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WO2006045565A1 - Xanthine derivatives with hm74a receptor activity - Google Patents

Xanthine derivatives with hm74a receptor activity Download PDF

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Publication number
WO2006045565A1
WO2006045565A1 PCT/EP2005/011376 EP2005011376W WO2006045565A1 WO 2006045565 A1 WO2006045565 A1 WO 2006045565A1 EP 2005011376 W EP2005011376 W EP 2005011376W WO 2006045565 A1 WO2006045565 A1 WO 2006045565A1
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Prior art keywords
aryl
heteroaryl
alkyl
heterocyclyl
cycloalkyl
Prior art date
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PCT/EP2005/011376
Other languages
French (fr)
Inventor
Richard Jonathan Daniel Hatley
Ivan Leo Pinto
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Smithkline Beecham Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GB0423568A external-priority patent/GB0423568D0/en
Priority claimed from GB0427079A external-priority patent/GB0427079D0/en
Application filed by Smithkline Beecham Corporation filed Critical Smithkline Beecham Corporation
Priority to JP2007537228A priority Critical patent/JP2008517029A/en
Priority to CA002584904A priority patent/CA2584904A1/en
Priority to AU2005298891A priority patent/AU2005298891A1/en
Priority to BRPI0517458-9A priority patent/BRPI0517458A/en
Priority to EP05810272A priority patent/EP1805180A1/en
Priority to MX2007004882A priority patent/MX2007004882A/en
Publication of WO2006045565A1 publication Critical patent/WO2006045565A1/en
Priority to IL182586A priority patent/IL182586A0/en
Priority to NO20072548A priority patent/NO20072548L/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
    • C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3

Definitions

  • the present invention relates to therapeutically active compounds which are xanthine derivatives, processes for the manufacture of said derivatives, pharmaceutical formulations containing the active compounds and the use of the compounds in therapy, particularly in the treatment of diseases where under-activation of the HM74A receptor contributes to the disease or where activation of the receptor will be beneficial.
  • Dyslipidaemia is a general term used to describe individuals with aberrant lipoprotein profiles.
  • the main classes of compounds used for the treatment of patients with dyslipidaemia, and therefore at risk of cardiovascular disease are the statins, fibrates, bile- acid binding resins and nicotinic acid. Nicotinic acid (Niacin, a B vitamin) has been used clinically for over -40 years in patients with various forms of dyslipidaemia.
  • nicotinic acid produces a very desirable alteration in lipoprotein profiles; reducing levels of VLDL and LDL whilst increasing HDL. Nicotinic acid has also been demonstrated to have disease mod ifying benefits, reducing the progression and increasing the regression of atherosclerotic lesions and reducing the number of cardiovascular events in several trials.
  • HSL hormone-sensitive triglyceride lipase
  • NEFA plasma non-esterified fatty acids
  • CETP cholesterol ester transfer protein
  • nicotinic acid produces a very desirable alteration in lipoprotein profiles; reducing levels of VLDL and LDL whilst increasing HDL. Nicotinic acid has also been demonstrated to have disease mod ifying benefits, reducing the progression and increasing the regression of atherosclerotic lesions and reducing the number of cardiovascular events in several trials.
  • HM74A in fact HM74A and in the Soga paper HM74b is identical to HM74A.
  • Cells transfected to express HM74A and/or HM74 gain the ability to elicit Gi G-protein mediated responses following exposure to nicotinic acid.
  • mice lacking the homologue of HM74A (m-PUMA-G) nicotinic acid fails to reduce plasma NEFA levels.
  • the present invention provides therapeutically active xanthine derivatives and the use of these derivatives in therapy, particularly in the treatment of diseases where under-activation of the HM74A receptor contributes to the disease or where activation of the receptor will be beneficial, in particular diseases of lipid metabolism including dyslipidaemia or hyperlipoproteinaemia such as diabetic dyslipidaemia and mixed dyslipidaemia, heart failure, hypercholesteraemia, cardiovascular disease including atherosclerosis, arteriosclerosis, and hypertriglyceridaemia.
  • diseases of lipid metabolism including dyslipidaemia or hyperlipoproteinaemia such as diabetic dyslipidaemia and mixed dyslipidaemia, heart failure, hypercholesteraemia, cardiovascular disease including atherosclerosis, arteriosclerosis, and hypertriglyceridaemia.
  • the compounds may also find favour as therapeutics for coronary artery disease, thrombosis, angina, chronic renal failure, peripheral vascular disease and stroke, as well as the cardiovascular indications associated with type Il diabetes mellitus, type I diabetes, insulin resistance, hyperlipidaemia, anorexia nervosa and obesity.
  • the compounds may also be of use in the treatment of inflammatory diseases or conditions, as set out further below.
  • R 1 represents a group selected from: hydrogen, C 1-10 alkyl, C 2- - I0 alkenyl, C 2 -io alkynyl, and -(alk) m -X-(alk) n -Y,
  • X represents A, A1 , A2 or a direct link
  • A represents a group selected from: cycloalkylene, cycloalkenylene, aryl, heteroaryl, heterocyclyl, -CH 2 -OC(O)-;
  • A1 represents a group selected from:
  • Y represents a group selected from: heteroaryl, heterocyclyl, aryl, cycloalkyl, cycloalkenyl, -O(CH 2 ) n -aryl, -C(O)O-aryl, -CH(aryl) 2l -CH(heteroaryl) 2 , -C 1-6 haloalkyl, -C(O)R 4 ' , -NR 5 R 7 , -C(O)NR 5 R 7 , -NR 5 C(O)R 7 , -NR 5 C(O)OR 7 , -C(O)(CH 2 ) q OR 4 , halogen, cyano, -N(R 5 )C(O)OR 7 , -OC(O)NR 5 R 6 , -NR 5 C(O)R 8 , -OR 5 , -OC(O)R 4 ;
  • n is an integer selected from 2, 3, 4 and 5;
  • n is an integer selected from 1 , 2, 3, 4 and 5;
  • Y represents a group selected from:
  • Y incorporates a ring
  • that ring may be optionally substituted by one or more of: Ci. 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen, -NH 2 , (CH 2 ) q -NR 5 R 7 , -(CH 2 ) q -(O) p -(CH 2 ) q -N(R 5 )C(O)OR 8 , -(CH 2 ) q -N(R 5 )C(0)R 8 , -(CH 2 ) q -(0) p -(CH 2 ) q -C(O)NR 5 R 6 , -(CH 2 ) q -N(R 5 )C(O)N(R 5 )R 6 , -(CH 2 ) q -C(O)N((CH 2 ) m OH)R 5 , -(CH 2 ) q -N(R 5 )-S
  • R 2 is selected from: hydrogen; or C 1- - I0 alkyl, C 2-10 alkenyl, C 2 .io alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, and heteroaryl, each of which may be optionally substituted by one or more of: Ci -10 alkyl, C 2-10 alkenyl, C 2- io alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C 1-6 haloalkyl, halogen, -CN, -OR 4 , -(CH 2 ) n COR 4 , -C(O)OR 4 , -OCOR 4 , -(CHz) n NR 5 R 6 , -(NH) p CON R 5 R 6 , -OCONR 5 R 7 , and -NHC(O)OR 7 ;
  • R 3 is selected from: halogenated C 1-6 alkyl
  • R 4 is selected from: hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -(CH 2 ) n cycloalkyl, -(CH 2 ) n cycloalkenyl, -(CH 2 ) n heterocyclyl, -(CH 2 ) n aryl, and -(CH 2 ) n heteroaryl;
  • R 5 and R 6 are selected from: hydrogen and C 1-4 alkyl
  • R 7 is selected from: hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -(CH 2 ) t cycloalkyl, -(CH 2 ) n cycloalkenyl, -(CH 2 X heterocyclyl, -(CH 2 ) t aryl, and -(CH 2 ) t heteroaryl;
  • R 8 is selected from C 1-4 alkyl;
  • R 9 is selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -(CH 2 ) n cycloalkyl, -(CH 2 ) n cycloalkenyl, -(CH 2 ) n heterocyclyl, -(CH 2 ) n aryl, and -(CH 2 ) n heteroaryl, CN;
  • m represents an integer selected from: 0, 1 , 2, 3, 4 and 5;
  • n represents an integer selected from: 0, 1, 2, 3, 4 and 5;
  • p represents an integer selected from: 0 and 1 ;
  • R 1 represents hydrogen or a group selected from: C 1-10 alkyl, C 2-1O alkenyl, C 2-I0 alkynyl,
  • R 2 is selected from: C 1-10 alkyl, C 2-10 alkenyl, C 2 - I0 alkynyl, -(CH 2 ) n cycloalkyl, ⁇ (CH 2 ) n heterocyclyl, -(CH 2 ) n aryl and -(CH 2 ) n heteroaryl, each of which may be optionally substituted by one or more of: cycloalkyl, heterocyclyl, aryl, heteroaryl, C 1-6 haloalkyl, halo, cyano, -OR 4 , -(CH 2 ) n COR 4 , -CO 2 R 4 , -OCOR 4 , -(CH 2 ) n NR 5 R 6 , -(NH) m CONR 5 R 6 , -OCONR 5 R 7 , and -NHCO 2 R 7 ;
  • R 3 is selected from: halogenated Ci -6 alkyl
  • R 4 is selected from: hydrogen, C 1-6 alkyl C 2-6 alkenyl, C 2-6 alkynyl, -(CH 2 ) ⁇ cycloalkyl, -(CH 2 ) n heterocyclyl, -(CH 2 ) n aryl, and -(CH 2 ) n heteroaryl;
  • R 5 and R 6 are independently selected from: hydrogen and C 1-4 alkyl ;
  • R 7 is selected from: hydrogen, C 1-6 alkyl C 2-6 alkenyl, C 2-6 alkynyl, -(CH 2 ) p cycloalkyl, -(CH 2 ) p heterocyclyl, -(CH 2 ) p aryl, and -(CH 2 ) p heteroaryl;
  • n represents an intege r selected from: 0, 1 , 2, 3 and 4;
  • n represents an integer selected from: 0 and 1 ;
  • p represents an intege r selected from: 1 and 2.
  • R 1 represents H or C 1-3 alkyl, R 2 is different to R 1 ;
  • R 1 represents Methyl and R 3 represents CF 3 , R 2 is other than i-butyl.
  • halogen or halo refer to fluorine, chlorine, bromine and iodine.
  • alkyl refers to a straight or branched hydrocarbon chain unless specified otherwise, containing the specified number of carbon atoms.
  • C 3 -Ci 0 alkyl means a straight or branched hydrocarbon chain containing at least 3 and at most 10 carbon atoms.
  • alkyl as used herein include, but are not limited to methyl (Me), ethyl (Et), n-propyl and i-propyl.
  • alkenyl refers to a straight or branched hydrocarbon chain containing the specified number of carbon atoms which contains one or more double bonds. Suitable examples include but are not limited to ethenyl, 2-propenyl, 3-butenyl, 2-butenyl, 2- pentenyl, 3-pentenyl, 3-methyl-2-butenyl, 3-hexenyl and the like.
  • alkynyl refers to a straight or branched hydrocarbon chain containing the specified number of carbon atoms which contains one or more tri pie bonds. Suitable examples include but are not limited to acetylenyl, propynyl, 1-butynyl, "1 -pentynyl, 3-methyl-1-butynyl and the like.
  • C 1-6 haloalkyl' refers to a C 1-6 alkyl group as defined herein wherein at least one hydrogen atom is replaced with halogen. Examples of such groups include fluoroethyl, trifluoromethyl or trif luoroethyl and the like.
  • cycloalkyl refers to a hydrocarbon ring, containing between 3 and 6 carbon atoms, comprising no heteroatoms or conjugated double bonds.
  • Examples of cycloalkyl as used herein include, but are not limited to cyclopropyl and cyclohexyl.
  • 'cycloalkylene' refers to a saturated monocyclic hydrocarbon ring of 3 to 8 carbon linker goups. Examples of such groups include cyclopropylene, cyolobutylene, cyclopentylene, cyclohexylene, cycloheptylene or cyclooctylene and the like.
  • 'cycloalkenyl' refers to an unsaturated non-aromatic monocyclic hydrocarbon ring of 3 to 8 carbon atoms containing one or more carbon-carbon double bonds. Examples of such groups include cyclopropenyl, cyclobutenyl, cyolopentenyl, cyclohexenyl, cycloheptenyl or cyclooctenyl and the like.
  • 'cycloalkenylene' refers to an unsaturated non-aromatic monocyclic hydrocarbon ring of 3 to 8 carbon linker groups containing one or more carbon-carbon double bonds. Examples of such groups include cyclopropenylene, cyclobutenylene, cyclopentenylene, cyclohexenylene, cycloheptenylene or cyclooctenylene and the like.
  • aryl refers to a 5 or 6 membered, monocyclic aromatic group, or a fused 8-10 membered bicyclic aromatic group with at least one ring having a conjugated pi- electron system, containing up to two conjugated or fused ring systems.
  • Aryl includes carbocyclic aryl and biaryl groups. Suitable examples include but are not limited to phenyl, naphthyl and the like.
  • heteroaryl refers to a 5 or 6 membered, monocyclic aromatic group or a fused 8-10 membered bicyclic, aromatic group containing 1 to 3 heteroatoms independently selected from oxygen, nitrogen and sulphur with at least one ring having a conjugated pi-electron system, containing up to two conjugated or fused ring systems.
  • Suitable examples of such monocyclic aromatic rings include but are not limited to thienyl, furyl, pyrrolyl, triazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, pyrazolyl, pyrimidyl, pyridazinyl, pyrazinyl and pyridyl.
  • fused aromatic rings include but are not limited to benzofused aromatic rings such as quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, cinnolinyl, naphthyridinyl, indolyl, indazolyl, pyrrolopyridinyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzoxadiazolyl, benzothiadiazolyl and the like.
  • benzofused aromatic rings such as quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, cinnolinyl, naphthyridinyl, indolyl, indazolyl, pyrrolopyridinyl, benzofuranyl, benzothienyl, benzimidazo
  • heterocyclyl refers to a 5 or 6 membered, saturated cyclic hydrocarbon group, containing 1 to 3 heteroatoms independently selected from oxygen, nitrogen and sulphur. Suitable examples include but are not limited to pyrrolidinyl, morpholinyl, imidazolidinyl and piperazinyl.
  • '3 or 4 ring fused system' refers to a fused 12-18 membered tricyclic or tetracyclic ring which contains 1 to 4 heteroatoms of N and wherein at least one ring is aromatic. There may be one or more optional oxo substituents on the ring carbon atoms. Examples of such fused aromatic rings include carbazolyl , acenaphthyl, naphthotriazolyl and the like.
  • the term "pharmaceutically acceptable derivative” refers to any pharmaceutically acceptable derivative of a compound of the present invention, for example salts, solvates or esters which, upon administration to a mammal, such as a human, are capable of providing (directly or indirectly) a compound of formula (I) or an active metabolite or residue thereof.
  • pharmaceutically acceptable derivative refers to any pharmaceutically acceptable derivative of a compound of the present invention, for example salts, solvates or esters which, upon administration to a mammal, such as a human, are capable of providing (directly or indirectly) a compound of formula (I) or an active metabolite or residue thereof.
  • Such derivatives are clear to those skilled in the art, without undue experimentation, and with reference to the teaching of Burger's Medicinal Chemistry And Drug Discovery, 5th Edition, VoI 1 : Principles And Practice, which is incorporated herein by reference.
  • the compounds of the invention may be modified to provide pharmaceutically acceptable derivatives thereof at any of the functional groups in the compounds, and that the compounds of the invention may be so modified at more than one position.
  • pharmaceutically acceptable derivative refers to salts or solvates.
  • the term "pharmaceutically acceptable” used in relation to an ingredient (active ingredient or excipient) which may be included in a pharmaceutical formulation for administration to a patient refers to that ingredient being acceptable in the sense of being compatible with any other ingredients present in the pharmaceutical formulation and not being deleterious to the recipient thereof.
  • the term “solvate” refers to a complex of variable stoichiometry formed by a solute (in this invention, a compound of formula (I), a salt thereof or a pharmaceutically acceptable derivative thereof) and a solvent. Such solvents for the purposes of the present invention may not interfere with the biological activity of the solute.
  • the solvent used may be a pharmaceutically acceptable solvent.
  • suitable pharmaceutically acceptable solvents include water, ethanol and acetic acid.
  • An example of a solvent that may be used is water, in which case the solvate may be referred to as a hydrate of the solute in question.
  • salt or solvate referred to above will be a pharmaceutically acceptable salt or solvate.
  • other salts or solvates may find use, for example, in the preparation of a compound of formula (I) or in the preparation of a pharmaceutically acceptable salt or solvate thereof.
  • Suitable pharmaceutically acceptable salts include those described by Berge, Bighley and Monkhouse, J. Pharm. Sci., 1977, 66, 1-19.
  • Suitable pharmaceutically acceptable salts include alkali metal salts formed from the addition of alkali metal bases such as alkali metal hydroxides. Examples of suitable alkali metal salts are sodium salt or potassium salt.
  • Other suitable pharmaceutically acceptable salts include alkaline earth metal salts such as calcium salt or magnesium salt, ammonium salts; or salts with organic bases such as ethanolamine, triethanolamine, ethylene diamine, triethylmine, choline and meglumine; or salts with amino acids such as arginine, lysine and histidine.
  • the compounds are of use in the treatment of diseases where under-activation of the HM74A receptor contributes to the disease or where activation of the receptor will be beneficial, in particular diseases of lipid metabolism including dyslipidaemia or hyperlipoproteinaemia such as diabetic dyslipidaemia and mixed dyslipidaemia, heart failure, hypercholesteraemia, cardiovascular disease including atherosclerosis, arteriosclerosis, and hypertriglyceridaemia.
  • diseases of lipid metabolism including dyslipidaemia or hyperlipoproteinaemia such as diabetic dyslipidaemia and mixed dyslipidaemia, heart failure, hypercholesteraemia, cardiovascular disease including atherosclerosis, arteriosclerosis, and hypertriglyceridaemia.
  • the compounds may also find favour as therapeutics for coronary artery disease, thrombosis, angina, chronic renal failure, peripheral vascular disease and stroke, as well as the cardiovascular indications associated with type Il diabetes mellitus, type I diabetes, insulin resistance, hyperlipidaemia, anorexia nervosa, obesity.
  • Compounds of the invention are of potential therapeutic benefit in the treatment and amelioration of the symptoms of many diseases of lipid metabolism including dyslipidaemia or hyperlipoproteinaemia such as diabetic dyslipidaemia and mixed dyslipidaemia, heart failure, hypercholesteraemia, cardiovascular disease including atherosclerosis, arteriosclerosis, and hypertriglyceridaemia, type Il diabetes mellitus, type I diabetes, insulin resistance, hyperlipidaemia, anorexia nervosa, obesity.
  • the compounds may also find favour as therapeutics for coronary artery disease, thrombosis, angina, chronic renal failure, peripheral vascular disease and stroke.
  • HM74 and HM74A receptors are involved in inflammation.
  • Inflammation represents a group of vascular, . cellular and neurological responses to trauma. Inflammation can be characterised as the movement of inflammatory cells such as monocytes, neutrophils and granulocytes into the tissues. This is usually associated with reduced endothelial barrier function and oedema into the tissues. Inflammation with regards to disease typically is referred to as chronic inflammation and can last up to a lifetime. Such chronic inflammation may manifest itself through disease symptoms. The aim of anti-inflammatory therapy is therefore to red uce this chronic inflammation and allow for the physiological process of healing and tissue repair to progress.
  • inflammatory diseases or conditions for which the compounds of the present invention may demonstrate utility include those of the joint, particularly arthritis (e.g. rheumatoid arthritis, osteoarthritis, prosthetic joint failure), or the gastrointestinal tract (e.g. ulcerative colitis, Crohn's disease, and other inflammatory bowel and gastrointestinal diseases, gastritis and mucosal inflammation resulting from infection, the enteropathy provoked by non-steroidal anti-inflammatory drugs), of the lung (e.g. adult respiratory distress syndrome, asthma, cystic fibrosis, or chronic obstructive pulmonary disease), of the heart (e.g. myocarditis), of nervous tissue (e.g. multiple sclerosis), of the pancreas, (e.g.
  • arthritis e.g. rheumatoid arthritis, osteoarthritis, prosthetic joint failure
  • the gastrointestinal tract e.g. ulcerative colitis, Crohn's disease, and other inflammatory bowel and gastrointestinal diseases, gastritis and mucosal inflammation
  • kidney e.g. glomerulonephritis
  • the skin e.g. dermatitis, psoriasis, eczema, urticaria, burn injury
  • the eye e.g. glaucoma
  • transplanted organs e.
  • references herein to treatment extend to prophylaxis, prevention of recurrence and suppression of symptoms as well as the treatment of established conditions.
  • Nicotinic acid has a significant side effect profile, possibly because it is dosed at high level (gram quantities daily). The most common side effect is an intense cutaneous flushing.
  • the compounds may exhibit reduced side effects compared to nicotinic acid.
  • HM74A has been identified as a high affinity receptor for nicotinic acid whilst HM74 is a lower affinity receptor.
  • the compounds of the present invention may find use as selective HM74A agonists or partial agonists; in which case they will show greater affinity for HM74A than for HM74.
