KR20010033017A - Antihyperlipidemic Statin-LP(a) Inhibitor Combinations - Google Patents

Abstract

The present invention includes Lp (a) inhibitors and statins that inhibit HMG-CoA reductase and are useful pharmaceutical compositions for the treatment of vascular diseases.

Description

Anti-hyperlipidemic Statin-LP (a) Inhibitor Combinations}

Several clinical studies have lowered certain forms of cholesterol in mammals to treat and prevent atherosclerosis, sudden death, and angina in individuals with high cholesterol levels as well as those with normal cholesterol levels. It was found to be effective. Today, lowering the harmful form of cholesterol, LDL, treats patients suffering from or at high risk of developing cardiovascular diseases such as coronary atherosclerosis, atherosclerosis, myocardial infarction, seizures, cerebral infarction and even restenosis following balloon angioplasty. That is one of the doctor's main goals. Many doctors prevent the development of cardiovascular disease by using cholesterol-lowering agents as a prophylactic treatment for healthy individuals with normal cholesterol levels.

The most commonly used cholesterol lowering agent is statins, which are enzymes 3-hydroxy-3-methylglutaryl, an enzyme that catalyzes the conversion of HMG-CoA to mevalonate, an early and rate limiting step in the cholesterol biosynthetic pathway. Coenzyme A (HMG-CoA) is a compound that inhibits reductase.

There are many forms of blood cholesterol that form naturally in mammals. Some forms are considered "harmful" cholesterol while others are considered "good" cholesterol and are essential for good health. Good cholesterol forms have been demonstrated with high density lipoprotein (HDL). Low density lipoprotein (LDL) is "harmful" cholesterol. Another form of LDL cholesterol, which is the major deleterious form, is lipoprotein (a), a modified LDL called "Lp (a)". Currently, high levels of Lp (a) are believed to be dangerous, can cause cardiovascular disease, and are one of the major risk factors leading to death from heart disease.

Since vascular diseases such as coronary heart disease, seizures, and even peripheral vascular diseases remain the leading cause of death and disorder worldwide, new improved methods of treatment as well as drugs that can actually prevent the development of these diseases Needs to be developed.

We have found that administration of a combination of Lp (a) inhibitors and statins can treat and prevent heart disease. Typical Lp (a) inhibitors are retinoids as described in US Pat. No. 5,489,611, which is incorporated herein by reference.

<Summary of invention>

The present invention provides a pharmaceutical composition comprising an effective amount of a statin and an effective amount of an Lp (a) inhibitor. More particularly, one embodiment of the present invention is a combination formulation of a retinoid Lp (a) inhibitor with statins.

In addition, the combination preparation of this invention can use the pharmaceutically acceptable salt of each active compound.

Preferred retinoids are those described in US Pat. No. 5,489,611. Particularly preferred compositions are 9-cis-retinoic acid or 13-cis-retinoic acid. Preference is also given to 13-cis-retinol, 13-cis-retinal, 9-cis-retinol and 9-cis-retinal as well as trans-retinal and trans-retinol.

Another class of preferred Lp (a) inhibitors used are the aminophosphonates of formula (I) or a pharmaceutically acceptable salt thereof.

Where

X ¹ and X ² are independently hydrogen, straight or branched C ₁ -C ₈ alkyl and C ₁ -C ₈ alkoxy, hydroxy or nitro,

X ³ is hydrogen or C ₁ -C ₈ alkyl, or X ³ O is an alkylidene dioxy ring having 1 to 4 carbon atoms with one of X ¹ or X ² ,

R ¹ and R ² are independently hydrogen or straight or branched C ₁ -C ₆ alkyl,

B is CH ₂ , -CH ₂ CH ₂ -or CH = CH-,

n is 0 or 1,

Z is hydrogen, straight or branched C ₁ -C ₈ alkyl, aryl group Ar or R ³ CO, where R ³ is C ₁ -C ₄ alkyl or perfluoro C ₁ -C ₄ alkyl,

A is hydrogen, CH ₂ CH = CH ₂ , straight or branched C ₁ -C ₈ alkyl or

, -COO-R, where k is an integer from 2 to 4, m is 0 or an integer from 1 to 5, the same or different X ⁴ , X ⁵ , X ⁶ is H, linear with 1 to 8 carbon atoms or Branched alkyl or alkoxy groups, hydroxy, trifluoromethyl, nitro, amino, dimethylamino, diethylamino groups, halogen atoms (F, Cl, Br, I), X ⁴ and X ⁵ have from 1 to ⁴ carbon atoms May form an alkylidenedioxy ring of 4, X ⁷ is H or CH ₃ , and R is a straight or branched alkyl group of 1 to 6 carbon atoms, an aryl or arylalkyl group of 6 to 9 carbon atoms) to be.

Such compounds are disclosed in US Pat. No. 5,424,303, which is incorporated herein by reference.

Preferred compositions are aminophosphonates of formula II.

Another class of Lp (a) inhibitors is diazoaniline derivatives, which are compounds of Formula III.

