HK1047111B - Purine derivatives - Google Patents

Description

Purine derivatives

Technical Field

The present invention relates to purine derivatives. More particularly, the present invention relates to 9- (tetrahydro-2-furanyl) -9H-purine-2-carboxamide derivatives, and to processes for the preparation of, intermediates used in the preparation of, compositions containing and the uses of, such derivatives.

Background

These derivatives are selective, functional agonists of the human adenosine A2a receptor and are useful as anti-inflammatory agents for the treatment of, inter alia, respiratory diseases.

Adenosine is a ubiquitous molecule that plays an important role in the intermediary metabolism of mammals. Adenosine acts independently on a variety of surface receptors to produce a wide variety of responses. The classification of adenosine receptors shows at least four subtypes: a1, A2a, A2b and A3. Stimulation of the human neutrophil surface by adenosine a2 receptors has been reported to potently inhibit a range of neutrophil functions. Activated neutrophils may release reactive oxygen species such as superoxide anion radical (O), among other inflammatory mediators₂ ^-) And particulate products such as Human Neutrophil Elastase (HNE) damage lung tissue. In addition, activated neutrophils undergo de novo synthesis and release of arachidonic acid salt products such as leukotriene B₄(LTB₄)。LTB₄Is a strong chemoattractant that recruits additional neutrophils to the inflammatory foci, releasing O that adversely affects the extracellular matrix of the lung₂ ^-And HNE. Mediate many of these reactions (O)₂ ^-And LTB₄HNE release and cell adhesion) was identified as A2 a. The subtype A2 (A2a or A2b) that mediates other effects has yet to be determined.

Selective agonist activity at the A2a receptor is believed to provide greater therapeutic benefit than the use of non-selective adenosine receptor agonists, since interaction of the A2a receptor with other subtypes has been shown to be associated with deleterious effects in the lung in animal models and human tissue studies. For example, asthmatic, rather than non-asthmatic, bronchoconstriction may occur when stimulated by inhaled adenosine. This response is due, at least in part, to activation of the a1 receptor subtype. Activation of the a1 receptor also promotes neutrophil chemotaxis and adhesion to endothelial cells, thereby promoting lung injury.

In addition, many respiratory disease patients will be co-assigned 32 agonists, and negative interactions between isoproterenol negatively coupled to adenylate cyclase and adenosine receptors have been shown in animal studies.

Degranulation of human mast cells is facilitated by activation of the adenosine A2b receptor, and thus selectivity for the A2b receptor is also beneficial.

Brief description of the invention

We have now surprisingly found that: the purine derivatives of the present invention inhibit neutrophil function and are selective agonists of the adenosine A2a receptor. They may also have antagonistic activity at the adenosine a3 receptor. The compounds of the present invention may be used to treat any disease for which an agonist of the adenosine A2a receptor is indicated. They may be used in the treatment of diseases in which tissue damage is induced by leukocytes (e.g. neutrophils, eosinophils, basophils, lymphocytes, macrophages) is implicated. They are useful as anti-inflammatory agents for the treatment of respiratory diseases such as Adult Respiratory Distress Syndrome (ARDS), bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, asthma, emphysema, bronchiectasis, chronic sinusitis and rhinitis. The compounds of the invention may also be useful in the treatment of septic shock, male erectile dysfunction, hypertension, stroke, epilepsy, cerebral ischemia, peripheral vascular disease, post-ischemic reperfusion injury, diabetes, rheumatoid arthritis, multiple sclerosis, psoriasis, dermatitis, allergic dermatitis, eczema, ulcerative colitis, crohn's disease, inflammatory bowel disease, heliobacter pylori gastritis, non-steroidal anti-inflammatory drug-induced damage to the gastrointestinal tract or psychosis, or for wound healing.

Detailed Description

Accordingly, the present invention provides a compound of formula (I):

or a pharmaceutically acceptable salt or solvate thereof,

wherein R is¹Is hydrogen or C optionally substituted with 1 or 2 substituents each independently selected from phenyl and naphthyl₁-C₆Alkyl, said phenyl and naphthyl optionally substituted by C₁-C₆Alkyl radical, C₁-C₆Alkoxy, halogen or cyano;

R²is H or C₁-C₆An alkyl group;

a is C₁-C₆An alkylene group;

R³is (i) hydrogen, C₁-C₆Alkyl, -COOR⁴、-CN、-CONR⁴R⁴、C₃-C₈Cycloalkyl, phenyl or naphthyl, said C₃-C₈Cycloalkyl, phenyl and naphthyl optionally substituted by C₁-C₆Alkyl, phenyl, C₁-C₆Alkoxy (C)₁-C₆) Alkyl radical, R⁴R⁴N(C₁-C₆) Alkyl, halo (C)₁-C₆) Alkyl, fluoro (C)₁-C₆) Alkoxy radical, C₂-C₅Alkanoyl, halogen, -OR⁴Cyano, -COOR⁴、C₃-C₈Cycloalkyl, -S (O)_mR⁵、-NR⁴R⁴、-SO₂NR⁴R⁴、-CONR⁴R⁴、-NR⁴COR⁵or-NR⁴SO₂R⁵The substitution is carried out on the raw materials,

or (ii) when A is C₂-C₆When alkylene is-NR⁴R⁴、-OR⁴、-OCOR⁵、-SO₂R⁵、-SO₂NR⁴R⁴or-NR⁴COR⁵，

Or is(iii) C-linked, 4-to 11-membered, mono-or bicyclic, heterocyclic ring having 1 to 4 ring nitrogen atoms, or having 1 or 2 nitrogen and 1 oxygen or 1 sulphur ring atom, optionally oxygen, C₁-C₆Alkoxy (C)₁-C₆) Alkyl radical, R⁶R⁶N(C₁-C₆) Alkyl, halo (C)₁-C₆) Alkyl, fluoro (C)₁-C₆) Alkoxy, fluoro (C)₂-C₅) Alkanoyl, halogen, cyano, -OR⁶、R⁷、-COR⁶、-NR⁶R⁶、-COOR⁶、-S(O)_mR⁷、-SO₂NR⁶R⁶、-CONR⁶R⁶、-NR⁶SO₂R⁷or-NR⁶COR⁷Is substituted, and N is optionally substituted with C₁-C₆Alkoxy (C)₁-C₆) Alkyl radical, R⁶R⁶N(C₁-C₆) Alkyl, halo (C)₁-C₆) Alkyl, fluoro (C)₂-C₅) Alkanoyl radical, R⁷、-COR⁶、-COOR⁷、-SO₂R⁷、-SO₂NR⁶R⁶or-CONR⁶R⁶The substitution is carried out on the raw materials,

or (iv) when A is C₂-C₆Alkylene, when it is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl or morpholinyl, each optionally substituted at C by C₁-C₆Alkyl, phenyl, C₁-C₆Alkoxy (C)₁-C₆) Alkyl radical, R⁴R⁴N(C₁-C₆) Alkyl, halo (C)₁-C₆) Alkyl, fluoro (C)₁-C₆) Alkoxy radical, C₂-C₅Alkanoyl, halogen, -OR⁴Cyano, -COOR⁴、C₃-C₈Cycloalkyl, -S (O)_mR⁵、-NR⁴R⁴、-SO₂NR⁴R⁴、-CONR⁴R⁴、-NR⁴COR⁵or-NR⁴SO₂R⁵And said piperazinyl and homopiperazinyl groups are optionally substituted with C on the N₁-C₆Alkyl, phenyl, C₁-C₆Alkoxy (C)₂-C₆) Alkyl radical, R⁴R⁴N(C₂-C₆) Alkyl, fluoro (C)₁-C₆) Alkyl radical, C₂-C₅Alkanoyl, -COOR⁵、C₃-C₈Cycloalkyl, -SO₂R⁵、-SO₂NR⁴R⁴or-CONR⁴R⁴Substituted;

R⁴is H, C₁-C₆Alkyl radical, C₃-C₈Cycloalkyl or phenyl;

R⁵is C₁-C₆Alkyl radical, C₃-C₈Cycloalkyl or phenyl;

R⁶is H, C₁-C₆Alkyl radical, C₃-C₈Cycloalkyl, phenyl, naphthyl, or het;

R⁷is C₁-C₆Alkyl radical, C₃-C₈Cycloalkyl, phenyl, naphthyl, or het;

m is 0, 1 or 2; and

at R⁶And R⁷"het" as used in the definition of (a) means pyrrolyl, imidazolyl, triazolyl, thienyl, furyl, thiazolyl, oxazolyl, thiadiazolyl, oxadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, indolyl, isoindolyl, quinolinyl, isoquinolinyl, benzimidazolyl, quinazolinyl, 2, 3-naphthyridinyl, benzoxazolyl or quinoxalinyl, each optionally substituted with C₁-C₆Alkyl radical, C₁-C₆Alkoxy, cyano or halogen.

In the above definitions, halogen means fluorine, chlorine, bromine or iodine, and alkyl, alkylene, alkanoyl and alkoxy groups containing the necessary number of carbon atoms may be straight-chain or branched. As described aboveR³The heterocyclic ring defined in part (iii) of (iv) may be aromatic or fully or partially saturated. At R³And het, the phrase "attached to C" as used in the definition of het means that the group is attached to the adjacent atom via a ring carbon atom. At R³The phrase "attached to N" as used in the definition of (a) means that the group is attached to the adjacent atom through a ring nitrogen atom. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy. Examples of alkanoyl groups include acetyl and propionyl. Examples of the alkylene group include methylene, 1-ethylene, 1, 2-ethylene, 1, 3-propylene and 1, 2-propylene. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

In relation to R³(iii) Preferred heterocycles included in the definition of "heterocycle" of (a) are pyrrolyl, imidazolyl, triazolyl, thienyl, furyl, thiazolyl, oxazolyl, thiadiazolyl, oxadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, indolyl, isoindolyl, quinolinyl, isoquinolinyl, benzimidazolyl, quinazolinyl, 2, 3-naphthyridinyl, benzoxazolyl and quinoxalinyl, plus partially or fully saturated versions thereof such as azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl and morpholinyl.

In a second aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R¹Is hydrogen or C substituted by 1 or 2 substituents each independently selected from phenyl and naphthyl₁-C₆An alkyl group;

R²is hydrogen or C₁-C₆An alkyl group;

a is C₁-C₆An alkylene group; and

R³is phenyl, naphthyl, C₃-C₈Cycloalkyl, azetidinyl, pyridinePyrrolidinyl, piperidinyl, amino, -NH (C)₁-C₆Alkyl) or-N (C)₁-C₆Alkyl radical)₂Said phenyl, naphthyl, C₃-C₈Cycloalkyl, azetidinyl, pyrrolidinyl and piperidinyl groups optionally substituted with 1 or more substituents each independently selected from C₁-C₆Alkyl radical, C₁-C₆Alkoxy, halo (C)₁-C₆) Alkyl, halogen and cyano;

with the proviso that when R³Is N-linked, optionally substituted azetidinyl, pyrrolidinyl or piperidinyl, or is amino, -NH (C)₁-C₆Alkyl) or-N (C)₁-C₆Alkyl radical)₂When A is C₂-C₆An alkylene group.

Pharmaceutically acceptable salts of the compounds of formula (I) include the acid addition and base salts thereof.

Suitable acid addition salts are formed with acids which form non-toxic salts, examples being hydrochloride, hydrobromide, hydroiodide, sulphate, bisulphate, nitrate, phosphate, hydrogenphosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, succinate, saccharate, benzoate, methanesulphonate, ethanesulphonate, benzenesulphonate, p-toluenesulphonate and pamoate salts.

Suitable base salts are formed with bases which form non-toxic salts, examples being the sodium, potassium, aluminium, calcium, magnesium, zinc and diethanolamine salts.

See Berge et al, J.Med.Sci.66, 1-19, 1977 for a general summary of suitable salts.

Pharmaceutically acceptable solvates of the compounds of formula (I) include hydrates thereof.

Also included within the present scope are polymorphs thereof of the compounds of formula (I).

The compounds of formula (I) may contain one or more additional asymmetric carbon atoms and thus exist in two or more stereoisomeric forms. The present invention includes individual stereoisomers of the compounds of formula (I) and mixtures thereof.

Separation of the diastereomers may be carried out using conventional techniques, for example by subjecting a stereoisomeric mixture of the compound of formula (I) or a suitable salt or derivative thereof to fractional crystallization, chromatography or h.p.l.c.. The individual enantiomers of the compounds of formula (I) can also be prepared from the corresponding optically pure intermediates, or by resolution, for example by h.p.l.c. of the corresponding racemates with suitable chiral carriers, or by fractional crystallisation of diastereomeric salts, where appropriate, formed by reaction of the corresponding racemates with a suitable optically active acid or base.

Preferably, R¹Is C optionally substituted by 1 or 2 phenyl substituents₁-C₆An alkyl group.

Preferably, R¹Is C substituted by 1 or 2 phenyl substituents₁-C₆An alkyl group.

Preferably, R¹Is C substituted by 1 or 2 phenyl substituents₁-C₄An alkyl group.

Preferably, R¹Is C substituted by 1 or 2 phenyl substituents₁-C₂An alkyl group.

Preferably, R¹Is phenethyl or diphenylethyl.

Preferably, R¹Is 2, 2-diphenylethyl.

Preferably, R²Is H.

Preferably, A is C₁-C₄An alkylene group.

Preferably, A is a linear chain C₁-C₄An alkylene group.

Preferably, a is methylene, ethylene or propylene.

Preferably, A is methylene, 1, 2-ethylene or 1, 3-propylene.

Preferably, A is 1, 2-ethylene.

Preferably, R³Is optionally substituted phenyl as hereinbefore defined in the relevant definitions for compounds of formula (I).

Preferably, R³Is phenyl.

Preferably, when A is C₂-C₆When it is alkylene, R³is-NR⁴R⁴。

Preferably, when A is C₂-C₆When it is alkylene, R³is-NR⁴R⁴Wherein R is⁴Is C₁-C₆An alkyl group.

Preferably, when A is C₂-C₆When it is alkylene, R³is-N (CH)₃)₂。

Preferably, R³Is a C-linked, 5-to 7-membered monocyclic heterocycle which contains 1 to 4 ring nitrogen atoms or 1 or 2 nitrogen and 1 oxygen or 1 sulphur ring atom, optionally substituted as hereinbefore defined for the compounds of formula (I).

Preferably, R³Is a C-linked, 5-or 6-membered monocyclic aromatic heterocycle which contains 1 to 4 ring nitrogen atoms or 1 or 2 nitrogen and 1 oxygen or 1 sulphur ring atom, optionally substituted as hereinbefore defined for the compounds of formula (I).

