WO2006083214A1 - Pharmaceutical composition comprising a p2x7 receptor antagonist and a hmg-coa reductase inhibitor - Google Patents

Pharmaceutical composition comprising a p2x7 receptor antagonist and a hmg-coa reductase inhibitor Download PDF

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Publication number
WO2006083214A1
WO2006083214A1 PCT/SE2006/000136 SE2006000136W WO2006083214A1 WO 2006083214 A1 WO2006083214 A1 WO 2006083214A1 SE 2006000136 W SE2006000136 W SE 2006000136W WO 2006083214 A1 WO2006083214 A1 WO 2006083214A1
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Prior art keywords
tricyclo
ylmethyl
chloro
dec
benzamide
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PCT/SE2006/000136
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French (fr)
Inventor
Nigel Boughton-Smith
Martin Braddock
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Astrazeneca Ab
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    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/402—1-aryl substituted, e.g. piretanide
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • 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
    • 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
    • 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

Definitions

  • the present invention relates to combinations of pharmaceutically active substances of use in the treatment of cardiovascular disorders.
  • HMG-CoA reductase inhibitors are a class of therapeutic agent used to lower cholesterol levels in patients with hypercholesterolemia and at risk of cardiovascular disorders. They act by competitively inhibiting 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, a rate-limiting enzyme that converts 3-hydroxy-3-methylglutaryl coenzyme A to mevalonate, a precursor of cholesterol. By inhibiting the rate-controlling step in cholesterol biosynthesis, these agents effectively lower the plasma concentrations of atherogenic particles containing cholesterol such as low-density (LDL-C) and very low- density lipoprotein (VLDL-C).
  • LDL-C low-density
  • VLDL-C very low- density lipoprotein
  • Partial inhibition of hepatic cholesterol synthesis causes up- regulation of hepatic membrane LDL-C receptors that are responsible for the clearance of LDL-C from the circulation.
  • reduced hepatic synthesis of cholesterol is thought to result in the secretion of VLDL-C particles by the liver.
  • HMG-CoA reductase inhibitors are marketed, and are collectively referred to as 'statins'.
  • the P2X 7 receptor (previously known as P2Z receptor), which is a ligand-gated ion channel, is present on a variety of cell types, largely those known to be involved in the inflammatory/immune process, specifically, macrophages, mast cells and lymphocytes (T and B).
  • a pharmaceutical composition comprising, in admixture, a first active ingredient which is a P2X 7 receptor antagonist, and a second active ingredient which is a HMG-CoA reductase inhibitor.
  • the pharmaceutical composition of the present invention comprises as a first active ingredient a P2X 7 receptor antagonist.
  • An antagonist of the P2X 7 receptor is a compound or other substance that is capable of preventing, whether fully or partially, activation of the P2X 7 receptor.
  • the assay is carried out.by taking a 96-well flat bottomed microtitre plate and filling the wells with 250 ⁇ l of test solution comprising 200 ⁇ l of a suspension of THP-I cells (2.5 x 10 6 cells/ml) containing 10 '4 M ethidium bromide, 25 ⁇ l of a high potassium buffer solution containing 10 "5 M benzoylbenzoyl adenosine triphosphate (bbATP, a known P2X 7 receptor agonist), and 25 ⁇ l of the high potassium buffer solution containing 3 x 10 "5 M test compound. The plate is covered with a plastics sheet and incubated at 37 0 C for one hour.
  • test solution comprising 200 ⁇ l of a suspension of THP-I cells (2.5 x 10 6 cells/ml) containing 10 '4 M ethidium bromide, 25 ⁇ l of a high potassium buffer solution containing 10 "5 M benzoylbenzoyl adenosine tri
  • the plate is then read in a Perkin-Elmer fluorescent plate reader, excitation 520 run, emission 595 nm, slit widths: Ex 15 nm, Em 20 nm.
  • bbATP a P2X 7 receptor agonist
  • pyridoxal 5-phosphate a P2X 7 receptor antagonist
  • a pICso figure is calculated for the test compound, this figure being the negative logarithm of the concentration of test compound necessary to reduce the bbATP agonist activity by 50%.
  • a pIC 5 o figure greater than 5.5 is normally indicative of an antagonist.
  • P2X 7 receptor antagonists which may be used in accordance with the present invention are described in WO 00/61569, WO 01/42194, WO 01/44170, WO 01/44213, WO 01/46200, WO 01/94338, WO 03/041707, WO 03/042190, WO 03/042191, WO 03/080579, WO 04/058270, WO 04/058731, WO 04/074224, WO 04/099146, WO 04/106305 and WO05/009968, the entire contents of which are incorporated herein by reference.
  • the P2X 7 receptor antagonist is an adamantyl derivative, for example as described in WO 00/61569, WO 01/42194, WO 01/44170 and WO 03/41707.
  • the P2X 7 receptor antagonist is an adamantyl derivative of formula
  • A represents C(O)NH or NHC(O);
  • Y represents N or CH
  • X represents a bond, CO, (CH 2 ) 1-6 , O(CH 2 ) 1-6 , (CH 2 ) 1-6 NH(CH 2 ) 1-6 , (CH 2 ) L6 O(CHa) 1-6 ,
  • Z represents NR 2 R 3 ;
  • R 1 represents halogen, cyano, nitro, amino, hydroxyl, Ci-C 6 alkyl or C 3 -C 8 cycloalkyl, which alkyl or cycloalkyl group group can be optionally substituted by one or more fluorine atoms;
  • R 2 and R 3 each independently represent a hydrogen atom, Ci-C 6 alkyl or C 3 -C 8 cycloalkyl, which alkyl or cycloalkyl group can be optionally substituted by one or more groups selected from hydroxyl, halogen or Ci-C 6 alkoxy, or R 2 and R 3 together with the nitrogen atom to which they are attached form a 3- to 9- membered saturated mono- or bicyclic heterocyclic ring comprising from 1 to 2 nitrogen atoms and optionally an oxygen atom, which heterocyclic ring can be optionally substituted by one or more groups selected from hydroxyl, halogen or Ci-C 6 alkoxy; or
  • Adamantyl derivatives of formula (I) may be prepared according to known chemistry, for example by methods according or analogous to those described in WO 00/61569, WO 01/42194, WO 01/44170 and WO 03/41707.
  • V2X-] receptor antagonist used in the present invention may be capable of existing in stereoisomeric forms. It will be understood that the invention encompasses all geometric and optical isomers of the active ingredient and mixtures thereof including racemates. Tautomers and mixtures thereof also form an aspect of the present invention. Moreover, it will be understood that certain compounds of the present invention may exist in solvated, for example hydrated, as well as unsolvated forms.
  • the P2X 7 receptor antagonist is selected from
  • Pharmaceutically acceptable salts include, where applicable, acid addition salts derived from pharmaceutically acceptable inorganic and organic acids such as a chloride, bromide, sulphate, phosphate, maleate, fumarate, tartrate, citrate, benzoate, 4-methoxybenzoate, 2- o or 4-hydroxybenzoate, 4-chlorobenzoate, p-toluenesulphonate, methanesulphonate, ascorbate, acetate, succinate, lactate, glutarate, gluconate, tricarballylate, hydroxynaphthalene-carboxylate of oleate salt; and salts prepared from pharmaceutically acceptable inorganic and organic bases.
