TW200540172A - Compounds - Google Patents

Abstract

The present invention provides a compound of formula (I), and salts and solvates thereof. Compounds of formula (I) are agonists of the adenosine A2A receptor and are believed to be of potential use in the treatment of inflammatory diseases such as asthma and chronic obstructive pulmonary disease.

Description

200540172 IX. Description of the invention: [Technical field to which the invention belongs] The present invention relates to new compounds, their preparation methods, their medicinal preparations and their therapeutic uses. [Previous technique] Inflammation is the main response to tissue injury or microbial invasion, and it is characterized by the attachment of white blood cells to endothelial cells, exudation of blood cells and activation of tissues. Leukocyte activation results in the production of toxic oxygen species (such as superoxide anions) and release of particulate products (such as peroxidases and proteases). White blood cells circulating in the blood include t-eosinophils, eosinophils, basophils, monocytes, and lymphocytes. Different types of inflammation involve different types of infiltration into white blood cells, and their special circumstances are regulated by the expression of attachment molecules, cytokines and chemokines in the tissue. The main function of white blood cells is to protect the host from invading organisms such as bacteria and parasites. Once the tissue is injured or infected, a series of events will occur 'which will result in the local recruitment of white blood cells from the bloodstream to the affected tissue. Leukocyte supplementation is controlled to allow orderly destruction and phagocytosis of foreign or dead cells, followed by tissue repair and resolution of inflammatory infiltrates. However, in a chronic inflammatory state, recruitment is usually inappropriate, the solution is not adequately controlled, and the inflammatory response causes tissue destruction. Studies by live invitations and live invitations have evidence that compounds that are active on adenosine-receptors have anti-inflammatory effects. This area has been commented (1 &4; b). Studies on isolated neutrophils have shown that ^ receptor mediators inhibit superoxide production, degranulation, aggregation, and attachment 101952.doc 200540172, etc. 1983 and 1985; Burkey and Webster, 1993; Richter, 1992;

Skubitz et al., 1988). When using agents that are more selective for receptors than A2b receptors (eg, CGS2168), the inhibition appears to be consistent with the effect on A2a stylistic subtypes (Dianzani et al. 994). Adenosine agonists can also control other types of white blood cells down (Beijing 101 and Lianxianyi, Peachell et al., 1989). Studies on whole animals have shown that the anti-inflammatory effects of methotrexate are mediated by adenosine and M receptor activation (AsakO et al., 1993; = et al., 1993 and 1994). Glandular bitter itself and compounds that increase the content of adenosine in the blood stream also show anti-inflammatory effects in vivo, etc., Zhou; Roseng⑽ #, 1995). In addition, the increased adenosine tritium in human bloodstream (as a result of adenosine deaminase deficiency) can cause immunosuppression (Hirschorn, 1993). [Summary of the Invention] The present invention relates to the inhibition and activation of white globules The compound (and its salt and solvate) 'is a potent, active agent of A2a (hereafter called A2a) receptor. Therefore, 'the compound may have potential therapeutic effects, which provide protection against white-ball-induced tissues in diseases involving inflammation sites in the white ball, such as α. The compounds of the present invention may also represent a safer choice than corticosteroids in the treatment of inflammatory diseases' The use of the latter may be limited by the circumstances of its side effects. Even the compounds of the present invention show an improvement over known selective agonists, because they are edible and have the following properties: (1) The selectivity for Α2Α is Human As receptor is about 100 times more, (Π) is more selective for A2α than human Asb receptor is about 100101952.doc 200540172 times, and (III) is more selective for Aa than human VIII] There are about 100 times more receptors, (IV) binding to human serum albumin is greater than about 90%, and less significant cardiovascular effects than (V), especially reduced tachycardia. This situation can be considered to be of interest because A3 receptors are also found in white blood cells (such as 'eosinophils') and other inflammatory cells (such as mast cells); and activation of these receptors may have a pre-inflammatory effect (Kohno et al., 1996, Van Schaick et al., 1996). It has even been suggested that the effect of adenosine on bronchial sphincter in asthmatic patients may be via the adenosine a3 receptor mediator (Kohno et al., 1996). Ab receptors are also found in mast cells and may therefore be involved in mast cell activation. Al receptors are distributed in a wide range of tissues and can be found especially in the heart, adipose tissue, airway smooth muscle, neutrophils, kidneys, hippocampus and cerebral cortex. Al receptor activation may therefore result in decreased lipolysis, polyuria, and CNS activation (Fozard J. R., Thai McCarthy C5 Current Opinion in Investigational Drugs 2002 Vol. 3, No. 1 pp. 69-77). Binding to human serum albumin exhibited greater than about 90 ° /. Compounds such as about 95% or more are expected to have improved side effects. For example, such compounds may be expected to have less pronounced cardiac effects, such as tachycardia. Therefore, according to the present invention we provide compounds of formula (I)

R R s R is 200540172 h3c

, CHU (丨) and their salts and solvates. The compound of formula (I) requires about the tetrahydrofuran ring—with absolute stereoscopy ', so about this stereochemistry of each tetrahydrofuran ring is as follows:

However, 'the individual stereochemistry in the other tetrahydro D ring is not necessarily fixed. Within this requirement, the present invention encompasses all stereoisomers of the formula di-complex (ie, non-mirromeric isomers, whether individually or substantially free of other stereoisomers (ie, pure). Isolated stereoisomers, or mixtures thereof. The individual stereoisomers that are separated without substantially containing the two isomers will be separated so that 101952.doc 200540172 exists. Its: less isomers At about 10%, such as less than about 1% or less than about _compounds, where all two tetrahydros are involved. The stereochemistry of the furan ring 2 Each stereocenter in the tetrahydrocrane ring is as described above The fixed compounds shown by the compounds of formula ㈣ are better. This formula also covers all geometric isomers of the compounds of formula ，, regardless of :: isomers or mixtures thereof. Therefore, the formula of the 'trans and cis configuration' Mouthpieces, especially the trans-forms, form a further aspect of the invention. Salts of the compounds of the invention are also covered by the invention. Because of their possible use in medicine: the salts of the compounds of formula 以 are medicinally acceptable. Accepted salt. Medically acceptable salts can include acid addition Salt. Pharmaceutically acceptable acid addition salts can be borrowed from the compound of formula 与 or organic acid, chloric acid, formic acid, sulfuric acid, nitric acid, phosphoric acid, succinic acid = ::, terephthalic acid, orthophthalic acid. Formic acid, acetic acid, fumaric acid]] t phthalic acid m toluic acid, formic acid or naphthalene acid) 'and optionally in a suitable solvent, such as an organic solvent, to form the reaction' the salt produced is usually By crystallization or filtration, separation. Therefore, a pharmaceutically acceptable acid addition salt of the compound may be, for example, hydrogen acid, > acid, formic acid, sulfuric acid, nitric acid, dish acid, hyaluronic acid, maleic acid, phthalic acid, p-benzene Dicarboxylic acid, acetic acid, fumaric acid, citric acid, tartaric acid, benzic acid, p-toluene, formic acid or naphthalene; acid salts. It is stated that all possible chemically non-stoichiometric forms of the compounds of formula ⑴ are included. The formula t and the scope of the invention also include all solvents of the compounds and salts of the invention 101952.doc -10- 200540172 compounds, hydrates, complexes and polymorphisms. A compound of formula (I) or a protected derivative thereof can be used as an alternative method. A method of borrowing a compound of formula (II) (where L represents, for example, ii ', especially chlorine's leaving laughter) or a protected derivative thereof Thing,

It is made by reacting with [2- (1-methyl-17 / -imidamidinyl) ethyl] amine.

nh2 η3〇 " This reaction usually involves heating the reagent to 50 in an inert solvent such as DMS〇. (: -150. (:, Such as 10 (TC-13 (rc, in particular about 110 < 5 (: -20 C) Alternatively, the reaction may be at a lower temperature (e.g., about} 00. ), For a long time (such as, 18-24 hours). The compound of formula (11) can use its hydroxy earth, ,,, or other conformable forms, such as via acetone or acetamyl, especially acetamyl. π) The compound or a protected derivative thereof can be a compound of formula (III) (wherein 101952.doc 200540172 L represents a leaving group as defined above) or a protected derivative thereof

It is made by reacting 1,1-diaminocyclohexane, such as trans-M • diaminocyclohexane. This reaction is usually carried out at a high temperature (for example, 50 ° C to 60 ° C) in the presence of a base such as an amine base (for example, diisopropylethylamine in a suitable solvent such as an alcohol such as isopropanol). Compounds of formula (III) or protected derivatives thereof and methods for their preparation are disclosed in 98/28319. The compound of formula (III) is intermediate 7 of WO 98/28319. U, compounds of formula _ can be derived from compounds of formula (IV) or their derivatives

And 2,6-—Air-throat 'in a suitable solvent under inert conditions, in a trimethyl dream house containing such as trifluoromethane! It is made by reacting the conditions of the intended Lewis acid. "Compounds of formula (I) and formula (IV) can be used in the form protected by a suitable protecting group, such as acetone or ethenyl, especially ethenyl. Compounds of formula σν) can be borrowed from wo 9δ / 28319 The method disclosed is prepared by a method similar to 101952.doc 12 200540172. The compound of formula (IV) is the intermediate 6 of WO 98/283 19. According to the second method (B), the compound of formula (I) or its protected Derivatives can be obtained from compounds of formula (V)

It is made by reacting with a compound of formula (IV) or a protected derivative thereof as defined herein above. This reaction can be carried out under conditions containing a hindered base such as DBU and a Lewis acid such as trimethylsilyl difluoromethanesulfonate.

