ZA200306769B

ZA200306769B - Chemical compounds.

Info

Publication number: ZA200306769B
Application number: ZA200306769A
Authority: ZA
Inventors: Adrian Hall; Jandu Karamjit Singh; Lunniss Christopher James; Vinader Maria Victoria; West Robert Ian
Original assignee: Glaxo Group Ltd
Priority date: 2001-03-20
Filing date: 2003-08-29
Publication date: 2004-06-18
Also published as: GB0106877D0

Description

CHEMICAL COMPOUNDS

Field of the Invention

The present invention is concerned with pharmaceutical compositions containing certain adenosine derivatives having an acetylene group in the 4' position, which are adenosine A1 agonists, and to their use in therapy. In particular, it is concerned with the use of these adenosine derivatives in treating conditions where there is an advantage in decreasing plasma free fatty acid concentration, or reducing heart rate or which subject is suffering from or susceptible to ischaemic heart disease, peripheral vascular disease or stroke or which subject is suffering pain, a CNS disorder, sleep apnoea or emesis.

Background of the Invention

A variety of compounds which are agonists at the adenosine A1 receptor have been described in the art. These include compounds described in published patent applications W099/24449, W099/24450, W099/24451, WO97/43300,

WO98/16539, WO98/04126, WO98/01459, EP0322242, GB2226027,

EP222330, W098/08855, W094/0707, W099/67262 and WO00/23447.

For example, WO 99/67262 (Glaxo Group Limited) discloses compounds of formula (I) which are agonists at the adenosine A1 receptor and their use in treating a patient suffering from a condition where there is an advantage in decreasing plasma free fatty acid concentration, or reducing heart rate or which subject is suffering from or susceptible to ischaemic heart disease, peripheral vascular disease or stroke or which subject is suffering pain, a CNS disorder or sleep apnoea:

f rR’ ’ NH

A . 0)

ZZ

Y X

O os wo

R'0" OR? wherein Y and Z represent O, N, CH, N(C_s alkyl);

W represents CH, O, N, S, N(C1 alkyl); and wherein at least one of W and Z represents a heteroatom (and when Y, Z and/or W is N, the presence or absence of an additional H would be apparent to a person skilled in the art); with the proviso that when W represents CH, Z represents N and Y represents 0, R® cannot be H.

The compounds disclosed in W099/67262 (Glaxo Group Limited) are made, for example, via intermediates which have an acetylene group in the 4’ position.

The present inventors have surprisingly found that adenosine derivatives with an acetylene group in the 4’ position exhibit Adenosine A1 agonist activity.

Summary of the Invention

The present invention provides compounds of formula (la):

‘ rR i oe

AP o

RG" oR" (1a) wherein X represents O or CH;

R' represents: () -(alk)s-(Cag)cycloalkyl or -(alk),~(Cs.g)cycloalkenyl, said cycloalkyl or cycloalkenyl group being optionally substituted by one or more substituents selected from OH, halogen, Cisalkyl, -Cisalkoxy, C,. salkenyloxy-, Caesalkynyloxy- and phenyl, wherein (alk) represents Ci. salkyl and n represents 0 or 1, and said (alk) group may be optionally substituted by a Cs.scycloalkyl group; (i) a phenyl group optionally substituted by one or more substituents selected from: halogen, CFj; cyano, -Cisalkyl, -Cpealkenyl, -Cogalkynyl, Ci. salkoxy-, -C16alkylOH, -CO-H and -CO,Ci5 alkyl; (iii) a Casheterocyclic group containing at least one heteroatom selected from

O, Nor S, and optionally substituted by one or more substituents selected from: OH, -C.salkyl, -C.salkoxy, -COC1.salkyl, -COC1.4alkyl, -CO,aryl or -

COx(alk)s(Cas)cycloalkyl, wherein (alk) represents Cjsalkyl and n represents O or 1; (iv) a straight or branched Cj.j,alkyl group optionally substituted by one or more groups selected from phenyl, halogen, hydroxy, and Cs; cycloalkyl, ‘ wherein one or more carbon atoms of the Ci.i2alkyl group may be optionally replaced by a group independently selected from S(=0), . (where nis 0, 1 or 2) and N; (v) a fused bicyclic ring wherein A represents C4scycloalkyl or phenyl and B represents phenyl optionally substituted by Ci.salkyl, and the bicyclic ring is attached to the purine-6-amino moiety via a ring atom of ring A;

R? represents -C1.salkyl, halogen, hydrogen or C4_salkoxy group;

R® and R* independently represent H or a -C1.¢alkyl group; or pharmaceutically acceptable derivatives thereof.

Further aspects of the invention are: - A pharmaceutical composition comprising a compound of formula (la) or a pharmaceutically acceptable derivative thereof together with a pharmaceutical carrier and/or excipient. - Use of a compound of formula (la) or a pharmaceutically acceptable derivative thereof for the manufacture of a medicament for the treatment of a patient suffering from a condition where there is an advantage in decreasing plasma free fatty acid concentration, or reducing heart. - Use of a compound of formula (la) or a pharmaceutically acceptable derivative thereof for the manufacture of a medicament for the treatment of a patient suffering from or susceptible to ischaemic heart disease, peripheral vascular disease or stroke or which subject is suffering pain, a CNS disorder, sleep apnoea or emesis. - A method of treating a patient suffering from a condition where there is an advantage in decreasing plasma free fatty acid concentration, or reducing . heart rate comprising administering a therapeutically effective amount of a compound of formula (la) or a pharmaceutically acceptable derivative thereof. - A method of treating a patient suffering or susceptible to ischaemic heart disease, peripheral vascular disease or stroke or which subject is suffering

’ pain, a CNS disorder, sleep apnoea, or emesis comprising administering a therapeutically effective amount of a compound of formula (la) or a ' pharmaceutically acceptable derivative thereof. 5 Detailed Description of the Invention

The compounds useful in the invention are agonists at the adenosine A1 receptor. Preferably they are selective agonists at the adenosine A1 receptor.

By selective is meant that the affinity for the A1 receptor is at least 2 times, preferably 5 times and more preferably 10 times greater than the other adenosine receptor subtypes, particularly A3. Agonist selectivity of compounds against other human adenosine receptors can be determined using Chinese hamster ovary (CHO) cells transfected with the gene for the relevant human adenosine receptor following a method based on that of Castanon, KV. and

Spevak, W. (1994) Biochem. Biophys. Res. Commun. 198, 626-631. The CHO cells are also transfected with cyclic AMP response elements promoting the gene for secreted placental alkaline phosphatase (SPAP) (Wood, KV. (1995)

Curr. Opinion. Biotechnology, 8, 50-58). The effect of test compounds is determined by their effects on basal levels of cAMP (A2a) or on forskolin- enhanced cAMP (A1 and A3) as reflected by changes in levels of SPAP. ECs, values for compounds are determined as a ratio to that of the non-selective agonist N-ethyl carboxamidoadenosine (NECA). "Adenosine receptors: New opportunities for future drugs” (S.A. Poulsen ef al, Bioorg. Med. Chem,. 1998, 6, 619-641) summarises disease conditions that may be treated with adenosine A1 agonists.

