Europäisches Patentamt *EP000981343B1* (19) European Patent Office Office européen des brevets (11) EP 0 981 343 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.7: A61K 31/225, A61P 9/00 of the grant of the patent: 14.09.2005 Bulletin 2005/37 (86) International application number: PCT/US1998/009773 (21) Application number: 98923411.7 (87) International publication number: (22) Date of filing: 14.05.1998 WO 1998/051289 (19.11.1998 Gazette 1998/46) (54) MONOESTERS OF PROBUCOL FOR THE TREATMENT OF CARDIOVASCULAR AND INFLAMMATORY DISEASE PROBUCOL MONOESTER ZUR BEHANDLUNG VON KREISLAUF- UND ENTZÜNDUNGSERKRANKUNGEN MONOESTERS DE PROBUCOL DESTINES AU TRAITEMENT DE TROUBLES CARDIO-VASCULAIRES ET INFLAMMATOIRES (84) Designated Contracting States: (74) Representative: Howard, Paul Nicholas AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU Carpmaels & Ransford MC NL PT SE 43 Bloomsbury Square Designated Extension States: London WC1A 2RA (GB) AL LT LV MK RO SI (56) References cited: (30) Priority: 14.05.1997 US 47020 P WO-A-95/30415 US-A- 5 262 439 (43) Date of publication of application: • L. COMINACINI ET AL: FREE RADICAL BIOL. 01.03.2000 Bulletin 2000/09 MED., vol. 22, no. 1/2, 1996, pages 117-127, XP002095164 (73) Proprietor: AtheroGenics, Inc. • J.W. BARNHART ET AL: PHARMACOCHEM. Alpharetta, GA 30004 (US) LIBR. , no. 17, 1991, pages 277-299, XP002095165 (72) Inventor: SOMERS, Patricia, K. Atlanta, GA 30319 (US) Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 0 981 343 B1 Printed by Jouve, 75001 PARIS (FR) 1 EP 0 981 343 B1 2 Description effective agents currently on the market for hypercho- lesterolemia, and include pravastatin (Pravchol, Bristol [0001] This invention refers to a method and compo- Myers Squibb), atrovastatin (Warner Lambert/Pfizer), sition for the inhibition of VCAM-1, and in particular for simvastatin (Zocor, Merck), lovastatin (Mevacor, Mer- the treatment of cardiovascular disease selected from 5 ck), and fluvastatin (Lescol). angina and small artery disease or inflammatory dis- [0006] For many patients, diet plus one of the hypoli- ease that includes the administration of an effective pidemic agents will be sufficient. However, for patients amount of an ester of probucol. with an initial LDL cholesterol level of greater than 200 mg/dl, therapy needs to lower LDL levels by 50% or BACKGROUND OF THE INVENTION 10 more. Although a single agent may occasionally achieve this degree of LDL lowering, it is far more common to [0002] Cardiovascular disease is currently the leading see decreases of only 20 to 30%. Thus, for the patient cause of death in the United States. Approximately nine- with heterozygous farnilial hypercholesterolemia with ty percent of cardiovascular disease is presently diag- an LDL cholesterol of 200 to 400 mg/dl, a combination nosed as atherosclerosis. Cardiovascular disease has 15 of two, or occasionally, three hypolipidemic drugs will be been linked to several causative factors, which include required to achieve an LDL cholesterol level of less than hypercholesterolemia, hyperlipidemia, and the expres- 100 mg/ml. Combinations of a bile sequestrant resin and sion of VCAM-1 in vascular endothelial cells. nicotinic acid can lower LDL levels by 45% to 55%, a resin plus a statin, by about 50% to 60%, nicotinic acid Hypercholesterolemia and hyperlipidemia 20 plus a statin by about 50%, and triple drug therapy, using a combination of a bile acid -binding resin, a statin, and [0003] Hypercholesterolemia is an important risk fac- nicotinic acid, by as much as 70%. tor associated with cardiovascular disease. Serum lipo- [0007] Evidence suggests that the atherogenic ef- proteins are the carriers for lipids in the circulation. Li- fects of low density lipoprotein (LDL) may be in part me- poproteins are classified according to their density: chy- 25 diated through its oxidative modification. Probucol has lomicrons, very low-density lipoproteins (VLDL), low been shown to possess potent antioxidant properties density lipoproteins (LDL) and high-density lipoproteins and to block oxidative modification of LDL. Consistent (HDL). Chylomicrons primarily participate in transport- with these findings, probucol has been shown to actually ing dietary triglycerides and cholesterol from the intes- slow the progression of atherosclerosis in LDL receptor- tine to adipose tissue and liver. VLDL deliver endog- 30 deficient rabbits as discussed in Carew et al. Proc. Natl. enously synthesized triglycerides from liver to adipose Acad Sci. U.S.A. 84:7725-7729 (1987). Most likely, and other tissues. LDL transports cholesterol to periph- probucol is effective because it is highly lipid soluble and eral tissues and regulate endogenous cholesterol levels is transported by lipoproteins, thus protecting them in those tissues. HDL transports cholesterol from pe- against oxidative damage. ripheral tissues to the liver. Arterial wall cholesterol is 35 [0008] Probucol is chemically related to the widely derived almost exclusively from LDL. Brown and Gold- used food additives 2,[3]-tert-butyl-4-hydroxyanisole stein, Ann. Rev. Biochem. 