TECHNICAL FIELD

The invention relates to a combination product or medicament or therapy comprising at least one substituted pyrrole derivative and one or more dyslipidemic agent(s). Also provided herein are pharmaceutical compositions comprising at least one novel substituted pyrrole derivative and one or more dyslipidemic agent(s), together with at least one pharmaceutically acceptable carrier. Also provided herein are methods for the treatment or prophylaxis of cardiovascular diseases, Alzheimer's disease, obesity, diabetes or inflammatory diseases comprising administering to a mammal in need thereof therapeutically effective amounts of combination pharmaceutical composition comprising at least one substituted pyrrole derivative and one or more dyslipidemic agent(s).

BACKGROUND OF INVENTION

Cardiovascular disease and its associated maladies, dysfunctions and complications are a principal cause of disability and the chief cause of death in the developed world. One specific factor significantly contributing to this pathophysiologic process is atherosclerosis, which has been generally recognized as a leading health care problem with respect to mortality and health care costs. Atherosclerosis is characterized by the deposition of fatty substances, primarily cholesterol, resulting in plaque formation on the inner surface of the arterial wall and degenerative changes to the arteries.

It is now well established that cardiovascular disorders including myocardial infarction, coronary heart disease, hypertension and hypotension, cerebrovascular disorders including stroke, cerebral thrombosis and memory loss due to stroke; peripheral vascular disease and intestinal infarction are caused by blockage of arteries and arterioles by atherosclerotic plaque. Atherosclerotic plaque formation is multi-factorial in its production. Numerous studies have demonstrated that a low plasma concentration of high-density lipoprotein (HDL) cholesterol is a powerful risk factor for the development of atherosclerosis. HDL is one of the major classes of lipoproteins that function in the transport of lipids through the blood. The major lipids found associated with HDL include cholesterol; cholesteryl ester, triglycerides, phospholipids and fatty acids. The other classes of lipoproteins found in the blood are low density lipoprotein (LDL), intermediate density lipoprotein (IDL), and very low density lipoprotein (VLDL). Since low levels of HDL cholesterol increase the risk of atherosclerosis, methods for elevating plasma HDL cholesterol are be beneficial for the treatment of atherosclerosis and other diseases associated with the accumulation of lipid in the blood vessels.

Combination therapies for the treatment of diseases, which are affected by low levels of HDL-cholesterol and/or high levels of LDL-cholesterol and triglycerides, for example, atherosclerosis and cardiovascular diseases, have been described in the literature. For example, U.S. Patent No. 6,586,448 discloses pharmaceutical combination

compositions comprising CETP inhibitor and other therapeutic agents, for example, HMG-CoA reductase inhibitor, a PPAR agonist or fibrate, for the treatment of diseases which are exacerbated by low levels of HDL cholesterol and/or high levels of LDL- cholesterol and triglycerides. U.S. Patent No. 6,462,091 discloses combinations of CETP inhibitor and HMG-CoA reductase inhibitor for cardiovascular indications. Combinations of CETP inhibitor and HMG-CoA reductase inhibitor have also been disclosed in PCT publication Nos. WO 04/004778, WO 04/056359 or WO 04/098583; U.S. Patent application Nos. 20040053842 or 20040132771. U.S. Patent No. 6,534,088 discloses combinations of HMG-CoA reductase inhibitor and fibrate for treatment of patients with dyslipidemia, hyperlipidemia, hypercholesterolemia and related conditions. Combinations of fibrate and HMG-CoA reductase inhibitor have also been disclosed in U.S. Patent No. 6,51 1,985; PCT Publication Nos. WO 2005/034908, WO 03/013607, WO 01/37831. U.S. Patent No. 6,420,417 discloses combinations of ileal bile acid transport inhibiting benzothiepines and HMG-CoA reductase inhibitors for treating hyperlipidemic conditions. Combinations of ileal bile acid transport inhibitor and HMG-CoA reductase inhibitor have also been disclosed in U.S. Patent Nos. 6,642,268 and 6,268,392. PCT Publication No. WO 03/080070 discloses combinations of HMG-CoA reductase inhibitor and insulin secretion enhancer or insulin sensitizer. Other references describing such combinations are European Patent Application No. 0753298, 1510208, 1523316; PCT Publication No. WO 2005/018626. PCT Publication No. WO 03/088962 discloses combination therapy using a PPAR agonist and other therapeutic agents, for example, HMG-CoA reductase inhibitor, a bile acid sequestrant or CETP inhibitor. Other references disclosing such combinations are PCT Publication No. 03/013608; U.S Patent application No. 2005/0032878. PCT

Publication No. WO 04/004777 discloses CETP inhibitors and antihypertensive agents as well as optionally HMG-CoA reductase inhibitors.

