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  Method of preventing and treating airway remodeling and pulmonary inflammation using a2b adenosine receptor antagonistsUSPTO Application #: 20060159627Title: Method of preventing and treating airway remodeling and pulmonary inflammation using a2b adenosine receptor antagonists Abstract: The present invention relates to methods of preventing airway remodeling using A2B adenosine receptor antagonists. This invention finds utility in the treatment and prevention of asthma, COPD, pulmonary fibrosis, emphysema, and other pulmonary diseases. The invention also relates to pharmaceutical compositions for use in the method. (end of abstract) Agent: J. Elin Hartrum Cv Therapeutics, Inc. - Palo Alto, CA, US Inventors: Dewan Zeng, Michael R. Blackburn, Luiz Belardinelli USPTO Applicaton #: 20060159627 - Class: 424045000 (USPTO) Related Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Effervescent Or Pressurized Fluid Containing, Organic Pressurized Fluid The Patent Description & Claims data below is from USPTO Patent Application 20060159627. Brief Patent Description - Full Patent Description - Patent Application Claims
FIELD OF THE INVENTION [0001] The present invention relates to methods of preventing airway remodeling and/or pulmonary inflammation using A.sub.2B adenosine receptor antagonists. This invention finds utility in the treatment and prevention of asthma, COPD, pulmonary fibrosis, emphysema, and other pulmonary diseases. The invention also relates to pharmaceutical compositions for use in the method. BACKGROUND [0002] According to the Asthma and Allergy Foundation of America and the National Pharmaceutical Council, an estimated 17 million Americans currently suffer from asthma. It is the most common chronic childhood disease, affecting more than one child in 20, nearly 5 million children in all, and it is the only chronic disease, besides AIDS and tuberculosis, with an increasing death rate. Each year over 5,000 Americans die from asthma. [0003] The annual cost of asthma in 1998 was estimated to be $11.3 billion. Direct costs accounted for $7.5 billion and indirect costs were $3.8 billion. Hospitalizations accounted for the single largest portion of the cost and amount to nearly a half million hospitalizations, 1.6 million emergency room visits, and over 10 million office visits. Clearly there is a great need for new methods of treating the condition. [0004] As discussed by Elias et al. (1999), J. Clin. Inv., 104(8):1001-1006, the effects of airway remodeling in the development of asthma were previously unknown as the condition was thought to be an entirely reversible disorder. More recent investigations have revealed, however, that significant airway remodeling occurs during asthma and that the degree of this remodeling is usually proportional to symptom severity. Remodeling typically takes the form of airway wall thickening, the development of subepithelial fibrosis, increased myocyte muscle mass, myofibroblast hyperplasia, and mucus metaplasia. Airway remodeling is also a common factor in the progression of chronic obstructive pulmonary disorder (COPD), and pulmonary fibrosis. Pulmonary inflammation is also a common component in the development of airway remodeling and may be typified by bronchiolitis, alveolitis, and/or vasculitis. [0005] The correlation between airway remodeling and asthma presents a new avenue of asthma research. Recently the ability of cortical steroids and leukotrine receptor antagonists to prevent or treat airway remodeling has been reported (see Hoshino (2004) Clin Rev Allergy Immunol. 