The compound of formula (V) can be obtained by combining the compound of formula (VI)

Wherein L is a suitable amine protecting group such as 2'hydropiperan, which is prepared by deprotecting 101952.doc -13-200540172. Deprotection can be achieved by scorching a suitable acid, such as HC1, from acid to water. Compounds of formula (VI) can be obtained by compounds of formula (VII)

(VII) wherein L and L 'are as defined above, and are prepared by reacting with methyl good · imidazol-4-yl) ethyl] fee. The reaction usually involves heating the reagent to a temperature of 501-500 ° C in an inert solvent such as Dms〇 or ethylene glycol, such as 100 ° C-130 ° C, especially about 100 ° C-12 (TC. External bases such as dipotassium hydrogenate can also be used to enhance reactivity. Compounds of formula (νπ) can be prepared by compounds of formula (VIII)

(VIII) where L and L 'are the leaving groups as defined above, and reacted with cis-diaminocyclohexane, 101952.doc 14 200540172 such as trans-1,4-diaminocyclohexane production. This reaction is usually in the presence of a base such as an amine (for example, diisopropylethylamine in a suitable solvent such as an alcohol such as isopropanol or n-butanol) at a high temperature (for example, 6 (rc to 80.0). ). The compound of formula (VIII) can be made according to the method disclosed in WO 03/080613 or by a similar method. The compound of formula (VIII) is the intermediate product 1 of 03/080613. The compound of formula (I) can be further based on A third method (c) is made by deprotecting a protected derivative of a compound of formula (I), such as one in which the catenary group on the sugar moiety is protected by ethenyl. As described above, Protected derivatives of the compounds of the invention can be used, or intermediates of the compounds of the invention can be prepared. Examples of protecting groups and methods for their removal can be found in TW Greene and PGM Wuts "

Organic Synthesis " (J Wiley & sons, 1991). Suitable hydroxy-protecting groups include alkyls (for example, methyl), acetals (for example: #fluorenyl) and fluorenyl (for example, ethylfluorenyl or benzyl) which can be removed by hydrolysis, and catalytic hydrogen Aromatic radicals (eg, benzyl) are removed. Suitable amine protecting groups include hindering groups (for example, tolyl), fluorenyl groups (for example, benzyl or tertiary butoxycarbonyl), and aromatic groups (for example, benzyl), which may be borrowed when appropriate. Removal by hydrolysis or chlorolysis. The potential of compounds of formula VII and their salts or solvates to inhibit white blood cell function can be stimulated, for example, by their inhibition by chemical attractants such as N • methylmethylthiothiamine-white aminoamine-phenylalanine (fMLP) The ability of neutral spheres to produce superoxide (CV) is shown. Accordingly, diseases of the compound of formula (I) in white blood cells involving 101952.doc -15-200540172 and inflamed sites may have potential therapeutic benefits in providing protection from white blood cell-induced tissue damage. Examples of disease states where compounds that inhibit white blood cell function may have potentially beneficial anti-inflammatory effects include beer-sucker diseases such as adult respiratory stress syndromes (ARDS), bronchitis (including chronic bronchitis), fibrocysts, asthma ( Including asthma induced by allergens), emphysema, rhinitis and septic shock. Other related disease states include gastrointestinal diseases, # • Intestinal inflammatory diseases, including inflammatory bowel disease (eg, Crohn's disease or ulcerative colitis), Helicobacter_pyl〇r gastritis with radiation exposure or allergen exposure Secondary intestinal inflammatory diseases, and non-steroidal anti-inflammatory agents-induced gastric lesions. Further diseases may include skin diseases such as psoriasis, allergic dermatitis and allergic reactions, and neurological diseases with inflammatory components such as Alzheimer's disease and multiple sclerosis. Further examples of disease states where Class 2 compounds may have potentially beneficial effects include heart disease, such as peripheral vascular disease, post-ischemic reperfusion • injury and pathological hypereosinophilic leukemia syndrome. However, compounds that inhibit white blood cell function may have potential as immunosuppressive agents and have uses in the treatment of autoimmune diseases such as rheumatoid arthritis and diabetes; moreover, they may inhibit cancer metastasis. Those skilled in the art will understand that the treatment referred to in this article extends to the prevention and treatment of established diseases. Particularly advantageous is the treatment and / or prevention of gas in mammals (e.g., humans) and Mann's pulmonary obstructive disease (COPD), chronic bronchitis and emphysema ', especially asthma and COPD. 101952.doc -16- 200540172 As mentioned above, the compound of formula (I) and its salts and solvates may have human or veterinary use, especially as anti-inflammatory agents. Therefore, the present invention further provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for human or veterinary use, and in particular, it is susceptible to leukocyte-induced tissue damage due to inflammatory conditions: : Sick. According to another aspect of the present invention, we provide the use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof ^ for the manufacture of patients with inflammatory conditions that are susceptible to the effects of tissue damage caused by white blood cells. drug. In terms of advancement or replacement, we provide a method of treating a patient with an inflammatory condition and / or an allergic condition that is susceptible to the effects of tissue damage caused by white blood cells. The method includes administering an effective amount to the human or animal patient. Compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof. When used for medical purposes, the compounds of the present invention are generally used as drug combinations. Accordingly, the present invention provides in a further aspect a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, optionally with one or more pharmaceutically acceptable carriers and / or excipients. The pharmaceutical composition may have uses for treating and / or preventing any of the conditions described herein. The compounds of formula (I) and their salts and solvates and / or pharmaceutical compositions containing them can be administered, for example, parenterally (eg, intravenously, subcutaneously or intramuscularly), by inhalation, nasal, transdermal or rectal , Or as a topical treatment (for example, ointment or glue). Particularly advantageous routes of administration include inhalation and nasal 101952.doc 200540172. Administration by inhalation involves a topical composition. For lungs, for example, aerosol or dry powder hydrazone compounds and their salts with ^, wn πη / ςΛΛ and / cereals and / or pharmaceutical compositions may be borrowed as described in WO 00/50011. ^ N A 待'Release formulation applied. Parenteral compositions may include, a & a, a sterile aqueous carrier or a parenterally acceptable wormwood compound or a medical treatment, a solution or suspension of the incorporated salt. Alternatively, the solution may be cold-bundled and the freeze-dried parenteral pharmaceutical composition may be backflushed with a suitable solvent immediately before administration. — Compositions for administration by nasal inhalation may be conveniently formulated as aerosols, solutions, suspensions, drops, eves or dry powders, plus aqueous or non-aqueous vehicles, and optionally agents such as thickeners, buffers Salt, or pH adjusting acid, isotonic adjusting agent, antioxidant and / or preservative. Capsules and medicines such as gelatin, or "vacuum forming such as laminated aluminum", which are administered as inhalers or human organs, can be formulated into a powder mixture containing the compound of the present invention and a suitable powder base such as lactose or starch. . We also provide a method for preparing such a pharmaceutical formulation, comprising mixing the ingredients. For those who are suitable and / or modified for inhalation administration, the compound or the salt or solvate of the compound of formula (I) is typically a reduced particle size version, In particular, the size reduction type is obtained (or can be obtained by micronization). Generally, the particle size of a particle-reducing (e.g., micronized) compound or salt can be defined by a D50 value of about 0.5 to about 10 microns (e.g., measured using laser refraction). "Aerosol formulations, such as those for inhalation, may include active substance solutions or fine suspensions in medically accessible 101952.doc • 18- 200540172 S: aqueous or non-aqueous solvents. Aerosol formulations may be taken in sealed containers Aseptic version and single or multiple dose presentations' It can be used as a cartridge or refill with a nebulizer or inhaler. Alternatively, the sealed container can be a single dispersive device, such as a single dose nasal inhaler or An aerosol disperser equipped with a metering valve (fixed dose inhaler), which can be discarded once the contents of the container are used up. When the dosage form includes an aerosol disperser, it is preferable to include pressurized air and carbon dioxide Suitable pressurized propellants, or organic propellants such as chlorofluorocarbons (cfc) or hydrofluorocarbons (HFC). Suitable CFC propellants include fluoromonomethyl, dichlorofluoromethane and dichloromethane. Tetrafluoroethane. Suitable hfc propellants include 1,1,1,253,3,3-heptafluoropropane and 1,1,1,2-tetrafluoroethane. This rolling sol dosage form can also be used in Bangpu nebulizer. Type, as the case may be, For dry powder inhalation compositions, the pharmaceutical composition for inhalation administration can be incorporated into multiple sealed dose containers (eg, dry powder-containing compositions) in a line or ribbon placed in a suitable inhalation device in a straight line. This content: when needed Will rupture or peel and open, and dosages such as dry powder compositions can be administered by inhalation via the device, such as Glaxo SmithKHne's commercially available device. The DISKusTM inhalation device is described in, for example, GB2242134A, and in the device In the two peelable films that do not interfere with each other, at least one of the cereals for the powder type pharmaceutical composition (the one or more containers is preferably placed in a line or a ribbon in a straight line) multiple seals Dosage capacity _ range; the device includes ...-a dream for the open range of the container for the-or evening container „: 1 Vision device 'A device that peels off the film of the open station and opens the container. May be six. ≪ 罝, open valley-like outlets (through this, 101952.doc -19- 200540172 users can inhale powdered pharmaceutical compositions from open containers). In accordance with the present invention The proportion of the active compound of formula VII or its salt or solvate in the topical composition depends on the correct form of the formulation to be prepared, but may generally range from 0.001 to 10 wt. For the formulation of the state, 'usually used ratio ranges from 0.0005 to!%, Such as from 0 · (Π to 0.5%'. However, in the case of powder for inhalation or blowing, the ratio used May fall in the range from 0.1 to 5%.

Or 8 times each: underdose, for example, u 2 or 3 doses. What is the total daily dose of the aerosol? It is preferably 10 (^ g-10mg ') in order of 2000. 2000. The total daily dose and fixed dose delivered by capsules and inhalers of inhalers or insufflators, usually aerosol formulations. The aerosol formulation should preferably be arranged as a fixed dose or "one shot" of aerosol containing 20 steps of 2_ called 'preferably about 20 compounds of formula (I). Administration can be for each Once or several times, such as 2, 3, * The compounds (or their salts and solvates) according to the invention and the pharmaceutical formulations can be combined or include-or multiple other therapeutic agents, such as selected from anti-inflammatory agents , Anticholinergic agents (especially% min, _2 or% receptor antagonists), β2 • adrenergic receptor agonists, anti-infective agents (eg, antibiotics, antivirals) 'or antihistamines. Therefore, In a further aspect, the present invention provides a combination 'comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, a solvent = bio: functional street organisms' plus one or more other therapeutically active drugs ^; an anti-inflammatory agent (eg, a corticosteroid or NSAID), antibiliary test agent, β2 · adrenergic receptor agonist, anti-infective agent (example (Eg, antibiotics or antivirals) or antihistamines. A particular combination of the present invention includes a compound of formula ⑴ 101952.doc -20- 200540172, or a physiologically acceptable salt or solvate thereof, plus a steroid, β2-adrenal Receptor agonists, anticholinergic agents, and / or ρOE · 4 inhibitors. Preferred combinations are those that include one or two other therapeutic agents. (Eg, hydrates) in order to combine the activity of the therapeutic ingredients And / or stability and / or physical characteristics (for example, solubility) are optimized. It is also reported that the therapeutic ingredient may be applied in a light purity form when appropriate. It is clear to those skilled in the art 'as long as appropriate, other Therapeutic ingredients can use the following types of salts (such as' alkali metal salts or ammonium salts or acid addition salts), or prodrugs, or vinegar (❹'low carbon number base based), or a solvent

Thus, the present invention provides in a further aspect a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, plus one or more other therapeutically active agents, such as a β2-adrenergic receptor agonist, Antihistamines, antiallergic drugs, anti-inflammatory agents (including steroids or PDE_4 inhibitors), anticholinergics or anti-infective agents (eg antibiotics, antivirals). Examples of β2-adrenoceptor agonists include salmeter (which may be a racemic mixture or a single mirror image isomer, such as R_ mirror image isomer), salbutamol, aspirin Form (form〇ter〇1), salmefamol (salmefamol), fenotero (ternotea), terbutaline (terbutaline) and its salts, such as stilbene hydroxy naphthoate, sabutan sulfate Either free state test or suction will expand the succinate. Long-acting βπ adrenergic agonists such as Shi Liwen or Biquan may be better. Other long-acting β2_adrenergic receptor agonists are included in W.