  • Salts derived from inorganic bases include aluminium, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic,
  • Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary and tertiary amines, cyclic amines like arginine, betaine, choline and the like.
  • P2X 7 receptor antagonists that may give particularly good results when employed in accordance with the present invention include:-
  • the second active ingredient of the present invention is a HMG-CoA reductase inhibitor.
  • a HMG-CoA reductase inhibitor is a compound or substance capable of lowering cholesterol by inhibting 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase.
  • HMG-CoA reductase inhibitors examples include atorvastatin (commercially available under the trade name “Lipitor”), fluvastatin (commercially available under the trade name “Lescol”), lovastatin (commercially available under the trade name “Mevacor”), pravastatin (commercially available under the trade name “Pravachol”), rosuvastatin (commercially available under the trade name “Crestor), and simvastatin (commercially available under the trade name "Zocor”).
  • atorvastatin commercially available under the trade name "Lipitor
  • fluvastatin commercially available under the trade name "Lescol
  • lovastatin commercially available under the trade name "Mevacor”
  • pravastatin commercially available under the trade name "Pravachol”
  • rosuvastatin commercially available under the trade name "Crestor
  • simvastatin commercially available under the trade name "Zocor”
  • HMG-CoA reductase inhibitor includes all pharmaceutically acceptable salts or derivatives that may be formed from said HMG-CoA reductase inhibitor.
  • the HMG-CoA reductase inhibitor is rosuvastatin. In a further aspect of this embodiment, the HMG-CoA reductase inhibitor is rosuvastatin calcium.
  • the HMG-CoA reductase inhibitor is atorvastatin.
  • the HMG-CoA reductase inhibitor is fluvastatin.
  • the HMG-CoA reductase inhibitor is lovastatin. In another embodiment of the present invention the HMG-CoA reductase inhibitor is pravastatin.
  • the HMG-CoA reductase inhibitor is simvastatin.
  • compositions of the present invention may be prepared by mixing the first active ingredient with a second active ingredient. Therefore, in a further aspect of the present invention, there is provided a process for the preparation of a pharmaceutical composition which comprises mixing a first active ingredient which is a P2X 7 receptor antagonist with a second active ingredient which is a HMG-CoA reductase inhibitor.
  • the first and second active ingredients may alternatively be administered simultaneously (other than in admixture as described above), sequentially or separately to treat cardiovascular disorders.
  • sequential it is meant that the first and second active ingredients are administered, in any order, one immediately after the other. They still have the desired effect if they are administered separately but less than 4 hours apart, preferably less than 2 hours apart, more preferably less than 30 minutes apart.
  • a pharmaceutical product comprising, in combination, a preparation of a first active ingredient which is a P2X 7 receptor antagonist (as described herein above) and a preparation of a second active ingredient which is a HMG-CoA reductase inhibitor (as described herein above) for simultaneous, sequential or separate use in therapy.
  • kits comprising a preparation of a first active ingredient which is a P2X 7 receptor antagonist (as described herein above) and a preparation of a second active ingredient which is a HMG-CoA reductase inhibitor (as described herein above), and instructions for the simultaneous, sequential or separate administration of the preparations to a patient in need thereof.
  • the first and second active ingredients may be conveniently administered by oral or parenteral (e.g. intravenous, subcutaneous, intramuscular, intraarticular or inhaled) administration using conventional systemic dosage forms, such as tablets, capsules, pills, powders, aqueous or oily solutions or suspensions, emulsions and sterile injectable aqueous or oily solutions or suspensions.
  • oral or parenteral e.g. intravenous, subcutaneous, intramuscular, intraarticular or inhaled
  • conventional systemic dosage forms such as tablets, capsules, pills, powders, aqueous or oily solutions or suspensions, emulsions and sterile injectable aqueous or oily solutions or suspensions.
  • These dosage forms will usually include one or more pharmaceutically acceptable ingredients which may be selected, for example, from adjuvants, carriers, binders, lubricants, diluents, stabilising agents, buffering agents, emulsifying agents, viscosity-regulating agents, surfactants, preservatives, flavourings and colorants.
  • pharmaceutically acceptable ingredients may be selected, for example, from adjuvants, carriers, binders, lubricants, diluents, stabilising agents, buffering agents, emulsifying agents, viscosity-regulating agents, surfactants, preservatives, flavourings and colorants.
  • the most appropriate method of administering the active ingredients is dependent on a number of factors. However, in a preferred embodiment the first and second active ingredients are delivered orally.
  • each active ingredient will, of course, vary with the particular active ingredient employed, the mode of administration, the treatment desired and the condition or disorder indicated. However, in general satisfactory results will be obtained when the total, combined, daily dosage of first and second active ingredient is in the range from 10 to 2000 milligrammes (mg), 10 to 1800mg, 10 to 1500mg, 10 to 1200mg, 10 to lOOOmg, 10 to 800 mg, 10 to 700 mg, 10 to 600mg, 10 to 500mg, 10 to 400mg, 10 300mg, 10 to 200mg, 10 to lOOmg, 10 to 50mg, 10 to 40mg ; 10 to 30mg, 10 to 20mg, 20 to 2000 mg, 20 to 1800mg, 20 to 1500mg, 20 to 1200mg, 20 to lOOOmg, 20 to 800 mg, 20 to 700 mg, 20 to 600mg, 20 to 500mg, 20 to 400mg, 20 to 300mg, 20 to 200mg, 20 to lOOmg
  • the pharmaceutical composition, pharmaceutical product or kit according to the invention may be administered as divided doses from 1 to 4 times a day, and preferably once or twice a day.
  • the molar ratio between the first and second active ingredients may be in the range of from 1000:1 to 1:1000, preferably 300:1 to 1:300, more preferably 50: 1 to 1 :50.
  • the daily dosage of the first active ingredient in the pharmaceutical composition, product or kit is in the range of from 5 to 1000 mg, 5 to 800mg, 5 to 600mg, 5 to 500mg, 5 to 400mg, 5 to 300mg, 5 to 200mg, 5 to lOOmg, 5 to 50mg, 20 to 1000 mg, 20 to 800mg, 20 to 600mg, 20 to 500mg, 20 to 400mg, 20 to 300mg, 20 to 200mg, 20 to lOOmg, 20 to 50mg, 50 to 1000 mg, 50 to 800mg 3 50 to 600mg, 50 to 500mg, 50 to 400mg, 50 to 300mg, 50 to 200mg, 50 to lOOmg, 100 to 1000 mg, 100 to 800mg, 100 to 600mg, 100 to 500mg, 100 to 400mg, 100 to 300mg, or 100 to 200mg; whilst the daily dose of the second active ingredient is in the range of from 1 to 200mg, 1 to
  • Second active ingredients that may be used in accordance with this embodiment include at ⁇ rvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin and simvastatin.
  • the present invention also provides the use of a pharmaceutical composition, product or kit according to the invention in the manufacture of a medicament for treating cardiovascular disorders, in particular atherosclerosis, particularly in patients suffering from hypercholesterolemia and hyperlipoproteinemia.
