PatentDe  


Dokumentenidentifikation EP1413331 15.11.2007
EP-Veröffentlichungsnummer 0001413331
Titel Kombinationen vom PPAR-Aktivator Fenofibrat mit dem Hemmer der Sterol-Absorption Ezetimibe zur Behandlung von kardiovaskulären Indikationen
Anmelder Schering Corp., Kenilworth, N.J., US
Erfinder Kosoglou, Teddy, Jamison PA 18929-1178, US;
Davis, Harry R., Berkeley Heights NJ 07922, US;
Picard, Gilles Jean Bernard, 1420 Braine L'Alleud, BE
Vertreter derzeit kein Vertreter bestellt
DE-Aktenzeichen 60222773
Vertragsstaaten AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LI, LU, MC, NL, PT, SE, TR
Sprache des Dokument EN
EP-Anmeldetag 25.01.2002
EP-Aktenzeichen 040001612
EP-Offenlegungsdatum 28.04.2004
EP date of grant 03.10.2007
Veröffentlichungstag im Patentblatt 15.11.2007
IPC-Hauptklasse A61P 9/00(2006.01)A, F, I, 20051017, B, H, EP
IPC-Nebenklasse A61K 31/397(2006.01)A, L, I, 20051017, B, H, EP   
IPC additional class A61K 31/215  (2006.01)  A,  L,  N,  20051017,  B,  H,  EP

Beschreibung[en]
CROSS-REFERENCE TO RELATED APPLICATION

This application claims the benefit of priority from U.S. Provisional Patent Application Serial No. 60/264,396 filed January 26, 2001 and U.S. Provisional Patent Application Serial No. 60/323,839 filed September 21, 2001 .

FIELD OF THE INVENTION

The present invention relates to compositions and therapeutic combinations comprising the peroxisome proliferator-activated receptor (PPAR) activator and fenofibrate sterol absorption inhibitor of formula (II) for treating vascular and lipidemic conditions such as are associated with atherosclerosis, hypercholesterolemia and other vascular conditions in mammals.

BACKGROUND OF THE INVENTION

Atherosclerotic coronary heart disease (CHD) represents the major cause for death and vascular morbidity in the western world. Risk factors for atherosclerotic coronary heart disease include hypertension, diabetes mellitus, family history, male gender, cigarette smoke and serum cholesterol. A total cholesterol level in excess of 225-250 mg/dl is associated with significant elevation of risk of CHD.

Cholesteryl esters are a major component of atherosclerotic lesions and the major storage form of cholesterol in arterial wall cells. Formation of cholesteryl esters is also a step in the intestinal absorption of dietary cholesterol. Thus, inhibition of cholesteryl ester formation and reduction of serum cholesterol can inhibit the progression of atherosclerotic lesion formation, decrease the accumulation of cholesteryl esters in the arterial wall, and block the intestinal absorption of dietary cholesterol.

The regulation of whole-body cholesterol homeostasis in mammals and animals involves the regulation of dietary cholesterol and modulation of cholesterol biosynthesis, bile acid biosynthesis and the catabolism of the cholesterol-containing plasma lipoproteins. The liver is the major organ responsible for cholesterol biosynthesis and catabolism and, for this reason, it is a prime determinant of plasma cholesterol levels. The liver is the site of synthesis and secretion of very low density lipoproteins (VLDL) which are subsequently metabolized to low density lipoproteins (LDL) in the circulation. LDL are the predominant cholesterol-carrying lipoproteins in the plasma and an increase in their concentration is correlated with increased atherosclerosis. When intestinal cholesterol absorption is reduced, by whatever means, less cholesterol is delivered to the liver. The consequence of this action is decreased hepatic lipoprotein (VLDL) production and an increase in the hepatic clearance of plasma cholesterol, mostly as LDL. Thus, the net effect of inhibiting intestinal cholesterol absorption is a decrease in plasma cholesterol levels.

Fibric acid derivatives ("fibrates"), such as fenofibrate, gemfibrozil and clofibrate, have been used to lower triglycerides, moderately lower LDL levels and increase HDL levels. Fibric acid derivatives are also known to be peroxisome proliferator-activated receptor alpha activators.

U.S. Patents Nos. 5,767,115 , 5,624,920 , 5,668,990 , 5,656,624 and 5,688,787 , respectively, disclose hydroxy-substituted azetidinone compounds and substituted &bgr;-lactam compounds useful for lowering cholesterol and/or in inhibiting the formation of cholesterol-containing lesions in mammalian arterial walls. U.S. Patents Nos. 5,846,966 and 5,661,145 , respectively, disclose hydroxy-substituted azetidinone compounds or substituted &bgr;-lactam compounds in combination with HMG CoA reductase inhibitors for preventing or treating atherosclerosis and reducing plasma cholesterol levels.

PCT Patent Application No. WO 00/38725 discloses cardiovascular therapeutic combinations including an ileal bile acid transport inhibitor or cholesteryl ester transport protein inhibitor in combination with a fibric acid derivative, nicotinic acid derivative, microsomal triglyceride transfer protein inhibitor, cholesterol absorption antagonist, phytosterol, stanol, antihypertensive agent or bile acid sequestrant.

U.S. Patent No. 5,698,527 discloses ergostanone derivatives substituted with disaccharides as cholesterol absorption inhibitors, employed alone or in combination with certain other cholesterol lowering agents, which are useful in the treatment of hypercholesterolemia and related disorders.

WO9535277 discloses the use of substituted azetidinone compounds as hypercholesterolemic agents, in combination with cholesterol biosynthesis inhibitors including HMG-CoA reductase inhibitors (statins) or squalene synthesis inhibitors

Despite recent improvements in the treatment of vascular disease, there remains a need in the art for improved compositions and treatments for hyperlipidaemia, atherosclerosis and other vascular conditions.

SUMMARY OF THE INVENTION

there is provided a composition comprising: (a) fenofibrate and (b) a compound represented by Formula (II) below: or pharmaceutically acceptable salt or solvate thereof.

Therapeutic combinations are also provided comprising (a) a first amount of fenofibrate and (b) a second amount of sterol absorption inhibitor represented by Formula (II) above or isomers thereof or pharmaceutically acceptable salts or solvates of the compounds of Formula (II) or of the isomers thereof, wherein the first amount and the second amount together comprise a therapeutically effective amount for the treatment or prevention of a vascular condition, diabetes, obesity or lowering a concentration of a sterol in plasma of a mammal.

Pharmaceutical compositions for the treatment or prevention of a vascular condition, diabetes, obesity or lowering a concentration of a sterol in plasma of a mammal, comprising a therapeutically effective amount of the above compositions or therapeutic combinations and a pharmaceutically acceptable carrier also are provided. Use for the manufacture of a medicament for treating or preventing a vascular condition, diabetes, obesity or lowering a concentration of a sterol in plasma of a mammal, also are are provided.

Other than in the operating examples, or where otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term "about."

DETAILED DESCRIPTION

The compositions and therapeutic combinations of the present invention comprise the activator for peroxisome proliferator-activated receptors (PPAR), fenofibrate. This activator acts as agonist for the peroxisome proliferator-activated receptors. Three subtypes of PPAR have been identified, and these are designated as peroxisome proliferator-activated receptor alpha (PPAR&agr;), peroxisome proliferator-activated receptor gamma (PPAR&ggr;) and peroxisome proliferator-activated receptor delta (PPAR&dgr;). It should be noted that PPAR&dgr; is also referred to in the literature as PPAR&bgr; and as NUC1, and each of these names refers to the same receptor.

PPAR&agr; regulates the metabolism of lipids. PPAR&agr; is activated by fibrates and a number of medium and long-chain fatty acids, and it is involved in stimulating &bgr;-oxidation of fatty acids. The PPAR&ggr; receptor subtypes are involved in activating the program of adipocyte differentiation and are not involved in stimulating peroxisome proliferation in the liver. PPAR&dgr; has been identified as being useful in increasing high density lipoprotein (HDL) levels in humans. See, e.g., WO 97/28149 .

