U.S. patent application number 11/741702 was filed with the patent office on 2007-08-30 for benzimidazole compounds for modulating ige and inhibiting cellular proliferation.
Invention is credited to Mark L. Richards, Jagadish C. Sircar.
Application Number | 20070202133 11/741702 |
Document ID | / |
Family ID | 34115140 |
Filed Date | 2007-08-30 |
United States Patent
Application |
20070202133 |
Kind Code |
A1 |
Sircar; Jagadish C. ; et
al. |
August 30, 2007 |
BENZIMIDAZOLE COMPOUNDS FOR MODULATING IgE AND INHIBITING CELLULAR
PROLIFERATION
Abstract
The present invention is directed to small molecule inhibitors
of the IgE response to allergens, which are useful in the treatment
of allergy and/or asthma or any diseases where IgE is pathogenic.
This invention also relates to benzimidazole molecules that are
cellular proliferation inhibitors and thus are useful as anticancer
agents.
Inventors: |
Sircar; Jagadish C.; (San
Diego, CA) ; Richards; Mark L.; (San Diego,
CA) |
Correspondence
Address: |
KNOBBE MARTENS OLSON & BEAR LLP
2040 MAIN STREET
FOURTEENTH FLOOR
IRVINE
CA
92614
US
|
Family ID: |
34115140 |
Appl. No.: |
11/741702 |
Filed: |
April 27, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10795006 |
Mar 5, 2004 |
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11741702 |
Apr 27, 2007 |
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10090044 |
Feb 27, 2002 |
6759425 |
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10795006 |
Mar 5, 2004 |
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09422304 |
Oct 21, 1999 |
6369091 |
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10090044 |
Feb 27, 2002 |
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60275260 |
Mar 12, 2001 |
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Current U.S.
Class: |
424/275.1 ;
514/338; 514/394; 546/273.4; 548/309.7 |
Current CPC
Class: |
C07D 401/12 20130101;
A61K 45/06 20130101; C07D 235/18 20130101; A61K 2300/00 20130101;
C07D 403/14 20130101; A61K 2300/00 20130101; A61P 35/00 20180101;
A61K 31/4184 20130101; A61K 2300/00 20130101; A61P 43/00 20180101;
A61K 31/422 20130101; C07D 413/12 20130101; A61K 31/422 20130101;
A61P 11/06 20180101; C07D 403/12 20130101; C07D 401/14 20130101;
A61K 31/4439 20130101; A61P 37/08 20180101; A61K 31/4184 20130101;
A61K 31/4439 20130101 |
Class at
Publication: |
424/275.1 ;
514/338; 514/394; 546/273.4; 548/309.7 |
International
Class: |
A61K 39/35 20060101
A61K039/35; A61K 31/4184 20060101 A61K031/4184; C07D 235/06
20060101 C07D235/06; C07D 401/02 20060101 C07D401/02; A61K 31/4439
20060101 A61K031/4439 |
Claims
1. A compound or salt thereof having the one of the following
formulas: ##STR82## wherein R is selected from the group consisting
of H, C.sub.1-C.sub.5 alkyl, benzyl, p-fluorobenzyl and
dialkylamino alkyl, wherein said C.sub.1-C.sub.5 alkyl is selected
from the group consisting of a straight chain, branched or cyclic
alkyl; wherein R.sub.1 and R.sub.2 are independently selected from
the group consisting of H, alkyl, substituted alkyl,
C.sub.3-C.sub.9 cycloalkyl, substituted C.sub.3-C.sub.9 cycloalkyl,
polycyclic aliphatic groups, substituted polycyclic aliphatic
groups, phenyl, substituted phenyl, naphthyl, substituted naphthyl,
five-member ring heteroaryl, and substituted five-member ring
heteroaryl, wherein said five-member ring heteroaryl and said
substituted five-member ring heteroaryl contain 1-2 heteroatoms,
wherein said heteroatom is independently selected from the group
consisting of nitrogen, oxygen and sulfur; wherein R.sub.3 and
R.sub.4 are independently selected from the group consisting of H,
alkyl, aryl, heteroaryl and COR'; wherein R' is selected from the
group consisting of alkyl, substituted alkyl, C.sub.3-C.sub.9
cycloalkyl, substituted C.sub.3-C.sub.9 cycloalkyl, polycyclic
aliphatic group, substituted polycyclic aliphatic group, phenyl,
substituted phenyl, naphthyl, substituted naphthyl, heteroaryl and
substituted heteroaryl, wherein said heteroaryl, and said
substituted heteroaryl contain 1-3 heteroatoms, wherein said
heteroatom is independently selected from the group consisting of
nitrogen, oxygen and sulfur; wherein R' is not haloalkyl and
provided that when R' is pyridyl, substituted pyridyl or
pyridyl-N-oxide, R.sub.1 and R.sub.2 are not adamantyl or
substituted adamantyl; wherein said substituted alkyl, substituted
polycyclic aliphatic groups, substituted phenyl, substituted
naphthyl and substituted heteroaryl contain 1-5 substituents,
wherein said substituent is selected from the group consisting of
H, halogens, polyhalogens, alkoxy group, substituted alkoxy, alkyl,
substituted alkyl, dialkylaminoalkyl, hydroxyalkyl, OH, OCH.sub.3,
COOH, OCOR', COOR', COR', CN, CF.sub.3, OCF.sub.3, NO.sub.2, NR'R',
NHCOR' and CONR'R'; wherein the substituent on R.sub.1, R.sub.2,
and R' is selected from the group consisting of H, halogens,
polyhalogens, alkoxy group, substituted alkoxy, alkyl, substituted
alkyl, dialkylaminoalkyl, hydroxyalkyl, carbonyl, OH, OCH.sub.3,
COOH, OCOR', COOR', COR', CN, CF.sub.3, OCF.sub.3, NO.sub.2, NR'R',
NHCOR' and CONR'R'; wherein X and Y are independently selected from
the group consisting of H, halogens, alkoxy, substituted alkoxy,
alkyl, substituted alkyl, dialkylaminoalkyl, hydroxyalkyl, OH,
OCOR'', OCH.sub.3, COOH, CN, CF.sub.3, OCF.sub.3, NO.sub.2, COOR'',
CHO and COR''; wherein R'' is a C.sub.1-C.sub.8 alkyl, wherein said
C.sub.1-C.sub.8 alkyl is selected from the group consisting of a
straight chain, branched or cyclic alkyl; wherein at least one of
R.sub.1, R.sub.2, R.sub.3, or R.sub.4 is not H; ##STR83## wherein R
is selected from the group consisting of H, C.sub.1-C.sub.5 alkyl,
benzyl, p-fluorobenzyl and di-alkylamino alkyl, wherein said
C.sub.1-C.sub.5 alkyl is selected from the group consisting of a
straight chain, branched or cyclic alkyl; wherein R.sub.1 and
R.sub.2 are independently selected from the group consisting of H,
alkyl, substituted alkyl, C.sub.3-C.sub.9 cycloalkyl, substituted
C.sub.3-C.sub.9 cycloalkyl, polycyclic aliphatic groups, phenyl,
substituted phenyl, naphthyl, substituted naphthyl, heteroaryl and
substituted heteroaryl, wherein said heteroaryl and said
substituted heteroaryl contain 1-3 heteroatoms, wherein said
heteroatom is independently selected from the group consisting of
nitrogen, oxygen and sulfur; wherein said substituted phenyl,
substituted naphthyl and substituted heteroaryl contain 1-5
substituents, wherein said substituent is selected from the group
consisting of H, halogens, polyhalogens, alkoxy group, substituted
alkoxy, alkyl, substituted alkyl, dialkylaminoalkyl, hydroxyalkyl,
OH, OCH.sub.3, COOH, COOR' COR', CN, CF.sub.3, OCF.sub.3, NO.sub.2,
NR'R', NHCOR' and CONR'R'; wherein R.sub.3 and R.sub.4 are
independently selected from the group consisting of H, alkyl, aryl,
heteroaryl and COR'; wherein R' is selected from the group
consisting of H, alkyl, substituted alkyl, C.sub.3-C.sub.9
cycloalkyl, substituted C.sub.3-C.sub.9 cycloalkyl, polycyclic
aliphatics, phenyl, substituted phenyl, naphthyl, substituted
naphthyl, heteroaryl and substituted heteroaryl, wherein said
heteroaryl and said substituted heteroaryl contain 1-3 heteroatoms,
wherein said heteroatom is independently selected from the group
consisting of nitrogen, oxygen and sulfur; wherein X and Y are
independently selected from the group consisting of H, halogens,
alkoxy, substituted alkoxy, alkyl, substituted alkyl,
dialkylaminoalkyl, hydroxyalkyl, OH, OCOR'', OCH.sub.3, COOH, CN,
CF.sub.3, OCF.sub.3, NO.sub.2, COOR'', CHO and COR''; and wherein
R'' is a C.sub.1-C.sub.8 alkyl, wherein said C.sub.1-C.sub.8 alkyl
is selected from the group consisting of a straight chain, branched
or cyclic alkyl.
2. The compound of claim 1, wherein said polycyclic aliphatic group
is selected from the group consisting of adamantyl, bicycloheptyl,
camphoryl, bicyclo[2,2,2]octanyl and norbornyl.
3. The compound or salt thereof of claim 1, wherein said heteroaryl
and said substituted heteroaryl is selected from the group
consisting of pyridines, thiazoles, isothiazoles, oxazoles,
pyrimidines, pyrazines, furans, thiophenes, isoxazoles, pyrroles,
pyridazines, 1,2,3-triazines, 1,2,4-triazines, 1,3,5-triazines,
pyrazoles, imidazoles, indoles, quinolines, isoquinolines,
benzothiophines, benzofurans, parathiazines, pyrans and
chromenes.
4. A pharmaceutical composition for treating asthma or an allergic
reaction associated with an increase in IgE levels in a mammal
comprising at least one compound or salt thereof of claim 1.
5. The pharmaceutical composition of claim 4, further comprising at
least one additional ingredient which is active in reducing at
least one symptom associated with said allergic reaction.
6. A pharmaceutical composition for inhibiting cell proliferation
in a mammal comprising at least one compound or salt thereof of
Genus I as defined in claim 1.
7. The pharmaceutical composition of claim 6, further comprising at
least one additional ingredient which is active in reducing at
least one symptom associated with said cell proliferation.
8. A method for treating an allergic reaction in a mammal wherein
said reaction is caused by an increase in IgE levels comprising
administering an IgE-suppressing amount of at least one compound or
salt thereof of claim 1.
9. The method of claim 8 further comprising administering at least
one additional ingredient which is active in reducing at least one
symptom associated with said allergic reaction.
10. The method of claim 9, wherein said at least one additional
ingredient is selected from the group consisting of a short-acting
.beta..sub.2-adrenergic agonist, a long-acting
.beta..sub.2-adrenergic agonist, an antihistamine, a
phosphodiesterase inhibitor, an anticholinergic agent, a
corticosteroid, an inflammatory mediator release inhibitor and a
leukotriene receptor antagonist.
11. The method of claim 9, wherein said at least one additional
ingredient is combined with said at least one IgE-suppressing
compound or salt thereof in a pharmaceutically acceptable diluent
and co-administered to the mammal.
12. The method of claim 11, wherein said at least one
IgE-suppressing compound or salt thereof is administered at a dose
of about 0.01 mg to about 100 mg per kg body weight per day.
13. The method of claim 12, wherein said dose is administered in
divided doses at regular periodic intervals.
14. The method of claim 13, wherein said regular periodic intervals
occur daily.
15. A method for treating asthma in a mammal comprising
administering an IgE-suppressing amount of at least one compound or
salt thereof of claim 1.
16. The method of claim 15 further comprising administering at
least one additional ingredient which is active in reducing at
least one symptom associated with said asthma.
17. The method of claim 16, wherein said additional ingredient is
selected from the group consisting of a short-acting
.beta..sub.2-adrenergic agonist, a long-acting
.beta..sub.2-adrenergic agonist, an antihistamine, a
phosphodiesterase inhibitor, an anticholinergic agent, a
corticosteroid, an inflammatory mediator release inhibitor and a
leukotriene receptor antagonist.
18. A method for inhibiting cellular proliferation in a mammal
comprising administering an amount of at least one compound or salt
thereof of Genus I as defined in claim 1.
19. The method of claim 18 further comprising administering at
least one additional ingredient which is active in reducing at
least one symptom associated with said cellular proliferation.
20. The method of claim 19, wherein said at least one additional
ingredient is selected from the group consisting of antifungals,
antivirals, antibiotics, anti-inflammatories, and anticancer
agents.
21. The method of claim 19, wherein said at least one additional
ingredient is selected from the group consisting of alkylating
agent, antimetabolite, DNA cutter, topoisomerase I poison,
topoisomerase II poison, DNA binder, and spindle poison.