Inflammatory diseases are all characterized by the presence of mediators that recruit and activate different inflammatory cells which release enzymes or oxygen radicals causing symptoms, the persistence of inflammation and when chronic, destruction or disruption of normal tissue.

Combination therapies for the treatment of inflammatory diseases have been described in the literature. For example, U.S. Patent Publication No. 2002/0052312A1 discloses combination therapy of chronic obstructive pulmonary disease using muscarinic receptor antagonists in combination with beta-2 -agonist, antitussive, corticosteroid, decongestant, histamine HI antagonist (antihistamine), dopamine antagonist, leukotriene antagonist, 5-lipooxygenase inhibitor, phosphodiesterase IV inhibitor, VLA-4 antagonist, and theophylline. PCT Publication No. WO 2005/009340 describes methods for the treatment or prevention of respiratory disorders with a cycloxygenase-2 inhibitor in combination with a muscarinic receptor antagonist and compositions thereof. U.S.

Publication No. 2005/0063911 discloses combined doses of Formoterol and an

anticholinergic agent. PCT Publication No. WO 04/019985 discloses pharmaceutical products and compositions comprising specific anticholinergic agents, beta-2 agonists and corticosteriods. PCT Publication No. WO 02/096422 discloses combinations of a dopamine D2 -receptor agonist and tiotropium or a derivative thereof for treating obstructive airways and other inflammatory diseases. PCT Publication No. WO 03/066063 discloses pharmaceutical compositions comprising 17alpha-furanylesters of 17beta- carbothiate androstanes with a muscarinic receptor antagonists. U.S. Publication No. 2004/0097555 discloses pharmaceutical agents comprising one or more kinds of a p38 MAP kinase inhibitor and/or a TNF- alpha production inhibitor and one or more kinds of drugs selected from (1) a non-steroidal anti-inflammatory drug, (2) a disease-modifying anti-rheumatic drug, (3) an-anti-cytokine drug, (4) an immunomodulator, (5) a steroid and (6) a c-Jun N-terminal kinase inhibitor in combination, which has been said to be useful as a prophylactic or therapeutic agent of the diseases rheumatism, arthritis and other diseases. PCT Publication No. WO 95/28926 discloses a pharmaceutical composition for treating multiple sclerosis comprising an effective amount of a combination of a PDE IV inhibitor and an anti-inflammatory or immunomodulatory drug in a pharmaceutically acceptable carrier. PCT Publication No. WO 01/13953 and U.S. Publication No. 20040034087 disclose the combined administration of PDE inhibitors and beta 2 adrenoceptor agonists for the treatment of respiratory tract disorders. PCT Publication No. WO 01/32127 discloses the treatment of pulmonary diseases such as chronic obstructive pulmonary disease or asthma by administering a phosphodiesterase 4 inhibitor in combination with anti-inflammatory corticosteroid. PCT Publication No. WO 2004/067006 discloses treatments and methods for PDE IV-related conditions and for TNF-alpha-related conditions using a combination of a PDE IV inhibitor and a TNF-alpha antagonist. PCT Publication No. WO 2005/041864 discloses a method for the prevention and/or treatment of respiratory inflammation, and in particular asthma and COPD, in a subject in need of such prevention or treatment, the method comprising administering to the subject a cycloogenase-2 inhibitor in combination with a phosphodiesterase 4 inhibitor.

Despite the existence of such combinations for the treatment or prophylaxis of cardiovascular diseases or inflammatory diseases, there remains a need for safe and effective combination products or medicaments for the treatment or prophylaxis of cardiovascular diseases and/or inflammatory diseases.

