CA2291471A1 - Lowering blood levels of lipoprotein(a) - Google Patents
Lowering blood levels of lipoprotein(a) Download PDFInfo
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- CA2291471A1 CA2291471A1 CA002291471A CA2291471A CA2291471A1 CA 2291471 A1 CA2291471 A1 CA 2291471A1 CA 002291471 A CA002291471 A CA 002291471A CA 2291471 A CA2291471 A CA 2291471A CA 2291471 A1 CA2291471 A1 CA 2291471A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/472—Non-condensed isoquinolines, e.g. papaverine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/472—Non-condensed isoquinolines, e.g. papaverine
- A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The invention relates to methods of lowering blood levels of lipoprotein(a) in a mammal which comprises administering to a mammal in need thereof a lipoprotein(a) blood level-lowering amount of an apolipoprotein B secretion/microsomal triglyceride transfer protein inhibitor.
Description
LOWERING BLOOD LEVELS OF LIPOPROTEIN(a ) Back4round Of The Invention The glycoprotein apolipoprotein (a) (apo(a)) is synthesized and secxeted from hepatic cells and, in humans, drculates largely in assodation with low density lipoprotein (LDL) in the form of a hybrid lipoprotein referred to as Lp(a).
The association between apo(a) and the major protein moiety of LDL, namely apolipoprotein B100 (apo B100), is mediated through covalent linkage of a single unpaired cysteine residue in apo(a) to a complimentary unpaired cysteine residue in the extreme carboxyl terminus of apo 8100.
Interest in the biology of this lipoprotein species is driven by the observation that elevated levels of Lp(a) in humans is assodated with an increased risk for atherosderotic heart and vascular disease. The lowering of Lp(a) levels, however, has proven problematic since various conventional methods that are effective in redudng levels of LDL are not as efficadous or consistent in lowering levels of Lp(a).
For example, it has been reported that neomycin, alone or in combination with niadn, is effective in redudng Lp(a) levels when administered over a period of several weeks to years. See Spinier, et al., J. Ann. Phamnacother., 28, 343 (1994). The administration of high doses of niacin and neomydn, however, limits the desirability of this regimen due to many undesirable dinical side-effects. Alternatively, oral doses of fosinopril, an angiotensin-converting enzyme inhibitor, have been demonstrated to lower Lp(a) levels after 12 weeks of treatment, however, Lp(a) reduction was signficant only in patients that showed improvement in renal function and, therefore, the Lp(a) towering ability of fosinopril may simply be attributable to the indirect consequence of improved kidney function. See Keilani, et al., Ann. Inter. Med., 118, 246 (1993).
Additionally, certain steroidal hormones, estrogen for example, are known to down-regulate Lp(a) levels. See, for example, Frazer, et al., Nature Genet., 9_, 424 (1995).
However, estrogen therapy alone is assodated with an increased risk of endometrial cardnoma and, for this reason, estrogen is nom~any administerea in commnauownntn progesterone. Although short-term treatment with this estrogeNpmgesterone combination is an effective therapeutic strategy for redudng Lp(a) levels, long-term treatment, i.e. six months or more, does not result in the same degree of decreased inhibition as that observed for treatment with estrogen alone. See Soma, et al., Arch.
_2_ Internal. Med., 153, 1462 (1993) and Soma, et al., Chem. Phys. Lipids, 345, 67 (1994). Furthermore, LDL apheresis has been shown to be an effective means for lowering Lp(a) levels. See Koizumi, et al., Atherosclerosis, 100, 65 (1993).
Mowever, apheresis is an invasive approach requiring weekly treatments and, therefore, is not regarded as a current treatment of choice. Accordingly, improved methods of inhibiting Lp(a), or formation of the precursors thereof, will have utility in the treatment of conditions and diseases arising from hyperlipoproteinemia, including, for example, atherosderosis, premature myocardial infarction, stroke, restenosis following coronary bypass surgery and so forth.
Microsomal triglyceride transfer protein (MTP) is known to mediate the transport of triglyceride, cholesteryl ester and phospholipids and has been implicated as a mediator in the assembly of apolipoprotein B containing lipoproteins, chylomicrons and VLDL (very low density lipoprotein). Spedfically, the subcellular (lumen of the microsomal fraction) and tissue distribution (liver and intestine) of MTP
have led to speculation that it plays a role in the assembly of plasma lipoproteins, as these are the sites of plasma lipoprotein assembly. The ability of MTP to catalyze the transport of triglyceride between membranes is consistent with this speculation and suggests that MTP may catalyze the transport of triglyceride from its site of synthesis in the endoplasmic reticulum membrane to nascent lipoprotein particles within the lumen of the endoplasmic re6culum. Accordingly, compounds that inhibit MTP
and/or otherwise inhibit apo B secretion are useful in the treatment of atherosderosis and other conditions related thereto. Such compounds are also useful in the treatment of other diseases or conditions in which, by inhibiting MTP and/or apo B
secretion, serum cholesterol and triglyceride levels may be reduced. Such conditions may include, for example, hypercholesterolemia, hypertriglyceridemia, pancreatitis, obesity and hypercholesterolemia, hypertriglyceridemia and hyperiipidemia assodated with pancrea6tis, obesity and diabetes. For a detailed discussion see, for example, Wetterau et al., Silence, 258, 999-1001 (1992) and Wetterau et al., Biochem.
Biophys. Ada., 875, 610-617 (1986).
While the preclse mechanisms governing blood levels of Lp(a) are presently unknown, there is evidence to suggest that Lp(a) levels are regulated at the level of synthesis rather than catabolism. Accordingly, because it is known thatzinhibition. of _ ~ -hepatic secretion of VLDL and apolipoprotein B (apo B) results in the pre-secretory degradation of apo B and concomitant decrease in hepatic apo B levels and because each Lp(a) particle contains one copy of apo(a) bound to apo B, it is believed that decreasing the concentration of hepatic apo B, by the administration of an apo B secretion/-MTP inhibitor, will result in a lowering of Lp(a) secreted and, thereby, a lowering of blood Lp(a) levels.
Summary of the Invention The instant invention is directed to pharmaceutical compositions for lowering blood levels of lipoprotein(a) (Lp (a) ) in a mammal, which comprise (i) an effective Lp (a) blood level-lowering amount of an apolipoprotein B secretion/-microsomal triglyceride transfer protein inhibitor and (ii) a pharmaceutically acceptable carrier or diluent.
Another aspect of the present invention provides commercial packages comprising the above-described pharma ceutical compositions and written matters including indications that the pharmaceutical compositions can or should be used for lowering blood levels of Lp(a) in a mammal.
