TECHNICAL FIELD

The present invention relates to novel nucleotides and to pharmaceutical compositions comprising the compounds, as well as to the use of the compounds in medicine and for the preparation of a medicament.

More particularly, the present invention relates to novel nucleotides compounds that have direct beneficial effects on type 2 diabetes, glucose intolerance, hyperinsulinemia, insulin resistance, dyslipidemia, hypercholesterolemia, high blood pressure, obesity, fatty liver conditions, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, cardiovascular disease, atherosclerosis, cerebrovascular conditions and stroke. Further, the compounds may have beneficial effects against cancer.

BACKGROUND OF THE INVENTION

Overweight is leading to increased insulin resistance and, in the worst case, to the development of type 2 diabetes and its complications. Examples of diabetic complications are cardiovascular disease, atherosclerosis, cerebrovascular conditions, diabetic nephropathy, diabetic neuropathy and diabetic retinopathy. Further, the obese patient typically develops fatty liver, dyslipidemia, hypercholesterolemia and high blood pressure. At an early stage and often before the onset of the disease, type 2 diabetics exhibit a combination of hyperinsulinemia and reduced action of insulin in liver, skeletal muscle and fat. Later, when the diabetic state progresses, insulin secretion from the pancreatic β-cell is reduced.

Obesity plays a pivotal role in the pathogenic process leading to type 2 diabetes and likely to cancer. There is a link between obesity/free fatty acids, lipids, fatty liver, hepatic insulin resistance and diabetes. Also in cancer, obesity, free fatty acids and hyperinsulinemia are likely to play an important role. Studies indicate that obesity contributes to the increased incidence of and death from cancers of the colon, breast (in postmenopausal women), endometrium, kidney (renal cell), oesophagus

(adenocarcinoma), gastric cardia, pancreas, gallbladder and liver, colon and possibly other cancers (Eugenia, E., et al. Nature reviews - Cancer (2004) 4:579-591). The fuel- sensing enzyme 5 '-AMP-acivated protein kinase (AMPK) has a major role in the regulation of lipid metabolism. Recently, several findings point to a link between AMPK and the growth and/or survival of some cancer cells (Zhijun et al., TRENDS in Pharmacological Sciences. (2005) 26(2):69-76).

Visceral obesity is typically associated with elevated levels of free fatty acids and is linked to glucose intolerance and type 2 diabetes. Free fatty acids exert divergent effects on insulin secretion from β-cells: acute exposure to free fatty acids stimulates insulin secretion, whereas chronic exposure impairs insulin secretion. It has been shown that elevated levels of free fatty acids promote lipid accumulation and insulin resistance in target tissues. In the non-diabetic person a prominent role of insulin is to reduce glucose output and to control synthesis of triglyceride and very low density lipoproteins from the liver. However, in the type 2 diabetic patient hyperinsulinemia and elevated hepatic glucose output are also hallmarks of insulin resistance, and hyperinsulinemia per se has been proposed to contribute to the development of insulin resistance, fatty liver/hepatic steatosis, and increased hepatic glucose output. Thus, under conditions of visceral obesity, free fatty acid-stimulated insulin secretion may promote hyperinsulinemia that contributes to hepatic steatosis, increased liver output of triglycerides and highly atherogenic very low density lipoproteins, increased hepatic glucose output, and impaired glucose homeostasis, events and factors that contribute to vascular damage leading to for example cardiovascular disease. Fatty liver and hepatic insulin resistance are major components behind hyperglycemia and type 2 diabetes.

A link between obesity, free fatty acids, fatty liver, hepatic insulin resistance, elevated glucose levels and the function of the GPR40 receptor has been established. (Steneberg, P., et al., Cell Metabolism, (2005) 1, 245-258).

Today type 2 diabetes and associated conditions are pharmacologically treated by various approaches. Treatment options include insulin secretagogues, such as sulphonylureas, that act only on the β-cell, metformin mainly acts on glucose production by the liver, the

peroxisome proliferator-activated receptor-j/ (PPAR-j) agonists, such as the thiazolidinediones, enhances insulin action; and α-glucosidase inhibitors interfere with gut glucose production. However, all of these medicaments apparently fail to stop the progression of the disease, and over time they also fail to normalize glucose levels or to stop subsequent complications of the disease. In addition, these drugs are associated with non-desirable side effects. For instance insulin secretagogues and insulin injections may cause hypoglycemia and weight gain. Furthermore, patients often lose responsiveness to insulin secretagogues over time. Metformin is associated with lactic acidosis. Metformin and α-glucosidase inhibitors often lead to gastrointestinal problems, and PPAR-j agonists tend to cause increased weight gain and edema.

Even Exenatide, a recently approved Glucagon Like Peptide (GLP-I) analogue that has an effect on insulin secretion, is not devoid of hypoglycaemic events. However, these events occur less frequently as compared to classic insulin secretagogues such as sulphonylureas. Further, it needs to be stored under cold conditions and has to be administrated by injection. Conditions associated with type 2 diabetes usually need to be treated separately. For example, hyperlipidemia is treated with statins and high blood pressure is treated with beta-adrenergic blocking drugs or calcium channel blockers.

Because of the unsatisfactory profile of existing medications for the treatment of type 2 diabetes, there is a strong need for novel oral drugs with superior efficacy and less side effects. Preferably, those drugs should also be efficacious with respect to other conditions associated with type 2 diabetes. In order to effectively treat the multiple disorders present in type 2 diabetes, it is vital to improve liver function and, in that way, reduce hepatic glucose output, triglycerides and very low density lipoproteins.

WO 03/028712 relates to purinergic and pyrimidinergic receptor agonists and methods for treatment of inflammation, allergy and autoimmune diseases, particularly type 1 diabetes. WO 03/028712 particularly lists known and hypothetical P2-R agonists and the scope of ribose modifications is limited to two explicit examples being the 4-benzoyl- benzoyl ester and the methyl ether. In other examples, the ribose moiety is kept unmodified. Further, nothing is mentioned about the following potential indications type

2 diabetes or fatty liver conditions, glucose intolerance, hyperinsulinemia, insulin resistance, dyslipidemia, hypercholesterolemia, high blood pressure, obesity, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, cardiovascular disease, atherosclerosis, cerebrovascular conditions and stroke.

SUMMARY OF TEDE INVENTION

The inventors have surprisingly found that compounds according to the present invention has a better effect than other compounds relating to the disorders type 2 diabetes, glucose intolerance, hyperinsulinemia, insulin resistance, dyslipidemia, hypercholesterolemia, high blood pressure, obesity, fatty liver conditions, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, cardiovascular disease, atherosclerosis, cerebrovascular conditions, stroke and cancer. Therefore, it is an object of the present invention to solve the above mentioned problems and provide compounds, for preparing a medicament for treatment of the above mentioned disorders. Further, the results indicates that the compounds may have direct beneficial effect on cancer. The compounds according to the present invention embraces novel compounds according to the general Formula (I)

wherein,

when X is selected from heterocycles depicted in formulae II or III

R and R are the same or different and are selected from

H, halogen, OH, -OR ³ , -O-CO-R ³ , -O-CO-OR ³ , -O-CO-NHR ³ , -NH-R ³ , -NH-CO-R ³ , - NH-CO-OR ³ , -NH-CO-NHR ³ , with the proviso that R ¹ and R ² are not simultaneously OH, and

in case R ¹ is OH, R ² can be neither OCH ₃ nor 4-benzoyl-benzoyl, and in case R ² is OH, R ¹ can be neither OCH ₃ nor 4-benzoyl-benzoyl,

R independently represents the same or different groups selected from H, substituted or non-substituted lower alkyls, saturated or non saturated, substituted or non-substituted cycloalkyl, substituted or non-substituted benzyl groups, substituted or non-substituted aryl or mono-, bi-, tricyclic unsubstituted or substituted heteroaromatic ring(s) with one or more heteroatoms and non-aromatic heterocycles wherein the substituents of the substituted groups are selected from lower alkyl, halogens, substituted or non-substituted aryl, substituted or non-substituted hetero-aromatic compounds, non- aromatic heterocycles, R ⁴ is represented by formula IV

wherein,

Z is selected independently from O or S, with the proviso that at least one atom represented by Z is S,

Q is selected from O or C(R ⁵ ) ₂ ,

R ⁵ is selected independently from H or halogen,

Y is selected independently from OH or SH, while n is O, 1 or 2,

and in case n is O,

Z can be O and Y can simultaneously be OH, with the proviso that R ¹ is OH and R ² is selected from -O-CO-R ⁸ , -O-CO-OR ³ , -O-CO-NHR ³ , -NH-CO-R ³ , -NH-CO-OR ³ , -NH- CO-NHR ³ , with the proviso that R ² is OH and R ¹ is selected from -O-CO-R ⁸ , -O-CO-R ³ , -O-CO-OR ³ , -O-CO-NHR ³ , -NH-CO-R ³ , -NH-CO-OR ³ , -NH-CO-NHR ³ , wherein,

R ⁸ is selected from H, saturated or non saturated, substituted or non-substituted cycloalkyl, substituted or non-substituted benzyl groups, substituted or non-substituted aryl or mono-, bi-, tricyclic unsubstituted or substituted heteroaromatic ring(s) with one or more heteroatoms and non-aromatic heterocycles wherein the substituents of the substituted groups are selected from lower alkyl, halogens, substituted or non-substituted aryl, substituted or non-substituted hetero-aromatic compounds, non-aromatic heterocycles,

wherein,

R ⁴ is -0-PZ(OH)O- forming together with R ² a cyclic phosphate ring as in cAMP according to formula V,

Z is selected from O or S, and; in the case of cAMP, R ¹ is neither OH nor O-(4-benzoyl-benzoyl)

or; when X is represented by formula VI,

wherein,

R ⁶ is selected from H, R ³ , -CO-R ³ , -CO-OR ³ or -CO-NHR ³ , and in the case R ⁶ is either -CO-R ³ , -CO-OR ³ or -CO-NHR ³ , R ¹ and R ² of formula

(I) can simultaneously be OH, R ⁷ is selected from halogen, H, R ³ , -SR ³ or -OR ³ ,

R ¹ and R ² are the same as previously defined, and in case R ¹ is OH, R ² can be neither OCH ₃ nor 4-benzoyl-benzoyl, in case R ² is OH, R ¹ can be neither OCH ₃ nor 4-benzoyl-benzoyl,

R is the same as previously defined,

R ⁴ is the same as previously defined, and;

R ⁸ is the same as previously defined,

including salts, solvates and pharmaceutically functional derivates thereof,

with the proviso of the following copounds:

2 ' ,3 ' -O, O-diacetyl-adenosine 5 ' -triphosphate- αS

2 ' ,3 ' -O, Odiacety 1-uridine 5 ' -triphosphate- αS

3 ' -O-acetyl-2 ' -deoxy-adenosine 5 ' -triphosphate- aS

3'-O-[2,5-dihydro-2,2,5 ₅ 5-tetra(methyl-d3)-l-oxy-lH-ρyrrole-4-d-3-carbonyl]-a denosine

5 ' -0-(β, /-methylene-triphosphate)

3'-O-(3-(4-azido-2-nitrophenyl)propanoyl)-adenosine 5'-O-(yfi, /-methylene-triphosphate)

3'-0-(4-methoxybenzyl)-adenosine 5 '-O-(/?, ^-methylene-triphosphate)

2 ' -<9-(2-(N-methylamino)benzoyl)-adenosine 5'-0-(β, ^-methylene-triphosphate)

2'-O-[2,5-dihydro-2,2,5,5-tetra(methyl-d3)-l-oxy-lH-ρyrr olyl-4-d-3-carbonyl]- adenosine 5 ' -0-(β, f-methylene-triphosphate)

T-O- [4-((naρhthalen- 1 -yl)methyl)] -adenosine 5'-0-(β, /-methylene-triphosphate)

2 ' -amino-2 ' -deoxy-adenosine 5'-O-(β, /-methylene-triphosphate)

2'-amino-2'-deoxy-adenosine 5'-0-(α,^-methylene-triphosphate)

2'-deoxy-2'-fluoro-3'-O-(tetrahydro-2H-pyran-2-yl)-adenos ine 5'-O-(a,y?- difluoromethylene-diphosphate)

2 ' -deoxy-2 ' -fluoro-3 '-O-(tetrahydro-2H-pyran-2-yl)-adenosine 5 ' -O-{ α,j#-methy lene- diphosphate)

3 ' -deoxy-3 ' -fluoro-2'-O-(tetrahydro-2H-pyran-2-yl)-adenosine 5 '-O-(a,β- difluoromethylene-diphosphate)

3 '-deoxy-3 ' -fluoro-2'-O-(tetrahydro-2H-pyran-2-yl)-adenosine 5 ' -(9-(α,y#-methylene- diphosphate)

2 ' ,3 ' -O, O-(dibenzoyl)-uridine 5 ' -thiophosphate

3 ' -dimethylamino-3 ' -deoxy-adenosine 5 ' -thiophosphate

3 ' -amino-3 ' -deoxy-adenosine 5 ' -thiophosphate

3 ' -isopropylamino-3 ' -deoxy-adenosine 5 ' -thiophosphate

3 '-benzylamino-3' -deoxy-adenosine 5 '-thiophosphate

3'-0-(I -N-acetyl-(2-pyrrolidinyl)carbonyl)-adenosine 5 ' -monophosphate

3 '-0-(5-(dimethylamino)-2-naphthalenecarbonyl)-adenosine 5 '-monophosphate

3'-0-(5-(dimethylamino)-l-naphthalenecarbonyl)-adenosine 5 '-monophosphate

3 ' -0-(4-(dimethylamino)- 1 -naphthalenecarbonyl)-adenosine 5 ' -monophosphate

3 '-O-(l-naphthalenecarbonyl)-adenosine 5 '-monophosphate

3 ' -0-(2-(N-methylamino)benzoyl)-adenosine 5 ' -monophosphate)

3 '-0-(2-aminobenzoyl)-adenosine 5 '-monophosphate)

3 ' -O-(2-aminobenzoyl)-uridine 5 ' -monophosphate)

3 '-O-(2,5-dihydro-2,2,5,5-tetramethyl- 1 -oxy- lH-ρyrrolyl-3-carbonyl)-adenosine 5 '- monophosphate)

3'-0-((pyrrolidin-2-yl)carbonyl)-adenosine 5 '-monophosphate

2 ' -O-(5-(dimethylamino)- 1 -naphthalenecarbonyl)-adenosine 5 ' -monophosphate 2 ' -O-( 1 -N-acetyl-(2-pyrrolidinyl)carbonyl)-adenosine 5 ' -monophosphate 2 ' -O-((pyrrolidin-2-yl)carbonyl)-adenosine 5 ' -monophosphate

2'-O-(2,5-dihydro-2,2,5,5-tetramethyl-l-oxy-lH-ρyrrolyl-3-c arbonyl)-uridine 5'- monophosphate)

2'-O-(2,5-dihydro-2.2,5,5-tetramethyl-l-oxy-lH-pyrrolyl-3 -carbonyl)-adenosine 5'- monophosphate)

2'-O-(3-nicotinoyl)-adenosine 5'-monophosphate

2'-O-(2-aminobenzoyl)-adenosine 5 '-monophosphate

2'-O-(2-aminobenzoyl)-uridine 5 '-monophosphate

2 ' -deoxy-2 ' -(3-methoxybenzamido)-N ⁶ -(( 1 -naphthalyl)methy l)-adenosine 5 ' - monophosphate.