02 / 66422Α, WO 02/270490, WO 02/076933, WO 03/024439, WO 03/072539, WO 03/091204, WO 04/016578, WO 101952.doc 200540172 04/022547, WO 04/037807, WO 04 / 037773, WO 04/037768, WO 04/039762, WO 04/039766, WO 01/42193 and WO 03/042160. A special long-acting β2-adrenergic receptor agonist is 3- (4-{[6-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) benzene Group] ethyl} amino) hexyl] oxy} butyl) benzenesulfonamide, 3- (3-{[7-({(2R) -2_hydroxy-2- [4-hydroxy-3- (hydroxymethyl ) Phenyl] ethyl} amino) heptyl] oxy} propyl) benzite flavamine, 4-{(lR) -2-[(6- {2-[(2,6-dichlorobenzyl) ) Oxy] ethoxy} hexyl) amino] -1_hydroxyethyl} -2- (hydroxyfluorenyl) phenol, 4-{(lR) -2-[(6- {4- [3- (Cyclopentylsulfonyl) phenyl] butoxy} hexyl) amino] -1-hydroxyethyl} -2- (hydroxymethyl) phenol, N- [2-hydroxy · 5-[(1ΙΙ) · 1-hydroxy-2-[[2-4-[[(2R) -2-hydroxy-2-phenethyl] amino] phenyl] ethyl] amino] ethyl] phenyl] formamidine , With N-2 {2- [4- (3-phenyl-4-oxophenyl) aminephenyl] ethyl} 2_hydroxy_2_ (8 · hydroxy-2 (17 /)-quinolinone -5-yl) ethylamine. Anti-inflammatory agents that can be incorporated in the combination include corticosteroids, particularly inhaled corticosteroids and their prodrugs with anti-inflammatory activity. Examples of corticosteroids include methyl prednisolone, prednisolone, dexamethasone, fiuticasone propionate, 6α, 9α-difluoro-17-17- [(2-furancarbonyl) oxyl ηβ_hydroxy-16α-methyl-3 -oxy-androsta-1,4-diene-17β-thiocarboxylic acid s · fluoromethyl ester, 6α, 9α-difluoro Group-11β-hydroxy-16α-methyl-3-oxy-17α-propionyloxy-androst-14-diene-Ι7β-thiocarboxylic acid sense (2-oxy-tetrahydro-furan_38_ Group) 101952.doc -22- 200540172 ester, 6cx, 9a-difluoro 11-11-hydroxy-16α-methyl-l7α- (1-fluorenylcyclopropenyl) oxy-3-oxy-androst- 1,4-diene-7β-thiocarboxylic acid ^ fluoromethyl, 6a, 9cx-difluoro-11-11-hydroxy-16α-methyl-3-oxy-17α- (2,2,3,3_ Tetramethylcyclopropanecarbonyl) oxy] -androst-1,4-diene-ΐ7β-carboxylic acid cyanocyanate, beclomethasone ester (such as 17-propionate or 17,21 · Dipropionate), budesonide, flunisoiide, mometasone ester (such as its fllroate), acetone cortisol triamcinolone acetonide), rofleponide, ciclesonide, (16α, 17-[[(Λ) -cyclohexylsulfenylidene] bis (oxy)]-11 β, 2 1- Dimensyl-pregnant-1,4-bis (3,20-dione), butixocort propionate, rpr-106541 and ST-126. Preferred corticosteroids include fluticasone propionate, 6α, 9α-difluoro-11β-hydroxy · 16α-fluorenyl-17α-[(4-methyl-1,3-thiazole-5-carbonyl) oxy ] -3-oxy-androst-1,4-diene-17β-thiocarbofluoromethyl ester and 6α, 9α-difluoro-17α-[(2-furancarbonyl) oxy] -ΐΐβ- Hydroxy-16α-methyl-3-oxy-androst-1,4-diene] 7β-thiocarboxylic acid cardiofluoromethyl ester, more preferably 6α, 9α-difluoro-17-17-[(2 -Chrysanyl) oxy] -fluorene β-mercapto-16 α-methyl-3 -oxy-androst-1,4-diene-17β-thiocarboxylic acid perfluoromethyl ester. Non-steroidal compounds that may have glucocorticoid activity include those covered by the following patent applications: WO 03/082827, WO 01/10143,

WO 98/54159, WO 04/005229, WO 04/009016, WO 04/009017, WO 04/018429, WO 03/104195, WO 03/082787, WO 03/082280, WO 03/059899, WO 03/101932, WO 02/02565, WO 01/16128, WO 101952.doc -23- 200540172 00/66590, WO 03/086294, WO 04/026248, WO 03/06165 1, WO 03/08277. Anti-inflammatory agents include non-steroidal anti-inflammatory drugs (NSAID'S). NSAIDs that may be used in combination include sodium cromoglycate, nedocromil sodium, and phosphodiesterase (PDE) inhibitors (such as theophylline, PDE4 inhibitors, or mixed PDE3 / PDE4 inhibitors) , Leukotriene antagonists, leukotriene synthesis inhibitors (eg montelukast), iNOS inhibitors, trypsin and elastase inhibitors, β-2 integrin antagonists and adenosine receptor agonists or antagonist Agents (for example, adenosine 2a agonists), cytokine antagonists (for example, chemokine antagonists such as CCR3 antagonists) or cytokinin synthesis inhibitors or 5-lipoxygenase inhibitors. iNOS (including nitric oxide synthase inhibitors) is preferably for oral administration. Other iNOS inhibitors include those disclosed in WO 93/13055, WO 98/30537, WO 02/50021, WO 95/34534 and WO 99/62875. Suitable CCR3 inhibitors include those disclosed in WO 02/26722. Possible phosphodiesterase 4 (PDE 4) inhibitors in the combination include any compounds known to inhibit PDE4 enzymes or found to be PDE4 inhibitors, and are only PDE4 inhibitors, not other members of the PDE family. Compounds such as PDE3 and PDE5 and PDE4. The compounds include 膺 4 ^ 4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohex-1-carboxylic acid, 2-carbonylmethoxy-4-cyano-4- ( 3-Cyclopropylmethoxy-4-difluorofluorenyloxyphenyl) cyclohexyl-buconone and 4- [4-cyano-4- (3-cyclopropylmethoxy-4-difluorofluorenyloxybenzene) Group) cyclohex-1-ol]. Another compound of interest is Cantonyl-4-cyano 101952.doc -24- 200540172 4--4- (3- (cyclopentyloxy) -4-methoxyphenyl] cyclohexane-i-carboxylic acid ( Also known as cilomilast) and its salts, esters, prodrugs or physical forms, which are disclosed in U.S. Patent No. 5,552,438, published on September 3, 1996; this patent is listed alongside its disclosed compounds This article is for reference.

Other PDE4 inhibitors include AWD-12-281 (Hofgen, N, etc., 15th EFMC Int Symp Med Chem (Sept 6-10, Edinburgh) 1998, Abst P. 98; CAS reference number 247584020-9) from Elbion, 9 -Benzyl adenosine derivative named NCS-613 (INSERM), D-441 from Chiroscience and Schering-Plough 8, benzodiazepine PDE4 inhibitor named Cl-1018 (PD-168787) produced by Pfizer Agent, benzodioxolane derivatives disclosed by Kywa Hakko in WO 99/16766, K-34 from Kyowa Hakko, V-11294A from Napp (Landells, LJ, etc.Eur Resp J [Annu Cong Eur Resp Soc (Sept 19-23, Geneva) 1998] 1998, 12 (Suppl · 28): Abst P23 93), roflumilast (CAS reference number 162401-32-3), and those obtained from Byk-Gulden Pthalazinone (WO 99/47505, whose disclosure is hereby incorporated by reference), and Arofylline in the development of Almirall-Prodesfarma, VM554 / UM565 or T-440 (Tanabe Seiyaku) from Vernalis Fuji, K. et al. J Pharmacol Exp Ther, 1998, 284 (1): 162) and T2585. Further compounds are disclosed in published international patent applications WO 04/024728 (Glaxo Group Ltd), PCT / EP 2003/014867 (Glaxo Group Ltd) and PCT / EP 2004/005494 (Glaxo Group Ltd). Compounds that act as antagonists at the muscarinic receptors, especially 101952.doc -25- 200540172

In particular, those antagonists of the Mi or M3 receptors, double antagonists of the MJM3 or M2 / M3 receptors, or Mi / MVM; ubiquitin-antagonists of the receptors. Examples of compounds administered by inhalation include ipratropium (for example, bromide, CAS 22254-24-6, trade name Atrovent), oxitropium (for example, bromide, CAS 30286-75- 0) and tiotropium (for example, desert, CAS 1363 1 0-93-5, trade name Spiriva). Also of interest are revatropate (for example, hydrobromide, CAS 262586_79-8) and LAS-34273 disclosed in WO 01/04118. Exemplary compounds for oral administration include pirenzepine (e.g., CAS 28797-61-7), darifenacin (e.g., CAS 133099-04-4 or hydrobromide under the tradename Enablex) (CAS 133099-07-7), oxybutynin (for example, CAS 5633-20-5, trade name Ditropan), terodiline (for example, CAS 15793_40-5), Tolterodine (for example, CAS 124937-5 1-5, or the tartrate CAS 124937-52-6 under the trade name Detrol), otilonium (for example, bromide, CAS 26095-59 -0, trade names are Spasmomen), trospium chloride (for example, CAS 10405-02-4), and solifenacin (for example, CAS 242478-37-1 or CAS 242478- 38-2 or succinate with the trade name Vesicare or YM-905). Other anticholinergic agents include compounds of formula (XXI), which are disclosed in U.S. Patent Application 60/487981: 101952.doc -26- 200540172 as γ-Η (XXI), R31 R32 of which 3 are attached to the The preferred direction of the base chain is inward, and ^ 1 and R3 2 are independently selected from the group consisting of straight or branched low carbon number cyanine groups preferably composed of ι 6 anatomic atoms, and Carbon alkyl cycloalkyl, cycloalkyl-alkyl having 6 to 10 carbon atoms, 2-thienyl, 2-bidyl, phenyl, phenyl substituted with alkyl having no more than 4 carbon atoms, and having An alkoxy-substituted phenyl group of not more than 4 carbon atoms, X represents an anion bonded to the positive charge of the N atom. χ_may be, but is not limited to, chloro, bromo, iodo, sulfate, benzenesulfonate, and tosylate including, for example: (3-inward) -3- (2,2-di-2-thiophenevinyl Difluorenyl-8 · nitrobicyclo [3 · 2 · 1] Octane bromide, (3-intro) -3- (2,2-diphenylvinyl) _8,8_dimethyl_8 _Nitrobicyclo [3 · 2 · 1] Xanzao Brookate, (3-Inward) -3 · (2,2-diphenylvinyl) _8,8_Dimethylnitrobicyclo [3 · 2 · 1] octane 4-fluorenylbenzenesulfonate, (3_inward) -8,8 · dimethyl-3- [2-phenyl-2- (2-thienyl) vinyl] -8 -Azabicyclo [3.2.1] octane bromide, and / or (3_inward > 8,8-diamidino-3- [2-phenylpyridinyl) -vinyl] _8_ Cyclo [3 · 2 · 1] octane bromide. Further anticholinergic agents include compounds of formula (χχπ) or (χχπι), as disclosed in 101952.doc -27- (XXIII) 200540172