Preferably, R³Is a C-linked, 5-or 6-membered monocyclic aromatic heterocycle which contains 1 to 4 ring nitrogen atoms and is optionally substituted as defined hereinbefore in relation to the definition of the compound of formula (I).

Preferably, R³Is optionally-OR⁶、R⁷、C₁-C₆Alkoxy (C)₁-C₆) Alkyl radical, R⁶R⁶N(C₁-C₆) Alkyl or-NR⁶R⁶Substituted pyridyl attached to C.

Preferably, R³Is a 2-pyridyl group.

Preferably, when A is C₂-C₆When it is alkylene, R³Is N-linked pyrrolidinyl, piperidinyl or morpholinyl, each optionally substituted on C as defined hereinbefore in relation to the definition of the compound of formula (I).

Preferably, when A is C₂-C₆When it is alkylene, R³Is N-linked pyrrolidinyl, piperidinyl or morpholinyl, each optionally substituted at C by C₁-C₆Alkyl OR-OR⁴And (4) substituting.

Preferably, when A is C₂-C₆When it is alkylene, R³Is pyrrolidin-1-yl, piperidin-1-yl, 4-isopropylpiperidin-1-yl or morpholin-4-yl.

Preferably, when A is C₂-C₆When it is alkylene, R³Is piperidin-1-yl.

Preferably, -A-R³Is phenethyl, 2- (dimethylamino) ethyl, 2-pyridylmethyl, 2- (2-pyridyl) ethyl, 3- (1-pyrrolidinyl) propyl, 2- (1-piperidyl) ethyl, 2- (4-isopropyl-1-piperidyl) ethyl or 2- (4-morpholinyl) ethyl.

Preferably, -A-R³Is 2- (1-piperidinyl) ethyl.

Examples of particularly preferred compounds of the formula (I) are:

9- [ (2R, 3R, 4S, 5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydro-2-furanyl ] -6- [ (2, 2-diphenylethyl) amino ] -N- [2- (1-piperidinyl) ethyl ] -9H-purine-2-carboxamide;

9- [ (2R, 3R, 4S, 5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydro-2-furanyl ] -6- [ (2, 2-diphenylethyl) amino ] -N-phenethyl-9H-purine-2-carboxamide;

9- [ (2R, 3R, 4S, 5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydro-2-furanyl ] -6- [ (2, 2-diphenylethyl) amino ] -N- [2- (4-isopropyl-1-piperidinyl) ethyl ] -9H-purine-2-carboxamide;

9- [ (2R, 3R, 4S, 5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydro-2-furanyl ] -6- [ (2, 2-diphenylethyl) amino ] -N- [3- (1-pyrrolidinyl) propyl ] -9H-purine-2-carboxamide;

9- [ (2R, 3R, 4S, 5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydro-2-furanyl ] -6- [ (2, 2-diphenylethyl) amino ] -N- [2- (4-morpholinyl) ethyl ] -9H-purine-2-carboxamide;

9- [ (2R, 3R, 4S, 5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydro-2-furanyl ] -6- [ (2, 2-diphenylethyl) amino ] -N- (2-pyridylmethyl) -9H-purine-2-carboxamide;

9- [ (2R, 3R, 4S, 5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydro-2-furanyl ] -6- [ (2, 2-diphenylethyl) amino ] -N- [2- (2-pyridyl) ethyl ] -9H-purine-2-carboxamide; and

9- [ (2R, 3R, 4S, 5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydro-2-furanyl ] -N- [2- (dimethylamino) ethyl ] -6- [ (2, 2-diphenylethyl) amino ] -9H-purine-2-carboxamide;

and pharmaceutically acceptable salts and solvates thereof.

The compounds of formula (I) can be prepared by conventional procedures, such as those set forth below, wherein R is R unless otherwise indicated¹、R²、R³And A is as hereinbefore defined for the compound of formula (I).

1. All compounds of formula (I) can be prepared by reacting a compound of formula (II):

wherein X is a suitable leaving group such as bromine, iodine, -Sn (C)₁-C₁₂Alkyl radical)₃Or CF₃SO₂O-, preferably iodine-, is preferably added to the reaction mixture,

by aminocarbonylation with a compound of formula (III) in the presence of carbon monoxide and a suitable coupling catalyst:

R²NH-A-R³ (III)

preferably, the catalyst is a palladium (II) catalyst, more preferably 1, 1' -bis (diphenylphosphino) ferrocene dichloropalladium (II) (optionally a 1: 1 complex with dichloromethane). Alternatively, palladium (II) acetate may be used in the presence of a suitable ligand such as 1, 1 ' -bis (diphenylphosphino) ferrocene, triphenylphosphine, tri (o-tolyl) phosphine or (R) -, (S) -or racemic 2, 2 ' -bis (diphenylphosphino) -1, 1 ' -binaphthyl.

In a typical operation, the reaction is carried out in a sealed vessel in the presence of carbon monoxide at elevated pressure such as about 345kPa (50psi), at elevated temperature such as about 60 ℃, in a suitable solvent such as tetrahydrofuran, methanol or ethanol. Alternatively, a suitable organic base such as a tertiary amine, e.g. triethylamine, N-ethyldiisopropylamine or 4-methylmorpholine, may be present.

Intermediates of formula (II) can be prepared as shown in scheme 1.

Scheme 1

Wherein X is as defined hereinbefore for the compound of formula (II) and "Ac" is acetyl.

In a typical procedure, a compound of formula (IV) is reacted with a compound of formula R in the presence of a suitable acid acceptor such as triethylamine, in a suitable solvent such as acetonitrile, and if desired at elevated temperature¹NH₂The amine of (2) is reacted. The resulting product of formula (V) may be deprotected by hydrolysis to give a compound of formula (II), which may be carried out by conventional procedures, such as by using a suitable inorganic base, e.g. sodium carbonate, sodium hydroxide,potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate or cesium carbonate in a suitable solvent such as methanol, ethanol, isopropanol, 1, 2-dimethoxyethane, tetrahydrofuran, dimethylformamide, acetone, 2-butanone or 4-methyl-2-pentanone, optionally under aqueous conditions, at from 0 ℃ to the reflux temperature of the solvent, e.g. at room temperature. On the other hand, the deprotection can be carried out using a suitable amine base such as triethylamine, diisopropylethylamine, 4-methylmorpholine, ammonia, methylamine, ethylamine or dimethylamine in a suitable solvent such as methanol, ethanol, n-propanol, isopropanol, tetrahydrofuran or dichloromethane at a temperature from 0 ℃ to the reflux temperature of the solvent.

The intermediates of formula (III) and formula (IV) are either known compounds or can be prepared by conventional procedures.

2. All compounds of formula (I) can be prepared by deprotection of a compound of formula (VI):

wherein when R is⁸And R⁹When taken separately, are suitable protecting groups such as acetyl or benzoyl, or when taken together, are suitable protecting groups such as C₁-C₆Alkylene groups such as 1, 1-dimethylmethylene.

In typical operation, when R⁸And R⁹When taken together as 1, 1-dimethylmethylene, the compounds of formula (VI) are treated with a suitable acid, such as hydrochloric acid, trifluoroacetic acid, sulfuric acid, p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, acetic acid or formic acid, or mixtures thereof, optionally in the presence of a suitable solvent such as ethanol and optionally under aqueous conditions. The reaction may be carried out at an elevated temperature, such as at the reflux temperature of the solvent.

Intermediates of formula (VI) can be prepared as shown in scheme 2.

Scheme 2

Wherein R is⁸And R⁹As hereinbefore defined for compounds of formula (VI), and R¹⁰Suitable protecting groups are, for example, trialkylsilyl groups, such as tert-butyldimethylsilyl, or tert-butyldiphenylsilyl.

In a typical procedure, a compound of formula (VII) (which may be prepared by conventional procedures, for example, wherein R⁸And R⁹Taken together are 1, 1-dimethylmethylene and R¹⁰Is tert-butyldimethylsilyl) is treated with a compound of formula (XI) in the presence of a suitable solvent such as methanol, ethanol, acetonitrile or isopropanol, optionally in the presence of an additional acid acceptor such as a tertiary amine like triethylamine, N-ethyldiisopropylamine or 4-methylmorpholine:

R¹NH₂ (XI)

the reaction is preferably carried out at an elevated temperature, such as at the reflux temperature of the solvent.

The compound of formula (VIII) produced may be treated with iodine in a suitable solvent such as tetrahydrofuran or dichloromethane at elevated temperature such as about 50 c to provide the iodinated compound of formula (IX).

The compound of formula (IX) may be converted to the amide of formula (X) by aminocarbonylation in the presence of an amine of formula (III) and carbon monoxide under conditions analogous to those described in method 1 for preparing the compound of formula (I) from the compound of formula (II).

R¹⁰The group is selectively removed under suitable deprotection conditions to give the compound of formula (VI). When R is¹⁰When it is tert-butyldimethylsilyl, the reaction may be carried out using a suitable fluorine source such as tetra-n-butylammonium fluoride or hydrogen fluoride/pyridine in a suitable solvent such as acetonitrileOr in tetrahydrofuran at room temperature.

3. All compounds of formula (I) can be prepared by deprotection of a compound of formula (XII):

wherein R is¹¹、R¹²And R¹³Are suitable protecting groups. When R is¹¹、R¹²And R¹³When values are taken separately, examples include acetyl or benzoyl. In another aspect, R¹²And R¹³Values may be taken together and examples include 1, 1-dimethylmethylene.

Conventional deprotection conditions may be used and will depend on the nature of the protecting group to be removed. In a typical operation, when R¹¹、R¹²And R¹³Where each is acetyl, deprotection may be achieved using conditions analogous to those described for the conversion of a compound of formula (V) to a compound of formula (II).

Deprotection of a compound of formula (XII) to give a compound of formula (I) may also be accomplished in situ after conversion of a compound of formula (XIII) to a compound of formula (XII) as described below. At this time, when R is¹¹、R¹²And R¹³When each is acetyl, deprotection using an inorganic base is preferred, for example the reaction mixture containing the compound of formula (XII) is treated with aqueous sodium hydroxide in 1, 2-dimethoxyethane at 5-20 ℃.

The compounds of formula (XII) can be prepared as shown in scheme 3.

Scheme 3

Scheme 3 (continue)

Wherein R is¹⁴Are suitable protecting groups, e.g. tetrahydro-2H-pyran-2-yl, while R¹⁵And R¹⁶Each is C₁-C₄Alkyl groups, such as methyl or ethyl.

The compounds of the formula (XIV) can be prepared under conventional conditions using suitable protecting groups R¹⁴And (5) protecting. For example, if R¹⁴Is tetrahydro-2H-pyran-2-yl, which is obtainable by reacting a compound of formula (XIV) with 2, 3-dihydropyran in a suitable solvent such as ethyl acetate, toluene, dichloromethane, dimethylformamide, tert-butyl methyl ether, diisopropyl ether, tetrahydrofuran or acetonitrile in the presence of a suitable acid catalyst such as p-toluenesulfonic acid, benzenesulfonic acid, camphorsulfonic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid or pyridinium p-toluenesulfonate, at a temperature from 0 ℃ to the reflux temperature of the solvent. Preferably, the reaction is carried out in ethyl acetate using p-toluenesulfonic acid.

Treating a compound of formula (XV) with a compound of formula (XI) in a suitable solvent such as methanol, ethanol or isopropanol and in the presence of a suitable acid acceptor such as a tertiary amine, for example triethylamine, N-ethyldiisopropylamine or 4-methylmorpholine, at a temperature not exceeding the reflux temperature of the solvent:

R¹NH₂ (XI)

to give a compound of formula (XVI).

The compound of formula (XVI) may be prepared by reaction with C in a suitable solvent such as dimethyl sulfoxide, dimethylformamide or N-methylpyrrolidin-2-one, preferably at an elevated temperature, e.g. 100 ℃₁-C₄Sodium or potassium thioalkoxides are converted to thioethers of the formula (XVIII).

The oxidation of the thioether of formula (XVIII) may be accomplished using a suitable oxidizing agent such as Oxone (trade mark) (potassium peroxymonosulfate), dimethyldioxirane, m-chloroperbenzoic acid or peracetic acid, in a suitable solvent such as water, acetone or dichloromethane or mixtures thereof, optionally in the presence of a base such as sodium bicarbonate. The sulfone of formula (XIX) so produced may be treated with a suitable cyanide source such as potassium cyanide, zinc cyanide, sodium cyanide or copper cyanide in a suitable solvent such as dimethyl sulfoxide, dimethylformamide, N-methylpyrrolidin-2-one, tetrahydrofuran or acetonitrile, preferably at elevated temperature, to give a nitrile of formula (XVII).

The direct conversion of a compound of formula (XVI) to a nitrile of formula (XVII) may be carried out by reaction of the nitrile of formula (XVII) in a suitable solvent such as dimethyl sulfoxide, dimethylformamide, N-methylpyrrolidin-2-one, tetrahydrofuran or acetonitrile, in a suitable palladium catalyst such as tetrakis (triphenylphosphine) palladium (O) or palladium (II) acetate together with a suitable ligand such as triphenylphosphine, tri-O-tolylphosphine, 1' -bis (diphenylphosphino) ferrocene or (R) -, in the presence of (S) -or racemic 2, 2 '-bis (diphenylphosphino) -1, 1' -binaphthyl, and in the presence of a suitable base such as a tertiary amine, e.g. triethylamine, N-ethyldiisopropylamine or 4-methylmorpholine, with a suitable cyanide source such as potassium cyanide, zinc cyanide, sodium cyanide or copper cyanide. The reaction may be carried out at a temperature not exceeding the reflux temperature of the solvent and optionally under an inert gas pressure such as argon. The reaction may also be carried out with a suitable cyanide source such as sodium cyanide or potassium cyanide in a suitable solvent such as dimethyl sulfoxide, dimethylformamide or N-methylpyrrolidin-2-one at a temperature of 20-120 ℃.

The compound of formula (XVII) may be deprotected according to the protecting group to be removed using conventional conditions to give a compound of formula (XXIII). When R is¹⁴When tetrahydro-2H-pyran-2-yl, deprotection may be effected under acidic conditions, such as by use of a suitable acid, for example hydrochloric acid, trifluoroacetic acid, sulfuric acid, trichloroacetic acid, phosphoric acid, p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid or camphorsulfonic acid, and preferably in an alcoholic solvent which may optionally contain water, such as ethanol or isopropanol, generally at from room temperature to the reflux temperature of the solvent.

