| PATENT NUMBER | This data is not available for free |
| PATENT GRANT DATE | July 6, 2004 |
| PATENT TITLE |
Benzimidazole compounds for modulating IgE and inhibiting cellular proliferation |
| PATENT 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 |
| PATENT INVENTORS | This data is not available for free |
| PATENT ASSIGNEE | This data is not available for free |
| PATENT FILE DATE | February 27, 2002 |
| PATENT REFERENCES CITED |
Ashton, Michael et al., "New Low-Density Lipoprotein Receptor Upregulators Acting via a Novel Mechanism", Journal of Medicinal Chemistry vol. 39, pp. 3343-3356, 1996. Cheney, B. Vernon, "Structure-Activity Correlations for a Series of Antiallergy Agents. 3. Develpoment of a Quantitative Model", Journal of Medicinal Chemistry vol. 26, pp. 726-737, 1983. Karag'ozov, S., "Synthesis of N-acyl Derivatives of 6-amino-1-4-benzodioxane", Farmatsiya vol. 39, No. 2, pp.5-8, 1989. (Bulgaria). Pozdnyakov et al., "Mass Spectrometric Study of Dissociative Ionization of Low-Molecular Modules of Aromatice Polyamides", Khim Vys. Energ., vol. 21, No. 1, pp. 38-44, 1987. (Russia). Japanese Application No. 10273013 entitled, Antagonist for Gonadotrophic Hormone-Releasing Hormone, filed on Sep. 28, 1998, English abstract only. Database Crossifre Beilstein Online!, Beilstein Institut zur Forderung der Chemischen Wissenchaften, Frankurt am Main, De; Beilstein Registry No. 563073 & Khim. Farm. Zh., vol. 22, No. 6, 1988, pp. 697-699. Denny W A et al., "Potential antitumor agents. 59. Structure-activity relationships for 2-phenylbenzimidazole-4-carboxamides, a new class of "minimal" DNA-intercalating agents which may not act via topoisomerase II", Journal of Medicinal Chemistry, vol. 33, No. 2, Feb. 1990, pp. 814-819. White A W et al., "Resistance-modifying agents. 9. Synthesis and biological properties of benzimidazole inhibitors of the DNA repair enzyme poly(ADP-ribose) polymerase", Journal of Medicinal Chemistry, vol. 43, No. 2, Nov. 2, 2000, pp. 4084-4097. Database Caplus Online! Chemical Abstracts Service, Columbus, Ohio, US; Database accession No. 2000:214835 & JP 2000 095767 (Takeda Chemical Industries, Ltd.), Apr. 4, 2000. Kreimeyer A et al., "Suramin analogues with a 2-phenylbenzimidazole moiety as partyial structure; HIV- and angiostic drugs, 2: Sulfanilic acid, benzendisulfonic, and naphthalenetrisulfonic acid analogues" Archi Der Pharmazie, vol. 331, No. 3, Mar. 1998, pp.97-103. |
| PATENT PARENT CASE TEXT | This data is not available for free |
| PATENT CLAIMS |
What is claimed is: 1. A pharmaceutical composition for treating allergic reaction associated with increased IgE levels in a mammal comprising any one or more of the following compounds: ##STR95## 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, pyridyl, substituted pyridyl, pyridyl-N-oxide, adamantyl and substituted adamantyl; provided one of R.sub.1 and R.sub.2 is an adamantyl or a substituted adamantyl; wherein substituents on substituted adamantyl and substituted pyridyl are independently 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 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, substituted 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. 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 of claim 1. 3. A method for treating asthma in a mammal comprising administering an IgE-suppressing amount of at least one compound of claim 1. 4. The pharmaceutical composition of claim 1, wherein the compound is selected from the group consisting of: ##STR96## ##STR97## ##STR98## 5. A pharmaceutical composition comprising a compound represented by the formula below: ##STR99## 6. A pharmaceutical composition comprising a compound represented by the formula below: ##STR100## 7. A pharmaceutical composition comprising a compound represented by the formula below: ##STR101## 8. A pharmaceutical composition comprising a compound represented by the formula below: ##STR102## 9. A pharmaceutical composition comprising a compound represented by the formula below: ##STR103## 10. A pharmaceutical composition comprising a compound represented by the formula below: ##STR104## 11. A pharmaceutical composition comprising a compound represented by the formula below: ##STR105## 12. A pharmaceutical composition comprising a compound represented by the formula below: ##STR106## 13. A pharmaceutical composition comprising a compound represented by the formula below: ##STR107## 14. A pharmaceutical composition comprising a compound represented by the formula below: ##STR108## 15. A pharmaceutical composition comprising a compound represented by the formula below: ##STR109## 16. A pharmaceutical composition comprising a compound represented by the formula below: ##STR110## 17. A pharmaceutical composition comprising a compound represented by the formula below: ##STR111## 18. A pharmaceutical composition comprising a compound represented by the formula below: ##STR112## 19. A pharmaceutical composition comprising a compound selected from the group consisting of: ##STR113## ##STR114## 20. The pharmaceutical composition of claim 1, wherein the compound is selected from the group consisting of ##STR115## ##STR116## -------------------------------------------------------------------------------- |
| PATENT DESCRIPTION |
BACKGROUND OF THE INVENTION 1. Field of the Invention 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. 2. Description of the Related Art Allergies and Asthma 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 12:13S-21S (1997)). 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. 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. 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. 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. 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. 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. 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. 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 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. 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. 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. 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 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## 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 1-3 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'; 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, 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. 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. 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. 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. 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## 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 1-3 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'; 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, 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.9 alkyl is selected from the group consisting of a straight chain, branched or cyclic alkyl. 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. 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. 