(XXII) shown in U.S. patent application 60/511009: \ n: 〆 R41 ·

R " where the fluorene atom is an outward position, and R represents an anion bound to the positive charge of the N atom. R1 · Possible but not limited ^ air soil / styrenyl, sulfate, sparganite and toluate,

R and R43 are independently selected from the group consisting of the following fine A and 直 j: straight or branched chain low carbon number alkyl (having preferably Η carbon atoms), cycloalkyl (having 5 to 6 carbons) Atom)% alkyl-alkyl (having 6) carbon atoms, heterocycloalkyl (having 5 to 6 slave atoms) and N * 〇 is a heteroatom, heterocycloalkyl_alkyl (having 6, Carbon atom) and N or O is heteroatom, aryl, optionally substituted aryl, heteroaryl and optionally substituted heteroaryl, R is selected from the group consisting of: alkyl, ⑴re] ) Cycloalkyl, ((^-(: 7) heterophosphino, (Ci_C6) alkyl (Cycycycloalkyl, (Ci_C6) alkyl (CVC7) heterocycloalkyl, aryl, heteroaryl, alkane Aryl_aryl, (CVC6) alkyl-heteroaryl, -〇R45, -CH2〇r45, CH2OH, -CN, -CF3, -CH2〇 (c〇) R46, _c〇2R47, _CH2NH2, -CH2N (R47) S02R45 ^ " S02N (R47) (R48), -CON (R47) (R48) > -CH2N (R48) CO (R46) > -CH2N (R48) S〇2 (R46) >. CH2N (R48) C02 (R45)-CH2N (R48) CONH (R47), R45 is selected from the group consisting of (Ci-C6) alkyl, (Ci-c6) alkyl (c3_ 101952.doc -28 -200540172 heterocycloalkane , (CVC6) alkyl -

Cu) cycloalkyl, (Cl_c6) alkyl (CVC7) aryl, (CVC6) alkyl · heteroaryl, R46 is selected from the group consisting of π alkyl, (C3-C12) cycloalkyl, and heterocyclic M, (c ... alkyl (CVC12) cycloalkyl, (C1-C6) alkyl 3 C7) hetero% alkyl, aryl, heteroaryl, (CVC6) alkyl-aryl, (C1-C6) alkyl -Heteroaryl,

R47 and R48_iL are selected from the group consisting of: H, (c "c6) alkyl, (C3-C12) alkyl, (CVC7) heterocycloalkyl, (C1-C6) alkyl ((VCi2) cycloalkyl (CkC6) alkyl (c3-c7) heterocycloalkyl, (Ci-C6) alkyl · aryl and (Ci-C6) alkyl-heteroaryl, including, for example: (inward) -3- (2 -Methoxy-2,2-di-thiophene-2-yl-ethyl) -8,8-dimethyl-8-nitro [beta] cyclo [3.2.1] octane iodide, 3-(( Inward) -8-methyl_8_aza_bicyclo [3 · 2 · 1] oct-3-yl) -2,2-diphenyl-propionitrile, (inward) -8-methyl- 3_ (2,2,2_triphenyl-ethyl) -8_aza-bicyclo [32J] octane, 3 _ ((inward) -8_methyl-8-aza-bicyclo [ 3.2.1] oct-3-yl) -2,2-diphenyl-propanamide, 3-((inward) -8-methyl-8-aza-bicyclo [3 · 2 · ι] octane -3_yl) -2,2-diphenyl-propionic acid, (inward) -3- (2-cyano-2,2-diphenyl-ethyl) -8,8-dimethyl-8 -Nitrogen-bicyclo [3.2.1] octane iodide, (inward) -3- (2-cyano_2,2_diphenyl_ethyl) _8,8-dimethyl-8_nitrogen _Bicyclo [3 · 2 · 1] octane bromide, 3 _ ((inward L8-fluorenyl · 8-aza-bicyclo [3.2.1] oct-3-yl) -2,2-di Benzene 101952.d oc -29- 200540172 propyl-propan-1-Sf · 'Benzyl-3-((inward) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl)- 2.2- diphenyl-propanamide, (inward) -3- (2-aminomethylamido-2,2-diphenyl-ethyl) -8,8-dimethyl-8-nitro-bicyclo Benzo [3.2.1] octane iodide, 1-benzyl-3- [3-((inward) -8-methyl-8-aza-bicyclo [3 · 2 · 1] oct-3- Yl) -2,2-diphenyl-propyl] -urea '1-ethyl-3- [3-((inward) -8-methyl-8- aza-dioxine [3.2.1] Octyl-3 -yl) · 2.2-diphenyl-propyl] -urea, #-[3-((inward) -8-methyl-8-aza-bicyclo [3.2.1] octyl-3 -Yl) -2,2-diphenyl-propyl] -acetamidamine, #-[3-((inward) -8-methyl-8-aza-bicyclo [3.2.1] octyl- 3-yl) -2,2-diphenyl-propyl] benzamine, 3-((inward) -8-methyl-8-aza-diazapyrene [3.2.1] octam-3- Yl) -2,2-di- ° cephen-2-yl-propionate '(inward) -3- (2-arsenyl-2,2-dithiophen-2-yl-ethyl) -8, 8-dimethyl_8-gas-bicyclo [3.2.1] octane iodide, #-[3-((inward) -8-methyl-8-aza-bicyclo [3 · 2 · 1] oct-3-yl) -2,2-diphenyl-propyl] -benzenesulfonamide, [3-((inward) -8- -8-aza-bicyclo [3.2.1] oct-3-yl) -2,2-diphenyl-propyl] -urea '# · [3-((inward) -8-methyl -8-aza-bicyclo [3 · 2 · 1] oct-3-yl) -2,2-diphenyl-propyl] -pyranesulfonamide, and / or (inward) -3- {2 , 2-diphenyl-3-[(l-phenyl-methylamidino) -amino] -propyl 101952.doc -30- 200540172 8'8-dimethyl_8_aza-bicyclo [ 321] Burnt desert, more preferred compounds that can be used in the present invention include: (inward) -3- (2-methoxy_2,2_di_thiodo-A-ethyl) -8,8- Dimethyazepine-bicyclo [3 · 2 · 1] octane iodide, (inward) -3- (2-cyano-2,2-diphenyl_? | ,. . ,, peptone ethyl) -8,8-dimethyl_8_nitro_bicyclo [3.2.1] octane hindering compounds, and (inward) -3 cyano_2,2 diphenyl · Ethyl) · μ • dimethyl_8_nitrogen_

And [3 · 2 · 1] octane bromide, "(inward) -3- (2-aminomethylamido-2,2_diphenyl_ethyl) · μ_dimethyl_8_nitrogen_ Bicyclo [3 · 2 · 1] octane hindering compounds, (inward) -3- (2-cyano-2,2_diphene_2_yl_ethyl) · μ • dimethyl_8 _Nitrogen_Cyclo [3.2.1] sintered arsenic compound, and / or (inward) -3- {2,2-diphenyl-3-[(1_phenyl · methylamidino > amino) • Propyl 8,8-dimethyl-8-aza-bicyclo [m] octane bromide. Antihistamines (also known as H1-receptor antagonists) include any one or more of the myriad known It is an antagonist that inhibits the H1-receptor and is safe for human use. The first generation of antagonists includes bamboo organisms such as ethanolamine, ethylenediamine and alkylamines, such as diphenylhydramine and pyrilamine. ), Ciemastine, chlorpheniramine. The second-generation antagonists are non-sedative, including loratidine, desioratidine , Terfenadine, asteinizole, acrivastine, azelastine, left Levocetirizine, fexofenadine, cetirizine 101952.doc -31-200540172 and efletirizine. Therefore, the present invention provides a combination in a further aspect, including formula (I) The compound or a pharmaceutically acceptable salt or solvate thereof, plus a pDE4 inhibitor Receptor agonist.