These needs are met by the pharmaceutical compositions and combination therapies of this invention. Additionally, the pharmaceutical compositions and therapeutic methods of this invention achieve other advantages discussed more fully below.

SUMMARY OF INVENTION

Provided herein are combination products or medicaments comprising at least one novel substituted pyrrole derivative, and a dyslipidemic agent, for the treatment or prophylaxis of cardiovascular diseases, Alzheimer's disease, obesity, diabetes or inflammatory diseases.

Also provided herein are pharmaceutical compositions comprising a)

therapeutically effective amounts of a substituted pyrrole derivative, optionally together with at least one pharmaceutically acceptable carrier, and b) therapeutically effective amounts of one or more dyslipidemic agent(s), optionally together with at least one pharmaceutically acceptable carrier.

Also provided herein is a single pharmaceutical composition comprising at least one substituted pyrrole derivative, and one or more dyslipidemic agents, with at least one pharmaceutically acceptable carrier.

Also provided herein are pharmaceutical packages comprising single compositions comprising therapeutically effective amounts of at least one substituted pyrrole derivative, and one or more dyslipidemic agents, optionally together with at least one

pharmaceutically acceptable carrier.

Also provided herein are pharmaceutical packages comprising a first

pharmaceutical composition comprising therapeutically effective amounts of at least one substituted pyrrole derivative, optionally together with at least one pharmaceutically acceptable carrier; and a second pharmaceutical composition comprising one or more dyslipidemic agents, optionally together with at least one pharmaceutically acceptable carrier. The separate compositions can be given separately, simultaneously or sequentially.

Also provided herein are pharmaceutical kits containing a single composition comprising therapeutically effective amounts of at least one substituted pyrrole derivative, and one or more dyslipidemic agents, optionally together with at least one

pharmaceutically acceptable carrier, prescribing information and a container.

Also provided herein are pharmaceutical kits containing a first pharmaceutical composition of at least one substituted pyrrole derivative, optionally together with at least one pharmaceutically acceptable carrier; a second pharmaceutical composition of one or more dyslipidemic agents, optionally together with at least one pharmaceutically acceptable carrier; prescribing information and a container. The prescribing information may describe the administration and or use of these separate compositions simultaneously, separately or sequentially.

Also provided herein are methods for the treatment or prophylaxis of

cardiovascular diseases, Alzheimer's disease, obesity, diabetes or inflammatory diseases comprising administering to a mammal in need thereof therapeutically effective amounts of any of the above-described combination pharmaceutical compositions, including, for example, the pharmaceutical compositions comprising at least one substituted pyrrole derivative and a dyslipidemic agent.

One specific embodiment is a method of preventing or treating a disorder related to lipid levels in a subject selected from the group consisting of cardiovascular diseases, Alzheimer's disease, obesity, diabetes or inflammatory diseases comprising administering to a subject in need thereof about 40 mg/dose to about 160 mg/dose of a compound selected from the group consisting of the compound of Formula I:

the compound of Formula II:

Formula II,

or pharmaceutically acceptable salts thereof, and about 300 mg/dose to about 600 mg/dose of gemfibrozil, wherein the gemfibrozil is administered simultaneously, separately or sequentially with the compounds of Formula I and Formula II.

Other aspects will be set forth in accompanying detailed description, which follows and will be apparent from the description or may be learnt by the practice of the invention. However, it should be understood that the following detailed description is given by way of illustration only since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art and are encompassed within the scope of this invention.

DESCRIPTION OF EMBODIMENTS

The combination product or medicament, pharmaceutical composition, pharmaceutical package, pharmaceutical kit and method for treatment or prophylaxis of cardiovascular diseases, Alzheimer's disease, obesity, diabetes or inflammatory diseases involve therapeutically effective amounts of at least one substituted pyrrole derivative and one or more dyslipidemic agents, antiobesity agents, antihyperglycaemic agents, antiinflammatory agents or mixtures thereof.

