Patent Publication Number: US-2004048875-A1

Title: Compounds and methods for treatment of asthma, allergy and inflammatory disorders

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS  
     [0001] This is a application is a divisional of U.S. Ser. No. 10/242,346, filed Sep. 12, 2002, which is a continuation of application Ser. No. 09/534,947, filed Mar. 24, 2000, now U.S. Pat. No. 6,451,801 issued Sep. 17, 2002, which claims the benefit of U.S. Provisional Application No. 60/126,521 filed Mar. 26, 1999. 
    
    
     
       BACKGROUND OF THE INVENTION  
       [0002] 1. Field of the Invention  
       [0003] The invention relates to the field of 1,4 substituted piperazines, 1,4 substituted piperidines, and 1-substituted, 4-alkylidenyl piperidines.  
       [0004] 2. Summary of the Related Art  
       [0005] Leukotrienes are potent local mediators, playing a major role in inflammatory and allergic responses including arthritis, asthma, psoriasis, and thrombotic disease. Leukotrienes are straight chain eicosanoids produced by the oxidation of arachidonic acid by lipoxygenases. Arachidonic acid is oxidized by 5-lipoxygenase and ultimately converted to leukotrienes A4, B4, C4, D4 or E4. 15-Lipoxygenase is responsible for the conversion of arachidonic acid to various biologically active metabolites including 15-hydroxy-5,8,11,13-eicosatetraenoic acid (15-HETE). Both of these mediators have been implicated in the pathogenesis of airway and allergic diseases such as asthma by contributing to bronchoconstriction, mucus secretion, and eosinophil migration. A mixture of one or more of such leukotrienes are known to be potent bronchoconstrictors. Thus, leukotrienes have been shown to play an important role in the pathology of asthma. Rigorous proof for the role of leukotrienes in asthma has been provided by several pivotal clinical trials in which orally administered 5-lipoxygenase (5-LO) inhibitors (or LTD4 receptor antagonists) produce clear therapeutic benefit in asthma patients. These benefits include reduction in the use of classic asthma therapies such as beta agonists and corticosteroids.  
       [0006] It is well known in the art that certain hydroxyurea- and hydroxyamide- substituted aromatic compounds can function as 5-LO inhibitors. For example, WO 92/09567 and WO 92/09566 disclose a wide variety of N-hydroxyurea and hydroxamic acid compounds as inhibitors of the lipoxygenase enzyme.  
       [0007] Histamine has been established to play a role in inflammation in general. Antihistamines are well established most notably for allergy control. Furthermore, histamine is believed to play a role in asthma. For example, histamine and cysteinyl leukotrienes (cLT&#39;s) are both known to be key mediators in airway tone. Clinical studies have shown that a combination therapy of a cLT receptor antagonist and an antihistamine administered to twelve asthma patients, reduced early asthmatic responses (EAR) and late asthmatic responses (LAR) to a greater extent than either single-acting agent alone (A. Roquet, et al.,  Am. J. Respir Crit. Care Med,  155, 1856 (1997)). This indicates that histamine plays a role in asthma.  
       [0008] It is well known that certain [bis(substituted and/or unsubstituted aryl) methyl- and methylene]-1-piperidyl compounds possess antihistaminergic activity, and numerous publications disclose such. For example, Yanni et al. (U.S. Pat. No. 4,810,713 and 4,950,674) disclose [[bis(aryl)methyl- or methylene-]-1-piperidinyl]alkoxy -aryl and -heteroaryl compounds for the treatment of allergic phenomena, including asthma and rhinitis. Teng et al. (U.S. Pat. No. 5,070,087) disclose [bis(aryl)methyl- and methylene]-N-[(phenoxy and phenylthio)alkyl]piperidines for countering effects of histamine in allergies.  
       [0009] Others have shown [bis(aryl)methyl]piperazin-1-yl compounds for use as antiasthmatics and antiallergics that inhibit leukotriene release (e.g., JP 97077754). U.S. Pat. No. 4,525,358 teaches 2-[4-(diphenylmethyl)-1-piperazinyl]-acetic acid and its amides as antiallergic, spasmolytic, and antihistamine agents. JP 7138230 discloses 4-aralkyl-1-piperazinyl-unsaturated carboxylic acid derivatives useful an antiallergic agents for the treatment of, for example, asthma and rhinitis. WO 97/23466 describes the preparation of N-diarylmethylpiperazines as analgesics.  
       [0010] None of the art, however, teaches, suggests, or contemplates combining the 5-LO and 15-LO inhibiting functionality of hydroxyurea moieties with the antihistaminergic properties of [bis(substituted and/or unsubstituted aryl) methyl- and methylene]-1-piperidyl or -1-piperazinyl moieties in a single entity to yield a compound possessing the dual functions as an antihistaminergic and a 5-LO/15-LO inhibitor.  
       SUMMARY OF THE INVENTION  
       [0011] The present invention provides novel compounds having dual properties, each compound possessing both lipoxygenase inhibition properties as well as antihistaminergic properties. In a preferred embodiment, each of the novel compounds of the invention functions as both a 5-LO and/or 15-LO inhibitor as well as a histamine H1 receptor antagonist.  
       [0012] The compounds of the invention are useful for treating conditions in which there is likely to be a histamine and/or leukotriene component. These conditions include preferably asthma, seasonal and perennial allergic rhinitis, sinusitus, conjunctivitis, food allergy, scombroid poisoning, psoriasis, urticaria, pruritus, eczema, rheumatoid arthritis, inflammatory bowel disease, chronic obstructive pulmonary disease, thrombotic disease and otitis media. Accordingly, the invention also provides pharmaceutical compositions comprising the compounds of the invention and methods of treating asthma and rhinitis with the pharmaceutical compositions.  
       [0013] The compounds disclosed herein can also be used as research tools to study biological pathways involving both leukotrienes and histamine and, in particular, further elucidate the role histamine plays in bronchoconstriction.  
       [0014] All patent applications, patents, and other publications recited herein are hereby incorporated by reference in their entirety. 
     
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
     [0015]FIG. 1 displays the synthesis of compound  1 .  
     [0016]FIG. 2 displays the synthesis of compound  12 .  
     [0017]FIG. 3 displays the synthesis of compound  17 .  
     [0018]FIG. 4 displays the synthesis of compound  35  and  36 .  
     [0019]FIG. 5 displays the synthesis of compound  37 .  
     [0020]FIG. 6 displays the synthesis of compound  80 .  
     [0021]FIG. 7 displays the synthesis of compound  32 .  
     [0022]FIG. 8 displays the synthesis of compound  46 .  
     [0023]FIG. 9 displays the synthesis of compound  27 . 
    
    
     DETAILED DESCRIPTION OF THE INVENTION  
     The Compounds  
     [0024] In one aspect, the present invention comprises compounds of formula I, including geometrical isomers, enantiomers, diastereomers, racemates, and pharmaceutically acceptable salts thereof:  
                 
 
     [0025] wherein:  
     [0026] X and X′ independently are hydrogen, halo, alkyl, alkenyl, alkynyl, alkoxy, trifluoromethyl or —(Y′) m —W′;  
     [0027] G and G′ together form  
                 
 
     [0028] D is —CH═ or ═N—;  
     [0029] R 1  and R 2  independently are hydrogen or together are —(CH 2 ) n — in which n is equal to 0, 1, 2, or 3;  
     [0030] m and m′ are independently 0 or 1;  
     [0031] Y and Y′ are -L 1 - or -L 2 -V(Z) t -L 3 - in which t is 0 or 1;  
     [0032] L 1  is alkylene, alkenylene, alkynylene, or one of the foregoing in which one or more methylenes are replaced by —O—, —S—, —S(O)—, —S(O) 2 —, —N(Q)-, or —N(R 3 )—;  
     [0033] L 2  is (a) alkylene, alkenylene, alkynylene, or one of the foregoing in which one or more methylenes are replaced by —O—, —S—, —S(O)—, —S(O) 2 —, —N(Q′)-, or —N(R 4 )—, or (b) -L 4 -C(O)—N(Q′)- or -L 4 (Q′)-, or (c) a direct bond;  
     [0034] L 3  is (a) alkylene, alkenylene, alkynylene, or one of the foregoing in which one or more methylenes are replaced by —O—, —S—, —S(O)—, —S(O) 2 —, —N(Q″)-, or —N(R 5 )—, or (b) a direct bond;  
     [0035] L 4  is (a) alkylene, alkenylene, alkynylene, or one of the foregoing in which one or more methylenes are replaced by —O—, —S—, —S(O)—, —S(O) 2 —, —N(Q″)-, or —N(R 5 )—, or (b) a direct bond;  
     [0036] V is (a) a divalent arene, a divalent heteroarene, or a divalent saturated heterocycle when t is 0, or (b) a trivalent arene or trivalent heteroarene when t is 1;  
     [0037] Q, Q′, and Q″ independently are hydrogen, -AC(O)OR 6 , or -AC(O)NR 6 R 7 ;  
     [0038] W and W′ independently are —N(OM)C(O)N(R 8 )R 9 , —N(R 8 )C(O)N(OM)R 9 , —N(OM)C(O)R 8 , —C(O)NR 8 R 9 , or —C(O)OR 8 , provided that at least one of W and W′ is —N(OM)C(O)N(R 8 )R 9 , —N(R 8 )C(O)N(OM)R 9 , or —N(OM)C(O)R 8 .  
     [0039] Z is -A″N(OM′)C(O)N(R 10 )R 11 , -A″N(R 10 )C(O)N(OM′)R 11 , -A″N(OM′)C(O)R″, -A′C(O)N(OM′)R 11 , -A′C(O)NR 10 R 11 , -A′C(O)OR 10 , halo, CH 3 , NR 3 R 4 , NR 3 C(O)R 4 , NO 2 , CN, CF 3 , S(O) 2 NR 3 R 4 , S(O) 2 R 3 , SR 3 , or S(O)R 3 .  
     [0040] A, A′ and A″ independently are a direct bond, alkylene, alkenylene, alkynylene, yloalkylaryl, yloarylalkyl, or diyloalkylarene or one of the foregoing in which one or more methylenes are replaced by —O—, —NH—, —S—, —S(O)—, or —S(O) 2 — and/or one or more methylidenes are replaced by ═N—;  
     [0041] M and M′ independently are hydrogen, a pharmaceutically acceptable cation, or a metabolically cleavable group; and  
     [0042] R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11  are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkylaryl, alkylarylalkyl, or one of the foregoing in which one or more methylenes are replaced by —O—, —NH—, —S—, —S(O)—, or —S(O) 2 — and/or one or more methylidenes are replaced by ═N—;  
     [0043] provided that, other than the oxygens bound to the sulfurs in —S(O)— and —S(O) 2 —, when one or more methylenes are replaced with —O—, —NH—, —S—, —S(O)—, or —S(O) 2 — and when one or more methylidenes are replaced with ═N—, such replacement does not result in two heteroatoms being covalently bound to each other;  
     [0044] and further provided that when m is 0, W is not —C(O)NR 8 R 9 , or —C(O)OR 8 ,  
     [0045] and further provided that in the substituent -AC(O)OR 6 , R 6  cannot be hydrogen when A is a direct bond.  
     [0046] Preferably, compounds of the present invention are those having formula I′:  
                 
 
     [0047] and the geometrical isomers, enantiomers, diastereomers, and pharmaceutically acceptable salts thereof, wherein each of the variables is as defined above, except that:  
     [0048] X and X′ independently are hydrogen, halo, alkyl, alkenyl, alkynyl, alkoxy, or trifluoromethyl; and  
     [0049] W is —N(OM)C(O)N(R 8 )R 9 , —N(R 8 )C(O)N(OM)R 9 , or —N(OM)C(O)R 8 .  
     [0050] In another preferred embodiment, the compounds of the present invention are given by formula I″:  
                 
 
     [0051] and the geometrical isomers, enantiomers, diastereomers, and pharmaceutically acceptable salts thereof, wherein each of the variables is as defined above.  
     [0052] In other preferred embodiments, compounds of formula I are represented by the following formulas, II and III:  
                 