22. The method of claim 19, wherein said at least one additional
ingredient is combined with said at least one compound or salt
thereof in a pharmaceutically acceptable diluent and
co-administered to the mammal.
23. The method of claim 22, wherein said at least one compound or
salt thereof is administered at a dose of about 0.01 mg to about
100 mg per kg body weight per day.
24. The method of claim 23, wherein said dose is administered in
divided doses at regular periodic intervals.
25. The method of claim 24, wherein said regular periodic intervals
occur daily.
26. The method of claim 18 further comprising administering at
least one other therapy which is effective in ameliorating at least
one symptom associated with cellular proliferation.
27. The method of claim 26, wherein said therapy is an anti-cancer
therapy.
28. The method of claim 26, wherein said therapy is selected from
the group consisting of radiation, immunotherapy, gene therapy, and
surgery.
29. A method of preparing a compound or salt thereof of claim 1
comprising: reacting a 3,4-diaminobenzoic acid with a
4-nitrobenzaldehyde to yield a first intermediate or salt thereof,
aminating said first intermediate or salt thereof to yield a second
intermediate or salt thereof, reducing said second intermediate or
salt thereof to yield a third intermediate or salt thereof, and
acylating said third intermediate or salt thereof to obtain said
compound or salt thereof.
30. A method of preparing a compound or salt thereof of Genus II as
defined in claim 1 comprising: reacting a
4-nitro-1,2,-phenylenediamine with an alkyl 4-formylbenzoate to
yield a first intermediate or salt thereof, treating said first
intermediate or salt thereof with an aqueous base to yield a second
intermediate or salt thereof, aminating said second intermediate or
salt thereof to yield a third intermediate or salt thereof,
reducing said third intermediate or salt thereof to yield a fourth
intermediate or salt thereof, and acylating said fourth
intermediate or salt thereof to obtain said compound or salt
thereof.
31. A method of preparing a compound or salt thereof of Genus III
as defined in claim 1 comprising: reacting a 3,4-diaminobenzoic
acid with a 4-alkoxycarbonyl benzaldehyde to yield a first
intermediate or salt thereof, treating said first intermediate or
salt thereof with an agent selected from the following group:
inorganic acid halide, organic acid chlorides and mixed anhydrides,
to yield a second intermediate or salt thereof, aminating said
second intermediate or salt thereof to yield a third intermediate
or salt thereof, treating said third intermediate or salt thereof
with an aqueous base to yield a fourth intermediate or salt
thereof, and aminating said fourth intermediate or salt thereof to
obtain said compound or salt thereof.
32. A compound or salt thereof selected from the group consisting
of: ##STR84## ##STR85## ##STR86## ##STR87## ##STR88## ##STR89##
##STR90## ##STR91## ##STR92## ##STR93## ##STR94## ##STR95##
##STR96## ##STR97## ##STR98## ##STR99## ##STR100## ##STR101##
##STR102## ##STR103## ##STR104## ##STR105## ##STR106## ##STR107##
##STR108##
33. A compound or salt thereof selected from the group consisting
of: ##STR109## ##STR110## ##STR111## ##STR112## ##STR113##
##STR114## ##STR115##
34. A compound or salt thereof selected from the group consisting
of: ##STR116## ##STR117## ##STR118## ##STR119## ##STR120##
35. A compound or salt thereof selected from the group consisting
of: ##STR121## ##STR122## ##STR123## ##STR124##
36. A compound or salt thereof selected from the group consisting
of: ##STR125## ##STR126## ##STR127##
37. A compound or salt thereof selected from the group consisting
of: ##STR128## ##STR129## ##STR130## ##STR131## ##STR132##
##STR133## ##STR134## ##STR135##
38. A compound or salt thereof selected from the group consisting
of: ##STR136## ##STR137## ##STR138## ##STR139## ##STR140##
##STR141## ##STR142## ##STR143## ##STR144## ##STR145## ##STR146##
##STR147## ##STR148## ##STR149##
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a division of U.S. application Ser. No.
10/795,006, filed Mar. 5, 2004, which is a division of U.S.
application Ser. No. 10/090,044, filed Feb. 27, 2002, now U.S. Pat.
No. 6,759,425, which is a continuation-in-part of U.S. application
Ser. No. 09/422,304, filed on Oct. 21, 1999, now U.S. Pat. No.
6,369,091, and also claims priority under 35 U.S.C. .sctn.119(e) to
U.S. Provisional Application No. 60/275,260, filed on Mar. 12,
2001.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] This invention relates to small molecule inhibitors of the
IgE response to allergens that are useful in the treatment of
allergy and/or asthma or any diseases where IgE is pathogenic. This
invention also relates to small molecules that are proliferation
inhibitors and thus they are useful as anticancer agents.
[0004] 2. Description of the Related Art
Allergies and Asthma
[0005] An estimated 10 million persons in the United States have
asthma, about 5% of the population. The estimated cost of asthma in
the United States exceeds $6 billion. About 25% of patients with
asthma who seek emergency care require hospitalization, and the
largest single direct medical expenditure for asthma has been
inpatient hospital services (emergency care), at a cost of greater
than $1.6 billion. The cost for prescription medications, which
increased 54% between 1985 and 1990, was close behind at $1.1
billion (Kelly, Pharmacotherapy 12:13 S-21S (1997)).
[0006] According to the National Ambulatory Medical Care Survey,
asthma accounts for 1% of all ambulatory care visits, and the
disease continues to be a significant cause of missed school days
in children. Despite improved understanding of the disease process
and better drugs, asthma morbidity and mortality continue to rise
in this country and worldwide (U.S. Department of Health and Human
Services; 1991, publication no. 91-3042). Thus, asthma constitutes
a significant public health problem.
[0007] The pathophysiologic processes that attend the onset of an
asthmatic episode can be broken down into essentially two phases,
both marked by bronchoconstriction, that causes wheezing, chest
tightness, and dyspnea. The first, early phase asthmatic response
is triggered by allergens, irritants, or exercise. Allergens
cross-link immunoglobulin E (IgE) molecules bound to receptors on
mast cells, causing them to release a number of pre-formed
inflammatory mediators, including histamine. Additional triggers
include the osmotic changes in airway tissues following exercise or
the inhalation of cold, dry air. The second, late phase response
that follows is characterized by infiltration of activated
eosinophils and other inflammatory cells into airway tissues,
epithelial desquamonon, and by the presence of highly viscous mucus
within the airways. The damage caused by this inflammatory response
leaves the airways "primed" or sensitized, such that smaller
triggers are required to elicit subsequent asthma symptoms.
[0008] A number of drugs are available for the palliative treatment
of asthma; however, their efficacies vary markedly. Short-acting
.beta..sub.2-adrenergic agonists, terbutaline and albuterol, long
the mainstay of asthma treatment, act primarily during the early
phase as bronchodilators. The newer long-acting
.beta..sub.2-agonists, salmeterol and formoterol, may reduce the
bronchoconstrictive component of the late response. However,
because the .beta..sub.2-agonists do not possess significant
antiinflammatory activity, they have no effect on bronchial
hyperreactivity.
[0009] Numerous other drugs target specific aspects of the early or
late asthmatic responses. For example, antihistamines, like
loratadine, inhibit early histamine-mediated inflammatory
responses. Some of the newer antihistamines, such as azelastine and
ketotifen, may have both antiinflammatory and weak bronchodilatory
effects, but they currently do not have any established efficacy in
asthma treatment. Phosphodiesterase inhibitors, like
theophylline/xanthines, may attenuate late inflammatory responses,
but there is no evidence that these compounds decrease bronchial
hyperreactivity. Anticholinergics, like ipratopium bromide, which
are used in cases of acute asthma to inhibit severe
bronchoconstriction, have no effect on early or late phase
inflammation, no effect on bronchial hyperreactivity, and
therefore, essentially no role in chronic therapy.
[0010] The corticosteroid drugs, like budesonide, are the most
potent antiinflammatory agents. Inflammatory mediator release
inhibitors, like cromolyn and nedocromil, act by stabilizing mast
cells and thereby inhibiting the late phase inflammatory response
to allergen. Thus, cromolyn and nedocromil, as well as the
corticosteroids, all reduce bronchial hyperreactivity by minimizing
the sensitizing effect of inflammatory damage to the airways.
Unfortunately, these antiinflammatory agents do not produce
bronchodilation.
[0011] Several new agents have been developed that inhibit specific
aspects of asthmatic inflammation. For instance, leukotriene
receptor antagonists (ICI-204, 219, accolate), specifically inhibit
leukotriene-mediated actions. The leukotrienes have been implicated
in the production of both airway inflammation and
bronchoconstriction.
[0012] Thus, while numerous drugs are currently available for the
treatment of asthma, these compounds are primarily palliative
and/or have significant side effects. Consequently, new therapeutic
approaches which target the underlying cause rather than the
cascade of symptoms would be highly desirable. Asthma and allergy
share a common dependence on IgE-mediated events. Indeed, it is
known that excess IgE production is the underlying cause of
allergies in general and allergic asthma in particular (Duplantier
and Cheng, Ann. Rep. Med. Chem. 29:73-81 (1994)). Thus, compounds
that lower IgE levels may be effective in treating the underlying
cause of asthma and allergy.
[0013] None of the current therapies eliminate the excess
circulating IgE. The hypothesis that lowering plasma IgE may reduce
the allergic response, was confirmed by recent clinical results
with chimeric anti-IgE antibody, CGP-51901, and recombinant
humanized monoclonal antibody, rhuMAB-E25. Indeed, three companies,
Tanox Biosystems, Inc., Genentech Inc. and Novartis AG are
collaborating in the development of a humanized anti-IgE antibody
(BioWorld.RTM. Today, Feb. 26, 1997, p. 2) which will treat allergy
and asthma by neutralizing excess IgE. Tanox has already
successfully tested the anti-IgE antibody, CGP-51901, which reduced
the severity and duration of nasal symptoms of allergic rhinitis in
a 155-patient Phase II trial (Scrip #2080, Nov. 24, 1995, p. 26).
Genentech recently disclosed positive results from a 536 patient
phase-II/III trials of its recombinant humanized monoclonal
antibody, rhuMAB-E25 (BioWorld.RTM. Today, Nov. 10, 1998, p. 1).
The antibody, rhuMAB-E25, administered by injection (highest dose
300 mg every 2 to 4 weeks as needed) provided a 50% reduction in
the number of days a patient required additional "rescue" medicines
(antihistimines and decongestants), compared to placebo. More
recently, Dr. Henry Milgrom et. al. of the National Jewish Medical
and Research Center in Denver, Colo., published the clinical
results of rhuMAB-25 in moderate to severe asthma patients (317
patients for 12 weeks, iv injection every two weeks) and concluded
that this drug is "going to be a breakthrough" (New England Journal
of Medicine, Dec. 23, 1999). A Biologics License Application (BLA)
for this product has been submitted to the FDA in June, 2000
jointly by Novartis Pharmaceuticals Corporation, Tanox Inc., and
Genetech, Inc. The positive results from anti-IgE antibody trials
suggest that therapeutic strategies aimed at IgE down-regulation
may be effective.
Cancer and Hyperproliferation Disorders
[0014] Cellular proliferation is a normal process that is vital to
the normal functioning of most biological processes. Cellular
proliferation occurs in all living organisms and involves two main
processes: nuclear division (mitosis), and cytoplasmic division
(cytokinesis). Because organisms are continually growing and
replacing cells, cellular proliferation is essential to the
vitality of the healthy cell. The disruption of normal cellular
proliferation can result in a variety of disorders. For example,
hyperproliferation of cells may cause psoriasis, thrombosis,
atherosclerosis, coronary heart disease, myocardial infarction,
stroke, smooth muscle neoplasms, uterine fibroid or fibroma, and
obliterative diseases of vascular grafts and transplanted organs.
Abnormal cell proliferation is most commonly associated with tumor
formation and cancer.
[0015] Cancer is a major disease and is one of the leading causes
of mortality both in the United States and internationally. Indeed,
cancer is the second leading cause of death in the United States.
According to the National Institute of Health, the overall annual
cost for cancer is approximately $107 billion, which includes $37
billion for direct medical costs, $11 billion for indirect costs of
lost productivity due to illness and $59 billion for indirect costs
of lost productivity due to premature death. Not surprisingly,
considerable efforts are underway to develop new treatments and
preventative measures to combat this devastating illness.
[0016] Currently, cancer is primarily treated using a combination
of surgery, radiation and chemotherapy. Chemotherapy involves the
use of chemical agents to disrupt the replication and metabolism of
cancerous cells. Chemotherapeutic agents which are currently being
used to treat cancer can be classified into five main groups:
natural products and their derivatives; anthacyclines; alkylating
agents; antiproliferatives and hormonal agents.
[0017] One embodiment of the present invention discloses
benzimidazole compounds that modulate IgE and inhibit cell
proliferation. Benzimidazole compounds are known in the prior art,
for example in European Patent No. 719,765 and U.S. Pat. No.
