JPH07501551A - Methods and compositions for treating hypertension, angina and other diseases using optically pure S(-)felodipine - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Hypertension, angina and other diseases using optically pure 5(-) felodipine METHODS AND COMPOSITIONS FOR TREATMENT 1, BACKGROUND OF THE INVENTION The present invention contains optically pure 5(-) felodipine. A novel composition comprising: These compositions reduce systolic and diastolic hypertension. Highly active in the treatment of both, including limb edema, headache and glare (However, without limitation) It does not have any side effects. These side effects are It involves the administration of a racemic mixture of lodipine. In addition, optically active These novel compositions containing S<->felodipine can be used to treat angina pectoris and calcium chloride. Other factors that may be related to the activity of 5(-)felodipine as a channel antagonist symptoms (including cerebral ischemia, cerebral damage, arrhythmia, cardiac hypertrophy, coronary vasospasm, including but not limited to myocardial infarction, renal impairment and acute renal failure ) and the side effects associated with the administration of racemic mixtures of felodipine. I don't have it. In addition, by administering the S (-) isomer of felodipine to humans, , avoiding the side effects associated with racemic mixtures of felodibin and the above in humans. Also disclosed are methods for treating the symptoms of.

1.1. Steric relationships and drug effects Many organic compounds exist in optically active forms. That is, these compounds has the ability to rotate the plane of plane-polarized light. optically active compounds When writing, use the prefix and ri or R and S to write shows the absolute configuration of the molecule with respect to the center. The prefix d and soil, or (+) or and (=) to indicate the direction of rotation of plane-polarized light by that compound. (−) or above means the compound is levorotatory. There is. Compounds with the prefix (+) or Wataru are dextrorotatory. some chemistry In terms of structure, compounds called stereoisomers are molecules that are other than mirror images of each other. are the same. Certain stereoisomers are sometimes referred to as enantiomers; A mixture of such isomers is often called a chiral or racemic mixture .

12 of the 20 most commonly prescribed drugs exhibit chirality. Stereochemical purity is important in the pharmaceutical field. A suitable example is L-shape Propranolol, a β-adrenergic blocker, is mentioned; - It is known to be 100 times more potent than the enantiomer.

Additionally, certain isomers may be harmful rather than simply inert. In practice, optical purity is important. For example, thalidomide D-enane Thiomers are safe and have been shown to have sedative effects when prescribed to control morning sickness during pregnancy. It has been suggested that the corresponding L-enantiomer is a strong teratogen. It is considered.

The active compound of the present compositions and methods is one of the optical isomers of the felodipine compound. However, this is described in BerntSSOn et al., U.S. Pat. No. 4,264,611. It is listed. Chemically, this 5(-) isomer is ethylmethyl 4-(2,3 -dichlorophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridi -dicarboxylate. This isomer is hereinafter referred to as 5(-)phelogibin. I decided to. 5(-) felodipine is optically pure and substantially optical Contains pure 5(-) felodipine isomer.

Phelodibin, which is the subject of the present invention, is commercially available only as a racemic mixture with ■ = 1 It has not been. In other words, this compound has optical isomers called enantiomers. Available only as a 1:1 mixture of

■、2.　Pharmacological effects The racemic mixture of felodipine is a calcium antagonist or calcium channel Belongs to a class of compounds known as blockers. in the excitation-contraction process The concept of a specific mechanism of pharmacological action related to antagonism of calcium mobilization is As suggested by Fleckenstein et al. (Fleckenstein, A. ,,Calcium Antagonism in Heartand Smo oth Muscle: ll! experimental facts and TherapeuticProspects, New York, Wil ey, 1983; Swamy, V. and D. Triggle.

Modern Pharmacology, 2nd, Ed, Crai g and 5tize1. Eds.

Little, Brown and Co5. Boston, 1986.　 Chapter, 26.373-380; Triggle, D, J, and R, A, Janis, Ann, Rev, Pharm, and Tox .

27:347-369.1987). Currently available calcium channel blockers Calcium is mostly transmitted through voltage-gated channels in the plasma membrane of cells. This seems to counteract the influx of

The pharmacological class of calcium antagonists consists of three major compound types. That is, Phenylalkylamines (e.g. verapamil), benzothiazepines (e.g. basiltiazem), and l,4-dihydropyridines (e.g. nifedipine) It is. Given the structural heterogeneity of this class, its pharmacological action is uniform. More than one site or mechanism of action may be involved.