In one embodiment of the present invention R ³ preferably is esters, more preferably aromatic or heteroaromatic esters, and most preferably benzoyl ester.

In one embodiment of the present invention R ⁴ preferably is γ-S-triphosphates, β-S- diphosphates, α-S-monophosphates, α,β-methylene-triphosphates, β,γ-methylene- triphosphates.

In one embodiment of the present invention R ⁷ preferably is thioethers or halogens, more preferably 2-methylthio, 2-hexylthio, 2-(4-aminophenylethylthio), 2-benzylthio, chloride or bromide, and most preferably 2-methylthio and chloride.

In one embodiment of the present invention R ⁶ is a lower alkyl.

In one preferred embodiment of the present invention R is H and R is H.

In one embodiment of the present invention a compound is selected from the prefered compounds:

2'(3 ')-O-(benzoyl)-adenosine 5 '-triphosphate-γS

2'(3 ')-O-(2-methylbenzoyl)-adenosine 5 '-triphosphate- γS

2'(3 ')-O-(2,6-dimethylbenzoyl)-adenosine 5 '-triphosphate-γS

2'(3 ')-O-(N-phenylcarbamoyl)-adenosine 5 '-triphosphate-γS

' (3 ')-<9-(phenoxycarbonyl)-adenosine 5 ' -triphosphate- ^S ' (3 ' )-O-(benzyl)-adenosine 5 ' -triphosphate- ^S ' (3 ' )-(benzylamino)-2 ' (3 ')-deoxy-adenosine 5 ' -triphosphate- γS ' (3 ')-(benzamido)-2' (3 ')-deoxy-adenosine 5 ' -triphosphate- ^S '(3')-(phenoxycarbonylamino)-2'(3')-deoxy-adenosine 5 '-triphosphate- ^S '(3 ')-(3-phenylureido)-2'(3 ')-deoxy-adenosine 5 '-triphosphate- ^S ' (3 ' )-O-(benzoyl)-adenosine 5 ' -diphosphate-/^ '(3')-O-(2-methylbenzoyl)-adenosine 5 '-diphosphate-/^ '(3')-(9-(2,6-dimethylbenzoyl)-adenosine 5 '-diphosphate-/^ ' (3 ' )-0(N-phenylcarbamoyl)-adenosine 5 ' -diphosphate-/2S ' (3 ' )-O-(phenoxy carbonyl)-adenosine 5 ' -diphosphate-/^ ' (3 ' )-<9-(benzy l)-adenosine 5 ' -diphosphate-/?S '(3 ')-(benzylamino)-2'(3 ')-deoxy-adenosine 5 '-diphosphate-/?S ' (3 ' )-(benzamido)-2 ' (3 ' )-deoxy-adenosine 5 ' -diphosphate-/^ ' (3 ' )-(phenoxycarbonylamino)-2 ' (3 ' )-deoxy-adenosine 5 ' -diphosphate-/^ ' (3 ')-(3-phenylureido)-2 ' (3 ' )-deoxy-adenosine 5 ' -diphosphate-/^ ' (3 ' )-O-(benzoyl)-adenosine 5 ' -thiophosphate ' (3 ' )-(9-(2-methylbenzoyl)-adenosine 5 ' -thiophosphate ' (3 ')-0-(2,6-dimethylbenzoyl)-adenosine 5 ' -thiophosphate '(3 ')-O-(N-phenylcarbamoyl)-adenosine 5 '-thiophosphate ' (3 ' )-(9-(phenoxy carbonyl)-adenosine 5 ' -thiophosphate ' (3 ' )-O-(benzyl)-adenosine 5 ' -thiophosphate ' (3 ' )-(benzylamino)-2 ' (3 ' )-deoxy-adenosine 5 ' -thiophosphate ' (3 ' )-(benzamido)-2 ' (3 ' )-deoxy -adenosine 5 ' -thiophosphate ' (3 ' )-(ρhenoxy carbonylamino)-2 ' (3 ' )-deoxy-adenosine 5 ' -thiophosphate '(3')-(3-phenylureido)-2'(3')-deoxy-adenosine 5'-thiophosphate ' (3 ' )-O-(benzoyl)-adenosine 5 ' -monophosphate ' (3 ')-O-(2-methylbenzoyl)-adenosine 5 ' -monophosphate '(3')-O-(2 ₅ 6-dimethylbenzoyl)-adenosine 5'-monophosphate ' (3 ')-O-(N-ρhenylcarbamoyl)-adenosine 5 ' -monophosphate

'(3 ')-O-(phenoxycarbonyl)-adenosine 5 '-monophosphate ' (3 ' )-(benzamido)-2 ' (3 ' )-deoxy-adenosine 5 ' -monophosphate '(3')-(phenoxycarbonylamino)-2'(3')-deoxy-adenosine 5 '-monophosphate ' (3 ' )-(3 -pheny lureido)-2 ' (3 ' )-deoxy-adenosine 5 ' -monophosphate ' (3 ')-0-(benzoy l)-adenosine 5 ' -(β, ^-methylene-triphosphate) ' (3 ' )-O-(2-methylbenzoyl)-adenosine 5 ' -(/?, /-methylene-triphosphate) '(3 ')-0-(2,6-dimethylbenzoyl)-adenosine 5 '-(/?, /-methylene-triphosphate) ' (3 ' )-0-(N-phenylcarbamoyl)-adenosine 5 ' -(/?, /-methylene-triphosphate) ' (3 ' )-O-(phenoxycarbonyl)-adenosine 5 ' -(/?, /-methylene-triphosphate) ' (3 ')-O-(benzyl)-adenosine 5 '-(/?, /-methylene-triphosphate) ' (3 ' )-(benzylamino)-2 ' (3 ' )-deoxy-adenosine 5 ' -(β, /-methy lene-triphosphate) ' (3 ' )-(benzamido)-2 ' (3 ' )-deoxy-adenosine 5 ' -(/?, /-methylene-triphosphate) ' (3 ' )-(phenoxycarbonylamino)-2 ' (3 ' )-deoxy-adenosine 5 ' -(/?, /-methylene-triphosphate) ' (3 ' )-(3 -pheny lureido)-2 ' (3 ' )-deoxy-adenosine 5 '-(/?, /-methylene-triphosphate) ' (3 ')-0-(benzoyl)-adenosine 5 ' -( α,/^methylene-triphosphate) '(3 ')-O-(2-methylbenzoyl)-adenosine 5 '-(α,/?-methylene-triphosphate) ' (3 ' )-O-(2,6-dimethylbenzoyl)-adenosine 5 ' -( α,/^methylene-triphosphate) '(3 ')-O-(N-phenylcarbamoyl)-adenosine 5 '-(α,/^methylene-triphosphate) ' (3 ')-0-(phenoxycarbonyl)-adenosine 5 ' -(α,/^methylene-triphosphate) ' (3 ' )-O-(benzyl)-adenosine 5 ' -( α,y5-methylene-triphosphate) ' (3 ' )-(benzylamino)-2 ' (3 ' )-deoxy-adenosine 5 ' -(α ₅ y5-methylene-triphosphate) '(3')-(benzamido)-2'(3')-deoxy-adenosine 5'-(α,y5-methylene-triphosphate) ' (3 ' )-(phenoxy carbonylamino)-2 ' (3 ' )-deoxy-adenosine '(3 ')-(3-ρhenylureido)-2'(3 ')-deoxy-adenosine 5 '-(α,/?-methylene-triphosphate) '(3 ')-O-(benzoyl)-adenosine 5 '-(α,^-methylene-diphosphate) '(3')-O-(2-methylbenzoyl)-adenosine 5'-(α,/^methylene-diphosphate) '(3 ')-0-(2,6-dimethylbenzoyl)-adenosine 5 '-(α _j; β-methylene-diρhosphate) '(3 ')-0-(N-phenylcarbamoyl)-adenosine 5 '-(α^methylene-diphosphate) '(3 ')-0-(phenoxycarbonyl)-adenosine 5 '-(<z,y#-methylene-diphosphate)

' (3 ' )-O-(benzyl)-adenosine 5 ' -(α,/^methylene-diphosphate) ' (3 ')-(benzylamino)-2 ' (3 ' )-deoxy-adenosine 5 ' -(α,/^methylene-diphosphate) ' (3 ')-(benzamido)~2 ' (3 ')-deoxy-adenosine 5 ' -(α,/^methylene-diphosphate) ' (3 ' )-(phenoxycarbonylamino)-2 ' (3 ')-deoxy-adenosine 5 ' -(α,/?-methylene-diphosρhate) ' (3 ' )-(3 -phenylureido)-2 ' (3 ' )-deoxy-adenosine 5 ' -( α,/?-rnethylene-diphosphate) '(3')-O-(benzoyl)-uridine 5 '-triphosphate- ^S '(3')-O-(2-methylbenzoyl)-uridine 5'-triρhosρhate-^S ' (3 ' )-O-(2,6-dimethylbenzoyl)-uridine 5 ' -triphosphate- γS ' (3 ' )- O-(N-phenylcarbamoyl)-uridine 5 ' -triphosphate- ^S '(3 ')-O-(phenoxycarbonyl)-uridine 5'-triphosphate-^S '(3 ')-O-(benzyl)-uridine 5 '-triphosphate- ^S ' (3 ' )-(benzylamino)-2 ' (3 ' )-deoxy-uridine 5 ' -triphosphate- ^S ' (3 ' )-(benzamido)-2 ' (3 ')-deoxy-uridine 5 ' -triphosphate- yS '(3')-(phenoxycarbonylamino)-2'(3')-deoxy-uridine 5'-triρhosphate-^S ' (3 ')-(3 -phenylureido)-2 ' (3 ' )-deoxy-uridine 5 ' -triphosphate-;^ '(3')-O-(benzoyl)-uridine 5'-diρhosρhate-/?S '(3 ')-O-(2-methylbenzoyl)-uridine 5 '-diphosphate-/^ '(3')-O-(2,6-dimethylbenzoyl)-uridine 5'-diρhosphate-/3S ' (3 ')-O-(N-phenylcarbamoyl)-uridine 5 ' -diphosphate-/^ ' (3 ')-O-(phenoxycarbonyl)-uridine 5 ' -diphosphate-^S '(3 ')-O-(benzyl)-uridine 5 '-diphosphate-^ '(3 ')-(benzylamino)-2'(3 ')-deoxy-uridine 5 '-diphosphate-^ ' (3 ' )-(benzamido)-2 ' (3 ')-deoxy-uridine 5 ' -diphosphate-^ '(3')-(phenoxycarbonylamino)-2'(3')-deoxy-uridine 5 '-diphosphate-/^ '(3 ')-(3-ρhenylureido)-2'(3 ')-deoxy-uridine 5 '-diphosphate-/^ '(3 ')-O-(benzoyl)-uridine 5'-thiophosphate '(3 ')-O-(2-methylbenzoyl)-uridine 5 '-thiophosphate '(3 ')-O-(2 ₅ 6-dimethylbenzoyl)-uridine 5 '-thiophosphate '(3 ')-O-(N-phenylcarbamoyl)-uridine 5 '-thiophosphate

