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 2-adrenergic agonists, terbutaline and albuterol, long the mainstay of asthma treatment, act primarily during the early phase as bronchodilators. The newer long-acting ß2-agonists, salmeterol and formoterol, may reduce the bronchoconstrictive component of the late response. However, because the pz-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 are currently being 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 Today, February 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/lII trials of its recombinant humanized monoclonal antibody, rhuMAB-E25 (BioWorld@ Today, November 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. An NDA filing for this product is projected to be in the year 2000. The positive results from anti-IgE antibody trials suggest that therapeutic strategies aimed at IgE down-regulation may be effective.

Summary of the Invention The present invention discloses a family of related compounds for use in the treatment of a condition associated with an excess IgE level. The benzimidazole inhibitors of IgE in accordance with the present invention are represented by the generic formula: X and Y are independently selected from the group consisting of H, alkyl, alkoxy, aryl, substituted aryl, hydroxy, halogen, amino, alkylamino, nitro, cyano, CF3, OCF3, CONH2, CONHR and NHCORl. R is selected from the group consisting of H, CH3, C2H5, C3H7, C4H9, CH2Ph, and CH2C6H4-F (p-). R, and R2 are independently selected from the group consisting of H, aryl, substituted aryl, cycloaryl substituted cycloaryl, multi-ring cycloaryl, benzyl, substituted benzyl and the like. Substitutions are alkyl, aryl, CF3, CH3, OCH3, OH, CN, COOR, COOH and the like.

In accordance with another aspect of the invention, there is disclosed a composition for use in the treatment of an allergic condition comprising the diacyl benzimidazole inhibitor of IgE disclosed above and at least one additional active ingredient, combined in a pharmaceutically acceptable diluent. The additional active ingredients may be selected from the group consisting of short-acting 2-adrenergic agonists, like terbutaline and albuterol, long-acting ß2-adrenergic agonists, like salmeterol and formoterol, antihistamines, like loratadine, azelastine and ketotifen, phosphodiesterase inhibitors, anticholinergic agents, corticosteroids, inflammatory mediator release inhibitors and leukotriene receptor antagonists.