 
     [0053] and the geometrical isomers, enantiomers, diastereomers, and pharmaceutically acceptable salts thereof, wherein each of the variables is as defined above.  
     [0054] More preferred embodiments of the compounds of formula II and III and the geometrical isomers, enantiomers, diastereomers, and pharmaceutically acceptable salts thereof, are those wherein each of the variables is as defined above except that:  
     [0055] 1. X is —Cl, X′ is hydrogen, m is 1 and W is —N(OH)C(O)NH 2 ;  
     [0056] 2. X is —Cl, X′ is hydrogen, m is 1, Y is -L 1 -, wherein L 1  is alkynylene, yloalkoxy, or yloalkoxyalkyl;  
     [0057] 3. X is —Cl, X′ is hydrogen, m is 1, Y is -L 2 -V(Z) t -L 3 -, t is 0, V is 1,4-phenylene or 1,3-phenylene, L 2  is yloalkoxy, and L 3  is alkylene, alkenylene, or alkynylene;  
     [0058] 4. X is —Cl, X′ is hydrogen, m is 1, Y is -L 2 -V(Z) t -L 3 -, t is 0, V is 2,5-furylene, L 2  is alkylene, and L 3  is alkylene, alkenylene, or alkynylene; or  
     [0059] 5. X is —Cl, X′ is hydrogen, m is 1, Y is -L 2 -V(Z) t -L 2 -, t is 1, L 2  is yloalkoxy, V is trivalent heteroarene, Z is -A′C(O)NR 10 R 11  or -A′C(O)OR 10  and W is —N(OH)C(O)NH 2 .  
     [0060] 6. X and X′ are F, m is 1, Y is -L 2 -V(Z) t -L 3 -, t is 0, V is 1,4-phenylene or 1,3-phenylene, L 2  is yloalkoxy, and L 3  is alkylene, alkenylene, or alkynylene;  
     [0061] Compounds of the invention include those shown in TABLE I as follows:  
                                                                               MS               CPD       Stereo-       Melt.   Obs       #   Structure   Chem 1     Salt   Temp   Mass   LogP   Name                                                                                                    1                         CR           3.07       N-{{4-(2-[4-[(1R)(4-chlorophenyl) phenylmethyl]piperazinyl}ethoxy) phenyl]methyl} amino-N-hydroxyamide               2                         CR               2.72   N-{{4-(2-[4-[(1R)(4-chlorophenyl) phenylmethyl]piperazinyl}ethoxy) phenyl]methyl}amino aminooate               3                         CR               3.62   N-{[4-(3-{4-[(1R)(4-chlorophenyl) phenylmethyl] piperazinyl}prop-1-ynyl) phenyl] methyl}amino-N-hydroxyamide               4                         CR               3.27   N-{[4-(3-{4-[(1R)(4-chlorophenyl) phenylmethyl] piperazinyl}prop-2-ynyl) phenyl]methyl}aminocarbonylamino aminooate               5                         CR               3.18   N-{[3-(2-{4-[(1R)(4-chlorophenyl) phenylmethyl)piperazinyl}ethoxy) phenyl]methyl]amino-N-hydroxyamide               6                         CR               2.82   N-{[3-(2-{4-[(1R)(4-chlorophenyl) phenylmethyl]piperazinyl}ethoxy) phenyl]methyl}aminocarbonylamino amiooate               7                         CR               3.08   N-{[2-(2-{4-[(1R)(4-chlorophenyl) phenylmethyl]piperazinyl}ethoxy) phenyl]methyl}amino-N-hydroxyamide               8                         CR               3.62   N-{[3-(3-{4-[(1R)(4-chlorophenyl) phenylmethyl]piperazinyl}prop-2-ynyl) phenyl]methyl]amino-N-hydroxyamide               9                         CR               1.76   N-(4-{4-[(1R)(4-chlorophenyl)phenyl methyl]piperazinyl}but-2-ynyl) amino-N- hydroxyamide               10                                         3.65   amino-N-{4-[4-(8-chloro(5,6-dihydro benzo[f]pyridino[2,3-b][7]annulen-11- ylidene))piperidyl]but-2-ynyl}-N- hydroxyamide               11                         R               3.18   amino-N-{[4-(2-{4-[bis(4-fluorophenyl) methyl]piperazinyl}ethoxy)phenyl]ethyl}-N-hydroxyamide               12                         CR           533.3   4.19   N-{4-[4-(2-{4-[(1R)(4-chlorophenyl) phenylmethyl]piperazinyl}ethoxy) phenyl]but-3-ynyl}amino-N- hydroxyamide               13                         CR               3.98   N-{[4-(3-{4-[(1R)(4-chlorophenyl) phenylmethyl]piperazinyl}propyl) phenyl]methyl}amino-N-hydroxyamide               14                         R               1.65   tert-butyl2-{2-[4-({4-[(aminohydroxy carbonylamino)methyl]phenyl}phenylmethyl)piperazinyl]ethoxy}acetate               15                         R               2.77   tert-butyl2-{2-[4-({4-[4-(aminohydroxy carbonylamino)but-1-ynyl]phenyl}phenylmethyl)piperazinyl]ethoxy}acetate               16                                         1.33   amino-N-(4-{4-[bis(4-fluorophenyl) methyl]piperazinyl}but-2-ynyl)-N- hydroxyamide               17                         CR       148-150   536.64   4.55   N-{4-[4-(2-{4-[(1R)(4-chlorophenyl) phenylmethyl]piperazinyl}ethoxy) phenyl]butyl}amino-N-hydroxamide               18                         R               1.05   amino-N-[2-(2-{4-[(4-chlorophenyl) phenylmethyl]piperazinyl}ethoxy)ethyl]- N-hydroxyamide               19                         CR               2.37   N-(4-[4-[(1R)(4-chlorophenyl)phenyl methyl]piperazinyl}butyl)amino-N- hydroxyamide               20                         R   2 HCl           −0.04   2-{2-[4-({4-[(aminohydroxycarbonyl amino)methyl]phenyl}phenylmethyl) piperazinyl]ethoxy}acetic acid               21                         R   2 HCl           1.08   2-{2-[4-({4-[4-aminohydroxycarbonyl amino)but-1-ynyl]phenyl}phenyl methyl)piperazinyl]ethoxy}acetic acid               22                         CR               1.34   N-[2-(2-[(1R)(4-chlorophenyl) phenylmethyl]piperazinyl}ethoxy)ethyl]amino-N-hydroxyamide               23                         CR           533.2   4.19   N-{4-[3-(2-{4-[(1R)(4-chlorophenyl) phenylmethyl]piperazinyl}ethoxy) phenyl]but-3-ynyl}amino-N- hydroxyamide               24                         CR           509.2   3.82   N-{[3-(2-{4-[(1R)(4-chlorophenyl) phenylmethyl]piperazinyl}ethoxy) phenyl]methyl}(methyl{hydroxyamino)) carboxamide               25                         Chiral S               1.34   N-[2-(2-{4-[(1S)(4-chlorophenyl) phenylmethyl]piperazinyl}ethoxy)ethyl]amin-N-hydroxyamide               26                         CR           455   2.44   N-{[5-({4-[(1R)(4-chlorophenyl) phenylmethyl]piperazinyl}methyl)(2- furyl)}methyl]amino-N-hydroxyamide               27                         CR           493.2   3.45   N-{4-[5-({4-[(1R)(4-chlorophenyl) phenylmethyl]piperazinyl}methyl)(2- furyl)]but-3-ynyl}amino-N- hydroxyamide               28                         R   2 TFA       480.2   1.08   2-{2-[4-({4-[4-(aminohydroxycarbonyl amino)but-1-ynyl}phenyl}phenyl methyl)piperazinyl]ethoxy}acetic acid               29                         R   2 TFA       442.2   −0.04   2-{2-[4-({4-[(aminohydroxycarbonyl amino)mthyl]phenyl}phenylmethyl) piperazinyl]ethoxy}acetic acid               30                                     503.4   3.93   amin-N-[4-(3-{2-[4-(diphenylmethyl) piperazinyl]ethoxy}phenyl)butyl]-N- hydroxyamide               31                         CR           537.1   4.64   N-{4-[3-(2-{4-[(1R)(4-chlorophenyl) phenylmethyl]piperazinyl}ethoxy) phenyl]butyl}amino-N-hydroxyamide               32                                     557.14   6.08   amino-N-[4-(4-{2-[4-(8-chloro[5,6- dihydrobenzo[f]pyridino[2,3-b][7]annulen-11-ylidene))piperidyl]ethoxy}phenyl)but-3-ynyl]-N-hydroxyamide               33                         M           493.2   3.48   N-{3-[5-({4-[(1R)(4-chlorophenyl) phenylmethyl]piperazinyl}methyl)(2- furyl)]-1-methylprop-2-ynyl}amino-N- hydroxyamide               34                                     494   3.03   amino-N-{4-[5-({4-[bis(4-fluorophenyl) methyl]piperazinyl}methyl)(2-furyl)] but- 3-ynyl}-N-hydroxyamide               35                         CR       156-158   575.45   3.14   2-(2-{4-[(1R)(4-chlorophenyl) phenylmethyl]piperazinyl}ethoxy)-5-[4- (aminohydroxycarbonylamino)but-1- ynyl]benzamide               36                         CR           591.1   4.33   methyl2-(2-{4-[(1R)(4-chlorophenyl) phenylmethyl]piperazinyl}ethoxy)-5-[4- (aminohydroxycarbonylamino)but-1- ynyl]benzoate               37                         CR           577.1   3.89   2-(2-{4-[(1R)(4-chlorophenyl) phenylmethyl]piperazinyl}ethoxy)-5-[4- (aminohydroxycarbonylamino)but-1- ynyl]benzoic acid               38                         CR           616.1   3.64   ethyl2-(2-{4-[(1R)(4-chlorophenyl) phenylmethyl]piperazinyl}-N-{4-[4- (aminohydroxycarbonylamino)but-1- ynyl]phenyl}acetylamino)acetate               39                         CR           672.1   7.37   methyl2-(2-{4-[(1R)(4-chlorophenyl) (phenyl)methyl]-1-piperazinyl}ethoxy)-5- {4-[hydroxy(phenoxycarbonyl) amino]butyl}benzoate               40                         CR           595.2   4.83   methyl2-(2-{4-[(1R)(4-chlorophenyl) phenylmethyl]piperazinyl}ethoxy)-5-[4- (aminohydroxycarbonylamino)butyl]benzoate               41                         CR           581.2   4.39   2-(2-{4-[(1R)(4-chlorophenyl) phenylmethyl]piperazinyl}ethoxy)-5-[4- (aminohydroxycarbonylamino)butyl]benzoic acid               42                         CR           580.2   3.64   2-(2-{4-[(1R)(4-chlorophenyl) phenylmethyl]piperazinyl}ethoxy)-5-[4- (aminohydroxycarbonylamino)butyl]benzamide               43                         CR   2 HCl       581.2   4.39   2-(2-{4-[(1R)(4-chlorophenyl) phenylmethyl]piperazinyl}ethoxy)-5-[4- (aminohydroxycarbonylamino)butyl]benzoic acid               44                         CR   2 HCl       577   3.89   2-(2-{4-[(1R)(4-chlorophenyl) phenylmethyl]piperazinyl}ethoxy)-5-[4- (aminohydroxycarbonylamino)but-1- ynyl]benzoic acid               45                                     593.3   3.91   methyl5-[4-(aminohydroxycarbonyl amino)but-1-ynyl]-2-(2-{4-[bis(4- fluorophenyl)methyl]piperazinyl}ethoxy)benzoate               46                         Chiral           497   2.75   N-{4-[5-({4-[(1R)(4-chlorophenyl) phenylmethyl]piperazinyl}methyl)(2S, 5S)oxolan-2-yn]but-3-ynyl}amino-N- hydroxyamide               47                         M           633   4.8   ethyl3-[({4-[4-(aminohydroxycarbonyl amino)but-1-ynyl]phenyl)methyl) amino]-4-{4-[(4-chlorophenyl) phenylmethyl]piperazinyl}butanoate               48                         CR           621.2   4.97   methyl(2E)-3-[2-(2-{4-[(1R)(4-chloro phenyl)phenylmethyl]piperazinyl}ethoxy)-5-[4-(aminohydroxycarbonyl amino)butyl]phenyl]prop-2-enoate               49                         CR           617.1   4.63   methyl(2E)-3-[2-(2-{4-[(1R)(4-chloro phenyl)phenylmethyl]piperazinyl}ethoxy)- 5-[4-(aminohydroxycarbonyl amino)but-1-ynyl]phenyl]prop-2-enoate               50                             2 HCl       579   3.47   5-[4-(aminohydroxycarbonylamino)but- 1-ynyl]-2-(2-{4-[bis(4-fluorophenyl) methyl]piperazinyl}ethoxy)benzoic acid               51                         R           517.1   2.94   methyl3-{[4-({5-[4-(aminohydroxy carbonylamino)but-1-ynyl)(2-furyl)}methyl)piperazinyl]phenylmethyl}benzoate               52                         CR           547.07   4.54   N-{4-[4-(3-{4-[(1R)(4-chlorophenyl) phenylmethyl]piperazinyl}propoxy) phenyl]but-3-ynyl}amino-N- hydroxyamide               53                         R           559.1   5.42   amino-N-[4-(4-{2-[4-(8-chloro(5,6,11- trihydroxybenzo[b]pyridino[3,2-f][7]annulen-11-yl))piperidyl]ethoxy}phenyl)but-3-ynyl]-N-hydroxyamide               54                                     571.14   6.44   amino-N-[4-(4-{3-[5-(8-chloro(5,6- dihydroxybenzo[f]pyridino[2,3-b][7]annulen-11-ylidene))piperidyl]propoxy}phenyl)but-3-ynyl]-N-hydroxyamide               55                         CR   2 HCl       603.2   4.19   (2E)-3-[2-(2-{4-[(1R)(4-chlorophenyl) phenylmethyl]piperazinyl}ethoxy)-5-[4- (aminohydroxycarbonylamino)but-1- ynyl]phenyl]prop-2-enoic acid               56                         CR           602   3.44   N-{4-[3-((1E)-2-carbamoylvinyl)-4-(2-{4- [(1R)(4-chlorophenyl)phenylmethyl]piperazinyl}ethoxy)phenyl]but-3-ynyl}amino-N-hydroxyamide               57                         CR           551.64   4.35   N-{4-[4-(2-{4-[(1R)(4-chlorophenyl) phenylmethyl]piperazinyl}ethoxy)-3- fluorophenyl]but-3-ynyl}amino-N- hydroxyamide               58                                     578.02   2.71   5-[4-(aminohydroxycarbonylamino)but- 1-ynyl]-2-(2-{4-[bis(4-fluorophenyl) methyl]piperazinyl}ethoxy)benzoamide               59                                     552.96   3.92   amino-N-{4-[4-(2-{4-[bis(4-fluoro phenyl)methyl]piperazinyl}ethoxy)-3- fluorophenyl]but-3-ynyl}-N- hydroxyamide               60                         Chiral Trans           499   2.33   N-{4-[(2S,5S)-5-({4-[bis(4-fluoro phenyl)methyl]piperazinyl}methyl) oxolan-2-yl]but-3-ynyl}amino-N- hydroxyamide               61                                     599.82   5.03   5-[4-(aminohydroxycarbonylamino)but- 1-ynyl]-2-{2-[4-(8-chloro(5,6- dihydroxybenzo[f]pyridino[2,3-b][7]annulen-11-ylidene))piperidyl]ethoxy}benzamide               62                         CR       153-155   589.21   3.49   2-(3-{4-[(1R)(4-chlorophenyl) phenylmethyl]piperazinyl}propoxy)-5-[4- (aminohydroxycarbonylamino)but-1- ynyl]benzamide               63                         CR           590.06   3.65   2-(2-{4-[(1R)(4-chlorophenyl) phenylmethyl]piperazinyl}ethoxy)-5-[5- (aminohydroxycarbonylamino)pent-1-ynyl]benzamide               64                         CR   2 HCl   208   576.2   3.14   2-(2-{4-[(1R)(4-chlorophenyl) phenylmethyl]piperazinyl}ethoxy)-5-[4- (aminohydroxycarbonylamino]but-1- ynyl]benzamide               65                         CR               5.34   N-{4-[4-(2-{4-[(1R)(4-chlorophenyl) phenylmethyl]piperazinyl}ethoxy)-3- (trifluoromethyl)phenyl]but-3- ynyl}amino-N-hydroxyamide               66                         CR   2 HCl       600.36   5.34   N-{4-[4-(2-[(1R)(4-chlorophenyl) phenylmethyl]piperazinyl}ethoxy)-3- (trifluoromethyl)phenyl;]but-3-ynyl}amin-N-hydroxyamide               67                         CR           557.5   4.1   N-{4-[4-(2-{4-[(1R)(4-chlorophenyl) phenylmethyl]piperazinyl}ethoxy)-3- cyanophenyl]but-3-ynyl}amino-N- hydroxyamide               68                         CR           560.59   5.05   N-{4-[4-(4-{4-[(1R)(4-chlorophenyl) phenylmethyl]piperazinyl}butoxy)phenyl]but-3-ynyl}amino-N-hydroxyamide               69                         CR           561.57   2.63   2-(2-{4-[(1R)(4-chlorophenyl) phenylmethyl]piperazinyl}ethoxy)-5-(3- (aminohydroxycarbonylamino)prop-1- ynyl]benzamide               70                         CR           564.56   5.41   N-{4-[4-(4-{4-[(1R)(4-chlorophenyl) phenylmethyl)piperazinyl}butoxy)phenyl]butyl}amino-N-hydroxyamide               71                         CR           604.56   5.84   N-{4-[4-(2-{4-[(1S)(4-chlorophenyl) phenylmethyl]piperazinyl}ethoxy)-3- (trifluoromethyl)phenyl]butyl}amino-N- hydroxyamide               72                         CR   2 HCl       604.44   5.84   N-{4-[4-(2-{4-[(1R)(4-chlorophenyl) phenylmethyl]piperazinyl}ethoxy)-3- (trifluoromethyl)phenyl]butyl}amino-N- hydroxyamide               73                                         6.95   amino-N-[4-(4-{4-[4-(8-chloro(5,6- dihydroxbenzo[f]pyridino[2,3-b][7]annulen-11-ylidene))piperidyl]butoxy}phenyl)but-3-ynyl]-N-hydroxyamide               74                                         7.31   amino-N-[4-(4-{4-[4-(8-chloro(5,6- dihydrobenzo[f]puridino[2,3-b][7]annulen-11-ylidene))piperidyl]butoxy}phenyl)butyl]-N-hydroxyamide               75                         CR           561.57   5.4   N-{4-[4-(2-{4-[(1R)(4-chlorophenyl) phenylmethyl]piperazinyl}ethoxy) phenyl]but-3-ynyl}ethoxy-N- hydroxycarboxamide               76                         CR   2 HCl   121-123   564.64   5.41   N-{4-[4-(4-{4-[(1R)(4-chlorophenyl) phenylmethyl]piperazinyl}butoxy) phenyl]butyl}amino-N-hydroxyamide               77                         CR       90-95   589.45   3.19   N-[2-(2-{4-[(1R)(4-chloophenyl) phenylmethyl]piperazinyl}ethoxy)-5-[4- (aminohydroxycarbonylamino)but-1- ynyl]phenyl]acetamide               78                         CR   2 HCl   400   589.7   3.19   N-[2-(2-{4-[(1R)(4-chlorophenyl) phenylmethyl]piperazinyl}ethoxy)-5-[4- (aminohydroxycarbonylamino)but-1- ynyl]phenyl]acetamide               79                         CR       60-65   550.49   4.9   N-{4-[4-(3-{4-[(1R)(4-chlorophenyl) phenylmethyl)piperazinyl}propoxy) phenyl]butyl}amino-N-hydroxyamide               80                                 64-68   562.5   4.63   amino-N-{4-[4-(4-{4-[bis(4-fluoro phenyl)methyl]piperazinyl}butoxy) phenyl]but-3-ynyl}-N-hydroxyamide               81                         Chiral (R,R,R)       42   496.57   4.39   N-{4-[(2R)-5-({4-[(1R)(4-chlorophenyl) phenylmethyl]piperazinyl}methyl) oxolan-2-yl]but-3-ynyl}amino-N- hydroxyamide               82                         CR       52-90   536.52   2.75   N-{3-[4-(3-{4-[(1R)(4-chlorophenyl) phenylmethyl)piperazinyl}propxy) phenyl]propyl}amino-N-hydroxyamide               83                                 78   549.1   4.12   amino-N-{4-[4-(3-{4-[bis(4-fluoro phenyl)methyl]piperazinyl}propoxy) phenyl]but-3-ynyl}-N-hydroxyamide               84                         CR       123-125   594.3   4   2-(3-{4-[(1R)(4-chlorophenyl) phenylmethyl]piperazinyl}propoxy)-5-[4- (aminohydroxycarbonylamino) butyl]benzamide               85                                 138-140   582.5   3.22   5-{4-[(aminocarbonyl)(hydroxy)amino]butyl}-2-(2-{4-[bis(4-fluorophenyl) methyl]-1-piperazinyl}ethoxy) benzamide               86                                 30-80   539.4   3.97   N-{3-[4-(3-{4-[bis(4-fluorophenyl) methyl]-1-piperazinyl}propoxy)phenyl]propyl}-N-hydroxyurea               87                                 65-70   580.1   3.74   N-{4-[4-(2-{4-[bis(4-fluorophenyl) methyl]-1-piperazinyl}ethoxy)-2- nitrophenyl]-4-butynyl}-N-hydroxyurea               88                                 140-145   539.2   4.12   N-{4-[4-(2-{4-[bis(4-fluorophenyl) methyl]-1-piperazinyl)ethoxy)phenyl]butyl}-N-hydroxyurea               89                         CR   Fumarate   162-165   576.2   3.14   5-{4-[(aminocarbonyl)(hydroxy)amino]- 1-butynyl}-2-(2-{4-[(R)-(4- chlorophenyl)(phenyl)methyl]-1- piperazinyl)ethoxy)benzamide               90                         CR       70-75   577.9   4.17   N-{4-[4-(2-[(R)-(4-chlorophenyl) (phenyl)methyl]-1-piperazinyl}ethoxy)-2- nitrophenyl]-3-butynyl}-N-hydroxyurea               91                         CR   Maleate   169-172   576.2   3.14   5-{4-[(aminocarbonyl)(hydroxy)amino]- 1-butynyl}-2-(2-{4-[(R)-(4- chlorophenyl)(phenyl)methyl]-1- piperazinyl}ethoxy)benzamide               92                         CR   L-tartrate   155-158   576.2   3.14   5-{4-[(aminocarbonyl)(hydroxy)amino]- 1-butynyl}-2-(2-{4-[(R)-(4- chlorophenyl)(phenyl)methyl]-1- piperazinyl}ethoxy)benzamide               93                         CR   Citrate   153-156   576   3.14   5-{4-[(aminocarbonyl)(hydroxy)amino]- 1-butynyl}-2-(2-{4-[(R)-(4- chlorophenyl)(phenyl)methyl]-1- piperazinyl}ethoxy)benzamide               94                         CR       64-66   538   4.39   N-{3-[4-(3-{4-[(R)-(4-chlorophenyl) (phenyl)methyl]-1-piperazinyl}propyl) phenoxy]propyl}-N-hydroxyurea               95                         CR       127-130   557   4.44   N-(4-{4-[(4-{4-[(R)-(4-chlorophenyl) (phenyl)methyl]-1-piperazinyl}-2- butynyl)oxy]phenyl}-3-butynyl)-N- hydroxyurea                          
 
