WO1999020110A1 - Therapie d'association permettant de reduire les risques lies aux maladies cardio-vasculaires et cerebro-vasculaires - Google Patents

Therapie d'association permettant de reduire les risques lies aux maladies cardio-vasculaires et cerebro-vasculaires Download PDF

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Publication number
WO1999020110A1
WO1999020110A1 PCT/US1998/021901 US9821901W WO9920110A1 WO 1999020110 A1 WO1999020110 A1 WO 1999020110A1 US 9821901 W US9821901 W US 9821901W WO 9920110 A1 WO9920110 A1 WO 9920110A1
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Prior art keywords
phenyl
methylsulfonyl
inhibitor
dimethyl
furan
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PCT/US1998/021901
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English (en)
Inventor
Melvin Winokur
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Merck & Co., Inc.
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Priority claimed from GBGB9806688.9A external-priority patent/GB9806688D0/en
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to CA002306646A priority Critical patent/CA2306646A1/fr
Priority to AU13612/99A priority patent/AU753657B2/en
Priority to JP2000516533A priority patent/JP2001520174A/ja
Priority to EP98957328A priority patent/EP1024696A4/fr
Publication of WO1999020110A1 publication Critical patent/WO1999020110A1/fr

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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • 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
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • 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
    • A61K31/365—Lactones
    • 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
    • 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
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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 instant invention involves a drug combination comprising a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (or HMG-CoA RI) in combination with an inhibitor of cyclooxygenase-2.
  • HMG-CoA 3-hydroxy-3-methylglutaryl coenzyme A
  • HMG-CoA RI 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor
  • Inhibitors of cyclooxygenase-2 are a sub-class of the class of drugs known as non-steroidal antiinflammatory drugs (NSAIDs).
  • NSAIDs non-steroidal antiinflammatory drugs
  • the NSAIDs are active in reducing the prostaglandin-induced pain and swelling associated with the inflammation process but are also active in affecting other prostaglandin-regulated processes not associated with the inflammation process.
  • use of high doses of most common NSAIDs can produce severe side effects, including life threatenting ulcers, that limit their therapeutic potential.
  • An alternative to NSAIDs is the use of corticosteroids, which have even more drastic side effects, especially when long term therapy is involved.
  • Previous NSAIDs have been found to prevent the production of prostaglandin by inhibiting enzymes in the human arachidonic acid/prostaglandin pathway including the enzyme cyclooxygenase (COX).
  • COX cyclooxygenase
  • LDL low density lipoprotein
  • HDL high density lipoprotein
  • this therapy is not easy to administer or tolerate and was therefore often unsuccessful except in specialist lipid clinics.
  • the fibrates produce a moderate reduction in LDL cholesterol accompanied by increased HDL cholesterol and a substantial reduction in triglycerides, and because they are well tolerated these drugs have been more widely used.
  • Probucol produces only a small reduction in LDL cholesterol and also reduces HDL cholesterol, which, because of the strong inverse relationship between HDL cholesterol level and CHD risk, is generally considered undesirable.
  • lovastatin the first inhibitor of HMG-CoA reductase to become available for prescription in 1987, for the first time physicians were able to obtain large reductions in plasma cholesterol with very few adverse effects.
  • lovastatin, simvastatin and pravastatin all members of the HMG-CoA reductase inhibitor class, slow the progression of atherosclerotic lesions in the coronary and carotid arteries.
  • Simvastatin and pravastatin have also been shown to reduce the risk of coronary heart disease events, and in the case of simvastatin a highly significant reduction in the risk of coronary death and total mortality has been shown by the Scandinavian Simvastatin Survival Study. This study also provided some evidence for a reduction in cerebrovascular events.
  • the instant invention addresses this problem by providing a combination therapy comprised of an HMG-CoA RI with a COX-2 inhibitor.
  • a combination therapy comprised of an HMG-CoA RI with a COX-2 inhibitor.
  • the COX-2 inhibitor together with the HMG-CoA RI provide enhanced treatment options as compared to administration of either the HMG-CoA RI or the COX-2 inhibitor alone.
  • the instant invention provides a novel drug combination comprised of an HMG-CoA reductase inhibitor in combination with a COX-2 inhibitor, which is useful for treating, preventing, and/or reducing the risk of developing atherosclerosis and atherosclerotic disease events.
  • One object of the instant invention is to administer the above-described combination therapy to people who do not yet show clinical signs of atherosclerosis, but who are at risk of developing atherosclerosis and associated diseases.