In accordance with another aspect of the invention, there is disclosed a family of symmetric and asymmetric diacyl and monoacyl benzimidazole compounds for use in the treatment of an allergic condition comprising the following species: Structure BIAA Structure BIAB 7 C27H2oN402 402 CLOGP CLOGP 5.47 6.24 Structure BIAC Structure BIAD C26Hl9N502 CLOGP CLOGP CLOGP CLOGP Structure BIAE Structure BIAF -. 5.584.28 'B! AE"""BtAF CL"'-T.--------\ °-------- C H CLOGP ° CLOGP 4.82 6. 97 Structure _Structure BIAI C27Hl8Cl2N402 0 cl \,-a C27Hl8Cl2N402 CLOGP CLOGP CLOGP CLOGPCLOGP 5.31 6. 14 Structure BIAI Structure BIAJ BIAI N C27H26N402 C26H24N402 CLOGP CLOGP 6. 01 5. 45 Structure Structure BIAL BIAI ANA C25HieN402S0""0r C25HN402S CLOGP CLOGP CLOGPCLOGP 5.20 5. 20 Structure BIAM Structure BIAN 0 N I o °/ C30H24N42, 1 i C22H18N42 /N \ I N I O CLOGP CLOGP 3 90 5. 74 3.98 Structure Structure BIAO BIAP 0 C31 H3oN402-0 C28H28N402 N \/ CLOGP CLOGP CLOGP646. 57 Structure BIAQ Structure BIAR BIAI C28H26N402 C28H24N402 CLOGP CLOGP CLOGP 5.76 5. 28 StrIICtUf2 StfUCtUA BIBA BIBB N N C27Hl8Cl2N402 CLOGP CLOGP 7. 04 6.2604 7. Structure Structure BIBI C26H18CIN502 C28H21CIN403 CLOGP CLOGP 6. 38 5. 08 Structure BIBE Structure BIBF BIBI ""Ty-r C3oH25C ! N05" ('"OY./ C27Hi7C402 ri CLOGP CLOGP 5.62 7. 77 Structure Structure BIBG BIBH C27Hl7Cl3N y a y CLOGP CLOGP 6. 11 6. 94 Structure Structure BIBI BIBJ % 402 zon CLOGP CLOGP 6.81 6.25 Structure Structure BIBK BIBL a v S a °-' _________°'J _________ CLOGP CLOGP 6.00 6.00 Structure Structure BIBM BIBN \, ru "°/v a C30H23CIN402 a 1 \N° C22H17CIN402 \ v/\ H o CLOGP CLOGP 6. 54 4. 78 Structure Structure ci BIBO BIBP °ßtl a n a C31 H29CIN402 C28H27CIN402 N i/ CLOGP CLOGP 7.43 7.37 Structure Structure 0 0 N C28H25CIN402 C28H23CIN402 CLOGP CLOGP cLoGpr ° 6.56 6. 08 Structure Structure BICA BICB o o- N C28H22N403 C28H21CIN403 CLOGPCLOGP CL 5P CLOGP 5.58 6.35 Structure Structure BICD BICS /> h<° °5/AhA C m CLOGP CLOGP 5. 70 4. 39 5.704.39 Structure BICE Structure BICF BICS rV-rC-\ C3lH28N406 403 / CLOGP u CLOGP 7. 09 4.93 Structure Structure BICG BICH C28H2OCl2N403 CLOGP CLOGPCLOGP 5.43 6.26 Structure Structure BICS A IN-n\ C27H26N403 CLOGP CLOGP 5. 56 Structure Stucture BICS BICS ""0 C26H20N403S"OOr C2eH2oN403S CLOGP CLOGP 5. 32 5. 32 Structure Structure BICM BICN C23H2oN403 "°----o C31H26N43'lo i,"/\23H20N43 CLOGP CLOGP 5.85 4. 09 Structure Structure frr J. C32H32N03'LY-J C29H3c, N403 N CLOGP CLOGP 6. 68 6. 75 Structure Structure BICQ BICR C29H28N43 C29H26N43 CLOGP CLOGP xi '5. 885. 39 Structure Structure BIDA BIDB C26Hl8CIN502 CLOGP CLOGP C. 60 CLOGP Structure BIDC Structure BIDD BIDE 0 C27H2lN503 C25Hl8N602 CLOGP-CLOGP 4. 71 3. 41 Structure Structure BIDF bide I _O N N I'G poC29H25N505 C26Hl7Cl2N502 v l CLOGP CLOGP 3.95 6. 10 Structure Structure BIDE BIDE C26Hl7 V \1 C26Hl7Cl2N G CLOGP CLOGP 4. 44 5. 27 Structure Structure BIDE BIDE ANC26H25N502 C25H23N502 CLOGP CLOGP 5.14 4.58 Structure BIDK Structure BIDL N S o-Q, C24Hl7N502S 0 CLOGP CLOGP 4. 33 4. 33 Structure BIDM Structure BIDN N N C29H23N502-0 C2lHl7N502 /\ o i/\ CLOGP CLOGP 4. 87 3. 11 Structure BIDO Structure BIDP BIDO O I/N N o N w"C30H29N52 1 N N" o C27H27N52 i /\ CLOGP CLOGP ___ 5.70 Structure Structure BIDR BIDE 0 0 C27H25N502 C27H23N502 CLOGP CLOGP CLOGP 4. 89 4. 41 4.89 Structure BIEA Structure BIEB 0AZ 0@ C30H26 4 5 o Sh_% o. <a L / y n \J, e CLOGP CLOGP 4.82 5. 59 SBtECMED Structure BIEC Structure BIED bien C29H CI. OGP CLOGP 4. 93 3. 63 Structure Structure BIEF BIEN C33H32N408 C3oH24Cl2N405 r4 i CLOGP CLOGP 4. 17 6. 32 Structure BIEG Structure BIEH BIEG "0 CHCNs". C, oH,, a, N, 0, o ° I OU24 4. 66 5. 49 Structure BIEI Structure BIEN °S °) ° L ANA °S~° h h -ru CLOGP CLOGP 5. 36 4. 80 Structure BIEK Structure BIEL BIEN oc ". °0 C28H24N405S"0"- C28H2405S CLOGP CLOGP- 4.55 art Structure BIEM Structure BIEN o 0 C33H3oN405 C25H24N405 CLOGP CLOGP 5. 09 3. 33 5.09 3.33 Structure BIEO Structure BIEP BIEF ° C34H36N405 A + C3rH34N405 CLOGP CLOGP 5. 99 N-N Structure Structure BIEQ BIER C3lH32N405 C3lH3oN405 0 CLOGP CLOGP 5. 11 4. 63 Structure Structure cri t ; t k 1 « hA 0<0 Z w O G CLOGP CLOGP 7.00 Structure BIFC Structure BIFD cl a 0 C2eH2oC. 2N-OQ 0270.02 o' CLOGP CLOGP 7. 12 5. 82 Structure Structure BIFF biffe a c " cIBGp-----°' ciGP----- CLOGP CLOGP 6.3551 8. Structure BIFG Structure BIFH ci Au, -E-LO-GP CLOGP CLOGP CLOGP 6. 85 7. 68 Structure Structure BIFQ aa aßf; 27H24Cl2N402 N C26H22Cl2N402 abi/r\\ r CLOGP CLOGP 7.54 6.99 Structure Structure BIFK G a /\ o i S25h'16C2N4 2 a,'N//\ 0\5 C25H162N4 2 i 1 W l"-J S CLOGP CLOGP 6.74 6.74 Structure Structure BIFM BIFN a C4 /non C30H C22Hl6Cl2N v/\ G \ roi 5. 51 Structure BIFO Structure BIFP BIFO o C3lH28Cl2N402 C28H26Cl2N402 Nul O N O CLOGP/ CLOGP / 8. 10 8. 17 Structure Structure BIFQ BIFR C28H24Cl2N402 C28H22Cl2N402 o CLOGP o CLOGP 7. 30 6. 82 7.30° 6.82 Structure 5Structure BIGA CLOGPCLOGP N 12N402 CLOGP CLOGP 5. 34 6.12 Structure Structura BIGC BIGD G L C26Hl7Cl2N502 o CLOGP CLOGP 5. 46 4. 16 Structure BIGE Structure BIGF Bigue G h ° \, _Fy'' _________h ° tj-'y"_________ v a / CLOGP CLOGP Structure BIGG Structure BIGH 0 G G G G 27 16 4 4 2 '\ _________°"-y _________ CLOGP CLOGP 4.696.85 S"BGSB! GH 5.19 6.02 Structure Structure cl a SB) G.'B) GJ oa N C27H24Cl2N40 C26H22Cl2N402 CLOGP CLOGP CLOGP 5.88 5.33 Structure BIGK Structure BIGL BIGK C H O C25H162 4 2 G"i N °/ 25 162N4 2 g o S |CLOGP N |CLOGP 0 s 5.085. 08 Structure Structure Ci a 22 16 2 4 2 LYfy"" ___ ° \-fY"___ a CLOGP CLOGP 3. 85 3. 85 5. 62 Structure G Structure BIGP BIAI p II G o ci C28H26Cl2N402 N\ /\, CLOGP CLOGP 6. 44 6. 