or as part of
another substituent, mean, unless otherwise stated, a fluorine,
chlorine, bromine, or iodine atom. Additionally, terms such as
"haloalkyl," are meant to include monohaloalkyl and polyhaloalkyl.
For example, the term "halo(C.sub.1-C.sub.4)alkyl" is mean to
include, but not be limited to, trifluoromethyl,
2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the
like.
[0039] The term "aryl" means, unless otherwise stated, a
polyunsaturated, aromatic, substituent that can be a single ring or
multiple rings (preferably from 1 to 3 rings), which are fused
together or linked covalently. The term "heteroaryl" refers to aryl
groups (or rings) that contain from one to four heteroatoms. In an
exemplary embodiment, the heteroatom is selected from B, N, O, and
S, wherein the nitrogen and sulfur atoms are optionally oxidized,
and the nitrogen atom(s) are optionally quatemized. A heteroaryl
group can be attached to the remainder of the molecule through a
heteroatom. Non-limiting examples of aryl and heteroaryl groups
include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl,
2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl,
pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl,
3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl,
5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl,
3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl,
purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl,
2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl.
Substituents for each of the above noted aryl and heteroaryl ring
systems are selected from the group of acceptable substituents
described below.
[0040] For brevity, the term "aryl" when used in combination with
other terms (e.g., aryloxy, arylthioxy, arylalkyl) includes both
aryl and heteroaryl rings as defined above. Thus, the term
"arylalkyl" is meant to include those radicals in which an aryl
group is attached to an alkyl group (e.g., benzyl, phenethyl,
pyridylmethyl and the like) including those alkyl groups in which a
carbon atom (e.g., a methylene group) has been replaced by, for
example, an oxygen atom (e.g., phenoxymethyl, 2-pyridyloxymethyl,
3-(1-naphthyloxy)propyl, and the like).
[0041] Each of the above terms (e.g., "alkyl," "heteroalkyl,"
"aryl" and "heteroaryl") are meant to include both substituted and
unsubstituted forms of the indicated radical. Preferred
substituents for each type of radical are provided below.
[0042] Substituents for the alkyl and heteroalkyl radicals
(including those groups often referred to as alkylene, alkenyl,
heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl,
heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) are
generically referred to as "alkyl group substituents," and they can
be one or more of a variety of groups selected from, but not
limited to: --OR', .dbd.O, .dbd.NR', .dbd.N--OR', --NR'R'', --SR',
-halogen, --OC(O)R', --C(O)R', --CO.sub.2R', --CONR'R'',
--OC(O)NR'R'', --NR''C(O)R', --NR'--C(O)NR''R'''',
--NR''C(O).sub.2R', --NR--C(NR'R''R''').dbd.NR'''',
--NR--C(NR'R'').dbd.NR''', --S(O)R', --S(O).sub.2R',
--S(O).sub.2NR'R'', --NRSO.sub.2R', --CN and --NO.sub.2 in a number
ranging from zero to (2m'+1), where m' is the total number of
carbon atoms in such radical. R', R'', R''' and R'''' each
preferably independently refer to hydrogen, substituted or
unsubstituted heteroalkyl, substituted or unsubstituted aryl, e.g.,
aryl substituted with 1-3 halogens, substituted or unsubstituted
alkyl, alkoxy or thioalkoxy groups, or arylalkyl groups. When a
compound of the invention includes more than one R group, for
example, each of the R groups is independently selected as are each
R', R'', R''' and R'''' groups when more than one of these groups
is present. When R' and R'' are attached to the same nitrogen atom,
they can be combined with the nitrogen atom to form a 5-, 6-, or
7-membered ring. For example, --NR'R'' is meant to include, but not
be limited to, 1-pyrrolidinyl and 4-morpholinyl. From the above
discussion of substituents, one of skill in the art will understand
that the term "alkyl" is meant to include groups including carbon
atoms bound to groups other than hydrogen groups, such as haloalkyl
(e.g., --CF.sub.3 and --CH.sub.2CF.sub.3) and acyl (e.g.,
--C(O)CH.sub.3, --C(O)CF.sub.3, --C(O)CH.sub.2OCH.sub.3, and the
like).
[0043] Similar to the substituents described for the alkyl radical,
substituents for the aryl and heteroaryl groups are generically
referred to as "aryl group substituents." The substituents are
selected from, for example: halogen, --OR', .dbd.O, .dbd.NR',
.dbd.N--OR', --NR'R'', --SR', -halogen, --OC(O)R', --C(O)R',
--CO.sub.2R', --CONR'R'', --OC(O)NR'R'', --NR''C(O)R',
--NR'--C(O)NR''R''', --NR''C(O).sub.2R',
--NR--C(NR'R''R''').dbd.NR'''', --NR--C(NR'R'').dbd.NR''',
--S(O)R', --S(O).sub.2R', --S(O).sub.2NR'R'', --NRSO.sub.2R', --CN
and --NO.sub.2, --R', --N.sub.3, --CH(Ph).sub.2,
fluoro(C.sub.1-C.sub.4)alkoxy, and fluoro(C.sub.1-C.sub.4)alkyl, in
a number ranging from zero to the total number of open valences on
the aromatic ring system; and where R', R'', R''' and R'''' are
preferably independently selected from hydrogen, substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted aryl and substituted or unsubstituted
heteroaryl. When a compound of the invention includes more than one
R group, for example, each of the R groups is independently
selected as are each R', R'', R''' and R'''' groups when more than
one of these groups is present.
[0044] Two of the substituents on adjacent atoms of the aryl or
heteroaryl ring may optionally be replaced with a substituent of
the formula -T-C(O)--(CRR').sub.q--U--, wherein T and U are
independently --NR--, --O--, --CRR'-- or a single bond, and q is an
integer of from 0 to 3. Alternatively, two of the substituents on
adjacent atoms of the aryl or heteroaryl ring may optionally be
replaced with a substituent of the formula
-A-(CH.sub.2).sub.r--B--, wherein A and B are independently
--CRR'--, --O--, --NR--, --S--, --S(O)--S(O).sub.2--,
--S(O).sub.2NR'-- or a single bond, and r is an integer of from 1
to 4. One of the single bonds of the new ring so formed may
optionally be replaced with a double bond. Alternatively, two of
the substituents on adjacent atoms of the aryl or heteroaryl ring
may optionally be replaced with a substituent of the formula
--(CRR').sub.s--X--(CR''R''').sub.d--, where s and d are
independently integers of from 0 to 3, and X is --O--, --NR'--,
--S--, --S(O)--, --S(O).sub.2--, or --S(O).sub.2NR'--. The
substituents R, R', R'' and R''' are preferably independently
selected from hydrogen or substituted or unsubstituted
(C.sub.1-C.sub.6)alkyl.
[0045] "Ring" as used herein means a substituted or unsubstituted
cycloalkyl, substituted or unsubstituted heterocycloalkyl,
substituted or unsubstituted aryl, or substituted or unsubstituted
heteroaryl. A ring includes fused ring moieties. The number of
atoms in a ring is typically defined by the number of members in
the ring. For example, a "5- to 7-membered ring" means there are 5
to 7 atoms in the encircling arrangement. The ring optionally
included a heteroatom. Thus, the term "5- to 7-membered ring"
includes, for example pyridinyl and piperidinyl. The term "ring"
further includes a ring system comprising more than one "ring",
wherein each "ring" is independently defined as above.
[0046] As used herein, the term "heteroatom" includes atoms other
than carbon (C) and hydrogen (H). Examples include oxygen (O),
nitrogen (N) sulfur (S), silicon (Si), germanium (Ge), aluminum
(Al) and boron (B).
[0047] The symbol "R" is a general abbreviation that represents a
substituent group that is selected from substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted aryl, substituted or unsubstituted
heteroaryl, substituted or unsubstituted cycloalkyl and substituted
or unsubstituted heterocycloalkyl groups.
[0048] By "effective" amount of a drug, formulation, or permeant is
meant a sufficient amount of a active agent to provide the desired
local or systemic effect. A "Topically effective," "Cosmetically
effective," "pharmaceutically effective," or "therapeutically
effective" amount refers to the amount of drug needed to effect the
desired therapeutic result.
[0049] "Topically effective" refers to a material that, when
applied to the skin, nail, hair, claw or hoof produces a desired
pharmacological result either locally at the place of application
or systemically as a result of transdermal passage of an active
ingredient in the material.
[0050] "Cosmetically effective" refers to a material that, when
applied to the skin, nail, hair, claw or hoof, produces a desired
cosmetic result locally at the place of application of an active
ingredient in the material.
[0051] The term "pharmaceutically acceptable salts" is meant to
include salts of the compounds of the invention which are prepared
with relatively nontoxic acids or bases, depending on the
particular substituents found on the compounds described herein.
When compounds of the present invention contain relatively acidic
functionalities, base addition salts can be obtained by contacting
the neutral form of such compounds with a sufficient amount of the
desired base, either neat or in a suitable inert solvent. Examples
of pharmaceutically acceptable base addition salts include sodium,
potassium, calcium, ammonium, organic amino, or magnesium salt, or
a similar salt. When compounds of the present invention contain
relatively basic functionalities, acid addition salts can be
obtained by contacting the neutral form of such compounds with a
sufficient amount of the desired acid, either neat or in a suitable
inert solvent. Examples of pharmaceutically acceptable acid
addition salts include those derived from inorganic acids like
hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic,
phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric,
monohydrogensulfuric, hydriodic, or phosphorous acids and the like,
as well as the salts derived from relatively nontoxic organic acids
like acetic, propionic, isobutyric, maleic, malonic, benzoic,
succinic, suberic, fumaric, lactic, mandelic, phthalic,
benzenesulfonic, p-tolylsulfonic, citric, tartaric,
methanesulfonic, and the like. Also included are salts of amino
acids such as arginate and the like, and salts of organic acids
like glucuronic or galactunoric acids and the like (see, for
example, Berge et al., "Pharmaceutical Salts", Journal of
Pharmaceutical Science 66: 1-19 (1977)). Certain specific compounds
of the present invention contain both basic and acidic
functionalities that allow the compounds to be converted into
either base or acid addition salts.
[0052] The neutral forms of the compounds are preferably
regenerated by contacting the salt with a base or acid and
isolating the parent compounds in the conventional manner. The
parent form of the compound differs from the various salt forms in
certain physical properties, such as solubility in polar
solvents.
[0053] In addition to salt forms, the present invention provides
compounds which are in a prodrug form. Prodrugs of the compounds or
complexes described herein readily undergo chemical changes under
physiological conditions to provide the compounds of the present
invention. Additionally, prodrugs can be converted to the compounds
of the present invention by chemical or biochemical methods in an
ex vivo environment.
[0054] Certain compounds of the present invention can exist in
unsolvated forms as well as solvated forms, including hydrated
forms. In general, the solvated forms are equivalent to unsolvated
forms and are encompassed within the scope of the present
invention. Certain compounds of the present invention may exist in
multiple crystalline or amorphous forms. In general, all physical
forms are equivalent for the uses contemplated by the present
invention and are intended to be within the scope of the present
invention.
[0055] Certain compounds of the present invention possess
asymmetric carbon atoms (optical centers) or double bonds; the
racemates, diastereomers, geometric isomers and individual isomers
are encompassed within the scope of the present invention.
[0056] The compounds of the present invention may also contain
unnatural proportions of atomic isotopes at one or more of the
atoms that constitute such compounds. For example, the compounds
may be radiolabeled with radioactive isotopes, such as for example
tritium (.sup.3H), iodine-125 (.sup.125I) or carbon-14 (.sup.14C).
All isotopic variations of the compounds of the present invention,
whether radioactive or not, are intended to be encompassed within
the scope of the present invention.
[0057] The term "pharmaceutically acceptable carrier" or
"pharmaceutically acceptable vehicle" refers to any formulation or
carrier medium that provides the appropriate delivery of an
effective amount of a active agent as defined herein, does not
interfere with the effectiveness of the biological activity of the
active agent, and that is sufficiently non-toxic to the host or
patient. Representative carriers include water, oils, both
vegetable and mineral, cream bases, lotion bases, ointment bases
and the like. These bases include suspending agents, thickeners,
penetration enhancers, and the like. Their formulation is well
known to those in the art of cosmetics and topical pharmaceuticals.
Additional information concerning carriers can be found in
Remington: The Science and Practice of Pharmacy, 21st Ed.,
Lippincott, Williams & Wilkins (2005) which is incorporated
herein by reference.
[0058] "Pharmaceutically acceptable topical carrier" and equivalent
terms refer to pharmaceutically acceptable carriers, as described
herein above, suitable for topical application. An inactive liquid
or cream vehicle capable of suspending or dissolving the active
agent(s), and having the properties of being nontoxic and
non-inflammatory when applied to the skin, nail, hair, claw or hoof
is an example of a pharmaceutically-acceptable topical carrier.
This term is specifically intended to encompass carrier materials
approved for use in topical cosmetics as well.
[0059] The term "pharmaceutically acceptable additive" refers to
preservatives, antioxidants, fragrances, emulsifiers, dyes and
excipients known or used in the field of drug formulation and that
do not unduly interfere with the effectiveness of the biological
activity of the active agent, and that is sufficiently non-toxic to
the host or patient. Additives for topical formulations are
well-known in the art, and may be added to the topical composition,
as long as they are pharmaceutically acceptable and not deleterious
to the epithelial cells or their function. Further, they should not
cause deterioration in the stability of the composition. For
example, inert fillers, anti-irritants, tackifiers, excipients,
fragrances, opacifiers, antioxidants, gelling agents, stabilizers,
surfactant, emollients, coloring agents, preservatives, buffering
agents, other permeation enhancers, and other conventional
components of topical or transdermal delivery formulations as are
known in the art.
[0060] The terms "enhancement," "penetration enhancement" or
"permeation enhancement" relate to an increase in the permeability
of the skin, nail, hair, claw or hoof to a drug, so as to increase
the rate at which the drug permeates through the skin, nail, hair,
claw or hoof. The enhanced permeation effected through the use of
such enhancers can be observed, for example, by measuring the rate
of diffusion of the drug through animal or human skin, nail, hair,
claw or hoof using a diffusion cell apparatus. A diffusion cell is
described by Merritt et al. Diffusion Apparatus for Skin
Penetration, J of Controlled Release, 1 (1984) pp. 161-162. The
term "permeation enhancer" or "penetration enhancer" intends an
agent or a mixture of agents, which, alone or in combination, act
to increase the permeability of the skin, nail, hair or hoof to a
drug.
[0061] The term "excipients" is conventionally known to mean
carriers, diluents and/or vehicles used in formulating drug
compositions effective for the desired use.
[0062] The term "topical administration" refers to the application
of a pharmaceutical agent to the external surface of the skin,
nail, hair, claw or hoof, such that the agent crosses the external
surface of the skin, nail, hair, claw or hoof and enters the
underlying tissues. Topical administration includes application of
the composition to intact skin, nail, hair, claw or hoof, or to an
broken, raw or open wound of skin, nail, hair, claw or hoof.
Topical administration of a pharmaceutical agent can result in a
limited distribution of the agent to the skin and surrounding
tissues or, when the agent is removed from the treatment area by
the bloodstream, can result in systemic distribution of the
agent.
[0063] The term "transdermal delivery" refers to the diffusion of
an agent across the barrier of the skin, nail, hair, claw or hoof
resulting from topical administration or other application of a
composition. The stratum comeum acts as a barrier and few
pharmaceutical agents are able to penetrate intact skin. In
contrast, the epidermis and dermis are permeable to many solutes
and absorption of drugs therefore occurs more readily through skin,
nail, hair, claw or hoof that is abraded or otherwise stripped of
the stratum corneum to expose the epidermis. Transdermal delivery
includes injection or other delivery through any portion of the
skin, nail, hair, claw or hoof or mucous membrane and absorption or
permeation through the remaining portion. Absorption through intact
skin, nail, hair, claw or hoof can be enhanced by placing the
active agent in an appropriate pharmaceutically acceptable vehicle
before application to the skin, nail, hair, claw or hoof. Passive
topical administration may consist of applying the active agent
directly to the treatment site in combination with emollients or
penetration enhancers. As used herein, transdermal delivery is
intended to include delivery by permeation through or past the
integument, i.e. skin, nail, hair, claw or hoof.
II. Introduction
[0064] The present invention is directed to methods of treating
inflammatory-related diseases associated with pro-inflammatory
cytokine expression and/or reduced anti-inflammatory expression.
The methods of the present invention involve administering to a
human or an animal in need of such treatment one or more compounds
of the invention, either alone or as part of a pharmaceutical
formulation. In a preferred embodiment, the compound being
administered is in an amount sufficient to treat the
inflammatory-related disease by inhibiting pro-inflammatory
cytokine expression and/or by stimulating anti-inflammatory
cytokines, but less than sufficient to substantially inhibit cyclin
dependent kinases (CDKs).
III. Compounds of Use in the Invention
[0065] In a first aspect, the invention provides a compound
described herein. In an exemplary embodiment, the compound has a
structure according to Formula I:
##STR00003##
wherein B is boron. R.sup.1a is a member selected from a negative
charge, a salt counterion, H, cyano, substituted or unsubstituted
alkyl, substituted or unsubstituted heteroalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, and
substituted or unsubstituted heteroaryl. M is a member selected
from oxygen, sulfur and NR.sup.2a. R.sup.2a is a member selected
from H, substituted or unsubstituted alkyl, substituted or
unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted heterocycloalkyl, substituted or
unsubstituted aryl, and substituted or unsubstituted heteroaryl. J
is a member selected from (CR.sup.3aR.sup.4a).sub.n1 and CR.sup.5a.
R.sup.3a, R.sup.4a, and R.sup.5a are members independently selected
from H, cyano, substituted or unsubstituted alkyl, substituted or
unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted heterocycloalkyl, substituted or
unsubstituted aryl, and substituted or unsubstituted heteroaryl.
The index n1 is an integer selected from 0 to 2. W is a member
selected from C.dbd.O (carbonyl), (CR.sup.6aR.sup.7a).sub.m1 and
CR.sup.8a. R.sup.6a, R.sup.7a, and R.sup.8a are members
independently selected from H, cyano, substituted or unsubstituted
alkyl, substituted or unsubstituted heteroalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, and
substituted or unsubstituted heteroaryl. The index m1 is an integer
selected from 0 and 1. A is a member selected from CR.sup.9a and N.
D is a member selected from CR.sup.10a and N. E is a member
selected from CR.sup.11a and N. G is a member selected from
CR.sup.12a and N. R.sup.9a, R.sup.10a, R.sup.11a and R.sup.12a are
members independently selected from H, OR*, NR*R**, SR*, --S(O)R*,
--S(O).sub.2R*, --S(O).sub.2NR*R**, --C(O)R*, --C(O)OR*,
--C(O)NR*R**, nitro, halogen, cyano, substituted or unsubstituted
alkyl, substituted or unsubstituted heteroalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, and
substituted or unsubstituted heteroaryl. Each R* and R** are
members independently selected from H, nitro, halogen, cyano,
substituted or unsubstituted alkyl, substituted or unsubstituted
heteroalkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocycloalkyl, substituted or unsubstituted
aryl, and substituted or unsubstituted heteroaryl. The combination
of nitrogens (A+D+E+G) is an integer selected from 0 to 3. A member
selected from R.sup.3a, R.sup.4a and R.sup.5a and a member selected
from R.sup.6a, R.sup.7a and R.sup.8a, together with the atoms to
which they are attached, are optionally joined to form a 4 to 7
membered ring. R.sup.3a and R.sup.4a, together with the atoms to
which they are attached, are optionally joined to form a 4 to 7
membered ring. R.sup.6 and R.sup.7a, together with the atoms to
which they are attached, are optionally joined to form a 4 to 7
membered ring. R.sup.9a and R.sup.10a, together with the atoms to
which they are attached, are optionally joined to form a 4 to 7
membered ring. R.sup.10a and R.sup.11a, together with the atoms to
which they are attached, are optionally joined to form a 4 to 7
membered ring. R.sup.11a and R.sup.12a, together with the atoms to
which they are attached, are optionally joined to form a 4 to 7
membered ring.
[0066] In an exemplary embodiment, the compound has a structure
according to Formula (Ia):
##STR00004##
[0067] In another exemplary embodiment, each R.sup.3a and R.sup.4a
is a member independently selected from H, cyano, substituted or
unsubstituted methyl, substituted or unsubstituted ethyl,
trifluoromethyl, substituted or unsubstituted hydroxymethyl,
substituted or unsubstituted hydroxyalkyl, substituted or
unsubstituted benzyl, substituted or unsubstituted phenyl,
substituted or unsubstituted mercaptomethyl, substituted or
unsubstituted mercaptoalkyl, substituted or unsubstituted
aminomethyl, substituted or unsubstituted alkylaminomethyl,
substituted or unsubstituted dialkylaminomethyl, substituted or
unsubstituted arylaminomethyl, substituted or unsubstituted indolyl
and substituted or unsubstituted amido. In another exemplary
embodiment, each R.sup.3a and R.sup.4a is a member independently
selected from cyano, substituted or unsubstituted methyl,
substituted or unsubstituted ethyl, trifluoromethyl, substituted or
unsubstituted hydroxymethyl, substituted or unsubstituted
hydroxyalkyl, substituted or unsubstituted benzyl, substituted or
unsubstituted phenyl, substituted or unsubstituted mercaptomethyl,
substituted or unsubstituted mercaptoalkyl, substituted or
unsubstituted aminomethyl, substituted or unsubstituted
alkylaminomethyl, substituted or unsubstituted dialkylaminomethyl,
substituted or unsubstituted arylaminomethyl, substituted or
unsubstituted indolyl, substituted or unsubstituted amido.