  • Clinical manifestations of atherosclerosis include atherosclerotic cardiovascular disease such as coronary heart disease (also known as ischemic heart disease), cerebrovascular disease, and peripheral vessel disease.
  • the instant invention provides methods for preventing or reducing the risk of developing atherosclerotic cardiovascular disease, coronary heart disease, cerebrovascular disease and peripheral vessel disease, and preventing or reducing the risk of a first or subsequent occurrence of a coronary heart disease event, a cerebrovascular event, and/or intermittent claudication, by administering the above-described combination therapy to said at-risk persons.
  • a second object of the instant invention is to provide the above-described combination therapy to people who have clinical signs of atherosclerosis.
  • the instant invention provides methods for halting or slowing the progression of atherosclerotic cardiovascular disease, coronary heart disease, ischemic heart disease, cerebrovascular disease and peripheral vessel disease, and preventing or reducing the risk of a first or subsequent occurrence of a coronary heart disease event, a cerebrovascular event, and/or intermittent claudication, by administering the above-described combination therapy to said persons who have clinically manifest atherosclerotic disease.
  • a third object of the instant invention involves the above- described methods further comprising the administration of one or more additional active agents either in separate or combined dosage formulations.
  • a fourth object is to provide pharmaceutical compositions which can be used in the above-described methods. Additional objects will be evident from the following detailed description.
  • the instant invention provides methods for preventing or reducing the risk of developing atherosclerosis, as well as for halting or slowing the progression of atherosclerotic disease once it has become clinically evident, comprising the administration of a therapeutically effective amount of an HMG-CoA RI in combination with a COX-2 inhibitor to a mammal who is at risk of developing atherosclerosis or who already has atherosclerotic disease.
  • Atherosclerosis encompasses vascular diseases and conditions that are recognized and understood by physicians practicing in the relevant fields of medicine.
  • Atherosclerotic cardiovascular disease, coronary heart disease (also known as coronary artery disease or ischemic heart disease), cerebrovascular disease and peripheral vessel disease are all clinical manifestations of atherosclerosis and are therefore encompassed by the terms “atherosclerosis” and "atherosclerotic disease.”
  • the combination comprised of an HMG-CoA RI and a COX- 2 inhibitor may be administered to prevent or reduce the risk of occurrence, or recurrence where the potential exists, of a coronary heart disease event, a cerebrovascular event, and/or intermittent claudication.
  • Coronary heart disease events are intended to include CHD death, myocardial infarction (i.e., a heart attack), and coronary revascularization procedures.
  • Cerebrovascular events are intended to include ischemic or hemorrhagic stroke (also known as cerebrovascular accidents) and transient ischemic attacks. Intermittent claudication is a clinical manifestation of peripheral vessel disease.
  • an atherosclerotic disease event is intended to encompass coronary heart disease events, cerebrovascular events, and intermittent claudication. It is intended that persons who have previously experienced one or more non-fatal atherosclerotic disease events are those for whom the potential for recurrence of such an event exists.
  • the instant invention also provides a method for preventing or reducing the risk of a first or subsequent occurrence of an atherosclerotic disease event comprising the administration of a prophylactically effective amount of an HMG-CoA reductase inhibitor in combination with a COX-2 inhibitor to a patient at risk for such an event.
  • the patient may already have atherosclerotic disease at the time of administration, or may be at risk for developing it.
  • the instant invention also provides a method for treating, preventing, and/or reducing the risk of developing atherosclerosis and atherosclerotic disease events and reducing total cholesterol levels alone, or in conjunction with the treatment for a COX-2 mediated disease or disorder comprising the administration of a therapeutically effective amount of an HMG-CoA reductase inhibitor in combination with a COX- 2 inhibitor to a patient in need of such treatment.
  • COX-2 mediated diseases and disorders includes inflammatory diseases susceptible to treatment with a non-steroidal anti-inflammatory agent, arthritis including rheumatoid arthritis, and degenerative joint diseases (osteoarthritis).
  • Persons to be treated with the instant combination therapy include those at risk of developing atherosclerotic disease and of having an atherosclerotic disease event.
  • Standard atherosclerotic disease risk factors are known to the average physician practicing in the relevant fields of medicine. Such known risk factors include but are not limited to hypertension, smoking, diabetes, low levels of high density lipoprotein (HDL) cholesterol, and a family history of atherosclerotic cardiovascular disease.
  • HDL high density lipoprotein
  • NCEP national cholesterol education program
  • Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II), JAMA, 1993, 269, pp. 3015-23.
  • People who are identified as having one or more of the above-noted risk factors are intended to be included in the group of people considered at risk for developing atherosclerotic disease.