  • the present invention provides a method of treating cardiovascular disorders which comprises simultaneously, sequentially or separately administering: (a) a (therapeutically effective) dose of a first active ingredient which is a P2X 7 receptor antagonist; and
  • Said method may be used, for example, in treating atherosclerosis, particularly in patients suffering from hypercholesterolemia and hyperlipoproteinemia.
  • the term “therapy” also includes “prophylaxis” unless there are specific indications to the contrary.
  • the terms “therapeutic” and “therapeutically” should be construed accordingly. Prophylaxis is expected to be particularly relevant to the treatment of persons who have suffered a previous episode of, or are otherwise considered to be at increased risk of, the condition or disorder in question. Persons at risk of developing a particular condition or disorder generally include those having a family history of the condition or disorder, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the condition or disorder.

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Abstract

The invention provides a pharmaceutical composition, product or kit comprising a first active ingredient which is a P2X7 receptor antagonist and a second active ingredient which is a HMG-CoA reductase inhibitor. The P2X7 receptor antagonist is optionally an adamantly derivate and the HMG-CoA reductase inhibitor a statin. The invention is intended for use in the treatment of cardiovascular disorders, especially atherosclerosis.

Description

NEW COMBINATION
The present invention relates to combinations of pharmaceutically active substances of use in the treatment of cardiovascular disorders.
HMG-CoA reductase inhibitors are a class of therapeutic agent used to lower cholesterol levels in patients with hypercholesterolemia and at risk of cardiovascular disorders. They act by competitively inhibiting 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, a rate-limiting enzyme that converts 3-hydroxy-3-methylglutaryl coenzyme A to mevalonate, a precursor of cholesterol. By inhibiting the rate-controlling step in cholesterol biosynthesis, these agents effectively lower the plasma concentrations of atherogenic particles containing cholesterol such as low-density (LDL-C) and very low- density lipoprotein (VLDL-C). Partial inhibition of hepatic cholesterol synthesis causes up- regulation of hepatic membrane LDL-C receptors that are responsible for the clearance of LDL-C from the circulation. In addition, reduced hepatic synthesis of cholesterol is thought to result in the secretion of VLDL-C particles by the liver. Various HMG-CoA reductase inhibitors are marketed, and are collectively referred to as 'statins'.
The P2X7 receptor (previously known as P2Z receptor), which is a ligand-gated ion channel, is present on a variety of cell types, largely those known to be involved in the inflammatory/immune process, specifically, macrophages, mast cells and lymphocytes (T and B). Activation of the P2X7 receptor by extracellular nucleotides, in particular adenosine triphosphate, leads to the release of interleukin-lβ (IL- lβ) and giant cell formation (macrophages/microglial cells), degranulation (mast cells) and proliferation (T cells), apoptosis and L-selectin shedding (lymphocytes).
There is a constant need for new medications to treat or prevent cardiovascular disorders such as atherosclerosis, for example in patients suffering from hyperlipidemia including hypercholesterolemia, and atherosclerotic disease including myocardial infarction, cerebrovascular disease (stroke), angina perctoris and peripheral arterial disease. In accordance with the present invention there is provided a pharmaceutical composition comprising, in admixture, a first active ingredient which is a P2X7 receptor antagonist, and a second active ingredient which is a HMG-CoA reductase inhibitor.
The pharmaceutical composition of the present invention comprises as a first active ingredient a P2X7 receptor antagonist. An antagonist of the P2X7 receptor is a compound or other substance that is capable of preventing, whether fully or partially, activation of the P2X7 receptor. •
Methods for assaying for P2X7 receptor antagonism are known in the art, for example from WO 01/42194 which describes an assay based on the observation that when the P2X7 receptor is activated using a receptor agonist in the presence of ethidium bromide (a fluorescent DNA probe), an increase in the fluorescence of intracellular DNA-bound ethidium bromide is observed. Thus, an increase in fluorescence can be used as a measure of P2X7 receptor activation and therefore to quantify the effect of a compound or substance on the P2X7 receptor.
In WO 01/42194, the assay is carried out.by taking a 96-well flat bottomed microtitre plate and filling the wells with 250 μl of test solution comprising 200 μl of a suspension of THP-I cells (2.5 x 106 cells/ml) containing 10'4M ethidium bromide, 25 μl of a high potassium buffer solution containing 10"5M benzoylbenzoyl adenosine triphosphate (bbATP, a known P2X7 receptor agonist), and 25 μl of the high potassium buffer solution containing 3 x 10"5M test compound. The plate is covered with a plastics sheet and incubated at 37 0C for one hour. The plate is then read in a Perkin-Elmer fluorescent plate reader, excitation 520 run, emission 595 nm, slit widths: Ex 15 nm, Em 20 nm. For the purposes of comparison, bbATP (a P2X7 receptor agonist) andpyridoxal 5-phosphate (a P2X7 receptor antagonist) are used separately in the test as controls. From the readings obtained, a pICso figure is calculated for the test compound, this figure being the negative logarithm of the concentration of test compound necessary to reduce the bbATP agonist activity by 50%. A pIC5o figure greater than 5.5 is normally indicative of an antagonist.
Examples of P2X7 receptor antagonists which may be used in accordance with the present invention are described in WO 00/61569, WO 01/42194, WO 01/44170, WO 01/44213, WO 01/46200, WO 01/94338, WO 03/041707, WO 03/042190, WO 03/042191, WO 03/080579, WO 04/058270, WO 04/058731, WO 04/074224, WO 04/099146, WO 04/106305 and WO05/009968, the entire contents of which are incorporated herein by reference.
In an embodiment of the present invention the P2X7 receptor antagonist is an adamantyl derivative, for example as described in WO 00/61569, WO 01/42194, WO 01/44170 and WO 03/41707.
In an embodiment of the present invention, the P2X7 receptor antagonist is an adamantyl derivative of formula
Figure imgf000004_0001
(I) wherein m represents 1, 2 or 3;
A represents C(O)NH or NHC(O);
Y represents N or CH;
X represents a bond, CO, (CH2)1-6, O(CH2)1-6, (CH2)1-6NH(CH2)1-6, (CH2)L6O(CHa)1-6,
NH(CH2)1-6;
Z represents NR2R3; R1 represents halogen, cyano, nitro, amino, hydroxyl, Ci-C6 alkyl or C3-C8 cycloalkyl, which alkyl or cycloalkyl group group can be optionally substituted by one or more fluorine atoms; R2 and R3 each independently represent a hydrogen atom, Ci-C6 alkyl or C3-C8 cycloalkyl, which alkyl or cycloalkyl group can be optionally substituted by one or more groups selected from hydroxyl, halogen or Ci-C6 alkoxy, or R2 and R3 together with the nitrogen atom to which they are attached form a 3- to 9- membered saturated mono- or bicyclic heterocyclic ring comprising from 1 to 2 nitrogen atoms and optionally an oxygen atom, which heterocyclic ring can be optionally substituted by one or more groups selected from hydroxyl, halogen or Ci-C6 alkoxy; or a pharmaceutically acceptable salt thereof.
Adamantyl derivatives of formula (I) may be prepared according to known chemistry, for example by methods according or analogous to those described in WO 00/61569, WO 01/42194, WO 01/44170 and WO 03/41707.