In a preferred embodiment of the invention, the apo B secretion/MTP inhibitor is a compound selected from the group consisting of 4'-trifluoromethylbiphenyl-2-carboxylic acid-[2-(1H-[1,2,4]triazol-3-ylmethyl)-1,2,3,4-tetrahydro-isoquinolin-6-yl]-amide., 4'-trifluoromethylbiphenyl-2-carboxylic acid-[2-(2-acetylaminoethyl)-1,2,3,4-tetrahydro-isoquinolin-6-yl]-amide, 9H-(4-~4-[4'-trifluoromethylbiphenyl-2-carbonyl)amino]-piperidin-1-yl}butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoroethyl)-amide 9-{4-[4-(2-benzothiazol-2-ylbenzoylamino)piperidin-1-yl]butyl}-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoroethyl)amide, [lla-R]-8-[(4-cyanophenyl)methoxy]-2-cyclopentyl-7-(prop-2-enyl)-2,3,11,11a-tetrahydro-6H-pyrazino[1,2b]isoquinoline-1,4-dione, [lla-R]-cyclopentyl-7-(prop-2-enyl)-8-[(pyridin-2-yl)methoxy]-2,3,ll,lla-tetrahydro-6H-pyrazino[1,2b]iso-quinoline-1,4-dione, 2-cyclopentyl-2-[4-(2,4-dimethylpyrido-[2,3b]indol-9-ylmethyl)phenyl]-N-(2-hydroxy-1-phenylethyl)-acetamide and 2-cyclopentyl-N-(2-hydroxy-1-phenylethyl)-2-[4-(quinolin-2-ylmethoxy)-phenyl]acetamide, a hydrate or stereoisomer thereof, or a pharmaceutically acceptable salt of the compound, hydrate or stereoisomer.
Especially preferred apo B secretion/MTP inhibitors useful in the practice of invention are the compounds 4'-trifluoromethylbiphenyl-2-carboxylic acid-[2-(1H-[1,2,4]-triazol-3-ylmethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide and 4'-trifluoromethylbiphenyl-2-carboxylic acid-[2-(2-acetylaminoethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide, hydrates thereof or the pharmaceutically acceptable salts of the compounds or hydrates.
Detailed Description of the Invention This invention provides pharmaceutical compositions for lowering blood levels of lipoprotein (a) (Lp (a) ) in a mammal, which comprise an effective Lp(a) blood level-lowering amount of an apolipoprotein B secretion/microsomal triglyceride transfer protein inhibitor.
As employed throughout the instant specification including appendant claims, the term "blood", when employed in relation to the term "blood levels", includes whole blood, plasma, i. e. the fluidic portion of the blood in which particulate components are suspended and serum, i. e. the fluidic portion of the blood obtained following removal of the fibrin clot and corpuscles.
As employed throughout the instant specification including appendant claims, the term "apo B secretion/MTP
inhibitor" means a compound having the ability to inhibit the secretion of apolipoprotein B and/or the ability to inhibit the transfer action of microsomal triglyceride transfer protein.
A variety of apo B secretion/MTP inhibitors are, or will be, known to one of ordinary skill in the art.
Although any apo B secretion/MTP inhibitor may be used in the practice of the instant invention, generally preferred apo B secretion/MTP inhibitors include those compounds, hydrates or stereoisomers thereof, or the pharmaceutically acceptable salts of the compounds, hydrates or stereoisomers -4a-which are disclosed in, for example, European Patent Publication Nos. EP 643057, EP 719763, EP 753,517, EP 764647, EP 765878, EP 779276, EP 779279, EP 799828, EP 799829, EP
802186, EP 802188, EP 802192 and EP 802197; PCT Patent Publication Nos. WO 96/13499, WO 96/33193, WO 96/40640, WO
97/26240, WO 97/43255, WO 97/43257, WO 98/16526 and WO
98/23593; and U. S. Pat. Nos. 5,595,872; 5,646,162, 5,684,014; 5,712,279; 5,739,135 and 5,789,197.
Especially preferred apo B secretion/MTP inhibitors are those biphenyl-2-carboxylic acid-tetrahydroisoquinolin-6-yl amide derivatives, and the stereoisomers, hydrates, prodrugs and pharmaceutically acceptable salts thereof disclosed in commonly assigned PCT Patent Publication Nos.
WO 96/40640 and WO 98/23593, each of which designate, inter alia, the United States. Especially preferred apo B
secretion/MTP inhibitors disclosed in PCT Patent Publication Nos. WO 96/40640 and WO 98/23593, and useful in the present invention, are the compounds illustrated hereinbelow: 4'-trifluoromethyl-biphenyl-2-carboxylic acid-[2-(1 H-[1,2,4]triazol-3-ylmethyl)-1,2,3,4-tetrahydroisoquin-6-yl]-amide and 4'-trifluoromethyl-biphenyl-2-carboxylic acid-[2-(acetylaminoethyl)-1,2,3,4-tetrahydroisoquinolin-6-ylJ-amide, or the hydrates thereof, or the pharmaceutically acceptable salts of the compounds or the hydrates.
H
/ O I \ N~N'NH / O
/ N~ ~ _ / _ O
H I H
/ /
Another especially preferred Gass of apo B secretioNMTP inhibitors is disGosed in U.S. Pat. Nos. 5,595,872; 5,712,279; 5,739,135 and 5,789,197 and includes compounds having the structural formula Q p N
Rs' N-R~ and Rs' Especially preferred apo B secretionMITP inhibitors disclosed in U.S. Pat.
Nos.
5,595,872; 5,712,279; 5,739,135 and 5,789,197, and useful in the methods of the present invention, are 9H-(4-{4-[4'trifluoromethyl-biphenyl-2-carbonyl}-amino]-piperidin-1-yl}-butyl-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoroethyl)-amide and 9-{4-[4-(2-benzothiazol-2-yl-benzoylamino)-piperidin-1-ylj-butyl}-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoroethyl)-amide.
Another Gass of espeaally preferred apo B secretioNMTP inhibitors is disGosed in PCT Application Publication No. WO 98/16526 and includes compounds having the structural formula i~
-- ~ - _ Especially preferred Apo-B secretionMITP inhibitors disGosed in PCT
Application Publication No. WO 98/16526, and useful in the methods of the present invention, are [11 a-R]-8-[(4-cyanophenyl)methoxyJ-2-cyclopentyl-7-(prop-2-enyl)-2,3,11,11 a-tetrahydro-6H-pyrazino[1,2b]isoquinoline-1,4-dione and [11a-R]-cyclopentyl-7-(prop-2-enyl)-8-[(pyridin-2-yl)methoxyJ-2,3,11,11 a-tetrahydro-6H-pyrazino[1,2b]isoquinoline-1,4-dione.
