TW200932243A - Pharmaceutical compositions - Google Patents

Abstract

The present invention provides aqueous pharmaceutical compositions which comprise a compound which is 4-[(4-chlorophenyl)methyl]-2-({(2R)-l-[4-(4-{[3-(hexahydro-1H-azepin-1-yl)propyl]oxy}phenyl)butyl]-2-pyrrolidinyl}methyl)-1(2H)-phthalazinone or a pharmaceutically acceptable salt thereof, and to their use in the treatment of various inflammatory and/or allergic diseases such as allergic rhinitis.

Description

200932243 . , ninth invention, the present invention relates to a pharmaceutical composition comprising an antagonist of histamine H1 and histamine H3 receptor or a pharmaceutically acceptable salt thereof, and a preparation thereof Methods, and for their use in the treatment of various inflammatory and/or allergic diseases, such as allergic rhinitis. [Prior Art] Antagonists of histamine H1 receptor are known and widely used for the treatment of inflammatory and/or allergic diseases associated with the release of histamine from fine ecells. For example, H1 receptor antagonists (commonly referred to as antihistamines) are known and widely used to treat allergic rhinitis. Activation of the H1 receptor in blood vessels and nerve endings can cause many symptoms of allergic rhinitis, including itching, sneezing, and nasal spray. Oral antihistamine compounds for selective m receptor antagonists (such as chlorphenyramine, cetirizine, desloratidine, and fexofenadine (fex) 〇fena (jine) and intranasal anti-tissue © amines (such as azelastine and lev〇cabastine) are effective in treating itching, sneezing and rhinorrhea associated with allergic rhinitis However, there is no effect against nasal congestion symptoms [Aar〇ns〇n," ww W/era, 67:54i_ 547' (1991)]. Therefore, HI receptor antagonists have been associated with such as pseudoephedrine or oxymetazole. The combination of sympathomimetic agents of porphyrins is used to treat nasal congestion symptoms commonly associated with allergic rhinitis. These drugs are believed to produce decongestive effects by activating a-adrenergic receptors and increasing vascular tone of blood vessels in the nasal mucosa. The use of sympathomimetic drugs for nasal congestion is often limited by CNS irritability and its effects on stress and heart rate. Therefore, treatments that reduce nasal congestion without affecting the CNS and cardiovascular system can provide superior treatment. The advantages of existing therapies. Organization H3 receptors are widely expressed on CNS and peripheral nerve endings and mediate the inhibition of neurotransmitter release. In vitro electrical stimulation of peripheral sympathetic nerves in isolated human saphenous veins leads to increased release of norepinephrine and smoothing of * muscle contraction, It can be inhibited by histamine H3 receptor agonist [Molderings et al, Naunyn-Schmiedeberg's Arch. Pharmacol., 346: 46-50, (1992); Valentine^ A > Eur. J. Pharmacol., 366:73-78, 〇(1999)]. H3 receptor agonists also inhibit the effects of sympathetic activation on vascular tone in pig nasal mucosa [Varty & Hey, JSwr. ·/. /^ar/waco/ ·, 452: 339-345, (2002)]. In vivo, H3 receptor agonists inhibit the reduction of nasal airway resistance caused by sympathetic activation [Hey et al., Jrzweim-Forsc/z Drwg βα·, 48 :881-888, (1998)]. Activating histamine H3 receptors in human nasal mucosa inhibits sympathetic vasoconstriction [Varty et al., £wr. 丄P/mrmaco/., 484:83-89, (2004) In addition, H3 receptor antagonists in combination with histamine® HI receptor antagonists have been shown to reverse mast cell activation for nasal airway resistance And the effect of nasal volume (an indicator of nasal congestion) [Mcleod et al. - Human, Jm. «/· 13:391-399, (1999)], and the H3 receptor contributes to the group. Other evidence of adenosine-induced nasal congestion is caused by For histamine nasal challenge studies performed in normal human individuals [Taylor-Clark et al., /. Pharmacol., 1-8, (2005)], but in this respect, the Η3 mechanism appears to be novel and unprecedented and can ultimately It has been proven to be asymptomatic. Other compounds which are effective for the treatment of inflammatory and/or allergic diseases such as allergic 134966.doc 200932243 rhinitis include glucocorticoid receptor agonists (referred to herein as glucocorticoids). Such corticosteroids having proven anti-inflammatory properties and marketed for the treatment of allergic rhinitis include, but are not limited to, beci〇methas〇ne sold under the trademark Bec〇naseTM under the trademark Fluticas〇ne sold by VeramystTM and fluticasone propionate sold under the trademark 'Flix〇naseTM. • Allergic rhinitis, lung inflammation, and congestion are medical conditions commonly associated with other conditions such as asthma and chronic obstructive pulmonary disease (COPD). In general, these conditions are mediated, at least in part, by inflammation associated with the release of histamine from various cells, particularly mast cells. Including ‘hay fever, allergic rhinitis affects most people around the world. There are two types of allergic rhinitis: seasonal and year-round. The clinical symptoms of seasonal allergic rhinitis usually include nasal pain and irritation, nozzles, and runny nose that is usually accompanied by nasal congestion. The clinical symptoms of year-round allergic rhinitis are similar except for nasal congestion that may be more pronounced. Any type of allergic rhinitis can also cause other symptoms such as throat and/or itchy eyes, tears and edema around the eyes. The intensity of symptoms of allergic rhinitis can vary from annoying to debilitating levels. Thus, there is a need for a pharmaceutical composition that is effective for the treatment of a broad spectrum of inflammatory and/or allergic conditions, which provides a convenient dosage regimen and has an improved side effect profile. SUMMARY OF THE INVENTION Thus, in one embodiment, an aqueous pharmaceutical composition comprising 4-[(4-phenylphenyl)methyl]-2-({(2;?)-1-[4-( 4-{[3-(hexahydro-1//-azepine-1-134966.doc 200932243) propyl]oxy}phenyl)butyl]_2-oxaridinyl}indenyl)·1 ( 2//)- oxazine compound

Or a pharmaceutically acceptable salt thereof. 4-[(4-Gasyl)methyl]_2-({(2/?)-1-[4-(4-{[3-(hexahydro-l/f· defeated-1 1-yl)) Propyl]oxy}phenyl)butyl]_2-"pyrrolidyl}indenyl)_1(2)-indolone and its pharmaceutically acceptable salts are disclosed in November 1, 2007 International Patent Application No. PCT/Ep2〇〇7/〇53773 (Glaxo Group Ltd), published by W. 2007/122156. This compound is disclosed as a dual antagonist of histamine n-receptor and histamine H3 receptor, and is accordingly applicable to the treatment of various inflammatory and/or allergic diseases associated with the release of histamine from cells (eg, allergic rhinitis). ). In addition, this compound has an extended duration of action and exhibits relatively low CNS penetration. Contains 4-[(4-chlorobenzyl)methyl]-2.({(2Λ)-1-[4-(4-{[3-(hexahydro-1//_azhen-1-yl)) Aqueous pharmaceutical compositions of propyl]oxy}phenyl)butyl]_2_β-pyrrolyl)-(1//)-oxazinone or a pharmaceutically acceptable salt thereof are particularly suitable for use. It can be delivered intranasally, and/or can be administered once and/or can have an improved side effect profile compared to other existing therapies. 4-[(4-Chlorophenyl)indenyl]_2-({(2i?)-l-[4-(4-{[3-(hexahydroazhen-1-yl)propyl)oxy}) Phenyl)butyl]-2-.pyrrolidinyl}methyl)4(2")·sniff 134966.doc 200932243 Brewing i can be in its free base form or a pharmaceutically acceptable salt (eg, monohydrate 1 , 5 naphthalene disulfonate or dihydrochloride salt) is used. Compositions comprising antihistamines and glucocorticoids are particularly effective in the treatment of inflammatory and/or allergic diseases. Thus, in another embodiment, an aqueous pharmaceutical composition comprising:

(i) 4-[(4-Phenylphenyl)methyl]-2-({(2/?)-1_[4-(4-{[3-(hexahydro_1//__) -yl)propyl]oxy}phenyl)butyl]-2-"pyrrolidyl}methyl)_1(2H)_pyridazinone

Or a pharmaceutically acceptable salt thereof;

(ii) 6a,9a-difluoro-l7α-[(2-Bfutyl)oxy]-1lβ-pyridyl-16α-methyl-3-oxirane·xionggu-1,4- Diene-1^7β·thiocarbonate*s^-fluoromethyl ester compound ch2f 〇〆

Or a solvate thereof. 6〇1,9〇1-difluoro-17〇1-[(2-indolyl)-yl]oxy]_11-pyridyl-16^1-a 134966.doc • 10· 200932243 -Xionggu - "Two women - bismuth thiocarbonate heart vinegar (hereinafter referred to as fluticasone citrate) and its solvate are disclosed in International Patent Application No. 2/12265 and International Patent Application No. 03/0 Following 4, fluticasone furoate is sold in Europe by VeramvQtTM Hill #7, veramyst for the treatment of seasonal allergic symptoms. '# Acid fluticasone can be used in solvated or unsolvated forms. Because ' & 'in an embodiment The aqueous pharmaceutical composition of the present invention comprises fluticasone furoate in an unsolvated form. In another embodiment, as defined in w〇φ 02/12265, the composition comprises unsolvated fluticasone citrate in polymorph 1. It should be understood that the transferable 4-[(4-Phenylphenyl)methyl]_2_({(2 phantom {[3-(hexahydro-1//a-heptan-1-yl)propyl)oxy}phenyl) Aqueous]·2·β-pyridylpyridyl}methyl)-1(2//)-pyridazinone or a pharmaceutically acceptable salt thereof and fluticasone furoate or a solvate thereof Pharmaceutical combination The compounds may be delivered sequentially in separate pharmaceutical compositions or may be delivered in combination with a pharmaceutical composition. The aqueous pharmaceutical compositions of the present invention are in the form of aqueous suspensions and/or aqueous solutions. Partial suspensions and/or partial solutions are encompassed by the present invention. A composition comprising a compound in solution and another compound in suspension is also included within the scope of the invention. In one embodiment, the compound of the aqueous pharmaceutical composition of the invention is in suspension. The aqueous component of the compositions of the present invention is typically premium water, such as pure water (e.g., centistoke (1) hydrazine... water). 134966.doc -11 - 200932243 The compounds used in the compositions of the present invention typically have, for example, a laser Diffraction measures a mass average diameter (MMD) of less than 2 μm (such as 0.5 to 10 μηη, such as 1 to 1 μμηη). The particle size reduction (if needed) can be achieved by techniques well known in the art (such as micronized powder) Achieving, grinding and/or microfluidization. The aqueous pharmaceutical composition of the present invention is suitable for topical administration, including intranasal, inhalation. And ocular administration. Special attention compositions suitable for intranasal administration of the drug.

4-[(4-Phenylphenyl)methyl]_2-({(2))-1_[4-(4-{[3-(hexahydro-1//-azhen-1-yl)) used Dosage of propyl]oxy}phenyl)butyl]_2_„pyrrolidyl}methyl)-1(2//)-pyridazinone or a pharmaceutically acceptable salt thereof will be treated in the usual manner The severity of the disease is treated as well as other factors (e.g., patient weight). However, as a general guide, a suitable unit dose can range from about 5 to about 1000 mg, such as from about 0.05 to about 200 mg, such as about 〇〇. 5 to about 2 mg, or about 〇·〇5 to about 1 mg, and the unit doses may be administered once a day or more than once a day, for example two or three times a day, or as needed. The therapy may last for weeks or months. The "% (weight ratio)" as used herein means the weight of the substance expressed as a percentage relative to the weight of the total composition, for example 5% by weight = per!邑 total composition 0.5 g substance. 4 In the aqueous pharmaceutical composition of the present invention, 4_[(4-chlorophenyl)methyl bh ({(2i?)-l-[4-(4-{[3-( Hexahydro-1//-azepine-propyl)propyl]oxy}phenyl)butyl]-2-"pyrrolidyl} The ratio of the base _i(2i/)_pyridazine oxime or its pharmaceutically acceptable salt will depend on the composition to be prepared and the particular route of administration & 1 Ή 134966.doc 12- 200932243 generally in the composition The total weight is in the range of from about 005 to about 2% by weight, such as from about 0.01 to about 1% by weight. The free base form of 4-[(4•phenyl)methyl]-2-( {(2Λ)-1-[4-(4·{[3-(hexahydro-1//-azah-bu)propyl]oxy}phenyl)butyl]-2-»pyrrolidine The specific concentration of the base methyl group 4(2//)-pyridazinone is 01.01% by weight, 〇〇25% by weight, 0.05% by weight based on the total weight of the composition. 〇.1% by weight, 〇25% by weight, and 0.5% by weight. In one embodiment, the pharmaceutically acceptable salt is the dihydrochloride salt. When 4-[(4·气笨基)methyl]_2-({(2/〇-1-[4·(4-{[3-(hexahydro-1//-azhen_1_yl)) When propyl]oxy}phenyl)butyl]_2-^pyridyl)methylpyridazinone is used in the form of a pharmaceutically acceptable salt, the concentration will depend on the salt selected, but will provide a compound in the form of a free base in a desired concentration Therefore, 4-[(4-phenylphenyl)methylhexahydro-1//-azhen-1-yl)propyl]oxy}phenyl)butylpyrrolidyl}indenyl U2/ /) - pyridazinone monohydrate hydrazine, the specific concentration of 5-naphthalene disulfonate is from about 0,01 to about 0.75% by weight, based on the total weight of the composition, for example from about 1478 to about A range of 0.739% by weight provides a free base of from about 1 to about 5% by weight. The ratio of the solvate of fluticatica citrate (IV) in the aqueous pharmaceutical composition of the invention will depend on the composition to be prepared and the specific dosage of the administration, but is generally from about 0. 01 to the total weight of the composition. Approximately 1% by weight, such as from about 〇·〇ι to about 5% by weight, such as about qq5% by weight. Typically, the 50 composition will deliver about 27 of the fluticasone citrate or potted I34966.doc 200932243 formulation to give a daily dose of about 55 to lio fluticasone citrate. In one embodiment, the aqueous pharmaceutical compositions of the present invention are suitable for intranasal administration. The intranasal composition allows for the delivery of the compound to all areas of the nasal cavity (target tissue) and, in addition, allows the compound to remain in contact with the target tissue for a longer period of time. A suitable dosage regimen for the intranasal composition should be after the patient has cleaned the nasal cavity • Slow nasal inhalation. The composition should be administered to one nostril during inhalation while the other nostril is squeezed by hand. This procedure is then repeated for the other nostril. Typically, one or two sprays per nostril are administered by the procedure described above, up to two or three times, ideally once a day. Particular attention is paid to the application of the intranasal composition for each dose.

The aqueous pharmaceutical compositions of the present invention (such as intranasal compositions) may optionally contain one or more suspending agents, one or more preservatives, one or more wet diterpenes, and &lt;RTI ID=0.0&gt;&gt; Furthermore, the compositions of the invention (for example for intranasal administration) may optionally contain other excipients, such as antioxidants (for example sodium metabisulfite), taste masking agents (such as thin and sweeteners (eg dextrose) , glycerin, saccharin and/or sorbitol) compositions may also optionally contain one or more co-solvents as needed. Those skilled in the art will readily appreciate the nature and amount of excipients that may be used in the group of subjects. And the towel contains the above-mentioned functions. "Special-characteristics, in one embodiment, provides a suspension-containing compound. <Aqueous pharmaceutical group floats (if included) are usually 134966.doc • 14 - 200932243 5. / ❶ (weight ratio), such as from about 15% to about 24% (by weight, especially about 2.4% by weight). Examples of pharmaceutically acceptable suspending agents include (but are not limited to) Avicel® (microcrystalline cellulose and sodium carboxylate cellulose), sodium decyl cellulose, veegum, tragacanth, bentonite, sulfhydryl cellulose and polyethylene glycol. Other examples include three Fairy Knee and Polyacrylic Acid. In one embodiment, the suspending agent is microcrystalline cellulose and sodium carboxymethylcellulose. In one embodiment, an aqueous pharmaceutical composition of the invention comprising a preservative is provided. 出于 For the purpose of stability, One or more preservatives are included to protect the compositions of the present invention (eg, intranasal compositions) from microbial or fungal contamination and from microbial or fungal growth. Examples of pharmaceutically acceptable antimicrobials or preservatives can include (but not limited to) a fourth ammonium compound (eg, gasified benzoquinone ammonium, benzethonium chloride, cetrimonium bromide, and cetylated gasified pyridine, and other examples are tetradecyl vaporization) And Laura ammonium chloride), amalgam (such as phenylmercury nitrate, stupid mercuric mercury and thimerosal), alcohol agents (such as butanol, phenylethyl alcohol and benzyl alcohol), antibacterial esters (such as p-hydroxyl Benzoate), ketones such as disodium edetate (EDTA) and other antimicrobial agents, such as hexidine, gas cresol, sorbic acid and its salts (such as potassium sorbate) and many more . colistin. pharmaceutically acceptable antifungal or antiseptic Examples include, but are not limited to, sodium benzoate. Other antifungal agents include sorbic acid, sodium propionate, methyl p-benzoate, ethyl p-hydroxybenzoate, propyl p-propyl benzoate and Butyl hydroxybenzoate. The preservative, if included, may comprise from about 0.001 to about 1% by weight, such as from about 15% to about 0.5% by weight, based on the total weight of the composition, for example about 〇.〇 The amount of 15% to about 3% by weight is stored 134966.doc -15- 200932243. In another embodiment, the preservative is selected from the group consisting of gasified benzalkonium chloride, EDTA and/or potassium sorbate. In another embodiment, the preservative is edta and/or potassium sorbate. In another embodiment, the preservative is at a concentration of about 0.015% (by weight) of EdtA and about 0.3% by weight of the total composition ( Weight ratio) concentration of sorbic acid clock. In another embodiment, the aqueous pharmaceutical composition of the present invention is provided without a preservative. ❹

In one embodiment, an aqueous pharmaceutical composition of the invention comprising a humectant is provided. The composition (e.g., wherein the compound is in suspension) may include one or more wetting agents for wetting the agent particles to promote dispersion in the aqueous phase of the composition. Generally, the amount of humectant used will not cause foaming of the dispersion during mixing. Examples of pharmaceutically acceptable wetting agents include, but are not limited to, fatty alcohols, esters, and ethers (such as polyethylene oxide (2〇) sorbitan monooleate (polysorbate 8 〇), polyethyl b Glycol ether and poloxamer (polo-1)). The humectant may be from about 5 to about 0.05%, such as from about 0.01 to about 5% by weight, such as from about 2 (four) by weight, or from about 1.5 to 2.5% by weight of the total composition of the composition. An amount such as about 2.0% by weight is present. In the examples, the wetting agent is polyethylene oxide (iv) sorbitan monooleate (polysorbate 8). Drug = in the example of providing a water-containing eye of the present invention comprising an isotonicity regulating agent: two: or an isotonicity adjusting agent to achieve a stimuli level (for example, a nasal limb flow* or), resulting in a reduced level of stimulation 1 Pharmacologically 134966.doc ^ 16- 200932243 Examples of acceptable osmotic modulators include, but are not limited to, sodium vaporification, dextrorotatory = xylitol and gasification dance. The amount may be included in the total weight of the composition : to :), such as from about 4. 5 to about 5.5 • (by weight) or from about 5 5 to about 1% by weight, such as the weight ratio of the shape (four) Isotonicity adjusting agent (if present). In another embodiment, the osmolality agent is dextrose (e.g., anhydrous dextrose) and/or xylitol. In another embodiment, the isotonicity adjusting agent is xylitol. In other embodiments, the isotonicity adjusting agent is xylitol at a concentration of about 75% by weight based on the total weight of the composition. In another embodiment, the composition does not contain an isotonicity adjusting agent. In the embodiment, an aqueous pharmaceutical composition of the present invention comprising a buffer is provided.