     [0062] Particularly preferred compounds are those listed in Table I, infra.  
     [0063] More preferred are compounds 1, 5, 11, 12, 13, 17, 23, 24, 31, 32, 33, 34, 35, 36, 37, 40, 41, 42, 43, 44, 45, 46, 48, 49, 50, 52, 53, 54, 55, 56, 57, 58, 59, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, and 94. The most preferred compounds are 17, 32, 34, 35, 46, 52 and 80.  
     Definitions  
     [0064] The following paragraphs provide definitions of the various chemical moieties that make up the compounds of the invention and are intended to apply uniformly throughout the specification and claims unless expressly stated otherwise.  
     [0065] The term alkyl refers to a univalent C 1  to C 6  saturated straight, branched, or cyclic alkane moiety and specifically includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, cyclopentyl, isopentyl, neopentyl, hexyl, isohexyl, cyclohexyl, 3-methylpentyl, 2,2-dimethylbutyl, and 2,3-dimethylbutyl. The alkyl group can be optionally substituted with any appropriate group, including but not limited to R 3  or one or more moieties selected from the group consisting of halo, hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate, either unprotected, or protected as necessary, as known to those skilled in the art or as taught, for example, in Greene, et al., “Protective Groups in Organic Synthesis,” John Wiley and Sons, Third Edition, 1999.  
     [0066] The term alkoxy refers to an alkyl moiety having a terminal —O— with free a valence, e.g., CH 3 CH 2 —O—;  
     [0067] The term yloalkoxy is an alkoxy (as defined above) in which a hydrogen atom has been removed from the alkyl moiety to yield a divalent radical, .e.g., —CH 2 CH 2 O— or —CH(CH 3 )O—.  
     [0068] The term yloalkoxyalkyl refers to a divalent, dialkyl ether moiety having one free valence on each of the alkyl moieties, which alkyl moieties are the same or different, e.g., —CH 2 CH 2 CH 2 —O—CH 2 —.  
     [0069] The term alkylene refers to an alkyl moiety (as defined above) in which a hydrogen atom has been removed to yield a divalent radical, e.g., —CH 2 CH(CH 3 )CH 2 CH 2 —.  
     [0070] The term alkenyl refers to a univalent C 2 -C 6  straight, branched, or in the case of C 5-6 , cyclic hydrocarbon with at least one double bond, optionally substituted as described above.  
     [0071] The term alkenylene refers to an alkenyl moiety (as defined above) in which a hydrogen atom has been removed to yield a divalent radical, e.g., —CH 2 CH═CHCH 2 —.  
     [0072] The term alkynyl refers to a univalent C 2  to C 6  straight or branched hydrocarbon with at least one triple bond (optionally substituted as described above) and specifically includes acetylenyl, propynyl, and —C≡C—CH 2 (alkyl), including —C≡C—CH 2 (CH 3 ).  
     [0073] The term alkynylene refers to an alkynyl moiety (as defined above) in which a hydrogen atom has been removed to yield a divalent radical, e.g., —C≡C—CH(CH 3 )—.  
     [0074] The term aryl refers to a univalent phenyl (preferably), biphenyl, or napthyl. The aryl group can be optionally substituted with any suitable group, including but not limited to one or more moieties selected from the group consisting of halo, hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate, either unprotected, or protected as necessary, as known to those skilled in the art, for example, as taught in Greene, et al., “Protective Groups in Organic Synthesis,” John Wiley and Sons, Third Edition, 1999, and preferably with halo (including but not limited to fluoro), alkoxy (including methoxy), aryloxy (including phenoxy), W, cyano, or R 3 .  
     [0075] The terms arylene and divalent arene refer to an aryl moiety (as defined above) in which a hydrogen atom has been removed to yield a divalent radical, e.g., —C 6 H 4 —.  
     [0076] The term trivalent arene refers to an arylene moiety (as defined above) in which a hydrogen atom has been removed to yield a trivalent radical, e.g.,  
                 