Substituted pyrrole derivatives may be compounds having the structure of Formula

I,

Formula I its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, tautomers, racemates, pure enantiomers, polymorphs, diastereoisomers or N-

Ri is Q-C6 alkyl, C3-C6 cycloalkyl, or optionally substituted phenyl (wherein up to three substituents are independently selected from halogens, C\-Ce alkyl, cyano, or C1-C3 perfluoroalkyl);

R ₂ is optionally substituted phenyl (wherein up to three substituents are independently selected from cyano, acetyl, or optionally substituted amino, wherein up to two amino substituents are independently selected from C]-C ₆ alkyl, C ₃ -C ₆ cycloalkyl, acetyl, or sulfonamide);

R3 is optionally substituted Ci-C ₆ alkyl or C ₃ -C ₆ cycloalkyl (wherein substituents are independently selected from halogens, hydroxyl, Q-C3 alkoxy and protected hydroxyl); or

R3 is -NR ₈ R9, wherein R _g and R are optionally substituted C _\ -C ₆ alkyl (wherein the optional substituent(s) is/are selected from halogens, hydroxy, C1-C3 alkoxy and protected hydroxyl);

R ₄ is

wherein R5 and R6 are independently hydrogen, or aryl substituted with Ci-C ₆ alkyl substituted with up to two substituents independently selected from hydroxyl, protected hydroxyl, and halogens,

with the provisio that R ₂ is phenyl only when R ₅ or ¾ is phenyl substituted with hydroxyalkyl.

Particular illustrative compounds of Formula I include: (3R,5R)-7-[2-(4- fiuorophenyl)-5- isopropyl-3-phenyl-4-[(4- hydroxymethylphenylamino)carbonyl]-pyrrol- l-yl]-3, 5-dihydroxy-heptanoic acid.

Substituted pyrrole derivatives may also be compounds having the structure of Formula II:

its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, tautomers, racemates, polymorphs, pure enantiomers, diastereoisomers, metabolites, pro

Ri is Ci-C ₆ alkyl, C3-C6 cycloalkyl, or optionally substituted phenyl (wherein the substituent(s) is/are selected from halogens, Q-C6 alkyl, cyano and Q-C3

perfluoroalkyl);

R ₂ is optionally substituted phenyl (wherein the substituent(s) is/are selected from cyano, acetyl and optionally substituted amino);

R ₃ is optionally substituted Ci-C ₆ alkyl or C3-C6 cycloalkyl (wherein the substituent(s) is/are selected from halogens, hydroxyl, Cj-C ₃ alkoxy, and protected hydroxyl); R ₃ can also be - R6R7 wherein R^ and R ₇ are optionally substituted Q- C6 alkyl (wherein the optional substituent(s) is/are selected from halogens, hydroxyl, Q-C ₃ alkoxy, and protected hydroxyl);

R4 is -COR ₁₀ (wherein Ri ₀ is selected from Ci-C ₂ alkoxy, hydroxyl and -NRnRi ₂ (wherein Rn and Ri are independently selected from hydrogen, alkyl, aryl, C ₃ -C ₇ cycloalkyl, aralkyl and Rn and R] ₂ together form 5-7 membered ring with one or more optional heteroatom(s) wherein

the heteroatom(s) is/are independently selected from nitrogen, oxygen and sulphur); and

R ₅ is hydrogen, Ci-Ce alkyl or C ₃ -C ₆ cycloalkyl, optionally substituted aryl or aralkyl (wherein the substituents are selected from halogens, cyano, optionally substituted Ci-C ₆ alkyl (wherein the substituents are independently selected from hydroxyl, protected hydroxyl, and halogen(s))), optionally substituted amino, acetyl, trifluoromethyl and C]-C ₆ alkoxycarbonyl.

Particular illustrative compounds of Formula II include: (3R,5R)-7-[2-(4- fluorophenyl)-5-isopropyl-3-phenyl-4-[4-carboxyphenyl)amino) carbonyl]-pyrrol-l-yl]- 3,5-dihydroxy-heptanoic acid).

Compounds of Formula I and II have been described in PCT Publication No. WO 04/106299, which is incorporated herein by reference, in its entirety. Substituted pyrrole derivatives as described herein may have the following attributes: (a) compounds ranging from being equipotent to 4-fold more potent than atorvastatin;

(b) compounds being more potent than atorvastatin in inhibiting cholesterol synthesis in an in vivo rat model;

(c) compounds having intrinsic clearance in human liver microsome significantly less than atorvastatin and not acting as a major substrate for CYP3A4 (cytochrome p450 3A4); and

(d) compounds exhibiting potency and selectivity greater than atorvastatin in

inhibition of cholesterol synthesis in rat primary hepatocytes over inhibition of cholesterol synthesis in extra hepatic cells/cell lines [e.g. NRK-49F (Fibroblast) and L6 (Myoblast)].

