WO2009005469A2 - The use of compounds such as pyridoxal derivatives for the treatment of diabetes or diseases associated with the metabolic syndrome - Google Patents

The use of compounds such as pyridoxal derivatives for the treatment of diabetes or diseases associated with the metabolic syndrome Download PDF

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WO2009005469A2
WO2009005469A2 PCT/SE2008/050831 SE2008050831W WO2009005469A2 WO 2009005469 A2 WO2009005469 A2 WO 2009005469A2 SE 2008050831 W SE2008050831 W SE 2008050831W WO 2009005469 A2 WO2009005469 A2 WO 2009005469A2
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alkyl
alkylene
cooh
compound according
halogen
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PCT/SE2008/050831
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French (fr)
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WO2009005469A3 (en
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David Erlinge
Albert S. Salehi
Stefan Amisten
Sandra Meidute-Abaravecien
Olov Sterner
Johan Wingstrand
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David Erlinge
Salehi Albert S
Stefan Amisten
Sandra Meidute-Abaravecien
Olov Sterner
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Application filed by David Erlinge, Salehi Albert S, Stefan Amisten, Sandra Meidute-Abaravecien, Olov Sterner filed Critical David Erlinge
Publication of WO2009005469A2 publication Critical patent/WO2009005469A2/en
Publication of WO2009005469A3 publication Critical patent/WO2009005469A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/68—One oxygen atom attached in position 4
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/76—Nitrogen atoms to which a second hetero atom is attached
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/576—Six-membered rings
    • C07F9/58—Pyridine rings

Definitions

  • the present invention relates to a novel class of compounds, useful for the treatment or prevention of the metabolic syndrome, diabetes mellitus as well as diseases, disorders and medical risks related to the metabolic syndrome and diabetes mellitus. Further the invention relates to use of such compounds to manufacture a medicament.
  • the metabolic syndrome is a disease characterized by a group of metabolic risk factors in a person. They include:
  • Atherogenic dyslipidemia blood fat disorders — high triglycerides, low HDL cholesterol and high LDL cholesterol — that foster plaque buildups in artery walls
  • Insulin resistance or glucose intolerance the body can't properly use insulin or blood sugar
  • Prothrombotic state e.g., high fibrinogen or plasminogen activator inhibitor-1 in the blood
  • Proinflammatory state e.g., elevated C-reactive protein in the blood
  • Diabetes is a separate disease, as well as a component within the scope of the metabolic syndrome.
  • One of the hallmarks of the metabolic syndrome is insulin resistance resulting in a dysfunctional glucose homeostasis.
  • the insulin resistance is usually coupled with a gradual loss of pancreatic beta cell function.
  • the insulin resistance results in a gradual loss of glucose uptake in the skeletal muscle cells and an increased glucose production from the liver. Both the hyperglycemia and the increased free fatty acid levels are considered to be underlying causes of the gradual loss of insulin secretion in patients with type 2 diabetes.
  • the metabolic syndrome is triggering a complex series of events resulting in microvascular damage involving i.e. inflammatory changes, which result in vascular atheromatous damage.
  • the first step is characterized by an endothelial dysfunction which is what sets off a series of events including e.g. adhesion molecule expression, local vascular inflammatory responses, accumulation of atherogenic lipoproteins, macrophage conversion to foam cells, and the establishment of a fibrous-lipid vascular atherosclerotic cap.
  • diabetes mellitus may cause a range of other medical risks and adverse outcomes usually coupled to macrovascular as well as microvascular complications. While myocardial infarction and stroke dominate the macrovascular complications, microvascular complications usually include ocular complications (retinopathy and maculopathy), nephropathy (micro and macroalbuminuria). In about 10% of patients, such complications may present at the debut of diabetes. Diabetes is popularly classified into four major types: type 1 diabetes, type 2 diabetes, gestational diabetes, and pre-diabetes.
  • the prevalence is increasing due to urbanisation and sedentary life styles.
  • age ranges of 80 years and older the overall prevalence of diabetes is around 20%.
  • the prevalence in males and females is similar, but the mean age of the disease is lower in males as compared with females.
  • About 85-90% of all diabetes is type 2 diabetes.
  • Type 1 diabetes results from the body's failure to produce insulin and these patients therefore usually need insulin therapy. Of people with diabetes, it is estimated that 15 to 10% of patients in the Western world have type 1 diabetes.
  • Type 2 diabetes results from insulin resistance combined with an overproduction of insulin.
  • Insulin resistance is a condition in which the body fails to properly respond to insulin.
  • the majority of adult middle-aged and elderly persons who are diagnosed with diabetes have type 2 diabetes.
  • Gestational diabetes which presents a risk for the fetus as well as the mother affects about 4% of all pregnant women, and is characterised by a development of diabetes during pregnancy.
  • Pre-diabetes or insulin resistance is a condition that occurs when the glucose levels of a person's blood are higher than normal, but not high enough for a diagnosis of type 2 diabetes. There are at least twice as many people who can be classified as pre-diabetic, as compared to those with overt diabetes.
  • ATP and its degradation product ADP (adenosine diphosphate) was not just an energy source for cells matured with the cloning of the first P2Y nucleotide receptor in 1993.
  • ADP adenosine diphosphate
  • the P2Y and P2X receptor family is a part of an extensive system involving a wide variety of extracellular nucleotides (ATP and ADP, UTP and UDP), their receptors, metabolizing enzymes and transporters.
  • ATP is rapidly degraded by ectonucleotidases to ADP, which can act on P2Y1, P2Y12 and PY 13 receptors.
  • ADP is then degraded by ecto-5 '-nucleotidase to adenosine, which in turn can activate four different adenosine receptors.
  • the PY 13 receptor is activated by ADP, and has been shown to be expressed in inflammatory cells, spleen, liver, red blood cells and the brain.
  • MRS2211 is a specific P2Y13 receptor antagonist (Kim et al., Biochem Pharmacol, 70 (2005) 266-274).
  • WO 03/082881 discloses the use of pyroxidal-5 -phosphate derivatives as HIV integrase inhibitors. Hence, a new treatment of the metabolic syndrome, and specifically diabetes, would be advantageous and in particular compounds, compositions, and the use thereof, for said treatment.
  • embodiments of the present invention preferably seeks to mitigate, alleviate or eliminate one or more of the above-identified deficiencies in the art and disadvantages singly or in any combination and solves at least the above mentioned problems by providing a compound according to formula I, II or III
  • A represents, independently of each other, hydrogen, groups that may receive and/or donate a hydrogen bond at a reasonable distance or electron withdrawing groups, such groups that may donate and/or accept a hydrogen bond(s) or which are electron withdrawing may be selected from the group consisting of halogen, nitro,
  • (CO)C0-5 alkyl COOH, S(O)C 1-5 alkyl, SO2C1-5 alkyl, S(O)OC0-5 alkyl, SO2OC0-5 alkyl, C 1-2 alkylenehydroxy and trihalomethyl, such as trifluormethyl;
  • B represents, independently of each other, hydrogen or lipophilic groups, such lipophilic groups may be selected from the group consisting halogen, C1-C5 alkyl, OC1-C5 alkyl and C 1-5 fluoroalkyl;
  • C represents H, C 1-5 alkyl, C 1-5 fluoroalkyl, halo, hydroxy, CO-3 alkyleneOCl-5 alkyl, CO-3 alkyleneOCl-5 fluorolkyl, CO-3 alkyleneNH2, CO-3 alkyleneNHCl-3 alkyl, CO-3 alkyleneN(Cl-5 alkyl)2, which C 1-5 alkyl may be the same or different, C 1-5 alkylthio, S(O)C
  • G together with F, might represent a group that comprises an oxdizable phosphor or carbon such as an alkyl with a terminal hydroxyl group that can be oxidized to a carboxylic acid;
  • lipophilic groups may be selected from the group consisting halogen, short alkyl, alkoxy;
  • X represents N and CH, as a free base, an acid in its non-charged protonated form or a pharmaceutically acceptable salt, solvate or solvate of a salt thereof
  • Such a compound or a composition comprising such a compound may be used in medicine and/or therapy. Such compounds or compositions may also be used to manufacture a medicament.
  • a medicament comprising a compound according to formula I may be used to treat or prevent a disease or disorder, such as the metabolic syndrome, all types of diabetes, such as diabetes mellitus type 1 , diabetes mellitus type 2, gestational diabetes mellitus and pre-diabetes mellitus, and complications related to diabetes and the metabolic syndrome.
  • Fig. 1 depicts experimental data supporting that the P2Y13 receptor is expressed in beta cells.
  • Fig. 2 depicts experimental data supporting that the P2Y13 antagonist MRS2211 stimulates insulin release.
  • Fig. 3 depicts the effect of the stable ADP analogue 2-MeSADP on insulin secretion from Langerhans islets.
  • addition salt is intended to mean salts formed by the addition of a acid, such as organic or inorganic acids, or by addition of a base.
  • the organic acid may be, but is not limited to, acetic, propanoic, methanesulfonic, benzenesulfonic, lactic, malic, citric, tartaric, succinic or maleic acid.
  • the inorganic acid may be, but is not limited to, hydrochloric, hydrobromic, sulfuric, nitric acid or phosphoric acid.
  • the base may be, but is not limited to, ammonia and hydroxides of alkali or alkaline earth metals.
  • addition salt also comprises the hydrates and solvent addition forms, such as hydrates and alcoholates.
  • halo refers to fiuoro, chloro, bromo, and iodo.
  • alkyl alkylenyl or “alkylene” used alone or as a suffix or prefix, is intended to include both branched and straight chain saturated aliphatic hydrocarbon groups having from 1 to 12 carbon atoms or if a specified number of carbon atoms is provided then that specific number would be intended.
  • Cl-6 alkyl denotes alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms.
  • a hydrogen-atom is intended as the substituent at the position of the alkyl-group.
  • N(CO alkyl)2 is equivalent to "NH2" (amino).
  • a bond is intended to link the groups onto which the alkylenyl or alkylene-group is substituted.
  • NH(CO alkylene)NH2 is equivalent to "NHNH2" (hydrazino).
  • the groups linked by an alkylene or alkylenyl-group are intended to be attached to the first and to the last carbon of the alkylene or alkylenyl-group.