The nitrile of the formula (XXIII) can be hydrolyzed under basic conditionsIs an acid of the formula (XXIV), e.g. by using an inorganic base such as lithium, sodium or potassium hydroxide, C in water₁-C₄Alcohol solvents such as methanol, ethanol, isopropanol or industrial methanol denatured alcohol.

The acid of formula (XXIV) can be converted to the amide of formula (XIII) using conventional peptide coupling conditions, for example by activating the acid with a suitable reagent, optionally in the presence of a catalyst, and then by treating the activated intermediate with an amine of formula (III) in a suitable solvent. Suitable activating agents include N, N' -carbonyldiimidazole, thionyl chloride, oxalyl chloride or phosphorus oxychloride, and suitable solvents include tetrahydrofuran, dimethylformamide, ethyl acetate, acetonitrile, toluene, acetone or dichloromethane. Alternatively, the acid may be activated by treatment with 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride or dicyclohexylcarbodiimide and 1-hydroxy-7-azabenzotriazole or 1-hydroxybenzotriazole hydrate followed by treatment with an amine of formula (III) in the presence of an acid acceptor such as 4-methylmorpholine, triethylamine or N-ethyldiisopropylamine in a solvent such as tetrahydrofuran, dimethylformamide, ethyl acetate, acetonitrile, toluene, acetone or dichloromethane to give an amide of formula (XIII). Alternatively, the acid may be treated with benzotriazol-1-yloxytris (pyrrolidinyl) phosphonium hexafluorophosphate, bromo-trispyrrolidinylphosphonium hexafluorophosphate or 2-chloro-1-methylpyridinium iodide and an amine of formula (III) in the presence of an acid acceptor such as 4-methylmorpholine, triethylamine or N-ethyldiisopropylamine in a solvent such as tetrahydrofuran, dimethylformamide, ethyl acetate or dichloromethane to give an amide of formula (XIII).

A compound of formula (XIII) may be converted to a compound of formula (XII) by reaction with a compound of formula (XXVIII):

wherein Y is a suitable leaving group such as acetoxy, benzoyloxy, methoxy or halogen, e.g. chloro, and R¹¹、R¹²And R¹³Is a suitable protecting group as hereinbefore defined for a compound of formula (XII), the reaction being carried out in the presence of a suitable acid or lewis acid, for example trimethylsilyl trifluoromethanesulfonate. The reaction can be carried out with a compound of formula (XXVIII) in the form of the 2R-or 2S-diastereoisomer, or an epimeric mixture thereof. The reaction is generally carried out in a suitable solvent, for example 1, 2-dimethoxyethane, dichloromethane, acetonitrile, 1, 1, 1-trichloroethane or toluene, or mixtures thereof, preferably before the addition of the compound of formula (XXVIII), the compound of formula (XIII) is previously treated in situ with a suitable silylating agent, for example trimethylsilyl trifluoromethanesulfonate, N, O-bis (trimethylsilyl) acetamide, trimethylsilyl chloride or hexamethyldisilazane. Elevated temperatures may be used in the reaction.

The compound of formula (XXVIII) may be prepared by conventional procedures.

The nitrile of the formula (XVII) may be obtained by reacting the corresponding C₁-C₄In alcoholic solvents such as methanol or ethanol, with catalytic amounts or an excess of the appropriate C₁-C₄Sodium or potassium alkoxides such as sodium or potassium methoxide or ethoxide, followed by treatment with a suitable acid such as aqueous hydrochloric acid, are converted to esters of formula (XX).

The ester of formula (XX) may be converted to the amide of formula (XXI) by treatment with an amine of formula (III), optionally in a suitable solvent such as 1, 2-dimethoxyethane or 2-methoxyethyl ether. The reaction may be carried out at elevated temperature and pressure.

The amides of the formula (XXI) can be converted into compounds of the formula (XIII) under customary deprotection conditions, depending on the protective group to be removed. When R is¹⁴Is tetrahydro-2H-pyran-2-yl, this may be achieved under acidic conditions in a suitable solvent, typically using an acid such as hydrochloric acid, trifluoroacetic acid, sulfuric acid, trichloroacetic acid, phosphoric acid, p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid or camphorsulfonic acid, in an alcoholic solvent which may optionally contain water, such as isopropanol. Elevated temperatures may be used in the reaction.

The compounds of the formula (XVII) can be converted to the acids of the formula (XXII) under basic conditions, for example using inorganic bases such as lithium, sodium or potassium hydroxide, in aqueous C₁-C₄Alcohol solvents such as methanol, ethanol, isopropanol or industrial methanol denatured alcohol. The reaction is preferably carried out at elevated temperature.

The acid of formula (XXII) may be converted to the amide of formula (XXI) under conditions analogous to those used to convert the compound of formula (XXIV) to the compound of formula (XIII).

The ester of formula (XX) can be converted to the acid of formula (XXII) under basic conditions, for example using an inorganic base such as lithium hydroxide, sodium hydroxide or potassium hydroxide, in an aqueous solvent containing ethanol, methanol, isopropanol, butanol, industrial methylated spirits, tetrahydrofuran, dimethylformamide or 1, 2-dimethoxyethane, optionally at elevated temperature.

As the compound of formula (XVI), carbon monoxide and C can be used₁-C₄An alcohol, a suitable palladium catalyst, optionally another suitable solvent, and a suitable base such as a tertiary amine, are converted to the ester of formula (XX) by alkoxycarbonylation. In a typical reaction, a catalytic amount of palladium (II) acetate together with a suitable ligand such as 1, 1 ' -bis (diphenylphosphino) ferrocene, triphenylphosphine, tri-o-tolylphosphine or (R) -, (S) -or racemic 2, 2 ' -bis (diphenylphosphino) -1, 1 ' -binaphthyl, suitably C, is used under carbon monoxide at elevated temperature and pressure₁-C₄Alcohols such as methanol, ethanol, 1-propanol, isopropanol or 1-butanol, and tertiary amine bases such as triethylamine, N-ethyldiisopropylamine or 4-methylmorpholine.

The compound of formula (XVI) can be converted to the acid of formula (XXII) by hydroxycarbonylation using carbon monoxide, a suitable palladium catalyst and a suitable base under aqueous conditions. In a typical procedure, a catalytic amount of palladium (II) acetate together with a suitable ligand such as 1, 1 ' -bis (diphenylphosphino) ferrocene, triphenylphosphine, tri-o-tolylphosphine or (R) -, (S) -or racemic 2, 2 ' -bis (diphenylphosphino) -1, 1 ' -binaphthyl, a base such as an alkali metal hydroxide, e.g. sodium hydroxide or a tertiary amine, and water, optionally together with a suitable water-miscible solvent such as methanol, ethanol, 1-propanol, tetrahydrofuran, 1, 2-dimethoxyethane, dimethylformamide or isopropanol, is used under an atmosphere of carbon monoxide at elevated temperature and pressure.

The compound of formula (XVI) can be converted to the compound of formula (XXI) by aminocarbonylation using carbon monoxide, an amine of formula (III), a suitable palladium catalyst and a suitable solvent, optionally in the presence of a suitable base. In a typical procedure, a catalytic amount of palladium (II) acetate is used in combination with a suitable ligand such as 1, 1 ' -bis (diphenylphosphino) ferrocene, triphenylphosphine, tri-o-tolylphosphine or (R) -, (S) -or racemic 2, 2 ' -bis (diphenylphosphino) -1, 1 ' -binaphthyl, under an atmosphere of carbon monoxide at elevated temperature and pressure, a solvent such as tetrahydrofuran, dimethylformamide, 1, 2-dimethoxyethane, ethyl acetate, N-methyl-2-pyrrolidone, tert-butyl methyl ether or diisopropyl ether, and a tertiary amine base such as triethylamine, N-ethyldiisopropylamine or 4-methylmorpholine.

4. All compounds of formula (I) can be prepared by reacting a compound of formula (XXV):

wherein R is¹⁷Is H or a suitable ester-forming group such as C₁-C₄Alkyl or benzyl, with an amine of the formula (III), and when R is¹⁷When it is H, the reaction is carried out in the presence of a suitable peptide coupling agent under conventional conditions. In a typical procedure, the reagents are heated together, optionally in the presence of a suitable solvent such as 1, 2-dimethoxyethane or 2-methoxyethyl ether, at an elevated temperature, for example 60-120 ℃, and optionally under pressure.

The compounds of formula (XXV) can be prepared as shown in scheme 4.

Scheme 4

Wherein R is¹⁷Are suitable ester-forming groups such as C₁-C₄Alkyl or benzyl, and R¹¹、R¹²And R¹³Are suitable protecting groups as hereinbefore defined for compounds of formula (XXVIII).

In a typical procedure, a nitrile of the formula (XXIII) is converted under basic conditions into an ester of the formula (XXVII), for example using C₁-C₄Sodium or potassium alkoxides such as sodium or potassium methoxide or ethoxide, in the corresponding C₁-C₄In an alkanol such as methanol or ethanol at from room temperature to the reflux temperature of the solvent, followed by treatment with a suitable acid such as aqueous hydrochloric acid.

Esters of formula (XXVII) may be converted to compounds of formula (XXVI) by reaction with compounds of formula (XXVIII) under conditions analogous to those used to convert compounds of formula (XIII) to compounds of formula (XII).

Compounds of formula (XXVI) may be converted to compounds of formula (XXV) under conditions similar to those used to convert compounds of formula (XII) to compounds of formula (I), such as when R is¹¹、R¹²And R¹³Each acetyl group is prepared by using sodium carbonate in methanol. Formula (XXV) (R)¹⁷H) can be prepared from the corresponding ester by conventional procedures.

All the reactions described above and the preparation of the novel starting materials used in the processes described above are conventional and suitable reagents and reaction conditions for their implementation or preparation and procedures for isolating the desired products will be well known to those skilled in the art after reference to the prior art and the examples and preparations hereof. In particular, suitable protection and deprotection methods are well known in the art, for example as described by Greene et al in "protecting groups in organic synthesis", third edition, John Wiley & Sons ltd.

Pharmaceutically acceptable salts of the compounds of formula (I) can be readily prepared by mixing together a solution of the compound of formula (I) as appropriate with the desired acid or base. The salt may be precipitated from the solution and collected by filtration, or may be recovered by evaporation of the solvent.

The anti-inflammatory properties of the compounds of formula (I) are illustrated by their ability to inhibit neutrophil function, which is indicative of A2a receptor agonist activity. This was assessed by determining the profile of the compound in an assay that measures superoxide production by fMLP-activated neutrophils. Neutrophils were isolated from human peripheral blood using dextran sedimentation and then centrifuged through a Ficoll-Hypaque solution. Any contaminating erythrocytes in the granulocytes were removed by lysis with ice-cold distilled water. Superoxide production from neutrophils was induced by fMLP in the presence of a priming concentration of cytochalasin B. Adenosine deaminase was added to the assay to remove any endogenously produced adenosine that might inhibit superoxide production. The effect of compounds on fMLP-induced responses was monitored colorimetrically from the reduction of cytochrome C in assay buffer. Potency utilization of the compounds resulted in 50% Inhibition (IC) compared to control response to fMLP₅₀) Is evaluated.

The compounds of formula (I) may be administered alone but will generally be administered in admixture with suitable pharmaceutical excipients, diluents or carriers selected with regard to the intended route of administration and standard pharmaceutical practice.

For example, the compounds of formula (I) may be administered orally, buccally or sublingually in the form of tablets, capsules, ovules, elixirs, solutions or suspensions and the like, which may contain flavouring or colouring agents, for immediate-, delayed-, sustained-, pulsed-or controlled-release applications.

Such tablets may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate and glycine, disintegrants such as starch (preferably corn, potato or tapioca starch), sodium starch glycolate, croscarmellose sodium and certain complex silicates, and granulation binders such as polyvinylpyrrolidone, Hydroxypropylmethylcellulose (HPMC), Hydroxypropylcellulose (HPC), sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, stearic acid, glyceryl behenate and talc may be included.

Solid compositions of similar form may also be used as fillers in gelatin capsules. Preferred excipients in this regard include lactose, starch, cellulose, lactose or high molecular weight polyethylene glycols. For aqueous suspensions and/or elixirs, the compounds of formula (I) may be combined with various sweetening or flavouring agents, colouring matter or dyes, emulsifying and/or suspending agents and diluents such as water, ethanol, propylene glycol or glycerin, and combinations thereof.

The compounds of formula (I) may also be administered parenterally, for example intravenously, intraarterially, intraperitoneally, intrathecally, intraventricularly, intrasternally, intracranially, intramuscularly or subcutaneously, or they may be administered using infusion techniques. They are best used in the form of sterile aqueous solutions which may contain other substances, for example, enough salts or glucose to render the solution isotonic with blood. The aqueous solution should be suitably buffered (preferably to a pH of 3-9) if desired. Preparation of suitable parenteral formulations under sterile conditions can be readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.

For oral and parenteral administration to a patient, the daily dosage level of the compound of formula (I) will generally be from 0.01 to 100mg/kg, preferably from 0.1 to 100mg/kg (administered as a single dose or as divided doses).

Thus, tablets or capsules of a compound of formula (I) may contain 5-500mg of the active compound for administration in a single tablet (granule) or 2 or more tablets (granules) at a time as appropriate. The physician will decide on the actual dosage in any event, which will be most suitable for any individual patient and will vary with the age, weight and response of the particular patient. The above dosages are exemplary of the general case. Of course, in individual cases, higher or lower dosage ranges may be required and are within the scope of the invention.

The compounds of formula (I) may also be administered intranasally or by inhalation and are conveniently delivered in the form of a dry powder inhaler or aerosol spray from a pressurised container, pump, nebuliser or nebuliser, with or without the use of a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, a hydrofluoroalkane such as 1, 1, 1, 2-tetrafluoroethane (HFA134A [ trade mark ]) or 1, 1, 1, 2, 3, 3, 3-heptafluoropropane (HFA 227EA [ trade mark ]), carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by the addition of a valve capable of releasing a metered amount of the drug. The pressurised container, pump, spray or atomiser may contain a solution or suspension of the active compound, for example using a mixture of ethanol and propellant as the solvent, and may additionally contain a lubricant such as sorbitan trioleate. Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated containing a powder mix of a compound of formula (I) and a suitable powder base such as lactose or starch.

The aerosol or dry powder formulation is preferably formulated so that each metered dose or "puff contains from 20 to 4000 μ g of the compound of formula (I) for delivery to the patient. The total daily dose administered with the aerosol will range from 20 μ g to 20mg, which may be administered in one dose, or more usually in divided doses throughout the day.

Alternatively, the compounds of formula (I) may be administered in the form of suppositories or vaginal rings, or they may be applied topically in the form of lotions, solutions, creams, ointments or dusting powders. The compounds of formula (I) may also be administered transdermally, for example, by the use of a transdermal patch.

