JP2003524582A - Antihyperlipidemic statin-Lp (a) inhibitor formulation - Google Patents

Abstract

  (57) [Summary] The present invention relates to a pharmaceutical composition comprising an Lp (a) inhibitor that inhibits HMG-CoA reductase and a statin, which is useful for treating a vascular disease.

Description

Detailed Description of the Invention

[0001]

[Industrial applications]

The present invention relates to statin compounds known to reduce plasma levels of low density lipoprotein (LDL) cholesterol and compounds that inhibit the formation of lipoprotein (a), Lp (a), It relates to formulations with compounds which are modified but not affected by statins. This formulation is useful in the treatment of vascular disorders and diabetes.

[0002]

[Prior art]

Reducing some form of cholesterol in a mammal is for treating and preventing heart attack, sudden death, and angina in both subjects with higher than normal levels of circulating cholesterol, as well as subjects with normal levels of cholesterol. Has been established in several clinical studies. Lowering LDL, a poor form of cholesterol, is currently associated with coronary heart disease, atherosclerosis, myocardial infarction, stroke, cerebral infarction and even restenosis after balloon angioplasty. It is one of the main goals of physicians to treat patients with cardiovascular disease or those at high risk of developing cardiovascular disease. Many physicians use cholesterol-lowering agents purely as a preventative treatment in healthy subjects with normal levels of cholesterol, thereby preventing the development of cardiovascular disease.

The most commonly used cholesterol-lowering agent is the statin, which is the enzyme 3-hydroxy-3-methylglutarilu coenzyme A (HMG-CoA) reductase, an enzyme that is early in the pathway of cholesterol biosynthesis. It is also a compound that inhibits the enzyme that catalyzes the conversion of HMG-CoA to mevalonate, which is a rate limiting step.

There are several forms of circulating blood cholesterol that occur naturally in mammals. Some forms are considered "bad" cholesterol, while other forms are considered "good" cholesterol and are essential to health. It has been established that the good form of cholesterol is high density lipoprotein (HDL). Low density lipoprotein (LDL) is "bad" cholesterol. L is the main bad form
Another form of DL cholesterol is a modified form of LDL called lipoprotein (a) or "Lp (a)". High levels of Lp (a) are now considered harmful and cause cardiovascular disease and are one of the major risk factors leading to death from heart disease.

[0005] Since vascular diseases such as coronary heart disease, stroke and even peripheral vascular disease are major causes of death and disability worldwide, new and improved treatments, as well as the formation of these diseases. It is necessary to develop a drug that actually prevents

The present inventors have discovered that the treatment and prevention of vascular disease is carried out by administering a combination of statins and Lp (a) inhibitors. Typical Lp (a) inhibitors are the retinoids described in US Pat. No. 5,489,611, which is incorporated herein by reference.

[0007]

[Outline of the Invention]

The present invention provides a pharmaceutical composition comprising an effective amount of statin and an effective amount of Lp (a) inhibitor. More specifically, one aspect of the invention is a combination of a statin and a retinoid Lp (a) inhibitor. The formulations according to the invention can also use pharmaceutically acceptable salts of the respective active ingredients.

Preferred retinoids are those described in US Pat. No. 5,489,611. Particularly preferred compositions use 9-cis-retinoic acid or 13-cis-retinoic acid. Also preferred are trans-retinal and trans-retinol, as well as 13-cis-retinol, 13-cis-retinal, 9-cis-.
Retinol and 9-cis-retinal.

[0009]   Another class of preferred Lp (a) inhibitors used is Formula I:

[Chemical 1] [In the formula,   X¹And X²Are independently hydrogen, straight chain or branched C₁~ C₈Alkyl and C ₁ ~ C₈Alkoxy, hydroxy or nitro;   X³Is hydrogen or C₁~ C_FourIs alkyl; or X³O is X¹And X²of
An alkylidene dioxy ring having from 1 to 4 carbon atoms together with one;   R¹And R²Are independently hydrogen, straight chain or branched C₁~ C₆Alkyl;   B is CH₂, -CH₂CH₂-Or CH = CH-;   n is 0 or 1;   Z is hydrogen, linear or branched C₁~ C₈Alkyl, aryl group Ar, or R³ CO (where R³Is C₁~ C_FourAlkyl or perfluoro C₁~ C_FourIn alkyl
Yes);   A is hydrogen, CH₂CH = CH₂, Linear or branched C₁~ C₈Alkyl, or
The following formula

[Chemical 2] (Here, k is an integer of 2 to 4, m is 0 or an integer of 1 to 5, X ⁴ ,
X ⁵ and X ⁶ are the same or different and are H, a linear or branched alkyl or alkoxy group having 1 to 8 carbon atoms, hydroxy, trifluoromethyl, nitro, amino, dimethylamino, diethylamino group. , Halogen atom (F, Cl, Br
, I) or X ⁴ and X ⁵ may form an alkylidene dioxy ring having 1 to 4 carbon atoms, X ⁷ is H or CH ₃ and R is 1 to 6 Which is a linear or branched alkyl group having carbon atoms, an aryl or arylalkyl group having 6 to 9 carbon atoms)], or a pharmaceutically acceptable salt thereof.

These compounds are described in US Pat. No. 5,424,3, which is incorporated herein by reference.
No. 03.

[0011]   A preferred composition has the formula II

[Chemical 3] Of amino phosphonate of.