The compounds of formula (la) contain chiral (asymmetric) centres. The individual stereoisomers (enantiomers and diastereocisomers) and mixtures of these are within the scope of the present invention. . 30

As used herein, the terms “alkyl” and “alkoxy” mean both straight and branched . chain saturated hydrocarbon groups. Examples of alkyl groups include methyl, ethyl, propyl and butyl groups. Examples of alkoxy groups include methoxy and ethoxy groups. Other examples include propoxy and butoxy. Alkyl groups may be unsubstituted, or substituted with one to four substituents, preferably one to three substituents as defined hereinabove.

One to three, preferably one or two, carbon atoms of an alkyl chain may be replaced by a group independently selected from S(=0), (where n is 0, 1 or 2) and N. When the heteroatom N replaces a carbon atom in a Cy_1palkyl group the

N atom will, where appropriate be substituted by one or two substituents selected from hydrogen and C_salkyl.

As used herein, the terms “alkenyl”, "alkenyloxy”, “alkynyl” and "alkynyloxy” mean both straight and branched chain unsaturated hydrocarbon groups.

Examples of alkenyl groups include ethylene and propylene. Examples of alkynyl groups include ethynyl and propynyl. Examples of alkenyloxy groups include propenyioxy and ethenyloxy. Examples of alkynyloxy groups include propynyloxy and ethylyloxy.

As used herein, the term “halogen” means fluorine, chlorine, bromine or iodine.

As used herein, the term “aryl” means monocyclic or bicyclic aromatic carbocyclic groups such as phenyl and naphthyl, especially phenyl.

As used herein, the term “cycloalkyl” means an aliphatic group having 3 to 9 carbon atoms in the ring system unless otherwise defined. The cycloalkyl group can be monocyclic or bicyclic. A bicyclic group may be fused or bridged.

Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl and cyclopentyl. Other examples of monocyclic cycloalkyl groups are cyclohexyl, cycloheptyl and cyclooctyl. Examples of bicyclic cycloalkyl groups include bicyclo[2.2.1]hept-2-yl. Preferably, the cycloalkyl group is monocyclic.

Cycloalkyl groups may be unsubstituted, or substituted with one to four substituents, preferably one or two substituents as defined hereinabove. . As used herein, the term “cycloalkenyl” means a partially unsaturated aliphatic group having 3 to 9 carbon atoms in the ring system. The cycloalkenyl! group can be monocyclic or bicyclic. Preferably, the cycloalkyl group is monocyclic.

Examples of monocyclic cycloalkenyl groups include cyclopentenyl and cyclohexenyl. Cycloalkenyl groups may be unsubstituted, or substituted with one to four substituents, preferably one or two substituents.

As used herein, the term “heterocyclic” means a cyclic group of 4 to 7 carbon atoms wherein one or more of the carbon atoms is/are replaced by heteroatoms independently selected from nitrogen, oxygen or sulfur. The heterocycle may be aromatic or non-aromatic, i.e., may be saturated (i.e. aliphatic), partially or fully unsaturated. This group may optionally be substituted as defined hereinabove.

The heteroatom is preferably O or N. The heterocycle is preferably non- aromatic. Examples of heterocyclyl groups include piperidinyl, tetrahydrofuranyl and tetrahydropyranyl. Cycloalkyl groups may be unsubstituted, or substituted with one to four substituents, preferably one or two substituents. Heterocyclyl groups may be unsubstituted, or substituted with one to four substituents, preferably one or two substituents.

As used herein, the term “pharmaceutically acceptable derivative’, means any pharmaceutically acceptable salt, solvate, ester or amide, or salt or solvate of such ester or amide, of the adenosine A1 agonist, or any other compound which upon administration to the recipient is capable of providing (directly or indirectly) the adenosine A1 agonist or an active metabolite or residue thereof, e.g. a prodrug. Preferred pharmaceutically acceptable derivatives according to the invention are any pharmaceutically acceptable salts, solvates and prodrugs, more preferably pharmaceutically acceptable salts and solvates.

As used herein, the term “pharmaceutically acceptable” means a compound which is suitable for pharmaceutical use.

Pharmaceutically acceptable salts of the compounds of formula (la) include those derived from pharmaceutically acceptable inorganic and organic acids. : 30 Examples of suitable acids include hydrochloric, hydrobromic, sulphuric, nitric, perchloric, fumaric, maleic, phosphoric, giycollic, lactic, salicylic, succinic, ‘ toluene-p-sulphonic, tartaric, acetic, citric, methanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic and benzenesulfonic acids. Other acids such as oxalic, while not in themselves pharmaceutically acceptable, may be useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts.

Those skilled in the art of organic chemistry will appreciate that many organic compounds can form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as “solvates”. For example, a complex with water is known as a “hydrate”.

Solvates of the compound of formula (la) are within the scope of the invention.

As used herein, the term “prodrug” means a compound which is converted within the body, e.g. by hydrolysis in the blood, into its active form that has medical effects. Pharmaceutically acceptable prodrugs are described in T. Higuchi and

V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium

Series; and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design,

American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.

In an alternative aspect R' represents: (i) -(alk)a~(Cs.g)cycloalkyl, including bridged cycloalkyl, optionally substituted by one or more substituents selected from OH, halogen, Cs.;alkoxy- and phenyl, wherein (alk) represents Cqsalkyl and n represents 0 or 1; (ii) a phenyl group optionally substituted by one or more substituents selected from: halogen, CFs, cyano, -Cisalkyl, -C,.galkenyl, -Cogalkynyl, Cig alkoxy-, -C1.salkylOH, -CO2H and -C0O.C1.6 alkyl; (iif) a Cssheterocyclic group containing at least one heteroatom selected from

O, Nor S, and optionally substituted by one or more substituents selected from: OH, -Cisalkyl, -Cisalkoxy, -CO2(Cis)alkyl, -CO(Ci4)alkyl or -COqaryl; (iv) a straight or branched Ci.i.alkyl substituted by one or more groups : 30 selected from: S(=0), (where n is 0, 1 or 2) substituted within the alkyl chain, N substituted within the alkyl chain, phenyl, halogen, hydroxy or Cs. ‘ 7 cycloalkyl; (v) afused bicyclic ring wherein A represents C,.¢cycloalkyl or phenyl and B represents phenyl optionally substituted by Ci.3alkyl, and the bicyclic ring is attached to the nitrogen atom of formula (1) via a ring atom of ring A.

In a further aspect R' represents: () -(alkk)s-(Cazg)cycloalkyl, said cycloalkyl group being optionally substituted by one or more substituents selected from: OH, halogen, -Ci alkyl, C16 alkoxy-, and phenyl, wherein (alk) represents C.3alkyl and n represents 0 or 1; (i) a Cyraliphatic heterocyclic group containing at least one heteroatom selected from O, N or S, optionally substituted by one or more substituents selected from: -Cy.salkyl, -CO(C.4)alkyl, -CO4(C1.4)alkyl, and -COyphenyl; (ii) a straight or branched Cj.12alkyl group optionally substituted by one or more groups selected from: phenyl, S(=0), (where nis 0, 1 or 2) and N wherein each S(=0O),, or N replaces a carbon of the alkyl group.