[0068] In another exemplary embodiment, each R.sup.3a and R.sup.4a
is a member selected from H, substituted or unsubstituted methyl,
substituted or unsubstituted ethyl, substituted or unsubstituted
propyl, substituted or unsubstituted isopropyl, substituted or
unsubstituted butyl, substituted or unsubstituted t-butyl,
substituted or unsubstituted phenyl and substituted or
unsubstituted benzyl. In another exemplary embodiment, R.sup.3a and
R.sup.4a is a member selected from methyl, ethyl, propyl,
isopropyl, butyl, t-butyl, phenyl and benzyl. In another exemplary
embodiment, R.sup.3a is H and R.sup.4a is a member selected from
methyl, ethyl, propyl, isopropyl, butyl, t-butyl, phenyl and
benzyl. In another exemplary embodiment, R.sup.3a is H and R.sup.4a
H.
[0069] In another exemplary embodiment, each R.sup.9a, R.sup.10a,
R.sup.11a and R.sup.12a is a member independently selected from H,
OR*, NR*R**, SR*, --S(O)R*, --S(O).sub.2R*, --S(O).sub.2NR*R**,
--C(O)R*, --C(O)OR*, --C(O)NR*R**, halogen, cyano, nitro,
substituted or unsubstituted methoxy, substituted or unsubstituted
methyl, substituted or unsubstituted ethoxy, substituted or
unsubstituted ethyl, trifluoromethyl, substituted or unsubstituted
hydroxymethyl, substituted or unsubstituted hydroxyalkyl,
substituted or unsubstituted benzyl, substituted or unsubstituted
phenyl, substituted or unsubstituted phenyloxy, substituted or
unsubstituted phenyl methoxy, substituted or unsubstituted
thiophenyloxy, substituted or unsubstituted pyridinyloxy,
substituted or unsubstituted pyrimidinyloxy, substituted or
unsubstituted benzylfuran, substituted or unsubstituted methylthio,
substituted or unsubstituted mercaptomethyl, substituted or
unsubstituted mercaptoalkyl, substituted or unsubstituted
phenylthio, substituted or unsubstituted thiophenylthio,
substituted or unsubstituted phenyl methylthio, substituted or
unsubstituted pyridinylthio, substituted or unsubstituted
pyrimidinylthio, substituted or unsubstituted benzylthiofuranyl,
substituted or unsubstituted phenylsulfonyl, substituted or
unsubstituted benzylsulfonyl, substituted or unsubstituted
phenylmethylsulfonyl, substituted or unsubstituted
thiophenylsulfonyl, substituted or unsubstituted pyridinylsulfonyl,
substituted or unsubstituted pyrimidinylsulfonyl, substituted or
unsubstituted sulfonamidyl, substituted or unsubstituted
phenylsulfinyl, substituted or unsubstituted benzylsulfinyl,
substituted or unsubstituted phenylmethylsulfinyl, substituted or
unsubstituted thiophenylsulfinyl, substituted or unsubstituted
pyridinylsulfinyl, substituted or unsubstituted
pyrimidinylsulfinyl, substituted or unsubstituted amino,
substituted or unsubstituted alkylamino, substituted or
unsubstituted dialkylamino, substituted or unsubstituted
trifluoromethylamino, substituted or unsubstituted aminomethyl,
substituted or unsubstituted alkylaminomethyl, substituted or
unsubstituted dialkylaminomethyl, substituted or unsubstituted
arylaminomethyl, substituted or unsubstituted benzylamino,
substituted or unsubstituted phenylamino, substituted or
unsubstituted thiophenylamino, substituted or unsubstituted
pyridinylamino, substituted or unsubstituted pyrimidinylamino,
substituted or unsubstituted indolyl, substituted or unsubstituted
morpholino, substituted or unsubstituted alkylamido, substituted or
unsubstituted arylamido, substituted or unsubstituted ureido,
substituted or unsubstituted carbamoyl, and substituted or
unsubstituted piperizinyl. In an exemplary embodiment, R.sup.9a,
R.sup.10a, R.sup.11a and R.sup.12a are selected from the previous
list of substituents with the exception of --C(O)R*, --C(O)OR*,
--C(O)NR*R**.
[0070] In another exemplary embodiment, R.sup.9a, R.sup.10a,
R.sup.11a and R.sup.12a are members independently selected from
fluoro, chloro, bromo, nitro, cyano, amino, methyl, hydroxylmethyl,
trifluoromethyl, methoxy, trifluoromethyoxy, ethyl,
diethylcarbamoyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl,
pyrimidinyl, piperizino, piperizinyl, piperizinocarbonyl,
piperizinylcarbonyl, carboxyl, 1-tetrazolyl,
1-ethoxycarbonylmethoxy, carboxymethoxy, thiophenyl,
3-(butylcarbonyl) phenylmethoxy, 1H-tetrazol-5-yl,
1-ethoxycarbonylmethyloxy-, 1-ethoxycarbonylmethyl-,
1-ethoxycarbonyl-, carboxymethoxy-, thiophen-2-yl,
thiophen-2-ylthio-, thiophen-3-yl, thiophen-3-ylthio,
4-fluorophenylthio, butylcarbonylphenylmethoxy,
butylcarbonylphenylmethyl, butylcarbonylmethyl,
1-(piperidin-1-yl)carbonyl)methyl,
1-(piperidin-1-yl)carbonyl)methoxy,
1-(piperidin-2-yl)carbonyl)methoxy,
1-(piperidin-3-yl)carbonyl)methoxy,
1-(4-(pyrimidin-2-yl)piperazin-1-yl)carbonyl)methoxy,
1-(4-(pyrimidin-2-yl)piperazin-1-yl)carbonyl)methyl,
1-(4-(pyrimidin-2-yl)piperazin-1-yl)carbonyl,
1-(4-(pyrimidin-2-yl)piperazin-1-yl,
1-(4-(pyridin-2-yl)piperazin-1-yl)carbonyl),
1-(4-(pyridin-2-yl)piperazin-1-yl)carbonylmethyl,
(1-(4-(pyridin-2-yl)piperazin-1-yl)carbonyl)-methoxy),
1-(4-(pyridin-2-yl)piperazin-1-yl, 1H-indol-1-yl, morpholino-,
morpholinyl, morpholinocarbonyl, morpholinylcarbonyl, phenylureido,
phenylcarbamoyl, acetamido, 3-(phenylthio)-1H-indol-1-yl,
3-(2-cyanoethylthio)-1H-indol-1-yl, benzylamino,
5-methoxy-3-(phenylthio)-1H-indol-1-yl,
5-methoxy-3-(2-cyanoethylthio)-1H-indol-1-yl)),
5-chloro-1H-indol-1-yl,
5-chloro-3-(2-cyanoethylthio)-1H-indol-1l-yl)), dibenzylamino,
benzylamino, 5-chloro-3-(phenylthio)-1H-indol-1-yl)),
4-(1H-tetrazol-5-yl)phenoxy, 4-(1H-tetrazol-5-yl)phenyl,
4-(1H-tetrazol-5-yl)phenylthio, 2-cyanophenoxy, 3-cyanophenoxy,
4-cyanophenoxy, 2-cyanophenylthio, 3-cyanophenylthio,
4-cyanophenylthio, 2-chlorophenoxy, 3-chlorophenoxy,
4-chlorophenoxy, 2-fluorophenoxy, 3-fluorophenoxy, 4-fluorophenoxy,
2-cyanobenzyloxy, 3-cyanobenzyloxy, 4-cyanobenzyloxy,
2-chlorobenzyloxy, 3-chlorobenzyloxy, 4-chlorobenzyloxy,
2-fluorobenzyloxy, 3-fluorobenzyloxy, 4-fluorobenzyloxy,
unsubstituted phenyl, unsubstituted benzyl. In an exemplary
embodiment, R.sup.9a is H and R.sup.12a is H.
[0071] In an exemplary embodiment, the compound according to
Formula (I) or Formula (Ia) is a member selected from:
##STR00005## ##STR00006##
[0072] In an exemplary embodiment, the compound has a structure
according to one of Formulae I-Io with substituent selections for
R.sup.9a, R.sup.10a, R.sup.11a and R.sup.12a including all the
possibilities contained in paragraph 69 except for H. In an
exemplary embodiment, the compound has a structure according to one
of Formulae Ib-Io with substituent selections for R.sup.9a,
R.sup.10a, R.sup.11a and R.sup.12a including all the possiblities
contained in paragraph 70 except for H.
[0073] In an exemplary embodiment, the compound has a formula
according to Formulae (Ib)-(Ie) wherein R.sup.1a is a member
selected from H, a negative charge and a salt counterion and the
remaining R group (R.sup.9a in Ib, R.sup.10a in Ic, R.sup.11a in
Id, and R.sup.12a in Ie) is a member selected from fluoro, chloro,
bromo, nitro, cyano, amino, methyl, hydroxylmethyl,
trifluoromethyl, methoxy, trifluoromethyoxy, ethyl,
diethylcarbamoyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl,
pyrimidinyl, piperizino, piperizinyl, piperizinocarbonyl,
piperizinylcarbonyl, carboxyl, 1-tetrazolyl,
1-ethoxycarbonylmethoxy, carboxymethoxy, thiophenyl,
3-(butylcarbonyl) phenylmethoxy, 1H-tetrazol-5-yl,
1-ethoxycarbonylmethyloxy-, 1-ethoxycarbonylmethyl-,
1-ethoxycarbonyl-, carboxymethoxy-, thiophen-2-yl,
thiophen-2-ylthio-, thiophen-3-yl, thiophen-3-ylthio,
4-fluorophenylthio, butylcarbonylphenylmethoxy,
butylcarbonylphenylmethyl, butylcarbonylmethyl,
1-(piperidin-1-yl)carbonyl)methyl,
1-(piperidin-1-yl)carbonyl)methoxy,
1-(piperidin-2-yl)carbonyl)methoxy,
1-(piperidin-3-yl)carbonyl)methoxy,
1-(4-(pyrimidin-2-yl)piperazin-1-yl)carbonyl)methoxy,
1-(4-(pyrimidin-2-yl)piperazin-1-yl)carbonyl)methyl,
1-(4-(pyrimidin-2-yl)piperazin-1-yl)carbonyl,
1-4-(pyrimidin-2-yl)piperazin-1-yl,
1-(4-(pyridin-2-yl)piperazin-1-yl)carbonyl),
1-(4-(pyridin-2-yl)piperazin-1-yl)carbonylmethyl,
(1-(4-(pyridin-2-yl)piperazin-1-yl)carbonyl)-methoxy),
1-(4-(pyridin-2-yl)piperazin-1-yl, 1H-indol-1-yl, morpholino-,
morpholinyl, morpholinocarbonyl, morpholinylcarbonyl, phenylureido,
phenylcarbamoyl, acetamido, 3-(phenylthio)-1H-indol-1-yl,
3-(2-cyanoethylthio)-1H-indol-1-yl, benzylamino,
5-methoxy-3-(phenylthio)-1H-indol-1-yl,
5-methoxy-3-(2-cyanoethylthio)-1H-indol-1-yl)),
5-chloro-1H-indol-1-yl,
5-chloro-3-(2-cyanoethylthio)-1H-indol-1-yl)), dibenzylamino,
benzylamino, 5-chloro-3-(phenylthio)-1H-indol-1-yl)),
4-(1H-tetrazol-5-yl)phenoxy, 4-(1H-tetrazol-5-yl)phenyl,
4-(1H-tetrazol-5-yl)phenylthio, 2-cyanophenoxy, 3-cyanophenoxy,
4-cyanophenoxy, 2-cyanophenylthio, 3-cyanophenylthio,
4-cyanophenylthio, 2-chlorophenoxy, 3-chlorophenoxy,
4-chlorophenoxy, 2-fluorophenoxy, 3-fluorophenoxy, 4-fluorophenoxy,
2-cyanobenzyloxy, 3-cyanobenzyloxy, 4-cyanobenzyloxy,
2-chlorobenzyloxy, 3-chlorobenzyloxy, 4-chlorobenzyloxy,
2-fluorobenzyloxy, 3-fluorobenzyloxy and 4-fluorobenzyloxy.
[0074] In an exemplary embodiment, the compound has a formula
according to Formulae (If)-(Ik) wherein R.sup.1a is a member
selected from H, a negative charge and a salt counterion and each
of the remaining two R groups (R.sup.9a and R.sup.10a in If,
R.sup.9a and R.sup.11a in Ig, R.sup.9a and R.sup.12a in Ih,
R.sup.10a and R.sup.11a in Ii, R.sup.10a and R.sup.12a in Ij,
R.sup.11a and R.sup.12a in Ik) is a member independently selected
from fluoro, chloro, bromo, nitro, cyano, amino, methyl,
hydroxylmethyl, trifluoromethyl, methoxy, trifluoromethyoxy, ethyl,
diethylcarbamoyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl,
pyrimidinyl, piperizino, piperizinyl, piperizinocarbonyl,
piperizinylcarbonyl, carboxyl, 1-tetrazolyl,
1-ethoxycarbonylmethoxy, carboxymethoxy, thiophenyl,
3-(butylcarbonyl) phenylmethoxy, 1H-tetrazol-5-yl,
1-ethoxycarbonylmethyloxy-, 1-ethoxycarbonylmethyl-,
1-ethoxycarbonyl-, carboxymethoxy-, thiophen-2-yl,
thiophen-2-ylthio-, thiophen-3-yl, thiophen-3-ylthio,
4-fluorophenylthio, butylcarbonylphenylmethoxy,
butylcarbonylphenylmethyl, butylcarbonylmethyl,
1-(piperidin-1-yl)carbonyl)methyl,
1-(piperidin-1-yl)carbonyl)methoxy,
1-(piperidin-2-yl)carbonyl)methoxy,
1-(piperidin-3-yl)carbonyl)methoxy,
1-(4-(pyrimidin-2-yl)piperazin-1-yl)carbonyl)methoxy,
1-(4-(pyrimidin-2-yl)piperazin-1-yl)carbonyl)methyl,
1-(4-(pyrimidin-2-yl)piperazin-1-yl)carbonyl,
1-4-(pyrimidin-2-yl)piperazin-1-yl,
1-(4-(pyridin-2-yl)piperazin-1-yl)carbonyl),
1-(4-(pyridin-2-yl)piperazin-1-yl)carbonylmethyl,
(1-(4-(pyridin-2-yl)piperazin-1-yl)carbonyl)-methoxy),
1-(4-(pyridin-2-yl)piperazin-1-yl, 1H-indol-1-yl, morpholino-,
morpholinyl, morpholinocarbonyl, morpholinylcarbonyl, phenylureido,
phenylcarbamoyl, acetamido, 3-(phenylthio)-1H-indol-1-yl,
3-(2-cyanoethylthio)-1H-indol-1-yl, benzylamino,
5-methoxy-3-(phenylthio)-1H-indol-1-yl,
5-methoxy-3-(2-cyanoethylthio)-1H-indol-1-yl)),
5-chloro-1H-indol-1-yl,
5-chloro-3-(2-cyanoethylthio)-1H-indol-1-yl)), dibenzylamino,
benzylamino, 5-chloro-3-(phenylthio)-1H-indol-1-yl)),
4-(1H-tetrazol-5-yl)phenoxy, 4-(1H-tetrazol-5-yl)phenyl,
4-(1H-tetrazol-5-yl)phenylthio, 2-cyanophenoxy, 3-cyanophenoxy,
4-cyanophenoxy, 2-cyanophenylthio, 3-cyanophenylthio,
4-cyanophenylthio, 2-chlorophenoxy, 3-chlorophenoxy,
4-chlorophenoxy, 2-fluorophenoxy, 3-fluorophenoxy, 4-fluorophenoxy,
2-cyanobenzyloxy, 3-cyanobenzyloxy, 4-cyanobenzyloxy,
2-chlorobenzyloxy, 3-chlorobenzyloxy, 4-chlorobenzyloxy,
2-fluorobenzyloxy, 3-fluorobenzyloxy, and 4-fluorobenzyloxy.
[0075] In an exemplary embodiment, the compound has a formula
according to Formulae (Il)-(Io) wherein R.sup.1a is a member
selected from H, a negative charge and a salt counterion and each
of the remaining three R groups (R.sup.9a, R.sup.10a, R.sup.11a in
(Il), R.sup.9a, R.sup.10a, R.sup.12a in (Im), R.sup.9a, R.sup.11a,
R.sup.12a in (In), R.sup.10a, R.sup.11a, R.sup.12a in (Io)) is a
member independently selected from fluoro, chloro, bromo, nitro,
cyano, amino, methyl, hydroxylmethyl, trifluoromethyl, methoxy,
trifluoromethyoxy, ethyl, diethylcarbamoyl, pyridin-2-yl,
pyridin-3-yl, pyridin-4-yl, pyrimidinyl, piperizino, piperizinyl,
piperizinocarbonyl, piperizinylcarbonyl, carboxyl, 1-tetrazolyl,
1-ethoxycarbonylmethoxy, carboxymethoxy, thiophenyl,
3-(butylcarbonyl) phenylmethoxy, 1H-tetrazol-5-yl,
1-ethoxycarbonylmethyloxy-, 1-ethoxycarbonylmethyl-,
1-ethoxycarbonyl-, carboxymethoxy-, thiophen-2-yl,
thiophen-2-ylthio-, thiophen-3-yl, thiophen-3-ylthio,
4-fluorophenylthio, butylcarbonylphenylmethoxy,
butylcarbonylphenylmethyl, butylcarbonylmethyl,
1-(piperidin-1-yl)carbonyl)methyl,
1-(piperidin-1-yl)carbonyl)methoxy,
1-(piperidin-2-yl)carbonyl)methoxy,
1-(piperidin-3-yl)carbonyl)methoxy,
1-(4-(pyrimidin-2-yl)piperazin-1-yl)carbonyl)methoxy,
1-(4-(pyrimidin-2-yl)piperazin-1-yl)carbonyl)methyl,
1-(4-(pyrimidin-2-yl)piperazin-1-yl)carbonyl,
1-4-(pyrimidin-2-yl)piperazin-1-yl,
1-(4-(pyridin-2-yl)piperazin-1-yl)carbonyl),
1-(4-(pyridin-2-yl)piperazin-1-yl)carbonylmethyl,
(1-(4-(pyridin-2-yl)piperazin-1-yl)carbonyl)-methoxy),
1-(4-(pyridin-2-yl)piperazin-1-yl, 1H-indol-1-yl, morpholino-,
morpholinyl, morpholinocarbonyl, morpholinylcarbonyl, phenylureido,
phenylcarbamoyl, acetamido, 3-(phenylthio)-1H-indol-1-yl,
3-(2-cyanoethylthio)-1H-indol-1-yl, benzylamino,
5-methoxy-3-(phenylthio)-1H-indol-1-yl,
5-methoxy-3-(2-cyanoethylthio)-1H-indol-1-yl)),
5-chloro-1H-indol-1-yl,
5-chloro-3-(2-cyanoethylthio)-1H-indol-1-yl)), dibenzylamino,
benzylamino, 5-chloro-3-(phenylthio)-1H-indol-1-yl)),
4-(1H-tetrazol-5-yl)phenoxy, 4-(1H-tetrazol-5-yl)phenyl,
4-(1H-tetrazol-5-yl)phenylthio, 2-cyanophenoxy, 3-cyanophenoxy,
4-cyanophenoxy, 2-cyanophenylthio, 3-cyanophenylthio,
4-cyanophenylthio, 2-chlorophenoxy, 3-chlorophenoxy,
4-chlorophenoxy, 2-fluorophenoxy, 3-fluorophenoxy, 4-fluorophenoxy,
2-cyanobenzyloxy, 3-cyanobenzyloxy, 4-cyanobenzyloxy,
2-chlorobenzyloxy, 3-chlorobenzyloxy, 4-chlorobenzyloxy,
2-fluorobenzyloxy, 3-fluorobenzyloxy, and 4-fluorobenzyloxy.
[0076] In an exemplary embodiment, the compound of the invention
has a structure which is a member selected from:
##STR00007##
in which q is a number between 0 and 1. R.sup.g is halogen.
R.sup.a, R.sup.b, R.sup.c, R.sup.d and R.sup.e are members
independently selected from a member selected from H, substituted
or unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl,
and substituted or unsubstituted heteroaryl. In an exemplary
embodiment, there is a proviso that the compound is not a member
selected from
##STR00008##
[0077] In an exemplary embodiment, the compound has a structure is
a member selected from:
##STR00009##
[0078] In an exemplary embodiment, R.sup.a, R.sup.d and R.sup.e are
each members independently selected from:
##STR00010##
[0079] In an exemplary embodiment, R.sup.b and R.sup.c are members
independently selected from H, methyl,
##STR00011##
[0080] In another exemplary embodiment, R.sup.b is H and R.sup.c is
a member selected from: H, methyl,
##STR00012##
In another exemplary embodiment, R.sup.b and R.sup.c are, together
with the nitrogen to which they are attached, optionally joined to
form a member selected from
##STR00013##
[0081] In an exemplary embodiment, R.sup.a is a member selected
from
##STR00014##
[0082] In an exemplary embodiment, R.sup.d is a member selected
from
##STR00015##
[0083] In an exemplary embodiment, R.sup.e is a member selected
from
##STR00016##
[0084] In an exemplary embodiment, the compound is a member
selected from
##STR00017## ##STR00018## ##STR00019## ##STR00020## ##STR00021##
##STR00022## ##STR00023##
[0085] In an exemplary embodiment, the compound has a structure
which is described in FIGS. 2A-2K. In an exemplary embodiment, the
compound has a structure which is described in FIGS. 3A-3H.
[0086] In an exemplary embodiment, the compound has a structure
according to a member selected from Formulae I(b), I(c), I(d), and
I(e) wherein said remaining R group (R.sup.9a for I(b), R.sup.10a
for I(c), R.sup.1la for I(d) and R.sup.12a for I(e)) is
carboxymethoxy.