[0012]   Another class of Lp (a) inhibitors is the diazoaniline derivatives, namely the formula III

[Chemical 4] Wherein R ¹ and R ² are independently hydrogen, straight chain or branched C ₁ -C ₆ alkyl, or together with the nitrogen to which they are attached, optionally C ₁ -C ₆ alkyl. Or C ₁
-C ₆ to 5 not may be substituted with an alkoxy to complete a 7-membered ring; R ³ is C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, hydroxy, halo, nitro,
Perfluoroalkyl, amino, C ₁ -C ₆ alkyl or di-C ₁ -C ₆ alkylamino, or cyano; and Ar is optionally carboxyl, C ₁ -C ₆ alkoxycarbonyl, cyano, CO
_{NH 2, SO 2 NH 2,} C 1 ~C 6 alkyl, C ₁ -C ₆ alkoxy, hydroxy, halo, nitro, amino, C ₁ -C ₆ alkyl or di -C ₁ -C ₆ alkylamino,
Or phenyl which may be substituted with C ₁ -C ₆ arylamino].

The composition preferably comprises a compound of formula III as follows: 4-[(4- (N, N-diethylamino) phenyl) azo] -benzonitrile; 4-[(2-chloro-4-N, N-dimethylamino) phenyl) azo] -benzonitrile; 4-[( 4- (N, N-diethylamino) phenyl) azo] -benzoic acid ethyl ester; 3-[(4- (N-piperidyl) phenyl) azo] -benzonitrile; 4-[(4- (N, N-dimethyl) Amino) phenyl) azo] -benzamide; and 4-[(4- (N, N-dimethylamino) phenyl) azo] -benzsulfonamide.

Such phenylazo compounds are disclosed in US Pat. Nos. 4,397,944 and 3,978,2.
01 and WO 97/26890, all of which are incorporated herein by reference.

Typical statins for use in combination with the compounds of formula I include atorvastatin, simvastatin, pravastatin
vastatin), cerivastatin (cerivastatin), mevastatin (mevastatin),
Velostatin, fluvastatin, lovastatin, dalvastatin and fluindatin
luindostatin) is included. Statins can be used as pharmaceutically acceptable salts such as atorvastatin calcium.

A particularly preferred composition of the present invention comprises a retinoid, atorvastatin calcium,
For use with a statin selected from pravastatin sodium, simvastatin, lovastatin and cerivastatin. The most preferred composition uses a compound of formula III with atorvastatin calcium.

The present invention also provides a method of treating vascular diseases such as peripheral vascular disease, coronary heart disease, stroke and restenosis. The present invention relates to Lp (a), plasma triglyceride,
Very low density lipoprotein (VLDL) cholesterol, LDL cholesterol,
And a method of reducing apolipoprotein B. The invention further provides plasma HDL cholesterol, apolipoprotein AI and apolipoprotein E.
Provide a way to increase The present invention also provides methods of treating and preventing non-insulin dependent diabetes by increasing insulin sensitivity by administering the formulations of the present invention.

[0018]

Detailed description of the invention

The present inventors have discovered that combining statins with Lp (a) inhibitors provides a surprisingly effective composition for treating and preventing vascular disease and diabetes. Lp (a) inhibitors are compounds effective in reducing Lp (a) in mammals. As noted above, Lp (a) inhibitors used in the present invention are described in US Pat.
489,611 and 5,424,303, both of which are incorporated herein by reference. The compounds can be in the free acid or salt form.

Another active ingredient of the formulations of the present invention is a statin. The term "statin"
As used in the specification and claims, it is synonymous with the terms "3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor" and "HMG-CoA reductase inhibitor". These three terms are used interchangeably throughout the specification and claims. As the synonyms suggest, statins are inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase and as such are effective in lowering blood plasma cholesterol levels. Statins and their pharmaceutically acceptable salts are particularly useful for lowering low density lipoprotein cholesterol (LDL-C) levels in mammals, especially humans.

HMG-CoA reductase inhibitors suitable for use in the present invention include simvastatin, pravastatin, rivastatin, mevastatin, fluindostatin, cerivastatin, verostatin, fluvastatin, dalvastatin, dihydrocompactin, dihydrocompactin, Compactin or lovastatin; or a pharmaceutically acceptable salt of simvastatin, pravastatin, rivastatin, cerivastatin, mevastatin, fluindostatin, verostatin, fluvastatin, dalvastatin, dihydrocompactin, compactin, lovastatin or a pharmaceutically acceptable salt thereof. Including but not limited to. However, it should be noted that atorvastatin calcium is a particularly preferred statin for use in the formulations of the present invention. See US Pat. No. 5,273,995, which is incorporated herein by reference.

The statins disclosed in the present invention are produced by methods known to those skilled in the art. In particular, simvastatin is described in US Pat. No. 4,444,7, which is hereby incorporated by reference.
It can be produced by the method disclosed in No. 84. Pravastatin may be prepared by the method disclosed in US Pat. No. 4,346,227, which is incorporated herein by reference. Cerivastatin is described in US Pat.
It can be produced by the method disclosed in 2,199. Alternatively, cerivastatin may be produced by the method disclosed in European Patent Application Publication No. EP617019. Mevastatin may be produced by the method disclosed in US Pat. No. 3,983,140, incorporated herein by reference. Velostatin may be produced by the methods disclosed in US Pat. No. 4,448,784 and US Pat. No. 4,450,171, incorporated herein by reference. Fluvastatin may be produced by the method disclosed in US Pat. No. 4,739,073, which is incorporated herein by reference. Compactin may be produced by the method disclosed in US Pat. No. 4,804,770, which is hereby incorporated by reference. Lovastatin may be produced by the method disclosed in US Pat. No. 4,231,938, which is incorporated herein by reference. Delvastatin may be produced by the method disclosed in European Patent Application Publication No. 738510 A2. Fluindostatin is described in European Patent Application Publication No. 36393.
4 A1. Dihydrocompactin may be produced by the method disclosed in US Pat. No. 4,450,171, which is incorporated herein by reference.