  • HM74A The potential for compounds of formula (I) to activate HM74A may be demonstrated, for example, using the following in vitro whole cell assays:
  • HEK293T cells HEK293 cells stably expressing the SV40 large T-antigen
  • DMEM fetal calf serum
  • 2mM glutamine 10% foetal calf serum
  • Cells were seeded in 90mm culture dishes and grown to 60-80% confluence (18-24h) prior to transfection.
  • Human HM74A GenBankTM accession number AY148884
  • pcDNA3 mammalian expression vector
  • F-12 HAM media containing 10% foetal calf serum and 2mM glutamine. 48h post- transfection the media was supplemented with 400 ⁇ g/ml Geneticin (G418, Gibco) for selection of antibiotic resistant cells. Clonal CHO-K1 cell lines stably expressing HM74A were confirmed by [ 35 S]-GTPyS binding measurements, following the addition of nicotinic acid.
  • P2 membrane preparation - Plasma membrane-containing P2 particulate fractions were prepared from cell pastes frozen at -80 0 C after harvest. All procedures were carried out at 4°C. Cell pellets were resuspended in 1 ml of 1OmM Tris-HCl and 0.1 rnM EDTA, pH 7.5 (buffer A) and by hornogenisation for 20s with a Ultra Turrax followed by passage (5 times) through a 25-gauge needle. Cell lysates were centrifuged at 1 ,000g for 10 min in a microcentrifuge to pellet the nuclei and unbroken cells and P2 particulate fractions were recovered by microcentrifugation at 16,00Og for 30min. P2 particulate fractions were resuspended in buffer A and stored at -80 0 C until required.
  • [ 35 S]-GTPyS binding - assays were performed at room temperature in 384-well format based on methods described previously, (Wieland, T. and Jakobs, K.H. (1994) Methods Enzymol. 237, 3-13). Briefly, the dilution of standard or test compounds were prepared and added to a 384-well plate in a volume of 10 ⁇ l.
  • Membranes (HM74A or HM74) were diluted in assay buffer (2OmM HEPES, 10OmM NaCI, 1OmM MgCI 2 , pH7.4) supplemented with saponin (60 ⁇ g/ml), Leadseeker WGA beads (Amersham; 250 ⁇ g/well) and 10 ⁇ M GDP, so that the 20 ⁇ l volume added to each well contains 5 ⁇ g of membranes.
  • [ 35 S]-GTPyS 1170 Ci/mmol, Amersham was diluted (1 :1500) in assay buffer and 20 ⁇ l added to each well. Following the addition of the radioligand, the plates were sealed, pulse spun and incubated for 4hours at room temperature.
  • HM74A agonists can be tested in male Spague-Dawley rats (200-250g) which have been fasted for at least 12 hours prior to the study.
  • the compounds are dosed intravenously at either 1 or 3mg/kg (5ml/kg) or by oral gavage at doses ranging from 1-30rng/kg (10ml/kg).
  • Blood samples O .3ml tail vein bleed
  • Each blood sample is transferred to a heparin tube (Becton Dickinson Microtainer, PST LH) and centrifuged (10,000g for 5 minutes) to produce a plasma sample.
  • NEFA non- esterified fatty acids
  • HM74A compounds exhibit the flushing response associated with nicotinic acid they can be dosed to conscious guinea-pigs.
  • Pre-study blood samples 0.5ml are taken from each animal by cardiac puncture under recovery anaesthesia (Isoflurane 3.5% with additional O2 (1 L/min)).
  • Ear temperature measurements are taken by placing the left ear of each animal over an infra-red temperature probe. Measurements are taken at one minute intervals from 5 minutes pre-dose to 30 minutes post-dose.
  • Compounds of Formula (I) may find use in human or veterinary med icine, in particular as activators of HM74A, in the management of dyslipidaemia and hyperlipoproteinaemia.
  • R 1 represents a group selected from: hydrogen, C 1-10 alkyl, C 2-10 alkenyl , C 2-10 alkynyl, and -(alk) m -X-(alk) n -Y,
  • X represents A, A1 , A2 or a direct link
  • A represents a group selected from: cycloalkylene, cycloalkenylene, aryl, heteroaryl, heterocyclyl, -CH 2 -OC(O)-;
  • A1 represents a group selected from: -CH 2 -0-(CH 2 ) q aryl-O-, -CH 2 -O-(CH 2 ) W N(R 5 )C(O)O-, -CH 2 -N(R 5 )C(O)O-, -CH 2 -N(R 5 )C(O)-, -CH 2 -(O)p-(CH 2 ) q C(O)NR 5 -, -CH 2 -N(R 5 )C(O)N(R 5 )-, -CH 2 -C(0)N((CH 2 ) W OH)-, -CH 2 -NR 5 -S(O) 2 -, CH 2 -S(O) 2 NR 5 -, -CH 2 -C(O)O-, -O-, -NR 5 -, -S-;
  • A2 represents: -CH(OH)-
  • Y represents a group selected from: heteroaryl, heterocyclyl, aryl, cycloalkyl, cycloalkenyl, -O(CH 2 ) n -aryl, -C(0)O-aryl, -CH(aryl) 2 , -CH(heteroaryl) 2 , -C 1-6 haloalkyl, -C(O)R 4 ' , -NR 5 R 7 , -C(O)NR 5 R 7 , -NR 5 C(O)R 7 , -NR 5 C(O)OR 7 , -C(O)(CH 2 ) q OR 4 , halogen, cyano, -N(R 5 )C(O)OR 7 , -OC(O)NR 5 R 6 , -NR 5 C(O)R 8 , -OR 5 , -OC(O)R 4 ;
  • n is an integer selected from 2, 3, 4 and 5;
  • n is an integer selected from 1 , 2, 3, 4 and 5;
  • Y represents a group selected from:
  • That ring may be optionally substituted by one or more of: C 1-6 alkyl, C 2 . 6 alkenyl, C 2-6 alkynyl, halogen, -NH 2 , (CH 2 ) q -NR 5 R 7 , -(CH 2 ) q -(O)p-(CH 2 ) q -N(R 5 )C(O)OR 8 , -(CH 2 ) q -N(R 5 )C(O)R 8 , -(CH 2 ) q -(O) p -(CH 2 ) q -C(O)NR 5 R 6 , -(CH 2 ) q -N(R 5 )C(O)N(R 5 )R 6 , -(CH 2 ) q -C(0)N((CH 2 ) m 0H)R 5 , -(CH 2 ) q -N(R 5 )
  • R 2 is selected from: hydrogen; or C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, and heteroaryl, each of which may be optionally substituted by one or more of: C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, cycloaikyl, heterocyclyl, aryl, heteroaryl, C 1-6 haloalkyl, halogen, -CN, -OR 4 , -(CH 2 ) n COR 4 , -C(O)OR 4 , -OCOR 4 , -(CH 2 ) n NR 5 R 6 , -(NH) P CONR 5 R 6 , -OCONR 5 R 7 , and -NHC(O)OR 7 ;
  • R 3 is selected from: halogenated Ci -6 alkyl
  • R 4 is selected from: hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -(CH 2 ) n cycloalkyl, -(CH 2 ) n cycloalkenyl, -(CH 2 ) n heterocyclyl, -(CH 2 ) n aryl, and -(CH 2 ) n heteroaryl;
  • R 5 and R 6 are selected from: hydrogen and Ci -4 alkyl
  • R 7 is selected from: hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -(CH 2 ) t cycloalkyl, -(CH 2 ) n cycloalkenyl, -(CH 2 ) t heterocyclyl, -(CH 2 ) t aryl, and -(CH 2 ) t heteroaryl;
  • R 8 is selected from C 1-4 alkyl
  • R 9 is selected from Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -(CH 2 ) ⁇ cycloalkyl, -(CH 2 ) n cycloalkenyl, -(CH 2 ) n heterocyclyl, -(CH 2 ) n aryl, and -(CH 2 ) n heteroaryl, CN;
  • m represents an integer selected from: 0, 1 , 2, 3, 4 and 5;
  • n represents an integer selected from: 0, 1 , 2, 3, 4 and 5;
  • p represents an integer selected from: 0 and 1 ;
  • a compound of Formula (II) in the manufacture of a medicament for the treatment of disorders of lipid metabolism including dyslipidaemia or hyperlipoproteinaemia.
  • the use is provided of a compound of Formula (II) in the manufacture of a medicament for the treatment of diabetic dyslipidaemia or mixed dyslipidaemia, heart failure, hypercholesteraemia, type Il diabetes mellitus, type I diabetes, insulin resistance, hyperlipidaemia, anorexia nervosa, obesity, coronary artery disease, thrombosis, angina, chronic renal failure, stroke and cardiovascular disease including atherosclerosis, arteriosclerosis, and hypertriglyceridaemia.
  • a compound of formula (I) or (II) or a pharmaceutically derivative thereof for use in the treatment of disorders of lipid metabolism including dyslipidaemia or hyperlipoproteinaemia.
  • the use is provided of a compound of Formula (I) or (II) in the manufacture of a medicament for the treatment of diabetic dyslipidaemia or mixed dyslipidaemia, heart failure, hypercholesteraemia, type Il diabetes mellitus, type I diabetes, insulin resistance, hyperlipidaemia, anorexia nervosa, obesity, coronary artery disease, thrombosis, angina, chronic renal failure, stroke and cardiovascular disease including atherosclerosis, arteriosclerosis, and hypertriglyceridaemia.
  • dyslipidaemia or hyperlipoproteinaemia such as diabetic dyslipidaemia and mixed dyslipidaemia
  • heart failure hypercholesteraemia
  • cardiovascular disease including atherosclerosis, arteriosclerosis, and hypertriglyceridaemia
  • type Il diabetes mellitus type I diabetes
  • insulin resistance hyperlipidaemia
  • anorexia nervosa obesity
  • the compounds are also provided for use in the treatment of coronary artery disease, thrombosis, angina, chronic renal failure, peripheral vascular disease and stroke.
  • dyslipidaemia or hyperlipoproteinaemia such as diabetic dyslipidaemia and mixed dyslipidaemia
  • heart failure hypercholesteraemia
  • cardiovascular disease including atherosclerosis, arteriosclerosis, and hypertriglyceridaemia
  • type Il diabetes mellitus type I diabetes
  • insulin resistance hyperlipidaemia
  • anorexia nervosa obesity
  • the compounds are also provided for use in the treatment of coronary artery disease, thrombosis, angina , chronic renal failure, peripheral vascular disease and stroke.
  • the present invention provides the use of a compound of formula (I) or (II) or a pharmaceutically acceptable derivative thereof, in the manufacture of a medicament for the treatment of inflammatory diseases or conditions of the joint, particularly arthritis (e.g. rheumatoid arthritis, osteoarthritis, prosthetic joint failure), or of the gastrointestinal tract (e.g. ulcerative colitis, Crohn's disease, and other inflammatory bowel and gastrointestinal diseases, gastritis and mucosal inflammation resulting from infection, the enteropathy provoked by non-steroidal anti-inflammatory drugs), of the lung (e.g. adult respiratory distress syndrome, asthma, cystic fibrosis, or chronic obstructive pulmonary disease), of the heart (e.g.
  • arthritis e.g. rheumatoid arthritis, osteoarthritis, prosthetic joint failure
  • the gastrointestinal tract e.g. ulcerative colitis, Crohn's disease, and other inflammatory bowel and gastrointestinal diseases, gastritis and mucosal inflammation resulting from infection
  • myocarditis of nervous tissue (e.g. multiple sclerosis), of the pancreas, (e.g. inflammation associated with diabetes melitus and complications thereof, of the kidney (e.g. glomerulonephritis), of the skin (e.g. dermatitis, psoriasis, eczema, urticaria, burn injury), of the eye (e.g. glaucoma) as well as of transplanted organs (e.g. rejection) and multi-organ diseases (e.g.
  • systemic lupus erythematosis, sepsis systemic lupus erythematosis, sepsis
  • the compounds of formula (I) or (II) or pharmaceutically acceptable derivatives thereof are useful in the treatment and prevention of inflammation, diabetes and cardiovascular diseases or conditions including atherosclerosis, arteriosclerosis, hypertriglyceridemia, and mixed dyslipidaemia.
  • a method for the treatment of a human or animal subject with a condition where under-activation of the HM74A receptor contributes to the condition or where activation of the receptor will be beneficial comprises administering to said human or animal subject an effective amount of a compound of formula (I) or (II) or a pharmaceutically acceptable derivative thereof.
  • the present invention provides a method for the treatment of disorders of lipid metabolism including dyslipidaemia or hyperlipoproteinaemia such as diabetic dyslipidaemia and mixed dyslipidaemia, heart failure, hypercholesteraemia, cardiovascular disease including atherosclerosis, arteriosclerosis, and hypertrig lyceridaemia, type Il diabetes mellitus, type I diabetes, insulin resistance, hyperlipidaemia, anorexia nervosa, obesity, which method comprises administering to said human or animal subject an effective amount of a compound of formula (I) or (II) or a pharmaceutically acceptable derivative thereof.
  • dyslipidaemia or hyperlipoproteinaemia such as diabetic dyslipidaemia and mixed dyslipidaemia
  • cardiovascular disease including atherosclerosis, arteriosclerosis, and hypertrig lyceridaemia
  • type Il diabetes mellitus type I diabetes
  • insulin resistance hyperlipidaemia
  • anorexia nervosa obesity
  • these compounds may also find favour in methods for the treatment of coronary artery disease, thrombosis, angina, chronic renal failure, peripheral vascular disease and stroke, which methods comprise administering to said human or animal subject an effective amount of a compound of formula (I) or (II) or a pharmaceutically acceptable derivative thereof.
  • R 1 is selected from hydrogen C 1-10 alkyl, and -(alk) m -X-(alk) n -r.
  • X represents A or A1.
  • A is selected from heteroaryl, heterocyclyl, and A1 is selected from CH 2 -O- (CH 2 ) w N(R 5 )C(0)O-, for example CH 2 O(CHs) 2 NHC(O)O-, CH 2 -N(R 5 )C(O)O- for example CH 2 -NHC(O)O, CH 2 -N(R 5 )C(O)- for example, CH 2 -NHC(O)-, CH 2 -(O) p -(CH 2 ) q C(O)NR 5 - for example CH 2 C(O)NCH 3 - , CH 2 -N(R 5 )C(O)N(R 5 )- for example CH 2 -NHC(O)NCH 3 -, CH 2 - C(0)N((CH 2 ) W OH)- for example CH 2
  • X represents A and A represents a heteroaryl.
  • A represents a heteroaryl comprising a nitrogen heteroatom, for example, triazolyl, furazanyl, oxadiazolyl, tetrazolyl, imidazolyl or pyrazolyl.
  • X represents A, for example heteroaryl or heterocyclyl, or a direct link.
  • Y represents an optionally substituted group selected from: aryl, for example phenyl or napthyl, heteroaryl, for example pyridinyl, thiazolyl, thienyl, benzofuranyl or indolyl, and O-aryl, for example O-phenyl.
  • Y is substituted by one or more groups selected from OR 5 for example OH or OCH 3 , halogen, for example F or Cl, aryl, for example phenyl, C 1-6 haloalkyl for example CF 3 or CH 2 CF 3 , OCF 3 , (R 8 ) P CN for example CN, (CH 2 ) q -N(R 5 )-S(0) 2 R 8 for example NHS(O) 2 CH 3 and S(O) 2 R 9 for example S(O) 2 CH 3 .
  • X represents A or A1
  • A represents cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocyclyl
  • A1 represents -CH 2 -O-(CH 2 ) W N(R 5 )C(O)O-, -CH 2 -N(R 5 )C(O)O-, -CH 2 -N(R 5 )C(O)- , -CH 2 -(O) p -(CH 2 ) q C(O)NR 5 -, -CH 2 -N(R 5 )C(O)N(R 5 )-, or -CH 2 -C(O)N((CH 2 ) W OH)-
  • Y represents a ring, for example when X represents oxadizolyl, tetrazolyl or pyrazolyl and Y represents phenyl, pyridinyl, or
  • R 1 is selected from: hydrogen; and C 1-10 alkyl which may be optionally substituted by one or more of: cycloalkyl, heterocyclyl, aryl, heteroaryl, C 1- 6 haloalkyl, halo, cyano, -OR 4 , -(CH 2 ) n COR 5 , -CO 2 R 4 , -OCOR 4 , -(CH 2 ) n NR 5 R 7 , and - (NH) m CONR 5 R 7 .
  • R 1 is selected from: hydrogen; and C 1-10 alkyl which may be optionally substituted by one or more of: halo, cyano, -OR 4 , - (CH 2 ) n COR 4 , -CO 2 R 4 , -OCOR 4 , -(CH 2 ) n NR 5 R 6 , and -(NH) m CONR 5 R 6 .
  • R 1 is selected from: hydrogen and C 1-6 alkyl optionally substituted with -OH, for example methyl, butyl or CH 2 CH 2 OH.
  • R 1 is selected from: hydrogen and C 1-6 alkyl, for example methyl or butyl.
  • R 2 is selected from: C 4-10 alkyl and C 2-10 alkenyl, each of which may be optionally substituted by one or more of cycloalkyl, heterocyclyl, aryl, heteroaryl, C 1-6 haloalkyl, halo, cyano, -OR 4 , -(CH 2 ) n COR 5 , -CO 2 R 4 , -OCOR 4 , -(CH 2 ) n NR 5 R 6 , and -(NH) m C0NR 5 R 6 .
  • R 2 may represent C 4-10 alkyl which may be optionally substituted by one or more of cycloalkyl , heterocyclyl, aryl, heteroaryl, C 1-6 haloalkyl, halo, cyano, -OR 4 , -(CH 2 ) n COR 4 , -CO 2 R 4 , -OCOR 4 , -(CH 2 ) n NR 5 R 6 , and -(NH) m CONR 5 R 6 .
  • R 2 is selected from C 4-6 alkyl, for example butyl or pentyl.
  • R 2 represents C 1-I0 alkyl which may be optionally substituted by one or more of: cycloalkyl, heterocyclyl, aryl, heteroaryl, C 1-6 haloalkyl, halogen, -CN, -OR 4 , -(CH 2 ) n COR 5 , -C(O)OR 4 , -OCOR 4 , -(CH 2 ) n NR 5 R 6 , and -(NH) P CONR 5 R 6 .
  • R 2 is selected from C 3-6 alkyl, for example butyl or pentyl.
  • R 3 is selected from: fluorinated C 1-6 alkyl. In another embodiment of formula (I) or (II), R 3 is selected from: fluorinated C 1-4 alkyl, for example CF 3 , CHF 2 or CF 2 CF 3 .
  • R 4 is selected from: hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -(CH 2 ) n cycloalkyl, -(CH 2 ) n heterocyclyl, -(CH 2 ) n aryl, and -(CH 2 ) n heteroaryl.
  • R 4 is selected from: hydrogen and C 1-4 alkyl.
  • R 1 is selected from: hydrogen and C 1-6 alkyl optionally substituted with -OH
  • R 2 is selected from: C 4-6 alkyl
  • R 3 is selected from: fluorinated C 1-4 alkyl, with the proviso that when R 1 represents Methyl and R 3 represents CF 3 , R 2 cannot be i-butyl.
  • R 5 is hydrogen
  • R 7 is selected from: hydrogen and Ci -4 alkyl.
  • X is Av1
  • A1 is -O-
  • Y is a ring which is substituted by aryl or heteroaryl, then m is an integer selected from 3, 4 and 5.
  • R 1 and R 2 are different.
  • Particular compounds of the present invention include:
  • the daily dose wil l be in the range of 0.1 mg - 1g/kg, typically 0.1 - 100mg/kg.
  • An intravenous dose may, for example, be in the range of 0.01 mg to 0.1g/kg, typically 0.01 mg to 10mg/kg, which may conveniently be administered as an infusion of from 0.1 ⁇ g to 1mg, per minute.
  • Infusion flu ids suitable for this purpose may contain, for example, from 0.01 ⁇ g to 0.1 mg, per millilitre.
  • Unit doses may contain, for example, from 0.01 ⁇ g to 1g of a HM74A modulator.
  • ampoules for injection may contain, for example, from 0.01 ⁇ g to 0.1g and orally adrninistrable unit dose formulations, such as tablets or capsules, may contain, for example, from 0.1 mg to 1g. No toxicological effects are indicated/expected when a compound of the invention is administered in the above mentioned dosage range.
  • a compound of the present invention may be employed as the compound per se in the treatment of a disease where under-activation of the HM74A receptor contributes to the disease or where activation of the receptor will be beneficial, an example of this is where a compound of the present invention is presented with an acceptable carrier in the form of a pharmaceutical formulation.
  • the carrier must, of course, be acceptable in the sense of being compatible with the other ingredients of the formulation and must not be deleterious to the recipient.
  • the carrier may be a solid or a liquid, or both, and may be formulated with the HM74A modulator as a unit-dose formulation, for example, a tablet, which may contain from 0.05% to 95% by weight of the HM74A modulator.
  • the formulations include those suitable for oral, rectal, topical, buccal (e.g. sub-lingual) and parenteral (e.g. subcutaneous, intramuscular, intradermal or intravenous) administration.
  • buccal e.g. sub-lingual
  • parenteral e.g. subcutaneous, intramuscular, intradermal or intravenous
  • Formulations suitable for oral administration may be presented in discrete units, such as capsules, cachets, lozenges or tablets, each containing a predetermined amount of a HM74A modulator; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion.
  • the formulations are prepared by uniformly and intimately admixing the active HM74A modulator with a liquid or finely divided solid carrier, or both, and then, if necessary, shaping the product.