Where

R ¹ and R ² are independently hydrogen or straight or branched C ₁ -C ₆ alkyl, or together with the nitrogen to which they are attached 5 to 7 membered optionally substituted with C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy Complete the loop,

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 alkyl amino or cyano ego,

Ar is carboxyl, C ₁ -C ₆ alkoxycarbonyl, cyano, CONH ₂ , SO ₂ NH ₂ , C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, hydroxy, halo, nitro, amino, C ₁ Phenyl optionally substituted with -C ₆ alkyl or di-C ₁ -C ₆ alkylamino, or C ₁ -C ₆ arylamino.

The composition is preferably

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-dimethylamino) phenyl) azo] -benzamide, and

Compounds of formula III such as 4-[(4- (N, N-dimethylamino) phenyl) azo] -benzsulfonamide.

All such phenylazo compounds are described in US Pat. Nos. 4,397,944 and 3,978,201 and WO 97/26890, which are incorporated herein by reference.

Conventional statins used in combination with compounds of formula (I) include atorvastatin, simvastatin, pravastatin, cerivastatin, merivastatin, mevastatin, velostatin, fluvastatin ( fluvastatin), lovastatin, dalvastatin and fludodostatin. Statins can be used, for example, as pharmaceutically acceptable salts of statins such as atorvastatin calcium.

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

The present invention also provides a method of treating cardiovascular diseases such as peripheral vascular disease, coronary heart disease, seizures and restenosis. The present invention provides a method for lowering Lp (a), plasma triglycerides, ultralow density lipoprotein (VLDL) cholesterol, LDL cholesterol and apolipoprotein B. The present invention further provides methods for increasing plasma HDL cholesterol, apolipoprotein A-I and apolipoprotein E. The present invention also provides a method of treating and preventing insulin independent diabetes mellitus by administering the inventive combination to increase insulin sensitivity.

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 lipoproteins (a) and Lp (a) that are modified by LDL but not affected by statins. It relates to a combination formulation. This combination preparation is useful for the treatment of vascular diseases and diabetes mellitus.

The inventors have found that a combination formulation of statins and Lp (a) inhibitors surprisingly provides compositions effective for the treatment and prevention of vascular diseases as well as diabetes mellitus. Lp (a) inhibitors are any compounds that are effective in lowering Lp (a) in a mammal. As described above, Lp (a) inhibitors used herein are compounds such as those described in US Pat. Nos. 5,489,611 and 5,424,303, which are incorporated herein by reference. The compound may be in free acid or salt form.

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

Suitable HMG-CoA reductase inhibitors for use herein include simvastatin, pravastatin, rivastatin, mevastatin, florinstatin, cerivastatin, velostatin, fluvastatin, dalvastatin, dihydrocomptin, compectin or lovastatin Or pharmaceutically acceptable salts of simvastatin, pravastatin, rivastatin, cerivastatin, mevastatin, fluindostatin, belosstatin, fluvastatin, dalvastatin, dihydrocomptin, compectin or lovastatin, but are not limited thereto It doesn't happen. However, atorvastatin calcium is a particularly preferred statin for use in this combination formulation. See US Pat. No. 5,273,995, which is incorporated herein by reference.

Statins disclosed herein are prepared by methods well known to those skilled in the art. In particular, simvastatin may be prepared according to the methods disclosed in US Pat. No. 4,444,784, which is incorporated herein by reference. Pravastatin can be prepared according to the methods disclosed in US Pat. No. 4,346,227, which is incorporated herein by reference. Cerivastatin may be prepared according to the methods disclosed in US Pat. No. 5,502,199, which is incorporated herein by reference. Alternatively cerivastatin can be prepared according to the method disclosed in European Patent Application Publication No. EP617019. Mevastatin can be prepared according to the methods disclosed in US Pat. No. 3,983,140, which is incorporated herein by reference. Belostatin can be prepared according to the methods disclosed in US Pat. Nos. 4,448,784 and 4,450,171, which are incorporated herein by reference. Fluvastatin can be prepared according to the methods disclosed in US Pat. No. 4,739,073, which is incorporated herein by reference. Compactin may be prepared according to the method disclosed in US Pat. No. 4,804,770, which is incorporated herein by reference. Lovastatin can be prepared according to the methods disclosed in US Pat. No. 4,231,938, which is incorporated herein by reference. Dalvastatin may be prepared according to the method disclosed in European Patent Application Publication No. 738510 A2. Fluindostatin can be prepared according to the method disclosed in European Patent Application Publication No. 363934 A1. Dihydrocomptin can be prepared according to the methods disclosed in US Pat. No. 4,450,171, which is incorporated herein by reference.

It will be appreciated that any of the statins include free carboxylic acid or free amine groups as part of the chemical structure. In addition, certain statins within the scope of the present invention include lactone residues that are in equilibrium with the free carboxylic acid form. Such lactones can be maintained as carboxylate salts by preparing pharmaceutically acceptable salts of lactones. As such, the present invention includes pharmaceutically acceptable salts of carboxylic acid or amine groups. The expression “pharmaceutically acceptable salts” includes both pharmaceutically acceptable acid addition salts and pharmaceutically acceptable cationic salts. The expression “pharmaceutically acceptable cationic salts” refers to alkali metal salts (eg sodium and potassium), alkaline earth metal salts (eg calcium and magnesium), aluminum salts, ammonium salts, and benzatin (N, N′-dibenzylethylenediamine ), Choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), benetamine (N-benzylphenethylamine), diethylamine, piperazine, tromethamine (2-amino-2- Hydroxymethyl-1,3-propanediol) and salts with organic amines such as procaine, but are not limited thereto. The expression "pharmaceutically acceptable acid addition salt" includes hydrochloride, hydrobromide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, dihydrogen phosphate, acetate, succinate, citrate, methanesulfonate (mesylate) and It is defined as a p-toluenesulfonate (tosylate) salt, but is not limited thereto.