The compositions of the present invention may be suitably prepared by the addition of, for example, sodium citrate, citric acid, phosphates such as disodium phosphate (e.g., dodecahydrate, heptahydrate, dihydrate, and anhydrous forms) or sodium phosphate, and mixtures thereof. The buffer is buffered. Another buffer is trometarol. In another embodiment, the buffer is sodium citrate and/or citric acid. In another embodiment, the buffer is sodium citrate at a concentration of about 1. 48% by weight based on the total weight of the composition and citric acid (which may be anhydrous) at a concentration of about 0.96% by weight. In one embodiment, an aqueous pharmaceutical composition of the invention comprising a cosolvent is provided. One or more cosolvents may be included to aid in the solubility of the active compound and/or other excipients. Examples of pharmaceutically acceptable cosolvents include, but are not limited to, propylene glycol, dipropylene glycol, ethylene glycol, glycerol, ethanol, polyethyl alcohol (e.g., PEG 300 or PEG 400), and sterols. It can be included in the total weight of the composition 134966.doc -17- 200932243. From about 0.05 to about 2% by weight, such as from about 5 to about 175% by weight, or from about 1.5 to about 7.5% by weight or from about 5% to about 5% by weight. a co-solvent (if present) in an amount greater than). In another embodiment, the aqueous pharmaceutical composition of the present invention is further provided, which additionally comprises: ^ ' a) a suspending agent; b) a preservative; c) a wetting agent; and 〇 d) an isotonicity adjusting agent. In another embodiment, an aqueous pharmaceutical composition of the present invention is provided, which additionally comprises: a) a suspending agent; b) a preservative; c) a wetting agent; d) an isotonicity adjusting agent; and e) a cosolvent. In another embodiment, there is provided an aqueous pharmaceutical composition comprising microcrystalline cellulose and sodium carboxymethylcellulose (as a suspending agent); gasified stupid, ammonium, EDTA and/or sorbic acid Potassium (as a preservative); polyoxyethylene • (2〇) sorbitan monooleate (supplied with polysorbate 80) (as a wetting agent); and dextrose and/or xylitol (as Isotonicity regulator). In another embodiment, there is provided an aqueous pharmaceutical composition comprising microcrystalline cellulose and a m-methylcellulose nano (as a suspending agent); gasified benzoquinone ammonium, EDTA and/or potassium sorbate ( As a preservative); polyoxyethylene 134966.doc -18- 200932243 (2 0) dehydrated sorbitan monooleate cool (暇 from θ (supplied with polysorbate 80) (as a wet full agent), dextrose And/or xylose Iπ π , _ U 乍 is an isotonicity adjusting agent); and propylene dioxime (as co-solvent P-alcohol in another example xin' provides an aqueous pharmaceutical composition comprising microcrystalline cellulose And dimethylcellulose sodium (as a suspending agent); coffee eight and / or sorbic acid unloading (as a preservative); polyoxyethylene bake (20) sorbitan • ^ by acid vinegar (to polysorbate vinegar 80 supply) (as a humectant); xylitol (as an isotonicity regulator); and propylene glycol (as a cosolvent). 组合 局部 局部 局部 局部 局部 局部 局部 局部 局部 局部 局部 局部 局部 局部 局部 局部 局部 局部 局部 局部 局部 局部 局部 局部 局部The pressurized aqueous aerosol composition and aqueous composition delivered to the nasal cavity by the pressure pump are non-pressurized and Aqueous compositions for topical administration to the nasal cavity are of particular interest. Aqueous compositions can also be administered to the nose by spraying. Thus, the aqueous pharmaceutical compositions of the present invention are provided in a suitable container depending on the route of administration. Combinations of the two compounds, it is understood that the container may be capable of delivering the compounds sequentially in separate pharmaceutical compositions and simultaneously delivering the compounds in a combined pharmaceutical composition. Typically used to deliver the aqueous pharmaceutical compositions of the present invention to the nasal cavity The fluid dispenser can have a dispensing nozzle or dispensing orifice that dispenses a &quot;ten amount of fluid composition via the dispensing nozzle or dispensing orifice after application of a force applied by the user to the pumping mechanism of the fluid dispenser. The fluid dispensers generally have The equal amount of the reservoir of the plurality of metered fluid compositions can be dispensed after continuous pump actuation. The dispensing nozzle or orifice can be configured to be inserted into the nostrils of the user for dispensing the fluid composition to the spray. In the nasal cavity. Fluid dispensers of the above type are described and illustrated in WO 05/044354, the entire contents of which are incorporated by reference. No. 134966.doc -19-200932243 is incorporated herein by reference. The dispenser has a housing containing a fluid discharge device having a compression pump mounted on a container containing the fluid composition. The housing has at least one finger operable a side bar movable inwardly relative to the outer casing to cam the container up in the outer casing to cause the squeezing and pumping of the metering composition out of the pump conduit via the nose nozzle of the outer casing. In one embodiment The fluid dispenser is of the general type illustrated in Figure 30-4 of WO 05/044354.

Further, the aqueous pharmaceutical composition of the present invention can be as disclosed in WO 2007/138084 (for example as disclosed in reference to Figures 22-46) or as disclosed in GB 〇 72 241 8 (for example as disclosed with reference to Figures 7-32) Pump delivery, both of which are incorporated herein by reference in their entirety. The pump can be actuated by the actuator disclosed in Figures 1-6 of GB 〇 723418. Typically, a fluid dispenser for use with the aqueous pharmaceutical compositions of the present invention will be sufficient to hold 8 to 5 mL (or less) of the composition and each spray will typically deliver 50 to (10) calls (or less). , for example, 25 is called a composition. Therefore, usually, the L-body dispenser will be able to provide at least 1 〇〇 metering. Thus, in another aspect, a container comprising an aqueous pharmaceutical composition of the present invention is provided. In an embodiment, the container is adapted to deliver the aqueous pharmaceutical composition of the present invention to the nasal cavity. In another example, the container is adapted to deliver the compound to the eye. The composition of the present invention has a potentially beneficial effect, especially in the case of k and/or anti-allergic effects, such as 4-[(4-phenylphenyl) 曱 134966.doc -20· 200932243 ]-2-({(2))-1_[4-(4-{[3-(hexahydro-17/-azahryl)propyl]oxy}phenyl)butyl]pyrrolidine The ability of the base methyl}-1(2//)-pyridazinone or its pharmaceutically acceptable salt to antagonize the Η1 and Η3 receptors in a long-term manner, and the glucocortinone citrate is known to the glucocorticoid receptor. Confirmed by activity. Accordingly, the aqueous pharmaceutical compositions of the present invention are useful for the treatment of inflammatory and/or allergic diseases, particularly inflammatory and/or allergic diseases of the respiratory tract.

Examples of diseased conditions in which the aqueous pharmaceutical compositions of the present invention may have potentially beneficial anti-inflammatory and/or anti-allergic effects include inflammatory and/or allergic diseases of the respiratory tract, such as allergic rhinitis (seasonal and year-round) or such as Bronchitis (including chronic bronchitis), asthma (including allergen-induced asthmatic reactions), chronic obstructive pulmonary disease (C0PD), and other diseases of sinusitis. Further, the aqueous pharmaceutical composition of the present invention can be used for the treatment of nephritis, skin diseases (such as psoriasis, eczema, atopic dermatitis) and hypersensitivity reactions. Further, the aqueous pharmaceutical composition of the present invention is suitable for treating insect bites. The aqueous pharmaceutical composition of the present invention can also be used for the treatment of nasal polyposis, conjunctivitis (e.g., allergic conjunctivitis) or pruritus. A disease of particular concern is allergic rhinitis. Other diseases in which histamine can have a pathophysiological effect include non-allergic rhinitis. Therefore, the aqueous pharmaceutical composition of the present invention can also be used for the treatment of non-allergic familiarity. The person skilled in the art should understand the prevention and treatment of the disease that has been produced. Therefore, it is possible to provide a 4-[(4-gas t Alkyl]-2-({(2i?)-l-[4· 134966.doc •21- 200932243 (4_{[3·(hexahydro-l/f-azhen-1-yl)propyl) ]oxy}phenyl)butyl]-2-&quot;pyrrolidyl}methyl)-1(2//)-pyridazinone compound or a pharmaceutically acceptable salt thereof and, as the case may be, fluticasone The aqueous pharmaceutical composition of the invention of the compound or its solvate is used in therapy. In another embodiment, a method comprising 4-[(4. gasphenyl)methyl]_2. ({(2i?)-l-[4-(4-{[3-(hexahydro-1/)) /-Azinc-l-yl)propyl]oxy}phenyl)butyl]-2-nb-pyridyl}methyl)_1 (2 ugly)-pyridazinone compound or its pharmaceutically acceptable Salts and, as the case may be, fluticasone citrate compounds or solvates thereof The aqueous pharmaceutical compositions of the present invention are useful for treating (or preventing) inflammatory and/or allergic diseases. In another embodiment, there is provided a method comprising 4-[(4-phenylphenyl)methyl]_2_({(2))-1-[4-(4-{[3-(hexahydro-1///) -azeo-l-yl)propyl]oxy}phenyl)butyl]-2-»pyrrolidyl}methyl)_1(2dan)-pyridazinone compound or pharmaceutically acceptable The aqueous pharmaceutical composition of the present invention, which is a salt and, as the case may be, a fluticasone citrate compound or a solvate thereof, is for use in the treatment (or prevention) of respiratory tract inflammatory @ and/or allergic diseases such as allergic rhinitis. In another aspect, there is provided a method comprising 4_[(4-hydroxyphenyl)methyl]_2_ ({(2i〇-K[4-(4-{[3·(hexahydro-17^) )propyl]oxy}phenyl)butyl]-2-3⁄4 pyridyl}methyl)_丨(2//) pyridazinone or its pharmaceutically acceptable salt and, as appropriate, The aqueous pharmaceutical composition of the present invention of the fluticasone compound or a solvate thereof for use in the manufacture of a therapeutic (or prophylactic) inflammatory and/or allergic disease (such as an inflammatory and/or allergic disease of the respiratory tract, such as allergic rhinitis) Use of a medicament. In another aspect, a method for treating (or preventing) any of the above diseases, 134966.doc -22 200932243, which comprises administering a pharmaceutically effective amount to a patient in need thereof The aqueous pharmaceutical composition of the present invention comprises 4_[(4_气phenyl)methyl]_2-({(2/?)-1-[4-(4-{[3-(hexahydrozine) Phenyl) propyl]oxy} phenyl)butyl]-2-»pyrrolidyl}methyl) (2) oxazinone compounds or pharmaceutically acceptable salts thereof and, if appropriate, citric acid a fluticasone compound or a solvate thereof. In one embodiment, provided Method for treating allergic rhinitis. [Embodiment] The aqueous pharmaceutical composition of the present invention can be prepared by the following method or by a similar method. The following examples illustrate the preparation of an aqueous pharmaceutical composition, but are not considered to be in any way. Limitation of the scope of the disclosure. Preparation of 4-indole (4-phenylphenyl)methyl-2 gas (hexahydroazin-1-yl)propyl]oxy}phenyl)butyl]_2_pyrrolidine }}methyl)_1(2) 酞 pyrazinone 4-[(4-phenylphenyl)methyl] small [4 (4_{[3_(hexa-argon·17/_azhen· 1-yl)) Alkyloxy}phenyl)butylpyrrolidyl}methyl)_1(2 ugly)_pyridazine® ketones and their salts can be used in accordance with International Patent Application No. 2007/122156 published on November 1, 2007 (Glaxo Group Ltd) (in detail, see the methods disclosed in Examples 24A, '24C and 24D) for preparation. Abbreviation BOC(Boc): DMSO : HPLC : LCMS : Third Butoxycarbonyl Disulfoxide High Performance Liquid Chromatography Liquid Chromatography Mass Spectrometry 134966.doc -23- 200932243 mbar : mbar (pressure) MDAP : Quality-guided automatic preparation of acetonitrile : acetonitrile NMR : NMR PTFE : polytetraethylene SiO 2 : cerium oxide TLC : thin layer chromatography h : hour min : minute RT : residence time general procedure 急石石胶 means Merck Art 93 No. 85; Shi Xijiao refers to] VIerck Art No. 7734. The SCX cartridge is an ion exchange SPE column with a stationary phase of polymerized benzenesulfonic acid. These cartridges are used to separate amines. The SCX2 cartridge is an ion exchange SPE column with a stationary phase of polymerized propyl sulfonic acid. These cartridges are used to separate amines. LCMS uses the following dissolution gradient 0.0-7 min 0% B, 0.7-4.2 min 100% B, 4.2-5.3 min 0% B, 5.3-5.5 min 0% B in water at a flow rate of 3 mlmin·1 0.1% Formic acid and 0.01 M ammonium acetate (solvent A) and 0.05% citric acid 5 ° / hydrazine (solvent B) in acetonitrile were dissolved and applied to a Supelcosil LCABZ + PLUS column (3.3 cm &gt;&lt; 4.6 mm ID). The mass spectra were recorded on a Fisons VG Platform mass spectrometer using positive and negative electrospray modes (ES+ve and ES-ve). 134966.doc -24- 200932243

The Flashmaster II is an automated multi-user flash chromatography system available from Argonaut Technologies Ltd that utilizes a disposable normal phase SPE cartridge (2 g to 100 g). It provides quaternary on-line solvent mixing to enable the gradient process to proceed. The samples were arranged using a multi-function open access software that manages the solvent, flow rate, gradient profile, and collection conditions. The system is equipped with Knauer's variable wavelength UV detector and two Gilson FC204 dissolving collectors, enabling automatic peak cutting, collection and traceability. Mass Guided Automated Preparation (MDAP) HPLC was performed on a Waters Fraction Lynx system containing a Waters 600 with an extended pump head, a Waters 2700 autosampler, a Waters 996 diode array, and a Gilson 202 dissolver collector at 10 cm &gt; 2.54 cm inner diameter ABZ + pipe column, with 0.1 in water. / decanoic acid (solvent A) and 0.1% formic acid (solvent B) in acetonitrile are dissolved, using a dissolution gradient at a flow rate of 20 ml min·1 for 15 min (if appropriate) and at room temperature at 200-320 nm Detection is done. The mass spectra were recorded on a Micromass ZMD mass spectrometer using alternating electrospray or negative electrospray mode alternate scanning. The software used was MassLynx 3.5® with OpenLynx and FractionLynx options. The 1H NMR spectra were recorded on a Bruker AV400 operating at 400 MHz. Use standard deuterated solvents. Typically, NMR is used to obtain NMR for reference. Tetradecyl decane is used as an internal standard, as appropriate. The reaction is usually monitored by methods well known to those skilled in the art, such as TLC, LCMS and/or HPLC. These methods are used to assess whether the reaction has been completed and the reaction time can be varied accordingly. The compounds were named using ACD/Name PRO 6.02 chemical naming software Advanced Chemistry Developments Inc.; Toronto, Ontario, 134966.doc • 25· 200932243 M5H2L3, Canada. According to one method, 4-[(4-phenylphenyl)methyl]-2-({(2Λ)-1-[4-(4-{[3-(hexahydro-l) can be prepared according to the following Scheme 1 /ί-azhen-1-yl)propyl]oxy}phenyl)butyl]-2-«pyrrolidyl}indenyl-1(2//)-pyridazinone and its 1,5 - Naphthalene disulfonate. 4-[(4-chlorophenyl)methyl]-2-({(2/〇-1-[4-(4-{[3-(hexahydro-1//-azhen-1-yl)) Propyl]oxy}phenyl)butyl]-2-&quot;pyrrolidyl}indenyl)·1(2//)·pyridazinone and its salts may also be based on November 2, 2007 Prepared by Method G disclosed in the published International Patent Application WO 2007/122 156 (Glaxo Group Ltd) (see Example 24). Scheme 1: Synthesis of 4·[(4-Phenylphenyl)methyl]_2-( {(2/?)-1-[4-(4-{[3-(hexa-argon-1-good-azhen-1-yl)propyl]oxy}phenyl)butyl]2-pyrrole Pyridyl}methylpyridazinone, free base and 1&gt;5•naphthalene disulfonate