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. 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## 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 1-3 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'; 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, 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. 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. 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. 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. 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. 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. 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. 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. 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). 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. 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. 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. 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. 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 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 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 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). 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. 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. 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 200400 pg/ml and there was less than 0.001% cross-reactivity with any other Ig isotype in the ELISA for IgE. In vivo Assay 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. 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. 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 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 One family of small molecule IgE inhibitors in accordance with the present invention include benzimidazole carboxamides, defined by the following genus (Genus I): ##STR4## 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 1-3 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'; 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, 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. 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## 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: ##STR37## Synthesis of the Compounds of Genus 1 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. 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.2 SO.sub.4 or other dehydrating agents at an ambient temperature to generate the benzimidazole ring. 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. 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. 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. Compound D is representative of the compounds in Genus I. 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. 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. The products of the reactions described herein are isolated by conventional means such as extraction, distillation, chromatography, and the like. Starting materials not described herein are available commercially, are known, or can be prepared by methods known in the art. 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 Another family of small molecule IgE inhibitors in accordance with the present invention include benzimidazole-2-benzamides, defined by the following genus (Genus II): ##STR38## 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 1-3 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'; 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, 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. The following specific compounds are encompassed within the definition of Genus II: ##STR39## ##STR40## ##STR41## ##STR42## ##STR43## ##STR44## ##STR45## ##STR46## ##STR47## ##STR48## ##STR49## ##STR50## ##STR51## ##STR52## ##STR53## 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: ##STR54## Synthesis of the Compounds of Genus II 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. 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.2 SO.sub.4 or other dehydrating agents at an ambient temperature to generate the benzimidazole ring. 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. 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 inlcude 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. 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. 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). 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.3 P, and diethyl azodicarboxylate (EtOOCN.dbd.NCOOEt) at room temperature. Compound I(b) is representative of the compounds in Genus II. 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). 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. The products of the reactions described herein are isolated by conventional means such as extraction, distillation, chromatography, and the like. Starting materials not described herein are available commercially, are known, or can be prepared by methods known in the art. 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 Another family of small molecule IgE inhibitors in accordance with the present invention include benzimidazole-bis-carboxamides, defined by the following genus (Genus III): ##STR55## 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 1-3 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'; 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, 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. The following specific compounds are encompassed within the definition of Genus III: ##STR56## ##STR57## ##STR58## ##STR59## ##STR60## ##STR61## ##STR62## ##STR63## ##STR64## ##STR65## ##STR66## ##STR67## ##STR68## ##STR69## ##STR70## ##STR71## ##STR72## ##STR73## ##STR74## ##STR75## ##STR76## ##STR77## ##STR78## ##STR79## ##STR80## ##STR81## ##STR82## ##STR83## ##STR84## ##STR85## ##STR86## ##STR87## ##STR88## ##STR89## ##STR90## ##STR91## ##STR92## ##STR93## 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: ##STR94## Synthesis of the Compounds of Genus III 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. 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.2 SO.sub.4 or other dehydrating agents at an ambient temperature to generate the benzimidazole ring. 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. 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. 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. 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. 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. 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. Compound O is representative of the compounds in Genus III. 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. 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. The products of the reactions described herein are isolated by conventional means such as extraction, distillation, chromatography, and the like. Starting materials not described herein are available commercially, are known, or can be prepared by methods known in the art. 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 |
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