  • a tablet may be prepared by compressing or moulding a powder or granules of the HM74A modulator optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing, in a suitable machine, the compound in a free-flowing form, such as a powder or granules optionally mixed with a binder, lubricant, inert diluent and/or surface active/dispersing agent(s).
  • Moulded tablets may be made by moulding, in a suitable machine, the powdered compound moistened with an inert liquid diluent.
  • Tablets and capsules for oral administration may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, mucilage of starch or polyvinyl pyrrolidone; fillers, for example, lactose, microcrystalline cel lulose, sugar, maize- starch, calcium phosphate or sorbitol; lubricants, for example, magnesium stearate, stearic acid, talc, polyethylene glycol or silica; disintegrants, for example, potato starch, croscarmellose sodium or sodium starch glycollate; or wetting agents such as sodium lauryl sulphate.
  • the tablets may be coated according to methods well known in the art.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, for example, sorbitol syrup, methyl cellulose, glucose/sugar syrup, gelatin, hydroxymethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats; emulsifying agents, for example, lecithin, sorbitan mono-oleate or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters, propylene glycol or ethyl alcohol; or preservatives, for example, methyl or propyl ⁇ -hydroxybenzoates or sorbic acid.
  • the preparations may also contain buffer salts, flavouring, colouring and/or sweetening agents
  • Formulations suitable for buccal (sub-lingual) administration include lozenges comprising a HM74A modulator in a flavoured base, usually sucrose and acacia or tragacanth, and pastilles comprising the HM74A modulator in an inert base such as gelatin and glycerin or sucrose and acacia.
  • Formulations for oral administration may be suitably formulated to give controlled/extended release of the active compound.
  • Formulations of the present invention suitable for parenteral administration conveniently comprise sterile aqueous preparations of an HM74A modulator, the formulation may be isotonic with the blood of the intended recipient. These preparations could be administered intravenously, although administration may also be effected by means of subcutaneous, intramuscular, or intradermal injection. Such preparations may conveniently be prepared by admixing the HM74A modulator with water and rendering the resulting solution sterile and isotonic with the blood. Injectable compositions according to the invention will generally contain from 0.1 to 5% w/w of the HM74A modulator.
  • formulations of the present invention suitable for parenteral administration comprising a compound accord ing to the invention may be formulated for parenteral administration by bolus injection or continuous infusion and may be presented in unit dose form, for instance as ampoules, vials, small volume infusions or pre-filled syringes, or in rnulti-dose containers with an added preservative.
  • the compositions may take such forms as solutions, suspensions, or emulsions in aqueous or non-aqueous vehicles , and may contain formulatory agents such as anti-oxidants, buffers, antimicrobial agents and/or toxicity adjusting agents.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use.
  • the dry solid presentation may be prepared by filling a sterile powder aseptically into individual sterile containers or by filling a sterile solution aseptically into each container and freeze-drying.
  • Formulations suitable for rectal administration may be presented as unit-dose suppositories. These may be prepared by admixing a HM74A modulator with one or more conventional solid carriers, for example, cocoa butter or glycerides and then shaping the resulting mixture. Formulations suitable for topical application to the skin may take the form of an ointment, cream, lotion, paste, gel, spray, aerosol, or oil. Carriers which may be used include vaseline, lanolin, polyethylene glycols, alcohols, and combinations of two or more thereof.
  • the HM74A modulator is generally present at a concentration of from 0.1 to 15% w/w of the composition, for example, from 0.5 to 2%.
  • topical administration as used herein, we include administration by insufflation and inhalation .
  • preparation for topical administration include ointments, creams, lotions, powders, pessaries, sprays, aerosols, capsules or cartridges for use in an inhaler or insufflator or drops (e.g. eye or nose drops).
  • Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents and/or solvents.
  • bases may thus, for example, include water and/or an oil such as liquid paraffin or a vegetable oil such as arachis oil or castor oil or a solvent such as a polyethylene glycol.
  • Thickening agents which may be used include soft paraffin, aluminium stearate, cetostearyl alcohol, polyethylene glycols, microcrystalline wax and beeswax.
  • Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilising agents, dispersing agents, suspending agents or thickening agents.
  • Powders for external application may be formed with the aid of any suitable powder base, for example, talc, lactose or starch. Drops may be formulated with an aqueous or non-aqueous base also comprising one or more dispersing agents, solubilising agents or suspending agents.
  • Spray compositions may be formulated, for example, as aqueous solutions or suspensions or as aerosols delivered from pressurised packs, with the use of a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, 1 ,1 ,1 ,2,3,3,3- heptafluoropropane, 1 ,1 ,1 ,2- tetrafluorethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, 1 ,1 ,1 ,2,3,3,3- heptafluoropropane, 1 ,1 ,1 ,2- tetrafluorethane, carbon dioxide or other suitable gas.
  • Capsules and cartridges for use in an inhaler or insufflator, of for example gelatin may be formulated containing a powder mix of a compound of the invention and a suitable powder base such as lactose or starch.
  • compositions according to the invention may also be used in combination with other therapeutic agents, for example in combination with other classes of dyslipidaemic drugs (e.g. statins, fibrates, bile-acid binding resins or nicotinic acid).
  • dyslipidaemic drugs e.g. statins, fibrates, bile-acid binding resins or nicotinic acid.
  • the compounds of the instant invention may be used in combination with one or more other therapeutic agents for example in combination with other classes of dyslipidaemic drugs e.g. S-hydroxy-S-methylglutaryl-coenzyme A reductase inhibitors (statins) or fibrates or bile acid binding resins or nicotinic acid.
  • dyslipidaemic drugs e.g. S-hydroxy-S-methylglutaryl-coenzyme A reductase inhibitors (statins) or fibrates or bile acid binding resins or nicotinic acid.
  • the invention thus provides, in a further aspect, the use of such a combination in the treatment of diseases where under-activation of the HM74A receptor contributes to the disease or where activation of the receptor will be beneficial and the use of a compound of formula (I) or (II), or a pharmaceutically acceptable salt, solvate or pharmaceutically acceptable derivative thereof in the manufacture of a medicament for the combination therapy of disorders of lipid metabolism including dyslipidaemia or hyperlipoproteinaemia such as diabetic dyslipidaemia and mixed dyslipidaemia, heart failure, hypercholesteraemia, cardiovascular disease including atherosclerosis, arteriosclerosis, and hypertriglyceridaemia, type Il diabetes mellitus, type I diabetes, insulin resistance, hyperlipidaemia, anorexia nervosa or obesity.
  • disorders of lipid metabolism including dyslipidaemia or hyperlipoproteinaemia such as diabetic dyslipidaemia and mixed dyslipidaemia, heart failure, hypercholesteraemia, cardiovascular disease including atherosclerosis, arteriosclerosis, and hypertriglyce
  • the compounds of the present invention are used in combination with other therapeutic agents, the compounds may be administered either sequentially or simultaneously by any convenient route.
  • compositions comprising a combination as defined above optimally together with a pharmaceutically acceptable carrier or excipient comprise a further aspect of the invention.
  • the individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations.
  • the two components When combined in the same formulation it will be appreciated that the two components must be stable and compatible with each other and the other components of the formulation and may be formulated for administration. When formulated separately they may be provided in any convenient formulation, conveniently in such a manner as are known for such compounds in the art.
  • each component When in combination with a second therapeutic agent active against the same disease, the dose of each component may differ from that when the compound is used alone. Appropriate doses will be readily appreciated by those skilled in the art.
  • the invention thus provides, in a further aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable derivative thereof together with another therapeutically active agent.
  • compositions comprising a combination as defined above together with a pharmaceutically acceptable diluent, excipient or carrier thereof represent a further aspect of the invention.
  • a pharmaceutical formulation comprising a compound or pharmaceutically acceptable derivative thereof and one or more pharmaceutically acceptable diluents, excipients or carriers.
  • MS mass spectra
  • BiotageTM chromatography refers to purification carried out using equipment sold by Dyax Corporation (either the Flash 4Oi or Flash 15Oi) and cartridges pre-packed with KPSiI.
  • Mass directed autoprep refers to methods where the material was purified by high performance liquid chromatography on a HPLCABZ+ 5 ⁇ m column (5cm x 10mm i.d.) with 0.1 % HCO 2 H in water and 95% MeCN, 5% water (0.5% HCO 2 H) utilising the following gradient elution conditions: 0-1.0 minutes 5%B, 1.0-8.0 minutes 5 ⁇ 30%B, 8.0-8.9 minutes 30%B, 8.9-9.0 minutes 30 ⁇ 95%B, 9.0-9.9 minutes 95%B, 9.9-10 minutes 95 ⁇ 0%B at a flow rate of 8ml minutes "1 (System 2).
  • the Gilson 202-fraction collector was triggered by a VG Platform Mass Spectrometer on detecting the mass of interest.
  • Preparative h.p.l.c. refers to methods where the material was purified by high performance liquid chromatography on a HPLCABZ+ 5 ⁇ m column (10cm x 21.2mm i.d.) with 0.1% HCO 2 H in water (A) and MeCN (0.5% HCO 2 H) (B) utilising the generic gradient elution conditions expressed as "x to y" gradient with a gradient system as follows: 0-1.45minut.es x%B, 1.45-20 minutes x ⁇ y%B, 20-24 minutes y ⁇ 95%B, 24-30 minutes 95%B, 32-34 minutes 95 ⁇ x%B at a flow rate of 8ml minutes "1 .
  • the Gilson 233 fraction collector was triggered by UV (254nm).
  • SPE solid phase extraction
  • Strata Phenyl SPE refers to the use of cartridges sold by Phenomenex.
  • the compound was loaded onto a cartridge previously conditioned with MeCN and equilibrated with 5% MeCN in water.
  • the compound was eluted with 0.1 % HCO 2 H in water and MeCN (0.5% HCO 2 H) in a suitable gradient on a Combiflash Optix 10.
  • the compounds of the present invention and pharmaceutically derivatives thereof may be prepared by the methodology described hereinafter, constituting a further aspect of this invention.
  • a process according to the invention for preparing a compound of formula (1) or formula (II) in which R 1 is H or alkyl wherein R 1 and R 2 ma/ be the same or different, comprises:
  • a process according to the invention for prepari ng a compound of formula (I) or formula (II) in which R 1 and R 2 may be the same or different, comprises:
  • a resultant compound of formula (I) or (II) can be converted into a pharmaceutically acceptable salt form or vice versa or converting one salt form into another pharmaceutically acceptable salt form.
  • LiHMDS Lithium hexamethyldisilylamide The following non-limiting examples illustrate the present invention:
  • 2M NaOH(aq) 15ml was added to the crude residue and heated at 100°C for 3O minutes. After allowing to cool to rt. the mixture was acidified to ca. pH 5 with 2M HCI(aq). The resulting precipitate was collected by filtration and then taken up into MeOH with heating and then passed down an amino propyl column (5g), eluting with 2% AcOH/MeOH, 5% AcOH/MeOH, 10% AcOH/MeOH and 15% AcOH/MeOH. The product fraction was concentrated, giving the title compound as an off- white solid (52mg).
  • 6-Amino-1-butyl-2,4(1/-/,3/-/)-pyrimidinedione (5.9g, 32.2mmol) and caesium carbonate O (11.54g, 35.4mmol) were added to anhydrous dimethylformamide under a nitrogen atmosphere.
  • Ethyl 4-bromobutyrate (5.07ml, 35.4mmol) was added and the mixture stirred at room temperature for 22h.
  • the reaction mixture was diluted with ethyl acetate (350ml) and washed with saturated sodium chloride solution (2 x 50ml). The combined aqueous phases were back extracted with ethyl acetate.
  • Example 8 (a): 3-Butyl-1-r4-f3-phenyl-1,2,4-oxadiazol-5-yl)butvn-8-(trifluoromethyl)-3,7- dihvdro-1 H-purine-2,6-dione 5
  • Example 12 3-Butyl-8-(trifluoromethyl)-1-(3-f3-r(2,4,6-trifluorophenyl)methvn -1.2.4- oxadiazol-5-yl)propyl)-3,7-dihvdro-1 H-purine-2.6-dione

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Abstract

The present invention relates to therapeutically active compounds of formula (I) which are xanthine derivatives, processes for the manufacture of said derivatives, pharmaceutical formulations containing the active compounds and the use of the compounds in therapy, particularly in the treatment of diseases where under-activation of the HM74A receptor contributes to the disease or where activation of the receptor will be beneficial.

Description

XANTHINE DERIVATIVES WITH HM74A RECEPTOR ACTIVITY
The present invention relates to therapeutically active compounds which are xanthine derivatives, processes for the manufacture of said derivatives, pharmaceutical formulations containing the active compounds and the use of the compounds in therapy, particularly in the treatment of diseases where under-activation of the HM74A receptor contributes to the disease or where activation of the receptor will be beneficial.
Dyslipidaemia is a general term used to describe individuals with aberrant lipoprotein profiles. Clinically, the main classes of compounds used for the treatment of patients with dyslipidaemia, and therefore at risk of cardiovascular disease are the statins, fibrates, bile- acid binding resins and nicotinic acid. Nicotinic acid (Niacin, a B vitamin) has been used clinically for over -40 years in patients with various forms of dyslipidaemia. The primary mode of action of nicotinic acid is via inhibition of hormone-sensitive triglyceride lipase (HSL), which results in a lowering of plasma non-esterified fatty acids (NEFA) which in turn alters hepatic fat metabolism to reduce the output of LDL and VLDL (low and very low density lipoprotein). Reduced VLDL levels are thought to lower cholesterol ester transfer protein (CETP) activity to result in increased HDL (high density lipoprotein) levels wh ich may be the cause of the observed cardiovascular benefits. Thus, nicotinic acid produces a very desirable alteration in lipoprotein profiles; reducing levels of VLDL and LDL whilst increasing HDL. Nicotinic acid has also been demonstrated to have disease mod ifying benefits, reducing the progression and increasing the regression of atherosclerotic lesions and reducing the number of cardiovascular events in several trials.
The observed inhibition of HSL by nicotinic acid treatment is mediated by a decrease in cellular cyclic adenosine monophosphate (cAMP) caused by the G-protein-mediated inhibition of adenylyl cyclase. Recently, the G-protein coupled receptors HM74 and HM74A have been identified as receptors for nicotinic acid (PCT patent application WO02/84298; Wise et. al. J Biol Chem., 2003, 278 (11 ), 9869-9874). The DNA sequence of human HM74A may be found in Genbank; accession number AY148884. Two further papers support this discovery, (Tunaru et. al. Nature Medicine, 2003, 9(3), 352-255 and Soga et. al. Biochem Biophys Res Commun., 2003, 303 (1) 364-369), however the nomenclature differs slightly. In the Tunaru paper what they term human HM74 is in fact HM74A and in the Soga paper HM74b is identical to HM74A. Cells transfected to express HM74A and/or HM74 gain the ability to elicit Gi G-protein mediated responses following exposure to nicotinic acid. In mice lacking the homologue of HM74A (m-PUMA-G) nicotinic acid fails to reduce plasma NEFA levels.
We now present a group of xanthine derivatives which are selective agonists of the nicotinic acid receptor HIV174A and are thus of benefit in the treatment, prophylaxis and suppression of diseases where under-activation of this receptor either contributes to the disease or where activation of the receptor will be beneficial. Summary of the Invention
The present invention provides therapeutically active xanthine derivatives and the use of these derivatives in therapy, particularly in the treatment of diseases where under-activation of the HM74A receptor contributes to the disease or where activation of the receptor will be beneficial, in particular diseases of lipid metabolism including dyslipidaemia or hyperlipoproteinaemia such as diabetic dyslipidaemia and mixed dyslipidaemia, heart failure, hypercholesteraemia, cardiovascular disease including atherosclerosis, arteriosclerosis, and hypertriglyceridaemia. As such, the compounds may also find favour as therapeutics for coronary artery disease, thrombosis, angina, chronic renal failure, peripheral vascular disease and stroke, as well as the cardiovascular indications associated with type Il diabetes mellitus, type I diabetes, insulin resistance, hyperlipidaemia, anorexia nervosa and obesity. The compounds may also be of use in the treatment of inflammatory diseases or conditions, as set out further below.
Intermediates, formulations, methods and processes described herein form further aspects of the invention.
Detailed Description of the Invention
According to one aspect of this invention, we provide at least one chemical entity selected from compounds of formula (I)
Figure imgf000003_0001
(I) and pharmaceutically acceptable derivatives thereof, wherein
R1 represents a group selected from: hydrogen, C1-10 alkyl, C2--I0 alkenyl, C2-io alkynyl, and -(alk)m-X-(alk)n-Y,
Wherein X represents A, A1 , A2 or a direct link;
A represents a group selected from: cycloalkylene, cycloalkenylene, aryl, heteroaryl, heterocyclyl, -CH2-OC(O)-;
A1 represents a group selected from:
-CH2-O-(CH2)qaryl-O-, -CH2-0-(CH2)wN(R5)C(0)0-, -CH2-N(R5)C(O)O-, -CH2-N(R5)C(O)-, -CH2-(O)p-(CH2)qC(O)NR5-, -CH2-N(R5)C(O)N(R5)-, -CH2-C(O)N((CH2)WOH)-, -CH2-NR5-S(O)2-, CH2-S(O)2NR5-, -CH2-C(O)O-, -O-, -NR5-, -S-; A2 represents: -CH(OH)-;
When X is A, A1 or A2, Y represents a group selected from: heteroaryl, heterocyclyl, aryl, cycloalkyl, cycloalkenyl, -O(CH2)n-aryl, -C(O)O-aryl, -CH(aryl)2l -CH(heteroaryl)2, -C1-6 haloalkyl, -C(O)R4' , -NR5R7, -C(O)NR5R7, -NR5C(O)R7, -NR5C(O)OR7, -C(O)(CH2)qOR4, halogen, cyano, -N(R5)C(O)OR7, -OC(O)NR5R6, -NR5C(O)R8, -OR5, -OC(O)R4;
When X is A1 and Y is selected from:
-O(CH2)n-aryl, -O-heteroaryl, -OR5, -OC(O)R5, -NH-aryl, -OC(O)NR5R6, n is an integer selected from 2, 3, 4 and 5;
When X is A1 and Y is -CF3, or when X is A2, n is an integer selected from 1 , 2, 3, 4 and 5;
When X is a direct link, Y represents a group selected from:
-C(O)(CH2)qOR5, -C(O)-aryl, -C(O)-heteroaryl, -C(O)-heterocyclyl, -heteroaryl, -heterocyclyl, -aryl, -cycloalkyl, -cycloalkenyl, -C1-6 haloalkyl, -halo, -cyano, 3 or 4 ring fused system, - CH(aryl)2, -CH(heteroaryl)2, -OR5, -NR5R7, -NCOOR8, -(O)PC(O)NR5R6, -MR5C(O)R8, -OR5, - (O)PC(O)R4;
When Y incorporates a ring, that ring may be optionally substituted by one or more of: Ci.6 alkyl, C2-6 alkenyl, C2-6 alkynyl, halogen, -NH2, (CH2)q-NR5R7, -(CH2)q-(O)p-(CH2)q-N(R5)C(O)OR8, -(CH2)q-N(R5)C(0)R8, -(CH2)q-(0)p-(CH2)q-C(O)NR5R6, -(CH2)q-N(R5)C(O)N(R5)R6 , -(CH2)q-C(O)N((CH2)mOH)R5, -(CH2)q-N(R5)-S(O)2R8, -CH2-S(O)2N(R5)R6, -C1-6 haloalkyl, -OCF3, -OCH(F)2, -OCH2F, -COOR5, -OR5, -(R8)PCN, -S(O2)R9, -(CH2)nheteroaryl, -(CH2)nheterocycyl, -(CH2)ncycloalkyl, -(CH2)neycloalkenyl, - (CH2)naryl;
R2 is selected from: hydrogen; or C1--I0 alkyl, C2-10 alkenyl, C2.io alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, and heteroaryl, each of which may be optionally substituted by one or more of: Ci-10 alkyl, C2-10 alkenyl, C2-io alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-6 haloalkyl, halogen, -CN, -OR4, -(CH2)nCOR4, -C(O)OR4, -OCOR4, -(CHz)nNR5R6, -(NH)pCON R5R6, -OCONR5R7, and -NHC(O)OR7;
R3 is selected from: halogenated C1-6 alkyl;
R4 is selected from: hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -(CH2)n cycloalkyl, -(CH2)n cycloalkenyl, -(CH2)n heterocyclyl, -(CH2)n aryl, and -(CH2)n heteroaryl;
R5 and R6 are selected from: hydrogen and C1-4 alkyl;
R7 is selected from: hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -(CH2)t cycloalkyl, -(CH2)n cycloalkenyl, -(CH2X heterocyclyl, -(CH2)taryl, and -(CH2)t heteroaryl; R8 is selected from C1-4 alkyl;
R9 is selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -(CH2)n cycloalkyl, -(CH2)ncycloalkenyl, -(CH2)nheterocyclyl, -(CH2)n aryl, and -(CH2)nheteroaryl, CN; m represents an integer selected from: 0, 1 , 2, 3, 4 and 5; n represents an integer selected from: 0, 1, 2, 3, 4 and 5;
p represents an integer selected from: 0 and 1 ;
q represents an integer selected from: 0, 1 and 2; t represents an integer selected from: 1 and 2; w represents an integer selected from: 2, 3 and 4.
with the proviso that: i) when R1 represents hydrogen or Ci-3 alkyl, R2 is different to R1; ii) when R1 represents ethyl and R3 represents CF3, R2 is other than CH2-CH=CH2; and iii) when R1 represents Methyl and R3 represents CF3, R2 is other than i-butyl.