PPAR&agr; activator compounds are useful for, among other things, lowering triglycerides, moderately lowering LDL levels and increasing HDL levels. Examples of PPAR&agr; activators include fibrates as clofibrate (such as ethyl 2-(p-chlorophenoxy)-2-methyl-propionate, for example ATROMID-S® Capsules which are commercially available from Wyeth-Ayerst); genifibrozil (such as 5-(2,5-dimethylphenoxy)-2.2-dimethylpentanoic acid, for example LOPID® tablets which are commercially available from Parke Davis); ciprofibrate (C.A.S. Registry No. 52214-84-3, see U.S. Patent No. 3.948.973 bezafibrate (C.A.S. Registry No. 41859-67-0, see U.S. Patent No. 3,781,328 clinofibrate (C.A.S. Registry No. 30299-08-2, binifibrate (C.A.S. Registry No. 69047-39-8, see BE 884722; lifibrol (C.A.S. Registry No. 96609-16-4); fenofibrate (such as TRICOR® micronized fenofibrate (2-[4-(4-chlorobenzoyl) phenoxy]-2-methyl-propanoic acid, 1-methylethyl ester) which is commercially available from Abbott Laboratories or LIPANTHYL® micronized fenofibrate which is commercially available from Labortoire Founier, France) and mixtures thereof. These compounds can be used in a variety of forms, including but not limited to acid form, salt form, racemates, enantiomers, zwitterions and tautomers.

The peroxisome proliferator-activated receptor activator fenofibrate is administered in a therapeutically effective amount to treat the specified condition, for example in a daily dose can range from 0.1 to 1000 mg per day, preferably 0.25 to 50 mg/day, and more preferably about 10 mg per day, given in a single dose or 2-4 divided doses. The exact dose, however, is determined by the attending clinician and is dependent on such factors as the potency of the compound administered, the age, weight, condition and response of the patient.

The term "therapeutically effective amount" means that amount of a therapeutic agent of the composition, such as the peroxisome proliferator-activated receptor activator fenofibrate sterol absorption inhibitor of formula (II) and other pharmacological or therapeutic agents described below, that will elicit a biological or medical response of a tissue, system, animal or mammal that is being sought by the administrator (such as a researcher, doctor or veterinarian) which includes alleviation of the symptoms of the condition or disease being treated and the prevention, slowing or halting of progression of one or more conditions, for example vascular conditions, such as hyperlipidaemia (for example atherosclerosis, hypercholesterolemia or sitosterolemia), vascular inflammation, stroke, diabetes, obesity and/or to reduce the level of sterol(s) (such as cholesterol) in the plasma.

As used herein, "combination therapy" or "therapeutic combination" means the administration of two or more therapeutic agents, such as peroxisome proliferator-activated receptor activator fenofibrate and sterol absorption inhibitor of formula (II), to prevent or treat a vascular condition, such as hyperlipidaemia (for example atherosclerosis, hypercholesterolemia or sitosterolemia), vascular inflammation, stroke, diabetes, obesity and/or reduce the level of sterol(s) (such as cholesterol) in the plasma. As used herein, "vascular" comprises cardiovascular, cerebrovascular and combinations thereof. The compositions, combinations and treatments of the present invention can be administered by any suitable means which produce contact of these compounds with the site of action in the body, for example in the plasma, liver or small intestine of a mammal or human. Such administration includes coadministration of these therapeutic agents in a substantially simultaneous manner, such as in a single tablet or capsule having a fixed ratio of active ingredients or in multiple, separate capsules for each therapeutic agent. Also, such administration includes use of each type of therapeutic agent in a sequential manner. In either case, the treatment using the combination therapy will provide beneficial effects in treating the condition. A potential advantage of the combination therapy disclosed herein may be a reduction in the required amount of an individual therapeutic compound or the overall total amount of therapeutic compounds that are effective in treating the condition. By using a combination of therapeutic agents, the side effects of the individual compounds can be reduced as compared to a monotherapy, which can improve patient compliance. Also, therapeutic agents can be selected to provide a broader range of complimentary effects or complimentary modes of action. The sterol inhibitor useful in the compositions, therapeutic combinations and methods of the present invention is represented by Formula (11) (ezetimibe) below: or pharmaceutically acceptable salts or solvates of the compound of Formula (II)

Compound of Formula II can be prepared as in the Example below.

In another embodiment. compositions, pharmaceutical compositions, therapeutic combinations, kits and uses in the manufacture of a medicament for a treatment as described above are provided which comprise: (a) the peroxisome proliferator-activated receptor activator fenofibrate; and (b) substituted azetidinone compound of formula (II) or isomers of the substituted azetidinone compound of formula (II) or pharmaceutically acceptable salts or solvate of the substituted azetidinone compound of formula (II) or of the isomers of the substituted azetidinone compound of formula (II) wherein the first amount and the second amount together in their totality (whether administered concurrently or consecutively) comprise a therapeutically effective amount for the treatment or prevention of a vascular condition, diabetes, obesity or lowering a concentration of a sterol in plasma of a mammal.

The daily dose of the sterol absorption inhibitor of formula (II) can range from 0.1 to 1000 mg per day, preferably 0.25 to 50 mg/day, and more preferably about 10 mg per day, given in a single dose or 2-4 divided doses. The exact dose, however, is determined by the attending clinician and is dependent on the potency of the compound administered, the age, weight, condition and response of the patient.

For administration of pharmaceutically acceptable salts of the above compounds, the weights indicated above refer to the weight of the acid equivalent or the base equivalent of the therapeutic compound derived from the salt.

In one embodiment of the present invention, the compositions or therapeutic combinations can further comprise one or more pharmacological or therapeutic agents or drugs such as cholesterol biosynthesis inhibitors and/or lipid-lowering agents discussed below.

In another embodiment, the composition or treatment can further comprise one or more cholesterol biosynthesis inhibitors coadministered with or in combination with the peroxtjspme.prqtiferator-activated receptor activator fenofibrate and sterol absorption inhibitor of formula (II) discussed above.

Cholesterol biosynthesis inhibitors for use in the compositions, therapeutic combinations and methods of the present invention include competitive inhibitors of HMG CoA reductase, the rate-limiting step in cholesterol biosynthesis, squalene synthase inhibitors, squalene epoxidase inhibitors and mixtures thereof. Suitable HMG CoA reductase inhibitors include statins such as lovastatin (for example MEVACOR® which is available from Merck & Co.), pravastatin (for example PRAVACHOL® which is available from Bristol Meyers Squibb), fluvastatin, simvastatin (for example ZOCOR® which is available from Merck & Co.), atorvastatin, cerivastatin, CI-981, rivastatin (sodium 7-(4-fluorophenyl)-2,6-diisopropyl-5-methoxymethylpyridin-3-yl)-3,5-dihydroxy-6-heptanoate), rosuvastatin, pitavastatin (such as NK-104 of Negma Kowa of Japan); HMG CoA synthetase inhibitors, for example L-659,699 ((E,E)-11-[3'R-(hydroxymethyl)-4'-oxo-2'R-oxetanyl]-3,5,7R-trimethyl-2,4-undecadienoic acid); squalene synthesis inhibitors, for example squalestatin 1; and squalene epoxidase inhibitors, for example, NB-598 ((E)-N-ethyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-3-[(3,3'-bithiophen-5-yl)methoxy]benzene-methanamine hydrochloride) and other sterol biosynthesis inhibitors such as DMP-565. Preferred HMG CoA reductase inhibitors include lovastatin, pravastatin and simvastatin. The most preferred HMG CoA reductase inhibitor is simvastatin.

Generally, a total daily dosage of cholesterol biosynthesis inhibitor(s) can range from 0.1 to 160 mg per day, and preferably 0.2 to 80 mg/day in single or 2-3 divided doses.

In another preferred embodiment, the composition or treatment comprises the compound of Formula (II) in combination with peroxisome proliferator-activated receptor(s') activator fenofibrate and one or more cholesterol biosynthesis inhibitors. Preferably the cholesterol biosynthesis inhibitor comprises one or more HMG CoA reductase inhibitors, such as, for example, lovastatin, pravastatin and/or simvastatin. More preferably, the composition or treatment comprises the compound of Formula (II) in combination with simvastatin and fenofibrate.