27(1):59-64). Given the potential negative side effects of long term treatment with cortical steroids and the uncertainties regarding the efficacy of leukotrine receptor antagonists, the exists a strong need for other methods of inhibiting airway remodeling. [0006] Adenosine is known to play a role in asthma and COPD (See, Spicuzza et al. (2003) TiPS 24(8):409-4130; Mann et al, (1986) J Appl Physiol 61:1667-1676; and Feoktistov et al, (1998) Trends Pharmacol Sci 19:148-153.) The clinical evidence supporting the involvement of adenosine includes: [0007] 1) Plasma concentrations of adenosine are increased by allergen challenge in asthmatic patients and adenosine levels in the bronchoalveolar lavage fluid are elevated in asthmatic and COPD patients (Driver et al, (1993). Am Rev Respir Dis 148:91-97) [0008] 2) Adenosine (given as AMP) induces bronchoconstriction in asthmatics but not in normal subjects (Cushley et al, (1983) Br J Clin Pharmacol 15:161-165), and it increases the concentrations of mediators released from mast cells, such as histamine, tryptase, LTC4 and PDG2 (Crimi et al, (1997) Allergy 52:48-54). The adenosine-induced bronchoconstriction is attenuated by drugs that either inhibit mast cell activation or serve as antagonists to the mediators released from the mast cells. Thus, the potential mechanism of adenosine-induced bronchoconstriction is likely due to its effect on mast cell activation (Polosa et al, (2002) Thorax 57:649-654 and Polosa (2002) Eur Respir J 20:488-496.). [0009] 3) Adenosine has also been shown to induce eosinophilia and inflammation. The overall effects and potential clinical utilities of AMP-challenge are summarized in a recent review article by Spicuzza and Polosa, (2003) Curr Opin Allergy Clin Immunol 3:65-69. [0010] Adenosine is a naturally occurring nucleoside, which exerts its biological effects by interacting with a family of adenosine receptors known as A.sub.1, A.sub.2A, A.sub.2B, and A.sub.3, all of which modulate important physiological processes. Of the various receptors, A.sub.2B adenosine receptors are believed to be most significantly involved in asthma via their connection to mast cell activation, vasodilation, and regulation of cell growth (See Adenosine A.sub.2B Receptors as Therapeutic Targets, Drug Dev Res 45:198; Feoktistov et al., Trends Pharmacol Sci 19:148-153). Specifically, adenosine A.sub.2B receptor antagonists have been shown to affect the activation of mast cell and have thus been implicated in the inhibition of the acute airway hyperresponsiveness. Surprisingly, it has now been found that A.sub.2B adenosine receptor antagonists are also useful in the prevention of airway remodeling and pulmonary inflammation. [0011] Accordingly, it is desired to provide a method of preventing airway remodeling and/or pulmonary inflammation by administration of compounds that are potent, fully or partially selective, A.sub.2B antagonists, i.e., compounds that inhibit the A.sub.2B adenosine receptor. SUMMARY OF THE INVENTION [0012] In one embodiment of the invention, a method is provided for the treatment and prevention of airway remodeling and/or pulmonary inflammation by administration of a therapeutically effective amount of an A.sub.2B receptor antagonist to a mammal that is genetically and/or environmentally predisposed to airway remodeling and pulmonary inflammation. [0013] In another embodiment of the invention, a method is provided for the treatment and prevention of airway remodeling and/or pulmonary inflammation by administration to a mammal that is genetically and/or environmentally predisposed to airway remodeling, a therapeutically effective amount of an A.sub.2B receptor antagonist having the structure of Formula I or Formula II: wherein: [0014] R.sup.1 and R.sup.2 are independently chosen from hydrogen, optionally substituted