Another especlally preferred lass of apo B secretion/MTP inhibitors is disclosed in U.S. Pat. No. 5,684,014 and includes compounds having the structural formula R3 R~
HyC
Rs E~
L Rg R~
D
An especially prefer-ed apo B secretioNMTP inhibitor disclosed in U.S. Pat.
No.
5,684,014, and useful in the methods of the present invention, is 2-cydopentyl-2-[4-(2,4-dimethyl-pyrido[2,3-b]indol-9-ylmethyl)-phenyl]-N-(2-hydroxy-1-phenyl-ethyl)-acetamide.
Yet another class of especially preferred apo B secretioNMTP inhibitors is disclosed in U.S. Pat. No. 5,646,162 and includes compounds having the structural formula E
A~O
O
~ OH
~L~N
H
An especially preferred apo B seaetioNMTP inhibitor disclosed in U.S. Pat. No.
5,646,162, and useful in the methods of the present invention, is 2-cydopentyl-N-(2-hydroxy-1-phenyl-ethyl)-2-[4-(quinolin-2-ylmethoxy)-phenyl]-acetamide.
The apo B secretioNMTP inhibitors, including the prefer-ed and espedally preferred embodiments and the pharmaceutically acceptable salts, hydrates or .
stereoisomers thereof, or the pharmaceutically acceptable salts of the hydrates or stereoisomers employed in the methods of the instant invention may be prepared _7_ according to the disclosures of the aforementioned European, PCT and U.S.
patents and application publication documents.
The apo B secretion/MTP inhibitors, the pharmaceutically acceptable salts, hydrates or stereoisomers thereof, or the phamnaceutically acceptable salts of the hydrates or stereoisomers employed in the methods of the invention, are preferably administered in the form of a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent. Accordingly, the apo B
secretion/MTP
inhibitors, the pharmaceutically acceptable salts; hydrates or stereoisomers thereof, or the pharmaceutically acceptable salts of the hydrates or stereoisomers of this invention, can be administered individually or together in any conventional oral, parenteral or transdemial dosage form.
Suitable pharmaceutically-acceptable carriers indude inert solid fillers or diluents and sterile aqueous or organic solutions. The apo B secretion/MTP
inhibitors, the pharmaceutically acceptable salts, hydrates or stereoisomers thereof, or the pharmaceutically acceptable salts of the hydrates or stereoisomers of this invention will be present in such pharmaceutical compositions in amounts sufficient to provide the desired dosage amount in the range described hereinbelow. Thus, for oral administration, the compounds can be combined with a suitable solid or liquid carrier or diluent to form capsules, tablets, powders, syrups, solutions, suspensions and the like. The pharmaceutical compositions may, if desired, contain additional components such as flavorants, sweeteners, excipients and the like.
The tablets, pills, capsules, and the like may also contain a binder such as gum tragacanth, acacia, com starch or gelatin; exdpients such as dicaldum phosphate; a disintegrating agent such as com starch, potato starch, alginic add; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin. When a dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.
Various other materials may be present as coatings or to modify the physical form of the dosage unit. For instance, tablets may be coated with shellac, sugar or both. A syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry or orange flavor. ~ - -The pharmaceutical compositions of this invention may also be administered parenteraliy. For parenteral administration the pharmaceutical compositions can be _g_ combined with sterile aqueous or organic media to form injectable solutions or suspensions. Solutions or suspensions of these pharmaceutical compositions can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose.
Dispersions can also be prepared in sesame or peanut oil, ethanol, water, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, vegetable oils, N-methyl glucamine, polyvinylpyrrolidone and mixtures thereof in oils as well as aqueous solutions of water-soluble pharmaceutically acceptable salts of the compounds. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms. The injectable solutions prepared in this manner can then be administered intravenously, intraperitoneally, subcutaneously, or intramuscularly, with intramuscular administration being the preferred parenteral route in humans. Solutions prepared for intravenous administration are preferably rendered isotonic prior to usage.
The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against contamination by microorganisms such as bacteria and fungi.
The pharmaceutical compositions may also be administered transdemially.
Suitable formulations for transdermal application include an effective lipoprotein(a) blood level-lowering amount of a compound or pharmaceutical composition of the invention with a suitable transdermal carrier. Preferred transdemial carriers include absorbable pharmacologically acceptable solvents to promote and assist passage through the skin of the subject being treated. Characteristically, transdemial devices comprise the form of a bandage having a backing member, a reservoir containing the compound, optionally with carriers, optionally a rate-controlling barrier to deliver the compound to the skin of the subject being treated at a controlled and predetermined rate over a prolonged period of time and means to secure the device to the skin of the subject being treated.
Methods of preparing the various pharmaceutical compositions with a desired amount of ari active ingredient are known, or will be apparent in light of this_disclosu~e, . - - _ to one of ordinary skill in the art. See, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, 15th Edition (1975).
_g_ The dosage of the apo B secretioNMTP inhibitor or the pharmaceutically acceptable salt, hydrate or stereoisomer thereof, or the pharmaceutically acceptable salt of the hydrate or stereoisomer necessary to achieve the desired therapeutic effect according to this invention is within the ordinary skill of those who practice in the art of having the benefit of the disclosure herein.
In general, dosage ranges for certain apo B secretioNMTP inhibitors have been reported with representative effective ranges being from about 0.01 mg/kg/day to about 15.0 mg/kg/day. Generally preferable dosages range from about 0.1 to about 5.0 mg/kg/day and especially preferred dosages range from about 0.1 to about 1.0 mg/kg/day. Dosage ranges for the particular compounds described hereinabove are set forth in the above-referenced patents and patent application publications.
However, some variability in the general dosage range may be required depending upon the age and weight of the patient, the intended route of administration, and the progress and degree of severity of the illness being treated.
It will be appreciated that, when treating a mammal according to the methods of the instant invention, the actual preferred route of administration and optimum dosage utilized will be at the sound professional discretion of the person responsible for the treatment and may vary according to the severity of the condition to be treated, the intended route of administration and patient characteristics such as age, weight, rate of excretion, concurrently administered medications and general physical condition of the subject. Normally, the optimum dosage for the subject being treated will be determined by generally administering smaller doses initially and thereafter incrementally modifying the regimen, if required, to determine the most suitable dosage. This may vary according to the particular compound employed and with the nature of the subject being treated.
EXPERIMENTAL
The utility of apo B secretioNMTP inhibitors in the lowering of blood levels of lipoprotein (a) according to the practice of the methods of the invention may be demonstrated according to protocols disclosed in Nassir, et al., J. Biological Chem., 273, 17793-17800 (1998), which protocols are summarized hereinbelow.