Nifedipine was the first commercially available 1,4-dihydropyridine, but it is an achiral (ac hirat) and therefore cannot exist in an optically active form. some Chiral ones have been made with second generation 1,4-dihydropyridines, R or Exists as S enantiomer [or (+) or (-) enantiomer] are doing. These include amlodipine, nisoldipine, nimodipine, nitrendipine Contains pin, isradipine, felodipine, nisoldipine and nilvazibine. Ru. The enantiomers of each of these compounds are known in vitro.

have very different biological activities both in vivo and in vivo. It is shown. Due to the fact that each enantiomer is pharmacologically distinct Nevertheless, all commercially available preparations of these compounds are racemic mixtures. Ru.

The enantiomers of felodipine have different pharmacokinetic and pharmacological properties. do. In a study, a racemic mixture of felodipine was administered orally to healthy human subjects. did. The R(+) isomer of felodipine has a 2.4 times higher clearance than the 5(=) isomer. balance, and the 5(-) isomer may exhibit a 2.1-fold higher maximum plasma concentration. Okay, so the terminal half-lives of the two enantiomers are equivalent. (Soons, P, A,, et al, J, Chromat,, 528:343-356.1990). This difference is due to 1,4-dihydropi Stereoselective oxidation of lysine to the corresponding pyridine metabolite is shown. This oxidation occurs in the liver and produces pharmacologically inactive pyridine (Edgar, B., et al.

, Biopharmaceutics & Prug Disposition n, 8: 235-248.1987; Baarnhielm, C, et al., Xenobiotica, 14: 719-726.1984. (see).

A study by Er1ksson et al. The pharmacokinetic parameters of the nanthiomers are similar, and the predisposition for felogibine is reported that it was not stereoselective [Ercksson, U. See G., Xenobiotica 21(1) + 75-84 (1991) ].

The 5(-) isomer of felodipine was found to be the R(+) isomer in in vitro studies. It was disclosed that the potency is stronger than that of the sex body. For each enantiomer, simulated mboxane-induced coronary vasoconstriction in the guinea pig Langenodorf heart. The ability to suppress was studied.

S(-) felodipine is 13 times more effective than R(+) felodipine This was confirmed by this in VitrO assay. Enantiomeric guinea pig skeleton We also investigated competitive binding to muscle.

Each isomer is radiolabeled isradipine, another 1,4-dihydropyridine. competed with for the binding site. 5(-)felodipine has It was found to be 12 times more effective than R(+) felodipine. spontaneous high As a result of a tnvitro study using blood pressure rats, S (-) felodipine lowered blood pressure. It was shown to be 13 times more effective in lowering al,, Chirality2: 233-240. (see 1990).

At present, the racemic mixture of felodipine is mainly used as an antihypertensive drug. It is generally administered orally. As mentioned above, the racemic mixture of felodipine When used as an antihypertensive drug, the compound dilates peripheral blood vessels, resulting in Lowers both systolic and diastolic blood pressure. This antihypertensive effect affects heart rate. Occurs even in conditions where there is a relative absence of significant or lasting effects.

Although still the subject of extensive research, hypertension is the product of a genetic predisposition. be. This also involves dietary, emotional, and environmental factors; Provides structural regulation of muscles and large blood vessels. In many patients, the sympathetic Although the vascular and cardiac responses to stimulation are increased, sympathetic stimulation and this disease The exact relationship with the etiology of the disease has not been shown. Despite this, hypertension is associated with cardiovascular Chronic readjustment of hemodynamics, vessel wall changes, cardiovascular resistance and local limbal wall bring pressure.

Pharmacological treatment of hypertension generally restores altered hemodynamic parameters to normal. Many drugs and drug classes can be used as monotherapy or in combination. Either can be used to lower and regulate elevated blood pressure. but , in response to treatment of hypertension, the morbidity and mortality of that condition necessarily decrease. Do not mean. This is because chronic hypertension is associated with other serious and irreversible cardiac problems. vascular changes or that current drugs may cause some other cardiovascular diseases. This is because it may have an adverse effect on the risk factors of Rather, current drug treatments It would be better to say that it simply maintains a decrease in arterial pressure.

In addition, racemic mixtures of felodipine may be useful in the treatment of other diseases, such as angina pectoris. One.

Angina pectoris is a highly variable and poorly understood clinical condition that reflects myocardial ischemia. This is a group of people. The function of the heart or the oxygen demand of the myocardium affects the oxygen supply capacity of the coronary vasculature. When exceeded, the resulting ischemia stimulates the sensory nerves of the heart, causing precordial compression and Pleasant sensations or intense, intense pressure that may spread to several areas, including the left shoulder and left arm. producing a sensation of angina characterized by episodes of crushing pain . Physical activity, or exertion, characteristically causes this symptom, and rest or drug treatment is The law will save it. The signs and symptoms of an episode last for 2-3 minutes and are It can be induced or intensified by exposure to cold weather or cold. treatment is directed to the underlying disease, usually atherosclerosis, or Drugs that reduce muscle oxygen demand or improve oxygen supply are directed. Hue Calcium channel blockers such as Lodivin are effective against calcium blockade on the smooth muscle of the heart and blood vessels. Due to channel antagonist action, angina of effo rt) has been particularly useful in the treatment of prevascular angina and unstable angina.