  • the first and the last carbon is the same.
  • “H2N(C2 alkylene)NH2”, “H2N(C3 alkylene)NH2”, “N(C4 alkylene)”, “N(C5 alkylene)” and “N(C2 alkylene)2NH” is equivalent to 1,2-diamino ethane, 1,3-diamino propane, pyrrolidinyl, piperidinyl and piperazinyl, repectively.
  • alkyl examples include, but are not limited to, methyl, ethyl, n-propyl, i- propyl, n-butyl, i-butyl, sec-butyl, t-butyl, pentyl, and hexyl.
  • alkylene or alkylenyl examples include, but are not limited to, methylene, ethylene, propylene, and butylene.
  • alkoxy or "alkyloxy” is intended to mean an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy, n-pentoxy, isopentoxy, cyclopropylmethoxy, allyloxy and propargyloxy.
  • alkylthio or “thioalkoxy” represent an alkyl group as defined above with the indicated number of carbon atoms attached through a sulphur bridge.
  • fiuoroalkyl refers to groups in which one, two, or three of the hydrogen(s) attached to the carbon(s) of the corresponding alkyl, alkylene and alkoxy-groups are replaced by fiuoro.
  • examples of fiuoroalkyl include, but are not limited to, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 2-fluoroethyl and 3- fluoropropyl.
  • the inventors of the present invention found for the first time evidence for the expression of the P2Y 13 receptor in pancreatic islets of Langerhans and its beta-cells. Furthermore, the present inventors found that ADP has both a stimulatory effect on insulin via P2Yi receptors, but most importantly, that ADP inhibits insulin release via P2Yi3 receptors. The involvement of P2Y 13 receptors was an unexpected finding that has never been shown before. It demonstrates a previously unrecognised role for the P2Yi3 receptor. The P2Yi 3 antagonist MRS2211 was shown to antagonise the inhibitory effects of ADP on insulin secretion. Surprisingly, it was established that ADP constitutes an autocrine regulatory pathway for insulin regulation.
  • MRS2211 blocks this autocrine pathway resulting in increased insulin secretion. MRS2211 has never before been shown to regulate insulin secretion.
  • the regulation of this pathway means that MRS 2211, and analogs thereof described herein, may be used to treat diseases and disorders which would benefit from a blockade of the autocrine pathway regulated by ADP acting on P2Y13 receptors.
  • diseases and disorders are the metabolic syndrome and all types of diabetes, such as diabetes mellitus type 1, diabetes mellitus type 2, gestational diabetes mellitus and pre-diabetes mellitus.
  • macrovascular complications which includes, but not are limited to myocardial infarction and stroke
  • microvascular complications which includes, but nor are limited to, ocular complications (retinopathy and maculopathy), nefropathy (micro and macroalbuminuria), and which may result from the metabolic syndrome and diabetes may be treated or prevented by compounds of the invention.
  • MRS2211 or similar P2Y13 antagonists of the kind described herein, may be used in the treatment of diseases and disorders such as the metabolic syndrome and of all types of diabetes, such as diabetes mellitus type 1, diabetes mellitus type 2, gestational diabetes mellitus and pre-diabetes mellitus, to increase insulin secretion.
  • MRS2211 augments the natural release of insulin in response to high levels of glucose, which will give an adequate dynamic release of insulin at times when it is needed (e.g. after a meal), with less risk of to high insulin levels at other times, which could result in hypoglycaemia, which is a common side effect of subcutaneous insulin therapy.
  • one embodiment of the present invention relates to a compound according to formula (I), (II) or (III),
  • A represents, independently of each other, hydrogen, groups that may receive and/or donate a hydrogen bond at a reasonable distance or electron withdrawing groups, wherein such groups that may donate and/or accept hydrogen bond(s) or which are electron withdrawing may be selected from the group consisting of halogen, nitro, (CO)C0-5 alkyl, COOH, S(O)C 1-5 alkyl, SO2C1-5 alkyl, S(0)0C0-5 alkyl, SO2OC0- 5 alkyl, C 1-2 alkylenehydroxy and trihalomethyl, such as trifluormethyl; B represents, independently of each other, hydrogen or lipophilic groups, wherein such lipophilic groups may be selected from the group consisting of halogen, C1-C5 alkyl, OC1-C5 alkyl and C 1-5 fluoroalkyl; C represents H, C 1-5 alkyl, C 1-5 fluoroalkyl, halo, hydroxy, CO-3 alkyleneOCl-5 alkyl, CO-3 alkyleneOC
  • A represents, independently of each other, hydrogen, halogen, such as fluorine and chlorine, nitro, SO2C1-5 alkyl, such as SO2Me, SO2OC0- 5 alkyl, such as SO2OH, or trifiuormethyl.
  • B represents, independently of each other, hydrogen, halogen, such as fluorine and chlorine, C1-C5 alkyl, such as methyl, OC1-C5 alkyl, such as OMe and C 1-5 fiuoroalkyl, such as CF3;
  • halogen such as fluorine and chlorine
  • C1-C5 alkyl such as methyl
  • OC1-C5 alkyl such as OMe
  • C 1-5 fiuoroalkyl such as CF3
  • C represents H, C 1-5 alkyl, C 1-5 fiuoroalkyl, halo, hydroxy, CO-3 alkyleneOCl-5 alkyl, CO-3 alkyleneOCl-5 fluorolkyl, CO-3 alkyleneNH2, CO-3 alkyleneNHCl-3 alkyl, CO-3 alkyleneN(Cl-5 alkyl)2, which C 1-5 alkyl may be the same or different, C 1-5 alkylthio, S(O)C 1-5 alkyl, SO2C1-5 alkyl, Cl- 5 fiuoroalkylthio, NH(CO)C 1-5 alkyl, NH(CO)C 1-5 alkoxy, NHSO2C1-5 alkyl, (CO)C 1-5 alkyl, COOH, (CO)C 1-5 alkoxy, (C0)NH2, (CO)NHC 1-5 alkyl, (CO)N(Cl- 5 alkyl)2, which C 1-5 alkyl may be the same or different, cyano,
  • D represents hydroxy, C 1-3 alkylenehydroxy, such as CH20H, or COOH. In a preferred embodiment D represents hydroxy.
  • E represents an (CO)C0-5 alkyl, nitro, SO2C1-5 alkyl, S(O)OC0-5 alkyl, SO 2 OH or S(O)OH.
  • E represents an (CO)C0-5 alkyl, such as C(O)H or C(O)Me.
  • E represents C(O)H.
  • F represents a C0-C5 alkylene, such as a direct bond or a methylene, a heteroatom such as nitrogen, sulphur or oxygen, CO-3 alkyleneOCO-3 alkylene, CO-3 alkylene NHCO-3 alkylene, CO-3 alkyleneSCO-3 alkylene.
  • F represents a C0-C5 alkylene, such a direct bond or as a methylene, or CO-3 alkyleneOCO-1 alkylene, such as Cl alkyleneO and Cl alkyleneOCl alkylene.
  • G represents P(O)(OH)2, COOH or C(COOH)2.
  • G represents P(O)(OH)2.
  • G might also represent COOH or C(COOH)2, such as C(COOH)2.
  • G might represent a prodrug of P(O)(OH)2, COOH or C(COOH)2, such as an esters, which may be hydrolyzed in vivo to form phosphate or carboxylate, or G may, together with F, represent a group that comprises an oxdizable phosphor or carbon, such as an alkyl with a terminal hydroxyl group, that can be oxidized to a carboxylic acid.
  • lipophilic groups may be selected from the group consisting halogen, short alkyl, such as C1-C3 alkyl (e.g. methyl), alkoxy.
  • X represents N or CH. In a preferred embodiment X represents N.
  • Another embodiment relates to a compound according to formula (I), wherein A to H and X is as defined herein.
  • A represents, independently of each other, hydrogen, halogen, nitro, SO2C1-5 alkyl, SO2OC0-5 alkyl, such as SO2OH or trifluormethyl
  • B represents, independently of each other, hydrogen, halogen, C1-C5 alkyl, OC1-C5 alkyl and C 1-5 fluoroalkyl
  • C represents H, C 1-5 alkyl, C 1-5 fluoroalkyl or halo
  • D represents hydroxy, C 1-3 alkylenehydroxy or COOH
  • E represents an (CO)C0-5 alkyl, nitro, SO2C1-5 alkyl, S(O)OC0-5 alkyl, SO 2 OH or S(O)OH
  • F represents a C0-C5 alkylene, such as a direct bond or as a methylene, or CO-3 alkyleneOCO-1 alkylene, such as Cl alkyleneO and Cl alkyleneOCl alkylene
  • G represents P(O
  • A represents, independently of each other, hydrogen, halogen, such as fluorine and chlorine, nitro, S020H or trifluormethyl
  • B represents, independently of each other, hydrogen, halogen, such as fluorine and chlorine, C1-C5 alkyl, such as Me, OC1-C5 alkyl, such as OMe, and C 1-5 fluoroalkyl, such as CF3
  • C represents H, C 1-3 alkyl, such as Me, C 1-3 fluoroalkyl, such as CF3, or halo, such as fluorine and chlorine
  • D represents hydroxy
  • E represents (CO)C0-5, such as C(O)H
  • F represents methylene, Cl alkyleneO or Cl alkyleneOCl alkylene
  • G represents P(O)(OH)2, COOH or
  • A represents, independently of each other, hydrogen, halogen, nitro, SO2C1-5 alkyl, SO2OC0-5 alkyl, such as SO2OH or trifluormethyl
  • B represents, independently of each other, hydrogen, halogen, C1-C5 alkyl, OC1-C5 alkyl and C 1-5 fluoroalkyl
  • C represents H, C 1-5 alkyl, C 1-5 fluoroalkyl or halo
  • D represents hydroxy, C 1-3 alkylenehydroxy or COOH
  • E represents an (CO)C0-5 alkyl, nitro, SO2C1-5 alkyl, S(O)OC0-5 alkyl, SO 2 OH or S(O)OH
  • F represents a C0-C5 alkylene, such as a direct bond or as a methylene, or CO-3 alkyleneOCO-1 alkylene, such as Cl alkyleneO and Cl alkyleneOCl alkylene
  • G represents COOH or
  • A represents, independently of each other, hydrogen, halogen, such as fluorine and chlorine, nitro, S020H or trifluormethyl
  • B represents, independently of each other, hydrogen, halogen, such as fluorine and chlorine, C1-C5 alkyl, such as Me, 0C1-C5 alkyl, such as OMe, and C 1-5 fluoroalkyl, such as CF3
  • C represents H, C 1-3 alkyl, such as Me, C 1-3 fluoroalkyl, such as CF3, or halo, such as fluorine and chlorine
  • D represents hydroxy
  • E represents (CO)C0-5, such as C(O)H
  • F represents methylene, Cl alkyleneO or Cl alkyleneOCl alkylene
  • G represents COOH or C(COOH)2
  • X represents N.