44 6.51 Structure Structure. BIGQ BIGR C28H24Cl2N402 C28H22Cl2N402 CLOGP CLOGP CLOGP CL GP 5.64 \ ° 5.16 Structure Stucture co-0 BIRB 'B. HA'"B. HB CLOGP CLOGP CLOGP CLOGP Structure BIHC Structure BIHD cul- C C28H2OCl2N403 0 26Hl7Cl2N502 CLOGPCLOGP 6. 29 4. 99 Structure Structure BIHF BIHE N O U CLOGP° CLOGP v/vl CLOGP ° COGP 5.52 7. 68 Structure BIHG Structure BIHH BtHGBtHH C27Hl6Cl4N402 CLOGP CLOGP CLOGP"CLOGP 6.02 6. 85 Structure BIHI Structure BIHJ BtH! B! HJ °"Q""0°-CC27H24C ! 2N402"0''"C"y 0220402 CLOGP CLOGP 6. 16 6.71 6.16 Structure BIHK Structure BIHL s"jry s" /G O/I S CLOGP CLOGP 5. 91 5. 91 Structure BIHM Structure BIHN G "G/v a C30H22C2N42 402 C22Hl6Cl2N402 CLOGP CLOGP 6.45 4.68 Structure BIHO Structure BIHP ° pN< C31 H28CI2N4 2 TN A ° ; > L) C28H26Cl2N4 2 N CLOGP CLOGP 7. 27 7.34 Structure BIHQ Structure BIHR O C28H24Cl2N402 C28H22Cl2N402 CLOGP CLOGP 6. 47 5. 99 Structure Structure BIKB a "-\/_________'-/--------- CLOGP CLOGP 5.20 5.98 Structure BIKC Structure BIKD N "0° CH, oN403S""0 CHNS 0 C24Hl7N502S C. 32 4. 02 CS Structure BIKE Structure BIKF Ah_St _28 24 4 5++X25 16 2 4 2co C25Hl6Cl2N402 'B. KG'BH C28H24N405S s CLOGP ° CLOGP 4. 55 StfUCtUfB SlfUC2Uf2 BIKG BIKH t w. i m v 15\ oN \1/N \ ° a/ S25 16 2 4 2/5\ oH /N/\ ° G/"25 162 4 2 s 0 s CLOGP CLOGP 5.055.88 Structure BIKI Structue I \ N AN0 C.. HN40, Sr0 CH,, N40, S CLOGP CLOGP 5.74 5. 19 Structure Structure BIKL BIAI 0 '-\/_________-\--------- CLOGP CLOGP A u 4 94 Structure Structure BIKM BIKN ° l \ N i C28H22N402 _ OH I N 5. 483. 71 Structure Structure s-- BIKO BIKP CLOGP CLOGP 29 28 4 2 , w- N CLOGP CLOGP 6.37 6.30 Structure Structure BIKQ BIKR C26H24N402S N-C26H22N402S N I CLOGP CLOGP 5. 50"-'o 5.02 Structure BILA Structure BILB BILA 'w/1 (H \ 1H/'25f"18N42S '"oN i \ a C25E"17C'IN402S 402S CLOGP CLOGP 5. 20 Structure BILC Structure BILD bill bill / C26H2oN403S C24Hl7NS02S 24 97 5 2 CLOG. CLOGP 5.32 4.02 Structure Structure bill R o tr V IY v A 5 6. 71 o CLOGP ° CLOGP 4.55 Structure BILG structure BILH v iN N ° a/ 25H162N4 2 s"\"° a"25H162 4 2 w \/' N CLOGP CLOGP CLOGP CLOGP Structure BILI Structure BILJ C25H24N402S 22N402S o CLOGP CLOGP 5.74 5.19 Structure BILK Structure BILL 0 N s ANC23Hl6N402S2 CLOGP CLOGP 4. 94 4. 94 Structure BILM structure BILN N C28H22C2oHl6N402S J CLOGP CLOGP 5. 48 3. 71 Structure s BILO Structure BILP OY-ID/-N °YA _________ ________ N C29H28N402S C26H26N402S }- i CLOGP CLOGP 6.37 6.30 Structure BILQ Structure BILR BIFQ CLOGP CLOGP i i" i CLOGP" CLOGP o/o 5.50 5. 02 Structure BIJG Structure BIJH BIAI a a \ C26H22C2N402 v 1 (N/" o/\ a C26"22C2N402 CLOGP CLOGP 5. 29 6. 12 avanir viib. db Structure BIIA Structure BIIB 0 C27H26N402 -\---------/________ CLOGP CLOGP 6.01 6. 78 Structure Structure BIC BIAI 28H28N403 C26H25N502 CLOGP CLOGP 6.12 4. 82 Structure Structure BIIE BIIF C3oH32N405 C27H24Cl2N402 CLOGP c'CLOGP CLOGP ° CLOGP 5.36 Structure BIIG Structure BIIH Cri a °\Ct C'''J C27H24C'2N402C"-. '° C27H24C! 2N402 CLOGP CLOGP 5. 85 6.68 Structure Structure BIIK BIIL s s C25H24N40C25H24N402S '/ CLOGP CLOGP 5.74 5.74 Structure BIJA Structure o \ ('H/o C26H24N402 C26H23CIN402 CLOGP CLOGP 6. 45 6. 22 Structure Structure BIJC BIJD °r0 CH26N403- CH23N502 CLOGPCLOGP 5.56 4. 26 Structure Structure BIJE BIJF C29H3oN405 C26H22Cl2N402 CLOGP CLOGP 4.80 6. 95 Structure Structure BIOK BIOL fV n0 H O Y\ ! w o % 2gE"28N42S o G2gH28N42s "S I I H N P CLOGP 6.37 6.37 avanir vlib. db Structure Structure BIOA BIOB a o C3 C3lH29CIN402 2 CLOGPa CLOGP 6. 64 6.64 7. 41 Structure Structure BIOC BIOD '13-- Aa N t 32 32 4 3 > oNo C33h9N5O2 / o-CLOGP CLOGP 6.75 5. 45 Structure Structure BIOE BIOF O \ i d C34H36N45 \/ i ° C H CI N O C3lH28Cl2N402 I CLOGP CLOGP I ° CLOGPr CLOGP 5.99 8. 14 Structure Structure BIOG BIOH C31 H28Cl2N402 C31 H28Cl2N H/NN/ CLOGP CLOGP 6.48 Structure BIPG Structure BIPH cul r CLOGP CLOGP 6. 41 7. 24 Structure Structure BIFQ CLOGP"CLOGP 6. 30 CL26p26 402SI 6. 30 Structure Structure BISA BIRB N402. CHC, 0, _ 1/ CLOGP"CLOGP 6. 57 7.34 Structure Structure B) PCB) PD C29H3oN403 C27H27N502 -, CLOGP CLOGP 6. 68 5. 38 Structure BIPE Structure BIPF B ! PEB) PF " °'31"34N45N C28H26C'2N402 28 26 2 4 2 CLOGP CLOGP 5.92 8. 07 Structure Structure BISA BIRB C28H26N402 C28H25CIN402 CLOGP CLOGP 5. 76 6. 54 Structure BIQC Structure BIQD C29H28N403 C27H25N5O2 CLOGP CLOGP J.'CLOGP'CLOGP 5. 88 4. 57 Structure BIQE Structure BIQF . C3, H32N405. 1p C28H24Cl2N402 CLOGP CLOGP 5. 11 7.27 Structure ? q | BIQG Structure ffi BiQH _ CLOIGP CLOGP CLOGP CLOGP , y-CLOGPJ.. CLOGP 5. 61 6. 44 Structure BIQK Structure BIQL j BIQK C26H24N402SJ C26W24N402S C26H24N402S C26H24N402S CLOGP CLOGP 5. 50 5. 50 IStructure t BI2L . BIRK BI L I tS t ; v1 I ¢d ; r L1C26H22N402S C26H22N402S CLOGP CLOGP 5.02 5. 02 Structure BIRG tructure BIRH BIRR CLOGP CLOGP CLOGP CLOGP 'u"y Structure., Structure BIRA BIRB C28H24N402 C2, H2, CIN4021 CLOGP CLOGP 6. 05 5.28 Structure "Stmcture BIRC S BIRD C27H23N52 'C29H26N43' CLOGP CLOGP 4.09 5.39 Structure | BIRF i BIRR C31H3oN405 CLOGP CLOGP i 4. 63 In accordance with another aspect of the present invention, there is disclosed a method for the preparation of a medicament for treatment of a condition associated with an excess IgE level. The compound has the formula: X and Y are independently selected from the group consisting of H, alkyl, alkoxy, aryl, substituted aryl, hydroxy, halogen, amino, alkylamino, nitro, cyano, CF3, OCF3, CONH2, CONHR and NHCOR,. R is selected from the group consisting of H, CH3, C2H5, C3H7, C4H9, CH2Ph, and CH2C6H4-F (p-). R, and R2 are independently selected from the group consisting of H, aryl, substituted aryl, cycloaryl substituted cycloaryl, multi-ring cycloaryl, benzyl, substituted benzyl and the like. Substitutions are alkyl, aryl, CF3, CH3, OCH3, OH, CN, COOR, COOH and the like.