The V2X-] receptor antagonist used in the present invention may be capable of existing in stereoisomeric forms. It will be understood that the invention encompasses all geometric and optical isomers of the active ingredient and mixtures thereof including racemates. Tautomers and mixtures thereof also form an aspect of the present invention. Moreover, it will be understood that certain compounds of the present invention may exist in solvated, for example hydrated, as well as unsolvated forms.
In another embodiment of the present invention, the P2X7 receptor antagonist is selected from
2-Chloro-5-[[2-(2-hydroxy-ethylamino)-ethylamino]-methyl]-N- (tricyclo[3.3.1.13>7]dec- l-ylmethyl)-benzamide,
2-Chloro-5-[3 -[(3-hydroxypropyl)amino]propyl]-N-(tricyclo[3.3.1.1 ]dec- 1 -ylmethyl)- benzamide, (i?)-2-Chloro-5-[3-[(2-hydroxy-l-methylethyl)amino]propyl]-N- (tricyclo[3.3.1.13'7]dec- 1 -ylmethyl)-benzamide,
2-Chloro-5-[[2-[(2-hydroxyethyl)amino]ethoxy]methyl]-N-(tricyclo[3.3.1.13>7]dec-l - ylmethyl)-benzamide, s 2-Chloro-5-[3-[3-(methylamino)propoxy]propyl]-iV-(tricyclo[3.3.1.13'7]dec-l- ylmethyl)benzamide,
2-Chloro-5-[3-(3-hydroxy-propylamino)-propoxy]-N-(tricyclo[3.3.1. I3>7]dec-1 - ylmetbyl)-benzamide,
2-Chloro-5-[2-(3-hydroxypropylamino)ethylamino]-7V-(tricyclo[3.3.1.13'7]dec-l- o ylmethyl)-benzamide,
2-Chloro-5-[2-(3-hydroxypropylsulfonyl)ethoxy]-N-(tricyclo[3.3.1.13>7]dec- 1- ylmethyl)-benzamide,
2-Chloro-5-[2-[2-[(2-hydroxyethyl)amino]ethoxy]ethoxy]-N-(tricyclo[3.3.1.13>7]dec- 1- ylmethyl)-benzamide, is 2-Chloro-5-[[2-[[2-(l-methyl-lH-imidazol-4-yl)ethyl]amino]ethyl]amino]-N-
(tricyclo[3.3.1.13'7]dec-l-ylmethyl)-benzamide,
2-Chloro-5-piperazin- l-ylmethyl-N-(tricyclo[3.3.1. l]dec- 1 -ylmethyl)-benzamide, 2-Chloro-5-(4-piperidinyloxy)-iV-(tricyclo[3.3.1.13>7]dec-l-ylmethyl)-benzaniide, 2-Chloro-5-(255-diazabicyclo[2.2.1]hept-2-ylmethyl)-N-(tricyclo[3.3.1.1]dec-l- 2o ylmethyl)-benzamide,
2-Chloro-5-(piperidin-4-ylsulfmyl)-N-(tricyclo[3.3.1.13'7]dec-l-ylmethyl)-benzamide, 5-Chloro-2-[3-[(3-hydroxypropyl)amino]propyl]-iV-(tricyclo[3.3.1.13l7]dec-l- ylmethyl)-4-pyridinecarboxamide,
2-Chloro-5-[3-[[(li?)-2-hydroxy-l-methylethyl]amino]propyl]-iV- 25 (tricyclo[3.3.1. l3'7]dec-l-ylmethyl)-3-pyridinecarboxamide,
5-Chloro-2-[3-(ethylamino)propyl]-N-(tricyclo[3.3.1.13>7]dec-l-ylmethyl)-4- pyridinecarboxamide,
5-Chloro-2-[3-[(2-hydroxyethyl)amino]propyl]-N-(tricyclo[3.3.1.13>7]dec-l-ylmethyl)- 4-pyridinecarboxamide, 5-Chloro-2-[3-[[(2,S)-2-hydroxypropyl]amino]ρropyl]-N'-(tricyclo[3.3.1.13>7]dec-l- ylmethyl)-4-pyridinecarboxamide,
N-[2-Methyl-5-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-ylcarbonyl)phenyl]- txicyclo[3.3.1.13>7]decane- 1 -acetamide, 5 or a pharmaceutically acceptable salt thereof.
Pharmaceutically acceptable salts include, where applicable, acid addition salts derived from pharmaceutically acceptable inorganic and organic acids such as a chloride, bromide, sulphate, phosphate, maleate, fumarate, tartrate, citrate, benzoate, 4-methoxybenzoate, 2- o or 4-hydroxybenzoate, 4-chlorobenzoate, p-toluenesulphonate, methanesulphonate, ascorbate, acetate, succinate, lactate, glutarate, gluconate, tricarballylate, hydroxynaphthalene-carboxylate of oleate salt; and salts prepared from pharmaceutically acceptable inorganic and organic bases. Salts derived from inorganic bases include aluminium, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic,
15 manganous, potassium, sodium, zinc and bismuth salts. Particularly preferred are the ammonium, calcium, magnesium, potassium and sodium salts. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary and tertiary amines, cyclic amines like arginine, betaine, choline and the like.
2.0 Examples of P2X7 receptor antagonists that may give particularly good results when employed in accordance with the present invention include:-
2-Chloro-5-[[2-(2-hydroxy-ethylamino)-ethylamino]-methyl]-N- (tricyclo[3.3.1.13'7]dec-l-ylmethyl)-benzamide, dihydrochloride
2-Chloro-5-[3-[(3-hydroxypropyl)amino]propyl]-N-(tricyclo[3.3.1.1]dec-l-ylmethyl)- 25 benzamide, hydrochloride
(i?)-2-Chloro-5-[3-[(2-hydroxy-l-methylethyl)amino]propyl]-N- (tricyclo[3.3.1.13>7]dec-l-yhnethyl)-benzamide, hydrochloride
2-Chloro-5-[[2-[(2-hydroxyethyl)amino]ethoxy]methyl]-N-(tricyclo[3.3.1.13>7]dec-l- ylmethyl)-benzamide, acetate (1:1) salt 2-Chloro- 5 - [3 - [3 -(methylamino)propoxy]propyl] -_V-(tricyclo [3.3.1.13>7] dec- 1 - ylmethyl)benzamide, hydrochloride
2-Chloro-5-[3 -(3 -hydroxy-propylamino)-propoxy] -iV-(tricyclo [3.3.1.13'7] dec- 1 - ylmethyl)-benzamide, hydrochloride 2-Chloro-5-[2-(3-hydroxypropylamino)ethylamino]-N-(tricyclo[3.3.1.13'7]dec-l- ylmethyl)-benzamide, acetate (1:1) salt
2-Chloro-5-[2-(3-hydroxypropylsulfonyl)ethoxy]-N-(tricyclo[3.3.1.13'7]dec-l- ylmethyl)-benzamide
2-Chloro-5-[2-[2-[(2-hydroxyethyl)amino]ethoxy]ethoxy]-N-(tricyclo[3.3.1.13>7]dec-l- ylmethyl)-benzamide, hydrochloride
2-Chloro-5-[[2-[[2-( 1 -methyl- lH-imidazol-4-yl)ethyl] amino] ethyl] amino] -N- (tricyclo [3.3.1.13'7]dec- 1 -ylmethyl)-benzamide
2-Chloro-5-piperazin-l-ylmethyl-N-(tricyclo[3.3.1.1]dec-l-ylmethyl)-benzamide, dihydrochloride 2-Chloro-5-(4-piperidinyloxy)-N-(tricyclo[3.3.1.13'7]dec-l-ylmethyl)-benzamide, hydrochloride
2-Chloro-5-(2,5-diazabicyclo[2.2.1]hept-2-ylmethyl)-N-(tricyclo[3.3.1.1]dec-l- ylmethyl)-benzamide, hydrochloride
2-Chloro-5-(piperidin-4-ylsulfinyl)-iV-(tricyclo[3.3.1.13'7]dec-l-ylmethyl)-benzamide 5-Chloro-2-[3-[(3-hydroxypropyl)amino]propyl]-iV-(tricyclo[3.3.1.13'7]dec-l- ylmethyl) -4-pyridinecarboxamide,
2-Chloro-5-[3-[[(li?)-2-hydroxy-l-methylethyl]amino]proρyl]-N- ' (tricyclo[3.3.1.13j7]dec- 1 -ylmethyl)-3 -pyridinecarboxamide,
5-Chloro-2-[3-(ethylamino)propyl]-N-(tricyclo[3.3.1.13>7]dec- 1 -ylmethyl)-4- pyridinecarboxamide, hydrochloride
5-Chloro-2-[3-[(2-hydroxyethyl)amino]propyl]-N-(tricyclo[3.3.1.13'7]dec-l-ylmethyl)- 4-pyridinecarboxamide, hydrochloride
5-Chloro-2-[3 -[[(25)-2-hydroxypropyl]amino]ρroρyl]-N-(tricyclo[3.3.1.13l7]dec- 1 - ylmethyl)-4-pyridinecarboxamide, dihydrochloride, and N-[2-Methyl-5-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-ylcarbonyl)phenyl]- tricyclo[3.3.1.13'7]decane-l-acetamide, hydrochloride.