For topical application to the skin, the compounds of formula (I) may be formulated in a suitable ointment containing the active compound suspended or dissolved, for example, in a mixture of one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water. Alternatively, they may be formulated as a suitable lotion or cream, suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, sorbitan monostearate, polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

The compounds of formula (I) may also be used in combination with cyclodextrins. Cyclodextrins are known to form entrapped and non-entrapped complexes with drug molecules. The formation of drug-cyclodextrin complexes can alter the solubility, dissolution rate, bioavailability, and/or stability of the drug molecule. Drug-cyclodextrin complexes are generally useful in most dosage forms and routes of administration. As an alternative to direct complexation with the drug, cyclodextrins may also be used as an auxiliary additive, e.g. as a carrier, diluent or solubiliser. alphA-, betA-and gammA-cyclodextrins are the most commonly used, suitable examples being described in WO-A-91/11172, WO-A-94/02518 and WO-A-98/55148.

It should be understood that: all treatments mentioned herein include curative, palliative and prophylactic treatments.

Thus, the present invention provides:

(i) a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof;

(ii) a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof;

(iii) a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, in association with a pharmaceutically acceptable excipient, diluent or carrier;

(iv) a compound of formula (I) or a pharmaceutically acceptable salt, solvate or composition thereof, for use as a medicament;

(v) use of a compound of formula (I) or a pharmaceutically acceptable salt, solvate or composition thereof, for the manufacture of a medicament having A2a receptor agonist activity;

(vi) use of a compound of formula (I) or a pharmaceutically acceptable salt, solvate or composition thereof, in the manufacture of an anti-inflammatory agent;

(vii) use of a compound of formula (I) or a pharmaceutically acceptable salt, solvate or composition thereof in the manufacture of a medicament for the treatment of a respiratory disorder;

(viii) (vii) use as described in (vii), wherein the disease is selected from the group consisting of: adult Respiratory Distress Syndrome (ARDS), bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, asthma, emphysema, bronchiectasis, chronic sinusitis, and rhinitis;

(ix) use of a compound of formula (I) or a pharmaceutically acceptable salt, solvate or composition thereof in the manufacture of a medicament for the treatment of septic shock, male erectile dysfunction, hypertension, stroke, epilepsy, cerebral ischaemia, peripheral vascular disease, post-ischaemic reperfusion injury, diabetes, rheumatoid arthritis, multiple sclerosis, psoriasis, dermatitis, allergic dermatitis, eczema, ulcerative colitis, crohn's disease, inflammatory bowel disease, heliobacter pylori gastritis, non-steroidal anti-inflammatory drug-induced damage to the gastrointestinal tract or a psychotic disorder, or for wound healing;

(x) A method of treatment of a mammal, including a human being, with an A2a receptor agonist comprising treating said mammal with an effective amount of a compound of formula (I) or with a pharmaceutically acceptable salt, solvate or composition thereof;

(xi) A method of treatment of a mammal, including a human being, to treat an inflammatory disease, comprising treating said mammal with an effective amount of a compound of formula (I) or with a pharmaceutically acceptable salt, solvate or composition thereof;

(xii) A method of treatment of a mammal, including a human being, to treat a respiratory disease, comprising treating said mammal with an effective amount of a compound of formula (I) or with a pharmaceutically acceptable salt, solvate or composition thereof;

(xiii) The method of (xii), wherein the disease is selected from the group consisting of: adult Respiratory Distress Syndrome (ARDS), bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, asthma, emphysema, bronchiectasis, chronic sinusitis, and rhinitis;

(xiv) A method of treatment of a mammal, including a human, to treat septic shock, male erectile dysfunction, hypertension, stroke, epilepsy, cerebral ischaemia, peripheral vascular disease, post-ischaemic reperfusion injury, diabetes, rheumatoid arthritis, multiple sclerosis, psoriasis, dermatitis, allergic dermatitis, eczema, ulcerative colitis, crohn's disease, inflammatory bowel disease, heliobacter pylori gastritis, non-steroidal anti-inflammatory drug-induced damage to the gastrointestinal tract or a psychotic disorder, or to treat wound healing, comprising treating said mammal with an effective amount of a compound of formula (I) or with a pharmaceutically acceptable salt, solvate or composition thereof; and

(xv) Certain novel intermediates disclosed herein.

Examples

The following examples illustrate the preparation of compounds of formula (I):

example 1

9- [ (2R, 3R, 4S, 5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydro-2-furan Base of]-6- [ (2, 2-diphenylethyl) amino group]-N- [2- (1-piperidinyl) ethyl]-9H-purine -2-carboxamides

A solution of (2R, 3R, 4S, 5R) -2- {6- [ (2, 2-diphenylethyl) amino ] -2-iodo-9H-purin-9-yl } -5- (hydroxymethyl) tetrahydro-3, 4-furandiol (5g, 8.7mmol) (preparation 2), 1' -bis (diphenylphosphino) ferrocene dichloropalladium (II) (1: 1 complex with dichloromethane) (0.7g, 0.9mmol) and 1- (2-aminoethyl) piperidine (3.4g, 26.5mmol) in dry tetrahydrofuran (250ml) was heated in a sealed vessel at 60 ℃ under an atmosphere of carbon monoxide for 24 hours at 345kPa (50 psi). The mixture was cooled, filtered through a pad of Arbocel (trade mark) and the filtrate diluted with tetrahydrofuran (150ml) and ethyl acetate (400 ml). The resulting solution was washed with water (3X 300ml) and the organic phase was extracted with 2M aqueous hydrochloric acid (50 ml). The acidic aqueous phase was washed with ethyl acetate (20ml) and the pH was adjusted to > 7 by the addition of 0.88 aqueous ammonia solution. Ethyl acetate (100ml) was added and the mixture was stirred for 10 minutes after which time a white solid formed. The solid was filtered, washed successively with water and ethyl acetate and dried at 70 ℃ under reduced pressure to give the title compound as a white solid (2.8 g).

¹H-NMR(300MHz，CDCl₃)δ：8.50(1H，br s)，8.35(1H，s)，7.35-7.20(10H，m)，5.95(1H，d)，5.90(1H，br s)，4.70-4.60(2H，m)，4.40-4.30(3H，m)，4.20(1H，m)，4.10-4.00(2H，m)，3.50-3.40(2H，m)，2.55-2.45(2H，m)，2.30(4H，br s)，1.40-1.20(6H，m).

LRMS(thermospray)：m/z[MH⁺]602

Analysis：Found C，63.61；H，6.51；N，16.26％；C₃₂H₃₉N₇O₅ requires C，63.88；H，6.53；N，16.30％

Example 2

9- [ (2R, 3R, 4S, 5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydro-2-furan Base of]-6- [ (2, 2-diphenylethyl) amino group]-N-phenethyl-9H-purine-2-carboxamide

A solution of 9- [ (3aR, 4R, 6R, 6aR) -6- (hydroxymethyl) -2, 2-dimethyltetrahydrofuro [3, 4-d ] [1, 3] dioxol-4-yl ] -6- [ (2, 2-diphenylethyl) amino ] -N-phenethyl-9H-purine-2-carboxamide (0.58g, 0.91mmol) (preparation 7) and formic acid (0.5ml) in a mixture of acetic acid and water (1: 1, vol., 25ml) was heated at reflux for 1 hour. The mixture was then cooled and basified with saturated aqueous sodium bicarbonate to pH 8. The resulting precipitate was filtered off to give the crude product. The solid was purified by column chromatography on silica gel eluting with a solvent system of dichloromethane: methanol: 0.88 ammonia (90: 10: 1.5 by volume) to give a solid which was triturated with ether, filtered and dried to give the title compound as a solid (186 mg).

¹H-NMR(300MHz，CDCl₃+DMSO-d₆)δ：7.70-7.92(2H，m)，6.90-7.21(15H，m)，6.23(1H br s)5.76(1H，br s)，5.36-5.63(1H br s)，4.82(2H，m)，4.18-4.38(3H，m)，4.14(1H，s)，3.90-4.13(2H，br s)，3.82(1H，d)，3.66(1H，d)，3.56(2H，q)，2.76(2H，t).

LRMS(thermospray)：m/z[MH⁺]595

Analysis：Found C，66.11；H，5.82；N，14.01％；C₃₃H₃₄N₆O₅.0.25 H₂O requiresC，66.16；H，5.76；N，14.03％

Example 3

9- [ (2R, 3R, 4S, 5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydro-2-furan Base of]-6- [ (2, 2-diphenylethyl) amino group]-N- [2- (4-isopropyl-1-piperidinyl) ethyl Base of]-9H-purine-2-carboxamide

A mixture of methyl 9- [ (2R, 3R, 4S, 5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydro-2-furanyl ] -6- [ (2, 2-diphenylethyl) amino ] -9H-purine-2-carboxylate (preparation 18) (92mg, 0.18mmol) and 2- (4-isopropyl-1-piperidinyl) ethylamine (preparation 20) (100mg, 0.6mmol) was heated at 120 ℃ under nitrogen for 75 minutes. The reaction mixture was allowed to cool to room temperature and diethyl ether (2ml) was added to precipitate the crude product. The solvent was decanted off and the resulting gum was then triturated with ethyl acetate (2 ml). The resulting white solid was filtered off and dried to give the title compound (59 mg).

¹H-NMR(300MHz，CD₃OD)δ：8.40(1H，br s)，7.40-7.10(10H，m)，6.05(1H，d)，4.60(1H，m)，4.50-4.30(4H，m)，4.15(1H，m)；3.90，3.80(2H，AB system)，3.60(2H，m)，3.00(2H，m)，2.60(2H，m)，2.05(2H，m)，1.65(2H，m)，1.40-1.20(3H，m)，1.05(1H，m)，0.90(6H，d).

LRMS(thermospray)：m/z[MH⁺]644

Example 4

9- [ (2R, 3R, 4S, 5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydro-2-furan Base of]-6- [ (2, 2-diphenylethyl) amino group]-N- [3- (1-pyrrolidinyl) propyl]-9H-purine (IV) -2-carboxamides

A mixture of methyl 9- [ (2R, 3R, 4S, 5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydro-2-furanyl ] -6- [ (2, 2-diphenylethyl) amino ] -9H-purine-2-carboxylate (preparation 18) (92mg, 0.18mmol) and N- (3-aminopropyl) pyrrolidine (0.25ml, 1.95mmol) was heated at 120 ℃ under nitrogen for 75 minutes. The reaction mixture was allowed to cool to room temperature and diethyl ether (2ml) was added to precipitate the crude product. The solvent was decanted and the gum was purified by column chromatography on silica gel eluting with methylene chloride: methanol (80: 20 by volume). Trituration with ether gave the title compound as a white solid (34 mg).

¹H-NMR(300MHz，CD₃OD)δ：8.40(1H，br s)，7.40-7.05(10H，m)，6.05(1H，d)，4.60(1H，m)，4.50-4.30(4H，m)，4.15(1H，m)；3.90，3.80(2H，AB system)，3.50(2H，m)，2.60(6H，m)，1.90-1.80(6H，m).

LRMS(thermospray)：m/z[MH⁺]602

Example 5

9- [ (2R, 3R, 4S, 5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydro-2-furan Base of]-6- [ (2, 2-diphenylethyl) amino group]-N- [2- (4-morpholinyl) ethyl]-9H-purine- 2-carboxamides

A mixture of methyl 9- [ (2R, 3R, 4S, 5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydro-2-furanyl ] -6- [ (2, 2-diphenylethyl) amino ] -9H-purine-2-carboxylate (preparation 18) (92mg, 0.18mmol) and N- (2-aminoethyl) morpholine (0.25ml, 1.9mmol) was heated at 120 ℃ under nitrogen for 75 minutes. The reaction mixture was allowed to cool to room temperature and diethyl ether (2ml) was added to precipitate the title compound as a white solid, which was filtered and dried (68 mg).

¹H-NMR(300MHz，CDCl₃)δ：8.50(1H，br s)，8.40(1H，s)，7.40-7.20(10H，m)，6.00(2H，m)，4.65-4.60(2H，m)，4.40-4.20(4H，m)，4.15(2H，m)；3.60-3.40(6H，m)，2.60-2.50(3H，m)，2.40-2.35(4H，m).

LRMS(thermospray)：m/z[MH⁺]604

Example 6

9- [ (2R, 3R, 4S, 5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydro-2-furan Base of]-6- [ (2, 2-bis)Phenylethyl) amino]-N- (2-pyridylmethyl) -9H-purine-2-carboxylic acid Amides of carboxylic acids

A mixture of methyl 9- [ (2R, 3R, 4S, 5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydro-2-furanyl ] -6- [ (2, 2-diphenylethyl) amino ] -9H-purine-2-carboxylate (preparation 18) (92mg, 0.18mmol) and 2- (aminomethyl) pyridine (0.25ml, 2.4mmol) was heated at 120 ℃ under nitrogen for 75 minutes. The reaction mixture was allowed to cool to room temperature and diethyl ether (2ml) was added to precipitate the crude product. The solvent was decanted off and the resulting gum was then triturated with ethyl acetate (2 ml). The resulting white solid was filtered off and dried to give the title compound (73 mg).

¹H-NMR(300MHz，d₆-DMSO)δ：9.15(1H，m)，8.50-8.40(2H，m)，8.05(1H，m)，7.80(1H，m)，7.40-7.10(12H，m)，5.95(1H，d)，5.45(1H，br s)，5.20(1H，br s)，5.10(1H，br s)，4.70-4.50(4H，m)，4.30(2H，m)，4.20(1H，m)；3.95(1H，m)，3.70-3.50(2H，m).

LRMS(thermospray)：m/z[MH⁺]582

Example 7

9- [ (2R, 3R, 4S, 5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydro-2-furan Base of]-6- [ (2, 2-diphenylethyl) amino group]-N- [2- (2-pyridyl) ethyl]-9H-purine- 2-carboxamides

A mixture of methyl 9- [ (2R, 3R, 4S, 5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydro-2-furanyl ] -6- [ (2, 2-diphenylethyl) amino ] -9H-purine-2-carboxylate (preparation 18) (92mg, 0.18mmol) and 2- (2-aminoethyl) pyridine (0.25ml, 2.1mmol) was heated at 120 ℃ under nitrogen for 75 minutes. The reaction mixture was allowed to cool to room temperature and diethyl ether (2ml) was added to precipitate the crude product. The solvent was decanted and the resulting gum was purified by column chromatography on silica gel, eluting with dichloromethane: methanol (95: 5 by volume). Trituration with ether gave the title compound as a white solid (49 mg).