In another alternative embodiment, the compositions, therapeutic combinations of the present invention can further comprise one or more bile acid sequestrants (insoluble anion exchange resins), coadministered with or in combination with the PPAR activator fenofibrate and sterol absorption inhibitor of formula (II) discussed above.

Bile acid sequestrants bind bile acids in the intestine, interrupting the enterohepatic circulation of bile acids and causing an increase in the faecal excretion of steroids. Use of bile acid sequestrants is desirable because of their non-systemic mode of action. Bile acid sequestrants can lower intrahepatic cholesterol and promote the synthesis of apo B/E (LDL) receptors that bind LDL from plasma to further reduce cholesterol levels in the blood.

Suitable bile acid sequestrants include cholestyramine (a styrene-divinylbenzene copolymer containing quaternary ammonium cationic groups capable of binding bile acids, such as QUESTRANO or QUESTRAN LIGHT® cholestyramine which are available from Bristol-Myers Squibb), colestipol (a copolymer of diethylenetriamine and 1-chloro-2.3-epoxypropane, such as COLESTID® tablets which are available from Pharmacia), colesevelam hydrochloride (such as WeIChol® Tablets (poly(allylamine hydrochloride) cross-linked with epichlorohydrin and alkylated with 1-bromodecane and (6-bromohexyl)-trimethylammonium bromide) which are available from Sankyo), water soluble derivatives such as 3,3·ioene, N-(cycloalkyl) alkylamines and poliglusam, insoluble quatemized polystyrenes, saponins and mixtures thereof. Other useful bile acid sequestrants are disclosed in PCT Patent Applications Nos. WO 97/11345 and WO 98/57652 , and U.S. Patents Nos. 3,692,895 and 5.703,188 . Suitable inorganic cholesterol sequestrants include bismuth salicylate plus montmorillonite clay, aluminum hydroxide and calcium carbonate antacids.

Generally, a total daily dosage of bile acid sequestrant(s) can range from 1 to 50 grams per day, and preferably 2 to 16 grams per day in single or 2-4 divided doses.

In an alternative embodiment, the compositions or treatments of the present invention can further comprise one or more ileal bile acid transport ("IBAT") inhibitors (or apical sodium co-dependent bile acid transport ("ASBT") inhibitors) coadministered with or in combination with the peroxisome proliferator-activated receptor activator fenofibrate and sterol absorption inhibitor of formula (II) discussed above. The IBAT inhibitors can inhibit bile acid transport to reduce LDL cholesterol levels. Suitable IBAT inhibitors include benzothiepines such as therapeutic compounds comprising a 2,3,4,5-tetrahydro-1-benzothiepine 1,1-dioxide structure such as are disclosed in PCT Patent Application WO 00/38727

Generally, a total daily dosage of IBAT inhibitor(s) can range from 0.01 to 1000 mg/day, and preferably 0.1 to 50 mg/day in single or 2-4 divided doses.

In another alternative embodiment, the compositions or treatments of the present invention can further comprise nicotinic acid (niacin) and/or derivatives thereof coadministered with or in combination with the peroxisome proliferator-activated receptor activator fenofibrate and sterol absorption inhibitor of formula (II) discussed above.

As used herein, "nicotinic acid derivative" means a compound comprising a pyridine-3-carboxylate structure or a pyrazine-2-carboxylate structure, including acid forms, salts, esters, zwitterions and tautomers, where available. Examples of nicotinic acid derivatives include niceritrol, nicofuranose and acipimox (5-methyl pyrazine-2-carboxylic acid 4-oxide). Nicotinic acid and its derivatives inhibit hepatic production of VLDL and its metabolite LDL and increases HDL and apo A-1 levels. An example of a suitable nicotinic acid product is NIASPAN® (niacin extended-release tablets) which are available from Kos.

Generally, a total daily dosage of nicotinic acid or a derivative thereof can range from 500 to 10,000 mg/day, preferably 1000 to 8000 mg/day, and more preferably 3000 to 6000 mg/day in single or divided doses.

In another alternative embodiment, the compositions or treatments of the present invention can further comprise one or more AcylCoA:Cholesterol O-acyltransferase ("ACAT") Inhibitors, which can reduce LDL and VLDL levels, coadministered with or in combination with the peroxisome proliferator-activated receptor activator fenofibrate and sterol absorption inhibitor of formula (II) discussed above. ACAT is an enzyme responsible for esterifying excess intracellular cholesterol and may reduce the synthesis of VLDL, which is a product of cholesterol esterification, and overproduction of apo B-100-containing lipoproteins.

Useful ACAT inhibitors include avasimibe ([[2,4,6-tris(1-methylethyl)phenyl]acetyl]sulfamic acid, 2,6-bis(1-methylethyl)phenyl ester, formerly known as Cl-1011), HL-004, lecimibide (DuP-128) and CL-277082 (N-(2,4-difluorophenyl)-N-[[4-(2,2-dimethylpropyl)phenyl]methyl]-N-heptylurea). See P. Chang et al., "Current, New and Future Treatments in Dyslipidaemia and Atherosclerosis". Drugs 2000 Jul;60(1); 55-93 .

Generally, a total daily dosage of ACAT inhibitor(s) can range from 0.1 to 1000 mg/day in single or 2-4 divided doses.

In another alternative embodiment, the compositions or treatments of the present invention can further comprise one or more Cholesteryl Ester Transfer Protein ("CETP") Inhibitors coadministered with or in combination with the peroxisome proliferator-activated receptor activator fenofibrate and sterol absorption inhibitor of formula (II) discussed above. CETP is responsible for the exchange or transfer of cholesteryl ester carrying HDL and triglycerides in VLDL.

Suitable CETP inhibitors are disclosed in PCT Patent Application No. WO 00/38721 and U.S. Patent No. 6,147,090 , Pancreatic cholesteryl ester hydrolase (pCEH) inhibitors such as WAY-121898 also can be coadministered with or in combination with the peroxisome proliferator-activated receptor(s) activator fenofibrate and sterol absorption inhibitor of formula (II) discussed above.

Generally, a total daily dosage of CETP inhibitor(s) can range from 0.01 to 1000 mg/day, and preferably 0.5 to 20 mg/kg body weight/day in single or divided doses.

In another alternative embodiment, the compositions or treatments of the present invention can further comprise probucol or derivatives thereof (such as AGI-1067 and other derivatives disclosed in U.S. Patents Nos. 6,121,319 and 6,147,250 ), which can reduce LDL levels, coadministered with or in combination with the peroxisome protiferator-activated receptor activator fenofibrate and sterol absorption inhibitor of formula (II) discussed above.

Generally, a total daily dosage of probucol or derivatives thereof can range from 10 to 2000 mg/day, and preferably 500 to 1500 mg/day in single or 2-4 divided doses.

In another alternative embodiment, the compositions or treatments of the present invention can further comprise low-density lipoprotein (LDL) receptor activators, coadministered with or in combination with the peroxisome pryliferator-activated receptor activator fenofibrate and sterol absorption inhibitor of formula (II) discussed above. Suitable LDL-receptor activators include HOE-402, an imidazolidinyl-pyrimidine derivative that directly stimulates LDL receptor activity. See M. Huettinger et al., "Hypolipidemic activity of HOE-402 is Mediated by Stimulation of the LDL Receptor Pathway", Arterioscler. Thromb. 1993; 13:1005-12 .

Generally, a total daily dosage of LDL receptor activator(s) can range from to 1000 mg/day in single or 2-4 divided doses.

In another alternative embodiment, the compositions or treatments of the present invention can further comprise fish oil, which contains Omega 3 fatty acids (3-PUFA), which can reduce VLDL and triglyceride levels, coadministered with or in combination with the peroxisome proliferator-activated receptor activator fenofibrate and sterol absorption inhibitor of formula (II) discussed above. Generally, a total daily dosage of fish oil or Omega 3 fatty acids can range from 1 to 30 grams per day in single or 2-4 divided doses.