The second active ingredient of the present invention is a HMG-CoA reductase inhibitor. A HMG-CoA reductase inhibitor is a compound or substance capable of lowering cholesterol by inhibting 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase.
Examples of HMG-CoA reductase inhibitors that may be used in the invention include atorvastatin (commercially available under the trade name "Lipitor"), fluvastatin (commercially available under the trade name "Lescol"), lovastatin (commercially available under the trade name "Mevacor"), pravastatin (commercially available under the trade name "Pravachol"), rosuvastatin (commercially available under the trade name "Crestor), and simvastatin (commercially available under the trade name "Zocor").
In the context of the present specification, unless otherwise indicated any reference to a HMG-CoA reductase inhibitor includes all pharmaceutically acceptable salts or derivatives that may be formed from said HMG-CoA reductase inhibitor.
In an embodiment of the present invention the HMG-CoA reductase inhibitor is rosuvastatin. In a further aspect of this embodiment, the HMG-CoA reductase inhibitor is rosuvastatin calcium.
In another embodiment of the present invention the HMG-CoA reductase inhibitor is atorvastatin.
In another embodiment of the present invention the HMG-CoA reductase inhibitor is fluvastatin.
In another embodiment of the present invention the HMG-CoA reductase inhibitor is lovastatin. In another embodiment of the present invention the HMG-CoA reductase inhibitor is pravastatin.
In another embodiment of the present invention the HMG-CoA reductase inhibitor is simvastatin.
The pharmaceutical compositions of the present invention may be prepared by mixing the first active ingredient with a second active ingredient. Therefore, in a further aspect of the present invention, there is provided a process for the preparation of a pharmaceutical composition which comprises mixing a first active ingredient which is a P2X7 receptor antagonist with a second active ingredient which is a HMG-CoA reductase inhibitor.
The first and second active ingredients may alternatively be administered simultaneously (other than in admixture as described above), sequentially or separately to treat cardiovascular disorders. By sequential it is meant that the first and second active ingredients are administered, in any order, one immediately after the other. They still have the desired effect if they are administered separately but less than 4 hours apart, preferably less than 2 hours apart, more preferably less than 30 minutes apart.
Therefore, in a further aspect of the present invention there is provided a pharmaceutical product comprising, in combination, a preparation of a first active ingredient which is a P2X7 receptor antagonist (as described herein above) and a preparation of a second active ingredient which is a HMG-CoA reductase inhibitor (as described herein above) for simultaneous, sequential or separate use in therapy.
In another aspect of the present invention there is provided a kit comprising a preparation of a first active ingredient which is a P2X7 receptor antagonist (as described herein above) and a preparation of a second active ingredient which is a HMG-CoA reductase inhibitor (as described herein above), and instructions for the simultaneous, sequential or separate administration of the preparations to a patient in need thereof.
In the pharmaceutical composition, pharmaceutical product or kit according to the present invention, the first and second active ingredients may be conveniently administered by oral or parenteral (e.g. intravenous, subcutaneous, intramuscular, intraarticular or inhaled) administration using conventional systemic dosage forms, such as tablets, capsules, pills, powders, aqueous or oily solutions or suspensions, emulsions and sterile injectable aqueous or oily solutions or suspensions. These dosage forms will usually include one or more pharmaceutically acceptable ingredients which may be selected, for example, from adjuvants, carriers, binders, lubricants, diluents, stabilising agents, buffering agents, emulsifying agents, viscosity-regulating agents, surfactants, preservatives, flavourings and colorants. As will be understood by those skilled in the art, the most appropriate method of administering the active ingredients is dependent on a number of factors. However, in a preferred embodiment the first and second active ingredients are delivered orally.