' (3 ')-O-(phenoxycarbonyl)-uridine 5 '-thiophosphate ' (3 ')-0-(benzyl)-uridine 5 ' -thiophosphate ' (3 ' )-(benzylamino)-2 ' (3 ')-deoxy-uridine 5 ' -thiophosphate '(3')-(benzamido)-2'(3')-deoxy-uridine 5 '-thiophosphate ' (3 ')-(phenoxycarbonylamino)-2 ' (3 ' )-deoxy-uridine 5 ' -thiophosphate ' (3 ')-(3 -phenylureido)-2 ' (3 ' )-deoxy-uridine 5 ' -thiophosphate ' (3 ' )-O-(benzoyl)-uridine 5 ' -monophosphate ' (3 ' )-O-(2-methylbenzoyl)-uridine 5 ' -monophosphate '(3')-O-(2,6-dimethylbenzoyl)-uridine 5 '-monophosphate '(3 ')-O-(N-phenylcarbamoyl)-uridine 5 '-monophosphate ' (3 ' )-O-(phenoxycarbonyl)-uridine 5 ' -monophosphate ' (3 ')-(benzamido)-2 ' (3 ' )-deoxy-uridine 5 ' -monophosphate '(3')-(phenoxycarbonylamino)-2'(3')-deoxy-uridine 5'-monophosphate ' (3 ' )-(3 -phenylureido)-2 ' (3 ')-deoxy-uridine 5 ' -monophosphate ' (3 ')-0-(benzoyl)-uridine 5 ' -(β, ^-methylene-triphosphate) '(3')-O-(2-methylbenzoyl)-uridine 5'-(/?,;κ-methylene-triphosphate) '(3 ')-O-(2,6-dimethylbenzoyl)-uridine 5 ' -(/?, ^-methylene-triphosphate) ' (3 ' )-O-(N-phenylcarbamoyl)-uridine 5 ' -(/?, /-methylene-triphosphate) '(3 ')-O-(phenoxycarbonyl)-uridine 5 '-(/?, ^-methylene-triphosphate) ' (3 ' )-0-(benzyl)-uridine 5 ' -(β, /-methylene-triphosphate) ' (3 ' )-(benzylamino)-2 ' (3 ' )-deoxy-uridine 5 ' -(β, ^-methylene-triphosphate) ' (3 ')-(benzamido)-2 ' (3 ')-deoxy~uridine 5 ' -(β, f-methylene-triphosphate) ' (3 ')-(phenoxycarbonylamino)-2 ' (3 ' )-deoxy-uridine 5 ' -(/?, ^-methylene-triphosphate) '(3')-(3-phenylureido)-2'(3')-deoxy-uridine 5'-(yfi,χ-methylene-triphosphate) '(3')-O-(benzoyl)-uridine 5'-(α,^-methylene-triphosρhate) '(3')-O-(2-methylbenzoyl)-uridine 5'-(α ₃ y^-methylene-triphosphate) ' (3 ' )-O-(2,6-dimethylbenzoyl)-uridine 5 ' -( «,^-methylene-triphosphate) '(3')-O-(N-phenylcarbamoyl)-uridine 5'-(α,^-methylene-triphosphate) '(3')-(9-(phenoxycarbonyl)-uridine 5'-(α,^-methylene-triphosρhate) '(3 ')-(9-(benzyl)-uridine 5'-(α,^-methylene-triphosphate)

2'(3')-(benzylamino)-2'(3')-deoxy-uridine 5'-(α,β-methylene-triphosphate)

2'(3')-(benzamido)-2'(3')-deoxy-uridine 5'-( α,β-methylene-triphosphate)

2'(3')-(phenoxycarbonylamino)-2'(3')-deoxy-uridine 5'-(α,β-methylene-triphosphate)

2'(3 ')-(3-phenylureido)-2'(3 ')-deoxy-uridine 5'-( α,β-methylene-triphosphate)

2'(3')-O-(benzoyl)-uridine 5'-( α,β-methylene-diphosphate)

2'(3')-O-(2-methylbenzoyl)-uridine 5'-(α,β-methylene-diphosphate)

2'(3 ')-Ο-(2,6-dimethylbenzoyl)-uridine 5 '-( α,β-methylene-diphosphate)

2'(3 ')-O-(N-phenylcarbamoyl)-uridine 5 '-( α,β-methylene-diphosphate)

2'(3')-O-(ρhenoxycarbonyl)-uridine 5'-(α,β-methylene-diphosρhate)

2'(3 ')-O-(benzyl)-uridine 5'-(α,β-methylene-diphosρhate)

2 ' (3 ' )-(benzy lamino)-2 ' (3 ' )-deoxy-uridine 5 ' -( α,β-methylene-diphosphate)

2 ' (3 ' )-(benzamido)-2 ' (3 ' )-deoxy-uridine 5 ' -( α,β-methylene-diphosphate)

2 ' (3 ')-(phenoxycarbonylamino)-2 ' (3 ')-deoxy-uridine 5 ' -( α,β-methylene-diphosphate)

2'(3')-(3-phenylureido)-2'(3')-deoxy-uridine 5'-(α,β-methylene-diphosphate)

N ¹ -(β -D-2'(3')-O-benzoyl-5'-phosphoribofuranosyl)-5-aminoimidazol e-4-carboxamide

N ¹ -(β -D-2'(3')-O-(2-methylbenzoyl)-5'-phosphoribofuranosyl)-5-ami noimidazole-4- carboxamide

N ¹ -(β -D-2'(3')-O-(2,6-dimethylbenzoyl)-5'-phosphoribofuranosyl)-5 -aminoimidazole-4- carboxamide

N ¹ -(β -D-2'(3')-O-(N-phenylcarbamoyl)-5'-phosphoribofuranosyl)-5-a minoimidazole^- carboxamide

N ¹ -(β -D-2'(3')-O-phenoxycarbonyl-5'-phosphoribofuranosyl)-5-amino imidazole-4- carboxamide

N ¹ -(β -D-2'(3')-O-benzyl-5'-phosphoribofuranosyl)-5-aminoimidazole -4-carboxamide

N ¹ -(β -D-2'(3')-benzylamino-2'(3')-deoxy-5'-phosphoribofuranosyl)- 5-aminoimidazole-4- carboxamide

N ¹ -(β -D-2'(3')-benzylamino-2'(3')-deoxy-5'-phosphoribofuranosyl)- 5-aminoimidazole-4- carboxamide

N ¹ -(^-D-2'(3')-phenoxycarbonylamino-2'(3')-deoxy-5'-phos phoribofuranosyl)-5- aminoimidazole-4-carboxamide

N ¹ -(^-D-2 ^t (3 ^l )-(3-phenylureido)-2'(3')-deoxy-5 ^I -phosphoribofuranosyl)-5- aminoimidazole-4-carboxamide

2 ' (3 ^-O-benzoyl-Λ^-methyladenosine 5 ' -triphosphate- ^S

2 ' (3 ' )-O-benzoyl-2-methylthioadenosine 5 ' -triphosphate- γS

2 ' (3 ' )-O-benzoyl-2-hexylthioadenosine 5 ' -triphosphate- ^S

2'(3')-O-benzoyl-2-(4-aminophenylethylthio)adenosine 5'-triphosphate-^S

2 ' (3 ')-O-benzoyl-2-benzylthioadenosine 5 ' -triphosphate- ^S

2'(3 ')-O-benzoyl-2-chloroadenosine 5 '-triphosphate- ^S

2'(3 ')-O-benzoyl-2-methoxyadenosine 5 '-triphosphate- ^S

2'(3')-O-benzoyl-2-methyladenosine 5 '-triphosphate- ^S

Λ^-benzoyl-adenosine 5 ' -triphosphate-β ^■

2 ' (3 ' )-O-benzoyl-N ^δ -methyladenosine 5 ' -diphosphate-/^

2'(3 ')-O-benzoyl-2-methylthioadenosine 5 '-diphosphate-/^

2'(3 ')-O-benzoyl-2-hexylthioadenosine 5 '-diphosphate-/^

2'(3')-O-benzoyl-2-(4-aminophenylethylthio)adenosine 5 '-diphosphate-/^

2 ' (3 ')-0-benzoyl-2-benzylthioadenosine 5 ' -diphosphate-/^

2 ' (3 ' )-O-benzoyl-2-chloroadenosine 5 ' -diphosphate-yflS

2'(3 ')-O-benzoyl-2-methoxyadenosine 5 '-diphosphate-^S

2 ' (3 ' )-O-benzoyl-2-methyladenosine 5 ' -diphosphate-/^

Λ^-benzoyl-adenosine 5 ' -diphosphate-/^

2 ' (3 ' )- O-benzoy l-N^methy ladenosine 5 ' -thiophosphate

2 ' (3 ')-O-benzoyl-2-methy lthioadenosine 5 ' -thiophosphate

2 ' (3 ' )-<9-benzoyl-2-hexy lthioadenosine 5 ' -thiophosphate

2 ' (3 ' )-O-benzoyl-2-(4-aminophenylethylthio)adenosine 5 ' -thiophosphate

2'(3 ')-O-benzoyl-2-benzylthioadenosine 5 '-thiophosphate

2'(3 ')-O-benzoyl-2-chloroadenosine 5 '-thiophosphate

2 ' (3 ')-O-benzoyl-2-methoxyadenosine 5 ' -thiophosphate

2 ' (3 ' )-O-benzoyl-2-methyladenosine 5 ' -thiophosphate

N^benzoyl-adenosine 5 '-thiophosphate

2 ' (3 ^-O-benzoyl-Λ^-methyladenosine 5 ' -monophosphate

2'(3 ')-O-benzoyl-2-methylthioadenosine 5 '-monophosphate

2'(3')-O-benzoyl-2-hexylthioadenosine 5 '-monophosphate

2 ' (3 ' )-O-benzoyl-2-(4-aminophenylethylthio)adenosine 5 ' -monophosphate

2'(3 ')-O-benzoyl-2-benzylthioadenosine 5 '-monophosphate

2'(3')-O-benzoyl-2-chloroadenosine 5 '-monophosphate

2 ' (3 ')-O-benzoyl-2-methoxyadenosine 5 ' -monophosphate

2 ' (3 ')-O-benzoyl-2-methyladenosine 5 '-monophosphate i^-benzoyl-adenosine 5 '-monophosphate

2 ' (3 ')-O-(4-benzyl-benzoyl)-adenosine 5 ' -triphosphate- γS

2'(3 ')-O-(acetyl)-adenosine 5 '-diphosphate-/^

2',3 '-O,0-(dibenzoyl)-adenosine 5 '-diphosphate-/^

2 ' (3 ')-O-(4-nitrobenzoyl)-adenosine 5 ' -diphosphate-/?S

2'(3 ')-O-(4-methoxybenzoyl)-adenosine 5 '-diphosphate-/^

2'(3 ')-O-(3-nicotinoyl)-adenosine 5 '-diphosphate-/^

2'(3')-O-(2-furoyl)-adenosine 5'-diphosρhate-/?S

2'-Ο-(benzoyl)-adenosine 3',5'-cyclophosphate

2'(3')-O-(cinnamoyl)-adenosine 5'-diphosphate-yβS

2'(3')-O-(2-phenylacetyl)-adenosine 5'-diphosphate-^S

2 ' (3 ' )-O-(4-trifluoromethoxybenzoyl)-adenosine 5 ' -diphosphate-^

2'(3')-O-(bicyclo[2.2.1]hept-5-ene-2-carbonyl)-adenosine 5 '-diphosphate-/^

2'(3 ')-O-(hexahydrobenzoyl)-adenosine 5 '-diphosphate-yβS

2'(3')-O-(α-thenoyl)-adenosine 5 '-diphosphate-/^

In one more preferred embodiment of the present invention a compound is selected from the compounds:

2'(3')-O-(benzoyl)-adenosine 5'-triphosphate-^S

2'(3 ')-O-(2-methylbenzoyl)-adenosine 5 '-triphosphate- ^S

2'(3 ')-O-(2,6-dimethylbenzoyl)-adenosine 5 '-triphosphate- ^S

2'(3 ')-O-(N-phenylcarbamoyl)-adenosine 5 '-triphosphate-^

2'(3 ')-O-(phenoxycarbonyl)-adenosine 5 '-triphosphate- ^S

2'(3 ')-O-(benzoyl)-adenosine 5'-diphosphate-/?S

2 ' (3 ')-0-(2-methylbenzoyl)-adenosine 5 ' -diphosphate-/5S

2'(3')-O-(2 ₅ 6-dimethylbenzoyl)-adenosine 5 '-diphosphate-/^

2'(3')-O-(N-phenylcarbamoyl)-adenosine 5 '-diphosphate-/^

2'(3 ')-O-(phenoxycarbonyl)-adenosine 5 '-diphosphate-/^

2'(3 ')-O-(benzoyl)-adenosine 5 '-thiophosphate

2'(3')-0-(2-methylbenzoyl)-adenosine 5 '-thiophosphate

2 ' (3 ' )-O-(2,6-dimethylbenzoyl)-adenosine 5 ' -thiophosphate

2'(3 ')-O-(N-phenylcarbamoyl)-adenosine 5 '-thiophosphate

2 ' (3 ' )-O-(phenoxycarbonyl)-adenosine 5 ' -thiophosphate

2'(3 ')-O-(benzoyl)-adenosine 5 '-monophosphate

2'(3')-O-(2-methylbenzoyl)-adenosine 5 '-monophosphate

2'(3 ')-O-(2,6-dimethylbenzoyl)-adenosine 5 '-monophosphate

2 ' (3 ')-0-(N-phenylcarbamoyl)-adenosine 5 ' -monophosphate

2'(3 ')-O-(phenoxycarbonyl)-adenosine 5 '-monophosphate

2'(3')-O-(benzoyl)-uridine 5'-triρhosphate-^S

2'(3')-O-(benzoyl)-uridine 5'-diρhosphate-/3S

2'(3')-Ο-(benzoyl)-uridine 5'-thiophosphate

2 ' (3 ' )-O-(benzoyl)-uridine 5 ' -monophosphate

2 ' (3 ' )-O-(2-methylbenzoyl)-uridine 5 ' -monophosphate

N ¹ -(^-D-2 ^l (3')-0-benzoyl-5'-phosphoribofuranosyl)-5-aminoimidazo le-4-carboxamide