  • People identified as having one or more of the above-noted risk factors, as well as people who already have atherosclerosis, are intended to be included within the group of people considered to be at risk for having an atherosclerotic disease event.
  • a compound which inhibits HMG-CoA reductase is used in combination with a COX-2 inhibitor to practice the instant invention.
  • Compounds which have inhibitory activity for HMG-CoA reductase can be readily identified by using assays well-known in the art. For example, see the assays described or cited in U.S. Patent 4,231,938 at col. 6, and WO 84/02131 at pp. 30-33.
  • HMG-CoA reductase inhibitors examples include but are not limited to lovastatin (MEVACOR®; see US Patent No. 4,231,938), simvastatin (ZOCOR®; see US Patent No.
  • HMG-CoA reductase inhibitor is intended to include all pharmaceutically acceptable salt, ester and lactone forms of compounds which have HMG-CoA reductase inhibitory activity, and therefor the use of such salts, esters and lactone forms is included within the scope of this invention.
  • the HMG-CoA RI is selected from lovastatin and simvastatin, and most preferably simvastatin.
  • salts of HMG-CoA reductase inhibitors may include, but are not limited to, acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynapthoate, iodide, isothionate, lactate, lactobionate, laurate,
  • Ester derivatives of the described compounds may act as prodrugs which, when absorbed into the bloodstream of a warm-blooded animal, may cleave in such a manner as to release the drug form and permit the drug to afford improved therapeutic efficacy.
  • inhibitor of cyclooxygenase-2 "cyclooxygenase-
  • the compounds have a cyclooxygenase-2 IC50 of less than about 2 ⁇ M in the human whole blood COX-2 assay, yet have a cyclooxygenase-1 IC50 of greater than about 5 ⁇ M in the human whole blood COX-1 assay.
  • the compounds have a selectivity ratio of cyclooxygenase-2 inhibition over cyclooxygenase-1 inhibition of at least 10, and more preferably of at least 40.
  • the resulting selectivity may indicate an ability to reduce the incidence of common NSAID-induced side effects.
  • a second class is the tricyclic inhibitor class, which can be further divided into the sub-classes of tricyclic inhibitors with a central carbocyclic ring (examples include SC-57666, 1, and 2); those with a central monocyclic heterocyclic ring (examples include DuP 697, SC- 58125, SC-58635, and 3, 4 and 5); and those with a central bicyclic heterocyclic ring (examples include 6, 7, 8, 9 and 10).
  • Compounds 3, 4 and 5 are described in U.S. Patent No. 5,474,995 .
  • the third identified class can be referred to as those which are structurally modified NSAIDS, and includes L-761,066 and structure 11 as example members.
  • COX-2 inhibitor compounds which are included in the scope of this invention include:
  • Patent No. 5,474,995. See Examples herein for compounds 13 and 25 .
  • Particularly preferred compounds of formula (I) include:
  • the compounds of use in this invention may have one or more chiral centers and the present compounds may occur as racemates, racemic mixtures and as individual diasteriomers or enantiomers with all such isomeric forms and mixtures thereof being included within the scope of this invention.
  • some of the crystalline forms for compounds of the present invention may exist as polymorphs and as such are intended to be included in the present invention.
  • some of the compounds of the instant invention may form solvates with water or common organic solvents. Such solvates and hydrates, as well as anhydrous compositions, are encompassed within the scope of this invention.
  • Some of the compounds described herein may contain olefinic double bonds, and unless specified otherwise, are meant to include both E and Z geometric isomers.
  • COX-2 inhibitors that may be used with this invention encompass all pharmaceutically acceptable salt forms of the compounds.
  • Examples of such salt forms of COX-2 inhibitors include but are not limited to salts derived from inorganic bases including aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N- dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2- dimethylaminoethanol, ethanolamine, ethylene4diamine, N- ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
  • the instant pharmaceutical combination comprising an
  • HMG-CoA reductase inhibitor in combination with a COX-2 inhibitor includes administration of a single pharmaceutical dosage formulation which contains both the HMG-CoA reductase inhibitor and the COX-2 inhibitor, as well as administration of each active agent in its own separate pharmaceutical dosage formulation.
  • the HMG-CoA reductase inhibitor and the COX-2 inhibitor can be administered at essentially the same time, i.e., concurrently, or at separately staggered times, i.e, sequentially.
  • the instant pharmaceutical combination is understood to include all these regimens.
  • Administration in these various ways are suitable for the present invention as long as the beneficial pharmaceutical effect of the HMG-CoA reductase inhibitor and the COX-2 inhibitor are realized by the patient at substantially the same time.