  • the compound is MRS221, presented by the formula ⁇ ven below.
  • Another embodiment relates to a compound, as defined in the preceding embodiments, in the form of an addition salt.
  • Another embodiment relates to a compound, as defined in the preceding embodiments, as a free base, an acid in its non-charged protonated form or a pharmaceutically acceptable salt, solvate or solvate of a salt thereof.
  • the compounds as disclosed herein may be used in the treatment of diseases and disorders and for the manufacture of a medicament.
  • a medicament or a composition such as a pharmaceutical composition, comprising a compound as disclosed herein.
  • a medicament or a composition may be used in the treatment of diseases and disorders.
  • Such a composition may also be used for the manufacture of a medicament.
  • the term “therapy” and “treatment” includes prevention and/or prophylaxis, unless there are specific indications to the contrary.
  • the terms “therapeutic” and “therapeutically” should be construed accordingly.
  • the compounds, medicaments or compositions disclosed herein may be used in the treatment of diseases such as the metabolic syndrome and all types of diabetes, such as diabetes mellitus type 1 , diabetes mellitus type 2, gestational diabetes mellitus and pre-diabetes mellitus. Furthermore compounds disclosed herein may be used to delay the onset of all types of diabetes such as diabetes mellitus type 1, diabetes mellitus type 2, gestational diabetes mellitus and pre-diabetes mellitus.
  • compounds disclosed herein may be used to treat or prevent complications of the metabolic syndrome or diabetes, such as, but not limited to macrovascular complications, which includes, but not are limited to myocardial infarction and stroke, and microvascular complications, which includes, but nor are limited to, ocular complications (retinopathy and maculopathy), nefropathy (micro and macroalbuminuria).
  • macrovascular complications which includes, but not are limited to myocardial infarction and stroke
  • microvascular complications which includes, but nor are limited to, ocular complications (retinopathy and maculopathy), nefropathy (micro and macroalbuminuria).
  • Another embodiment relates to a method of prevention and/or treatment of diseases such as the metabolic syndrome and/or all types of diabetes, such as diabetes mellitus type 1, diabetes mellitus type 2, gestational diabetes mellitus and pre-diabetes mellitus, comprising administering to a mammal, including man in need of such prevention and/or treatment, a therapeutically effective amount of compound as disclosed herein or a pharmaceutical composition comprising a therapeutically effective amount of a compound as disclosed herein.
  • diseases such as the metabolic syndrome and/or all types of diabetes, such as diabetes mellitus type 1, diabetes mellitus type 2, gestational diabetes mellitus and pre-diabetes mellitus
  • Another embodiment relates to a method of prevention and/or treatment of complications of the metabolic syndrome and/or diabetes, such as, but not limited to macrovascular complications, which includes, but not are limited to myocardial infarction and stroke, and microvascular complications, which includes, but nor are limited to, ocular complications (retinopathy and maculopathy), nefropathy (micro and macroalbuminuria), comprising administering to a mammal, including man in need of such prevention and/or treatment, a therapeutically effective amount of compound as disclosed herein or a pharmaceutical composition comprising a therapeutically effective amount of a compound as disclosed herein.
  • macrovascular complications which includes, but not are limited to myocardial infarction and stroke
  • microvascular complications which includes, but nor are limited to, ocular complications (retinopathy and maculopathy), nefropathy (micro and macroalbuminuria)
  • retinopathy and maculopathy retinopathy and maculopathy
  • nefropathy micro and macroalbuminuria
  • the compounds disclosed herein may also be used for the manufacture of a medicament for the treatment of diseases, such as the metabolic syndrome and of all types of diabetes, such as diabetes mellitus type 1, diabetes mellitus type 2, gestational diabetes mellitus and pre-diabetes mellitus. Additionally, compounds disclosed herein may be used for the manufacture of a medicament used to delay the onset of all types of diabetes, such as diabetes mellitus type 1, diabetes mellitus type 2, gestational diabetes mellitus and pre-diabetes mellitus.
  • compounds disclosed herein may be used for the manufacture of a medicament for the treatment or prevention of complications of the metabolic syndrome or diabetes, such as, but not limited to macro vascular complications, which includes, but not are limited to myocardial infarction and stroke, and microvascular complications, which includes, but nor are limited to, ocular complications (retinopathy and maculopathy), nephropathy (micro and macroalbuminuria).
  • macro vascular complications which includes, but not are limited to myocardial infarction and stroke
  • microvascular complications which includes, but nor are limited to, ocular complications (retinopathy and maculopathy), nephropathy (micro and macroalbuminuria).
  • Such a medicament may further comprise pharmaceutically acceptable carriers, diluents, stabilisers or excipients.
  • “Pharmaceutically acceptable” means a carrier, stabiliser, diluent or excipient that, at the dosage and concentrations employed, does not cause any unwanted effects in the patients to whom it is administered.
  • Such pharmaceutically acceptable carriers, stabilisers, dilutents or excipients are well-known in the art (see for example Remington's Pharmaceutical Sciences, 18th edition, A.R Gennaro, Ed., Mack Publishing Company (1990) or handbook of Pharmaceutical Excipients, 3rd edition, A. Kibbe, Ed., Pharmaceutical Press (2000)).
  • the medicament will be administered to a patient in a pharmaceutically effective dose.
  • pharmaceutically effective dose is meant a dose that is sufficient to produce the desired effects in relation to the condition for which it is administered. The exact dose is dependent on the activity of the compound, manner of administration, nature and severity of the disorder and/or disease and the general conditions, such as age and body weight of the patient.
  • the medicament as disclosed herein may be administered alone or in combination with other therapeutic agents. These agents may be incorporated as part of the same medicament or may be administered separately.
  • Examples of such therapeutic agents which may administered in combination with the medicament as disclosed herein, are Sulfonylureas, Biguanides, Alpha-glucosidase inhibitors, Thiazolidinediones, Meglitinides, D-phenylalanine derivatives, Amylin synthetic derivatives, Incretin mimetics and Insulins.
  • a compound according to embodiments of the present invention By combining a compound according to embodiments of the present invention with another therapeutic agent, such as Sulfonylureas, Biguanides, Alpha-glucosidase inhibitors, Thiazolidinediones, Meglitinides, D-phenylalanine derivatives, Amylin synthetic derivatives, Incretin mimetics and Insulins, it may be possible to achieve better effect, synergistic effects, better glucose control, prolonged duration of the effect, reduced secondary complications, prolonged life and fewer side effects, compared to if only a compound according to the present invention was administrated.
  • another therapeutic agent such as Sulfonylureas, Biguanides, Alpha-glucosidase inhibitors, Thiazolidinediones, Meglitinides, D-phenylalanine derivatives, Amylin synthetic derivatives, Incretin mimetics and Insulins
  • the medicament as disclosed herein may be administered through different routes such as, but not limited to, intravenously, intraperitonealy, intramuscularly, intranasaleously, subcutaneously, sublingually, rectally, orally or through inhalation or insufflation.
  • Particular suitable formulations of the medicament as disclosed herein are formulations suitable to be taken orally or to be administrated through inhalation or insufflation.
  • the compounds of formula [ are also useful as pharmacological tools in the development and standardisation of in vitro and in vivo test systems for die evaluation of the effects of inhibitors of P2Y13 related activity, such as insulin secretion, as pa.i1 of die search for new therapeutics agents,
  • the highest mRNA levels were found for the ADP receptor P2Y1 and P2Y13 (6.7 ⁇ 0.6 x 10-3 and 1.3 ⁇ 0.6 x 10-3 respectively in mouse pancreatic islets (ratio of GAPDH mRNA expression) and 4.0 ⁇ 3.0 x 10-3 and 1.8 ⁇ 0.3 x 10-3 respectively in mouse beta cells, see fig. 1).
  • the ATP/UTP receptor P2Y2 could only be detected at thousand times lower levels (0.003 ⁇ 0.0004 x 10-3 in mouse pancreatic islets and 0.009 ⁇ 0.004 x 10-3 in mouse beta cells, see figure 1).
  • the ADP receptor P2Y12 and the ATP/UTP receptor P2Y4 could not be detected at all.
  • MRS2211 is a selective antagonist blocking the binding of ADP to the P2Y13 receptor.
  • Raising the glucose level to 20 mM resulted as expected in increased insulin release to 1.96 ⁇ 0.15 ng/islet*hour.
  • this increase was further increased to 2.70 ⁇ 0.19 ng/islet*hour (fig 2).
  • 30 ⁇ M MRS2211 had similar effects.
  • the stable ADP analogue 2-MeSADP alone did not alter insulin secretion from mouse pancreatic islets induced by 8.3 mM glucose.
  • Pre-treatment with the selective P2Y1 receptor antagonist MRS2179 resulted in a marked significant decrease in insulin secretion (fig 3).
  • pre-treatment with the selective P2Y13 receptor antagonist MRS2211 resulted in a marked significant increase in insulin secretion (fig 3).
  • Nilsson J Nilsson LM, Chen YW, Molkentin JD, Erlinge D, Gomez MF. High glucose activates nuclear factor of activated T cells in native vascular smooth muscle. Arterioscler Thromb Vase Biol. 2006;26:794-800.

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Abstract

The invention relates to compounds having the general formula (I), (II) or (III), and which are useful for the treatment or prevention of diabetes or diseases associated with the metabolic syndrome.