5,821,258. Both references, however, disclose compounds that
contain an active ingredient that acts on DNA, and are structurally
different from the benzimidazole derivatives of the current
invention. The compounds of the prior art alkylate DNA and there is
no suggestion in the references that the disclosed benzimidazole
compounds modulate IgE or inhibit the cell proliferation. Further,
the compounds described in both references are described as
anticancer, antiviral or antimicrobial agents. The anti-allergy or
anti-asthma properties of the benzimidazole compounds of the
current invention have not previously been recognized. Further, in
describing the anticancer properties of benzimidazole compounds,
these references disclose chemotherapeutic agents that are DNA
alkylating agents. The inhibition of cell proliferation using
compounds of the present invention is not disclosed.
SUMMARY OF THE INVENTION
[0018] The present invention discloses several compounds that are
active in down-regulating the IgE response to allergens and other
provocative stimuli. One compound disclosed for use in the
treatment of a condition associated with an excess IgE level and/or
abnormal cell proliferation has a formula: ##STR1##
[0019] wherein R is selected from the group consisting of H,
C.sub.1-C.sub.5 alkyl, benzyl, p-fluorobenzyl and di-alkylamino
alkyl, wherein said C.sub.1-C.sub.5 alkyl is selected from the
group consisting of a straight chain, branched or cyclic alkyl;
[0020] wherein R.sub.1 and R.sub.2 are independently selected from
the group consisting of H, alkyl, substituted alkyl,
C.sub.3-C.sub.9 cycloalkyl, substituted C.sub.3-C.sub.9 cycloalkyl,
polycyclic aliphatic groups, phenyl, substituted phenyl, naphthyl,
substituted naphthyl, heteroaryl and substituted heteroaryl,
wherein said heteroaryl and said substituted heteroaryl contain 1-3
heteroatoms, wherein said heteroatom is independently selected from
the group consisting of nitrogen, oxygen and sulfur;
[0021] wherein said substituted phenyl, substituted naphthyl and
substituted heteroaryl contain 1-3 substituents, wherein said
substituent is selected from the group consisting of H, halogens,
polyhalogens, alkoxy group, substituted alkoxy, alkyl, substituted
alkyl, dialkylaminoalkyl, hydroxyalkyl, OH, OCH.sub.3, COOH, COOR'
COR', CN, CF.sub.3, OCF.sub.3, NO.sub.2, NR'R', NHCOR' and
CONR'R';
[0022] wherein R.sub.3 and R.sub.4 are independently selected from
the group consisting of H, alkyl, aryl, heteroaryl and COR';
[0023] wherein R' is selected from the group consisting of H,
alkyl, substituted alkyl, C.sub.3-C.sub.9 cycloalkyl, substituted
C.sub.3-C.sub.9 cycloalkyl, polycyclic aliphatics, phenyl,
substituted phenyl, naphthyl, substituted naphthyl, heteroaryl and
substituted heteroaryl, wherein said heteroaryl and said
substituted heteroaryl contain 1-3 heteroatoms, wherein said
heteroatom is independently selected from the group consisting of
nitrogen, oxygen and sulfur;
[0024] wherein X and Y are independently selected from the group
consisting of H, halogens, alkoxy, substituted alkoxy, alkyl,
substituted alkyl, dialkylaminoalkyl, hydroxyalkyl, OH, OCH.sub.3,
COOH, CN, CF.sub.3, OCF.sub.3, NO.sub.2, COOR'', CHO and COR'';
and
[0025] wherein R'' is a C.sub.1-C.sub.8 alkyl, wherein said
C.sub.1-C.sub.8 alkyl is selected from the group consisting of a
straight chain, branched or cyclic alkyl.
[0026] A compound of the aforementioned genus may contain a
polycyclic aliphatic group which is selected from the group
consisting of adamantyl, bicycloheptyl, camphoryl,
bicyclo[2,2,2]octanyl and norbornyl.
[0027] A compound of the aforementioned genus may contain a
heteroaryl and a substituted heteroaryl which is selected from the
group consisting of pyridines, thiazoles, isothiazoles, oxazoles,
pyrimidines, pyrazines, furans, thiophenes, isoxazoles, pyrroles,
pyridazines, 1,2,3-triazines, 1,2,4-triazines, 1,3,5-triazines,
pyrazoles, imidazoles, indoles, quinolines, iso-quinolines,
benzothiophines, benzofurans, parathiazines, pyrans, chromenes,
pyrrolidines, pyrazolidines, imidazolidines, morpholines,
thiomorpholines, and the corresponding heterocyclics.
[0028] Specific compounds of Genus I are also disclosed in
accordance with the current invention. These compounds are
identified as Compounds I.1 to I.192 and their representative
structures are illustrated below.
[0029] Another compound for use in the treatment of a condition
associated with an excess IgE level and/or abnormal cell
proliferation is disclosed in accordance with the present
invention. The compound has a formula: ##STR2##
[0030] wherein R is selected from the group consisting of H,
C.sub.1-C.sub.5 alkyl, benzyl, p-fluorobenzyl and di-alkylamino
alkyl, wherein said C.sub.1-C.sub.5 alkyl is selected from the
group consisting of a straight chain, branched or cyclic alkyl;
[0031] wherein R.sub.1 and R.sub.2 are independently selected from
the group consisting of H, alkyl, substituted alkyl,
C.sub.3-C.sub.9 cycloalkyl, substituted C.sub.3-C.sub.9 cycloalkyl,
polycyclic aliphatic groups, phenyl, substituted phenyl, naphthyl,
substituted naphthyl, heteroaryl and substituted heteroaryl,
wherein said heteroaryl and said substituted heteroaryl contain 1-3
heteroatoms, wherein said heteroatom is independently selected from
the group consisting of nitrogen, oxygen and sulfur;
[0032] wherein said substituted phenyl, substituted naphthyl and
substituted heteroaryl contain 1-3 substituents, wherein said
substituent is selected from the group consisting of H, halogens,
polyhalogens, alkoxy group, substituted alkoxy, alkyl, substituted
alkyl, dialkylaminoalkyl, hydroxyalkyl, OH, OCH.sub.3, COOH, COOR'
COR', CN, CF.sub.3, OCF.sub.3, NO.sub.2, NR'R', NHCOR' and
CONR'R';
[0033] wherein R.sub.3 and R.sub.4 are independently selected from
the group consisting of H, alkyl, aryl, heteroaryl and COR';
[0034] wherein R' is selected from the group consisting of H,
alkyl, substituted alkyl, C.sub.3-C.sub.9 cycloalkyl, substituted
C.sub.3-C.sub.9 cycloalkyl, polycyclic aliphatics, phenyl,
substituted phenyl, naphthyl, substituted naphthyl, heteroaryl and
substituted heteroaryl, wherein said heteroaryl and said
substituted heteroaryl contain 1-3 heteroatoms, wherein said
heteroatom is independently selected from the group consisting of
nitrogen, oxygen and sulfur;
[0035] wherein X and Y are independently selected from the group
consisting of H, halogens, alkoxy, substituted alkoxy, alkyl,
substituted alkyl, dialkylaminoalkyl, hydroxyalkyl, OH, OCH.sub.3,
COOH, CN, CF.sub.3, OCF.sub.3, NO.sub.2, COOR'', CHO and COR'';
and
[0036] wherein R'' is a C.sub.1-C.sub.8 alkyl, wherein said
C.sub.1-C.sub.8 alkyl is selected from the group consisting of a
straight chain, branched or cyclic alkyl.
[0037] A compound of the aforementioned genus may contain a
polycyclic aliphatic group which is selected from the group
consisting of adamantyl, bicycloheptyl, camphoryl,
bicyclo[2,2,2]octanyl and norbornyl.
[0038] A compound of the aforementioned genus may contain a
heteroaryl and a substituted heteroaryl which is selected from the
group consisting of pyridines, thiazoles, isothiazoles, oxazoles,
pyrimidines, pyrazines, furans, thiophenes, isoxazoles, pyrroles,
pyridazines, 1,2,3-triazines, 1,2,4-triazines, 1,3,5-triazines,
pyrazoles, imidazoles, indoles, quinolines, iso-quinolines,
benzothiophines, benzofurans, parathiazines, pyrans, chromenes,
pyrrolidines, pyrazolidines, imidazolidines, morpholines,
thiomorpholines, and the corresponding heterocyclics.
[0039] Specific compounds of Genus II are also disclosed in
accordance with the current invention. These compounds are
identified as Compounds II.1 to II.90 and their representative
structures are illustrated below.
[0040] Another compound for use in the treatment of a condition
associated with an excess IgE level and/or abnormal cell
proliferation is disclosed in accordance with the present
invention. The compound has a formula: ##STR3##
[0041] wherein R is selected from the group consisting of H,
C.sub.1-C.sub.5 alkyl, benzyl, p-fluorobenzyl and di-alkylamino
alkyl, wherein said C.sub.1-C.sub.5 alkyl is selected from the
group consisting of a straight chain, branched or cyclic alkyl;
[0042] wherein R.sub.1 and R.sub.2 are independently selected from
the group consisting of H, alkyl, substituted alkyl,
C.sub.3-C.sub.9 cycloalkyl, substituted C.sub.3-C.sub.9 cycloalkyl,
polycyclic aliphatic groups, phenyl, substituted phenyl, naphthyl,
substituted naphthyl, heteroaryl and substituted heteroaryl,
wherein said heteroaryl and said substituted heteroaryl contain 1-3
heteroatoms, wherein said heteroatom is independently selected from
the group consisting of nitrogen, oxygen and sulfur;
[0043] wherein said substituted phenyl, substituted naphthyl and
substituted heteroaryl contain 1-3 substituents, wherein said
substituent is selected from the group consisting of H, halogens,
polyhalogens, alkoxy group, substituted alkoxy, alkyl, substituted
alkyl, dialkylaminoalkyl, hydroxyalkyl, OH, OCH.sub.3, COOH, COOR'
COR', CN, CF.sub.3, OCF.sub.3, NO.sub.2, NR'R', NHCOR' and
CONR'R';
[0044] wherein R.sub.3 and R.sub.4 are independently selected from
the group consisting of H, alkyl, aryl, heteroaryl and COR';
[0045] wherein R' is selected from the group consisting of H,
alkyl, substituted alkyl, C.sub.3-C.sub.9 cycloalkyl, substituted
C.sub.3-C.sub.9 cycloalkyl, polycyclic aliphatics, phenyl,
substituted phenyl, naphthyl, substituted naphthyl, heteroaryl and
substituted heteroaryl, wherein said heteroaryl and said
substituted heteroaryl contain 1-3 heteroatoms, wherein said
heteroatom is independently selected from the group consisting of
nitrogen, oxygen and sulfur;
[0046] wherein X and Y are independently selected from the group
consisting of H, halogens, alkoxy, substituted alkoxy, alkyl,
substituted alkyl, dialkylaminoalkyl, hydroxyalkyl, OH, OCH.sub.3,
COOH, CN, CF.sub.3, OCF.sub.3, NO.sub.2, COOR'', CHO and COR'';
and
[0047] wherein R'' is a C.sub.1-C.sub.8 alkyl, wherein said
C.sub.1-C.sub.8 alkyl is selected from the group consisting of a
straight chain, branched or cyclic alkyl.
[0048] A compound of the aforementioned genus may contain a
polycyclic aliphatic group which is selected from the group
consisting of adamantyl, bicycloheptyl, camphoryl,
bicyclo[2,2,2]octanyl and norbornyl.
[0049] A compound of the aforementioned genus may contain a
heteroaryl and a substituted heteroaryl which is selected from the
group consisting of pyridines, thiazoles, isothiazoles, oxazoles,
pyrimidines, pyrazines, furans, thiophenes, isoxazoles, pyrroles,
pyridazines, 1,2,3-triazines, 1,2,4-triazines, 1,3,5-triazines,
pyrazoles, imidazoles, indoles, quinolines, iso-quinolines,
benzothiophines, benzofurans, parathiazines, pyrans, chromenes,
pyrrolidines, pyrazolidines, imidazolidines, morpholines,
thiomorpholines, and the corresponding heterocyclics.
[0050] Specific compounds of Genus III are also disclosed in
accordance with the current invention. These compounds are
identified as Compounds III.1 to III.154 and their representative
structures are illustrated below.
[0051] For each chemical structure disclosed herein, the hydrogen
atoms on the heteroatoms have been omitted for clarity purposes.
Where open valences on heteroatoms are indicated, it is assumed
that these valences are filled by hydrogen atoms.
[0052] A method for treating a disease condition associated with
excess IgE and/or abnormal cell proliferation (i.e. cancer) in a
mammal is also disclosed. In one aspect, the method comprises the
step of administering to the mammal an IgE-suppressing amount or
anti-cell proliferation amount of a pharmaceutical formulation
comprising at least one benzimidazole compound from the
above-disclosed small molecule families.