[0087] In an exemplary embodiment, the compound has a structure
which is a member selected from Formulae (If)-(Ik), wherein either
R.sup.9a or R.sup.10a for Formula (If), either R.sup.9a or
R.sup.10a for Formula (Ig), either R.sup.9a or R.sup.12a for
Formula (Ih), either R.sup.10a or R.sup.11a for Formula (Ii),
either R.sup.10a or R.sup.12a for Formula (Ij), either R.sup.11a or
R.sup.12a for Formula (Ik) is halogen, and the other substituent in
the pairing (ex. if R.sup.9a is F in Formula (If), then R.sup.10a
is selected from the following substituent listing), is a member
selected from NH.sub.2, N(CH.sub.3)H, and N(CH.sub.3).sub.2.
[0088] In another exemplary embodiment, the compound has a
structure which is a member selected from:
##STR00024##
in which R* and R** are members selected from: H, substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl,
and substituted or unsubstituted heteroaryl. In an exemplary
embodiment, the compound is a member selected from
##STR00025##
wherein R.sup.1a is a member selected from a negative charge, H and
a salt counterion.
[0089] In another exemplary embodiment, the compound has a
structure which is a member selected from:
##STR00026##
wherein q is 1 and R.sup.g is a member selected from fluoro, chloro
and bromo.
[0090] In another exemplary embodiment, the compounds and
embodiments described above in Formulae (I)-(Io) can form a hydrate
with water, a solvate with an alcohol (e.g. methanol, ethanol,
propanol); an adduct with an amino compound (e.g. ammonia,
methylamine, ethylamine); an adduct with an acid (e.g. formic acid,
acetic acid); complexes with ethanolamine, quinoline, amino acids,
and the like.
[0091] In another exemplary embodiment, the compound has a
structure according to Formula (Ip):
##STR00027##
in which R.sup.x2 is a member selected from substituted or
unsubstituted C.sub.1-C.sub.5 alkyl and substituted or
unsubstituted C.sub.1-C.sub.5 heteroalkyl. R.sup.y2 and R.sup.z2
are members independently selected from H, substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl,
and substituted or unsubstituted heteroaryl.
[0092] In another exemplary embodiment, the compound has a
structure according to Formula (Iq):
##STR00028##
wherein B is boron. R.sup.x2 is a member selected from substituted
or unsubstituted C.sub.1-C.sub.5 alkyl and substituted or
unsubstituted C.sub.1-C.sub.5 heteroalkyl. R.sup.y2 and R.sup.z2
are members independently selected from H, substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl,
and substituted or unsubstituted heteroaryl. In another exemplary
embodiment, at least one member selected from R.sup.3a, R.sup.4a,
R.sup.5a, R.sup.6a, R.sup.7a, R.sup.8a, R.sup.9a, R.sup.10a,
R.sup.11a and R.sup.12a is a member selected from nitro, cyano and
halogen.
[0093] In another exemplary embodiment, the compound has a
structure which is a member selected from the following
Formulae:
##STR00029##
[0094] In another exemplary embodiment, the compound has a formula
according to Formulae (Ib)-(Ie) wherein at least one member
selected from R.sup.3a, R.sup.4a, R.sup.5a, R.sup.6a,
R.sup.7aR.sup.8a, R.sup.9a, R.sup.10a, R.sup.11a and R.sup.12a is a
member selected from nitro, cyano, fluro, chloro, bromo and
cyanophenoxy. In another exemplary embodiment, the compound is a
member selected from
##STR00030##
[0095] In another exemplary embodiment, the compound is a member
selected from
##STR00031##
[0096] In another exemplary embodiment, the invention provides
poly- or mutli-valent species of the compounds of the invention. In
an exemplary embodiment, the invention provides a dimer of the
compounds described herein. In an exemplary embodiment, the
invention provides a dimer of the compounds described herein. In an
exemplary embodiment, the invention provides a dimer of a compound
which is a member selected from C1-C100. In an exemplary embodiment
the dimer is a member selected from
##STR00032##
[0097] In an exemplary embodiment, the invention provides an
anhydride of the compounds described herein. In an exemplary
embodiment, the invention provides an anhydride of the compounds
described herein. In an exemplary embodiment, the invention
provides an anhydride of a compound which is a member selected from
C1-C100. In an exemplary embodiment the anhydride is a member
selected from
##STR00033##
[0098] In an exemplary embodiment, the invention provides a trimer
of the compounds described herein. In an exemplary embodiment, the
invention provides a trimer of the compounds described herein. In
an exemplary embodiment, the invention provides a trimer of a
compound which is a member selected from C1-C100. In an exemplary
embodiment the trimer is a member selected from
##STR00034## ##STR00035##
[0099] In another exemplary embodiment, the compound has a
structure which is a member selected from:
##STR00036##
[0100] In another exemplary embodiment, the compound is
##STR00037##
[0101] In another exemplary embodiment, the compound is a member
selected from:
##STR00038##
[0102] In another exemplary embodiment, the compound is a member
selected from:
##STR00039##
[0103] In another exemplary embodiment, R.sup.1a is H. In another
exemplary embodiment, R.sup.10a and R.sup.11a are H. In another
exemplary embodiment, one member selected from R.sup.10a and
R.sup.11a is H and the other member selected from R.sup.10a and
R.sup.11a is a member selected from halogen, methyl, cyano,
methoxy, hydroxymethyl and p-cyanophenyloxy. In another exemplary
embodiment, R.sup.10a and R.sup.11a are members independently
selected from fluoro, chloro, methyl, cyano, methoxy,
hydroxymethyl, and p-cyanophenyl.
[0104] Additional compounds which are useful in the methods of the
invention are disclosed in U.S. Prov. Pat. App. 60/654,060; Filed
Feb. 16, 2005 (Attorney Docket No. 064507-5014PR); U.S. patent
application Ser. No. 11/357,687, Filed Feb. 16, 2006 (Attorney
Docket No. 064507-5014US); U.S. patent application Ser. No.
11/505,591, Filed Aug. 16, 2006 (Attorney Docket No.
064507-5014US01), which are herein incorporated by reference in
their entirety for all purposes. Methods of producing the compounds
of the invention are also described in these patent
applications.
IIIa. Compositions of Matter
[0105] The invention also provides novel compositions of matter. In
an exemplary embodiment, the composition of matter is described
herein. In another exemplary embodiment, the composition of matter
has a structure according to Formula II:
##STR00040##
wherein B is boron. R.sup.20, R.sup.21 and R.sup.22 are members
independently selected from a negative charge, a salt counterion,
H, substituted or unsubstituted alkyl, substituted or unsubstituted
heteroalkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocycloalkyl, substituted or unsubstituted
aryl, and substituted or unsubstituted heteroaryl. A is a member
selected from CR.sup.9a and N. D is a member selected from
CR.sup.10a and N. E is a member selected from CR.sup.11a and N. G
is a member selected from CR.sup.12a and N. R.sup.9a, R.sup.10a,
R.sup.11a and R.sup.12a are members independently selected from H,
OR*, NR*R**, SR*, --S(O)R*, --S(O).sub.2R*, --S(O).sub.2NR*R**,
--C(O)R*, --C(O)OR*, --C(O)NR*R**, nitro, halogen, cyano,
substituted or unsubstituted alkyl, substituted or unsubstituted
heteroalkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocycloalkyl, substituted or unsubstituted
aryl, and substituted or unsubstituted heteroaryl. Each R* and R**
are members independently selected from H, nitro, halogen, cyano,
substituted or unsubstituted alkyl, substituted or unsubstituted
heteroalkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocycloalkyl, substituted or unsubstituted
aryl, and substituted or unsubstituted heteroaryl. The combination
of nitrogens (A+D+E+G) is an integer selected from 0 to 3. R.sup.9a
and R.sup.10a, together with the atoms to which they are attached,
are optionally joined to form a 4 to 7 membered ring. R.sup.10a and
R.sup.11a, together with the atoms to which they are attached, are
optionally joined to form a 4 to 7 membered ring. R.sup.11a and
R.sup.12a, together with the atoms to which they are attached, are
optionally joined to form a 4 to 7 membered ring.
[0106] In another exemplary embodiment, the compound has a
structure according to Formula (IIa):
##STR00041##
[0107] In another exemplary embodiment, the compound has a
structure according to the following formula:
##STR00042##
wherein R.sup.10z is a member selected from substituted or
unsubstituted cyanophenoxy and substituted or unsubstituted
cyanophenylthio and R.sup.22 is a member selected from H,
substituted or unsubstituted methyl, substituted or unsubstituted
ethyl and substituted or unsubstituted propyl. In an exemplary
embodiment, R.sup.10z is a member selected from para-cyanophenoxy
and paracyanophenylthio. In an exemplary embodiment, R.sup.20 and
R.sup.21 are members independently selected from a negative charge,
a salt counterion and H.
[0108] In another exemplary embodiment, the compound has a
structure which is a member selected from:
##STR00043##
wherein R.sup.22 is a member selected from H, substituted or
unsubstituted methyl, substituted or unsubstituted ethyl and
substituted or unsubstituted propyl. In an exemplary embodiment,
R.sup.20 and R.sup.21 are members independently selected from a
negative charge, a salt counterion and H.
[0109] In another exemplary embodiment, the compound has a
structure which is a member selected from:
##STR00044## ##STR00045## ##STR00046##
In an exemplary embodiment, R.sup.22 is H. In an exemplary
embodiment, R.sup.22 is substituted or unsubstituted methyl. In an
exemplary embodiment, R.sup.22 is methyl. In an exemplary
embodiment, R.sup.20 and R.sup.21 are members independently
selected from a negative charge, a salt counterion and H.
[0110] In another exemplary embodiment, the compound has a
structure which is a member selected from:
##STR00047## ##STR00048## ##STR00049##
In an exemplary embodiment, R.sup.22 is H. In an exemplary
embodiment, R.sup.22 is substituted or unsubstituted methyl. In an
exemplary embodiment, R.sup.22 is methyl.
[0111] In another exemplary embodiment, the compound is a member
selected from:
##STR00050##
[0112] The compounds described herein can be synthesized by a
similar route to that used in the synthesis of the oxaboroles (2)
described herein. However, the synthesis of the phenylboronic acid
and phenylbromide precursors is simplified by the absence of a
protected ortho-hydroxymethyl group present on (1). Therefore, in
many cases, a similar range of ortho-, meta- and para-substituted
boronic acids (4) can be synthesized.
##STR00051##
[0113] Examples of the production of these boronic acids are
provided in the Examples section. Additionally, phenylthio
derivatives can be synthesized by using the phenyloxy derivative
protocols and substituting the phenolic reactant with its
thiophenolic analog. For example,
4-(4-cyanophenylthio)phenylboronic acid can be synthesized using
the protocol for 4-(4-cyanophenoxy)phenylboronic acid described
herein and substituting 4-bromothiophenol for 4-bromophenol.
[0114] In another exemplary embodiment, the composition of matter
described herein can be used in a method of the invention described
herein. In another exemplary embodiment, the invention provides a
method of treating or preventing an inflammatory-related disease in
a human or an animal, said method comprising administering to the
human or the animal a therapeutically effective amount of a
compound described herein in section IIIa. In another exemplary
embodiment, the compound has a structure according to Formula II or
Formula IIa. In another exemplary embodiment, the compound has a
structure which is a member selected from:
##STR00052##
In another exemplary embodiment, the method further comprises
administering said compound as part of a pharmaceutical
formulation, said formulation further comprising a pharmaceutically
acceptable excipient. In another exemplary embodiment, the compound
described in section IIIa is in an amount sufficient to treat the
inflammatory-related disease by inhibiting pro-inflammatory
cytokine expression or by stimulating anti-inflammatory cytokine
expression, but the amount is less than sufficient to substantially
inhibit cyclin dependent kinases. In another exemplary embodiment,
the disease is a member selected from arthritis, rheumatoid
arthritis, an inflammatory bowel disease, psoriasis, multiple
sclerosis, a neurodegenerative disorder, congestive heart failure,
stroke, aortic valve stenosis, kidney failure, lupus, pancreatitis,
allergy, fibrosis, anemia, atherosclerosis, a metabolic disease, a
bone disease, a cardiovascular disease, a chemotherapy/radiation
related complication, diabetes type I, diabetes type II, a liver
disease, a gastrointestinal disorder, an ophthamological disease,
allergic conjunctivitis, diabetic retinopathy, Sjogren's syndrome,
uvetitis, a pulmonary disorder, a renal disease, dermatitis,
HIV-related cachexia, cerebral malaria, ankylosing spondolytis,
leprosy, anemia and fibromyalgia. In another exemplary embodiment,
the disease is actinic keratosis. In another exemplary embodiment,
the disease is atopic dermatitis. In another exemplary embodiment,
the compound has a structure which is a member selected from:
##STR00053##
[0115] In another exemplary embodiment, the neurodegenerative
disorder is a member selected from Alzheimer's disease and
Parkinson disease, the inflammatory bowel disease is a member
selected from Crohn's disease or uncerative colitis; the
gastrointestinal complication is diarrhea; the liver disease is a
member selected from an autoimmune hepatitis, hepatitis C, primary
biliary cirrhosis, primary sclerosing cholangitis and fulminant
liver failure; the gastrointestinal disorder is a member selected
from celiac disease and non-specific colitis; the pulmonary
disorder is a member selected from allergic rhinitis, asthma,
chronic obstructive pulmonary disease, chronic granulomatous
inflammation, cystic fibrosis, and sarcoidosis; the cardiovascular
disease is a member selected from atheroscleotic cardiac disease,
congestive heart failure and restenosis; and the renal disease is a
member selected from glomerulpnephritis and vasculitis. In another
exemplary embodiment, the compound is administered at a
concentration sufficient to inhibit a cytokine which is a member
selected from IL-1.alpha., .beta., IL-2, IL-3, IL-6, IL-7, IL-9,
IL-12, IL-17, IL-18, IL-23, TNF-.alpha., LT, LIF, Oncostatin, and
IFNc1.alpha., .beta., .gamma.. In another exemplary embodiment, the
compound is administered at a concentration sufficient to stimulate
expression of a cytokine which is a member selected from IL-4,
IL-10, IL-11, W-13 and TGF-.beta.. In another exemplary embodiment,
the invention provides a method of treating an inflammatory-related
disease associated with cytokine expression levels, which comprises
administering to a human or an animal in need of such treatment a
compound described in section IIIa. In an exemplary embodiment, the
compound is in an amount sufficient to treat the
inflammatory-related disease by inhibiting pro-inflammatory
cytokine expression or by stimulating anti-inflammatory cytokine
expression, but the amount is less than sufficient to substantially
inhibit cyclin dependent kinases. In an exemplary embodiment, the
animal is a human being. In another exemplary embodiment, the
compound has a structure which is a member selected from:
##STR00054##
In another exemplary embodiment, the invention provides a method
for inhibiting the production of an inflammatory cytokine protein
by cells capable of producing said inflammatory cytokine protein,
said method comprising: combining said cells with a therapeutic
amount of a compound of section IIIa, wherein production of said
inflammatory cytokine by said cells is inhibited. In another
exemplary embodiment, the therapeutic amount is sufficient to
inhibit the production of said inflammatory cytokine protein
between about 50% and about 99%. In another exemplary embodiment,
the invention provides a method for inhibiting an inflammatory
response in a human or an animal, said method comprising:
contacting said human or animal with a therapeutic amount of a
compound in section IIIa, wherein said inflammatory response is
inhibited. In another exemplary embodiment, the compound has a
structure which is a member selected from:
##STR00055##
IV. Therapeutic Indications of the Compounds of the Invention
[0116] It should be understood that the present methods include,
but are not limited to, treating an inflammatory-related disease
with a compound of the invention.
[0117] In another aspect, the invention provides methods of
preventing or treating diseases mediated by cytokines which
comprise administering to a subject in need of such treatment a
therapeutically effective amount of a compound of the invention. In
an exemplary embodiment, the compound is a member selected from
C1-C100. In an exemplary embodiment, the compound is
5-(4-cyanophenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole. Such
cytokine-mediated diseases include periodontitis, dry eye disease,
rheumatoid arthritis, osteoarthritis, Crohn's disease, ulcerative
colitis, psoriatic arthritis, traumatic arthritis, rubella
arthritis, inflammatory bowel disease, multiple sclerosis,
psoriasis, graft versus host disease, systemic lupus erythematosus,
toxic shock syndrome, irritable bowel syndrome, muscle
degeneration, allograft rejections, pancreatitis, insulinitis,
glomerulonephritis, diabetic nephropathy, renal fibrosis, chronic
renal failure, gout, leprosy, acute synovitis, Reiter's syndrome,
gouty arthritis, Behcet's disease, spondylitis, endometriosis,
non-articular inflammatory conditions, such as intervertbral disk
syndrome conditions, bursitis, tendonitis, tenosynovitis or
fibromyalgic syndrome; and acute or chronic pain, including but not
limited to neurological pain, neuropathies, polyneuropathies,
diabetes-related polyneuropathies, trauma, migraine, tension and
cluster headache, Horton's disease, varicose ulcers, neuralgias,
musculo-skeletal pain, osteo-traumatic pain, fractures,
algodystrophy, spondylarthritis, fibromyalgia, phantom limb pain,
back pain, vertebral pain, post-surgery pain, herniated
intervertebral disc-induced sciatica, cancer-related pain, vascular
pain, visceral pain, childbirth, or HIV-related pain. Other
cytokine mediated diseases are allergy, a metabolic disease, a
chemotherapy/radiation related complication; diabetes type I;
diabetes type II; a liver disease; a gastrointestinal disorder; an
ophthamological disease; allergic conjunctivitis; diabetic
retinopathy; Sjogren's syndrome; uvetitis; a pulmonary disorder, a
renal disease; dermatitis; HIV-related cachexia; cerebral malaria;
ankylosing spondolytis; leprosy; anemia; fibromyalgia, kidney
failure, stroke, chronic heart failure, endotoxemia, reperfusion
injury, ischemia reperfusion, myocardial ischemia, restenosis,
thrombosis, angiogenesis, Coronary Heart Disease, Coronary Artery
Disease, acute coronary syndrome, Takayasu arteritis, cardiac
failure such as heart failure, aortic valve stenosis,
cardiomyopathy, myocarditis, vasculitis, vascular restenosis,
valvular disease or coronary artery bypass; hypercholesteremia,
diseases or conditions related to blood coagulation or
fibrinolysis, such as for example, acute venous thrombosis,
pulmonary embolism, thrombosis during pregancy, hemorrhagic skin
necrosis, acute or chronic disseminated intravascular coagulation
(DIC), clot formation from surgery, long bed rest or long periods
of immobilization, venous thrombosis, fulminant meningococcemia,
acute thrombotic strokes, acute coronary occlusion, acute
peripheral arterial occlusion, massive pulmonary embolism, axillary
vein thrombosis, massive iliofemoral vein thrombosis, occluded
arterial or venous cannulae, cardiomyopathy, venoocclusive disease
of the liver, hypotension, decreased cardiac output, decreased
vascular resistance, pulmonary hypertension, diminished lung
compliance, leukopenia or thrombocytopenia; or atherosclerosis. Yet
others are allergic conjunctivitis, uveitis, glaucoma, optic
neuritis, retinal ischemia, diabetic retinopathy, laser induced
optic damage, or surgery or trauma-induced proliferative
vitreoretinopathy. Cytokine mediated diseases further include
allergic rhinitis, asthma, adult respiratory distress syndrome,
chronic pulmonary inflammation, chronic obstructive pulmonary
disease, emphysema, bronchitis, mucus hypersecretion, silicosis,
SARS infection and respiratory tract inflammation. Also included
are psoriasis, eczema, atopic dermatitis, contact dermatitis, or
acne. Yet other cytokine mediated diseases are Guillain-Barre
syndrome, Parkinson's disease, Huntington's disease, Alzheimer's
disease, amyotrophic lateral sclerosis, multiple sclerosis and
other demyelinating diseases, viral and bacterial meningitis, CNS
trauma, spinal cord injury, seizures, convulsions,
olivopontocerebellar atrophy, AIDS dementia complex, MERRF and
MELAS syndromes, Leber's disease, Wemicke's encephalophathy, Rett
syndrome, homocysteinuria, hyperprolinemia, hyperhomocysteinemia,
nonketotic hyperglycinemia, hydroxybutyric aminoaciduria, sulfite
oxidase deficiency, combined systems disease, lead encephalopathy,
Tourett's syndrome, hepatic encephalopathy, drug addiction, drug
tolerance, drug dependency, depression, anxiety and schizophrenia,
aneurism, or epilepsy. In another aspect of the invention, the
cytokine mediated diseases include bone resorption diseases,
osteopetrosis, osteoporosis, or osteoarthritis. Also included are
diabetes, systemic cachexia, cachexia secondary to infection or
malignancy, cachexia secondary to acquired immune deficiency
syndrome (AIDS), obesity, anorexia or bulimia nervosa. Additonally,
the cytokine mediated disease can be sepsis, HIV, HCV, malaria,
infectious arthritis, leishmaniasis, Lyme disease, cancer,
including but not limited to breast cancer, colon cancer, lung
cancer, prostatic cancer, multiple myeloma, acute myelogenous
leukemia, myelodysplastic syndrome, non-Hodgkins lymphoma, or
follicular lymphoma, Castleman's disease, or drug resistance.
[0118] In another aspect, the invention provides methods of
treating neutrophil-mediated diseases which comprise administering
to a subject in need of such treatment a therapeutically effective
amount of a compound of the invention, wherein the
neutrophil-mediated disease is bronchial asthma, rhinitis,
influenza, stroke, myocardial infarction, thermal injury, adult
respiratory distress syndrome (ARDS), multiple organ injury
secondary to trauma, acute glomerulonephritis, dermatoses with
acute inflammatory components, acute purulent meningitis,
hemodialysis, leukopheresis, granulocyte transfusion associated
syndromes, or necrotizing enterocolitis.