2 ' (3 ^-O-benzoyl-Λ^-methyladenosine 5 ' -triphosphate- ^S

2'(3 ')-0-benzoyl-2-methylthioadenosine 5 '-triphosphate- ^S

2 ' (3 ' )-O-benzoyl-2-hexylthioadenosine 5 ' -triphosphate- ^S

2'(3 ')-O-benzoyl-2-(4-aminophenylethylthio)adenosine 5 '-triphosphate- ^S

2 ' (3 ')-O-benzoyl-2-benzylthioadenosine 5 ' -triphosphate- ^S

2'(3 ')-O-benzoyl-2-chloroadenosine 5 '-triphosphate-^S

2'(3 ')-O-benzoyl-2-methoxyadenosine 5 '-triphosphate- ^S

2'(3 ')-O-benzoyl-2-methyladenosine 5'-triphosphate-^S

Λ^-benzoyl-adenosine 5 ' -triphosphate- ^S

2'(3 O-O-benzoyl-Λ^-methyladenosine 5 '-diphosphate-/^

2'(3 ')-O-benzoyl-2-methylthioadenosine 5 '-diphosphate-/^

2'(3 ')-O-benzoyl-2-hexylthioadenosine 5 '-diphosphate-/^

2 ' (3 ' )-0-benzoyl-2-(4-aminophenylethylthio)adenosine 5 ' -diphosphate-/^

2 ' (3 ')-O-benzoyl-2-benzylthioadenosine 5 ' -diphosphate-/7S

2 ' (3 ')-O-benzoyl-2-chloroadenosine 5 ' -diphosphate-/3S

2'(3 ')-O-benzoyl-2-methoxyadenosine 5 '-diphosphate-/^

2'(3 ')-O-benzoyl-2-methyladenosine 5 '-diρhosphate-/7S

./^-benzoyl-adenosine 5 ' -diphosphate-/^

2'(3')-O-benzoyl-N ^δ -methyladenosine 5'-thiophosphate

2'(3')-(9-benzoyl-2-methylthioadenosine 5'-thiophosphate

2 ' (3 ')-O-benzoyl-2-hexylthioadenosine 5 ' -thiophosphate

2'(3')-O-benzoyl-2-(4-aminophenylethylthio)adenosine 5 '-thiophosphate

2 ' (3 ')-0-benzoyl-2-benzylthioadenosine 5 ' -thiophosphate

2 ' (3 ')-0-benzoyl-2-chloroadenosine 5 ' -thiophosphate

2 ' (3 ' )-O-benzoyl-2-methoxyadenosine 5 ' -thiophosphate

2'(3')-O-benzoyl-2-methyladenosine 5'-thiophosphate

Λ^-benzoyl-adenosine 5 ' -thiophosphate

2 ' (3 ^-O-benzoyl-Λ^-methyladenosine 5 ' -monophosphate

2'(3 ')-O-benzoyl-2-methylthioadenosine 5 '-monophosphate

2'(3 ')-O-benzoyl-2-hexylthioadenosine 5 '-monophosphate

2'(3 ')-O-benzoyl-2-(4-aminophenylethylthio)adenosine 5 '-monophosphate

2'(3 ')-O-benzoyl-2-benzylthioadenosine 5 '-monophosphate

2'(3 ')-O-benzoyl-2-chloroadenosine 5 '-monophosphate

2'(3 ')-O-benzoyl-2-methoxyadenosine 5 '-monophosphate

2 ' (3 ')-O-benzoyl-2-methyladenosine 5 ' -monophosphate

Λ^-benzoyl-adenosine 5 '-monophosphate

2'(3 ')-O-(4-benzyl-benzoyl)-adenosine 5 '-triphosphate- ^S

2 ' (3 ')-O-(acetyl)-adenosine 5 ' -diphosphate-/^

2',3 '-O,O-(dibenzoyl)-adenosine 5 '-diphosphate-/^

2'(3')-O-(4-nitrobenzoyl)-adenosine 5 '-diphosphate-/^

2'(3')-O-(4-methoxybenzoyl)-adenosine 5'-diphosphate-y0S

2 ' (3 ' )-O-(3 -nicotinoyl)-adenosine 5 ' -diphosphate-/^

2'(3')-0-(2-furoyl)-adenosine 5'-diphosphate-/?S

2'-0-(benzoyl)-adenosine 3',5'-cyclophosphate

2 ' (3 ')-0-(cinnamoyl)-adenosine 5 ' -diphosphate-/^

2'(3 ')-O-(2-phenylacetyl)-adenosine 5 '-diphosphate-/^

2'(3 ')-O-(4-trifluoromethoxybenzoyl)-adenosine 5 '-diphosphate-yβS

2'(3')-O-(bicyclo[2.2.1]hept-5-ene-2-carbonyl)-adenosine 5'-diphosphate-yβS

2'(3 ')-0-(hexahydrobenzoyl)-adenosine 5 '-diphosphate-/^

2'(3 ')-0-(α-thenoyl)-adenosine 5'-diphosphate-^S

In the most preferred embodiment of the present invention a compound is selected from the compounds:

2'(3 ')-O-(benzoyl)-adenosine 5 '-triphosphate- ^S

2'(3 ')-O-(2-methylbenzoyl)-adenosine 5 '-triphosphate- ^S

2'(3')-0-(2,6-dimethylbenzoyl)-adenosine 5'-triphosphate-^S

2'(3')-0-(N-phenylcarbamoyl)-adenosine 5'-triphosphate-^S

2 ' (3 ')-O-(phenoxycarbonyl)-adenosine 5 ' -triphosphate- ^S

2'(3')-O-(benzoyl)-adenosine 5'-diphosphate-y0S

2 ' (3 ')-O-(2-methylbenzoyl)-adenosine 5 ' -diphosphate-βS

2 ' (3 ' )-<9-(2 ,6-dimethylbenzoyl)-adenosine 5 ' -diphosphate-/7S

2 ' (3 ' )-0-(N-phenylcarbamoyl)-adenosine 5 ' -diphosphate-/^

2'(3')-O-(phenoxycarbonyl)-adenosine 5'-diphosphate-y0S

2'(3 ')-O-(benzoyl)-adenosine 5'-thiophosphate

2'(3 ')-O-(2-methylbenzoyl)-adenosine 5'-thioρhosphate

2 ' (3 ' )-0-(2,6~dimethylbenzoyl)-adenosine 5 ' -thiophosphate

2 ' (3 ' )-O-(N-phenylcarbamoyl)-adenosine 5 ' -thiophosphate

2 ' (3 ')-O-(phenoxycarbonyl)-adenosine 5 ' -thiophosphate

2 ' (3 ')-O-(benzoyl)-adenosine 5 ' -monophosphate

2 ' (3 ')-O-(2-methylbenzoyl)-adenosine 5 ' -monophosphate

2'(3 ')-0-(2,6-dimethylbenzoyl)-adenosine 5 '-monophosphate

2'(3')-O-(N-phenylcarbamoyl)-adenosine 5 '-monophosphate

2 ' (3 ')-(9-(phenoxycarbonyl)-adenosine 5 ' -monophosphate

2 ' (3 ')-O-(benzoyl)-uridine 5 ' -triphosphate-^

2 ' (3 ' )-O-(benzoyl)-uridine 5 ' -diρhosρhate-/3S

2 ' (3 ' )-O-(benzoyl)-uridine 5 ' -thiophosphate

2'(3')-0-(benzoyl)-uridine 5 '-monophosphate

2 ' (3 ')-O-(2-methylbenzoyl)-uridine 5 ' -monophosphate

N ¹ -( _/ ^β -D-2'(3')-0-benzoyl-5'-phosphoribofuranosyl)-5-aminoim idazole-4-carboxamide

2'(3')-O-benzoyl-2-methylthioadenosine 5 '-triphosphate- ^S

2'(3')-O-benzoyl-2-chloroadenosine 5 '-triphosphate-;^

2 ' (3 ' )-O-benzoyl-2-methylthioadenosine 5 ' -diphosphate-^S

2 ' (3 ')-O-benzoyl-2-chloroadenosine 5 ' -diphosphate-/^

2 ' (3 ')-O-benzoyl-2-methylthioadenosine 5 ' -thiophosphate

2 ' (3 ')-O-benzoyl-2-chloroadenosine 5 ' -thiophosphate

2 ' (3 ')-O-benzoyl-2-methylthioadenosine 5 ' -monophosphate

2'(3')-O-benzoyl-2-chloroadenosine 5 '-monophosphate

Λ^-benzoyl-adenosine 5 ' -triphosphate- ^S

Λ^-benzoyl-adenosine 5 '-diphosphate-ySS

Λ^-benzoyl-adenosine 5 '-thiophosphate

Λ^-benzoyl-adenosine 5 '-monophosphate

2'(3 ')-O-(4-benzyl-benzoyl)-adenosine 5 '-triphosphate- ^S

2'(3 ')-O-(acetyl)-adenosine 5 '-diphosphate-yβS

2',3 '-O ₅ 0-(dibenzoyl)-adenosine 5 '-diphosphate-^

2'(3 ')-O-(4-nitrobenzoyl)-adenosine 5 '-diphosphate-^S

2'(3')-O-(4-methoxybenzoyl)-adenosine 5'-diρhosphate-y0S

2'(3')-O-(3-nicotinoyl)-adenosine 5'-diphosphate-y^S

2' (3 ')-O-(2-furoyl)-adenosine 5 ' -diphosphate-^

2 ' -0-(benzoyl)-adenosine 3 ' ,5 ' -cyclophosphate

2 ' (3 ' )-0-(cinnamoyl)-adenosine 5 ' -diphosphate-/^

2'(3')-O-(2-phenylacetyl)-adenosine 5'-diphosphate-/?S

2'(3')-O-(4-trifluoromethoxybenzoyl)-adenosine 5'-diphosphate-y0S

2'(3 ')-<^-(bicyclo[2.2. l]hept-5-ene-2-carbonyl)-adenosine 5 '-diphosphate-/^

2'(3 ')-O-(hexahydrobenzoyl)-adenosine 5'-diphosphate-/?S

2'(3 ')-(9-(α-thenoyl)-adenosine 5 '-diphosphate-/?S

One embodiment of the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound according to Formula (I), or a pharmaceutically acceptable salt or prodrug thereof, and at least one pharmaceutically acceptable excipient

wherein,

when X is selected from heterocycles depicted in formulae II or III

R ¹ and R ² are the same or different and are selected from

H ₅ halogen, OH, -OR ³ , -O-CO-R ³ , -O-CO-OR ³ , -O-CO-NHR ³ , -NH-R ³ , -NH-CO-R ³ , - NH-CO-OR ³ , -NH-CO-NHR ³ , with the proviso that R ¹ and R ² are not simultaneously OH, and

in case R ¹ is OH, R ² can be neither OCH3 nor 4-benzoyl-benzoyl, and in case R ² is OH, R ¹ can be neither OCH ₃ nor 4-benzoyl-benzoyl,

R ³ independently represents the same or different groups selected from H, substituted or non-substituted lower alkyls, saturated or non saturated, substituted or non-substituted cycloalkyl, substituted or non-substituted benzyl groups, substituted or non-substituted aryl or mono-, bi-, tricyclic unsubstituted or substituted heteroaromatic ring(s) with one or more heteroatoms and non-aromatic heterocycles wherein the substituents of the substituted groups are selected from lower alkyl, halogens, substituted or non-substituted aryl, substituted or non-substituted hetero-aromatic compounds, non- aromatic heterocycles, R is represented by formula IV

wherein,

Z is selected independently from O or S, with the proviso that at least one atom represented by Z is S,

Q is selected from O or C(R ⁵ ) ₂ ,

R ⁵ is selected independently from H or halogen,

Y is selected independently from OH or SH, while n is O, 1 or 2,

and in case n is O,

Z can be O and Y can simultaneously be OH, with the proviso that R ¹ is OH and R ² is selected from -O-CO-R ⁸ , -O-CO-OR ³ , -O-CO-NHR ³ , -NH-CO-R ³ , -NH-CO-OR ³ , -NH-

CO-NHR ³ , with the proviso that R ² is OH and R ¹ is selected from -O-CO-R ⁸ , -O-CO-R ³ ,

-O-CO-OR ³ , -O-CO-NHR ³ , -NH-CO-R ³ , -NH-CO-OR ³ , -NH-CO-NHR ³ , wherein,

R is selected from H, saturated or non saturated, substituted or non-substituted cycloalkyl, substituted or non-substituted benzyl groups, substituted or non-substituted aryl or mono-, bi-, tricyclic unsubstituted or substituted heteroaromatic ring(s) with one or more heteroatoms and non-aromatic heterocycles wherein the substituents of the substituted groups are selected from lower alkyl, halogens, substituted or non-substituted aryl, substituted or non-substituted hetero-aromatic compounds, non-aromatic heterocycles,

wherein,

R ⁴ is -0-PZ(OH)O- forming together with R ² a cyclic phosphate ring as in cAMP according to formula V,

Z is selected from O or S, and; in the case of cAMP, R ¹ is neither OH nor O-(4-benzoyl-benzoyl)

or; when X is represented by formula VI,

wherein,

R ⁶ is selected from H ₅ R ³ , -CO-R ³ , -CO-OR ³ or -CO-NHR ³ , and in the case R ⁶ is either -CO-R ³ , -CO-OR ³ or -CO-NHR ³ , R ¹ and R ² of formula

(I) can simultaneously be OH,

R ⁷ is selected from halogen, H ₅ R ³ , -SR ³ or -OR ³ ,

R ¹ and R ² are the same as previously defined, and in case R ¹ is OH, R ² can be neither OCH ₃ nor 4-benzoyl-benzoyl, in case R ² is OH, R ¹ can be neither OCH ₃ nor 4-benzoyl-benzoyl,

R ³ is the same as previously defined,

R ⁴ is the same as previously defined, and;

R ⁸ is the same as previously defined,

including salts, solvates and pharmaceutically functional derivates thereof.