 
     [0077] The term yloalkylaryl refers to a divalent alkyl-substituted aryl moiety in which one open valence is on the alkyl moiety and one is on the aryl moiety, e.g., —CH 2 —CH 2 —C 6 H 4 —.  
     [0078] The term yloarylalkyl refers to a divalent aryl-substituted alkyl moiety in which one open valence is on the alkyl moiety and one is on the aryl moiety, e.g., —C 6 H 4 —CH 2 —CH 2 —.  
     [0079] The term diylodialkylarene refers to a divalent, dialkyl-substituted arene in which there is one open valence on each of the alkyl moieties (which may be the same or different), e.g., —CH 2 —C 6 H 4 —CH 2 CH 2 — 
     [0080] The term heteroatom means O, S, or N.  
     [0081] The term heterocycle refers to a cyclic alkyl, alkenyl, or alkynyl moiety as defined above wherein one or more ring carbon atoms is replaced with a heteroatom.  
     [0082] The terms heteroarylene and divalent heteroarene refer to an arylene (or divalent heteroarene) that includes at least one sulfur, oxygen, or nitrogen in the aromatic ring, which can optionally be substituted as described above for the aryl groups. Non-limiting examples are, furylene, pyridylene, 1,2,4-thiadiazolylene, pyrimidylene, thienylene, isothiazolylene, imidazolylene, tetrazolylene, pyrazinylene, pyrimidylene, quinolylene, isoquinolylene, benzothienylene, isobenzofurylene, pyrazolylene, indolylene, purinylene, carbazolylene, benzimidazolylene, and isoxazolylene.  
     [0083] The term trivalent heteroarene refers to a heteroarylene moiety (as defined above) in which a hydrogen atom has been removed to yield a trivalent radical, e.g.,  
                 