In one embodiment of this invention, we provide at least one chemical entity selected from compounds of formula (I)
Figure imgf000005_0001
(I) and pharmaceutically acceptable derivatives thereof, wherein R1 represents hydrogen or a group selected from: C1-10 alkyl, C2-1O alkenyl, C2-I0 alkynyl,
~(CH2)ncycloalkyl, -(CH2)nheterocyclyl, -(CH2)naryl and -(CH2)nheteroaryl, each of which may be optionally substituted by one or more of: -(CH2)ncycloalkyl, -(CH2)nheterocycIyl, -(CH2)naryl, -(CH2)nheteroaryl, C1-6haloalkyl, halo, cyano, -OR4, -(CH2)nCOR4, -CO2R4, -OCOR4, -(CH2)nNR5R7, -(NH)171CONR5R7, -OCONR5R7, and -NHCO2R7;
R2 is selected from: C1-10 alkyl, C2-10 alkenyl, C2-I0 alkynyl, -(CH2)ncycloalkyl, ~(CH2)nheterocyclyl, -(CH2)naryl and -(CH2)nheteroaryl, each of which may be optionally substituted by one or more of: cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-6 haloalkyl, halo, cyano, -OR4, -(CH2)nCOR4, -CO2R4, -OCOR4, -(CH2)nNR5R6, -(NH)mCONR5R6, -OCONR5R7, and -NHCO2R7;
R3 is selected from: halogenated Ci-6 alkyl;
R4 is selected from: hydrogen, C1-6 alkyl C2-6 alkenyl, C2-6 alkynyl, -(CH2)πcycloalkyl, -(CH2)nheterocyclyl, -(CH2)naryl, and -(CH2)nheteroaryl;
R5 and R6 are independently selected from: hydrogen and C1-4 alkyl ;
R7 is selected from: hydrogen, C1-6 alkyl C2-6 alkenyl, C2-6 alkynyl, -(CH2)pcycloalkyl, -(CH2)pheterocyclyl, -(CH2)paryl, and -(CH2)pheteroaryl;
n represents an intege r selected from: 0, 1 , 2, 3 and 4;
m represents an integer selected from: 0 and 1 ;
p represents an intege r selected from: 1 and 2.
with the proviso that:
i) when R1 represents H or C1-3 alkyl, R2 is different to R1;
ii) when R1 represents ethyl and R3 represents CF3, R2 is other than CH2-CH=CH2; and
iii) when R1 represents Methyl and R3 represents CF3, R2 is other than i-butyl.
Throughout the present specification and the accompanying claims the words "comprise" and "include" and variations such as "comprises", "comprising", "includes" and "including" are to be interpreted inclusively. That is, these words are intended to convey the possible inclusion of other elements or integers not specifically recited, where the context allows.
As used herein, the terms "halogen" or "halo" refer to fluorine, chlorine, bromine and iodine.
As used herein, the term "alkyl" (when used as a group or as part of a group) refers to a straight or branched hydrocarbon chain unless specified otherwise, containing the specified number of carbon atoms. For example, C3-Ci0alkyl means a straight or branched hydrocarbon chain containing at least 3 and at most 10 carbon atoms. Examples of alkyl as used herein include, but are not limited to methyl (Me), ethyl (Et), n-propyl and i-propyl.
As used herein, the term "alkenyl" refers to a straight or branched hydrocarbon chain containing the specified number of carbon atoms which contains one or more double bonds. Suitable examples include but are not limited to ethenyl, 2-propenyl, 3-butenyl, 2-butenyl, 2- pentenyl, 3-pentenyl, 3-methyl-2-butenyl, 3-hexenyl and the like. As used herein, the term "alkynyl" refers to a straight or branched hydrocarbon chain containing the specified number of carbon atoms which contains one or more tri pie bonds. Suitable examples include but are not limited to acetylenyl, propynyl, 1-butynyl, "1 -pentynyl, 3-methyl-1-butynyl and the like.
The term 'C1-6 haloalkyl' as used herein refers to a C1-6 alkyl group as defined herein wherein at least one hydrogen atom is replaced with halogen. Examples of such groups include fluoroethyl, trifluoromethyl or trif luoroethyl and the like.
As used herein, the term "cycloalkyl" refers to a hydrocarbon ring, containing between 3 and 6 carbon atoms, comprising no heteroatoms or conjugated double bonds. Examples of cycloalkyl as used herein include, but are not limited to cyclopropyl and cyclohexyl.
The term 'cycloalkylene' as used herein refers to a saturated monocyclic hydrocarbon ring of 3 to 8 carbon linker goups. Examples of such groups include cyclopropylene, cyolobutylene, cyclopentylene, cyclohexylene, cycloheptylene or cyclooctylene and the like.
The term 'cycloalkenyl' as used herein refers to an unsaturated non-aromatic monocyclic hydrocarbon ring of 3 to 8 carbon atoms containing one or more carbon-carbon double bonds. Examples of such groups include cyclopropenyl, cyclobutenyl, cyolopentenyl, cyclohexenyl, cycloheptenyl or cyclooctenyl and the like.
The term 'cycloalkenylene' as used herein refers to an unsaturated non-aromatic monocyclic hydrocarbon ring of 3 to 8 carbon linker groups containing one or more carbon-carbon double bonds. Examples of such groups include cyclopropenylene, cyclobutenylene, cyclopentenylene, cyclohexenylene, cycloheptenylene or cyclooctenylene and the like.
As used herein, the term "aryl" refers to a 5 or 6 membered, monocyclic aromatic group, or a fused 8-10 membered bicyclic aromatic group with at least one ring having a conjugated pi- electron system, containing up to two conjugated or fused ring systems. "Aryl" includes carbocyclic aryl and biaryl groups. Suitable examples include but are not limited to phenyl, naphthyl and the like.
As used herein, the term "heteroaryl" refers to a 5 or 6 membered, monocyclic aromatic group or a fused 8-10 membered bicyclic, aromatic group containing 1 to 3 heteroatoms independently selected from oxygen, nitrogen and sulphur with at least one ring having a conjugated pi-electron system, containing up to two conjugated or fused ring systems. Suitable examples of such monocyclic aromatic rings include but are not limited to thienyl, furyl, pyrrolyl, triazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, pyrazolyl, pyrimidyl, pyridazinyl, pyrazinyl and pyridyl. Suitable examples of such fused aromatic rings include but are not limited to benzofused aromatic rings such as quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, cinnolinyl, naphthyridinyl, indolyl, indazolyl, pyrrolopyridinyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzoxadiazolyl, benzothiadiazolyl and the like.
As used herein, the term "heterocyclyl" refers to a 5 or 6 membered, saturated cyclic hydrocarbon group, containing 1 to 3 heteroatoms independently selected from oxygen, nitrogen and sulphur. Suitable examples include but are not limited to pyrrolidinyl, morpholinyl, imidazolidinyl and piperazinyl.
The term '3 or 4 ring fused system' as used herein refers to a fused 12-18 membered tricyclic or tetracyclic ring which contains 1 to 4 heteroatoms of N and wherein at least one ring is aromatic. There may be one or more optional oxo substituents on the ring carbon atoms. Examples of such fused aromatic rings include carbazolyl , acenaphthyl, naphthotriazolyl and the like.
As used herein, where a group is referred to as being "substituted" by another group or having "one or more substituents" unless a particular position for such a substitution is specified it is to be understood that a substitution may be present at any position in the group.
As used herein, the term "pharmaceutically acceptable derivative" refers to any pharmaceutically acceptable derivative of a compound of the present invention, for example salts, solvates or esters which, upon administration to a mammal, such as a human, are capable of providing (directly or indirectly) a compound of formula (I) or an active metabolite or residue thereof. Such derivatives are clear to those skilled in the art, without undue experimentation, and with reference to the teaching of Burger's Medicinal Chemistry And Drug Discovery, 5th Edition, VoI 1 : Principles And Practice, which is incorporated herein by reference.
It will be appreciated by those skilled in the art that the compounds of the invention may be modified to provide pharmaceutically acceptable derivatives thereof at any of the functional groups in the compounds, and that the compounds of the invention may be so modified at more than one position.
In one embodiment, "pharmaceutically acceptable derivative" refers to salts or solvates.
As used herein, the term "pharmaceutically acceptable" used in relation to an ingredient (active ingredient or excipient) which may be included in a pharmaceutical formulation for administration to a patient, refers to that ingredient being acceptable in the sense of being compatible with any other ingredients present in the pharmaceutical formulation and not being deleterious to the recipient thereof. As used herein, the term "solvate" refers to a complex of variable stoichiometry formed by a solute (in this invention, a compound of formula (I), a salt thereof or a pharmaceutically acceptable derivative thereof) and a solvent. Such solvents for the purposes of the present invention may not interfere with the biological activity of the solute. The solvent used may be a pharmaceutically acceptable solvent. Examples of suitable pharmaceutically acceptable solvents include water, ethanol and acetic acid. An example of a solvent that may be used is water, in which case the solvate may be referred to as a hydrate of the solute in question.
It will be appreciated that, for pharmaceutical use, the "salt or solvate" referred to above will be a pharmaceutically acceptable salt or solvate. However, other salts or solvates may find use, for example, in the preparation of a compound of formula (I) or in the preparation of a pharmaceutically acceptable salt or solvate thereof.
Pharmaceutically acceptable salts include those described by Berge, Bighley and Monkhouse, J. Pharm. Sci., 1977, 66, 1-19. Suitable pharmaceutically acceptable salts include alkali metal salts formed from the addition of alkali metal bases such as alkali metal hydroxides. Examples of suitable alkali metal salts are sodium salt or potassium salt. Other suitable pharmaceutically acceptable salts include alkaline earth metal salts such as calcium salt or magnesium salt, ammonium salts; or salts with organic bases such as ethanolamine, triethanolamine, ethylene diamine, triethylmine, choline and meglumine; or salts with amino acids such as arginine, lysine and histidine.
The compounds are of use in the treatment of diseases where under-activation of the HM74A receptor contributes to the disease or where activation of the receptor will be beneficial, in particular diseases of lipid metabolism including dyslipidaemia or hyperlipoproteinaemia such as diabetic dyslipidaemia and mixed dyslipidaemia, heart failure, hypercholesteraemia, cardiovascular disease including atherosclerosis, arteriosclerosis, and hypertriglyceridaemia. As such, the compounds may also find favour as therapeutics for coronary artery disease, thrombosis, angina, chronic renal failure, peripheral vascular disease and stroke, as well as the cardiovascular indications associated with type Il diabetes mellitus, type I diabetes, insulin resistance, hyperlipidaemia, anorexia nervosa, obesity. As such the compounds of the present invention may find use as agonists or partial agonists of HM74A.
Compounds of the invention are of potential therapeutic benefit in the treatment and amelioration of the symptoms of many diseases of lipid metabolism including dyslipidaemia or hyperlipoproteinaemia such as diabetic dyslipidaemia and mixed dyslipidaemia, heart failure, hypercholesteraemia, cardiovascular disease including atherosclerosis, arteriosclerosis, and hypertriglyceridaemia, type Il diabetes mellitus, type I diabetes, insulin resistance, hyperlipidaemia, anorexia nervosa, obesity. As such, the compounds may also find favour as therapeutics for coronary artery disease, thrombosis, angina, chronic renal failure, peripheral vascular disease and stroke. Furthermore, it is also believed that the HM74 and HM74A receptors are involved in inflammation. Inflammation represents a group of vascular, . cellular and neurological responses to trauma. Inflammation can be characterised as the movement of inflammatory cells such as monocytes, neutrophils and granulocytes into the tissues. This is usually associated with reduced endothelial barrier function and oedema into the tissues. Inflammation with regards to disease typically is referred to as chronic inflammation and can last up to a lifetime. Such chronic inflammation may manifest itself through disease symptoms. The aim of anti-inflammatory therapy is therefore to red uce this chronic inflammation and allow for the physiological process of healing and tissue repair to progress.
Examples of inflammatory diseases or conditions for which the compounds of the present invention may demonstrate utility include those of the joint, particularly arthritis (e.g. rheumatoid arthritis, osteoarthritis, prosthetic joint failure), or the gastrointestinal tract (e.g. ulcerative colitis, Crohn's disease, and other inflammatory bowel and gastrointestinal diseases, gastritis and mucosal inflammation resulting from infection, the enteropathy provoked by non-steroidal anti-inflammatory drugs), of the lung (e.g. adult respiratory distress syndrome, asthma, cystic fibrosis, or chronic obstructive pulmonary disease), of the heart (e.g. myocarditis), of nervous tissue (e.g. multiple sclerosis), of the pancreas, (e.g. inflammation associated with diabetes melitus and complications thereof, of the kidney (e.g. glomerulonephritis), of the skin (e.g. dermatitis, psoriasis, eczema, urticaria, burn injury), of the eye (e.g. glaucoma) as well as of transplanted organs (e.g. rejection) and multi-organ diseases (e.g. systemic lupus erythematosis, sepsis) and inflammatory sequelae of viral or bacterial infections and inflammatory conditions associated with atherosclerosis and following hypoxic or ischaemic insults (with or without reperfusion), for example in the brain or in ischaemic heart disease.
It will be appreciated that references herein to treatment extend to prophylaxis, prevention of recurrence and suppression of symptoms as well as the treatment of established conditions.
Nicotinic acid has a significant side effect profile, possibly because it is dosed at high level (gram quantities daily). The most common side effect is an intense cutaneous flushing. In certain embodiments of the present invention the compounds may exhibit reduced side effects compared to nicotinic acid. HM74A has been identified as a high affinity receptor for nicotinic acid whilst HM74 is a lower affinity receptor. The compounds of the present invention may find use as selective HM74A agonists or partial agonists; in which case they will show greater affinity for HM74A than for HM74.
The potential for compounds of formula (I) to activate HM74A may be demonstrated, for example, using the following in vitro whole cell assays:
In -vitro testing For transient transfections, HEK293T cells (HEK293 cells stably expressing the SV40 large T-antigen) were maintained in DMEM containing 10% foetal calf serum and 2mM glutamine. Cells were seeded in 90mm culture dishes and grown to 60-80% confluence (18-24h) prior to transfection. Human HM74A (GenBank™ accession number AY148884) was subcloned in to a mammalian expression vector (pcDNA3; Invitrogen) and transfected using Lipofectamine reagent. For transfection, 9μg of DNA was mixed with 30μ.I Lipofectamine in 0.6ml of Opti-MEM (Life Technologies Inc.) and was incubated at room temperature for 30min prior to the addition of 1.6ml of Opti-MEM. Cells were exposed to the Lipofectamine/DNA mixture for 5h and 6ml of 20% (v/v) foetal calf serum in DMEM was then added. Cells were harvested 48h after transfection. Pertussis toxin treatment was carried out by supplementation into media at 50ngmr1 for 16h. All transient transfection studies involved co-transfection of receptor together with the Gj/0 G protein, G01 α.
For generation of stable cell lines the above method was used to transfect CHO-K1 cells seeded in six well dishes grown to 30% confluence. These cells were maintained in DMEM
F-12 HAM media containing 10% foetal calf serum and 2mM glutamine. 48h post- transfection the media was supplemented with 400μg/ml Geneticin (G418, Gibco) for selection of antibiotic resistant cells. Clonal CHO-K1 cell lines stably expressing HM74A were confirmed by [35S]-GTPyS binding measurements, following the addition of nicotinic acid.
P2 membrane preparation - Plasma membrane-containing P2 particulate fractions were prepared from cell pastes frozen at -800C after harvest. All procedures were carried out at 4°C. Cell pellets were resuspended in 1 ml of 1OmM Tris-HCl and 0.1 rnM EDTA, pH 7.5 (buffer A) and by hornogenisation for 20s with a Ultra Turrax followed by passage (5 times) through a 25-gauge needle. Cell lysates were centrifuged at 1 ,000g for 10 min in a microcentrifuge to pellet the nuclei and unbroken cells and P2 particulate fractions were recovered by microcentrifugation at 16,00Og for 30min. P2 particulate fractions were resuspended in buffer A and stored at -800C until required.
[35S]-GTPyS binding - assays were performed at room temperature in 384-well format based on methods described previously, (Wieland, T. and Jakobs, K.H. (1994) Methods Enzymol. 237, 3-13). Briefly, the dilution of standard or test compounds were prepared and added to a 384-well plate in a volume of 10μl. Membranes (HM74A or HM74) were diluted in assay buffer (2OmM HEPES, 10OmM NaCI, 1OmM MgCI2, pH7.4) supplemented with saponin (60μg/ml), Leadseeker WGA beads (Amersham; 250μg/well) and 10μM GDP, so that the 20μl volume added to each well contains 5μg of membranes. [35S]-GTPyS (1170 Ci/mmol, Amersham) was diluted (1 :1500) in assay buffer and 20μl added to each well. Following the addition of the radioligand, the plates were sealed, pulse spun and incubated for 4hours at room temperature. At the end of the incubation period the plates were read on a Leadseeker machine (VIEWLUX PLUS; Perkin-Elmer) to determine the levels of specific binding. These assays were refined by reducing the final assay volume to 10 μl. For this 10 μl assay a revised protocol was used. This involved the use of only 100 nl of standard or test compound per well of a 384-well plate and 1.5 μg membrane and 100 μg Leadseeker WGA beads. For the low volume protocol, membrane, beads and [35S]-GTPyS were mixed together and then 10 μl of this mix were dispensed to each well. Incubation and plate read were identical for the 10μl and 50 μl assays.
All exemplified compounds were tested in one or both of the [35S]-GTPyS binding assays described above (i.e. the 10μl and 50μl assays).
Data was analysed by curve fitting as carried out using a Four Parameter Logistical equation using the XC50 software package (max 2 points deleted from any one curve). Specific binding is expressed as pEC50 and as % efficacy compared to the maximal response of nicotinic acid bind ing.
In-vivo testing
HM74A agonists can be tested in male Spague-Dawley rats (200-250g) which have been fasted for at least 12 hours prior to the study. The compounds are dosed intravenously at either 1 or 3mg/kg (5ml/kg) or by oral gavage at doses ranging from 1-30rng/kg (10ml/kg). Blood samples (O .3ml tail vein bleed) can be taken pre-dose and at three times post-dose (times ranging from 15 minutes to 6 hours post-dose). Each blood sample is transferred to a heparin tube (Becton Dickinson Microtainer, PST LH) and centrifuged (10,000g for 5 minutes) to produce a plasma sample. The plasma samples are assayed for levels of non- esterified fatty acids (NEFA) using a commercially available kit (Randox). Inhibition of plasma NEFA levels, relative to pre-dose levels, are used as a surrogate for HM74A agonist activity.
In order to determine whether HM74A compounds exhibit the flushing response associated with nicotinic acid they can be dosed to conscious guinea-pigs. Male Dunkin Hartley guinea pigs (300-60Og; n=10-20 per group) are fasted for at least 12 hours, but not in excess of 24 hours prior to experimention. Pre-study blood samples (0.5ml) are taken from each animal by cardiac puncture under recovery anaesthesia (Isoflurane 3.5% with additional O2 (1 L/min)). Ear temperature measurements are taken by placing the left ear of each animal over an infra-red temperature probe. Measurements are taken at one minute intervals from 5 minutes pre-dose to 30 minutes post-dose. Temperature measurements are then taken at 15 minute intervals up to 2 hours post-dose. Animals receive test compounds by oral gavage (5ml/kg). Blood samples (0.5ml) are taken by cardiac puncture under terminal anaesthesia. Blood samples are taken from individual animals to provide data at 0.5, 1 , 2, 3, and 4 hours post-dose. All blood samples are placed on a blood roller for 5 minutes then stored on ice until the end of the study. Following centrifugation (1200Og for 5min) the plasma is transferred into fresh tubes and stored at -2O0C until assayed for NEFA concentrations.
Compounds according to Formula (I) have been synthesised (see synthetic examples below) and tested in the [35S]-GTP^ binding assays described above. AJI of the exemplified compounds have a pEC50 of 4.3 or greater and an efficacy of 30% or greater (in relation to nicotinic acid).
Compounds of Formula (I) may find use in human or veterinary med icine, in particular as activators of HM74A, in the management of dyslipidaemia and hyperlipoproteinaemia.