In another alternative embodiment, the compositions or treatments of the present invention can further comprise natural water soluble fibers, such as psyllium, guar, oat and pectin, which can reduce cholesterol levels, coadministered with or in combination with the peroxisome proliferator-activated receptor activated fenofibrate and sterol absorption inhibitor of formula (II) discussed above. Generally, a total daily dosage of natural water soluble fibers can range from 0.1 to 10 grams per day in single or 2-4 divided doses.

In another alternative embodiment, the compositions or treatments of the present invention can further comprise plant sterols, plant stanols and/or fatty acid esters of plant stanols, such as sitostanol ester used in BENECOL® margarine, which can reduce cholesterol levels, coadministered with or in combination with the peroxisome proliferator-activated receptor activator fenofibrate and sterol absorption inhibitor of formula (II) discussed above. Generally, a total daily dosage of plant sterols, plant stanols and/or fatty acid esters of plant stanols can range from 0.5 to 20 grams per day in single or 2-4 divided doses.

In another alternative embodiment, the compositions or treatments of the present invention can further comprise antioxidants, such as probucol, tocopherol, ascorbic acid, &bgr;-carotene and selenium, or vitamins such as vitamin B6 or vitamin B12. coadministered with or in combination with the peroxisome proliferator-activated receptor activator fenofibrate and sterol absorption inhibitor of formula (II) discussed above. Generally, a total daily dosage of antioxidants or vitamins can range from 0.05 to 10 grams per day in single or 2-4 divided doses.

In another alternative embodiment, the compositions or treatments of the present invention can further comprise monocyte and macrophage inhibitors such as polyunsaturated fatty acids (PUFA), thyroid hormones including throxine analogues such as CGS-26214 (a thyroxine compound with a fluorinated ring), gene therapy and use of recombinant proteins such as recombinant apo E, coadministered with or in combination with the peroxisome proliferator-activated receptor activator fenofibrate and sterol absorption inhibitor of formula (II) discussed above. Generally, a total daily dosage of these agents can range from 0.01 to 1000 mg/day in single or 2-4 divided doses.

Also useful with the present invention are compositions or therapeutic combinations which further comprise hormone replacement agents and compositions. Useful hormone agents and compositions for hormone replacement therapy of the present invention include androgens, estrogens, progestins, their pharmaceutically acceptable salts and derivatives thereof. Combinations of these agents and compositions are also useful.

The dosage of androgen and estrogen combinations vary, desirably from 1 mg to 4 mg androgen and from 1 mg to 3 mg estrogen. Examples include, androgen and estrogen combinations such as the combination of esterified estrogens (sodium estrone sulfate and sodium equilin sulfate) and methyltestosterone (17-hydroxy-17-methyl-, (17B)- androst-4-en-3-one) available from Solvay Pharmaceuticals, Inc., Marietta. GA, under the tradename Estratest™.

Estrogens and estrogen combinations may vary in dosage from 0.01 mg up to 8 mg, desirably from 0.3 mg to 3.0 mg. Examples of useful estrogens and estrogen combinations include:

  1. (a) the blend of nine (9) synthetic estrogenic substances including sodium estrone sulfate, sodium equilin sulfate, sodium 17 &agr; -dihydroequilin sulfate, sodium 17 &agr; -estradiol sulfate, sodium 17 &bgr; -dihydroequilin sulfate, sodium 17 &agr; -dihydroequilenin sulfate, sodium 17 &bgr; -dihydroequilenin sulfate, sodium equilenin sulfate and sodium 17 &bgr; -estradiol sulfate; available from Duramed Pharmaceuticals, Inc., Cincinnati, OH, under the tradename Cenestin™.
  2. (b) ethinyl estradiol (19-nor-17 &agr; -pregna-1,3,5(10)-trien-20-yne-3,17-diol; available by Schering Plough Corporation, Kenilworth, NJ, under the tradename - Estiny™.
  3. (c) esterified estrogen combinations such as sodium estrone sulfate and sodium equilin sulfate; available from Solvay under the tradename Estratab and from Monarch Pharmaceuticals, Bristol, TN, under the tradename Menest™;
  4. (d) estropipate (piperazine estra-1,3,5(10)-trien-17-one, 3-(sulfooxy)-estrone sulfate); available from Pharmacia & Upjohn, Peapack, NJ, under the tradename Ogen™ and from Women First Health Care, Inc., San Diego, CA, under the tradename Ortho-Est™, and
  5. (e) conjugated estrogens (17 &agr;-dihydroequilin, 17 &agr;-estradiol, and 17 &bgr;-dihydroequilin); available from Wyeth-Ayerst Pharmaceuticals. Philadelphia, PA, under the tradename Premarin™.

Progestins and estrogens may also be administered with a variety of dosages, generally from 0.05 to 2.0 mg progestin and 0.001 mg to 2 mg estrogen, desirably from 0.1 mg to 1 mg progestin and 0.01 mg to 0.5 mg estrogen. Examples of progestin and estrogen combinations that may vary in dosage and regimen include:

  1. (a) the combination of estradiol (estra-1, 3, 5 (10)-triene-3, 17 &bgr;-diol hemihydrate) and norethindrone (17 &bgr;-acetoxy-19-nor-17 &agr;-pregn-4-en-20-yn-3-one); which is available from Pharmacia & Upjohn, Peapack, NJ, under the tradename Activella™;
  2. (b) the combination of levonorgestrel (d(-)-13 &bgr;-ethyl-17 &agr;-ethinyl-17 &bgr;-hydroxygon- 4-en-3-one) and ethinyl estradial; available from Wyeth-Ayerst under the tradename Alesse™, from Watson Laboratories, Inc., Corona, CA, under the tradenames Levora™ and Trivora™, Monarch Pharmaceuticals, under the tradename Nordette™, and from Wyeth-Ayerst under the tradename Triphasil™;
  3. (c) the combination of ethynodiol diacetate (19-nor-17 &agr;-pregn-4-en-20-yne-3 &bgr;, 17-diol diacetate) and ethinyl estradiol; available from G.D. Searle & Co., Chicago. IL, under the tradename Demule™ and from Watson under the tradename Zovia™;
  4. (d) the combination of desogestrel (13-ethyl-11- methylene-18,19-dinor-17 &agr;-pregn- 4-en- 20-yn-17-ol) and ethinyl estradiol; available from Organon under the tradenames Desogen™ and Mircette™, and from Ortho-McNeil Pharmaceutical, Raritan, NJ, under the tradename Ortho-Cept™;
  5. (e) the combination of norethindrone and ethinyl estradiol; available from Parke-Davis, Morris Plains, NJ, under the tradenames Estrostep™ and femhrt™, from Watson under the tradenames Microgestin™, Necon™, and Tri-Norinyl™, from Ortho-McNeil under the tradenames Modicon™ and Ortho-Novum™, and from Warner Chilcott Laboratories, Rockaway, NJ, under the tradename Ovcon™,
  6. (f) the combination of norgestrel ((±)-13-ethyl-17-hydroxy-18, 19-dinor-17 &agr;-preg-4-en-20-yn-3-one) and ethinyl estradiol; available from Wyeth-Ayerst under the tradenames Ovral™ and Lo/Ovral™, and from Watson under the tradenames Ogestrel™ and Low-Ogestrel™;
  7. (g) the combination of norethindrone, ethinyl estradiol, and mestranol (3-methoxy-19-nor-17 &agr;-pregna-1,3,5(10)-trien-20-yn-17-ol); available from Watson under the tradenames Brevicon™ and Norinyl™;
  8. (h) the combination of 17 &bgr;-estradiol (estra-1,3,5(10)-triene-3,17 &bgr;-diol) and micronized norgestimate (17 &agr;-17-(Acetyloxyl)-13-ethyl-18,19-dinorpregn-4-en-20-yn-3-one3-oxime); available from Ortho-McNeil under the tradename Ortho-Prefest™;
  9. (i) the combination of norgestimate (18,19-dinor-17-pregn-4-en-20-yn-3-one, 17--(acetyloxy)-13-ethyl-,oxime, (17(&agr;)-(+)-) and ethinyl estradiol; available from Ortho-McNeil under the tradenames Ortho Cyclen™ and Ortho Tri-Cyclen™; and
  10. (j) the combination of conjugated estrogens (sodium estrone sulfate and sodium equilin sulfate) and medroxyprogesterone acetate (20-dione, 17-(acetyloxy)-6-methyl-, (6(&agr;))- pregn-4-ene-3); available from Wyeth-Ayerst under the tradenames Premphase™ and Prempro™.