134966.doc 200932243 Reagents and conditions: stage υ suitable test, such as sodium acetate, suitable solvent, such as 沁methyl-2-pyrrolidone 'usually at high temperatures such as (10); stage 2) bismuth or barium sulphate and Sodium hydroxide, in a suitable solvent such as ethanol; stage 3) suitable test, such as the carbonation stage is called a suitable activator, such as a continuous brewing gas, suitable test, such as triethylamine, a suitable solvent, such as diethyl ether; stage 4b) suitable a base such as triethylamine and/or potassium carbonate, suitable as a gluten, such as decyl isobutyl ketone, optionally using an activator such as potassium iodide, usually heated to a high temperature such as reflux; stage 5) such as two gas Methane® In a suitable solvent, use a suitable reagent such as tri-boron boron or aqueous desertification hydrogen and acetic acid to deprotect, optionally cooling to, for example, about hydrazine. Suitable low temperature for the hydrazine; stage 6) suitable solvent, such as 2-butanone, a suitable base such as potassium carbonate; stage 7) a suitable base such as potassium carbonate, in a suitable solvent such as 2-butanone, optionally using activation such as potassium iodide Stage 8) Step 丨: a suitable solvent such as methyl isobutyl ketone and/or methanol, aqueous hydrogen chloride solution, 5-naphthomonosulfonic acid (available, for example, from Aldrich); step 2 (optional): Recrystallization from w. dimethyl argon and tetrahydrofuran aqueous solution. The compound of formula (1) 'phthalic anhydride can be purchased, for example, from Sigma_Aldrich. * Compound of formula (11) '4-Phenylphenylacetic acid can be obtained, for example, from Sigma-Aldrich. The compound of formula (III), 4-oxobenzylidene benzoquinone (for example;) is commercially available from Honeywell. The compound of formula (IV) '4-[(4-Phenylphenyl)methyl]-1(2H)-pyridazinone is also disclosed in U.S. Patent 3,813,384, the disclosure of which is incorporated herein by reference. 134966.doc -27- 200932243 The compound of formula (V) '(2 external 2)[(methyl sulfhydryl)oxy]methyl}1 〇 唆 唆 唆 l l'l-dimethyl ethane can be used Prepared by methods well known to those skilled in the art, for example, by making correspondingly constitutable alcohols, for example,

Prepared by Aldrich (2/〇-2-(yl)methyl) 0-pyridinecarboxylic acid u-dimethylacetate for acidification. The activation reaction can usually be carried out at a low temperature such as 〇 to 20 C. 'In a suitable solvent such as tert-butyl methyl ether, a suitable activator such as methylsulfonate is used, for example, using a suitable activator (see Stage 3a). © Compound (VII) '4-[ 4-(Methyloxy)phenyl]-1-butanol is commercially available, for example, from Sigma-Aldrich. The compound of formula (XI) ' 1- Desert _3·propane can be purchased, for example, from Sigma Aldrich. ΧΠΙ) The compound 'hexamethyleneimine is commercially available, for example, from Aldrich. Further, a pharmaceutically acceptable salt form of 4_[(4-hydroxyphenyl)indolyl 2-({(2Λ)_1· [4_(4_{[3-(hexahydro-1open-azhen-1-yl)propyl]oxy}phenyl) butyl]_2_pyrrolidinyl}methyl)-1 (2 feet)- Pyridazinone can be prepared by exchanging a counter ion or precipitating the salt from a free base. It is further understood that 4-[(4-phenylphenyl)methyl]-2.({(27?)- . Hexahydro-17/-azoh_1-yl)propyl]oxy}phenyl)butyl]-2- «byrrolidine曱 ) ) -1 -1 ( 意 意 意 意 意 意 意 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- //Nitrogen _ 1-yl)propyl]oxy} phenyl)butyl]_2·βpyrrolidyl}methyl)_1(2//)pyridazine 134966.doc -28- 200932243 The pharmaceutically acceptable salt form and/or can be administered in the form of a pharmaceutically acceptable salt. A discussion of suitable salts 'see Berg e et al, j Phann·Sci 1977, 66' 1-19. Suitable pharmaceutically acceptable salts include acid addition salts. The term used herein is pharmaceutically "Acceptable salt" means any pharmaceutically acceptable salt or solvate of a compound of formula (1) which is capable of providing (directly or indirectly) a compound of formula (1) or an active metabolite or residue thereof, upon administration to a recipient. Generally, the 'pharmaceutically acceptable salt can be readily prepared by using the desired beta acid as needed. The salt can be precipitated from solution and collected by filtration or can be recovered by evaporating the solvent. Pharmaceutically acceptable The acid addition salt can be obtained by making 4_[(4-hydroxyphenyl)methyl]-2-({(2))-1-[4-(4-{[3-(hexahydro-1//-- Alkyl-l-yl)propyl]oxy}phenyl)butyl]-2·-pyrrolidyl}indenyl)_1(2F)-pyridazinone with a suitable inorganic or organic acid (such as hydrobromine Acid, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, succinic acid, maleic acid, citric acid, acetic acid, propionic acid, transbutanic acid, citric acid, tartaric acid, lactic acid, benzoic acid, salicylic acid, glutamic acid ,day Amines® acid, p-toluenesulfonic acid, benzenesulfonic acid, decanesulfonic acid, ethane acid, naphthalenesulfonic acid (eg 2-naphthalenesulfonic acid), naphthalenedisulfonic acid or caproic acid), such as in organic solvents - The reaction is carried out in a suitable solvent to give a salt which is usually isolated, for example, by crystallization or filtration. The pharmaceutically acceptable acid addition salt of the compound of formula (1) may comprise or be, for example, a hydrobromide salt, Hydrochloride, sulfate, nitrate, phosphate, succinate, maleate, formate, acetate, propionate, citrate, tartrate, tartrate Salt, benzoate, salicylate, glutamate, aspartate, p-toluene 134966.doc -29- 200932243 salt benzene sulfonate, methane sulfonate, ethane sulfonate , naphthalene sulfonate (such as 2-naphthalene sulfonate), naphthalene disulfonate (such as hydrazine, 5-naphthalene disulfonate) or hexanoic acid ruthenium should be known about 4_[(4 · phenyl) methyl ]-2-({(27Μ-[4·(4-{[3-(hexahydro)azetidinyl)propyl]oxy}phenyl)butyl]-2·indolyl)曱 )) _ () 駄 酮 ketone can be used with / gluten (in the solvent) The complex should be formed from or in the solvent. The complex is called, solvate. For example, the complex formed with water is called &quot;hydrate&quot; It should be understood that 4-[(4 胃 ® phenyl) methyl] chuan 2 illusion "- (4) (1) gas hexahydro-1 / / · arso-1-yl) propyl] oxy} phenyl) butyl ]_2 "Thank bite base} 曱 base)" (10) offer celestial or its present; granulated form, especially in the form of hydrates. The specific solvating form is monohydrate 1,5-naphthalene dihydrochloride. Intermediate 1 (2Λ) 2-{[4-[(4·Phenylphenyl)methyl]j-side oxy-2(1)-etazinyl]methyl}-1_pyrrolidinecarboxylic acid l,i Add azobis(tetra)diiso(tetra)(ι 12仏(10) mmol) to a solution of monophenylphosphine (15 g, 7.09 mmol) at 15 C in anhydrous tetrahydrofuran (6 liters). The thick suspension was stirred at _15 for 2 min under the armpits. To aid in the search, add more anhydrous tetrahydrocough (2) followed by [(4 chlorophenyl)methyl]-1 (2) /0_pyridazinone (eg as US patent)

3,8 1 3,3 84, in the real | 】n. L ear iJ1〇, as disclosed in step 1) (0 57i g, 2 η mmo丨) and W third butoxy group _d_ guanamine Alcohol (can be purchased, for example, from

Fluka) (0.650 g ' 3.23 mm〇1) is suspended in anhydrous tetrahydroanthracene (10)

The float treatment reaction mixes the private j. &amp; A m The reaction mixture was allowed to warm to room temperature and stirred at 20 ° C for 134966.doc 200932243 for 23 h. Methanol (20 ml) was then added and the solvent was removed in vacuo. By 0-50〇/. The residue obtained was purified by flash-chromatography (70 g of cerium dioxide filter cartridge) eluting with ethyl acetate-cyclohexane over 40 min. The solvent was removed in vacuo to give the title compound (ljjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj · 咕 啶 啶 基 甲基 甲基 ( ( ( ( ( ( ( ( 向 向 向 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 (2i?) //)-pyridazinyl] ® 1,1-dimethylethyl methopyrrolidine phthalate (for example, as prepared for Intermediate 1) (1.05 §, 2.311111111 〇 1) in anhydrous 1,4 A solution of hydrogenation of hydrogen in 1,4-dioxane (4.0 Torr, 6 ml) was added to the solution in dimethyl alcohol (12 1111). The solution was stirred at 20 ° C for 2 h. Trifluoroacetic acid (1 ml) was added to the mixture and stirred for 30 min, then more trifluoroacetic acid (3 X about 1 mi) was added at 1 pm intervals until deprotection was complete. The solvent was removed in vacuo and the residue was applied to EtOAc (20 g) eluting with EtOAc (2 times) and then eluting with 10 〇 / 〇 ammonia (2 x 5 〇 ml) in methanol. The solvent was removed in vacuo' and the residue obtained was purified by flashmaster II chromatography (50 g of cerium dioxide filter cartridge) over a period of 40 min with 0-30% methanol + oxime/0 triethylamine. The title compound (0.351 g) was obtained as a dark brown foam. LCMS RT = 2.45 min. Intermediate 3 ^[(3-Actyl)oxy]-4-iodobenzene Benzene 4-iodophenol (available, for example, from Aldrich) (20 g), 1-bromo-3-propane (for example The mixture, which was purchased from Aldrich) (17.91 g) and potassium carbonate (25.2 g) in 2-butylid 134966.doc • 31-200932243 (400 ml) was stirred under a nitrogen atmosphere for 18 hours under reflux. The mixture was allowed to cool and filtered. The filtrate was evaporated and the residue was taken up in hexanes </ RTI> and purified with &lt;RTIgt;&lt;/RTI&gt; </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; The title compound was obtained as a colorless oil (yield crystallized upon standing) (15.928 g). [CMS RT = 3.70 min. An additional portion of the title compound was obtained as a pale yellow oil (yield solidified upon standing) (6.668 g). 4 NMR (CDC13;) δ © (2Η, quintuple, 17=6 Hz), 3.74 (2Η, t, J=6 Ηζ), 4.09 (2Η, t, J=6 Hz), 6.70 (2H, m ), 7.57 (2H, m) ° Intermediate 4 l-{3-[(4-Iodophenyl)oxy]propyl sulfonium hexahydro-1H_azine will be 1-[(3- propyl)oxy Base]_4_deuterated benzene (for example as prepared for intermediate 3) (1 5.855 g), moth (8 g) and hexamethylene imide (for example, available from

A mixture of Aldrich) (15.1 ml) in 2-butanone (200 ml) was at 80. The underarm was spoiled for about 22 h under a nitrogen emulsion. The reaction mixture was filtered and the filtrate evaporated to give a white crystal. This material was triturated with diethyl ether and the solid solid was collected by filtration to dissolve the solid between dioxane (2?) and saturated sodium bicarbonate (2?). The organic layer was dried over anhydrous sodium sulfate and evaporated to give a residue. &lt;&quot;&quot;&quot;&quot;&quot;&quot;&quot;&quot;&quot;&quot;&quot; The residue was purified by flashmaster II chromatography over 50 min. The title compound (1.2708 g) was obtained as a yellow solid. LCMS RT = 2.39 min, ES+Ve m/z 360 (M+H). Evaporation of the filtrate from the wet mill yielding a brown residue using -30966.doc -32 · 200932243 1% triethylamine 0-30% methanol - A two-gas methane gradient was purified by flashmaster II chromatography on a 2xl 〇〇g cerium dioxide filter cartridge over 50 min. The title compound (15,9 g) was obtained as a yellow oil. LCMS RT = 2.40 min, ES+ ve m/z 360 (M+H)+. Intermediate 5 4-(4-U3-(hexahydro-1H-azhen-1-yl)propyl]oxy}phenyl)_3-butyne·j alcohol Stirs iodine under nitrogen atmosphere at room temperature Phenyl)oxy]propyl}hexahydro-1//-aza (for example, as prepared for Intermediate 4) (1 268 g),

3-butyn-1-ol (available, for example, from Aldrich) (668 μl), triethylamine (ml), gasified bis(diphenylphosphine)palladium (π) (ι 24 mg), and copper iodide (i) The mixture (34 mg) in tetrahydrofuran (15 ml) was stirred for about 5 h. The mixture was filtered (6 〇 mi PTFE filter) and the filtrate was evaporated to give a residue. Using a 〇- 30% methanol-two gas compression gradient containing trimethylamine, i 〇 〇 g on the sulphur dioxide

This material was purified by flashmaster chromatography for 60 min. The residue (9) g) dissolved in a methanol towel and loaded on a scx ion exchange cartridge was obtained from an appropriate solvent to evaporate the solvent. (4) Wash the knee with decyl alcohol and then dissolve in 2 M oxygen in the f alcohol. The title compound (823 mg) was obtained as a dark yellow residue. LCMS RT = 2 1 〇 _, _ 3 〇 2 (M+H)+. Intermediate 6 hexa-argon-heart nitrogen small base) two-base oxy}phenyl) butylbutanol to -U3-(hexahydro-nitrogen-hydrogenyl)propyl]oxy}phenyl)butan -1-Alcohol (for example, as prepared for the intermediate) (823 mg) is added to a solution of ethanol (20 ml) in 1.25 Μmethanol φ + * liquefaction of the gasified milk (3.25 ml) and will 134966.doc • 33 - 200932243 The mixture was hydrogenated over 10% by weight of palladium on the carbon π Μ 3 50 mg) for about 4 h. The reaction mixture was passed through the algae soil and a brigade was taken and the solvent was evaporated. The residue was dissolved in a second gas institute (125 yd and the resulting solution was made up of 2 Ν sodium hydroxide (10) _ and salt water 〇〇〇 ml) and dried over anhydrous water. Evaporation (iv) gave the title compound ( s. Lcms lamp = 2 Paradox, ES+ve m/z 306 (M+H)+. Intermediate 7 ❹ A succinic acid 4-(Μ[3·(hexa-argon·1Η•azetidyl)propyl Ioxy)phenyl)butyl milling ml to 4-(4-{[3-(six Hydrogen-(8)azetidyl)propyl]oxy}phenyl)butanol (for example, as prepared for Intermediate 6) (〇.〇77 g, 〇25 bribe in anhydrous two gas (2 mi) Diisopropylethylamine (〇〇53, 0.30 mmol) was added to the solution and then methanesulfonate was added (available, for example,

Aldnch) (0.023 ml '〇·3〇 mmol). The solution was stirred for 2 h at 2 『c. The solution was diluted with di-methane (1 〇 ml) &amp; saturated sodium bicarbonate 〇 1}. The two phase mixture was shaken and the phases were separated using a hydrophobic sintered glass frit. The organic phase was removed in vacuo to give the title compound ( </ </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Butyl ester to 4-[4-(decyloxy)phenyl pi•butanol (available, for example, from Aldrich) (0.36 g, 2 mmol) and triethylamine (1.39 nu, 1 Torr) under nitrogen Mm 〇 1) In a cooled 〇 ° C solution in anhydrous diethyl ether (10 ml), a solution of turmeric (available, for example, from Aldrich) (0.46 ml '6 mmol) was added dropwise. After a few hours, the reaction mixture was separated between diethyl ether and water. EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc The title compound (〇.52 g). 1 NMR (400 MHz, CDC13) δ 7.10 (d, J = 8.8 Hz, 2H), 6.84 (d, J = 8.8 Hz, 2H), 4.24 (t, J = 6.3 Hz, 2H), 3.80 (s, 3H), 2.99 (s, 3H), 2.61 (t, J=7 Hz, 2H), 1.82-1.68 (m, 4H). Intermediate 9 4-[(4- Phenyl)methyl]-2-[((2R)-l-{4-[4-(methyloxy)phenyl]butyl}-2-oxaridinyl)methyl]-1 2H)-酞4- Under nitrogen, to 4-[(4-phenylphenyl)methyl]-2-[(2/?)-2-»pyrrolidylmethyl]-1 (2//)- Adding decanesulfonic acid 4_[4_(fluorenyloxy)phenyl] butyl to a solution of ketone (for example as prepared for intermediate 2) (35.3 5 g, 100 mmol) in 2-butanone (250 ml) An ester (for example as prepared for intermediate 8) (3 1 g, 120 mmol) and potassium carbonate (27_6 g, 200 mmol). The reaction mixture is heated under reflux for 24 h. The solid is removed by filtration and taken to 2 -butanone (3 XI 〇〇ml) wash. The combined filtrate and washings were evaporated in vacuo and the residue was dissolved in dichloromethane (70 ml). applied to cerium dioxide Biotage cartridge (800 g) and dissolved in methylene chloride (5000 ml) followed by 5% methanol (5000 ml) in di-methane. The desired fractions were evaporated in vacuo and dissolved in dichloromethane (70 ml It was applied to an aminopropyl filter cartridge (8 χ 7 〇g) and dissolved in a 0-1 00% two-gas-fired gradient in cyclohexane over 30 min. The desired lysate was separated and placed in vacuo. Evaporation gave the title compound (30.96 g). LCMS RT = 2_95 min, ES+ ve m/z 5 1 6/5 1 8 [M+H]+. Intermediate 10 134966.doc -35- 200932243 M(4-Phenylphenyl)methyl]^(...small oxime (4) hydroxyphenyl) butyl] n aridinoyl}methyl)-1 (2 good) -pyridazinone to 4-[(4-phenylphenyl)methyl]-2-[((2/?)-1-{4-[4-(methyloxy)phenyl]] under nitrogen Butyl 2-pyridyl)methyl]-1(2//)-pyridazine network (for example as prepared for intermediate 9) (24.35 g, 47 mmol) in anhydrous digastric hospital (100 ml) In the cooling _6〇 °c solution, add tribromide to dichloromethyl. I.0 Μ solution (52 ml, 52 mmol) in the hospital. The reaction mixture was allowed to warm to room temperature and stirred under nitrogen for 8 h. The reaction mixture was cooled in an ice/water bath and then quenched with 2 EtOAc (50 mL). The reaction mixture was basified with saturated sodium hydrogencarbonate and extracted with dichloromethane (5 mL). The isolated organic phase was dried over anhydrous MgSO.sub. LCMS RT = 2.80 min, ES+ ve m/z 502/504 [M+H]+. Intermediate 11 4-[(4-Phenylphenyl)methyl b-2-{[(2R)-l-(4-{4-[(3-A)propyl)]phenyl}butyl)- 2-吼(rhohexidyl)methyl}·1(2Η)_pyridazinone ϋ Under nitrogen, to 4-[(4-phenylphenyl)indolyl]-2-({(2/〇-1-) [4-(4-Hydroxyphenyl)butyl]-2-&quot;bibridyl}methyl)-1(2//)-pyridazinone (for example as prepared for 'Intermediate 10) (22.03) g, 44 mmol) in 2-butanone (220 ml). Add 1-bromo-3-chloropropane (available, for example, from Aldrich) (5.2 m b 53 mmol) and potassium carbonate (12.2 g ' 88). The reaction mixture was heated under nitrogen for 18 h under reflux. The solid was removed by filtration and washed with 2-butanone (200 ml). The combined filtrate and washings were evaporated in vacuo and residue The product was dissolved in di-methane (60 ml) and applied to the dioxide dioxide 134966.doc -36- 200932243