Description

COMPOUNDS AND USE THEREOF
FIELD OF THE INVENTION
The present invention relates to a novel class of compounds, useful for the treatment or prevention of the metabolic syndrome, diabetes mellitus as well as diseases, disorders and medical risks related to the metabolic syndrome and diabetes mellitus. Further the invention relates to use of such compounds to manufacture a medicament.
BACKGROUND OF THE INVENTION:
The metabolic syndrome is a disease characterized by a group of metabolic risk factors in a person. They include:
• Abdominal obesity (excessive fat tissue in and around the abdomen)
• Atherogenic dyslipidemia (blood fat disorders — high triglycerides, low HDL cholesterol and high LDL cholesterol — that foster plaque buildups in artery walls)
• Elevated blood pressure
• Insulin resistance or glucose intolerance (the body can't properly use insulin or blood sugar)
• Prothrombotic state (e.g., high fibrinogen or plasminogen activator inhibitor-1 in the blood)
• Proinflammatory state (e.g., elevated C-reactive protein in the blood)
People with the metabolic syndrome are at increased risk of coronary heart disease and other diseases related to plaque buildups in artery walls (e.g., stroke and peripheral vascular disease) and type 2 diabetes. The metabolic syndrome has become increasingly common in the world.
Diabetes is a separate disease, as well as a component within the scope of the metabolic syndrome. One of the hallmarks of the metabolic syndrome is insulin resistance resulting in a dysfunctional glucose homeostasis. The insulin resistance is usually coupled with a gradual loss of pancreatic beta cell function. The insulin resistance results in a gradual loss of glucose uptake in the skeletal muscle cells and an increased glucose production from the liver. Both the hyperglycemia and the increased free fatty acid levels are considered to be underlying causes of the gradual loss of insulin secretion in patients with type 2 diabetes.
The metabolic syndrome, as well as its component risks, is triggering a complex series of events resulting in microvascular damage involving i.e. inflammatory changes, which result in vascular atheromatous damage. Usually, the first step is characterized by an endothelial dysfunction which is what sets off a series of events including e.g. adhesion molecule expression, local vascular inflammatory responses, accumulation of atherogenic lipoproteins, macrophage conversion to foam cells, and the establishment of a fibrous-lipid vascular atherosclerotic cap.
In addition to that, diabetes mellitus may cause a range of other medical risks and adverse outcomes usually coupled to macrovascular as well as microvascular complications. While myocardial infarction and stroke dominate the macrovascular complications, microvascular complications usually include ocular complications (retinopathy and maculopathy), nephropathy (micro and macroalbuminuria). In about 10% of patients, such complications may present at the debut of diabetes. Diabetes is popularly classified into four major types: type 1 diabetes, type 2 diabetes, gestational diabetes, and pre-diabetes.
The overall prevalence of diabetes in the whole population differs between countries, and in the Western world it ranges between 2-4%. The prevalence is increasing due to urbanisation and sedentary life styles. In age ranges of 80 years and older, the overall prevalence of diabetes is around 20%. The prevalence in males and females is similar, but the mean age of the disease is lower in males as compared with females. About 85-90% of all diabetes is type 2 diabetes.
Type 1 diabetes results from the body's failure to produce insulin and these patients therefore usually need insulin therapy. Of people with diabetes, it is estimated that 15 to 10% of patients in the Western world have type 1 diabetes.
Type 2 diabetes results from insulin resistance combined with an overproduction of insulin. Insulin resistance is a condition in which the body fails to properly respond to insulin. The majority of adult middle-aged and elderly persons who are diagnosed with diabetes have type 2 diabetes. Gestational diabetes, which presents a risk for the fetus as well as the mother affects about 4% of all pregnant women, and is characterised by a development of diabetes during pregnancy. Pre-diabetes or insulin resistance is a condition that occurs when the glucose levels of a person's blood are higher than normal, but not high enough for a diagnosis of type 2 diabetes. There are at least twice as many people who can be classified as pre-diabetic, as compared to those with overt diabetes.
More than 65% of people who suffer from diabetes, die as an result of its cardiovascular consequences, usually coronary heart disease or stroke. With diabetes, cardiovascular complications occur earlier in life and more often result in death. By managing diabetes, people with diabetes can reduce their risk of heart attacks. In a normal individual, not suffering from diabetes, an increased level of glucose in the blood will result in the release of insulin from the beta-cells in the islets of Langerhans in the pancreas. The effects of insulin reduce the level of glucose in the blood. In a patient, with one of the forms of diabetes mentioned above, this release of insulin is insufficient. Evidence for biological activity of extracellular nucleotides followed the notion that ATP (adenosine triphosphate) was a non-adrenergic, non-cholinergic neurotransmitter. The idea that ATP and its degradation product ADP (adenosine diphosphate) was not just an energy source for cells matured with the cloning of the first P2Y nucleotide receptor in 1993. Now, the P2Y and P2X receptor family is a part of an extensive system involving a wide variety of extracellular nucleotides (ATP and ADP, UTP and UDP), their receptors, metabolizing enzymes and transporters.
High levels of glucose stimulates the release of ATP to the extracellular spatium from several cell types such as endothelial cells, blood vessels, mesangial cells, macrophages and beta-cells 1-5. The net pharmacological effects of extracellular ATP are difficult to predict. ATP by itself can stimulate P2Y2, P2Y4 (in rodents), P2Y11 and P2X1-P2X7 receptors present on the cell surfaceό. Furthermore, ATP is rapidly degraded by ectonucleotidases to ADP, which can act on P2Y1, P2Y12 and PY 13 receptors. ADP is then degraded by ecto-5 '-nucleotidase to adenosine, which in turn can activate four different adenosine receptors. The PY 13 receptor is activated by ADP, and has been shown to be expressed in inflammatory cells, spleen, liver, red blood cells and the brain. MRS2211 is a specific P2Y13 receptor antagonist (Kim et al., Biochem Pharmacol, 70 (2005) 266-274).
Various P2Y and P2X receptor antagonists have been disclosed by Brown et al in Drug Development Research 53:281-291 (2001), by Kim et al in J. Med. Chem. 2001, 44, 340-349, by Kim et al in Drug Development Research 45:52-66 (1998) and by Ziganshin et al in Pharmaceutical Chemistry Journal 1998, 32:8, 399-401.
WO 03/082881 discloses the use of pyroxidal-5 -phosphate derivatives as HIV integrase inhibitors. Hence, a new treatment of the metabolic syndrome, and specifically diabetes, would be advantageous and in particular compounds, compositions, and the use thereof, for said treatment.
SUMMARY OF THE INVENTION Accordingly, embodiments of the present invention preferably seeks to mitigate, alleviate or eliminate one or more of the above-identified deficiencies in the art and disadvantages singly or in any combination and solves at least the above mentioned problems by providing a compound according to formula I, II or III
Figure imgf000005_0001
wherein A represents, independently of each other, hydrogen, groups that may receive and/or donate a hydrogen bond at a reasonable distance or electron withdrawing groups, such groups that may donate and/or accept a hydrogen bond(s) or which are electron withdrawing may be selected from the group consisting of halogen, nitro,
(CO)C0-5 alkyl, COOH, S(O)C 1-5 alkyl, SO2C1-5 alkyl, S(O)OC0-5 alkyl, SO2OC0-5 alkyl, C 1-2 alkylenehydroxy and trihalomethyl, such as trifluormethyl; B represents, independently of each other, hydrogen or lipophilic groups, such lipophilic groups may be selected from the group consisting halogen, C1-C5 alkyl, OC1-C5 alkyl and C 1-5 fluoroalkyl; C represents H, C 1-5 alkyl, C 1-5 fluoroalkyl, halo, hydroxy, CO-3 alkyleneOCl-5 alkyl, CO-3 alkyleneOCl-5 fluorolkyl, CO-3 alkyleneNH2, CO-3 alkyleneNHCl-3 alkyl, CO-3 alkyleneN(Cl-5 alkyl)2, which C 1-5 alkyl may be the same or different, C 1-5 alkylthio, S(O)C 1-5 alkyl, SO2C1-5 alkyl, C 1-5 fiuoroalkylthio, NH(CO)C 1-5 alkyl, NH(CO)C 1-5 alkoxy, NHSO2C1-5 alkyl, (CO)C 1-5 alkyl, COOH, (CO)C 1-5 alkoxy, (CO)NH2, (CO)NHC 1-5 alkyl, (CO)N(C 1-5 alkyl)2, which C 1-5 alkyl may be the same or different, cyano, SO2NHC0-5 alkyl and nitro; D represents a hydrogen bond donor or hydrogen bond acceptor such as hydroxyl, C 1-3 alkylenehydroxy, COOH, NH2, NH(C 1 -5 alkyl), N(C 1 -5 alkyl)2, C(O)C0-5 alkyl; E represents an (CO)C0-5 alkyl, nitro, SO2C1-5 alkyl, S(0)0C0-5 alkyl, SO2OH or S(O)OH; F represents a C1-C5 alkylene, such as methylene, a heteroatom such as nitrogen, sulphur or oxygen, CO-3 alkyleneOCO-3 alkylene, CO-3 alkylene NHCO-3 alkylene or CO-3 alkyleneSCO-3 alkylene; G represents a group, which is charged at pH:7; Such groups may be selected from the group consisting P(O)(OH)2j P(O)(OH)O P(O)(OH)2, COOH and C(COOH)2; G might also represent esters of phosphates, carboxylates, which may be hydrolyzed in vivo to form phosphate or carboxylate. Furthermore, G, together with F, might represent a group that comprises an oxdizable phosphor or carbon such as an alkyl with a terminal hydroxyl group that can be oxidized to a carboxylic acid; H represents a linker selected from the group consisting C1-C5 alkylene, such as methylene, -N=N- and -CH=CH- (trans); said linker is optionally substituted with lipophilic groups. Such lipophilic groups may be selected from the group consisting halogen, short alkyl, alkoxy; X represents N and CH, as a free base, an acid in its non-charged protonated form or a pharmaceutically acceptable salt, solvate or solvate of a salt thereof
Such a compound or a composition comprising such a compound may be used in medicine and/or therapy. Such compounds or compositions may also be used to manufacture a medicament. A medicament comprising a compound according to formula I may be used to treat or prevent a disease or disorder, such as the metabolic syndrome, all types of diabetes, such as diabetes mellitus type 1 , diabetes mellitus type 2, gestational diabetes mellitus and pre-diabetes mellitus, and complications related to diabetes and the metabolic syndrome.