In general, a dosage of progestins may vary from 0.5 mg to 10 mg or up to about 200 mg if microsized progesterone is administered. Examples of progestins include norethindrone: available from ESI Lederle, Inc., Philadelphia, PA, under the tradename Aygestin™, from Ortho-McNeil under the tradename Micronor™, and from Watson under the tradename Nor-QD™; norgestrel: available from Wyeth-Ayerst under the tradename Ovrette™; micronized progesterone (pregn-4-ene-3, 20-dione); available from Solvay under the tradename Promettium™; and medroxyprogesterone acetate; available from Pharmacia & Upjohn under the tradename Provera™.

The compositions, therapeutic combinations or methods of the present invention can further comprise one or more obesity control medications. Useful obesity control medications include, drugs that reduce energy intake or suppress appetite, drugs that increase energy expenditure and nutrient-partitioning agents. Suitable obesity control medications include, noradrenergic agents (such as diethylpropion, mazindol, phenylpropanolamine, phentermine, phendimetrazine, phendamine tartrate, methamphetamine, phendimetrazine and tartrate); serotonergic agents (such as sibutramine, fenfluramine, dexfenfluramine, fluoxetine, fluvoxamine and paroxtine); thermogenic agents (such as ephedrine, caffeine, theophylline, and selective &bgr;3-adrenergic agonists); alpha-blocking agents; kainite or AMPA receptor antagonists; leptin-lipolysis stimulated receptors; phosphodiesterase enzyme inhibitors; compounds having nucleotide sequences of the mahogany gene; fibroblast growth factor-10 polypeptides; monoamine oxidase inhibitors (such as befloxatone, moclobemide, brofaromine, phenoxathine, esuprone, befol, toloxatone, pirlindol, amiflamine, sercloremine, bazinaprine, lazabemide, milacemide and caroxazone); compounds for increasing lipid metabolism (such as evodiamine compounds); and lipase inhibitors (such as orlistat). Generally, a total dosage of the above-described obesity control medications can range from 1 to 3,000 mg/day, desirably from 1 to 1,000 mg/day and more desirably from 1 to 200 mg/day in single or 2-4 divided doses.

The compositions, therapeutic combinations or methods of the present invention can further comprise one or more blood modifiers which are chemically different from the substituted azetidinone of formula (II) and the PPAR receptor activator fenofibrate discussed above Useful blood modifiers include anti-coagulants (argatroban, bivalirudin, dalteparin sodium, desirudin, dicumarol, lyapolate sodium, nafamostat mesylate, phenprocoumon, tinzaparin sodium, warfarin sodium); antithrombotic (anagrelide hydrochloride, bivalirudin, cilostazol, dalteparin sodium, danaparoid sodium, dazoxiben hydrochloride, efegatran sulfate, enoxaparin sodium, fluretofen, ifetroban, ifetroban sodium, lamifiban, lotrafiban hydrochloride, napsagatran, orbofiban acetate, roxifiban acetate, sibrafiban, tinzaparin sodium, trifenagrel, abciximab, zolimomab aritox); fibrinogen receptor antagonists (roxifiban acetate, fradafiban, orbofiban, lotrafiban hydrochloride, tirofiban, xemilofiban, monoclonal antibody 7E3, sibrafiban); platelet inhibitors (cilostazol, clopidogrel bisulfate, epoprostenol, epoprostenol sodium, ticlopidine hydrochloride, aspirin, ibuprofen, naproxen, sulindae, idomethacin, mefenamate, droxicam, diclofenac, sulfinpyrazone, piroxicam, dipyridamole); platelet aggregation inhibitors (acadesine, beraprost, beraprost sodium, ciprostene calcium, itazigrel, lifarizine, lotrafiban hydrochloride, orbofiban acetate, oxagrelate, fradafiban, orbofiban, tirofiban, xemilofiban); hemorrheologic agents (pentoxifylline): lipoprotein associated coagulation inhibitors; Factor Vlla inhibitors (4H-31-benzoxazin-4-ones, 4H-3,1-benzoxazin-4-thiones, quinazolin-4-ones, quinazolin-4-thiones, benzothiazin-4-ones, imidazolyl-boronic acid-derived peptide analogues TFPI-derived peptides, naphthalene-2-sulfonic acid {1-[3-(aminoiminomethyl)-benzyl]-2-oxo-pyrrolidin-3-(S)-yl} amide trifluoroacetate, dibenzofuran-2-sulfonic acid {1-[3-(aminomethyl)-benzyl]-5-oxo-pyrrolidin-3-yl}-amide, tolulene-4-sulfonic acid {1-[3-(aminoiminomethyl)-benzyl]-2-oxo-pyrrolidin-3-(S)-yl}-amide trifluoroacetate. 3,4-dihydro-1H-isoquinoline-2-sulfonic acid {1-[3-(aminoiminomethyl)-benzyl]-2-oxo-pyrrolin-3-(S)-yl}-amide trifluoroacetate); Factor Xa inhibitors (disubstituted pyrazolines, disubstituted triazolines, substituted n-[(aminoiminomethyl)phenyl] propylamides, substituted n-[(aminomethyl)phenyl] propylamides, tissue factor pathway inhibitor (TFPI), low molecular weight heparins, heparinoids, benzimidazolines, benzoxazolinones, benzopiperazinones, indanones, dibasic (amidinoaryl) propanoic acid derivatives, amidinophenyl-pyrrolidines, amidinophenyl-pyrrolines, amidinophenyl-isoxazolidines, amidinoindoles, amidinoazoles, bis-arlysulfonylaminobenzamide derivatives, peptidic Factor Xa inhibitors).

The compositions, therapeutic combinations of the present invention can further comprise one or more cardiovascular agents which are chemically different from the substituted azetidinone of formula (II) and the PPAR receptor activator fenofibrate discussed above. Useful cardiovascular agents include calcium channel blockers (clentiazem maleate, amlodipine besylate, isradipine, nimodipine, felodipine, nilvadipine, nifedipine, teludipine hydrochloride, diltiazem hydrochloride, belfosdil, verapamil hydrochloride, fostedil); adrenergic blockers (fenspiride hydrochloride, labetalol hydrochloride, proroxan, alfuzosin hydrochloride, acebutolol, acebutolol hydrochloride, alprenolol hydrochloride, atenolol, bunolol hydrochloride, carteolol hydrochloride, celiprolol hydrochloride, cetamolol hydrochloride, cicloprolol hydrochloride, dexpropranolol hydrochloride, diacetolol hydrochloride, dilevalol hydrochloride, esmolol hydrochloride, exaprolol hydrochloride, flestolol sulfate, labetalol hydrochloride, levobetaxolol hydrochloride, levobunolol hydrochloride, metalol hydrochloride, metoprolol, metoprolol tartrate, nadolol, pamatolol sulfate, penbutolol sulfate, practolol, propranolol hydrochloride, sotalol hydrochloride, timolol, timolol maleate, tiprenolol hydrochloride, tolamolol, bisoprolol, bisoprolol fumarate, nebivolol); adrenergic stimulants; angiotensin converting enzyme (ACE) inhibitors (benazepril hydrochloride, benazeprilat, captopril, delapril hydrochloride, fosinopril sodium, libenzapril, moexipril hydrochloride, pentopril, perindopril, quinapril hydrochloride, quinaprilat, ramipril, spirapril hydrochloride, spiraprilat, teprotide, enalapril maleate, lisinopril, zofenopril calcium, perindopril erbumine); antihypertensive agents (althiazide, benzthiazide, captopril, carvedilol, chlorothiazide sodium, clonidine hydrochloride, cyclothiazide, delapril hydrochloride, dilevalol hydrochloride, doxazosin mesylate, fosinopril sodium, guanfacine hydrochloride, methyldopa, metoprolol succinate, moexipril hydrochloride, monatepil maleate, pelanserin hydrochloride, phenoxybenzamine hydrochloride, prazosin hydrochloride, primidolol, quinapril hydrochloride, quinaprilat, ramipril, terazosin hydrochloride, candesartan, candesartan cilexetil, telmisartan, amlodipine besylate, amlodipine maleate, bevantolol hydrochloride); angiotensin II receptor antagonists (candesartan, irbesartan, losartan potassium, candesartan cilexetil, telmisartan); anti-anginal agents (amlodipine besylate, amlodipine maleate, betaxolol hydrochloride, bevantolol hydrochloride, butoprozine hydrochloride, carvedilol, cinepazet maleate, metoprolol succinate, molsidomine, monatepil maleate, primidolol, ranolazine hydrochoride, tosifen, verapamil hydrochloride); coronary vasodilators (fostedil, azaclorzine hydrochloride, chromonar hydrochloride, clonitrate, diltiazem hydrochloride, dipyridamole, droprenilamine, erythrityl tetranitrate, isosorbide dinitrate, isosorbide mononitrate, lidoflazine, mioflazine hydrochloride, mixidine, molsidomine, nicorandil, nifedipine, nisoldipine, nitroglycerine, oxprenolol hydrochloride, pentrinitrol, perhexiline maleate, prenylamine, propatyl nitrate, terodiline hydrochloride, tolamolol, verapamil); diuretics (the combination product of hydrochlorothiazide and spironolactone and the combination product of hydrochlorothiazide and triamterene).