[0119] Preferably the neurodegenerative disorder is selected from
the group consisting of: Alzheimer's disease and Parkinson disease;
the inflammatory bowel disease is selected from the group
consisting of: Crohn's disease or uncerative colitis; the
gastrointestinal complication is diarrhea; the liver disease is
selected from the group consisting of: an autoimmune hepatitis,
hepatitis C, primary biliary cirrhosis, primary sclerosing
cholangitis, or fulminant liver failure; the gastrointestinal
disorder is selected from the group consisting of: celiac disease
and non-specific colitis; the bone disease is osteoporosis; the
pulmonary disorder is selected from the group consisting of:
allergic rihinitis, asthma, chronic obstructive pulmonary disease,
chronic granulomatous inflammation, cystic fibrosis, and
sarcoidosis; the cardiovascular disease is selected from the group
consisting of: atheroscleotic cardiac disease, congestive heart
failure and restenosis; and the renal disease is selected from the
group consisting of: glomerulpnephritis and vasculitis.
[0120] In a preferred embodiment the disease is inflammatory bowel
disease (IBD), specifically including Crohn's disease and
uncerative colitis. In another preferred embodiment the disease
being treated is arthritis, rheumatoid arthritis, psoriasis,
Alzheimer's disease, or Parkinson disease. In yet another preferred
embodiment the disease is post-radiotherapy related disease or
atherosclerosis. In yet another preferred embodiment the disease is
atopic dermatitis. In yet another preferred embodiment the disease
is actinic keratosis.
[0121] Preferably the compound is in an amount to inhibit
pro-inflammatory cytokine expression and/or to stimulate
anti-inflammatory cytokine expression. In an exemplary embodiment,
the compound is a member selected from C1-C100. In an exemplary
embodiment, the compound is
5-(4-cyanophenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole. In one
embodiment, the compound is preferably in an amount to inhibit at
least 30 to 100% expression of one or more of the pro-inflammatory
cytokines selected from the group consisting of: IL-1.alpha.,
.beta., IL-2, IL-3, IL-6, IL-7, IL-9, IL-12, IL-17, IL-18, IL-23,
TNF-.alpha., LT, LIF, Oncostatin, and IFNc1.alpha., .beta.,
.gamma.. In an exemplary embodiment, the compound is in an amount
to inhibit at least 40 to 100% expression of one or more of the
pro-inflammatory cytokines. In an exemplary embodiment, the
compound is in an amount to inhibit at least 50 to 100% expression
of one or more of the pro-inflammatory cytokines. In an exemplary
embodiment, the compound is in an amount to inhibit at least 60 to
100%. In an exemplary embodiment, the compound is in an amount to
inhibit at least 70 to 100%. In an exemplary embodiment, the
compound is in an amount to inhibit at least 30 to 70% expression
of one or more of the pro-inflammatory cytokines. In an exemplary
embodiment, the compound is in an amount to inhibit at least 40 to
90% expression of one or more of the pro-inflammatory cytokines. In
an exemplary embodiment, the compound is in an amount to inhibit at
least 45 to 80% expression of one or more of the pro-inflammatory
cytokines. In an exemplary embodiment, the compound is in an amount
to inhibit at least 55 to 75% expression of one or more of the
pro-inflammatory cytokines. In an exemplary embodiment, the
compound is in an amount to inhibit at least 75 to 98% expression
of one or more of the pro-inflammatory cytokines. In an exemplary
embodiment, the compound is in an amount to inhibit between about
50% and about 99% expression of one or more of the pro-inflammatory
cytokines. In another embodiment, the compound is preferably in an
amount to stimulate anti-inflammatory cytokine expression. In this
embodiment, the compound is preferably in an amount to increase the
anti-inflammatory cytokine selected from the group consisting of:
cytokine IL-4, IL-10, IL-11, W-13 or TGF-.beta. by at least 25%,
more preferably at least 50%, and most preferably at least 75%.
[0122] This invention provides a method of using a class of
boron-containing small molecules for the treatment of various
inflammatory-related diseases in humans or animals. In an exemplary
embodiment, the small molecule is a compound described herein. In
an exemplary embodiment, the compound is a member selected from
C1-C100. In an exemplary embodiment, the compound is
5-(4-cyanophenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole. These
inflammatory-related diseases include, but are not limited to
inflammatory bowel diseases (IBD), psoriasis, rheumatoid arthritis
(RA), multiple sclerosis (MS), neurodegenerative disorders,
cardiovascular disease (CVD) and atherosclerosis, and metabolic
disease (the metabolic syndrome and diabetes) as well as
infection-related inflammation.
[0123] The invention also provides a method of treating an
inflammatory-related disease associated with cytokine expression
levels, which comprises administering to a human or an animal in
need of such treatment the compound of the invention.
[0124] The invention also provides a method wherein the animal
being treated is a member selected from a human, a horse, a cow and
a pig. In an exemplary embodiment, the animal is a human.
[0125] In an exemplary embodiment, the invention provides a method
of inhibiting a cytokine that is a member selected from IL-1.beta.,
IL-4, TNF-.alpha. and IFN.gamma.. In this method, the cytokine is
contacted with a compound of the invention. In an exemplary
embodiment, the compound is a member selected from C1-C100. In an
exemplary embodiment, the compound is
5-(4-cyanophenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole. Tumor
necrosis factor-.alpha. (TNF-.alpha.) and interleukin-1 (IL-1) are
proinflammatory cytokines that mediate inflammatory responses
associated with infectious agents and other cellular stresses.
Overproduction of cytokines such as IL-1 and TNF-.alpha. is
believed to underlie the progression of many inflammatory diseases
including rheumatoid arthritis (RA), Crohn's disease, inflammatory
bowel disease, multiple sclerosis, endotoxin shock, osteoporosis,
Alzheimer's disease, congestive heart failure, and psoriasis among
others (Dinarello, C. A. et al., Rev. Infect. Diseases 1984, 6:51;
Salituro et al., Curr. Med. Chem. 1999, 6:807-823; Henry et al.,
Drugs Fut. 1999, 24:1345-1354). An accepted therapeutic approach
for potential drug intervention in these conditions is the
reduction of proinflammatory cytokines such as TNF-.alpha. (also
referred to as TNFa) and interleukin-1.beta. (IL-1b).
[0126] Inflammatory Bowel Disease (IBD): IBD comprises Crohn's
disease (CD) and ulcerative colitis (UC), which are two overlapping
chronic inflammatory-related diseases of the gastrointestinal tract
caused by dysregulation of the immune system (Rutgeerts, P.,
Aliment Pharmacol Ther, 17: 185-192 (2003)). Patients with IBD have
defective intestinal epithelial barrier function, which allows
bacterial colonization of the epithelia. As a result, bacterial
products and pro-inflammatory cytokines (TNF-.alpha., IL-1 and
IL-6) cause persistent inflammatory stimulation. Bacterial antigens
are introduced into the immune system by mucosal dendritic cells
and macrophases. In response, intestinal phagocytes (mainly
monocytes and neutrophils) proliferate and increase expression and
secretion of pro-inflammatory cytokines.
[0127] Psoriasis: Cytokines are intercellular messengers that have
an important role in the development and maintenance of cutaneous
inflammation. A number of cytokines have been reported to play
crucial roles in the pathogenesis of inflammatory skin disorders.
IL-1, TNF-.alpha., and IFN-.gamma. induce expression of ICAM-1 and
major histocompatibility complex (MHC) class II (Dustin, M. L., J
Immunol, 137: 245-254, (1986); Strange, P., J Invest Dermatol, 102:
150-154, (1994)). IL-1, TNF-.alpha., and granulocyte-macrophage
colony-stimulation factor are able to induce activation,
maturation, and migration of dendritic cells, and IL-1 activates
mast cells (50). IL-6 and TGF-.alpha. enhance keratinocyte
proliferation. IL-1, TNF-.alpha., TGF-.alpha., and VEGF induce
angiogenesis and attract inflammatory cells (Grossman, R. M., Proc
Natl Acad Sci USA, 86: 6367-6371, (1989); Schreiber, A. B.,
Science, 232: 1250-1253, (1986); Detmar, M., J Exp Med, 180:
1141-1146, (1994)). The primacy of cytokines in eliciting cutaneous
immune responses makes them a highly attractive target for new
biological response modifiers (Williams, J. D., Clin Exp Dermatol,
27: 585-590, (2002)).
[0128] Rheumatoid arthritis (RA): The role of the cytokine network
in mediating inflammation and joint destruction in RA has been
extensively investigated in recent years. In addition to
TNF-.alpha., IL-1 plays a pivotal role in the pathogenesis and the
clinical manifestations of RA (54). The ability of IL-1 to drive
inflammation and joint erosion and to inhibit tissue repair
processes has been clearly established in in vitro systems and in
animal models, and alleviation of inflammatory symptoms in RA
patients has been achieved by blockage of IL-1 (Bresnihan, B.,
Arthritis Rheum, 41: 2196-2204, (1998)). IL-6 is a multifunctional
cytokine that regulates the immune response, hematopoiesis, the
acute phase response, and inflammation. Deregulation of IL-6
production is implicated in the pathology of several diseases
including RA. A therapeutic approach to block the IL-6 signal has
been carried out by using humanized anti-IL-6R antibody for RA
among other diseases (Ito, H., Curr Drug Targets Inflamm Allergy,
2: 125-130, (2003); Ishihara, K Cytokine Growth Factor Rev, 13:
357-368, (2002)). IL-10 is an anti-inflammatory cytokine.
Expressing IL-10 has been shown to prevent arthritis or ameliorate
the disease in animal models (57, 58). While it is obvious that
cytokines such as TNF-.alpha., IL-1, IL-6 and IL-10 have
independent roles, they act in concert in mediating certain
pathophysiological processes in RA. The finding of a class of
molecules described in this invention, which are able to modulate
these different cytokines, will result in dramatic therapeutic
progress in the treatment of RA.
[0129] Multiple Sclerosis (MS): MS is an autoimmune inflammatory
disorder. Although the cause of the body attacking its own myelin
in MS patients remains unclear, deregulated cytokines are clearly
involved in the process of the disease. Using experimental
autoimmune encephalomyelitis (EAE), a widely used model for studies
of MS based on autoimmune, histopathological, genetic and clinical
similarities, it has been shown that in the early active stage,
both EAE and MS are characterized by the presence of perivascular
inflammatory cuffs disseminated in the CNS, a process in which
chemoattractant cytokines (chemokines) play an important role.
There is evidence that the expression of chemokines (IL-8 family
members) during CNS autoimmune inflammation is regulated by some
pro-inflammatory cytokines, such as TNF (Glabinski, A. R., Scand J
Immunol, 58: 81-88, (2003)). The roles of other
pro-/anti-inflammatory cytokines such as IL-1.beta., IL-6 and IL-10
were also confirmed in EAE animal models (Diab, A., J Neuropathol
Exp Neurol, 56: 641-650, (1997); Samoilova, E. B., J Immunol, 161:
6480-6486, (1998); Robertson, J., J Cell Biol, 155: 217-226,
(2001)) as well as in humans (de Jong, B. A., J Neuroimmunol, 126:
172-179, (2002)). IL-1.beta. is present in MS lesions. IL-1
receptor antagonist (IL-1Ra) moderates the induction of
experimental autoimmune encephalomyelitis (EAE). Increased risk of
MS has been seen in individuals with High IL-1 (3 over IL-1Ra
production ratio and high TNF over IL-10 production ratio (de Jong,
B. A., J Neuroimmunol, 126: 172-179, (2002)).
[0130] Neurodegenerative disorders: Alzheimer's disease (AD) and
Parkinson's disease (PK) are the 2 most common neurodegenerative
disorders related to neuroinflammation. Neuroinflammation is a
characteristic of pathologically affected tissue in several
neurodegenerative disorders. These changes are particularly
observed in affected brain areas of AD cases (McGeer, E. G., Prog
Neuropsychopharmacol Biol Psychiatry, 27: 741-749, (2003)). The
role of cytokines has been implicated in the pathogenesis of AD,
although the mechanism by which cytokines contribute to the
pathogenesis is not fully understood. In AD, microglia, especially
those associated with amyloid deposits, have a phenotype that is
consistent with a state of activation, including immunoreactivity
with antibodies to class II major histocompatibility antigens and
to inflammatory cytokines, IL-1.beta. and TNF-.alpha. (Dickson, D.
W., Glia, 7: 75-83, (1993)). One of the major neuropathological
characteristics of AD is the brain deposition of senile plaques
that are mainly composed of toxic amyloid beta-peptide (Abeta),
which is generated from a family of Abeta containing precursor
proteins (AbetaPP). Cytokines have been shown to stimulate gene
expression of transcription of AbetaPP. Analysis of genetic linkage
of loci controlling age-at-onset in AD and PK revealed a
significant association of AD with glutathione S-transferase,
omega-1 and 2 (GSTO1, GSTO2) genes. The function of GSTO1 appears
related to the post-translational processing of pro-inflammatory
cytokine IL-1.beta. (Laliberte, R. E., J Biol Chem, 278:
16567-16578, (2003)).
[0131] Post-radiotherapy related Inflammation: Radiation damage
related inflammatory diseases to the rectum and sigmoid colon are
most common complications with radiation therapy for cancers in the
pelvic region, which include cancers of the cervix, uterus,
prostate, bladder, and testes. Radiation proctosigmoiditis is the
most common clinically apparent form of colonic damage after pelvic
irradiation with an incidence of 5% to 20%. Patients typically
exhibit symptoms of tenesmus, bleeding, low-volume diarrhea, and
rectal pain. Rarely, low-grade obstruction or fistulous tracts into
adjacent organs may develop.
[0132] The mechanism of radiation therapy is through its damage to
DNA in actively proliferating cells. The pathological damages after
localized radiation therapy to the intestine/colon can be divided
into acute and chronic phases. The initial pathological changes
include a loss of lymphocytes in the lamina propria and microscopic
damage to mucosal epithelial cells and vascular endothelial cells.
These changes manifest as villous blunting and a decrease in crypt
regenerative cells and are followed by marked submucosal edema with
increase of vascular permeability.
[0133] Progressive endarteritis appears to be the major mechanism
by which the chronic effects occur, which later manifest as
progressive fibrosis leading to mucosal atrophy, stricture
formation, and thrombosis, causing secondary ischemic damage.
Radiation colitis in the chronic phase demonstrates a very
significant crypt distortion, vascular telangiectasia, and fibrosis
of the lamina propria. Interestingly, some of these pathological
changes are also present in long-standing IBD (Haboubi, N. Y., J
Clin Pathol, 45: 272, (1992).
[0134] Thus, cytokines may play a key role among various
gastrointestinal diseases in which inflammation exhibits a
significant part. Recent studies have focused on the crucial role
of cytokines in chronic IBD (Brynskov, J., Gut, 33: 55-58, (1992);
Matsuura, T., Gastroenterology, 104: 448-458, (1993); Beagley, K.
W., Gastroenterol Clin North Am, 21: 347-366, (1992); MacDermott,
R. P., Med Clin North Am, 78: 1207-1231, (1994); Isaacs, K. L.,
Gastroenterology, 103: 1587-1595, (1992); Indaram, A. V., World J
Gastroenterol, 6: 49-52, (2000)). To elucidate the role of
cytokines in radiation proctitis, Indaram et al. (Indaram, A. V.,
Am J Gastroenterol, 95: 1221-1225, (2000)) examined the colonic
mucosal cytokine levels in patients with radiation proctitis and
compared these values with those obtained from normal controls and
patients with IBD. They found that the mucosal levels of IL-2,
IL-6, and IL-8 were significantly higher and statistically
significant (p<0.05) in both diseased (5.62.+-0.0.13,
1.60.+-0.0.31, 21.45.+-0.4.03 pg/mg) and normal-appearing mucosa
(3.83.+-0.0.78, 1.36.+-0.0.34, 13.45.+-0.3.18 pg/mg) in the
radiation proctitis group, compared with those of normal controls
(1.74.+-0.0.23, 0.67.+-0.0.05, 4.99.+-0.1.39 pg/mg).
[0135] Thus, these findings demonstrate a similar activation of
cytokines in patients with radiation proctitis and IBD. In the
radiation proctitis patients it was demonstrated that IL-2, IL-6,
and IL-8 levels in the mucosa were significantly greater compared
to normal controls. In comparison, the IBD (UC and CD) patients
demonstrated significantly higher levels of the cytokines including
IL-1, IL-2, IL-6, and IL-8 compared to the normal controls.
[0136] The similarity in mucosal cytokine expression in these two
diseases plausibly relates directly to the intense inflammatory
nature of the diseases. It has been postulated that this similarity
in cytokine activation in these two diseases may translate into the
similar pathological changes seen in chronic IBD and radiation
proctitis. This hypothesis is supported by that fact that the
medical management of radiation proctitis, albeit rather
unsatisfactorily, includes treatment with various aminosalicylic
acid derivatives and corticosteroids given orally or topically.
These treatment options are identical to the management of IBD.
[0137] Other Cytokine Deregulation Related Diseases: Cardiovascular
disease (CVD), atherosclerosis, and metabolic disease (the
metabolic syndrome) also have been linked to the improper
secretion/expression of pro/anti-inflammatory cytokines (DeGraba,
T. J., Adv Neurol, 92: 29-42, (2003); von der Thusen, J. H.,
Pharmacol Rev, 55: 133-166, (2003); Schmidt, M. I., Clin Chem Lab
Med, 41: 1120-1130, (2003); Virdis, A., Curr Opin Nephrol
Hypertens, 12: 181-187, (2003); Ito, T., Curr Drug Targets Inflamm
Allergy, 2: 257-265, (2003)).
[0138] Diabetes: A fundamental defect in type II diabetes is
insulin resistance, by which insulin fails to suppress glucose
production from the liver and to promote consumption by peripheral
tissues, resulting in hyperglycemia. Pancreatic .beta. cells
respond to excess plasma glucose by secreting more insulin to
overcome the effects of insulin resistance. As insulin resistance
progresses and the P cells are no longer able to meet the
requirement for increasing amount of insulin secretion, plasma
glucose levels increase and type II diabetes develops.
[0139] Many factors may contribute to the onset of type II
diabetes. Since 80% of the patients with type II diabetes are obese
and obesity is always associated with insulin resistance, molecular
mediators that link obesity to insulin resistance have been under
extensive research. A variety of factors have been identified as
contributing causes of insulin resistance in obesity and
obesity-linked type II diabetes, notable those produced by adipose
tissue, FFAs (free fatty acids), TNF-.alpha., IL-6, leptin,
adiponectin, and resistin. Both mRNA and protein levels of
TNF-.alpha. are highly increased in the adipose tissues of obese
animals (Hotamisligil, G. S., Science, 259: 87-91, (1993)) and
human subjects (Hotamisligil, G. S., J Clin Invest, 95: 2409-2415,
(1995)). All different types of cell in the adipose tissue are
capable of producing cytokines. Adipocytes express TNF-.alpha.
receptors and are also the major source of TNF-.alpha., which is
thought to function predominantly in an autocrine/paracrine manner
in adipose tissue.
[0140] Long-term exposure of cultured cells (Hotamisligil, G. S.,
Proc Natl Acad Sci USA, 91. 4854-4858, (1994)) or animals (Lang, C.
H., Endocrinology, 130: 43-52, (1992)) to TNF-.alpha. induces
insulin resistance, whereas neutralization of TNF-.alpha. increases
insulin sensitivity and reduces hyperglycemia in a type II diabetes
animal model (Hotamisligil, G. S., Diabetes, 43: 1271-1278,
(1994)). Absence of TNF-.alpha. or TNF-.alpha. receptors by gene
knock-out significantly improves insulin sensitivity in obesity
animal models (Uysal, K. T., Nature, 389: 610-614, (1997)).
[0141] Mechanisms have been proposed for TNF-.alpha. induced
insulin resistance in adipocytes as well as systemically (Ruan, H.,
Cytokine Growth Factor Rev, 14: 447-455, (2003)). TNF-.alpha.
inhibits phosphorylation of insulin receptor and insulin receptor
substrate-1 (IRS-1) through the inhibitor kB kinase-.beta.
(IKK-.beta.). NF-kB activation by TNF-.alpha. is obligatory for
repression of adipocyte-abundant genes essential for adipocyte
function, and is also sufficient to inhibit PPAR-gamma-mediated
gene transcription. TNF-.alpha. also stimulate lipolysis and other
cytokine expression in adipose tissue, and triggers FFA release. In
fact, plasma FFVs levels increase before overt hyperglycemia in
some animal models of insulin resistance (Ruan, H., Cytokine Growth
Factor Rev, 14: 447-455, (2003)). There are extensive evidence
implicating excess plasma FFA in induction and progression of
systemic insulin resistance. In hepatocytes, FFAs contribute to
excessive glucose and VLDL production. In muscle cells, high level
of FFA impair insulin signaling and promote FFA oxidation leading
to greatly decreased glucose ox.
[0142] Currently available insulin sensitizing drugs, which belong
to PPAR-gamma agonist, inhibit TNF-.alpha.-induced adipocytes gene
expression profile through NF-kB pathway (Ruan, H., J Biol Chem,
278: 28181-28192, (2003). As adipocyte-derived TNF-.alpha.
functions as autocrine or paracrine factor, systemic delivery of
TNF-.alpha. antibody may not be effective in blocking the
biological activity of locally expressed TNF-.alpha. in adipose
tissue (Ofei, F., Diabetes, 45: 881-885, (1996)). NATURA, which
represents a new type of small molecule TNF-.alpha. inhibitor
distributing through simple diffusion, could therefore be effective
agent to block the function of locally expressed TNF-.alpha. and
potentially useful in the treatment of type 2 diabetes.