Advantageous features of the invention are defined in the dependent claims.
BRIEF DESCRIPTION OF THE DRAWINGS
These and other aspects, features and advantages of which the invention is capable of will be apparent from the following description of illustrative embodiments and examples of the present invention, reference being made to the accompanying drawings, in which Fig. 1 depicts experimental data supporting that the P2Y13 receptor is expressed in beta cells.
Fig. 2 depicts experimental data supporting that the P2Y13 antagonist MRS2211 stimulates insulin release. Fig. 3 depicts the effect of the stable ADP analogue 2-MeSADP on insulin secretion from Langerhans islets.
DETAILED DESCRIPTION OF THE INVENTION:
Definitions:
The term "addition salt" is intended to mean salts formed by the addition of a acid, such as organic or inorganic acids, or by addition of a base. The organic acid may be, but is not limited to, acetic, propanoic, methanesulfonic, benzenesulfonic, lactic, malic, citric, tartaric, succinic or maleic acid. The inorganic acid may be, but is not limited to, hydrochloric, hydrobromic, sulfuric, nitric acid or phosphoric acid. The base may be, but is not limited to, ammonia and hydroxides of alkali or alkaline earth metals. The term addition salt also comprises the hydrates and solvent addition forms, such as hydrates and alcoholates.
As used herein, "halo" or "halogen" refers to fiuoro, chloro, bromo, and iodo. As used herein, "alkyl", "alkylenyl" or "alkylene" used alone or as a suffix or prefix, is intended to include both branched and straight chain saturated aliphatic hydrocarbon groups having from 1 to 12 carbon atoms or if a specified number of carbon atoms is provided then that specific number would be intended. For example "Cl-6 alkyl" denotes alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms. When the specific number denoting the alkyl-group is the integer 0 (zero), a hydrogen-atom is intended as the substituent at the position of the alkyl-group. For example, "N(CO alkyl)2" is equivalent to "NH2" (amino). When the specific number denoting the alkylenyl or alkylene-group is the integer 0 (zero), a bond is intended to link the groups onto which the alkylenyl or alkylene-group is substituted. For example, "NH(CO alkylene)NH2" is equivalent to "NHNH2" (hydrazino). As used herein, the groups linked by an alkylene or alkylenyl-group are intended to be attached to the first and to the last carbon of the alkylene or alkylenyl-group. In the case of methylene, the first and the last carbon is the same. For example, "H2N(C2 alkylene)NH2", "H2N(C3 alkylene)NH2", "N(C4 alkylene)", "N(C5 alkylene)" and "N(C2 alkylene)2NH" is equivalent to 1,2-diamino ethane, 1,3-diamino propane, pyrrolidinyl, piperidinyl and piperazinyl, repectively. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i- propyl, n-butyl, i-butyl, sec-butyl, t-butyl, pentyl, and hexyl.
Examples of alkylene or alkylenyl include, but are not limited to, methylene, ethylene, propylene, and butylene. As used herein, "alkoxy" or "alkyloxy" is intended to mean an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy, n-pentoxy, isopentoxy, cyclopropylmethoxy, allyloxy and propargyloxy. Similarly, "alkylthio" or "thioalkoxy" represent an alkyl group as defined above with the indicated number of carbon atoms attached through a sulphur bridge.
As used herein, "fiuoroalkyl", "fluoroalkylene" and "fluoroalkoxy", used alone or as a suffix or prefix, refers to groups in which one, two, or three of the hydrogen(s) attached to the carbon(s) of the corresponding alkyl, alkylene and alkoxy-groups are replaced by fiuoro. Examples of fiuoroalkyl include, but are not limited to, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 2-fluoroethyl and 3- fluoropropyl.
The inventors of the present invention found for the first time evidence for the expression of the P2Y13 receptor in pancreatic islets of Langerhans and its beta-cells. Furthermore, the present inventors found that ADP has both a stimulatory effect on insulin via P2Yi receptors, but most importantly, that ADP inhibits insulin release via P2Yi3 receptors. The involvement of P2Y13 receptors was an unexpected finding that has never been shown before. It demonstrates a previously unrecognised role for the P2Yi3 receptor. The P2Yi3 antagonist MRS2211 was shown to antagonise the inhibitory effects of ADP on insulin secretion. Surprisingly, it was established that ADP constitutes an autocrine regulatory pathway for insulin regulation. When islets are stimulated with glucose, ADP levels outside the beta-cells are increased and turns off the insulin secretion via stimulation of the P2Y13 receptor. MRS2211 blocks this autocrine pathway resulting in increased insulin secretion. MRS2211 has never before been shown to regulate insulin secretion. The regulation of this pathway means that MRS 2211, and analogs thereof described herein, may be used to treat diseases and disorders which would benefit from a blockade of the autocrine pathway regulated by ADP acting on P2Y13 receptors. Without limitation examples of such diseases and disorders are the metabolic syndrome and all types of diabetes, such as diabetes mellitus type 1, diabetes mellitus type 2, gestational diabetes mellitus and pre-diabetes mellitus. Further complications such as macrovascular complications, which includes, but not are limited to myocardial infarction and stroke, and microvascular complications, which includes, but nor are limited to, ocular complications (retinopathy and maculopathy), nefropathy (micro and macroalbuminuria), and which may result from the metabolic syndrome and diabetes may be treated or prevented by compounds of the invention.
As shown in fig. 2, Langerhans islets, stimulated with glucose, release insulin both at the glucose concentrations 8.3 and 20 mM, thus mimicking the normal situation in vivo. When the P2Y13 antagonist MRS2211 was added, the glucose stimulated release of insulin was significantly increased. Thus, MRS2211, or similar P2Y13 antagonists of the kind described herein, may be used in the treatment of diseases and disorders such as the metabolic syndrome and of all types of diabetes, such as diabetes mellitus type 1, diabetes mellitus type 2, gestational diabetes mellitus and pre-diabetes mellitus, to increase insulin secretion. Furthermore, MRS2211 augments the natural release of insulin in response to high levels of glucose, which will give an adequate dynamic release of insulin at times when it is needed (e.g. after a meal), with less risk of to high insulin levels at other times, which could result in hypoglycaemia, which is a common side effect of subcutaneous insulin therapy.
Ivanov at el (J Comput Aided MoI Des (2006) 20:417-426) and Costanzi et al (J. Med. Chem. 2004, 47, 5393-5404) have disclosed advanced homology models of
P2Y13 based on the known structure of rhodopsin, a protein structural related to P2Y13. Further, it was possible to draw conclusions about structure activity relationships (SAR: s) of the activity of MRS2211 and structurally related analogues on P2Y13 and other P2-receptors from reports in the literature (Kim et al., Biochem Pharmacol, 70 (2005) 266-274, Brown et al in Drug Development Research 53:281-291 (2001), Kim et al in J. Med. Chem. 2001, 44, 340-349, Kim et al in Drug Development Research 45:52- 66 (1998) and Ziganshin et al in Pharmaceutical Chemistry Journal 1998, 32:8, 399- 401).
By use of this advanced homology model of P2Y13 and representative conformers of MRS2211, it was possible to identify interactions important to the binding of MRS2211 to P2Y13 and to identify structural requirements of P2Y13- antagonists. Thereby, it was possible to put forward a generic structure deemed to cover compounds able to bind to P2Y13 and act as antagonists. This generic structure was then adjusted in accordance with the SAR:s. Accordingly one embodiment of the present invention relates to a compound according to formula (I), (II) or (III),
Figure imgf000010_0001
wherein A represents, independently of each other, hydrogen, groups that may receive and/or donate a hydrogen bond at a reasonable distance or electron withdrawing groups, wherein such groups that may donate and/or accept hydrogen bond(s) or which are electron withdrawing may be selected from the group consisting of halogen, nitro, (CO)C0-5 alkyl, COOH, S(O)C 1-5 alkyl, SO2C1-5 alkyl, S(0)0C0-5 alkyl, SO2OC0- 5 alkyl, C 1-2 alkylenehydroxy and trihalomethyl, such as trifluormethyl; B represents, independently of each other, hydrogen or lipophilic groups, wherein such lipophilic groups may be selected from the group consisting of halogen, C1-C5 alkyl, OC1-C5 alkyl and C 1-5 fluoroalkyl; C represents H, C 1-5 alkyl, C 1-5 fluoroalkyl, halo, hydroxy, CO-3 alkyleneOCl-5 alkyl, CO-3 alkyleneOCl-5 fαiorolkyl, CO-3 alkyleneNH2, CO-3 alkyleneNHCl-3 alkyl, CO-3 alkyleneN(Cl-5 alkyl)2, which C 1-5 alkyl may be the same or different, C 1-5 alkylthio, S(O)C 1-5 alkyl, SO2C1-5 alkyl, C 1-5 fiuoroalkylthio, NH(CO)C 1-5 alkyl, NH(CO)C 1-5 alkoxy, NHSO2C1-5 alkyl, (CO)C 1-5 alkyl, COOH, (CO)C 1-5 alkoxy, (C0)NH2, (CO)NHC 1-5 alkyl, (CO)N(C 1-5 alkyl)2, which C 1-5 alkyl may be the same or different, cyano, SO2NHC0-5 alkyl or nitro; D represents a hydrogen bond donor or hydrogen bond acceptor such as hydroxyl, C 1-3 alkylenehydroxy, COOH, NH2, NH(C 1-5 alkyl), N(C 1-5 alkyl)2, C(O)C0-5 alkyl; E represents an (CO)C0-5 alkyl, nitro, SO2C1-5 alkyl, S(0)0C0-5 alkyl, SO2OH, S(O)OH; F represents a C1-C5 alkylene, such as methylene, a heteroatom such as nitrogen, sulphur or oxygen, CO-3 alkyleneOCO-3 alkylene, CO-3 alkylene NHCO-3 alkylene, CO-3 alkyleneSCO-3 alkylene; G represents a group, which is charged at pH 7, wherein such a group may be selected from the group consisting P(O)(OH)2j P(O)(OH)OP(O)(OH)2, COOH and C(C00H)2; G might also represent esters of phosphates and carboxylates, which may be hydrolyzed in vivo to form phosphate or carboxylate; further G might, together with F, represent a group that comprises an oxdizable phosphor or carbon, such as an alkyl with a terminal hydroxyl group, that can be oxidized to a carboxylic acid; H represents a linker selected from the group consisting of C1-C5 alkylene, such as methylene, -N=N- and -CH=CH- (trans); said linker is optionally substituted with lipophilic groups, wherein such lipophilic groups may be selected from the group consisting of halogen, short alkyl, alkoxy; X represents N or CH; as a free base, an acid in its non-charged protonated form or a pharmaceutically acceptable salt, solvate or solvate of a salt thereof In another embodiment A represents, independently of each other, hydrogen, halogen, nitro, (CO)C0-5 alkyl, COOH, S(O)C 1-5 alkyl, SO2C1-5 alkyl, S(O)OC0-5 alkyl, SO2OC0-5 alkyl, C 1-2 alkylenehydroxy or trihalomethyl, such as trifiuormethyl. In a preferred embodiment A represents, independently of each other, hydrogen, halogen, such as fluorine and chlorine, nitro, SO2C1-5 alkyl, such as SO2Me, SO2OC0- 5 alkyl, such as SO2OH, or trifiuormethyl.