In a further aspect R' represents a phenyl group optionally substituted by one or more substituents selected from: halogen, CFs, cyano, -C.salkyl, -Ca.salkenyl, - (C26)alkynyl, (C1.)alkoxy-, -(C1.g)alkylOH, -CO,H and -CO,(C15)alkyl.

In a yet further aspect R1 represents phenyl optionally substituted by one or more substituents selected from: halogen and -Cjgalky!; R? represents hydrogen or halogen; and R® and R* independently represent H or —C4_salkyl.

Conveniently, R' may represent (alk)n-(Cs-g)cycloalkyl wherein n is 0 or 1 and the said cycloalkyl is either unsubstituted or substituted by at least one substituent selected from -Cyealkyl, Cy.salkoxy-, phenyl and OH. Alternative substituents . 30 include at least one substituent selected from halogen, and Cas alkenyloxy-.

Preferably the cycloalkyl group is unsubstituted or monosubstituted by C,. salkyloxy-, Csalkenyloxy-, -Cs.ecycloalkyl, C4. alkyl, phenyl! or OH, or is mono- or disubstituted by halogen, for example fluorine. Alternatively the cycloalkyl group is unsubstituted or substituted with OH or Cy; alkyl. Preferably n is zero.

Preferably the cycloalkyl ring has 3 to 8 carbon atoms, more preferably 5 or 6 ’ carbon atoms. Cycloalkyl groups include hydroxycyclopentyl or methoxycyclohexyl. Other cycloalkyl groups include propenyloxycyclohexyl, difluorocyclohexyl, ethoxycyclohexyl, dicyclopropylmethyl, cyclooctyl and cycloheptyl. When n is 1, the (alk) group may be substituted, for example by cyclopropyl.

R' may represent (alk)n-(Cs.g)cycloalkenyl wherein n is 0 or 1 and the said cycloalkenyl is either substituted by at least one substituent selected from -C;. ealkyl, Cisalkoxy-, phenyl and OH or is unsubstituted. Alternative substituents include at least one substituent selected from halogen, -C..¢ alkenyloxy, and -Cs. 6 cycloalkyl. Preferably n is zero. More preferably, the cycloalkenyl group is unsubstituted. Preferably the cycloalkenyl ring has 5 or 6 carbon atoms, more preferably the ring is cyclohexenyl.

Alternatively, R' may represent a substituted or unsubstituted aliphatic heterocyclic group, the substitutent being selected from C;alkyl, -CO2(C1.4)alkyl or -COzphenyl. The substituent may also be -COx(alk)s(Css)cycloalky!.

Preferably the heterocyclic ring is 6 membered and more preferably contains only one O or N heteroatom. Conveniently, the aliphatic heterocyclic group is unsubstituted or, when substituted, the substituent is -CO2(Ci4)alkyl or -

CO2(alk)n(Cag)cycloalkkyl, the heteroatom is N and the substituent is directly attached to said ring nitrogen atom. Preferably when the heterocycle is substituted the substituent is -CO,(Ci4)alkyl, the heteroatom is N and the substituent is directly attached to said ring nitrogen atom. Most preferably when the heterocyclic ring is unsubstituted the heteroatom is O. Most preferably when the heterocyclic ring is substituted the heteroatom is N. : 30 Alternatively, R' may represent a straight or branched alkyl of 1-6 carbon atoms including one or more S(=0), groups (where n is 0, 1 or 2) each replacing a . carbon atom of the alkyl group, optionally substituted with N replacing a carbon atom at a position adjacent to the S(=0), group. Preferably n is 1 or 2, more preferably n is 2.

Alternatively, R' may represent phenyl optionally substituted one or two substitutents selected from halogen or Ci.galkyl. More preferably, R' preferably represents phenyl optionally substituted one or two substitutents selected from halogen or methyl. Preferably the halogen is fluorine, chlorine or bromine, more preferably fluorine or chlorine. Preferably the phenyl is disubstituted. Preferably the phenyl is disubstituted in the 2,3 or 2,4 or 2,5 positions. In an alternative aspect the phenyl is monosubstituted by Cj. alkyl, for example methyl.

In a preferred aspect of the invention, R* represents: (1) -(alk)n(Cs-0) cycloalkyl, said cycloalkyl group being optionally substituted by one or more substituents selected from OH, halogen, Cisalkyl, -C;. salkoxy, Casalkenyloxy- and phenyl, wherein (alk) represents Ci.zalkyl and n represents 0 or 1, and said (alk) group may be optionally substituted by a Cjecycloalkyl group; or R' represents (alk)n-(Cs. g)cycloalkenyl; (i) a Cusheterocyclic group containing at least one heteroatom selected from

O or N, optionally substituted by -Cigalkyl, -CO.Cisalkyl, or -

CO2(alk)n(Cs.s)cycloalkyl; or (ii) phenyl optionally substituted by halogen or Cq_salkyl.

In an alternative aspect of the invention, R' represents: (I -(alk)n(Csg) cycloalkyl, including bridged cycloalkyl, said cycloalkyl group being optionally substituted by one or more substituents selected from

OH, Ci.¢ alkyl, C1 alkoxy, and phenyl, wherein (alk) represents Ci.salkyl and n represents 0 or 1; (ii) a Caz heterocyclic group containing at least one heteroatom selected from

O or N, optionally substituted by -C,_galkyl, or -CO,C1.4alkyl; or (ii) phenyl optionally substituted by halogen or C,salkyl. in another aspect of the invention, R' represents: (i) ~(alk)a~(Csg)cycloalkyl, including bridged cycloalkyl, said cycloalkyl group - optionally substituted by one or more substituents selected from OH, -C,. ealkyl, -Cq.salkoxy, and phenyl; wherein (alk) represents Cy.zalkyl and n represents 0 or 1; or

(i) a C47 aliphatic heterocyclic group containing at least one heteroatom selected from O or N, optionally substituted by -C4.ealkyl or -CO,C_salkyl.

R? preferably represents hydrogen or halogen. More preferably, R? represents hydrogen or chlorine. Most preferably, R? represents hydrogen.

R® and R* preferably both represent hydrogen.

X preferably represents O.

When R'is Ci-12alkyl, the group is preferably substituted.

It is to be understood that the present invention covers all combinations of particular and preferred groups mentioned above.