In accordance with another aspect of the present invention, there is disclosed a method of treating a mammal having a condition associated with an excess IgE level. The method comprises administering to the mammal an amount of a compound sufficient to reduced IgE levels in the mammal. The compound has the formula: X and Y are independently selected from the group consisting of H, alkyl, alkoxy, aryl, substituted aryl, hydroxy, halogen, amino, alkylamino, nitro, cyano, CF3, OCF3, CONH2, CONHR and NHCOR. R is selected from the group consisting of H, CH3, C2H5, C3H7, C4H9, CH2Ph, and CH2C6H4-F (p-). R, and R2 are independently selected from the group consisting of H, aryl, substituted aryl, cycloaryl substituted cycloaryl, multi-ring cycloaryl, benzyl, substituted benzyl, alkyl, cycloalkyl substituted cycloalkyl, multi-ring cycloalkyl, fused-ring aliphatic, cyclopropyl, substituted cyclopropyl, cyclobutyl, substituted cyclobutyl, cyclopentyl, substituted cyclopentyl, cyclohexyl, substituted cyclohexyl, cycloheptyl, substituted cycloheptyl, bicycloheptyl, bicyclooctyl, bicyclononyl, substituted bicycloalknyl, adamantyl, substituted adamantyl and the like, wherein at least one of Rl and R2 are aromatic groups. Substitutions are alkyl, aryl, CF3, CH3, OCH3, OH, CN, COOR, COOH and the like.