¹H-NMR(300MHz，CD₃OD)δ：8.40(2H，m)，7.70(1H，m)，7.40-7.10(12H，m)，6.05(1H，d)，4.60(1H，m)，4.45(1H，m)，4.35(3H，m)，4.15(1H，m)，3.95-3.70(4H，m)，3.10(2H，m).

LRMS(thermospray)：m/z[MH⁺]596

Example 8

9- [ (2R, 3R, 4S, 5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydro-2-furan Base of]-N- [2- (dimethylamino) ethyl group]-6- [ (2, 2-diphenylethyl) amino group]-9H-purine- 2-carboxamides

A mixture of methyl 9- [ (2R, 3R, 4S, 5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydro-2-furanyl ] -6- [ (2, 2-diphenylethyl) amino ] -9H-purine-2-carboxylate (preparation 18) (92mg, 0.18mmol) and N, N-dimethylethylenediamine (0.25ml, 2.3mmol) was heated at 120 ℃ under nitrogen for 75 minutes. The reaction mixture was allowed to cool to room temperature and diethyl ether (2ml) was added to precipitate the crude product. The solvent was decanted and the gum was purified by column chromatography on silica gel eluting with dichloromethane: methanol: concentrated aqueous ammonia (90: 10: 1 by volume). Trituration with ether gave the title compound as a white solid (51 mg).

¹H-NMR(400MHz，CDCl₃)δ：8.50(1H，br s)，8.20(1H，s)，7.30-7.15(10H，m)，6.05(1H，br s)，5.90(1H，m)，4.70(1H，m)，4.60(1H，m)，4.40-4.30(3H，m)，4.20(1H，m)；4.00(2H，m)，3.40(2H，m)，2.50(2H，m)，2.15(6H，s).

LRMS(thermospray)：m/z[MH⁺]562

Example 9

9- [ (2R, 3R, 4S, 5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydro-2-furan Base of]-6- [ (2, 2-diphenylethyl) amino group]-N- [2- (1-piperidinyl) ethyl]-9H-purine- 2-carboxamides

To a stirring solution of 6- [ (2, 2-diphenylethyl) amino ] -N- [2- (1-piperidinyl) ethyl ] -9- (2, 3, 5-tri-O-acetyl-. beta. -D-ribofuranosyl) -9H-purine-2-carboxamide (assumed to be 310g, 0.426 mol) (preparation example 24) and 1, 2-dimethoxyethane (1600ml) was added a 5M aqueous sodium hydroxide solution (640ml, 3.2 mol) over 45 minutes while cooling in ice. The resulting mixture was stirred at room temperature for 3 hours, and then the layers were separated. The stirred organic phase was then diluted with deionised water (1800ml) while cooling. After complete addition, the resulting mixture is heated to 50-55 ℃ whereupon crystallization begins. To the heated and stirred suspension was added additional deionized water (1800ml) over 50 minutes. Once the addition was complete, the resulting slurry was cooled to 10 ℃ over 45 minutes, and the resulting solid was collected by filtration. The solid was washed with a solution of 1, 2-dimethoxyethane (400ml) and deionised water (800ml) and then dried under reduced pressure at 55 ℃ to give the crude title compound as a brown solid (203 g).

This material was mixed with the material obtained with the operation carried out under similar conditions and purified in the following manner. To a suspension of the crude title compound (398g, 0.661 moles) in isopropanol (7050ml) was added deionized water (1760ml) and the resulting mixture was stirred and heated until a clear solution was obtained. The solution was filtered, then the filtrate was distilled under nitrogen at atmospheric pressure with regular addition of filtered isopropanol to maintain the distillation volume. After distillation, a total of 29100ml of distillate was collected and a total of 26100ml of filtered isopropanol was added. By the end of the distillation, the amount of water present in the distillate was < 0.5% by weight, as determined by Karl-Fischer analysis. The mixture was then cooled to 40 ℃ over 3.5 hours while stirring, during which time crystallization occurred. The resulting slurry was stirred at room temperature for 12.5 hours and then cooled to 2 ℃ over 5.5 hours in an ice bath. The solids were collected by filtration and the filter cake was washed with cooled, filtered isopropanol (2X 1500 ml). The filter cake was dried at 60 ℃ under reduced pressure to give the title compound as a pale beige solid (306g), m.p.182 ℃.

LRMS (positive atmospheric chemical ionization): m/z [ MH⁺]602。

¹H-NMR(500MHz，d₆-DMSO)δ：8.50(1H，br t)，8.40(1H，s)，8.00(1H，br t)，7.35(4H，d)，7.26(4H，t)，7.15(2H，t)，5.91(1H，d)，5.39(1H，d)，5.14(1H，d)，5.06(1H，t)，4.64-4.50(2H，m)，4，28-4.18(2H，m)，4.18-4.10(1H，m)，3.96-3.90(1H，m)，3.70-3.61(1H，m)，3.60-3.50(1H，m)，3.46-3.37(2H，m)，2.50-2.44(2H，m，partly obscured by DMSO peak)，2.40-2.32(4H，m)，1.46-1.38(4H，m)，1.36-1.28(2H，m).

[α]_D ²⁵(c＝0.1 in methanol)：-30°

The following preparations describe the preparation of certain intermediates used in the preceding examples.

Preparation example 1

(2R, 3R, 4R, 5R) -4- (acetoxy) -2- [ (Acetoxy) methyl group]-5-{6- [2, 2-Diphenylethyl) amino group]-2-iodo-9H-purin-9-yl } tetrahydro-3-furanylacetic acid Esters

A mixture of (2R, 3R, 4R, 5R) -4- (acetoxy) -2- [ (acetoxy) methyl ] -5- (6-chloro-2-iodo-9H-purin-9-yl) tetrahydro-3-furanylacetate (journal of medicinal chemistry 35, 248, (1992)) (15.2g, 28.2mmol), 2-diphenylethylamine (6.1g, 30.9mmol), triethylamine (11.4g, 112.8mmol) and acetonitrile (200ml) was stirred at room temperature under a nitrogen atmosphere for 24 hours, followed by heating at reflux for 90 minutes. The solvent was removed under reduced pressure and the residue partitioned between dichloromethane (500ml) and water (200 ml). The organic phase was separated and the solvent was removed under reduced pressure to give the title compound as a pale yellow foam (18.8 g).

¹H-NMR(CDCl₃)δ：7.70(1H，s)，7.20-7.39(10H，m)，6.11(1H，d)，5.75(2H，t)，5.61(1H，m)，4.20-4.48(6H，m)，2.19(3H，s)，2.13(3H，s)，2.09(3H，s).

Preparation example 2

(2R, 3R, 4S, 5R) -2- {6- [ (2, 2-Diphenylethyl) amino group]-2-iodo-9H-purine -9-yl } -5- (hydroxymethyl) tetrahydro-3, 4-furandiol

(2R, 3R, 4R, 5R) -4- (acetoxy) -2- [ (acetoxy) methyl ] -5- {6- [ (2, 2-diphenylethyl) amino ] -2-iodo-9H-purin-9-yl } tetrahydro-3-furanylacetate (1.7g, 2.43mmol) (preparation 1) was dissolved in 10: 1 (by volume) methanol: water (88 ml). Sodium carbonate solid (1.5g, 14.1mmol) was added and the mixture was stirred at room temperature for 90 minutes and then methanol was removed by evaporation under reduced pressure. The residual aqueous solution was diluted with water (50ml) and extracted with ethyl acetate (150 ml). The organic phase was washed sequentially with water and brine, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to give the title compound as a white solid (1.4 g).

¹H-NMR(CDCl₃)δ：7.58(1H，s)，7.19-7.37(10H，m)，5.95(1H，br d)，5.69(1H，br d)，5.00(1H，q)，4.50-4.62(1H，br)，4.20-4.40(3H，m)，3.90-4.05(1H，m)，3.75(1H，t).

Preparation example 3

9- [ (3aR, 4R, 6R, 6aR) -6- ({ [ tert-butyl (dimethyl) silyl)]Oxy } A Yl) -2, 2-dimethyltetrahydrofuro [3.4-d][1，3]Dioxol-4-yl]-6- Chloro-2- (tributylstannyl) -9H-purines

A solution of 2, 2, 6, 6-tetramethylpiperidine (17.6g, 125mmol) in dry tetrahydrofuran (350ml) was cooled to-50 ℃ under a nitrogen atmosphere and treated with n-butyllithium (78ml, 1.6M in hexane, 125mmol) for more than 15 minutes. The reaction mixture was then cooled to-70 ℃ and a solution of 9- [ (3aR, 4R, 6R, 6aR) -6- ({ [ tert-butyl (dimethyl) silyl ] oxy } methyl) -2, 2-dimethyltetrahydrofuro [3, 4-d ] [1, 3] dioxol-4-yl ] -6-chloro-9H-purine (letters. Bioorganic and medicinal Chemicals, 8, 695-one 698, (1998)) (11.0g, 25mmol) in dry tetrahydrofuran (150ml) was added dropwise while maintaining the temperature below-70 ℃. The reaction mixture was stirred for 30 minutes. Tri-n-butyltin chloride (40.7g, 125mmol) was then added to the reaction and the mixture was stirred at-70 ℃ for 30 minutes. To the reaction was added a saturated aqueous solution (100ml) of ammonium chloride, which was then allowed to rise to 0 ℃. A saturated aqueous solution (150ml) of sodium hydrogencarbonate was added to the solution, and the mixture was extracted with ethyl acetate (3X 100 ml). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system gradually changing from hexane: ethyl acetate (95: 5 by volume) to hexane: ethyl acetate (80: 20 by volume) to give the title compound (13.0 g).

¹H-NMR(CDCl₃)δ：8.24(1H，s)，6.24(1H，d)，5.35(1H，dd)，4.93(1H，dd)，4.42(1H，m)，3.84(1H，dd)，3.77(1H，dd)，1.50-1.70(9H，m)，1.10-1.45(15H，m)，0.90(9H，t)，0.84(9H，s)，0.00(6H，s).

LRMS(thermospray)：m/z[MH⁺]732

Preparation example 4

9- [ (3aR, 4R, 6R, 6aR) -6- ({ [ tert-butyl (dimethyl) silyl)]Oxy } A Yl) -2, 2-dimethyltetrahydrofuro [3, 4-d][1，3]Dioxol-4-yl]-N- (2, 2-Diphenylethyl) -2- (tributylstannyl) -9H-purin-6-amine

A mixture of 9- [ (3aR, 4R, 6R, 6aR) -6- ({ [ tert-butyl (dimethyl) silyl ] oxy } methyl) -2, 2-dimethyltetrahydrofuro [3, 4-d ] [1, 3] dioxol-4-yl ] -6-chloro-2- (tributylstannyl) -9H-purine (12.0g, 16.4mmol) (preparation 3), 2-diphenylethylamine (3.56g, 18.0mmol), triethylamine (3.30g, 33.0mmol) and acetonitrile (50ml) was heated at 80 ℃ for 18 hours. Additional 2, 2-diphenylethylamine (0.75g, 3.8mmol) was then added and heating continued for 5 hours. The mixture was cooled, poured into water and extracted with ethyl acetate (3X 50 ml). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system gradually changing from hexane: ethyl acetate (4: 1 by volume) to hexane: ethyl acetate (2: 1 by volume) to give the title compound as an oil (10.3 g).

¹H-NMR(CDCl₃)δ：7.74(1H，s)，7.14-7.37(10H，m)，6.10(1H，d)，5.52-5.62(2H，m)，5.00(1H，dd)，4.44(1H，t)，4.25-4.38(3H，m)，3.78(1H，dd)，3.72(1H，dd)，1.48-1.78(9H，m)，1.30-1.44(9H，m)，1.17(6H，t)，0.88(9H，t)，0.82(9H，s)，-0.06(6H，s).

LRMS(thermospray)：m/z[MH⁺]891

Preparation example 5

9- [ (3aR, 4R, 6R, 6aR) -6- ({ [ tert-butyl (dimethyl) silyl)]Oxy } A Yl) -2, 2-dimethyltetrahydrofuro [3, 4-d][1，3]Dioxol-4-yl]-N- (2, 2-Diphenylethyl) -2-iodo-9H-purin-6-amine

A mixture of 9- [ (3aR, 4R, 6R, 6aR) -6- ({ [ tert-butyl (dimethyl) silyl ] oxy } methyl) -2, 2-methyltetrahydrofuro [3, 4-d ] [1, 3] dioxol-4-yl ] -N- (2, 2-diphenylethyl) -2- (tributylstannyl) -9H-purin-6-amine (1.0g, 1.12mmol) (preparation 4), iodine (0.43g, 1.68mmol) and tetrahydrofuran (30ml) was stirred at 50 ℃ for 30 minutes. The mixture was cooled, dissolved in ethyl acetate and washed sequentially with saturated aqueous sodium thiosulfate and water. The organic phase was separated, dried over anhydrous sodium sulfate, filtered and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system gradually changing from hexane to hexane: ethyl acetate (50: 50 by volume) to give the title compound (1.05 g).

¹H-NMR(CDCl₃)δ：7.77(1H，br s)，7.16-7.36(10H，m)，6.06(1H，br s)，5.72(1H，br s)，5.20(1H，dd)，4.96(1H，dd)，4.15-4.42(4H，m)，3.84(1H，dd)，3.78(1H，dd)，1.62(3H，s)，1.38(3H，s)，0.86(9H，s)，0.02(6H，s).

LRMS(thermospray)：m/z[MH⁺]728

Preparation example 6

9- [ (3aR, 4R, 6R, 6aR) -6- ({ [ tert-butyl (dimethyl) silyl)]Oxy } A Yl) -2, 2-dimethyltetrahydrofuro [3, 4-d][1，3]Dioxol-4-yl]-6- [ (2, 2-Diphenylethyl) amino]-N-phenethyl-9H-purine-2-carboxamide

9- [ (3aR, 4R, 6R, 6aR) -6- ({ [ tert-butyl (dimethyl) silyl ] oxy } methyl) -2, 2-dimethyltetrahydrofuro [3, 4-d ] [1, 3] dioxol-4-yl ] -N- (2, 2-diphenylethyl) -2-iodo-9H-purin-6-amine (1.0g, 1.37mmol) (preparation 5), 1' -bis (diphenylphosphino) ferrocene dichloropalladium (II) (1: 1 complex with dichloromethane) (0.1g, 0.14mmol), a mixture of phenethylamine (0.5g, 4.1mmol) and tetrahydrofuran (30ml) was heated in a sealed vessel at 60 ℃ under a carbon monoxide atmosphere at 345kPa (50psi) for 18 h. The mixture was cooled and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system gradually changing from hexane: ethyl acetate (2: 1 by volume) to hexane: ethyl acetate (1: 1 by volume) to give the title compound as a foam (0.72 g).