It is recognized that certain of the above statins contain free carboxylic acid or free amine groups as part of their chemical structure. Furthermore, certain statins within the scope of the present invention contain a lactone moiety, which lactone moiety exists in equilibrium with the free carboxylic acid form. These lactones can be maintained as carboxylic acid salts by preparing pharmaceutically acceptable salts of the lactones. Thus, the present invention includes pharmaceutically acceptable salts of these carboxylic acid or amine groups. "Pharmaceutically acceptable salt"
The expression comprises pharmaceutically acceptable acid addition salts and pharmaceutically acceptable cationic salts. The expression "pharmaceutically acceptable cation salt" refers to alkali metal salts (eg sodium and potassium), alkaline earth metal salts (eg calcium and magnesium), aluminum salts, ammonium salts, and benzathine (N, N'-dibenzyl). Ethylenediamine), choline, diethanolamine, ethylenediamine,
Salts with organic amines such as meglumine (N-methylglucamine), benetamine (N-benzylphenethylamine), diethylamine, piperazine, tromethamine (2-amino-2-hydroxymethyl-1,3-propanediol) and procaine. It is intended to be defined, but not limited to. The expression "pharmaceutically acceptable acid addition salt" refers to hydrochloride, bromine chloride, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, dihydrogen phosphate, acetate, succinate, It is intended to define salts such as, but not limited to, citrate, methanesulfonate (mesylate) and p-toluenesulfonate (tosylate).

A pharmaceutically acceptable cationic salt containing a free carboxylic acid can be readily prepared by reacting the free acid form of statin with one equivalent, usually an appropriate base, in a cosolvent. Typical bases are sodium hydroxide, sodium methoxide, sodium ethoxide, sodium hydride, potassium methoxide, magnesium hydroxide, calcium hydroxide, benzathine, choline, diethanolamine, piperazine and tromethamine. The salt is isolated by concentration to dryness or by the addition of a non-solvent.
In many cases, it is preferred that the salt be prepared by mixing a solution of the acid with a solution of the salt of various cations (sodium or potassium ethylhexanoate, magnesium oleate) using a solvent such as ethyl acetate. From there, the desired cationic salt precipitates or can otherwise be isolated by concentration and / or addition of a non-solvent.

The pharmaceutically acceptable acid addition salts of statins containing free amine groups can be readily prepared by reacting the free base form of statins with the appropriate acid. The salt is a monobasic acid (
For example, in the case of a salt of hydrochloride, hydrobromide, p-toluenesulfonate, acetate), hydrogen salt of dibasic acid (eg hydrogen sulfate, hydrogen succinate) or dihydrogen salt of tribasic acid. (Eg dihydrogen phosphate, dihydrogen citrate) is used in at least 1 molar equivalent and usually in molar excess of acid. However, where salts such as sulfates, hemi-succinates, hydrogen phosphates, or phosphates are preferred, the appropriate and precise chemical equivalents of acid are generally used. The free base and acid are usually combined in a co-solvent from which the desired salt precipitates or otherwise can be isolated by concentration and / or addition of a non-solvent.

Furthermore, the statins of the invention and pharmaceutically acceptable salts of the statins of the invention may also be formed as hydrates or solvates. Such hydrates and solvates are also within the scope of the invention. The same applies to Lp (a) inhibitors such as retinoids.

The pharmaceutical compositions and methods of the present invention are for the prevention and treatment of atherosclerosis, angina, and conditions characterized by the presence of both hypertension and hyperlipidemia in mammals, especially humans. All suitable for therapeutic use as a drug. Furthermore, because these diseases and conditions are closely associated with the development of heart disease and adverse cardiac conditions, these formulations and methods are useful for their anti-atherosclerosis, anti-angina pectoris, anti-hypertension and anti-hypertension. It is useful in managing the risk of the heart in subjects at risk of developing an adverse heart condition due to the effects of lipemia, and in subjects at risk of developing an adverse heart disease.

The usefulness of the compositions of the invention as a medicament for the treatment of atherosclerosis in mammals (eg humans) is demonstrated by conventional compounds and compounds of the invention in clinical protocols as described below. Indicated by activity.

Effect of Lp (a) inhibitors and statins, alone and in combination, on the treatment of atherosclerosis: This study shows that 9-cis-retinoic acid or its pharmaceutically acceptable salts and statins. Is a prospective randomized assessment of the effect of the combination with and on progression / regression of coronary and carotid artery disease. This study indicates that the combination of statins with 9-cis-retinoic acid or a pharmaceutically acceptable acid addition salt is demonstrated by changes in coronary angiography or carotid ultrasound in subjects with confirmed disease. Is used to indicate that it is effective in slowing or stopping the progression or regression of existing coronary artery disease (CAD).

This study is an angiographic study of coronary artery disease performed as a double-blind, placebo-controlled trial of a minimum of about 500 subjects, preferably about 780 to about 1200 subjects. It is particularly preferred to survey about 1200 subjects in this study.
Subjects are allowed to participate in the study after meeting certain of the following participation criteria.

Participation Criteria: Subjects who are allowed to participate in this study must meet certain participation criteria. Subjects must be 18 to 80 year old adult males or females clinically indicated for coronary angiography. The subjects are the following 3
At least one segment (non-PTCA) determined to require no intervention for more than a year
Subsequent evaluation by quantitative coronary angiography (QCA) of non-bypass or non-MI vessels), significant lesion lesions such as 30-50% are present on the angiogram. It is necessary that the segment being analyzed was not intervened. Percutaneous transluminal cardiovascular angioplasty (PTCA) requires a non-PTCA segment for analysis because the segment is intervened by the insertion of a balloon catheter. It is necessary that the segment being analyzed did not suffer from thrombotic symptoms such as myocardial infarction (MI). Therefore, non-MI vessels are required. The segments analyzed include:
Left major, proximal, medial, and distal left anterior downward, first and second oblique branch, proximal and distal left convolution, first or maximal spatial obtuse edge, proximal, median, and distal Right coronary artery. Subjects should have a catheterized or radionuclide ventriculogram or ECHO heart curve at the time of angiography or within 3 months prior to angiography, provided there is no surgical intervention such as thrombosis or PTCA. Determined by 30
With an ejection fraction greater than%.