Therefore, the present invention provides a combination of further steps, including a compound of formula E or a salt or solvate that can be added to χ, plus an anticholinergic agent. The combinations mentioned above are now available Use; therefore, the diluent or carrier surface is 0. Therefore, the present invention provides a combination of further steps, including a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, plus an antihistamine. It is convenient to adopt a pharmaceutical formulation type presentation, including the combination defined above, plus a medically accessible pharmaceutical formulation representing a further aspect of the present invention: the two substances may be administered sequentially or simultaneously in separate or combined pharmaceutical formulations. Preferably, the individual ingredients will take the form of human and medicinal formulations, and at the same time, youtiangu "^" wood to take the mouth and the appropriate pharmaceutical agents known. "I understand the compound of formula (I) and its ^ ^, The mixture can be borrowed by the following methods, deduction

It constitutes one aspect of the invention I < overnight. The combinations mentioned above are now available for use; therefore, one or more medicines are acceptable, and it is convenient to take a pharmaceutical composition in the form of a combination including the above-defined combinations, plus a carrier and / or excipient as appropriate The composition represents 101952.doc -32- 200540172 a further aspect of the invention. The individual compounds of such combinations can be taken according to the specifications; sequential or simultaneous administration of 7 or combined pharmaceutical composition types. Intermediate compounds described herein can be used. The compounds of the present invention may have the following advantageous properties: more effective, showing greater selectivity, Sl 丨 from, ^ Γ field j less action, longer action duration, The best route is more peak-capturing and / or bio-available, showing less systemic activity when inhaled, toiletry / blow-up, a, and / or more compatible with similar known compounds. Nature of need. In particular, 'the compounds of the present invention may have a strong effect on A2a receptors, show greater selectivity for A2A receptor subtypes than other adenoid receptor subtypes (especially, receptor subtypes), and can interact with human serum Albumin is highly synonymous (above about 90%, especially above about 95%) and / or may exhibit less significant cardiac effects than currently known compounds. The compounds of the present invention can be tested biologically outside or in vivo according to the following or similar assays / modes. The agonist activity of the compound on the adenoids and ~ receptors. The agonist potency and selectivity of the compounds for human adenosine receptors is the use of transgenically infected Chinese guinea pig ovary (CH0) cells or Determined by yeast cells. (A) CHO cells. Two methods can be used for CHO cells. ⑴ Analysis of sspAp, 101952.doc -33 · 200540172 Cells are also transfected with a circular AMP (cAMP) response unit to promote secretion. Sexual placental alkaline phosphatase (SPAP) gene. Changes in cAMP were determined as changes in the amount of SPAP. (Ii) DiscoveRx analysis, which involved two fragments of β-galactase, enzyme recipient (EA) and enzyme donation (ED) enzyme complementation analysis. After cAMP EA is combined with ED, an active enzyme will be produced, and a luminescent product will be formed after adding the substrate. For both methods, the effect of the test compound is determined by its effect on The amount of basal A2B) may be determined by the effect of forskolin fortification of 08] \ 4? (Eight 1 and eight 3). (B) Yeast cells For yeast analysis, receptor stimulation causes reporter gene , That is, the activation of FUS1-HIS3, causing Production of histidine necessary for cell growth. Yeast cell lines are cultured in a medium lacking histidine, and the addition of test compounds causes histamine production, which in turn stimulates cell growth. This response is caused by exoglucan The enzyme production assay is an enzyme that is structurally secreted by yeast cells. In all in vivo analyses, the activity of the test compound is expressed as a non-selective adenosine receptor agonist, N-ethylpyrimidin. Adenosine ratio (NECA). In these or similar analyses, it has been shown that the formate salt of the compound of formula (I) is highly selective-the selectivity for A2A is 100 times higher than for A !, A2B, and A3. At A2A Efficacy < 0.5 (EMR vs NECA), and is usually < 0.02 (EMR VS NECA). Lilly cold anti-inflammatory agonist activity LPS mode: Prior to exposure to LPS, the test compound is administered to male CD Bai Zi Da 101952 .doc -34- 200540172 rats. The compound (or vehicle) was injected into the trachea through a perforated catheter at a volume of 200 μΐ while the animals were anesthetized with isoflurane. After a 30-minute recovery period, the rats were placed in In the small room and exposed to large Aerobic aerosol derived from Bacillus sp. For 15 minutes. After 4 hours of LPS challenge, rats were killed, lungs were lavaged, and the total number and difference of cells were determined. Decided to produce 50% reduction in neutrophil accumulation (ED50) Dosage of the compound. In this or similar analysis, the formate salt of the compound of formula (1) at a dose of 30 pg / kg or less produced a cumulative decrease in neutrophil greater than 50%. 3) Therapeutic index (TI Cardiovascular model: Male Wistar rats were anesthetized with alfalose / phenobarbital, and the jugular vein, left carotid artery, and trachea were intubated. Connect the arterial catheter to the transducer for continuous measurement of blood pressure and heartbeat. The compound (or vehicle) was administered to the trachea in a volume of 100 μΐ, and the dose of the test compound to increase blood pressure and heartbeat (ED20) by 20% was determined. The Ti of the test compound is calculated as the ratio of ED20 in cardiovascular mode to ED50 in LPS mode. The formate dose of the compound of formula (I) determined in this or a similar mode is about 7 pg / kg. (4) HAS combined with the instrument: The Agilent HP 1100 HPLC instrument was used throughout. / iTLC column: Chromtech Immobilised HSA HPLC column 50x3 mm was purchased from Chromtech (Cheshire, UK). Yinying and Guangdu · Mobile phase A is 50 mM Ph 7.4 ammonium acetate solution, and 101952.doc -35- 200540172 Mobile phase B is 2-propanol (HPLC grade, Runcrn, helmet 1 Ο 1 / y second mobile phase flow rate is Qin in. The column temperature is maintained at a 3Gte gradient and the running time per column is 〇_3 minutes by the linear gradient of ㈣% 2 • propanol. From 3-10 minutes, the mobile phase composition is constant 30% 孓 propanol and 70% 5. Ammonium acetate β φ1 (Μ 〇5 minutes, move; mesh composition: changed to ammonium acetate buffer solution containing only noodles and continued until the end of the run: the same. Each separation is stopped after 15 minutes. Canton ·· By using bipolar array UV absorption Detector, record at 23 ° C and 254 nm at room temperature. Protein # 营 在 之 # 丘: Column performance check and correction is performed before each "slot analysis. Used to calibrate the column The compound is separately dissolved in 50% propyl alcohol and 50% ammonium acetate solution at pH 7.4 to a concentration of 0.5. Binding with its literature% plasma protein, its linear conversion value (logK lit), and typical retention time, its logarithmic value, logK derived from the calibration curve, and binding ❶ /. The data are listed in Table j. Table 1. Compounds Calibration set and its literature and typical color analysis data obtained using HSA columns (literature information is obtained from reference i 6). Compound literature% PPB tR logtR lit logic logK determination% HSA determination warfarin 2 98 4.393 0.64 1.51 1.53 98.1 Nizatidine 35 0.6 -0.22 -0.28 -0.35 31.1 Bromazepam 60 1.299 0.11 0.17 0.38 71.2 Rupingtong 75 1.48 0.17 0.46 0.550 76.8 Can relieve asthma 88 1.826 0.26 0.83 0.70 84 · 2 Pirosika 94,5 2.787 0.45 1.16 1.10 93.6 Nicardipine 95 3.768 0.58 1.20 1.38 97.0 Quitoprofen 98.7 3.916 0.59 1.63 1.42 97.3 Fine wine 99 6.023 0.78 1.69 1.83 99.5 Tokefina 99.8 5.94 0.77 1.92 1.81 99.5 101952.doc -36- 200540172 Literature ° / oPPB (plasma binding) value is converted to a linear free Shaw b-related logK value (logarithm of apparent affinity constant) using the following equation

% PPB

LogK = l〇g [------------------- l · [plasma protein] (101-% PPB) A of the compound of formula (I) analyzed here or similarly The acid salt showed a binding of more than about 90% to Hs A. Different aspects of the invention will now be described with reference to the following examples. These examples are for illustrative purposes only and should not be construed as limiting the scope of the invention. General Experimental Details Unless otherwise stated, all reactions were performed under nitrogen pressure. All temperatures are in Celsius. When the product is purified by column color analysis, "quick stone gum" means the silica gel for color analysis, 0.035-0.070 mm (220-440 mesh) (such as Fiuka Silicone 60), and the column dissolution system is applied by Accelerate at a nitrogen pressure of 10 psi. When using thin layer color separation (TLC), it means a silicone TLC (e.g., typically using 4 x 10 cm silicon on an aluminum foil disk with a fluorescent indicator (254 nm)

Fluka 60778). Biotage said that pre-filled silicone caRTridges with KP-Sil were run on the rapid 12i color analysis module. The solid phase extraction (81 >) column was used with pre-packed caRTridges for parallel purification, usually under vacuum. These are all sold by Varian. SCX caRTHdges are ion exchange SPE columns with benzenesulfonic acid as the stationary phase. These are used to separate. H ^ nmr spectra were recorded using Bruker AV400 400 operating at 400 MHz or Bruker DPX-250 operating at 250 MHz. Unless stated otherwise 101952.doc -37- 200540172, d6-dmso is used as the solvent. Tetramethylsilane is used as the internal standard. The LC / MS system used a liquid chromatography mass spectrometry (LC / MS) system: LC / MS system: LC / MS was performed on a Supelcosil LCABZ + PLUS column (3.3 cm x 4.6 mm ID) with 0.1% HC02H and 0.01 Μ The ammonium acetate solution (solution A) and 0.05% HC02H 5% water in acetonitrile solution (solution B) were used for dissociation, using the following dissolution gradient: 0.0-7 min 0% B, 0.7-4.2 min 100% B, 4.2-5.3 min 100% B, 5.3-5.5 min 0% B, flow rate is 3 mL / min. The mass spectrometer uses electron spray positive and negative modes (ES + ve and ES-ve) to record on a Fisons VG Platform spectrophotometer. Preparative HPLC conditions When the product was purified using preparative HPLC, this was performed on a C-18 reversed-phase column (10 \ 2.1.111 丨. (1.06116 8 丨 8 column, particle size 7 4111) The dissolution first uses an equal gradient of 10% acetonitrile phase, then a gradient of water (containing 0.1% trifluoroacetic acid) in acetonitrile (containing 0.1% trifluoroacetic acid) with a flow rate of 5 mL / min. The gradient starts from 10% acetonitrile and 1% increase per minute. Unless otherwise stated, UV detection at 230 nm is used. Mass-Directed Automated Preparative (MDAP) HPLC Conditions Preparative mass-driven HPLC was performed on the Waters FractionLynx system, including the addition of Waters 600 Bangpu, Yanpuzhipu Putou, Waters 2700 autosampler, Waters 996 bipolar arrangement and Gilson 202 segmented collector at 10 cmx 2.5 4 cm ill ABZ + column, dissolution system uses 0.1% formic acid aqueous solution ( Solvent A) and 0.1% formic acid in acetonitrile solution (solution B), using the following dissolution gradient of 101952.doc -38- 200540172: 0.0-1.0 min 15% B, 1.0 · 10 · 0 min 55% B, 10.0-14.5 min 99% B, 14.5-14.9 min 99% B, 14.9-15.0 min 15% B, flow rate 20 ml / min, and room temperature 200-320 nm debt measurement. The mass spectrometer is recorded in a Micromass ZMD mass spectrometer using the electron spray positive and negative modes of alternating scanning. The software used is Mα / 3.5 and OpenLynx and FractionLynx are selected. The XRPD analysis of some salts is based on Perform the following or similar method: Manufacturer PANalytical-The Netherlands Instrument X 丨 Pert Pro Refractometer Type DY1850 Cathode Tube Cu κ-αΙ Wavelength (Α °) 1.54056 κ-α2 Wavelength (Α °) 1.54439 Quantitative α 1: 2 0.50000 Bifurcated Pore Prog.Div.Slit Accepts Porosity Prog.Rec.Slit Voltage CkV) 40 Current 〇valent A) 45 Detector X'celerator Data Angle Range (° 2Θ) 2.000-40.000 Scanning Type Continuous Scanning Miao Step Spoke 0.0167 Scanning Step Hours (seconds) 31.75 Sample preparation Flush Silicon wafer