¹H-NMR(CDCl₃)δ：7.90-8.10(2H，m)，7.10-7.40(15H，m)，6.26(1H，d)，5.78(1H，m)，5.14(1H m)，4.97(1H，m)，4.10-4.44(4H，m)，3.88(1H，dd)，3.82(1H，dd)，3.73(2H，q)，2.94(2H，t)，1.62(3H，s)，1.38(3H，s)，0.84(9H，s)，0.02(6H，s).

LRMS(thermospray)：m/z[MH⁺]749

Preparation example 7

9- [ (3aR, 4R, 6R, 6aR) -6- (hydroxymethyl) -2, 2-dimethyltetrahydrofurano [3，4-d][1，3]Dioxol-4-yl]-6- [ (2, 2-diphenylethyl) amino group]-N- phenethyl-9H-purine-2-carboxamide

A solution of 9- [ (3aR, 4R, 6R, 6aR) -6- ({ [ tert-butyl (dimethyl) silyl ] oxy } methyl) -2, 2-dimethyltetrahydrofuro [3, 4-d ] [1, 3] dioxol-4-yl ] -6- [ (2, 2-diphenylethyl) amino ] -N-phenethyl-9H-purine-2-carboxamide (0.72g, 0.96 mmol) (preparation 6) in acetonitrile (10ml) was treated with tetra-N-butylammonium fluoride (1.44ml, 1M in tetrahydrofuran, 1.4mmol), and the resulting mixture was stirred at room temperature for 1 hour. The solution was then partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was separated and the aqueous phase was extracted again with ethyl acetate. The combined organic phases were then washed with brine, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system gradually changing from dichloromethane to dichloromethane: methanol (95: 5 by volume) to give the title compound as an off-white foam (580 mg).

¹H-NMR(CDCl₃)δ：7.92(1H，t)，7.77(1H，s)，7.02-7.40(15H，m)，5.94(1H，brs)，5.70-5.85(2H，m)，5.18-5.36(2H，m)，4.52(1H，s)，3.96-4.38(4H，m)，3.58-3.92(3H，m)，2.92(2H，t)，1.64(3H，s)，1.37(3H，s).

LRMS(thermospray)：m/z[MH⁺]635

Preparation example 8

2, 6-dichloro- (9-tetrahydro-2H-pyran-2-yl) -9H-purine

2, 6-dichloro-9H-purine (20g, 0.11mol) and 4-toluenesulfonic acid monohydrate (0.2g) were dissolved in ethyl acetate (300ml), the mixture was heated to 50 ℃ and a solution of 2, 3-dihydropyran (12.6ml, 0.14mol) in ethyl acetate (50ml) was added slowly over 30 minutes. The reaction mixture was cooled to room temperature, water (100ml) was added and the pH of the solution was adjusted to 7 by addition of saturated aqueous sodium bicarbonate solution. The organic layer was separated, washed with water and brine in this order, dried over anhydrous magnesium sulfate, filtered and the solvent was removed under reduced pressure. The residue was azeotroped twice with pentane to give the slightly impure title compound as a white solid (30.9 g).

¹H-NMR(400MHz，CDCl₃)δ：8.30(1H，s)，5.75(1H，dd)，4.25-4.15(1H，m)，3.85-3.70(1H，m)，2.20-1.60(6H，m).

Preparation example 9

2-chloro-N- (2, 2-diphenylethyl) - (9-tetrahydro-2H-pyran-2-yl) -9H-purine- 6-amines

A solution of 2, 6-dichloro- (9-tetrahydro-2H-pyran-2-yl) -9H-purine (preparation 8) (30.9g, 0.11mol) in isopropanol (600ml) was treated with N-ethyl-N-isopropyl-2-propylamine (47.5ml, 0.27mol) and 2, 2-diphenylethylamine (24.8g, 0.13mol), and the resulting mixture was heated under reflux for 3 hours. The solvent was removed under reduced pressure and the residue was azeotroped with ethyl acetate. The residue was then purified by column chromatography on silica gel eluting with a gradient system gradually changing from ethyl acetate: hexane (40: 60 by volume) to ethyl acetate: hexane (60: 40 by volume) to give the title compound as a foam (49.7 g).

¹H-NMR(400MHz，CDCl₃)δ：7.95-7.75(1H，br s)，7.35-7.15(10H，m)，5.80-5.70(1H，br s)，5.65(1H，d)，4.35(1H，m)，4.30-4.18(1H，br s)，4.10(1H，d)，3.70(1H，t)，2.05-1.95(2H，m)，1.95-1.80(1H，m)，1.80-1.55(3H，m).

Preparation example 10

N- (2, 2-diphenylethyl) -2- (methylsulfanyl) -9- (tetrahydro-2H-pyran-2- Yl) -9H-purin-6-amines

A solution of 2-chloro-N- (2, 2-diphenylethyl) -9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine (preparation 9) (49.7g, 0.11mol) and dry N, N-dimethylformamide (200ml) was treated with sodium thiomethoxide (10g, 0.14mol) and the resulting mixture was heated at 100 ℃ for 90 minutes under a nitrogen atmosphere. The mixture was stirred at room temperature for 72 hours and heated at 100 ℃ for a further 2 hours. The reaction mixture was cooled and diluted with water (1000 ml). The resulting suspension was extracted with diethyl ether (2X 500 ml). The combined organic layers were washed sequentially with water and brine, dried over anhydrous magnesium sulfate, filtered and the solvent was removed under reduced pressure. The residue was azeotroped with diethyl ether and then with pentane to give the title compound as a foam (48.9 g).

¹H-NMR(400MHz，CDCl₃)δ：7.80(1H，s)，7.20-7.10(10H，m)，5.70-5.55(2H，d)，4.40-4.20(3H，m)，4.20-4.05(1H，m)，3.80-3.65(1H，m)，2.60(3H，s)，2.15-1.90(3H，m)，1.90-1.60(3H，m).

Preparation example 11

N- (2, 2-diphenylethyl) -2- (methylsulfonyl) -9- (tetrahydro-2H-pyran-2- Yl) -9H-purin-6-amines

An aqueous solution (200ml) of Oxone (trade mark) (potassium peroxymonosulfate) (44g, 71.7mmol) was added dropwise over 2 hours to a solution of N- (2, 2-diphenylethyl) -2- (methylsulfanyl) -9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine (preparation 10) (25g, 56.2mmol), sodium bicarbonate (20g, 238mmol), acetone (1000ml) and water (250 ml). The resulting mixture was stirred at room temperature for 24 hours, filtered and the residue was washed with acetone. Acetone was removed from the filtrate by evaporation under reduced pressure and the resulting aqueous residue was extracted with ethyl acetate and then dichloromethane. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered and the solvent was removed under reduced pressure. The residue was triturated with ether, filtered, washed with ether and pentane and then dried to give the title compound as a white solid (20.32 g).

¹H-NMR(CDCl₃)δ：8.00(1H，s)，7.35-7.15(10H，m)，6.05-5.95(1H，br s)，5.75(1H，d)，4.40-4.35(1H，m)，4.35-4.20(2H，br s)，4.15-4.05(1H，m)，3，75(1H，t)，3.30(3H，s)，2.18-2.05(1H，m)，2.05-1.98(1H，m)，1.98-1.80(1H，m)，1.80-1.60(3H，m).

Preparation example 12

6- [ (2, 2-Diphenyl group)Ethyl) amino group]-9- (tetrahydro-2H-pyran-2-yl) -9H-purine -2-carbonitrile

A solution of N- (2, 2-diphenylethyl) -2- (methylsulfonyl) -9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine (preparation 11) (20.1g, 42.1mmol) and dry N, N-dimethylformamide (100ml) was treated with potassium cyanide (5.5g, 84.6mmol) and the mixture was heated at 120 ℃ for 24H under a nitrogen atmosphere. The mixture was allowed to cool to room temperature, poured into water (1000ml) and stirring continued for a further 1 hour. The resulting solid was slowly filtered off and washed several times with water. The solid was dissolved in dichloromethane, the solution was washed with water, dried over anhydrous magnesium sulfate, filtered and the solvent was removed under reduced pressure. The residue was azeotroped with diethyl ether (twice) to give the title compound as an oil (17 g).

¹H-NMR(400MHz，CDCl₃)δ：8.00(1H，s)，7.40-7.20(10H，m)，6.00-5.75(1H，br s)，5.70(1H，d)，4.40-4.20(3H，m)，4.20-4.10(1H，m)，3.80-3.70(1H，m)，2.20-1.90(3H，m)，1.90-1.60(3H，m).

Preparation example 13

6- [ (2, 2-Diphenylethyl) amino group]-9- (tetrahydro-2H-pyran-2-yl) -9H-purine -2-carbonitrile

A solution of 2-chloro-N- (2, 2-diphenylethyl) -9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine (preparation 9) (1.0g, 2.31mmol), zinc cyanide (0.162g, 1.38mmol), triethylamine (0.28g, 2.77mmol), tetrakis (triphenylphosphine) palladium (O) (0.133g, 0.12mmol) and N, N-dimethylformamide (3ml) was heated at 100 ℃ under nitrogen for 6 hours. The reaction mixture was allowed to cool and partitioned between ethyl acetate (100ml) and 2M aqueous sodium hydroxide (100 ml). The organic layer was separated, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The resulting 1: 1 mixture of 6- [ (2, 2-diphenylethyl) amino ] -9- (tetrahydro-2H-pyran-2-yl) -9H-purine-2-carbonitrile and 6- [ (2, 2-diphenylethyl) amino ] -9H-purine-2-carbonitrile (see, e.g., preparation 15) was separated by column chromatography on silica gel eluting with a gradient system gradually changing from ethyl acetate: hexane (40: 60 by volume) to ethyl acetate: hexane (60: 40 by volume) to give the title compound as a white solid (0.4 g).

¹H-NMR(400MHz，CDCl₃)δ：8.00(1H，s)，7.40-7.20(10H，m)，6.00-5.75(1H，br s)，5.70(1H，d)，4.40-4.20(3H，m)，4.20-4.10(1H，m)，3.80-3.70(1H，m)，2.20-1.90(3H，m)，1.90-1.60(3H，m).

Preparation example 14

6- [ (2, 2-Diphenylethyl) amino group]-9- (tetrahydro-2H-pyran-2-yl) -9H-purine -2-Carboxylic acid methyl ester

A suspension of 6- [ (2, 2-diphenylethyl) amino ] -9- (tetrahydro-2H-pyran-2-yl) -9H-purine-2-carbonitrile (preparation 12 or 13) (1.00g, 2.36mmol) in methanol (20ml) was treated with sodium methoxide (0.14g, 2.59mmol), and the resulting mixture was heated at reflux under nitrogen for 20H. TLC analysis showed some starting material still remaining so further sodium methoxide (64mg, 1.18mmol) was added and the mixture was heated under nitrogen at reflux for 1 hour. The mixture was cooled to room temperature and the solvent was removed under reduced pressure. Tetrahydrofuran (30ml) and water (10ml) were added to the residue and the pH was adjusted to 4 by the addition of glacial acetic acid (1 ml). The mixture was heated at reflux for 1 hour. TLC analysis showed some starting material still remaining and therefore further acetic acid (0.5ml) was added and heating continued at reflux for 18 hours. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was separated, washed with brine, dried over anhydrous magnesium sulfate, filtered and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with dichloromethane: methanol (98.5: 1.5 by volume) to give the title compound (521 mg).

¹H-NMR(400MHz，CDCl₃)δ：8.05(1H，br s)，7.18-7.37(10H，m)，5.84(2H，m)，4.40(3H，m)，4.14(1H，d)，4.00(3H，s)，3.78(1H，t)，1.60-2.17(6H，m).

LRMS(thermospray)：m/z[MH⁺]458，[MNa⁺]480

Preparation example 15

6- [ (2, 2-Diphenylethyl) amino group]-9H-purine-2-carbonitrile

A solution of 6- [ (2, 2-diphenylethyl) amino ] -9- (tetrahydro-2H-pyran-2-yl) -9H-purine-2-carbonitrile (preparation 12 or 13) (17g, 40.1mmol) and ethanol (850ml) was treated with 2N aqueous hydrochloric acid (50ml), and the mixture was stirred at room temperature for 24 hours. The solvent was removed under reduced pressure, the residue was dissolved in ethanol and the solvent was removed again under reduced pressure. The residue was triturated with ether, filtered, washed with ether and pentane and dried to give the title compound as a solid (13.6 g).

¹H-NMR(400MHz，DMSO-d₆)δ：8.30(1H，s)，8.20-8.05(1H，br s)，7.40-7.10(10H，m)，4.60-4.40(1.4H，m)，4.20-4.00(1.6H，m).

LRMS(thermospray)：m/z[MH⁺]341

Preparation example 16

6- [ (2, 2-Diphenylethyl) amino group]-9H-purine-2-carboxylic acid methyl ester

6- [ (2, 2-Diphenylethyl) amino ] -9H-purine-2-carbonitrile (preparation example 15) (5.0g, 14.7mmol) and a solution of sodium methoxide (4.0g, 74.1mmol) in methanol (300ml) were heated under reflux for 24 hours. Sodium methoxide (2.0g, 37mmol) and methanol (100ml) were then added and heating continued for an additional 24 hours. The reaction mixture was cooled and the solvent was removed under reduced pressure. The residue was dissolved in tetrahydrofuran (375ml), a 2M aqueous brine solution (125ml) was added, and the mixture was stirred at room temperature for 24 hours. The tetrahydrofuran was removed under reduced pressure and the pH of the suspension was adjusted to 7 with saturated aqueous sodium bicarbonate solution. Ethyl acetate (100ml) was then added and the suspended white solid was filtered off, washed with a little water, then ethyl acetate and dried. Purification by column chromatography on silica gel eluting with a gradient system varying gradually from dichloromethane: methanol (90: 10 by volume) to dichloromethane: methanol (75: 25 by volume) gave the title compound as a white solid (1.25g) (note: evaporation of the ethyl acetate filtrate gave 2.6g of starting material).

¹H-NMR(400MHz，CDCl₃)δ：12.40(1H，br s)，8.05(1H，s)，7.55(1H，s)，7.30-7.20(10H，m)，4.80(2H，m)，4.75(1H，m)，3.80(3H，s).