Preferred compounds of the invention include: (2R,3R,4S,5R)-2-{6-[(4-chloro-2-fluorophenyl)amino]-9H-purin-9-yl}-5- ethynyltetrahydrofuran-3,4-diol; (2R,3R,48,5R)-2-{2-chloro-6-[(4-chloro-2-fluorophenyl)amino]-9H-purin-9-yl}-5- ethynyitetrahydrofuran-3,4-diol; (2R,3R,48,5R)-2-{6-[(2-chloro-4-fluorophenyl)amino]-9H-purin-9-yl}-5- ethynyltetrahydrofuran-3,4-diol; (2R,3R,4S,5R)-5-ethynyl-2-{6-[(4-fluoro-2-methylphenyl)amino}-9H-purin-9- yljtetrahydrofuran-3,4-diol: (2R,3R,4S,5R)-2-{6-[(2,4-difluorophenyl)amino}-9H-purin-9-yl}-5- ethynylitetrahydrofuran-3,4-diol; (2R,3R,4S,5R)-5-ethynyl-2-{6-[(3-fluoro-2-methylphenyl)amino]-9H-purin-9- yiitetrahydrofuran-3,4-diol; (2R,3R,4S,5R)-2-{6-[(3-chloro-2-methylphenyl)amino}-9H-purin-9-yl}-5- : 30 ethynyltetrahydrofuran-3,4-diol; (2R,3R,4S,5R)-2-{6-[(4-chloro-2-methylphenyl)amino]-9H-purin-9-yi}-5- . ethynyltetrahydrofuran-3,4-diol; (2R,3R,4S,5R)-2-{6-[(5-chloro-2-methylphenyl)amino]-9H-purin-9-yl}-5- ethynyltetrahydrofuran-3,4-diol; :

’ (2R,3R 48,5R)-2-{6-[(2-bromo-4-fluorophenyl)amino]-9H-purin-9-yl}-5- ethynyltetrahydrofuran-3,4-diol; ’ (2R,3R,48,5R)-2-{2-chloro-6-[(3-fluoro-2-methylphenyl)amino}-9H-purin-9-yl}-5- ethynyltetrahydrofuran-3,4-diol; (2R,3R,48 5R)-2-{6-[(3,4-difluorophenyl)amino}-9H-purin-9-yl}-5- ethynyltetrahydrofuran-3,4-diol;

N-ethyl-2-({9-[(2R,3R,4S,5R)-5-ethynyl-3,4-dihydroxytetrahydrofu ran-2-yl]-9H- purin-6-yl}amino)ethanesulfonamide:; ethyl 4-({9-{(2R,3R,48,5R)-5-ethynyl-3,4-dihydroxytetrahydrofuran-2-yl}-9H- purin-6-yl}amino)piperidine-1-carboxylate; (2R,3R 48 5R)-5-ethynyl-2-(6-{[(1S,2S)-2-hyd roxycyclopentyl]lamino}-9H-purin- 9-yl)tetrahydrofuran-3,4-diol; (2R,3R 4S 5R)-2-[6-indan-2-ylamino)-9H-pu rin-9-yl}-5-ethynyltetrahydrofuran- 3,4-diol; 16 (2R,3R ,48,5R)-2-[6-(cyclobutylamino)-9H-purin-9-yi}-5-ethynyitetrahydrofuran- 3,4-diol; (2R,3R,48,5R)-5-ethynyl-2-{B-[(2-phenylethyl)amino}-9H-purin-9- yljtetrahydrofuran-3,4-diol; (2R,3R,4S,5R)-2-[6-(cyclohexylamino)-9H-purin-9-yl}-5-ethynyltetrahydrofuran- 3,4-diol; (2R,3R,48,5R)-5-ethynyl-2-(6-{[(15*,25*,3S*,4R*)-3-methylbicyclo[2.2. 1]hept-2- ylJamino}-9H-purin-9-yl)tetrahydrofuran-3,4-diol: (2R,3R 4S ,5R)-5-ethynyl-2-(6-{[(1R**2S)-2-methoxy-2- phenylcyclopentyllamino}-9H-purin-9-yhtetrahydrofuran-3,4-diol; (2R,3R,4S,5R)-2-[6-(cyclopropylamino)-9H-purin-8-yi]-5-ethynyltetrahydrofuran- 3,4-diol; (2R,3R,4S,5R)-2-{6-[(cyclopropylmethyl)amino]-9H-purin-9-yl}-5- ethynyltetrahydrofuran-3,4-diol; (2R,3R,4S,5R)-2-[6-(cyclopentylamino)-9H-purin-9-yl}-5-ethynyltetrahydrofuran- 3,4-diol; (2R,3R,48,5R)-5-ethynyl-2-(6-{[(2R,3R)-2-methyltetrahydrofuran-3-ylJamino}-9H- . purin-9-yl)tetrahydrofuran-3,4-diol; (2R,3R,4S,5R)-5-ethynyl-2~(6-{[(2S,3S)-2-methyltetrahyd rofuran-3-yllamino}-9H- purin-9-yltetrahydrofuran-3,4-diol;

(2R,3R,48,5R)-5-ethynyl-2-{6-[(trans-4-methoxycyclohexyl)amino}-9H-purin-9- yl}tetrahydrofuran-3,4-diol; ’ 2R,3R,4S,5R)-5-ethynyl-2-{6-[(trans-4-ethoxycyclohexyl)amino]-9H-purin-9- yi}tetrahydrofuran-3,4-diol;

2R,3R,48,5R)-5-ethynyl-2-{6-[(trans-4-propenyloxycyclohexyl)amino}-9H-purin- 9-yl}tetrahydrofuran-3,4-diol; (2R,3R,48,5R)-5-ethynyl-2-[6-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9- ylltetrahydrofuran-3,4-diol;

(2R,3R,4S,5R)-2-{6-[(1 R*,5R*,65*)-bicyclo[3.2.0}hept-6-ylamino}-9H-puri n-9-yl}-

5-ethynyltetrahydrofuran-3,4-diol; (2R,3R,48,5R)-2-{6-](2,2-dimethylcyclopropyl)amino}-9H-purin-9-yl}-5- ethynyltetrahydrofuran-3,4-diol;

(2R,3R,4S,5R)-5-ethynyl-2-{6-[(trans-4-hyd roxycyclohexyl)amino}-9H-purin-9- yl}tetrahydrofuran-3,4-diol;

(2R,3R,4S,5R)-2-{6-[(2-methylphenyl)amino]-9H-purin-9-yi}-5- ethynyltetrahydrofuran-3,4-diol; (2R,3R,48,5R)-2-{6-[(4-methylphenyi)amino]-9H-purin-9-yl}-5- ethynyitetrahydrofuran-3,4-diol; (2R,3R,4S,5R)-2-{6-[(3-chloro-2-fluorophenyl)amino}-9H-purin-9-yl}-5-

ethynyltetrahydrofuran-3,4-diol: (2R,3R,4S,5R)-2-{6-(2-fluoro-5-methylphenyl)amino}-9H-purin-9-y1}-5- ethynyltetrahydrofuran-3,4-diol; buty! 4-({9-[(2R,3R,48,5R)-5-ethynyl-3,4-dihyd roxytetrahydrofuran-2-yl}-9H- purin-6-yl}amino)piperidine-1-carboxylate;

cyclopropylmethyl 4-({9-[(2R,3R,4S,5R)-5-ethynyl-3,4-dihydroxytetrahydrofuran- 2-yl}-9H-purin-6-yl}amino)piperidine-1-carboxylate: (2R,3R,4S,5R)-5-ethynyl-2-{(6-[(1 S,28)-2-methoxycyclopentylJamino}-9H-purin- 9-yltetrahydrofuran-3,4-diol; (2R,3R,4S,5R)-5-ethynyl-2-{6-[(4,4-difluoro)cyclohexyljamino}-9H-purin-9-

yl)tetrahydrofuran-3,4-diol; (2R,3R4S,5R)-5-ethynyl-2-{6-[(cyclohex-3-enyl)amino]}-9H-purin-9-

. yhtetrahydrofuran-3,4-diol; (2R,3R,4S,5R)-5-ethynyl-2-{6-(dicyclopropylmethyl)amino]-9H-purin-9- yhtetrahydrofuran-3,4-diol;

(2R,3R,4S,5R)-5-ethynyl-2-[6-(cyclooctyl)amino]-9H-purin-9-yl)tetrahydrofuran- 3,4-diol; (2R,3R,4S,5R)-5-ethynyl-2-[6-(cycloheptyl)amino]-9H-purin-9-yltetrahydrofuran- 3,4-diol; (2R,3R,4S,5R)-5-ethynyl-2-{6-[(1R*,4S*)-4-methoxy-cyclohept-2-enylamino)-9H- purin-9-yl}-tetrahydrofuran-3,4-diol; or (2R,3R,4S,5R)-5-ethynyl-2-{6-[(1S*,4R*)-4-methoxy-cyclohept-2-enylamino)-9H- : purin-9-ylj-tetrahydrofuran-3,4-diol.