Dyslipidemic agents useful in the compositions and methods of the invention can be selected from, but are not limited to: cholesteryl ester transfer protein (CETP) inhibitors, fibric acid derivatives/fibrates, antihypertensive agents, bile acid sequestrants, Acyl CoA -cholesterol acyltranferase inhibitors, cholesterol absorption inhibitors or other dyslipidemic agents.

Preferred dyslipidemic agents useful in the compositions and methods of the invention are fibric acid derivatives or fibrates selected, for example, from compounds described in U.S. Patent Nos. 4,051,143; 3,723,446; 4,058,552; 3,674,836; 3,781,328; 3,948,943; 3,716,583 and 3,984,413. Preferred examples of fibric acid derivatives or fibrates include, but are not limited to, etofibrate, fenofibrate, clofibrate, gemfibrozil, bezafibrate, ciprofibrate, clinofibrate or theofibrate.

Preferred embodiments of the invention include pharmaceutical compositions containing about 80mg of a compound of Formula I and about 600mg of gemfibrozil.

The present inventors have discovered that food has an impact on the

pharmacokinetics of the compounds of Formula I by increasing the extent and decreasing the rate of absorption, and that gemfibrozil (an inhibitor of OATPIB l) increases the exposure of compounds of Formula I.

Other preferred embodiments of the invention include pharmaceutical compositions containing about 80mg of a compound of Formula II and about 600mg of gemfibrozil. The present inventors have discovered that gemfibrozil (an inhibitor of OATPIB l) increases the exposure (i.e., area under the curve (AUC)) but not the maximum concentration (Cmax) of compounds of Formula II, when administered concurrently with gemfibrozil. The term "cardiovascular disease" as used herein refers to any disorder in any of the various parts of cardiovascular system, which is made up of heart and blood vessels throughout the body. The combination pharmaceutical compositions disclosed herein are intended to be used for the treatment or prophylaxis of disease or disorder of heart (cardio) and the disease or disorder of blood vessels (vascular). Some examples of cardiovascular disease include, but are not limited to, arteriosclerosis, atherosclerosis,

hypercholesterolemia, hyperlipidemia, hyperlipoproteinemia, hypertriglyceridemia, hypertension, stroke, ischemia, peripheral vascular disease, peripheral arterial disease, coronary heart disease, myocardial infarction, cerebral infraction, myocardial

microvascular disease, osteoporosis, osteopenia, angina, resterosis or diabetes and related disorders.

The term "inflammatory disease" as used herein refers to any disease, condition, trait, genotype or phenotype characterized by an inflammatory or allergic process as is known in the art such as inflammation, acute inflammation, chronic inflammation, respiratory disease, atherosclerosis, restenosis, asthma, COPD, allergic rhinitis, atopic dermatitis, septic shock, rheumatoid arthritis, inflammatory bowel disease, inflammatory pelvic disease, pain, ocular inflammatory disease, celiac disease, Leigh Syndrome, Glycerol Kinase Deficiency, Familial eosinophilia (FE), autosomal recessive spastic ataxia, laryngeal inflammatory disease; Tuberculosis, Chronic cholecystitis,

Bronchiectasis, Silicosis and other pneumoconioses, and any other inflammatory disease, condition, trait, genotype or phenotype that can respond to the modulation of disease related gene expression in a cell or tissue, alone or in combination with other therapies.