Pharmaceutically acceptable cation salts of statins, including free carboxylic acids, can be readily prepared by reacting the free acid form of the statins with a suitable base, usually 1 equivalent, in a cosolvent. Typical bases are sodium hydroxide, sodium methoxide, sodium ethoxide, sodium hydride, potassium methoxide, magnesium hydroxide, calcium hydroxide, benzatin, choline, diethanolamine, piperazine and tromethamine to be. Salts are isolated by concentration to dryness or by addition of nonsolvents. In many cases, the salt is preferably a solution of the salt of the various cations (sodium ethylhexanoate, potassium ethylhexanoate, magnesium oleate) using a solvent (e.g. ethyl acetate) on which the desired cation salt is precipitated. Can be prepared by mixing with, or concentrated and / or isolated by addition of a nonsolvent.

Pharmaceutically acceptable acid addition salts of statins containing free amine groups can be readily prepared by reacting the free base form of the statins with an appropriate acid. The salt is a salt of monobasic acid (e.g. hydrochloride, hydrobromide, p-toluenesulfonate, acetate), a salt in the hydrogen form of dibasic acid (e.g. hydrogen sulphate, succinate), or dihydrogen of tribasic acid In the case of salts in the form (eg dihydrogen phosphate, citrate), at least 1 molar equivalent of acid is usually used in excess moles. However, when salts such as sulphate, hemisuccinic acid, hydrogen phosphate or phosphate are desired, it will be common to use the acid in an appropriate and accurate chemical equivalent. The free base and acid can usually be isolated by combining in a cosolvent in which the desired salt will precipitate, or by concentrating and / or adding a nonsolvent.

In addition, the statins of the present invention and their pharmaceutically acceptable salts can be prepared as hydrates or solvates. Such hydrates and solvates are also within the scope of the present invention. The same is true for Lp (a) inhibitors such as retinoids.

The combination formulations and methods of the present invention are suitable for therapeutic use as agents for the prophylaxis and treatment of atherosclerosis, angina pectoris, and symptoms characterized by both hypertension and hyperlipidemia in mammals, especially humans. In addition, since these diseases and symptoms are closely related to the development of heart disease and adverse symptoms of the heart, the development of harmful symptoms of the heart by their action as a drug for treating atherosclerosis, angina, hypertension and hyperlipidemia It is useful for controlling the risk of heart disease in at-risk individuals and in individuals suffering from adverse symptoms of the heart.

The utility of the compositions of the present invention as therapeutic agents for atherosclerosis in mammals (eg, humans) is demonstrated through the efficacy of the compounds of the present invention in conventional assays and clinical protocols.

When Lp (a) Inhibitor and Statins Are Administered and Co-administered

Atherosclerosis Treatment Effect

This study is a planned randomized assessment of the combined effect of 9-cis-retinoic acid or its pharmaceutically acceptable salts and statins on the progression / regression of coronary artery disease and carotid artery disease. This study demonstrates that a combination of 9-cis-retinoic acid or its pharmaceutically acceptable acid addition salts and statins can slow, stop, or reverse the progression of existing coronary artery disease (CAD) in a diseased subject. This effect is demonstrated by changes in the results of coronary angiography or carotid ultrasonography.

This study is an angiographic study of coronary artery disease performed in at least about 500, preferably from about 780 to about 1200, double placebo-controlled trials. It is particularly desirable to conduct this study for about 1200 people. Subjects who meet the specific acceptance criteria described below are used in the study.

Acceptance Criteria: Subjects under this test must meet certain criteria. For example, the subject should be an adult male or female aged 18 to 80 years who is clinically in need of coronary angiography. Subjects will later assess quantitative coronary angiography (QCA) for at least one portion (vascular without angioplasty, no bypass, or myocardial infarction) that will not require intervention for the next three years. When done, significant lesion areas of 30% to 50% should be observed on the angiogram. The part performing the analysis must not have been damaged. Because percutaneous transvascular angiogenesis (PTCA) damages parts by balloon catheterization, parts that have not undergone PTCA procedures are required for analysis. The part to be analyzed should also not have had a thrombosis such as myocardial infarction (MI). Thus, blood vessels without myocardial infarction are needed. Areas of examination include the left main artery, proximal, medial and distal anterior descending arteries, first and second diagonal bifurcation arteries, proximal and distal convolutional arteries, first or longest gluteal artery, proximal, median and distal right coronary There is an artery. Subjects underwent catheterization, radionuclide ventricular angiography, or ECHO heartbeat curves within three months prior to receiving an angiogram or upon receiving an angiogram under the premise of injury such as thrombosis or no procedure such as PTCA. The ejection rate should be greater than 30%.