Pulse-Chase Studies Transfected HepG2 and McA-RH7777 cells are grown to 90% confluence in T-25 flasks. On the day of the experiment, the cells are washed twice with phosphate s buffered saline, preincubated in methionine- and cysteine-free DMEM for 1 hr without serum, pulse-labeled for 4 hr in the same medium containing 250 ~Ci/ml Tran35S-label and the apo B secretion/MTP inhibitor and then chased in complete medium containing 3 mM cysteine and 10 mM methionin~ for a predetermined time. The apo B
secretaon/MTP inhibitor is dissolved in dimethyl sulfoxide at a concentration of 100 mg/ml and diluted to an appropriate concentration in media just prior to incubation with the cells. Dimethyl sulfoxide, at identical final concentrations, is added alone to control cells. At pre-determined times following radiolabeling, media are collected on ice and adjusted to a final concentration of the following protease inhibitors (100 mM
leupeptin, 450 mM apoprotin, 2 mM pepstatin, 1 mM phenylmethylsulfonyl fluoride and 1 mM benzamidine). The cells are washed three times with ice-cold, phosphate-buffered saline and subsequently lysed in cold lysis buffer (100 mM Tris, pH
8.0, 100 mM NaCI, 10 mM EDTA, 1 % Triton X-100, 0.1 % SDS) containing protease inhibitors and, for HepG2 cells, 100 mM E-aminocaproic acrd. Cell lysates and media are clarified by centrifugation at 10,000 rpm at 4 C for 5 min to remove cellular debris and immunopreapitations are then conducted as described hereinbelow. Incorporation of radioactivity into total protein is determined by trichloroacetic acid precipitation of cell lysates, in all cases demonstrating comparable values between control and experimental groups.
Immunooreapita6ons Both medium and lysates are precleared by incubation with protein G-agarose for 2-3 hr at 4 C. Aliquots are immunoprecipitated with saturating quantities of anti apo(a), anti-apo B, and apoA-I or anti-albumin antisera. After overnight incubation at 4 C, protein G-agarose beads are added and the inarbation continued for another 2-3 hr at 4 C. The final pellet is washed four times in immunoprecipitation wash buffer (50 mM Tris, pt~ 7.4, 0.65 M NaCI. 10 mM EDTA, 1 % Triton X-100, 1 % sodium _ deoxycholate, 01.% SDS), two times in water and boiled for 10 min in SDS
sample buffer (4% SDS, 20% gycerol, 0.001 % bromphenol blue, 125 mM Tris, pH 6.8 and _11_ 100 mM dithiothreitol). After centrifugation, the supernatant is analyzed by SDS-PAGE
and fluorography. Quantitation is then effected by standard techniques.
The association between apo(a) and the major protein moiety of LDL, namely apolipoprotein B100 (apo B100), is mediated through covalent linkage of a single unpaired cysteine residue in apo(a) to a complimentary unpaired cysteine residue in the extreme carboxyl terminus of apo 8100.
Interest in the biology of this lipoprotein species is driven by the observation that elevated levels of Lp(a) in humans is assodated with an increased risk for atherosderotic heart and vascular disease. The lowering of Lp(a) levels, however, has proven problematic since various conventional methods that are effective in redudng levels of LDL are not as efficadous or consistent in lowering levels of Lp(a).
For example, it has been reported that neomycin, alone or in combination with niadn, is effective in redudng Lp(a) levels when administered over a period of several weeks to years. See Spinier, et al., J. Ann. Phamnacother., 28, 343 (1994). The administration of high doses of niacin and neomydn, however, limits the desirability of this regimen due to many undesirable dinical side-effects. Alternatively, oral doses of fosinopril, an angiotensin-converting enzyme inhibitor, have been demonstrated to lower Lp(a) levels after 12 weeks of treatment, however, Lp(a) reduction was signficant only in patients that showed improvement in renal function and, therefore, the Lp(a) towering ability of fosinopril may simply be attributable to the indirect consequence of improved kidney function. See Keilani, et al., Ann. Inter. Med., 118, 246 (1993).
Additionally, certain steroidal hormones, estrogen for example, are known to down-regulate Lp(a) levels. See, for example, Frazer, et al., Nature Genet., 9_, 424 (1995).
However, estrogen therapy alone is assodated with an increased risk of endometrial cardnoma and, for this reason, estrogen is nom~any administerea in commnauownntn progesterone. Although short-term treatment with this estrogeNpmgesterone combination is an effective therapeutic strategy for redudng Lp(a) levels, long-term treatment, i.e. six months or more, does not result in the same degree of decreased inhibition as that observed for treatment with estrogen alone. See Soma, et al., Arch.
_2_ Internal. Med., 153, 1462 (1993) and Soma, et al., Chem. Phys. Lipids, 345, 67 (1994). Furthermore, LDL apheresis has been shown to be an effective means for lowering Lp(a) levels. See Koizumi, et al., Atherosclerosis, 100, 65 (1993).
Mowever, apheresis is an invasive approach requiring weekly treatments and, therefore, is not regarded as a current treatment of choice. Accordingly, improved methods of inhibiting Lp(a), or formation of the precursors thereof, will have utility in the treatment of conditions and diseases arising from hyperlipoproteinemia, including, for example, atherosderosis, premature myocardial infarction, stroke, restenosis following coronary bypass surgery and so forth.
Microsomal triglyceride transfer protein (MTP) is known to mediate the transport of triglyceride, cholesteryl ester and phospholipids and has been implicated as a mediator in the assembly of apolipoprotein B containing lipoproteins, chylomicrons and VLDL (very low density lipoprotein). Spedfically, the subcellular (lumen of the microsomal fraction) and tissue distribution (liver and intestine) of MTP
have led to speculation that it plays a role in the assembly of plasma lipoproteins, as these are the sites of plasma lipoprotein assembly. The ability of MTP to catalyze the transport of triglyceride between membranes is consistent with this speculation and suggests that MTP may catalyze the transport of triglyceride from its site of synthesis in the endoplasmic reticulum membrane to nascent lipoprotein particles within the lumen of the endoplasmic re6culum. Accordingly, compounds that inhibit MTP
and/or otherwise inhibit apo B secretion are useful in the treatment of atherosderosis and other conditions related thereto. Such compounds are also useful in the treatment of other diseases or conditions in which, by inhibiting MTP and/or apo B
secretion, serum cholesterol and triglyceride levels may be reduced. Such conditions may include, for example, hypercholesterolemia, hypertriglyceridemia, pancreatitis, obesity and hypercholesterolemia, hypertriglyceridemia and hyperiipidemia assodated with pancrea6tis, obesity and diabetes. For a detailed discussion see, for example, Wetterau et al., Silence, 258, 999-1001 (1992) and Wetterau et al., Biochem.