XRPD analysis was performed using X’Celerator detector on PANalytical X’Pert Pro X-ray powder refractometer, model XTert Pro PW3040 / 60, serial number DY1 850. The acquisition conditions are: · radiation · Cu K, voltage: 40 kV, current 45 mA: start angle: 2.000. 20, end angle: 40.000 ° 2Θ, step size: 0.0167, time per step: 31.75 seconds. The samples were made using flash silicon wafers. 101952.doc -39- 200540172 [Embodiment] The abbreviations used in the experimental part are as follows: IPA = isopropanol DCM = dichloromethane THF = tetrahydrofuran MeOH = methanol DMF = diamidinofluorene DIPEA = diisopropyl Ethylethylamine EtOAc = ethyl acetate ACN = acetonitrile CHC = cyclohexane DMSO = dimethylsulfone RT = room temperature DMAP = 4-methylaminopyridine HATU = 0- (7-azabenzotriazole-1- Group) -N, N, N ', N'-tetramethylphosphonium hexafluorophosphate NBS = N-bromosuccinimide IMS = industrial methanol-containing alcohol TFA = trifluoroacetic acid

Boc tertiary butoxycarbonyl

Rt = retention time h: hour min: minute

Rapid Silicone means Merck ART No. 9385, Silicone means Merck ART 101952.doc -40- 200540172

No. 7734 Intermediate 1 and cyclohexanediyl bis [imino (2-chloro-9-purine-6,9-diyl and 5i?)-5- (2-ethyl-2 and- Tetrazol-5-yl) tetrahydrofuran-2,3,4-triyl] tetraacetic acid

Let (211,311,411,511) _2_ (2,6-dioxo-911 ^ piperidinyl) -5- (2-ethyl-2h-tetrazol-5-yl) tetrahydrofuran_3,4 _Diyldiacetate (Intermediate 7 of WO 98/2 8319) (2.36 g, 5 mmol), trans-1,4-diaminocyclohexane (630 mg, 5.5 mmol) and DIPEA (0,960 mL) of IPA (30 niL) mixture was heated at 60 C for 19.5 h. After cooling, the solvent was removed in vacuo. The crude reaction mixture was purified in a Flash Silica Isolute cartridge (50 g) and dissolved in a gradient of cyclohexane to cyclohexane / ethyl acetate (1: 3 to 1: 1) to clean acetic acid. The appropriate fractions were combined and the solvent was removed in vacuo to give the title compound (1.46 g) as a white solid. LC / MS Rt 3.58 min m / z 983 [MH] + Intermediate products 2 and 4 ^, #,-bis [2-Chloroto (tetrahydro-2ug-piran-2_yl) _9ug_purine- 6-yl] -1,4-cyclohexanediamine 101952.doc -41-200540172

Let 2,6-dichloro-9- (tetrahydro-2 / f-Lukounan-2-yl) -97 /-σ ticket (intermediate product 1 of WO 03/080613) (17 g, 62.3 mmol A stirred suspension of isopropyl alcohol (500 ml) was treated with -1,4-diaminocyclohexane (3.6 g, 31.5 mmol) and diisopropylethylamine (15 ml) at 75 ° C was heated for 6 hours. Additional sum of formula-1,4-diamino hexane (0.9 g, 7.9 mmol) was added and heated for a further 16 hours. Add another part of sum 1,4-diaminocyclohexane (0.9 g, 7.9 mmol) and continue heating at 85 ° C for 7 hours. Let the suspended φ liquid cool to room temperature and let it stand. The solid was filtered off, washed with isopropanol followed by ethyl bonds, and then blotted dry. The solid (18.5 g) was distinguished between ethyl acetate and saturated sodium bicarbonate solution. The aqueous phase was separated from the solid and extracted with ethyl acetate. Undissolved solids were filtered and distinguished between aerosol and saturated sodium bicarbonate solution. The combined organic extracts were dried over sodium sulfate and the solvent was evaporated. The resulting foam was suspended in ethyl acetate to form a solid. The solvent was evaporated and the residue was triturated with diethyl ether to give a solid, which was filtered off and washed with ethyl acetate and dried to give the title compound (3 g) as a white solid. LC / MS Rt 3.33 min m / z 587, 589 [MH] + 101952.doc -42- 200540172 Intermediate products 3 and 4 -1,4-cyclohexanediylbis [7V2- [2- (l-fluorenyl) _17 ^ imidazole_4yl) ethyl] -9- (tetrazol-2ug-Luwei-2-yl) -9ug-thumb + _2,6-diamine]

A mixture of intermediate product 2 (10 g, 17.0 mmol) and N-methylhistamine (25.4 g, from 100 g of dimethyl toluate, 203 mmol) in anhydrous dimethicone (20 mL) was dried at 115 ° C. Heat for 24 hours. The dark solution was allowed to cool to room temperature and then slowly diluted with water (400 ml) followed by ethyl acetate (75 ml). The mixture was stirred vigorously until the viscous lumps solidified and cracked. The solid was filtered off, washed with water and dried to give the title compound (12.2 g). LC / MS Rt 2.08 min m / z 383 [(M + 2H) / 2] +, 765 [ΜΗ] + Intermediate 4 # 6, iV6_ and 4 · -1,4-cyclohexanediylbis {7V2_ [2- (1-methyl-If imidazole · 4-yl) ethyl] -3ug-purine-2,6-diamine} 101952.doc -43- 200540172

A solution of 7 intermediate product 3 (11.8 g, 15.4 mmol) in methanol (loo ml) was treated with 2M hydrochloric acid (25 ml), and was allowed to incubate at room temperature for 4 hours. The mixture was concentrated to s, methanol was removed, and then diluted with water (50% melamine 1). Saturated sodium bicarbonate solution (70 mi) was added and the mixture was allowed to stir for 17 hours. The solid was filtered off and washed with water and dried. The solid was allowed to stir with water for 15 minutes. The suspension was mixed with aerosol and water. Methanol was added and the mixture was shaken. The mixture was concentrated in vacuo, methanol was added and evaporated. This process was performed three times to provide a solid. This solid was triturated with ethyl acetate, filtered and dried under vacuum to give the title compound (8.2 g;). LC / MS Rt 1.73 min m / z 299 [(M + 2H) / 2] +5 597 [MH] + Intermediate 5 and formula-1,4-cyclohexanediylbis [iminomethyl "and -Imidazole_4_yl) ethyl] amino group 9_purine-6,9-diyl) (2β, 3Λ, 4Ι?, 5Λ) -5_ (2-ethyl-2 / f-tetrazole-5 _Yl) tetrahydrofuran-2,3,4_triyl] tetraacetate 101952.doc -44- 200540172

A suspension of intermediate 4 (5.5 g, 9.22 mmol) in ethyl acetate (50 ml) was passed over rel-acetic acid 4R, 5-diethylfluorenyl-2R- (2-ethyl-2H-tetrazole-5- Group) Tetrahydrofuran-3R-based ester treatment (Intermediate 6 of WO 98/28319) (11.4 g, 33.2 mmol) in ethyl acetate solution (50 ml), and cooled to zero. 〇. DBU (3.54 ml, 23.6 mmol) was added, followed by trimethylsilyl trifluoromethanesulfonate (15 · 4 ml, 92.9 mmol). The reaction was allowed to stir at room temperature for 4.5 hours, and then heated at 50 ° C for 3 hours. Allow the reaction to cool and then let it stand overnight. Water was added followed by a saturated sodium bicarbonate solution. Three phases were obtained after stirring. The aqueous and oil phases were separated and extracted with chloroform (X3). The combined organic extracts (chloroform and ethyl acetate) were dried over sodium sulfate and the solvent was evaporated. The residue was separated into a silica gel column (Merck ART 9385 600 ml), and then dissolved in chloroform (400 ml), followed by a gas-form / methanol / 〇.88 aqueous ammonia solution (95: 5: 04). The appropriate fractions were combined and the solvent was evaporated to give the title compound (9.5 §, approximately 4.2 g of 90% pure product). LC / MS Rt 2.33 min m / z 58 1 [(M + 2H) / 2] + 101952.doc -45- 200540172 Example 1 Formic acid-(2 and, 3 and, 4 & 57 ?, 2, and 3, 7?, 4,5,5,; ^ 2,2,-{and 4, -1,4-cyclohexanediylbis [imino (2-{[2- (1-methyl-If imidazole -4-yl) ethyl] amino group 9 and -purin-6,9_diyl)]} bis [5- (2-ethyl-2ug_tetrazol-5-yl) tetrazine_3, 4-furandiase) (4 ·· 1)

[2- (1-methyl-1 //-imidazol-4-yl) ethyl] amine (763 mg, 6.1 mM) was added to the intermediate product 1 (300 mg, 0.31 mM), and the mixture was stirred under nitrogen at 120 ° C for 21 hours, and then cooled. Water (20 ml) was added and the precipitate was filtered off and allowed to purify by quality-prepared automated HPLC. The appropriate fractions were combined and evaporated to provide the title compound (36 mg) as an off-white solid. MDAP LC / MS Rt 2.39 min m / z 993.7 [MH] + ^ nmr. ^ SO MHz +

Transfer (ppm) Multiple 8.15 s 2H 7.80 s br 2H 7.40 s 2H 6.80 s 2H 6.30 s br 2H 101952.doc -46- 200540172

6.00 d 2H 5.85 s br 2H 5.20 d 2H 4.82 m 4H 4.68 q 4H 4.18 s br 2H —3.60 s 6H 3.52 t br 4H 2.78 t 4H —2.08 d br 4H 1.54 t + m 10H Example 2

(2 and, 3i ?, 45 >, s and, 2'7 ?, 3, and 4,5,5 'and) -2,2,-{and 4,1,4-cyclohexanediylbis丨 Imine (2-{[2- (1_methyl-1ug_imidazol-4-yl) ethyl} amino} -9ug-purine

Amin-6,9-diyl)]} bis [5_ (2 · ethyl_2ug-tetrazol-5-yl) tetrahydro-3,4-furandiol]

A solution of the intermediate product 5 (18.1 g, 15.6 mmol) in yeast (150 ml) was treated with sodium methoxide (1 g, 18.5 mmol). After 30 minutes, Dowex 50 [H +] was added to neutralize the solution, and additional methanol (100 mi) was added. The resin 'was filtered off and the filtrate was evaporated to retain the title compound (13.3 g) as a foam / gum. LC / MS Rt 2.06 min m / z 497 [(M + 2H) / 2] + 101952.doc • 47- 200540172 ^ nmr ^ OOMHz