According to another aspect of the invention, there is provided the use of at least one chemical entity selected from compounds of formula (II)
Figure imgf000013_0001
(II) and pharmaceutically acceptable derivatives thereof, wherein
R1 represents a group selected from: hydrogen, C1-10 alkyl, C2-10 alkenyl , C2-10 alkynyl, and -(alk)m-X-(alk)n-Y,
Wherein X represents A, A1 , A2 or a direct link;
A represents a group selected from: cycloalkylene, cycloalkenylene, aryl, heteroaryl, heterocyclyl, -CH2-OC(O)-;
A1 represents a group selected from: -CH2-0-(CH2)qaryl-O-, -CH2-O-(CH2)WN(R5)C(O)O-, -CH2-N(R5)C(O)O-, -CH2-N(R5)C(O)-, -CH2-(O)p-(CH2)qC(O)NR5-, -CH2-N(R5)C(O)N(R5)-, -CH2-C(0)N((CH2)WOH)-, -CH2-NR5-S(O)2-, CH2-S(O)2NR5-, -CH2-C(O)O-, -O-, -NR5-, -S-;
A2 represents: -CH(OH)-;
When X is A, A1 or A2, Y represents a group selected from: heteroaryl, heterocyclyl, aryl, cycloalkyl, cycloalkenyl, -O(CH2)n-aryl, -C(0)O-aryl, -CH(aryl)2, -CH(heteroaryl)2, -C1-6 haloalkyl, -C(O)R4' , -NR5R7, -C(O)NR5R7, -NR5C(O)R7, -NR5C(O)OR7, -C(O)(CH2)qOR4, halogen, cyano, -N(R5)C(O)OR7, -OC(O)NR5R6, -NR5C(O)R8, -OR5, -OC(O)R4;
When X is A1 and Y is selected from:
-O(CH2)n-aryl, -O-heteroaryl, -OR5, -OC(O)R5, -NH-aryl, -OC(O)NR5R6, n is an integer selected from 2, 3, 4 and 5;
When X is A1 and Y is -CF3, or when X is A2, n is an integer selected from 1 , 2, 3, 4 and 5;
When X is a direct link, Y represents a group selected from:
-C(O)(CH2)qOR5, -C(O)-aryl, -C(O)-heteroaryl, -C(O)-heterocyclyl, -heteroaryl, -heterocyclyl, -aryl, -cycloalkyl, -cycloalkenyl, -C1-6 haloalkyl, -halo, -cyano, 3 or 4 ring fused system, -CH(aryl)2, -CH(heteroaryl)2, -OR5, -NR5R7, -NCOOR8, -(O)PC(O)NR5R6, -NR5C(O)R8, -OR5, -(0)pC(0)R4;
When Y incorporates a ring, that ring may be optionally substituted by one or more of: C1-6alkyl, C2.6 alkenyl, C2-6 alkynyl, halogen, -NH2, (CH2)q-NR5R7, -(CH2)q-(O)p-(CH2)q-N(R5)C(O)OR8, -(CH2)q-N(R5)C(O)R8, -(CH2)q-(O)p-(CH2)q-C(O)NR5R6, -(CH2)q-N(R5)C(O)N(R5)R6, -(CH2)q-C(0)N((CH2)m0H)R5, -(CH2)q-N(R5)-S(0)2R8, -CH2-S(O)2N(R5)R6, -C1-6 haloalkyl, -OCF3, -OCH(F)2, -OCH2F, -COOR5, -OR5, -(R8)PCN, -S(O2)R9, -(CH2)nheteroaryl, -(CH2)nheterocycyl, -(CH2)ncycloalkyl, -(CH2)ncycloalkenyl, -(CH2)naryl;
R2 is selected from: hydrogen; or C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, and heteroaryl, each of which may be optionally substituted by one or more of: C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, cycloaikyl, heterocyclyl, aryl, heteroaryl, C1-6 haloalkyl, halogen, -CN, -OR4, -(CH2)nCOR4, -C(O)OR4, -OCOR4, -(CH2)nNR5R6, -(NH)PCONR5R6, -OCONR5R7, and -NHC(O)OR7;
R3 is selected from: halogenated Ci-6 alkyl;
R4 is selected from: hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -(CH2)n cycloalkyl, -(CH2)n cycloalkenyl, -(CH2)n heterocyclyl, -(CH2)n aryl, and -(CH2)n heteroaryl;
R5 and R6 are selected from: hydrogen and Ci-4 alkyl;
R7 is selected from: hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -(CH2)t cycloalkyl, -(CH2)n cycloalkenyl, -(CH2)t heterocyclyl, -(CH2)taryl, and -(CH2)t heteroaryl;
R8 is selected from C1-4 alkyl;
R9 is selected from Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -(CH2)π cycloalkyl, -(CH2)ncycloalkenyl, -(CH2)nheterocyclyl, -(CH2)n aryl, and -(CH2)nheteroaryl, CN; m represents an integer selected from: 0, 1 , 2, 3, 4 and 5; n represents an integer selected from: 0, 1 , 2, 3, 4 and 5;
p represents an integer selected from: 0 and 1 ;
q represents an integer selected from: 0, 1 and 2; t represents an integer selected from: 1 and 2; w represents an integer selected from: 2, 3 and 4;
in the manufacture of a medicament for the treatment of disorders of lipid metabolism including dyslipidaemia or hyperlipoproteinaemia. In particular, the use is provided of a compound of Formula (II) in the manufacture of a medicament for the treatment of diabetic dyslipidaemia or mixed dyslipidaemia, heart failure, hypercholesteraemia, type Il diabetes mellitus, type I diabetes, insulin resistance, hyperlipidaemia, anorexia nervosa, obesity, coronary artery disease, thrombosis, angina, chronic renal failure, stroke and cardiovascular disease including atherosclerosis, arteriosclerosis, and hypertriglyceridaemia.
In one embodiment of the invention, there is provided a compound of formula (I) or (II) or a pharmaceutically derivative thereof for use in the treatment of disorders of lipid metabolism including dyslipidaemia or hyperlipoproteinaemia. In another embodiment, the use is provided of a compound of Formula (I) or (II) in the manufacture of a medicament for the treatment of diabetic dyslipidaemia or mixed dyslipidaemia, heart failure, hypercholesteraemia, type Il diabetes mellitus, type I diabetes, insulin resistance, hyperlipidaemia, anorexia nervosa, obesity, coronary artery disease, thrombosis, angina, chronic renal failure, stroke and cardiovascular disease including atherosclerosis, arteriosclerosis, and hypertriglyceridaemia.
Thus, there is provided as a further aspect of the present invention a compound of formula
(I) or (II) or a pharmaceutically acceptable derivative thereof, for use in human or veterinary medicine, particularly in the treatment of disorders of lipid metabolism including dyslipidaemia or hyperlipoproteinaemia such as diabetic dyslipidaemia and mixed dyslipidaemia, heart failure, hypercholesteraemia, cardiovascular disease including atherosclerosis, arteriosclerosis, and hypertriglyceridaemia, type Il diabetes mellitus, type I diabetes, insulin resistance, hyperlipidaemia, anorexia nervosa, obesity. As such, the compounds are also provided for use in the treatment of coronary artery disease, thrombosis, angina, chronic renal failure, peripheral vascular disease and stroke.
There is provided as a further aspect of the present invention a compound of formula (I) or
(II) or a pharmaceutically acceptable derivative thereof, for use in the manufacture of a medicament for the treatment of disorders of lipid metabolism including dyslipidaemia or hyperlipoproteinaemia such as diabetic dyslipidaemia and mixed dyslipidaemia, heart failure, hypercholesteraemia, cardiovascular disease including atherosclerosis, arteriosclerosis, and hypertriglyceridaemia, type Il diabetes mellitus, type I diabetes, insulin resistance, hyperlipidaemia, anorexia nervosa, obesity. As such, the compounds are also provided for use in the treatment of coronary artery disease, thrombosis, angina , chronic renal failure, peripheral vascular disease and stroke.
In a further embodiment the present invention provides the use of a compound of formula (I) or (II) or a pharmaceutically acceptable derivative thereof, in the manufacture of a medicament for the treatment of inflammatory diseases or conditions of the joint, particularly arthritis (e.g. rheumatoid arthritis, osteoarthritis, prosthetic joint failure), or of the gastrointestinal tract (e.g. ulcerative colitis, Crohn's disease, and other inflammatory bowel and gastrointestinal diseases, gastritis and mucosal inflammation resulting from infection, the enteropathy provoked by non-steroidal anti-inflammatory drugs), of the lung (e.g. adult respiratory distress syndrome, asthma, cystic fibrosis, or chronic obstructive pulmonary disease), of the heart (e.g. myocarditis), of nervous tissue (e.g. multiple sclerosis), of the pancreas, (e.g. inflammation associated with diabetes melitus and complications thereof, of the kidney (e.g. glomerulonephritis), of the skin (e.g. dermatitis, psoriasis, eczema, urticaria, burn injury), of the eye (e.g. glaucoma) as well as of transplanted organs (e.g. rejection) and multi-organ diseases (e.g. systemic lupus erythematosis, sepsis) and inflammatory sequelae of viral or bacterial infections and inflammatory conditions associated with atherosclerosis and following hypoxic or ischaemic insults (with or without reperfusion), for example in the brain or in ischaemic heart disease.
In one embodiment, the compounds of formula (I) or (II) or pharmaceutically acceptable derivatives thereof are useful in the treatment and prevention of inflammation, diabetes and cardiovascular diseases or conditions including atherosclerosis, arteriosclerosis, hypertriglyceridemia, and mixed dyslipidaemia.
In a further or alternative aspect there is provided a method for the treatment of a human or animal subject with a condition where under-activation of the HM74A receptor contributes to the condition or where activation of the receptor will be beneficial, which method comprises administering to said human or animal subject an effective amount of a compound of formula (I) or (II) or a pharmaceutically acceptable derivative thereof.
In one embodiment the present invention provides a method for the treatment of disorders of lipid metabolism including dyslipidaemia or hyperlipoproteinaemia such as diabetic dyslipidaemia and mixed dyslipidaemia, heart failure, hypercholesteraemia, cardiovascular disease including atherosclerosis, arteriosclerosis, and hypertrig lyceridaemia, type Il diabetes mellitus, type I diabetes, insulin resistance, hyperlipidaemia, anorexia nervosa, obesity, which method comprises administering to said human or animal subject an effective amount of a compound of formula (I) or (II) or a pharmaceutically acceptable derivative thereof. As such, these compounds may also find favour in methods for the treatment of coronary artery disease, thrombosis, angina, chronic renal failure, peripheral vascular disease and stroke, which methods comprise administering to said human or animal subject an effective amount of a compound of formula (I) or (II) or a pharmaceutically acceptable derivative thereof.
In one embodiment of formula (I) or (II), R1 is selected from hydrogen C1-10 alkyl, and -(alk)m-X-(alk)n-r.
In one embodiment of formula (I) or (II), X represents A or A1. In a further embodiment of formula (I) or (II), A is selected from heteroaryl, heterocyclyl, and A1 is selected from CH2-O- (CH2)wN(R5)C(0)O-, for example CH2O(CHs)2NHC(O)O-, CH2-N(R5)C(O)O- for example CH2-NHC(O)O, CH2-N(R5)C(O)- for example, CH2-NHC(O)-, CH2-(O)p-(CH2)qC(O)NR5- for example CH2C(O)NCH3- , CH2-N(R5)C(O)N(R5)- for example CH2-NHC(O)NCH3-, CH2- C(0)N((CH2)WOH)- for example CH2-C(O)N((CH2)2OH)-, CH2-N R5-S(O)2- for example CH2- NH-S(O)2-, CH2-S(O)2NR5- for example CH2-S(O)2NCH3-, and CH2-C(O)O-. In another embodiment of formula (I) or (II), X represents A and A represents a heteroaryl. In another embodiment of formula (I) or (II), A represents a heteroaryl comprising a nitrogen heteroatom, for example, triazolyl, furazanyl, oxadiazolyl, tetrazolyl, imidazolyl or pyrazolyl.
In a further embodiment of formula (I) or (II), X represents A, for example heteroaryl or heterocyclyl, or a direct link.
In one embodiment of formula (I) or (II), Y represents an optionally substituted group selected from: aryl, for example phenyl or napthyl, heteroaryl, for example pyridinyl, thiazolyl, thienyl, benzofuranyl or indolyl, and O-aryl, for example O-phenyl.
In a further embodiment of formula (I) or (II), Y is substituted by one or more groups selected from OR5 for example OH or OCH3, halogen, for example F or Cl, aryl, for example phenyl, C1-6 haloalkyl for example CF3 or CH2CF3 , OCF3, (R8)PCN for example CN, (CH2)q-N(R5)-S(0)2R8for example NHS(O)2CH3 and S(O)2R9 for example S(O)2CH3.
In one embodiment of of formula (I) or (II), when X represents A or A1 , and A represents cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocyclyl, and A1 represents -CH2-O-(CH2)WN(R5)C(O)O-, -CH2-N(R5)C(O)O-, -CH2-N(R5)C(O)- , -CH2-(O)p-(CH2)qC(O)NR5-, -CH2-N(R5)C(O)N(R5)-, or -CH2-C(O)N((CH2)WOH)-, and Y represents a ring, for example when X represents oxadizolyl, tetrazolyl or pyrazolyl and Y represents phenyl, pyridinyl, or thienyl, m is an integer selected from 3 and 4 and n is an integer selected from O and 1 , for example m is 4 and n is O, or m is 3 and n is 1 ;
In one embodiment of formula (I) or (II), R1 is selected from: hydrogen; and C1-10 alkyl which may be optionally substituted by one or more of: cycloalkyl, heterocyclyl, aryl, heteroaryl, C1- 6 haloalkyl, halo, cyano, -OR4, -(CH2)nCOR5, -CO2R4, -OCOR4, -(CH2)nNR5R7, and - (NH)mCONR5R7. In another embodiment of formula (I) or (II), R1 is selected from: hydrogen; and C1-10 alkyl which may be optionally substituted by one or more of: halo, cyano, -OR4, - (CH2)nCOR4, -CO2R4, -OCOR4, -(CH2)nNR5R6, and -(NH)mCONR5R6. In a further embodiment of formula (I) or (II), R1 is selected from: hydrogen and C1-6 alkyl optionally substituted with -OH, for example methyl, butyl or CH2CH2OH.
In one embodiment of formula (I) or (II), R1 is selected from: hydrogen and C1-6 alkyl, for example methyl or butyl.
In one embodiment of formula (I) or (II), R2 is selected from: C4-10 alkyl and C2-10 alkenyl, each of which may be optionally substituted by one or more of cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-6 haloalkyl, halo, cyano, -OR4, -(CH2)nCOR5, -CO2R4, -OCOR4, -(CH2)nNR5R6, and -(NH)mC0NR5R6. In another embodiment of formula (I) or (II), R2 may represent C4-10 alkyl which may be optionally substituted by one or more of cycloalkyl , heterocyclyl, aryl, heteroaryl, C1-6 haloalkyl, halo, cyano, -OR4, -(CH2)nCOR4, -CO2R4, -OCOR4, -(CH2)nNR5 R6, and -(NH)mCONR5 R6. In a further embodiment R2 is selected from C4-6 alkyl, for example butyl or pentyl.
In one embodiment of formula (I) or (II), R2 represents C1-I0 alkyl which may be optionally substituted by one or more of: cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-6 haloalkyl, halogen, -CN, -OR4, -(CH2)nCOR5, -C(O)OR4, -OCOR4, -(CH2)nNR5R6, and -(NH)PCONR5R6. In a further embodiment of formula (I) or (II), R2 is selected from C3-6 alkyl, for example butyl or pentyl.
In one embodiment of formula (I) or (II), R3 is selected from: fluorinated C1-6 alkyl. In another embodiment of formula (I) or (II), R3 is selected from: fluorinated C1-4 alkyl, for example CF3, CHF2 or CF2CF3.
In one embodiment of formula (I) or (II), R4 is selected from: hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -(CH2)ncycloalkyl, -(CH2)nheterocyclyl, -(CH2)naryl, and -(CH2)nheteroaryl. In another embodiment of formula (I) or (II) R4 is selected from: hydrogen and C1-4 alkyl.
In one embodiment of formula (I) or (II), R1 is selected from: hydrogen and C1-6 alkyl optionally substituted with -OH, R2 is selected from: C4-6 alkyl and R3 is selected from: fluorinated C1-4 alkyl, with the proviso that when R1 represents Methyl and R3 represents CF3, R2 cannot be i-butyl.
In one embodiment of formula (I) or (II), R5 is hydrogen.
In one embodiment of formula (I) or (II), R7 is selected from: hydrogen and Ci-4 alkyl. In further embodiment of formula (I) or (II,) it is provided that when X is Av1 , A1 is -O- and Y is a ring which is substituted by aryl or heteroaryl, then m is an integer selected from 3, 4 and 5.
In one embodiment of formula (I) or (II), R1 and R2 are different.
It is to be understood that the present invention includes any combination of particular embodiments and covers all combinations of particular substituents described hereinabove for compounds of Formula (I) or (II).
Particular compounds of the present invention include:
3-butyl-1-methyl-8-(trifluoromethyl)-3,7-dihydro-1/-/-purine-2,6-dione,
1 ,3-dibutyl-8-(trifluoromethyl)-3,7-dihydro-1/-/-purine-2,6-dione, 3-butyl-1 -methyl-8-(pentafluoroethyl)-3,7-dihydro-1 /-/-purine-2,6-dione,
8-(difluoromethyl)-1-methyl-3-pentyl-3,7-dihydro-1H-purine-2,6-dione ,
3-pentyl-8-(trifluoromethyl)-3,7-dihydro-1/-/-purine-2,6-dione,
1 -(2-hydroxyethyl )-3-pentyl-8-(trifluoromethyl)-3,7-dihydro-1 H-purine-2,6-d ione,
3-Butyl-1-{3-[3-(phenylmethyl)-1 ,2,4-oxadiazol-5-yl]propyl}-8-(trifluoromethyl)-3,7-dihydro- 1 H-purine-2,6-dione,
4-[3-Butyl-2,6-dioxo-8-(trifluoromethyl)-2,3,6,7-tetrahydro-1 H-purin-1-yl]butanoic acid,
3-Butyl-1-[4-(3-phenyl-1 ,2,4-oxadiazol-5-yl)butyl]-8-(trifluoromethyl)-3,7-dihydro-1 /-/-purine-
2,6-dione,
S-^-butyl^.θ-dioxo-δ-^rifluoromethyO^.S.ΘJ-tetrahydro-I H-purin-i-ylJpentanoic acid, 3-Butyl-1 -{4-[3-(2-f luorophenyl)-1 ,2,4-oxadiazol-5-yl]butyl}-8-(trif luoromethyl)-3,7-dihydro-1 H- purine-2,6-dione,
3-Butyl-1-{4-[3-(4-fluorophenyl)-1 ,2,4-oxadiazol-5-yl]butyl}-8-(trifluoromethyl)-3,7-dihydro-1 H- purine-2,6-dione,
3-Butyl-1 -{4-[3-(2-pyridinyl)-1 ,2,4-oxadiazol-5-yl]butyl}-8-(trifluoromethyl)-3 ,7-dihydro-1 H- purine-2,6-dione,
3-Butyl-8-(trifluoromethyl)-1-(3-{3-[(2,4,6-trifluorophenyl)methyl]-1 ,2,4-oxadiazol-5-yl}propyl)-
3,7-dihydro-1H-purine-2,6-dione,
1-Methyl-3-pentyI-8-(trifluoromethyl)-3,7-dihydro-1 H-purine-2,6-dione.
The amount of a HM74A modulator which is required to achieve the desired biological effect will, of course, depend on a number of factors, for example, the mode of administration and the precise clinical condition of the recipient. In general, the daily dose wil l be in the range of 0.1 mg - 1g/kg, typically 0.1 - 100mg/kg. An intravenous dose may, for example, be in the range of 0.01 mg to 0.1g/kg, typically 0.01 mg to 10mg/kg, which may conveniently be administered as an infusion of from 0.1 μg to 1mg, per minute. Infusion flu ids suitable for this purpose may contain, for example, from 0.01 μg to 0.1 mg, per millilitre. Unit doses may contain, for example, from 0.01μg to 1g of a HM74A modulator. Thus ampoules for injection may contain, for example, from 0.01 μg to 0.1g and orally adrninistrable unit dose formulations, such as tablets or capsules, may contain, for example, from 0.1 mg to 1g. No toxicological effects are indicated/expected when a compound of the invention is administered in the above mentioned dosage range.
A compound of the present invention may be employed as the compound per se in the treatment of a disease where under-activation of the HM74A receptor contributes to the disease or where activation of the receptor will be beneficial, an example of this is where a compound of the present invention is presented with an acceptable carrier in the form of a pharmaceutical formulation. The carrier must, of course, be acceptable in the sense of being compatible with the other ingredients of the formulation and must not be deleterious to the recipient. The carrier may be a solid or a liquid, or both, and may be formulated with the HM74A modulator as a unit-dose formulation, for example, a tablet, which may contain from 0.05% to 95% by weight of the HM74A modulator.
The formulations include those suitable for oral, rectal, topical, buccal (e.g. sub-lingual) and parenteral (e.g. subcutaneous, intramuscular, intradermal or intravenous) administration.
There is also provided according to the invention a process for preparation of such a pharmaceutical composition which comprises mixing the ingredients.
Formulations suitable for oral administration may be presented in discrete units, such as capsules, cachets, lozenges or tablets, each containing a predetermined amount of a HM74A modulator; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion. In general, the formulations are prepared by uniformly and intimately admixing the active HM74A modulator with a liquid or finely divided solid carrier, or both, and then, if necessary, shaping the product. For example, a tablet may be prepared by compressing or moulding a powder or granules of the HM74A modulator optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing, in a suitable machine, the compound in a free-flowing form, such as a powder or granules optionally mixed with a binder, lubricant, inert diluent and/or surface active/dispersing agent(s). Moulded tablets may be made by moulding, in a suitable machine, the powdered compound moistened with an inert liquid diluent.