In general, studies were conducted at several sites due to the number of patients and the physical limitations of any one facility. When entering the study, subjects perform quantitative coronary angiography as well as B-mode carotid ultrasonography and carotid artery compliance assessment at designated test centers. This establishes a baseline for each subject. Once in the trial, subjects were randomly challenged with 9-cis-retinoic acid (200 mg) and placebo, or statins (dosage was determined based on the particular statin used, but usually 80 mg was initially used) and Placebo, or 9-cis-retinoic acid (200 mg) and statins (80 mg) are administered. Those skilled in the art will appreciate that the free base form or other salt form of 9-cis-retinoic acid or the free base form or other salt form of statins may be used in the present invention. Dosages of these other forms of statins and 9-cis-retinoic acid are readily calculated by obtaining a simple ratio to the molecular weight of the compounds involved. The amount of 9-cis-retinoic acid may vary from case to case. In general, begin with a 200 mg dose to the subject, and this dosage will be titrated in small doses of about 50 mg, as determined by the clinician. If the use of statins is determined by a physician who is very interested in this subject, it may be similarly titrated to 80 mg. It is desirable to monitor the subject for one to three years, typically three years. During the study, B-mode carotid ultrasonography and purity testing of atherosclerosis are performed at regular intervals.

Generally, six month intervals are appropriate. Typically the examination is performed using a B-mode ultrasound machine. However, one skilled in the art can use other methods to perform this test. Coronary angiography is performed after the end of the treatment period of 1 to 3 years. The progression of new or existing atherosclerotic lesions is examined by baseline and post-treatment angiography and injured carotid B-mode ultrasonography. Arterial purity is measured through changes from baseline over the six month examination period.

The primary purpose of this study was to assess the progression of atherosclerosis in patients with clinical coronary artery disease, as measured by quantitative coronary angiography (QCA), in combination with Lp (a) inhibitors or pharmaceutically acceptable acid addition salts and statins. To show that it decreases. The luminal inlet of the measured artery was measured by QCA.

The primary endpoint of this study is the change in the mean diameter of a portion of the coronary artery. Thus, the diameter of an artery portion is measured at several sites along the length of the portion. Next, the average diameter of this part is calculated | required. After measuring the average diameter of the various parts, the average value of all the parts was averaged to obtain an average average part diameter. The average partial diameter of the subject administered statin and 9-cis-retinoic acid or a pharmaceutically acceptable acid addition salt will decrease, stop or increase more gently. These results indicate that the progression of atherosclerosis was slowed down, the progression of atherosclerosis was not changed, or atherosclerosis was reversed.

A secondary objective of this study was to determine the slope (maximum mean) of the maximum endovascular-mean thickness measurements, averaged over 12 different vessel parts as a function of time, to obtain 9-cis-retinoic acid or a pharmaceutically acceptable It is shown that the combination of Lp (a) inhibitors or pharmaceutically acceptable acid addition salts and statins slows the progression of atherosclerosis in the carotid artery compared to the use of acid addition salts or statins alone. The endovascular-average thickness of the subject administered statins and 9-cis-retinoic acid or a pharmaceutically acceptable acid addition salt thereof will increase, stop or decrease more slowly. These results indicate that the progression of atherosclerosis has slowed, the progression of atherosclerosis has stopped, or the atherosclerosis has reversed, respectively. These results can also be used to aid in dosage determination.

The utility of the compounds of the invention as drugs for the treatment of angina in mammals (eg, humans) is demonstrated through the efficacy of the compounds of the invention by conventional assays and the clinical tests described below.

When 9-cis-retinoic acid and statin are administered alone or in combination

Angena healing effect

This study is a double-blind, parallel, randomized study to demonstrate the angular or therapeutic effect of 9-cis-retinoic acid or its pharmaceutically acceptable acid addition salts and statin combinations.

Acceptance criteria: Subjects should be (1) elevated by more than about 1 millimeter in the stress test area as confirmed by ECG, (2) positive results of the treadmill stress test, (3) new vascular wall motility abnormality during ultrasound examination, or (4) A male or female aged 18 to 80 years with a history of typical chest pain with objective evidence of cardiac ischemia such as one of the coronary angiograms showing significant stenosis identified. In general, a stenosis of about 30% to 50% is considered significant.

Each subject is examined for about 10 to 32 weeks. Generally, more than 10 weeks are required to complete the study. Sufficient subjects are selected to study about 200 to 800, preferably about 400. Subjects meeting the acceptance conditions described below were selected and performed as follows consecutively for 4 weeks. After screening subjects that meet the acceptance criteria, wash-out conventional angiers or treatments, and long-term active nitrates such as nitroglycerin, isosorbide-5-monitrate, or isosorbide dinitrate Stabilize. The term "drug removal" as used in this test refers to the removal of the therapeutic agent such that all angina or therapeutic agent is substantially removed from the subject's body. The drug is removed for a period of eight weeks, and subjects are stabilized upon stable administration of the nitrate. While long-term active nitrates are being stably administered, the drug removal step may generally be skipped for those subjects who have had anger or seizures once or twice per week. After the subject has been stabilized with nitrates, the randomization phase is initiated for subjects that continue to have seizures or seizures once or twice per week. In the randomization step, subjects are randomly placed in one of four methods of the study described below. After the end of the drug elimination phase, subjects who meet the acceptance criteria are measured for 24-hour mobility ECG, such as Holter monitoring, performing stress tests such as treadmills, and using positron injection tomography (PET) injection. Myocardial perfusion is examined to establish a baseline for each subject. When performing the stress test, the speed of the treadmill and the slope of the treadmill can be adjusted by the skilled person. In general, the speed of the treadmill and the angle of inclination increase during the test. In general, the time interval between angular velocity and slope increase is measured using the Bruce protocol variant.