In a variation of the above-disclosed method, at least one additional active ingredient may be administered in conjunction with the administration of the compound. The additional active ingredient may be combined with said compound in a pharmaceutically acceptable diluent and co-administered to the mammal. The additional active ingredient may be a short-acting B2- adrenergic agonist selected from the group consisting of terbutaline and albuterol. In a variation, the additional active ingredient may be a long-acting 2-adrenergic agonist selected from the group consisting of salmeterol and formoterol or an antihistamine selected from the group consisting of loratadine, azelastine and ketotifen. In another variation, the additional active ingredient may be a phosphodiesterase inhibitor, an anticholinergic agent, a corticosteroid, an inflammatory mediator release inhibitor or a leukotriene receptor antagonist.

The compound is preferably administered at a dose of about 0.01 mg to about 100 mg per kg body weight per day in divided doses of said compound for at least two consecutive days at regular periodic intervals.

Other variations within the scope of the present invention may be more fully understood with reference to the following detailed description.

Detailed Description of the Preferred Embodiment The present invention is directed to small molecule inhibitors of IgE (synthesis and/or release) which are useful in the treatment of allergy and/or asthma or any diseases where IgE is pathogenic. The particular compounds disclosed herein were identified by their ability to suppress IgE levels in both ex vivo and in vivo assays. 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 Yivo Assav This assay 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, _foetal bovine serum (FBS) batch that will permit optimal IgE response in vitro, the importance of prirned 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 yg 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 ug/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/lg/ml and 50 ng/ml) were added to the spleen cell cultures containing antigen and incubated at 37 ° C for 8 days in an atmosphere of 10% CO2.

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 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° 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 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 Assav 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 sensitization 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 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 yg 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 Al/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 llg 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 IgG 1 (1: 1600 to 1: 12800).

Diacyl Benzimidazole Inhibitors of IgE Several species embraced by the following generic formula were synthesized and evaluated for their effectiveness in down-regulating IgE in the ex vivo and in vivo assays.