[0143] Type I diabetes mellitus is an autoimmune disease
characterized by mononuclear cell infiltration in the islets of
Langerhans and selective destruction of the insulin producing beta
cells. While CD8+ T cells may be important initiators, CD4+ T cells
(Suri, A., Immunol Rev, 169: 55-65, (1999)) and macrophages (Jun,
H. S., Diabetes, 48: 34-42, (1999); Yoon, J. W., Autoimmunity, 27:
109-122, (1998)), are the major cellular effectors of the immune
process leading to beta cell death. Activated macrophages directly
secrete IL-1.beta., IL-6, IL-12, TNF-.alpha., indirectly trigger
INF-gamma production from activated T cells. The involvement of
cytokines like TNF-.alpha., INF-.gamma., IL-.beta., IL-6 and IL-10,
in the pathogenesis of type 1 diabetes has been well clarified
through correlation studies of cytokine expression and development
of type I diabetes, cytokine augmentation studies and cytokine
deficiency studies. (Rabinovitch, A., Rev Endocr Metab Disord, 4:
291-299, (2003)). In addition to cytokine neutralizing antibodies
and soluble cytokine receptors, anti-inflammatory compounds also
show the effects of delaying or preventing the onset of type 1
diabetes in animal models.
[0144] In summary, dysregulation of cytokines is involved in a
variety of diseases, including inflammatory-related diseases and
those normally not considered inflammatory-related diseases. A
molecule that is capable of modulating both pro- and
anti-inflammatory cytokines should provide therapeutic benefits
with minimal side effects for all types of diseases related to
dysfunction of these inflammation components.
V. Pharmaceutical Formulations
[0145] The pharmaceutical formulations of the invention can take a
variety of forms adapted to the chosen route of administration.
Those skilled in the art will recognize various synthetic
methodologies that may be employed to prepare non-toxic
pharmaceutical formulations incorporating the compounds described
herein. Those skilled in the art will recognize a wide variety of
non-toxic pharmaceutically acceptable solvents that may be used to
prepare solvates of the compounds of the invention, such as water,
ethanol, propylene glycol, mineral oil, vegetable oil and
dimethylsulfoxide (DMSO).
[0146] The compositions of the invention may be administered
orally, topically, parenterally, by inhalation or spray or rectally
in dosage unit formulations containing conventional non-toxic
pharmaceutically acceptable carriers, adjuvants and vehicles. It is
further understood that the best method of administration may be a
combination of methods. Oral administration in the form of a pill,
capsule, elixir, syrup, lozenge, troche, or the like is
particularly preferred. The term parenteral as used herein includes
subcutaneous injections, intradermal, intravascular (e.g.,
intravenous), intramuscular, spinal, intrathecal injection or like
injection or infusion techniques.
[0147] The pharmaceutical formulations containing compounds of the
invention are preferably in a form suitable for oral use, for
example, as tablets, troches, lozenges, aqueous or oily
suspensions, dispersible powders or granules, emulsion, hard or
soft capsules, or syrups or elixirs.
[0148] Compositions intended for oral use may be prepared according
to any method known in the art for the manufacture of
pharmaceutical formulations, and such compositions may contain one
or more agents selected from the group consisting of sweetening
agents, flavoring agents, coloring agents and preserving agents in
order to provide pharmaceutically elegant and palatable
preparations. Tablets may contain the active ingredient in
admixture with non-toxic pharmaceutically acceptable excipients
that are suitable for the manufacture of tablets. These excipients
may be for example, inert diluents, such as calcium carbonate,
sodium carbonate, lactose, calcium phosphate or sodium phosphate;
granulating and disintegrating agents, for example, corn starch, or
alginic acid; binding agents, for example starch, gelatin or
acacia; and lubricating agents, for example magnesium stearate,
stearic acid or talc. The tablets may be uncoated or they may be
coated by known techniques to delay disintegration and absorption
in the gastrointestinal tract and thereby provide a sustained
action over a longer period. For example, a time delay material
such as glyceryl monostearate or glyceryl distearate may be
employed.
[0149] Formulations for oral use may also be presented as hard
gelatin capsules wherein the active ingredient is mixed with an
inert solid diluent, for example, calcium carbonate, calcium
phosphate or kaolin, or as soft gelatin capsules wherein the active
ingredient is mixed with water or an oil medium, for example peanut
oil, liquid paraffin or olive oil.
[0150] Aqueous suspensions contain the active materials in
admixture with excipients suitable for the manufacture of aqueous
suspensions. Such excipients are suspending agents, for example
sodium carboxymethylcellulose, methylcellulose,
hydroxypropylmethylcellulose, sodium alginate,
polyvinylpyrrolidone, gum tragacanth and gum acacia; and dispersing
or wetting agents, which may be a naturally-occurring phosphatide,
for example, lecithin, or condensation products of an alkylene
oxide with fatty acids, for example polyoxyethylene stearate, or
condensation products of ethylene oxide with long chain aliphatic
alcohols, for example heptadecaethyleneoxycetanol, or condensation
products of ethylene oxide with partial esters derived from fatty
acids and a hexitol such as polyoxyethylene sorbitol monooleate, or
condensation products of ethylene oxide with partial esters derived
from fatty acids and hexitol anhydrides, for example polyethylene
sorbitan monooleate. The aqueous suspensions may also contain one
or more preservatives, for example ethyl, or n-propyl
p-hydroxybenzoate, one or more coloring agents, one or more
flavoring agents, and one or more sweetening agents, such as
sucrose or saccharin.
[0151] Oily suspensions may be formulated by suspending the active
ingredients in a vegetable oil, for example arachis oil, olive oil,
sesame oil or coconut oil, or in a mineral oil such as liquid
paraffin. The oily suspensions may contain a thickening agent, for
example beeswax, hard paraffin or cetyl alcohol. Sweetening agents
such as those set forth above, and flavoring agents may be added to
provide palatable oral preparations. These compositions may be
preserved by the addition of an anti-oxidant such as ascorbic
acid.
[0152] Dispersible powders and granules suitable for preparation of
an aqueous suspension by the addition of water provide the active
ingredient in admixture with a dispersing or wetting agent,
suspending agent and one or more preservatives. Suitable dispersing
or wetting agents and suspending agents are exemplified by those
already mentioned above. Additional excipients, for example
sweetening, flavoring and coloring agents, may also be present.
[0153] Pharmaceutical formulations of the invention may also be in
the form of oil-in-water emulsions and water-in-oil emulsions. The
oily phase may be a vegetable oil, for example olive oil or arachis
oil, or a mineral oil, for example liquid paraffin or mixtures of
these. Suitable emulsifying agents may be naturally-occurring gums,
for example gum acacia or gum tragacanth; naturally-occurring
phosphatides, for example soy bean, lecithin, and esters or partial
esters derived from fatty acids and hexitol; anhydrides, for
example sorbitan monooleate; and condensation products of the said
partial esters with ethylene oxide, for example polyoxyethylene
sorbitan monooleate. The emulsions may also contain sweetening and
flavoring agents.
[0154] Syrups and elixirs may be formulated with sweetening agents,
for example glycerol, propylene glycol, sorbitol or sucrose. Such
formulations may also contain a demulcent, a preservative, and
flavoring and coloring agents. The pharmaceutical formulations may
be in the form of a sterile injectable aqueous or oleaginous
suspension. This suspension may be formulated according to the
known art using those suitable dispersing or wetting agents and
suspending agents, which have been mentioned above. The sterile
injectable preparation may also be a sterile injectable solution or
suspension in a non-toxic parenterally acceptable diluent or
solvent, for example as a solution in 1,3-butanediol. Among the
acceptable vehicles and solvents that may be employed are water,
Ringer's solution and isotonic sodium chloride solution. In
addition, sterile, fixed oils are conventionally employed as a
solvent or suspending medium. For this purpose any bland fixed oil
may be employed including synthetic mono- or diglycerides. In
addition, fatty acids such as oleic acid find use in the
preparation of inj ectables.
[0155] The composition of the invention may also be administered in
the form of suppositories, e.g., for rectal administration of the
drug. These compositions can be prepared by mixing the drug with a
suitable non-irritating excipient that is solid at ordinary
temperatures but liquid at the rectal temperature and will
therefore melt in the rectum to release the drug. Such materials
are cocoa butter and polyethylene glycols.
[0156] Alternatively, the compositions can be administered
parenterally in a sterile medium. The drug, depending on the
vehicle and concentration used, can either be suspended or
dissolved in the vehicle. Advantageously, adjuvants such as local
anesthetics, preservatives and buffering agents can be dissolved in
the vehicle.
[0157] For administration to non-human animals, the composition
containing the therapeutic compound may be added to the animal's
feed or drinking water. Also, it will be convenient to formulate
animal feed and drinking water products so that the animal takes in
an appropriate quantity of the compound in its diet. It will
further be convenient to present the compound in a composition as a
premix for addition to the feed or drinking water. The composition
can also added as a food or drink supplement for humans.
[0158] Dosage levels of the order of from about 5 mg to about 250
mg per kilogram of body weight per day and more preferably from
about 25 mg to about 150 mg per kilogram of body weight per day,
are useful in the treatment of the above-indicated conditions. The
amount of active ingredient that may be combined with the carrier
materials to produce a single dosage form will vary depending upon
the condition being treated and the particular mode of
administration. Dosage unit forms will generally contain between
from about 1 mg to about 500 mg of an active ingredient.
[0159] Frequency of dosage may also vary depending on the compound
used and the particular disease treated. However, for treatment of
most disorders, a dosage regimen of 4 times daily or less is
preferred. It will be understood, however, that the specific dose
level for any particular patient will depend upon a variety of
factors including the activity of the specific compound employed,
the age, body weight, general health, sex, diet, time of
administration, route of administration and rate of excretion, drug
combination and the severity of the particular disease undergoing
therapy.
[0160] Preferred compounds of the invention will have desirable
pharmacological properties that include, but are not limited to,
oral bioavailability, low toxicity, low serum protein binding and
desirable in vitro and in vivo half-lives. Penetration of the blood
brain barrier for compounds used to treat CNS disorders is
necessary, while low brain levels of compounds used to treat
peripheral disorders are often preferred.
[0161] Assays may be used to predict these desirable
pharmacological properties. Assays used to predict bioavailability
include transport across human intestinal cell monolayers,
including Caco-2 cell monolayers. Toxicity to cultured hepatocyctes
may be used to predict compound toxicity. Penetration of the blood
brain barrier of a compound in humans may be predicted from the
brain levels of laboratory animals that receive the compound
intravenously.
[0162] Serum protein binding may be predicted from albumin binding
assays. Such assays are described in a review by Oravcova, et al.
(Journal of Chromatography B (1996) volume 677, pages 1-27).
[0163] Compound half-life is inversely proportional to the
frequency of dosage of a compound. In vitro half-lives of compounds
may be predicted from assays of microsomal half-life as described
by Kuhnz and Gieschen (Drug Metabolism and Disposition, (1998)
volume 26, pages 1120-1127).
[0164] The amount of the composition required for use in treatment
will vary not only with the particular compound selected but also
with the route of administration, the nature of the condition being
treated and the age and condition of the patient and will
ultimately be at the discretion of the attendant physician or
clinician.
V. A) Topical Formulations
[0165] In a preferred embodiment, the methods of the invention can
be used employed through the topical application of the compounds
described herein.
[0166] The compositions of the present invention comprises fluid or
semi-solid vehicles that may include but are not limited to
polymers, thickeners, buffers, neutralizers, chelating agents,
preservatives, surfactants or emulsifiers, antioxidants, waxes or
oils, emollients, sunscreens, and a solvent or mixed solvent
system. The solvent or mixed solvent system is important to the
formation because it is primarily responsible for dissolving the
drug. The best solvent or mixed solvent systems are also capable of
maintaining clinically relevant levels of the drug in solution
despite the addition of a poor solvent to the formulation. The
topical compositions useful in the subject invention can be made
into a wide variety of product types. These include, but are not
limited to, lotions, creams, gels, sticks, sprays, ointments,
pastes, foams, mousses, and cleansers. These product types can
comprise several types of carrier systems including, but not
limited to particles, nanoparticles, and liposomes. If desired,
disintegrating agents can be added, such as the cross-linked
polyvinyl pyrrolidone, agar or alginic acid or a salt thereof such
as sodium alginate. Techniques for formulation and administration
can be found in Remington: The Science and Practice of Pharmacy,
supra. The formulation can be selected to maximize delivery to a
desired target site in the body.
[0167] Lotions, which are preparations that are to be applied to
the skin, nail, hair, claw or hoof surface without friction, are
typically liquid or semi-liquid preparations in which finely
divided solid, waxy, or liquid are dispersed. Lotions will
typically contain suspending agents to produce better dispersions
as well as compounds useful for localizing and holding the active
agent in contact with the skin, nail, hair, claw or hoof, e.g.,
methylcellulose, sodium carboxymethyl-cellulose, or the like.
[0168] Creams containing the active agent for delivery according to
the present invention are viscous liquid or semisolid emulsions,
either oil-in-water or water-in-oil. Cream bases are
water-washable, and contain an oil phase, an emulsifier and an
aqueous phase. The oil phase is generally comprised of petrolatum
or a fatty alcohol, such as cetyl- or stearyl alcohol; the aqueous
phase usually, although not necessarily, exceeds the oil phase in
volume, and generally contains a humectant. The emulsifier in a
cream formulation, as explained in Remington: The Science and
Practice of Pharmacy, supra, is generally a nonionic, anionic,
cationic or amphoteric surfactant.
[0169] Gel formulations can also be used in connection with the
present invention. As will be appreciated by those working in the
field of topical drug formulation, gels are semisolid. Single-phase
gels contain organic macromolecules distributed substantially
uniformly throughout the carrier liquid, which is typically
aqueous, but also may be a solvent or solvent blend.
[0170] Ointments, which are semisolid preparations, are typically
based on petrolatum or other petroleum derivatives. As will be
appreciated by the ordinarily skilled artisan, the specific
ointment base to be used is one that provides for optimum delivery
for the active agent chosen for a given formulation, and,
preferably, provides for other desired characteristics as well,
e.g., emolliency or the like. As with other carriers or vehicles,
an ointment base should be inert, stable, nonirritating and
non-sensitizing. As explained in Remington: The Science and
Practice of Pharmacy, 19th Ed. (Easton, Pa.: Mack Publishing Co.,
1995), at pages 1399-1404, ointment bases may be grouped in four
classes: oleaginous bases; emulsifiable bases; emulsion bases; and
water-soluble bases. Oleaginous ointment bases include, for
example, vegetable oils, fats obtained from animals, and semisolid
hydrocarbons obtained from petroleum. Emulsifiable ointment bases,
also known as absorbent ointment bases, contain little or no water
and include, for example, hydroxystearin sulfate, anhydrous lanolin
and hydrophilic petrolatum. Emulsion ointment bases are either
water-in-oil (W/O) emulsions or oil-in-water (O/W) emulsions, and
include, for example, cetyl alcohol, glyceryl monostearate, lanolin
and stearic acid. Preferred water-soluble ointment bases are
prepared from polyethylene glycols of varying molecular weight;
again, reference may be had to Remington: The Science and Practice
of Pharmacy, supra, for further information.
[0171] Useful formulations of the invention also encompass sprays.
Sprays generally provide the active agent in an aqueous and/or
alcoholic solution which can be misted onto the skin, nail, hair,
claw or hoof for delivery. Such sprays include those formulated to
provide for concentration of the active agent solution at the site
of administration following delivery, e.g., the spray solution can
be primarily composed of alcohol or other like volatile liquid in
which the drug or active agent can be dissolved. Upon delivery to
the skin, nail, hair, claw or hoof, the carrier evaporates, leaving
concentrated active agent at the site of administration.
[0172] The topical pharmaceutical compositions may also comprise
suitable solid or gel phase carriers. Examples of such carriers
include but are not limited to calcium carbonate, calcium
phosphate, various sugars, starches, cellulose derivatives,
gelatin, and polymers such as polyethylene glycols.
[0173] The topical pharmaceutical compositions may also comprise a
suitable emulsifier which refers to an agent that enhances or
facilitates mixing and suspending oil-in-water or water-in-oil. The
emulsifying agent used herein may consist of a single emulsifying
agent or may be a nonionic, anionic, cationic or amphoteric
surfactant or blend of two or more such surfactants; preferred for
use herein are nonionic or anionic emulsifiers. Such surface-active
agents are described in "McCutcheon's Detergent and Emulsifiers,"
North American Edition, 1980 Annual published by the McCutcheon
Division, MC Publishing Company, 175 Rock Road, Glen Rock, N.J.
07452, USA.
[0174] Preferred for use herein are high molecular weight alcohols
such as cetearyl alcohol, cetyl alcohol, stearyl alcohol,
emulsifying wax, glyceryl monostearate. Other examples are ethylene
glycol distearate, sorbitan tristearate, propylene glycol
monostearate, sorbitan monooleate, sorbitan monostearate (SPAN 60),
diethylene glycol monolaurate, sorbitan monopalmitate, sucrose
dioleate, sucrose stearate (CRODESTA F-160), polyoxyethylene lauryl
ether (BRIJ 30), polyoxyethylene (2) stearyl ether (BRIJ 72),
polyoxyethylene (21) stearyl ether (BRIJ 721), polyoxyethylene
monostearate (Myrj 45), polyoxyethylene sorbitan monostearate
(TWEEN 60), polyoxyethylene sorbitan monooleate (TWEEN 80),
polyoxyethylene sorbitan monolaurate (TWEEN 20) and sodium oleate.
Cholesterol and cholesterol derivatives may also be employed in
externally used emulsions and promote w/o emulsions.
[0175] Especially suitable nonionic emulsifying agents are those
with hydrophile-lipophile balances (HLB) of about 3 to 6 for w/o
system and 8 to 18 for o/w system as determined by the method
described by Paul L. Lindner in "Emulsions and Emulsion", edited by
Kenneth Lissant, published by Dekker, New York, N.Y., 1974, pages
188-190. More preferred for use herein are one or more nonionic
surfactants that produce a system having HLB of about 8 to about
18.
[0176] Examples of such nonionic emulsifiers include but are not
limited to "BRIJ 72", the trade name for a polyoxyethylene (2)
stearyl ether having an HLB of 4.9; "BRIJ 721", the trade name for
a polyoxyethylene (21) stearyl ether having an HLB of 15.5, "Brij
30", the trade name for polyoxyethylene lauryl ether having an HLB
of 9.7; "Polawax", the trade name for emulsifying wax having an HLB
of 8.0; "Span 60", the trade name for sorbitan monostearate having
an HLB of 4.7; "Crodesta F-160", the trade name for sucrose
stearate" having an HLB of 14.5. All of these materials are
available from Ruger Chemicals Inc.; Croda; ICI Americas, Inc.;
Spectrum Chemicals; and BASF. When the topical formulations of the
present invention contain at least one emulsifying agent, each
emulsifying agent is present in amount from about 0.5 to about 2.5
wt %, preferably 0.5 to 2.0%, more preferably 1.0% or 1.8%.
Preferably the emulsifying agent comprises a mixture of steareth 21
(at about 1.8%) and steareth 2 (at about 1.0%).
[0177] The topical pharmaceutical compositions may also comprise
suitable emollients. Emollients are materials used for the
prevention or relief of dryness, as well as for the protection of
the skin, nail, hair, claw or hoof. Useful emollients include, but
are not limited to, cetyl alcohol, isopropyl myristate, stearyl
alcohol, and the like. A wide variety of suitable emollients are
known and can be used herein. See e.g., Sagarin, Cosmetics, Science
and Technology, 2nd Edition, Vol. 1, pp. 32-43 (1972), and U.S.
Pat. No. 4,919,934, to Deckner et al., issued Apr. 24, 1990, both
of which are incorporated herein by reference in their entirety.
These materials are available from Ruger Chemical Co, (Irvington,
N.J.).
[0178] When the topical formulations of the present invention
contain at least one emollient, each emollient is present in an
amount from about 0.1 to 15%, preferably 0.1 to about 3.0, more
preferably 0.5, 1.0, or 2.5 wt %. Preferably the emollient is a
mixture of cetyl alcohol, isopropyl myristate and stearyl alcohol
in a 1/5/2 ratio. The emollient may also be a mixture of cetyl
alcohol and stearyl alcohol in a 1/2 ratio.
[0179] The topical pharmaceutical compositions may also comprise
suitable antioxidants, substances known to inhibit oxidation.
Antioxidants suitable for use in accordance with the present
invention include, but are not limited to, butylated
hydroxytoluene, ascorbic acid, sodium ascorbate, calcium ascorbate,
ascorbic palmitate, butylated hydroxyanisole,
2,4,5-trihydroxybutyrophenone,
4-hydroxymethyl-2,6-di-tert-butylphenol, erythorbic acid, gum
guaiac, propyl gallate, thiodipropionic acid, dilauryl
thiodipropionate, tert-butylhydroquinone and tocopherols such as
vitamin E, and the like, including pharmaceutically acceptable
salts and esters of these compounds. Preferably, the antioxidant is
butylated hydroxytoluene, butylated hydroxyanisole, propyl gallate,
ascorbic acid, pharmaceutically acceptable salts or esters thereof,
or mixtures thereof. Most preferably, the antioxidant is butylated
hydroxytoluene. These materials are available from Ruger Chemical
Co, (Irvington, N.J.).
[0180] When the topical formulations of the present invention
contain at least one antioxidant, the total amount of antioxidant
present is from about 0.001 to 0.5 wt %, preferably 0.05 to about
0.5 wt %, more preferably 0.1%.
[0181] The topical pharmaceutical compositions may also comprise
suitable preservatives. Preservatives are compounds added to a
pharmaceutical formulation to act as an anti-microbial agent. Among
preservatives known in the art as being effective and acceptable in
parenteral formulations are benzalkonium chloride, benzethonium,
chlorohexidine, phenol, m-cresol, benzyl alcohol, methylparaben,
propylparaben, chlorobutanol, o-cresol, p-cresol, chlorocresol,
phenylmercuric nitrate, thimerosal, benzoic acid, and various
mixtures thereof. See, e.g., Wallhausser, K.-H., Develop. Biol.
Standard, 24:9-28 (1974) (S. Krager, Basel). Preferably, the
preservative is selected from methylparaben, propylparaben and
mixtures thereof. These materials are available from Inolex
Chemical Co (Philadelphia, Pa.) or Spectrum Chemicals.