After baseline investigation, subjects were administered either (1) placebo, (2) statins (about 2.5 mg about 160 mg), (3) 9-cis-retinoic acid (about 25 mg about 200 mg) or (4) the administration Start with one of four methods of administering a combination formulation of an amount of 9-cis-retinoic acid and statin. The subject is then monitored for 2 to 24 weeks. Those skilled in the art will appreciate that the free base form or other salt form of 9-cis-retinoic acid or the free base form or other salt form of statins may be used in the present invention. Dosages of these other forms of statins and 9-cis-retinoic acid are readily calculated by obtaining a simple ratio to the molecular weight of the compounds involved.

At the end of the monitoring period, the subject was subjected to (1) 24-hour mobility ECG such as Holter monitoring, (2) stress testing (e.g., treadmill using the Bruce method) and (3) myocardial perfusion using PET scanning. Carry out an evaluation. Patients record painful ischemia events and nitroglycerin consumption daily. In general, it is desirable to accurately record the number of patients' seizures or seizures during the duration of the trial. Since patients typically take nitroglycerin to relieve anxiety or seizures, the number of times a patient has administered nitroglycerin provides an accurate record of angina or seizures.

In order to determine the effects and dosages of the drug combinations of the invention, the test subjects are evaluated for subjects performing the described tests. Successful treatment results in less ischemia as a result of ECG testing, subjects can exercise for longer periods of time or higher intensity on the treadmill, or exercise painlessly on the treadmill, or on PET testing Perfusion will be better or there will be fewer perfusion defects.

The utility of the compounds of the present invention as therapeutic agents for hypertension and hyperlipidemia in mammals (e.g. humans) suffering from the complications of hypertension and hyperlipidemia has shown the efficacy of the compounds of the invention in conventional assays and the clinical protocols described below. Is proven.

When Lp (a) Inhibitor and Statins Are Administered and Co-administered

Therapeutic Effect on Subjects with Both Hypertension and Hyperlipidemia

This study has shown the effects of inhibiting both hypertension and hyperlipidemia in combination with Lp (a) inhibitors or pharmaceutically acceptable acid addition salts and statins in subjects with mild, moderate and severe hypertension and hyperlipidemia. This is a double-blind parallel randomized study to show.

All subjects are evaluated for 10-20 weeks, preferably 14 weeks. Sufficient subjects will be used for screening to examine approximately 400 to 800 individuals and complete the study.

Acceptance Criteria: The subject is an adult male or female aged 18 to 80 years with both hyperlipidemia and hypertension. Hyperlipidemia is checked by examining the subject's LDL cholesterol level relative to a specific positive risk factor. If the subject does not have coronary heart disease (CHD) and the risk factor is less than two, the subject is considered hyperlipidemic and requires medication if the subject's LDL level is greater than 190 mg / dL. If the subject does not have CHD and there are two or more risk factors, the subject is considered hyperlipidemic and requires drug treatment if the LDL level is greater than 160 mg / dL. If the subject has CHD and the LDL level is greater than 160 mg / dL, the subject is considered to have hyperlipidemia.

Positive risk factors include (1) men over 45 years of age, (2) women over 55 years of age not receiving hormone replacement therapy (HRT), (3) families with a history of premature cardiovascular disease, and (4) subjects who are currently smokers. , (5) subjects with diabetes, (6) HDL levels below 45 mg / dL, and (7) subjects with hypertension. HDL levels above 60 mg / dL are considered negative risks and counteract one of the positive risk factors mentioned above.

Cardiac diastolic blood pressure (BP) greater than 90 mmHg or cardiac contractile BP greater than 140 mmHg is evidence of hypertension. All blood pressures are usually averaged over three measurements taken at five minute intervals.

Subjects who meet the acceptance criteria described above are selected. After all screening acceptance criteria have been met, the antihypertensive and lipid lowering agents being dosed from the subject are desubstituted and subjected to the NCEP ATP II Phase 1 diet. NCEP ATP II (adult treatment panel, 2nd edition) Step 1 The diet determines the amount of saturated and unsaturated fats that can be consumed as part of the total absorbed calories. The term "drug removal" as used in this screening test means the removal of all the therapeutic drugs from the subject's body by the removal of the antihypertensive agent and the lipid lowering agent. In general, newly diagnosed subjects are left untreated until the start of the study. These subjects also receive an NECP stage 1 diet. After 4 weeks of drug elimination and dietary stabilization, the subjects are baselined such as (1) blood pressure and (2) fasting lipid testing. Lipid examination at fasting establishes baseline lipid levels in the fasting state of the subject. In general, when measuring lipid levels, the subject is fasted for 12 hours.