The filter cartridge (330 g) was dissolved over a 12-column volume with a 0-25% methanol gradient in the two gas. The desired fractions were evaporated in vacuo. A portion of the residue (19.65 g) was dissolved in 2-butanone (200 ml) under nitrogen, and then 1-bromo-3-propanone (4.65 ml, 47 mmol) and potassium carbonate (1 〇8 g) were added thereto. , 78.4 mmol). The reaction mixture was heated under reflux for 18 h under nitrogen. More 1-bromo-3-aeropropane (1 ml) was added and the reaction mixture was heated at reflux for additional 5 h. The solid was removed by filtration and washed with 2-butanone (3×1 〇〇mi). The combined filtrate and washings were evaporated in vacuo and the residue was crystallised eluted eluted It was applied to a cerium oxide filter cartridge (33 〇 g) and was dissolved in a 10 column volume at a methanol gradient of 0-10% in di-methane. The desired fractions were evaporated in vacuo to give crystall LCMS RT = 3.18 min, ES + ve w/z 578 / 580 [M+H]+. 4-[(4-Phenylphenyl)methyl]-2-({(2))-1-[4-(4-{[3-(hexa-ar-111-aza-h--;!-yl)) Propyl]oxy}phenyl)butyl]-2-oxaridinyl}methyl)_l(2H)_酞嗓_ free base

'To 4-[(4-Phenylphenyl)methyl]_2-{[(2i?)-l-(4-{4-[(3-)propyl)oxy]phenyl} Kebirdinyl] fluorenyl}-1 (2)-pyridazinone 134966.doc -37- 200932243 (for example as prepared for the intermediate &quot;) (20 g, 34 6 with 〇 1) at 2_ Potassium iodide (11 5g, 69 2 mm〇i), carbonated (9.6 g, 69. 2 mmol) and hexamethyleneimine (available, for example, from Alddch) were added to the solution in Ding (20 ml). The reaction mixture was heated under reflux for 41 h. The solid was removed by hydrazine and washed with EtOAc (2 &quot;&lt; Evaporate in vacuo and dissolve the residue in methanol- s-methane (3 〇ml' 1:1). Apply it to a C18 reverse phase cartridge (2 x 330 g). 50% was dissolved in water (0.05% trifluoroindoleacetic acid) in a gradient of B (0.05% difluoroacetic acid). The desired fraction was evaporated in vacuo and the residue was dissolved in methanol. Aminopropyl filter cartridge (4 x 70 g) and dissolved in methanol. The desired fraction was evaporated in vacuo to give orange The title compound (1074 g) was obtained.

LCMS RT = 2.67 min, ES + ve τ η / ζ 641 / 643 [M+H]+. NMR (400 MHz, CDC13) δ 8.46 (m, 1 Η), 7.74-7.62 (m, 3H), 7.26 (d, J = 8.5 Hz, 2H), 7.20 (d, J = 8.5 Hz, 2H), 7.06 ( d, 7=8.5 Hz, 2H), 6.81 (d, /=8.5 Hz, 2H), 4.42 (dd, J=4,13 Hz, 1H), ❹ 4.24 (s, 2H), 4.07 (dd, “7 =8,13 Hz,1H),3.98 (t,J=6.3 Hz, 2H), 3.16 (m,1H), 2.97 (m,1H), 2.90 (m,1H), 2.65 (m, • 6H), 2.55 (m, 2H), 2.37 (m, 1H), 2.21 (m, 1H), 1.93 (m, . 2H), 1.89 -1.52 (m, 16H) 〇 Method 2 under nitrogen atmosphere 'at 8 〇 ° C 4-[(4-Phenylphenyl)methyl]-2-[(27?)-2-pyrrolidinylmethyl]-1 (2 milk-pyridazinone (for example as prepared for Intermediate 2) ) (1.017§, 2.87 111111〇1), methanesulfonic acid 4-(4-{[3-(hexahydro-1)-nitrogen 134966.doc •38·200932243h-1 -yl)propyl]oxy} A mixture of phenyl)butyl ester (for example, prepared for Intermediate 7) (1.115 g, 2.91 mmol) and sodium bicarbonate (474 mg, 5.64 mmol) in anhydrous acetonitrile (50 ml) was stirred for 5 days with stirring. The cooled reaction mixture was partitioned between EtOAc (EtOAc) (EtOAc) 2X 5 〇ml). The combined organic extracts were dried (MgSO4) and concentrated in vacuo. The residue (1.35 g) was dissolved in dimethylformamide (1 〇ml) and divided into ten portions Each was diluted with trifluoroacetic acid (0.5 ml). The fractions were prepared by preparative HPLC using a ❹ Kromasil C8 column (25 cm x 5 cm), 5% to 45% over 40 minutes (0.25% in water) It was purified by gradient elution in fluoroacetic acid (0.25% trifluoroacetic acid in acetonitrile), followed by maintaining the final concentration for 15 minutes. The relevant dissolved fractions from each run were combined and concentrated in vacuo to leave an aqueous solution. It was applied to an Amberchrom CG-161M column (25 cm x 2.5 cm) to adsorb the compound. The column was washed with water to remove excess trifluoroacetic acid and dissolved in acetonitrile to give the product as a trifluoroacetate salt. A scx cartridge (2 〇g) was washed with methanol and then washed with acetonitrile. A portion of the above product (0.98 g) was dissolved in acetonitrile and applied to a syringe cartridge, eluted with acetonitrile, and then with 10% aqueous ammonia. The solution in acetonitrile (200 ml) was dissolved. The title compound (651 mg) was obtained as an orange color in vacuo. LCMS RT = 2.52 min, ES+ve m/z 641 [M+H] + and 321/322 [M/2 +H]+. NMR (400 MHz, DMSO_c/6) δ ppm 8.38 (dd, J=7.1, 1.6 Hz, 1 H), 7.93 (m, 1 H), 7.86 (m, 1 H), 7.82 (m5 1 H), 7.30 (m, 4 H), 7.03 (d, 7=8.5 Hz, 2H), 6.80 (d, /=8.5

Hz, 2 H), 4.36 (m, 1 H), 4.33 (s, 2 H), 4.14 (dd, *7=13.1, 8.0 134966.doc •39· 200932243

Hz, 1 Η), 3.98 (t, J=6A Hz, 2 H), 3.14 (m, 1 H), 3.03 (dd, /=7.8, 4.5 Hz, 1 H), 2.84 (m, 1 H), 2.75 (m, 6 H), 2.50 (t, /=6.9 Hz, 2 H), 2.31 (m, 2 H), 1.97 (m, 2 H), 1.82 (m, 4 H), 1.68 (m, 8 H), 1.55 (m, 4 H) ° 4-[(4-Phenylphenyl)methyl]_2-({(2/?)-1-[4-(4-{[3-(hexa-argon-) 1 ugly-aza-n-yl)propyl]oxy}phenyl)butyl]-2-oxaridinyl}methyl)-1 (2 ugly)-pyridazinone, dihydrochloride salt 4 -[(4-Phenylphenyl)methyl]_2-({(2/〇-1-[4-(4-{[3-(hexahydro-1F-azepine-l-yl)propyl]] Ethyl}phenyl)butyl]-2-pyrrolidyl}indenyl-1(27/)-pyridazinone (3.85 g, 6.0 mmol) dissolved in MeOH (100 ml) and 2 N hydrochloric acid ( The solvent was removed in vacuo <RTI ID=0.0></RTI> <RTI ID=0.0></RTI> <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; </RTI> <RTIgt; 10.49 (1H, br s), 8.30 (1H, dd, 7=7.5, 1.5 Hz), 7.96 (1H, d, /=7.5 Hz), 7.88-7.93 (1H, m), 7.84-7.89 (1H, m), 7.38 (2H, d, J=8.5

Hz), 7.34 (2H, d, J=8.5 Hz), 7.09 (2H, d, J=8.5 Hz), 6.84 (2H, d, 7=8.5 Hz), 4.62 (1H, dd, 7=14.0, 4.5 Hz), 4.55 (1H, • dd, J=14.0, 7.0 Hz), 4.37 (1H, d, /=16.5 Hz), 4.33 (1H, d, /=16.5 Hz), 4.00 (2H, t, /= 6.0 Hz), 3.77-3.85 (1H, m)j 3.55-3.64 (1H, m), 3.31-3.46 (3H, m), 3.15-3.22 (2H, m)} 3.02-3.14 (4H, m), 2.47 -2.53 (2H, m), 2.07-2.23 (4H, m)5 1.49-1.99 (14H, m). 134966.doc -40· 200932243 4-[(4-Phenylphenyl)methyl]-2-({(2))-1-[4-(4-{[3-(hexahydro-1孖-nitrogen) -1--1-yl)propyl]oxy}phenyl)butyl]-2-indole-pyridyl}methyl)-l (2/〇-pyridazinone, monohydrate 1,5-naphthalene disulfide Acid Method 1 4-[(4-Phenylphenyl)methyl]-2-({(2))-1-[4-(4-{[3-(hexahydro-1//-) -1-yl)propyl]oxy}phenyl)butyl]-2-&quot;pilotidinyl}indenyl-1(2//)--pyridazinone free base (400 mg) dissolved in A solution of 1,5-naphthalene disulfonic acid (232 mg) in methanol (1 ml) and the resulting colloidal solution was heated with gas. A small amount of solid began to form and was cooled. There was solid precipitation followed by stirring the slurry at room temperature for about 1 h. Adding sterol (2 ml) to move the polymer 'The slurry was heated and cooled again and stirred for an additional hour. The solid was separated by filtration. Drying in vacuo to give the title compound (464.5 mg, <RTI ID=0.0></RTI> <RTIgt; 4-(4-{[3-(hexahydro-1//-azhen-1-yl)propyl]oxy}phenyl)butyl; 1-2-&quot;pyrrolidyl}fluorenyl Add water (200 ml) and hydrochloric acid (2 N, 12 ml) to the oxazinone free test (3.82 g, 5.96 mmol). Heat the reaction mixture to 9 ° C to obtain a clear solution. After 20 min. A solution of monohydrate i,5-naphthalenedisulfonic acid (22 g, 6 • mmol) in water (1 mL) was added thereto. The suspension was stirred at 9 ° C for 2 min and then allowed to The mixture was cooled to rt.~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ =2.58 min, ES+ve m/z 641 (M+H)+ 〇

134966.doc •4U 200932243 Method 3 (above process) For this method, the following abbreviations are used: eq: equal amount (1 eq = per 1 molar starting material! Moore reagent) v〇l : volume (1 ν〇 ι = starting material per gram 丨 ml) vol / vol : volume / volume wt : weight (1 wt = 1 g reagent per i § starting material) • wt / vol: weight / volume intermediate 12 (stage 1) © (3E)_3-[(4-Phenylphenyl) methine M-benzobenzone _i(3H)-_

4-chlorophenylacetic acid (available, for example, from Aldrich) (1.00 eq), phthalic anhydride (available, for example, from Aldrich) (ll 〇 eq), and sodium acetate (0.04 eq) at iV-methyl η ratio Mix in bromoketone (3 vol). The resulting suspension was heated to about 200 C and the resulting brown solution was stirred for 2 days. During the reaction, iV-methyl &quot;bitone/water (0_45 vol) was taken up under ambient pressure. After checking for complete conversion (99%, HPLC), the reaction mixture was cooled to about 7 Torr over 1 h. Ethyl alcohol (4_5 vol) was added at about 70 ° C for 1 h. The resulting brown solution was allowed to cool to about 50 ° C over 15 h during which time the brown solution became a brown suspension. Ethanol (3.8 vol) was added at about 5 (rc) and the resulting brown suspension was cooled to about 2 °C over 1 h and stirred at about 0-5 ° C for 1 h. Isolation by filtration through a suction filter 134966.doc -42· 200932243, washing with cold aqueous ethanol solution (ethanol/water = 1/1, vol/vol 'about 2 ° C, 3 x l ¥ 〇 1) and sucking under nitrogen The filter was dried and the product was obtained as a light brown and wet solid. The loss of drying was measured and the material was taken to the next stage. Yield (corrected for drying loss and H NMR assay): 80%. ' lH NMR (400 MHz, CDC13), δ 6.37 (s, 1H), 7.38 (d, 2H), 7-58 (t, 1H), 7.77 (m, 4H), 7.95 (d, 1H) Intermediate 13 (Phase 2) © 4- {丨4·gas phenyl]methyl}-l(2 ugly)_pyridazinone

(3 5)-3-[(4-Phenylphenyl) methine]_2·benzofuran·丨(3//) ketone (for example as prepared in Stage 1) (丨, 〇eq, for drying The loss was corrected by suspending in ethanol (3.7 V〇l) and heating to about 85 under slight reflux. Hey. A solution of hydrazine hydrate (available, for example, from Aldrich) (1.2 eq) in ethanol (0.63 vol) was added via a dropping funnel over 1 h, and ethanol was added to the reaction suspension via a dropping funnel while adding the knot (G· 63 VQl) to remove traces of hydrazine. The reaction suspension was heated at about 85 ° C for 14 h under slight reflux. It was cooled to about 2 (rc and samples were taken to check for conversion (99% conversion, HPLC). Acetone (Vo1) was added to the reaction mixture over 30 minutes (exothermic reaction). The quenched suspension was scrambled to 乂1 h and then cooled to about 2 by min. (: and stirred at about 2 ° C for 1 h. The product was isolated by filtration through a suction filter, i was cold ethanol 134966.doc -43- 200932243 (about 〇-5 Washing. The title compound was obtained as a light brown solid (yield for 丨HNMR). 〇_95%. NMR (4〇〇ΜΗζ, DMSO-^6), δ 4.3〇(s, 2Η), 7.35 (m, 4Η), 7.88 (m, 3H), 8.26 (d, 1H), 12.62 ( s, 1H) Intermediate 14 (stage 3a) 2-{[(methyl aryl)oxy] methyl hydrazine dimethyl carboxylate

A solution of WBoc-D-prolinol (available, for example, from Aldrich) (1.0 eq) in methyl isobutyl hydrazine (9.5 vol) was cooled to about 2. Add triethylamine (1 〇 3 vol). Methanesulfonate (1 2 eq) was added via a dropping funnel via a dropping funnel and a white suspension was formed. The dropping funnel was washed with additional methyl isobutyl ketone (0.5 vol). The reaction mixture was allowed to warm to about 22 ° C and stirred for 2 h. Take samples to check conversion rates (complete conversion by TLC). Add water (5.0 v〇l). Separate the phases _ (good and fast phase separation). The organic phase was washed with a saturated aqueous solution of sodium bicarbonate (5.0 vol) and finally washed with water (5.0 v 〇i) (good and fast phase separation). The organic phase was dried by filtration through a suction filter packed with magnesium sulfate (0.46 wt.). The volume of the dried organic phase (12.40 vol) was determined. The organic phase was concentrated to 43% wt/vol (based on 7V_Boc-D-hydrazinol/solution) by distillation to a final volume (2.20 vol) at about 40 ° C in a vacuum. The dried loss sample was taken and allowed to evaporate to dryness (about 40 ° C, &lt; 1 mbar); a yellow oil was formed for analysis. A concentrated yellow organic phase (2.0 vol) was used immediately in the alkylation reaction. Yield (for drying loss and 1H NMR calibration 134966.doc • 44- 200932243 positive): 100 〇 / 〇. Intermediate 2 (Stage 3b) M(4-Phenylphenyl)methyl]·2_Pyrrolidinylmethyl]-1 (2 ugly) _pyridinone, hydrochloride 0

4-U4-Phenylphenyl]fluorenyl}_1(2/f)-pyridazinone (as prepared, for example, in Stage 2) (1.0 eq) and Carbonate Plane (2.5) in decyl isobutyl ketone ( The suspension in 9.7 vol) is heated to about 1 Torr. 〇^ At a temperature of about 10 ° C, 2-{[(methylsulfonyl)oxy]methyl b-pyrrolidinecarboxylic acid 1,1-didecylethyl ester was added dropwise over 2 hours (for example A freshly prepared solution was prepared in stage 3a in decyl isobutyl ketone (calculated as 1.2 eq for WBoc-D. ketamine). The dropping funnel was washed with methyl isobutyl ketone (0.2 vol) added to the reaction mixture. The reaction mixture was stirred at about 100 ° C for 17 h. A brown suspension formed. The sample was taken after cooling to about 50 ° C to check the conversion (99% conversion, HPLC). The reaction mixture was cooled to about 22 ° C and water (16.7 vol) was added to the reaction mixture followed by methyl isobutyl ketone (16.7 vol). The phases were separated. The volume of the organic phase (18·8 vol) was determined and concentrated to 50% w/vol by distillation in a vacuum (about 45 ° C &&lt; 100 mbar) (4-{[4-phenylphenyl] A Base}-1 (2/〇-pyridazine-branched I/solution). Hydrochloric acid (5-6 Μ, 3 eq '2.00 vol) in isopropanol was added to the concentrated organic phase at about 22 °C. The gas was observed to form a light brown suspension over about 1 h. The reaction mixture was stirred at about 22 ° C for 14 h. 134966.doc -45- 200932243 A sample was taken to check the conversion (complete conversion, hplc). The brown suspension was cooled to about 1 ° C over 2 h and the product was isolated by filtration through a fritted funnel and washed with cold methyl isobutyl ketone (3×l ν ι). The light brown suspension was cooled to about 2 hours. The product was isolated by filtration through a fritted funnel at 1 ° C and washed with cold isobutyl ketone (3 χΐ ν ι). A white solid was obtained which was dried on suction filter and then in vacuo (45 〇, &lt; 2 〇 mbar) dry 'dry. Obtained the title compound as a white solid (as hydrochloride). Yield (corrected for NMR assay): 86%. NMR (400 MHz, DM SO-A) ® δ 176 (m&gt; 1Η), 1.95 (m, 2H), 2.14 (m, 1H), 3.15 (m, 1H), 3.27 (m, 1H), 3.91 (m, 1H), 4.36 ( d, 2H), 4.47 (m, 2H), 7.35 (d, 2H), 7.41 (d, 2H), 7.80-8.00 (m, 3H), 8.31 (d, 1H), 8.92 (bs, 1H), 9.48 (bs, 1H) Intermediate 8 (stage 4a) methyl sulfonate 4_丨4_(methyloxy)phenyl]