LRMS(thermospray)：m/z[MH⁺]375

Preparation example 17

9- { (2R, 3R, 4R, 5R) -3, 4-bis (acetoxy) -5- [ (acetoxy) methyl]Fourthly Hydro-2-furyl } -6- [ (2, 2-diphenylethyl) amino]-9H-purine-2-carboxylic acid methyl ester

A suspension of methyl 6- [ (2, 2-diphenylethyl) amino ] -9H-purine-2-carboxylate (preparation 16) (1.5g, 4.02mmol) in 1, 1, 1-trichloroethane (40ml) was treated with N, O-bis (trimethylsilyl) acetamide (4.8ml, 19.6 mmol). The mixture was heated at reflux for 2 hours. The solution was cooled to room temperature and the solvent was removed under reduced pressure. The residue was dissolved in dry toluene (40ml) and 1, 2, 3, 5-tetra-O-acetyl-. beta. -D-ribofuranose (1.65g, 5.19mmol) and trimethylsilyl trifluoromethanesulfonate (0.98ml, 5.43mmol) were added. The resulting solution was heated under nitrogen at reflux for 3 hours. The mixture was cooled to room temperature, diluted with ethyl acetate (200ml) and washed with saturated aqueous sodium bicarbonate. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient from ethyl acetate to pentane (70: 30 by volume) to ethyl acetate to pentane (80: 20 by volume) and then to ethyl acetate to give the title compound as a foam (2.05 g).

¹H-NMR(400MHz，CDCl₃)δ：8.00(1H，br s)，7.35-7.20(11H，m)，6.25(1H，m)，5.85-5.70(3H，m)，4.50-4.30(5H，m)，4.00(3H，s)，2.15(3H，s)，2.10(3H，s)，2.05(3H，s).

LRMS(thermospray)：m/z[MNa⁺]655

Preparation example 18

9- [ (2R, 3R, 4S, 5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydro-2-furan Base of]-6- [ (2, 2-diphenylethyl) amino group]-9H-purine-2-carboxylic acid methyl ester

A solution of methyl 9- { (2R, 3R, 4R, 5R) -3, 4-bis (acetoxy) -5- [ (acetoxy) methyl ] tetrahydro-2-furanyl } -6- [ (2, 2-diphenylethyl) amino ] -9H-purine-2-carboxylate (preparation 17) (2.0g, 3.17mmol), sodium carbonate (35mg) and dry methanol (40ml) was stirred at room temperature for 3.5 hours. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel eluting with a gradient from dichloromethane: methanol (94: 6 by volume) to dichloromethane: methanol (92: 8 by volume) to give the title compound as a white powder (1.5 g).

¹H-NMR(400MHz，CDCl₃)δ：7.80(1H，br s)，7.35-7.20(10H，m)，5.95(1H，brs)，5.75(2H，m)，5.10(1H，m)，4.90(1H，br s)，4.40(3H，m)，4.30(1H，s)，4.15(1H，m)，3.90(1H，m)，3.80-3.70(4H，m)；3.15(1H，s).

LRMS(thermospray)：m/z[MNa⁺]528

Preparation example 19

2- [2- (4-isopropyl-1-piperidinyl) ethyl]-1H-isoindole-1, 3(2H) -dione

A solution of 4-isopropylpiperidine (3.3g, 20.2mmol), 2-bromoethylphthalimide (5.4g, 21.3mmol), potassium carbonate (5.9g, 45.4mmol) and acetonitrile (100ml) was heated at reflux for 2.5 hours and then stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue partitioned between ethyl acetate (100ml) and water (100 ml). The organic layer was separated and the aqueous layer was extracted with additional ethyl acetate (100 ml). The combined organic extracts were dried (Na)₂SO₄) And the solvent was distilled off under reduced pressure. The resulting oil was purified by column chromatography on silica gel, changing from dichloromethane to diethyl ether (50: 1)50 by volume) was then eluted by a gradient system changing to ether to give the title compound (3.3 g).

¹H-NMR(400MHz，CDCl₃)δ：7.80(2H，m)，7.70(2H，m)，3.80(2H，t)，3.00(2H，m)，2.60(2H，t)，1.95(2H，m)，1.60(2H，m)，1.40(1H，m)，1.20(2H，qd)，0.95(1H，m)，0.80(6H，d).

LRMS(thermospray)：m/z[MH⁺]301

Preparation example 20

2- (4-isopropyl-1-piperidinyl) ethylamine

A solution of (2- [2- (4-isopropyl-1-piperidinyl) ethyl ] -1H-isoindole-1, 3(2H) -dione (preparation 19) (3.2g, 10.6mmol) in a 33% w/w ethanol solution of methylamine (60ml) was heated at reflux for 3 hours, the solvent was removed under reduced pressure, ethanol (60ml) was added and the solvent was removed again under reduced pressure, the residue was suspended in dichloromethane (100ml) and the solid was filtered off, washed with dichloromethane (100ml), the filtrate was evaporated under reduced pressure, the resulting oil was purified by column chromatography on silica gel, eluted with dichloromethane: methanol: 0.88 aqueous ammonia (90: 10: 1, by volume) to give a colorless oil, bulb-bulb distillation (150 mmHg, 160 ℃, 30) to give the title compound (1.0g, 55%).

¹H-NMR(400MHz，CDCl₃)δ：2.90(2H，m)，2.80(2H，t)，2.40(2H，t)，1.95(2H，m)，1.65(2H，m)，1.40(1H，m)，1.30-1.20(4H，m)，1.00(1H，m)，0.85(6H，d).

LRMS(thermospray)：m/z[MH⁺]171.

Preparation example 21

6- [ (2, 2-Diphenylethyl) amino group]-9- (tetrahydro-2H-pyran-2-yl) -9H-purine -2-carboxylic acid

To a suspension of 6- [ (2, 2-diphenylethyl) amino ] -9- (tetrahydro-2H-pyran-2-yl) -9H-purine-2-carbonitrile (176g, 0.415 mol) (preparation 13) in technical methanol denatured alcohol (770ml) was added a deionized water solution (110ml) of sodium hydroxide (33.3g, 0.83 mol). The resulting slurry was heated at reflux for 2.5 hours during which time a clear solution formed. The mixture was allowed to cool to room temperature over 16 hours, whereby a precipitate formed. Water (200ml) was then added and the mixture was distilled at atmospheric pressure. During the distillation, water (500ml) was added periodically to the mixture and a total of 720ml of distillate was collected. The resulting mixture was allowed to cool slowly to room temperature with stirring and a thick precipitate formed. The slurry was cooled in an ice bath and the solid was collected by filtration. The filter cake was washed with a solution of deionized water (225ml) and technical methanol denatured alcohol (25 ml). The moist filter cake was suspended in a mixture of deionised water (965ml) and dichloromethane (965ml) and the pH of the mixture was adjusted to pH1.2 by addition of concentrated hydrochloric acid. The phases were separated and the aqueous layer was extracted with dichloromethane (300 ml). The organic phases were combined and the solvent was distilled at atmospheric pressure until 750ml of distillate was collected. Ethyl acetate (1100ml) was added and distillation continued until 750ml of distillate had collected again and an off-white precipitate formed. The resulting slurry was cooled to room temperature and further cooled in an ice bath. The solid was collected by filtration and the filter cake was washed with cooled ethyl acetate (2X 350 ml). The resulting solid was dried in an oven at 70 ℃ under reduced pressure to give the title compound as an off-white solid (163g), m.p.155 ℃ (cleaved).

LRMS (positive atmospheric chemical ionization): m/z [ MH⁺]444。

¹H-NMR(300MHz，CDCl₃)δ：8.10(1H，s)，7.40-7.10(10H，m)，6.30(1H，br s)，5.90(1H，d)，4.50-4.20(3H，m)，4.15(1H，br d)，3.80(1H，br t)，2.20-1.60(6H，m).

Preparation example 22

6- [ (2, 2-Diphenylethyl) amino group]-N- [2- (1-piperidinyl) ethyl]-9- (tetrahydro-) 2H-pyran-2-yl) -9H-purine-2-carboxamide

To a suspension of 6- [ (2, 2-diphenylethyl) amino ] -9- (tetrahydro-2H-pyran-2-yl) -9H-purine-2-carboxylic acid (249g, 0.561 mol) (preparation 21) in anhydrous tetrahydrofuran (2500ml) was added N, N' -carbonyldiimidazole (109g, 0.672 mol) in two portions over 10 minutes. The resulting mixture was stirred at room temperature under nitrogen atmosphere whereupon the solid gradually dissolved to give a cloudy light orange solution. After stirring for 2.5 hours, the reaction mixture was cooled in an ice bath and a solution of 2- (1-piperidinyl) ethylamine (86.4g, 0.674 moles) in anhydrous tetrahydrofuran (100ml) was added over 55 minutes during which time a clear orange solution formed. The reaction mixture was stirred at room temperature for a further 17.5 hours. Deionized water (10ml) was then added and the reaction mixture was then distilled at atmospheric pressure until approximately 2400ml of distillate was collected. To the resulting amber oil was added isopropanol (2000ml) and distillation at atmospheric pressure was continued until approximately 50ml of distillate was collected. The resulting dark orange solution was allowed to cool to room temperature and isopropanol (600ml) was added to give an isopropanol solution of the title compound which was used without further purification.

Analytical samples were prepared using the following method. A sample of the above isopropanol solution of the title compound was concentrated under reduced pressure to an oil. The oil was dissolved in ethyl acetate and washed sequentially with water and saturated aqueous sodium chloride solution. The organic phase was then dried over magnesium sulfate and then concentrated under reduced pressure to give the title compound as an oil. The title compound may, if desired, be further purified by preparative chromatography, for example by flash chromatography.

LRMS (positive atmospheric chemical ionization): m/z [ MH⁺]554。

¹H-NMR(300MHz，CDCl₃)δ：8.40(1H，br s)，8.00(1H，s)，7.40-7.15(10H，m)，6.00-5.80(2H，br d)，4.50-4.20(3H，m)，4.10(1H，br d)，3.80(1H，br t)，3.55(2H，q)，2.55(2H，t)，2.50-2.25(4H，m)，2.20-1.60(6H，m)，1.60-.25(6H，m).

Preparation example 23

6- [ (2, 2-Diphenylethyl) amino group]-N- [2- (1-piperidinyl) ethyl]-9H-purine- 2-carboxamides

To a solution of 6- [ (2, 2-diphenylethyl) amino ] -N- [2- (1-piperidinyl) ethyl ] -9- (tetrahydro-2H-pyran-2-yl) -9H-purine-2-carboxamide from preparation 22 (ca. 2600ml) in isopropanol (ca. 2600ml) was added deionized water (1320ml) over 5 minutes to form a cloudy, light amber solution. Trifluoroacetic acid (257ml, 3.34 moles) was added to the stirred mixture over 30 minutes to bring the pH of the reaction mixture below 2. The resulting mixture was then heated at reflux for 1 hour, during which time a slurry was formed. The mixture was allowed to cool to room temperature and stirred for 16 hours. To the stirred slurry was slowly added aqueous sodium hydroxide (317ml of a 10M solution, 3.17 moles) over 30 minutes until the pH of the mixture reached 11. Trifluoroacetic acid (4ml) was added to adjust the pH to 10 and the resulting slurry was heated to 78 ℃. The mixture was allowed to cool to room temperature over 3 hours while stirring. The resulting slurry was filtered and the filter cake was washed with isopropanol (2X 350 ml). The moist filter cake was then suspended in 1-propanol (5000ml) and heated under reflux during which time a solution formed. The mixture was distilled at atmospheric pressure until 1800ml of distillate was collected. More 1-propanol (1800ml) was added to the mixture and distillation was continued until 2200ml of distillate had been collected. The distillation was stopped and the mixture was cooled to room temperature over 16 hours by stirring, during which time crystallization occurred. The resulting slurry was cooled to 8 ℃ in an ice bath and the solid was collected by filtration. The filter cake was washed with 1-propanol (1000ml) and then dried at 70 ℃ under reduced pressure to give the title compound as an off-white solid (206g), m.p.222 ℃.

LRMS (positive atmospheric chemical ionization): m/z [ MH⁺]470。

¹H-NMR(300MHz，CDCl₃)δ：15.25(1H，br s)，8.55(1H，br s)，8.30(1H，s)，7.40-7.15(10H，m)，5.90(1H，br s)，4.50-4.25(3H，m)，3.60(2H，q)，2.55(2H，t)，2.50-2.30(4H，m)，1.50-1.20(6H，m).

Preparation example 24

6- [ (2, 2-Diphenylethyl) amino group]-N- [2- (1-piperidinyl) ethyl]-9- (2, 3, 5-tri-O-acetyl-beta-D-ribofuranosyl) -9H-purine-2-carboxamide

To a stirred suspension of 6- [ (2, 2-diphenylethyl) amino ] -N- [2- (1-piperidinyl) ethyl ] -9H-purine-2-carboxamide (200g, 0.426 mol) (preparation 23) in anhydrous 1, 2-dimethoxyethane (800ml) under nitrogen atmosphere was added over 15 minutes a solution of trimethylsilyl trifluoromethanesulfonate (200g, 0.900 mol) in anhydrous 1, 2-dimethoxyethane (200 ml). During the addition, all solids dissolved to give a dark red/amber solution and the reaction temperature rose from 20 ℃ to 31.5 ℃. The resulting mixture was heated to 55-60 ℃ and a solution of 1, 2, 3, 5-tetra-O-acetyl-. beta. -D-ribofuranose (163g, 0.512 mol) in anhydrous 1, 2-dimethoxyethane (400ml) was added over 40 minutes. The addition apparatus was rinsed with anhydrous 1, 2-dimethoxyethane (200ml) and the rinse added to the reaction mixture. The reaction mixture was heated at 60 ℃ for 3 hours and allowed to cool to room temperature. The crude reaction solution was left at room temperature for 18 hours. The resulting mixture containing the title compound can be used without further purification.

An analytical sample was obtained in the following manner. A sample of the above solution was added to a saturated aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and the solvent was removed under reduced pressure to give a light brown foam. The crude product is further purified by preparative chromatography, for example by flash chromatography, on silica gel eluting with a gradient system of methanol: dichloromethane varying from 5: 95 to 15: 85 (by volume) as the mobile phase to give the title compound as a colourless foam.

LRMS (positive atmospheric chemical ionization): m/z [ MH⁺]728。

¹H-NMR(300MHz，CDCl₃)δ：8.35(1H，br s)，7.95(1H，s)，7.40-7.15(10H，m)，6.35(1H，br s)，5.90-5.70(2H，m)，5.70-5.55(1H，m)，4.55-4.20(6H，m)，3.55(2H，q)，2.55(2H，t)，2.50-2.30(4H，m)，2.15(3H，s)，2.05(6H，br s)，1.60-1.20(6H，m).