Biophys. Ada., 875, 610-617 (1986).
While the preclse mechanisms governing blood levels of Lp(a) are presently unknown, there is evidence to suggest that Lp(a) levels are regulated at the level of synthesis rather than catabolism. Accordingly, because it is known thatzinhibition. of _ ~ -hepatic secretion of VLDL and apolipoprotein B (apo B) results in the pre-secretory degradation of apo B and concomitant decrease in hepatic apo B levels and because each Lp(a) particle contains one copy of apo(a) bound to apo B, it is believed that decreasing the concentration of hepatic apo B, by the administration of an apo B secretion/-MTP inhibitor, will result in a lowering of Lp(a) secreted and, thereby, a lowering of blood Lp(a) levels.
Summary of the Invention The instant invention is directed to pharmaceutical compositions for lowering blood levels of lipoprotein(a) (Lp (a) ) in a mammal, which comprise (i) an effective Lp (a) blood level-lowering amount of an apolipoprotein B secretion/-microsomal triglyceride transfer protein inhibitor and (ii) a pharmaceutically acceptable carrier or diluent.
Another aspect of the present invention provides commercial packages comprising the above-described pharma ceutical compositions and written matters including indications that the pharmaceutical compositions can or should be used for lowering blood levels of Lp(a) in a mammal.
In a preferred embodiment of the invention, the apo B secretion/MTP inhibitor is a compound selected from the group consisting of 4'-trifluoromethylbiphenyl-2-carboxylic acid-[2-(1H-[1,2,4]triazol-3-ylmethyl)-1,2,3,4-tetrahydro-isoquinolin-6-yl]-amide., 4'-trifluoromethylbiphenyl-2-carboxylic acid-[2-(2-acetylaminoethyl)-1,2,3,4-tetrahydro-isoquinolin-6-yl]-amide, 9H-(4-~4-[4'-trifluoromethylbiphenyl-2-carbonyl)amino]-piperidin-1-yl}butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoroethyl)-amide 9-{4-[4-(2-benzothiazol-2-ylbenzoylamino)piperidin-1-yl]butyl}-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoroethyl)amide, [lla-R]-8-[(4-cyanophenyl)methoxy]-2-cyclopentyl-7-(prop-2-enyl)-2,3,11,11a-tetrahydro-6H-pyrazino[1,2b]isoquinoline-1,4-dione, [lla-R]-cyclopentyl-7-(prop-2-enyl)-8-[(pyridin-2-yl)methoxy]-2,3,ll,lla-tetrahydro-6H-pyrazino[1,2b]iso-quinoline-1,4-dione, 2-cyclopentyl-2-[4-(2,4-dimethylpyrido-[2,3b]indol-9-ylmethyl)phenyl]-N-(2-hydroxy-1-phenylethyl)-acetamide and 2-cyclopentyl-N-(2-hydroxy-1-phenylethyl)-2-[4-(quinolin-2-ylmethoxy)-phenyl]acetamide, a hydrate or stereoisomer thereof, or a pharmaceutically acceptable salt of the compound, hydrate or stereoisomer.
Especially preferred apo B secretion/MTP inhibitors useful in the practice of invention are the compounds 4'-trifluoromethylbiphenyl-2-carboxylic acid-[2-(1H-[1,2,4]-triazol-3-ylmethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide and 4'-trifluoromethylbiphenyl-2-carboxylic acid-[2-(2-acetylaminoethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide, hydrates thereof or the pharmaceutically acceptable salts of the compounds or hydrates.
Detailed Description of the Invention This invention provides pharmaceutical compositions for lowering blood levels of lipoprotein (a) (Lp (a) ) in a mammal, which comprise an effective Lp(a) blood level-lowering amount of an apolipoprotein B secretion/microsomal triglyceride transfer protein inhibitor.
As employed throughout the instant specification including appendant claims, the term "blood", when employed in relation to the term "blood levels", includes whole blood, plasma, i. e. the fluidic portion of the blood in which particulate components are suspended and serum, i. e. the fluidic portion of the blood obtained following removal of the fibrin clot and corpuscles.
As employed throughout the instant specification including appendant claims, the term "apo B secretion/MTP
inhibitor" means a compound having the ability to inhibit the secretion of apolipoprotein B and/or the ability to inhibit the transfer action of microsomal triglyceride transfer protein.
A variety of apo B secretion/MTP inhibitors are, or will be, known to one of ordinary skill in the art.
Although any apo B secretion/MTP inhibitor may be used in the practice of the instant invention, generally preferred apo B secretion/MTP inhibitors include those compounds, hydrates or stereoisomers thereof, or the pharmaceutically acceptable salts of the compounds, hydrates or stereoisomers -4a-which are disclosed in, for example, European Patent Publication Nos. EP 643057, EP 719763, EP 753,517, EP 764647, EP 765878, EP 779276, EP 779279, EP 799828, EP 799829, EP
802186, EP 802188, EP 802192 and EP 802197; PCT Patent Publication Nos. WO 96/13499, WO 96/33193, WO 96/40640, WO
97/26240, WO 97/43255, WO 97/43257, WO 98/16526 and WO
98/23593; and U. S. Pat. Nos. 5,595,872; 5,646,162, 5,684,014; 5,712,279; 5,739,135 and 5,789,197.
Especially preferred apo B secretion/MTP inhibitors are those biphenyl-2-carboxylic acid-tetrahydroisoquinolin-6-yl amide derivatives, and the stereoisomers, hydrates, prodrugs and pharmaceutically acceptable salts thereof disclosed in commonly assigned PCT Patent Publication Nos.
WO 96/40640 and WO 98/23593, each of which designate, inter alia, the United States. Especially preferred apo B
secretion/MTP inhibitors disclosed in PCT Patent Publication Nos. WO 96/40640 and WO 98/23593, and useful in the present invention, are the compounds illustrated hereinbelow: 4'-trifluoromethyl-biphenyl-2-carboxylic acid-[2-(1 H-[1,2,4]triazol-3-ylmethyl)-1,2,3,4-tetrahydroisoquin-6-yl]-amide and 4'-trifluoromethyl-biphenyl-2-carboxylic acid-[2-(acetylaminoethyl)-1,2,3,4-tetrahydroisoquinolin-6-ylJ-amide, or the hydrates thereof, or the pharmaceutically acceptable salts of the compounds or the hydrates.