The term "pharmaceutical package" as used herein refers to any package useful for stable storage of the dosage form, comprising (a) single pharmaceutical composition comprising a therapeutically effective amount of at least one substituted pyrrole derivative, at least one dyslipidemic agent, antiobesity, or antihyperglycaemic agent, antiinflammatory agent or mixtures thereof, optionally together with pharmaceutically acceptable carriers, or (b) a first pharmaceutical composition comprising a therapeutically effective amount of at least one substituted pyrrole derivative, optionally together with a pharmaceutically acceptable carrier, a second pharmaceutical composition comprising at least one dyslipidemic agent, antiobesity, or antihyperglycaemic agent, anti-inflammatory agent or mixtures thereof, optionally together with pharmaceutically acceptable carriers. The package may, for example, be a glass, plastic, strip pack or blister pack. The term "pharmaceutical kit" as used herein refers to a kit containing (a) a single pharmaceutical composition comprising a therapeutically effective amount of at least one substituted pyrrole derivative; one or more dyslipidemic agents, antiobesity,

antihyperglycaemic agents, anti-inflammatory agents or mixtures thereof, optionally together with pharmaceutically acceptable carriers; prescribing information and a container, or (b) a first pharmaceutical composition comprising a therapeutically effective amount of at least one substituted pyrrole derivative, optionally together with

pharmaceutically acceptable carriers, a second pharmaceutical composition comprising one or more dyslipidemic agents, antiobesity, antihyperglycaemic agents, anti- inflammatory agents or mixtures thereof, optionally together with pharmaceutically acceptable carriers; prescribing information and a container. The prescribing information, for example, may include pharmacodynamics, pharmacokinetics, indications and usages, direction of administration, warnings, dosage or adverse effects of each pharmaceutical. The container in the kit provides means for separating the first and second pharmaceutical compositions. The container may, for example, be a divided bottle or divided foil packet, for example, blister pack.

The term "combination pharmaceutical composition" as used herein refers to, in one embodiment; a single pharmaceutical composition comprising at least one substituted pyrrole derivative and one or more dyslipidemic agents, antiobesity, antihyperglycaemic agents, anti-inflammatory agents or mixtures thereof, optionally together with

pharmaceutically acceptable carriers. The combination pharmaceutical composition, in a second embodiment, refers to a first pharmaceutical composition comprising

therapeutically effective amount of at least one substituted pyrrole derivatives, optionally together with pharmaceutically acceptable carriers, a second pharmaceutical composition comprising one or more dyslipidemic agents, antiobesity, antihyperglycaemic agents, antiinflammatory agents or mixture thereof, optionally together with pharmaceutically acceptable carriers. The separate pharmaceutical composition can be administered simultaneously, separately or sequentially.

Included within the scope of this invention are pharmaceutically acceptable salts of compounds of Formula I. The pharmaceutically acceptable salts include, for example, alkali metal (e.g., sodium or potassium) or alkaline earth metal (e.g., calcium or magnesium) salts and addition salts of acids or bases. Suitable pharmaceutically acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid. Example of such inorganic acids include, but are not limited to, hydrochloric, hydrobromic, hydroiodic, sulfuric, phosphoric acid and like. Appropriate organic acids include, but not limited to, aliphatic, cycloaliphatic, aromatic, heterocyclic, carboxylic and sulfonic classes of organic acids, such as, formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, dihydroxytartaric acid, citric, ascorbic, glucuronic, maleic, tumeric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, salicylic, p- hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, toluenesulfonic, 2-hydroxyethanesulfonic, sulfanilic, stearic, algenic, beta-hydroxybutyric, cyclohexylaminosulfonic, galactaric and galacturonic acid and the like.

Pharmaceutically acceptable base addition salts include, but are not limited to, metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from primary, secondary and tertiary amines, cyclic amines, Ν,Ν'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, and procaine and the like.

The present invention also includes prodrugs of the active agents disclosed herein.

In general, such prodrugs will be functional derivatives of these compounds, which are readily convertible in vivo into the required compound. Conventional procedure for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", Bundgaard, Elsevier, 1985. The present invention also includes metabolites, which become active upon introduction into the biological system. Where the compounds have at least one chiral center, they may accordingly exist as enantiomers. Where the compounds according to invention possess two or more chiral centers, they may additionally exist as diastereomers. All such individual isomers and racemates therefore are encompassed within the scope of the present invention. Furthermore, some of the crystalline forms for compounds described herein may exist as polymorphs and are included in the present invention. In addition, some of the compounds described herein may form solvates with water (i.e., hydrates) or common organic solvents. Such solvates are also encompassed within the scope of this invention.