After performing a baseline irradiation, (1) a fixed amount, generally about 25 mg to 200 mg of 9-cis-retinoic acid, (2) a fixed amount, generally about 2.5 mg to about 160 mg statin, or (3 ) One of the combination of 9-cis-retinoic acid and statin at the above dose is initiated for the subject. Those skilled in the art will appreciate that the free base form or other salt form of 9-cis-retinoic acid or the free base form or other salt form of statins may be used in the present invention. Dosages of these other forms of statins and 9-cis-retinoic acid are readily calculated by obtaining a simple ratio to the molecular weight of the compounds involved. They are administered to the subject for a minimum of six weeks and generally for a period of up to eight weeks. After six to eight weeks, the subjects are sent to the test center and the baseline evaluation is repeated. The blood pressure of the subject at the end of the study is compared with the blood pressure at the start of the study. Lipid tests are performed to determine the total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides, apoB, ultra low density lipoprotein (VLDL), and other components of the lipid profile of the subject. The improvement of the value obtained after treatment relative to the value before treatment is indicative of the utility of the combination drug.

The utility of the compounds of the present invention as therapeutics for the treatment of heart disease in mammals (eg, humans) is demonstrated through routine assays and the efficacy of the compounds of the present invention in the clinical protocols described below.

To subjects at risk for cardiovascular disease

Effect of Lp (a) Inhibitors and Statins on Single or Concomitant Administration

This study demonstrates the combined use of an Lp (a) inhibitor or its pharmaceutically acceptable acid addition salts and statins to reduce the estimated total future risk of subjects at risk of developing cardiovascular disease in the future. It is a double blind parallel study. These risks were calculated using the Framingham risk calculation. If the subject has a standard deviation value of at least 1 higher than the mean obtained from the Framingham Risk Calculation, the subject is considered at risk for future cardiovascular disease. Cardiovascular disease by using this study to inhibit hypertension and hyperlipidemia in patients with mild or moderate hypertension and hyperlipidemia by a fixed amount combination of Lp (a) inhibitor or its pharmaceutically acceptable acid addition salt and statins Evaluate its effect on suppressing it.

All subjects are examined for 10-20 weeks, preferably 14 weeks. About 400 to 800 people will be examined and enough subjects will be recruited to complete the study.

Acceptance Criteria: Subjects are 18-80-year-old adult males or females with a 5-year risk baseline, and this risk demonstrates that the Framingham Heart Study (a specific risk factor can be used to predict the development of coronary heart disease). Risk factors that exceed the mean value for the age and sex of the subject. Determining whether a patient is at risk for harmful heart disease, including age, sex, cardiac and diastolic blood pressure, smoking habits, carbohydrate intolerance, left ventricular hypertrophy, serum cholesterol And both HDL values.

Subjects who met the acceptance conditions described above were selected. After all screening acceptance criteria are met, the antihypertensive and lipid lowering agents being dosed from the subject are desubstituted and subjected to the NCEP ATP II stage 1 diet as described above. In general, newly diagnosed subjects remained untreated until the start of the study. These subjects also receive a NCEP ATP II Phase 1 diet. After the 4-week drug elimination and dietary stabilization period, the subject was subjected to (1) blood pressure measurements, (2) fasting, (3) lipid testing, (4) glucose tolerance tests, (5) ECG and (6) cardiovascular ultrasound Set the same baseline. Such testing is performed using standard methods known to those skilled in the art. ECG and cardiovascular ultrasound have generally been used to determine the presence of left ventricular hypertrophy.

After performing a baseline irradiation, (1) a fixed amount, generally about 25 mg to 200 mg of 9-cis-retinoic acid, (2) a fixed amount, generally about 2.5 mg to about 160 mg statin, or (3 ) One of the combination of 9-cis-retinoic acid and statin at the above dose is initiated for the subject. The patient is kept at this dose and the subject is returned after 6-8 weeks to repeat the baseline assessment. At this time, the new value is substituted into the Framingham risk calculation to determine whether the risk of causing cardiovascular disease in the subject is reduced, increased or not changed.

In addition, the above assays demonstrating the effects of retinoid or its pharmaceutically acceptable acid addition salts and atorvastatin or its pharmaceutically acceptable salts in the management of both angina, atherosclerosis, hypertension and hyperlipidemia and heart risk are compounds of the invention It provides a method that can compare the efficacy of each other and with other known compounds. Such comparative results are useful for determining dosages in mammals, including humans, in the treatment of such diseases.

The following dosages and other dosages set forth herein and in the appended claims are for the average human subject being about 65 kg to about 70 kg in weight. The skilled person will readily be able to determine the dosage for a subject with a weight outside the range of 65 kg to 70 kg based on the subject's medical history and the presence of a disease such as diabetes. All dosages set forth herein and in the appended claims are daily dosages.