The dosages of each active ingredient will, of course, vary with the particular active ingredient employed, the mode of administration, the treatment desired and the condition or disorder indicated. However, in general satisfactory results will be obtained when the total, combined, daily dosage of first and second active ingredient is in the range from 10 to 2000 milligrammes (mg), 10 to 1800mg, 10 to 1500mg, 10 to 1200mg, 10 to lOOOmg, 10 to 800 mg, 10 to 700 mg, 10 to 600mg, 10 to 500mg, 10 to 400mg, 10 300mg, 10 to 200mg, 10 to lOOmg, 10 to 50mg, 10 to 40mg; 10 to 30mg, 10 to 20mg, 20 to 2000 mg, 20 to 1800mg, 20 to 1500mg, 20 to 1200mg, 20 to lOOOmg, 20 to 800 mg, 20 to 700 mg, 20 to 600mg, 20 to 500mg, 20 to 400mg, 20 to 300mg, 20 to 200mg, 20 to lOOmg, 20 to 50mg, 20 to 40mg, 20 to 30mg, 30 to 2000 mg, 30 to 1800mg, 30 to 1500mg, 30 to 1200mg, 30 to lOOOmg, 30 to 800 mg, 30 to 700 mg, 30 to 600mg, 30 to 500mg, 30 to 400mg, 30 to 300mg, 30 to 200mg, 30 to lOOmg, 30 to 50mg, 30 to 40mg, 40 to 2000 mg, 40 to 1800mg, 40 to 1500mg, 40 to 1200mg, 40 to lOOOmg, 40 to 800 mg, 40 to 700 mg, 40 to 600mg, 40 to 500mg, 40 to 400mg, 40 to 300mg, 40 to 200mg, 40 to lOOmg, 40 to 50mg, 50 to 2000 mg, 50 to 1800mg, 50 to 1500mg, 50 to 1200mg, 50 to lOOOmg, 50 to 800 mg, 50 to 700 mg, 50 to 600mg3 50 to 500mg, 50 to 400mg, 50 to 300mg, 50 to 200mg, 50 to lOOmg, 100 to 2000 mg, 100 to 1800mg, 100 to 1500mg, 100 to 1200mg, 100 to lOOOmg, 100 to 800 mg, 100 to 700 mg, 100 to 600mg, 100 to 500mg, 100 to 400mg, 100 to 300mg, 100 to 200mg, 200 to 2000 mg, 200 to 1800mg, 200 to 1500mg, 200 to 1200mg, 200 to lOOOmg, 200 to 800 mg, 200 to 700 mg, 200 to 600mg, 200 to 500mg, 200 to 400mg, 200 to 300mg, 300 to 2000 mg, 300 to 1800mg, 300 to 1500mg, 300 to 1200mg, 300 to lOOOmg, 300 to 800 mg, 300 to 700 mg, 300 to 600mg, 300 to 500mg, 300 to 400mg, 400 to 2000 mg, 400 to 1800mg, 400 to 1500mg, 400 to 1200mg, 400 to lOOOmg, 400 to 800 mg, 400 to 700 mg, 400 to 600mg, 400 to 500mg, 500 to 2000 mg, 500 to 1800mg, 500 to 1500mg, 500 to 1200mg, 500 to lOOOmg, 500 to 800 mg, 500 to 700 mg, 500 to 600mg, 600 to 2000 mg, 600 to 1800mg, 600 to 1500mg, 600 to 1200mg, 600 to lOOOmg, 600 to 800 mg, 600 to 700 mg, 700 to 2000 mg, 700 to 1800mg, 700 to 1500mg, 700 to 1200mg, 700 to lOOOmg, 700 to 800 mg, 800 to 2000 mg, 800 to 1800mg, 800 to 1500mg, 800 to 1200mg, 800 to lOOOmg, 1000 to 2000 mg, 1000 to 1800mg, 1000 to 1500mg or 1000 to 1200mg.
The pharmaceutical composition, pharmaceutical product or kit according to the invention may be administered as divided doses from 1 to 4 times a day, and preferably once or twice a day.
The molar ratio between the first and second active ingredients may be in the range of from 1000:1 to 1:1000, preferably 300:1 to 1:300, more preferably 50: 1 to 1 :50.
In an embodiment of the present invention the daily dosage of the first active ingredient in the pharmaceutical composition, product or kit is in the range of from 5 to 1000 mg, 5 to 800mg, 5 to 600mg, 5 to 500mg, 5 to 400mg, 5 to 300mg, 5 to 200mg, 5 to lOOmg, 5 to 50mg, 20 to 1000 mg, 20 to 800mg, 20 to 600mg, 20 to 500mg, 20 to 400mg, 20 to 300mg, 20 to 200mg, 20 to lOOmg, 20 to 50mg, 50 to 1000 mg, 50 to 800mg3 50 to 600mg, 50 to 500mg, 50 to 400mg, 50 to 300mg, 50 to 200mg, 50 to lOOmg, 100 to 1000 mg, 100 to 800mg, 100 to 600mg, 100 to 500mg, 100 to 400mg, 100 to 300mg, or 100 to 200mg; whilst the daily dose of the second active ingredient is in the range of from 1 to 200mg, 1 to lOOmg, 1 to 80mg, 1 to 50mg, 1 to 40mg, 1 to 30mg, 1 to 20mg, 5 to 200mg, 5 to lOOmg, 5 to 80mg, 5 to 50mg, 5 to 40mg, 5 to 30mg, 5 to 20mg, 10 to 200mg, 10 to lOOmg, 10 to 80mg, 10 to 50mg, 10 to 40mg, 10 to 30mg, or 10 to 20mg, which daily doses of first and second active ingredient may be administered as divided doses from 1 to 4 times a day, preferably once or twice a day, and which first and second active ingredients may be administered in admixture, simultaneously , sequentially or separately. The dosing regime of this embodiment may conveniently be adopted where both the first and second active ingredients are delivered by oral administration. Second active ingredients that may be used in accordance with this embodiment include atόrvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin and simvastatin.
The present invention also provides the use of a pharmaceutical composition, product or kit according to the invention in the manufacture of a medicament for treating cardiovascular disorders, in particular atherosclerosis, particularly in patients suffering from hypercholesterolemia and hyperlipoproteinemia.
Still further, the present invention provides a method of treating cardiovascular disorders which comprises simultaneously, sequentially or separately administering: (a) a (therapeutically effective) dose of a first active ingredient which is a P2X7 receptor antagonist; and
(b) a (therapeutically effective) dose of a second active ingredient which is a HMG-CoA reductase inhibitor; to a patient in need thereof. Said method may be used, for example, in treating atherosclerosis, particularly in patients suffering from hypercholesterolemia and hyperlipoproteinemia.
In the context of the present specification, the term "therapy" also includes "prophylaxis" unless there are specific indications to the contrary. The terms "therapeutic" and "therapeutically" should be construed accordingly. Prophylaxis is expected to be particularly relevant to the treatment of persons who have suffered a previous episode of, or are otherwise considered to be at increased risk of, the condition or disorder in question. Persons at risk of developing a particular condition or disorder generally include those having a family history of the condition or disorder, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the condition or disorder.

Claims

C L A I M S
1. A pharmaceutical composition comprising, in admixture, a first active ingredient which is a P2X7 receptor antagonist, and a second active ingredient which is a HMG-CoA reductase inhibitor.
2. A pharmaceutical composition according to claim 1 wherein the P2X7 receptor antagonist is a compound of formula
Figure imgf000015_0001
(I) wherein m represents 1, 2 or 3;
A represents C(O)NH or NHC(O); Y represents N or CH;
X represents a bond, CO3 (CH2)1-6, O(CH2)1-6, (CH2)]-6NH(CH2)1-6, (CH2)1-6O(CH2)1-6,
NH(CH2)1-6;
Z represents NR2R3;
R1 represents halogen, cyano, nitro, amino, hydroxyl, Cj-C6 alkyl or C3-C8 cycloalkyl, which alkyl or cycloalkyl group can be optionally substituted by one or more fluorine atoms;
R2 and R3 each independently represent a hydrogen atom, Ci-C6 alkyl or C3-C8 cycloalkyl, which alkyl or cycloalkyl group can be optionally substituted by one or more groups selected from hydroxyl, halogen or Ci-C6 alkoxy, or R2 and R3 together with the nitrogen atom to which they are attached form a 3- to 9- membered saturated mono- or bicyclic heterocyclic ring comprising from 1 to 2 nitrogen atoms and optionally an oxygen atom, which heterocyclic ring can be optionally . substituted by one or more groups selected from hydroxyl, halogen or C1-C6 alkoxy; 5 or a pharmaceutically acceptable salt thereof.