One embodiment of the present invention relates to the medical use of a compound with Formula (I) as described above.

One embodiment the present invention relates to the use of a compound with Formula (I) as described above for preparing a medicament for the treatment of a disorder selected from type 2 diabetes, glucose intolerance, hyperinsulinemia, insulin resistance, dyslipidemia, hypercholesterolemia, high blood pressure, obesity, fatty liver conditions, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, cardiovascular disease, atherosclerosis, cerebrovascular conditions, stroke and cancer.

One embodiment of the present invention relates to the use of a compound according to above listed preferred, more preferred and the most preferred compounds for preparing a medicament for the treatment of a disorder selected from type 2 diabetes, glucose intolerance, hyperinsulinemia, insulin resistance, dyslipidemia, hypercholesterolemia, high blood pressure, obesity, fatty liver conditions, diabetic nephropathy, diabetic

neuropathy, diabetic retinopathy, cardiovascular disease, atherosclerosis, cerebrovascular conditions, stroke and cancer.

One embodiment the present invention relates to the use of a compound with Formula (I) wherein R ⁶ is H and R ⁷ is H, as described above for preparing a medicament for the treatment of a disorder selected from type 2 diabetes, glucose intolerance, hyperinsulinemia, insulin resistance, dyslipidemia, hypercholesterolemia, high blood pressure, obesity, fatty liver conditions, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, cardiovascular disease, atherosclerosis, cerebrovascular conditions, stroke and cancer.

The yet most preferred embodiments of the present invention are compounds 2'(3')-O-(benzoyl)-adenosine 5 '-triphosphate- ^S, 2'(3')-O-(benzoyl)-adenosine 5'- diphosphate-yβS and 2'(3')-O-(benzoyl)-adenosine 5 '-monophosphate.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is a diagram showing the blood glucose (B-glucose) concentrations in C57BL/6JBomTac mice before treatment (BT) and after 19 days of intra peritoneal treatment with 1.0 mg/kg of compound A (AT).

Figure 2 is a diagram showing the blood glucose (B-glucose) concentrations in C57BL/6JBomTac mice before treatment (BT) and after 14 days of oral administration with 1.0 mg/kg of compound A (AT).

Figure 3 is a diagram showing the blood glucose (B-glucose) concentrations in C57BL/6JBomTac mice before treatment (BT) and after 19 days of intra peritoneal treatment with 0.5 mg/kg of compound B (AT).

Figure 4 is a diagram showing the blood glucose (B-glucose) concentrations in C57BL/6JBomTac mice before treatment (BT) and after 14 days of oral administration with 1.0 mg/kg of compound B (AT).

Figure 5 is a diagram showing the blood glucose (B-glucose) concentrations in B6.V/JUmeaTac-Lep ^ob mice before treatment (BT) and after 14 days of intra peritoneal treatment with 0.5 mg/kg of compound A (AT).

Figure 6 is a diagram showing the blood glucose (B-glucose) concentrations in B6.V/JUmeaTac-Lep ^ob mice before treatment (BT) and after 12 days of oral administration with 0.5 mg/kg of compound A (AT).

Figure 7 is a diagram showing the blood glucose (B-glucose) concentrations in B6.V/JUmeaTac-Lep ^ob mice before treatment (BT) and after 14 days of intra peritoneal treatment with 1.0 mg/kg of compound B (AT).

Figure 8 is a diagram showing the blood glucose (B-glucose) concentrations in B6.V/JUmeaTac-Lep ^ob mice before treatment (BT) and after 12 days of oral administration with 1.0 mg/kg of compound B (AT).

Figure 9 is a diagram showing the total body weight expressed in gram (g) of C57BL/6JBomTac mice after 14 days of intra peritoneal treatment with 0.5 mg/kg compound A and 0.5 mg/kg compound B.

Figure 10 is a diagram showing the plasma triglyceride concentrations in C57BL/6JBomTac mice before treatment (BT) and after 14 days of oral administration with 1.0 mg/kg compound A (AT).

Figure 11 is a diagram showing total liver lipids in C57BL/6JBomTac mice after 14 days of oral administration with 1.0 mg/kg compound A.

Figure 12 is a diagram showing the liver triglycerides in C57BL/6JBomTac mice after 14 days of oral administration with 1.0 mg/kg compound A.

Figure 13 is a diagram showing the liver cholesterol in C57BL/6JBomTac mice after 14 days of oral administration with 1.0 mg/kg compound A.

Figure 14 is a diagram showing the liver weight of C57BL/6JBomTac mice after 14 days of oral administration with 1.0 mg/kg compound A.

Figure 15 is a diagram showing plasma triglyceride concentrations in C57BL/6JBomTac mice before treatment (BT) and after 14 days of oral administration with 1.0 mg/kg compound B (AT).

Figure 16 is a diagram showing total liver lipids in C57BL/6JBomTac mice after 14 days of oral administration with 1.0 mg/kg compound B.

Figure 17 is a diagram showing liver triglycerides in C57BL/6JBomTac mice after 14 days of oral administration with 1.0 mg/kg compound B

Figure 18 is a diagram showing the liver cholesterol in C57BL/6JBomTac mice after 14 days of oral administration with 1.0 mg/kg compound B.

Figure 19 is a diagram showing the liver weight of C57BL/6JBomTac mice after 14 days of oral administration with 1.0 mg/kg compound B.

Figure 20 is a diagram showing the total liver lipids in B6.V/JUmeaTac-Lep ^ob mice after 14 days of oral administration with 0.2 mg/kg compound A.

Figure 21 is a diagram showing the liver triglycerides in B6.V/JUmeaTac-Lep ^ob mice after 14 days of oral administration with 0.2 mg/kg compound A.

Figure 22 is a diagram showing the cholesterol content in the liver in B6.V/JUmeaTac- Lep ^ob mice after 14 days of oral administration with 0.2 mg/kg compound A.

Figure 23 is a diagram showing the liver weight of B6.V/JUmeaTac-Lep ^ob after 14 days of oral administration with 0.2 mg/kg compound A.

Figure 24 is a diagram showing the glucose (B-glucose) concentrations in C57BL/6JBomTac mice before treatment (BT) and after 19 days of intra peritoneal treatment with 1.0 mg/kg of compound C (AT).

Figure 25 is a diagram showing the glucose (B-glucose) concentrations in B6.V/JUmeaTac-Lep ^ob mice before treatment (BT) and after 14 days of oral administration with 1.0 mg/kg of compound C (AT).

Figure 26 is a diagram showing the plasma triglyceride concentrations in C57BL/6JBomTac mice before treatment (BT) and after 14 days of oral administration with 1.0 mg/kg compound C (AT).

Figure 27 is a diagram showing the total liver lipids in C57BL/6JBomTac mice after 14 days of oral administration with 1.0 mg/kg compound C.

Figure 28 is a diagram showing the triglyceride content in liver lipids in C57BL/6JBomTac mice after 14 days of oral administration with 1.0 mg/kg compound C.

Figure 29 is a diagram showing the cholesterol content in liver in C57BL/6JBomTac mice after 14 days of oral administration with 1.0 mg/kg compound C.

Figure 30 is a diagram showing the liver weight of C57BL/6JBomTac mice after 14 days of oral administration with 1.0 mg/kg compound C.

Figure 31 is a diagram showing the plasma insulin concentration of C57BL/6JBomTac mice before treatment of compound A and compound B.

Figure 32 is a diagram showing the plasma insulin concentration of C57BL/6JBomTac mice after 14 days of oral administration with 1.0 mg/kg compound A and 1.0 mg/kg compound B.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to compounds that after either intraperitoneal or oral administration surprisingly have beneficial effects on glucose disposal in the diabetic mouse models C57BL/6JbomTac fed on high fat diet and B6.V/JUmeaTac-Lep ^ob . Further, these compounds after oral administration reduce plasma triglycerides in C57BL/6JbomTac fed on high fat diet. Further surprisingly, these compounds after oral administration drastically reduce the degree of fatty liver in the diabetic mouse models C57BL/6JbomTac fed on high fat diet and B6.V/JUmeaTac-Leρ ^ob> . Fatty liver is reduced without any reduction on liver weight. Further, the treated animals show no sign of weight increase or hyperinsulinemia during the course of treatment. The described compounds could be use as glucose lowering, fatty liver lowering and plasma triglyceride lowering agents, in the treatment of disorders wherein malfunctioning beta-cells and likely the liver or several other tissue targets having a role in type 2 diabetes and associated conditions and this discovery forms the basis of the present invention.

These compounds and analogues could therefore be used as agents that have beneficial effects on type 2 diabetes and associated conditions or related risk factors for cardiovascular disease. More particular the compounds, described in the present invention could be used as agents on, type 2 diabetes, glucose intolerance, hyperinsulinemia, insulin resistance, dyslipidemia, hypercholesterolemia, high blood pressure, obesity, fatty liver conditions, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, cardiovascular disease and prevention of heart infarction, atherosclerosis, cerebrovascular conditions and stroke. Moreover, these compounds could

be used as agents that may have direct beneficial effect on cancer. The treatment may be preventive, palliative or curative.

The present invention is described in terms known and appreciated by those skilled in the art. All terms used herein are believed to describe the invention such that one of ordinary skill can appreciate the scope of the present invention.

As used herein the term "lower alkyl" unless otherwise stated, means a unbranched or branched, cyclic, saturated or unsaturated (alkenyl or alkynyl) hydrocarbyl radical which may be substituted or unsubstituted. Where cyclic, the alkyl group is preferably C3 to C12, more preferably C5 to ClO, most preferably C5-C7. Where acyclic, the alkyl group is preferably Cl to ClO, more preferably Cl to C6, more preferably methyl, ethyl, propyl (n-propyl, isopropyl), butyl (branched or unbranched) or pentyl, most preferably methyl.

As used herein, the term "aryl" means an aromatic group, such as phenyl or naphthyl, or a mono-, bi-, or tricyclic heteroaromatic group containing one or ore heteroatom(s) preferably selected from N, O and S, such as pyridyl, pyrrolyl, quinolinyl, furanyl, thienyl, oxadiazolyl, thiadiazolyl, thiazolyl, oxazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrimidinyl, indolyl, pyrazinyl, indazolyl, pyrimidinyl, thiophenetyl, pyranyl, carbazolyl, acridinyl, quinolinyl, benzoimidazolyl, benzthiazolyl, purinyl, cinnolinyl, pterdinyl.

As used herein, the term "functional groups" means in the case of unprotected: hydroxy-, thiolo-, aminofunction, carboxylic acid and in the case of protected: lower alkoxy, N-, O- , S- acetyl, carboxylic acid ester.

As used herein, the term "heteroaryl" means an aromatic group containing one or more heteroatom(s) preferably selected from N, O and S, such as pyridyl, pyrrolyl, quinolinyl, furanyl, thienyl, oxadiazolyl, thiadiazolyl, thiazolyl, oxazolyl, pyrazolyl, triazolyl, imidazolyl, pyrimidinyl, indolyl, pyrazinyl or indazolyl.

As used herein, the term "non-aromatic heterocycle" means a non-aromatic cyclic group containing one or more heteroatom(s) preferably selected from N, O and S, such as a cyclic amino group such as pyrrolidinyl, piperidyl, piperazinyl, morpholinyl or a cyclic ether such as tetrahydrofuranyl, monosaccharide.

As used herein the term "halogen" means a fluorine, chlorine, bromine or iodine.

As used herein, and unless specified otherwise, the term "substituted" means that the concerned groups are substituted with functional group such as hydroxyl, amine, sulfide, silyl, carboxylic acid, halogen, aryl, etc.

Compounds of Formula (I) include all tautomers and isomers such as, for example, diastereomers and regioisomers such as, but not limiting to, adenosine nucleotides acylated at position 2'-O, V-O or N ⁶ . The present invention is meant to comprehend all such isomeric forms, including individual isomers as well as mixtures of isomers, as regards the compounds of Formula (I).

Further, the compounds according to Formula (I) include salts, solvates and pharmaceutically functional derivates thereof.

The compounds according to Formula (I) will be useful for treating or preventing various diseases such as type 2 diabetes, glucose intolerance, hyperinsulinemia, insulin resistance, dyslipidemia, hypercholesterolemia, high blood pressure, obesity, fatty liver conditions, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, cardiovascular disease, atherosclerosis, cerebrovascular conditions and stroke.

In another embodiment compounds of the present invention could also be used to treat cancer in prostate or any cancer where AMPK activation can be beneficial, vascular damage in cardiovascular disease, postischemic protection in heart.

In another embodiment compounds of the present invention could also be used in peripheral and central vascular diseases and protect in diseases such as stroke and heart infarction. The treatment may be preventive, palliative or curative.

In yet another embodiment compounds of the present invention with effect on hyperinsulinemia, lipid metabolism and on other risk factors described herein in obese subjects may protect or prevent cancer.

Examples of pharmaceutically acceptable addition salts for use in the pharmaceutical compositions of the present invention include those derived from mineral acids, such as hydrochlorid, hydrobromic, phosphoric, metaphosphoric, nitric and sulphuric acids, and organic acids, such as tartaric, acetic, citric, malic, lactic, fumaric, benzoic, glycolic, gluconic, succinic, and arylsulphonic acids. The pharmaceutically acceptable excipients described herein, for example, vehicles, adjuvants, carriers or diluents, are well-known to those who are skilled in the art and are readily available to the public. The pharmaceutically acceptable carrier may be one which is chemically inert to the active compounds and which have no detrimental side effects or toxicity under the conditions of use. Pharmaceutical formulations are found e.g. in Remington: The Science and Practice of Pharmacy, 19 ^th ed., Mack Printing Company, Easton, Pennsylvania (1995).