A single composition containing at least one substituted pyrrole derivative and one or more dyslipidemic agents, may be suitable for oral, parenteral, topical, or transdermal administration. The compositions may be formulated to provide immediate or sustained release of the therapeutic agents. The agents described herein can be administered concurrently as individual formulations, but will generally be administered as an admixture with a suitable "pharmaceutically acceptable carrier". The term

"pharmaceutically acceptable carrier" is intended to include non-toxic, inert solid, semisolid or liquid diluents(s), encapsulating material or formulation auxiliary of any type.

Solid form preparations for oral administration may include capsules, tablets, pills, powder, granules and suppositories. For solid form preparation, the active compound(s) are mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate, dicalcium phosphate and/or a filter an extender such as starch, lactose, sucrose, glucose, mannitol and silicic acid; binders such as carboxymethyl cellulose, alginates, gelatins, polyvinylpyrrolidinone, sucrose, acacia; disintegrating agents such as agar-agar, calcium carbonate, potato starch, aliginic acid, certain silicates and sodium carbonate; absorption accelerators such as quaternary ammonium compounds; wetting agents such as cetyl alcohol, glycerol, monostearate; adsorbents such as kaolin; lubricants such as talc, calcium stearate, magnesium stearate, solid polyethyleneglycol, sodium lauryl sulphate and mixtures thereof.

In case of capsules, tablets, pills, the dosage form may also comprise buffering agents. The solid preparation of tablets, capsules, pills, granules can be prepared with coating and shells such as enteric coating and other coatings well known in the pharmaceutical formulating art.

Liquid form preparation for oral administration includes pharmaceutically acceptable emulsions, solution, suspensions, syrups and elixirs. For liquid form preparation active compound is mixed with water or other solvent, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (such as cottonseed, groundnut, corn, germ, olive, castor and sesame oil), glycerol and fatty acid ester of sorbitan and mixtures thereof.

Besides inert diluents, the oral composition can also include adjuvants such as wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents and perfuming agent.

Injectable preparations such as sterile injections, aqueous or oleaginous suspensions may be formulated according to the art using suitable dispersing or wetting and suspending agents. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride.

Dosage form for topical or transdermal administration includes ointments, pastes, creams, lotions, gel, powders, solutions, spray, inhalants or patches. The active compound(s) are admixed under sterile condition with a pharmaceutically acceptable carrier and any needed preservatives or buffer as may be required.

The pharmaceutical preparation is in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active components.

The formulations described herein may be formulated so as to provide quick sustained, or delayed release of the active ingredient after administration to the patient by employing procedure well known to the art. The composition may be administered as a depot formulation that permits sustained release, limits access to general circulation. Such a formulation may be provided as a slow release implant, be microencapsulated, or attached to a biodegradable polymer. The compound is administered in a sustained release formulation as a tablet or capsule. A sustained release formulation is a preparation that releases the active component over a desired period of time after administration. A sustained release formulation is prepared by applying a biodegradable, bioerodible or bioabsorbable polymeric formulation that is compatible on the surface of the active component. Examples of sustained release formulation include, but are not limited to, hydroxypropylmethylcellulose (HPMC), hydrogenated vegetable oil (HVO),

ethylcellulose, polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacryl - amidephenol, polyhydroxy - ethylaspartamidephenol, or polyethyleneoxidepolylysin substituted with palmitoyl residues, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydro-pyrans, or polycyano acrylates.

The term "biodegradable" means that the polymeric formulation degrades overtime by the action of enzymes, by hydrolytic action and/or by other similar mechanisms in the human body. By "bioerodible" it is meant that the polymeric formulation erodes or degrades over time due, at least in part, to contact with substances found in the surrounding tissue fluids or cellular action. By "bioabsorbable", it is meant that the polymeric formulation is broken down and absorbed within the body of a mammal, for example, by a cell or tissue, "biocompatible" means that the polymeric formulation does not cause substantial tissue irritation or necrosis.

The pharmaceutical compositions as described herein can be administered together combined in a single dosage form or they can be administered separately, simultaneously or sequentially, each in its dosage form but as part of the same therapeutic treatment program or regimen. Separate administration of each compound, at different times and by different routes, will sometimes be recommended.