Preparation example 25

6- [ (2, 2-Diphenylethyl) amino group]-9H-purine-2-carboxylic acid

To a suspension of 6- [ (2, 2-diphenylethyl) amino ] -9H-purine-2-carbonitrile (12.5g, 0.0368 mol) (preparation 15) in a mixture of technical methanol-denatured alcohol (80ml) and deionized water (35ml) was added sodium hydroxide (1.2g, 0.13mol), and the resulting mixture was heated at reflux for 17 hours, during which time a clear solution formed. The mixture was cooled to room temperature and acidified by addition of 1M aqueous hydrochloric acid (105ml) to give a suspension. The solid was collected by filtration and dried at 50 ℃ under reduced pressure to give the title compound as a colourless solid (13.5g), m.p.241-249 ℃.

LRMS (negative atmospheric pressure chemical ionization): m/z [ M-H^-]358。

¹H-NMR(300MHz，d₆-DMSO)δ：8.20(1H，br s)，7.75(1H，br t)，7.40-7.00(10H，m)，4.65-4.40(1H，m)，4.25-4.05(2H，m).

Preparation example 26

6- [ (2, 2-Diphenylethyl) amino group]-N- [2- (1-piperidinyl) ethyl]-9H-purine- 2-carboxamides

To a suspension of 6- [ (2, 2-diphenylethyl) amino ] -9H-purine-2-carboxylic acid (0.52g, 1.45mmol) (preparation example 25) in N, N-dimethylformamide (20ml) was added N, N' -carbonyldiimidazole (0.24g, 1.48mmol), and the resulting mixture was stirred at room temperature for 5 hours. To this mixture was added 2- (1-piperidinyl) ethylamine (0.206ml, 1.45mmol) and the resulting mixture was stirred at room temperature for 20 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give an oil which was partitioned between ethyl acetate (30ml) and saturated aqueous sodium bicarbonate (20 ml). The layers were then separated and the aqueous phase was extracted with ethyl acetate (30 ml). The combined organic phases were washed successively with saturated aqueous sodium bicarbonate (30ml) and saturated aqueous sodium chloride (30ml) and then dried over magnesium sulfate. The solvent was removed under reduced pressure to give the title compound as a brown solid (0.10 g). If desired, the material can be purified by recrystallization from 1-propanol.

LRMS (positive atmospheric chemical ionization): m/z [ MH⁺]470。

¹H-NMR(300MHz，CDCl₃)δ：15.25(1H，br s)，8.55(1H，br s)，8.30(1H，s)，7.40-7.15(10H，m)，5.90(1H，br s)，4.50-4.25(3H，m)，3.60(2H，q)，2.55(2H，t)，2.50-2.30(4H，m)，1.50-1.20(6H，m).

Preparation example 27

6- [ (2, 2-Diphenylethyl) amino group]-9- (tetrahydro-2H-pyran-2-yl) -9H-purine -2-Carboxylic acid ethyl ester

A mixture of 2-chloro-N- (2, 2-diphenylethyl) -9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine (10g, 23mmol) (preparation 9), triethylamine (9.6ml, 69mmol), palladium (II) acetate (0.0103g, 0.046mmol) and 1, 1' -bis (diphenylphosphino) ferrocene (0.376g, 0.69mmol) in ethanol (46ml) was heated at 120 ℃ under a carbon monoxide atmosphere at 1725kPa (250psi) for 18 hours. The resulting slurry was cooled in an ice bath for 2 hours, and the solid was collected by filtration and washed with ethanol (20 ml). The material was then dried under reduced pressure to give an off-white solid (9.5 g). A part (8.5g) of the solid was suspended in ethyl acetate (170ml), and the resulting mixture was stirred at room temperature for 60 hours. The mixture was filtered and the filter cake was washed with ethyl acetate (20 ml). The filtrate was then concentrated under reduced pressure to give the title compound as a tan solid (6.45 g). A portion (0.7g) of this material was crystallized from ethanol (3ml) to give the title compound as a colourless solid (0.54g), m.p.138-140 ℃.

¹H-NMR(300MHz，CDCl₃)δ：8.05(1H，s)，7.45-7.15(10H，m)，5.95-5.80(2H，m)，4.60-4.30(5H，m)，4.15(1H，br d)，3.80(1H，br t)2.20-1.60(6H，m)，1.50(3H，t).

LRMS (positive atmospheric chemical ionization): m/z [ MH⁺]：472。

Preparation example 28

6- [ (2, 2-Diphenylethyl) amino group]-9- (tetrahydro-2H-pyran-2-yl) -9H-purine -2-carboxylic acid

To 6- [ (2, 2-diphenylethyl) amino group]Suspension of ethyl (9-tetrahydro-2H-pyran-2-yl) -9H-purine-2-carboxylate (0.55g, 1.16mmol) (preparation 27) in technical methanol denatured alcohol (2.2ml) was added deionized water (0.08ml) followed by 10M aqueous sodium hydroxide (0.23ml, 2.3 mmol). The resulting mixture was stirred at 65 ℃ for 30 minutes and then at room temperature for 18 hours, during which time a thick paste formed. To the mixture was added dichloromethane (10ml) and the pH was adjusted to 2 by addition of dilute aqueous hydrochloric acid. The phases were separated and the aqueous layer was extracted with dichloromethane (10 ml). The combined organic phases were then dried (MgSO)₄) And the solvent was removed under reduced pressure to give the title compound as a tan foam (0.43g) using¹H-NMR, high performance liquid chromatography, mass spectrometry and thin layer chromatography, which were the same as the compound prepared in preparation example 21.

Preparation example 29

6- [ (2, 2-Diphenylethyl) amino group]-9- (tetrahydro-2H-pyran-2-yl) -9H-purine -2-carboxylic acid

2-chloro-N- (2, 2-diphenylethyl) -9- (tetrahydro-l)A mixture of-2H-pyran-2-yl) -9H-purin-6-amine (0.87g, 2mmol) (preparation 9), palladium (II) acetate (0.002g, 0.009mmol), 1' -bis (diphenylphosphino) ferrocene (0.033g, 0.06mmol), 10M aqueous sodium hydroxide (0.6ml, 6mmol) and tetrahydrofuran (4ml) was heated at 140 ℃ under a carbon monoxide atmosphere for 12 hours at 1725kPa (250 psi). The mixture was allowed to cool and to stand at room temperature for 16 days, during which time a suspension formed. The solid was collected by filtration and washed with tetrahydrofuran (10 ml). This material was added to a mixture of dichloromethane (35ml) and water (25ml), and the pH of the mixture was adjusted to 1 by adding dilute aqueous hydrochloric acid with stirring. The layers were separated and the aqueous phase was extracted with dichloromethane (25 ml). The combined organic phases were dried (MgSO)₄) And the solvent was removed under reduced pressure to give the title compound as an amber foam (0.45g) using¹H-NMR, high performance liquid chromatography, mass spectrometry and thin layer chromatography, which were the same as the compound prepared in preparation example 21.

Pharmacological Activity

The compounds of each of the preceding examples were tested for their anti-inflammatory activity by determining their ability to inhibit neutrophil function (which is indicative of A2a receptor agonist activity) using the method described on page 19, all compounds IC₅₀Are all less than 1 micromolar.

Claims (21)

1. A compound of formula (I):

or a pharmaceutically acceptable salt or solvate thereof,

wherein R is¹Is 2, 2-diphenylethyl;

R²is H;

a is methylene, 1, 2-ethylene or 1, 3-propylene;

R³is phenyl, or R³Is a 2-pyridyl group, which is,

or when A is 1, 2-ethylene or 1, 3-propylene, R³is-N (CH)₃)₂，

Or when A is 1, 2-ethylene or 1, 3-propylene, R³Is pyrrolidin-1-yl, piperidin-1-yl, 4-isopropylpiperidin-1-yl or morpholin-4-yl.

2. The compound of claim 1, wherein a is 1, 2-ethylene.

3. The compound of claim 1, wherein-A-R³Is 2- (1-piperidinyl) ethyl.

4. The compound of claim 1, selected from the group consisting of:

9- [ (2R, 3R, 4S, 5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydro-2-furanyl ] -6- [ (2, 2-diphenylethyl) amino ] -N- [2- (1-piperidinyl) ethyl ] -9H-purine-2-carboxamide;

9- [ (2R, 3R, 4S, 5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydro-2-furanyl ] -6- [ (2, 2-diphenylethyl) amino ] -N-phenethyl-9H-purine-2-carboxamide;

9- [ (2R, 3R, 4S, 5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydro-2-furanyl ] -6- [ (2, 2-diphenylethyl) amino ] -N- [2- (4-isopropyl-1-piperidinyl) ethyl ] -9H-purine-2-carboxamide;

9- [ (2R, 3R, 4S, 5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydro-2-furanyl ] -6- [ (2, 2-diphenylethyl) amino ] -N- [3- (1-pyrrolidinyl) propyl ] -9H-purine-2-carboxamide;

9- [ (2R, 3R, 4S, 5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydro-2-furanyl ] -6- [ (2, 2-diphenylethyl) amino ] -N- [2- (4-morpholinyl) ethyl ] -9H-purine-2-carboxamide;

9- [ (2R, 3R, 4S, 5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydro-2-furanyl ] -6- [ (2, 2-diphenylethyl) amino ] -N- (2-pyridylmethyl) -9H-purine-2-carboxamide;

9- [ (2R, 3R, 4S, 5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydro-2-furanyl ] -6- [ (2, 2-diphenylethyl) amino ] -N- [2- (2-pyridyl) ethyl ] -9H-purine-2-carboxamide; and

9- [ (2R, 3R, 4S, 5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydro-2-furanyl ] -N- [2- (dimethylamino) ethyl ] -6- [ (2, 2-diphenylethyl) amino ] -9H-purine-2-carboxamide;

or a pharmaceutically acceptable salt or solvate thereof.

5. The compound of claim 1 which is 9- [ (2R, 3R, 4S, 5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydro-2-furanyl ] -6- [ (2, 2-diphenylethyl) amino ] -N- [2- (1-piperidinyl) ethyl ] -9H-purine-2-carboxamide, or a pharmaceutically acceptable salt or solvate thereof.

6. A pharmaceutical composition which comprises a compound of formula (I) as claimed in any one of the preceding claims, in association with a pharmaceutically acceptable excipient, diluent or carrier.

7. Use of a compound of formula (I) as defined in claim 1, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament having A2a receptor agonist activity.

8. Use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof as claimed in claim 1 in the manufacture of an anti-inflammatory agent.

9. Use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof as claimed in claim 1 in the manufacture of a medicament for use in the treatment of a respiratory disorder.

10. The use according to claim 9, wherein the disease is selected from the group consisting of: adult respiratory distress syndrome, bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, asthma, emphysema, bronchiectasis, chronic sinusitis and rhinitis.

11. A process for the preparation of a compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof, comprising:

a) a compound of formula (II):

wherein R is¹As defined in claim 1, and X is a leaving group selected from the group consisting of bromine, iodine, -Sn (C)₁-C₁₂Alkyl radical)₃Or CF₃SO₂O-，

Aminocarbonylation with a compound of formula (III) in the presence of carbon monoxide and a suitable coupling catalyst:

R²NH-A-R³ (III)

a, R therein²And R³As defined in claim 1; or

b) Deprotecting a compound of formula (VI):

a, R therein¹、R²And R³As defined in claim 1, when R is⁸And R⁹When taken separately, they are protecting groups, or when taken together, are a protecting group; or

c) Deprotecting a compound of formula (XII):

a, R therein¹、R²And R³As defined in claim 1, and R¹¹、R¹²And R¹³When taken separately, are all protecting groups, or R¹¹Is a protecting group and R¹²And R¹³Taken together as a protecting group; or

d) A compound of formula (XXV):

wherein R is¹As defined in claim 1, and R¹⁷Is H, C₁-C₄Alkyl or benzyl, with a compound of formula (III) as defined in part (a), and if R¹⁷When is H, in the presence of a peptide coupling agent;

any of the said one-step procedures may optionally be followed by a "conversion to a pharmaceutically acceptable salt thereof" step.

12. A compound of formula (II):

wherein X is a leaving group selected from the group consisting of bromine, iodine, -Sn (C)₁-C₁₂Alkyl radical)₃Or CF₃SO₂O-; or

A compound of formula (VI):

wherein when R is⁸And R⁹When taken separately, they are protecting groups, or when taken together, are a protecting group; or

A compound of formula (X):

wherein when R is⁸And R⁹When taken separately, they are all protecting groups, or when taken together, are a protecting group, and R is¹⁰Is a protecting group; or

A compound of formula (IX):

wherein when R is⁸And R⁹When taken separately, they are all protecting groups, or when taken togetherWhen it is a protecting group, and R¹⁰Is a protecting group; or

A compound of formula (XII):

wherein R is¹¹、R¹²And R¹³When taken separately, are all protecting groups, or R¹¹Is a protecting group and R¹²And R¹³Taken together as a protecting group; and A, R¹、R²And R³As defined in claim 1.

13. A compound of formula (II) as claimed in claim 12 wherein X is iodine.

14. A compound of formula (VI), (IX) or (X) as claimed in claim 12 wherein R⁸And R⁹When taken separately, are each acetyl or benzoyl, or when taken together are 1, 1-dimethylmethylene.

15. A compound of formula (IX) or (X) as claimed in claim 12 wherein R is¹⁰Is a silyl protecting group.

16. The compound as recited in claim 15 wherein R¹⁰Is tert-butyldimethylsilyl or tert-butyldiphenylsilyl.

17. A compound of formula (XII) as claimed in claim 12, wherein R is¹¹、R¹²And R¹³When taken separately, are each acetyl or benzoyl, or R¹²And R¹³When taken together, is 1, 1-dimethylmethylene.

18. A compound of formula (XXV):

wherein R is¹⁷Is H, C₁-C₄Alkyl or benzyl; or

A compound of formula (XXVI):

wherein R is¹¹、R¹²And R¹³When taken separately, are all protecting groups, or R¹¹Is a protecting group and R¹²And R¹³Taken together as a protecting group, and R¹⁷Is C₁-C₄Alkyl or benzyl; and R is¹As defined in claim 1.

19. A compound of formula (XXV) or (XXVI) as claimed in claim 18, wherein R is¹⁷Is C₁-C₄An alkyl group.

20. The compound as recited in claim 19 wherein R¹⁷Is methyl or ethyl.

21. A compound of formula (XXVI) as claimed in claim 18, wherein R is¹¹、R¹²And

R¹³when taken separately, are each acetyl or benzoyl, or R¹²And R¹³When taken together, is 1, 1-dimethylmethylene.