  • Such beneficial effect is preferably achieved when the target blood level concentrations of each active drug are maintained at substantially the same time. It is preferred that the HMG-CoA reductase inhibitor and the COX-2 inhibitor be co-administered concurrently on a once-a-day dosing schedule; however, varying dosing schedules, such as the HMG-CoA RI once per day and the COX-2 inhibitor once, twice or more times per day, is also encompassed herein.
  • a single oral dosage formulation comprised of both an HMG-CoA reductase inhibitor and the COX-2 inhibitor is preferred.
  • a single dosage formulation will provide convenience for the patient, which is an important consideration especially for patients who already have coronary heart disease and may be in need of multiple medications.
  • terapéuticaally effective amount is intended to mean that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, a system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.
  • prophylactically effective amount is intended to mean that amount of a pharmaceutical drug that will prevent or reduce the risk of occurrence of the biological or medical event that is sought to be prevented in a tissue, a system, animal or human by a researcher, veterinarian, medical doctor or other clinician.
  • the dosage regimen utilizing an HMG-CoA RI in combination with COX-2 inhibitor is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt or ester thereof employed. Since two different active agents are being used together in a combination therapy, the potency of each of the agents and the interactive effects achieved by combining them together must also be taken into account. A consideration of these factors is well within the purview of the ordinarily skilled clinician for the purpose of determining the therapeutically effective or prophylactically effective dosage amounts needed to prevent, counter, or arrest the progress of the condition.
  • patient includes mammals, especially humans, who take an HMG-CoA reductase inhibitor in combination with a COX-2 inhibitor for any of the uses described herein.
  • Administering of the drug combination to the patient includes both self-administration and administration to the patient by another person.
  • the daily dosage amounts of the HMG-CoA reductase inhibitor are intended to be the same or similar to those amounts which are employed for anti-hypercholesterolemic treatment and which are described in the Physicians' Desk Reference (PDR).
  • PDR Physicians' Desk Reference
  • the oral dosage amount of HMG-CoA RI is from about 1 to 200 mg/day, and more preferably from about 5 to 160 mg/day.
  • HMG-CoA reductase inhibitor may be administered from 1 to 4 times per day, and preferably once per day.
  • the daily dosage amount for simvastatin may be selected from 5 mg, 10 mg, 20 mg, 40 mg, 80 mg and 160 mg; for lovastatin, 10 mg, 20 mg, 40 mg and 80 mg; for fluvastatin sodium, 20 mg, 40 mg and 80 mg; for pravastatin sodium, 10 mg, 20 mg, and 40 mg; and for atorvastatin calcium, 10 mg, 20 mg, and 40 mg.
  • the inhibitor of cyclooxygenase-2 may be administered at a dosage level up to conventional dosage levels for NSAIDs. Suitable dosage levels will depend upon the antiinflammatory effect of the chosen inhibitor of cyclooxygenase-2, but typically suitable levels will be about 0.001 to 50 mg/kg per day, preferably 0.005 to 30mg/kg per day, and especially 0.05 to lOmg/kg per day.
  • the compound may be administered on a regimen of up to 6 times per day, preferably 1 to 4 times per day, and especially once per day. Additional active agents may be used in combination with the HMG-CoA RI and COX-2 inhibitor in a single dosage formulation, or may be administered to the patient in a separate dosage formulation, which allows for concurrent or sequential administration.
  • One or more additional active agents may be administered with the HMG-CoA RI and COX-2 inhibitor.
  • the additional active agent or agents can be cholesterol lowering compounds.
  • additional active agents which may be employed include HMG-CoA synthase inhibitors; squalene epoxidase inhibitors; squalene synthetase inhibitors (also known as squalene synthase inhibitors), acyl-coenzyme A: cholesterol acyltransferase (AC AT) inhibitors; probucol; niacin; fibrates such as clofibrate, fenofibrate, and gemfibrizol; cholesterol absorption inhibitors; bile acid sequestrants; LDL (low density lipoprotein) receptor inducers; platelet aggregation inhibitors, for example glycoprotein Ilb/IIIa fibrinogen receptor antagonists and aspirin; vitamin Q (also known as pyridoxine) and the pharmaceutically acceptable salts thereof such as the HC1 salt; vitamin
  • HMG-CoA synthase inhibitors include: the beta-lactone derivatives disclosed in U.S. Patent No. 4,806,564, 4,816,477, 4,847,271, and 4,751,237; the beta lactam derivatives disclosed in U.S. 4,983,597 and the substituted oxacyclopropane analogues disclosed in European Patent Publication EP O 411 703.