[0182] When the topical formulations of the present invention
contain at least one preservative, the total amount of preservative
present is from about 0.01 to about 0.5 wt %, preferably from about
0.1 to 0.5%, more preferably from about 0.03 to about 0.15.
Preferably the preservative is a mixture of methylparaben and
proplybarben in a 5/1 ratio. When alcohol is used as a
preservative, the amount is usually 15 to 20%.
[0183] The topical pharmaceutical compositions may also comprise
suitable chelating agents to form complexes with metal cations that
do not cross a lipid bilayer. Examples of suitable chelating agents
include ethylene diamine tetraacetic acid (EDTA), ethylene
glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA)
and
8-Amino-2-[(2-amino-5-methylphenoxy)methyl]-6-methoxyquinoline-N,N,N',N'--
tetraacetic acid, tetrapotassium salt (QUIN-2). Preferably the
chelating agents are EDTA and citric acid. These materials are
available from Spectrum Chemicals.
[0184] When the topical formulations of the present invention
contain at least one chelating agent, the total amount of chelating
agent present is from about 0.005% to 2.0% by weight, preferably
from about 0.05% to about 0.5 wt %, more preferably about 0.1% by
weight.
[0185] The topical pharmaceutical compositions may also comprise
suitable neutralizing agents used to adjust the pH of the
formulation to within a pharmaceutically acceptable range. Examples
of neutralizing agents include but are not limited to trolamine,
tromethamine, sodium hydroxide, hydrochloric acid, citric acid, and
acetic acid. Such materials are available from are available from
Spectrum Chemicals (Gardena, Calif.).
[0186] When the topical formulations of the present invention
contain at least one neutralizing agent, the total amount of
neutralizing agent present is from about 0.1 wt to about 10 wt %,
preferably 0.1 wt % to about 5.0 wt %, and more preferably about
1.0 wt %. The neutralizing agent is generally added in whatever
amount is required to bring the formulation to the desired pH.
[0187] The topical pharmaceutical compositions may also comprise
suitable viscosity increasing agents. These components are
diffusible compounds capable of increasing the viscosity of a
polymer-containing solution through the interaction of the agent
with the polymer. CARBOPOL ULTREZ 10 may be used as a
viscosity-increasing agent. These materials are available from
Noveon Chemicals, Cleveland, Ohio.
[0188] When the topical formulations of the present invention
contain at least one viscosity increasing agent, the total amount
of viscosity increasing agent present is from about 0.25% to about
5.0% by weight, preferably from about 0.25% to about 1.0 wt %, and
more preferably from about 0.4% to about 0.6% by weight.
[0189] The topical pharmaceutical compositions may also comprise
suitable nail penetration enhancers. Examples of nail penetration
enhancers include mercaptan compounds, sulfites and bisulfites,
keratolytic agents and surfactants. Nail penetration enhancers
suitable for use in the invention are described in greater detail
in Malhotra et al., J. Pharm. Sci., 91:2, 312-323 (2002), which is
incorporated herein by reference in its entirety.
[0190] The topical pharmaceutical compositions may also comprise
one or more suitable solvents. The ability of any solid substance
(solute) to dissolve in any liquid substance (solvent) is dependent
upon the physical properties of the solute and the solvent. When
solutes and solvents have similar physical properties the
solubility of the solute in the solvent will be the greatest. This
gives rise to the traditional understanding that "like dissolves
like." Solvents can be characterized in one extreme as non-polar,
lipophilic oils, while in the other extreme as polar hydrophilic
solvents. Oily solvents dissolve other non-polar substances by Van
der Wals interactions while water and other hydrophilic solvents
dissolve polar substances by ionic, dipole, or hydrogen bonding
interactions. All solvents can be listed along a continuum from the
least polar, i.e. hydrocarbons such as decane, to the most polar
solvent being water. A solute will have its greatest solubility in
solvents having equivalent polarity. Thus, for drugs having minimal
solubility in water, less polar solvents will provide improved
solubility with the solvent having polarity nearly equivalent to
the solute providing maximum solubility. Most drugs have
intermediate polarity, and thus experience maximum solubility in
solvents such as propylene glycol or ethanol, which are
significantly less polar than water. If the drug has greater
solubility in propylene glycol (for example 8% (w/w)) than in water
(for example 0.1% (w/w)), then addition of water to propylene
glycol should decrease the maximum amount of drug solubility for
the solvent mixture compared with pure propylene glycol. Addition
of a poor solvent to an excellent solvent will decrease the maximum
solubility for the blend compared with the maximum solubility in
the excellent solvent.
[0191] When compounds are incorporated into topical formulations
the concentration of active ingredient in the formulation may be
limited by the solubility of the active ingredient in the chosen
solvent and/or carrier. Non-lipophilic drugs typically display very
low solubility in pharmaceutically acceptable solvents and/or
carriers. For example, the solubility of some compounds in the
invention in water is less than 0.00025% wt/wt. The solubility of
the same compounds in the invention can be less than about 2% wt/wt
in either propylene glycol or isopropyl myristate. In one
embodiment of the present invention, diethylene glycol monoethyl
ether (DGME) is the solvent used to dissolve the compounds
described herein. In one embodiment of the present invention,
diethylene glycol monoethyl ether (DGME) is the solvent used to
dissolve a compound described herein, such as for example the
compounds of Formula (I) or Formula (II). The compounds in the
invention useful in the present formulation are believed to have a
solubility of from about 10% wt/wt to about 25% wt/wt in DGME. In
another embodiment a DGME water cosolvent system is used to
dissolve the compounds described herein. In another embodiment a
DGME water cosolvent system is used to dissolve a compound
described herein, such as for example the compounds of Formula (I)
or Formula (II). The solvent capacity of DGME drops when water is
added; however, the DGME/water cosolvent system can be designed to
maintain the desired concentration of from about 0.1% to about 5%
wt/wt active ingredient. Preferably the active ingredient is
present from about 0.5% to about 3% wt/wt, and more preferably at
about 1% wt/wt, in the as-applied topical formulations. Because
DGME is less volatile than water, as the topical formulation
evaporates upon application, the active agent becomes more soluble
in the cream formulation. This increased solubility reduces the
likelihood of reduced bioavailability caused by the drug
precipitating on the surface of the skin, nail, hair, claw or
hoof.
[0192] Liquid forms, such as lotions suitable for topical
administration or suitable for cosmetic application, may include a
suitable aqueous or nonaqueous vehicle with buffers, suspending and
dispensing agents, thickeners, penetration enhancers, and the like.
Solid forms such as creams or pastes or the like may include, for
example, any of the following ingredients, water, oil, alcohol or
grease as a substrate with surfactant, polymers such as
polyethylene glycol, thickeners, solids and the like. Liquid or
solid formulations may include enhanced delivery technologies such
as liposomes, microsomes, microsponges and the like.
[0193] Additionally, the compounds can be delivered using a
sustained-release system, such as semipermeable matrices of solid
hydrophobic polymers containing the therapeutic agent. Various
sustained-release materials have been established and are well
known by those skilled in the art.
[0194] Topical treatment regimens according to the practice of this
invention comprise applying the composition directly to the skin,
nail, hair, claw or hoof at the application site, from one to
several times daily.
[0195] Formulations of the present invention can be used to treat,
ameliorate or prevent conditions or symptoms associated with
bacterial infections, acne, inflammation and the like.
[0196] In an exemplary embodiment, the pharmaceutical formulation
includes a simple solution. In an exemplary embodiment, the simple
solution includes a polyether. In an exemplary embodiment, the
polyether is polyethylene glycol or polypropylene glycol. In an
exemplary embodiment, the simple solution includes an alcohol. In
an exemplary embodiment, the alcohol is methanol, ethanol,
propanol, isopropanol or butanol. In an exemplary embodiment, the
simple solution includes a polyether and an alcohol. In another
exemplary embodiment, the simple solution includes a polypropylene
glycol and ethanol. In another exemplary embodiment, the simple
solution is a member selected from about 10% polypropylene glycol
and about 90% ethanol; about 20% polypropylene glycol and about 80%
ethanol; about 30% polypropylene glycol and about 70% ethanol;
about 40% polypropylene glycol and about 60% ethanol; about 50%
polypropylene glycol and about 50% ethanol; about 60% polypropylene
glycol and about 40% ethanol; about 70% polypropylene glycol and
about 30% ethanol; about 80% polypropylene glycol and about 20%
ethanol; about 90% polypropylene glycol and about 10% ethanol.
[0197] In an exemplary embodiment, the pharmaceutical formulation
is a lacquer.
V. b) Additional Active Agents
[0198] The following are examples of the cosmetic and
pharmaceutical agents that can be added to the topical
pharmaceutical formulations of the present invention. The following
agents are known compounds and are readily available
commercially.
[0199] Anti-inflammatory agents include, but are not limited to,
bisabolol, mentholatum, dapsone, aloe, hydrocortisone, and the
like.
[0200] Vitamins include, but are not limited to, Vitamin B, Vitamin
E, Vitamin A, Vitamin D, and the like and vitamin derivatives such
as tazarotene, calcipotriene, tretinoin, adapalene and the
like.
[0201] Anti-aging agents include, but are not limited to,
niacinamide, retinol and retinoid derivatives, AHA, Ascorbic acid,
lipoic acid, coenzyme Q 10, beta hydroxy acids, salicylic acid,
copper binding peptides, dimethylaminoethyl (DAEA), and the
like.
[0202] Sunscreens and or sunburn relief agents include, but are not
limited to, PABA, jojoba, aloe, padimate-O, methoxycinnamates,
proxamine HCl, lidocaine and the like. Sunless tanning agents
include, but are not limited to, dihydroxyacetone (DHA).
[0203] Psoriasis-treating agents and/or acne-treating agents
include, but are not limited to, salicylic acid, benzoyl peroxide,
coal tar, selenium sulfide, zinc oxide, pyrithione (zinc and/or
sodium), tazarotene, calcipotriene, tretinoin, adapalene and the
like.
[0204] Agents that are effective to control or modify
keratinization, including without limitation: tretinoin,
tazarotene, and adapalene.
[0205] The compositions comprising an compound/active agent
described herein, such as for example in Formula (I) or Formula
(II), and optionally at least one of these additional agents, are
to be administered topically. In a primary application, this leads
to the compounds of the invention and any other active agent
working upon and treating the skin, nail, hair, claw or hoof.
Alternatively, any one of the topically applied active agents may
also be delivered systemically by transdermal routes.
[0206] In such compositions an additional cosmetically or
pharmaceutically effective agent, such as an anti-inflammatory
agent, vitamin, anti-aging agent, sunscreen, and/or acne-treating
agent, for example, is usually a minor component (from about 0.001%
to about 20% by weight or preferably from about 0.01% to about 10%
by weight) with the remainder being various vehicles or carriers
and processing aids helpful for forming the desired dosing
form.
V. c) Testing
[0207] Preferred compounds for use in the present topical
formulations will have certain pharmacological properties. Such
properties include, but are not limited to, low toxicity, low serum
protein binding and desirable in vitro and in vivo half-lives.
Assays may be used to predict these desirable pharmacological
properties. Assays used to predict bioavailability include
transport across human intestinal cell monolayers, including Caco-2
cell monolayers. Serum protein binding may be predicted from
albumin binding assays. Such assays are described in a review by
Oravcova et al. (1996, J. Chromat. B677: 1-27). Compound half-life
is inversely proportional to the frequency of dosage of a compound.
In vitro half-lives of compounds may be predicted from assays of
microsomal half-life as described by Kuhnz and Gleschen (Drug
Metabolism and Disposition, (1998) volume 26, pages 1120-1127).
[0208] Toxicity and therapeutic efficacy of such compounds can be
determined by standard pharmaceutical procedures in cell cultures
or experimental animals, e.g., for determining the LD50 (the dose
lethal to 50% of the population) and the ED.sub.50 (the dose
therapeutically effective in 50% of the population). The dose ratio
between toxic and therapeutic effects is the therapeutic index and
it can be expressed as the ratio between LD.sub.50 and ED.sub.50.
Compounds that exhibit high therapeutic indices are preferred. The
data obtained from these cell culture assays and animal studies can
be used in formulating a range of dosage for use in humans. The
dosage of such compounds lies preferably within a range of
circulating concentrations that include the ED.sub.50 with little
or no toxicity. The dosage can vary within this range depending
upon the dosage form employed and the route of administration
utilized. The exact formulation, route of administration and dosage
can be chosen by the individual physician in view of the patient's
condition. (See, e.g. Fingl et al., 1975, in "The Pharmacological
Basis of Therapeutics", Ch. 1, p. 1).
V. d) Administration
[0209] For any compound used in the method of the invention, the
therapeutically effective dose can be estimated initially from cell
culture assays, as disclosed herein. For example, a dose can be
formulated in animal models to achieve a circulating concentration
range that includes the EC.sub.50 (effective dose for 50% increase)
as determined in cell culture, i.e., the concentration of the test
compound which achieves a half-maximal inhibition of bacterial cell
growth. Such information can be used to more accurately determine
useful doses in humans.
[0210] In general, the compounds prepared by the methods, and from
the intermediates, described herein will be administered in a
therapeutically or cosmetically effective amount by any of the
accepted modes of administration for agents that serve similar
utilities. It will be understood, however, that the specific dose
level for any particular patient will depend upon a variety of
factors including the activity of the specific compound employed,
the age, body weight, general health, sex, diet, time of
administration, route of administration, and rate of excretion,
drug combination, the severity of the particular disease undergoing
therapy and the judgment of the prescribing physician. The drug can
be administered from once or twice a day, or up to 3 or 4 times a
day.
[0211] Dosage amount and interval can be adjusted individually to
provide plasma levels of the active moiety that are sufficient to
maintain bacterial cell growth inhibitory effects. Usual patient
dosages for systemic administration range from 0.1 to 1000 mg/day,
preferably, 1-500 mg/day, more preferably 10-200 mg/day, even more
preferably 100-200 mg/day. Stated in terms of patient body surface
areas, usual dosages range from 50-91 mg/m.sup.2/day.
[0212] The amount of the compound in a formulation can vary within
the full range employed by those skilled in the art. Typically, the
formulation will contain, on a weight percent (wt %) basis, from
about 0.01-10 wt % of the drug based on the total formulation, with
the balance being one or more suitable pharmaceutical excipients.
Preferably, the compound is present at a level of about 0.1-3.0 wt
%, more preferably, about 1.0 wt.sup.%.
[0213] The invention is further illustrated by the Examples that
follow. The Examples are not intended to define or limit the scope
of the invention.
EXAMPLES
[0214] Proton NMR are recorded on Varian AS 300 spectrometer and
chemical shifts are reported as .delta. (ppm) down field from
tetramethylsilane. Mass spectra are determined on Micromass Quattro
II.
Example 1
[0215] Preparation of 3 from 1
1.1 Reduction of Carboxylic Acid
[0216] To a solution of 1 (23.3 mmol) in anhydrous THF (70 mL)
under nitrogen was added dropwise a BH.sub.3 THF solution (1.0 M,
55 mL, 55 mmol) at 0.degree. C. and the reaction mixture was
stirred overnight at room temperature. Then the mixture was cooled
again with ice bath and MeOH (20 mL) was added dropwise to
decompose excess BH.sub.3. The resulting mixture was stirred until
no bubble was released and then 10% NaOH (10 mL) was added. The
mixture was concentrated and the residue was mixed with water (200
mL) and extracted with EtOAc. The residue from rotary evaporation
was purified by flash column chromatography over silica gel to give
20.7 mmol of 3.
1.2 Results
[0217] Exemplary compounds of structure 3 prepared by the method
above are provided below.
1.2.a 2-Bromo-5-chlorobenzyl Alcohol
[0218] .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 7.57 (d, J=8.7
Hz, 1H), 7.50-7.49 (m, 1H), 7.28-7.24 (m, 1H), 5.59 (t, J=6.0 Hz,
1H) and 4.46 (d, J=6.0 Hz, 2H) ppm.
1.2.b 2-Bromo-5-methoxybenzyl Alcohol
[0219] .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 7.42 (d, J=8.7
Hz, 1H), 7.09 (d, J=2.4 Hz, 1H), 6.77 (dd, J.sub.1=3 Hz, J.sub.2=3
Hz, 1H), 5.43 (t, J=5.7 Hz, 1H), 4.44 (d, J=5.1 Hz, 2H), 3.76 (s,
3H).
Example 2
[0220] Preparation of 3 from 2 2.1. Reduction ofAldehyde
[0221] To a solution of 2 (Z.dbd.H, 10.7 mmol) in methanol (30 mL)
was added sodium borohydride (5.40 mol), and the mixture was
stirred at room temperature for 1 h. Water was added, and the
mixture was extracted with ethyl acetate. The organic layer was
washed with brine and dried on anhydrous sodium sulfate. The
solvent was removed under reduced pressure to afford 9.9 mmol of
3.
2.2 Results
[0222] Exemplary compounds of structure 3 prepared by the method
above are provided below.
2.2.a 2-Bromo-5-(4-cyanophenoxy)benzyl Alcohol
[0223] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta. (ppm) 2.00 (br s,
1H), 4.75 (s, 2H), 6.88 (dd, J=8.5, 2.9 Hz, 1H), 7.02 (d, J=8.8 Hz,
1H), 7.26 (d, J=2.6 Hz, 1H), 7.56 (d, J=8.5 Hz, 1H), 7.62 (d, J=8.8
Hz, 2H).
2.2.b 2-Bromo-4-(4-cyanophenoxy)benzyl Alcohol
[0224] .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 7.83 (d, 2H),
7.58 (d, 1H), 7.39 (d, 1H), 7.18 (dd, 1H), 7.11 (d, 2H), 5.48 (t,
1H) and 4.50 (d, 2H) ppm.
2.2.c 5-(4-Cyanophenoxy)-1-Indanol
[0225] M.p.50-53.degree. C. MS (ESI+): m/z=252 (M+1). HPLC: 99.7%
purity at 254 nm and 99.0% at 220 nm. .sup.1H NMR (300 MHz,
DMSO-d.sub.6): .delta. 7.80 (d, 2H), 7.37 (d, 1H), 7.04 (d, 2H),
6.98-6.93 (m, 2H), 5.27 (d, 1H), 5.03 (q, 1H), 2.95-2.85 (m, 1H),
2.75-2.64 (m, 1H), 2.39-2.29 (m, 1H) and 1.85-1.74 (m, 1H) ppm.
2.2.d 2-Bromo-5-(tert-butyldimethylsiloxy)benzyl Alcohol
[0226] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta. (ppm) 0.20 (s,
6H), 0.98 (s, 9H), 4.67 (br s, 1H), 6.65 (dd, J=8.2, 2.6 Hz, 1H),
6.98 (d, J=2.9 Hz, 1H), 7.36 (d, J=8.8 Hz, 1H).
[0227] Additional examples of compounds which can be produced by
this method include 2-bromo-4-(3-cyanophenoxy)benzyl alcohol;
2-bromo-4-(4-chlorophenoxy)benzyl alcohol; 2-bromo-4-phenoxybenzyl
alcohol; 2-bromo-5-(3,4-dicyanophenoxy)benzyl alcohol;
2-(2-bromo-5-fluorophenyl)ethyl alcohol; 2-bromo-5-fluorobenzyl
alcohol; and 1-bromo-2-naphthalenemethanol.
Example 3
[0228] Preparation of 4 from 3
3.1 Protective Alkylation
[0229] Compound 3 (20.7 mmol) was dissolved in CH.sub.2Cl.sub.2
(150 mL) and cooled to 0.degree. C. with ice bath. To this solution
under nitrogen were added in sequence N,N-diisopropyl ethyl amine
(5.4 mL, 31.02 mmol, 1.5 eq) and chloromethyl methyl ether (2 mL,
25.85 mmol, 1.25 eq). The reaction mixture was stirred overnight at
room temperature and washed with NaHCO.sub.3-saturated water and
then NaCl-saturated water. The residue after rotary evaporation was
purified by flash column chromatography over silica gel to give
17.6 mmol of 4.
3.2 Results
[0230] Exemplary compounds of structure 4 prepared by the method
above are provided below.
3.2.a 2-Bromo-5-chloro-1-(methoxymethoxymethyl)benzene
[0231] .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 7.63 (d, J=8.7
Hz, 1H), 7.50 (dd, J=2.4 & 0.6 Hz, 1H), 7.32 (dd, J=8.4 &
2.4 Hz, 1H), 4.71 (s, 2H), 4.53 (s, 2H) and 3.30 (s, 3H) ppm.
3.2.b 2-Bromo-5-fluoro-1-[1-(methoxymethoxy)ethyl]benzene
[0232] .sup.1H-NMR (300.058 MHz, CDCl.sub.3) .delta. ppm 1.43 (d,
J=6.5 Hz, 3H), 3.38 (s, 3H), 4.55 (d, J=6.5 Hz, 1H), 4.63 (d, J=6.5
Hz, 1H), 5.07 (q, J=6.5 Hz, 1H), 6.85 (m, 1H), 7.25 (dd, J=9.7, 2.6
Hz, 1H), 7.46 (dd, J=8.8, 5.3 Hz, 1H).
3.2.c 2-Bromo-5-fluoro-1-[2-(methoxymethoxy)ethyl]benzene
[0233] .sup.1H-NMR (300.058 MHz, CDCl.sub.3) .delta. ppm 3.04 (t,
J=6.7 Hz, 2H), 3.31 (s, 3H), 3.77 (t, J=6.7 Hz, 2H), 4.62 (s, 2H),
6.82 (td, J=8.2, 3.2 Hz, 1H), 7.04 (dd, J=9.4, 2.9 Hz, 1H), 7.48
(dd, J=8.8, 5.3 Hz, 1H).
3.2.d 2-Bromo-4,5-difluoro-1-(methoxymethoxymethyl)benzene
[0234] .sup.1H-NMR (300.058 MHz, CDCl.sub.3) .delta. ppm 3.42 (s,
3H), 4.57 (d, J=1.2 Hz, 2H), 4.76 (s, 2H), 7.3-7.5 (m, 2H).