In general, studies are conducted in multiple locations due to the number of patients and physical limitations in one institution. Upon entry into the study, subjects were asked to perform quantitative coronary angiography and B
Undergoing modal carotid ultrasonography and carotid compliance at a designated testing center. This establishes the baseline for each subject. Once in the study, subjects were randomized to receive 9-cis-retinoic acid (2
00 mg) of the compound and placebo or statin (the dose depends on the particular statin used, but generally 80 mg is used initially), and placebo or 9-cis-
Given retinoic acid (200 mg) and statin (80 mg). Those skilled in the art will appreciate that the free base form or other salt forms of 9-cis-retinoic acid, or the free base form or other salt forms of statins can be used in the present invention. Calculation of doses of statins and these other forms of 9-cis-retinoic acid is facilitated by a simple ratio to the molecular weight of the substances concerned. The amount of 9-cis-retinoic acid can be varied as needed. Generally, subjects start with 200 mg,
The amount is titrated up to 50 mg as determined by the clinician. The amount of statin will also be titrated from 80 mg if the physician determines that the subject is most beneficial. Subjects are monitored for 1-3 years, with 3 years being generally preferred. B-mode carotid ultrasound assessment and compliance of carotid atherosclerosis is done at regular intervals throughout the study.

Intervals of 6 months are generally suitable. Typically, this evaluation is done using a B-mode ultrasound equipment. However, one of ordinary skill in the art may use other methods to make this evaluation. Coronary angiography is performed at the end of the 1-3 year treatment period. Baseline and post-treatment angiography, as well as intervening carotid B-mode ultrasonography, assess the progression of new lesions or existing atherosclerotic lesions. The arterial compliance measure was changed from baseline and 6
Evaluate changes over the monthly evaluation period.

The main purpose of this study was that a combination of carboxyalkyl ether or a pharmaceutically acceptable acid addition salt and a statin was administered by quantitative coronary angiography (QCA) in subjects with clinical coronary artery disease. It is to be measured and shown to reduce the progression of atherosclerotic lesions. QCA measures the opening in the lumen of the measured artery.

The first endpoint of the study is the change in average mean segment diameter of the coronary artery tree. Thus, the diameter of an arterial segment is measured at various points along the length of that segment. Next, the average diameter of the segment is determined. When the average segment diameter of many segments is determined, the average of all segment averages is determined to reach the average-average segment diameter. The mean segment diameter of subjects taking statins and 9-cis-retinoic acid or a pharmaceutically acceptable acid addition salt more gradually slopes downwards, stops altogether, or increases to the mean segment diameter. There is. These results respectively represent a delayed progression of atherosclerosis, no change in the progression of atherosclerosis, and a regression of atherosclerosis.

The second objective of this study is that the combination of statin with carboxyalkyl ether or pharmaceutically acceptable acid addition salt is more effective than Compound III or pharmaceutically acceptable acid addition salt or statin alone in coronary arteries. Is to reduce the rate of progression of atherosclerosis in, by means of the slope of the maximum intimal-medial thickness [Mean Max] measurement averaged over 12 distinct wall segments as a function of time. To be measured. Subjects who ingested statin and Compound III or a pharmaceutically acceptable acid addition salt thereof, have a more slow increase, stop increasing, or decrease in intimal-medial thickness. These results indicate delayed progression of atherosclerosis, arrest of atherosclerosis progression, and regression of atherosclerosis, respectively. In addition, these results can be used to facilitate dose determination.

The utility of the compounds of the invention as medicaments for treating angina in mammals (eg humans) is illustrated by the activity of the compounds of the invention in conventional assays and in the clinical protocols described below. .

Effect of 9-cis-retinoic acid and statins alone and in combination on the treatment of angina: This study showed that 9-cis-retinoic acid or its pharmaceutically acceptable acid addition salts were combined with statins. Double-blind, parallel-choice, randomized study to show efficacy in treating angina symptoms when given.

Participation Criteria: Subjects are male or female, 18-80 years old, with a history of typical chest pain with one of the following objective evidence of cardiac ischemia: (1) ECG From about 1 mm or more in the stress test segment; (2) Positive treadmill stress test; (3) Ultrasonic new wall motion abnormality; or (
4) Coronary angiographic image showing marked stenosis. Generally, a stenosis of about 30-50% is considered significant.

Each subject is evaluated for about 10-32 weeks. At least 10 weeks are required to complete the study. Sufficient subjects are used in this screening to ensure that about 200-800 subjects, preferably about 400 subjects, are evaluated to complete the study. Subjects are subjected to a four-week run in-phase eligibility screening to meet the participation criteria shown below. After meeting the eligibility criteria, the subject is washed off the current anti-angina medication and stabilized with a long-acting nitrate such as nitroglycerin, isosorbide-5-mononitrate or isosorbide dinitrate. The term "flush off" when used in connection with this qualification means to discontinue the current anti-angina medication and remove substantially all of the above medication from the subject's body. A period of 8 weeks is preferred for the washout period and for establishing a stable dosing of the nitrate in the subject. Subjects who have once or twice a week angina attacks during stable dosing of long-acting nitrates are generally allowed to omit washout conditions. After stabilizing the subject with nitrates, the subject will enter a randomized state if they have had one or two consecutive attacks of angina per week. In the randomized state, subjects enter one of four options in the study shown below. After completion of the washout condition, subjects meeting the inclusion criteria will have a 24-hour ambulatory electrocardiogram (ECG) such as Holter monitoring, a motor stress test like a treadmill, and a myocardium using photon emission tomography (PET) scanning Perfusion assessment will be performed to establish a baseline for each subject. When performing a stress test, the technician can control the speed of the tread and the grade of the tread. Tread speed and grade angle are generally increased during testing. The time interval between each speed and grade increase is generally modified Bruce
Determined using the protocol.