  • the squalene synthetase inhibitors suitable for use herein include, but are not limited to, those disclosed by Biller et al., J. Med. Chem., 1988 Vol. 31, No. 10, pp. 1869- 1871, including isoprenoid (phosphinylmethyl)-phosphonates such as those of the formula
  • squalene synthetase inhibitors suitable for use herein include the terpenoid pyrophosphates disclosed by P. Ortiz de Montellano et al., J. Med. Chem., 1977, 20, 243-249, the farnesyl diphosphate analog A and presqualene pyrophosphate (PSQ-PP) analogs as disclosed by Corey and Volante, J. Am. Chem. Soc. 1976, 98, 1291- 1293, phosphinylphosphonate reported by McClard, R. W.
  • the benzodiazepine squalene synthase inhibitors described in EP O 567 026 to Takeda Chemical Industries and the quinuclidinyl squalene synthase inhibitors described in PCT publications WO 94/03451, WO 93/09115, WO 93/21183, WO 93/21184, WO 93/24486, and U.S. 5,135,935, may be co-administered with the HMG-CoA RI plus COX-2 inhibitor combination of the present invention.
  • squalene epoxidase inhibitors are disclosed in European Patent Publication EP O 318 860 and in Japanese Patent Publication J02 169-571A.
  • LDL-receptor gene inducer molecules are disclosed in U.S. Patent No. 5,182,298.
  • bile acid sequestrants which may be employed in the present method include cholestyramine, colestipol, and poly[methyl-(3-trimethylaminopropyl)imino-trimethylene dihalide] and those disclosed in W095/34585 to Geltex Pharmaceuticals, Inc. and EP 0 622 078 assigned to Hisamitsu Pharmaceutical Co., Inc.
  • cholesterol absorption inhibitors which may be employed in the present method include those described in WO 95/18143 and WO 95/18144 both assigned to Pfizer Inc., and WO 94/17038, WO 95/08532 and WO 93/02048 each assigned to Schering Corp.
  • the additional active agents described above which may be employed along with the HMG-CoA RI and COX-2 inhibitor combination therapy can be used, for example, in amounts as indicated in the PDR or in amounts as indicated in the reference disclosures, as appropriate.
  • the active agents employed in the instant combination therapy can be administered in such oral forms as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions.
  • the instant invention includes the use of both oral rapid-release and time-controlled release pharmaceutical formulations.
  • a particular example of an oral time-controlled release pharmaceutical formulation is described in U.S Patent No. 5,366,738.
  • Oral formulations are preferred.
  • Such pharmaceutical compositions are known to those of ordinary skill in the pharmaceutical arts; for example, see Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA.
  • the active agents are typically administered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as "carrier” materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.
  • carrier suitable pharmaceutical diluents, excipients or carriers
  • the active drug component can be combined with a non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, modified sugars, modified starches, methyl cellulose and its derivatives, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and other reducing and non-reducing sugars, magnesium stearate, steric acid, sodium stearyl fumarate, glyceryl behenate, calcium stearate and the like.
  • a non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, modified sugars, modified starches, methyl cellulose and its derivatives, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and other reducing and non-reducing sugars, magnesium stearate, steric acid, sodium stearyl fumarate, glyceryl behenate, calcium stearate and the like.
  • suitable binders, lubricants, disintegrating agents and coloring and flavoring agents can also be incorporated into the mixture.
  • Stabilizing agents such as antioxidants (BHA, BHT, propyl gallate, sodium ascorbate, citric acid) can also be added to stabilize the dosage forms.
  • suitable components include gelatin, sweeteners, natural and synthetic gums such as acacia, tragacanth or alginates, carboxymethylcellulose, polyethylene glycol, waxes and the like.
  • the active drugs can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
  • Active drug may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled. Active drug may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinyl- pyrrolidone, pyran copolymer, polyhydroxy-propyl-methacrylamide- phenol, polyhydroxy-ethyl-aspartamide-phenol, or polyethyleneoxide- polylysine substituted with palmitoyl residues.
  • active drug may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross linked or amphipathic block copolymers of hydrogels.
  • biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross linked or amphipathic block copolymers of hydrogels.
  • the active agents of the present method may be administered in divided doses, for example two or three times daily, a single daily dose of each of the HMG-CoA RI and the COX-2 inhibitor is preferred, with a single daily dose of both agents in a single pharmaceutical composition being most preferred.