Prodrugs of the compounds of Formula (I) may be prepared by modifying functional groups present on the compound in such a way that the modifications are cleaved in vivo when such prodrug is administered to a mammalian subject. The modifications typically are achieved by synthesizing the parent compound with a prodrug substituent. General information on prodrugs may be found e.g. in Bundegaard, H. "Design of Prodrugs" pl- 92, Elesevier, New York-Oxford (1985).

The composition according to the invention may be prepared for any route of administration, e.g. oral, intravenous, cutaneous or subcutaneous, nasal, intramuscular, or intraperitoneal. The precise nature of the carrier or other material will depend on the route of administration. For a parenteral administration, a parenterally acceptable

aqueous solution is employed, which is pyrogen free and has requisite pH, isotonicity, and stability. Those skilled in the art are well able to prepare suitable solutions and numerous methods are described in the literature. A brief review of methods of drug delivery is also found in e.g. Langer, Science 249:1527-1533 (1990). The dose administered to an mammal, particularly a human, in the context of the present invention should be sufficient to effect a therapeutic response in the mammal over a reasonable time frame. One skilled in the art will recognize that dosage will depend upon a variety of factors including the potency of the specific compound, the age, condition and body weight of the patient, as well as the stage/severity of the disease. The dose will also be determined by the route (administration form) timing and frequency of administration. In the case of oral administration the dosage can vary from about 0.01 mg to about 1000 mg per day of a compound of Formula (I) or the corresponding amount of a pharmaceutically acceptable salt thereof.

The compounds of the present invention may be used or administered in combination with one or more additional drugs useful in the treatment of diseases such as metabolic syndrome, diabetes, impaired glucose tolerance, hyperinsulinemia, obesity and hyperlipidemia. The compounds could also be used as antihypersentive agent. The compounds could also be used to treat fatty liver disease. The compounds could also be used to treat cancer in prostate or any cancer where AMPK activation can be beneficial, vascular damage in cardiovascular disease, postischemic protection in heart. The compounds could also be used in peripheral and central vascular diseases and protect in diseases such as stroke and heart infarction.

The components may be in the same formulation or in separate formulations for administration simultaneously or sequentially.

Current diabetes therapies include diet, exercise, insulin, insulin secretagogues, such as sulphonylureas, metformin, the peroxisome proliferator-activated receptor-;; (PPAR-^) ₅ such as the thiazolidinediones, α-glucosidase inhibitors, and substances acting that affect the GLP-I receptor. In one embodiment of the present invention the compounds may be combined with these or other medical therapies to treat and/or prevent type 2 diabetes

and associated disorders and conditions, including but not limited to, glucose intolerance, hyperinsulinemia, insulin resistance, dyslipidemia, hypercholesterolemia, high blood pressure, obesity, fatty liver conditions, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, cardiovascular disease and heart infarction, atherosclerosis, cerebrovascular conditions and stroke.

Further, compounds according to the present invention may be superior than drugs of today, due to effects on more parameters in type 2 diabetes. These are glucose effect, no apparent hyperinsulinemia, effect on plasma lipids, effect on fatty liver, no weight gain. Since the drugs of today do not possess this profile there is a need for such compounds.

Diabetes and the liver

Obesity is typically associated with elevated levels of free fatty acid (FFAs) that promote lipid accumulation and insulin resistance in target tissues, i.e. reduced action of insulin primarily in skeletal muscle and liver. A prominent role of insulin is to reduce glucose output from the liver. FFAs stimulate hepatic gluconeogenesis which per se does not lead to increased hepatic glucose output as long as it is paralleled by a decrease in hepatic glycogenolysis, a compensatory process referred to as "hepatic autoregulation". FFAs stimulate insulin secretion and insulin blocks glycogenolysis in part by inhibiting secretion of glucagon, an inducer of glycogenolysis. However, long-term elevated levels of FFAs leads to hepatic insulin resistance and thus breakdown of hepatic autoregulation, resulting in increased hepatic glucose production and development of type 2 diabetes. The central role of hepatic insulin resistance in the progression of type 2 diabetes is highlighted by the fact that selective deletion of the insulin receptor gene in the liver results in severe insulin resistance and glucose intolerance, which is not observed when the insulin receptor is deleted specifically in muscle, fat or brain cells. The exact mechanism by which FFAs leads to hepatic insulin resistance is not known but it is tightly coupled to intra-hepatic lipid storage, i.e. hepatic steatosis or fatty liver. Thus, fatty liver and hepatic insulin resistance is a major driving force behind hyperglycemia and type 2 diabetes.

Therefore, it is a further object of the present invention to provide compounds that inhibit (improve) the fatty liver, resulting in that the insulin resistance in the liver is inhibited (improved) and thereby solving the basic problem in type 2 diabetes.

Type 1 diabetes

Type 1 diabetes results from autoimmune destruction of the pancreatic beta-cells. Markers of immune destruction of the beta-cell are present at the time of diagnosis in 90% of individuals and include antibodies to the islet cell (ICAs), to glutamic acid decarboxylase (GAD), and to insulin (IAAs). While this form of diabetes usually occurs in children and adolescents, it can occur at any age. Younger individuals typically have a rapid rate of beta-cell destruction and present with ketoacidosis, while adults often maintain sufficient insulin secretion to prevent ketoacidosis for many years. Eventually, all type 1 diabetic patients will require insulin therapy to maintain normglycemia.

Type 2 diabetes

Type 2 diabetes is characterized by insulin resistance and, at least initially, a relative deficiency of insulin secretion. In absolute terms, the plasma insulin concentration (both fasting and meal-stimulated) usually is increased, although "relative" to the severity of insulin resistance, the plasma insulin concentration is insufficient to maintain normal glucose homeostasis. With time, however, there is progressive beta cell failure and absolute insulin deficiency ensues. Most individuals with type 2 diabetes exhibit intra abdominal (visceral) obesity, fatty liver, which is closely related to the presence of insulin resistance. The patients liver becomes insulin resistance and glycogen breakdown is uncontrolled and the result is increased and unphysiological glucose delivery to the bloodstream. The liver generated cholesterol and VLDL particles is also uncontrolled. In addition, hypertension, dyslipidemia (high triglyceride and low HDL-cholesterol levels; postprandial hyperlipemia), and elevated PAI-I levels often are present in these individuals. This clustering of abnormalities is referred to as the "insulin resistance syndrome", or the "metabolic syndrome" or obesity related disorders. Because of these abnormalities, patients with type 2 diabetes are at increased risk of developing microvascular complications such as myocardial infarction and stroke. Type 2 diabetes

has a strong genetic predisposition. At present, no specific genes have been identified in the pathogenesis of this common metabolic disorder.

Type 1 diabetes, which is caused by an absolute deficiency of insulin, and type 2 diabetes, which is characterized by the presence of insulin resistance with an inadequate compensatory increase in insulin secretion. It has been established and is well known to the skilled person that type 1 and type 2 diabetes has different mechanisms and are different disorders.

According to another aspect of the present invention, methods of preparing the compounds according to Formula (I) are provided. Methods for different modifications have been described in the literature and are well-known for the person skilled in the art.

Methods of preparing the compounds according to Formula (I) are provided below. Not to be bound to any limitation for the synthesis the following reaction schemes should be considered only as examples for the synthesis of some compounds according to Formula

(I):

Examples of synthetic routes for the synthesis of modified adenosine/uridine derivatives

Acylation of the 2' and 3' position on the ribose unit could be formed by reacting carboxylic acid with the adenosine derivative according to the methods described by Gottikh et al. (Gottikh, B. P. et al. (1970) Tetrahedron, 26: 4419-4433).

A large number of modifications of the triphosphate chain have been described and could be used in the present invention for the synthesis of novel adenosine derivatives. These methods are well-known for the person skilled in the art.

Synthesis of 2'-0-modifϊed adenosine/uridine derivative

Silylation of position 3' and 5' followed by reaction on the unsubstituted 2'-hydroxyl, deprotection of the silyl group and finally synthesis of the triphosphate could be formed by following methods described by Wen et al ( Wen, K. et al. (2002) J. Org. Chem. 67:

7887-7889).

Synthesis of 3'-Amino-modifϊed adenosine/uridine derivatives

An azide is used to obtain epoxide formation and ring opening of the epoxide. Reduction of the azide gives an amine which could be selective coupled with aldehydes or carboxylic acid prior the triphosphate synthesis as described by van Calenbergh et al (van Calenbergh, S. et al. (2002) J. Med. Chem. 45:1845-1852).

Material and Methods

The compounds listed below were synthesized at Syngene Inc. (Bangalore, India) by reacting commercially available nucleotides in water with excess of 1,1- carbonyldiimidazole and excess of carboxylic acid in dimethylformamide. The reaction mixture was freeze-dried, triturated with acetone and purified by gel filtration (Akta Explorer, protein purification unit, AP-Biotech). Product fractions were pooled according to the chromatographic readout and identified by mass spectrometry.

Experimental procedure

Describing the synthesis of Example 4 (Compound B) and Example 5.

1,1-carbonyldiimidazole (25 mg, 0.16 mmol) and benzoic acid (6.2 mg, 0.051 mmol) in anhydrous N,N-dimethylformamide (0.1 ml) were stirred for 15 minutes at room temperature. Then, ADP-β-S (trilithium salt, 5.0 mg, 0.011 mmol) in deionized water (0.25 ml) was added and stirred overnight at room temperature. The reaction mixture was freeze-dried, and the residue was washed several times with distilled acetone to remove unreacted 1,1-carbonyldiimidazole and benzoic acid. Purification was performed by gel filtration (Akta Explorer) using a Sephadex LH-20 matrix that had been swollen for 15 hours in deionized water and equilibrated with 0.1M ammonium formate solution (~300 ml). The crude product was dissolved in 0.1 M ammonium formate (2 ml), injected into the column and eluted with 0.1 M ammonium formate solution (~300 ml) at a flow rate of lml/min. The fractions containing product 1 (corresponding to Example 4) as determined by mass analysis were pooled together and freeze dried. Yield = 1.3mg; MS Found: 546(M-I) ; Calculated : 547.38. The fractions containing product 2 (corresponding to Example 5) as determined by mass analysis were pooled together and freeze dried. Yield = 0.9mg; MS Found: 650(M-I) ; Calculated : 651.48.

Example 1

2'(3')-O-(benzoyl)-adenosine 5'-triphosphate-γS (Compound A)

Yield = 2mg ; MS Found: 529.8(Fragmented) ; Calculated: 627.36

Example 2

2'(3')-O-(4-benzyl-benzoyl)-adenosine 5'-triphosphate-γS

Yield = 3mg ; MS Found: 619.8(Fragmented) ; Calculated: 717.49

Example 3

2'(3')-0-(acetyl)-adenosine 5'-diphosphate-y0$

Yield = lmg; MS Found: 484.1(M-I) ; Calculated: 485.307

Example 4

2'(3')-0-(benzoyl)-adenosine 5'-diphosphate-/3$ (Compound B)

Yield = 1.3mg; MS Found: 546(M-I) ; Calculated: 547.38.

Example 5

2',3'-0,0~(dibenzoyl)-adenosme 5'-diphosphate-yflS

Yield = 0.9mg; MS Found: 650(M-I) ; Calculated : 651.48.

Example 6

2'(3')-O-(4-nitrobenzoyl)-adenosine 5'-diphosphate-/3$

Yield = l.lmg ; MS Found: 591(M-I) ; Calculated : 592.372.

Example 7 2'(3')-6>-(4-methoxybenzoyI)-adenosine 5'-diphosphate-y0S

Yield = 0.9mg ; MS Found: 578(M+1) ; Calculated : 577.4.

Example 8

2'(3')-0-(3-nicotinoyI)-adenosine 5'-diphosphate-^S

Yield = 8mg ; MS Found: 547.1(M-I) ; Calculated : 548.362.

Example 9 2'(3')-0-(2-furoyl)-adenosine 5'-diphosphate- ₇ 0S

Yield = 5mg ; MS Found: 536(M-I) ; Calculated : 537.336.

Example 10

2'(3')-0-(benzoyl)-adenosine 5'-monophosphate (Compound C)

Yield = 8mg ; MS Found: 450.1(M-I) ; Calculated : 451.33

Example 11

2 ' (3 ')-0-(benzoyl)-adenosine 5' -diphosphate- α,/?-methyIene

Yield = l.lmg ; MS Found: 528.1(M-I) ; Calculated : 529.335

Example 12

2 '-O-(benzoyl)-adenosine 3 ' ,5 '-cy diphosphate

Yield = 3.1mg ; MS Found: 432(M-I) ; Calculated : 433.312

Example 13

2'(3')-0-(cimiamoyl)-adenosme 5'-diphosphate-/3$

Yield= 0.8mg ; MS Found: 572(M-I) ; Calculated : 473.411

Example 14 2'(3')-O-(2-phenylacetyl)-adenosine 5'-diphosphate-^S

Yield = 2mg ; MS Found: 560.1(M-I) ; Calculated : 561.401

Example 15

2'(3')-0-(4-trifluoromethoxybenzoyl)-adenosine 5'-diphosphate-/3S

Yield = 0.9mg ; MS Found: 614(M-I) ; Calculated : 615.372

Example 16

2 '(3 ')-0-(bicyclo [2.2.1 ] hept-5-ene-2-carbonyl)-adenosine 5 '-diphosphate-/3$

Yield = lmg ; MS Found: 562.1(M-I) ; Calculated : 563.416

Example 17 2'(3')-0-(hexahydrobenzoyl)-adenosine 5'-diphosphate-/3S

Yield = l.lmg ; MS Found: 552.1(M-I) ; Calculated : 553.422

Example 18 2'(3')-0-(α-thenoyl)-adenosine 5'-diphosphate-βS

Yield = 1.5mg ; MS Found: 552(M-I) ; Calculated : 553.403

Example 19

N ¹ -(β -D-2'(3')-O -benzoyI-5'-phosphoribofuranosyl)-5-ammoimidazole-4- carboxamide

Yield = 1.9mg ; MS Found: 441.1(M-I) ; Calculated : 442.317

For the sake of clarity, above products are shown as the 2'-isomers. In fact, they are meant to represent either the 2'-isomer or the 3'-isomer or a mixture of both.