Transfer (ppm) Multiple integer 8.31 S 2H 7.92 s br 2H ^ 7.47 S 2H 7.08 s br 2H 6.90 s 2H 6.55 s br 2H 5.95 __d 2H 5.70 ~ __br 2H ~ 5.11 ~ d 2H 4.79 TBr 2H 4.66 _q 4H 4.04 ~ s br 2H 3.58 s 6H 3.41 m 4H 2.72 _ t 4H 1.92 ~ s br 4H 1.46 t + m 10H salt Preparation of monomaleic acid hydrate salt at 75 ° C Dissolve free base compound (300 mg ) In ethanol (4.4 ml, 14.7 volumes). Dissolve butenedioic acid (35.9 mg, .05 equivalent) in ethanol (1 ml, 3.3 volumes) at room temperature. The maleic acid solution was inoculated in its entirety into the compound / ethanol solution and heated to 75 t as appropriate :. The resulting suspension was aged at 75 C for 30 minutes, then cooled to room temperature over 2 hours, and then further aged at room temperature for 1 hour. The product was isolated by filtration, washed with ethanol (1 claw), and dried overnight under vacuum at room temperature. The yield was 84.9%. XRpD tracking is shown in Figure 1. The mono-terephthalate salt suspended the compound of free base (30011 ^) and terephthalic acid (49.2111§, 101952.doc, 〇200540172 1.05 equivalents) in ethanol (5.4 ... 18 volumes. Order the suspension The solution was heated at 75 ° C for 30 minutes, then cooled to 40t, and allowed to stand overnight under magnetic stirring at a temperature cycle of 0-40.0. The product was isolated by filtration, washed with ethanol (3 × 2 ml) and Dry overnight under vacuum at 60C. Yield is 717%. XRpD is shown in Figure 2. In an alternative method, terephthalic acid is prepared as follows: The free-state base compound (1 g) is suspended in ethanol (80%) (Bu8〇vol), # and heated at 80 ° C to form a solution. Then terephthalic acid (123 mg, 1.05 equivalents) was added to the solution over the entire 7 hours. Then the magnetic properties were added over two days. The suspension was cooled to room temperature by stirring; then it was allowed to stand at room temperature for three days without magnetic stirring. The product was isolated by filtration, washed with ethanol (3 × 5 ml), and dried overnight under vacuum. The yield was 55%. Monophthalate is a compound of free base (300 mg) and phthalic acid (49.2 mg, 1.05 equivalent ) Suspended in ethanol (5.4 m, 18 vol.). The suspension was heated to 75 ° C for 30 minutes, at which time it substantially formed a solution. The reaction mixture was cooled to 40 ° C and allowed to stand at 0-40 °. The temperature cycle of C was magnetically stirred overnight. The product was isolated by filtration, washed with ethanol (2x2 ml), and dried overnight under vacuum at 60 ° C. The yield was 80.0%. The XRPD tracking is shown in Figure 3. The inoculation can be used in the traditional way The required acids (e.g., maleic acid, hydrogen acid, terephthalic acid, and phthalic acid) are carried out by the methods described herein. The resulting seeds can be used subsequently for the subsequent typically the same Preparation of salt, but it may also be used to prepare different salts to improve the crystallinity of the salt product. 101952.doc -49- 200540172 Example 3 Further preparation by method A (2i ?, 3 and, 4S, 5i ?, 2fi ?, 3, iM, S, 5, i ^ 2 ,: 2 ,. {and 4'-1,4-cyclohexanediyl bis [imino (2 gas [2_ (1-methyl-1 And _imidazole_4 group) ethyl] amino group 9 / Γ_purine-6,9-diyl)]} bis [5_ (2_ethyl_2ug-tetrazol, 5-yl) tetrahydro_ 3,4_aragenol] Phase 1 'Acetic acid, 41 Ethoxy-2i?-(2,6-diazino-purine-9-yl) -51 (2-ethyl-2 / 7-tetrazol-yl) tetrahydro-aranoyl ester (wo. 98/28319 Intermediate 7)

Add trimethylsilyl trifluoromethanesulfonate (200 g, 009 mmol) to a suspension of 2,6-dichloropurine (85.1 g, 450.5 mmol) in acetonitrile (850 ml), and stir for 45 minutes. minute. Then, rel-acetic acid 4R, 5-diethoxyl-2R- (2-ethyl-2H-tetrazol-5-yl) -tetrahydrofuran-3R-yl ester (WO 9 8/283 19 was added over 55 minutes. Of intermediate 6) (123.2 g, 360.4 mmol) in acetonitrile (510 ml). The mixture was allowed to stir at room temperature overnight, and the reaction was quenched with water (200 ml) for 1 minute, then a saturated sodium bicarbonate solution (16 L). The acetonitrile was evaporated, and the resulting aqueous phase was extracted with two-gas-methane (2 x 400 ml). The combined organic extracts were washed with a saturated sodium bicarbonate solution (200 ml), water (200 ml), dried over anhydrous sodium sulfate and evaporated to an oil. The oil was dissolved in 5 (Γ (: IPA (IL)), cooled to about 42 ° C, and inoculated and oscillated by ultrasonic waves. 101952.doc -50- 200540172 Continued cooling to about 28 ° C, and let the The mixture was aged at 38_40 ° C for 30 minutes. The mixture was cooled to about 25 ° C, filtered, washed with ipA (3xi70 ml) and dried to give the title compound (111.5g). Stage 2 ·· and formula 1-4 -Cyclohexyl diyl bis [imino (2-chloro-9 //-thyrin-6,9-diyl (2 and, 37 ?, 4 / ?, 5 / 〇-5- (2- Ethyl-277-tetrazol-5-yl) tetrahydrofuran-2,3,4-triyl] tetraacetate (intermediate product 1)

Let stage l (ll0.33, 234.2 mmol), 1,4- and 4 · -diaminocyclohexane (16.02 g, 140.5 mmol), diisopropylethylamine (122.2 m, 702.6 mmol) and iso A mixture of propanol (550 ml) was heated at 80 ° C for 20 hours. Add additional 1,4- and diaminocyclohexane (0.8 g), diisopropylethylamine (6.1 ml) and continue to heat for an additional 24 hours. The mixture was cooled to 50 ° C, diluted with ethanol (250 ml), and heated at 50 ° C for 1 hour. The slurry was then cooled to room temperature, filtered and washed with ethanol (250 ml). The wet cake was adjusted to a slurry at 78 ° C with ethanol (550 ml) for 1 hour, cooled to room temperature (about 30 ° C), filtered, and washed with ethanol (250 ml). The wet cake was adjusted to a slurry at 78 ° C with ethanol 101952.doc 51 200540172 (550 ml) and water (110 ml) for 1 hour, cooled to room temperature, filtered, and subjected to 5: 1 ethanol / water (240 ml) was washed with ethanol (250 ml) and then dried to give the title compound (77 · 9 g). Stage 3, (37 ?, 4 & 5 and, 3,7 ?, 4,5 \ 5,7 ^ 2,2,-{and cyclohexanediylbis [imino (2 · amino-97 / -Purine-6,9-diyl)]} bis [5- (2-ethyl-2H-tetrazol-5-yl) tetrahydrofuran-3,4-diol]

Rhenium sodium oxide (0.63 g, 11.7 mmol) was added to a methanol (770 ml) slurry of stage 3 (77 g, 78.2 • mmo1) and stirred for 23 hours. The slurry was filtered, washed with methanol (380 ml) and dried to give the title compound (61.4 g). ] H NMR (d6 ^ DMS05 400 MHz) δ 1.45-1.68 (10 H5 m)? 1.83-2 · 07 (4 H, m), 4.03 (1.4 H, br s) *, 4.54-4.59 (2 H , M), 4.63 (0.6 H, br s) *, 4.69-4.82 (6 H, m), 5.22 (2 H, d), 5.86 (4 H, br s), 6.03-6.09 (2 H, m), 8.26_8 · 37 (2 H, m), 8.44 (1 H, s), 8.46 (1 H, S). * indicates that the part is not fully integrated because of the presence of the rotor. Stage 4 ·· Cyclohexanediylbis101952.doc -52- 200540172 [Imine (2-{[2- (l-methyl-li / -imidazol-4-yl) ethyl] aminopurine _ 6,9-monoyl)]] bis [5_ (2_ethyl-2 //-tetrazol-5-yl) tetrahydro_3,4_furandiol] maleic acid hydrate salt

Let a mixture of 1¾ Fung 3 (55 g, 67.4 mmol), ΔΓ-methylhistamine (87 · 4 g, 674 mmol) and anhydrous dimethylamine (138 ml) be heated at 1000 for 16 5 hours. The mixture was allowed to cool to room temperature and then added to water (1.4 L) over 45 minutes. The slurry was allowed to stir for 45 minutes, filtered, washed with water (2 x 700 ml), and dried. The crude product (60 g), maleic acid (7 g) and methanol (3 60 ml) were heated at 65 ° C for 90 minutes, cooled to 30 ° C and seeded, and then cooled to room temperature (20- 25 ° C) and stirred for 90 minutes. The slurry was filtered, washed with methanol (110 ml) and dried to give the title compound (39.2 g). ! H NMR (d4-MeOH, 400 MHz) δ 1.39-1.53 (4 Η5 m) 5 1.6 (6 Η, t), 2.10-2.21 (4 Η, m), 2.92 (4 Η, t) 5 3.64 (4 Η, t), 3.71 (6 Η, s), 4.06 (2 Η, br s), 4.70 (4 Η, q), 4.80 (2 Η, br s), 4.89 (2 Η, br s), 5.30 (2 Η, d), 6.09 (2 Η, d), 6.24 (2 Η, s), 7 · 08 (2 Η, s), 8.06 (2 Η , S), 8.08 (2 Η, s). * The signal is blurred due to HOD 101952.doc -53- 200540172 Example 4 Further preparation by method B (2 | ?, 3 and, 45, 51 ?, 2, and, 3,1,4,5,5, and) -2,2,-{and 4 · -1,4-cyclohexanediylbis [iminomethylimidazolyl) ethyl] amino}- 9ug-purine_6,9-diyl)]} bis [5- (2-ethyl-2ug-tetramethyl-5-yl) tetrahydro_3,4_furandiol] stage 1 · and 4 '_ #, #' · Bis [2-Gas-9- (tetrahydro-277-piperm-2-yl) -9 / · threonine] -1,4-cyclohexanediamine (Intermediate 2)