3. A composition according to claim 1 or claim 2 wherein the P2X7 receptor antagonist is selected from:
2-Chloro-5- [[2-(2-hydroxy-ethylamino)-ethylamino] -methyl] -N- i o (tricyclo [3.3.1.13'7] dec- 1 -ylmethyi)-benzarnide,
2-Chloro- 5- [3 - [(3 -hydroxypropyl)amino]propyl] -N-(tricyclo [3.3.1.1] dec- 1 -ylmethyl)- benzamide,
(i?)-2-Chloro-5-[3-[(2-hydroxy-l-methylethyl)amino]propyl]-N- (tricyclo[3.3.1.13>7]dec-l-yhnethyl)-benzamide, is 2-Chloro-5-[[2-[(2-hydroxyethyl)amino]ethoxy]methyl]-N-(tricyclo[3.3.1.13l7]dec-l- ylmethyl)-benzamide,
2-Chloro-5-[3-[3-(methylamino)propoxy]propyl]-N-(tricyclo[3.3.1.13'7]dec-l- ylmethyl)benzamide,
2-Chloro-5-[3-(3-hydroxy-propylamino)-propoxy]-N-(tricyclo[3.3.1.13>7]dec-1 - 20 ylmethyl)-benzamide,
2-Chloro-5-[2-(3-hydroxypropylamino)ethylamino]-N-(tricyclo[3.3.1.13>7]dec- 1 - ylmethyi)-benzamide,
2-Chloro-5-[2-(3-hydroxypropylsulfonyl)ethoxy]-iV-(tricyclo[3.3.1.13l7]dec-l- ylmethyl)-benzamide,
25 2-Chloro-5-[2-[2-[(2-hydroxyethyl)amino]ethoxy]ethoxy]-N-(tricyclo[3.3.1.13'7]dec-l- ylmethyl)-benzamide,
2-Chloro-5-[[2-[[2-(l-methyl-lH-imidazol-4-yl)ethyl]amino]ethyl]amino]-7V- (tricyclo[3.3.1.13>7]dec-l-ylmethyl)-benzamide,
2-Chloro-5-piperazin-l-ylmethyl-N-(tricyclo[3.3.1.1]dec-l-ylmethyl)-benzamide, 30 2-Chloro-5-(4-piperidinyloxy)-N-(tricyclo[3.3.1.13>7]dec- 1 -yhnethyl)-benzamide, 2-Chloro-5-(2,5-diazabicyclo[2.2.1]hept-2-ylmethyl)-iV-(tricyclo[3.3.1.1]dec-l- ylmethyl)-benzamide,
2-Chloro-5-(piperidin-4-ylsulfinyl)-N-(tricyclo[3.3.1.13>7]dec-l-ylmethyl)-benzamide,
5-Chloro-2-[3-[(3-hydroxypropyl)amino]propyl]-N-(tricyclo[3.3.1.13l7]dec-l- ylmethyl)-4-pyridinecarboxamide,
2-Chloro-5-[3-[[(li?)-2-hydroxy-l-methylethyl]amino]propyl]-N- (tricyclo[3.3.1 , 13>7]dec- l-ylmethyl)-3-pyridinecarboxamide,
5-Chloro-2-[3-(ethylamino)ρropyl]-N-(tricyclo[3.3.1.13'7]dec-l-ylmethyl)-4- pyridinecarboxamide, 5-Chloro-2-[3-[(2-b.ydroxyethyl)amino]propyl]-N-(tricyclo[3.3.1.13'7]dec-l-ylmethyl)-
4-pyridinecarboxamide,
5-Chloro-2-[3-[[(25)-2-hydroxyproρyl]ammo]proρyl]-N-(tricyclo[3.3.1.13>7]dec-l- ylmethyl)-4-pyridinecarboxamide,
N-[2-Methyl-5-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-ylcarbonyl)phenyl]- tricyclo[3.3.1.13'7]decane-l-acetamide, or a pharmaceutically acceptable salt of any one thereof.
4. A composition according to any one of claims 1 to 3 wherein the HMG-CoA reductase inhibitor is selected from atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin and simvastatin.
5. A composition according to claim 4 wherein the HMG-CoA reductase inhibitor is rosuvastatin calcium.
6. A process for the preparation of a pharmaceutical composition as defined in any one of claims 1 to 6, which comprises mixing a P2X7 receptor antagonist with a HMG-CoA reductase inhibitor.
7. A pharmaceutical product comprising, in combination, a preparation of a first active ingredient which is a P2X7 receptor antagonist and a preparation of a second active ingredient which is a HMG-CoA reductase inhibitor for simultaneous, sequential or separate use in therapy.
8. A pharmaceutical product according to claim 7 wherein the P2X7 receptor antagonist is selected from;-
2-Chloro-5-[[2-(2-hydroxy-ethylamino)-ethylamino]-methyl]-N- (tricyclo[3.3.1.13j7]dec- 1 -ylmethyl)-benzamide,
2-Chloro-5-[3-[(3-hydroxypropyl)amino]propyl]-N-(tricyclo[3.3.1. l]dec-l -ylmethyl)- benzamide, (i?)-2-Chloro-5-[3-[(2-hydroxy-l-methylethyl)amino]propyl]-N-
(tricyclo[3.3.1.13'7]dec- 1 -ylmethyl)-benzamide,
2-Chloro-5-[[2-[(2-hydroxyethyl)amino]ethoxy]methyl]-N-(tricyclo[3.3.1.13'7]dec-1 - ylmethyl)-benzamide,
2-Chloro-5-[3-[3-(methylamino)propoxy]propyl]-iV-(tricyclo[3.3.1.13>7]dec-l- ylmethyl)benzamide,
2-Chloro-5 - [3 -(3 -hydroxy-propy lamino)-propoxy] -N-(tricyclo [3.3.1.13'7] dec- 1 - ylniethyl)-benzamide,
2-Chloro-5-[2-(3 -hydroxyprbpylamino)ethylamino]-N-(tricyclo [3.3.1.13>7] dec- 1 - ylmethyl)-benzamide, 2-Chloro-5-[2-(3-hydroxypropylsulfonyl)ethoxy]-N-(tricyclo[3.3.1.13>7]dec- 1 - ylmethyl)-benzamide,
2-Chloro-5-[2-[2-[(2-hydroxyethyl)amino]ethoxy]ethoxy]-N-(tricyclo[3.3.1.13>7]dec-1- ylmethyl)-benzamide,
2-Chloro-5-[[2-[[2-(l-methyl-lif-imidazol-4-yl)ethyl]amino]ethyl]amino]-iV- (tricyclo[3.3.1.13>7]dec-l-ylmethyl)-benzamide,
2-Chloro-5-piperazin- 1 -ylmethyl-N-(tricyclo[3.3.1.1 ]dec- l-ylmethyl)-benzamide, 2-Chloro-5-(4-piperidinyloxy)-iV-(tricyclo[3.3.1.13'7]dec-l-ylmethyl)-benzamide, 2-Chloro-5-(2,5-diazabicyclo[2.2. l]hept-2-ylmethyl)-7V-(tricyclo[3.3.1. l]dec- 1- ylmethyl)-benzamide, o 2-Chloro-5-(piperidm-4-ylsulfinyl)-N-(tricyclo[3.3.1.13'7]dec-l-ylmethyl)-benzamide, 5-Chloro-2-[3-[(3-hydroxypropyl)amino]propyl]-N-(tricyclo[3.3.1.13'7]dec-l- ylmethyl)-4-pyridinecarboxamide,
2-Chloro-5-[3-[[(li?)-2-hydroxy-l-methylethyliamino]propyl]-N- (tricyclo[3.3.1.13>7]dec- 1 -ylmethyl)-3 -pyridinecarboxamide, 5-Chloro-2-[3-(ethylamino)propyl]-N-(tricyclo[3.3.1.13>7]dec-l-ylmethyl)-4- pyridinecarboxamide,
5-Chloro-2-[3-[(2-hydroxyethyl)amino]propyl]-N-(tricyclo[3.3.1.13|7]dec-l-ylmethyl)- 4-pyridinecarboxamide,
5-Chloro-2-[3-[[(2.S)-2-hydroxypropyl]amino]propyl]-N-(tricyclo[3.3.1.13'7] dec- 1 - ylmethyl)-4-pyridinecarboxamide,
N-[2-Methyl-5-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-ylcarbonyl)phenyl]- tricyclo[3.3.1.13'7]decane-l-acetamide, or a pharmaceutically acceptable salt of any one thereof.