3.2.e 2-Bromo-5-cyano-1-(methoxymethoxymethyl)benzene
[0235] .sup.1H-NMR (300.058 MHz, CDCl.sub.3) .delta. ppm 3.43 (s,
3H), 4.65 (s, 2H), 4.80 (s, 2H), 7.43 (dd, J=8.2, 4.1 Hz, 1H), 7.66
(d, J=8.2 Hz, 1H), 7.82 (d, J=4.1 Hz, 1H).
3.2.f 2-Bromo-5-methoxy-1-(methoxymethoxymethyl)benzene
[0236] .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 7.48 (dd,
J.sub.1=1.2 Hz, J.sub.2=1.2 Hz, 1H), 7.05 (d, J=2.7 Hz, 1H), 6.83
(dd, J.sub.1=3 Hz, J.sub.2=3 Hz, 1H), 4.69 (d, J=1.2 Hz, 2H), 4.5
(s, 2H), 3.74 (d, J=1.5 Hz, 3H), 3.32 (d, J=2.1 Hz, 3H) ppm.
3.2.g 1-Benzyl-1-(2-bromophenyl)-1-(methoxymethoxy)ethane
[0237] .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 7.70-7.67 (m,
1H), 7.25-7.09 (m, 6H), 6.96-6.93 (m, 2H), 4.61 (d, 1H), 4.48 (d,
1H), 3.36-3.26 (m, 2H), 3.22 (s, 3H) and 1.63 (s, 3H) ppm.
3.2.h 2-Bromo-6-fluoro-1-(methoxymethoxymethyl)benzene
[0238] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta. (ppm) 3.43 (s,
3H), 4.74 (s, 2H), 4.76 (d, J=2.1 Hz, 2H), 7.05 (t, J=9.1 Hz, 1H),
7.18 (td, J=8.2, 5.9 Hz, 1H), 7.40 (d, J=8.2 Hz, 1H).
3.2.i
2-Bromo-4-(4-cyanophenoxy)-1-(methoxymethoxymethyl)benzene
[0239] .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 7.84 (d, 2H),
7.56 (d, 1H), 7.44 (d, 1H), 7.19-7.12 (m, 3H), 4.69 (s, 2H), 4.56
(s, 2H) and 3.31 (s, 3H) ppm.
3.2.j
2-Bromo-5-(tert-butyldimethylsiloxy)-1-(methoxymethoxymethyl)benzene
[0240] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta. (ppm) 0.19 (s,
6H), 0.98 (s, 9H), 3.43 (s, 3H), 4.59 (s, 2H), 4.75 (s, 2H), 6.64
(dd, J=8.5, 2.9 Hz, 1H), 6.98 (d, J=2.9 Hz, 1H), 7.36 (d, J=8.5 Hz,
1H).
3.2.k
2-Bromo-5-(2-cyanophenoxy)-1-(methoxymethoxymethyl)benzene
[0241] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta. (ppm) 3.41 (s,
3H), 4.64 (s, 2H), 4.76 (s, 2H), 6.8-6.9 (m, 2H), 7.16 (td, J=7.6,
0.9 Hz, 1H), 7.28 (d, J=2.9 Hz, 1H), 7.49 (ddd, J=8.8, 7.6, 1.8 Hz,
1H), 7.56 (d, J=8.5 Hz, 1H), 7.67 (dd, J=7.9, 1.8 Hz, 1H).
3.2.1 2-Bromo-5-phenoxy-1-(methoxymethoxymethyl)benzene
[0242] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta. (ppm) 3.40 (s,
3H), 4.62 (s, 2H), 4.74 (s, 2H), 6.80 (dd, J=8.8, 2.9 hz, 1H), 7.01
(d, J=8.5 Hz, 2H), 7.12 (t, J=7.9 Hz, 1H), 7.19 (d, J=2.9 hz, 1H),
7.35 (t, J=7.6 Hz, 2H), 7.48 (d, J=8.5 Hz, 1H).
[0243] Additional examples of compounds which can be produced by
this method include 2-bromo-1-(methoxymethoxymethyl)benzene;
2-bromo-5-methyl-1-(methoxymethoxymethyl)benzene;
2-bromo-5-(methoxymethoxymethyl)-1-(methoxymethoxymethyl)benzene;
2-bromo-5-fluoro-1-(methoxymethoxymethyl)benzene;
1-bromo-2-(methoxymethoxymethyl)naphthalene;
2-bromo-4-fluoro-1-(methoxymethoxymethyl)benzene;
2-phenyl-1-(2-bromophenyl)-1-(methoxymethoxy)ethane;
2-bromo-5-(4-cyanophenoxy)-1-(methoxymethoxy methyl)benzene;
2-bromo-4-(3-cyanophenoxy)-1-(methoxymethoxymethyl)benzene;
2-bromo-4-(4-chlorophenoxy)-1-(methoxymethoxymethyl)benzene;
2-bromo-4-phenoxy-1-(methoxymethoxymethyl)benzene;
2-bromo-5-(3,4-dicyanophenoxy)-1-(methoxymethoxymethyl)benzene.
Example 4
[0244] Preparation of I from 4 via 5 4.1 Metallation and
boronylation
[0245] To a solution of 4 (17.3 mmol) in anhydrous THF (80 mL) at
-78.degree. C. under nitrogen was added dropwise tert-BuLi or
n-BuLi (11.7 mL) and the solution became brown colored. Then,
B(OMe).sub.3 (1.93 mL, 17.3 mmol) was injected in one portion and
the cooling bath was removed. The mixture was warmed gradually with
stirring for 30 min and then stirred with a water bath for 2 h.
After addition of 6N HCl (6 mL), the mixture was stirred overnight
at room temperature and about 50% hydrolysis has happened as shown
by TLC analysis. The solution was rotary evaporated and the residue
was dissolved in MeOH (50 mL) and 6N HCl (4 mL). The solution was
refluxed for 1 h and the hydrolysis was completed as indicated by
TLC analysis. Rotary evaporation gave a residue which was dissolved
in EtOAc, washed with water, dried and then evaporated. The crude
product was purified by flash column chromatography over silica gel
to provide a solid with 80% purity. The solid was further purified
by washing with hexane to afford 7.2 mmol of I.
4.2 Results
[0246] Analytical data for exemplary compounds of structure I are
provided below.
4.2.a 5-Chloro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (C1)
[0247] M.p. 142-150.degree. C. MS (ESI): m/z=169 (M+1, positive)
and 167 (M-1, negative). HPLC (220 nm): 99% purity. .sup.1H NMR
(300 MHz, DMSO-d.sub.6): .delta. 9.30 (s, 1H), 7.71 (d, J=7.8 Hz,
1H), 7.49 (s, 1H), 7.38 (d, J=7.8 Hz, 1H) and 4.96 (s, 2H) ppm.
4.2.b 1,3-Dihydro-1-hydroxy-2,1-benzoxaborole (C2)
[0248] M.p. 83-86.degree. C. MS (ESI): m/z=135 (M+1, positive) and
133 (M-1, negative). HPLC (220 nm): 95.4% purity. .sup.1H NMR (300
MHz, DMSO-d.sub.6): .delta. 9.14 (s, 1H), 7.71 (d, J=7.2 Hz, 1H),
7.45 (t, J=7.5 Hz, 1H), 7.38 (d, J=7.5 Hz, 1H), 7.32 (t, J=7.1 Hz,
1H) and 4.97 (s, 2H) ppm.
4.2.c 5-Fluoro-1,3-dihydro-1-hydroxy-3-methyl-2,1-benzoxaborole
(C3)
[0249] .sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta. ppm 1.37 (d,
J=6.4 Hz, 3H), 5.17 (q, J=6.4 Hz, 1H), 7.14 (m, 1H), 7.25 (dd,
J=9.7, 2.3 Hz, 1H), 7.70 (dd, J=8.2, 5.9 Hz, 1H), 9.14 (s, 1H).
4.2. d 6-Fluoro-1-hydroxy-1,2,3,4-tetrahydro-2,1-benzoxaborine
(C4)
[0250] .sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta. ppm 2.86 (t,
J=5.9 Hz, 2H), 4.04 (t, J=5.9 Hz, 2H), 7.0-7.1 (m, 2H), 7.69 (dd,
J=8.2, 7.2 Hz, 1H), 8.47 (s, 1H).
4.2.e 5,6-Difluoro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (C5)
[0251] .sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta. ppm 4.94 (s,
2H), 7.50 (dd, J=10.7, 6.8 Hz, 1H), 7.62 (dd, J=9.7, 8.2 Hz, 1H),
9.34 (s, 1H). 4.2.f 5-Cyano-1,3-dihydro-1-hydroxy-2,1-benzoxaborole
(C6)
[0252] .sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta. ppm 5.03 (s,
2H), 7.76 (d, J 8.2 Hz, 1H), 7.89 (d, J=8.2 Hz, 1H), 7.90 (s, 1H),
9.53 (s, 1H).
4.2.g 1,3-Dihydro-1-hydroxy-5-methoxy-2,1-benzoxaborole (C7)
[0253] M.p. 102-104.degree. C. MS ESI: m/z=165.3 (M+1) and 162.9
(M-1). .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 8.95 (s, 1H),
7.60 (d, J=8.1 Hz, 1H), 6.94 (s, 1H), 6.88 (d, J=8.1 Hz, 1H), 4.91
(s, 2H), 3.77 (s, 3H) ppm.
4.2.h 1,3-Dihydro-1-hydroxy-5-methyl-2,1-benzoxaborole (C8)
[0254] M.p. 124-128.degree. C. MS ESI: m/z=148.9 (M+1) and 146.9
(M-1). .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.05 (s, 1H),
7.58 (d, J=7.2 Hz, 1H), 7.18 (s, 1H), 7.13 (d, J=7.2 Hz, 2H), 4.91
(s, 2H), 2.33 (s, 3H) ppm.
4.2.i 1,3-Dihydro-1-hydroxy-5-hydroxymethyl-2,1-benzoxaborole
(C9)
[0255] MS: m/z=163 (M-1, ESI-). .sup.1H NMR (300 MHz,
DMSO-d.sub.6): .delta. 9.08 (s, 1H), 7.64 (d, 1H), 7.33 (s, 1H),
7.27 (d, 1H), 5.23 (t, 1H), 4.96 (s, 2H), 4.53 (d, 2H) ppm.
4.2.j 1,3-Dihydro-5-fluoro-1-hydroxy-2,1-benzoxaborole (C10)
[0256] M.p. 110-114.degree. C. MS ESI: m/z=150.9 (M-1). .sup.1H NMR
(300 MHz, DMSO-d.sub.6): .delta. 9.20 (s, 1H), 7.73 (dd, J.sub.1=6
Hz, J.sub.2=6 Hz, 1H), 7.21 (m, 1H), 7.14 (m, 1H), 4.95 (s, 2H)
ppm.
4.2.k 1,3-Dihydro-2-oxa-1-cyclopenta[{acute over
(.alpha.)}]naphthalene (C11)
[0257] M.P. 139-143.degree. C. MS ESI: m/z=184.9 (M+1). .sup.1H NMR
(300 MHz, DMSO-d.sub.6): .delta. 9.21 (s, 1H), 8.28 (dd,
J.sub.1=6.9 Hz, J.sub.2=0.6 Hz, 1H), 7.99 (d, J=8.1 Hz, 1H), 7.95
(d, J=7.5 Hz, 1H), 7.59-7.47 (m, 3H), 5.09 (s, 2H) ppm.
4.2.1 7-Hydroxy-2,1-oxaborolano[5,4-c]pyridine (C12)
[0258] .sup.1H-NMR (300 MHz, DMSO-d.sub.6): .delta. ppm 5.00 (s,
2H), 7.45 (d, J=5.0 Hz, 1H), 8.57 (d, J=5.3 Hz, 1H), 8.91 (s, 1H),
9.57 (s, 1H). ESI-MS m/z 134 (M-H).sup.-,
C.sub.6H.sub.6BNO.sub.2=135.
4.2. m 1,3-Dihydro-6-fluoro-1-hydroxy-2,1-benzoxaborole (C13)
[0259] M.p.110-117.5.degree. C. MS (ESI): m/z=151 (M-1, negative).
HPLC (220 nm): 100% purity. .sup.1H NMR (300 MHz, DMSO-d.sub.6):
.delta. 9.29 (s, 1H), 7.46-7.41 (m, 2H), 7.29 (td, 1H) and 4.95 (s,
2H) ppm.
4.2.n 3-Benzyl-1,3-dihydro-1-hydroxy-3-methyl-2,1-benzoxaborole
(C14)
[0260] MS (ESI): m/z=239 (M+1, positive). HPLC: 99.5% purity at 220
nm and 95.9% at 254 nm. .sup.1H NMR (300 MHz, DMSO-d.sub.6):
.delta. 8.89 (s, 1H), 7.49-7.40 (m, 3H), 7.25-7.19 (m, 1H),
7.09-7.05 (m, 3H), 6.96-6.94 (m, 2H), 3.10 (d, 1H), 3.00 (d, 1H)
and 1.44 (s, 3H) ppm.
4.2.0 3-Benzyl-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (C15)
[0261] MS (ESI+): m/z=225 (M+1). HPLC: 93.4% purity at 220 nm.
.sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.08 (s, 1H), 7.63
(dd, 1H), 7.43 (t, 1H), 7.35-7.14 (m, 7H), 5.38 (dd, 1H), 3.21 (dd,
1H) and 2.77 (dd, 1H) ppm.
4.2.p 1,3-Dihydro-4-fluoro-1-hydroxy-2,1-benzoxaborole (C16)
[0262] .sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta. (ppm) 5.06 (s,
2H), 7.26 (ddd, J=9.7, 7.9, 0.6 Hz, 1H), 7.40 (td, J=8.2, 4.7 Hz,
1H), 7.55 (d, J=7.0 Hz, 1H), 9.41 (s, 1H).
4.2. q 5-(4-Cyanophenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole
(C17)
[0263] .sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta. ppm 4.95 (s,
2H), 7.08 (dd, J=7.9, 2.1 Hz, 1H), 7.14 (d, J=8.8 Hz, 1H), 7.15 (d,
J=2.1 Hz, 1H), 7.78 (d, J=7.9 Hz, 1H), 7.85 (d, J=9.1 Hz, 2H), 9.22
(s, 1H).
4.2.r 6-(4-Cyanophenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole
(C18)
[0264] M.p.148-151.degree. C. MS: m/z=252 (M+1) (ESI+) and m/z=250
(M-1) (ESI-). HPLC: 100% purity at 254 nm and 98.7% at 220 nm.
.sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.26 (s, 1H), 7.82 (d,
2H), 7.50 (d, 1H), 7.39 (d, 1H), 7.26 (dd, 1H), 7.08 (d, 2H) and
4.99 (s, 2H) ppm
4.2.s 6-(3-Cyanophenoxy)-1,3-dihydro-1-hydroxy-2, I-benzoxaborole
(C19)
[0265] M.p.146-149.degree. C. MS: m/z=252 (M+1) (ESI+) and m/z=250
(M-1) (ESI-). HPLC: 100% purity at 254 nm and 97.9% at 220 nm.
.sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.21 (s, 1H),
7.60-7.54 (m, 2H), 7.50-7.45 (m, 2H), 7.34-7.30 (m, 2H), 7.23 (dd,
1H) and 4.98 (s, 2H) ppm.
4.2.t 6-(4-Chlorophenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole
(C20)
[0266] M.p.119-130.degree. C. MS: m/z=261 (M+1) (ESI+) and m/z=259
(M-1) (ESI-). HPLC: 100% purity at 254 nm and 98.9% at 220 nm.
.sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.18 (s, 1H),
7.45-7.41 (m, 3H), 7.29 (d, 1H), 7.19 (dd, 1H), 7.01 (d, 2H) and
4.96 (s, 2H) ppm.
4.2. u 6-Phenoxy-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (C21)
[0267] M.p.95-99.degree. C. MS: m/z=227 (M+1) (ESI+) and m/z=225
(M-1) (ESI-). HPLC: 100% purity at 254 nm and 98.4% at 220 nm.
.sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.17 (s, 1H),
7.43-7.35 (m, 3H), 7.28 (s, 1H), 7.19-7.09 (m, 2H), 6.99 (d, 2H)
and 4.96 (s, 2H) ppm.
4.2.v 5-(4-Cyanobenzyloxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole
(C22)
[0268] .sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta. (ppm) 4.90 (s,
2H), 5.25 (s, 2H), 6.98 (dd, J=7.9, 2.1 Hz, 1H), 7.03 (d, J=1.8 Hz,
1H), 7.62 (d, J=7.9 Hz, 1H), 7.64 (d, J=8.5 Hz, 2H), 7.86 (d, J=8.5
Hz, 1H), 9.01 (s, 1H).
4.2.w 5-(2-Cyanophenoxy)-, 3-dihydro-1-hydroxy-2,1-benzoxaborole
(C23)
[0269] .sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta. (ppm) 4.95 (s,
2H), 7.0-7.2 (m, 3H), 7.32 (td, J=7.6, 1.2 Hz, 1H), 7.68 (ddd,
J=9.1, 7.6, 1.8 Hz, 1H), 7.77 (d, J=7.9 Hz, 1H), 7.91 (dd, J=7.9,
1.8 Hz, 1H).
4.2.x 5-Phenoxy-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (C24)
[0270] .sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta. (ppm) 4.91 (s,
2H), 6.94 (s, 1H), 6.96 (d, J=8.8 Hz, 1H), 7.05 (d, J=7.6 Hz, 2H),
7.17 (t, J=7.3 Hz, 1H), 7.41 (t, J=7.3 Hz, 2H), 7.70 (d, J=8.5 Hz,
1H), 9.11 (s, 1H).
4.2.y
5-[4-(N,N-Diethylcarbamoyl)phenoxy]-1,3-dihydro-1-hydroxy-2,1-benzox-
aborole (C25)
[0271] .sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta. (ppm) 1.08 (br
s, 6H), 3.1-3.5 (m, 4H), 4.93 (s, 2H), 7.0-7.1 (m, 4H), 7.37 (d,
J=8.5 Hz, 2H), 7.73 (d, J=7.9 Hz, 1H), 9.15 (s, 1H).
4.2.z
1,3-Dihydro-1-hydroxy-5-[4-(morpholinocarbonyl)phenoxy]-2,1-benzoxab-
orole (C26)
[0272] .sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta. (ppm) 3.3-3.7
(m, 8H), 4.93 (s, 2H), 7.0-7.1 (m, 4H), 7.44 (d, J=8.8 Hz, 2H),
7.73 (d, J=7.9 Hz, 1H), 9.16 (s, 1H).
4.2.aa
5-(3,4-Dicyanophenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole
(C27)
[0273] .sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta. (ppm) 4.97 (s,
2H), 7.13 (dd, J=7.9, 2.1 Hz, 1H), 7.21 (d, J=1.5 Hz, 1H), 7.43
(dd, J=8.8, 2.6 Hz, 1H), 7.81 (d, J=7.9 Hz, 1H), 7.82 (d, J=2.6 Hz,
1H), 8.11 (d, J=8.5 Hz, 1H), 9.26 (s, 1H).
4.2.ab 6-Phenylthio-1,3-dihydro-1-hydroxy-2,1-benzoxaborole
(C28)
##STR00056##
[0275] M.p.121-124.degree. C. MS: m/z=243 (M+1) (ESI+) and m/z=241
(M-1) (ESI-). HPLC: 99.6% purity at 254 nm and 99.6% at 220 nm.
.sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.25 (s, 1H), 7.72
(dd, 1H), 7.48 (dd, 1H), 7.43 (dd, 1H), 7.37-7.31 (m, 2H),
7.29-7.23 (m, 3H), and 4.98 (s, 2H) ppm.
4.2.ac
6-(4-trifluoromethoxyphenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaboro-
le (C29)
##STR00057##
[0277] M.p.97-101.degree. C. MS: m/z=311 (M+1) (ESI+) and m/z=309
(M-1) (ESI-). HPLC: 100% purity at 254 nm and 100% at 220 nm.
.sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.20 (s, 1H), 7.45 (d,
1H), 7.37 (d, 2H), 7.33 (d, 1H), 7.21 (dd, 1H), 7.08 (d, 2H), and
4.97 (s, 2H) ppm.
4.2.ad 5-(N-Methyl-N-phenylsulfonylamino)-,
3-dihydro-1-hydroxy-2,1-benzoxaborole (C30)
##STR00058##
[0279] M.p.85-95.degree. C. MS: m/z=304 (M+1) (ESI+) and m/z=302
(M-1) (ESI-). HPLC: 96.6% purity at 254 nm and 89.8% at 220 nm.
.sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.23 (s, 1H),
7.72-7.63 (m, 2H), 7.56 (t, 2H), 7.50 (d, 2H), 7.16 (s, 1H), 7.03
(d, 1H), 4.91 (s, 2H) and 3.14 (s, 3H) ppm.
4.2.ae 6-(4-Methoxyphenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole
(C31)
##STR00059##
[0281] M.p.126-129.degree. C. MS: m/z=257 (M+1) (ESI+) and m/z=255
(M-1) (ESI-). HPLC: 98.4% purity at 254 nm and 98.4% at 220 nm.
.sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.14 (s, 1H), 7.36 (d,
1H), 7.19 (s, 1H), 7.12 (d, 1H), 6.98 (d, 2H), 6.95 (d, 2H), 4.93
(s, 2H) and 3.73 (s, 3H) ppm.
4.2.af
6-(4-Methoxyphenylthio)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole
(C32)
##STR00060##
[0283] M.p.95-100.degree. C. MS: m/z=272 (M+), 273 (M+1) (ESI+) and
m/z=271 (M-1) (ESI-). HPLC: 100% purity at 254 nm and 99.2% at 220
nm. .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.20 (s, 1H), 7.51
(d, 1H), 7.39-7.28 (m, 4H), 6.98 (d, 2H), 4.93 (s, 2H) and 3.76 (s,
3H) ppm.