Racemic phelogibine may also be useful in treating cerebral ischemia. Cerebral ischemia is often The result of telosclerotic disease or hypertension, but may result from insufficient cerebral circulation. Ru. Under normal circumstances, extensive collateral circulation ensures sufficient blood flow. death However, cerebral ischemia can be caused by disruption of arterial blood flow within the brain or by blood flow outside the brain. It can happen. If the disruption is temporary, brain tissue will recover and neurological symptoms will disappear. Ru. If ischemia persists for a somewhat prolonged period, infarction occurs; The resulting neurological damage is permanent. Prolonged ischemia resulting in infarction In this case, treatment focuses on the underlying vascular disease, platelet aggregation inhibitors, and antiaggregation therapy. Directed.

Due to its activity as a calcium channel antagonist, racemic felodibin has a It may also be useful in treating visceral arrhythmias. Cardiac arrhythmias are caused by mechanical properties of the heart and vasculature. A wide range of complex diseases that affect and alter normal heart rhythm, function, and blood output. represents a group of electrophysiological disorders. Normal heart rhythm begins at the sinoatrial node. This node has a high degree of inherent automaticity. Sufficient automaticity and conduction activation of ventricular fibers and subsequent activation of the components of a normal functional heartbeat. Membrane electricity Conditions in which calcium-related changes in position and conduction alter normal rhythms Therefore, calcium channel blockers may be of value. Without treatment, symptoms may be isolated. This varies depending on each patient's arrhythmia, but often the amount of blood pumped to the heart and the is the result of insufficient blood being pumped through the body, often leading to fatigue and exercise resistance. including a decrease in symptoms, fainting, shortness of breath, nausea, dizziness, etc.

Racemic felodipine may be useful in the treatment of cardiac hypertrophy. called systolic overload diastolic overload. Cardiomegaly is caused by excessive workload, whether due to an excess amount of blood being provided to the dilated heart. It can happen from

Systolic overload causes atrial ventricular hypertrophy. There, without an increase in volume, , the walls of the heart become thicker. Diastolic overload causes dilation and hypertrophy with increased blood volume. cause. Blood beats due to heart failure due to systolic or diastolic overload Insufficient output results in fatigue, shortness of breath, lung congestion, edema, etc. mosquito Lucium channel antagonists cause stress and also calcium channel blockers cardiac and It may be useful in treating cardiac hypertrophy due to its blood pressure-lowering effect on vascular smooth muscle. cormorant.

Racemic felodipine can also be used to treat coronary artery disease. coronary artery The disease can occur even in the absence of significant coronary atherosclerosis. , is thought to be the initiating event of modified angina and myocardial infarction. The precoronal chapter is , may occur without causing any significant discomfort to the patient. electrically unstable In the heart, various types of nerve stimulation to the heart can induce coronary vasospasm. child This results in enhanced myocardial ischemia and arrhythmia, which in turn leads to ventricular fibrosis and sudden cardiac arrest. It may cause visceral death. as in deformed or prevascular angina , calcium channel antagonists, due to their effects on the smooth muscle of the heart and blood vessels, It would be especially helpful.

Furthermore, racemic felodipine is associated with myocardial infarction, ischemic myocardial necrosis, and ischemic reirrigation injury. can be useful in the treatment of Myocardial infarction or ischemic myocardial necrosis typically occurs in certain areas of the heart muscle. Caused by a sudden decrease in coronary blood flow to the This symptom is caused by coronary artery disease. It also occurs from roamic arteriosclerosis. The cause is still a subject for future research. The symptoms are caused by acute coronary thrombosis in the coronary artery vasculature. Ru. Myocardial infarction is overwhelmingly a disease of the left ventricle. Precordial pain and left ventricular dysfunction characterizes this disease. Pain, which can be severe or compressive, can be anxiety-provoking. cause. Symptoms include left ventricular failure, pulmonary edema, shock or significant cardiac arrhythmia. It will be done.

Calcium channel antagonists have effects on coronary vasculature and blood pressure, or In the treatment of patients with myocardial infarction due to other effects on cardiac function or vascular smooth muscle. It will be helpful.

Racemic felodipine can be used to treat congestive heart failure.