In another embodiment B represents, independently of each other, hydrogen, halogen, such as fluorine and chlorine, C1-C5 alkyl, such as methyl, OC1-C5 alkyl, such as OMe and C 1-5 fiuoroalkyl, such as CF3;
In another embodiment C represents H, C 1-5 alkyl, C 1-5 fiuoroalkyl, halo, hydroxy, CO-3 alkyleneOCl-5 alkyl, CO-3 alkyleneOCl-5 fluorolkyl, CO-3 alkyleneNH2, CO-3 alkyleneNHCl-3 alkyl, CO-3 alkyleneN(Cl-5 alkyl)2, which C 1-5 alkyl may be the same or different, C 1-5 alkylthio, S(O)C 1-5 alkyl, SO2C1-5 alkyl, Cl- 5 fiuoroalkylthio, NH(CO)C 1-5 alkyl, NH(CO)C 1-5 alkoxy, NHSO2C1-5 alkyl, (CO)C 1-5 alkyl, COOH, (CO)C 1-5 alkoxy, (C0)NH2, (CO)NHC 1-5 alkyl, (CO)N(Cl- 5 alkyl)2, which C 1-5 alkyl may be the same or different, cyano, SO2NHC0-5 alkyl or nitro. In a preferred embodiment C represents H, C 1-5 alkyl, such as Me, C 1-5 fiuoroalkyl, such as CF3 or halo, such as fluorine and chlorine. In another preferred embodiment C represents H or Me, such as Me.
In another embodiment D represents hydroxy, C 1-3 alkylenehydroxy, such as CH20H, or COOH. In a preferred embodiment D represents hydroxy.
In another embodiment E represents an (CO)C0-5 alkyl, nitro, SO2C1-5 alkyl, S(O)OC0-5 alkyl, SO2OH or S(O)OH. In an preferred embodiment E represents an (CO)C0-5 alkyl, such as C(O)H or C(O)Me. In another preferred embodiment E represents C(O)H. In another embodiment F represents a C0-C5 alkylene, such as a direct bond or a methylene, a heteroatom such as nitrogen, sulphur or oxygen, CO-3 alkyleneOCO-3 alkylene, CO-3 alkylene NHCO-3 alkylene, CO-3 alkyleneSCO-3 alkylene. In a preferred embodiment F represents a C0-C5 alkylene, such a direct bond or as a methylene, or CO-3 alkyleneOCO-1 alkylene, such as Cl alkyleneO and Cl alkyleneOCl alkylene.
In another embodiment G represents P(O)(OH)2, COOH or C(COOH)2. Preferably G represents P(O)(OH)2. G might also represent COOH or C(COOH)2, such as C(COOH)2. Further, G might represent a prodrug of P(O)(OH)2, COOH or C(COOH)2, such as an esters, which may be hydrolyzed in vivo to form phosphate or carboxylate, or G may, together with F, represent a group that comprises an oxdizable phosphor or carbon, such as an alkyl with a terminal hydroxyl group, that can be oxidized to a carboxylic acid.
H represents a linker selected from the group consisting C1-C5 alkylene, such as methylene, -N=N-, -CH=CH- (trans); said linker is optionally substituted with lipophilic groups. Such lipophilic groups may be selected from the group consisting halogen, short alkyl, such as C1-C3 alkyl (e.g. methyl), alkoxy. In a preferred embodiment H represents unsubstituted methylene, -CH=CH- (trans) or -NH=NH- or even more preferred -NH=NH-.
In another embodiment X represents N or CH. In a preferred embodiment X represents N.
Another embodiment relates to a compound according to formula (I), wherein A to H and X is as defined herein.
Another embodiment relates to a compound according to formula (I), wherein A represents, independently of each other, hydrogen, halogen, nitro, SO2C1-5 alkyl, SO2OC0-5 alkyl, such as SO2OH or trifluormethyl; B represents, independently of each other, hydrogen, halogen, C1-C5 alkyl, OC1-C5 alkyl and C 1-5 fluoroalkyl; C represents H, C 1-5 alkyl, C 1-5 fluoroalkyl or halo; D represents hydroxy, C 1-3 alkylenehydroxy or COOH; E represents an (CO)C0-5 alkyl, nitro, SO2C1-5 alkyl, S(O)OC0-5 alkyl, SO2OH or S(O)OH; F represents a C0-C5 alkylene, such as a direct bond or as a methylene, or CO-3 alkyleneOCO-1 alkylene, such as Cl alkyleneO and Cl alkyleneOCl alkylene; G represents P(O)(OH)2, COOH or C(COOH)2; H represents unsubstituted methylene, -CH=CH- (trans) or -NH=NH-; and X represents N or CH.
Another embodiment relates to a compound according to formula (I), wherein A represents, independently of each other, hydrogen, halogen, such as fluorine and chlorine, nitro, S020H or trifluormethyl; B represents, independently of each other, hydrogen, halogen, such as fluorine and chlorine, C1-C5 alkyl, such as Me, OC1-C5 alkyl, such as OMe, and C 1-5 fluoroalkyl, such as CF3; C represents H, C 1-3 alkyl, such as Me, C 1-3 fluoroalkyl, such as CF3, or halo, such as fluorine and chlorine; D represents hydroxy; E represents (CO)C0-5, such as C(O)H; F represents methylene, Cl alkyleneO or Cl alkyleneOCl alkylene; G represents P(O)(OH)2, COOH or
C(COOH)2; H represents unsubstituted methylene, -CH=CH- (trans) or -NH=NH-; and X represents N.
Another embodiment relates to a compound according to formula (I), wherein A represents, independently of each other, hydrogen, halogen, nitro, SO2C1-5 alkyl, SO2OC0-5 alkyl, such as SO2OH or trifluormethyl; B represents, independently of each other, hydrogen, halogen, C1-C5 alkyl, OC1-C5 alkyl and C 1-5 fluoroalkyl; C represents H, C 1-5 alkyl, C 1-5 fluoroalkyl or halo; D represents hydroxy, C 1-3 alkylenehydroxy or COOH; E represents an (CO)C0-5 alkyl, nitro, SO2C1-5 alkyl, S(O)OC0-5 alkyl, SO2OH or S(O)OH; F represents a C0-C5 alkylene, such as a direct bond or as a methylene, or CO-3 alkyleneOCO-1 alkylene, such as Cl alkyleneO and Cl alkyleneOCl alkylene; G represents COOH or C(COOH)2; H represents unsubstituted methylene, -CH=CH- (trans) or -NH=NH-; and X represents N or CH.
Another embodiment relates to a compound according to formula (I), wherein A represents, independently of each other, hydrogen, halogen, such as fluorine and chlorine, nitro, S020H or trifluormethyl; B represents, independently of each other, hydrogen, halogen, such as fluorine and chlorine, C1-C5 alkyl, such as Me, 0C1-C5 alkyl, such as OMe, and C 1-5 fluoroalkyl, such as CF3; C represents H, C 1-3 alkyl, such as Me, C 1-3 fluoroalkyl, such as CF3, or halo, such as fluorine and chlorine; D represents hydroxy; E represents (CO)C0-5, such as C(O)H; F represents methylene, Cl alkyleneO or Cl alkyleneOCl alkylene; G represents COOH or C(COOH)2; H represents unsubstituted methylene, -CH=CH- (trans) or -NH=NH-; and X represents N.
In another embodiment a compound according formula I is selected from the group consisting of:
Figure imgf000014_0001
Figure imgf000014_0002
Figure imgf000015_0001
Figure imgf000015_0002
In another embodiment a compound according formula I is selected from the group consisting of:
Figure imgf000015_0003
Figure imgf000016_0001
Figure imgf000016_0002
In another embodiment the compound is MRS221, presented by the formula πven below.
Figure imgf000016_0003
Another embodiment relates to a compound, as defined in the preceding embodiments, in the form of an addition salt.
Another embodiment relates to a compound, as defined in the preceding embodiments, as a free base, an acid in its non-charged protonated form or a pharmaceutically acceptable salt, solvate or solvate of a salt thereof.
The compounds as disclosed herein may be used in the treatment of diseases and disorders and for the manufacture of a medicament.
Another embodiment relates to a medicament or a composition, such as a pharmaceutical composition, comprising a compound as disclosed herein. Further, such a medicament or a composition may be used in the treatment of diseases and disorders. Such a composition may also be used for the manufacture of a medicament. In the context of the present specification, the term "therapy" and "treatment" includes prevention and/or prophylaxis, unless there are specific indications to the contrary. The terms "therapeutic" and "therapeutically" should be construed accordingly. The compounds, medicaments or compositions disclosed herein may be used in the treatment of diseases such as the metabolic syndrome and all types of diabetes, such as diabetes mellitus type 1 , diabetes mellitus type 2, gestational diabetes mellitus and pre-diabetes mellitus. Furthermore compounds disclosed herein may be used to delay the onset of all types of diabetes such as diabetes mellitus type 1, diabetes mellitus type 2, gestational diabetes mellitus and pre-diabetes mellitus. Additionally compounds disclosed herein may be used to treat or prevent complications of the metabolic syndrome or diabetes, such as, but not limited to macrovascular complications, which includes, but not are limited to myocardial infarction and stroke, and microvascular complications, which includes, but nor are limited to, ocular complications (retinopathy and maculopathy), nefropathy (micro and macroalbuminuria).