  • the instant invention also encompasses a process for preparing a pharmaceutical composition
  • a process for preparing a pharmaceutical composition comprising combining the HMG-CoA RI and the COX-2 inhibitor with a pharmaceutically acceptable carrier, as well as the pharmaceutical composition which is made by combining the HMG-CoA RI and the COX-2 inhibitor with a pharmaceutically acceptable carrier.
  • a therapeutically effective amount of an HMG-CoA RI and a COX-2 inhibitor can be used together for the preparation of a medicament useful for preventing or reducing the risk of developing atherosclerotic disease, halting or slowing the progression of atherosclerotic disease once it has become clinically manifest, and preventing or reducing the risk of a first or subsequent occurrence of an atherosclerotic disease event.
  • the medicament may be comprised of a COX-2 inhibitor in combination with about 1 mg to 200 mg of an HMG-CoA RI, or more particularly about 5 mg to 160 mg of the HMG-CoA RI. More specific amounts of HMG-CoA RI which may be used in the medicament preparation include 1 mg, 5 mg, 10 mg, 20 mg, 40 mg, 80 mg, and 160 mg, as well as sub-milligram amounts of HMG- CoA RI's which have sufficient potency at such levels. As a further example, the medicament may be comprised of an HMG-CoA RI in combination with about 0.1 to 20 mg of a COX-2 inhibitor. The instant invention also encompasses the use of an HMG-
  • CoA reductase inhibitor for the preparation of a medicament for the combined use with a cyclooxygenase-2 inhibitor for preventing or reducing the risk of developing atherosclerotic disease, for halting or slowing the progression of atherosclerotic disease, or for preventing or reducing the risk of occurrence or recurrence of an atherosclerotic disease event; and the use of a cyclooxygenase-2 inhibitor for the preparation of a medicament for the combined use with an HMG-CoA reductase inhibitor for preventing or reducing the risk of developing atherosclerotic disease, for halting or slowing the progression of atherosclerotic disease, or for preventing or reducing the risk of occurrence or recurrence of an atherosclerotic disease event.
  • the medicament or pharmaceutical combination comprised of the HMG-Co RI and the COX-2 inhibitor may also be prepared with one or more additional active agents, such as those described supra. Examples of dosage formulations suitable for use in practicing the
  • All the ingredients except magnesium stearate are blended together in a suitable mixer.
  • the powder mixture is then granulated with adequate quantities of granulating solvent(s).
  • the wet granulated mass is dried in a suitable dryer.
  • the dried granulation is sized through a suitable screen.
  • the sized granulation is mixed with magnesium stearate before tableting.
  • the tablets may be coated if deemed necessary.
  • Additional ingredients that may be added to the above include suitable color and mixtures of colors.
  • Tablet dose strengths of between 5 and 125 mg can be accomodated by varying total tablet weight, and the ratio of the first three ingredients. Generally it is preferable to maintain a 1:1 ratio for microcrystalline cellulose : lactose monohydrate.
  • Tablet dose strengths of between 5 and 125 mg can be accomodated by varying total tablet weight, and the ratio of the first three ingredients. Generally it is preferable to maintain a 1:1 ratio for microcrystalline cellulose : lactose monohydrate.
  • Capsule dose strengths of between 1 and 50 mg can be accomodated by varying total fill weight, and the ratio of the first three ingredients. Generally it is preferable to maintain a 1:1 ratio for microcrystalline cellulose : lactose monohydrate.
  • Solution dose strengths of between 1 and 50 mg/5mL can be accomodated by varying the ratio of the two ingredients.
  • Suspension dose strengths of between 1 and 50 mg/5ml can be accomodated by varying the ratio of the first two ingredients.
  • Step 2 2-Methyl-5-trimethylstannylpyridine
  • 2-methyl- pyridin-5-yl ester 2.1 g
  • hexamethylditin 2.85 g
  • lithium chloride 1.1 g
  • palladium tetrakis(triphenylphosphine) 190 mg
  • the mixture was filtered through a bed of celite, washing with ethyl acetate. The filtrate was washed twice with 5% potassium fluoride, dried and concentrated.
  • Step 3 5-Chloro-3-(4-methylsulfonyl)phenyl-2-(2-methyl-5- pyridvDpyridine
  • Step 4 5-Chloro-2-hvdroxy-3-(4-methylsulfonyl)phenylpyridine
  • 2-benzyloxy-5-chloro-3-(4-methylsulfonyl)- phenylpyridine 72 g
  • trifluoroacetic acid 250 mL
  • the white solid was filtered, washed twice with a further 1 L of water and then air dried to provide the title compound.