After completion of the baseline study, subjects will begin one of four study options: (1) placebo; (2) statin (about 2.5 mg to about 160 mg); (3) 9-cis. -Retinoic acid (about 25 mg to about 200 mg); or (4) a combination of the above doses of 9-cis-retinoic acid and a statin. Subjects are then monitored for 2-24 weeks. Those skilled in the art will recognize that the free base form or other salt forms of Compound III, or the free base form or other salt forms of statins, can be used in the present invention. Dosage calculations for statins and other forms of Compound III are readily accomplished from simple ratios of related substances to molecular weight.

Following the end of the monitoring period, subjects will undergo the following investigations: (1) 24-hour ambulatory ECG such as Holter monitoring; (2) exercise stress test (eg treading using modified Bruce protocol); And (3) Assessment of myocardial perfusion using PET scanning. Patients continue to have painful ischemic symptoms and nitroglycerin consumption daily. It is desirable to accurately record the number of angina attacks in the patient during the test. Since patients generally take nitroglycerin to relieve the pain of angina attacks, the number of times the patient is given nitroglycerin provides a reasonably accurate record of the number of angina attacks.

To exemplify the efficacy and dose of the drug formulation of the present invention, the person conducting the test
Subjects are evaluated using the tests described. Successful treatment may result in fewer cases of ischemic symptoms detected on ECG, subject may be able to exercise on longer or more intense levels of tread, or treadless exercise without pain Yes or better perfusion or less perfusion defects in PET.

The utility of the compounds of the invention as pharmaceutical agents in the treatment of hypertension and hyperlipidemia in mammals (eg humans) suffering from a combination of hypertension and hyperlipidemia is described in conventional assays and below. Exemplified by the activity of the compounds of the invention in clinical protocols.

Effect of Lp (a) inhibitors and statins, alone and in combination, on the treatment of subjects with hypertension and hyperlipidemia: This study shows that carboxyalkyl ethers or their pharmaceutically acceptable acid additions. To show efficacy in suppressing both hypertension and hyperlipidemia in subjects with mild, moderate or severe hypertension and hyperlipidemia when given in combination with salt and statin, Double-blind, parallel-A randomized, randomized study.

Each subject is evaluated for about 10-20 weeks, preferably 14 weeks. This qualification will use sufficient subjects to ensure that about 400-800 subjects are evaluated and the study completed.

Participation Criteria: Subjects are adult males or females aged 18 to 80 with hypertension and hyperlipidemia. Hyperlipidemia is evidenced by the subject's assessment of LDL cholesterol levels for certain positive risk factors. A subject is considered hyperlipidemic if the subject does not have coronary heart disease (CHD) and a positive risk factor is less than 2, and if the subject's LDL is ≧ 190 mg / dL, drug treatment is necessary. If a subject does not have CHD and the positive risk factor is 2 or more, the subject is considered to have hyperlipidemia and the subject's LDL is ≧ 160 mg.
If it is / dL, drug treatment is required. If the subject has CHD, then the subject's L
A subject is considered to have hyperlipidemia if the DL is ≧ 130 mg / dL.

Positive risk factors include the following: (1) men over the age of 45, (2)
A woman over 55 years old who has not received hormone replacement therapy (HRT), (3) with a family history of premature cardiovascular disease, (4) subject is currently a smoker, (5) subject is diabetic Yes, (6) HDL is less than 45 mg / dL, and (7) subject is hypertensive. HDL greater than 60 mg / dL is considered a negative risk factor, offsetting one of the above positive risk factors.

Hypertension is manifested by diastolic blood pressure (BP) when sitting> 90 mmHg or systolic BP when sitting> 140 mmHg. Total blood pressure is generally determined as the average of 3 measurements with 5 separates.

Subjects are qualified to meet the above inclusion criteria. After meeting all eligibility criteria, subjects are flushed of their current hypotensive and hypolipidemic medications and provided with the NCEP ATP II Step 1 diet. NCEP ATP II (Adult Treatment Panel, Second Amendment) Step 1 Diet shows the amount of saturated and unsaturated fats that can be consumed as part of the total caloric intake. The term “wash out”, when used in connection with this qualification, means to discontinue the current antihypertensive and lipid-lowering medication and remove substantially all of the medication from the subject's body. Newly diagnosed subjects are generally not treated until the test begins. These subjects are also provided with the NCEP ATP II Step 1 diet. Following a 4-week washout and diet stabilization period, subjects undergo the following baseline study:
(1) Blood pressure and (2) Fasting lipid eligibility screening. The fasting lipid qualification screen determines baseline lipid levels in the subject's fasting state. Generally, subjects refrain from food for 12 hours, at which time lipid levels are measured.