H
/ O I \ N~N'NH / O
/ N~ ~ _ / _ O
H I H
/ /
Another especially preferred Gass of apo B secretioNMTP inhibitors is disGosed in U.S. Pat. Nos. 5,595,872; 5,712,279; 5,739,135 and 5,789,197 and includes compounds having the structural formula Q p N
Rs' N-R~ and Rs' Especially preferred apo B secretionMITP inhibitors disclosed in U.S. Pat.
Nos.
5,595,872; 5,712,279; 5,739,135 and 5,789,197, and useful in the methods of the present invention, are 9H-(4-{4-[4'trifluoromethyl-biphenyl-2-carbonyl}-amino]-piperidin-1-yl}-butyl-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoroethyl)-amide and 9-{4-[4-(2-benzothiazol-2-yl-benzoylamino)-piperidin-1-ylj-butyl}-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoroethyl)-amide.
Another Gass of espeaally preferred apo B secretioNMTP inhibitors is disGosed in PCT Application Publication No. WO 98/16526 and includes compounds having the structural formula i~
-- ~ - _ Especially preferred Apo-B secretionMITP inhibitors disGosed in PCT
Application Publication No. WO 98/16526, and useful in the methods of the present invention, are [11 a-R]-8-[(4-cyanophenyl)methoxyJ-2-cyclopentyl-7-(prop-2-enyl)-2,3,11,11 a-tetrahydro-6H-pyrazino[1,2b]isoquinoline-1,4-dione and [11a-R]-cyclopentyl-7-(prop-2-enyl)-8-[(pyridin-2-yl)methoxyJ-2,3,11,11 a-tetrahydro-6H-pyrazino[1,2b]isoquinoline-1,4-dione.
Another especlally preferred lass of apo B secretion/MTP inhibitors is disclosed in U.S. Pat. No. 5,684,014 and includes compounds having the structural formula R3 R~
HyC
Rs E~
L Rg R~
D
An especially prefer-ed apo B secretioNMTP inhibitor disclosed in U.S. Pat.
No.
5,684,014, and useful in the methods of the present invention, is 2-cydopentyl-2-[4-(2,4-dimethyl-pyrido[2,3-b]indol-9-ylmethyl)-phenyl]-N-(2-hydroxy-1-phenyl-ethyl)-acetamide.
Yet another class of especially preferred apo B secretioNMTP inhibitors is disclosed in U.S. Pat. No. 5,646,162 and includes compounds having the structural formula E
A~O
O
~ OH
~L~N
H
An especially preferred apo B seaetioNMTP inhibitor disclosed in U.S. Pat. No.
5,646,162, and useful in the methods of the present invention, is 2-cydopentyl-N-(2-hydroxy-1-phenyl-ethyl)-2-[4-(quinolin-2-ylmethoxy)-phenyl]-acetamide.
The apo B secretioNMTP inhibitors, including the prefer-ed and espedally preferred embodiments and the pharmaceutically acceptable salts, hydrates or .
stereoisomers thereof, or the pharmaceutically acceptable salts of the hydrates or stereoisomers employed in the methods of the instant invention may be prepared _7_ according to the disclosures of the aforementioned European, PCT and U.S.
patents and application publication documents.
The apo B secretion/MTP inhibitors, the pharmaceutically acceptable salts, hydrates or stereoisomers thereof, or the phamnaceutically acceptable salts of the hydrates or stereoisomers employed in the methods of the invention, are preferably administered in the form of a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent. Accordingly, the apo B
secretion/MTP
inhibitors, the pharmaceutically acceptable salts; hydrates or stereoisomers thereof, or the pharmaceutically acceptable salts of the hydrates or stereoisomers of this invention, can be administered individually or together in any conventional oral, parenteral or transdemial dosage form.
Suitable pharmaceutically-acceptable carriers indude inert solid fillers or diluents and sterile aqueous or organic solutions. The apo B secretion/MTP
inhibitors, the pharmaceutically acceptable salts, hydrates or stereoisomers thereof, or the pharmaceutically acceptable salts of the hydrates or stereoisomers of this invention will be present in such pharmaceutical compositions in amounts sufficient to provide the desired dosage amount in the range described hereinbelow. Thus, for oral administration, the compounds can be combined with a suitable solid or liquid carrier or diluent to form capsules, tablets, powders, syrups, solutions, suspensions and the like. The pharmaceutical compositions may, if desired, contain additional components such as flavorants, sweeteners, excipients and the like.
The tablets, pills, capsules, and the like may also contain a binder such as gum tragacanth, acacia, com starch or gelatin; exdpients such as dicaldum phosphate; a disintegrating agent such as com starch, potato starch, alginic add; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin. When a dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.
Various other materials may be present as coatings or to modify the physical form of the dosage unit. For instance, tablets may be coated with shellac, sugar or both. A syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry or orange flavor. ~ - -The pharmaceutical compositions of this invention may also be administered parenteraliy. For parenteral administration the pharmaceutical compositions can be _g_ combined with sterile aqueous or organic media to form injectable solutions or suspensions. Solutions or suspensions of these pharmaceutical compositions can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose.
Dispersions can also be prepared in sesame or peanut oil, ethanol, water, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, vegetable oils, N-methyl glucamine, polyvinylpyrrolidone and mixtures thereof in oils as well as aqueous solutions of water-soluble pharmaceutically acceptable salts of the compounds. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms. The injectable solutions prepared in this manner can then be administered intravenously, intraperitoneally, subcutaneously, or intramuscularly, with intramuscular administration being the preferred parenteral route in humans. Solutions prepared for intravenous administration are preferably rendered isotonic prior to usage.
The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against contamination by microorganisms such as bacteria and fungi.
The pharmaceutical compositions may also be administered transdemially.
Suitable formulations for transdermal application include an effective lipoprotein(a) blood level-lowering amount of a compound or pharmaceutical composition of the invention with a suitable transdermal carrier. Preferred transdemial carriers include absorbable pharmacologically acceptable solvents to promote and assist passage through the skin of the subject being treated. Characteristically, transdemial devices comprise the form of a bandage having a backing member, a reservoir containing the compound, optionally with carriers, optionally a rate-controlling barrier to deliver the compound to the skin of the subject being treated at a controlled and predetermined rate over a prolonged period of time and means to secure the device to the skin of the subject being treated.
Methods of preparing the various pharmaceutical compositions with a desired amount of ari active ingredient are known, or will be apparent in light of this_disclosu~e, . - - _ to one of ordinary skill in the art. See, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, 15th Edition (1975).
_g_ The dosage of the apo B secretioNMTP inhibitor or the pharmaceutically acceptable salt, hydrate or stereoisomer thereof, or the pharmaceutically acceptable salt of the hydrate or stereoisomer necessary to achieve the desired therapeutic effect according to this invention is within the ordinary skill of those who practice in the art of having the benefit of the disclosure herein.