Next, to 4-(4-formylphenyl)-indole-butanol (available, for example,

V〇l). The resulting solution is cooled to about 〇 _ 1 5, at about 21 ° C and added Λ π 1 over 1 h

Light yellow suspension. Spoon 2 C and stir it at about 22 ° C for 15 h. Existence Samples were taken to check conversion (complete conversion, 134966.doc • 46· 200932243 HPLC). The reaction mixture was cooled to about 1 Torr to 15 ° C and water (5 6 v〇l) was added to maintain the temperature below about 18 °C. The emulsion was mixed at about 22 ° C for more than 10 min. The phases were separated. The organic phase was washed with a saturated aqueous solution of NaHC(R) (&lt;/RTI&gt; The organic phase was dried by filtration through a suction filter packed with magnesium sulfate (0.5 wt.), and the sulfuric acid was washed with methyl isobutyl hydrazine (2 x 〇.2 vol). The volume of the dried organic phase was determined (12.40 v〇l). The organic phase was concentrated to 40% w/vol (4-(4-decyloxy)-indole-butanol/solution p by distillation in vacuo at about 45 ° C to 2.2 〇ν〇. The sample was lost and evaporated to dryness (approximately 4 (rc, &lt; 1 mbar) 'remaining yellow oil' was used for analysis. The product containing the yellow organic phase (2.5 v〇l) was used Subsequent alkylation (stage servant). Yield (corrected for loss on drying and 1H NMR): 1 〇 1% ❹ NMR (DMSO-A) δ 1.53-1.71 (m, 4H), 2 52 2 57 2H), 3.11-3.20 (s, 3H), 3.68-3-76 (s, 3H)5 4.15-4.26 2H),6·81-6·87 (m,2H), 7.08-7.15 (m,2H Intermediate 9 (stage 4b) (m, (m, M(4) phenyl) methyl]-2-[((10) small {4_[M methyloxy)phenyl] butyl 2-pyridinyl )methyl]-1 (2 good)-pyridazine network

MC4-chlorophenyl)methyl]_2_[2]biproxenmethyl]_](10)_pyridazinone, hydrochloride (as prepared, for example, in Stage 3b), (1.0 eq) and carbonic acid _ 134966.doc • 47· 200932243 (5.0 eq' 1.77 wt) was mixed in methyl isobutyl ketone (16.5 v〇i) and the resulting light brown suspension was heated to about 135 ° C under reflux. Addition of 4-[4-(methyloxy)phenyl]butyl methacrylate (as prepared, for example, in Stage 4&amp;) (2.4 eq' 1.59 wt) to decyl isobutyl ketone over 1 h ( Clarified orange solution in 4.9 vol). The resulting yellow-brown suspension was stirred under reflux for 2 〇h. A sample was taken to check the conversion (88.5% conversion, HPLC) at about 19. Add water (24.7 vol) (slightly exothermic). The turbid orange-brown mixture thus formed was stirred at about 2 Torr. (The mixture was stirred for 15 min. The phases were separated. The ® was filled with magnesium sulfate (0.92 wt)). The organic phase was dried by suction filtration, and the magnesium sulfate was washed with mercaptoisobutyl ketone (2χ4丨v〇1). The solvent of the obtained organic phase was completely removed in vacuo (about 4〇_45°c, 6〇〇) The obtained crude product (2 45 wt, dark brown oil, HPLC purity · 73.50% area/area) was combined with the crude product obtained in the same manner (241 wt) by mbar to complete inhalation) The plug was filtered (Si〇2) for purification. Therefore, the combined crude material (4_86 wt) was dissolved in dichloromethane and placed on a sputum filled with 8 丨〇2 (45.7 wt, height: 24.5) Cm, diameter · 30 cm) to wash away impurities in the second gas chamber (823 vol). The leaching agent gradually changed from only two gas methane to one gas hospital: methanol = 10:1 to dissolve the title compound. The product is in solution Obtained (494 V 〇 1). The title compound (2 46 wt) was obtained as a light brown oil. NMR calibrated for calibration): 86%. iH NMR (DMS 〇 £/6) § 1.32 1.53 (m, 4 Η), 1.61-1.79 (m, 4H), 2.08-2.18 (m, 1H), 2.20-2.27 (m , 1H), 2.37-2.45 (m, 2H), 2.66-2.76 (m, 1H), 2.84-2.93 (m, ih), 2.96-3.04 (m, 1H), 3.69-3.71 (m, 3H), 134966 .doc -48- 200932243 3.89-3.98 (m, 1H), 4.18-4.26 (m, lH) , 4.28-4.36 (m, 2H), 6.77-6.83 (m, 2H), 6.98-7.04 (m, 2H), 7.33-7.39 (m, 4H), 7.79-7.90 (m, 2H), 7.91-7.97 ( m, 1H), 8.26-8.31 (m, 1H). Intermediate 10 (stage 5) M(4-phenylphenyl)methyl]-2-({(2/〇-l-[4-(4-hydroxyphenyl)butyl)-2-oxaridinyl) }methyl)-1(2 ugly)-pyridazinone

4·[(4-Phenylphenyl)methyl]-2-[((2/〇-1-{4-[4-(methyloxy)phenyl]butyl}-2-pyrrolidinyl) The solution of fluorenyl]-1(2//)-pyridazinone (as prepared, for example, in Stage 4b) (1.0 eq) in dioxane (4.2 vol) was cooled to about 〇 ° C. Added over 20 min. A solution of boron tribromide (1.8 eq, 0.33 vol) in dichloromethane (3.4 vol) was maintained at a temperature below about 2 C. The reaction mixture was stirred overnight at about 20 C. Samples were taken for inspection. Conversion (90% conversion, HPLC). Additional boron tribromide (0.2 eq, 0.05 vol) was added over about 10 min at about 10 min. The reaction mixture was allowed to warm to about 2 ° C. After about 5 h. Another sample was taken to check the conversion (96% conversion, HPLC). Additional tribromination (0.2 eq' 0.05 vol) was added and the reaction was stirred overnight at about 25 ° C and another sample was taken to check the conversion (&gt 99% conversion, HPLC). The reaction mixture was cooled to about 15 C and aqueous hydrogen chloride (2 N, 2.4 vol) was added dropwise over 15 min to keep the temperature below about 19. Add about 2/3 After hydrogenation of hydrogen, an exothermic reaction phenomenon was observed. After the addition was completed, Into a brown suspension containing some brown oil 134966.doc -49· 200932243 "in the 丨〗. Under the ,, slowly add saturated aqueous sodium bicarbonate solution (5.1 v〇l) over 2 〇 min, keep the temperature below about A dark microturbid emulsion was formed at 13 ° C. The reaction mixture was warmed to about 20 ° C over 15 min, and the phases were separated. The aqueous phase was extracted with di-methane (4.28 vol). A 0.69 wt) suction filter was used to filter the combined organic phases, followed by washing the magnesium sulfate with di-methane (3 x 107 v.). The dried organic phase was dark and transparent. The solvent was removed in vacuo. 6 〇〇 mbar - completely sucked

During the period, 35-40 C), a brown foam is formed. The obtained brown solid (HPLC purity: 73.22 ° / area / area) contained residual di- methane and was dried again over the weekend (35. (:, &lt; 20 mbar). The material again dried showed a decrease of 11 ?1^(:purity (63.98% area/area). The crude product was divided into 2 equal portions (2x0.50 wt) and purified by column chromatography (2 column; si〇2 (2&gt;&lt;2 74 wt); height = 20.5 em; diameter = 14 cm; dichlorodecane methanol = 20:1). The product containing fractions were combined and concentrated in vacuo (about pit, 600 mbar to complete inhalation) to obtain a shallow The title compound was obtained as a brown foamy solid. Yield (corrected for &quot;H NMR assay): 65%. Towel nmr (DMSO-J6) δ 1.39-1.72 (m5 4 Η), 1.82-2.05 (m, 3H), 2.12- 2.24 (m,1H), 2.35-2.48 (m,2H), 3.00-3.25 (m,2H,),3 26-3.54 (m, 1H), 3.56-3.71 (m, 1H), 3.80-3.97 (m , 1H), 4.25. 4.43 (m, 2H), 4.49-4.62 (m, 2H), 6.58-6.74 (m, 2H), 6.91. 7.03 (m, 2H), 7.27-7.48 (m, 4H), 7.79 -8.04 (m, 3H), 8.23- 8.39 (m,1H), 9.06-9.37 b, 2H) Intermediate 11 (stage 6) {4_[(3-chloropropyl)oxy]benzene 4-[(4 -chlorobenzene ) A Ji Bu 134966.doc • 50 · 200932243 yl} butyl) -2 cushions slightly piperidinyl] methyl} -1 (2 B) - -phthalazinone

❹

4-[(4-Chlorophenyl)indenyl]-2·({(2Λ)-Bu [4-(4-yl)yl)butyl]-2-ylbiol at about 20 °C唆基}曱基)-1 (2/f)-European 嗣 (as prepared, for example, in Stage 5) (1.0 eq) and potassium carbonate (4.0 eq, 1.1 wt) in 2-丁 (7.1 vol) Mixed in. To the resulting brown suspension was added a solution of bromo-3-propane (2.0 eq' 0.4 vol) in 2-butanone (2.9 vol). The brown mixture was heated to reflux for 25 h. Get samples to check conversion rate (98% conversion rate, ^1?1^). At about 20. Under the armpit, add water (14.8乂〇1) via 5 111丨11 (slightly exothermic). Methyl isobutyl ketone (14.8 vol) was added and the orange mixture was stirred for 25 min; the phases were separated. The organic phase was dried by filtration through a suction filter packed with sodium sulfate 〇 9 〇 wt), and sodium sulfate was washed with decyl isobutyl ketone (2 χ 24 乂〇 1). The title compound (a mixture of a gas derivative and a bromine derivative) was obtained as a brown oil. Yield (corrected for HPLC purity): 91%. NMR (CDC13) δ 1.47-1.91 (m, 6H), 2.16-2.27 (m, 3H), 2-33-2.43 (m, 1H), 2.51-2.60 (m, 2H)5 2.80-3.04 (m, 2H ), 3.08-3.23 (m, 1H), 3.47-3.86 (m, 3H), 4.01-4.14 (m, 3H), 4.18-4.30 (m, 2H), 4.36-4.50 (m, 1H), 6.74-6.88 (m, 2H), 7.01-7.14 (m, 2H), 7.15-7.34 (m, 4H), 7.57-7.77 (m, 3H), 8.37-8.52 (m, 1H). 134966.doc 200932243 Stage 7 4_[ (4-Phenylphenyl)f-yl]-2·({(2/?)-1-[4·(4-{[3-(hexahydro·1/Γ-aza-i-yl))propyl 1 Oxy}phenyl)butyl-2-pyrrolidyl}methyl)·1(2 ugly)·pyridazine, free base

4-[(4-Chlorophenyl)methyl]_2·{[(2/〇-1-(4-{4-[(3-)propyl)oxy]phenyl}butyl)-2 - 吼 啶 啶 曱 曱 曱 ( 1 (2 / /) - oxazinone (as prepared, for example, in Stage 6) 〇 · 〇 eq), potassium iodide (3_0 called, ο.% wt), potassium carbonate (3.0 eq 〇·72 wt) and hexamethyleneimine (available from, for example, Aldrich) (3.0 eq' 0.59 vol) mixed with methyl isobutyl ketone (1 〇.9 v〇1) and heated under reflux Brown suspension for 18 h. Samples were taken to check conversion rates (complete conversion, HPLC). The light brown suspension was cooled to about 3 Torr: and water (6.9 vol) was added over 5 min. After stirring for 2 min, the phases were separated. The aqueous phase was extracted back with decyl isobutyl hydrazine (3.96 vol). The solvent was removed in vacuo (4 EtOAc, EtOAc (EtOAc) Yield (corrected for NMR assay): 83%. H NMR (CDC13) δ 1.41-2.05 (m, 14H), 2.13-2.27 (m5 1H), 2.29-2.44 (m, 1H), 2.47-2.72 (m, 6H), 2.81-3.02 (m&gt; 2H), 3.08-3.22 (m, 1H), 3.92-4.11 3H)&gt; 4.20-4.28 (ms 2H), 4.34-4-49 (m, 1H), 6.72-6.87 (m, 2H)5 6.96-7.12 (m, 2H), 7.14-7.31 (m, 4H), 7.59-7.77 (m, 3H), 8.38-8.52 (m, 134966.doc -52- 200932243 1H). Stage 8 4-[(4-Phenylphenyl)methyl]-2-({(2))-1-[4-(4-{[3-(hexa-argon-1 good-1h_1-yl) )propyl]oxy}phenyl)butyl]-2-oxaridinyl}methyl)-1(2)-pyridazinone, monohydrate 1,5-naphthalene disulfonate

Preparation 1: 4-[(4-Phenylphenyl)methyl]_2-({(27〇-1-[4-(4-{[3-(hexahydro-1-good-azhen-1-yl)) )propyl]oxy}phenyl)butyl]-2-»pyrrolidyl}indenyl)^(2//)-pyridazinone (as prepared, for example, in Stage 7) (l_〇eq The orange solution in decyl alcohol (41_41 v〇1) was cooled to about 15 t: An aqueous solution of hydrogenation (2 N, 41.4 vol) was added over 20 min while maintaining the temperature below about 〇8. The solvent is distilled off (about 80 ° C, 600 mbar to complete inhalation) and an orange oil remains, which is dissolved in water (32.1 V〇l) t. The resulting orange brown micro turbid solution is heated to about 100 C (reflow) And a solution of 1,5-naphthalene disulfonic acid tetrahydrate (1 〇eq, 〇57 wt) in water (6.0 vol) was added to the obtained yellow solution by adding methanol (61.1 ν〇ι) β. The solution remained yellow and was cooled from about 58 Torr to about 2 (TC. to form a white suspension, which was filtered at about 2 Torr under a suction filter). The solid was taken in aqueous methanol (methanol: water = 1). 1,2χΐ〇4 ν〇ι) Wash and dry the recovered light brown material in a vacuum (about 5 〇. 匸, The title compound was obtained as a light brown solid. Yield (corrected for HpLc 134966.doc • 53 · 200932243 purity): 69%. Preparation 2: 4-[(4-Phenylphenyl)methyl] -2-({(2/?)-1-[4-(4-{[3-(hexahydro-1//-azahr-1·yl)propyl)oxy}phenyl)butyl] _2- «Byrylidyl}indenyl) 4(2//)-pyridazinone (as prepared, for example, in Stage 7) (1.0 eq) in a brown solution in methanol (39.9 ν〇1) is cooled to about 15 ° C. Add hydrogenated aqueous hydrogen solution* (2 N, 42.6 wt) over 20 min to keep the temperature below about 18. 〇. Dissolve the solvent (about 80 ° C, 600 mbar to complete inhalation) and the rest An orange oil was dissolved in water (32.9 vol). The obtained orange-brown micro-turbid solution was washed with ethyl acetate (1×41 2 l×39 5 v〇1) and a white emulsion was formed and divided into two. The inorganic phase was evaporated to dryness and the orange brown oil remained. The oil was dissolved in methanol (79·9 vol) and the resulting orange-brown solution was heated under reflux at about 9 〇〇c. Min added 1,5-naphthalene dihydrochloride (1.0 eq, 0.56 wt) to water Solution in 4.8 vol) The solution remained clear and cooled to about 2 Torr over 100 min. A white solid suspension was obtained which was stirred at about 2 ° C for 30 min. The solid was separated by filtration (preferred) and Wash with cold methanol® solution (3x11.0 v〇i). The brown solid was dried in vacuo (5 〇 〇, 1 毫 mbar, 18 h). The light brown material contains particles and is mechanically pulverized. The title compound was obtained as a light brown solid. Total recovery (corrected for Hplc. purity): 74%. !H NMR (400MHz, DMSO-J6)5 δ 1.30-2.28 (m, 18Η), 3.13 (m, 4H), 3.20 (m, 2H), 3.27-3.53 (m, 9H), 3.62 (m, 1H) , 3.85 (m, 1H), 3.94 (m, 2H), 4.31 (m, 2H)} 4.55 (d, 2H), 6.82 (m, 2H), 7.05 (d, 2H), 7.29-7.51 (m, 6H ), 7.79- 134966.doc •54- 200932243 8.05 (m,5H),8.31 (m,1H),8.86 (d,2H),9.15 (m,2H) The biological data has been tested according to the following or similar tests4- [(4_气phenyl)甲义]_2 ({(2/〇-1-[4-(4-{[3-(hexahydro-1 ugly-azahr-1-yl)propyl)oxy) }Phenyl)butyl]-2-pyrrolidinyl}methyl)-1 (2H)-pyridazinone and various salts of in vitro and / or in vivo biological activity. H1 receptor cell line production and FLIPR assay Scheme 1 · Production of histamine H1 cell line 选 The human H1 receptor was selected using the known procedure described in the literature [Price chaos C (10) biliary 201 (2): 894 (1994)]. According to the description in the literature «/ A known procedure in corpse/zarwaco/., 117(6): 1071 (1996)] to produce Chinese hamster ovary (ch〇) cells stably expressing human H1 receptor. Histamine H1 functional antagonist assay: assay Functional pKi value of histamine 细胞1 cell line In an uncoated black-walled clear bottom 3 84-well tissue culture plate, with 10% dialyzed fetal bovine serum® (Gibco/Invitrogen, catalog number 12480-021) and 2 inM L-glutamine (Gibpo) /Invitrogen Cat. No. 25030-024) Supplemented in a minimum essential medium (Gibco/Invitrogen, Cat. No. 22561-021) and maintained overnight at 5% • C02, 37 ° C. Remove excess medium from each well to leave 1 0 μΐ Add 30 μΐ loading dye to each well (diluted in Tyrodes buffer + probenecid (145 mM NaCl, 2.5 mM KC 1 mM HEPES, 10 mM D-glucose, 1.2 mM MgCl2, 1.5 mM CaCl2, 2·5 mM propyl sulphate, adjust the pH of I34966.doc -55- 200932243 to 1.00) with 250 μΜ Brilliant Black, 2 μΜ Fluo-4) with 1.0 M NaOH, and at 5% CO 2 , 37 ° C The plates were incubated for 60 min. 1 〇μΐ test compound (or 10 μΐ Tyrodes buffer + propionol as a control) diluted to the desired concentration in Tyrodes buffer + probenecid was added to each well and the plate was incubated at 37 ° C. Incubate for 30 min at 5% C02. The * culture plate was then placed in FLIPRTM (Molecular Devices, UK) prior to and after addition of 10 μM histamine at a final concentration of histamine produced as EC8q, to Sullivan et al. (in Lambert DG) (Edit), Ca/cz'ww Q Signaling Protocols, New Jersey: Humana Press, 1999, 125-136) Monitoring Cell Fluorescence 〇 ex=488 nm, λΕΜ=540 nm) ° Functional Antagonism This is indicated by inhibition of histamine-induced increase in fluorescence by measurement as measured by the FLIPRTM system (Molecular Devices). Functional affinities were determined using standard pharmacological mathematical analysis by means of a concentration effect curve. Histamine H1 Functional Antagonist Test: Determination of Antagonist pA2 and Duration ® The histamine HI receptor expressing CHO cells was seeded in an uncoated black-walled clear bottom 96-well tissue culture dish as described above. After overnight incubation, the growth medium was removed from each well, washed with 200 μL phosphoric acid, saline buffered saline (PBS) and loaded with 50 μΐ of dye (diluted in