After performing the baseline study, subjects will be started on one of the following: (1) a fixed dose of 9-cis-retinoic acid, typically about 25 mg to 200 mg; (2) a fixed dose of statin, generally about 2.5 mg to about 160 mg; or (3) a combination of the above doses of 9-cis-retinoic acid and a statin. Those skilled in the art will recognize that the free base form or other salt forms of 9-cis-retinoic acid or the free base form or other salt forms of statins can be used in the present invention. Calculating doses of statins and other forms of 9-cis-retinoic acid is easily done from simple ratios to the molecular weight of related substances. Subjects will receive such administration for a minimum of 6 weeks, and generally no more than 8 weeks. The subject will return to the test center after 6-8 weeks so that the baseline assessment can be repeated. The subject's blood pressure at the end of the study is compared to the subject's blood pressure at the time of participation. The Lipid Eligibility Screen measures a subject's total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides, apo B, very low density lipoprotein (VLDL), and other components of the lipid profile. The improvement in the value obtained after treatment over the value before treatment indicates the utility of the drug combination.

The utility of the compounds of the invention as pharmaceuticals in the management of cardiac risk in mammals (eg, humans) at risk for adverse heart disease is demonstrated by conventional compounds and compounds in the clinical protocols described below. Is exemplified by the activity of

Effects of Lp (a) inhibitors and statins, alone and in combination, on subjects at risk for future cardiovascular symptoms: This study shows that carboxyalkyl ethers or their pharmaceutically acceptable acid additions. Double-blind, parallel-choice to show efficacy in reducing future predicted total risk for subjects at risk of future cardiovascular disease when given in combination with salt and statins It is a randomized survey. This risk is calculated using the Framingham risk formula. Subjects are considered at risk for future cardiovascular symptoms if they deviate more than one standard deviation from the mean calculated using the Framingham risk formula. This study shows that a fixed combination of statins with carboxyalkyl ethers or pharmaceutically acceptable acid addition salts of statins shows both hypertension and hyperlipidemia in patients with mild to moderate hypertension and hyperlipidemia. Is used to assess the efficacy of suppressing cardiovascular risk.

Each subject is evaluated for 10 to 20 weeks, preferably 14 weeks. Enroll sufficient subjects to ensure that approximately 400-800 subjects are evaluated to complete the study.

Participation Criteria: Subjects included in this study had a baseline 5-year risk of 1
Adult males or females aged 8 to 80 years, whose risk is greater than the median age and sex of the subjects as defined by the Framingham Heart Study. The Framingham Heart Study is an ongoing prospective study of adult males and females and shows that certain risk factors can be used to predict the development of coronary heart disease. Age, gender, systolic and diastolic blood pressure, smoking habits, carbohydrate intolerance,
Left ventricular hypertrophy, serum cholesterol, and Framingham population (Framingham
Any HDL that is greater than one standard deviation value above the criterion for Population) is evaluated to determine whether a patient is at risk for adverse cardiac symptoms. The value of the risk factor is inserted and calculated in the Framingham risk formula to determine if the subject is at risk for future cardiovascular symptoms.

Subjects are screened to meet the above inclusion criteria. After meeting all eligibility criteria, patients are flushed of current antihypertensive and lipid lowering medications, as well as medications that affect the outcome of the qualifications. The patient is then given the above NCEP
Provide ATP II Step 1 diet. Newly diagnosed subjects generally
Do not act until the test begins. These subjects also had the NCEP ATP II
Serve the regular diet of Step 1. After a 4-week washout and diet stabilization period,
Subjects will undergo the following baseline studies: (1) blood pressure; (2) fasting; (3) lipid eligibility screening; (4) glucose tolerance test; (5) ECG; and (6) cardiac ultrasound. These tests are performed using standard procedures well known to those skilled in the art. ECG and echocardiography are commonly used to measure the presence or absence of left ventricular hypertrophy.

After conducting a baseline study, subjects will be started on one of the following: (1) a fixed dose of 9-cis-retinoic acid (about 25-200 mg); (2) a fixed dose of statin (about 2.5).
mg to about 160 mg); or (3) a combination of the above doses of 9-cis-retinoic acid and a statin. Patients continue to receive such dosing and are returned for repeatable baseline assessments at 6-8 weeks. At this time, the new value is entered into the Framingham risk formula to determine whether the subject is at low risk, high risk of future cardiovascular symptoms, or unchanged.

Retinoids or pharmaceutically acceptable acid addition salts thereof, and atorvastatin or pharmaceutically thereof in the treatment of angina, atherosclerosis, hypertension and hyperlipidemia, and management of the risk of heart disease. The above assay, which illustrates the efficacy of the acceptable salts, also provides a means of comparing the activity of the compounds of the invention with the activity of other compounds of the invention, and with the activity of other known compounds. The result of these comparisons is
It is useful in determining synergistic dosages for mammals, including humans, for treating such disorders.

The dosages below and other dosages recited in the specification and claims are for an average human subject having a weight of about 65 kg to about 70 kg.
A skilled practitioner can readily determine the dosage required for a subject having a weight outside the range of 65-70 kg based on the subject's medical history and the presence of the subject's disease, eg, diabetes. All doses mentioned in the text and claims are daily doses.

Generally, in accordance with the present invention, Lp (a) inhibitors are generally administered in doses of about 25 mg to about 500 mg. Preferably, 9-cis-retinoic acid is administered at a dose of about 5 mg to about 100 mg. Those skilled in the art will recognize that the free base form or other salt forms of 9-cis-retinoic acid may be used in the present invention. Dose calculations for these other or free base or other salt forms of the Lp (a) inhibitor are readily accomplished by determining the simple ratio related to the molecular weight of the substance of interest.