Let 2,6-monokito (tetrahydroπ-chenan_2_yl) _9 good-σ-porin (intermediate product of 〇03 / 080613) (ι · 14 kg) of n-butanol (17 L) The stirred suspension was treated with 4, -1,4-diaminocyclohexane (239 · 2 g) and diisopropylethylamine (2 5 L) and then at 75 ° C. (: Likou heat for 17 hours. The suspension was cooled to room temperature, filtered, washed with n-butanol (2x2.3 L), and dried under vacuum for 6 generations to produce the title compound (0.9 kg). Stage 2 ·· # 6'6H1,4-Cyclohexanediyl bis {Eyes- [2air methyl] oxazole_4 · yl) ethyl] -3 //-purine-2,6-diamine} (intermediate product 4) 101952.doc -54- 200540172

Let a mixture of stage 1 (59.3 g, 100 mmol), #_ methylhistamine (505 g, 400 mmol), dipotassium hydrogen phosphate (35.1 g, 200 mmol) in ethylene glycol (60 ml) at 120 ° C was heated for 8 days. The mixture was allowed to cool to room temperature, and then a 5M hydrochloric acid solution (245 ml) was added under ice-cooling over 50 minutes. Methanol (296 ml) was added followed by diisopropylethylamine (246 ml) dropwise over 30 minutes and the solution was heated at 60 C for 1 hour. Water (178 ml) was slowly added at 60 ° C over 30 minutes, and then stirred at 25t: overnight. The resulting slurry was heated to 60 ° C and water (160 ml) was added dropwise. The slurry was cooled to room temperature, filtered, washed with water (120 ml), 1: 2 methanol / water (120 ml), methanol (120 ° F), and dried under vacuum at 40 ° C to produce a wet product ( 48.8 g). The wet product (40 · 8 g) was further dried under vacuum at 6 ° C for 2 days to give the title compound (38.9 g). Stage 3. · and formula -M-cyclohexanediylbis [imino (2 _ {[ 2_〇_methyl_ 丨 imidazole_4-yl) ethyl] amino} -9pyrimidine-6,9_diyl) (2λ, 3 / μλ, 5H · 5 (2_ ethyl-2 //-tetramethyl-5-yl) tetrahydrofuran 43, cardiotriyl] tetraacetic acid (intermediate product 5) 101952.doc -55- 200540172

Trimethylsilyl triflate (303 ml, 167 mmol) was added to a suspension of stage 2 (20 g, 33.9 mmol) in acetonitrile (200 ml), and then heated at 50 C for 30 minutes. Then, 4R, 5-diethylfluorenyloxy-2R- (2-ethyl-2H-tetrazol-5-yl) -tetrahydrofuran-3R-yl ester (WO 98/283 19 A solution of intermediate product 6) (28.7 g, 84 mmol) in acetonitrile (200 ml) was stirred for 20 hours. The reaction mixture was allowed to cool to room temperature, and the reaction was quenched with water spring (50 ml) for 35 minutes, and then a 5% hydrochloric acid solution (2 x 50 ml) for 90 minutes. The mixture was distinguished between methane (250 ml) and aqueous sodium bicarbonate solution (700 ml) and the methylene chloride layer was allowed to stand overnight at room temperature. Then, the organic portion was extracted with a 1 M hydrochloric acid solution (2 > < 300 melons). The acid extract was neutralized with saturated sodium bicarbonate solution (750 ml), and then extracted with dichloromethane (2 x 200 ml). The combined dioxane extracts were washed with brine (100 μ), dried over anhydrous magnesium sulfate, and concentrated to give the title compound (28.9 g), which was used without purification. Stage 4 101952.doc -56- 200540172 (2R, 3R ^ 4S 5 /? O, n 'π, 2 and, 3' and, 4 '$, 5,7〇-2,2,-{and 4'- 1,4-cyclohexanediylbis [imino (2_ 丨 "^, methyl_li / _imidazol-4-yl) ethyl] amino} -9-purine-6,9-di Group)] 丨 镳 η /! [5- (2_ethyl_2 // _ tetrazol-5-yl) tetrahydro-3,4-furandiol]

A solution of methanol (515 ml) in stage 3 (28.6 g, presumed to be 24 7 mm 〇1) was treated with sodium methoxide ((M4 g, 8.13 mm 〇1) for 90 minutes, and then further injured Treated with sodium oxide (0.44 g, 8.13 mm). After 30 minutes, Dowex 50 [H +] was added to neutralize the solution. The resin was filtered off and the filtrate was evaporated to leave the title compound (24 g).

Stage 5 Monomaleic acid hydrate salt. A solution of maleic acid (0.25 g, 2.11 mm) in methanol (2 ml) was added to a solution of 65 ° C. Outer 2,2, {and formula ", heart ring hexamethylene diimide bis [imino (2] [2 alkylmethyl_speaking of miso_4_yl) ethyl] amine} _grass_6 , 9, diyl)]} bis [5_ (2_ethyl-Cyclopentyl_5_yl) tetrahydro-3,4-ananediol] (2 g, 2.01 mm〇1) in methanol (8 Call and stir 1 101952.doc -57- 200540172 hours. Allow the mixture to cool to room temperature (inoculated at 40 ° C), then stir overnight, filter, wash with ethanol (2x2 ml), and leave at 55 ° C Dry in vacuum. The solid was further recrystallized (twice) from methanol (2x5 volume) to give maleate (0.6 g). [Simplified Illustration] Figure 1 shows the monocis-butene of the title compound of Example 2. XRPD pattern of diacid hydrate salt.

Figure 2 shows an XRPD pattern of the monoterephthalate salt of the title compound of Example 2. Figure 3 shows the XRPD pattern of the monophthalate salt of the title compound of Example 2. References

Asako H, Wolf, RE, Granger, DN (1993), Gastroenterology 104, pp 3 1-37;

Bedford CD, Howd RA, Dailey OD, Miller A, Nolen HW III, Kenley RA, Kern JR, Winterle JS, (1986), J. Med. Chem. 29, pp 2174-2183;

Burkey TH, Webster, RO, (1993), Biochem. Biophys Acta 1175, pp 312-318;

Castanon MJ, Spevak W? (1994), Biochem. Biophys Res. Commun. 198, pp 626-631;

Cronstein BN, Kramer SB, Weissmann G, Hirschhorn R, (1983), Trans Assoc Am Physicians 96, pp 384-91;

Cronstein BN, Kramer SB, Rosenstein ED, Weissmann G, Hirschhorn R, (1985), Ann N · Υ · Acad. Sci. 451, pp 291-301; 101952.doc -58-200540172

Cronstein BN, Naime D, Ostad E, (1993), J. Clin · Invest · 92, pp 2675-82;

Cronstein BN? Naime D5 Ostad E5 (1994), Adv. Exp. Med. Biol "370, pp 411-6;

Cronstein BN, (1994), J. Appl. Physiol. 76, pp 5-13;

Dianzani C, Brunelleschi S, Viano I, Fantozzi R, (1994), Eur. J. Pharmacol 263, pp 223-226;

Elliot KRF, Leonard EJ, (1989), FEBS Letters 254, pp 94-98;

Flora KP, van5t Riet B5 Wampler GL? (1978), Cancer Research, 38, pp 1291-1295;

Green PG, Basbaum AI, Helms C, Levine JD, (1991), Proc. Natl. Acad Sci. 88, pp 4162-4165;

Hirschorn R, (1993), Pediatr. Res 33, pp S35-41;

Kohno Y; Xiao-duo J; Mawhorter SD; Koshiba M; Jacobson KA. (1996). Blood 88 p3569-3574.

Peachell PT5 Lichtenstein LM, Schleimer RP, (1989), Biochem Pharmacol 38, pp 1717-1725;

Richter J, (1992), J. Leukocyte Biol. 51, pp 270-275;

Rosengren S, Bong GW, Firestein GS, (1995), J. Immunol. 154? Pp 5444-5451;

Sanjar S, McCabe PJ, Fattta D, Humbles AA, Pole SM, (1992), Am · Re · Respir · Dis · 145, A40;

Skubitz KM, Wickman NW, Hammerschmidt DE, (1988), Blood 72, pp 29-33

Valko K5 Nunhuck S? Bevan C5 Abraham MC5 Reynolds DP. (2003) J Pharm Sci 92 p2236-2248. 101952.doc • 59- 200540172

Van Schaick EA; Jacobson KA; Kim HO; Ijzerman AP; Danhof M. (1996) Eur J Pharmacol 3 08 p3 11-3 14.

Wood KV. (1995) Curr Opinion Biotechnology 6 p50-58. All publications cited in this patent application, including but not limited to patents and patent applications, are incorporated herein by reference 101952.doc 60-

Claims (1)

200540172 10. Scope of patent application: 1. A compound, (2 and, 3 and, 45,5 and, 2,7 ?, 3,7 ?, 4,6 \ 5,7〇-2,2, _ {and Formula-1,4-cyclohexanediylbis [imino (2-{[2- (1-methyl-iT / -imidazole_4-yl) ethyl] amino-97 / -purine-6 , 9-diyl)]] bis [5-Gas 2-ethyl ^ tetrazol_5-yl) tetrahydro-3,4-furandiol], HX CHU and its salts and solvates 2. 3.: Compounds (2 feet 3 cuts, 5 meaning 5, outer 2,2, _ {and m cyclohexyl diyl bis [imine (2 _ {[2 ( Bu m㈣_4 group) ethyl] & group} 9 " -vyin-6,9-diyl)]) bis [5_ (2_ethyl_2good_tetra. Sitting · 5_yl) tetrazine · 3 , 4_ ° Furandiol] is a pharmaceutically acceptable salt type. : A pharmaceutical composition, including the compound of claim 1 or 2, or a salt or solvate of which a drug can be added, optionally with one or more medically acceptable diluents or carriers. 101952.doc 200540172 4-The compound of claim 1 or 2, or a medically acceptable substance thereof, which is used for treatment. ... accepted salts or solvates 5. The compound of claim 1 or 2 or its medicinal acceptable substance, which is used to treat inflammatory diseases. ^ Linglinghe 6. 7. Species of 3 or 1 or 2 compounds' or their pharmaceutically acceptable tinctures for the manufacture of medicines for the treatment or prevention of inflammatory diseases. A method of the compound of the formula (I), including: (1) Let the compound of the formula (11) wherein L represents a leaving group or a protected derivative thereof HN (II) reacting with [2- (1-methylimidazol-4-yl) ethyl] amine, or ordering a compound of formula (V) 101952.doc 200540172 Η With compound of formula (IV) Or a protected derivative thereof; or (C) deprotect a protected derivative of a compound of formula VII. C 101952.doc