4.2.ag
6-(4-Methoxyphenylsulfonyl)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole
(C33)
##STR00061##
[0285] M.p.180-192.degree. C. MS: m/z=305 (M+1) (ESI+) and m/z=303
(M-1) (ESI-). HPLC: 96.8% purity at 254 nm and 95.5% at 220 nm.
.sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.46 (s, 1H), 8.28 (s,
1H), 7.99 (d, 1H), 7.85 (d, 2H), 7.61 (d, 1H), 7.11 (d, 2H), 5.02
(s, 2H) and 3.80 (s, 3H) ppm.
4.2.ah 6-(4-Methoxyphenylsulfinyl)-,
3-dihydro-1-hydroxy-2,1-benzoxaborole (C34)
##STR00062##
[0287] .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.37 (s, 1H),
8.02 (d, 1H), 7.71 (dd, 1H), 7.59 (d, 2H), 7.53 (d, 1H), 7.07 (d,
2H), 5.00 (s, 2H) and 3.76 (s, 3H) ppm.
4.2.ai 5-Trifluoromethyl-1,3-dihydro-1-hydroxy-2,1-benzoxaborole
(C35)
##STR00063##
[0289] M.p.113-118.degree. C. MS: m/z=203 (M+1) (ESI+) and m/z=201
(M-1) (ESI-). HPLC: 100% purity at 254 nm and 100% at 220 nm.
.sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.48 (s, 1H), 7.92 (d,
1H), 7.78 (s, 1H), 7.67 (d, 1H) and 5.06 (s, 2H) ppm.
4.2.aj 4-(4-Cyanophenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole
(C36)
[0290] For coupling reaction between 4-fluorobenzonitrile and
substituted phenol to give starting material 2, see Igarashi, S.;
et al. Chemical & Pharmaceutical Bulletin (2000), 48(11),
1689-1697.
##STR00064##
[0291] .sup.1H-NMR (300 MHz, DMSO-d.sub.6) (ppm) 4.84 (s, 2H), 7.08
(d, J=8.2 Hz, 2H), 7.18 (d, J=7.9 Hz, 1H), 7.45 (t, J=7.3 Hz, 1H),
7.63 (d, J=7.3 Hz, 1H), 7.82 (d, J=8.5 Hz, 2H).
7-(4-Cyanophenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole
(C100)
[0292] For coupling reaction between 4-fluorobenzonitrile and
substituted phenol to give starting material 2, see Igarashi, S.;
et al. Chemical & Pharmaceutical Bulletin (2000), 48(11),
1689-1697.
##STR00065##
[0293] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. (ppm) 5.02 (s,
2H), 6.97 (d, J=7.9 Hz, 1H), 7.01 (d, J=8.5 Hz, 2H), 7.30 (d, J=7.3
Hz, 1H), 7.56 (t, J=7.6 Hz, 1H), 7.77 (d, J=8.5 Hz, 2H).
4.2.ak 5-(3-Cyanophenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole
(C37)
[0294] For coupling between 3-fluorobenzonitrile and substituted
phenol to give starting material 2: Li, F. et al., Organic Letters
(2003), 5(12), 2169-2171.
##STR00066##
[0295] .sup.1H-NMR (300 MHz, DMSO-d.sub.6).quadrature. (ppm) 4.93
(s, 2H), 7.0-7.1 (m, 2H), 7.3-7.4 (m, 1H), 7.5-7.7 (m, 3H), 7.75
(d, J=8.2 Hz, 1H).
4.2.al 5-(4-Carboxyphenoxy)-1-hydroxy-2,1-benzoxaborole (C38)
[0296] To a solution of
5-(4-cyanophenoxy)-1-hydroxy-2,1-benzoxaborole obtained in C17 (430
mg, 1.71 mmol) in ethanol (10 mL) was added 6 mol/L sodium
hydroxide (2 mL), and the mixture was refluxed for 3 hours.
Hydrochloric acid (6 mol/L, 3 mL) was added, and the mixture was
extracted with ethyl acetate. The organic layer was washed with
brine and dried on anhydrous sodium sulfate. The solvent was
removed under reduced pressure, and the residue was purified by
silica gel column chromatography (ethyl acetate) followed by
trituration with diisopropyl ether to give the target compound (37
mg, 8%).
[0297] .sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta. (ppm) 4.94 (s,
2H), 7.0-7.1 (m, 4H), 7.76 (d, J=7.9 Hz, 1H), 7.94 (d, J=8.8 Hz,
2H), 9.19 (s, 1H), 12.8 (br s, 1H).
4.2.am 1-Hydroxy-5-[4-(tetrazole-1-yl)phenoxy]-2,1-benzoxaborole
(C39)
[0298] A mixture of 5-(4-cyanophenoxy)-1-hydroxy-2,1-benzoxaborole
(200 mg, 0.797 mmol), sodium azide (103 mg, 1.59 mmol), and
ammonium chloride (85 mg, 1.6 mmol) in N,N-dimethylformamide (5 mL)
was stirred at 80.degree. C. for two days. Water was added, and the
mixture was extracted with ethyl acetate. The organic layer was
washed with water and brine, and dried on anhydrous sodium sulfate.
The solvent was removed under reduced pressure, and the residue was
purified by silica gel column chromatography (ethyl acetate)
followed by trituration with ethyl acetate to give the target
compound (55 mg, 23%).
[0299] .sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta. (ppm) 4.95 (s,
2H), 7.0-7.1 (m, 2H), 7.23 (d, J=8.8 Hz, 2H), 7.76 (d, J=7.9 Hz,
1H), 8.05 (d, J=8.5 Hz, 2H), 9.18 (br s, 1H).
Example 5
[0300] Preparation of I from 2 via 6
5.1 Catalytic Boronylation, Reduction and Cyclization
[0301] A mixture of 2 (10.0 mmol), bis(pinacolato)diboron (2.79 g,
11.0 mmol), PdCl.sub.2(dppf) (250 mg, 3 mol %), and potassium
acetate (2.94 g, 30.0 mmol) in 1,4-dioxane (40 mL) was stirred at
80.degree. C. for overnight. Water was added, and the mixture was
extracted with ethyl acetate. The organic layer was washed with
brine and dried on anhydrous sodium sulfate. The solvent was
removed under reduced pressure. The crude product was dissolved in
tetrahydrofuran (80 mL), then sodium periodate (5.56 g, 26.0 mmol)
was added. After stirring at room temperature for 30 min, 2N HCl
(10 mL) was added, and the mixture was stirred at room temperature
for overnight. Water was added, and the mixture was extracted with
ethyl acetate. The organic layer was washed with brine and dried on
anhydrous sodium sulfate. The solvent was removed under reduced
pressure, and the residue was treated with ether to afford 6.3 mmol
of the corresponding boronic acid. To the solution of the obtained
boronic acid (0.595 mmol) in methanol (5 mL) was added sodium
borohydride (11 mg, 0.30 mmol), and the mixture was stirred at room
temperature for 1 h. Water was added, and the mixture was extracted
with ethyl acetate. The organic layer was washed with brine and
dried on anhydrous sodium sulfate. The solvent was removed under
reduced pressure, and the residue was purified by silica gel column
chromatography to give 0.217 mmol of I.
5.2 Results
[0302] Analytical data for exemplary compounds of structure I are
provided below.
5.2.a 1,3-Dihydro-5-fluoro-1-hydroxy-2,1-benzoxaborole (C10)
[0303] Analytical data for this compound is listed in 4.2.j.
Example 6
[0304] Preparation of I from 3
6.1 One-pot Boronylation and Cyclization
[0305] To a solution of 3 (4.88 mmol) and triisopropyl borate (1.35
mL, 5.86 mmol) in tetrahydrofuran (10 mL) was added n-butyllithium
(1.6 mol/L in hexanes; 6.7 mL, 10.7 mmol) dropwise over 15 min at
-78.degree. C. under nitrogen atmosphere, and the mixture was
stirred for 2 h while allowing to warm to room temperature. The
reaction was quenched with 2N HCl, and extracted with ethyl
acetate. The organic layer was washed with brine and dried on
anhydrous sodium sulfate. The solvent was removed under reduced
pressure, and the residue was purified by silica gel column
chromatography and treated with pentane to give 0.41 mmol of I.
6.2 Results
[0306] Analytical data for exemplary compounds of structure I are
provided below.
6.2.a 1,3-Dihydro-5-fluoro-1-hydroxy-2,1-benzoxaborole (C10)
[0307] Analytical data for this compound is listed in 4.2.j.
Example 7
[0308] Preparation of I from 3 7.1 One-pot Boronylation and
Cyclization with Distillation
[0309] To a solution of 3 (4.88 mmol) in toluene (20 mL) was added
triisopropyl borate (2.2 mL, 9.8 mmol), and the mixture was heated
at reflux for 1 h. The solvent, the generated isopropyl alcohol and
excess triisopropyl borate were removed under reduced pressure. The
residue was dissolved in tetrahydrofuran (10 mL) and cooled to
-78.degree. C. n-Butyllithium (3.2 mL, 5.1 mmol) was added dropwise
over 10 min, and the mixture was stirred for 1 h while allowing to
warm to room temperature. The reaction was quenched with 2N HCl,
and extracted with ethyl acetate. The organic layer was washed with
brine and dried on anhydrous sodium sulfate. The solvent was
removed under reduced pressure, and the residue was purified by
silica gel column chromatography to give 1.54 mmol of I.
7.2 Results
[0310] Analytical data for exemplary compounds of structure I are
provided below.
7.2.a 1,3-Dihydro-5-fluoro-1-hydroxy-2,1-benzoxaborole (C10)
[0311] Analytical data for this compound is listed in 4.2.j.
Example 8
[0312] Preparation of 8 from 7
8.1 Bromination
[0313] To a solution of 7 (49.5 mmol) in carbon tetrachloride (200
mL) were added N-bromosuccinimide (8.81 g, 49.5 mmol) and
N,N-azoisobutylonitrile (414 mg, 5 mol %), and the mixture was
heated at reflux for 3 h. Water was added, and the mixture was
extracted with chloroform. The organic layer was washed with brine
and dried on anhydrous sodium sulfate. The solvent was removed
under reduced pressure to give the crude methyl-brominated
intermediate 8.
Example 9
[0314] Preparation of 3 from 8
9.1 Hydroxylation
[0315] To crude 8 (49.5 mmol) were added dimethylformamide (150 mL)
and sodium acetate (20.5 g, 250 mmol), and the mixture was stirred
at 80.degree. C. for overnight. Water was added, and the mixture
was extracted with ether. The organic layer was washed with water
and brine, and dried on anhydrous sodium sulfate. The solvent was
removed under reduced pressure. To the residue was added methanol
(150 mL) and 1N sodium hydroxide (50 mL), and the mixture was
stirred at room temperature for 1 h. The reaction mixture was
concentrated to about a third of volume under reduced pressure.
Water and hydrochloric acid were added, and the mixture was
extracted with ethyl acetate. The organic layer was washed with
water and brine, and dried on anhydrous sodium sulfate. The solvent
was removed under reduced pressure, and the residue was purified by
silica gel column chromatography followed by trituration with
dichloromethane to give 21.8 mmol of 3.
9.2 Results
[0316] Exemplary compounds of structure 3 prepared by the method
above are provided below.
9.2.a 2-Bromo-5-cyanobenzyl Alcohol
[0317] .sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta. ppm 4.51 (d,
J=5.9 Hz, 2H), 5.67 (t, J=5.6 Hz, 1H), 7.67 (dd, J=8.2, 2.0 Hz,
1H), 7.80 (s, J=8.2 Hz, 1H), 7.83 (d, J=2.0 Hz, 1H).
[0318] Additional examples of compounds which can be produced by
this method include 2-bromo-5-(4-cyanophenoxy)benzyl alcohol.
Example 10
[0319] Preparation of 9 from 2
10.1 Reaction
[0320] A mixture of 2 (20.0 mmol),
(methoxymethyl)triphenylphosphonium chloride (8.49 g, 24.0 mmol),
and potassium tert-butoxide (2.83 g, 24.0 mol) in
N,N-dimethylformamide (50 mL) was stirred at room temperature for
overnight. The reaction was quenched with 6N HCl, and the mixture
was extracted with ethyl acetate. The organic layer was washed with
water (.times.2) and brine, and dried on anhydrous sodium sulfate.
The solvent was removed under reduced. To the residue were added
tetrahydrofuran (60 mL) and 6N HCl, and the mixture was heated at
reflux for 8 h. Water was added, and the mixture was extracted with
ether. The organic layer was washed with brine and dried on
anhydrous sodium sulfate. The solvent was removed under reduced
pressure to afford 16.6 mmol of 9.
Example 11
Preparation Method of Step 13
11.1 Reaction
[0321] A solution of I in an appropriate alcohol solvent
(R.sup.1--OH) was refluxed under nitrogen atmosphere and then
distilled to remove the alcohol to give the corresponding
ester.
Example 12
[0322] Preparation of Ib from Ia
12.1 Reaction
[0323] To a solution of Ia in toluene was added amino alcohol and
the participated solid was collected to give Ib.
12.2 Results
[0324] (500 mg, 3.3 mmol) was dissolved in toluene (37 mL) at
80.degree. C. and ethanolamine (0.20 mL, 3.3 mmol) was added. The
mixture was cooled to room temperature, then ice bath, and filtered
to give C38 as a white powder (600.5 mg, 94%).
[0325] 12.2a (C38)
[0326] .sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta. (ppm) 2.88 (t,
J=6.2 Hz, 2H), 3.75 (t, J=6.3 Hz, 2H), 4.66 (s, 2H), 5.77 (br, 2H),
6.85-6.91 (m, 2H), 7.31 (td, J=7.2, 1.2 Hz, 1H).
Example 13
5-(4-Carboxyphenoxy)-1-hydroxy-2,1-benzoxaborole
##STR00067##
[0328] To a solution of
5-(4-cyanophenoxy)-1-hydroxy-2,1-benzoxaborole obtained in C17 (430
mg, 1.71 mmol) in ethanol (10 mL) was added 6 mol/L sodium
hydroxide (2 mL), and the mixture was refluxed for 3 hours.
Hydrochloric acid (6 mol/L, 3 mL) was added, and the mixture was
extracted with ethyl acetate. The organic layer was washed with
brine and dried on anhydrous sodium sulfate. The solvent was
removed under reduced pressure, and the residue was purified by
silica gel column chromatography (ethyl acetate) followed by
trituration with diisopropyl ether to give the target compound (37
mg, 8%).
[0329] .sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta. (ppm) 4.94 (s,
2H), 7.0-7.1 (m, 4H), 7.76 (d, J=7.9 Hz, 1H), 7.94 (d, J=8.8 Hz,
2H), 9.19 (s, 1H), 12.8 (br s, 1H).
Example 14
1-Hydroxy-5-[4-(tetrazole-1-yl)phenoxy]-2,1-benzoxaborole
##STR00068##
[0331] A mixture of 5-(4-cyanophenoxy)-1-hydroxy-2,1-benzoxaborole
(200 mg, 0.797 mmol), sodium azide (103 mg, 1.59 mmol), and
ammonium chloride (85 mg, 1.6 mmol) in N,N-dimethylformamide (5 mL)
was stirred at 80.degree. C. for two days. Water was added, and the
mixture was extracted with ethyl acetate. The organic layer was
washed with water and brine, and dried on anhydrous sodium sulfate.
The solvent was removed under reduced pressure, and the residue was
purified by silica gel column chromatography (ethyl acetate)
followed by trituration with ethyl acetate to give the target
compound (55 mg, 23%).
[0332] .sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta. (ppm) 4.95 (s,
2H), 7.0-7.1 (m, 2H), 7.23 (d, J=8.8 Hz, 2H), 7.76 (d, J=7.9 Hz,
1H), 8.05 (d, J=8.5 Hz, 2H), 9.18 (br s, 1H).
Example 15
4-(4-Cyanophenoxy)phenylboronic acid (C97)
##STR00069## ##STR00070##
[0333] (a) (4-cyanophenyl)(4-bromophenyl)ether
[0334] Under nitrogen, the mixture of 4-fluorobenzonitrile (7.35 g,
60.68 mmol), 4-bromophenol (10 g, 57.8 mmol) and potassium
carbonate (12 g, 1.5 eq) in DMF (100 mL) was stirred at 100.degree.
C. for 16 h and then filtered. After rotary evaporation, the
residue was dissolved in ethyl acetate and washed with 1N NaOH
solution to remove unreacted phenol. The organic solution was dried
and passed through a short silica gel column to remove the color
and minor phenol impurity. Evaporation of the solution gave
(4-cyanophenyl)(4-bromophenyl)ether (13.82 g, yield 87.2%) as a
white solid. .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 7.83 (d,
2H), 7.63 (d, 2H), 7.13 (d, 2H) and 7.10 (d, 2H) ppm.
(b) 4-(4-cyanophenoxy)phenylboronic acid
[0335] The procedure described in Example 2d was used for the
synthesis of 4-(4-cyanophenoxy)phenylboronic acid using
(4-cyanophenyl)(4-bromophenyl)ether as starting material. The title
compound was obtained as a white solid. M.p.194-198.degree. C. MS:
m/z=239 (M+), 240 (M+1) (ESI+) and m/z=238 (M-1) (ESI-). HPLC:
95.3% purity at 254 nm and 92.1% at 220 nm. .sup.1H NMR (300 MHz,
DMSO-d.sub.6+D.sub.2O): .delta. 7.83-7.76 (m, 4H), 7.07 (d, 2H) and
7.04 (d, 2H) ppm.
Example 16
3-(4-Cyanophenoxy)phenylboronic acid (C98)
##STR00071##
[0337] By following the procedures described for the synthesis of
C21, the title compound was acquired from
(4-cyanophenyl)(3-bromophenyl)ether that was prepared using
3-bromophenol and 4-fluorobenzonitrile as starting materials. The
product was obtained as a white solid. M.p.153-162.degree. C. MS:
m/z=239 (M+), 240 (M+1) (ESI+) and m/z=238 (M-1) (ESI-). HPLC:
98.5% purity at 254 nm and 97.5% at 220 nm. .sup.1H NMR (300 MHz,
DMSO-d.sub.6+D.sub.2O): .delta. 7.78 (d, 2H), 7.64 (d, 1H),
7.45-7.40 (m, 2H), 7.18-7.14 (dd, 1H) and 7.03 (d, 2H) ppm.
Example 17
4-(4-Cyanophenoxy)-2-Methylphenylboronic acid (C99)
##STR00072##
[0339] By following the procedures described for the synthesis of
C21, the title compound was acquired from
(4-cyanophenyl)(4-bromo-3-methylphenyl)ether that was prepared
using 4-bromo-3-methylphenol and 4-fluorobenzonitrile as starting
materials. The product was obtained as a cream solid.
M.p.161-165.degree. C. MS: m/z=253 (M+), 254 (M+1) (ESI+) and
m/z=252 (M-1) (ESI-). HPLC: 97.1% purity at 254 nm and 95.1% at 220
nm. .sup.1H NMR (300 MHz, DMSO-d.sub.6+D.sub.2O): .delta. 7.95 (d,
2H), 7.81 (d, 1H), 7.09 (d, 2H), 6.92-6.88 (m, 2H) and 2.65 (s, 3H)
ppm.
Example 18
Anti-Inflammatory Testing
[0340] The ability of the compounds of the invention to inhibit
pro-inflammatory cytokines were tested. The effects of the
compounds on IL-1.beta., IL-4, TNF.alpha., and IFN.gamma. cytokine
release profiles in frozen human peripheral blood mononucleocytes
(PBMC) was examined. PBMC cells were exposed to 10 .mu.M
concentration of each sample prior to stimulation with 20 .mu.g/mL
Phytohemagglutinins (PHA). Cytokine release profiles are assayed
using the Luminex 4-plex assay. (IL-1.beta., IFN.gamma., IL-4,
TNF-.alpha.). Results of the testing are provided in FIGS.
1A-1B.
Methods:
[0341] Test Substances and Dosing Pattern
[0342] Frozen Human PBMC will be thawed and centrifuged.
Cryopreservation media was aspirated off of the cell pellet, and
the cells were resuspended in fresh culture media. The culture
media (CM) for PBMC was RPMI 1640, 10% FBS, 1% P/S, 2 mM
L-glutamine. Cells were incubated at 37.degree. C., 5% CO.sub.2.
Dissolve dry solid compound described herein, such as according to
Formula (I) or Formula (II) in DMSO to form a 20 mM sample (DMSO,
100%). The 20 mM samples were diluted to 200 .mu.M (10.times.) in
CM (DMSO, 1%). 10 .mu.L of diluted sample was added to 190 uL
CM+cells (n=3) for a final sample concentration of 10 .mu.M (Final
DMSO 0.05%). The sample was incubated with the cells at 37.degree.
C. for 15-30 mins prior to adding inducer (PHA, 20 ug/mL). Inducer
plus a vehicle (PHA+0.05% DMSO) was used as a control for this
experiment. Vehicle without inducer was used as a negative control.
Dexamethasone (50 nM, n=3) was used in the positive control.
Supernatant were extracted at 24 hours as well as 48 hours, and
stored at -80.degree. C. The supernatant was thawed, and assayed
with Alamar Blue for sample cytotoxicity. The supernatant were then
assayed for IL-1.beta., IL-4, TNF-.alpha. and IFN.gamma. using the
Luminex 4-plex assay.
Results:
[0343] Dexamethazone inhibition of cytokine secretion was within
the expected range confirming that the assay was valid. %
inhibition of IL-1.beta., IL-4, TNF-.alpha. and IFN.gamma. for the
various compounds of the invention are provided in FIGS. 1A-1B.
Example 19
Topical, Phorbol Ester Mouse Ear Assay
Methods:
[0344] Test Subs