The compositions, therapeutic combinations of the present invention can further comprise one or more antidiabetic medications for reducing blood glucose levels in a human. Useful antidiabetic medications include, drugs that reduce energy intake or suppress appetite, drugs that increase energy expenditure and nutrient-partitioning agents. Suitable antidiabetic medications include, sulfonylurea (such as acetohexamide, chlorpropamide, gliamilide, gliclazide, glimepiride, glipizide, glyburide, glibenclamide, tolazamide, and tolbutamide), meglitinide (such as repaglinide and nateglinide), biguanide (such as metformin and buformin), alpha-glucosidase inhibitor (such as acarbose, miglitol, camiglibose, and voglibose), certain peptides (such as amlintide, pramlintide, exendin, and GLP-1 agonistic peptides), and orally administrable insulin or insulin composition for intestinal delivery thereof. Generally, a total dosage of the above-described antidiabetic medications can range from 0.1 to 1,000 mg/day in single or 2-4 divided doses.

Mixtures of any of the pharmacological or therapeutic agents described above can be used in the compositions and therapeutic combinations of the present invention.

The compositions and therapeutic combinations of the present invention can be administered to a mammal in need of such treatment in a therapeutically effective amount to treat one or more conditions, for example vascular conditions such as atherosclerosis, hyperlipidaemia (including to hypercholesterolemia, hypertriglyceridaemia, sitosterolemia), vascular inflammation, stroke, diabetes, obesity, and/or reduce the level of sterol(s) in the plasma. The compositions can be administered by any suitable means which produce contact of these compounds with the site of action in the body, for example in the plasma, liver or small intestine of a mammal or human.

The daily dosage for the various compositions and therapeutic combinations described above can be administered to a patient in a single dose or in multiple subdoses, as desired. Subdoses can be administered 2 to 6 times per day, for example. Sustained release dosages can be used. Where the peroxisome proliferator-activated receptor activator fenofibrate and sterol absorption inhibitor of formula (II) are administered in separate dosages, the number of doses of each component given per day may not necessarily be the same, e.g., one component may have a greater duration of activity and will therefore need to be administered less frequently.

The pharmaceutical treatment compositions and therapeutic combinations of the present invention can further comprise one or more pharmaceutically acceptable carriers, one or more excipients and/or one or more additives. Pharmaceutically acceptable carriers include solids and/or liquids such as ethanol, glycerol, water. The amount of carrier.in the treatment composition can range from 5 to 99 weight percent of the total weight of the treatment composition or therapeutic combination. Suitable pharmaceutically acceptable excipients and additives include non-toxic compatible fillers, binders such as starch, disintegrants, buffers, preservatives, anti-oxidants, lubricants, flavorings, thickeners, coloring agents, emulsifiers. The amount of excipient or additive can range from 0.1 to 90 weight percent of the total weight of the treatment composition or therapeutic combination. One skilled in the art would understand that the amount of carrier(s), excipients and additives (if present) can vary.

The treatment compositions of the present invention can be administered in any conventional dosage form, preferably an oral dosage form such as a capsule, tablet, powder, cachet, suspension or solution. The formulations and pharmaceutical compositions can be prepared using conventional pharmaceutically acceptable and conventional techniques. Several examples of preparation of dosage formulations are provided below.

The following formulations exemplify some of the dosage forms of this invention. In each formulation, the term "Active Compound I" designates substituted azetidinone compound of Formula (II) described herein above, or isomers of the at least one substituted azetidinone compound of Formula (II) or pharmaceutically acceptable salts or solvates of the at least one substituted azetidinone compound of Formula (II) or of the isomers of the at least one substituted azetidinone compound of Formula (II), and the term "Active Compound II" designates PPAR activator fenobibrate described herein above.

EXAMPLE

Tablets No. Ingredient mg/tablet 1 Active Compound 1 10 2 Lactose monohydrate NF 55 3 Microcrystalline cellulose NF 20 4 Povidone (K29-32) USP 4 5 Croscarmellose sodium NF 8 6 Sodium lauryl sulfate 2 7 Magnesium stearate NF 1 Total 100

In the present invention, the above-described tablet can be coadministered with a tablet, capsule, etc. comprising a dosage of Active Compound II, for example a TRICOR® capsule as described above.

Method of Manufacture

Mix Item No. 4 with purified water in suitable mixer to form binder solution. Spray the binder solution and then water over Items 1, 2, 6 and a portion of Item 5 in a fluidized bed processor to granulate the ingredients. Continue fluidization to dry the damp granules. Screen the dried granules and blend with Item No. 3 and the remainder of Item 5. Add Item No. 7 and mix. Compress the mixture to appropriate size and weight on a suitable tablet machine.

For coadministration in separate tablets or capsules, representative formulations comprising a cholesterol absorption inhibitor such as are discussed above are well known in the art and representative formulations comprising a peroxisome proliferator-activated receptor activator such as are discussed above are well known in the art. It is contemplated that where the two active ingredients are administered as a single composition, the dosage forms disclosed above for substituted azetidinone or &bgr;-lactam compounds may readily be modified using the knowledge of one skilled in the art.

Since the present invention relates to treating conditions as discussed above, such as reducing the plasma sterol (especially cholesterol) concentrations or levels by treatment with a combination of active ingredients wherein the active ingredients may be administered separately, the invention also relates to combining separate pharmaceutical compositions in kit form. That is, a kit is contemplated wherein two separate units are combined: a pharmaceutical composition comprising at least one peroxisome proliferator-activated receptor activator and a separate pharmaceutical composition comprising at least one sterol absorption inhibitor as described above. The kit will preferably include directions for the administration of the separate components. The kit form is particularly advantageous when the separate components must be administered in different dosage forms (e.g., oral and parenteral) or are administered at different dosage intervals.

The treatment compositions and therapeutic combinations of the present invention can inhibit the intestinal absorption of cholesterol in mammals, as shown in the Example below, and can be useful in the treatment and/or prevention of conditions, for example vascular conditions, such as atherosclerosis, hypercholesterolemia and sitosterolemia, stroke, obesity and lowering of plasma levels of cholesterol in mammals, in particular in mammals.

In another embodiment of the present invention, the compositions and therapeutic combinations of the present invention can inhibit sterol absorption or reduce plasma concentration of at least one sterol selected from the group consisting of phytosterols (such as sitosterol, campesterol, stigmasterol and avenosterol), 5&agr;-stanols (such as cholestanol, 5&agr;-campestanol, 5&agr;-sitostanol), cholesterol and mixtures thereof. The plasma concentration can be reduced by administering to a mammal in need of such treatment an effective amount of at least one treatment composition or therapeutic combination comprising at least one PPAR activator and at least one sterol absorption inhibitor described above. The reduction in plasma concentration of sterols can range from about 1 to about 70 percent, and preferably about 10 to about 50 percent. Methods of measuring serum total blood cholesterol and total LDL cholesterol are well known to those skilled in the art and for example include those disclosed in PCT WO 99/38498 at page 11 . Methods of determining levels of other sterols in serum are disclosed in H. Gylling et al., "Serum Sterols During Stanol Ester Feeding in a Mildly Hypercholesterolemic Population", J. Lipid Res. 40: 593-600 (1999) .