[0053] In accordance with a variation of the method of treatment,
the small molecule IgE-suppressing compound may be administered in
conjunction with at least one additional agent, which is active in
reducing a symptom associated with an allergic reaction. In one
embodiment, the small molecule inhibitor may be mixed with at least
one additional active ingredient to form a pharmaceutical
composition. Alternatively, the small molecule inhibitor may be
co-administered at the same time or according to different
treatment regimens with the at least one additional active
agent.
[0054] The at least one additional active ingredient may be a
short-acting .beta..sub.2-adrenergic agonist selected from the
group consisting of terbutaline and albuterol; a long-acting
.beta..sub.2-adrenergic agonist selected from the group consisting
of salmeterol and formoterol; an antihistamine selected from the
group consisting of loratadine, azelastine and ketotifen; a
phosphodiesterase inhibitor, an anticholinergic agent, a
corticosteroid, an inflammatory mediator release inhibitor or a
leukotriene receptor antagonist.
[0055] In another embodiment, the benzimidazole compound may be
administered in conjunction with at least one additional active
agent. These active agents include antifungals, antivirals,
antibiotics, anti-inflammatories, and anticancer agents. Anticancer
agents include, but are not limited to, alkylating agents
(lomustine, carmustine, streptozocin, mechlorethamine, melphalan,
uracil nitrogen mustard, chlorambucil cyclophosphamide,
iphosphamide, cisplatin, carboplatin mitomycin thiotepa dacarbazine
procarbazine, hexamethyl melamine, triethylene melamine, busulfan,
pipobroman, and mitotane); antimetabolites (methotrexate,
trimetrexate pentostatin, cytarabine, ara-CMP, fludarabine
phosphate, hydroxyurea, fluorouracil, floxuridine,
chlorodeoxyadenosine, gemcitabine, thioguanine, and
6-mercaptopurine); DNA cutters (bleomycin); topoisomerase I poisons
(topotecan irinotecan and camptothecin); topoisomerase II poisons
(daunorubicin, doxorubicin, idarubicin, mitoxantrone, teniposide,
and etoposide); DNA binders (dactinomycin, and mithramycin); and
spindle poisons (vinblastine, vincristine, navelbine, paclitaxel,
and docetaxel).
[0056] In another embodiment, the benzimidazole compounds of the
current invention are administered in conjunction with one or more
other therapies. These therapies include, but are not limited to
radiation, immunotherapy, gene therapy and surgery. These
combination therapies may be administered simultaneously or
sequentially. For example, radiation may be administered along with
the administration of benzimidazole compounds, or may be
administered at any time before or after administration of
benzimidazole compounds.
[0057] A dose of about 0.01 mg to about 100 mg per kg body weight
per day of the small molecule IgE inhibitory compound is preferably
administered in divided doses daily.
[0058] A method for treating a disease condition associated with
excess IgE or abnormal cell proliferation in a mammal is also
disclosed which comprises the step of administering to the mammal
an therapeutic amount of a pharmaceutical formulation comprising at
least one compound selected from Genus I, Genus II and/or Genus
III.
[0059] The methods provided herein for treating diseases and
processes mediated by undesired, uncontrolled or abnormal cell
proliferation, such as cancer, involve administering to a mammal a
composition of the benzimidazole compounds disclosed herein to
inhibit cell proliferation. The method is particularly useful for
preventing or treating tumor formation and progresson. In one
embodiment of the invention, the compounds and methods disclosed
are especially useful in treating estrogen receptor positive and
estrogen receptor negative type breast cancers.
[0060] Other variations within the scope of the present invention
may be more fully understood with reference to the following
detailed description.
BRIEF DESCRIPTION OF THE DRAWINGS
[0061] FIG. 1 shows suppression of spleen cell proliferation
responses by Compound I.82. Spleen cell cultures were established
from naive BALB/c mice and incubated for 4 days in the presence of
stimulus and drug. Cultures were pulsed for 4 hours with
3H-thymidine and harvested.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
[0062] The present invention is directed to small molecule
inhibitors of IgE which are useful in the treatment of allergy
and/or asthma or any diseases where IgE is pathogenic. The
inhibitors may affect the synthesis, activity, release, metabolism,
degradation, clearance and/or pharmacokinetics of IgE. The
particular compounds disclosed herein were identified by their
ability to suppress IgE levels in both ex vivo and in vivo assays.
The compounds disclosed in the current invention are also useful in
the treatment of diseases associated with abnormal cellular
proliferation, including, but not limited to, tumorgenesis and
other proliferative diseases such as cancers, inflammatory
disorders and circulatory diseases. Development and optimization of
clinical treatment regimens can be monitored by those of skill in
the art by reference to the ex vivo and in vivo assays described
below.
Ex Vivo Assay
[0063] This system begins with in vivo antigen priming and measures
secondary antibody responses in vitro. The basic protocol was
documented and optimized for a range of parameters including:
antigen dose for priming and time span following priming, number of
cells cultured in vitro, antigen concentrations for eliciting
secondary IgE (and other Ig's) response in vitro, fetal bovine
serum (FBS) batch that will permit optimal IgE response in vitro,
the importance of primed CD4+ T cells and hapten-specific B cells,
and specificity of the ELISA assay for IgE (Marcelletti and Katz,
Cellular Immunology 135:471-489 (1991); incorporated herein by
reference).
[0064] The actual protocol utilized for this project was adapted
for a more high throughput analyses. BALB/cByj mice were immunized
i.p. with 10 .mu.g DNP-KLH adsorbed onto 4 mg alum and sacrificed
after 15 days. Spleens were excised and homogenized in a tissue
grinder, washed twice, and maintained in DMEM supplemented with 10%
FBS, 100 U/ml penicillin, 100 .mu.g/ml streptomycin and 0.0005%
2-mercaptoethanol. Spleen cell cultures were established (2-3
million cells/ml, 0.2 ml/well in quadruplicate, 96-well plates) in
the presence or absence of DNP-KLH (10 ng/ml). Test compounds (2
.mu.g/ml and 50 ng/ml) were added to the spleen cell cultures
containing antigen and incubated at 37.degree. C. for 8 days in an
atmosphere of 10% CO.sub.2.
[0065] Culture supernatants were collected after 8 days and Ig's
were measured by a modification of the specific isotype-selective
ELISA assay described by Marcelletti and Katz (supra). The assay
was modified to facilitate high throughput. ELISA plates were
prepared by coating with DNP-KLH or DNP-OVA overnight. After
blocking with bovine serum albumin (BSA), an aliquot of each
culture supernatant was diluted (1:4 in phosphate buffered saline
(PBS) with BSA, sodium azide and Tween 20), added to the ELISA
plates, and incubated overnight in a humidified box at 4.degree. C.
IgE levels were quantitated following successive incubations with
biotinylated-goat antimouse IgE (b-GAME), AP-streptavidin and
substrate.
[0066] Antigen-specific IgG1 was measured similarly, except that
culture supernatants were diluted 200-fold and biotinylated-goat
antimouse IgG1 (b-GAMG1) was substituted for b-GAME. IgG2a was
measured in ELISA plates that were coated with DNP-KLH following a
1:20 dilution of culture supernatants and incubation with
biotinylated-goat antimouse IgG2a (b-GAMG2a). Quantitation of each
isotype was determined by comparison to a standard curve. The level
of detectability of all antibody was about 200-400 pg/ml and there
was less than 0.001% cross-reactivity with any other Ig isotype in
the ELISA for IgE.
In Vivo Assay
[0067] Compounds found to be active in the ex vivo assay (above)
were further tested for their activity in suppressing IgE responses
in vivo. Mice receiving low-dose radiation prior to immunization
with a carrier exhibited an enhanced IgE response to challenge with
antigen 7 days later. Administration of the test compounds
immediately prior to and after antigen sensitization, measured the
ability of that drug to suppress the IgE response. The levels of
antigen specific IgE, IgG1 and IgG2a in serum were compared.
[0068] Female BALB/cByj mice were irradiated with 250 rads 7 hours
after initiation of the daily light cycle. Two hours later, the
mice were immunized i.p. with 2 .mu.g of KLH in 4 mg alum. Two to
seven consecutive days of drug injections were initiated 6 days
later on either a once or twice daily basis. Typically, i.p.
injections and oral gavages were administered as suspensions (150
.mu.l/injection) in saline with 10% ethanol and 0.25%
methylcellulose. Each treatment group was composed of 5-6 mice. On
the second day of drug administration, 2 .mu.g of DNP-KLH was
administered i.p. in 4 mg alum, immediately following the morning
injection of drug. Mice were bled 7-21 days following DNP-KLH
challenge.
[0069] Antigen-specific IgE, IgG1 and IgG2a antibodies were
measured by ELISA. Periorbital bleeds were centrifuged at 14,000
rpm for 10 min, the supernatants were diluted 5-fold in saline, and
centrifuged again. Antibody concentrations of each bleed were
determined by ELISA of four dilutions (in triplicate) and compared
to a standard curve: anti-DNP IgE (1:100 to 1:800), anti-DNP IgG2a
(1:100 to 1:800), and anti-DNP IgG1 (1:1600 to 1:12800).
Active Compounds of the Present Invention
[0070] The following series of compounds, identified under
subheadings Genus I, Genus II and Genus III, were found to be
potent inhibitors of IgE in both ex-vivo and in vivo models. These
compounds also exhibit anti-proliferative effects, and, as such,
may be used as agents to treat hyperproliferation disorders,
including cancer.
Compounds of Genus I
[0071] One family of small molecule IgE inhibitors in accordance
with the present invention include benzimidazole carboxamides,
defined by the following genus (Genus I): ##STR4##
[0072] wherein R is selected from the group consisting of H,
C.sub.1-C.sub.5 alkyl, benzyl, p-fluorobenzyl and di-alkylamino
alkyl, wherein said C.sub.1-C.sub.5 alkyl is selected from the
group consisting of a straight chain, branched or cyclic alkyl;
[0073] wherein R.sub.1 and R.sub.2 are independently selected from
the group consisting of H, alkyl, substituted alkyl,
C.sub.3-C.sub.9 cycloalkyl, substituted C.sub.3-C.sub.9 cycloalkyl,
polycyclic aliphatic groups, phenyl, substituted phenyl, naphthyl,
substituted naphthyl, heteroaryl and substituted heteroaryl,
wherein said heteroaryl and said substituted heteroaryl contain 1-3
heteroatoms, wherein said heteroatom is independently selected from
the group consisting of nitrogen, oxygen and sulfur;
[0074] wherein said substituted phenyl, substituted naphthyl and
substituted heteroaryl contain 1-3 substituents, wherein said
substituent is selected from the group consisting of H, halogens,
polyhalogens, alkoxy group, substituted alkoxy, alkyl, substituted
alkyl, dialkylaminoalkyl, hydroxyalkyl, OH, OCH.sub.3, COOH, COOR'
COR', CN, CF.sub.3, OCF.sub.3, NO.sub.2, NR'R', NHCOR' and
CONR'R';
[0075] wherein R.sub.3 and R.sub.4 are independently selected from
the group consisting of H, alkyl, aryl, heteroaryl and COR';
[0076] wherein R' is selected from the group consisting of H,
alkyl, substituted alkyl, C.sub.3-C.sub.9 cycloalkyl, substituted
C.sub.3-C.sub.9 cycloalkyl, polycyclic aliphatics, phenyl,
substituted phenyl, naphthyl, substituted naphthyl, heteroaryl and
substituted heteroaryl, wherein said heteroaryl and said
substituted heteroaryl contain 1-3 heteroatoms, wherein said
heteroatom is independently selected from the group consisting of
nitrogen, oxygen and sulfur;
[0077] wherein X and Y are independently selected from the group
consisting of H, halogens, alkoxy, substituted alkoxy, alkyl,
substituted alkyl, dialkylaminoalkyl, hydroxyalkyl, OH, OCH.sub.3,
COOH, CN, CF.sub.3, OCF.sub.3, NO.sub.2, COOR'', CHO and COR'';
and
[0078] wherein R'' is a C.sub.1-C.sub.8 alkyl, wherein said
C.sub.1-C.sub.8 alkyl is selected from the group consisting of a
straight chain, branched or cyclic alkyl.
[0079] The following specific compounds are encompassed within the
definition of the benzimidazole carboxamide genus (Genus I).