alkyl, or a group -D-E, in which D is a covalent bond or alkylene, and E is optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted alkenyl or optionally substituted alkynyl, with the proviso that when D is a covalent bond E cannot be alkoxy; [0015] R.sup.3 is hydrogen, optionally substituted alkyl or optionally substituted cycloalkyl; [0016] X is optionally substituted arylene or optionally substituted heteroarylene; [0017] Y is a covalent bond or alkylene in which one carbon atom can be optionally replaced by --O--, --S--, or --NH--, and is optionally substituted by hydroxy, alkoxy, optionally substituted amino, or --COR, in which R is hydroxy, alkoxy or amino; and [0018] Z is optionally substituted monocyclic aryl or optionally substituted monocyclic heteroaryl; or [0019] Z is hydrogen when X is optionally substituted heteroarylene and Y is a covalent bond. [0020] In yet another embodiment of the invention, pharmaceutical formulations are provided, comprising a therapeutically effective amount of an A.sub.2B receptor antagonist, and at least one pharmaceutically acceptable carrier. The formulation is preferably for oral administration. [0021] One preferred group of compounds of Formula I and II are those in which R.sup.1 and R.sup.2 are independently hydrogen, optionally substituted lower alkyl, or a group -D-E, in which D is a covalent bond or alkylene, and E is optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted alkenyl, or optionally substituted alkynyl, particularly those in which R.sup.3 is hydrogen. [0022] Within this group, a first preferred class of compounds include those in which R.sup.1 and R.sup.2 are independently lower alkyl optionally substituted by cycloalkyl, preferably n-propyl, and X is optionally substituted phenylene. Within this class, a preferred subclass of compounds are those in which Y is alkylene, including alkylene in which a carbon atom is replaced by oxygen, preferably --O--CH.sub.2--, more especially where the oxygen is the point of attachment to phenylene. Within this subclass, it is preferred that Z is optionally substituted oxadiazole, particularly optionally substituted [1,2,4]-oxadiazol-3-yl, especially [1,2,4]-oxadiazol-3-yl substituted by optionally substituted phenyl or optionally substituted pyridyl. [0023] A second preferred class of compounds include those in which X is optionally substituted 1,4-pyrazolene. Within this class, a preferred subclass of compounds are those in which Y is a covalent bond or alkylene, especially lower alkylene, and Z is hydrogen, optionally substituted phenyl, optionally substituted pyridyl, or optionally substituted oxadiazole. Within this subclass, one preferred embodiment includes compounds in which R.sup.1 is lower alkyl optionally substituted by cycloalkyl, and R.sup.2 is hydrogen. A more preferred embodiment includes those compounds in which Y is --(CH.sub.2)-- or --CH(CH.sub.3)-- and Z is optionally substituted phenyl, or Y is --(CH.sub.2)-- or --CH(CH.sub.3)-- and Z is optionally substituted oxadiazole, particularly 3,5-[1,2,4]-oxadiazole, or Y is --(CH.sub.2)-- or --CH(CH.sub.3)-- and Z is optionally substituted pyridyl. Within this subclass, also preferred are those compounds in which R.sup.1 and R.sup.2 are independently lower alkyl optionally substituted by cycloalkyl, especially n-propyl. More preferred are those compounds in which Y is a covalent bond, --(CH.sub.2)-- or --CH(CH.sub.3)-- and Z is hydrogen, optionally substituted phenyl, or optionally substituted pyridyl, particularly where Y is a covalent bond and Z is hydrogen. [0024] At present, the preferred compounds for use in the invention include, but are not limited to: [0025] 