Particularly preferred compounds of the invention include: (2R,3R,48,5R)-2-{6-[(2-chloro-4-fluorophenyl)amino]-9H-purin-9-yl}-5- ethynyltetrahydrofuran-3,4-diol; (2R,3R,4S,5R)-5-ethynyl-2-{6-[(4-fluoro-2-methylphenyl)amino]-9H-purin-9- yl{etrahydrofuran-3,4-diol; (2R,3R,48,5R)-5-ethynyl-2-{6-[(3-fluoro-2-methylphenyl)amino]-9H-purin-9- yl}tetrahydrofuran-3,4-diol; (2R,3R,4S,5R)-2-{6-[(3-chloro-2-methylphenyl)amino}-9H-purin-9-yl}-5- ethynyltetrahydrofuran-3,4-diol; (2R,3R,4S,5R)-2-{6-[(4-chloro-2-methyiphenyl)amino]-9H-purin-9-yi}-5- ethynyltetrahydrofuran-3,4-diol; ethyl 4-({9-[(2R,3R,48S,5R)-5-ethynyl-3,4-dihydroxytetrahydrofuran-2-yl}-9H- purin-6-yl}amino)piperidine-1-carboxylate; (2R,3R,48,5R)-5-ethynyl-2-(6-{[(1S,2S)-2-hydroxycyclopentylJamino}-9H-purin-9- yhtetrahydrofuran-3,4-diol; (2R,3R 4S,5R)-5-ethynyl-2-[6-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9- yljtetrahydrofuran-3,4-diol; (2R,3R,48,5R)-5-ethynyl-2-{6-[(trans-4-methoxycyclohexyl)amino]-9H-purin-9- yl}tetrahydrofuran-3,4-diol; 2R,3R,4S,5R)-5-ethynyl-2-{6-[(trans-4-ethoxycyclohexyl)amino]-9H-purin-9- yi}tetrahydrofuran-3,4-diol; 2R,3R,4S,5R)-5-ethynyl-2-{6-[(trans-4-propenyloxycyclohexyl)amino]-SH-purin- - 9-yi}tetrahydrofuran-3,4-diol; (2R,3R,45,5R)-2-{6-[(1R* 5R*,6 S*)-bicyclo[3.2.0]hept-6-ylamino]-9H-purin-9-yl}- 5-ethynyltetrahydrofuran-3,4-diol; or

(2R,3R,48,5R)-2-{6-[(2,2-dimethyicyclopropyl)amino}-9H-purin-9-yi}-5- ethynyltetrahydrofuran-3,4-diol.

Compounds according to the invention have applicability as inhibitors of lipolysis i.e. they decrease plasma free fatty acid concentrations. The compounds may thus be used in the treatment of hyperlipidaemias. Furthermore, as a consequence of their anti-lipolytic activity, the compounds have the ability to lower elevated blood glucose, insulin and ketone body levels and therefore may be of value in the therapy of diabetes. Since antilipolytic agents have hypolipidaemic and hypofibrinogenaemic activity, the compounds may also show anti-atherosclerotic activity. The assay described by P. Strong ef al. in Clinical

Science (1993), 84, 663-669 may be used to determine the anti-lipolytic activity of compounds of the invention by their ability to lower the concentration of non- esterified fatty acids (NEFA) in starved rats.

In addition to their anti-lipolytic effect, the compounds of the invention may independently affect cardiac function by reducing heart rate and conduction.

The compounds may thus be used in the therapy of a number of cardiovascular disorders, for example cardiac arrythmias, particularly following myocardial infarction, and angina. The compounds may also inhibit renin release and thus be of use in the therapy of hypertension and heart failure.

Furthermore, the compounds of the invention are useful as cardioprotective agents, having applicability in the treatment of ischaemic heart disease. As used herein the term “ischaemic heart disease” includes damage associated with both myocardial ischaemia and reperfusion, for example, associated with coronary artery bypass grafting (CABG), percutaneous translumenal coronary angioplasty (PTCA), cardioplegia, acute myocardial infarction, thrombolysis, stable and unstable angina and cardiac surgery including in particular cardiac transplantation. The compounds of the invention additionally are useful for treating ischaemic damage to other organs. The compounds of the invention : may also be valuable in the treatment of other disorders arising as a result of widespread atheromatous disease, for example, peripheral vascular disease (PVD) and stroke.

The compounds of the invention may also be useful as CNS agents (e.g. as hypnotics, sedatives, analgestics and/or anti-convulsants particularly finding use in the treatment of epilepsy). They are therefore useful in treating or preventing pain. They may be used to improve the condition of a host, typically of a human being, suffering from pain. They may be employed to alleviate pain in a host.

Thus, a compound of formula (la) and its pharmaceutically acceptable acid addition salts may be used as a preemptive analgesic to treat acute pain such as musculoskeletal pain, post operative pain and surgical pain, chronic pain such as chronic inflammatory pain (e.g. rheumatoid arthritis and osteoarthritis), neuropathic pain (e.g. post herpetic neuralgia, diabetic neuropathies associated with diabetes, trigeminal neuralgia, pain associated with functional bowel disorders, e.g. irritable bowel syndrome, non cardiac chest pain and sympathetically maintained pain) and pain associated with cancer and fibromyalgia. The compound of formula (la) may also be used in the treatment or prevention of migraine or of pain associated with migraine, tension headache and cluster headaches, pain associated with functional bowel disorders (e.g.

IBS), non cardiac chest pain and non ulcer dyspepsia. The compound of formula (la) may also be used in the treatment of nociceptive pain (e.g. headaches, labour pain, menstrual pain and early post-operative pain).

In addition, the compounds of the invention may find use in the treatment of sleep apnoea.

In addition, the compounds of the invention may find use in the treatment of emesis. Treatment of emesis includes treatment of nausea, retching and vomiting. Emesis includes acute emesis, delayed emesis and anticipatory emesis.

Accordingly, the invention provides a compound of formula (la) or a : 30 pharmaceutically acceptable derivative thereof for use in therapy, and in particular in the treatment of human or animal subjects suffering from a condition i in which there is an advantage in decreasing plasma free fatty acid concentration, or reducing heart rate and conduction, or whereby the therapy involves the treatment of ischaemic heart disease, peripheral vascular disease or stroke or which subject is suffering from a pain, a CNS disorder, sleep apnoea or emesis.