Generally, Lp (a) inhibitors belonging to the present invention are generally administered at a dosage of about 25 mg to about 500 mg. Preferably, 9-cis-retinoic acid is generally administered at a dosage of about 5 mg to about 100 mg. Those skilled in the art will appreciate that the free base form or other salt form of 9-cis-retinoic acid can be used in the present invention. Dosages in the free base form or other salt form of these other forms of Lp (a) inhibitors are readily calculated by obtaining simple molar ratios to the molecular weights of the compounds involved.

In general, the statin in the present invention,

For simvastatin generally about 2.5 mg to about 160 mg, preferably about 10 mg to about 40 mg,

For pravastatin generally about 2.5 mg to about 160 mg, preferably about 10 mg to about 40 mg,

For cerivastatin generally from about 25 μg to about 5 mg, preferably from about 1 mg to about 3.2 mg,

For fluvastatin generally about 2.5 mg to about 160 mg, preferably about 20 mg to about 80 mg,

For lovastatin generally about 2.5 mg to about 160 mg, preferably about 10 mg to about 80 mg and

For atorvastatin it is generally from about 2.5 mg to about 160 mg, preferably from about 10 mg to about 80 mg

It is administered at the dosage of.

Those skilled in the art will appreciate that the free base form or other salt forms of the statins may also be used in the present invention. Doses of the free base form or other salt form of such other forms of statins are readily calculated by obtaining a simple molar ratio with respect to the molecular weight of the compounds involved.

Generally, a compound of the present invention is administered in a drug form comprising at least one compound of the present invention together with a pharmaceutically acceptable carrier or diluent. Accordingly, the compounds of the present invention may be administered separately or together in any conventional oral, parenteral or transdermal dosage form.

For oral administration, the pharmaceutical compositions may be administered in the form of solutions, suspensions, tablets, pills, capsules, powders and the like. Tablets comprising a variety of excipients such as sodium citrate, calcium carbonate and calcium phosphate may contain starch, preferably tablet disintegrants such as potato starch or tapioca starch and certain complex silicates with polyvinylpyrrolidone, sucrose, gelatin and acacia. Used with the same binder. In addition, lubricants such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for purification. Solid compositions of a similar type may also be used as fillers in soft and hard gelatin filled capsules, with preferred materials in this regard as well as lactose or lactose, as well as high molecular weight polyethylene glycols. When aqueous suspensions and / or elixirs are used for oral administration, the compounds of the present invention may be used in various sweetening, flavoring, coloring, emulsifying and / or suspending agents, as well as water, ethanol, propylene glycol, Diluents such as glycerin and various combinations thereof.

In addition, the combination formulation of the present invention may be administered in a pre-shrinkage controlled formulation such as a sustained release formulation or a fast-acting formulation. Such controlled release formulations of the combination formulations of the invention may be prepared by methods known to those skilled in the art. The method of administration will be determined by examining the symptoms and requirements of the subject by a physician or other skilled person in the art. A generally preferred formulation of atorvastatin calcium is Lipitor® described in US Pat. No. 5,686,104, which is incorporated herein by reference.

For parenteral administration, solutions in sesame oil or peanut oil or solutions of aqueous propylene glycol alcohols, as well as sterile aqueous solutions of the corresponding water-soluble salts can be used. Such an aqueous solution may be suitably buffered as the case may be, or may be a liquid diluent made of a cotton bottom isotonic solution with sufficient saline or glucose. Such receptors are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal injection. In this regard, the sterile aqueous media used are all readily obtained by standard techniques known to those skilled in the art.

Methods for preparing various pharmaceutical compositions comprising a predetermined amount of active ingredient are known or will be apparent to those skilled in the art in view of the disclosure. See, eg, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easter, Pennsylvania., 15th Edition (1975).

Pharmaceutical compositions according to the invention comprise from 0.1% to 95%, preferably from 1% to 70% of a compound of the invention. In either case, the composition or formulation to be administered will comprise a compound according to the invention in an amount effective to treat a symptom or disease of the subject being treated.

The present invention relates to the treatment of diseases and conditions by using a combination of active ingredients which may be administered separately, and therefore also relates to combining the individual pharmaceutical compositions in kit form. Such kits include two separate pharmaceutical compositions, Lp (a) inhibitors or pharmaceutically acceptable acid addition salts thereof and statins or pharmaceutically acceptable salts thereof. The kit includes individual composition-containing containers, such as split bottles or split foil packets, but may be a single container that does not divide individual compositions. Typically, kits include dosage instructions for the individual ingredients to achieve a synergistic effect. The kit form is particularly advantageous when the individual components are preferably administered in different dosage forms (eg oral and parenteral), at different dosage intervals, or when the prescribing physician desires titration of each component of the combination formulation.

It is to be understood that the invention is not limited to the specific embodiments described herein, but that various changes and modifications can be made without departing from the spirit and scope of the new invention as defined in the following claims.