1-propyl-8-(1-{[3-(trifluoromethyl)phenyl]-methyl}pyrazol-4-yl)-1,3,7-tri- hydropurine-2,6-dione; [0026] 1-propyl-8-[1-benzylpyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione; [0027] 1-butyl-8-(1-{[3-fluorophenyl]methyl}pyrazol-4-yl)-1,3,7-trihydropurine-2- ,6-dione; [0028] 1-propyl-8-[1-(phenylethyl)pyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione; [0029] 8-(1-{[5-(4-chlorophenyl)(1,2,4-oxadiazol-3-yl)]methyl}pyrazol-4-y- l)-1-propyl-1,3,7-trihydropurine-2,6-dione; [0030] 8-(1-{[5-(4-chlorophenyl)(1,2,4-oxadiazol-3-yl)]methyl}pyrazol-4-yl)-1-bu- tyl-1,3,7-trihydropurine-2,6-dione; [0031] 1,3-dipropyl-8-pyrazol-4-yl-1,3,7-trihydropurine-2,6-dione; [0032] 1-methyl-3-sec-butyl-8-pyrazol-4-yl-1,3,7-trihydropurine-2,6-dione; [0033] 1-cyclopropylmethyl-3-methyl-8-{1-[(3-trifluoromethylphenyl)methyl- ]pyrazol-4-yl}-1,3,7-trihydropurine-2,6-dione; [0034] 1,3-dimethyl-8-{1-[(3-fluorophenyl)methyl]pyrazol-4-yl}-1,3,7-trihydropur- ine-2,6-dione; [0035] 3-methyl-1-propyl-8-{1-[(3-trifluoromethylphenyl)methyl]pyrazol-4-yl}-1,3- ,7-trihydropurine-2,6-dione; [0036] 3-ethyl-1-propyl-8-{1-[(3-trifluoromethylphenyl)methyl]pyrazol-4-yl}-1,3,- 7-trihydropurine-2,6-dione; [0037] 1,3-dipropyl-8-(1-{[3-(trifluoromethyl)phenyl]methyl}pyrazol-4-yl)-1,3,7-- trihydropurine-2,6-dione; [0038] 1,3-dipropyl-8-{1-[(3-fluorophenyl)methyl]pyrazol-4-yl}-1,3,7-trihydropur- ine-2,6-dione; [0039] 1-ethyl-3-methyl-8-{1-[(3-fluorophenyl)methyl]pyrazol-4-yl}-1,3,7-trihydr- opurine-2,6-dione; [0040] 1,3-dipropyl-8-{1-[(2-methoxyphenyl)methyl]pyrazol-4-yl}-1,3,7-trihydropu- rine-2,6-dione; [0041] 1,3-dipropyl-8-(1-{[3-(trifluoromethyl)-phenyl]ethyl}pyrazol-4-yl)-1,3,7-- trihydropurine-2,6-dione; [0042] 1,3-dipropyl-8-{1-[(4-carboxyphenyl)methyl]pyrazol-4-yl}-1,3,7-trihydropu- rine-2,6-dione; [0043] 2-[4-(2,6-dioxo-1,3-dipropyl(1,3,7-trihydropurin-8-yl))pyrazolyl]-2-pheny- lacetic acid; [0044] 8-{4-[5-(2-methoxyphenyl)-[1,2,4]oxadiazol-3-ylmethoxy]phenyl}-1,3-diprop- yl-1,3,7-trihydropurine-2,6-dione; [0045] 8-{4-[5-(3-methoxyphenyl)-[1,2,4]oxadiazol-3-ylmethoxy]phenyl}-1,3-diprop- yl-1,3,7-trihydropurine-2,6-dione; [0046] 8-{4-[5-(4-fluorophenyl)-[1,2,4]oxadiazol-3-ylmethoxy]phenyl}-1,3-dipropy- l-1,3,7-trihydropurine-2,6-dione. [0047] 1-(cyclopropylmethyl)-8-[1-(2-pyridylmethyl)pyrazol-4-yl]-1,3,7-trihydrop- urine-2,6-dione; [0048] 1-n-butyl-8-[1-(6-trifluoromethylpyridin-3-ylmethyl)pyrazol-4-yl]-1,3,7-t- rihydropurine-2,6-dione; [0049] 8-(1-{[3-(4-chlorophenyl)(1,2,4-oxadiazol-5-yl)]methyl}pyrazol-4-yl)-1,3-- dipropyl-1,3,7-trihydropurine-2,6-dione; [0050] 1,3-dipropyl-8-[1-({5-[4-(trifluoromethyl)phenyl]isoxazol-3-yl}methyl)pyr- azol-4-yl]-1,3,7-trihydropurine-2,6-dione; [0051] 1,3-dipropyl-8-[1-(2-pyridylmethyl)pyrazol-4-yl]-1,3,7-trihydropurine-2,6- -dione; [0052] 3-{[4-(2,6-dioxo-1,3-dipropyl-1,3,7-trihydropurin-8-yl)pyrazolyl]methyl}b- enzoic acid; [0053] 1,3-dipropyl-8-(1-{[6-(trifluoromethyl)(3-pyridyl)]methyl}pyrazol-4-yl)-1- ,3,7-trihydropurine-2,6-dione; [0054] 1,3-dipropyl-8-{1-[(3-(1H-1,2,3,4-tetraazol-5-yl)phenyl)methyl]pyrazol-4-- yl}-1,3,7-trihydropurine-2,6-dione; [0055] 6-{[4-(2,6-dioxo-1,3-dipropyl-1,3,7-trihydropurin-8-yl)pyrazolyl]methyl}p- yridine-2-carboxylic acid; [0056] 3-ethyl-1-propyl-8-[1-(2-pyridylmethyl)pyrazol-4-yl]-1,3,7-trihydropurine- -2,6-dione; [0057] 8-(1-{[5-(4-chlorophenyl)isoxazol-3-yl]methyl}pyrazol-4-yl)-3-ethyl-1-pro- pyl-1,3,7-trihydropurine-2,6-dione; [0058] 8-(1-{[3-(4-chlorophenyl)(1,2,4-oxadiazol-5-yl)]methyl}pyrazol-4-yl)-3-et- hyl-1-propyl-1,3,7-trihydropurine-2,6-dione; [0059] 3-ethyl-1-propyl-8-(1-{[6-(trifluoromethyl)(3-pyridyl)]methyl}pyrazol-4-y- l)-1,3,7-trihydropurine-2,6-dione; [0060] 1-(cyclopropylmethyl)-3-ethyl-8-(1-{[6-(trifluoromethyl)(3-pyridyl)]methy- l}pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione; and [0061] 3-ethyl-1-(2-methylpropyl)-8-(1-{[6-(trifluoromethyl)(3-pyridyl)]methyl}p- yrazol-4-yl)-1,3,7-trihydropurine-2,6-dione. SUMMARY OF THE FIGURES [0062] FIG. 1 depicts the differences in pulmonary histopathology in adenosine deaminase (ADA)-/- mice following treatment with adenosine A.sub.2B receptor antagonists as described in Example 21. The lungs were collected and processed for histological analysis using H&E staining. (A) Lung from ADA+ vehicle treated mouse. (B) Lung from ADA-/- vehicle treated mouse. (C) Lung from ADA-/- adenosine A.sub.2B receptor antagonist treated mouse. (D) Higher magnification section through the lung of an ADA+ vehicle treated mouse. (E) Higher magnification section though the lung of an ADA-/- vehicle treated mouse. (F) Higher magnification section of a lung of an ADA-/- adenosine A.sub.2B receptor antagonist treated mouse. Arrows denote alveolar macrophages. Scale bars in A-C=100 .mu.m, scale bars in D-F=10 .mu.m. Sections are representative of 6 different samples from each treatment. [0063] FIG. 2 shows the effects of an adenosine A.sub.2B receptor antagonist (A.sub.2B-A) on airway cellularity as described in Example 21. (A) Mice were lavalged with PBS and total cell counts determined. (B and C) Cells were cytospun onto microscope slides, stained with DiffQuick and cellular differentials were determined by counting at least 200 cells per sample. Values are presented as mean total cells.times.10.sup.4.+-.SEM. *, significant at p<0.05 compared to ADA.sup.+ animals using the students T test, n=8; #, significant at p<0.05 compared to vehicle-treated ADA.sup.-/- mice using the students T test, n=6-8. [0064] FIG. 3 presents the result of BAL cellularity in ADA-/- mice treated with an adenosine A.sub.2B receptor antagonist as described in Example 21. BAL fluid was collected from the lungs of mice and cells were cytospun onto microscope slides and stained with DiffQuick. (A) ADA+ vehicle treated, (B) ADA+ adenosine A.sub.2B receptor antagonist treated, (C) ADA-/- vehicle treated, (D) ADA-/- adenosine A.sub.2B receptor antagonist treated. Photographs are representative of 6 separate samples of each condition. Scale bar=10 .mu.m. [0065] FIG. 4 illustrates transcript levels of various pro-inflammatory cytokines were measure in whole lung extracts using quantitative RT-PCR as described in Example 21. (A) IL-6 (B) Eotaxin 1 (C) TARC. Results are presented as mean pg transcripts.+-.SEM. *, significant at p<0.05 compared to ADA.sup.+ animals using the students T test; #, significant at p<0.05 compared to vehicle-treated ADA.sup.-/- mice using the students T test, n=4 for ADA.sup.+ mice, n=8 for ADA.sup.-/- mice, n=not detected. [0066] FIG. 5 shows the results of .alpha.-smooth muscle actin immunostaining. Lung sections were stained with antiserum against .alpha.-smooth muscle actin to visualize myofibroblast (brown). (A) Lung from an ADA.sup.+ vehicle treated mouse. (B) Lung from an ADA.sup.-/- vehicle treated mouse. (C) Lung from an ADA.sup.-/- adenosine A.sub.2B receptor antagonist treated mouse. Sections are representative of 6 different mice from each treatment. Scale bar=100 .mu.m. Continue reading... Full patent description for Method of preventing and treating airway remodeling and pulmonary inflammation using a2b adenosine receptor antagonists Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Method of preventing and treating airway remodeling and pulmonary inflammation using a2b adenosine receptor antagonists patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. Each week you receive an email with patent applications related to your keywords. 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