Tablets and capsules for oral administration may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, mucilage of starch or polyvinyl pyrrolidone; fillers, for example, lactose, microcrystalline cel lulose, sugar, maize- starch, calcium phosphate or sorbitol; lubricants, for example, magnesium stearate, stearic acid, talc, polyethylene glycol or silica; disintegrants, for example, potato starch, croscarmellose sodium or sodium starch glycollate; or wetting agents such as sodium lauryl sulphate. The tablets may be coated according to methods well known in the art. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example, sorbitol syrup, methyl cellulose, glucose/sugar syrup, gelatin, hydroxymethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats; emulsifying agents, for example, lecithin, sorbitan mono-oleate or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters, propylene glycol or ethyl alcohol; or preservatives, for example, methyl or propyl β-hydroxybenzoates or sorbic acid. The preparations may also contain buffer salts, flavouring, colouring and/or sweetening agents (e.g. mannitol) as appropriate.
Formulations suitable for buccal (sub-lingual) administration include lozenges comprising a HM74A modulator in a flavoured base, usually sucrose and acacia or tragacanth, and pastilles comprising the HM74A modulator in an inert base such as gelatin and glycerin or sucrose and acacia.
Formulations for oral administration may be suitably formulated to give controlled/extended release of the active compound.
Formulations of the present invention suitable for parenteral administration conveniently comprise sterile aqueous preparations of an HM74A modulator, the formulation may be isotonic with the blood of the intended recipient. These preparations could be administered intravenously, although administration may also be effected by means of subcutaneous, intramuscular, or intradermal injection. Such preparations may conveniently be prepared by admixing the HM74A modulator with water and rendering the resulting solution sterile and isotonic with the blood. Injectable compositions according to the invention will generally contain from 0.1 to 5% w/w of the HM74A modulator.
Thus, formulations of the present invention suitable for parenteral administration comprising a compound accord ing to the invention may be formulated for parenteral administration by bolus injection or continuous infusion and may be presented in unit dose form, for instance as ampoules, vials, small volume infusions or pre-filled syringes, or in rnulti-dose containers with an added preservative. The compositions may take such forms as solutions, suspensions, or emulsions in aqueous or non-aqueous vehicles , and may contain formulatory agents such as anti-oxidants, buffers, antimicrobial agents and/or toxicity adjusting agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use. The dry solid presentation may be prepared by filling a sterile powder aseptically into individual sterile containers or by filling a sterile solution aseptically into each container and freeze-drying.
Formulations suitable for rectal administration may be presented as unit-dose suppositories. These may be prepared by admixing a HM74A modulator with one or more conventional solid carriers, for example, cocoa butter or glycerides and then shaping the resulting mixture. Formulations suitable for topical application to the skin may take the form of an ointment, cream, lotion, paste, gel, spray, aerosol, or oil. Carriers which may be used include vaseline, lanolin, polyethylene glycols, alcohols, and combinations of two or more thereof. The HM74A modulator is generally present at a concentration of from 0.1 to 15% w/w of the composition, for example, from 0.5 to 2%.
By topical administration as used herein, we include administration by insufflation and inhalation . Examples of various types of preparation for topical administration include ointments, creams, lotions, powders, pessaries, sprays, aerosols, capsules or cartridges for use in an inhaler or insufflator or drops (e.g. eye or nose drops).
Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents and/or solvents. Such bases may thus, for example, include water and/or an oil such as liquid paraffin or a vegetable oil such as arachis oil or castor oil or a solvent such as a polyethylene glycol. Thickening agents which may be used include soft paraffin, aluminium stearate, cetostearyl alcohol, polyethylene glycols, microcrystalline wax and beeswax.
Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilising agents, dispersing agents, suspending agents or thickening agents.
Powders for external application may be formed with the aid of any suitable powder base, for example, talc, lactose or starch. Drops may be formulated with an aqueous or non-aqueous base also comprising one or more dispersing agents, solubilising agents or suspending agents.
Spray compositions may be formulated, for example, as aqueous solutions or suspensions or as aerosols delivered from pressurised packs, with the use of a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, 1 ,1 ,1 ,2,3,3,3- heptafluoropropane, 1 ,1 ,1 ,2- tetrafluorethane, carbon dioxide or other suitable gas.
Capsules and cartridges for use in an inhaler or insufflator, of for example gelatin, may be formulated containing a powder mix of a compound of the invention and a suitable powder base such as lactose or starch.
The pharmaceutical compositions according to the invention may also be used in combination with other therapeutic agents, for example in combination with other classes of dyslipidaemic drugs (e.g. statins, fibrates, bile-acid binding resins or nicotinic acid).
The compounds of the instant invention may be used in combination with one or more other therapeutic agents for example in combination with other classes of dyslipidaemic drugs e.g. S-hydroxy-S-methylglutaryl-coenzyme A reductase inhibitors (statins) or fibrates or bile acid binding resins or nicotinic acid. The invention thus provides, in a further aspect, the use of such a combination in the treatment of diseases where under-activation of the HM74A receptor contributes to the disease or where activation of the receptor will be beneficial and the use of a compound of formula (I) or (II), or a pharmaceutically acceptable salt, solvate or pharmaceutically acceptable derivative thereof in the manufacture of a medicament for the combination therapy of disorders of lipid metabolism including dyslipidaemia or hyperlipoproteinaemia such as diabetic dyslipidaemia and mixed dyslipidaemia, heart failure, hypercholesteraemia, cardiovascular disease including atherosclerosis, arteriosclerosis, and hypertriglyceridaemia, type Il diabetes mellitus, type I diabetes, insulin resistance, hyperlipidaemia, anorexia nervosa or obesity.
When the compounds of the present invention are used in combination with other therapeutic agents, the compounds may be administered either sequentially or simultaneously by any convenient route.
The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical formulation and thus pharmaceutical formulations comprising a combination as defined above optimally together with a pharmaceutically acceptable carrier or excipient comprise a further aspect of the invention. The individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations.
When combined in the same formulation it will be appreciated that the two components must be stable and compatible with each other and the other components of the formulation and may be formulated for administration. When formulated separately they may be provided in any convenient formulation, conveniently in such a manner as are known for such compounds in the art.
When in combination with a second therapeutic agent active against the same disease, the dose of each component may differ from that when the compound is used alone. Appropriate doses will be readily appreciated by those skilled in the art.
The invention thus provides, in a further aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable derivative thereof together with another therapeutically active agent.
The combination referred to above may conveniently be presented for use in the form of a pharmaceutical formulation and thus pharmaceutical formulations comprising a combination as defined above together with a pharmaceutically acceptable diluent, excipient or carrier thereof represent a further aspect of the invention. For example, a pharmaceutical formulation comprising a compound or pharmaceutically acceptable derivative thereof and one or more pharmaceutically acceptable diluents, excipients or carriers. General purification and analytical methods:
The mass spectra (MS) were recorded on a Fisons VG Platform mass spectrometer using electrospray positive ionisation [(ES+ve to give MH+ and M(NH4)"1" molecular ions] or electrospray negative ionisation [(ES-ve to give (M-H)" molecular ion] modes.
1H NMR spectra were recorded using a Bruker DPX 400MHz spectrometer using tetramethylsilane as the external standard.
Biotage™ chromatography refers to purification carried out using equipment sold by Dyax Corporation (either the Flash 4Oi or Flash 15Oi) and cartridges pre-packed with KPSiI.
Mass directed autoprep refers to methods where the material was purified by high performance liquid chromatography on a HPLCABZ+ 5μm column (5cm x 10mm i.d.) with 0.1 % HCO2H in water and 95% MeCN, 5% water (0.5% HCO2H) utilising the following gradient elution conditions: 0-1.0 minutes 5%B, 1.0-8.0 minutes 5→30%B, 8.0-8.9 minutes 30%B, 8.9-9.0 minutes 30→95%B, 9.0-9.9 minutes 95%B, 9.9-10 minutes 95→0%B at a flow rate of 8ml minutes"1 (System 2). The Gilson 202-fraction collector was triggered by a VG Platform Mass Spectrometer on detecting the mass of interest.
Preparative h.p.l.c. refers to methods where the material was purified by high performance liquid chromatography on a HPLCABZ+ 5μm column (10cm x 21.2mm i.d.) with 0.1% HCO2H in water (A) and MeCN (0.5% HCO2H) (B) utilising the generic gradient elution conditions expressed as "x to y" gradient with a gradient system as follows: 0-1.45minut.es x%B, 1.45-20 minutes x→y%B, 20-24 minutes y→95%B, 24-30 minutes 95%B, 32-34 minutes 95→x%B at a flow rate of 8ml minutes"1 . The Gilson 233 fraction collector was triggered by UV (254nm).
SPE (solid phase extraction) refers to the use of cartridges sold by International Sorbent Technology Ltd.
Strata Phenyl SPE refers to the use of cartridges sold by Phenomenex. The compound was loaded onto a cartridge previously conditioned with MeCN and equilibrated with 5% MeCN in water. The compound was eluted with 0.1 % HCO2H in water and MeCN (0.5% HCO2H) in a suitable gradient on a Combiflash Optix 10. The compounds of the present invention and pharmaceutically derivatives thereof may be prepared by the methodology described hereinafter, constituting a further aspect of this invention.
Process A:
A process according to the invention for preparing a compound of formula (1) or formula (II) in which R1 is H or alkyl wherein R1 and R2 ma/ be the same or different, comprises:
Figure imgf000026_0001
i) Pyrimidinedione formation ii) Alkylation iii) Nitrosation iv) Reduction v) Xanthine formation
Process B:
A process according to the invention for prepari ng a compound of formula (I) or formula (II) in which R1 and R2 may be the same or different, comprises:
Figure imgf000026_0002
i) Selective alkylation at N3 ii) Alkylation at N1 iii) Formylation of C8 iv) Fluorination of carbonyl v) Palladium mediated deprotection
Where desired or necessary, as a final stage in any of the above synthetic processes, a resultant compound of formula (I) or (II) can be converted into a pharmaceutically acceptable salt form or vice versa or converting one salt form into another pharmaceutically acceptable salt form.
ABBREVIATIONS
AcOH Acetic acid br Broad (NMR)
GDI Carbonyldiimidazole d Doublet (NMR)
DBAD Di-f-butylazodicarboxylate
DCM Dichloromethane
DIPEA Diisopropylethylamine
DMSO Dimethylsulfoxide
DMF N,N-Dimethylformamide
EtOAc Ethyl acetate
EtOH Ethanol h Hour(s)
IPA lsopropyl alcohol m Multiplet (NMR)
MDAP Mass directed autoprep
MeCN Acetonitrile
MeOH Methanol min Minute(s)
NCS N-Chlorosuccinimide
PFPA pentafluoropropionic anhydride q Quartet (NMR) rt Room temperature
RT Retention time
S Singlet (NMR)
SPE Solid phase extraction cartridge t Triplet (NMR)
TFA Trifluoroacetic acid
TFAA Trifluoroacetic acid anhydride
THF Tetrahydrofuran
DMEM Dulbecco's Modified Eagle's Medium
HEPES 4-(2-Hydroxyethyl)piperazine-1 -ethanesulphonic acid
LiHMDS Lithium hexamethyldisilylamide The following non-limiting examples illustrate the present invention:
Synthetic Examples
Example 1 3-butyl-1-methyl-8-(trifluoromethvπ-3J-dihvdro-1/Y-p>urine-2,6-dione
A purple mix of 5,6-diamino-1-butyl-3-methyl-2,4(1/-/,3AY)-pyrimidinedione (European Journal of Medicinal Chemistry (1990), 25(8), 653-8)(290mg) and TFAA (6ml) was heated at reflux for 1 hour then concentrated in vacuo. The resulting residue was treated with 2N NaOH (aq)
(7ml) and the mixture heated at reflux for 30 minutes. Avfter cooling to ambient temperature, the mixture was acidified to ca. pH4 with 3M HCI(aq ). The precipitate was collected by filtration and washed with a solution of wateπEtOH (2:1) then water: EtOH (1 :1 ). The resulting beige solid was dried in vacuo (100mg, 25%). NMR; δH (400MHz, d6-DMSO) 0.90 (t, 3H,
J=7.5Hz), 1.25-1.36 (m, 2H), 1.59-1.69 (m, 2H)1 3.25 (s, 3H), 3.97 (t, 2H1 J=7Hz), NH not observed to δH 15; m/z 291.2[MH+].
Example 2
Figure imgf000028_0001
A purple mix of 5,6-diamino-1 ,3-dibutyl-2,4(1/-/,3H)-pyrimidinedione (Journal of Medicinal Chemistry (1991), 34(1), 466-9) (207mg) and TFAA (4ml) was heated at reflux for 1 hour then concentrated in vacuo. The resulting residue was treated with 2N NaOH(aq) (5ml) and the mixture heated at reflux for 30 minutes. After cooling to ambient temperature, the mixture was acidified to ca. pH4 with 3M HCI (aq). The precipitate was collected by filtration and purified by recrystallisation from a solution of wateπEtOH (2:1 ). The pale brown/ orange solid was dried under vacuum at 5O0C for 48 hours providing the title compound as a beige solid (35mg, 13%). δH (400MHz, d6-DMSO) 0.90 (t, 6H, J=7Hz), 1.26-1.34 (m, 4H), 1.48-1.68 (overlapping m, 4H), 3.89 (t, 2H, J=7Hz), 3.97 (t, 2H, J= 7Hz), NH not observed to δH15; m/z 333.2[MH+].
Example 3 3-butvl-1-methvl-8-(pentafluoroethvl)-3J-dihvdro-1/y--purine-2.6-dione
Figure imgf000029_0001
A purple mix of 5,6-diamino-1-butyl-3-methyl-2,4(1/-/,3H)-pyrimidinedione (European Journal of Medicinal Chemistry (1990), 25(8), 653-8) (300mg, 1.41 mmol) and pentafluoropropionic anhydride (PFPA) (6ml) was heated at 6O0C for 1 hour then concentrated in vacuo. The resulting residue was treated with 2N NaOH (aq) (7ml) and the mixture heated at 9O0C for 30 minutes. After cooling to room temperature the mixtu re was acidified to ca. pH4 with 3M
HCI(aq). The precipitate was collected by filtration, washed with water and dried under vacuum affording the title compound as a pale green/brown fluffy solid (163mg, 34%). δH
(400MHz, d6-DMSO) 0.89 (t, 3H, J=7.5Hz), 1.24-1.35 (m, 2H), 1.60-1.69 (m, 2H), 3.25 (s, 3H ), 3.98 (t, 2H, J=7Hz), NH not observed to δH 15; m/z: 358.4[MNH4 +].
Example 4 8-(difluoromethyl)-1-methyl-3-pentyl-3J-dihvdro-1^/-purine-2,6-dione
Figure imgf000029_0002
A solution of 8-(difluoromethyl)-1-methyl-3-pentyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine- 2,6-dione in anhydrous THF (3ml) and anhydrous DIVlSO (0.3ml) was degassed under a gentle vacuum and nitrogen introduced. This was repeated twice. Pd(PPh3)4 (74mg, O.064mmol) was added and the mixture degassed once more. Morpholine (374uL, 4.3mmol) was added and left to stir at rt for 4 hours. The mixture was partitioned between 2M HCI(aq) and EtOAc. The organic layer was separated, washed with brine, dried (MgSO4) and concentrated. The residue was taken up in MeOH and passed down and amino-propyl SPE column (5g), eluting with MeOH followed by 5% AcOH/MeOH. The product fraction was concentrated to afford the title compound as an off white solid (98mg, 80%). δH (400MHz, d6-DMSO) 0.85 (t, 3H, J=7Hz), 1.23-1.35 (m, 4H), 1.6 1-1.71 (m, 2H), 3.25 (s, 3H), 3.96 (t, 2H , J=7.5Hz), 7.12 (t, 1H1 J=53Hz), 14.59 (br. s, 1H); m/z 287.2[MH+].
8-(difluoromethyl)-1-methyl-3-pentyl-7-(2-propen-1-yl)-3,7-dihydro-1/-/-purine-2,6-dione
Figure imgf000029_0003
1-methyl-2,6-dioxo-3-pentyl-7-(2-propen-1-yl)-2,3,6,7-tetrahydro-1/-/-purine-8-carbaldehyde (133mg, 0.44mmol) was added to a pre-dried flask under nitrogen. Anhydrous DCM (3ml) was added followed by deoxofluor (161 ul, 0.87mrnol) and finally EtOH (1 drop, ca. 0.09mmol). The mixture was allowed to stir at rt. for 4 hours then partitioned between sat. NaHCO3(aq) and DCM. The organic layer was separated, washed with brine, dried (MgSO4) and concentrated to afford the title compound as a yellow oil (145mg). m/z 327.4[MH+].
1 -methyl-2,6-dioxo-3-pentyl-7-(2-propen-1 -yl)-2,3,6,7-tetrahydro-1 H-purine-8-carbaldehyde
Figure imgf000030_0001
To a solution of 1-methyl-3-pentyl-7-(2-propen-1-yl)-3,7'-dihydro-1H-purine-2,6-dione (1.05g, 3.8mmol) in THF (15ml) at -780C was added lithium hexamethyldisilylazide (1M solution in hexane, 4ml, 4mmol) over 10 min. The solution was stirred for 0.5h, then DMF (0.5ml, 6.5mmol) added, and the solution stirred for a further 0.5h at -780C after which it was allowed to warm to rt over 2h. The reaction was q uenched with 2N HCI solution then separated between EtOAc/brine. Chromatography over silica (gradient elution with DCM to 5:1 DCM/EtOAc) provided the title compound (0.35g, 3O%). m/z 305[MH+].
1 -methyl-3-pentyl-7-(2-propen-1 -yl)-3,7-dihydro-1 H-purine-2,6-dione
Figure imgf000030_0002
To a solution of 3-pentyl-7-(2-propen-1-yl)-3,7-d ihydro-1/-/-purine-2,6-dione (0.2Og, 0.76mmol) and methyl iodide (0.5ml, 4.9mmol) in DMF (5ml) was added potassium carbonate (0.4g, 2.9mmol) and the mixture heated at 5O0C for 3h, cooled and the mixture separated between EtOAc/brine. The organics were isolated, dried (MgSO4) and concentrated to yield the required product (0.21g, 100%). m/z 277[MH+].
3-pentyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione
Figure imgf000030_0003
To a solution of 7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (0.61 g, 3.2mmol) and pentyl iodide (0.64g, 3.2mmol) in DMF (7ml) was added sodium carbonate (0.6Og, 5.7mmol) and the mixture heated at 5O0C for 18h. After cooling and the mixture was separated between EtOAc/brine. The organics were isolated, dried (MgSO4) and concentrated to yield the crude product which was purified by chromatography over silica (gradient elution with DCM to 5:1 DCIWEtOAc) providing the title compound (0.47g, 56%). m/z 263[MH+].
Example 5
Figure imgf000031_0001
A mixture of 6-amino-5-nitroso-1-pentyl-2,4(1/-/,3H)-pyrimidinedione (500mg, 2.21 mmol), 10% Pd/C (100mg) and EtOH (100ml) was vigorously stirred under an atmosphere of hydrogen for 4 hours. The mixture was filtered through Celite and the filtrate concentrated in vacuo, giving 5,6-diamino-1-pentyl-2,4(1/-/,3H)-pyrimidinedione as a pale green solid (62mg) and as a mixture with an unknown product (2:1 ). Trifluoroacetic anhydride was added (5ml) and heated at reflux for 1 hour then concentrated in vacuo. 2M NaOH(aq) (15ml) was added to the crude residue and heated at 100°C for 3O minutes. After allowing to cool to rt. the mixture was acidified to ca. pH 5 with 2M HCI(aq). The resulting precipitate was collected by filtration and then taken up into MeOH with heating and then passed down an amino propyl column (5g), eluting with 2% AcOH/MeOH, 5% AcOH/MeOH, 10% AcOH/MeOH and 15% AcOH/MeOH. The product fraction was concentrated, giving the title compound as an off- white solid (52mg). NMR; (400MHz, d6-DMS0) δH 0.85 (t, 3H, J=7Hz), 1.22-1.31 (m, 4H), 1.61-1.66 (quintet, 2H, J=7Hz), 3.89 (t, 2H1 J=7Hz), 11.39 (s,1 H), 15.3 (br. s, 1 H). m/z 291.2 [MH+].
Figure imgf000031_0002
6-amino-5-nitroso-1 -pentyl-2,4(1 /-/,3H)-pyrimidined ione
Figure imgf000031_0003
A mixture of 6-amino-1-pentyl-2,4(1H,3H)-pyrimidinedione (3.Og, 15.2mmol), AcOH (6ml) and 6M HCI(aq) was cooled to O0C then treated dropwise with a solution of NaNO2 (1.2g, 16.7mmol) in water (4ml). The mixture was stirred for 45 minutes and water added (ca. 20OmI). The resulting purple solid was filtered, washed with water (ca. 200ml) and dried under high vacuum at 6O0C for 18 hours. Gave the title compound as a purple solid (2.08g, 60%). m/z 227.3 [MH+].
6-amino-1-pentyl-2,4(1/-/,3H)-pyrimidinedione
Figure imgf000032_0001
A mixture of 2-cyano-Λ/-[(pentylamino)carbonyl]acetamide (17.9g, 0.091 mol), EtOH (70ml) and water (40ml) was heated to 850C and then 10% MaOH(aq) (10ml) was added dropwise. The reaction was stirred for 1 hour before allowing to cool to rt. then diluted with water and acidified to ca. pH6 using 2M HCI(aq). The mixture was cooled (ice-bath) then filtered and the resulting solid washed with water then dried under vacuum at 4O0C. This gave the title compound as a white solid (11.Og, 61 %). m/z 198.2 [MH+].