In general, dosage ranges for certain apo B secretioNMTP inhibitors have been reported with representative effective ranges being from about 0.01 mg/kg/day to about 15.0 mg/kg/day. Generally preferable dosages range from about 0.1 to about 5.0 mg/kg/day and especially preferred dosages range from about 0.1 to about 1.0 mg/kg/day. Dosage ranges for the particular compounds described hereinabove are set forth in the above-referenced patents and patent application publications.
However, some variability in the general dosage range may be required depending upon the age and weight of the patient, the intended route of administration, and the progress and degree of severity of the illness being treated.
It will be appreciated that, when treating a mammal according to the methods of the instant invention, the actual preferred route of administration and optimum dosage utilized will be at the sound professional discretion of the person responsible for the treatment and may vary according to the severity of the condition to be treated, the intended route of administration and patient characteristics such as age, weight, rate of excretion, concurrently administered medications and general physical condition of the subject. Normally, the optimum dosage for the subject being treated will be determined by generally administering smaller doses initially and thereafter incrementally modifying the regimen, if required, to determine the most suitable dosage. This may vary according to the particular compound employed and with the nature of the subject being treated.
EXPERIMENTAL
The utility of apo B secretioNMTP inhibitors in the lowering of blood levels of lipoprotein (a) according to the practice of the methods of the invention may be demonstrated according to protocols disclosed in Nassir, et al., J. Biological Chem., 273, 17793-17800 (1998), which protocols are summarized hereinbelow.
Pulse-Chase Studies Transfected HepG2 and McA-RH7777 cells are grown to 90% confluence in T-25 flasks. On the day of the experiment, the cells are washed twice with phosphate s buffered saline, preincubated in methionine- and cysteine-free DMEM for 1 hr without serum, pulse-labeled for 4 hr in the same medium containing 250 ~Ci/ml Tran35S-label and the apo B secretion/MTP inhibitor and then chased in complete medium containing 3 mM cysteine and 10 mM methionin~ for a predetermined time. The apo B
secretaon/MTP inhibitor is dissolved in dimethyl sulfoxide at a concentration of 100 mg/ml and diluted to an appropriate concentration in media just prior to incubation with the cells. Dimethyl sulfoxide, at identical final concentrations, is added alone to control cells. At pre-determined times following radiolabeling, media are collected on ice and adjusted to a final concentration of the following protease inhibitors (100 mM
leupeptin, 450 mM apoprotin, 2 mM pepstatin, 1 mM phenylmethylsulfonyl fluoride and 1 mM benzamidine). The cells are washed three times with ice-cold, phosphate-buffered saline and subsequently lysed in cold lysis buffer (100 mM Tris, pH
8.0, 100 mM NaCI, 10 mM EDTA, 1 % Triton X-100, 0.1 % SDS) containing protease inhibitors and, for HepG2 cells, 100 mM E-aminocaproic acrd. Cell lysates and media are clarified by centrifugation at 10,000 rpm at 4 C for 5 min to remove cellular debris and immunopreapitations are then conducted as described hereinbelow. Incorporation of radioactivity into total protein is determined by trichloroacetic acid precipitation of cell lysates, in all cases demonstrating comparable values between control and experimental groups.
Immunooreapita6ons Both medium and lysates are precleared by incubation with protein G-agarose for 2-3 hr at 4 C. Aliquots are immunoprecipitated with saturating quantities of anti apo(a), anti-apo B, and apoA-I or anti-albumin antisera. After overnight incubation at 4 C, protein G-agarose beads are added and the inarbation continued for another 2-3 hr at 4 C. The final pellet is washed four times in immunoprecipitation wash buffer (50 mM Tris, pt~ 7.4, 0.65 M NaCI. 10 mM EDTA, 1 % Triton X-100, 1 % sodium _ deoxycholate, 01.% SDS), two times in water and boiled for 10 min in SDS
sample buffer (4% SDS, 20% gycerol, 0.001 % bromphenol blue, 125 mM Tris, pH 6.8 and _11_ 100 mM dithiothreitol). After centrifugation, the supernatant is analyzed by SDS-PAGE
and fluorography. Quantitation is then effected by standard techniques.
Claims (8)
1. A pharmaceutical composition for lowering blood levels of lipoprotein(a) in a mammal, which comprises (i) a lipoprotein(a) blood level-lowering amount of an apolipo-protein B secretion/microsomal triglyceride transfer protein inhibitor and (ii) a pharmaceutically acceptable carrier or diluent.
2. A pharmaceutical composition according to claim 1, wherein the apolipoprotein B secretion/microsomal triglyceride transfer protein inhibitor is a compound selected from the group consisting of 4'-trifluoromethylbiphenyl-2-carboxylic acid-[2-(1H-[1,2,4]triazol-3-ylmethyl)-1,2,3,4-tetrahydro-isoquinolin-6-yl]-amide, 4'-trifluoromethylbiphenyl-2-carboxylic acid-[2-(2-acetylaminoethyl)-1,2,3,4-tetrahydro-isoquinolin-6-yl]-amide, 9H-(4-{4-[4'-trifluoromethylbiphenyl-2-carbonyl)amino]-piperidim-1-yl}butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoroethyl)-amide, 9-{4-[4-(2-benzothiazol-2-ylbenzoylamino)piperidin-1-yl]butyl}-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoroethyl)amide, [lla-R]-8-[(4-cyanophenyl)methoxy]-2-cyclopentyl-7-(prop-2-enyl)-2,3,ll,lla-tetrahydro-6H-pyrazino[1,2b]isoquinoline-1,4-dione, [lla-R]-cyclopentyl-7-(prop-2-enyl)-8-[(pyridin-2-yl)methoxy]-2,3,ll,lla-tetrahydro-6H-pyrazino[1,2b]iso-quinoline-1,4-dione, 2-cyclopentyl-2-[4-(2,4-dimethylpyrido-[2,3b]indol-9-ylmethyl)phenyl]-N-(2-hydroxy-1-phenylethyl)-acetamide and 2-cyclopentyl-N-(2-hydroxy-1-phenylethyl)-2-[4-(quinolin-2-ylmethoxy)-phenyl]acetamide, a hydrate thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt of the compound, hydrate or stereoisomer.
3. A pharmaceutical composition according to claim 2, wherein the apolipoprotein B secretion/microsomal triglyceride transfer protein inhibitor is the compound 4'-trifluoromethyl-biphenyl-2-carboxylic acid-[2-(1H-[1,2,4]triazol-3-ylmethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide or a pharmaceutically acceptable salt thereof.