##STR5## ##STR6## ##STR7## ##STR8## ##STR9## ##STR10## ##STR11##
##STR12## ##STR13## ##STR14## ##STR15## ##STR16## ##STR17##
##STR18## ##STR19## ##STR20## ##STR21## ##STR22## ##STR23##
##STR24## ##STR25## ##STR26## ##STR27## ##STR28## ##STR29##
##STR30## ##STR31## ##STR32## ##STR33## ##STR34## ##STR35##
##STR36## ##STR37## ##STR38## ##STR39## ##STR40## ##STR41##
##STR42## ##STR43##
[0080] Compounds of Genus I may be synthesized by any conventional
reactions known in the art. Examples of syntheses include the
following reactions, designated Synthetic Scheme I: ##STR44##
Synthesis of the Compounds of Genus 1
[0081] Synthetic Scheme I shows one method that can be used to
prepare the compounds of Genus I. One skilled in the art will
appreciate that a number of different synthetic reaction schemes
may be used to synthesize the compounds of Genus I. Further, one
skilled in the art will understand that a number of different
solvents, coupling agents and reaction conditions can be used in
the syntheses reactions to yield comparable results.
[0082] In step one, compound A or salt thereof is prepared from a
cyclocondensation reaction of 3,4-diaminobenzoic acid or salt
thereof and 4-nitrobenzaldehyde. The cyclocondensation reaction may
be prepared in a solvent with heat. An example of the solvent is
nitrobenzene. The temperature of the cyclocondensation reaction is
from about 100.degree. C. to about 200.degree. C., preferably about
155.degree. C. to about 160.degree. C. The same compound can be
prepared by a two-step process, as follows: reacting the diamine
with p-nitrobenzoyl chloride in the presence of a base such as
tri-ethylamine, DIEP, DMAP, or pyridine, or other such base; and,
cyclizing the resulting amide (by elimination of a mole of water)
with PPA, H.sub.2SO.sub.4 or other dehydrating agents at an ambient
temperature to generate the benzimidazole ring.
[0083] In step 2, compound A or salt thereof is treated with
ammonia or amine to obtain compound B or salt thereof. The amide
formation reaction may occur in the presence of a coupling agent,
or by converting it to an acid chloride and then reacting it with
an amine (such as aromatic amines, aliphatic amines, heterocyclic
amines and the like) in a solvent in presence of another base to
absorb the acid produced. This can be carried out with or without
heating. An example of the coupling agent is
1,1'-carbonyldiimidazole (CDI), EDC, and other similar coupling
agents. An example of the solvent is N,N-dimethylformamide (DMF),
THF, pyridine, triethylamine or mixed solvent system such as DMF
and THF, and the like.
[0084] In step 3, compound B or salt thereof can undergo reduction
to yield compound C or salt thereof. The reduction may be
accomplished by catalytic hydrogenation in the presence of a
catalyst in a solvent system. The catalysts are Pd, Ni, Pt, and the
like. An example of the agent used for catalytic hydrogenation is
hydrogen in the presence of 5% Pd--C. The reduction can occur in a
hydroxylic solvent, such as methanol or ethanol, or a mixed solvent
system such as DMF-MeOH, or in acetic acid, or in the presence of
some acid in a hydroxylic solvent, and the like.
[0085] In step 4, compound C or salt thereof is alkylated or
acylated at the amine by treatment with the appropriate reagents.
In Synthetic Scheme I, compound C is shown to react with R.sub.3--X
and R.sub.4--X to alkylate or acylate the amine. It is understood
that R.sub.3 and R.sub.4 are groups that alkylate the amine and X
is a leaving group. The amino group can be acylated with reagents,
such as acyl halides, anhydrides, carboxylic acid, carboxylic
esters, or amides. The amino group can be alkylated with alkyl
halides in the presence of a base, preferably for the production of
a tertiary or hindered amine and the like. An alternative method to
alkylating the amino group is to reductive aminate. In a reductive
amination, the amine condenses with an aldehyde or ketone to give
an imine. Subsequently, the imine is reduced to yield an alkylated
amine. In a reductive amination, the R.sub.3 and R.sub.4 groups may
not have leaving groups upon reaction with the amine. Still another
alternative method is reaction of the amine with a diazo compound.
The acidity of amines is not great enough for the reaction to
proceed without a catalyst, but BF.sub.3, which converts the amine
to a complex, enables the reaction to take place. Cuprous cyanide
can also be used as a catalyst.
[0086] Compound D is representative of the compounds in Genus
I.
[0087] One skilled in the art will appreciate variations in the
sequence and further, will recognize variations in the appropriate
reaction conditions from the analogous reactions shown or otherwise
known which may be appropriately used in the processes above to
make compounds of compounds A-D.
[0088] In the processes described herein for the preparation of
compounds A-D of this invention, the requirements for protective
groups are generally well recognized by one skilled in the art of
organic chemistry, and accordingly the use of appropriate
protecting groups is necessarily implied by the processes of the
schemes herein, although such groups may not be expressly
illustrated. Introduction and removal of such suitable protecting
groups are well known in the art of organic chemistry; see for
example, T. W. Greene, "Protective Groups in Organic Synthesis",
Wiley (New York), 1981.
[0089] The products of the reactions described herein are isolated
by conventional means such as extraction, distillation,
chromatography, and the like.
[0090] Starting materials not described herein are available
commercially, are known, or can be prepared by methods known in the
art.
[0091] The salts of compounds A-D described above are prepared by
reacting the appropriate base or acid with a stoichiometric
equivalent of the compounds of compounds A-D.
Compounds of Genus II
[0092] Another family of small molecule IgE inhibitors in
accordance with the present invention include
benzimidazole-2-benzamides, defined by the following genus (Genus
II): ##STR45##
[0093] wherein R is selected from the group consisting of H,
C.sub.1-C.sub.5 alkyl, benzyl, p-fluorobenzyl and di-alkylamino
alkyl, wherein said C.sub.1-C.sub.5 alkyl is selected from the
group consisting of a straight chain, branched or cyclic alkyl;
[0094] wherein R.sub.1 and R.sub.2 are independently selected from
the group consisting of H, alkyl, substituted alkyl,
C.sub.3-C.sub.9 cycloalkyl, substituted C.sub.3-C.sub.9 cycloalkyl,
polycyclic aliphatic groups, phenyl, substituted phenyl, naphthyl,
substituted naphthyl, heteroaryl and substituted heteroaryl,
wherein said heteroaryl and said substituted heteroaryl contain 1-3
heteroatoms, wherein said heteroatom is independently selected from
the group consisting of nitrogen, oxygen and sulfur;
[0095] wherein said substituted phenyl, substituted naphthyl and
substituted heteroaryl contain 1-3 substituents, wherein said
substituent is selected from the group consisting of H, halogens,
polyhalogens, alkoxy group, substituted alkoxy, alkyl, substituted
alkyl, dialkylaminoalkyl, hydroxyalkyl, OH, OCH.sub.3, COOH, COOR'
COR', CN, CF.sub.3, OCF.sub.3, NO.sub.2, NR'R', NHCOR' and
CONR'R';
[0096] wherein R.sub.3 and R.sub.4 are independently selected from
the group consisting of H, alkyl, aryl, heteroaryl and COR';
[0097] wherein R' is selected from the group consisting of H,
alkyl, substituted alkyl, C.sub.3-C.sub.9 cycloalkyl, substituted
C.sub.3-C.sub.9 cycloalkyl, polycyclic aliphatics, phenyl,
substituted phenyl, naphthyl, substituted naphthyl, heteroaryl and
substituted heteroaryl, wherein said heteroaryl and said
substituted heteroaryl contain 1-3 heteroatoms, wherein said
heteroatom is independently selected from the group consisting of
nitrogen, oxygen and sulfur;
[0098] wherein X and Y are independently selected from the group
consisting of H, halogens, alkoxy, substituted alkoxy, alkyl,
substituted alkyl, dialkylaminoalkyl, hydroxyalkyl, OH, OCH.sub.3,
COOH, CN, CF.sub.3, OCF.sub.3, NO.sub.2, COOR'', CHO and COR'';
and
[0099] wherein R'' is a C.sub.1-C.sub.8 alkyl, wherein said
C.sub.1-C.sub.8 alkyl is selected from the group consisting of a
straight chain, branched or cyclic alkyl.
[0100] The following specific compounds are encompassed within the
definition of Genus II: ##STR46## ##STR47## ##STR48## ##STR49##
##STR50## ##STR51## ##STR52## ##STR53## ##STR54## ##STR55##
##STR56## ##STR57## ##STR58##
[0101] Compounds of Genus II may be synthesized by any conventional
reactions known in the art. Examples of syntheses include the
following reactions, designated Synthetic Scheme II: ##STR59##
Synthesis of the Compounds of Genus II
[0102] Synthetic Scheme II shows one method that can be used to
prepare the compounds of Genus II. One skilled in the art will
appreciate that a number of different syntheses reactions may be
used to synthesize the compounds of Genus II. Further, one skilled
in the art will understand that a number of different solvents,
coupling agents and reaction conditions can be used in the
syntheses reactions to yield comparable results.
[0103] In step one, compound E or salt thereof is prepared from a
cyclocondensation reaction of 4-nitro-1,2-phenylenediamine or salt
thereof and an alkyl (such as methyl 4-formylbenzoate) The
cyclocondensation reaction may be carried out in a solvent with
heat. Examples of solvents include nitrobenzene or other solvents
with an oxidizing agent to convert imidazolines to imidazoles. The
same compound can be prepared by a two-step process, as follows:
reacting the diamine with p-carboalkoxy benzoyl chloride in
presence of a base such as tri-ethylamine, DIEP, DMAP or pyridine
or such other base; and, cyclizing the resulting amide (by
elimination of a mole of water) with PPA, H.sub.2SO.sub.4 or other
dehydrating agents at an ambient temperature to generate the
benzimidazole ring.
[0104] In step 2, compound E or salt thereof is treated with a base
to hydrolyze the ester to the acid with a base such as a lithium
hydroxide solution or an aqueous sodium hydroxide, and the like,
thereby obtaining compound F or salt thereof. The deprotection
reaction may occur in the presence of solvents such as water or
alcohol such as methanol or ethanol, THF, and the like.
[0105] In step 3, compound F or salt thereof is treated with
ammonia or an amine to obtain compound G or salt thereof. The amide
formation reaction may occur in the presence of a coupling agent or
by converting it to an acid chloride and then reacting it with an
amine, such as aromatic amines, aliphatic amines, heterocyclic
amines, and the like, in a solvent in the presence of another base
to absorb the acid produced. This reaction can be carried out with
or without heating. Examples of the coupling agent include
1,1'-carbonyldiimidazole (CDI), EDC and other similar coupling
agents. Examples of solvents include N,N-dimethylformamide (DMF),
THF, pyridine, triethylamine, or mixed solvent systems such as DMF
and THF, and the like.
[0106] In step 4, compound G or salt thereof can undergo reduction
to yield compound H or salt thereof. The reduction may be
accomplished by catalytic hydrogenation, preferably in the presence
of a catalyst in a solvent system. The catalysts are Pd, Ni, Pt,
and the like. An example of the agent used for catalytic
hydrogenation is hydrogen in the presence of 5% Pd--C. The
reduction can occur in a hydroxylic solvent, such as methanol,
ethanol, in a mixed solvent system, such as DMF-MeOH, in acetic
acid, or in the presence of some acid in a hydroxylic solvent, and
the like.
[0107] In step 5, compound H or salt thereof is treated with an
acyl halide to obtain compound I or salt thereof. The acylation
reaction may occur in the presence of a base, such as
tri-ethylamine, DIEP, DMAP or pyridine, and the like, in a solvent
such as THF, DMF or Et3N, pyridine, and the like. The reaction may
occur with or without heating. One specific example of the base is
pyridine. One specific example of the solvent is tetrahydrofuran
(THF).
[0108] If necessary, in step 6, compound I or salt thereof is
treated with an alkyl halide in the presence of a base to perform
N-alkylation of the amide. Secondary amides can be alkylated by the
use of a base, such a sodium hydride, for proton abstraction,
followed by reaction with an alkyl halide. This reaction can be run
in a convention solvent system or under phase transfer conditions.
Amides can also be alkylated with diazo compounds. In another
method, N-alkyl amides can also be prepared starting from alcohols
by treatment of the latter with equimolar amounts of the amide,
Ph.sub.3P, and diethyl azodicarboxylate (EtOOCN.dbd.NCOOEt) at room
temperature.
[0109] Compound I(b) is representative of the compounds in Genus
II.
[0110] One skilled in the art will appreciate variations in the
sequence and further, will recognize variations in the appropriate
reaction conditions from the analogous reactions shown or otherwise
known which may be appropriately used in the processes above to
make compounds of compounds E-I(b).
[0111] In the processes described herein for the preparation of
compounds E-I(b) of this invention, the requirements for protective
groups are generally well-recognized by one skilled in the art of
organic chemistry, and accordingly the use of appropriate
protecting groups is necessarily implied by the processes of the
schemes herein, although such groups may not be expressly
illustrated. Introduction and removal of such suitable protecting
groups are well known in the art of organic chemistry; see for
example, T. W. Greene, "Protective Groups in Organic Synthesis",
Wiley (New York), 1981.
[0112] The products of the reactions described herein are isolated
by conventional means such as extraction, distillation,
chromatography, and the like.