  • Step 7 5-Chloro-3-(4-methvlsuIfonvl)phenvl-2-(2-pvridinvl)-pyridine

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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyridine Compounds (AREA)
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  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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Abstract

Cette invention propose une combinaison de médicaments contenant un inhibiteur de HMG-CoA réductase, associé à un inhibiteur de COX-2, servant à traiter, prévenir et/ou réduire les risques de développement de l'athérosclérose et d'apparition d'incidents pathologiques liés à l'athérosclérose.
PCT/US1998/021901 1997-10-22 1998-10-16 Therapie d'association permettant de reduire les risques lies aux maladies cardio-vasculaires et cerebro-vasculaires WO1999020110A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
CA002306646A CA2306646A1 (fr) 1997-10-22 1998-10-16 Therapie d'association permettant de reduire les risques lies aux maladies cardio-vasculaires et cerebro-vasculaires
AU13612/99A AU753657B2 (en) 1997-10-22 1998-10-16 Combination therapy for reducing the risks associated with cardio-and cerebrovascular disease
JP2000516533A JP2001520174A (ja) 1997-10-22 1998-10-16 心血管疾患および脳血管疾患に関するリスクを低下させる併用療法
EP98957328A EP1024696A4 (fr) 1997-10-22 1998-10-16 Therapie d'association permettant de reduire les risques lies aux maladies cardio-vasculaires et cerebro-vasculaires

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US6269197P 1997-10-22 1997-10-22
US60/062,691 1997-10-22
GBGB9806688.9A GB9806688D0 (en) 1998-03-27 1998-03-27 Combination therapy for reducing the risks associated with cardio-and cerebrovascular diease
GB9806688.9 1998-03-27

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Cited By (14)

* Cited by examiner, † Cited by third party
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WO2001034138A1 (fr) * 1999-11-08 2001-05-17 Massachusetts Institute Of Technology, Inc. Compositions et methodes de traitement de troubles neurologiques et de maladies neurodegeneratives
WO2002028270A2 (fr) * 2000-10-06 2002-04-11 Probiochem, Llc Combinaison et methode de traitement du cancer par un inhibiteur de cox-2 et un inhibiteur de 3-hydroxy-3-methylglutaryl-coenzyme-a (hmg-coa) reductase
EP1197228A1 (fr) * 1999-07-02 2002-04-17 Hisamitsu Pharmaceutical Co. Inc. Compositions medicamenteuses destinees au traitement du cancer colorectal
WO2002094021A1 (fr) * 2000-10-06 2002-11-28 Probiochem, Llc Combinaison et methode de traitement par un inhibiteur de la cox-2, un inhibiteur de la hmg-coa et la cystine pour ameliorer la fonction du glutathion
US6534540B2 (en) 2000-10-06 2003-03-18 George Kindness Combination and method of treatment of cancer utilizing a COX-2 inhibitor and a 3-hydroxy-3-methylglutaryl-coenzyme-a (HMG-CoA) reductase inhibitor
WO2004006919A1 (fr) * 2002-07-11 2004-01-22 Sankyo Company, Limited Composition medicale pour reduire le taux de lipides sanguins ou le taux d'homocysteine sanguine
US6825185B2 (en) 2000-12-21 2004-11-30 Nitromed, Inc. Substituted aryl compounds as novel cyclooxygenase-2 selective inhibitors, compositions and methods of use
WO2007054789A1 (fr) * 2005-11-08 2007-05-18 Ranbaxy Laboratories Limited Combinaison pharmaceutique
EP1982711A1 (fr) 2005-05-31 2008-10-22 Mylan Laboratories, Inc Compositions comportant du nebivolol
US20100166810A1 (en) * 2007-07-01 2010-07-01 Joseph Peter Habboushe Combination tablet with chewable outer layer
US7790738B2 (en) 2000-07-20 2010-09-07 Lauras As Methods of treating and preventing AIDS using of COX-2 inhibitors
US20130210778A1 (en) * 2000-04-10 2013-08-15 Nicholas J. Wald Formulation for the prevention of cardiovascular disease
US9226891B2 (en) 2011-10-28 2016-01-05 Vitalis Llc Anti-flush compositions
US10864255B2 (en) 2000-02-04 2020-12-15 Children's Hospital Medical Center Lipid hydrolysis therapy for atherosclerosis and related diseases

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* Cited by examiner, † Cited by third party