X and Y are independently selected from the group consisting of H, alkyl, alkoxy, aryl, substituted aryl, hydroxy, halogen, amino, alkylamino, nitro, cyano, CF3, OCF3, CONHz, CONHR and NHCORn R is selected from the group consisting of H, CH3, C2Hs, C3H7, C4H9, CH2Ph, and CH2C6H4-F (p-). R, and R2 are independently selected from the group consisting of H, aryl, substituted aryl, cycloaryl substituted cycloaryl, multi-ring cycloaryl, benzyl, substituted benzyl, alkyl, cycloalkyl substituted cycloalkyl, multi-ring cycloalkyl, fused-ring aliphatic, cyclopropyl, substituted cyclopropyl, cyclobutyl, substituted cyclobutyl, cyclopentyl, substituted cyclopentyl, cyclohexyl, substituted cyclohexyl, cycloheptyl, substituted cycloheptyl, bicycloheptyl, bicyclooctyl, bicyclononyl, substituted bicycloalknyl, adamantyl, substituted adamantyl and the like, wherein at least one of R1 and R2 are aromatic groups. Substitutions are alkyl, aryl, CF3, CH3, OCH3, OH, CN, COOR, COOH and the like.

Synthesis of the Combinatorial Liber The diacyl benzimidazole compounds of the present invention were prepared using the following synthesis reactions, wherein the desired acid chlorides are selected from the Rl and R2 groups provided in the Table. OZN POU" + % N u reflux 1 2 2 3 RCOCIZN I j N/NH 1 H2/Pd-C H2N I N/NH pyridine H NH H2/Pd-C N R reflux H 4 p H O 0 RZCOCI RZ N pyridine NH reflux 0 N H -R 0 Synthesis of 3: 4-Nitro-1,2-phenylenediamine (10 g, 65.3 mmol) and 4-aminobenzoic acid (8.95 g, 65.3 mmol) were taken in a round bottomed flask and phosphorus oxychloride (95 ml) was added slowly. The reaction mixture was allowed to stir under reflux conditions. After 18 h, the reaction was allowed to cool and then poured slowly into an ice water mixture in an Erlenmeyer flask with vigorous stirring. Greenish yellow precipitate fell out which was then filtered and washed with copious amounts of water. The residue was then dried to obtain 16.9 g of crude desired product. Mass spectrum analysis (positive ion) indicated presence of 3.

Synthesis of 4: Benzimidazole 3 (800 mg, 3.14 mmol) was dissolved in dry pyridine (5 ml) in a scintillation vial and the desired acid chlorides (1.1 eq) were added slowly. The reactions were carried out in an oven at 60C. After 16h, the reaction was cooled to RT and DI water was added. Precipitation took place, which was filtered off, washed with water and air dried. The aqueous layer was extracted with EtOAc (6 x 50 ml), dried over anhydrous Na2SO4 and the solvent was removed in vacuo to result in a colored solid. By positive ion MS the desired monoacylated product was found to be present in the initial precipitate as well as in the organic layer. Hence the solid residues obtained were combined and used as such for the reduction step.

Reduction of 4: Crude monoacylated nitro benzimidazole 4 (1. 22 g, 3.40 mmol) was dissolved in MeOH (20 ml) and minimum amount of THF was added for complete dissolution to occur. Catalytic amount of 10% Pd on C was added and the solution was degassed and allowed to stir at 3.4 atm pressure under H2 atmosphere for 4 h. Upon completion of reaction as observed via TLC, the reaction mixture was filtered through celite and the solvent was removed under reduced pressure to afford 979 mg of crude residue.

General Organic Analyses HPLC/MS data was obtained using a Gilson semi-prep HPLC with a Gilson 170 Diode Array UV detector and PE Sciex API 100LC MS based detector. A Waters 600E with a Waters 490E UV detector was also used for recording HPLC data. The compounds were eluted with a gradient of CH3CN (with 0.0035% TFA) and H20 (with 0.01% TFA). Both HPLC instruments used Advantage C18 60A 51l 50mm x 4.6mm columns from Thomson Instrument Company.

Mass spectra were obtained by direct injection and electrospray ionization on a PE Sciex API 100LC MS based detector. Thin layer chromatography was performed using Merck 60F-254 aluminum backed precoated plates. Flash chromatography was carried out on Merck silica gel 60 (230-400 mesh) purchased from EM Scientific.

Syntheses of Symmetrical Diamides The symmetrical diacyl benzimidazole compounds of the present invention were generally prepared from 2- (4-aminophenyl)-5-aminobenzimidazole, which was obtained by reduction of 2- (4-nitrophenyl)-6-nitrobenzimidazole.

2- (4-nitrophenyl)-6-nitrobenzimidazole The dinitro benzimidazole was prepared as follows: a mixture of 4-nitrophenylenediamine (6.4g, 41.83 mmol) and 4-nitrobenzoic acid (7.86 g, 47 mmol) was dissolved in POC13 (250 ml) and heated to reflux for 2 h. The reaction mixture was cooled, poured on to ice, and stirred for 30 min. The resulting solid was filtered and washed with methanol and sodium bicarbonate to remove unreacted acid and allowed to dry overnight to give the desired product as a brown solid (5.8 g). The product was characterized by electrospray mass spectroscopy (mp >300° C).