[0113] Starting materials not described herein are available
commercially, are known, or can be prepared by methods known in the
art.
[0114] The salts of compounds E-I(b) described above are prepared
by reacting the appropriate base or acid with a stoichiometric
equivalent of the compounds of compounds E-I(b).
Compounds of Genus III
[0115] Another family of small molecule IgE inhibitors in
accordance with the present invention include
benzimidazole-bis-carboxamides, defined by the following genus
(Genus III): ##STR60##
[0116] wherein R is selected from the group consisting of H,
C.sub.1-C.sub.5 alkyl, benzyl, p-fluorobenzyl and di-alkylamino
alkyl, wherein said C.sub.1-C.sub.5 alkyl is selected from the
group consisting of a straight chain, branched or cyclic alkyl;
[0117] wherein R.sub.1 and R.sub.2 are independently selected from
the group consisting of H, alkyl, substituted alkyl,
C.sub.3-C.sub.9 cycloalkyl, substituted C.sub.3-C.sub.9 cycloalkyl,
polycyclic aliphatic groups, phenyl, substituted phenyl, naphthyl,
substituted naphthyl, heteroaryl and substituted heteroaryl,
wherein said heteroaryl and said substituted heteroaryl contain 1-3
heteroatoms, wherein said heteroatom is independently selected from
the group consisting of nitrogen, oxygen and sulfur;
[0118] wherein said substituted phenyl, substituted naphthyl and
substituted heteroaryl contain 1-3 substituents, wherein said
substituent is selected from the group consisting of H, halogens,
polyhalogens, alkoxy group, substituted alkoxy, alkyl, substituted
alkyl, dialkylaminoalkyl, hydroxyalkyl, OH, OCH.sub.3, COOH, COOR'
COR', CN, CF.sub.3, OCF.sub.3, NO.sub.2, NR'R', NHCOR' and
CONR'R';
[0119] wherein R.sub.3 and R.sub.4 are independently selected from
the group consisting of H, alkyl aryl, heteroaryl and COR';
[0120] wherein R' is selected from the group consisting of H,
alkyl, substituted alkyl, C.sub.3-C.sub.9 cycloalkyl, substituted
C.sub.3-C.sub.9 cycloalkyl, polycyclic aliphatics, phenyl,
substituted phenyl, naphthyl, substituted naphthyl, heteroaryl and
substituted heteroaryl, wherein said heteroaryl and said
substituted heteroaryl contain 1-3 heteroatoms, wherein said
heteroatom is independently selected from the group consisting of
nitrogen, oxygen and sulfur;
[0121] wherein X and Y are independently selected from the group
consisting of H, halogens, alkoxy, substituted alkoxy, alkyl,
substituted alkyl, dialkylaminoalkyl, hydroxyalkyl, OH, OCH.sub.3,
COOH, CN, CF.sub.3, OCF.sub.3, NO.sub.2, COOR'', CHO and COR'';
and
[0122] wherein R'' is a C.sub.1-C.sub.8 alkyl, wherein said
C.sub.1-C.sub.8 alkyl is selected from the group consisting of a
straight chain, branched or cyclic alkyl.
[0123] The following specific compounds are encompassed within the
definition of Genus III: ##STR61## ##STR62## ##STR63## ##STR64##
##STR65## ##STR66## ##STR67## ##STR68## ##STR69## ##STR70##
##STR71## ##STR72## ##STR73## ##STR74## ##STR75## ##STR76##
##STR77## ##STR78## ##STR79## ##STR80##
[0124] Compounds of Genus III may be synthesized by any
conventional reactions known in the art. Examples of syntheses
include the following reactions, designated Synthetic Scheme III:
##STR81## Synthesis of the Compounds of Genus III
[0125] Synthetic Scheme 3 shows one method that can be used to
prepare the compounds of Genus III. One skilled in the art will
appreciate that a number of different syntheses reactions may be
used to synthesize the compounds of Genus III. Further, one skilled
in the art will understand that a number of different solvents,
coupling agents and reaction conditions can be used in the
syntheses reactions to yield comparable results.
[0126] In step 1, compound J is prepared from a cyclocondensation
reaction of 3,4-diaminobenzoic acid or salt thereof and
4-alkoxycarbonyl benzaldehyde. The cyclocondensation reaction may
be carried out in a solvent with heat. Examples of solvents are
nitrobenzene and other solvents with an oxidizing agent to convert
imidazolines to imidazoles. The same compound can be prepared by
two-step process, as follows: reacting the diamine with
p-carboalkoxy benzoyl chloride in the presence of a base such as
tri-ethylamine, DIEP, DMAP or pyridine or other such base; and,
cyclizing the resulting amide (by elimination of a mole of water)
with PPA, H.sub.2SO.sub.4 or other dehydrating agents at an ambient
temperature to generate the benzimidazole ring.
[0127] In step 2, compound J or salt thereof is treated with an
inorganic acid halide such as thionyl chloride, POCl.sub.3,
PCl.sub.5, and the like, or an organic acid chloride such as oxalyl
chloride, and the like, or a mixed anhydride, such as t-butyl
chloroformate, and the like, to obtain compound K, or similar
reactive intermediates, and salt thereof. The reaction may occur in
the presence of an inorganic acid halide agent or organic acid
chlorides or mixed anhydrides, and the like in a solvent. One
specific example of the inorganic acid halide agent is thionyl
chloride. One example of the solvent is DMF.
[0128] In step 3, compound K or salt thereof is treated with
ammonia or an amine to obtain compound L or salt thereof. The amide
formation reaction may occur in the presence of a coupling agent,
or by converting it to an acid chloride or mixed anhydride and then
reacting it with an amine, such as aromatic amines, aliphatic
amines, heterocyclic amines, and the like, in a solvent in the
presence of another base to absorb the acid produced. This can be
carried out with or without heating. Examples of the coupling
agents are 1,1'-carbonyldiimidazole (CDI), EDC, and other similar
coupling agents. The amide formation reaction may occur in the
presence of a base in a solvent. Examples of the solvent include
N,N-dimethylformamide (DMF), THF, pyridine, triethylamine or mixed
solvent system such as DMF and THF, and the like.
[0129] In step 4, compound L or salt thereof is treated with a base
to hydrolyze the ester to the acid, with a base such as a lithium
hydroxide solution or an aqueous sodium hydroxide, and the like,
thereby obtaining compound M or salt thereof. The deprotection
reaction may occur in the presence of solvents such as water or
alcohol, and the like, including methanol, ethanol, THF, and the
like.
[0130] In step 5, compound M or salt thereof is treated with
ammonia or an amine to obtain compound O or salt thereof. The amide
formation reaction may occur in the presence of a coupling agent or
by converting it to an acid chloride or mixed anhydride and then
reacting with an amine, including aromatic amines, aliphatic
amines, heterocyclic amines, and the like, in a solvent in the
presence of another base to absorb the acid produced. This can be
carried out with or without heating. An example of the coupling
agent is 1,1'-carbonyldiimidazole (CDI), EDC and other similar
coupling agents. The amide formation reaction may occur in the
presence of a base in a solvent. An example of the solvent is
N,N-dimethylformamide (DMF), THF, pyridine, triethylamine, and the
like, or a mixed solvent system such as DMF and THF, and the
like.
[0131] Alternatively, compound M or salt thereof is treated with an
inorganic acid halide to obtain compound N or salt thereof. The
reaction may occur in the presence of an inorganic acid halide
agent in a solvent. An example of the inorganic acid halide agent
is thionyl chloride. An example of the solvent is DMF.
[0132] Then, compound N or salt thereof is treated with ammonia or
an amine to obtain compound O or salt thereof. The amide formation
reaction may occur in the presence of a base in a solvent.
[0133] Compound O is representative of the compounds in Genus
III.
[0134] One skilled in the art will appreciate variations in the
sequence and further, will recognize variations in the appropriate
reaction conditions from the analogous reactions shown or otherwise
known which may be appropriately used in the processes above to
make compounds of compounds J-O.
[0135] In the processes described herein for the preparation of
compounds J-O of this invention, the requirements for protective
groups are generally well recognized by one skilled in the art of
organic chemistry, and accordingly the use of appropriate
protecting groups is necessarily implied by the processes of the
schemes herein, although such groups may not be expressly
illustrated. Introduction and removal of such suitable protecting
groups are well known in the art of organic chemistry; see for
example, T. W. Greene, "Protective Groups in Organic Synthesis",
Wiley (New York), 1981.
[0136] The products of the reactions described herein are isolated
by conventional means such as extraction, distillation,
chromatography, and the like.
[0137] Starting materials not described herein are available
commercially, are known, or can be prepared by methods known in the
art.
[0138] The salts of compounds J-O described above are prepared by
reacting the appropriate base or acid with a stoichiometric
equivalent of the compounds of compounds J-O.
EXAMPLE 1
Preparation of Compounds of Genus I
A. Preparation of Benzimidazole Carboxamides
Preparation of 2-[4-Nitrophenyl]benzimidazole-5-carboxylic acid
[0139] A mixture of 3,4-diamino benzoic acid (300 g; 1.97 mol) and
p-nitro benzaldehyde (298 g; 1.97 mol) in nitrobenzene (15 L) were
heated around 155.degree. C.-160.degree. C. overnight. The reaction
mixture was cooled to room temperature and the precipitated solid
was filtered, washed with ether several time to remove all
nitrobenzene. The product was treated with charcoal in hot DMF (2
L), filtered and then stirred at RT and diluted with ether (6 L) to
give 393 g of solid. The crude solid was again treated with
charcoal in hot DMF (1 L), filtered and then diluted with methanol
(5 L) and cooled around 0.degree. C. The product was then
crystallized again from DMF and ether to give 225 g of the pure
product. This was used in the next step.
Preparation of
2-[4-Nitrophenyl]benzimidazole-5-(N-cyclohexyl)carboxyl amide
[0140] The carboxylic acid was then converted to the cyclohexyl
amide as follows. A mixture of the acid (1.0 g; 3.53 mmol) and CDI
(0.6 g, 4.24 mmol) in DMF (20 mL) was stirred at RT for 3 h and
then cooled to 0.degree. C. and treated with cyclohexyl amine (0.36
g, 0.42 mL; 3.65 mmol) and stirred for 1 h and then filtered. The
crude product was recrystallized from DMF and ether to yield 0.68 g
of the desired product. This was used in the next step without any
further purification. The product showed a single spot on TLC and
different from the starting material.
Preparation of
2-[4-Amino-phenyl]benzimidazole-5-(N-cyclohexyl)carboxyl amide
[0141] A mixture of the above carboxyl amide (0.5 g; 1.37 mmol), 5%
Pd--C (0.35 g) and methanol was stirred in an atmosphere of
hydrogen gas until the required amount of hydrogen was taken up.
The catalyst was filtered off and the filtrate was concentrated to
give a solid (430 g). The product showed a TLC single spot,
different from the starting material.
Preparation of 2-[4-((5-methyl
isoxazolyl)-3-carbamido)phenyl]benzimidazole-5-(N-cyclohexyl)carboxyl
amide
[0142] A mixture of 5-methyl isoxazole-3-carboxylic acid (0.23 g;
1.80 mmol), oxalyl chloride (0.46 g; 3.58 mmol) and a drop of DMF
in CH.sub.2Cl.sub.2 (10 mL) was heated to reflux for an hour. The
reaction mixture was concentrated to dryness and the crude acid
chloride was used as is in the next reaction. A mixture of the
amine above (0.5 g; 1.50 mmol), the crude acid chloride, THF (50
mL) and pyridine (0.54 g) was refluxed overnight. The reaction
mixture was poured into water (600 mL). The crude product was
filtered, washed with water and hexane and dried. The yield was 380
mg, with a melting point>310.degree. C. The product showed a
single spot on TLC.
B. Preparation of
2-[4-(N-(1-adamantyl-carboxamido)phenyl]benzimidazole-5-(N-2-pyridyl)carb-
oxyl amide
Preparation of
2-[4-Nitrophenyl]benzimidazole-5-(N-2-pyridyl)carboxyl amide
[0143] A mixture of 2-[4-Nitrophenyl]benzimidazole-5-carboxylic
acid (20.0 g; 0.071 mol) and CDI (17.2 g; 0.11 mol) in DMF was
stirred at RT for three hours and then cooled to 0.degree. C. and
then added 2-amino pyridine (7.3 g; 0.078 mol) and continued to
stir at RT overnight. HPLC showed incomplete reaction. Additional
CDI (17.2 g) and 2-aminopyridine (7.3 g) were added and then heated
to make a clear solution and stirred an additional 24 hours. TLC
analysis showed the reaction to be incomplete, so additional amount
of 2-aminopyridine (7.3 g) was added along with DMAP (13.4 g; 0.11
mol) and stirred overnight. TLC showed the reaction was complete,
the reaction mixture was poured on into water (3.0 L), stirred for
an hour, filtered, washed with water and ether (3.times.100 mL) and
dried. The yield was 17 g (67%). This was used in the next step
without any other purification. TLC showed one spot
(CH.sub.2Cl.sub.2--CH.sub.3OH: 9:1).