Generally, according to the present invention, the above statins are administered in the following dosages: Simvastatin: generally from about 2.5 mg to about 160 mg, and preferably about 10 m
g to about 40 mg; pravastatin: generally about 2.5 mg to about 160 mg, and preferably about 10 m.
g to about 40 mg; cerivastatin: generally about 25 μg to about 5 mg, and preferably about 1 mg to about 3.2 mg; fluvastatin: generally about 2.5 mg to about 160 mg, and preferably about 20 m.
g to about 80 mg; Lovastatin: generally about 2.5 mg to about 160 mg, and preferably about 10 mg.
To about 80 mg; and atorvastatin: generally about 2.5 mg to about 160 mg, and preferably about 1.
0 mg to about 80 mg.

Those skilled in the art will recognize that the free base or other salt forms of the statins described above may be used in the present invention. Dose calculations for these other forms, or the free base forms, or other salt forms of statins are readily accomplished by determining the simple ratios associated with the molecular weight of the substances of interest.

The compounds of the invention are generally administered in the form of a pharmaceutical composition comprising at least one compound of the invention with a pharmaceutically acceptable carrier or diluent. in this way,
The compounds of the present invention can be administered individually or together in any conventional oral, parenteral or transdermal dosage form.

For oral administration, the pharmaceutical composition may be a solution, suspension, tablet, pill, capsule,
It can be in the form of powder or the like. Tablets containing various excipients such as sodium citrate, calcium carbonate and calcium phosphate can be combined with various binders, such as starch, and preferably potato or tapioca starch, and certain disintegrants such as some complex silicates. , For example, with polyvinylpyrrolidone, sucrose, gelatin, and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful in tabletting. Similar types of solid compositions are also used as fillers in soft-filled and hard-filled gelatin capsules, with preferred materials in this context also including lactose or lactose, and high molecular weight polyethylene glycols. When aqueous suspensions and / or elixirs are desired for oral administration, the compounds of the present invention can be used in various sweetening, flavoring, coloring, emulsifying and / or suspending agents as well as water, ethanol, propylene glycol, glycerin. Can be combined with diluents such as, and various combinations thereof.

The formulations of the present invention may also be administered as controlled release formulations, such as sustained or immediate release formulations. Such controlled release formulations of the combination of the present invention may be manufactured using methods known to those of ordinary skill in the art. The mode of administration is determined by the attending physician or other person skilled in the art after an assessment of the subject's condition and needs. Generally preferred formulations of atorvastatin calcium are described in US Pat. No. 5,686,1 which is incorporated herein by reference.
Lipitor ^(R) described in No. 04.

For parenteral administration, solutions in sesame or peanut oil or aqueous propylene glycol can be used, as well as sterile aqueous solutions of the corresponding water-soluble salts. Such aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose. These aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal injection purposes. In this connection
The sterile aqueous media used are all easily obtained by standard techniques known to those skilled in the art.

Methods of making various pharmaceutical compositions having an amount of active ingredient will be apparent to those skilled in the art from this disclosure. For example, Remington's Pharmaceutical Sciences, Mac
See kPublisher, Easter, Pennsylvania, 15th Edition (1975).

The pharmaceutical composition according to the invention may contain 0.1-95%, preferably 1-70% of a compound of the invention. In all cases, the composition or formulation administered is
It comprises a compound of the invention in an amount effective to treat the condition or disease of the subject being treated.

Since the present invention relates to the treatment of diseases and conditions with formulations of the active ingredient that can be administered separately, the invention also relates to combining the separate pharmaceutical compositions in the form of a kit. The kit comprises two separate pharmaceutical compositions: a carboxyalkyl ether or a pharmaceutically acceptable acid addition salt thereof, and a statin or a pharmaceutically acceptable salt thereof. The kit comprises container means for containing the separate compositions, such as divided bottles or divided foil packets; however, the separate compositions may also be contained in a single, undivided container. Typically, the kit will include instructions for administration of the separate components. The kit form is such that the separate components are preferably administered in different dosage forms (eg, oral and parenteral), when administered at different dosing intervals, or the prescribing physician desires to titrate the individual components of the formulation. In this case, it is particularly advantageous.

While the present invention is not limited to the particular embodiments described herein, it is to be understood that various changes and modifications can be made without departing from the spirit and scope of the novel concept as defined in the claims. Should be understood.

─────────────────────────────────────────────────── ─── Continued Front Page (51) Int.Cl. ⁷ Identification Code FI Theme Code (Reference) A61P 3/06 A61P 3/06 9/10 9/10 43/00 121 43/00 121 (81) Designated Country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SZ, UG, ZW), EA (AM, AZ , BY, KG, KZ, MD, RU, TJ, TM), AL, AU, BA, BB, BG, BR, CA, CN, CU, CZ, EE, GE, HR, HU, ID, IL, IS JP, KP, KR, LC, LK, LR, LT, LV, MG, MK, MN, MX, NO, NZ, PL, RO, SG, SI, SK, SL, TR, TT, UA, US, UZ , VN, YU (72) Inventor Roger Scofield Newton Michigan, USA 48105. Unover. Bardstown Trail 1425 (72) Inventor Randy Langer Ramharak Michigan, USA 48105. Unover. Antietam drive 2465 F term (reference) 4C084 AA20 MA02 NA14 ZA361 ZA401 ZA451 ZC022 ZC331 ZC351 4C086 AA01 AA02 BA17 BC04 MA02 MA04 NA14 ZA36 ZA40 ZA45 ZC02 ZC33 ZC35 Z0235

Claims (28)