Tyrodes buffer + propylene (145 mM NaCl, 2.5 mM KC1, 1 mM HEPES, 10 mM D-glucose, 1.2 mM MgCl2, 1.5 mM CaCl2, 2.5 mM propyl sulphate, pH adjusted to 1.0 M NaOH Substitution of 250 μΜ Brilliant Black, 1 μΜ Fluo-4) in 7.40). Place the cells at 134966.doc -56- 200932243 37. Raise for 45 minutes. The loading buffer was removed and the cells were washed as above and 90 μΐ Tyrodes buffer + propyl sulphate was added to each well. 1 () μ1 test compound (or 1 μμΐ Tyr〇des buffer + probenecid as a control) diluted to the desired concentration in Tyr〇des buffer + C4 was added to each well and the plate was incubated. Incubate for 30 min at 37 ° C, 5% C02. The plates were then placed in FLIPRTM (M〇leeuiar Deviees, υκ). before and after adding 50 μM of histamine in the range of 1 mM-0.1 ηΜ, as Sullivan et al. (in Lambert DG (eds.), Cell fluorescence (λ^=488 ηπι, λΕΜ = 54 〇 nm) was monitored in the manner described in Ca/d, New Jersey: Humana Press, 1999, 125-136). The histamine ec;5() (the tissue required for the reaction with maximal reaction to histamine 50°) was determined using a standard four-parameter logistic equation (i〇gistic equati〇n) by nonlinear regression analysis of the resulting concentration response curve. The amine concentration p antagonist pA2 was calculated using the following standard equation: pA2 = l〇g(DR-1)-l〇g[B], where DR = dose ratio 'defined as antagonist treated ec5()/control Ec50 and [B] = antagonist concentration. ® To determine the duration of the antagonist, cells were incubated overnight in uncoated black-walled clear bottom 96-well tissue culture plates, washed with pbs and selected to Incubation of antagonists at concentrations close to DR in the range of 30·300. 30 min. After the incubation period of the antibiotics, the cells were washed twice or three times with 200 μM PBS and then 100 μM ^ Tyrodes buffer was added to each well. To initiate dissociation of the antagonist. After incubation for a predetermined time (usually 30-270 min) at 37 ° C, the cells were then washed again with 200 μΐ PBS and, as described above, at 1 ° μ at 37 ° C. Tyrodes buffer containing Brilliant Black, Acrylic and Fluo-4 134966.doc -57· 200932243 育45 mi n. After this period, the cells were stimulated with histamine in FLIPRTM as described above. The dose ratio at each time point was used to determine the H1 receptor occupancy score by the following equation: receptor occupancy score = (DR-1) / DR. The decrease in receptor occupancy over time is close to a straight line and is analyzed by linear regression. The slope of this straight line fit is used as an indicator of the dissociation rate of the antagonist. The cells treated with the antagonist at each time point are used. The dose ratio of the cells treated and washed by the antagonist. The relative dose ratio (rel DR), which is also used as an indicator of the duration of the antagonist, is calculated. The antagonist with a long duration of action produces a rel DR ❹ value close to 1 and An antagonist with a short duration of action produces a rel 011 value close to the dose ratio obtained by treatment with a single antagonist. 2. H3 receptor cell line production, membrane preparation and functional GTPyS assay protocol. Histamine H3 cell line production. H3 cDNA was isolated from its holding vector pCDNA3.1 TOPO (InVitrogen) by restriction enzyme digestion with BamHl and Not-Ι, and ligated into the inducible expression vector pGene (InVitro) digested with the same enzyme. The GeneSwitchTM system (a system in which the transgene is expressed in the absence of an inducer and is opened in the presence of an inducer) is performed as described in U.S. Patent Nos. 5,364,791, 5,874,534, and 5,935,934. Transformed into active DH5a E. coli host bacteria. Cells were placed at 50 pg ml·1 in antibiotics containing ZeocinTM (which enabled selection of cells expressing the ί/z gene present on pGene and pSwitch)

Luria Broth (LB) on agar. The community containing the recombined plastids is identified by restriction analysis. DNA lines transfected into mammalian cells were prepared from 250 ml of host bacterial culture containing pGeneH3 plastids and used in accordance with manufacturer's instructions 134966.doc -58- 200932243 (Qiagen) using DNA preparation kits (Qiagen Midi-Prep) ) Isolation CHO K1 cells previously transfected with pSwitch-regulated plastids (InVitrogen) were seeded at 2χ106 cells per T75 flask 24 h prior to use. v/v dialyzed fetal bovine serum, L-glutamine and hygromycin (100 pgmr1) supplemented with Hams F12 (GIBCOBRL, Life Technologies) medium in 'complete medium. Plastid DNA was transfected into cells using Lipofectamine plus according to the manufacturer's instructions ^ (InVitrogen;). 48 h after transfection, the cells were placed in complete medium supplemented with 500 pgmr1 ZeocinTIV^. 10-14 days after the selection of Lu, 10 nM Mifepristone (InVitrogen) was added to the medium to induce receptor expression. 18 h after induction, cells were separated from the flask using ethylenediaminetetraacetic acid (EDTA; 1:5000; InVitrogen), then washed multiple times with PBS pH 7.4, and resuspended in minimal essential medium (MEM). It was not in the phenol red sorting medium and was supplemented with Earles salt and 3% fetal pure line II (Hyclone). The receptor expression of about 1χ1〇7 cells was examined by anti-sputum staining of rabbits produced against the N-terminal domain of histamine H3 receptor, which was incubated on ice for 60 min, followed by washing with ❿ picking medium. twice. Receptor binding antibodies were detected by incubating cells on ice with goat anti-rabbit antibody conjugated to Alexa 488 fluorescent label (Molecular Probes) for 60 min. After washing twice with the sorting medium, the cells were passed through 50 μιη FilconTM (BD Biosciences) and then analyzed on a FACS Vantage SE flow cytometer equipped with an automated cell precipitation unit. Control cells are uninduced cells that are treated in a similar manner. The positively stained cells were sorted in a single cell format into 96-well plates containing complete medium (containing 500 pg ml·1 ZeocinTM) and allowed to expand, 134966.doc •59- 200932243 followed by antibody and ligand binding studies Analyze receptor performance. A pure line of 3H3 was chosen for membrane preparation. Membrane Preparation from Cultured Cells All steps of this protocol were performed at 4 °C with pre-cooling reagents. Resuspend the cell pellet in 10 volumes of homogenization buffer (50 mM #-2-hydroxyethylpiperazine-#'-2-ethanesulfonic acid (HEPES), 1 mM ethylenediaminetetraacetic acid. (EDTA ), pH 7.4 with KOH, ΙΟ·6 Μ 抑 抑 肽 ( 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 Sigma Sigma Sigma Sigma Sigma ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; (bacitracin) (Sigma B0125), 1 mM phenylmethylsulfonate fluoride (PMSF) and 2χ10_6 pepsin A (Sigma) supplement). The cells were then homogenized by 2 x 15 seconds fragmentation in a 1 liter glass blender, followed by centrifugation at 500 g for 20 min. The supernatant was then spun at 48,000 g for 30 min. The pellet was resuspended in a homogenization buffer (4 times the volume of the original cell pellet) by vortexing for 5 sec and then homogenized with a Dounce homogenizer (10-15 strokes). At this time, the preparation was aliquoted into a polypropylene tube and stored at -80 °C. ® Histamine H3 Functional Antagonist Assay For each compound identified, add in a solid white 384-well plate - (a) 0.5 μΐ diluted to DMSO in the desired concentration of test compound (or 0.5) Μΐ DMSO as a control); (b) 30 μΐ bead/membrane/GDP mixture prepared by mixing Wheat Germ Agglutinin Polystyrene LeadSeeker® (WGA PS LS) Scintillation Proximity (SPA) beads and Membrane (prepared according to the above method 134966.doc -60-200932243) and diluted in assay buffer (20 mM #-2-hydroxyethyl oxazine _ V-ethane sulfonic acid (HEPES) + 100 mM NaCl + 10 mM MgCl2, pH 7.4 NaOH) obtained 30 μM per well containing 0.25 mg of beads and 〇 Μ μΜ final assay concentration of guanosine y diphosphate (GDP) (diluted in assay buffer) Volume, incubated on drum for 60 minutes at room temperature. • (c) 15 μΐ 0.38 nM [35S]-GTPYS (Amersham; radioactivity concentration = 37 MBqml·1; specific activity = 1160 Cimmol·1), histamine (concentration of the final assay concentration of histamine produced as φ ECso) . After 2-6 h, the plates were centrifuged at 15 rpm for 5 min and each plate was counted on a Viewlux counter for 5 min using a 613/55 filter. The data was analyzed using a 4-parameter logistic equation. The base activity was used as a minimum, ie no histamine was added to the wells. Intranasal stimulation method: All hoarding tracing method (a) Sensitive effect is 25 μΐ per nostril in ovalbumin (1)VA) and aluminum hydroxide β (Α1(ΟΗ)3 or Alum) per day 150-250 g female Dunkin- Hartley guinea pigs were sensitized twice for 5 days (week 1). The solution was made up with 2 〇 pg/mi 〇VA, 18 〇 mg/ml Alum. During the second and third weeks, the animals received once a day and received 25 M 〇VA (5 mg/ml) per nostril. During the fourth week, guinea pigs will enter the study but continue to sensitize according to weeks 2 and 3 until the day before administration of the compound or vehicle. (b) Compound/vehicle pretreatment The test compound is pre-treated at various times prior to histamine challenge. 134966.doc •61 - 200932243. The efficacy dose response curve was measured 1 h after administration, and the duration of the study was continued until 7 days after administration. The test compound was formulated as a solution in 9% sterile physiological saline or as a suspension in 〇.9% sterile physiological saline/tween 80. The guinea pigs were anesthetized with isoflurane (5%, 2-3 Ι/min 〇 2), placed in the supine position, and 25 μl of the test compound or vehicle was administered to each nostril using a GilS0n pipette. After administration, the animals remained supine for at least 3 sec seconds during recovery from anesthesia. 0 (c) histamine challenge protocol 30 minutes before the start of histamine challenge, atropine sulfate (Sigma A0257, dissolved in physiological saline)! Mg/kg 丨p was administered to guinea pigs. The animals are then placed in the entire plethysmography system (Buxc〇(g) EleetrQnks) 'where such as Hamelmann E., Schwarze, J., Takeda, K Oshiba, A·, Larsen, L, Irvin, CG and Gelfand, EW The parameter PenH area under the recording curve (AUC) outlined in 4m · / hWr. Cr&quot;. C core Md. 156: 766-775 (1997). Record the baseline AUC of l〇 min and if the value of this ® exceeds 1000, exclude the animals. After the prescribed pre-dosing time was reached, the guinea pig was re-anesthetized with isoflurane and administered with 15 mM histamine or phosphate buffered saline (PBS) (25 μl per nostril). The animals were returned to the individual volume description chamber after recovery from anesthesia and a 4x10 min continuous PenH AUC recording was performed. Over 40 min after each animal histamine challenge, these records were summed to obtain cumulative auc. Analytical data were adjusted using ANOVA with the post-hoc Fishers LSD test (general linear model, Statistica®) and finally Hochberg. Inhibition of histamine-induced hyperemia was determined by statistically significant differences between the mean responses of the compound pretreatment groups compared to the vehicle pre- 134966.doc -62.200932243 treated, histamine-excited group. CNS Penetration (i) CNS Penetration by Rapid Administration A nominal dose of 1 mg/kg of the compound was administered by intravenous administration. Male CD Sprague Dawley rats. Compounds were formulated in 50/〇. DMSO/45% PEG 200/50% water. Blood samples were taken under isoflurane anesthesia 5 min after dosing and the brain was also removed to assess brain penetration. Place the 0 blood sample directly into the heparinized tube. A blood sample was prepared for analysis using protein precipitation, and a brain sample was prepared by homogenizing the brain extracting drug and then protein precipitation. The concentration of prodrugs in blood and brain extracts was determined by quantitative LC-MS/MS analysis using compound-specific mass transitions. (ii) CNS breakthrough after steady-state intravenous infusion Male CD Sprague Dawley rats were administered a compound at a nominal dose of 0.4 mg/kg. The compound was then intravenously infused at a nominal dose level of 〇·1 mg/kg/h for 4 h. The compound was formulated in 2% DMSO / 30% PEG 200 / 68% water. Continuous or peripheral samples were obtained after 给药 5, j 5, 2 5, . 3, 3_5 and 4 h after administration. Under anesthesia with isoflurane • The final blood sample was collected and the brain removed to assess brain penetration. Place the blood sample directly into the heparinized tube. Blood samples were prepared for analysis using protein precipitation, and brain samples were prepared by homogenizing the brain extracting drug and then protein precipitation. The concentration of the prodrug in the liquid and brain extracts was determined by quantitative LC_MS/MS* analysis using compound-specific mass transfer. 134966.doc -63 - 200932243 Results The following data were obtained: i) the average pKKpKb in H1 exceeds 7.5, and the average pA2 value in H1 exceeds 8.5 〇 ii) The average pKi (pKb) exceeds 9 in H3. 111) At one or more time points, 'significantly longer than the duration of action of uralastine in the histamine H1 functional antagonist assay. Iv) Statistically significant nasal congestion inhibition was achieved in the whole plethysmographic model of guinea pigs compared to alalastine 24 hours after administration (see Figure 1). v) CNS penetration lower than urastatin. Preparation of 6«,9(*-difluoro-17(*-[(2-)-hydroxycarbonyl)oxy]_11-hydroxyl_16〇[_methyl-3-oxo-androst-4,4 — Diene_17p_8-fluoromethyl thiocarbonate 6α'9α_difluoro·17α-[(2·furanylcarbonyl)oxy]-11β·hydroxy-16α-methyl-3-oxirane-male Solid-L4-diene_17 (3_ thiocarbonate 8-fluoromethyl ester (fluticasone citrate), its solvate and preparation of polymorphs including polymorphs and their biological activity are disclosed in The entire disclosure of the International Patent Application No. WO 02/12265 and the International Patent Application No. WO / 〇 〇 〇 〇 〇 〇 〇 〇 〇 。 。 。 。 。 。 。 . . . . . . . . . 含水 含水 含水 含水 含水 含水 含水 含水 含水 含水 含水 含水 含水. : When appropriate, the isotonic regulator is fed into a suitable mixing vessel containing pure water and dissolved under agitation. The suspending agent is then fed into the mixing vessel and dispersed throughout the solution. The resulting suspension is hydrated for a suitable period of time. To ensure cross-linking and gelation, it can be 134966.doc .. • 64 - 200932243 It takes 60 minutes or more. Pre-dissolve the preservative in pure water in a separate container, optionally by adding To, for example, 50-60 ° C (depending on the preservative selected) to aid dissolution and then added to the isotonicity adjusting agent with continuous stirring. Dissolve the buffer (if included) in a minimum amount of pure water , if appropriate, optionally heated to, for example, about 50-60 ° C (depending on the chosen buffer) and stirred to dissolve in a separate container. The separated solutions are combined, thoroughly mixed and then continuously mixed Add to the bulk solution. ❹In a separate mixing vessel 'mix the humectant and, if appropriate, as appropriate, to, for example, about 50-6 (TC (depending on the humectant selected) of pure water, and Stirring to dissolve. The slurry or solution of the active compound can then be prepared by adding the resulting wetting agent solution to the active compound, the slurry or solution of the active compound can be reduced in particle size (eg, micronized) and Mix before homogenization/refining. In addition, in a separate mixing vessel, additional preservatives (if needed) can be mixed with pure water and mixed to dissolve. • After the active compound slurry is dispersed and refined, it is added to Mixture containing suspending agent The container is mixed with the τ. After the addition of the active compound slurry, any additional preservative can be added to the bulk suspension and continuously dispersed. Finally, by adding water and (4) the suspension is brought to its final in the addition buffer. A cosolvent (if included) may be added before or after the agent. Alternatively, a cosolvent may be added during the formation of the pharmaceutical slurry or solution. β Preservatives, if included, may be added before or after the addition of the suspending agent. 134966.doc •65 - 200932243 Use of unsolvated form of fluticasone furoate as polymorph 1. Add 4-[(4-chlorophenyl)methyl]-2-({(2R)-l-[4-(4-{[ 3-(hexahydro-li/-azhen-1-yl)propyl]oxy}phenyl)butyl]-2-°pyrrolidyl}methyl)-1(2//)-pyridazine The ketone is used in the form of its free base or in the form of the 1,5-naphthalene disulfonate monohydrate or in the form of the dihydrochloride. Example 1 Component % (weight ratio) anhydrous dextrose 5% EDTA 0.015% MC cellulose &amp; sodium carboxymethyl cellulose (Avicel RC591) 1.5% polysorbate 80 0.025% 4-[(4-chlorobenzene) Methyl]-2-({(2/〇-1-[4-(4-{[3-(hexahydro-1//-azapin-1-yl)propyl)oxy}phenyl) Butyl]-2_°Bylo base}methyl)-1(2//)-pyridazinone, free base# form 0.01-0.5% phenylhydrazine chloride 0.015% pure water to 100% 4-[(4-Phenylphenyl)indenyl]-2-({(2i?)-l-[4-(4-{[3-(hexahydro-1//-)-yl-yl )propyl]oxy}phenyl)butyl]-2-° ratio p ° ° base} methyl) _ 1 (2 / /) - pyridazinone monohydrate 1,5-naphthalene disulfonate Form use. Weigh the composition components. Feed the dextrose into a mixing vessel containing pure water and dissolve under stirring. Pre-dissolve the EDTA in pure water in a separate container and heat to 50-60 ° C. To assist dissolution, and then added to the dextrose solution under continuous stirring. The microcrystalline cellulose and sodium carboxymethylcellulose are then fed into a mixing vessel and dispersed throughout the solution. The resulting suspension is then formed. Or hydration for not less than 60 minutes Complete cross-linking and gelation. 134966.doc -66- 200932243 In a separate mixing vessel, polysorbate 80 is mixed with pure water that has been heated to 50-60 ° C and stirred to dissolve. A polysorbate 80 solution is added to the micronized compound to prepare a compound slurry and the compound slurry is mixed under shaking or stirring, followed by homogenization/refining with a high shear mixer. Further, in a separate mixing vessel, The chlorinated amphoteric ammonium hydroxide solution (50% w/v) is mixed and diluted with pure water and stirred to mix. - After the hydration period, the compound slurry is added to the mixing vessel containing the suspending agent and stirred. After dispersing. After adding the compound slurry, the pre-diluted φ benzylammonium chloride solution is slowly added to the bulk suspension and dispersed under continuous stirring. Finally, the suspension is brought to its final quality by adding water and stirring. Example 2 Example 2 can be prepared by a method substantially similar to the above method. Component % by weight Xylitol 4.5% EDTA 0.015% MC Cellulose &amp; Sodium Carboxymethyl Cellulose (Avicel CL611) 2.4% Potassium sorbate 0.3% Sodium citrate 1.48% anhydrous citric acid 0.96% polysorbate 80 0.025% 4-[(4-chlorophenyl)methyl]-2-({(2i〇-l-[4-(4-{[3 -(hexahydro-l/ί-azhen-1-0.01-0.5%)propyl]oxy}phenyl)butyl]-2-»pyrrolidyl}indenyl]1 (2 squares &gt ; glyzinone, free base form * pure water to 100% ^ micronized 4-[(4-chlorophenyl)methyl]-2-({(2/〇-1-[4-(4-{ [3-(hexahydro-1//- 134966.doc •67· 200932243 azuki-1_yl)propyl]oxy}phenyl)butyl]-2-«pyrrolidyl}methyl)- 1 (2//) ugly steel was used in the form of monohydrated i,5-naphthalene disulfonate. Example 3 Example 3 was prepared by a method substantially similar to that described above. Component &quot; % (weight ratio) anhydrous dextrose - 5% EDTA --- 0.015% (4) Cellulose pour 1.5% Polysorbate 80 I~ _ - 0.025% ^^^)^^2-({( 2 to do 1_[4-(4-{[3-(hexahydro-you-hydroxyl)-butyl]] 2_° than 嘻 基} methyl)-1(10)-pyridazinone, free base form 0.01 -0.5% pure water to 100% micronized 4-[(4-Phenylphenyl)methyl]_2_({(2幻—(4·{[3_(hexahydro-1/f_azhen-1-yl) Propyl]oxy}phenyl)butyl]_2_βpyrrolidyl}methyl)_1(2//)-oxazinone is used in the form of hydrazine monohydrate, 5-naphthalenedisulfonate. 4 实例 Example 4 can be prepared by a method substantially similar to the above method. Component % (by weight) anhydrous dextrose 5% EDTA 0.015% 1.5% 〇025%~~~ MC cellulose & carboxymethyl fiber Sodium (Avicel RC591) polysorbate 80 _ 4_[(4_ gas phenyl) fluorenyl]·2_({(2) 1-[4-(4-{[3-(hexahydro-17/-nitrogen) ·μμ) propyl]oxy}phenyl)butyl] each bite} methyl)-1 (2//)-European ketone, in the form of free base * 0.01-0.5% 134966.doc - 68 · 200932243 Fluticasone citrate (micronized unsolvated, polymorph 1) 0.05% benzyl chloride Ammonium 0.015% pure water to 100% *Micronized 4-[(4-chlorophenyl)indenyl]-2-({(2Λ)-1-[4-(4-{ [3-(hexahydro-) 1//--azhen-1-yl)propyl]oxy}phenyl)butyl]-2--pyrrolidyl}indenyl-1(2//)-pyridazinone is monohydrated Use in the form of 1,5-naphthalenedisulfonate. Example 5 Example 5 can be prepared by a method substantially similar to that described above. Component % by weight anhydrous dextrose 5% EDTA 0.015% MC Cellulose &amp; Sodium Carboxymethyl Cellulose (Avicel RC591) 1.5% Polysorbate 80 0.025% 4-[(4-Chlorophenyl)methyl]-2-({(2/?)-1-[4-(4 -{[3-(hexahydro-1//-azhen-1-yl)propyl]oxy}phenyl)butyl]-2-pyrrolidinyl}indenyl)-1(2//)- Pyridazinone, 0.01-0.5% free form fluticasone citrate (micronized unsolvated, polymorph 1) 0.05% pure water to 100% micronized 4-[(4-chlorophenyl)methyl] -2-({(2/^)-l-[4(4-{[3-(hexahydro-l/ί-azohl-yl)propyl]oxy}phenyl)butyl]- 2パpyrrolidyl}methyl)-l(2//)-pyridazinone is used in the form of mono-, 5-naphthalene disulfonate monohydrate. Example 6 Example 6 can be prepared by a method substantially similar to that described above. Component % (weight ratio) Xylitol 4.5% EDTA 0.015% 134966.doc -69- 200932243 _ 2.4% 03%&quot; MC Cellulose & Carboxymethyl Cellulose J^Avicel CL61 n Potassium Sorbate Lemon: Lemon Sodium acetate anhydrous citric acid 1.48% Polysorbate 80 0.025% 4-[(4-Phenylphenyl)methyl]-2-({(2) 1-[4-(4_{[3-(hexahydro) 1 isopropyl nitrogen hydrazide) propyl]oxy}phenyl)butyl]pyrrolidinyl}methyl)hydrolanazinone, in the form of the free base * 0-01-0.5% fluticasone furoate (micronized unsolvated) , polymorph 1) 0.05% pure water to 100% micronized 4-[(4-phenylphenyl)indolyl]-2-({(2i〇-l-[4-(4-{[3- (hexahydro-1F·gasheptyl-1-yl)propyl]oxy}phenyl)butyl]-2-indole fluorenyl) fluorenyl) l(2/f&gt;pyridazinone is monohydrated Use in the form of i,5-naphthalenedisulfonate. 实例 Example 7 Example 7 can be prepared by a method substantially similar to the above method. Component % by weight Xylitol 0.75% EDTA 0.015% Dispersible MC cellulose & sodium carboxymethylcellulose (Avicel CL611) ^4% sorbic acid _ 0.3% propylene glycol 1.5% sodium citrate 1 -48% anhydrous citric acid 0.96% polysorbate 80 &quot; 0.025% 4-[(4· Phenyl)methyl]-2-({(form)-1-[4-(4_{[3-(hexahydro-1//-azahryl)propyl]oxy}phenyl)butyl) R·pyrrolidinyl}indenyl)-1 (2--pyridazinone, in the form of free base + 0.01-0.5% pure water to 100% 134966.doc -70· 200932243 *Micronized 4-[(4- Chlorophenyl)methyl]_2_({(2Phase 444-(4-{[3-(hexahydro-1//--azhen-1-yl)propyl)oxy}phenyl)butyl]_2 -&quot;Byrridinyl}methyl)-1 (2/〇-oxazinone is used in the form of hydrazine monohydrate, 5-naphthalenedisulfonate. Example 8 Example 8 can be substantially similar to the above method. Method to prepare. Component % (weight ratio) EDTA 0.015% dispersible MC cellulose &amp; sodium carboxymethyl cellulose (Avicel CL611) 2.4% potassium sorbate 0.3% propylene glycol 1.5% sodium citrate 1.48% anhydrous citric acid 0.96 % Polysorbate 80 0.025% 4-[(4-chlorophenyl)methyl]_2-({(2/?)-1-[4-(4-{[3-(hexahydro-1///) -azhen-1-yl)propyl]oxy}phenyl)butyl]-2-pyrrolidinyl}methyl)-l (2fl&gt;pyridazinone, as free base form * 0.01-0.5% pure water Supplement to 100% micronized 4-[(4-phenylphenyl)methyl]_2-({(2^-1-[4-(4-{[3-(hexahydro-1//-)- 1-yl)propyl] Yl} stupid yl) butyl] -2-piperidyl} roar slightly Yue-yl) -1 (2 //) - -phthalazinone based monohydrate used in the form of a 1,5-naphthalene disulfonate. Example 9 Example 9 can be prepared by a method substantially similar to that described above. Component % (weight ratio) Xylitol 0.75% EDTA 0.015% Dispersible MC Cellulose &amp; Sodium Carboxymethyl Cellulose (Avicel CL611) 2.4% 134966.doc -71- 200932243 Potassium Sorbate 0.3% Propylene Glycol 7.5% Lemon Sodium 1.48% anhydrous citric acid 0.96% Polysorbate 80 0.025% 4·[(4_ chlorophenyl)indolyl]-2-({(2i?&gt;l-[4-(4-{[3- (hexahydro-1βazin-1-yl)propyl]oxy}benzene; 4) butyl]-2-pyrrolidine i}methyl)-1 (2--pyridazinone' is in the form of a free base* 0-01-0.5% pure water to 100% micronized 4-[(4-phenylphenyl)methyl]-2-({(2 magic-1-[4-(4-{[3_(hexahydro) _1/7_ © aza-n-yl)propyl]oxy} phenyl)butyl]-2-° ratio slightly biti) fluorenyl) _ 1(2//)-pyridazinone Used in the form of hydrated 1,5-naphthalene disulfonate or dihydrochloride. Example 10 Example 10 can be prepared by a method substantially similar to that described above.