4. A pharmaceutical composition according to claim 2, wherein the apolipoprotein B secretion/microsomal triglyceride transfer protein inhibitor is the compound 4'-trifluoromethyl-biphenyl-2-carboxylic acid-[2-(2-acetylaminoethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide, a hydrate thereof or a pharmaceutically acceptable salt of said compound or said hydrate.
5. A pharmaceutical composition according to any one of claims 1 to 4, wherein the apolipoprotein B secretion/-microsomal triglyceride transfer protein inhibitor is contained at a dosage 0.1 to 5.0 mg/kg/day.
6. A pharmaceutical composition according to any one of claims 1 to 4, wherein the apolipoprotein B secretion/-microsomal triglyceride transfer protein inhibitor is contained at a dosage 0.1 to 1.0 mg/kg/day.
7. A commercial package comprising the pharmaceutical composition as defined in any one of claims 1 to 6 and a written matter which includes an indication that the pharmaceutical composition can or should be used for lowering blood levels of lipoprotein(a) in a mammal.
8. A commercial package according to claim 7, wherein the mammal is a human.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US11110098P | 1998-12-04 | 1998-12-04 | |
| US60/111,100 | 1998-12-04 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2291471A1 true CA2291471A1 (en) | 2000-06-04 |
Family
ID=22336605
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002291471A Abandoned CA2291471A1 (en) | 1998-12-04 | 1999-12-02 | Lowering blood levels of lipoprotein(a) |
Country Status (6)
| Country | Link |
|---|---|
| JP (1) | JP2000169395A (en) |
| KR (1) | KR20000047857A (en) |
| CA (1) | CA2291471A1 (en) |
| HU (1) | HUP9904485A3 (en) |
| IL (1) | IL133201A0 (en) |
| ZA (1) | ZA997446B (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7432392B2 (en) | 2003-08-29 | 2008-10-07 | Japan Tobacco Inc. | Ester derivatives and medical use thereof |
| US7625948B2 (en) | 2002-02-28 | 2009-12-01 | Japan Tobacco Inc. | Ester compound and medicinal use thereof |
| US7932268B2 (en) | 2004-03-05 | 2011-04-26 | The Trustees Of The University Of Pennsylvania | Methods for treating disorders or diseases associated with hyperlipidemia and hypercholesterolemia while minimizing side effects |
| US8101774B2 (en) | 2004-10-18 | 2012-01-24 | Japan Tobacco Inc. | Ester derivatives and medicinal use thereof |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CO5271688A1 (en) * | 1999-11-10 | 2003-04-30 | Pfizer Prod Inc | USE OF APOLIPROTEIN B AND / OR SECRETION INHIBITOR OF MICROSMAL TRIGLICERID TRANSFER PROTEIN |
| IL139450A0 (en) * | 1999-11-10 | 2001-11-25 | Pfizer Prod Inc | Methods of administering apo b-secretion/mtp inhibitors |
| CA2324800A1 (en) * | 1999-11-10 | 2001-05-10 | Mary Anne Hickman | Use of apo b secretion/mtp inhibitors |
| CA2324801A1 (en) * | 1999-11-10 | 2001-05-10 | Andrew Gordon Swick | Use of apo b secretion/mtp inhibitors and anti-obesity agents |
-
1999
- 1999-11-29 IL IL13320199A patent/IL133201A0/en unknown
- 1999-12-02 KR KR1019990054413A patent/KR20000047857A/en not_active Application Discontinuation
- 1999-12-02 CA CA002291471A patent/CA2291471A1/en not_active Abandoned
- 1999-12-02 JP JP11342833A patent/JP2000169395A/en active Pending
- 1999-12-02 ZA ZA9907446A patent/ZA997446B/en unknown
- 1999-12-03 HU HU9904485A patent/HUP9904485A3/en unknown
Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7625948B2 (en) | 2002-02-28 | 2009-12-01 | Japan Tobacco Inc. | Ester compound and medicinal use thereof |
| US7432392B2 (en) | 2003-08-29 | 2008-10-07 | Japan Tobacco Inc. | Ester derivatives and medical use thereof |
| US7932268B2 (en) | 2004-03-05 | 2011-04-26 | The Trustees Of The University Of Pennsylvania | Methods for treating disorders or diseases associated with hyperlipidemia and hypercholesterolemia while minimizing side effects |
| US8618135B2 (en) | 2004-03-05 | 2013-12-31 | The Trustees Of The University Of Pennsylvania | Methods for treating disorders or diseases associated with hyperlipidemia and hypercholesterolemia while minimizing side effects |
| US9265758B2 (en) | 2004-03-05 | 2016-02-23 | The Trustees Of The University Of Pennsylvania | Methods for treating disorders or diseases associated with hyperlipidemia and hypercholesterolemia while minimizing side-effects |
| US9364470B2 (en) | 2004-03-05 | 2016-06-14 | The Trustees Of The University Of Pennsylvania | Methods for treating disorders or diseases associated with hyperlipidemia and hypercholesterolemia while minimizing side-effects |
| US9433617B1 (en) | 2004-03-05 | 2016-09-06 | The Trustees Of The University Of Pennsylvania | Methods for treating disorders or diseases associated with hyperlipidemia and hypercholesterolemia while minimizing side-effects |
| US9861622B2 (en) | 2004-03-05 | 2018-01-09 | The Trustees Of The University Of Pennsylvania | Methods for treating disorders or diseases associated with hyperlipidemia and hypercholesterolemia while minimizing side-effects |
| US10016404B2 (en) | 2004-03-05 | 2018-07-10 | The Trustees Of The University Of Pennsylvania | Methods for treating disorders or diseases associated with hyperlipidemia and hypercholesterolemia while minimizing side effects |
| US10555938B2 (en) | 2004-03-05 | 2020-02-11 | The Trustees Of The University Of Pennsylvania | Methods for treating disorders or diseases associated with hyperlipidemia and hypercholesterolemia while minimizing side effects |
| US11554113B2 (en) | 2004-03-05 | 2023-01-17 | The Trustees Of The University Of Pennsylvania | Methods for treating disorders or diseases associated with hyperlipidemia and hypercholesterolemia while minimizing side-effects |
| US8101774B2 (en) | 2004-10-18 | 2012-01-24 | Japan Tobacco Inc. | Ester derivatives and medicinal use thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| IL133201A0 (en) | 2001-03-19 |
| JP2000169395A (en) | 2000-06-20 |
| HUP9904485A3 (en) | 2000-09-28 |
| ZA997446B (en) | 2001-06-04 |
| HUP9904485A2 (en) | 2000-08-28 |
| KR20000047857A (en) | 2000-07-25 |
| HU9904485D0 (en) | 2000-02-28 |
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