 
     [0084] The term halo refers to chloro, fluoro, iodo, or bromo.  
     [0085] When a methylene of an alkyl, alkenyl, or alkynyl (or their divalent radical counterparts) is replaced by O, —NH—, —S—, —S(O)—, or —S(O) 2 —, it may be at any suitable position in the moiety, either at the terminal or internal positions, e.g., CH 3 CH 2 —O—, CH 3 —O—CH 2 —, CH 3 CH 2 NH—, and CH 3 NHCH 2 —.  
     [0086] Open valences on the radical moieties described herein can occur on any one (or more for divalent radicals) of the atoms within the moiety. For example, the monovalent C 3  alkyl moiety includes both propyl and isopropyl. As another example, the divalent C 4  alkylene moiety includes both tetramethylene (—CH 2 (CH 2 ) 2 CH 2 —) and ethylethylene (—CH(CH 2 CH 3 )CH 2 —).  
     [0087] The term organic or inorganic anion refers to an organic or inorganic moiety that carries a negative charge and can be used as the negative portion of a salt.  
     [0088] The term “pharmaceutically acceptable cation” refers to an organic or inorganic moiety that carries a positive charge and that can be administered in association with a pharmaceutical agent, for example, as a countercation in a salt. Pharmaceutically acceptable cations are known to those of skill in the art, and include but are not limited to sodium, potassium, and quaternary ammonium.  
     [0089] The term “metabolically cleavable group” refers to a moiety that can be cleaved in vivo from the molecule to which it is attached, and includes but is not limited to an organic or inorganic anion, a pharmaceutically acceptable cation, acyl (for example (alkyl)C(O), including acetyl, propionyl, and butyryl), alkyl, phosphate, sulfate and sulfonate, NH 2 C(O)— or (alkyl)OC(O)—.  
     [0090] The term 5-lipoxygenase inhibitor refers to a compound that inhibits the enzyme at 30 μM or lower. The term 15-lipoxygenase inhibitor refers to a compound that inhibits the enzyme at 30 μM or lower.  
     [0091] As used herein, the term pharmaceutically acceptable salts or complexes refers to salts or complexes that retain the desired biological activity of the above-identified compounds and exhibit minimal or no undesired toxicological effects. Examples of such salts include, but are not limited to acid addition salts formed with inorganic acids (for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like), and salts formed with organic acids such as fumaric acid, maleic acid, acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, and polygalacturonic acid. The compounds can also be administered as pharmaceutically acceptable quaternary salts known by those skilled in the art, which specifically include, but are not limited to the quaternary ammonium salt of the formula —NR + Z − , wherein R is hydrogen, alkyl, or benzyl, and Z is a counterion, including chloride, bromide, iodide, —O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (such as fumarate, benzoate, succinate, acetate, glycolate, maleate, malate, citrate, tartrate, ascorbate, benzoate, cinnamoate, mandeloate, benzyloate, and diphenylacetate).  
     [0092] The term pharmaceutically active derivative refers to any compound that upon administration to the recipient, is capable of providing directly or indirectly, the compounds disclosed herein.  
     Synthetic Schemes  
     [0093] The synthetic schemes displayed in FIGS.  1 - 9  and Examples 1-7 illustrate how compounds according to the invention can be made. Those skilled in the art will be able to routinely modify and/or adapt these schemes and descriptions to synthesize any compound of the invention.  
     Pharmaceutical Compositions, Methods of Treatment and Administration  
     [0094] The compounds of the invention are useful for treating conditions in which there is likely to be a histamine and/or leukotriene component. These conditions include preferably asthma, seasonal and perennial allergic rhinitis, sinusitus, conjunctivitis, food allergy, scombroid poisoning, psoriasis, urticaria, pruritus, eczema, rheumatoid arthritis, inflammatory bowel disease, chronic obstructive pulmonary disease, thrombotic disease and otitis media. The compounds exhibit this biological activity by acting as histamine H1 receptor antagonists, by inhibiting the lipoxygenase enzymes such as 5-lipoxygenase, or by exhibiting dual activity, i.e., by acting as both a histamine H1 receptor antagonist and inhibitor of lipoxygenase such as 5-lipoxygenase.  
     [0095] Subjects in need of treatment for a leukotriene-mediated and/or histamine-mediated condition (preferably, asthma, seasonal and perennial allergic rhinitis, sinusitus, conjunctivitis, food allergy, scombroid poisoning, psoriasis, urticaria, pruritus, eczema, rheumatoid arthritis, inflammatory bowel disease, chronic obstructive pulmonary disease, thrombotic disease and otitis media) can be treated by administering to the patient an effective amount of one or more of the above-identified compounds or a pharmaceutically acceptable derivative or salt thereof in a pharmaceutically acceptable carrier or diluent to reduce formation of oxygen radicals. The active materials can be administered by any appropriate route, for example, orally, parenterally, intravenously, intradermally, subcutaneously, intramuscularly or topically, in liquid, cream, gel or solid form, via a buccal or nasal spray, or aerosol.  
     [0096] The invention further concerns the use of the compounds of formula I for the manufacture of a medicament for therapeutic application. In particular, the invention concerns the use of the compounds of formula 1 for the manufacture of a medicament useful for treating conditions in which there is likely to be a histamine and/or leukotriene component. The invention concerns the use of the compound of formula 1 for the manufacture of a medicament useful for treating asthma, seasonal and perennial allergic rhinitis, sinusitus, conjunctivitis, food allergy, scombroid poisoning, psoriasis, urticaria, pruritus, eczema, rheumatoid arthritis, inflammatory bowel disease, chronic obstructive pulmonary disease, thrombotic disease and otitis media, and preferably asthma, seasonal and perennial allergic rhinitis.  
     [0097] The invention further concerns the compounds of formula I for use as medicaments. The invention concerns the compounds of formula I for use as a medicament for treating asthma, seasonal and perennial allergic rhinitis, sinusitis, conjunctivitis, food allergy, scombroid poisoning, psoriasis, urticaria, pruritus, eczema, rheumatoid arthritis, inflammatory bowel disease, chronic obstructive pulmonary disease, thrombotic disease and otitis media, and preferably asthma, seasonal and perennial allergic rhinitis.  
     [0098] The active compound is included in the pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver to a patient a therapeutically effective amount without causing serious toxic effects in the patient treated. A preferred dose of the active compound for all of the above-mentioned conditions is in the range from about 0.01 to 300 mg/kg, preferably 0.1 to 100 mg/kg per day, more generally 0.5 to about 25 mg per kilogram body weight of the recipient per day. A typical topical dosage will range from 0.01-3% wt/wt in a suitable carrier. The effective dosage range of the pharmaceutically acceptable derivatives can be calculated based on the weight of the parent compound to be delivered. If the derivative exhibits activity in itself, the effective dosage can be estimated as above using the weight of the derivative, or by other means known to those skilled in the art.  
     [0099] The methods of the invention comprise administration to a mammal (preferably human) suffering from a leukotriene-mediated and/or histamine-mediated condition (preferably, asthma and rhinitis) a pharmaceutical composition according to the invention in an amount sufficient to alleviate the condition. The compound is conveniently administered in any suitable unit dosage form, including but not limited to one containing 1 to 3000 mg, preferably 5 to 500 mg of active ingredient per unit dosage form. A oral dosage of 1-500, preferably 10-250, more preferably 25-250 mg is usually convenient.  
     [0100] The active ingredient should be administered to achieve peak plasma concentrations of the active compound of about 0.001-30 μM, preferably about 0.01-10 μM. This may be achieved, for example, by the intravenous injection of a solution or formulation of the active ingredient, optionally in saline, or an aqueous medium or administered as a bolus of the active ingredient.  
     [0101] The concentration of active compound in the drug composition will depend on absorption, distribution, inactivation, and excretion rates of the drug as well as other factors known to those of skill in the art. It is to be noted that dosage values will also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition. The active ingredient may be administered at once, or may be divided into a number of smaller doses to be administered at varying intervals of time.  
     [0102] Oral compositions will generally include an inert diluent or an edible carrier. They may be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition.  
     [0103] The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a dispersing agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterores; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring. When the dosage unit form is a capsule, it can contain, in addition to material of the above type, a liquid carrier such as a fatty oil. In addition, dosage unit forms can contain various other materials which modify the physical form of the dosage unit, for example, coatings of sugar, shellac, or enteric agents.  
     [0104] The active compound or pharmaceutically acceptable salt or derivative thereof can be administered as a component of an elixir, suspension, syrup, wafer, chewing gum or the like. A syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors.  
     [0105] The active compound or pharmaceutically acceptable derivatives or salts thereof can also be mixed with other active materials that do not impair the desired action, or with materials that supplement, the desired action, such as adrenergic agonists like pseudoephedrine, antibiotics, antifungals, other anti-inflammatories, or antiviral compounds.  
     [0106] Solutions or suspensions used for parenteral, intradermal, subcutaneous, intravenous, intramuscular or topical application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. The parental preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.  
     [0107] If administered intravenously, preferred carriers are physiological saline or phosphate buffered saline (PBS).  
     [0108] In one embodiment, the active compounds are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. The materials can also be obtained commercially from Alza Corporation (CA) and Guilford Pharmaceuticals (Baltimore, Md.). Liposomal suspensions may also be pharmaceutically acceptable carriers. These may be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,811 (which is incorporated herein by reference in its entirety). For example, liposome formulations may be prepared by dissolving appropriate lipid(s) (such as stearoyl phosphatidyl ethanolamine, stearoyl phosphatidylcholine, arachadoyl phosphatidylcholine, and cholesterol) in an inorganic solvent that is then evaporated, leaving behind a thin film of dried lipid on the surface of the container. An aqueous solution of the active compound or its monophosphate, diphosphate, and/or triphosphate derivatives are then introduced into the container. The container is then swirled by hand to free lipid material from the sides of the container and to disperse lipid aggregates, thereby forming the liposomal suspension.  
     [0109] The following Examples are provided for illustrative purposes only and are not intended, nor should they be construed, as limiting the invention in any manner. Those skilled in the art will appreciate that routine variations and modifications of the following Examples can be made without exceeding the spirit or scope of the invention.  
     EXAMPLES  
     Example 1  
     Preparation of N-{[4-( 2-{4 -[(1R)(4-chlorophenyl) phenylmethyl]piperazinyl}ethoxy)phenyl]methyl}-amino-N-hydroxyamide (compound  1 , FIG.  1 )  
     [0110] 4-(2-Bromoethoxy)benzylalcohol (compound  101 )  
     [0111] To a solution of 4-hydroxybenzylalcohol (2.0 g, 16.11 mmol) in DMF (10 mL) was added potassium carbonate (2.67 g, 19.32 mmol). The reaction was stirred at room temperature for 30 minutes and then 1,2-dibromoethane (3.03 g, 16.13 mmol) was added. The reaction was stirred at room temperature for additional 20 hours and then quenched with water, and extracted with ethyl acetate. The organic layer was washed with water and brine, evaporated to yield an oil which was purified by flash column chromatography (silica gel, 3:1 hexane/ethyl acetate) to yield  101  (1.7 g, 45.7%):  1 H NMR (CDCl 3 ) δ 3.64 (t, 2H), 4.29 (t, 2H), 4.62 (s, 2H), 6.91 (d, 2H), 7.30 (d, 2H).  
     [0112] 4-{12-[4 -((1R)(4-Chlorophenyl)phenylmethyl)piperazinyl]ethoxy}benzylalcohol (compound  103 )  
     [0113] To a solution of  101  (205 mg, 0.89 mmol), [(1R)(4-chlorophenyl) phenylmethyl]-piperazine ( 102 ) (230 mg, 0.80 mmol) in dichloromethane (2.5 mL) was added triethylamine (122.0 mg, 1.21 mmol). The reaction was stirred at 50° C. for 20 hours. The solvent was evaporated and the residue was purified by flash column chromatography (silica gel, 3:1 hexane/ethyl acetate) to yield  103  (330 mg, 94.1%):  1 H NMR (CDCl 3 ) δ 2.45 (m, 4H), 2.62 (m, 4H), 2.81 (t, 2H), 4.08 (t, 2H), 4.22 (s, 1H), 4.51 (s, 2H), 6.87 (d, 2H), 7.28 (m, 6H), 7.39 (m, 5H).  
     [0114] N-{[4-( 2-{4 -[(1R)(4-Chlorophenyl)phenylmethyl]piperazinyl}ethoxy)phenyl]methyl}phenoxycarbonylaminophenoxyformate (compound  104 )  
     [0115] To a stirred solution of  103  (330 mg, 0.76 mmol), phenoxycarbonylaminophenoxyformate (251.6 mg, 0.92 mmol) and triphenylphosphine (225.2 mg, 0.86 mmol) in THF (8 mL) at 0° C. was added diisopropylazodicarboxylate (174.1 mg, 0.86 mmol). After addition, the reaction was warmed to room temperature and stirred at room temperature for 2 hours. The solvent was evaporated and the residue was purified by flash column chromatography (silica gel, 2:1 hexane/ethyl acetate) to give  104  (410 mg, 78.4%):  1 H NMR (CDCl 3 ) δ 2.47 (m, 4H), 2.65 (m, 4H), 2.84 (t, 2H), 4.12 (t, 2H), 4.23 (s, 1H), 4.95 (s, 2H), 6.92 (d, 2H), 7.20 (m, 5H), 7.26 (m, 6H), 7.40 (m, 10H).  
     [0116] N-{[4-( 2-{4 -[(1R)(4-chlorophenyl)phenylmethyl]piperazinyl} ethoxy)phenyl]methyl}-amino-N-hydroxyamide (compound  1 )  
     [0117] In a screw top vessel was placed a solution of  104  (410 mg, 0.59 mmol) in methanol (15 mL) and cooled to −78° C. with dry ice-acetone bath. To this vessel was added liquid NH3 (2-3 mL) and sealed. The dry ice-acetone bath was then removed and the reaction was stirred at room temperature for 16 hours. The reaction was cooled again in a dry ice-acetone bath and the pressure released. The vessel was opened and the solvent was evaporated. Compound  1  was separated by flash column chromatography (silica gel, 19:1 CH 2 Cl 2 /CH 3 OH) (215 mg, 73.2%):  1 H NMR (CDCl 3 ) δ 2.42 (m, 4H), 2.59 (m, 4H), 2.74 (t, 2H), 3.98 (t, 2H), 4.20 (s, 1H), 4.57 (s, 2H), 5.22 (bs, 2H), 6.77 (d, 2H), 7.25 (m, 6H), 7.36 (m, 5H).  
     Example 2  
     Preparation of N-{ 4-[4 -( 2-{4 -[(1R)(4-chlorophenyl)phenylmethyl]piperazinyl}ethoxy)phenyl]but-3-ynyl}-amino-N-hydroxyamide (compound  12 , FIG.  2 )  
     [0118] 4-(2-Bromoethoxy)-1-iodobenzene (compound  105 )  
     [0119] To a solution of 4-iodophenol (10.0 g, 45.45 mmol) in DMF (50 mL) was added potassium carbonate (12.6 g, 91.17 mmol). The reaction was stirred at room temperature for 30 minutes and then 1,2-dibromoethane (17.07 g, 90.91 mmol) was added. The reaction was stirred at room temperature for additional 16 hours and then quenched with water and extracted with dichloromethane. The organic layer was washed with water and brine, evaporated to yield an oil which was purified by flash column chromatography (silica gel, hexane) to yield  105  (2.7 g, 18.2%):  1 H NMR (CDCl 3 ) δ 3.63 (t, 2H), 4.26 (t, 2H), 6.70 (d, 2H), 7.58 (d, 2H).  
     [0120] 4-[4 -(2-Bromoethoxy)phenyl]but-3-yn-1-ol (compound  106 )  
     [0121] To a mixture of  105  (2.7 g, 8.26 mmol), 3-butyn-1-ol (696.3 mg, 9.94 mmol), dichlorobis(triphenylphosphine)palladium(II) (1.15 g, 1.64 mmol) and cuprous iodide (317.1 mg, 1.67 mmol) was added triethylamine (45 mL). The reaction was stirred at room temperature for 16 hours. The solvent was evaporated and the residue purified by flash column chromatography (silica gel, 3:1 hexane/ethyl acetate) to yield  106  (1.3 g, 58.6%):  1 H NMR (CDCl 3 ) δ 2.70 (m, 4H), 3.65 (t, 2H), 3.82 (m, 2H), 4.30 (t, 2H), 6.83 (d, 2H), 7.37 (d, 2H).  
     [0122] 4-{4-[2 -(4-((1R)(4-Chlorophenyl)phenylmethyl)piperazinyl)ethoxy]phenyl}but-3-yn-1-ol (compound  107 )  
     [0123] To a solution of  106  (1.5 g, 5.58 mmol), [(1R)(4-chlorophenyl)phenylmethyl]piperazine ( 102 ) (1.6 g, 5.59 mmol) in DMF (15 mL) was added triethylamine (871.2 mg, 8.63 mmol). The reaction was stirred at 50° C. for 20 hours, water was added, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered and evaporated to an oil which was purified by flash column chromatography (silica gel, 1:1 hexane/ethyl acetate) to yield  107  (2.6 g, 98.1%):  1 H NMR (CDCl 3 ) δ 2.42 (m, 4H), 2.61 (m, 4H), 2.68 (t, 2H), 2.82 (t, 2H), 3.80 (t, 2H), 4.10 (t, 2H), 4.21 (s, 1H), 6.80 (d, 2H), 7.26 (m, 5H), 7.35 (m, 6H).  
     [0124] N- {4-[4 -(2-(4-((1R)(4-Chlorophenyl)phenylmethyl)piperazinyl)ethoxy)phenyl]but-3-ynyl}phenoxycarbonylaminophenoxyformate (compound  108 )  
     [0125] To a stirred solution of  107  (1.5 g, 3.16 mmol), phenoxycarbonylaminophenoxyformate (1.05 g, 3.85 mmol) and triphenylphosphine (937.1 mg, 3.57 mmol) in THF (35 mL) at 0° C. was added diisopropylazodicarboxylate (721.4 mg, 3.57 mmol). After addition, the reaction was warmed to room temperature and stirred at room temperature for 2 hours. The solvent was evaporated and the residue was purified by flash column chromatography (silica gel, 2:1 hexane/ethyl acetate) to give  108  (1.4 g, 60.6%):  1 H NMR (CDCl 3 ) δ 2.44 (m, 4H), 2.62 (m, 4H), 2.82 (m, 2H), 2.91 (t, 2H), 4.10 (m, 4H), 4.21 (s, 1H), 6.80 (d, 2H), 7.18 (m, 5H), 7.30 (m, 8H), 7.37 (m, 8H).  
     [0126] N- {4-[4 -( 2-[4 -[(1R)(4-chlorophenyl)phenylmethyl]piperazinyl}ethoxy)phenyl]but-3-ynyl]-amino-N-hydroxyamide (compound  12 )  
     [0127] In a screw top vessel was placed a solution of  108  (1.4 g, 1.92 mmol) in methanol (50 mL) and cooled to −78° C. with dry ice-acetone bath. To this vessel was added liquid NH 3  (6 mL) and sealed. The dry ice-acetone bath was then removed and the reaction was stirred at room temperature for 16 hours. The reaction was cooled again in a dry ice-acetone bath and the pressure released. The vessel was opened and the solvent evaporated. Compound  12  was separated by flash column chromatography (silica gel, 19:1 CH 2 Cl 2 /CH 3 OH) (580 mg, 56.9%):  1 H NMR (CDCl 3 ) δ 2.45 (m, 4H), 2.65 (m, 4H), 2.72 (t, 2H), 2.84 (t, 2H), 3.80 (t, 2H), 4.10 (t, 2H), 4.22 (s, 1H), 5.25 (bs, 2H), 6.80 (d, 2H), 7.25 (m, 5H), 7.36 (m, 6H).  
     Example 3  
     Preparation of N-{ 4-[4 -( 2-{4 -[(1R)(4-chlorophenyl)phenylmethyl]piperazinyl}ethoxy)phenyl]butyl}-amino-N-hydroxyamide (compound  17 , FIG.  3 )  
     [0128] 4-[4 -(2-Bromoethoxy)phenyl]butan-1-ol (compound  109 )  
     [0129] A solution of  106  (1.3 g, 4.83 mmol) in methanol (15 mL) was hydrogenated over 10% palladium on charcoal (130 mg) at balloon pressure for 7 hours. The catalyst was filtered off and the filtrate was evaporated to give  109  (1.31 g, 99.2%):  1 H NMR (CDCl 3 ) δ 1.65 (m, 4H), 2.60 (t, 2H), 3.66 (m, 4H), 4.28 (m, 2H), 6.83 (d, 2H), 7.10 (d, 2H).  
     [0130] 4-{4-[2 -(4-((1R)(4-Chlorophenyl)phenylmethyl)piperazinyl)ethoxy]phenyl}butan-1-ol (compound  110 )  
     [0131] To a solution of  109  (1.3 g, 4.76 mmol) and [(1R)(4-chlorophenyl)phenylmethyl]piperazine ( 102 ) (1.39 g, 4.86 mmol) in DMF (12 mL) was added triethylamine (762.3 mg, 7.55 mmol). The reaction was stirred at 500 C for 16 hours, water was added, and the reaction was extracted with dichloromethane. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered, and evaporated to an oil, which was purified by flash column chromatography (silica gel, 1:1 hexane/ethyl acetate) to yield  110  (2.42 g, 104%):  1 H NMR (CDCl 3 ) δ 1.65 (m, 4H), 2.45 (m, 4H), 2.62 (m, 6H), 2.81 (t, 2H), 3.66 (t, 2H), 4.08 (t, 2H), 4.21 (s, 1H), 6.81 (d, 2H), 7.08 (d, 2H), 7.25 (m, 4H), 7.36 (m, 5H), 8.02 (bs, 1H).  
     [0132] N- {4-[4 -(2-(4-((1R)(4-Chlorophenyl)phenylmethyl)piperazinyl)ethoxy)phenyl]butan-1-ol}phenoxycarbonylaminophenoxyformate (compound  111 )  
     [0133] To a stirred solution of  110  (1.5 g, 3.14 mmol), phenoxycarbonylaminophenoxyformate (1.05 g, 3.85 mmol) and triphenylphosphine (938.0 mg, 3.58 mmol) in THF (35 mL) at 0° C. was added diisopropylazodicarboxylate (724.0 mg, 3.58 mmol). After addition, the reaction was warmed to room temperature and stirred at room temperature for 2 hours. The solvent was evaporated and the residue was purified by flash column chromatography (silica gel, 2:1 hexane/ethyl acetate) to give  111  (1.58 g, 68.7%).  
     [0134] N-{ 4-[4 -( 2-{4 -[(1R)(4-chlorophenyl)phenylmethyl]piperazinyl}ethoxy) phenyl]butyl}-amino-N-hydroxyamide (compound  17 )  
     [0135] In a screw top vessel was placed a solution of  111  (1.58 g, 2.16 mmol) in methanol (50 mL) and cooled to −78° C. in a dry ice-acetone bath. To this vessel was added liquid ammonia (6 mL) and sealed. The dry ice-acetone bath was then removed and the reaction was stirred at room temperature for 16 hours. The reaction was cooled again in a dry ice-acetone bath and the pressure was released. The vessel was opened and the solvent was evaporated. Compound  17  was separated by flash column chromatography (silica gel, 19:1 CH 2 Cl 2 /CH 3 OH) and further purified by recrystallization using ethyl acetate-hexane as a solvent (550 mg, 47.4%):  1 H NMR (CDCl 3 ) δ 1.60 (m, 4H), 2.44 (m, 4H), 2.52 (t, 2H), 2.67 (m, 4H), 2.83 (t, 2H), 3.48 (t, 2H), 4.08 (t, 2H), 4.21 (s, 1H), 6.78 (d, 2H), 7.04 (d, 2H), 7.25 (m, 4H), 7.35 (m, 5H).  
     Example 4  
     Preparation of methyl-2-( 2-{4 -[(1R)(4-chlorophenyl)phenylmethyl]piperazinyl}ethoxy)- 5-[4 -(aminohydroxycarbonylamino)but-1-ynyl]benzoate (compound  36 , FIG.  4 ), 2-( 2-{4 -[(1R)(4-chlorophenyl)phenylmethyl]piperazinyl}ethoxy)- 5-[4 -(aminohydroxyarbonylamino) but-1-ynyl]benzamide (compound  35 , FIG.  4 ), and 2-( 2-{4 -[(1R)(4-chlorophenyl)phenylmethyl]piperazin-yl}ethoxy)- 5-[4 -(aminohydroxycarbonylamino)but-1-ynyl]benzoic acid (compound  37 , FIG.  5 )  
     [0136] 4-iodophenol, methyl acetate (compound  112 )  
     [0137] To a solution of 5-iodosalicylic acid (5.0 g, 18.94 mmol) in methanol (100 mL) was added a few drops of sulfuric acid. The reaction was stirred at reflux for 24 hours. The reaction solvent (methanol) was evaporated to small volume and water was added and extracted with dichloromethane. The organic layer was washed with 10% NaHCO 3  solution, water and brine, dried over magnesium sulfate, filtered and evaporated to give the title compound (3.5 g, 66.5%):  1 H NMR (CDCl 3 ) δ 3.96 (s, 3H), 6.78 (d, 1H), 7.70 (dd, 1H), 8.12 (d, 1H).  
     [0138] Methyl 2-hydroxy-5-(4-hydroxybut-1-ynyl)benzoate (compound  113 )  
     [0139] To a mixture of  112  (2.0 g, 7.19 mmol), 3-butyn-1-ol (655.2 mg, 9.35 mmol), dichlorobis(triphenylphosphine)palladium(II) (1.0 g, 1.42 mmol) and cuprous iodide (276.3 mg, 1.45 mmol) was added triethylamine (40 mL). The reaction was stirred at room temperature for 16 hours. The solvent was evaporated and the residue was purified by flash column chromatography (silica gel, 2:1 hexane/ethyl acetate) to yield  113  (1.6 g, 101.3%):  1 H NMR (CDCl 3 ) δ 2.68 (t, 2H), 3.81 (m, 2H), 3.96 (s, 3H), 6.92 (d, 1H), 7.50 (dd, 1H), 7.93 (d, 1H).  
     [0140] Methyl 2-(2-bromoethoxy)-5-(4-hydroxybut-1-ynyl)benzoate (compound  114 )  
     [0141] To a solution of  113  (1.6 g, 7.27 mmol) in DMF (8 mL) was added potassium carbonate (1.51 g, 10.91 mmol). The reaction was stirred at room temperature for 30 minutes and then 1,2-dibromoethane (5.47 g, 29.09 mmol) was added. The reaction was stirred at room temperature for additional 16 hours and then quenched with water and extracted with dichloromethane. The organic layer was washed with water and brine, evaporated to yield an oil which was purified by flash column chromatography (silica gel, 2:1 hexane/ethyl acetate) to yield  114  (710 mg, 29.8%):  1 H NMR (CDCl 3 ) δ 2.70 (t, 2H), 3.68 (t, 2H), 3.82 (t, 2H), 3.90 (s, 3H), 4.35 (t, 2H), 6.90 (d, 1H), 7.50 (dd, 1H), 7.88 (d, 1H).  
     [0142] Methyl 2-( 2-{4 -[(1R)(4-chlorophenyl)phenylmethyl]piperazinyl}ethoxy)-5-(4-hydroxybut-1-ynyl)benzoate (compound  115 )  
     [0143] To a solution of  114  (300.0 mg, 0.92 mmol), [(1R)(4-chlorophenyl) phenylmethyl]piperazine ( 102 ) (262.4 mg, 0.92 mmol) in DMF (2 mL) was added triethylamine (139.0 mg, 1.38 mmol). The reaction was stirred at 50° C. for 20 hours, water was added, and the reaction was extracted with dichloromethane. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered and evaporated to an oil which was purified by flash column chromatography (silica gel, ethyl acetate) to yield  115  (510 mg, 102.4%):  1 H NMR (CDCl 3 ) δ 2.44 (m, 4H), 2.68 (m, 6H), 2.90 (m, 2H), 3.81 (t, 2H), 3.84 (s, 3H), 4.08 (m, 2H), 4.21 (s, 1H), 6.90 (d, 1H), 7.25 (m, 4H), 7.38 (m, 5H), 7.49 (dd, 1H), 7.85 (d, 1H).  
     [0144] N-{ 4-[4 -( 2-{4 -[(1R)(4-chlorophenyl)phenylmethyl]piperazinyl}ethoxy)-3-(methoxycarbonyl) phenyl] but-3-ynyl}phenoxycarbonylamino phenoxylormate (compound  116 )  
     [0145] To a stirred solution of  115  (320.0 mg, 0.60 mmol), phenoxycarbonylaminophenoxyformate (198.4 mg, 0.73 mmol) and triphenylphosphine (55.7 mg, 0.21 mmol) in THF (2 mL) at 0° C. was added diisopropylazodicarboxylate (78.2 mg, 0.68 mmol). After addition, the reaction was warmed to room temperature and stirred at room temperature for 2 hours. The solvent was evaporated and the residue was purified by flash column chromatography (silica gel, 1:1 hexane/ethyl acetate) to give  116  (350 mg, 73.9%):  1 H NMR (CDCl 3 ) δ 2.42 (m, 4H), 2.65 (m, 6H), 2.90 (m, 2H), 3.82 (s, 3H), 4.15 (m, 4H), 4.21 (s, 1H), 6.85 (d, 1H), 7.25 (m, 8H), 7.40 (m, 12H), 7.82 (s, 1H).  
     [0146] Methyl 2-( 2-{4 -[(1R)(4-chlorophenyl)phenylmethyl]piperazinyl}ethoxy)- 5-[4 -(aminohydroxycarbonyl amino)but-1-ynyl]benzoate (compound  36 ) and 2-( 2-{4 -[(1R)(4-chlorophenyl)phenylmethyl]piperazinyl}ethoxy)- 5-[4 -(aminohydroxycarbonyl amino)but-1-ynyl]benzamide (compound  35 )  
     [0147] In a screw top vessel was placed a solution of  116  (350 mg, 0.44 mmol) in methanol (20 mL) and cooled to −78° C. in a dry ice-acetone bath. To this vessel was added liquid ammonia (3 mL) and sealed. The dry ice-acetone bath was then removed and the reaction was stirred at room temperature for 16 hours. The reaction was cooled again in a dry ice-acetone bath and the pressure released. The vessel was opened and the solvent was evaporated. Compound  36  was separated by flash column chromatography (silica gel, 9:1 CH 2 Cl 2 /CH 3 OH) as a white solid. The mixture of compound  35  and  36  was further purified by flash column chromatography (silica gel, 9:1 CH 2 Cl 2 /CH 3 OH) to give additional compound  36  (total 31 mg) and compound  35  (containing about 5% compound  36 ). Compound  35  was further separated from compound  36  by recrystallization using ethyl acetate-hexane as a solvent (35 mg).  
     [0148] Compound  36 :  1 H NMR (CDCl 3 ) δ 2.45 (m, 4H), 2.70 (m, 6H), 2.90 (t, 2H), 3.75 (t, 2H), 3.83 (s, 3H), 4.18 (t, 2H), 4.21 (s, 1H), 5.34 (bs, 2H), 6.85 (d, 1H), 7.25 (m, 4H), 7.37 (m, 5H), 7.43 (dd, 1H), 7.80 (s, 1H).  
     [0149] Compound  35 :  1 H NMR (CDCl 3 ) δ 2.40 (m, 4H), 2.54 (m, 4H), 2.75 (t, 2H), 2.80 (t, 2H), 3.80 (t, 2H), 4.20 (m, 3H), 5.42 (bs, 2H), 5.80 (bs, 1H), 6.87 (d, 1H), 7.25 (m, 4H), 7.36 (m, 5H), 7.45 (dd, 1H), 8.14 (d, 1H), 8.75 (bs, 1H).  
     [0150] 2-( 2-{4 -[(1R)(4-chlorophenyl)phenylmethyl]piperazinyl}ethoxy)- 5-[4 -(aminohydroxycarbonyl-amino)but-1-ynyl]benzoic acid (compound  37 )  
     [0151] In a small round-bottomed flask was placed compound  36  (30 mg, 0.05 mmol). To this flask was added 1M KOH/CH 3 OH (0.30 mL, 0.30 mmol). The reaction was stirred at room temperature for 48 hours and then cooled in an ice bath. 1M HCl/ether (0.30 mL, 0.30 mmol) was added and the mixture was purified by flash column chromatography (silica gel, 9:1 CH 2 Cl 2 /CH 3 OH) to give  37  as a white solid (9 mg, 31.4%):  1 H NMR (CD 3 OD) δ 2.56 (m, 4H), 2.66 (t, 2H), 2.96 (m, 4H), 3.10 (t, 2H), 3.68 (t, 2H), 4.32 (t, 2H), 4.34 (s, 1H), 6.98 (d, 1H), 7.20 (d, 1H), 7.30 (m, 4H), 7.44 (m, 6H).  
     Example 5  
     Preparation ofAmino N-{ 4-[4 -( 2-{4 -(8-chloro(5,6-dihydrobenzo[f]pyridino[2,3-b][7]annulen-11-ylidene))piperidyl}ethoxy)phenyl]but-3-ynyl}-N-hydroxyamide (compound  32 , FIG.  7 )  
     [0152] 4-(2-Bromoethoxy)-1-iodobenzene  
     [0153] To a stirring solution of 4-iodophenol (25 g, 110 mmol) and K 2 CO 3  (31 g, 220 mmol) in DMF (250 mL) was added 1,2-dibromoethane (5 mL, 55 mmol) over a period of 1 hr. The solution was heated at 50° C. and stirred overnight under Ar. In order to complete the reaction additional reagents were added: 1,2-dibromoethane (20 mL, 220 mmol) and K 2 CO 3  (6 g, 43 mmol) and the mixture was heated at 50° C. an additional 12 hours under Ar. Water was added and the reaction mixture was extracted with dichloromethane, dried over Na 2 SO 4 , filtered and the solvent evaporated under reduced pressure. The crude mixture was purified by silica gel chromatography eluted with 10% ethyl acetate in hexanes to give the title compound as a white solid (5.5 g, 17 mmol).  
     [0154] 4-[4 -(2-Bromoethoxy)phenol]but-3-yn-1-ol  
     [0155] To a mixture of 4-(2-Bromoethoxy)-1-iodobenzene (5.5 g, 17 mmol), 3-butyn-1-ol (1.9 mL, 25 mmol), CuI (952 mg, 5 mmol) and dichlorobis(triphenylphosphine)palladium(II) (3.5 g, 5 mmol) in dichloromethane (100 mL) was added dropwise Et 3 N (3.5 mL, 25 mmol). The reaction was stirred overnight at room temperature under Ar. The solvent was evaporated under reduced pressure and ethyl acetate was added to dissolve the reaction mixture, which was filtered over celite to remove most of the Pd. The crude product was purified by silica gel chromatography eluted with hexane/ethyl acetate (2:1). 4 g of the title compound were obtained as a light brown solid.  
     [0156] 4-[4 -( 2-{4 -(8-chloro-5,6-dihydrobenzo[f]pyridino[2,3-b][7]annulen-11-yliden)piperidyl}ethoxy)but-3-yn-1 ol  
     [0157] 8-chloro-11-(4-piperidylidene)-5,6-dihydrobenzo[a]pyridino[2,3-d][7]annulene (2.5 g, 7.75 mmol) and 4-[4-(2-bromoethoxy)phenol]but-3-yn-1-ol (2.5 g, 9.2 mmol) were disolved in dichloromethane. To this solution was added Et 3 N (2.6 mL, 18.5 mmol) and the reaction was heated at reflux overnight under Ar. The dichloromethane was evaporated under reduced pressure. The unreacted starting materials were recovered after purification by chromatography with 10% MeOH in dichloromethane. The title compound was obtained as a white solid (1.9 g, 3.76 mmol).  
     [0158] Phenyl {N-{ 4-[4 -( 2-{4 -(8-chloro(5,6-dihydrobenzo[f]pyridino[2,3-b][7]annulen-11-ylidene))piperidyl}ethoxy)phenyl]but-3-ynyl}phenoxycarbonylaminooxy}formate  
     [0159] A solution of  4-[4 -( 2-{4 -(8-chloro-5,6-dihydrobenzo[f]pyridino[2,3-b][7]annulen-11-yliden)piperidyl}ethoxy)but-3-yn-lol (1.9 g, 3.76 mmol), triphenylphosphine (1.2 g, 4.7 mmol) and N,O-bis-(phenoxycarbonyl)hydroxylamine (1.3 g, 4.7 mmol) in THF (20 mL) was cooled at 0° C. with an ice bath. Diisopropylazodicarboxlate (950 mg, 4.7 mmol) was added dropwise to the stirring solution. The reaction was allowed to warm to room temperature and stir for one hour. Once the reaction was complete, the solvent was evaporated under vacuum. The product was purified by silica gel chromatography using 10% MeOH in dichloromethane. 4;5 g of the title compound (slightly impure) were obtained.  
     [0160] Amino-N-{ 4-[4 -( 2-{4 -(8-chloro(5,6-dihydrobenzo[f]pyridino[2,3-b][7]annulen-11-ylidene))piperidyl}ethoxy)phenyl]but-3-ynyl]-N-hydroxyamide  
     [0161] Phenyl {N-{ 4-[4 -( 2-{4 -(8-chloro(5,6-dihydrobenzo[f]pyridino[2,3-b][7]annulen-11-ylidene))piperidyl}ethoxy)phenyl]but-3-ynyl}phenoxycarbonylaminooxy}formate (4.5 g) was disolved in MeOH saturated with NH3 (100 mL). The system was sealed with a rubber septum and the mixture was stirred at room temperature overnight. The the solvent was evaporated under vacuum and the crude compound was purified by chromatography on silica gel, eluted with 10% MeOH saturated with NH 3  in dichloromethane to give the title compound, compound  32  (800 mg) [Alternatively, the reaction may be run in a pressure tube].  
     Example 6  
     Preparation of N-( 4-[4 -( 3-{4 -[(1R)(4-chlorophenyl)phenylmethyl]piperazinyl}propoxy)phenyl]but-3-ynyl}-amino-N-hydroxyamide (compound  52 )  
     [0162] 4-(2-Bromopropoxy)-1-iodobenzene  
     [0163] To a stirring solution of 4-iodophenol (15 g, 70 mmol) and K 2 CO 3  (12.4 g, 90 mmol) in DMF (30 mL) was added 1,2-dibromopropane (7.8 mL, 90 mmol) over a period of 1 hr. The solution was heated at 50° C. and stirred overnight under Ar. Water (500 mL) was added and the reaction mixture was extracted with dichloromethane, dried over Na 2 SO 4 , filtered and the solvent evaporated under reduced pressure. Purified on silica gel chromatography, eluted with 10% ethyl acetate in hexanes to give the title compound as a white solid (10 g, 29 mmol).  
     [0164] 4-[4 -(2-Bromopropoxy)phenyl]but-3-yn-1-ol  
     [0165] To a solution of 4-(2-Bromopropoxy)-1-iodobenzene (10 g, 29 mmol), 3-butyn-1-ol (2.6 mL, 37 mmol), CuI (980 mg, 5.2 mmol) and dichlorobis(triphenylphosphine)palladium(II) (3.6 g, 5.2 mmol) in dichloromethane (40 mL) was added Et 3 N (6.0 mL, 44 mmol) dropwise. The reaction was stirred overnight at room temperature under Ar. The solvent was evaporated under reduced pressure and ethyl acetate was added to dissolve the compound, the solution was filtered over celite to remove most of the Pd. The crude product was purified by silica gel chromatography, eluted with hexane/ethyl acetate (2:1). 2.6 g of the title compound were obtained as a light brown solid  
     [0166] 4-{4-[3 -(4-((1R)(4-Chlorophenyl)phenylmethyl)piperazinyl)propoxy]phenyl}but-3-yn-1-ol  
     [0167] [(1R)(4-chlorophenyl)phenylmethyl]piperazine (1.6 g, 5.6 mmol) and  4-[4 -(2-bromopropoxy)phenyl]but-3-yn-1-ol (2.0 g, 7.04 mmol) were dissolved in dichloromethane (10 mL). Et 3 N (1 mL, 7.04 mmol) was added dropwise, the solution was heated at reflux under Ar overnight. The solvent was evaporated and the compound was purified by silica gel chromatography, eluted with ethyl acetate. 2.0 g of the title compound were obtained as a white solid.  
     [0168] N-{ 4-[4 -(3-(4-((1R)(4-chlorophenyl) phenylmethyl) piperazinyl) propoxy) phenyl]but-3-ynyl}phenoxycarbonylaminophenoxyformate  
     [0169] A solution of  4-{4-[3 -(4-((1R) (4-chlorophenyl) phenylmethyl) piperazinyl) propoxy]phenyl}but-3-yn-1-ol (1.6 g, 5.6 mmol), triphenylphosphine (1.3 g, 5.1 mmol) and N,O-bis-(phenoxycarbonyl)hydroxylamine (1.4 g, 5.1 mmol) in THF (20 mL) was cooled at 0° C. with an ice bath. Diisopropylazodicarboxlate (1.0 g, 5.1 mmol) was added dropwise to the stirring solution. Then the reaction was allowed to warm to room temperature and stir for one hour. After completion of the reaction, the solvent was evaporated under vacuum. No further purification of the compound was done.  
     [0170] N-{ 4-[4 -( 2-{4 -[(1R)(4-chlorophenyl)phenylmethyl]piperazinyl}propoxy)phenyl]but-3-ynyl}-Amino-N-hydroxyamide (compound  52 )  
     [0171] N-{ 4-[4 -(3-(4-((1R)(4-chlorophenyl)phenylmethyl)piperazinyl)propoxy)phenyl] but-3-ynyl}phenoxycarbonylaminophenoxyformate was dissolved in MeOH and added to 20 mL of condensed (dry ice/acetone) NH3 in a pressure tube. The pressure tube was closed, allowed to warm at room temperature. After stirring overnight, the pressure was released slowly and the cap removed opening the system to the air, then the solvent was evaporated under vacuum. Purification by silica gel chromatography, eluted with 10% MeOH saturated with NH3 in dichloromethane afforded the title compound, compound  52  (1.05 g)  
     Example 7  
     [0172] Preparation of Amino-N-{ 4-[4 -( 4-{4 -[bis(4 fluorophenyl)methyl]piperazinyl}butoxy) phenyl]but-3-ynyl}-N-hydroxyamide (compound  80 , FIG. 6)  
     [0173] 1-(4-bromobutoxy)-4-iodobenzene ( 117 ). To a stirring solution of 4-iodophenol (100 g, 0.5 mol) and K 2 CO 3  (70 g, 0.5 mol) in DMF (400 mL) was added 1,4 dibromobutane (100 mL, 0.84 mol) over a period of 1 hr. The solution was stirred overnight at room temperature under Ar. H 2 O (1000 mL) was added and the reaction mixture was extracted with CH 2 Cl 2 . The organic layer was then washed with 1000 mL of brine, dried over MgSO 4 , concentrated to gave a white solid (100 g);  1 H NMR (CD 3 Cl): δ 2.15-1.87 (m, 6H), 3.50-3.20 (m, 4H), 3.94 (t, 2H), 6.85 (d, 2H), 7.55 (d, 2H).  
     [0174] 4-[4 -(4-bromobutoxy)phenol]but-3-yn-1-ol ( 118 ). A solution of  117  (100 g, 0.3 mol), 3-butyn-1-ol (45 mL, 0.6 mol), CuI (800 mg, 4.2 mmol) and dichlorobis (triphenylphosphine) palladium (II) (2.9 g, 4.2 mmol) in dichloromethane (400 mL) was cooled at 0 C (ice bath). Et 3 N (84 mL, 0.6 mol) was added dropwise while maintaining the low temperature. Then the mixture was warmed at room temperature and stirred overnight under Ar. The dichloromethane was removed under vacuum. The semi-solid obtained, was dissolved in a minimum of CH 2 Cl 2  and passed over a large plug of silica gel eluting with 10% EtOAc in hexane, followed by 50% EtOAc: 50% hexane. 75 g of a light tan solid were obtained;  1 H NMR (CD 3 CI) δ 2.10-1.80 (m, 4H), 2.66 (t, 2H), 3.25 (t, 1H), 3.50 (t, 2H), 3.80 (t, 2H), 3.94 (t, 2H), 6.85 (d, 2H), 7.55 (d, 2H).  
     [0175] Compound  119 : 4-bis(4-fluorophenyl methyl piperazine (58 g, 0.2 mol) and  118  (74 g, 0.25 mol) were dissolved in CH 2 Cl 2  (500 mL). To this solution was added NEt 3  (43 mL, 0.31 mol). The mixture was allowed to stir for 48 hr at room temperature under Ar. After evaporation of the solvent under vacuum, the semi-solid obtained was dissolved in a minimum amount of CH 2 Cl 2  and passed over a large plug of silica gel eluting with 50% EtOAc:50% hexane, followed by EtOAc to remove the desired compound. Concentration of the solution gave an off-white foam (70 g) 90% pure;  1 H NMR (CD 3 CI) δ 1.78-1.75 (m, 6H), 2.72-2.45 (m, 12H), 3.78 (t, 2H), 3.94 (t, 2H), 4.23 (s, 1H), 6.76 (d, 2H), 6.97 (t, 4H), 7.37-7.25 (m, 6H).  
     [0176] Compound  80 : A solution of  119  (70 g, 0.14 mol), triphenylphosphine (45 g, 0,17 mol) and N,O-bis-(phenoxycarbonyl)hydroxylamine (46 g, 0.17 mol) in THF (500 mL) was cooled at 0° C. with an ice bath. Diisopropylazodicarboxylate (34 mL, 0.17 mol) was added dropwise to the stirring solution. The ice bath was removed, the reaction was allowed to warm at room temperature and stir for 1 hr. The reaction was checked by TLC for completion. The solvent was removed under vacuum, the crude material was dissolved in 700 mL of MeOH saturated with ammonia. The mixture was stirred overnight in a round bottom flask sealed with a rubber septa. The reaction was worked up by an acid/base extraction, concentrated and passed over a large plug of silica gel (45 g), eluted with 10% MeOH in dichloromethane. The product was recrystallized with 500 mL of refluxing EtOAc, and cooled at room temperature overnight to gave 20 g pure compound;  1 H NMR (CD 3 Cl) δ 1.78-1.75 (m, 6H), 2.57-2.45 (m, 10H), 2.72 (t, 2H), 3.78 (t, 2H), 3.94 (t, 2H), 4.23 (s, 1H), 5.34 (s br, 2H), 6.76 (d, 2H), 6.97 (t, 4H), 7.37-7.25 (m, 6H). The following Table II provides illustrative NMR data for the especially preferred compounds.  
                   TABLE II                       COMPOUND #     1 H-NMR (CDCl 3 ) δ (ppm)                  17   1.60 (m, 4 H), 2.44 (m, 4 H), 2.52 (t, 2 H), 2.67 (m, 4 H), 2.83 (t, 2 H), 3.48 (t,           2 H), 4.08 (t, 2 H), 4.21 (s, 1 H), 6.78 (d, 2 H), 7.04 (d, 2 H), 7.25 (m, 4 H),           7.35 (m, 5 H).       32   2.20-2.95 (m, 14 H), 3.35 (m, 2 H), 3.72 (t, 2 H), 4.05 (t, 2 H), 5.62 (brs, 2 H),           6.72 (d, 2 H), 7.10 (m, 4 H), 7.25 (d, 2 H), 7.45 (d, 1 H), 8.35 (d, 1 H).       34   2.45 (br d, 8 H); 2.75 (t, 2 H); 3.50 (s, 2 H); 3.70 (t, 2 H); 4.20 (s, 1 H); 5.57           (br s, 2 H); 6.15 (d, 1 H); 6.39 (d, 1 H); 6.95 (t, 4 H); 7.33 (dd, 4 H).       35   2.40 (m, 4 H), 2.54 (m, 4 H), 2.75 (t, 2 H), 2.80 (t, 2 H), 3.80 (t, 2 H), 4.20 (m,           3 H), 5.42 (br s, 2 H), 5.80 (br s, 1 H), 6.87 (d, 1 H), 7.25 (m, 4 H), 7.36 (m,           5 H), 7.45 (dd, 1 H), 8.14 (d, 1 H), 8.75 (br s, 1 H).       46   1.40-1.55 (m, 1 H); 1.85-1.96 (m, 1 H); 2.05-2.20 (m, 2 H); 2.30-2.70 (m,           12 H); 3.62 (ddd, 2 H); 4.18 (s, 1 H); 4.27 (br d, 1 H); 4.63 (br t, 1 H); 5.58 (br           s, 2 H); 7.15-7.35 (m, 9 H).       52   1.95 (m, 2 H), 2.65-2.35 (m, 10 H), 2.72 (t, 2 H), 3.78 (t, 2 H), 3.93 (t, 2 H),           4.20 (s, 1 H), 5.25 (brs, 2 H), 6.75 (d, 2 H), 7.15-7.40 (m, 11 H).       80   1.78-1.75 (m, 6 H), 2.57-2.45 (m, 10 H), 2.72 (t, 2 H), 3.78 (t, 2 H), 3.94 (t,           2 H), 4.23 (s, 1 H), 5.34 (s br, 2 H), 6.76 (d, 2 H), 6.97 (t, 4 H), 7.37-7.25 (m,           6 H).                  
 