52, 223 (1983); Miller, Ann. (BHA) and 2,6-di-tert-butyl-4-methyl phenol (BHT). Its Rev. Med. 31, 97 (1980)). In patients with low levels of full chemical name is 4,4'-(isopropylidenedithio) bis LDL, the development of atherosclerosis is rare. (2,6-di-tert-butylphenol). [0004] Elevated cholesterol levels are associated with 40 [0009] Today, probucol is used primarily to lower se- a number of disease states, including restenosis, angi- rum cholesterol levels in hypercholesterolemic patients. na, cerebral atherosclerosis, and xanthoma. It is desir- Probucol is commonly administered in the form of tab- able to provide a method for reducing plasma choles- lets available under the trademark Lorelco™. Unfortu- terol in patients with, or at risk of developing, restenosis, nately, probucol is almost insoluble in water and there- angina, cerebral arteriosclerosis, xanthoma, and other 45 fore cannot be injected intravenously. In fact, probucol disease states associated with elevated cholesterol lev- is difficult for cells to absorb in vitro because of its poor els. miscibility in buffers and media for cell culture. Solid [0005] If it has been determined that hypercholester- probucol is poorly absorbed into the blood, and is ex- olemia is due to elevated LDL (hyperlipidemia), the low- creted in substantially unchanged form. Further, the tab- ering of LDL levels by dietary therapy is attempted. 50 let form of probucol is absorbed at significantly different There are several drug classes that are commonly used rates and in different amounts by different patients. In to lower LDL levels, including bile acid sequestrants, one study (Heeg et al., Plasma Levels of Probucol in nicotinic acid (niacin), and 3-hydroxy-3-methylglutaryl Man After Single and Repeated Oral Doses, La Nouvelle coenzyme A (HMG CoA) reductase inhibitors. Probucol Presse Medicale, 9:2990-2994 (1980)), peak levels of and the fibrate derivatives are sometimes used as ad- 55 probucol in sera were found to differ by as much as a junctive therapy, usually in combination with other med- factor of 20 from patient to patient. In another study, Ka- ications. The HMG CoA reductase inhibitors have been zuya et al. J. Lipid Res. 32; 197-204 (1991) observed termed statins or vastatins. Statins are among the most an incorporation of less than about 1 µg of probucol/106 2 3 EP 0 981 343 B1 4 cells when endothelial cells are incubated for 24 h with kocytes. VCAM-1 is involved as a mediator in chronic 50 µM probucol. inflammatory disorders such as asthma, rheumatoid ar- [0010] U.S. Patent No. 5,262,439 to Parthasarathy thritis and autoimmune diabetes. For example, it is discloses soluble analogs of probucol in which one or known that the expression of VCAM-1 and ICAM-1 are both of the hydroxyl groups are replaced with ester 5 increased in asthmatics. Pilewski, J.M., et al. Am. J. groups that impart water solubility to the compound. In Respir. Cell Mol. Biol. 12, 1-3 (1995); Ohkawara, Y., et one embodiment, the soluble derivative is selected from al., Am. J Respir. Cell Mol. Biol. 12, 4-12 (1995). Addi- the group consisting of a mono- or di- succinic acid ester, tionally, blocking the integrin receptors for VCAM-1 and glutaric acid ester, adipic acid ester, suberic acid ester, ICAM-1 (VLA-4 and LFA-1, respectfully) suppressed sebacic acid ester, azelaic acid, or maleic acid ester of 10 both early and late phase responses in an ovalbumin- probucol. In another embodiment, the probucol deriva- sensitized rat model of allergic airway responses. Rabb, tive is a mono- or di- ester in which the ester contains 11. A., et al., Am. J. Respir. Care Med. 149, 1186-1191 an alkyl or alkenyl group that contains a functionality se- (1994). There is also increased expression of endothe- lected from the group consisting of a carboxylic acid lial adhesion molecules, including VCAM-1, in the mi- group, amine group, salt of an amine group, amide 15 crovasculature of rheumatoid synovium. Koch, A.E. et groups, amide groups, and aldehyde groups. al., Lab. Invest. 64, 313-322 (1991); Morales-Ducret, J. [0011] A series of French patents disclose that certain et al., Immunol. 149, 1421-1431 (1992). Neutralizing an- probucol derivatives are hypocholesterolemic and hy- tibodies directed against VCAM-1 or its counter recep- polipemic agents: Fr 2168137 (bis 4-hydroxyphenylth- tor, VI A-4, can delay the onset of diabetes in a mouse ioalkane esters); Fr 2140771 (tetralinyl phenoxy alkano- 20 model (NOD mice) which spontaneously develop the ic esters of probucol); Fr 2140769 (benzofuryloxyalka- disease.