I34966.doc •72· 200932243 *Micronized 4-[(4-chlorophenyl)methyl]-2-({(2/0-l-[4-(4-{[3-(hexahydro-l) Good-azepine-l-yl)propyl]oxy}phenyl)butyl]-2-indolyl}indenyl)-l(2/ί)-pyridazinone is monohydrated,5 - Naphthalene disulfonate or dihydrochloride salt form. Example 11 Example 11 can be prepared by a method substantially similar to that described above. Component % by weight Xylitol 0.75% EDTA 0.015% Dispersible MC fiber Sucrose &amp; sodium carboxymethyl cellulose (Avicel CL611) 2.4% potassium sorbate 0.3% propylene glycol 2.5% sodium citrate 1.48% anhydrous citric acid 0.96% polysorbate 80 0.025% 4-[(4-chlorophenyl) Methyl]-2-({(2/?)-1-[4-(4-{[3-(hexahydro-1/7-azhen-1-yl)propyl)oxy}phenyl) Butyl]-2-oxaridinyl}methyl)-1(2/7)-pyridazinone, as a free base + 0.01-0.5% pure water to 100% micronized 4-[(4_chlorobenzene)曱)]]-({(2Λ)-1-[4-(4-{[3-(hexahydro-lif-azhen-1-yl)propyl)oxy}phenyl)butyl] -2-.Byrridinyl}methyl)-1(2//)-pyridazinone is used in the form of 1,5-naphthalene disulfonate monohydrate. 134966.doc -73- 200932243 Example 12 Example 1 2 can be prepared by a method substantially similar to the above method. Component % by weight 0.015%

Dispersible MC Cellulose &amp; Carboxymethyl Cellulose Sodium (Avicel CL611)

0.01-0.5%

Polysorbate 80 4-[(4-Phenylphenyl)methyl^·]_2·({(2β)-^ΐ^4-{[3-(hexahydro-1H·azhen-1-yl)propane Alkyloxy]phenyl)butyl]-2-3⁄4 carbaryl ketone, in the form of a free base * μ pure water to 100% micronized 4-[(4·gasphenyl)methyl (Hexahydro "p-azhen-1-yl)propyl]oxy}phenyl)butyl]_2_βpyrrolidinyl)_ 1(2//)-pyridazinone is hydrazine monohydrate , used in the form of 5-naphthalene disulfonate. Example 13 Example 13 can be prepared by a method substantially similar to the above method. Component - % by weight ί sugar alcohol ' ~~~--- 0.75% EDTA ' ~~~-- 0.015% Disperse Sodium Carboxymethyl Cellulose (Avicel CL611) 2.4% Potassium Sorbate ' --- ~ ------- 0.3% Propylene Glycol 17.5% Sodium Citrate---- 1.48% 134966.doc -74- 200932243 Anhydrous citric acid 0.96% Polysorbate 80 0.025% 4-[(4-Phenylphenyl)indenyl]-2-({(2i?)-l-[4-(4- {[3-(Hexahydro-1//-azhen-1-yl)propyl]oxy}phenyl)butyl]-2-oxaridinyl}indenyl)-1 (2 work-pyridazine) Ketone, in the form of free base * 0.5% pure water to 100% * micronized 4-[(4-chlorophenyl)indolyl]-2-({(2 magic-1-[4-(4-{[ 3-(hexahydro_17/_ Alkyl-1-yl)propyl]oxy}phenyl)butyl]-2-. Tetidine-based hydrazino)-1(2H)-pyridazinone is used in the form of the dihydrochloride salt. 14 can be prepared by a method substantially similar to the above method. Component % by weight EDTA 0.015% dispersible MC cellulose & sodium carboxymethyl cellulose (Avicel CL611) 2.4% potassium sorbate 0.3% propylene glycol 17.5 % sodium citrate 1.48% anhydrous citric acid 0.96% polysorbate 80 0.025% 4-[(4-phenylphenyl)methyl]-2-({(2/?)-1-[4-(4- {[3-(hexahydro-1 ugly-aza-oxime 0.5%) propyl]oxy}phenyl)butyl]_2_&quot;pyrrolidyl}methyl)-1 (2 sentences -pyridazinone, In the form of free base 'pure water to 100% * micronized 4-[(4-chlorophenyl)indolyl]-2-({(2i^)-l-[4·(4·{[3-( Hexahydro-17/_azol-l-yl)propyl]oxy}phenyl)butyl]-2-π 嘻n-based fluorenyl)_l(2/f)-pyridazinone Used in the form of the dihydrochloride salt. Example 15 134966.doc -75- 200932243 Example 1 5 can be prepared by a method substantially similar to that described above. Component % (weight ratio) Xylitol 0.75% EDTA 0.015% MC cellulose & sodium carboxymethyl cellulose (Avicel CL611) 2.4% potassium sorbate 0.3% propylene glycol 1.5% sodium citrate 1.48% anhydrous citric acid 0.96 % Polysorbate 80 0.025% 4-[(4-Phenylphenyl)methyl]-2-({(2/〇-1-[4-(4-{[3-(hexahydro-1///) -ammonia-1-0.01-0.5% propyl)oxy}phenyl)butyl]-2-npyrrolidyl}methyl)-1(2//)- oxazinone, free Alkali form 'fluticasone citrate (micronized unsolvated, polymorph 1) 0.05% pure water to 100% micronized 4-[(4-chlorophenyl)methyl]-2-({(2杓- 1-[4-(4-{[3-(hexahydro-1//-azhen-1-yl)propyl]oxy}phenyl)butyl]-2-°pyrrolidyl}methyl -1 (2)-pyridazinone is used in the form of 1,5-naphthalene disulfonate monohydrate. 10 Example 16 Example 16 can be prepared by a method substantially similar to the above method. Ratio) EDTA 0.015% MC cellulose &amp; sodium carboxymethyl cellulose (Avicel CL611) 2.4% potassium sorbate 0.3% propylene glycol 1.5% sodium citrate 1.48% anhydrous citric acid 0.96% 134966.doc -76- 200932243 Polysorbate Ester 80 ^[(4_ gas Methyl]_2_({(2))-i-[4_(4-{[3-(hexahydro_speak 7^^7~ propylbutyl]_2_pyrrolidinyl}methyl)-1) Fluoric acid fluticasone (micronized unsolvated, polymorph 1) pure water * micronized 4-[(4-chlorophenyl)methyl (hexahydron-heptyl-1-yl)propyl]oxy }Phenyl)butyl]_2_pyrrolidinyl)·1(2//)-pyridazinone is used in the form of monohydrate 1 &gt; 5-naphthalene disulfonate. Example 17 Example 17 can be used by The above method is generally similar

MC cellulose &amp; sodium carboxymethyl cellulose (Avicd CL61 〇 sorbic acid unloading 2.4%

ϋ ( ( 四 四 ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ]·2·({(2々-1-[4-(Μ[3·(hexahydro_1/7 azinc-1-yl)propyl)oxy)]phenyl]butyl]·2_π ratio 1(2//)·pyridazinone is used in the form of hydrazine monohydrate, 5-naphthalene disulfonate. 134966.doc -77- 200932243 Example 18 Example 18 can be obtained by the method described above Prepared in a similar manner. Component % by weight EDTA 0.015% MC cellulose &amp; sodium carboxymethyl cellulose (Avicel CL611) 2.4% potassium sorbate 0.3% propylene glycol 2.5% sodium citrate 1.48% anhydrous bar Citric acid 0.96% polysorbate 80 0.025% 4-[(4-chlorophenyl)methyl]-2-({(2/〇-1-[4-(4-{[3-(hexahydro-) 1//--azhen-1-yl)propyl]oxy}phenyl)butyl]-2-oxaridinyl}methyl)-1(2//)-pyridazinone, as a free base #0.01-0.5% fluticasone citrate (micronized unsolvated, polymorph 1) 0.05% pure water to 100% micronized 4-[(4-chlorophenyl)methyl]-2-({(2 /?)-1-[4-(4-{[3-(hexahydro-1/ί-azhen-1-yl)propyl] The base phenyl)butyl]-2-»pyrrolidyl}indenyl-1(2//)-pyridazinone is used in the form of monohydrate 1,5-naphthalene disulfonate. Example 19 can be prepared by a method substantially similar to the above method. Component % by weight Xylitol 0.75% EDTA 0.015% MC Cellulose &amp; Carboxymethyl Cellulose Sodium (Avicel CL611) 2.4% Potassium Sorbate 0.3% propylene glycol 7.5% 134966.doc -78- 200932243

4-[(4·Phenylphenyl)methyl] 0.01-0.5% sodium citrate acid fluticasone (micronized non-solvent 彳T^j^a ^ pure water 0.05% 5.100%

Micronized 4-[(4-phenylphenyl)methyl]·2_({(2 hexachloro-W ❹ 呼 呼-i. phanyl) oxy}phenyl)butyl]H The base)-1(2//)-pyridazinone is used in the form of hydrazine monohydrate, 5-naphthalene disulfonate or dihydrochloride. Example 20 Example 20 can be prepared by a method substantially similar to that described above.