In another aspect, the invention provides a method of treatment of a human or animal subject suffering from a condition in which there is an advantage in decreasing plasma free fatty acid concentration, or reducing heart rate and conduction, or which subject is suffering from or susceptible to ischaemic heart disease, peripheral vascular disease or stroke, or which subject is suffering from pain, a CNS disorder, sleep apnoea or emesis, which method comprises administering to the subject an effective amount of a compound of formula (la) or a pharmaceutically acceptable derivative thereof.

In another aspect the invention also provides for the use of a compound of formula (la) or a pharmaceutically acceptable derivative thereof for the manufacture of a medicament for the treatment of human or animal subjects suffering .from a condition in which there is an advantage in decreasing plasma free fatty acid concentration, or reducing heart rate and conduction, or which subject is suffering from or susceptible to ischaemic heart disease, peripheral vascular disease (PVD) or stroke, or which patient is suffering from pain, a CNS disorder, sleep apnoea or emesis.

In respect of the above mentioned ischaemic treatment, the methods of the present invention are applicable not only where ischaemia is planned or expected, for example in cardiac surgery, but also in cases of sudden or unexpected ischaemia, for example in heart attack and unstable angina.

In a preferred aspect, the invention provides a compound of formula (la) or a pharmaceutically acceptable derivative thereof for use in therapy, and in particular in the treatment of human or animal subjects of conditions associated with pain including acute pain, chronic pain, inflammatory pain, neuropathic pain, nociceptive pain and pain associated with migraine, tension headaches, cluster : headaches and functional bowel disorder. In an alternative embodiment, the invention provides a compound of formula (la) or a pharmaceutically acceptable derivative thereof for use in therapy, and in particular in the treatment of human or animal subjects of conditions associated with pain including acute pain,

chronic pain, inflammatory pain, neuropathic pain and pain associated with migraine, tension headaches, cluster headaches and functional bowel disorder.

In another aspect, the invention provides a method of treatment of a human or animal subject suffering from a condition associated with pain including acute pain, chronic pain, inflammatory pain, neuropathic pain, nociceptive pain and pain associated with migraine, tension headaches, cluster headaches and functional bowel disorder; alternatively acute pain, chronic pain, inflammatory pain, neuropathic pain and pain associated with migraine, tension headaches, cluster headaches and functional bowel disorder; which method comprises administering to the subject an effective amount of a compound of formula (la) or a pharmaceutically acceptable derivative thereof.

In another aspect the invention also provides for the use of a compound of formula (la) or a pharmaceutically acceptable derivative thereof for the manufacture of a medicament for the treatment of human or animal subjects suffering from a condition associated with pain including acute pain, chronic pain, inflammatory pain, neuropathic pain, nociceptive pain and pain associated with migraine, tension headaches, cluster headaches and functional bowel disorder. In an alternative embodiment the invention provides for the use of a compound of formula (la) or a pharmaceutically acceptable derivative thereof for the manufacture of a medicament for the treatment of human or animal subjects suffering from a condition associated with pain including acute pain, chronic pain, inflammatory pain, neuropathic pain and pain associated with migraine, tension headaches, cluster headaches and functional bowel disorder.

It will be appreciated that reference to treatment includes acute treatment or prophylaxis as well as the alleviation of established symptoms.

While it is possible that compounds of the invention may be administered as the : 30 raw material, it is preferable to present the active ingredient as a pharmaceutical formulation.

In a further aspect, the invention provides a pharmaceutical composition comprising at least one compound of formula (la) or a pharmaceutically acceptable derivative thereof in association with a pharmaceutically acceptable carrier and/or excipient. The carrier and/or excipient must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not ) deleterious to the receipient thereof.

In another aspect, the invention provides a pharmaceutical composition comprising, as active ingredient, at least one compound of formula (la) or a pharmaceutically acceptable derivative thereof in association with a pharmaceutically acceptable carrier and/or excipient for use in therapy, and in particular in the treatment of human or animal subjects suffering from a condition in which there is an advantage in decreasing plasma free fatty acid concentration, or reducing heart rate and conduction, or which subject is suffering from or susceptible to ischaemic heart disease, peripheral vascular disease or stroke, or which subject is suffering from a CNS disorder, sleep apnoea, pain or emesis.

There is further provided by the present invention a process of preparing a pharmaceutical composition, which process comprises mixing at least one compound of formula (la) or a pharmaceutically acceptable derivative thereof, together with a pharmaceutically acceptable carrier and/or excipient.

Compositions according to the invention may be formulated for topical, oral, buccal, parenteral or rectal administration or in a form suitable for administration by inhalation or insufflation. Oral administration is preferred. The compositions may be adapted for sustained release.

For topical administration, the pharmaceutical composition may be given in the form of a transdermal patch.

Tablets and capsules for oral administration may contain conventional excipients : 30 such as binding agents, for example mucilage of starch or polyvinylpyrrolidone: fillers, for example, lactose, microcrystalline cellulose or maize-starch; lubricants, : for example, magnesium stearate or stearic acid; disintegrants, for example, potato starch, croscarmellose sodium or sodium starch glycollate; or wetting agents such as sodium lauryl sulphate. The tablets may be coated according to methods well known in the art. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example, sorbitol syrup, methyl cellulose, or carboxymethyl cellulose; emulsifying agents, for example, sorbitan mono-oleate; non-aqueous vehicles (which may include edible oils), for example, propylene glycol or ethyl alcohol; and preservatives, for example, methyl or propyl p- hydroxybenzoates or sorbic acid. The preparations may also contain buffer salts, flavouring, colouring and sweetening agents (e.g. mannitol) as appropriate.

For buccal administration the compositions may take the form of tablets or lozenges formulated in conventional manner.

The compounds of formula (la) or pharmaceutically acceptable derivatives 156 thereof may be formulated for parenteral administration by bolus injection or continuous infusion and may be presented in unit dose form in ampoules, or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.

The compounds of formula (la) or pharmaceutically acceptable derivatives thereof may also be formulated as suppositories, e.g. containing conventional suppository bases such as cocoa butter or other glycerides.

A proposed dose of the compounds of the invention for administration to man (of approximately 70kg body weight) is 0.1mg to 2g, preferably 1mg to 2g, more preferably 1mg to 100mg, of the active ingredient per unit dose which could be administered, for example, 1 to 4 times per day. It will be appreciated that it may : 30 be necessary to make routine variations to the dosage, depending on the age and condition of the patient. The dosage will also depend on the route of : administration.

The compounds of formula (la) may also be used in combination with other therapeutic agents. The invention thus provides, in a further aspect, a combination comprising a compound of formula (la) or a pharmaceutically acceptable derivative thereof together with a further therapeutic agent.