2- (4-Aminophenyl)-5-aminobenzimidazole was prepared by suspending the above solid (75 g) in THF (75 ml), to which was added Pd-C (10% Pd by weight). The flask was purged with hydrogen and stirred under a balloon of hydrogen over night. TLC and MS showed starting material was still present so the reaction was allowed to continue over the weekend. TLC indicated complete reaction, the reaction was filtered through celite and washed with methanol. The solvent was removed under reduced pressure to give a dark brown solid (0.37 g) that was used without further purification.

2- (4-aminophenyl)-5-aminobenzimidazole Alternatively, the 2- (4-aminophenyl)-5-aminobenzimidazole was prepared by the following reduction: 2- (4-nitrophenyl)-6-nitrobenzimidazole (8.9 g, 31 mmole) was suspended in concentrated HC1 (100 mi) to which was added stannous chloride (42.3 g 180 mmole). The reaction mixture was heated to reflux for 5 hrs. The mixture was cooled to RT and the HCl salt of the desired product was precipitated by the addition of ethanol. The resulting solid was filtered, re-dissolved in water and the solution made basic by the addition of concentrated ammonium hydroxide. The resulting precipitate was filtered and dried overnight under vacuum to yield the desired product as a gray solid (6.023 g, 26.9 mmole, 87%). The product characterized by electrospray mass spectroscopy and HPLC (mp. 222-227° C).

2- (4-Aminophenyl)-5-methoxy benzimidazole was synthesized from 2- (4-nitrophenyl)-5- methoxy benzimidazole, which was prepared as follows: 1,2-diamino-4-methoxybenzene (1.26 g, 10.0 mmole was mixed with 4-nitrobenzoic acid (1.67 g, 9.8 mmole) and dissolved in POC13 (10 ml) and heated to reflux for 2.5 hours. The reaction mixture was cooled and cautiously poured onto ice. The resulting solid was filtered, washed with NaHC03 and used without further purification.

2- (4-nitrophenyl)-5-methoxy benzimidazole 2- (4-Aminophenyl)-5-methoxy benzimidazole was prepared by dissolving 1 g of the above nitrobenzimidazole in 30% Na2S9H2O (20 ml) with stirring at RT for 21 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic extracts were dried over sodium sulfate and concentrated under vacuum. The product was characterized by mass spectroscopy.

2- (4-aminophenyl)-5-methoxy benzimidazole 2- (4-Aminophenyl)-5, 6-dichloro benzimidazole was synthesized from 2- (4-nitrophenyl)- 5,6-dichloro benzimidazole, which was prepared as follows: 1,2-diamino-4,5-dichlorobenzene (1.68 g, 10.0 mmole) was mixed with 4-nitrobenzoic acid (1.58 g, 9.3 mmole), dissolved in POCI3 (10 ml), and heated to reflux for 2.5 hours. The reaction mixture was cooled and cautiously ice.Theresultingonto solid was filtered, washed with NaHCO3 and used without further purification.

2- (4-nitrophenyl)-5, 6-dichloro benzimidazole 2- (4-Aminophenyl)-5, 6-dichloro benzimidazole was prepared by dissolving 1 g of the above nitrobenzimidazole in 30% Na2S9H20 (20 ml) with stirring at RT for 21 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic extracts were dried over sodium sulfate and concentrated under vacuum. The product was characterized by mass spectroscopy.

2- (4-Aminophenyl)-5,6-dichloro benzimidazole 2- (4-aminophenyl)-7-methyl benzimidazole was synthesized from 2- (4-nitrophenyl)-7- methyl benzimidazole, which was prepared by mixing 1,2-diamino-3-methylbenzene (1.24 g, 10.0 mmole) with 4-nitrobenzoic acid (1.69 g, 9.8 mmole), dissolved in POC13 (10 ml), and heated to reflux for 2.5 hours. The reaction mixture was cooled and cautiously poured onto ice.

The resulting solid was filtered, washed with NaHC03 and used without further purification.

2- (4-nitrophenyl)-7-methyl benzimidazole 2- (4-Aminophenyl)-7-methyl benzimidazole was synthesized by dissolving 1 g of the above nitrobenzimidazole in 30% Na2S9H2O (20 ml) with stirring at RT for 4.5 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic extracts were dried over sodium sulfate and concentrated under vacuum. The product was characterized by mass spectroscopy.

2- (4-aminophenyl)-7-methyl benzimidazole 2- (4-Aminophenyl)-6-methyl benzimidazole was synthesized from 2- (4-nitrophenyl)-6- methyl benzimidazole, which was prepared by mixing 1,2-diamino-4-methylbenzene (1.24 g, 9.8 mmole) with 4-nitrobenzoic acid (1.6 g, 9.9 mmole) and dissolved in POC13 (10 ml) and heated to reflux for 2.5 hours. The reaction mixture was cooled and cautiously poured onto ice. The resulting solid was filtered, washed with NaHC03 and used without further purification.