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JP4611622B2 (ja) * 2002-07-11 2011-01-12 第一三共株式会社 血中脂質改善又は血中ホモシステイン低下のための医薬組成物
US20070037797A1 (en) * 2005-08-15 2007-02-15 Hellstrom Harold R Method of reducing the risk of adverse cardiovascular (CV) events associated with the administration of pharmaceutical agents which favor CV events

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IL112639A0 (en) * 1994-03-11 1995-05-26 Bristol Myers Squibb Co A pharmaceutical composition containing pravastin
CN1212620A (zh) * 1996-03-05 1999-03-31 儿童医院医疗中心 作为环氧酶抑制剂的巯基衍生物

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DATABASE HCAPLUS ON STN, AN 1997:121345, PALLENBERG et al., "Stable Copper (1) Complexes as Active Therapeutic Substances"; & WO 9639144 A1 (12 December 1996). *
See also references of EP1024696A4 *

Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1197228A4 (fr) * 1999-07-02 2004-03-10 Hisamitsu Pharmaceutical Co Compositions medicamenteuses destinees au traitement du cancer colorectal
EP1197228A1 (fr) * 1999-07-02 2002-04-17 Hisamitsu Pharmaceutical Co. Inc. Compositions medicamenteuses destinees au traitement du cancer colorectal
WO2001034138A1 (fr) * 1999-11-08 2001-05-17 Massachusetts Institute Of Technology, Inc. Compositions et methodes de traitement de troubles neurologiques et de maladies neurodegeneratives
US10864255B2 (en) 2000-02-04 2020-12-15 Children's Hospital Medical Center Lipid hydrolysis therapy for atherosclerosis and related diseases
US10357503B2 (en) * 2000-04-10 2019-07-23 Nicholas J Wald Formulation for the prevention of cardiovascular disease
US20130210778A1 (en) * 2000-04-10 2013-08-15 Nicholas J. Wald Formulation for the prevention of cardiovascular disease
US7790738B2 (en) 2000-07-20 2010-09-07 Lauras As Methods of treating and preventing AIDS using of COX-2 inhibitors
US6534540B2 (en) 2000-10-06 2003-03-18 George Kindness Combination and method of treatment of cancer utilizing a COX-2 inhibitor and a 3-hydroxy-3-methylglutaryl-coenzyme-a (HMG-CoA) reductase inhibitor
WO2002028270A2 (fr) * 2000-10-06 2002-04-11 Probiochem, Llc Combinaison et methode de traitement du cancer par un inhibiteur de cox-2 et un inhibiteur de 3-hydroxy-3-methylglutaryl-coenzyme-a (hmg-coa) reductase
WO2002028270A3 (fr) * 2000-10-06 2002-06-13 Probiochem Llc Combinaison et methode de traitement du cancer par un inhibiteur de cox-2 et un inhibiteur de 3-hydroxy-3-methylglutaryl-coenzyme-a (hmg-coa) reductase
WO2002094021A1 (fr) * 2000-10-06 2002-11-28 Probiochem, Llc Combinaison et methode de traitement par un inhibiteur de la cox-2, un inhibiteur de la hmg-coa et la cystine pour ameliorer la fonction du glutathion
US6825185B2 (en) 2000-12-21 2004-11-30 Nitromed, Inc. Substituted aryl compounds as novel cyclooxygenase-2 selective inhibitors, compositions and methods of use
WO2004006919A1 (fr) * 2002-07-11 2004-01-22 Sankyo Company, Limited Composition medicale pour reduire le taux de lipides sanguins ou le taux d'homocysteine sanguine
EP2808015A1 (fr) 2005-05-31 2014-12-03 Mylan Laboratories, Inc Compositions comportant du nebivolol
EP2174658A1 (fr) 2005-05-31 2010-04-14 Mylan Laboratories, Inc Compositions comportant du nebivolol
EP1982711A1 (fr) 2005-05-31 2008-10-22 Mylan Laboratories, Inc Compositions comportant du nebivolol
WO2007054789A1 (fr) * 2005-11-08 2007-05-18 Ranbaxy Laboratories Limited Combinaison pharmaceutique
US8404275B2 (en) * 2007-07-01 2013-03-26 Vitalis Llc Combination tablet with chewable outer layer
US20100166810A1 (en) * 2007-07-01 2010-07-01 Joseph Peter Habboushe Combination tablet with chewable outer layer
US8652520B2 (en) 2007-07-01 2014-02-18 Vitalis Llc Combination tablet with chewable outer layer
US9226891B2 (en) 2011-10-28 2016-01-05 Vitalis Llc Anti-flush compositions

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CA2306646A1 (fr) 1999-04-29
EP1024696A4 (fr) 2004-07-14
AU753657B2 (en) 2002-10-24
AU1361299A (en) 1999-05-10
EP1024696A1 (fr) 2000-08-09
JP2001520174A (ja) 2001-10-30

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