2-cyano-Λ/-[(pentylamino)carbonyl]acetamide
H H
A mixture of pentyl urea (16.4g, 0.13mol), cyanoacetic acid (11.8g, 0.14mol) and acetic anhydride (30ml) was heated at 8O0C for 2 hours. The mixture was allowed to cool to rt. and stirred with Et2O (ca.100ml) for 1 hour. The mixture was cooled to O0C (ice-bath) and the solid collected by filtration giving the title compound as a white solid (17.9g, 72%). m/z 196.1 [MH+].
Example 5(b): 3-Pentyl-8-(trifluoromethyl)-3J-dihydro-1H-purine-2,6-dione (alternative method)
Figure imgf000032_0002
To a suspension of 6-amino-5-nitroso-1-pentyl-2,4(1 H,3H)-pyrimidinedione (0.227g, 1mmol) in anhydrous dichloromethane (5ml) was added trifluoroacetic anhydride (0.35ml, 2.5mmol). The resulting pale yellow suspension was stirred for 40min at room temperature and then the solution was concentrated in vacuo.
The residue was dissolved in dioxan (25ml) and added to 10% palladium on carbon (0.5g) and hydrogenated for 1 hr. The catalyst was filtered off, washed with dioxan and the filtrate concentrated in vacuo. Some starting material remained so the hydrogenation step was repeated. After a further 1.5h the catalyst was filtered off, washed with dioxan and the filtrate concentrated in vacuo.
The residue was dissolved in tetrahydrofuran (1 OmI) and 2N NaOH (5ml) was added. The solution was stirred at 6O0C for 2h. The crude reaction mixture was diluted with ethyl acetate and water and then acidified with 2N HCI. The organic phase was washed with brine, dried
(MgSO4) and concentrated in vacuo to give the title compound as an orange solid (140mg
48%).
LC/MS: m/z 291 [MH]+, RT 3.00min
1H NMR (DMSO-d6) δH 0.85 (3H, t, J = 7Hz), 1 .28 (4H, m), 1.64 (2H, m), 3.88 (2H, t, J = 7Hz), 1 1.22 (1 H, br s).
Example 6
Figure imgf000033_0001
A solution of 6-amino-1-pentyl-3-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-2,4(1 H,3H)- pyrimidinedione (970mg) in AcOH (10ml) was treated with 6M HCI(aq) (8ml) and then a solution of NaNO2 (247mg) in water (3ml) was added. After 15 minutes the mixture was partitioned between water and EtOAc. The organic layer was separated and the aqueous layer extracted with EtOAc (x7). The combined extracts were washed with brine, dried (MgSO4) and concentrated, giving a purple oil (446mg). A suspension of this oil in DCM (1 2ml) was treated with the dropwise addition of TFAA (12ml). After 10 minutes the mixture was concentrated giving a yellow/brown oil (798 mg). A portion of this material (150mg) was reacted under an atmosphere of hydrogen in THF (15ml) for 2.5 hours. The mixture was filtered through celite and washed through with THF. The filtrate was concentrated and treated once more with TFAA (5ml) and then concentrated in vacuo. 2M NaOH(aq) (4ml) was added to the residue and the mixture heated at 5O0C for 30 minutes. After cooling, the mixture was acidified to ca. pH 5 and the product extracted with EtOAc. The organic layer was separated, washed with brine, dried (MgSO4) and concentrated. The resulting residue was passed down an auotoprep hplc to furnish the title compound (32mg, 17%). NMR; (400MHz, d6-DMSO) δH 0.85 (t, 3H, J=7Hz), 1.23-1.36 (m, 4H), 1.62-1.70 (m, 2H), 3.52 (t, 2H, J=6.5Hz), 3.97 (m, 4H), 15.5 (br. S, 1 H). m/z 335.3 [MH+].
Figure imgf000034_0001
6-amino-1-pentyl-3-[2-(tetrahydro-2/-/-pyran-2-yloxy)ethyl]-2,4(1/-/,3/-0-pyrimidinedione
Figure imgf000034_0002
A mixture of 6-amino-1-pentyl-2,4(1 H,3H)-pyrirnidinedione (300mg, 1.5mmol), Cs2CO3 (595mg, 1.δmmol), 2-(2-bromoethoxy)tetrahydro-2H-pyran (276ul, 1.δmmol) and anhydrous DMF (5ml) was heated at 4O0C for 18 hours. The mixture was partitioned between water and EtOAc. The organic layer was separated, washed with brine, dried (MgSO4) and concentrated, giving a pale brown gum (198mg, 40%). m/z 326.3 [MH+].
Example 7(a): 3-Butyl-1-f3-r3-(phenylmethyl)-1 ,2,4-oxadiazol-5-vπpropyi}-8-
(trifluoromethyl)-3,7-dihydro-1 H-purine-2,6-dio ne
Example 7(b): 4-r3-Butyl-2,6-dioxo-8-(trifluoromethyl)-2,3,6,7-tetrahydro-1 H-purin-1- ylibutanoic acid
a) 3-Butyl-1 -{3-[3-(phenylmethyl)-1 ,2,4-oxad ϊazol-5-yl]propyl}-8-(trif luoromethyl)-3,7-
Figure imgf000034_0003
4-[3-Butyl-2,6-dioxo-8-(trifluoromethyl)-2,3,6,7-tetrahydro-1 H-purin-1 -yl]butanoic acid
(0.181g, O.δmmol) and CDI (0.089g, 0.55mmol) were dissolved in anhydrous dimethylformamide (6ml). After stirring the solution under nitrogen for 3h at room temperature, benzylamidoxime (0.083g, 0.55mmol) was added and the solution heated at 9O0C for 2Oh, then at 11 O0C for 4h. The reaction mixture was concentrated in vacuo to a yellow oil. This was purified on a Teledyne lsco CombiFlash® Companion® using a 4Og RediSep silica cartridge (gradient elution with chloroform/ethanol 0-15%). The appropriate fractions were evaporated in vacuo, than freeze dried from dioxan to give the title compound as a white lyophilate (142mg, 59%) LC/MS: m/z 477 [MH]+, RT 3.57 min
1H NMR (CDCI3) δH 0.98 (3H, t, J = 7Hz), 1.41 (2H , m), 1.76 (2H, m), 2.23 (2H, m), 2.95 (2H, 5 t, J = 8Hz), 4.00 (2H, s), 4.14 (2H, t, J = 8Hz), 4.22 (2H, t, J = 7Hz), 7.27 (5H, s)
b) 4-[3-Butyl-2,6-dioxo-8-(trifluoromethyl)-2,3,6,7-tetrahydro-1 H-purin-1-yl]butanoic acid
Figure imgf000035_0001
O
Anhydrous dichloromethane (50ml) was added to ethyl 4-(4-amino-3-butyl-5-nitroso-2,6- dioxo-3,6-dihydro-1 (2H)-pyrimidinyl)butanoate (3.26g,10mmol), followed by trifluoroacetic anhydride (3.53ml, 25mmol). The yellow solution was stirred at room temperature under an atmosphere of nitrogen for 15min and then concentrated in vacuo. The residue was 5 dissolved in dioxan (150ml) and added to 10% palladium on carbon (0.5g) and hydrogenated for 2h. The catalyst was filtered off, washed with dioxan and the filtrate concentrated in vacuo.
The residue was dissolved in tetrahydrofuran (100ml) and 2N NaOH (50ml) was added. The solution was stirred at 6O0C for 1.5h cooled and diluted with ethyl acetate (100ml) and water O (30ml). The organic phase was extracted with water (2x 30ml). The combined aqueous extracts were acidified to pH4 with 2N HCI. The resulting solid was filtered and washed with water to give the title compound as pale cream solid 2.17g (60%). LC/MS: m/z 363 [MH]+, RT 2.84min 1H NMR (DMSO-d6) δH 0.90 (3H, t, J = 7Hz), 1.31 (2H, m), 1.64 (2H, m), 1.80 (2H, m), 2.24 5 (2H, t, J = 7Hz), 3.89 (2H, t, J = 7Hz), 3.95 (4H, m), 12.01 , (1 H, br s), 15.36, (1 H, br s)
l-5-nitroso-2,6-dioxo-3,6-dihydro-1 (2/-/)-pyrimidinyl)butanoate
Figure imgf000035_0002
Ethyl 4-(4-amino-3-butyl-2,6-dioxo-3,6-dihydro-1 (2H)-pyrimidinyl)butanoate (8.5g, 29.8mmol) O was dissolved in a mixture of glacial acetic acid (45ml) and 6M hydrochloric acid (24ml). The solution was cooled to -10C and sodium nitrite (2.26g, 32.7mmol) in water (20ml) was added dropwise. After the addition was complete the ice bath was removed and the purple solution stirred for 1h. The solution was diluted with water (140ml) and the product, which separated out after a few minutes, was filtered, washed with water (total 350ml) and dried in vacuo at 5 500C to give the title compound as a bright pink solid (6.61 g). On standing a further crop was isolated (0.53g), then the mother liquors were basified to pH6 with 2N sodium hydroxide and extracted into ethyl acetate (2x 25OmL). The combined extracts were concentrated in vacuo to give a third crop of the title compound (1.23g). Total yield 8.37g 86% LC/MS: m/z 327 [MH]+, RT 2.58 min
tyl-2,6-dioxo-3,6-dihydro-1 (2H )-pyrimidinyl)butanoate
Figure imgf000036_0001
6-Amino-1-butyl-2,4(1/-/,3/-/)-pyrimidinedione (5.9g, 32.2mmol) and caesium carbonate O (11.54g, 35.4mmol) were added to anhydrous dimethylformamide under a nitrogen atmosphere. Ethyl 4-bromobutyrate (5.07ml, 35.4mmol) was added and the mixture stirred at room temperature for 22h. The reaction mixture was diluted with ethyl acetate (350ml) and washed with saturated sodium chloride solution (2 x 50ml). The combined aqueous phases were back extracted with ethyl acetate. The combined organic phases were washed with 5 saturated sodium chloride solution, dried (MgSO4) and concentrated in vacuo. The crude product was purified on a Teledyne lsco CombiFlash® Companion® using a 8Og RediSep silica cartridge (gradient elution using chloroform/ethanol 0-40%). The appropriate fractions were evaporated in vacuo to give the title compound as a yellow oil which crystallised on standing (5.36g, 56%) O LC/MS: m/z 298 [MH]+, RT 2.49 min
Example 8 (a): 3-Butyl-1-r4-f3-phenyl-1,2,4-oxadiazol-5-yl)butvn-8-(trifluoromethyl)-3,7- dihvdro-1 H-purine-2,6-dione 5 Example 8 (b): 5-r3-butyl-2.6-dioxo-8-ftrifluoroιnethyl)-2,3,6,7-tetrahvdro-1H-purin-1- vHpentanoic acid a) 3-Butyl-1 -[4-(3-phenyl-1 ,2,4-oxadiazol-5-yl)butyl]-8-(trifluoromethyl)-3,7-dihydro-1 H- purine-2,6-dione
Figure imgf000036_0002
A mixture of methyl 5-[3-butyl-2,6-dioxo-8-(trifluoromethyl)-2,3,6,7-tetrahydro-1/-/-purin-1- yl]pentanoate (0.156g, 0.4mmol), benzamidoxime (60rng, 0.44mmol), 21 % solution of NaOEt in EtOH (0.22ml, O.δmmol) and anhydrous EtOH (1 ml) was heated in the microwave at 14O0C for 10min. The mixture was diluted with EtOAc (30ml) and washed with water (20ml), 5 2N HCI (20ml) and brine (5ml). The organic layer was dried (Na2SO4) and concentrated in vacuo to a yellow oil and then freeze dried from dioxan to give the title compoundas a cream lyophilate (95mg, 50%) LC/MS: m/z 476 [MH]+, RT 3.73 min
1H NMR (CDCI3) δH 0.97 (3H, t, J = 7Hz), 1.41 (2H, m), 1.77 (2H, m), 1.87 (2H, m), 1.97 (2H, m), 3.02 (2H, t, J = 7Hz), 4.17 (4H, m), 7.47 (3H, rn), 8.04 (2H, m)
b) 5-[3-butyl-2,6-dioxo-8-(trifluoromethyl)-2,3,6,7-tetrahydro-1H-purin-1-yl]pentanoic acid
Figure imgf000037_0001
and methyl 5-[3-butyl-2,6-dioxo-8-(trifluoromethyl)-2,3,6,7-tetrahydro-1H-purin-1- yljpentanoate
Figure imgf000037_0002
Anhydrous dichloromethane (70ml) was added to methyl 4-(4-amino-3-butyl-5-nitroso-2,6- dioxo-3,6-dihydro-1(2H)-pyrimidinyl)pentanoate (5.06g,15.5mmol), followed by trifluoroacetic anhydride (22ml, 10equiv.). The yellow solution was stirred at room temperature under an atmosphere of nitrogen for 25min and then concentrated in vacuo. The residue was dissolved in dioxan (250ml) and added to 10% palladium on carbon (0.85g ) and hydrogenated for 2.25h. The catalyst was filtered off, washed with dioxan and the filtrate concentrated in vacuo. The residue was dissolved in tetrahydrofuran (100ml) and 2N NaOH (15.5ml) was added. The solution was stirred at room temperature for 3.5h. A further 8ml of 2N NaOH was added and the reaction mixture heated at 6O0C for 1.5h.The reaction mixture was cooled and concentrated in vacuo to a small volume and partitioned between ethyl acetate and water. The organic phase was washed with water (2x) and brine. The combined aqueous extracts were acidified to with 2N HCI, extracted into ethyl acetate (5x40ml) and then back extracted with saturated NaHCO3 (3x30ml) and brine (30ml). The combined aqueous phases were acidified to pH 4.5 with 2N HCI and resulting solid was filtered and washed with water to give 5-[3-butyl-2,6-dioxo-8-(trifluoromethyl)-2, 3,6,7- tetrahydro-1/-/-purin-1-yl]pentanoic acid as a crearn solid 2.19g (38%).
The organic phase was dried over MgSO4 and concentrated in vacuo to a yellow gum which solidified on standing to give methyl 5-[3-butyl-2,6-dioxo-8-(trifluoromethyl)-2, 3,6,7- tetrahydro-1/V-purin-1-yl]pentanoate as a peach coloured solid (0.9g, 15%) Data for 5-[3-butyl-2,6-dioxo-8-(tnfluorornethyl)-2,3,6,7-tetrahydro-1 /-/-purin-1 -yljpentanoic acid:
LC/MS: m/z 377 [MH]+, RT 2.91 min
1H NMR (DMSO-d6) δH 0.90 (3H, t, J = 7Hz), 1.30 (2H, t, J = 7Hz), 1.45-1.68 (6H, m), 2.24 5 (2H, t, J = 7Hz), 3.89 (2H, t, J = 7Hz), 3.97 (2H, t, J = 7Hz), 12.00 (1 H, br s)
Data for methyl 5-[3-butyl-2,6-dioxo-8-(trifluoromethyl)-2,3,6,7-tetrahydro-1H-purin-1- yl]pentanoate:
LC/MS: m/z 391 [MH]+, RT 3.15 min. 0 1H NMR (CDCI3) δH 0.95 (3H, t, J = 7Hz), 1.27 (2H, t, J = 7Hz), 1.38 (2H, m) 1.75 (2H, m), 2.06 (2H1 s), 2.36 (2H, t, J = 7Hz), 3.62 (3H , s), 4.03 (2H, br), 4.14 (2H, m)
c) Methyl 4-(4-amino-3-butyl-5-nitroso-2,6-dioxo-3,6-dihydro-1 (2H)-pyrimidinyl)pentanoate
Figure imgf000038_0001
5 Prepared in similar fashion to ethyl 4-(4-am ino-3-butyl-5-nitroso-2,6-dioxo-3,6-dihydro-1 (2H)- pyrimidinyl)butanoate LC/MS: m/z 327 [MH]+, RT 2.54 min
butyl-2,6-dioxo-3,6-dihydro-1 (2H)-pyrimidinyl)pentanoate
Figure imgf000038_0002
Prepared in the same way as ethyl 4-(4-amino-3-butyl-2,6-dioxo-3,6-dihydro-1 (2H)- pyrimidinyl)butanoate
LC/MS: m/z 298 [MH]+, RT 2.47 min
5 Example 9; 3-Butyl-1-(4-r3-(2-fluorophenyl)-1,2.4-oxadiazol-5-yl1butyl)-8-
(trifluoromethyl)-3,7-dihydro-1H-purine-2,6-dione
Figure imgf000038_0003
5-[3-butyl-2,6-dioxo-8-(trifluoromethyl)-2,3,6 ,7-tetrahydro-1 /-/-purin-1 -yljpentanoic acid O (0.301g, O.δmmol) and CDI (0.153g, 0.94mmol) were dissolved in anhydrous dimethylformamide (10ml). After stirring the solution under nitrogen for 4h at room temperature, 2-fluorobenzamidoxime (0.135g, O.δδmmol) was added and the solution heated at 850C for 19h. The reaction mixture was concentrated in vacuo and purified on a 1Og aminopropyl SPE (1Og) eluting with methanol. Evaporation of the methanol eluant gave an oil that was purified further by MDAP. The relevant fractions were combined and concentrated in vacuo and the residue was freeze dried from dioxan to give the title compound (0.037g, 9%) as a white lyophilate.LC/MS: m/z 495 [MH]+, RT 3.68 min 1H NMR (CDCI3) δH0.97 (3H, t, J = 7Hz), 1.40 (2H, m), 1.77 (2H, m), 1.88 (2H, m), 1.97 (2H, m),3.05 (2H, t, J = 7Hz), 4.17 (2H, q, J = 7Hz), 7.19-7.29 (2H, m) 7.45-7.48 (1 H, m) 8.02, (1H, dt, J = 8 and 2Hz)
Example 10; 3-ButvM-l4-r3-(4-fluorophenylM.2.4-oxadiazol-5-vπbutyl"}-8-
(trifluoromethyl)-3J-dihvdro-1 H-purine-2,6-dione
Figure imgf000039_0001
5-[3-butyl-2,6-dioxo-8-(trifluoromethyl)-2,3,6,7-tetrahydro-1H-purin-1-yl]pentanoic acid
(0.301g, O.δmmol) and CDI (0.153g, 0.94mmol) were dissolved in anhydrous dimethylformamide (10ml). After stirring the solution under nitrogen for 4h at room temperature 4-fluorobenzamido>cime (0.135g, 0.88mmol) was added and the solution heated at 850C for 22h. The reaction m ixture was concentrated in vacuo, taken up in ethyl acetate and washed with brine (2x20ml) and 0.1 N HCI. The organic phase was dried (MgSO4) and concentrated in vacuo to give the required product as a pale yellow oil which crystallised on standing. This material was freeze dried from dioxan to give the title compound as a cream lyophilate (0.225g, 57%). LC/MS: m/z 495 [MH]+, RT 3.77 rnin
1H NMR (CDCI3) δH 0.97 (3H, t, J = 7Hz), 1.27 (2H, m), 1.77 (2H1 m), 1.87 (2H, m,), 1 .97 (2H, m), 3.02 (2H, t, J = 7Hz), 4.17 (4H, m,), 7.15 (2H, m, J = 9Hz), 8.04 (2H, m).
Example 11 : 3-Butyl-1 -{4-f3-(2-pyridinyl)-1 ,2,4-oxadiazol-5-yllbutyl}-8-(trifluorometrt vD- 3.7-dihvdro-1 H-purine-2.6-dione
Figure imgf000039_0002
5-[3-butyl-2,6-dioxo-δ-(trifluoromethyl)-2,3,6,7-tetrahydro-1/-/-purin-1-yl]pentanoic acid (0.15g, 0.4mmol) and CDI (0.078g, 0.48mmol) were dissolved in anhydrous dimethylformamide (5ml). After stirring the solution under nitrogen for 1.5h at room temperature 2-pyridylamidoxime (0.06g, 0.44mmol) was added and the solution heated at 9O0C for 16.5h. The reaction mixture was concentrated in vacuo and purified by MDAP. The relevant fractions were evaporated to give the title compound as a tan solid (0.017g, 9^0). LC/MS: m/z 478 [MH]+, RT 3.28 min
1H NMR (CDCI3) δH 0.95 (3H, t, J = 7Hz), 1.39 (2H, m, J = 7Hz), 1.75 (2H, m), 1.84 (2H, m), 1.96 (2H, m), 3.07 (2H, t, J = 7Hz), 4.14 (4H, m), 7.41 (1 H, m) 7.84 (1 H, dt, J = 8 and 2Hz), 8.10 (1 H, d, J = 8Hz), 8.75 (1 H, d, J = 4Hz)
Example 12: 3-Butyl-8-(trifluoromethyl)-1-(3-f3-r(2,4,6-trifluorophenyl)methvn -1.2.4- oxadiazol-5-yl)propyl)-3,7-dihvdro-1 H-purine-2.6-dione
Figure imgf000040_0001
4-[3-Butyl-2,6-dioxo-8-(trifluoromethyl)-2,3,6,7-tetrahydro-1 H-purin-1-yl]butanoic acid (0.181g, O.δmmol) and CDI (0.089g, 0.55mmol) were dissolved in anhydrous dimethylformamide (6ml). After stirring the solution under nitrogen for 3h at room temperature. 2,4,6-trifluorobenzylamidoxime (0.112g, 0.55mmol) was added and the solution heated at 9O0C for 2Oh, then at 11O0C for 6h. The reaction mixture was concentrated in vacuo to a yellow oil. This was purified on a Teledyne lsco CombiFlash® Companion® using a 35g RediSep silica cartridge (gradient elution chloroform/ethanol 0-15%). The appropriate fractions were evaporated in vacuo to give after freeze drying from dioxan the title compound as a white solid (0.122g, 46%). LC/MS: m/z 531 [MH]+, RT 3.61 min
1H NMR (CDCI3) δH 0.97 (3H, t, J = 7Hz), 1.41 (2H, m), 1.76 (2H, m), 2.23 (2H, m), 2.95 (2H, t, J = 8Hz), 4.00 (2H, s), 4.14 (2H, t, J = 8Hz), 4.22 (2H, t, J = 7Hz), 6.67 (2H, t, J = 7H z).