[Claims] 1. A. An amount of Lp (a) inhibitor or a pharmaceutically acceptable salt thereof;   b. An amount of statin or a pharmaceutically acceptable salt thereof; and   c. A pharmaceutically acceptable carrier or diluent; A pharmaceutical composition comprising: 2. The statin is atorvastatin, simvastatin, pravastatin, rivastatin, mevastatin, fluindostatin, verostatin, fluvastatin, dalvastatin, dihydrocompactin, compactin, cerivastatin or lovastatin; or a pharmaceutically acceptable salt thereof. The pharmaceutical composition according to claim 1. 3. The pharmaceutical composition according to claim 2, wherein the statin is atorvastatin, simvastatin, pravastatin, mevastatin, lovastatin, cerivastatin or a pharmaceutically acceptable salt thereof. 4. The pharmaceutical composition according to claim 3, wherein the Lp (a) inhibitor is a retinoid. 5. The pharmaceutical composition according to claim 4, which comprises atorvastatin calcium and 9-cis-retinoic acid. 6. A first pharmaceutical composition which is used together with a second pharmaceutical composition to achieve a hypolipidemic effect in a mammal suffering from hyperlipidemia, the effect of which is: Greater than the sum of the blood lipid lowering effects achieved by administering the first and second pharmaceutical compositions separately, and the second pharmaceutical composition comprises an Lp (a) inhibitor or a pharmaceutically acceptable thereof. Of a statin or a pharmaceutically acceptable carrier or diluent, wherein the first pharmaceutical composition comprises an amount of statin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent. Wherein the statin is not atorvastatin or a pharmaceutically acceptable salt thereof, the first pharmaceutical composition. 7. The statin is atorvastatin, simvastatin, pravastatin, rivastatin, mevastatin, fluindostatin, verostatin, fluvastatin, dalvastatin, dihydrocompactin, compactin, cerivastatin or lovastatin; or simvastatin, pravastatin, rivastatin, mevastatin, fluindastatin. , Velostatin, Fluvastatin,
The composition according to claim 6, which is a pharmaceutically acceptable salt of dalvastatin, dihydrocompactin, compactin, cerivastatin or lovastatin. 8. The composition of claim 7, wherein the second pharmaceutical composition comprises a retinoid. 9. A first pharmaceutical composition, which is used together with a second pharmaceutical composition to achieve a hypolipidemic action in a mammal suffering from hyperlipidemia, the effect of which is: An amount of statin or a pharmaceutically acceptable salt thereof greater than the sum of the hypolipidemic effects in blood achieved by administering the first and second pharmaceutical compositions separately. And a pharmaceutically acceptable carrier or diluent, the first pharmaceutical composition comprising an amount of 9-cis-retinoic acid. 10. The statin is atorvastatin, simvastatin, pravastatin, rivastatin, mevastatin, fluindostatin, verostatin, fluvastatin, dalvastatin, dihydrocompactin, compactin, cerivastatin or lovastatin; or a pharmaceutically acceptable salt thereof. The composition according to claim 9. 11. A composition according to claim 10 which comprises 9-cis-retinoic acid. 12. A first pharmaceutical composition for use with a second pharmaceutical composition for the management of cardiac risk in a mammal at risk of adverse heart disease, the effect of which is first. And a second pharmaceutical composition is greater than the sum of the cardiac risk management effects achieved by administering the second pharmaceutical composition separately, and the second pharmaceutical composition comprises the amount of statin or a pharmaceutically acceptable salt thereof and the pharmaceutical composition. Wherein the first pharmaceutical composition comprises an amount of the Lp (a) inhibitor or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent. A pharmaceutical composition. 13. The statin is atorvastatin, simvastatin, pravastatin, rivastatin, mevastatin, fluindostatin, verostatin, fluvastatin, dalvastatin, dihydrocompactin, compactin, cerivastatin or lovastatin; or simvastatin, pravastatin, rivastatin, mevastatin, fluindastatin. 13. The composition according to claim 12, which is a pharmaceutically acceptable salt of velostatin, fluvastatin, dalvastatin, dihydrocompactin, compactin or lovastatin. 14. The composition according to claim 13, which comprises a retinoid. 15. A. An amount of Lp (a) inhibitor or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent in a first unit dosage form; b. An amount of statin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent in a second unit dosage form; and c. A container means for containing the above first and second unit dosage forms; provided that the statin is not atorvastatin or a pharmaceutically acceptable salt thereof, a kit for achieving a therapeutic effect in a mammal. 16. The statin is atorvastatin, simvastatin, pravastatin, rivastatin, mevastatin, fluindostatin, verostatin, fluvastatin, dalvastatin, dihydrocompactin, compactin, cerivastatin or lovastatin; or simvastatin, pravastatin, rivastatin, mevastatin, fluindastatin. 16. The kit according to claim 15, which is a pharmaceutically acceptable salt of velostatin, fluvastatin, dalvastatin, dihydrocompactin, compactin, cerivastatin or lovastatin. 17. The kit according to claim 16, which comprises a retinoid. 18. The kit according to claim 17, which uses 9-cis-retinoic acid. 19. The kit according to claim 15, wherein the therapeutic effect is treatment of hyperlipidemia. 20. The kit according to claim 15, wherein the therapeutic effect is treatment of angina. 21. The kit of claim 15, wherein the therapeutic effect is treatment of heart risk. 22. The kit according to claim 15, wherein the therapeutic effect is treatment of atherosclerosis. 23. The kit of claim 22, wherein the treatment of atherosclerosis slows the progression of atherosclerotic plaque. 24. The kit of claim 23, wherein the progression of atherosclerotic plaque is slowed in the coronary arteries. 25. The kit of claim 23, wherein the progression of atherosclerotic plaque is slowed down in the carotid artery. 26. The kit of claim 23, wherein the progression of atherosclerotic plaque is slowed in the peripheral arterial system. 27. The kit of claim 22, wherein the treatment of atherosclerosis regresses atherosclerotic plaque. 28. The kit of claim 27, wherein regression of atherosclerotic plaque occurs in coronary arteries.