Claims (28)

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. Pharmaceutically acceptable carriers or diluents Pharmaceutical composition comprising a. The method according to claim 1, wherein the statin is atorvastatin, simvastatin, pravastatin, rivastatin, mevastatin, fluindostatin, velostatin, fluvastatin, dalvastatin, dehydrocomptin, compactin, cerivastatin or lovastatin, or Pharmaceutical compositions which are pharmaceutically acceptable salts thereof. The pharmaceutical composition of claim 2, wherein the statin is atorvastatin, simvastatin, pravastatin, mevastatin, lovastatin, cerivastatin, or a pharmaceutically acceptable salt thereof. The pharmaceutical composition of claim 3, wherein the Lp (a) inhibitor is a retinoid. The pharmaceutical composition of claim 4 comprising atorvastatin calcium and 9-cis-retinoic acid. Exhibiting an effect greater than the sum of the hypolipidemic effects achieved by administering the first and second pharmaceutical compositions separately, wherein the second pharmaceutical composition comprises a predetermined amount of Lp (a) inhibitor or a pharmaceutically acceptable acid addition salt and pharmaceutical thereof A phase acceptable carrier or diluent, wherein the first pharmaceutical composition comprises a predetermined amount of statin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent, provided that the statin is atorvastatin or pharmaceutically acceptable A first pharmaceutical composition for use with a second pharmaceutical composition to achieve a hypolipidemic effect in a mammal suffering from hyperlipidemia but not a salt. The method according to claim 6, wherein the statin is atorvastatin, simvastatin, pravastatin, rivastatin, mevastatin, fluindostatin, velostatin, fluvastatin, dalvastatin, dehydrocomptin, compectin, cerivastatin or lovastatin, or A composition which is a pharmaceutically acceptable salt of simvastatin, pravastatin, rivastatin, mevastatin, fludostatin, velostatin, fluvastatin, dalvastatin, dihydrocomptin, compectin, cerivastatin or lovastatin. 8. The composition of claim 7, wherein said second pharmaceutical composition comprises a retinoid. Exhibits a greater than sum of hypolipidemic effect achieved by separately administering the first and second pharmaceutical compositions, the second pharmaceutical composition comprising a predetermined amount of statin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent Wherein the first pharmaceutical composition comprises a predetermined amount of 9-cis-retinoic acid, the first pharmaceutical used with the second pharmaceutical composition to achieve a hypolipidemic effect in a mammal suffering from hyperlipidemia Composition. The method according to claim 9, wherein the statin is atorvastatin, simvastatin, pravastatin, rivastatin, mevastatin, fluindostatin, velostatin, fluvastatin, dalvastatin, dehydrocomptin, compactin, cerivastatin or lovastatin, or A composition which is a pharmaceutically acceptable salt thereof. The composition of claim 10 comprising 9-cis-retinoic acid. Has a greater effect than the sum of the cardiac risk treatment effects achieved by separately administering the first and second pharmaceutical compositions, the second pharmaceutical composition comprising a predetermined amount of statin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or Wherein the first pharmaceutical composition comprises a predetermined amount of an Lp (a) inhibitor or a pharmaceutically acceptable acid addition salt and a pharmaceutically acceptable carrier or diluent, and is at risk of suffering from adverse symptoms of the heart First pharmaceutical composition for use with a second pharmaceutical composition to treat cardiac risk in a mammal. The method according to claim 12, wherein the statin is atorvastatin, simvastatin, pravastatin, rivastatin, mevastatin, fluindostatin, velostatin, fluvastatin, dalvastatin, dehydrocomptin, compectin, cerivastatin or lovastatin, or A composition which is a pharmaceutically acceptable salt of simvastatin, pravastatin, rivastatin, mevastatin, fluinstatin, velostatin, fluvastatin, dalvastatin, dihydrocomptin, compectin or lovastatin. The composition of claim 13 comprising a retinoid. 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 for containing the first and second dosage forms A kit for achieving a therapeutic effect in a mammal, wherein the statin is not atorvastin or a pharmaceutically acceptable salt thereof. The method according to claim 15, wherein the statin is atorvastatin, simvastatin, pravastatin, rivastatin, mevastatin, fluindostatin, velostatin, fluvastatin, dalvastatin, dehydrocomptin, compectin, cerivastatin or lovastatin, or A kit that is a pharmaceutically acceptable salt of simvastatin, pravastatin, rivastatin, mevastatin, fludostatin, velostatin, fluvastatin, dalvastatin, dihydrocomptin, compactin, cerivastatin or lovastatin. The kit of claim 16 comprising a retinoid. 18. The kit of claim 17, wherein 9-cis-retinoic acid is used. The kit of claim 15, wherein said therapeutic effect is a treatment of hyperlipidemia. The kit of claim 15 wherein said therapeutic effect is a treatment of angina. The kit of claim 15, wherein said therapeutic effect is a treatment of heart risk. The kit of claim 15 wherein said therapeutic effect is a treatment of atherosclerosis. The kit of claim 22, wherein the treatment of atherosclerosis slows the progression of atherosclerosis. 24. The kit of claim 23, wherein the atherosclerosis slows progression in the coronary artery. 24. The kit of claim 23, wherein the kit slows the progression of the atherosclerosis in the carotid artery. 24. The kit of claim 23, wherein said atherosclerosis slows progression in the peripheral arterial system. 23. The kit of claim 22, wherein said treating atherosclerosis reverses atherosclerosis. The kit of claim 27, wherein the retrograde of the atherosclerosis occurs in the coronary artery.