Example 13: 1-Methyl-3-pentyl-8-(trifluoromethyl)-3J-dihydro-1H-purine»2.6-diorie
H-purine-2,6-dione
Figure imgf000040_0002
A solution of 6-amino-3-methyl-5-nitroso-1-pentyl-2,4(1 H,3H)-pyrimidinedione (0.042g, 0.18mmol) in anhydrous DCM (2ml) was treated with trifluoroacetic anhydride (1ml) and left to stir at rt. for 10 mins. The solution was concentrated in vacuo and the residue taken up into 1 ,4-dioxane (15ml) and reacted with 10% Pd/C (70mg) and trifluoroacetic anhydride (O.1ml) under an atmosphere of hydrogen for 6h. The mixture was filtered through celite and the filtrate concentrated, givi ng a red oil. THF (2ml) was added followed by 2M NaOH(aq) solution. The mixture was heated to 5O0C for 10 mins. After cooling, the mixture was partitioned between 2M HCI(aq) and EtOAc. The organic layer was separated, washed with brine, dried (MgSO4) and concentrated. The title product was purified by MDAP to give the title compound as a white solid (10mg, 1 9%).
LC/MS m/z 305 [MH+], RT 3.2mins.
1 H NMR; (d6-DMSO) δH O.92 (3H, t, J =7 Hz), 1.38 (4H, m), 1.80 (2H, m), 3.51 (3H, s), 4.17
(2H, t, J = 8Hz), 13.5 (1 H, br s). methyl-5-nitroso-1-pentyl-2,4(1 H,3H)-pyrimidinedione
Figure imgf000041_0001
Prepared in similar fashion to ethyl 4-(4-amino-3-butyl-5-nitroso-2,6-dioxo-3,6-dihydro-1 (2H)- pyrimidinyl)butanoate.
All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth.

Claims

Claims
1. At least one chemical entity selected from compounds of formula (I)
Figure imgf000042_0001
(I) and pharmaceutically acceptable derivatives thereof, wherein
R1 represents a group selected from: hydrogen, C1-10 alkyl, C2-10 alkenyl , C2-io alkynyl, and -(alk)m-X-(alk)n-Y,
Wherein X represents A, A1 , A2 or a direct link;
A represents a group selected from: cycloalkylene, cycloalkenylene, aryl, heteroaryl, heterocyclyl, -CH2-OC(O)-;
A1 represents a group selected from:
-CH2-0-(CH2)qaryl-O-, -CH2-O-(CH2)WN(R5)C(O)O-, -CH2-N(R5)C(O)O-, -CH2-N(R5)C(O)-, -CH2-(0)p-(CH2)qC(O)NR5-, -CH2-N(R5)C(O)N(R5)-, -CH2-C(0)N((CH2)WOH)-, -CH2-NR5-S(O)2-, CH2-S(O)2NR5-, -CH2-C(O)O-, -0-, -NR5-, -S-;
A2 represents: -CH(OH)-;
When X is A, A1 or A2, Y represents a group selected from: heteroaryl, heterocyclyl, aryl, cycloalkyl, cycloalkenyl, -O(CH2)n-aryl, -C(O)O-aryl, -CH(aryl)2,
-CH(heteroaryl)2, -C1 -6 haloalkyl, -C(O)R4' , -NR5R7, -C(O)NR5R7, -NR5C(O)R7, -NR5C(O)OR7,
-C(O)(CH2)qOR4, halogen, cyano, -N(R5)C(O)OR7, -OC(O)NR5R6, -NR5C(O)R8, -OR5,
-OC(O)R4;
When X is A1 and Y is selected from:
-O(CH2)n-aryl, -O-heteroaryl, -OR5, -OC(O)R5, -NH-aryl, -OC(O)NR5R6, n is an integer selected from 2, 3, 4 and 5;
When X is A1 and Y is -CF3, or when X is A2, n is an integer selected from 1 , 2, 3, 4 and 5;
When X is a direct link, Y represents a group selected from: -C(O)(CH2)qOR5, -C(O)-aryl, -C(O)-heteroaryl, -C(O)-heterocyclyl, -heteroaryl, -heterocyclyl, -aryl, -cycloalkyl, -cycloalkenyl, -C1-6 haloalkyl, -halo, -cyano, 3 or 4 ring fused system, -CH(aryl)2> -CH(heteroaryl)2, -OR5, -NR5R7, -NCOOR8, -(O)PC(O)NR5R6, -NR5C(O)R8, -OR5, -(O)PC(O)R4;
When Y incorporates a ring, that ring may be optionally substituted by one or more of: C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, halogen, -NH2, (CH2)q-NR5R7,
-(CH2)q-(O)p-(CH2)q-N(R5)C(O)OR8, -(CH2)q-N(R5)C(O)R8, -(CH2)q-(O)p-(CH2)q-C(O)NR5R6, -(CH2)q-N(R5)C(O)N(R5)R6, -(CH2)q-C(O)N((CH2)mOH)R5, -(CH2)q-N(R5)-S(O)2R8, -CH2-S(O)2N(R5)R6, -C1-6 haloalkyl, -OCF3, -OCH(F)2, -OCH2 F, -COOR5, -OR5, -(R8)pCN, -S(O2)R9, -(CH2)nheteroaryl, -(CH2)nheterocycyl, -(CH2)ncycloalkyl, -(CH2)ncycloalkenyl, -(CH2)πaryl;
R2 is selected from: hydrogen; or C1--I0 alkyl, C2--I0 alkenyl, C2-10 alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, and heteroaryl, each of which may be optionally substituted by one or more of: C1-I0 alkyl, C2-io alkenyl, C2-10 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-6 haloalkyl, halogen, -CN, -OR4, -(CH2)nCOR4, -C(O)OR4, -OCOR4, -(CH2)nNR5R6, -(NH)PCONR5R6, -OCONR5R7, and -NHC(O)OR7;
R3 is selected from: halogenated C1-6 alkyl;
R4 is selected from: hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -(CH2)n cycloalkyl, -(CH2)n cycloalkenyl, -(CH2)n heterocyclyl, -(CH2)n aryl, and -(CH2)n heteroaryl; R5 and R6 are selected from: hydrogen and C1-4 alkyl;
R7 is selected from: hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -(CH2)t cycloalkyl, -(CH2)n cycloalkenyl, -(CH2)t heterocyclyl, -(CH2)taryl, and -(CH2)t heteroaryl;
R8 is selected from C1-4 alkyl;
R9 is selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -(CH2)n cycloalkyl, -(CH2)ncycloalkenyl, -(CH2)nheterocyclyl, -(CH2)n aryl, and -(CH2)nheteroaryl, CN; rn represents an integer selected from: 0, 1 , 2, 3, 4 and 5; n represents an integer selected from: 0, 1 , 2, 3, 4 and 5;
p represents an integer selected from: O and 1 ;
q represents an integer selected from: 0, 1 and 2; t represents an integer selected from: 1 and 2; w represents an integer selected from: 2, 3 and 4;
with the proviso that: i) when R1 represents hydrogen or C1-3 alky], R2 is different to R1; ii) when R1 represents ethyl and R3 represents CF3, R2 is other than CH2-CH=CH2; and iii) when R1 represents Methyl and R3 represents CF3, R2 is other than i-butyl.
2. At least one chemical entity according to claim 1 wherein R1 is selected from: hydrogen C1-10 alky], and -(alk)m-X-(alk)n-Y.
3. At least one chemical entity according to claim 1 or 2 wherein X represents A or a direct link.
4. At least one chemical entity according to claim 1 or 2 wherein R1 is selected from: hydrogen and C1-6 alkyl.
5. At least one chemical entity accordi ng to any preceding claim wherein R2 is selected from: C4-6 alkyl.
6. At least one chemical entity accordi ng to any preceding claim wherein R3 is selected from: fluorinated C1-6 alkyl.
7. At least one chemical entity according to any preceding claim wherein R3 represents C F3.
8. At least one chemical entity according to any preceding claim for use in human or veterinary medicine.
9. At least one chemical entity according to any one of claims 1-7, for use in the treatment of disorders of lipid metabolism including dyslipidaemia and hyperlipoproteinaemia and/or of inflammatory diseases or conditions.
10. At least one chemical entity according to any one of claims 1-7, for use in the treatment of diabetic dyslipidaemia, mixed dyslipidaemia, heart failure, hypercholesteraernia, cardiovascular disease including atherosclerosis, arteriosclerosis, and hypertriglyceridaerriia, type Il diabetes mellitus, type I diabetes, insulin resistance, hyperlipidaemia, anorexia nervosa, obesity, coronary artery disease, thrombosis, angina, chronic renal fail ure, peripheral vascular disease or stroke.
11. At least one chemical entity selected from compounds of formula (I)
Figure imgf000045_0001
(D and pharmaceutically acceptable derivatives thereof, wherein
R1 represents a group selected from: hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-io alkynyl, and -(alk)m-X-(alk)n-Y,
Wherein X represents A, A1 , A2 or a direct link;
A represents a group selected from: cycloalkylene, cycloalkenylene, aryl, heteroaryl, heterocyclyl, -CH2-OC(O)-;
A1 represents a group selected from:
-CH2-O-(CH2)CaIyI-O-, -CH2-O-(CH2)WN(R5)C(O)O-, -CH2-N(R5)C(O)O-, -CH2-N(R5)C(O)-,
-CH2-(O)p-(CH2)qC(O)NR5-, -CH2-N(R5)C(O)N(R5)-, -CH2-C(O)N((CH2)WOH)-, -CH2-NR5-S(0)2-, CH2-S(O)2NR5-, -CH2-C(O)O-, -0-, -NR5-, -S-;
A2 represents: -CH(OH)-;
When X is A, A1 or A2, Y represents a group selected from: heteroaryl, heterocyclyl, aryl, cycloalkyl, cycloalkenyl, -O(CH2)n-aryl, -C(O)O-aryi, -CH(aryl)2, -CH(heteroaryl)2, -C1-6 haloalkyl, -C(O)R4' , -NR5R7, -C(O)NR5R7, -NR5C(O)R7, -MR5C(O)OR7, -C(O)(CH2)qOR4, halogen, cyano, -N(R5)C(O)OR7, -OC(O)NR5R6, -NR5C(O)R8, -OR5, -OC(O)R4;
When X is A1 and Y is selected from: -O(CH2)n-aryl, -O-heteroaryl, -OR5, -OC(O)R5, -NH-aryl, -OC(O)NR5R6, n is an integer selected from 2, 3, 4 and 5;
When X is A1 and Y is -CF3, or when X is A2, n is an integer selected from 1, 2, 3, 4 and 5;
When X is a direct link, Y represents a group selected from:
-C(O)(CH2)qOR5, -C(O)-aryl, -C(O)-heteroaryl, -C(O)-heterocyclyl, -heteroaryl, -heterocyclyl, -aryl, -cycloalkyl, -cycloalkenyl, -C1-6 haloalkyl, -halo, -cyano, 3 or 4 ring fused system, -CH(aryl)2, -CH(heteroaryl)2, -OR5, -NR5R7, -NCOOR8, -(O)PC(O)NR5R6, -NR5C(O)R8, -OR5, -(O)PC(O)R4;
When Y incorporates a ring, that ring may be optionally substituted by one or more of: C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, halogen, -NH2, (CH2)q-NR5R7,
-(CH2)q-(0)p-(CH2)q-N(R5)C(O)OR8 ) -(CH2)q-N(R5)C(O)R8, -(CH2)q-(O)p-(CH2)q-C(O)NR5R6, -(CH2)q-N(R5)C(O)N(R5)R6, -(CH2)q-C(O)N((CH2)mOH)R5, -(CH2)q-N(R5)-S(O)2R8, -CH2- S(O)2N(R5)R6, -C1-6 haloalkyl, -OCF3, -OCH(F)2, -OCH2F, -COOR5, -OR5, -(R8)PCN, -S(O )2R9, -(CH2)nheteroaryl, -(CH2)nheterocycyl, -(CH2)ncycloalkyl, -(CH2)ncycloalkenyl, -(CH2)naιγl;
R2 is selected from: hydrogen; or C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, and heteroaryl, each of which may be optionally substituted by one or more of: C1-10 alkyl, C2--I0 alkenyl, C2-10 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, d_6 haloalkyl, halogen, -CN, -OR4, -(CH2)nCOR4, -C(O)OR4, -OCOR4, -(CH2)nNR5R6, -(NH)pCONR5R6, -OCONR5R7, and -NHC(O)OR7;
R3 is selected from: halogenated C1-6 alkyl;
R4 is selected from: hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -(CH2)n cycloalkyl, -(CH2)n cycloalkenyl, -(CH2)n heterocyclyl, -(CH2)n aryl, and -(CH2)n heteroaryl;
R5 and R6 are selected from: hydrogen and Ci-4 alkyl;
R7 is selected from: hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -(CH2)t cycloalkyl, -(CH2)n cycloalkenyl, -(CH2)t heterocyclyl, -(CH2)taryl, and -(CH2)t heteroaryl;
R8 is selected from C1-4 alkyl;
R9 is selected from Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -(CH2)n cycloalkyl, -(CH2)ncycloalkenyl, -(CH2)nheterocyclyl, -(CH2)n aryl, and -(CH2)nheteroaryl, CN; m represents an integer selected from: O, 1 , 2, 3, 4 and 5; n represents an integer selected from: O, 1 , 2, 3, 4 and 5;
p represents an integer selected from: O and 1 ;
q represents an integer selected from: O, 1 and 2; t represents an integer selected from: 1 and 2; w represents an integer selected from: 2, 3 and 4
for use in the manufacture of a medicament for treating diabetic dyslipidaemia, m ixed dyslipidaemia, heart failure, hypercholesteraemia, cardiovascular disease including atherosclerosis, arteriosclerosis, and hypertriglyceridaemia, type Il diabetes mellitus, ty^pe I diabetes, insulin resistance, hyperlipidaemia, anorexia nervosa, obesity, coronary artery disease, thrombosis, angina, chronic renal failure or stroke.
12. A method for the treatment of a human or animal subject having a condition where under-activation of the HM74A receptor contributes to the condition or where activation of the receptor will be beneficial, which method comprises administering to said human or animal subject an effective amount of at least one chemical entity selected from: compounds of formula (II)
Figure imgf000047_0001
(I I)
and pharmaceutically acceptable derivatives thereof, wherein
R1 represents a group selected from: hydrogen, Ci--I0 alkyl, C2-io alkenyl, C2-i0 alkynyl, and -(alk)m-X-(alk)n-Y,
Wherein X represents A, A1 , A2 or a direct link;
A represents a group selected from: cycloalkylene, cycloalkenylene, aryl, heteroaryl, heterocyclyl, -CH2-OC(O)-;
A1 represents a group selected from:
-CH2-O-(CH2)qaryl-O-, -CH2-0-(CH2)wN(R5)C(0)0-, -CH2-N(R5)C(O)O-, -CH2-N(R5)C(O)-, -CH2-(O)p-(CH2)qC(O)NR5-, -CH2-N(R5)C(O)N( R5)-, -CH2-C(O)N((CH2)WOH)-, -CH2-N R5-S(O)2-, CH2-S(O)2NR5-, -CH2-C(O)O-, -O-, -NR5-, -S-;
A2 represents: -CH(OH)-;
When X is A, A1 or A2, Y represents a group selected from: heteroaryl, heterocyclyl, aryl, cycloalkyl, cycloalkenyl, -O(CH2)n-aryl, -C(O)O-aryl, -CH(aryl)2, -CH(heteroaryl)2, -C1-6 haloalkyl, -C(O)R4' , -NR5R7, -C(O)NR5R7, -NR5C(O)R7, -NR5C(O)OR7, -C(O)(CH2)qOR4, halogen, cyano, -N(R5)C(0)OR7, -OC(O)NR5R6, -NR5C(O)R8, -OR5, -OC(O)R4;
When X is A1 and Y is selected from: -O(CH2)n-aryl, -O-heteroaryl, -OR5, -OC(O)R5, -NH-aryl, -OC(O)NR5R6, n is an integer selected from 2, 3, 4 and 5; When X is A1 and Y is -CF3, or when X is A2, n is an integer selected from 1 , 2, 3, 4 and 5;
When X is a direct link, Y represents a group selected from:
-C(O)(CH2)qOR5, -C(O)-aryl, -C(O)-heteraaryl, -C(O)-heterocyclyl, -heteroaryl, -heterocyclyl, -aryl, -cycloalkyl, -cycloalkenyl, -C1-6 haloalkyl, -halo, -cyano, 3 or 4 ring fused system,
-CH(aryl)2, -CH(heteroaryl)2, -OR5, -NR5R7, -NCOOR8, -(O)PC(O)NR5R6, -NR5C(O)R8, -OR5, -(O)PC(O)R4;
When Y incorporates a ring, that ring may be optionally substituted by one or more of: C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl , halogen, -NH2, (CH2)q-NR5R7,
-(CH2)q-(O)p-(CH2)q-N(R5)C(O)OR8, -(CH2)q-N(R5)C(O)R8, -(CH2)q-(O)p-(CH2)q-C(O)NR5R6, -(CH2)q-N(R5)C(O)N(R5)R6, -(CH2)q-C(O)N((CH2)mOH)R5, -(CH2)q-N(R5)-S(O)2R8, -CH2- S(O)2N(R5)R6, -C1-6 haloalkyl, -OCF3, -OCH(F)2, -OCH2F, -COOR5, -OR5, -(R8)PCN, -S(O)2R9, -(CH2)nheteroaryl, -(CH2)nheterocycyl, -(CH2)ncycloalkyl, -(CH2)ncycloalkenyl, -(CH2)naryl ;
R2 is selected from: hydrogen; or C1-10 alkyl, C2-10 alkenyl, C2--I0 alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, and heteroaryl, each of which may be optionally substituted by one or more of: C1-10 alkyl, C2-i0 alkenyl, C2--I0 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-6 haloalkyl, halogen, -CN, -OR4, -(CH2)nCOR4, -C(O)OR4, -OCOR4, - (CH2)nNR5R6, -(NH)pCONR5R6, -OCONR5R7, and -NHC(O)OR7;
R3 is selected from: halogenated C1-6 alkyl;
R4 is selected from: hydrogen, C1-e alkyl, C2-6 alkenyl, C2-6 alkynyl, -(CH2)n cycloalkyl, -(CH2)n cycloalkenyl, -(CH2)n heterocyclyl, -(CH2)n aryl, and -(CH2)n heteroaryl;
R5 and R6 are selected from: hydrogen and C1-4 alkyl;
R7 is selected from: hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -(CH2)t cycloalkyl, -(CH2)n cycloalkenyl, -(CH2)t heterocyclyl, -(CH2)taryl, and -(CH2)t heteroaryl;
R8 is selected from C1-4 alkyl;
R9 is selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -(CH2)n cycloalkyl, -(CH2)ncycloalkenyl, -(CH2)nheterocyclyl, -(CH2)n aryl, and -(CH2)nheteroaryl, CN; m represents an integer selected from: O, 1 , 2, 3, 4 and 5; n represents an integer selected from: O, 1 , 2, 3, 4 and 5;
p represents an integer selected from: O and 1 ;
q represents an integer selected from: O, 1 and 2; t represents an integer selected from: 1 and 2; w represents an integer selected from: 2, 3 and 4.
13. A method according to claim 12 wherein the human or animal subject has a disorder of lipid metabolism including dyslipidaemia or hyperlipoproteinaemia or an inflammatory disease or condition.
14. A pharmaceutical formulation comprising at least one chemical entity according to any one of claims 1-7 and one or more pharmaceutically acceptable diluents, excipients or carriers.
15. A combination for administration together or separately, sequentially or simultaneously in separate or combined pharmaceutical formulations, said combination comprising at least one chemical entity according to any one of claims 1-7 together with another therapeutically active agent.
16. A pharmaceutical formulation comprising: (i) At least one chemical entity according to any one of claims 1 -7;
(ii) one or more active ingredients selected from statins, fibrates, bile-acid binding resins and nicotinic acid; and (iii) one or more pharmaceutically acceptable diluents, excipients or carriers.
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EP1805180A1 (en) 2007-07-11
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NO20072548L (en) 2007-07-20
JP2008517029A (en) 2008-05-22
KR20070070231A (en) 2007-07-03
CA2584904A1 (en) 2006-05-04
RU2007118932A (en) 2008-11-27
BRPI0517458A (en) 2008-10-07
MA28940B1 (en) 2007-10-01
IL182586A0 (en) 2007-07-24

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