EXPERIMENTAL SECTION

Animals, diets and experimental setup

Male C57BL/6JBomTac mice, 8 weeks of age and B6.V/JUmeaTac-Lep ^ob mice, 6 weeks of age, were obtained from Taconic. Mice were maintained in a temperature-controlled (25°C) facility with a 12:12-h light-dark cycle and free access to food and water. Before the experiments, C57BL/6JBomTac mice were fed with a high fat diet for 8 weeks to induce obesity and diabetes. The diabetogenic diet (Research Diets, No. D12309) contained 35.9% fat, 35.5% carbohydrate and 23.0% protein. After 8 weeks on high fat diet, blood samples from the tail vein were collected after an overnight fast (16

h) for quantification of plasma glucose, insulin and triglycerides levels. A glucose tolerance test were then performed on all animals with an intraperitoneal injection of glucose (2 g/kg body weight) and blood samples from the tail vein were collected at 30, 60 and 120 minutes after the glucose injection. Mice were then placed into groups based on their glucose, insulin, triglycerides levels and body weights. Animals were dosed with either vehicle control (phosphate buffered saline (PBS), pH 7.4), compound A (0.2-2 mg/kg body weight), compound B (0.2-2 mg/kg body weight) or compound C (0.2-2 mg/kg body weight) for 10-19 continuous days of once or twice-daily intraperitoneal or oral administration. The day after administration of the last dose, plasma glucose, insulin, triglycerides and glucose tolerance test were assayed as described above. In addition, total body weight was measured.

B6.V/JUmeaTac-Lep ^ob mice were fed with rodent chow pellets containing 4.0% fat, 58.0% carbohydrate and 16.5% protein (Lactamin, No. R34). B6.V/JUmeaTac-Leρ ^ob mice were analysed by blood samples taken from the tail vein, and were collected after an overnight fast (16 h) for quantification of plasma glucose, insulin levels. A glucose tolerance test were then performed on all animals with an intraperitoneal injection of glucose (2 g/kg body weight) and blood samples from the tail vein were collected at 30, 60 and 120 minutes after the glucose injection. Mice were then placed into groups based on their glucose, insulin levels and weight. Animals were dosed with either vehicle control (PBS), compound A (0.2-2 mg/kg body weight), compound B (0.2-2 mg/kg body weight) or compound C (0.2-2 mg/kg body weight) for 12-14 continuous days of once or twice-daily intraperitoneal or oral administration. The day after administration of the last dose, plasma glucose, insulin, triglycerides and glucose tolerance test were assayed as described above.

At the end of the experiment, mice were sacrificed by cervical dislocation. Blood samples were collected in EDTA-coated tubes (Microvette CB 300 and 500; Sarstedt, Inc.) and centrifuged (10 000 rpm for 10 minutes at RT), and the plasma was stored at -20 ⁰ C until analysis. Tissues were harvested for analyses as described below. All experiments were approved by the Animal Care and Use Committee of Umea, Sweden (Protocol No. A 130- 03).

Plasma analyses, insulin and glucose tolerance test

For intraperitoneal glucose tolerance test, mice were fasted overnight (16 hours) before receiving an intraperitoneal injection with 20% D-glucose (Sigma) in sterile saline (0.9% NaCl) at a dose of 2 g glucose/kg body weight. Blood samples were collected from the tail vein for glucose quantification prior to and 30, 60 and 120 minutes after glucose injection. Glucose was quantified by using an Ascensia Elite XL Glucometer (Bayer Diagnostic). For other plasma analyses, different enzymatic colorimetric assays were used for each analyte, including plasma triglycerides (Serum triglyceride determination kit, Code No. TROlOO, Sigma-Aldrich CO., St Louis, MO, USA), and insulin (CrystalChem). All analyses were done according to the manufacturer's recommendations with a minor modification for triglyceride which was analyzed at 560 nm instead of 540 nm.

Isolation and purification of total lipids from mouse liver

Fresh liver samples (0.3-0.35 g) from fed mice were homogenized in 3 ml of PBS, pH 7.4 for 2 minutes. Total lipids were extracted by shaking the homogenates with 6 ml of chloroform/methanol (2:1). After incubation for 0.5 hours at room temperature, the biphasic system was separated into two phases by centrifugation for 5 minutes at 4500 rpm. The upper water phase was removed by water suction. The lower lipid containing chloroform phase was collected into a pre-weighted glass tubes and evaporated to dryness by a stream of nitrogen. To remove final traces of solvent, the samples were put into a Speed- Vac for 20 minutes. Total lipid content was then determined gravimetrically. The residue derived from the evaporation was resuspended in methanol containing 35% triton X-100 for analyzing triglyceride and cholesterol content.

Analysis of triglycerides and cholesterol in the liver lipid extracts

Triglycerides in the liver lipid extracts were quantified using an enzymatic colorimetric method at 560 nm with a commercially available test kit (Serum triglyceride determination kit, Code No. TROlOO ₅ Sigma-Aldrich CO., St Louis, MO, USA) and using glycerol as the standard. The proceeding is described in the manufacturer's protocol.

Total liver cholesterol was determined using an enzymatic colorimetric kit (CHOL-H L- rype WAKO 20R/30R, Code No. 419-43998, Wako Chemicals GmbH, Neuss, Germany) and using Wako system calibrator as the standard (Code No. 412-00302). The experimental procedure was performed manually and the following modifications from the manufacturer's protocol were made:

40 μl of the liver lipid extracts and each standard solution were transferred into separate test tubes. 675 μl of reagent 1 was added to each test tube and the mixtures were blended by gentle inversion. The tubes were incubated for 5 minutes at 37°C. After incubation, 225 μl of reagent 2 was added to each tube. The tubes were mixed by gentle inversion and incubated 5 minutes at 37°C. Absorbance was recorded at 620 nm and sample concentration was calculated by the standard curve using linear regression.

Compound preparation

Compounds A, B and C were obtained from Syngene Inc (Bangalore, India) and a 3.57 mg/ml stock solution was prepared by dissolving the compound/s in PBS, pH 7.4. PBS was used as vehicle control.

Histological procedures

Liver tissue was obtained from each animal and fixed overnight in 4% paraformaldehyde, washed in PBS and incubated overnight at 4 ⁰ C in 30% sucrose, embedded in OCT and frozen on dry ice. For histopathological analysis, liver samples were subjected to hematoxylin-eosin staining and the intra- and extracellular fat deposits were shown by Oil Red staining of frozen tissue sections.

Results

Figure 1 relates to the glucose tolerance test and the diagram describes the blood glucose (B-glucose) concentrations in C57BL/6JBomTac mice before treatment (BT) and after 19 days of intra peritoneal treatment with 1.0 mg/kg of compound A (AT). Time point zero describes fasted B-glucose concentration. Time points 30, 60 and 120 minutes refer to time after glucose injection. Blue line (♦ Vehicle, BT) represents B-glucose for the vehicle control group before treatment. Green line ( ^■ compound A, BT) represents B-

W

47 glucose for the compound A-group before treatment. Red line ( ^A Vehicle, AT) represents B-glucose for the vehicle control group the day after treatment (day 20). Brown line (• compound A, AT) represents B-glucose for the compound A-group the day after treatment (day 20). Data were expressed as mean ± SEM; n=12 for vehicle and n=6 for compound A.

Figure 2 relates to the glucose tolerance test and the diagram describes the blood glucose (B-glucose) concentrations in C57BL/6JBomTac mice before treatment (BT) and after 14 days of oral administration with 1.0 mg/kg of compound A (AT). Time point zero describes fasted B-glucose concentration. Time points 30, 60 and 120 minutes refer to time after glucose injection. Blue line (♦ Vehicle, BT) represents B-glucose for the vehicle control group before treatment. Green line (■ compound A, BT) represents B- glucose for the compound A-group before treatment. Red line (^ Vehicle, AT) represents B-glucose for the vehicle control group the day after treatment (day 15). Brown line (• compound A, AT) represents B-glucose for the compound A-group the day after treatment (day 15). Data were expressed as mean ± SEM; n=5 for vehicle and n=5 for compound A.

Figure 3 relates to the glucose tolerance test and the diagram describes the blood glucose (B-glucose) concentrations in C57BL/6JBomTac mice before treatment (BT) and after 19 days of intra peritoneal treatment with 0.5 mg/kg of compound B (AT). Time point zero describes fasted B-glucose concentration. Time points 30, 60 and 120 minutes refer to time after glucose injection. Blue line (♦ Vehicle, BT) represents B-glucose for the vehicle control group before treatment. Green line (■ compound B, BT) represents B- glucose for the compound B-group before treatment. Red line (^ Vehicle, AT) represents B-glucose for the vehicle control group the day after treatment (day 20). Brown line (• compound B ₅ AT) represents B-glucose for the compound B-group the day after treatment (day 20). Data were expressed as mean ± SEM; n=12 for vehicle and n=6 for compound B.

W

48

Figure 4 relates to the glucose tolerance test and the diagram describes the blood glucose (B-glucose) concentrations in C57BL/6JBomTac mice before treatment (BT) and after 14 days of oral administration with 1.0 mg/kg of compound B (AT). Time point zero describes fasted B-glucose concentration. Time points 30, 60 and 120 minutes refer to time after glucose injection. Blue line (♦ Vehicle, BT) represents B-glucose for the vehicle control group before treatment. Green line (■ compound B, BT) represents B- glucose for the compound B-group before treatment. Red line ( ■ Vehicle, AT) represents B-glucose for the vehicle control group the day after treatment (day 15). Brown line (• compound B, AT) represents B-glucose for the compound B-group the day after treatment (day 15). Data were expressed as mean ± SEM; n=5 for vehicle and n=5 for compound B.

Figure 5 relates to the glucose tolerance test and the diagram describes the blood glucose (B-glucose) concentrations in B6.V/JUmeaTac-Lep ^ob mice before treatment (BT) and after 14 days of intra peritoneal treatment with 0.5 mg/kg of compound A (AT). Time point zero describes fasted B-glucose concentration. Time points 30, 60 and 120 minutes refer to time after glucose injection. Blue line (♦ Vehicle, BT) represents B-glucose for the vehicle control group before treatment. Green line (■ compound A, BT) represents B- glucose for the compound A-group before treatment. Red line (^ Vehicle, AT) represents B-glucose for the vehicle control group the day after treatment (day 15). Brown line (• compound A, AT) represents B-glucose for the compound A-group the day after treatment (day 15). Data were expressed as mean ± SEM; n=5 for vehicle and n=5 for compound A.

Figure 6 relates to the glucose tolerance test and the diagram describes the blood glucose (B-glucose) concentrations in B6.V/JUmeaTac-Lep ^ob mice before treatment (BT) and after 12 days of oral administration with 0.5 mg/kg of compound A (AT). Time point zero describes fasted B-glucose concentration. Time points 30, 60 and 120 minutes refer to time after glucose injection. Blue line (♦ Vehicle, BT) represents B-glucose for the vehicle control group before treatment. Green line (■ compound A, BT) represents B- glucose for the compound A-group before treatment. Red line (^ Vehicle, AT)

represents B-glucose for the vehicle control group the day after treatment (day 13). Brown line (• compound A, AT) represents B-glucose for the compound A-group the day after treatment (day 13). Data were expressed as mean ± SEM; n=6 for vehicle and Ώ=5 for compound A.

Figure 7 relates to the glucose tolerance test and the diagram describes the blood glucose (B-glucose) concentrations in B6.V/JUmeaTac-Lep ^ob mice before treatment (BT) and after 14 days of intra peritoneal treatment with 1.0 mg/kg of compound B (AT). Time point zero describes fasted B-glucose concentration. Time points 30, 60 and 120 minutes refer to time after glucose injection. Blue line (♦ Vehicle, BT) represents B-glucose for the vehicle control group before treatment. Green line (■ compound B, BT) represents B- glucose for the compound B-group before treatment. Red line (■* Vehicle, AT) represents B-glucose for the vehicle control group the day after treatment (day 15). Brown line (• compound B, AT) represents B-glucose for the compound B-group the day after treatment (day 15). Data were expressed as mean ± SEM; n=6 for vehicle and n=6 for compound B.

Figure 8 relates to the glucose tolerance test and the diagram describes the blood glucose (B-glucose) concentrations in B6.V/JUmeaTac-Lep ^ob mice before treatment (BT) and after 12 days of oral administration with 1.0 mg/kg of compound B (AT). Time point zero describes fasted B-glucose concentration. Time points 30, 60 and 120 minutes refer to time after glucose injection. Blue line (♦ Vehicle, BT) represents B-glucose for the vehicle control group before treatment. Green line (■ compound B, BT) represents B- glucose for the compound B-group before treatment. Red line (^ Vehicle, AT) represents B-glucose for the vehicle control group the day after treatment (day 13). Brown line (• compound B, AT) represents B-glucose for the compound B-group the day after treatment (day 13). Data were expressed as mean ± SEM; n=6 for vehicle and n=5 for compound B.