     Example 8  
     CHO-K1 H1R Binding Assay Protocol  
     [0177] This assay is commonly used to measure the ability of a compound to act as a histamine H1 receptor binding ligand. As this assay employs human cloned H1 receptors it can provide a good approximation of what can be expected when a compound is administered to humans.  
     [0178] Details of the assay procedure are as follows. CHO-K1 cells expressing the human cloned H1 receptor are grown to confluence in tissue culture dishes. Cells are harvested using D-PBS buffer (JRH Biosciences), kept at 4° C., centrifuging to pellet cells (4° C., 500 g, 10 min). The final cell pellet is homogenized and resuspended using Tris/sucrose buffer (20 mM Tris, 250 mM sucrose, pH 7.4 at 4° C.). Aliquots of the membrane preparation are stored at −70° C.  
     [0179] On the day of assay, the membrane preparation is thawed and centrifuged (TLA100.3 rotor, 4° C., 15 min, 23,000 rpm). The pellet is resuspended in Tris/sucrose buffer initially and then diluted further as necessary using assay buffer A (50 mM Na/KPO 4 , 2 mM MgCl 2 , 0.5% (w/v) BSA, pH 7.5).  
     [0180] For the binding assay, the membrane preparation, test compound and  3 H-pyrilamine (2 nM final) in buffer A with 1% (v/v) DMSO final are incubated in a 96-well polypropylene plate for 3 hours at 37° C. Non-specific binding is determined in the presence of 10 μM pyrilamine. A 96-well harvester (Packard) is used to harvest the 96-well plate onto a GF/B filter plate pre-treated with 0.1% (v/v) PEI. The plate is counted in a Packard Topcounter after adding Microscint 20 (Packard) scintillation fluid. The K i  for each compound at the histamine H1 receptor is then calculated from these counts. The results are displayed in Table 1, infra.  
     Example 9  
     Inhibition of LTB 4  Production in Human Whole Blood  
     [0181] This assay examines the ability of a compound to inhibit leukotriene B 4  production from human blood stimulated with calcium ionophore. As this production of leukotriene B 4  is mediated via the activation of the 5-lipoxygenase enzyme, this assay is predictive of a compound&#39;s ability to inhibit the human 5-lipoxygenase enzyme.  
     [0182] The procedure for the assay is as follows. Blood is drawn from normal human volunteers into tubes containing heparin. 1 ml of the heparinized blood is pipetted into a 1.5 ml polypropylene tube. To this sample is added either different concentrations of the test compound (5 μl) dissolved in DMSO or 5 μl of DMSO as a vehicle control. These samples are incubated in a water bath, at 37° C. for 15 min. 5 μl of the calcium ionophore A23187 (at a final concentration of 50 μM) is then added to each sample, which is vortexed and placed back in the water bath for 30 min. The samples are then centrifuged at 2500 rpm for 10 min. at 4° C. 50 μl of the supernatant is transferred into pre-cooled Eppendorf tubes containing 950 μl of enzyme immunoassay (EIA) buffer. A commercially available EIA kit (Cayman Chemical Co., Ann Arbor, Mich., USA) is used to subsequently measure the LTB4 production in the samples. The LTB 4  levels produced in the vehicle control sample is then compared to those in which the test compound has been added. From this a percent inhibition of LTB 4  production by each concentration of test compound is calculated and the IC 50  for inhibition of LTB 4  production for each test compound is determined. The results are displayed in Table 1, infra.  
                       TABLE 1                           CHOH1   HWB       Cpd #   K 1  (nM)   IC 50  (nM)                                            1   24   1515       3   260   1681       5   23   2041       46   133   313       8   220   5768       9   12   4222       11   130   3626       12   380   267       80   27   78       13   10   2444       16   94   2657       87   58   251       18   15   2101       22   8   1473       23   10   287       24   7   253       26   4   1714       27   150   650       30   36   412       17   15   254       32   7   263       34   550   142       35   135   85       36   420   94       37   4   6589       40   120   122       42   35   106       52   6   105       43   2   2742                  
 