EDTA _ MC cellulose &amp; sodium carboxymethyl cellulose (Avicei CL611) potassium sorbate propylene glycol 0.015% 2.4% 〇 3% ~ 7.5% 1.48% 0.96% 0.025% 001-0.5%

Anhydrous citrate polysorbate 80 4-[(4-Phenylphenyl)indenyl]-2^ϊ(2Λ)-1-[4-(4-{[3-(hexahydro)propyl]oxy Phenyl)phenyl)butyl-pyrrolidyl}indenyl-1(2//)-nonanone, in the form of a free base; fluticasone phthalate (micronized unsolvated, polymorph 1 ) Pure water ~~ ' ' ~

134966.doc • 79- 200932243 *Micronized 4-[(4-chlorophenyl)methyl]-2-({(2/〇-l-[4-(4-{[3-(hexahydro-1) //-Azinc-l-yl)propyl]oxy}phenyl)butyl]-2-°pyrrolidyl}methyl)-1(2//)-pyridazinone is monohydrated 1 , used in the form of 5-naphthalenedisulfonate or dihydrochloride. Example 21 Example 2 1 can be prepared by a method substantially similar to the above method. Component % by weight Xylitol 0.75% EDTA 0.015% Disperse MC cellulose &amp; sodium carboxymethyl cellulose (Avicel CL611) 2.4% potassium sorbate 0.3% propylene glycol 17.5% sodium citrate 1.48% anhydrous citric acid 0.96% polysorbate 80 0.025% 4-[(4- Chlorophenyl)methyl]-2-({(2i?)-l-[4-(4-{[3-(hexahydro-1/f-azhen-1-0.5%))propyl]oxy Phenyl)phenyl]butyl]-2-&quot;pyrrolidyl}indenyl-1(2)-pyridazinone, in the form of the free base# fluticasone citrate (micronized unsolvated, polymorph 1 ) 0.05% pure water to 100% micronized 4-[(4-phenylphenyl)methyl]-2-({(2/?)-1-[4-(4-{[3-(hexahydro) -1//-azhen-1-yl)propyl]oxy}phenyl)butyl]-2-oxaridinyl}methyl)-1(2//)-pyridazinone Acid salt Example 22 Example 22 can be prepared by a method substantially similar to the above method. 134966.doc -80· 200932243 Component - one% by weight HD1A ... 0.015% dispersible MC cellulose &amp; Cellulose sodium (Avicel CL611) 2.4% potassium sorbate 0.3% propylene glycol 17.5% sodium citrate 1.48% anhydrous citric acid 0.96% polysorbate 80 0.025% 4_[(4_gasphenyl)methyl]-2-({ (2 and)-1-[4-(4][3_(hexahydro_17/_azepoxy)propyl]oxy}phenyl)butyl]-2"pyrrolidinylmethyl) _丨(Talking with oxazinone, 0.5% free base form fluticasone (micronized 'unsolvated, winter crystal η 0.05% pure water to 100% micronized 4-[(4-phenyl)) Base (hexahydro_17/_

Esteryl-1-yl)propyl]oxy}phenyl)butyl]_2_Dpyrrolidylmethyl)-1(2//)-pyridazinone is used in the form of the dihydrochloride salt. Example 23 Example 23 can be prepared by a method substantially similar to that described above. Component% (weight ratio) Xylitol 0.75% EDTA - 0.015% Can be bulk MC cellulose &amp; sodium carboxymethyl cellulose (such as bismuth (2) 丨 CL611) 2.4% potassium sorbate - - 0.3% propanol ''''' 2.5% Sodium citrate^~ 1.48% Anhydrous citric acid ''''~~一-&quot; 0.96% Polysorbate 80 2.0% 134966.doc 200932243 4-[(4_Chlorophenyl)曱^]-2-({(2))7[4_(4_{[3_(hexahydrolezinyl)propyl)oxy}benyl)butyl]ylhydrazinemethyl)-1(2/ /)-pyridazinone, in the form of free base * 0.01-0.5% pure water ^'-- make up to 100% 4-[(4-phenylphenyl)indolyl]_2-({(2 pheno-hexahydro) The oxazinone is used in the form of a free base. Example 24 ❹ 实例 Example 24 can be prepared by a method substantially similar to that described above.

Propylene glycol sodium citrate 2.5% anhydrous citrate polysorbate 80 4-[(4_ gas phenyl)methyl]-2-({(2/^[^ϊ^ί^ΤΓ base;&gt; propyl] oxygen Benzene^0 butyl]-2-%pyridinyl hydrazine methyl is 2 ketone, pure water is used as the free base form 1.48% to make up 100% 4-[(4_ phenyl) methyl b 2 ^2^小[4_(4_{[3_(六气·他气呼_ 1-yl)propyl]oxy}phenyl)butyl]·2_pyrrolidinyl}indenyl)] (called pyridazine) The ketone is used as the free base.Example 25 Example 25 can be prepared by a method substantially similar to that described above. 134966.doc • 82- 200932243 Component Xylitol - _ % (weight ratio) 0.75%

EDTA 0.015% dispersible MC cellulose &amp; slow methyl cellulose sodium (ΑνΜ CL611) potassium sorbate propylene glycol sodium citrate anhydrous citrate polysorbate 80 2.4% 0.3% 2.5% 1.48% 0.96% 2.0% 0.01-0.5 % 0.05% complement to 100% 4 [(4 gas stupid) methyl]·2·({(2Λ)-1-[4-(4-{[3-(hexahydro-li/-azep-1) )) propyl]oxy} phenyl) butyl] _2. than slightly biting yl} methyl)-1 (2 / 〇 - 噃 ketone is used in the form of the free base Example 26 can be used by Method is generally similar to the method of preparation

I34966.doc -83- 200932243 4-[(4-Chlorophenyl)indenyl]_2-({(2 and -1-[4-(4-{[3-(hexahydro-1//--) -1-yl)propyl]oxy}phenyl)butyl]-2-oxaridinyl}methyl)-1(2^)-pyridazinone, in the form of the free base * 0.01-0.5% decanoic acid Fluticasone (micronized unsolvated, polymorph 1) 0.05% pure water to 100% 4-[(4-phenylphenyl)methyl]-2-({(2/?)-1-[4- (4-{[3-(hexahydro-1/^-azhen-1-yl)propyl]oxy}phenyl)butyl]·2_&quot;pyrrolidyl}methyl)-1(2Η) - Pyridazinone is used in the form of the free base. In Examples 1 to 26, micronized 4-[(4-phenylindolyl)methyl]-2-({(2i〇-l) is given as the free base form. -[4-(4-{[3-(hexahydro-1//-azahr-1)yl)propyl]oxy}phenyl)butyl]-2-oxaridinyl}methyl)-1 (2//)-pyridazinone concentration '% of the total weight of the composition 〇.〇1% by weight, 〇.〇25〇/. (weight ratio), 0.05% by weight 〇1% by weight, 0.25% by weight, and 0.5% by weight. It should be understood that 4-[(4-chlorophenyl)indenyl]_2-({(2;〇-1) ·[4-(4·{[3-(hexahydro-1 Η-azhen-1-yl)propyl]oxy}phenyl)butyl b 2_ The pyridyl}methyl)- 1 (2/f)-pyridazinone can be used in the form of a pharmaceutically acceptable salt in an appropriate concentration depending on the selected salt G to provide the free base in the desired concentration. Thus, in Examples 1 to 12 and 15 to 20, 4-[(4-chlorophenyl)methyl]-2-.hexahydro-1open-azin-1-yl)propyl]oxy}benzene The concentration of butyl, benzylidene-2-pyrrolidyl} fluorenyl-1(2//)-pyridazinone monohydrate 1,5-naphthalene disulfonate (micronized) is the composition The total weight is 〇1478% (by weight), 0.03695% (by weight), 〇.〇739°/. (weight ratio), 〇1478°/. (weight ratio), 0.3695% by weight, and 〇_739 (weight ratio)' will provide a 〇1 to 0.5% (by weight) free test. 134966.doc •84· 200932243 In Examples 9, 10, 13, 14, 19, 20, 21 and 22, 4-[(4-indolyl)methyl]-2-({(2/?)- 1_[4-(4-{[3-(hexahydro-1//-azhen-1-yl)propyl]oxy}phenyl)butyl]-2-oxaridinyl}methyl)- 1 (2/〇-pyridazinone, the concentration of the dihydrochloride is such that a concentration of 0.01 to 0.5% by weight of the free base is provided. In Examples 23 to 26, the micronization of the free base form is given 4-[ (4-Phenylphenyl)methyl]-2-({(2i?)-l-[4-(4-{[3-(hexahydro-1//-azhen-1-yl)propyl]] The concentration of oxy}phenyl)butyl]-2-oxaridinyl}indenyl-1(2//)-pyridazinone is at a concentration of 0.01% by weight based on the total weight of the composition. Ratio), 0.025% by weight, 0_05% by weight, 〇1% by weight, 0.25% by weight, and 5% by weight. Depending on the route of administration selected, The example compositions are filled into suitable containers. For intranasal administration, suitable containers are as described above and are typically made of plastic and dispense 50 to 1 〇〇 pL of composition per actuation. [Simplified illustration] φ 二展: In the whole plethysmographic model of the guinea pig 24 hours after administration of 'significant inhibition compared to the nose of the charge on the ash and La Siting statistics. I34966.doc -85-

Claims (1)

200932243 X. Patent application scope: 1 * An aqueous pharmaceutical composition comprising 4-[(4·gasphenyl)methyl]_2_ ({(211)-1-[4-(4-{[3-( Hexahydro-111-azhen-1-yl)propyl]oxy}phenyl)butyl]-2-pyrrolidinyl}indenyl)_ι(2Η)_pyridazinone Or a pharmaceutically acceptable salt thereof. 2. An aqueous pharmaceutical composition comprising (i) 4-[(4-phenylphenyl)methyl]-2-({(2i?)-l-[4-(4-{[3-( Hexahydro-1 Ηazhen-1-yl)propyl]oxy}phenyl)butyl]-2-indolyl}methyl)·1(2//)-pyridazinone Cr , or a pharmaceutically acceptable salt thereof; and (ii) 6a, 9ot-difluoro-indenyl 7α-[(2-furylcarbonyl)oxy]-11β-hydroxyl 16α-methyl-3-oxooxy - androgen-1,4-diene-17β-thiocarbonate S-fluorodecyl ester compound (fluticasone citrate) 134966.doc 200932243 Or a solvate thereof. * 3. The aqueous pharmaceutical composition of claim 1 or claim 2, which comprises from 0.005% to 2% by weight, based on the total weight of the composition, of 4-[(4_气笨基)甲甲❹ :]2 ((((10)小卜(4)(1), hexahydro-1 _ 呼 ·· 1-yl) propyl]oxy} phenyl)butyl]-2-indolyl}methyl)_ i (2//) _ pyridazinone or a pharmaceutically acceptable salt thereof. 4. The aqueous pharmaceutical composition according to claim 3, which comprises from 0.01% to 1% by weight of the total weight of the composition of 4_[(4_气phenyl)methyl]_2· ({( 2/?)-ΐ_[4·(4_{[3-(hexahydro-1//-azeto-i-yl)propyl]oxy}phenyl) butyl]-2·°pyrrolidyl }Methyl)-1(2//)-pyridazinone or a pharmaceutically acceptable salt thereof. The aqueous pharmaceutical composition according to any one of claims 2 to 4, which comprises 氟1 to 1% by weight of fluticasone furoate or a solvate thereof, based on the total weight of the composition. 6. The aqueous pharmaceutical composition according to claim 5, which comprises about 0.05% by weight of fluticasone furoate or a solvate thereof, based on the total weight of the composition. The aqueous pharmaceutical composition according to any one of claims 1 to 6, further comprising a) a suspending agent; b) a preservative; 134966.doc 200932243 c) a wetting agent; and d) an isotonicity adjusting agent. 8. The aqueous pharmaceutical composition of claim 7, which additionally comprises a cosolvent. 9. The aqueous pharmaceutical composition of claim 7 or claim 8 which comprises from 1.5% to 2.4% by weight, based on the total weight of the composition, of a suspending agent. The aqueous pharmaceutical composition according to any one of claims 7 to 9, wherein the suspension comprises microcrystalline cellulose and/or sodium carboxymethyl cellulose. The aqueous pharmaceutical composition according to any one of claims 7 to 1 which contains 0.001 to 1% by weight of a preservative, based on the total weight of the composition. 12. The aqueous pharmaceutical composition according to Item 11, which comprises 0.015% to 0.3% by weight of a preservative based on the total weight of the composition. The aqueous pharmaceutical composition according to any one of claims 7 to 12, wherein the preservative comprises disodium edetate (EDTA) and/or potassium sorbate. The aqueous pharmaceutical composition according to any one of claims 7 to 13, wherein the preservative comprises about 5% by weight of disodium edetate (by weight) based on the total weight of the composition. EDTA) and about 0.3% by weight of potassium sorbate. The aqueous pharmaceutical composition according to any one of claims 7 to 14, which comprises a humectant in an amount of from 0.001 to 5% by weight based on the total weight of the composition. 16. The aqueous pharmaceutical composition of claim 15 which comprises about 0.025% by weight of a wetting agent based on the total weight of the composition. The aqueous pharmaceutical composition according to any one of claims 7 to 16, wherein the humectant comprises polyoxyethylene (20) sorbitan monooleate (polysorbate 80). 18. The aqueous pharmaceutical composition according to any one of claims 7 to 17, which comprises isotonic adjustment of 1341 to 1% by weight, based on the total weight of the σ, 134966.doc 200932243 Agent. An aqueous pharmaceutical composition according to claim 18, which comprises an isotonicity adjusting agent in an amount of from 4.5 to 5.5% by weight based on the total weight of the composition. The aqueous pharmaceutical composition according to any one of claims 7 to 19, wherein the isotonicity adjusting agent comprises dextrose and/or xylitol. The aqueous pharmaceutical composition according to any one of claims 8 to 20, which comprises from about 1.5 to 17.5% by weight, based on the total weight of the composition, of a cosolvent. 22. The aqueous pharmaceutical composition according to claim 21, which comprises a cosolvent of from about 2.5, about 7.5 or about 17.5% by weight, based on the total weight of the composition, of about 2.5, about 7.5 or about 17.5% by weight. The aqueous pharmaceutical composition according to any one of claims 8 to 22, wherein the cosolvent is propylene glycol. The aqueous pharmaceutical composition according to any one of claims 7 to 23, which additionally comprises a buffer. 25. The aqueous pharmaceutical composition of any one of claims 7 to 24 which is isotonic with the nasal fluid. A. The aqueous pharmaceutical composition of any one of claims 7 to 24 which is isotonic with the eye fluid. The aqueous pharmaceutical composition according to any one of claims 1 to 26, which is an aqueous, suspension. The aqueous pharmaceutical composition according to any one of claims 1 to 26, which is an aqueous solution. The aqueous pharmaceutical composition according to any one of claims 1 to 28, which comprises 4_[(4-chlorophenyl)methyl]_2-({(2R)-i_[4-(4-{[3 -(hexahydro-1H-azhen_1β 134966.doc -4- 200932243 yl) propyl]oxy}phenyl)butyl]-2-pyrrolidinylmethyl)-1 (2H)-酞Beryllium copper 'monohydrate 1,5-naphthalene disulfonate. The aqueous pharmaceutical composition according to any one of claims 2 to 28, which comprises fluticasone citrate in an unsolvated form. 31. The aqueous pharmaceutical composition of claim 3, which comprises fluticasone saccharide in polymorph type 1. 32. An aqueous pharmaceutical composition which is a composition as described in any one of Examples 1 to %. ❹ 33. A container comprising an aqueous pharmaceutical composition according to any one of claims 1 to 32 which is adapted to deliver the composition into the nasal cavity. 34. A container comprising an aqueous pharmaceutical composition according to any one of claims 1 to 32 which is adapted to deliver the composition into the eye. The aqueous pharmaceutical composition according to any one of claims 1 to 32, which is for the treatment of an inflammatory and/or allergic disease. ' It is used to treat allergic nose 36. The aqueous pharmaceutical composition of claim 35, inflammation 0 37. The treatment of an aqueous pharmaceutical composition according to claim 35 or claim 36 once a day. It is used for the use of an aqueous pharmaceutical composition according to any one of claims 1 to 32 for the manufacture of a medicament for the treatment of an inflammatory and/or allergic disease. , 39_ As used in claim 38, it is used for daily-people's metallurgy. 40. If the purpose of claim 38 or claim 39 is used, inflammation. It is used to treat allergic nose 134966.doc