Preparation of
2-[4-Amino-phenyl]benzimidazole-5-(N-2-pyridyl)carboxyl amide
[0144] A mixture of
2-[4-Nitrophenyl]benzimidazole-5-(N-2-pyridyl)carboxyl amide (17 g;
0.47 mol) and 5% Pd--C 93.0 g) in methanol; (1.0 L) and DMF (200
mL) was stirred under hydrogen until the reaction is complete. The
catalyst was filtered off and concentrated and then poured into
water (5.0 L), filtered, washed with water and ether (3.times.100
mL) and oven dried under vacuum at 80.degree. C. The yield was 10
g, with a melting point of 260.degree. C.-265.degree. C. TLC showed
a single spot with CH.sub.2Cl.sub.2--CH.sub.3OH (9:1) as
eluents.
2-[4-(N-(1-adamantyl-carboxamido)phenyl/benzimidazole-5-(N-2-pyridyl)carbo-
xyl amide
[0145] A mixture of
2-[4-Amino-phenyl]benzimidazole-5-(N-2-pyridyl)carboxy]amide (2.6
g; 0.7.89 mmol) and pyridine (2.9 mL) in THF (250 mL) was heated to
make a clear solution. The reaction mixture was then treated with
1-adamantylcarbonyl chloride (1.88 g; 9.47 mmol) in THF (10 mL) and
the mixture was heated to reflux for 24 hours. The mixture was
poured into water (1.5 L) and stirred for one hour, filtered,
washed with water (3.times.50 mL) and ether (3.times.50 mL) and
dried. It was treated with charcoal and re-crystallized from THF
and methanol. The filtrate was diluted with ether (150 mL) and
cooled to -70.degree. C. for 4 hours when the product crystallized
out. It was filtered, washed with ether and dried. The yield was
2.9 g, with a melting point of 333.degree. C.-336.degree. C. TLC
showed one spot with CH.sub.2Cl.sub.2--CH.sub.3OH (9:1) as
eluent.
EXAMPLE 2
Preparation of Compounds of Genus II
A. Preparation of
2-(4-N-(2-methyl-cyclohexyl)benzamido)-5-(benzamido)-benzimidazole
Preparation of 2-(4-carbomethoxy-phenyl)-5-nitro-benzimidazole
[0146] A mixture of 4-nitrophenylene-1,2-diamine (634 g) and
methyl-4-formyl benzoate (680 g) was heated in nitrobenzene (17 L)
at 150-155.degree. C. for 24 hours, cooled to RT and the product
filtered, washed with ether (3.times.1.0 L) and dried to give the
desired product. Yield 800 g. TLC one spot:
(9:1)-CH.sub.2Cl.sub.2--CH.sub.3OH.
Preparation of 2-(4-carboxy-phenyl)-5-nitro-benzimidazole
[0147] A mixture of the above ester (800 g), THE (2.7 L) and water
(2.6 L) was treated with LiOH (339 g) and stirred at RT. The
progress of the reaction was followed by TLC until the hydrolysis
was complete. The reaction mixture was diluted with hot water (2.0
L), charcoal and then filtered. The filtrate was diluted with 2.0
kg of ice and water (1.0 L) and acidified with conc. HCl. The
product was filtered, washed with water and then recrystallized
from hot DMF (7.0 L) (with charcoal treatment) and filtered. The
filtrate was diluted with ether (7.0 L) and chilled to 4.0.degree.
C. The product was filtered, washed with ether and dried. Yield 537
g; m.p.>35.degree. C. TLC one spot:
(9:1)-CH.sub.2Cl.sub.2--CH.sub.3OH.
Preparation of
2-(4-N-(2-methyl-cyclohexyl)benzamido)-5-nitro-benzimidazole
[0148] A mixture of the above acid (20.0 g) in DMF (400 mL) was
treated with CDI (13.7 g) and the mixture was stirred at RT for 2.0
hours and then treated with 2-methyl-cyclohexyl amine (11.2 g). The
reaction mixture was heated to reflux for 16 hours. It was poured
into ice-water (3.0 L) and stirred at RT for 16 hours. The crude
product was filtered, washed with water (3.times.100 mL) and ether
and dried. Yield 19 g; TLC one spot:
(9:1)-CH.sub.2Cl.sub.2--CH.sub.3OH.
Preparation of 2-(4-N-(2-methyl-cyclohexyl)benzamido)-5-amino
benzimidazole
[0149] The above nitro amide (19.0 g) was hydrogenated in presence
of 5% Pd--C (4.0 g) in MeOH (600 mL). The catalyst was filtered off
and the filtrate was concentrated under vacuum and the residue was
treated with ether (200 mL) and filtered. The residue was then
recrystallized from THF, MeOH and hexane. The product was filtered,
washed with hexane and oven dried. Yield 10.5 g; TLC one spot:
(9:1)-CH.sub.2Cl.sub.2--CH.sub.3OH.
Preparation of
2-(4-N-(2-methyl-cyclohexyl)benzamido)-5-(benzamido)-benzimidazole
[0150] A mixture of the above amine (0.5 g) in THF (50 mL) and
pyridine (0.53 mL) was heated to a clear solution and the solution
was treated drop wise with benzoyl chloride (0.24 g) in 10 mL THF.
The reaction mixture was heated to reflux for 24 hours, cooled and
then poured into water (600 mL). The product was filtered, washed
with water, ether and dried. The crude product was treated with
charcoal in hot THF-methanol and filtered. The filtrate was diluted
with ether and chilled. The product was filtered, washed with ether
and dried. Yield 338 mg; m.p. 285-289.degree. C.; TLC one spot:
(9:1)-CH.sub.2Cl.sub.2--CH.sub.3OH.
EXAMPLE 3
Preparation of Compounds of Genus III
A. Preparation of
2-(4-Cyclohexylcarbamoyl-phenyl)-3H-benzoimidazole-5-carboxylic
acid cyclohexyamide
Preparation of
2-(4-methoxycarbonyl-phenyl)-3H-benzoimidazole-5-carboxylic
acid
[0151] A mixture of 3,4-diaminobenzoic acid (300 g) and
methyl-4-formyl benzoate (324 g) in nitrobenzene (8.0 L) was heated
at 150-155.degree. C. for 24 hours and then cooled to
<10.degree. C. when the product crystallized out. It was
filtered and then washed with ether (3.times.200 mL) and vacuum
dried. Yield 320 g, m.p. 308-309.degree. C. This was used in the
next step without any additional purification.
Preparation of 2-(4-carboxy-phenyl)-3H-benzoimidazole-5-carboxylic
acid
[0152] A mixture of
2-(4-methoxycarbonyl-phenyl)-3H-benzoimidazole-5-carboxylic acid
(4.1 g) in THF (15 mL) and water (18 mL) and LiOH (1.74 g) was
stirred for 16 hours at room temperature and then mixed with hot
water (100 mL) and charcoal. The mixture was filtered and the
filtrate was diluted with ice and water (100 mL) and acidified with
conc. HCl. The crude diacid was filtered, washed with water and
ether and then recrystallized from THF and MeOH. Yield 3.3 g; TLC
single spot [CH.sub.2Cl.sub.2--CH.sub.3OH (9:1)].
Preparation of
2-(4-Cyclohexylcarbamoyl-phenyl)-3H-benzoimidazole-5-carboxylic
acid cyclohexyamide
[0153] A mixture of
2-(4-carboxy-phenyl)-3H-benzoimidazole-5-carboxylic acid (0.50 g)
in DMF (50 mL) and N-methylmorpholine (0.72 g) was chilled to
-10-20.degree. C. and then added isobutyl chloroformate (0.60 g)
dropwise maintaining the temperature. After 10 min, cyclohexylamine
(0.53 g) in DMF (10 mL) was added dropwise. The mixture was then
slowly allowed to come to room temperature and stirred for 48
hours. The reaction was followed by TLC for completion. The mixture
was then poured in water (600 mL), filtered, washed with water and
ether and recrystallized from THF and MeOH. A second
recrystallization was done using charcoal to give pure product.
Yield 270 mg, m.p. 334-337.degree. C.
B. Preparation of
2-(4-Carbomethoxy-phenyl)-5-(N-cyclohexyl-carboxamido)-benzimidazole
[0154] A mixture of
2-(4-methoxycarbonyl-phenyl)-3H-benzoimidazole-5-carboxylic acid
(5.0 g) in DMF (250 mL) and CDI (7.1 g) was stirred at RT for 3.0
hours and then treated with cyclohexyl amine (2.0 g) and refluxed
for 96 hours. The reaction mixture was cooled and then poured into
water (2.0 L) and stirred at RT for 16 hours. The product was
filtered, washed with water and ether and then recrystallized from
THF, methanol and ether. Yield 0.4 g. TLC one spot
(9:1)-CH.sub.2Cl.sub.2--CH.sub.3OH.
[0155] This ester was hydrolyzed to give the acid which was used to
couple with various amines to give the unsymmetrical bis
amides.
C. Preparation of
2-(4-(N-cyclohexyl)-benzamido)-benzimidazole-5-carboxylic acid and
unsymmetrical bis-amides
[0156] A mixture of 3,4-diaminobenzoic acid (1.71 g) and
4-(N-cyclohexyl)-benzamido)-benzaldehyde (2.6 g) in 200 mL
nitrobenzene was heated at 150 155.degree. C. for 16 hours. It was
cooled, filtered, washed with ether and dried. Yield 1.9 g; TLC one
spot (9:1)-CH.sub.2Cl.sub.2--CH.sub.3OH.
[0157] The acid was then coupled with various amines with CDI in
DMF and/or THF to give the unsymmetrical bis amides.
D. Preparation of
2-(4-carboxy-phenyl)-5-(N-cyclohexyl-carboxamido)-benzimidazole
[0158] A mixture of 5.2 g of
2-(4-carbomethoxy-phenyl)-5-(N-cyclohexyl-carboxamido)-benzimidazole
in THF (50 mL) and water (40 mL) was added LiOH (1.73 g). The
mixture was stirred at RT for 2 hours and then mixed with charcoal
and stirred with slight heating and then filtered. The filtrate was
chilled in ice and then acidified with conc. HCl to pH 1.0. The
acid was filtered, washed with water and ether and dried. Yield 4.7
g, HPLC 95%, m.p. 311-314.degree. C. This was coupled with various
amines to give unsymmetrical bis amides using CDI or isobutyl
chloroformate as coupling agent. One such example is as follows: A
mixture of the acid (0.5 g) in THF (50 mL) and N-methyl morpholine
(0.64 g) was cooled to -10-20.degree. C. and then drop wise treated
with isobutyl chloroformate (0.3 g). The reaction mixture was
stirred for 10 min and then 1-adamantane amine was added to the
mixture and the reaction mixture was stirred for 15 hours. The
reaction mixture was poured into water and ice and then filtered,
washed with water, ether and then recrystallized from THF/MeOH to
give the desired product. Yield 320 mg, m.p.>355.degree. C.
EXAMPLE 4
Suppression of IgE Response
[0159] The inhibitory activity of the small molecules of the
present invention were assayed using both the ex vivo and in vivo
assays as described above. All of the compounds presented above
were active in suppressing the IgE response. In the ex vivo assay,
compounds in Genuses I-III produced 50% inhibition at
concentrations ranging from 1 pM to 100 .mu.M. In the in vivo
assay, the compounds were effective at concentrations ranging from
less than about 0.01 mg/kg/day to about 100 mg/kg/day, when
administered in divided doses (e.g., two to four times daily) for
at least two to seven consecutive days. Thus, the small molecule
inhibitors of the present invention are disclosed as being useful
in lowering the antigen-induced increase in IgE concentration, and
consequently, in the treatment of IgE-dependent processes such as
allergies in general and allergic asthma in particular.
EXAMPLE 5
Effects on Cellular Proliferation
[0160] A variety of experiments were performed in an effort to
determine the effect of the benzimidazole compounds on cellular
proliferation. These experiments ultimately measured
.sup.3H-thymidine incorporation into proliferating cell DNA. The
specific procedure varied with the cells and the stimuli. Cells
derived from mouse spleen were cultured at 3 million per ml; cell
lines were seeded at 0.1 to 1 million per ml. Splenic B cells were
isolated by T cell depletion and stimulated with phorbol myristate
acetate (PMA) (10 ng/ml) plus ionomycin (100 nM), or IL-4 (10
ng/ml) plus anti-CD40 Ab (100 ng/ml). T cells were depleted prior
to culture by incubating spleen cells first with a cocktail of
anti-Thy1 ascites (10%), anti-CD4 Ab (0.5 .mu.g/ml) and anti-CD8 Ab
(0.5 .mu.g/ml), followed by guinea pig complement (adsorbed). Cell
lines were unstimulated or stimulated with Human Epidermal Growth
Factor (EGF) (100 ng/ml). All cells were cultured in 96-well plates
for 2-3 days and pulsed for 6 to 14 hours with 50 .mu.l of
3H-thymidine (50 .mu.Ci/ml).