When a compound of formula (la) or a pharmaceutically acceptable derivative thereof is used in combination with a second therapeutic agent active against the same disease state the dose of each compound may differ from that when the compound is used alone. Suitable second therapeutic agents for the treatment of pain include, for example, COX-2 inhibitor e.g. celecoxib, rofecoxib, valdecoxib, parecoxib, 4-(4-cyclohexyl-2-methyi-5-oxazolyi)-2- fluorobenzenesulfonamide (JTE-522), MK663, nimesulide, DFP, 2-(4-ethoxy- phenyl)-3-(4-methanesulfonyl-phenyl)-pyrazolo[1,5-b]pyridazine; 5HT1 agonists e.g. sumatriptan, naratriptan, zolmitriptan, eletriptan, rizatriptan, frovatriptan, almotriptan, alniditan, dihydroergotamine, donitriptan, PNU-142633, ALX-0646,

LY334370, U1092291, IS159, PNY142633; sodium channel blockers e.g. lamotrigine, R(-)-2,4-diamino-5-(2,3-dichlorophenyl)-6-fluoromethyl pyrimidine, 2,6-diamino-3-(2,3,5-trichlorophenyl)pyrazine, 5-amino-6-{2,3,5-trichlorophenyl}- 1,2,4-triazine; SHT3 antagonists e.g. alosetron; gabapentin; pregabalin; EP1 antagonists e.g. ZD6416, ZD6804; and opioids e.g. alfentanil, buprenorphine, codeine, dextropropoxyphene, diamorphine, dihydrocodeine, fentanyl, methadone, morphine, oxycodone, levorphanol, pentazocine, pethidine.

The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical formulation and thus pharmaceutical formulations comprising a combination as defined above together with a pharmaceutically acceptable carrier or excipient comprise a further aspect of the invention. The individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations by any convenient route.

When administration is sequential, either the adenosine A1 agonist or the : 30 second therapeutic agent may be administered first. When administration is simultaneous, the combination may be administered either in the same or : different pharmaceutical composition.

When combined in the same formulation it will be appreciated that the two compounds must be stable and compatible with each other and the other

Claims

1. A compound of formula (la): rR’ NH (7 AL] RO’ oR" (la) wherein X represents O or CHa; R! represents: () -~(alk)n-(Cs.o)cycloalkyl or -(alk),-(Cso)cycloalkenyl, said cycloalkyl or cycloalkenyl group being optionally substituted by one or more substituents selected from OH, halogen, Cisalkyl, -Cisalkoxy, Co. salkenyloxy-, Casalkynyloxy- and phenyl, wherein (alk) represents Cj. salkyl and n represents 0 or 1, and said (alk) group may be optionally substituted by a Cs scycloalkyl group; (ii) a phenyl group optionally substituted by one or more substituents selected from: halogen, CFs, cyano, -Ciealkyl, -C.ealkenyl, -Cagalkynyl, Ci. salkoxy-, -Cy_salkylOH, -CO,H and -CO,C1 alkyl; (ii) a Carheterocyclic group containing at least one heteroatom selected from O, N or §, and optionally substituted by one or more substituents selected from: OH, -C1alkyl, -Cigalkoxy, -CO2C14alkyl, -COC alkyl, -COzaryl or - COz(alk)n(Cse)cycloalkyl, wherein (alk) represents Cisalkyl and n represents O or 1; (iv) a straight or branched C;.i.alkyl group optionally substituted by one or more groups selected from phenyl, halogen, hydroxy, and Cs.; cycloalkyl, wherein one or more carbon atoms of the Cji.jzalkyl group may be optionally replaced by a group independently selected from S(=0), (where nis 0, 1 or 2) and N; (v) afused bicyclic ring wherein A represents Ca.scycloalkyl or phenyl and B represents phenyl optionally substituted by Cy.salkyl, and the bicyclic ring is attached to the purine-6-amino moiety via a ring atom of ring A; R? represents -C4.zalkyl, halogen, hydrogen or -C1.zalkoxy group; R® and R* independently represent H or a -Csalkyl group; or a pharmaceutically acceptable salt and/or solvate thereof.

2. A compound according to claim 1 wherein R? represents hydrogen or halogen.

3. A compound according to claim 1 or claim 2 wherein R® and R* each represent hydrogen. 4, A compound according to any one of claims 1 to 3 wherein X represents

0.

5. A compound selected from: (2R,3R 4S,5R)-2-{6-[(4-chloro-2-fluorophenyl)amino]-9H-purin-9-yi}-5- ethynyltetrahydrofuran-3,4-diol; (2R,3R,48,5R)-2-{2-chloro-6-[ (4-chloro-2-fluorophenyl)amino}-9H-purin-9-yl}-5- ethynyltetrahydrofuran-3,4-diol; (2R,3R,4S,5R)-2-{6-[(2-chloro-4-fluorophenyl)amino}-9H-purin-9-yl}-5- ethynyltetrahydrofuran-3,4-diol; (2R,3R 4S,5R)-5-ethynyl-2-{6-[(4-fluoro-2-methylphenyl)amino}-9H-purin-9- yltetrahydrofuran-3,4-diol; (2R,3R,4S,5R)-2-{6-{(2,4-difluorophenyl)amino}-9H-purin-9-yl}-5- ethynyltetrahydrofuran-3,4-diol;

(2R,3R,4S 5R)-5-ethynyl-2-{6-{(3-fluoro-2-methylphenyl)amino]-9H-purin-9- yi}tetrahydrofuran-3,4-diol; (2R,3R 48,5R)-2-{6-[(3-chloro-2-methylphenyl)amino]-9H-purin-9-yl}-5- ethynyltetrahydrofuran-3,4-diol;

(2R,3R 48,5R)-2-{6-[(4-chloro-2-methylphenyl)amino]-9H-purin-9-y1}-5- ethynyltetrahydrofuran-3,4-diol; (2R,3R,48,5R)-2-{6-[(5-chloro-2-methylphenyl)amino]-9H-purin-9-y}-5- ethynyltetrahydrofuran-3,4-diol; (2R,3R,4S,5R)-2-{6-[(2-bromo-4-fluorophenyl)amino]-9H-purin-9-yl}-5-

ethynyltetrahydrofuran-3,4-diol; (2R,3R,4S,5R)-2-{2-chloro-6-[(3-fluoro-2-methylphenyl)amino}-9H-purin-9-y1}-5- ethynyltetrahydrofuran-3,4-diol; (2R,3R,4S,5R)-2-{6-](3,4-difluorophenyl)amino]-9H-purin-9-yl}-5- ethynyltetrahydrofuran-3,4-diol;

N-ethyl-2-({9-[(2R,3R,4S,5R)-5-ethynyl-3,4-dihydroxytetrahydrofuran-2-yl}-9H- purin-6-yl}amino)ethanesulfonamide; ethyl 4-({9-(2R,3R 4S,5R)-5-ethynyl-3,4-dihydroxytetrahydrofuran-2-yl}-9H- purin-6-yl}amino)piperidine-1-carboxylate; (2R,3R4S,5R)-5-ethynyl-2-(6-{[(18,2S)-2-hydroxycyclopentyllamino}-9H-purin-

9-yi)tetrahydrofuran-3,4-diol, (2R,3R,4S,5R)-2-[6-indan-2-ylamino)-9H-purin-9-yl}-5-ethynyltetrahydrofuran- 3,4-diol; (2R,3R,45,5R)-2-[6-(cyclobutylamino)-9H-purin-9-yl]-5-ethynyitetrahydrofuran- 3,4-diol;