Another embodiment relates to a method of prevention and/or treatment of diseases such as the metabolic syndrome and/or all types of diabetes, such as diabetes mellitus type 1, diabetes mellitus type 2, gestational diabetes mellitus and pre-diabetes mellitus, comprising administering to a mammal, including man in need of such prevention and/or treatment, a therapeutically effective amount of compound as disclosed herein or a pharmaceutical composition comprising a therapeutically effective amount of a compound as disclosed herein.
Another embodiment relates to a method of prevention and/or treatment of complications of the metabolic syndrome and/or diabetes, such as, but not limited to macrovascular complications, which includes, but not are limited to myocardial infarction and stroke, and microvascular complications, which includes, but nor are limited to, ocular complications (retinopathy and maculopathy), nefropathy (micro and macroalbuminuria), comprising administering to a mammal, including man in need of such prevention and/or treatment, a therapeutically effective amount of compound as disclosed herein or a pharmaceutical composition comprising a therapeutically effective amount of a compound as disclosed herein.
The compounds disclosed herein may also be used for the manufacture of a medicament for the treatment of diseases, such as the metabolic syndrome and of all types of diabetes, such as diabetes mellitus type 1, diabetes mellitus type 2, gestational diabetes mellitus and pre-diabetes mellitus. Additionally, compounds disclosed herein may be used for the manufacture of a medicament used to delay the onset of all types of diabetes, such as diabetes mellitus type 1, diabetes mellitus type 2, gestational diabetes mellitus and pre-diabetes mellitus. Further, compounds disclosed herein may be used for the manufacture of a medicament for the treatment or prevention of complications of the metabolic syndrome or diabetes, such as, but not limited to macro vascular complications, which includes, but not are limited to myocardial infarction and stroke, and microvascular complications, which includes, but nor are limited to, ocular complications (retinopathy and maculopathy), nephropathy (micro and macroalbuminuria). Such a medicament, as has been described above, may further comprise pharmaceutically acceptable carriers, diluents, stabilisers or excipients.
"Pharmaceutically acceptable" means a carrier, stabiliser, diluent or excipient that, at the dosage and concentrations employed, does not cause any unwanted effects in the patients to whom it is administered. Such pharmaceutically acceptable carriers, stabilisers, dilutents or excipients are well-known in the art (see for example Remington's Pharmaceutical Sciences, 18th edition, A.R Gennaro, Ed., Mack Publishing Company (1990) or handbook of Pharmaceutical Excipients, 3rd edition, A. Kibbe, Ed., Pharmaceutical Press (2000)).
The medicament will be administered to a patient in a pharmaceutically effective dose. By "pharmaceutically effective dose" is meant a dose that is sufficient to produce the desired effects in relation to the condition for which it is administered. The exact dose is dependent on the activity of the compound, manner of administration, nature and severity of the disorder and/or disease and the general conditions, such as age and body weight of the patient. The medicament as disclosed herein may be administered alone or in combination with other therapeutic agents. These agents may be incorporated as part of the same medicament or may be administered separately. Examples of such therapeutic agents, which may administered in combination with the medicament as disclosed herein, are Sulfonylureas, Biguanides, Alpha-glucosidase inhibitors, Thiazolidinediones, Meglitinides, D-phenylalanine derivatives, Amylin synthetic derivatives, Incretin mimetics and Insulins.
By combining a compound according to embodiments of the present invention with another therapeutic agent, such as Sulfonylureas, Biguanides, Alpha-glucosidase inhibitors, Thiazolidinediones, Meglitinides, D-phenylalanine derivatives, Amylin synthetic derivatives, Incretin mimetics and Insulins, it may be possible to achieve better effect, synergistic effects, better glucose control, prolonged duration of the effect, reduced secondary complications, prolonged life and fewer side effects, compared to if only a compound according to the present invention was administrated.
The medicament as disclosed herein may be administered through different routes such as, but not limited to, intravenously, intraperitonealy, intramuscularly, intranasaleously, subcutaneously, sublingually, rectally, orally or through inhalation or insufflation.
Particular suitable formulations of the medicament as disclosed herein are formulations suitable to be taken orally or to be administrated through inhalation or insufflation.
In addition to their use in therapeutic medicine, the compounds of formula [ are also useful as pharmacological tools in the development and standardisation of in vitro and in vivo test systems for die evaluation of the effects of inhibitors of P2Y13 related activity, such as insulin secretion, as pa.i1 of die search for new therapeutics agents,
EXAMPLES:
Compounds according to formula I to III may be synthesized as described by Kim et al (Biochem. Pharmacol. 70 (2005) 266-274, J. Med. Chem. 2001, 44, 340-349 and Drug Development Research 45:52-66 (1998)), by Brown et al (Drug Development Research 53:281-291 (2001)), by Ziganshin et al in Pharmaceutical Chemistry Journal 1998, 32:8, 399-401 or as disclosed in WO 03/082881, which all or incorporated in their entirety by reference. Further, these procedures may be modified by the one skilled in the art to give access to molecules of the type described herein. Guidance for such modifications are given in textbooks known to the one skilled in the art such as
"Heterocyclic chemistry" 4:th ed. Blackwell Publishing by J.A. Joule and L. Mills, "March's advanced organic chemistry" 5:th ed. Wiley Interscience by: M. B. Smith and J. March, "Organic Synthesis" 2:nd ed., McGraw Hill by. M. B. Smith and "Comprehensive Organic Transformations - A Guide to Functional Group Preparations", 2nd ed., Wiley- VCH by R. C. Larock and references given therein.
Intermediates useful to synthesize compounds according to formula I, II or III, wherein G is COOH or C(COOH)2 may be synthesized as disclosed in scheme I below. Various 2-hydroxymethyl-pyridines may be de-protonated by using a base, preferably a sterically hindered base, such as tert-butoxide and reacted with a carboxylic acid ester or a di-carboxylic acid di-ester having a leaving group, such as chlorine or bromine, alfa to the carbonyl. Either the free carboxylic acid or the corresponding ester may then be used in the further synthesis of compounds according to formula I, II, or III as disclosed in prior art and in herein.
Figure imgf000020_0001
hydrolysis
Figure imgf000020_0002
Figure imgf000020_0003
Scheme 1
In scheme 2, a more specific pathway to preferred intermediates is depicted.
Figure imgf000021_0001
R=CH2CO2H, CH(CO2H)2
MnO2
Figure imgf000021_0002
R=CH2CO2H, CH(CO2H)2
Scheme 2
Compounds according to formula I, II or III, wherein H is -CH=CH- (trans), may be synthesized as disclosed by Kim et al in Synthesis 2000, no. 1 p. 119-120.
Compounds according to formula II or III may be synthesized by replacing the aniline derivative used on the synthesis of compounds according to formula I with the corresponding 5-aminoindole or adenosine derivative.
P 2Y receptor expression in mouse islets and beta-cells
Among the P2Y receptors sensitive to purines the highest mRNA levels were found for the ADP receptor P2Y1 and P2Y13 (6.7 ± 0.6 x 10-3 and 1.3 ± 0.6 x 10-3 respectively in mouse pancreatic islets (ratio of GAPDH mRNA expression) and 4.0 ± 3.0 x 10-3 and 1.8 ± 0.3 x 10-3 respectively in mouse beta cells, see fig. 1). The ATP/UTP receptor P2Y2 could only be detected at thousand times lower levels (0.003 ± 0.0004 x 10-3 in mouse pancreatic islets and 0.009 ± 0.004 x 10-3 in mouse beta cells, see figure 1). The ADP receptor P2Y12 and the ATP/UTP receptor P2Y4 could not be detected at all.
Effects ofglucos on insulin and glucagon secretion in the presence of the P2Y13 antagonist MRS2211
MRS2211 is a selective antagonist blocking the binding of ADP to the P2Y13 receptor. Addition of 10 μM MRS 2211 to pancreatic islets augmented the insulin- releasing effect of 8.3 mM glucose from 0.72±0.08 to 1.43=1=0.11 ng/islet*hour (fig. 2). Raising the glucose level to 20 mM resulted as expected in increased insulin release to 1.96±0.15 ng/islet*hour. In the presence 10 μM MRS2211 this increase was further increased to 2.70±0.19 ng/islet*hour (fig 2). 30 μM MRS2211 had similar effects.
Effects of ADP on insulin secretion
The stable ADP analogue 2-MeSADP alone did not alter insulin secretion from mouse pancreatic islets induced by 8.3 mM glucose. Pre-treatment with the selective P2Y1 receptor antagonist MRS2179 resulted in a marked significant decrease in insulin secretion (fig 3). In contrast, pre-treatment with the selective P2Y13 receptor antagonist MRS2211 resulted in a marked significant increase in insulin secretion (fig 3).
References:
1. Parodi J, Flores C, Aguayo C, Rudolph MI, Casanello P, Sobrevia L. Inhibition of nitrobenzylthioinosine-sensitive adenosine transport by elevated D-glucose involves activation of P2Y2 purinoceptors in human umbilical vein endothelial cells. Ore Res. 2002;90:570-577.
2. Nilsson J, Nilsson LM, Chen YW, Molkentin JD, Erlinge D, Gomez MF. High glucose activates nuclear factor of activated T cells in native vascular smooth muscle. Arterioscler Thromb Vase Biol. 2006;26:794-800.
3. Solini A, Iacobini C, Ricci C, Chiozzi P, Amadio L, Pricci F, Di Mario U, Di Virgilio F, Pugliese G. Purinergic modulation of mesangial extracellular matrix production: role in diabetic and other glomerular diseases. Kidney Int. 2005;67:875-885.
4. Hazama A, Hayashi S, Okada Y. Cell surface measurements of ATP release from single pancreatic beta cells using a novel biosensor technique. Pflugers Arch. 1998;437:31-35. 5. Chen YJ, Hsu KW, Chen YL. Acute glucose overload potentiates nitric oxide production in lipopolysaccharide-stimulated macrophages: the role of purinergic receptor activation. Cell Biol Int. 2006;30:817-822.