[0161] In spleen cells, Compound I.82 suppressed B cell
proliferation responses to PMA/ionomycin and IL-4/anti-CD40 Ab
(FIG. 1) with approximately the same potencies as it suppressed in
vitro IgE responses to IL-4/anti-CD40 Ab. Similar inhibition
potencies were obtained for Compound I.82 in ConA-stimulated T cell
proliferation and LPS-stimulated B cell proliferation (preformed by
MDS Pharma), suggesting a lack of specificity in the action of
these drugs. On the other hand, a battery of immunological tests
performed with Compound I.82 demonstrated little other effects
other than inhibition of ConA-stimulated cytokine release.
[0162] In tumor cells, the results with splenic lymphocytes led to
a further analysis of cellular proliferation by measuring the
growth of tumor cells in the presence of these drugs. The initial
analysis was performed with murine M12.4.1 lymphoma cells, either
un-stimulated or stimulated with IL-4/anti-CD40 Ab. Compound I.82
suppressed the proliferation of M12.4.1 cells but with lower
potency that observed in stimulated spleen cells. However, the
potency of Compound I.82 increased when the cells were cultured
with IL-4/anti-CD40 Ab. This stimulation is known to induce the
activity of NF-.kappa.B in M12.4.1 cells.
[0163] A similar approach was used to establish selectivity of the
anti-proliferative activity by testing a battery of tumor lines
derived from a variety of tissues, mostly human in origin. An
attempt was made to generate proliferation data from at least 2
cell lines from each tissue selected. Only a handful of cell lines
were inhibited by 100 nM or less of each compound while most the
balance of the cells required much higher concentrations. Because
of the known character of some of the tested cell lines and
previous Western blot results with the compounds, there is evidence
to suggest a link between NF-.kappa.B inhibition and the action of
the drugs. Breast cancer cells offer a good model for testing this
phenomenon because they are predominantly of 2 types; estrogen
receptor (ER)-positive and ER-negative. The latter cells tend to be
less differentiated, have a higher density of EGF receptor
expression, and are more resilient to treatment. Proliferation of
ER-negative/EGFR-positive cells also tends to be driven by
NF-.kappa.B and thus a selection of these cells were tested for
proliferation responses to drug in vitro. The proliferation of all
of the EGF-responsive cell lines was potently inhibited by Compound
I.82 in vitro. Conversely, only 2 of the 5 ER-positive cell lines
were potently inhibited by drug.
[0164] Compound I.82 exert an anti-proliferative activity to T and
B lymphocytes exposed to a variety of immunogenic stimuli in vitro.
These actions are highly potent and parallel their IgE-suppression
activity. Although the mechanism of this action is unresolved, much
is known about the mechanism of IL-4/anti-CD40 Ab-induced IgE
production. A major factor in this response is the transcription
activator, NF-.kappa.B. This factor has been implicated in the
proliferation of a number of tumor cells and thus these drugs were
tested for activity on the proliferation of various tumor cell
lines in vitro. Our experiments revealed that a number of tumor
cell lines are sensitive to the effects of Compound I.82, and that
proliferation of many of the sensitive lines may be driven by
NF-.kappa.B factors. However, other cell lines known to be driven
by factors other than NF-.kappa.B (e.g., the ER-positive HCC 1500
and ZR-75-1). Thus, Compound I.82 appears to selectively act on
certain tumor cells. Other compounds disclosed in accordance with
the present invention are also expected to exhibit similar
characteristics, particularly those compounds which are
structurally similar to Compound I.82.
Treatment Regimens
[0165] The amount of the benzimidazole compounds which may be
effective in treating a particular allergy or used as an
anti-proliferation agent will depend on the nature of the disorder,
and can be determined by standard clinical techniques. The precise
dose to be employed in a given situation will also depend on the
choice of compound and the seriousness of the condition, and should
be decided according to the judgment of the practitioner and each
patient's circumstances.
[0166] As an anti-allergy therapy, appropriate dosages can be
determined and adjusted by the practitioner based on dose response
relationships between the patient's IgE levels as well as standard
indices of pulmonary and hemodynamic changes. Moreover, those
skilled in the art will appreciate that dose ranges can be
determined without undue experimentation by following the
protocol(s) disclosed herein for ex vivo and in vivo screening (See
for example Hasegawa et al., J. Med. Chem. 40: 395-407 (1997) and
Ohmori et al., Int. J. Immunopharmacol. 15:573-579 (1993);
employing similar ex vivo and in vivo assays for determining
dose-response relationships for IgE suppression by naphthalene
derivatives; incorporated herein by reference).
[0167] Initially, to exert anti-allergic or anti-asthmatic effects,
suitable dosages of the compounds will generally range from about
0.001 mg to about 300 mg per kg body weight per day in divided
doses, more preferably, between about 0.01 mg and 100 mg per kg
body weight per day in divided doses. The compounds are preferably
administered systemically as pharmaceutical formulations
appropriate to such routes as oral, aerosol, intravenous,
subcutaneously, or by any other route which may be effective in
providing systemic dosing of the active compound. The compositions
of pharmaceutical formulations are well known in the art. The
treatment regimen preferably involves periodic administration.
Moreover, long-term therapy may be indicated where allergic
reactions appear to be triggered by continuous exposure to the
allergen(s). Daily or twice daily administration has been effective
in suppressing the IgE response to a single antigen challenge in
animals when carried out continuously from a period of two to seven
consecutive days. Thus, in a preferred embodiment, the compound is
administered for at least two consecutive days at regular periodic
intervals. However, the treatment regimen, including frequency of
dosing and duration of treatment may be determined by the skilled
practitioner, and modified as needed to provide optimal IgE
down-regulation, depending on nature of the allergen, the dose,
frequency, and duration of the allergen exposure, and the standard
clinical indices.
[0168] In one embodiment of the present invention, an
IgE-suppressing compound may be administered in conjunction with
one or more of the other small molecule inhibitors disclosed, in
order to produce optimal down-regulation of the patient's IgE
response. Further, it is envisioned that one or more of the
compounds of the present invention may be administered in
combination with other drugs already known or later discovered for
treatment of the underlying cause as well as the acute symptoms of
allergy or asthma. Such combination therapies envisioned within the
scope of the present invention include mixing of one or more of the
small molecule IgE-inhibitors together with one or more additional
ingredients, known to be effective in reducing at least one symptom
of the disease condition. In a variation, the small molecule
IgE-inhibitors herein disclosed may be administered separately from
the additional drugs, but during the same course of the disease
condition, wherein both the IgE-inhibitor(s) and the palliative
compounds are administered in accordance with their independent
effective treatment regimens.
[0169] As an anti-proliferative therapy, the appropriate dose of
the benzimidazole compounds disclosed herein may be determined by
one skilled in the art. Pharmacologists and oncologists can readily
determine the appropriate dose required for each individual patient
without undue experimentation, based upon standard treatment
techniques used for other anti-proliferation and chemotherapeutic
agents.
[0170] Initially, suitable dosages of the anti-proliferation
benzimidazole compounds will generally range from about 0.001 mg to
about 300 mg per kg body weight per day in divided doses, more
preferably, between about 0.01 mg and 100 mg per kg body weight per
day in divided doses. Most preferably, to exert anticancer effects,
the dose will range from about 1 mg to 100 mg per kg body weight
per day. The compounds are preferably administered systemically as
pharmaceutical formulations appropriate to such routes as oral,
aerosol, intravenous, subcutaneously, or by any other route which
may be effective in providing systemic dosing of the active
compound.
[0171] Ideally one or more benzimidazole compounds of the present
invention should be administered to achieve peak plasma
concentrations of the active agent, as determined by one of skill
in the art. To achieve adequate plasma levels, the pharmaceutical
formulation may be injected intravenously in an appropriate
solution, such as a saline solution or administered as a bolus of
the active ingredient.
[0172] The treatment regimen used in accordance with several
embodiments of the current invention preferably involves periodic
administration. Moreover, as with other chemotherapeutic agents,
long-term therapy may be indicated. Weekly, daily or twice daily
administration for a period of one to three years may be required
for some patients. Thus, in a preferred embodiment, the compound is
administered for at least six months at regular periodic intervals.
However, the treatment regimen, including frequency of dosing and
duration of treatment may be determined by the skilled
practitioner, and modified as needed to provide optimal
anti-proliferation effects, depending on nature of the disease, the
extent of abnormal cell growth, the type of cancer, the tissues
affected, and standard clinical indices.
[0173] One skilled in the art will understand that the ideal
concentration of the anti-proliferation compounds in the
formulation depends upon several pharmacokinetic parameters, such
as, absorption, inactivation, metabolism and clearance rates of the
drug as well as other known factors. One skilled in the art will
also appreciate that the concentration will vary with the severity
of the condition to be treated. Other factors which may affect the
treatment dose include, tumor location, age and gender of the
patient, other illnesses, prior exposure to other drugs, and the
like. One skilled in the art will appreciate that for any
particular patient, specific treatment regimens will be evaluated
and adjusted over time according to the individual patient's
requirements and according to the professional judgment of the
medical practitioner administering the treatment.
[0174] In one preferred embodiment, compounds of the current
invention are orally administered. Preferably, oral formulations
will include inert diluents or edible carriers. Oral dosages may be
encapsulated in gelatin or formed into tablets. Oral administration
may also be accomplished by using granules, grains or powders,
syrups, suspensions, or solutions. One skilled in the art will
understand that many acceptable oral compositions may be used in
accordance with several embodiments of the present invention. For
example, the active compound may be combined with standard
excipients, adjuvants, lubricants, sweetening agents, enteric
coatings, buffers, stabilizing agents and the like.
[0175] In one embodiment of the present invention, the active
compound may be modified to include a targeting moiety that targets
or concentrates the compound at the active site. Targeting moieties
include, but are not limited to, antibodies, antibody fragments or
derivatives, cytokines, and receptor ligands expressed on the cells
to be treated.
[0176] In several embodiments, compounds of the current invention
are administered in conjunction with other active agents, which
either supplement or facilitate the action of the benzimidazole
compound or cause other independent ameliorative effects. These
additional active agents include, but are not limited to,
antifungals, antivirals, antibiotics, anti-inflammatories, and
anticancer agents. Protectants, which include carriers or agents
which protect the active benzimidazole compound from rapid
metabolism, degradation or elimination may also be used. Controlled
release formulations can also be used in accordance with several
embodiments of the current invention.
[0177] In one embodiment of the present invention, one or more
anti-proliferation compounds may be administered in conjunction
with one or more other anti-cancer agents or treatments to produce
optimal anti-proliferative effects. Anti-cancer agents include, but
are not limited to, alkylating agents (lomustine, carmustine,
streptozocin, mechlorethamine, melphalan, uracil nitrogen mustard,
chlorambucil cyclophosphamide, iphosphamide, cisplatin, carboplatin
mitomycin thiotepa dacarbazine procarbazine, hexamethyl melamine,
triethylene melamine, busulfan, pipobroman, and mitotane);
antimetabolites (methotrexate, trimetrexate pentostatin,
cytarabine, ara-CMP, fludarabine phosphate, hydroxyurea,
fluorouracil, floxuridine, chlorodeoxyadenosine, gemcitabine,
thioguanine, and 6-mercaptopurine); DNA cutters (bleomycin);
topoisomerase I poisons (topotecan irinotecan and camptothecin);
topoisomerase II poisons (daunorubicin, doxorubicin, idarubicin,
mitoxantrone, teniposide, and etoposide); DNA binders
(dactinomycin, and mithramycin); and spindle poisons (vinblastine,
vincristine, navelbine, paclitaxel, and docetaxel).
[0178] Further, it is envisioned that one or more of the compounds
of the present invention can be administered in combination with
other therapies, such as radiation, immunotherapy, gene therapy
and/or surgery, in order to treat hyperproliferative diseases,
including cancer. Such combination therapies envisioned within the
scope of the present invention include mixing of one or more of the
benzimidazole compounds together with one or more additional
ingredients, known to be effective in reducing at least one symptom
of the disease condition. In a variation, the benzimidazole
compounds herein disclosed may be administered separately from the
additional drugs, but during the same course of the disease
condition, wherein both the benzimidazole compound and the
palliative compounds are administered in accordance with their
independent effective treatment regimens.
[0179] While a number of preferred embodiments of the invention and
variations thereof have been described in detail, other
modifications and methods of use will be readily apparent to those
of skill in the art. Accordingly, it should be understood that
various applications, modifications and substitutions may be made
of equivalents without departing from the spirit of the invention
or the scope of the claims.
* * * * *