(2R,3R,4S,5R)-5-ethynyl-2-{6-[(2-phenylethyl)amino]-9H-purin-9- ylitetrahydrofuran-3,4-diol; (2R,3R,4S,5R)-2-[6-(cyclohexylamino)-9H-purin-9-yl}-5-ethynyltetrahydrofuran- 3,4-diot;

(2R,3R,4S,5R)-5-ethynyl-2-(6-{[(1S*,2S*,35* 4R*)-3-methylbicycio[2.2.1]hept-2- . 30 yllamino}-9H-purin-9-yl)tetrahydrofuran-3,4-diol; (2R,3R,4S,5R)-5-ethynyl-2-(6-{[(1R*,*2S)-2-methoxy-2- ‘ phenylcyclopentyllamino}-9H-purin-9-yl)tetrahydrofuran-3,4-diol: (2R,3R,4S,5R)-2-[6-(cyclopropylamino)-9H-purin-9-yl}-5-ethynyltetrahydrofuran- 3,4-diol;

(2R,3R,48,5R)-2-{6-[(cyclopropylmethyl)amino}-9H-purin-9-yl}-5- ethynyltetrahydrofuran-3 4-diol; (2R,3R 48,5R)-2-[6-(cyclopentylamino)-9H-purin-9-yl}-5-ethynyltetrahydrofuran- 3,4-diol;

(2R,3R,4S,5R)-5-ethynyl-2-(6-{[(2R,3R)-2-methyltetrahydrofuran-3-ylJamino}-9H- purin-9-yl)tetrahydrofuran-3,4-diol; (2R,3R,4S,5R)-5-ethynyl-2-(6-{[(2S,3S)-2-methyltetrahydrofuran-3-ylJamino}-9H-- purin-9-yl)tetrahydrofuran-3,4-diol;

(2R,3R 48,5R)-5-ethynyl-2-{6-[(trans-4-methoxycyclohexyl)amino]-9H-purin-9-

yiftetrahydrofuran-3,4-diol; 2R,3R,4S,5R)-5-ethynyl-2-{6-[(trans-4-ethoxycyclohexyl)amino]-9H-purin-9- yl}tetrahydrofuran-3,4-diol; 2R,3R ,48,5R)-5-ethynyl-2-{6-[(trans-4-propenyloxycyclohexyl)amino]-9H-purin- 9-yl}tetrahydrofuran-3,4-diol;

(2R,3R 4S,5R)-5-ethynyl-2-[6-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9- ylltetrahydrofuran-3,4-diol;

(2R,3R,4S,5R)-2-{6-[(1R*,6R*,6 S*)-bicyclo[3.2.0}hept-6-ylamino]-9H-purin-9-yl}- 5-ethynyltetrahydrofuran-3,4-diol; (2R,3R,4S,5R)-2-{6-[(2,2-dimethylcyclopropyl)amino}-9H-purin-9-yl}-5-

ethynyltetrahydrofuran-3,4-diol;

(2R,3R ,4S,5R)-5-ethynyl-2-{6-[(trans-4-hydroxycyclohexyl)amino]-9H-purin-9- yl}tetrahydrofuran-3,4-diol; (2R,3R,4S,5R)-2-{6-[(2-methylphenyl)amino}-9H-purin-9-yi}-5- ethynyltetrahydrofuran-3,4-diol;

(2R,3R,4S,5R)-2-{6-[(4-methylphenyl)amino]-9H-purin-9-yi}-5- ethynyltetrahydrofuran-3,4-diol; (2R,3R,48,5R)-2-{6-[(3-chloro-2-fluorophenyl)amino}-9H-purin-9-yl}-5- ethynyltetrahydrofuran-3,4-diol;

(2R,3R 48,5R)-2-{6-[(2-fluoro-5-methylphenyl)amino}-9H-purin-9-yi}-5- . 30 ethynyltetrahydrofuran-3,4-diol; butyl 4-({9-[(2R,3R,4S,5R)-5-ethynyl-3,4-dihydroxytetrahydrofuran-2-yl}-9H- . purin-6-yi}amino)piperidine-1-carboxylate; cyclopropylmethyl 4-({9-[(2R,3R,4S,5R)-5-ethynyl-3,4-dihydroxytetrahydrofuran- 2-yl}-9H-purin-6-yl}amino)piperidine-1-carboxylate;

(2R,3R 48,5R)-5-ethynyl-2-{(6-[(1S,2S)-2-methoxycyclopentyllamino}-9H-purin- 9-yhtetrahydrofuran-3,4-diol: (2R,3R 4S,5R)-5-ethynyl-2-{6-[(4,4-difluoro)cyclohexyllamino}-9H-purin-9- yhtetrahydrofuran-3,4-diot;

5. (2R,3R 48,5R)-5-ethynyl-2-{6-[(cyclohex-3-enyl)amino[}-9H-purin-9- yDhtetrahydrofuran-3,4-diol; (2R,3R,4S,5R)-5-ethynyl-2-[6-(dicyclopropylmethyl)amino}-9H-purin-9- yhtetrahydrofuran-3,4-diol; (2R,3R 4S,5R)-5-ethynyl-2-[6-(cyclooctyl)amino]-9H-purin-9-ylytetrahydrofuran- 3,4-diot; (2R,3R48,5R)-5-ethynyi-2-[6-(cycloheptyl)amino}-9H-purin-9-yltetrahydrofuran- 3,4-diol; (2R,3R,4S,5R)-5-ethynyl-2-{6-[(1 R*,45%)-4-methoxy-cyclohept-2-enylam ino)-9H- purin-9-yl]-tetrahydrofuran-3,4-diol; and (2R,3R,4S,5R)-5-ethynyl-2-{6-[(1 S$*,4R*)-4-methoxy-cyclohept-2-enylamino)-9H- : purin-9-yl}-tetrahydrofuran-3,4-diol.

6. Apharmaceutical composition comprising a compound of formula (la) or a pharmaceutically acceptable salt and/or solvate thereof together with a pharmaceutical carrier and/or excipient.

7. Use of a compound of formula (la) or a pharmaceutically acceptable salt and/or solvate thereof for the manufacture of a medicament for the treatment of a patient suffering from a condition where there is an advantage in decreasing plasma free fatty acid concentration, or reducing heart rate.

8. Use of a compound of formula (la) or a pharmaceutically acceptable salt and/or solvate thereof for the manufacture of a medicament for the treatment of a patient suffering from or susceptible to ischaemic heart disease, peripheral vascular disease or stroke or which subject is suffering pain, a CNS disorder, sleep apnoea or emesis.

9. A compound of formula (la) or a pharmaceutically acceptable salt and/or solvate thereof, for use in treating a patient suffering from a condition AMENDED SHEET ;

where there is an advantage in decreasing plasma free fatty acid concentration, or reducing heart rate.

10. A compound of formula (la) or a pharmaceutically acceptable salt and/or solvate thereof, for use in treating a patient suffering from or susceptible to ischaemic heart disease, peripheral vascular disease or stroke or which subject is suffering pain, a CNS disorder, sleep apnoea or emesis.

11. A compound according to claim 1, 9 or 10, substantially as herein described and exemplified.

12. A pharmaceutical composition according to claim 6, substantially as herein described and exemplified.

13. Use according to claim 7 or 8, substantially as herein described and exemplified. oo AMENDED SHEET