6. Burnstock G. Purinergic signalling. Br J Pharmacol. 2006;147 Suppl 1:S172-181.

Claims

1. A compound according to formula (I), (II) or (III),
Figure imgf000024_0001
wherein
A represents, independently of each other, hydrogen or groups selected from the group consisting of halogen, nitro, (CO)C0-5 alkyl, COOH, S(0)Cl-5 alkyl, SO2C1-5 alkyl, S(O)OC0-5 alkyl, SO2OC0-5 alkyl, C 1-2 alkylenehydroxy and trihalomethyl;
B represents, independently of each other, hydrogen or groups selected from the group consisting halogen, C1-C5 alkyl, OC1-C5 alkyl and C 1-5 fiuoroalkyl; C represents H, C 1-5 alkyl, C 1-5 fiuoroalkyl, halo, hydroxy, CO-3 alkyleneOCl-5 alkyl, CO-3 alkyleneOCl-5 fluorolkyl, CO-3 alkyleneNH2, CO-3 alkyleneNHCl-3 alkyl, CO-3 alkyleneN(Cl-5 alkyl)2, which C 1-5 alkyl may be the same or different, C 1-5 alkylthio, S(O)C 1-5 alkyl, SO2C1-5 alkyl, C 1-5 fiuoroalkylthio, NH(CO)C 1-5 alkyl, NH(CO)C 1-5 alkoxy, NHSO2C1-5 alkyl, (CO)C 1-5 alkyl, COOH, (CO)C 1 -5 alkoxy, (C0)NH2, (CO)NHC 1 -5 alkyl, (CO)N(C 1 -5 alkyl)2, which C 1 -5 alkyl may be the same or different, cyano, SO2NHC0-5 alkyl or nitro; D represents hydroxyl, C 1-3 alkylenehydroxy, COOH, NH2, NH(C 1-5 alkyl), N(C 1-5 alkyl)2 or C(O)C0-5 alkyl;
E represents an (CO)C0-5 alkyl, nitro, SO2C1-5 alkyl, S(O)OC0-5 alkyl, SO2OH or S(O)OH; F represents a C1-C5 alkylene, nitrogen, sulphur, oxygen, CO-3 alkyleneOCO-3 alkylene, CO-3 alkylene NHCO-3 alkylene or CO-3 alkyleneSCO-3 alkylene;
G represents P(O)(OH)2, P(O)(OH)OP(O)(OH)2, COOH or C(C00H)2;
H represents a linker, substituted or unsubstituted, selected from the group consisting of C1-C5 alkylene, -N=N- and -CH=CH- (trans); and X represents N or CH; as a free base, an acid in its non-charged protonated form or a pharmaceutically acceptable salt, solvate or solvate of a salt thereof for use in the treatment or prevention of a disease or disorder selected from the group consisting of the metabolic syndrome and diabetes.
2. The compound according to claim 1, wherein (I), (II) or (III) is (I).
3. The compound according to claim 1 or 2, wherein
A represents, independently of each other, hydrogen, halogen, nitro, SO2C1-5 alkyl, SO2OC0-5 alkyl or trifluormethyl;
B represents, independently of each other, hydrogen, halogen, C1-C5 alkyl, 0C1-C5 alkyl or C 1-5 fiuoroalkyl;
C represents H, C 1-5 alkyl, C 1-5 fiuoroalkyl or halo;
D represents hydroxy, C 1-3 alkylenehydroxy or COOH; E represents an (CO)C0-5 alkyl, nitro, SO2C1-5 alkyl, S(O)OC0-5 alkyl,
SO2OH or S(O)OH;
F represents a C0-C5 alkylene or CO-3 alkyleneOCO-1 alkylene;
G represents P(O)(OH)2, COOH or C(C00H)2;
H represents unsubstituted methylene, -NH=NH-, -CH=CH- (trans); and X represents N or CH.
4. The compound according to claim 3, wherein
A represents, independently of each other, hydrogen, halogen, nitro, S020H or trifluormethyl; B represents, independently of each other, hydrogen, halogen, C1-C5 alkyl, OC1-C5 alkyl or C 1-5 fiuoroalkyl;
C represents H, C 1-3 alkyl, C 1-3 fiuoroalkyl or halo;
D represents hydroxy;
E represents (CO)C0-5;
F represents methylene, Cl alkyleneO or Cl alkyleneOCl alkylene;
G represents P(O)(OH)2, COOH or C(COOH)2;
H represents unsubstituted methylene, -NH=NH- or -CH=CH- (trans); and
X represents N.
5. The compound according to claim 2 to 4, wherein G represents P(O)(OH)2
6. The compound according to claim 1, wherein said compound is selected from the group consisting of:
Figure imgf000026_0001
Figure imgf000026_0002
7. The compound according to claim 1, wherein said compound is
Figure imgf000027_0001
8. The compound according to any of the preceding claims, wherein said disease is diabetes.
9. A compound according to formula (I), (II) or (III),
Figure imgf000027_0002
wherein
A represents, independently of each other, hydrogen or groups selected from the group consisting of halogen, nitro, (CO)C0-5 alkyl, COOH, S(0)Cl-5 alkyl, SO2C1-5 alkyl, S(O)OC0-5 alkyl, SO2OC0-5 alkyl, C 1-2 alkylenehydroxy and trihalomethyl;
B represents, independently of each other, hydrogen or groups selected from the group consisting halogen, C1-C5 alkyl, OC1-C5 alkyl and C 1-5 fiuoroalkyl; C represents H, C 1-5 alkyl, C 1-5 fluoroalkyl, halo, hydroxy, CO-3 alkyleneOCl-5 alkyl, CO-3 alkyleneOCl-5 fluorolkyl, CO-3 alkyleneNH2, CO-3 alkyleneNHCl-3 alkyl, CO-3 alkyleneN(Cl-5 alkyl)2, which C 1-5 alkyl may be the same or different, C 1-5 alkylthio, S(O)C 1-5 alkyl, SO2C1-5 alkyl, C 1-5 fiuoroalkylthio, NH(CO)C 1 -5 alkyl, NH(CO)C 1 -5 alkoxy, NHSO2C 1 -5 alkyl, (CO)C 1 -5 alkyl, COOH, (CO)C 1-5 alkoxy, (C0)NH2, (CO)NHC 1-5 alkyl, (CO)N(C 1-5 alkyl)2, which C 1-5 alkyl may be the same or different, cyano, SO2NHC0-5 alkyl or nitro;
D represents hydroxyl, C 1-3 alkylenehydroxy, COOH, NH2, NH(C 1-5 alkyl), N(C 1-5 alkyl)2 or C(O)C0-5 alkyl;; E represents an (CO)C0-5 alkyl, nitro, SO2C1-5 alkyl, S(O)OC0-5 alkyl,
SO2OH or S(O)OH;
F represents a C1-C5 alkylene, nitrogen, sulphur, oxygen, CO-3 alkyleneOCO-3 alkylene, CO-3 alkylene NHCO-3 alkylene or CO-3 alkyleneSCO-3 alkylene;
G represents COOH or C(C00H)2; H represents a linker, substituted or unsubstituted, selected from the group consisting of C1-C5 alkylene, -N=N- and -CH=CH- (trans); and
X represents N or CH; as a free base, an acid in its non-charged protonated form or a pharmaceutically acceptable salt, solvate or solvate of a salt thereof
10. The compound according to claim 9, wherein (I), (II) or (III) is (I).
11. The compound according to claim 9 or 10, wherein
A represents, independently of each other, hydrogen, halogen, nitro, SO2C1-5 alkyl, SO2OC0-5 alkyl or trifluormethyl;
B represents, independently of each other, hydrogen, halogen, C1-C5 alkyl, 0C1-C5 alkyl or C 1-5 fluoroalkyl;
C represents H, C 1-5 alkyl, C 1-5 fluoroalkyl or halo;
D represents hydroxy, C 1-3 alkylenehydroxy or COOH; E represents an (CO)C0-5 alkyl, nitro, SO2C1-5 alkyl, S(O)OC0-5 alkyl,
SO2OH or S(O)OH;
F represents a C0-C5 alkylene or CO-3 alkyleneOCO-1 alkylene;
G represents COOH or C(COOH)2;
H represents unsubstituted methylene, -NH=NH-, -CH=CH- (trans); and X represents N or CH.
12. The compound according to claim 11, wherein
A represents, independently of each other, hydrogen, halogen, nitro, SO2OH or trifluormethyl;
B represents, independently of each other, hydrogen, halogen, C1-C5 alkyl, OC1-C5 alkyl or C 1-5 fluoroalkyl;
C represents H, C 1-3 alkyl, C 1-3 fluoroalkyl or halo;
D represents hydroxy;
E represents (CO)C0-5;
F represents methylene, Cl alkyleneO or Cl alkyleneOCl alkylene;
G represents COOH or C(COOH);
H represents unsubstituted methylene, -NH=NH- or -CH=CH- (trans); and
X represents N.
13. The compound according to claim 1, wherein said compound is selected from the group consisting of:
Figure imgf000029_0001
Figure imgf000029_0002
Figure imgf000030_0001
Figure imgf000030_0002
14. A pharmaceutical composition comprising a compound according to any of the claims 9 to 13 and at least one pharmaceutically acceptable carrier, diluent, stabiliser or excipient.
15. A composition according to claim 14, further comprising another therapeutic agent.
16. A pharmaceutical composition comprising a compound according to any of the claims 1 to 7 and at least one pharmaceutically acceptable carrier, diluent, stabiliser or excipient for use in the treatment or prevention of a disease or disorder selected from the group consisting of the metabolic syndrome and diabetes.
17. The composition according to claim 16, further comprising another therapeutic agent.
18. A method of prevention and/or treatment of the metabolic syndrome and/or diabetes, comprising administering to a mammal, including man in need of such prevention and/or treatment, a therapeutically effective amount of compound according to any of the claims 1 to 7 or a composition according to any of the claims 16 to 17 comprising a therapeutically effective amount of a compound according to any of the claims 1 to 7.
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