9. A pharmaceutical product according to claim 7 or 8, wherein the HMG-CoA reductase inhibitor is selected from atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin and simvastatin.
10. A kit comprising a preparation of a first active ingredient which is a P2X7 receptor antagonist and a preparation of a second active ingredient which is a HMG-CoA reductase inhibitor and instructions for the simultaneous, sequential or separate administration of the preparations to a patient in need thereof.
11. A kit according to claim 10 wherein the P2X7 receptor antagonist is selected from;- 2-Chloro-5-[[2-(2-hydroxy-ethylamino)-ethylamino]-methyl]-iV-
(tricyclo[3.3.1.13'7] dec- l-ylmethyl)-benzamide,
2-Chloro-5-[3-[(3-hydroxypropyl)amino]propyl]-iV-(tricyclo[3.3.1.1]dec-l-ylmethyl)- benzamide,
(i?)-2-Chloro-5-[3-[(2-hydroxy-l-methylethyl)amino]propyl]-N- (tricyclo[3.3.1.13'7] dec- 1 -ylmethyl)-benzamide, 2-Chloro-5-[[2-[(2-hydroxyethyl)amino]ethoxy]methyl]-N-(tricyclo[3.3.1.13'7]dec-l- ylmethyl)-benzamide,
2-Chloro-5-[3-[3-(methylamino)propoxy]propyl]-N-(tricyclo[3.3.1.13>7]dec-l- ylmethyl)benzamide, 2-Chloro-5-[3-(3-hydroxy-propylamino)-propoxy]-N-(tricyclo[3.3.1.13'7]dec-l- ylmethyl)-benzamide,
2-Chloro-5-[2-(3-hydroxypropylamino)ethylamino]-N-(tricyclo[3.3.1.13j7]dec-l- ylmethy l)-benzamide ,
2-Chloro-5-[2-(3-hydroxypropylsulfonyl)ethoxy]-N-(tricyclo[3.3.1.13>7]dec- 1 - ylmethyl)-benzamide,
2-Chloro-5-[2-[2-[(2-hydroxyethyl)amino]ethoxy]ethoxy]-iV-(tricyclo[3.3.1.13'7]dec-l- ylmethyl)-benzamide,
2-Chloro-5-[[2^[2-(l-methyl-lH-imidazol-4-yl)ethyl]amino]etibyl]amino]-iV- (tricyclo[3.3.1.13'7]dec- 1 -ylmethyl)-benzamide, 2-Chloro-5-piperazin- 1 -ylmethyl-7V-(tricyclo[3.3.1.1 ]dec- 1 -ylmethyl)-benzamide,
2-Chloro-5-(4-piperidinyloxy)-N-(tricyclo[3.3.1.13>7]dec-l-ylmethyl)-benzamide, 2-Chloro-5-(2,5-diazabicyclo[2.2.1 ]hept-2-ylmethyl)-N-(tricyclo [3.3.1.1 ] dec- 1 - ylmethyl)-benzamide,
2-Chloro-5-(piperidin-4-ylsulfinyl)-N-(tricyclo[3.3.1.13>7]dec-l-ylmethyl)-benzamide, 5-Chloro-2-[3-[(3-hydroxypropyl)amino]propyl]-N-(tricyclo[3.3.1.13'7]dec- 1 - ylmethyl)-4-pyridinecarboxamide,
2-Chloro-5-[3-[[(li?)-2-hydroxy-l-methylethyl]amino]propyl]-N- (tricyclo[3.3.1.13'7]dec-1 -ylmethyl)-3-pyridinecarboxamide,
5-Chloro-2-[3-(ethylamino)propyl]-N-(tricyclo[3.3.1. l3l7]dec-l-ylmethyl)-4- pyridinecarboxamide,
S-Chloro^-p-^-hydroxyethy^aminojpropyll-N-^cyclotS.S .1.13>7]dec-l-ylmethyl)- 4-pyridinecarboxamide,
5-Chloro-2-[3-[[(2,S)-2-hydroxypropyl]amino]propyl]-iV-(tricyclo[3.3.1.13'7]dec-l- ylmethyl)-4-pyridinecarboxamide, N-[2-Methyl-5-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-ylcarbonyl)phenyl]- tricyclo[3.3.1.13>7]decane-l-acetamide, or a pharmaceutically acceptable salt of any one thereof.
12. A kit according to claim 10 or 11, wherein the HMG-CoA reductase inhibitor is selected from atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin and simvastatin.
13. Use of a pharmaceutical composition, product or kit according to any one of the proceeding claims in manufacture of a medicament for the treatment of a cardiovascular disorder.
14. Use according to claim 13, wherein the cardiovascular disorder is atherosclerosis.
15. A method of treating a cardiovascular disorders which comprises simultaneously, sequentially or separately administering:
(a) a (therapeutically effective) dose of a first active ingredient which is a P2X7 receptor antagonist; and
(b) a (therapeutically effective) dose of a second active ingredient which is a HMG-CoA reductase inhibitor; to a patient in need thereof.
16. A method according to claim 15, wherein the cardiovascular disorder is atherosclerosis.
PCT/SE2006/000136 2005-02-02 2006-01-31 Pharmaceutical composition comprising a p2x7 receptor antagonist and a hmg-coa reductase inhibitor WO2006083214A1 (en)

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WO2011054947A1 (en) 2009-11-09 2011-05-12 Glaxo Group Limited Thiadiazolidinedioxide p2x7 receptor antagonists
WO2011109833A2 (en) 2010-03-05 2011-09-09 President And Fellows Of Harvard College Induced dendritic cell compositions and uses thereof
WO2015003246A1 (en) * 2013-07-09 2015-01-15 Mcmaster University Combination of a statin with an inflammasome inhibitor

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WO2009074519A1 (en) * 2007-12-12 2009-06-18 Glaxo Group Limited Combinations of pyrazolyl or isoxazolyl p2x7 modulators with further therapeutic agents
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WO2015003246A1 (en) * 2013-07-09 2015-01-15 Mcmaster University Combination of a statin with an inflammasome inhibitor

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