Figure 9 relates to the total body weight and the diagram describes the total body weight expressed in gram (g) of C57BL/6JBomTac mice after 14 days of intra peritoneal

treatment with 0.5 mg/kg compound A and 0.5 mg/kg compound B. Blue bar to the left (Vehicle) represents total body weight of the vehicle control group after treatment. Yellow bar in the middle (Compound A) represents total body weight of the compound A-group after treatment. Green bar to the right (Compound B) represents total body weight of the compound B-group after treatment. Data were expressed as mean ± SEM; n=6 for vehicle, n=5 for compound A and n=6 for compound B.

Figure 10 relates to the measurement of the triglyceride concentration in plasma and the diagram describes the plasma triglyceride concentrations in C57BL/6JBomTac mice before treatment (BT) and after 14 days of oral administration with 1.0 mg/kg compound A (AT). Blue bar (Vehicle, BT) represents plasma triglycerides for the vehicle control group before treatment. Green bar (Compound A, BT) represents plasma triglycerides for the compound A group before treatment. Purple bar (Vehicle, AT) represents plasma triglycerides for the vehicle control group the day after treatment (day 15). Brown bar (Compound A, AT) represents plasma triglycerides for the compound A group the day after treatment (day 15). Data were expressed as mean ± SEM; n=5 for vehicle and n=5 for compound A.

Figure 11 relates to the measurement of the total liver lipids and the diagram describes the total liver lipids in C57BL/6JBomTac mice after 14 days of oral administration with 1.0 mg/kg compound A. Blue bar (Vehicle) represents total liver lipids of the vehicle control group after treatment. Green bar (Compound A) represents total liver lipids of the compound A-group after treatment. Data were expressed as mean ± SEM; n=5 for vehicle and n=5 for compound A.

Figure 12 relates to the measurement of the triglyceride content in the liver and the diagram describes the triglyceride content in the liver in C57BL/6JBomTac mice after 14 days of oral administration with 1.0 mg/kg compound A. Blue bar (Vehicle) represents liver triglycerides of the vehicle control group after treatment. Green bar (Compound A) represents liver triglycerides of the compound A-group after treatment. Data were expressed as mean ± SEM; n=5 for vehicle and n=5 for compound A.

Figure 13 relates to the measurement of the cholesterol content in liver and the diagram describes the cholesterol content in liver in C57BL/6JBomTac mice after 14 days of oral administration with 1.0 mg/kg compound A. Blue bar (Vehicle) represents liver cholesterol of the vehicle control group after treatment. Green bar (Compound A) represents liver cholesterol of the compound A-group after treatment. Data were expressed as mean ± SEM; n=5 for vehicle and n=5 for compound A.

Figure 14 relates to the liver weight of C57BL/6JBomTac mice after 14 days of oral administration with 1.0 mg/kg compound A. Blue bar (Vehicle) represents liver weight of the vehicle control group after treatment. Green bar (Compound A) represents liver weight of the compound A-group after treatment. Data were expressed as mean ± SEM; n=5 for vehicle and n=5 for compound A.

Figure 15 relates to the measurement of the triglyceride concentration in plasma and the diagram describes the plasma triglyceride concentrations in C57BL/6JBomTac mice before treatment (BT) and after 14 days of oral administration with 1.0 mg/kg compound B (AT). Blue bar (Vehicle, BT) represents plasma triglycerides for the vehicle control group before treatment. Green bar (compound B, BT) represents plasma triglycerides for the compound B-group before treatment. Purple bar (Vehicle, AT) represents plasma triglycerides for the vehicle control group the day after treatment (day 15). Brown bar (compound B, AT) represents plasma triglycerides for the compound B-group the day after treatment (day 15). Data were expressed as mean ± SEM; n=5 for vehicle and n=5 for compound B.

Figure 16 relates to the measurement of the total liver lipids and the diagram describes the total liver lipids in C57BL/6JBomTac mice after 14 days of oral administration with 1.0 mg/kg compound B. Blue bar (Vehicle) represents total liver lipids of the vehicle control group after treatment. Green bar (Compound B) represents total liver lipids of the compound B-group after treatment. Data were expressed as mean ± SEM; n=5 for vehicle and n=5 for compound B.

Figure 17 relates to the measurement of the triglyceride content in liver and the diagram describes the triglyceride content in liver in C57BL/6JBomTac mice after 14 days of oral administration with 1.0 mg/kg compound B. Blue bar (Vehicle) represents liver triglycerides of the vehicle control group after treatment. Green bar (Compound B) represents liver triglycerides of the compound B-group after treatment. Data were expressed as mean ± SEM; n=5 for vehicle and n=5 for compound B.

Figure 18 relates to the measurement of the cholesterol content in liver and the diagram describes the cholesterol content in liver in C57BL/6JBomTac mice after 14 days of oral administration with 1.0 mg/kg compound B. Blue bar (Vehicle) represents liver cholesterol of the vehicle control group after treatment. Green bar (compound B) represents liver cholesterol of the compound B-group after treatment. Data were expressed as mean ± SEM; n=5 for vehicle and n=5 for compound B.

Figure 19 relates to the liver weight and the diagram describes the liver weight of C57BL/6JBomTac mice after 14 days of oral administration with 1.0 mg/kg compound B. Blue bar (Vehicle) represents liver weight of the vehicle control group after treatment. Green bar (Compound B) represents liver weight of the compound B-group after treatment. Data were expressed as mean ± SEM; n=5 for vehicle and n=5 for compound B.

Figure 20 relates to the measurement of the total liver lipids and the diagram describes the total liver lipids in B6.V/JUmeaTac-Lep ^ob mice after 14 days of oral administration with 0.2 mg/kg compound A. Blue bar (Vehicle) represents total liver lipids of the vehicle control group after treatment. Green bar (Compound A) represents total liver lipids of the compound A-group after treatment. Data were expressed as mean ± SEM; n=5 for vehicle and n=5 for compound A.

Figure 21 relates to the measurement of the triglyceride content in liver and the diagram describes the triglyceride content in liver in B6.V/JUmeaTac-Leρ ^ob mice after 14 days of

oral administration with 0.2 mg/kg compound A. Blue bar (Vehicle) represents liver triglycerides of the vehicle control group after treatment. Green bar (Compound A) represents liver triglycerides of the compound A-group after treatment. Data were expressed as mean ± SEM; n=5 for vehicle and n=5 for compound A.

Figure 22 relates to the measurement of the cholesterol content in the liver and the diagram describes the cholesterol content in the liver in B6.V/JUmeaTac-Lep ^ob mice after 14 days of oral administration with 0.2 mg/kg compound A. Blue bar (Vehicle) represents liver cholesterol of the vehicle control group after treatment. Green bar (Compound A) represents liver cholesterol of the compound A-group after treatment. Data were expressed as mean ± SEM; n=5 for vehicle and n=5 for compound A.

Figure 23 relates to the measurement of the liver weight the diagram describes the liver weight of B6.V/JUmeaTac-Lep ^ob after 14 days of oral administration with 0.2 mg/kg compound A. Blue bar (Vehicle) represents liver weight of the vehicle control group after treatment. Green bar (Compound A) represents liver weight of the compound A-group after treatment. Data were expressed as mean ± SEM; n=5 for vehicle and n=5 for compound A.

Figure 24 relates to the glucose tolerance test and the diagram describes the glucose (B- glucose) concentrations in C57BL/6JBomTac mice before treatment (BT) and after 19 days of intra peritoneal treatment with 1.0 mg/kg of compound C (AT). Time point zero describes fasted B-glucose concentration. Time points 3O ₅ 60 and 120 minutes refer to time after glucose injection. Blue line (♦ Vehicle, BT) represents B-glucose for the vehicle control group before treatment. Green line (■ compound C, BT) represents B- glucose for the compound C-group before treatment. Red line (-*■ Vehicle, AT) represents B-glucose for the vehicle control group the day after treatment (day 20). Brown line (• compound C, AT) represents B-glucose for the compound C-group the day after treatment (day 20). Data were expressed as mean ± SEM; n=12 for vehicle and n=8 for compound C.

Figure 25 relates to the glucose tolerance test and the diagram describes the glucose (B- glucose) concentrations in B6.V/JUmeaTac-Lep ^ob mice before treatment (BT) and after 14 days of oral administration with 1.0 mg/kg of compound C (AT). Time point zero describes fasted B-glucose concentration. Time points 30, 60 and 120 minutes refer to time after glucose injection. Blue line (♦ Vehicle, BT) represents B-glucose for the vehicle control group before treatment. Green line (■ compound C, BT) represents B- glucose for the compound C-group before treatment. Red line (■* Vehicle, AT) represents B-glucose for the vehicle control group the day after treatment (day 15). Brown line (• compound C, AT) represents B-glucose for the compound C-group the day after treatment (day 15). Data were expressed as mean ± SEM; n=7 for vehicle and n=6 for compound C.

Figure 26 relates to the measurement of triglyceride concentration in plasma and the diagram describes the plasma triglyceride concentrations in C57BL/6JBomTac mice before treatment (BT) and after 14 days of oral administration with 1.0 mg/kg compound C (AT). Blue bar (Vehicle, BT) represents plasma triglycerides for the vehicle control group before treatment. Green bar (Compound C ₅ BT) represents plasma triglycerides for the compound C-group before treatment. Purple bar (Vehicle, AT) represents plasma triglycerides for the vehicle control group the day after treatment (day 15). Brown bar (Compound C, AT) represents plasma triglycerides for the compound C-group the day after treatment (day 15). Data were expressed as mean ± SEM; n=7 for vehicle and n=6 for compound C.

Figure 27 relates to the measurement of the total liver lipids and the diagram describes the total liver lipids in C57BL/6JBomTac mice after 14 days of oral administration with 1.0 mg/kg compound C. Blue bar (Vehicle) represents total liver lipids of the vehicle control group after treatment. Green bar (Compound C) represents total liver lipids of the compound C-group after treatment. Data were expressed as mean ± SEM; n=7 for vehicle and n=6 for compound C.

Figure 28 relates to the measurement of the triglyceride content in liver lipids and the diagram describes the triglyceride content in liver lipids in C57BL/6JBomTac mice after 14 days of oral administration with 1.0 mg/kg compound C. Blue bar (Vehicle) represents liver triglycerides of the vehicle control group after treatment. Green bar (Compound C) represents liver triglycerides of the compound C-group after treatment. Data were expressed as mean ± SEM; n=7 for vehicle and n=6 for compound C.

Figure 29 relates to the measurement of the cholesterol content in liver and the diagram describes the cholesterol content in liver in C57BL/6JBomTac mice after 14 days of oral administration with 1.0 mg/kg compound C. Blue bar (Vehicle) represents liver cholesterol of the vehicle control group after treatment. Green bar (Compound C) represents liver cholesterol of the compound C-group after treatment. Data were expressed as mean ± SEM; n=7 for vehicle and n=6 for compound C.

Figure 30 relates to the liver weight and the diagram describes the liver weight of C57BL/6JBomTac mice after 14 days of oral administration with 1.0 mg/kg compound C. Blue bar (Vehicle) represents liver weight of the vehicle control group after treatment. Green bar (Compound C) represents liver weight of the compound C-group after treatment. Data were expressed as mean ± SEM; n=7 for vehicle and n=6 for compound C.

Figure 31 relates to the plasma insulin concentration and the diagram describes the insulin concentration in plasma of C57BL/6JBomTac mice before treatment of compound A and compound B. Blue bar to the left (Vehicle) represents insulin concentration of the vehicle control group before treatment. Green bar in the middle (Compound A) represents insulin concentration of the compound A-group before treatment. Purple bar to the right (Compound B) represents insulin concentration of the compound B-group before treatment. Data were expressed as mean ± SEM; n=5 for vehicle, n=5 for compound A and n=5 for compound B.

Figure 32 relates to the plasma insulin concentration and the diagram describes the insulin concentration in plasma of C57BL/6JBomTac mice after 14 days of oral administration with 1.0 mg/kg compound A and 1.0 mg/kg compound B. Blue bar to the left (Vehicle) represents insulin concentration of the vehicle control group after treatment. Green bar in the middle (Compound A) represents insulin concentration of the compound A-group after treatment. Purple bar to the right (Compound B) represents insulin concentration of the compound B-group after treatment. Data were expressed as mean ± SEM; n=5 for vehicle, n=5 for compound A and n=5 for compound B.

Comparative results

Comparative studies on the 4-benzoyl-benzoyl esters of ATP-γS and ADT-βS gave no in vivo effect on glucose lowering, while the corresponding benzoyl esters did, see Example 1 and 9. The compounds below have been prepared according to the experimental procedurs above.

2'(3')-O-(benzoyl)-adenosine 5 '-triphosphate- ^S (Example 1)

Yield = 2mg ; MS Found: 529.8(Fragmented) ; Calculated: 627.36

2'(3')-O-(4-benzoyl-benzoyl)-adenosine 5 '-triphosphate-β -

Yield = 5mg ; MS Found: 633.8(Fragmented) ; Calculated: 731.47

2'(3')-O-(2-furoyl)-adenosine 5 '-diphosphate-^ (Example 9)

Yield = 5mg ; MS Found: 536(M-I) ; Calculated : 537.336.

2'(3 ')-O-(4-benzoyl-benzoyl)-adenosine 5 '-diphosphate-/^

Yield = 2mg. ; MS Found: 650(M-I) ; Calculated: 651.49