Illustrating the invention are the following examples. Unless otherwise indicated, all parts and percentages in the following examples, as well as throughout the specification, are by weight.

EXAMPLES PREPARATION OF COMPOUND OF FORMULA (II)

Step 1): To a solution of (S)-4-phenyl-2-oxazolidinone (41 g, 0.25 mol) in CH2Cl2 (200 ml), was added 4-dirnethylaminopyridine (2.5 g, 0.02 mol) and triethylamine (84.7 ml, 0.61 mol) and the reaction mixture was cooled to 0°C. Methyl-4-(chloroformyl)butyrate (50 g, 0.3 mol) was added as a solution in CH2Cl2 (375 ml) dropwise over 1 h, and the reaction was allowed to warm to 22°C. After 17 h, water and H2SO4 (2N, 100 ml), was added the layers were separated, and the organic layer was washed sequentially with NaOH (10%), NaCI (sat'd) and water. The organic layer was dried over MgSO4 and concentrated to obtain a semicrystalline product.

Step 2): To a solution of TiCl4 (18.2 ml, 0.165 mol) in CH2Cl2 (600 ml) at 0°C, was added titanium isopropoxide (16.5 ml, 0.055 mol). After 15 min, the product of Step 1 (49.0 g. 0.17 mol) was added as a solution in CH2Cl2 (100 ml). After 5 min., diisopropylethylamine (DIPEA) (65.2 ml, 0.37 mol) was added and the reaction mixture was stirred at 0°C for 1 h, the reaction mixture was cooled to -20°C, and 4-benzyloxybenzylidine(4-fluoro)aniline (114.3 g, 0.37 mol) was added as a solid. The reaction mixture was stirred vigorously for 4 h at -20°C, then acetic acid was added as a solution in CH2Cl2 dropwise over 15 min, the reaction mixture was allowed to warm to 0°C. and H2SO4 (2N) was added. The reaction mixture was stirred an additional 1 h, the layers were separated, washed with water, separated and the organic layer was dried. The crude product was crystallized from ethanol/water to obtain the pure intermediate.

Step 3): To a solution of the product of Step 2 (8.9 g. 14.9 mmol) in toluene (100 ml) at 50°C, was added N,O-bis(trimethylsilyl)acetamide (BSA) (7.50 ml, 30.3 mmol). After 0.5 h, solid TBAF (0.39 g, 1.5 mmol) was added and the reaction mixture stirred at 50°C for an additional 3 h. The reaction mixture was cooled to 22°C. CH3OH (10 ml.), was added. The reaction mixture was washed with HCI (1N), NaHCO3 (1N) and NaCl (sat'd.), and the organic layer was dried over MgSO4.

Step 4): To a solution of the product of Step 3 (0.94 g. 2.2 mmol) in CH3OH (3 ml), was added water (1 ml) and LiOH·H2O (102 mg, 2.4 mmole). The reaction mixture was stirred at 22°C for 1 h and then additional LiOH·H2O (54 mg, 1.3 mmole) was added. After a total of 2 h, HCI (1 N) and EtOAc was added, the layers were separated, the organic layer was dried and concentrated in vacuo. To a solution of the resultant product (0.91 g, 2.2 mmol) in CH2Cl2 at 22°C, was added CICOCOCI (0.29 ml, 3.3 mmol) and the mixture stirred for 16 h. The solvent was removed in vacuo.

Step 5): To an efficiently stirred suspension of 4-fluorophenylzinc chloride (4.4 mmol) prepared from 4-fluorophenylmagnesium bromide (1M in THF, 4.4 ml, 4.4 mmol) and ZnCl2 (0.6 g, 4.4 mmol) at 4°C, was added tetrakis(triphenylphosphine)palladium (0.25 g, 0.21 mmol) followed by the product of Step 4 (0.94 g, 2.2 mmol) as a solution in THF (2 ml). The reaction was stirred for 1 h at 0°C and then for 0.5 h at 22°C. HCl (1N, 5 ml) was added and the mixture was extracted with EtOAc. The organic layer was concentrated to an oil and purified by silica gel chromatography to obtain 1-(4-fluorophenyl)-4(S)-(4-hydroxyphenyl)-3(R)-(3-oxo-3-phenylpropyl)-2-azetidinone:

HRMS calc'd for C24H19F2NO3 = 408.1429, found 408.1411.

Step 6): To the product of Step 5 (0.95 g, 1.91 mmol) in THF (3 ml), was added (R)-tetrahydro-1-methyl-3.3-diphenyl-1H,3H-pyrrolo-[1,2-c][1,3,2] oxazaborole (120 mg. 0.43 mmol) and the mixture was cooled to -20°C. After 5 min, borohydride-dimethylsulfide complex (2M in THF, 0.85 ml, 1.7 mmol) was added dropwise over 0.5 h. After a total of 1.5 h , CH3OH was added followed by HCI (1 N) and the reaction mixture was extracted with EtOAc to obtain 1-(4-fluorophenyl)-3(R)-[3(S)-(4-fluorophenyl)-3-hydroxypropyl)]-4(S)-[4-(phenylmethoxy)phenyl]-2-azetidinone (compound 6A-1) as an oil. 1H in CDCl3 d H3 = 4.68. J = 2.3 Hz. Cl (M+H) 500.

Use of (S)-tetra-hydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo-[1,2-c][1,3,2] oxazaborole gives the corresponding 3(R)-hydroxypropyl azetidinone (compound 6B-1). 1H in CDCl3 d H3 = 4.69. J = 2.3 Hz. Cl (M+H) 500.

To a solution of compound 6A-1 (0.4 g, 0.8 mmol) in ethanol (2 ml), was added 10% Pd/C (0.03 g) and the reaction mixture was stirred under a pressure (60 psi) of H2 gas for 16 h. The reaction mixture was filtered and the solvent was concentrated to obtain compound 6A. Mp 164-166°C; Cl (M+H) 410. &agr; D 25 = - 28.1 ° (c 3, CH3OH). Elemental analysis calc'd for C24H21F2NO3: C 70.41; H 5.17; N 3.42; found C 70.25; H 5.19; N 3.54.

Similarly treat compound 6B-1 to obtain compound 6B. Mp 129.5-132.5°C; Cl (M+H) 410. Elemental analysis calc'd for C24H21F2NO3: C 70.41; H 5.17; N 3.42; found C 70.30; H 5.14; N 3.52.

Step 6' (Alternative): To a solution of the product of Step 5 (0.14 g, 0.3 mmol) in ethanol (2 ml), was added 10% Pd/C (0.03 g) and the reaction was stirred under a pressure (60 psi) of H2 gas for 16 h. The reaction mixture was filtered and the solvent was concentrated to afford a 1:1 mixture of compounds 6A and 6B.

In Vivo Evaluation

In a randomized, evaluator-blind; placebo-controlled, parallel-group study 32 healthy hypercholesterolemic humans (screening LDL-C ≥130 mg/dL) stabilized and maintained on a NCEP Step I Diet were randomized to one of the following four treatments:

  • Treatment A - placebo given orally as 1 dose per day.
  • Treatment B - 10 mg of Compound II given orally as 1 dose per day,
  • Treatment C - 200 mg of LIPANTHYLO® micronized Fenofibrate (available from
  • Labortoire Fournier of France) given orally as 1 dose per day, or
  • Treatment D - 200 mg of LIPANTHYL® micronized Fenofibrate plus 10 mg of

Compound II given orally as 1 dose per day every morning for 14 days. Serum lipids were assessed predose (after a minimum of a 10-hour fast) on Day 1 (Baseline), Day 7 and Day 14.