2- (4-nitrophenyl)-6-methyl benzimidazole 2- (4-Aminophenyl)-6-methyl benzimidazole was synthesized by dissolving 1 g of the above nitrobenzimidazole in 30% Na2S-9H20 (20 ml) with stirring at RT for 4.5 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic extracts were dried over sodium sulfate and concentrated under vacuum. The product was characterized by mass spectroscopy.

2- (4-aminophenyl)-6-methyl benzimidazole 2- (4-Aminophenyl)-5,6-dimethyl benzimidazole was synthesized from 2- (4-nitrophenyl)- 5,6-dimethyl benzimidazole, which was prepared by mixing 1,2-diamino-4,5-dimethylbenzene (1.38 g, 10.1 mmole) with 4-nitrobenzoic acid (1.69 g, 9.9 mmole) and dissolved in POC13 (10 ml) and heated to reflux for 2.5 hours. The reaction mixture was cooled and cautiously poured onto ice. The resulting solid was filtered, washed with NaHC03 and used without further purification.

2- (4-nitrophenyl)-5, 6-dimethyl benzimidazole 2- (4-Aminophenyl)-5,6-dimethyl benzimidazole was synthesized by dissolving 1 g of the above nitrobenzimidazole (31.1) in 30% Na2S9H20 (20 ml) with stirring at RT for 4.5 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic extracts were dried over sodium sulfate and concentrated under vacuum. The product was characterized by mass spectroscopy.

2- (4-aminophenyl)-5, 6-dimethyl benzimidazole The subsequent preparation of symmetrical diamides was accomplished by one of the followingmethods: Method A: 2- (4-Aminophenyl)-6-aminobenzimidazole (1 mmole) was suspended in THF (5 ml) to which was added DIEA (2.5 mmole) and mixture cooled to-78° C. To the above cooled mixture was added the acid chloride (2.5 mmole) and let warm to RT overnight. Water (2 ml) is added to the reaction and extracted with EtOAc. The combined organic extracts were combined washed with NaHC03 (aq.) and concentrated under reduced pressure. The resulting residue was purified on silica gel (hexanes/EtOAc or MeOH/CH2Cl2) or reverse phase HPLC (CH3CN/H20).

Method B: 2- (4-Aminophenyl)-6-aminobenzimidazole (1 mmole) and DMAP (cat.) was dissolved in pyridine (5 ml). To the above solution was added the acid chloride (2.5 mmole) and the reaction stirred overnight at 60° C. The reaction was cooled to room temperature and water added to precipitate the product. The resulting solid was collected by filtration with the solid being washed by hexanes and water and NaHC03 (aq.). The resulting residue was purified on silica gel (hexanes/EtOAc or MeOH/CH2C12) or reverse phase HPLC (CH3CN/H2O).

Method C : 2- (4-Aminophenyl)-6-aminobenzimidazole (1 mmole) was suspended in THF (10 ml) to which was added K2CO3 (2.5 mmole) in water (0.5 ml). and mixture cooled to-78° C.

To the above cooled mixture was added the acid chloride (2.5 mmole) and let warm to RT overnight. Water (10 ml) was added to the reaction and extracted with EtOAc. The combined organic extracts were combined washed with NaHCO3 (aq.) and concentrated under reduced pressure. The resulting residue was purified on silica gel (hexanes/EtOAc or MeOH/CH2Cl2) or reverse phase HPLC (CH3CN/H20).

Method D : The carboxylic acid (2.2 mmole), EDC (2.2 mmole) and DMAP (cat.) was dissolved in hot pyridine. To the above solution was added 2- (4-aminophenyl)-6- aminobenzimidazole (1 mmole) and heated to 60° C overnight. The cooled reaction mixture was partitioned between water and EtOAc. The organic layer was washed with NaHC03, dried over Na2SO4 and concentrated under vacuum. The resulting residue was purified on silica gel (hexanes/EtOAc or MeOH/CH2CIz) or reverse phase HPLC (CH3CN/H20).

Diacyl Benzimidazole Species The following species encompassed within the disclosed generic formula were synthesized and tested for their ability to suppress IgE. The species are presented & vu IgE Down-Regulatory Activity All of the disclosed species were tested for their ability to suppress IgE in both the ex vivo and in vivo assays. They were all active in both-assays. Activities (ICso) of the species in the ex vivo assay ranged from about 100 pM to 1 nM. In the in vivo assay, the ICso dose ranged from approximately 100 pg/kg body weight/day to about 10 mg/kg body weight/day. The diacyl benzimidazole compounds were generally more potent than the monoacyl compounds.

Suppression of IgE Response 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-XI produced 50% inhibition at concentrations ranging from 1 pM to 10 AM. In the in vivo assay, the compounds were effective at concentrations ranging from less than about 0.01 mg/kg/day to about 25 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.

Treatment Regimens The amount of the IgE inhibitor compound which may be effective in treating a particular allergy or condition 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. 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).

Initially, 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.

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.