     Example 10  
     Antihistaminergic Activity In Vivo  
     [0183] Male, Hartley guinea pigs are obtained from Charles River Labs at a body weight of 350-400 grams. Inhibition of histamine activity is measured by the method of Konzett and Rössler ( Naonyn-Schmiedebergs Arch. Exp. Path. Pharmakol.  195, 71-74 (1940). Aneasthetized guinea pigs are subjected to artificial ventilation. The endotracheal pressure is recorded. Bronchoconstriction is induced by successive intravenous injections of histamine. The test compounds are administered orally in a 1% methocellulose suspension at set timepoints prior to the administration of histamine.  
     [0184] The results (Table 2) show the percent inhibition of histamine-induced bronchoconstriction by selected compounds at multiple time points post oral dosing. 50% inhibition or greater is considered significant.  
                                   TABLE 2                                   Cpd #   Dose of test cpd   Time (in hours)   % inhibition                                                            1   5 mg/kg   3 hrs   56%           12   2 mg/kg   3 hrs   62%           12   2 mg/kg   6 hrs   66%           87   2 mg/kg   3 hrs   66%           87   2 mg/kg   6 hrs   73%           23   2 mg/kg   3 hrs   80%           23   2 mg/kg   6 hrs   92%           27   2 mg/kg   3 hrs   86%           27   2 mg/kg   6 hrs   91%           32   2 mg/kg   3 hrs   65%           34   2 mg/kg   3 hrs   81%           34   2 mg/kg   6 hrs   89%           17   2 mg/kg   3 hrs   66%           17   2 mg/kg   6 hrs   73%           35   2 mg/kg   3 hrs   72%           35   2 mg/kg   6 hrs   88%           52   2 mg/kg   3 hrs   69%           80   2 mg/kg   3 hrs   98%                      
 