The dosage forms disclosed herein can be prepared by conventional methods known to a person ordinary skilled in the art. The dosage of the pharmaceutical composition of the present invention may be appropriately determined with reference to the dosages recommended for the respective active components and can be selected according to the recipient, the age and body weight, current clinical status, administration time, dosage form, method of administration, and combination of the active components, among other factors.

The pharmaceutical composition of the present invention can show a marked synergistic effect compared with administration of either active component alone.

Furthermore, since the pharmaceutical composition of the present invention develops sufficient efficacy with reduced doses as compared with the administration of any one of the active components alone, the side effects of the respective components can be reduced.

Another embodiment of the invention is any of the compounds of Formula I or

Formula II with a fibrate for use in the treatment or prophylaxis of cardiovascular diseases, Alzheimer's disease, obesity, diabetes or inflammatory diseases.

Another embodiment of the invention relates to the use of any of the compounds of Formula I or Formula II with a fibrate in the preparation of a medicament for the treatment or prophylaxis of cardiovascular diseases, Alzheimer's disease, obesity, diabetes or inflammatory diseases.

The invention now being generally described will be more readily understood by reference to the following examples, which are included merely for the purposes of illustration of certain aspects of the embodiments of the present invention. The examples are not intended to limit the invention, as one of skill in the art would recognize from the above teachings and the following examples that other techniques and methods can satisfy the claims and can be employed without departing from the scope of the claimed invention.

EXAMPLE

Example 1: Effect of Food and Gemfibrozil on Pharmacokinetics of PPD10558

The effect of food on the rate and extent of absorption of compounds of Formula I was evaluated using a novel statin with high potency at FTMG-CoA reductase inhibition, while additionally exploring potential drug-drug interaction (DDI) between the novel statin and gemfibrozil. A randomized, open-label study was performed in 2 stages with 30 healthy males. Stage 1 was a 2-period crossover design, and 80 mg single dose of PPD10558:

PPD10558 was given under fasted and fed conditions. Serial samples were collected after dosing for plasma levels of PPD10558 and its active metabolite, PPD11901 :

PPD11901

Stage 2 was a 3-period crossover design in which PPD10558 (80 mg) and gemfibrozil (600 mg) were administered alone and together once daily for 6 days. There was 7-day washout between periods. Serial samples were collected after dosing on Day 6 for plasma levels of PPDl 0558, PPDl 1901, and gemfibrozil. Noncompartmental pharmacokinetic (PK) parameters were estimated for all analytes. An analysis of variance was performed on AUC and Cmax to assess the effect of food and the DDI.

AUC of PPD10558 increased by 68% and Cmax decreased by 20% under the fed condition as compared to the fasted condition. For PPDl 1901, AUC and Cmax decreased by 30% and 55%, respectively, under fed conditions compared to the fasted condition. Concomitant dosing with gemfibrozil increased the AUC and Cmax of PPDl 0558 by approximately 55%. For PPDl 1901, AUC increased by approximately 17% while there was no change in Cmax in the presence of gemfibrozil. There was no impact on gemfibrozil PK observed when gemfibrozil was coadministered with PPD 10558.

This example demonstrates that food had an impact on PK of PPD10558 by increasing the extent and decreasing the rate of absorption. The reduction in PPDl 1901 exposure may be due to increased bile flow in the presence of food and the possibility of inhibition in biotransformation from PPD10558 to PPDl 1901 by food ingredients.

Gemfibrozil (an inhibitor of OATPIB 1 ) increased PPD 10558 exposures, but had minimal impact on PPDl 1901. The relatively small increases observed indicate that organic anion transporting polypeptide 1B1 (OATPIBl) is one of the transporters of PPDl 0558.

PPD 10558 had no apparent effect on gemfibrozil PK. The foregoing description of the present invention has been presented for purposes of illustration and description. Furthermore, the description is not intended to limit the invention to the form disclosed herein. Consequently, variations and modifications commensurate with the above teachings, and the skill or knowledge of the relevant art, are within the scope of the present invention. The embodiments described hereinabove are further intended to explain the best mode known for practicing the invention and to enable others skilled in the art to utilize the invention in such, or other, embodiments and with various modifications required by the particular applications or uses of the present invention. It is intended that the appended claims be construed to include alternative embodiments to the extent permitted by the prior art.