Results: The mean (S.E.) Day 14 percent (%) change from Baseline in serum lipids (n=8) are shown in Table 1 below: <u>Table 1</u> Treatment LDL-C Total-C HDL-C TG A -10.1 (4.9) -8.38 (4.0) -14.1 (2.2) 19.1 (13.9) B -22.3 (5.7) -19.6 (4.0) -13.3 (4.4) -4.57 (12.8) C -13.5 (3.1 ) -13.0(2.4) -6.1 (3.6) 0.28(11.4) D -36.3 (3.5) -27.8 (1.7) -1.97 (4.7) -32.4 (4.5)

The coadministration of 10 mg of Compound II and 200 mg of Fenofibrate (Treatment D) was well tolerated and caused a significant (p≤ 0.03) reduction in LDL-C compared to either drug alone or placebo. In this inpatient study where the subjects' physical activity was restricted, in general HDL-C concentrations tended to decrease and triglycerides tended to increase. The group receiving Treatment C had the least decrease in HDL-C and the greatest decrease in triglyceride levels.


Anspruch[de]
Zusammensetzung, umfassend Fenofibrat und einen Sterolabsorptionsinhibitor, repräsentiert durch die folgende Formel (II): oder ein pharmazeutisch akzeptables Salz oder Solvat hiervon. Therapeutische Kombination, umfassend (a) eine erste Menge von Fenofibrat und (b) eine zweite Menge des Sterolabsorptionsinhibitors, der durch die folgende Formel (II) repräsentiert wird: oder ein pharmazeutisch akzeptables Salz oder Solvat hiervon. Therapeutische Kombination gemäß Anspruch 2, worin das Fenofibrat begleitend zu dem zumindest einen Sterolabsorptionsinhibitor gemäß Formel (II) verabreicht wird. Therapeutische Kombination gemäß Anspruch 2, worin das Fenofibrat und der zumindest eine Sterolabsorptionsinhibitor gemäß Formel (II) in separaten Behandlungszusammensetzungen vorliegen. Zusammensetzung oder therapeutische Kombination gemäß irgendeinem der Ansprüche 1 oder 2, worin das Fenofibrat an einen Säuger in einer Menge im Bereich von 50 bis 3.000 mg Fenofibrat/Tag zu verabreichen ist. Zusammensetzung oder therapeutische Kombination gemäß irgendeinem der Ansprüche 1 oder 2, worin der Sterolabsorptionsinhibitor gemäß Formel (II) an einen Säuger in einer Menge von 0,1 bis 1.000 mg Sterolabsorptionsinhibitor/Tag zu verabreichen ist. Zusammensetzung oder therapeutische Kombination gemäß Anspruch 6, ferner umfassend zumindest einen HMG CoA-Reduktaseinhibitor, ausgewählt aus der Gruppe, die aus Lovastatin, Pravastatin, Fluvastatin, Simvastatin, Atorvastatin, Rosuvastatin, Cerivastatin und Mischungen hiervon besteht. Pharmazeutische Zusammensetzung, die eine Zusammensetzung oder therapeutische Kombination gemäß irgendeinem der vorhergehenden Ansprüche umfaßt. Zusammensetzung oder therapeutische Kombination gemäß irgendeinem der vorhergehenden Ansprüche zur Verwendung als Medikament. Verwendung einer Zusammensetzung oder einer therapeutischen Kombination gemäß irgendeinem der vorhergehenden Ansprüche zur Herstellung eines Medikaments zur Behandlung oder Vorbeugung von Diabetes, Fettleibigkeit, Hyperlipidämie, Atherosklerose, Hypercholesterinämie, Sitosterolämie, Apoplexie, vaskulärer Entzündungen oder Hypertriglyceridämie.
Anspruch[en]
A composition comprising: (a) fenofibrate, and b) a sterol absorption inhibitor represented by Formula (II) below: or a pharmaceutically acceptable salt or solvate thereof. A therapeutic combination comprising: (a) a first amount of fenofibrate, ; and (b) a second amount of the sterol absorption inhibitor represented by Formula (II) below: or a pharmaceutical acceptable salt or solvate thereof. A therapeutic combination according to claim 2, wherein the fenofibrate is administered concomitantly with the at least one sterol absorption inhibitor according to formula (II). A therapeutic combination according to claim 2, wherein the fenofibrate and the at least one sterol absorption inhibitor according to formula (II) are present in separate treatment compositions. The composition or therapeutic combination according to any one of claims 1 or 2, wherein the fenofibrate is to be administered to a mammal in an amount ranging from 50 to 3000 milligrams of fenofibrate per day. The composition or therapeutic combination according to any one of claims 1 or 2, wherein the sterol absorption inhibitor according to formula (II) is to be administered to a mammal in an amount ranging from 0.1 to 1000 milligrams of sterol absorption inhibitor per day. The composition or therapeutic combination according to claim 6, further comprising at least one HMG CoA reductase inhibitor, selected from the group consisting of lovastatin pravastatin, fluvastatin, simvastatin, atorvastatin, rosuvastatin, cerivastatin and mixtures thereof. A pharmaceutical composition comprising a composition or therapeutic combination according to any one of the preceding claims. The composition or therapeutic combination according to any one of the preceding claims for use as a medicament. The use of a composition or therapeutic combination according to any one of the preceding claims for the manufacture of a medicament for the treatment or prevention of diabetes, obesity, hyperlipidemia, atherosclerosis hypercholesterolemia, sitosterolemia, stroke, vascular inflammation, or hypertriglyceridaemia.
Anspruch[fr]
Composition comprenant : a) du fénofibrate, b) et un inhibiteur d'absorption de stérols, représenté par la formule (II) figurant ci-dessous : ou un sel ou solvat pharmacologiquement admissible de ce composé. Combinaison thérapeutique comprenant : a) du fénofibrate, en une première quantité, b) et, en une deuxième quantité, de l'inhibiteur d'absorption de stérols représenté par la formule (II) figurant ci-dessous : ou un sel ou solvat pharmacologiquement admissible de ce composé. Combinaison thérapeutique conforme à la revendication 2, le fénofibrate étant administré en même temps que ledit inhibiteur d'absorption de stérols de formule (II). Combinaison thérapeutique conforme à la revendication 2, le fénofibrate et ledit inhibiteur d'absorption de stérols de formule (II) se trouvant dans des compositions pour traitement distinctes. Composition ou combinaison thérapeutique conforme à la revendication 1 ou 2, au moyen de laquelle le fénofibrate peut être administré à un mammifère en une quantité de 50 à 3000 milligrammes de fénofibrate par jour. Composition ou combinaison thérapeutique conforme à la revendication 1 ou 2, au moyen de laquelle l'inhibiteur d'absorption de stérols de formule (II) peut être administré à un mammifère en une quantité de 0,1 à 1000 milligrammes de cet inhibiteur d'absorption de stérols par jour. Composition ou combinaison thérapeutique conforme à la revendication 6, comprenant en outre au moins un inhibiteur de HMG-CoA réductase, choisi dans l'ensemble formé par les lovastatine, pravastatine, fluvastatine, simvastatine, atorvastatine, rosuvastatine et cérivastatine, ainsi que leurs mélanges. Composition pharmaceutique comprenant une composition ou combinaison thérapeutique conforme à l'une des revendications précédentes. Composition ou combinaison thérapeutique conforme à l'une des revendications précédentes, conçue pour servir de médicament. Emploi d'une composition ou d'une combinaison thérapeutique conforme à l'une des revendications précédentes, en vue de la fabrication d'un médicament conçu pour le traitement ou la prévention d'un diabète, de l'obésité, de l'hyperlipidémie, de l'athérosclérose, de l'hypercholestérolémie, de la sitostérolémie, d'une attaque, d'une inflammation vasculaire ou de l'hypertriglycéridémie.






IPC
A Täglicher Lebensbedarf
B Arbeitsverfahren; Transportieren
C Chemie; Hüttenwesen
D Textilien; Papier
E Bauwesen; Erdbohren; Bergbau
F Maschinenbau; Beleuchtung; Heizung; Waffen; Sprengen
G Physik
H Elektrotechnik

Anmelder
Datum

Patentrecherche

Patent Zeichnungen (PDF)

Copyright © 2008 Patent-De Alle Rechte vorbehalten. eMail: info@patent-de.com