     [0185] It can be seen from this Table that compounds of the present invention possess good activity with regard to their ability to inhibit histamine-induced bronchoconstriction. Furthermore, several of the compounds administered at a single dose possess antihistaminergic activity of long duration. For example,  27 , at a dose of 2 mg/kg, still inhibits histamine-induced bronchoconstriction by 91% at 6 hours post oral dosing.  
     [0186] These experiments also indicate that the compounds tested are orally bioavailable.  
     Example 11  
     5-Lipoxygenase Inhibitory Activity In Vivo  
     [0187] Male, Hartley guinea pigs are obtained from Charles River Labs at a body weight of 350-400 grams. Compounds are prepared at a volume of [1-2 mg/ml] in 1% methocellulose for oral dosing. Animals are separated into groups of five (5). Each assay includes a control group dosed with vehicle. Each group of animals is dosed with either vehicle or compound by oral gavage. Animals are allowed to rest for one, three, or six hours after dosing. Control animals are allowed to rest for three hours. At the appropriate times, the animals are anesthetized with Urethane at 1.5 g/kg, ip. Blood is drawn into a heparinized syringe via cardiac puncture.  
     [0188] Blood (0.5 ml) is aliquoted into separately-labeled 1.5 ml eppendorf tubes. Each sample is loaded with 5 μl of [15 mM] Arachidonic Acid, and placed in a 37° C. water bath for five minutes. After five minutes, the blood is stimulated with 5 μl of [5 mM] A23187 (Calcium lonophore) and retained in the water bath for an additional 30 minutes. After the thirty minutes, the blood samples are removed from the water bath and centrifuged at 14,000 rpm for 2 minutes. Plasma is diluted to EIA buffer and an EIA is performed following manufacturer instructions (Cayman Chemical Co., Ann Arbor, Mich., USA).  
     [0189] The results (Table 3) show the percent inhibition of 5-lipoxygenase by selected compounds at multiple time points post oral dosing. 50% inhibition or greater is considered significant.  
                                   TABLE 3                                   Cpd #   Dose   Time in hours   % inhibition                                                            1   2 mg/kg   1 hour       62%           12   2 mg/kg   6 hours   80%           87   2 mg/kg   1 hour       70%           87   2 mg/kg   6 hours   94%           23   2 mg/kg   1 hour       80%           27   2 mg/kg   1 hour       88%           32   2 mg/kg   1 hour       88%           17   2 mg/kg   3 hours   70%           17   2 mg/kg   6 hours   94%           35   2 mg/kg   1 hour       87%           35   2 mg/kg   3 hours   97%           52   2 mg/kg   3 hours   61%           80   2 mg/kg   3 hours   73%           80   2 mg/kg   6 hours   88%           34   2 mg/kg   3 hours   38%                      
 
     [0190] It can be seen from this Table that compounds of the present invention possess good activity with regard to their ability to inhibit the 5-lipoxygenase enzyme. Furthermore, several of the compounds administered at a single dose possess 5-lipoxygenase inhibitory activity of long duration. For example,  87  at a dose of 2 mg/kg, still inhibits 5-lipoxygenase activity by 94% at 6 hours post oral dosing.  
     [0191] These experiments also indicate that the compounds tested are orally bioavailable.  
     Example 12  
     Inhibition of 15-Lipoxygenase  
     [0192] This assay examines the ability of a compound to inhibit production of 15-hydroxy-5, 8, 11, 13-eicosateraenoic acid (15-HETE) via the action of 15-lipoxygenase on arachidonic acid. 15-lipoxygenase was purified from rabbit peritoneal polymorphonuclear leukocytes. The enzyme is responsible for the conversion of arachidonic acid (via oxygenation at carbon 15 of arachidonic acid) to 15-hydroperoxy-5, 8, 11, 13-eicosatetraenoic acid (15-HPETE), which then reduced to 15-hydroxy-5, 8, 11, 13-eicosatetraenoic acid (15-HETE).  
     [0193] The procedure for the assay is as follows. Arachidonic acid is co-incubated with 15-HETE for 5 min at 37° C. in the presence or absence of different concentrations of test compound (10 −8  to 10 −5  M). Production of 15-HETE in each sample is then measured by radioimmunoassay. The 15-HETE levels produced in the vehicle control sample are then compared to those in which the test compound has been added. From this a percent inhibition of 15-HETE production by each concentration of test compound is calculated and the IC 50  for inhibition of 15-HETE production for each test compound is determined. The IC 50  s (nM) are 1300, 170, 46, 61, and 110 for compounds  1 ,  32 ,  35 ,  52  and  80 , respectively.