Congestive heart failure is caused by hypertension, cardiomyopathy, coronary artery disease, or valvular heart disease. can be caused by Congestive failure is caused by poor cardiac blood stroke volume and left ventricular diastolic pressure It causes increased strength, causing dyspnea, fatigue, peripheral edema, and cough. some kind of calcium channel blockers, which dilate peripheral blood vessels without significantly affecting muscle contraction. The ability to reduce afterload is of interest in the treatment of congestive heart failure. will increase their use in

Racemic felodipine can also be used to treat migraine headaches.

A standard migraine typically begins with a visual aura (a　u　r　a) followed by Severe headaches often accompany nausea and vomiting. A common migraine is caused by a preceding visual acuity. Although he does not have a mental illness, he has similar symptoms.

Although the cause of migraine has been intensely researched, it remains a matter of debate.

The most widely accepted cause is hypoxia due to decreased blood flow to the brain.

Calcium channel antagonists can increase blood flow in the brain, so unilateral It has been used to prevent pain.

Furthermore, racemic phelogibine is associated with Raynaud's disease, which is characterized by limb vasospasm. It may also be useful in treating Raynaud's phenomenon. These vasospasms are caused by cold May be caused by anxiety or stress. The finger arteries become severely constricted. As a result, paleness or cyanosis is usually present. This phenomenon is often secondary Diseases associated with arterial disease or connective tissue diseases such as scleroderma, arthritis, and lupus erythematosus. It was shown to be effective in treatment.

Racemic felodipine may be useful in the treatment of asthma and bronchial spasms. I'm coughing Asthma symptoms of wheezing and difficulty breathing are caused by contraction of the cervical bronchial smooth muscles. It's triggered. Asthma attacks can be caused by antigenic stimuli (pollen, dust) or non-antigenic stimuli. triggered by physical stimuli (exercise, pollution, infection). response to these stimuli results in the secretion of chemical mediators that cause smooth muscle contraction.

Calcium channel antagonists may control bronchial constriction and reduce asthma attacks. It can be used for.

Additionally, racemic mixtures of felodipine may also be useful in the treatment of renal impairment and acute renal failure. Ru. Renal damage and acute renal failure are clinical conditions with diverse causes, including azotemia or blood with an increase in urea nitrogen in the blood and often oliguria or fluid intake compared to Accompanied by decreased urine output. The pathophysiology originates pre-renally and may be due to extracellular fluid depletion or cardiac May manifest as inadequate renal perfusion due to insufficiency. Endogenous renal failure The most common cause is prolonged renal ischemia. Postrenal azotemia may be due to obstruction or It may be associated with renal glomerular and tubular dysfunction. Lab findings disclosed progressive azotemia, acidemia, hyperkalemia, and hyponatremia. ing. Factors that exacerbate liver damage or failure must be specifically treated. stomach. These factors include heart failure, occlusion, etc.

Moderate or severe hypertension has a detrimental effect on kidney function.

Treating hypertension with various drugs including calcium channel antagonists It is an effective treatment.

Additionally, racemic mixtures of felodipine may be useful in treating cognitive disorders. cognitive impairment Harms include, but are not limited to, dementia and age-related memory loss. stomach.

Dementia can occur at any age. This is a structurally induced intellectual A permanent or progressive decline in some dimension of a person's normal social functioning. materially interfere with commercial or economic activity;

One specific type of dementia is Alzheimer's dementia. This dementia is caused by cerebral cortex This is thought to be due to a degenerative process that involves massive cell loss from other areas of the brain. ing. Acetylcholine transmitting nerves and their target nerve cells are particularly affected.

The brain shows marked atrophy, with wide sulci and dilated ventricles. Senile plaques and neurogens There are tangled fibers. Memory loss is the most prominent early symptom. Awakening mix Riots do not occur in the early stages. Presenile and early senile dementia of Alzheimer's They are similar in both floor and pathological characteristics. The former is usually 50 or 6 It begins in one's 00s, and the latter in one's 70s or 80s. Dementia usually progresses steadily, and ~ Considerable progress will be made within 3 years. Some cases of dementia that begin in presenia are difficult to classify. dementia, which is sometimes classified as idiopathic or simply presenile dementia.

Signs and symptoms of dementia in certain types of Alzheimer's disease include depression, paranoia, anxiety, anxiety, or other symptoms (including some psychological symptoms; the most common clinical manifestations) is the slow decay of personality and intellect due to impaired insight and judgment, and emotional loss. It is. Memory loss begins with difficulty remembering recent events and names. It's getting worse. Disabilities vary significantly from time to time, and often It changes from moment to moment. Dementia in general is insidious, slowly progressing, and untreatable. This is a symptom. However, there are large variations in the speed of progress, and depending on the cause, be done.

Another type of cognitive impairment is age-associated memory impairment (AAMI). AAMI is a healthy, non-demented person who has experienced memory loss during their life. used to describe the Most commonly, the word is memorized during adult life. Used to describe adults over the age of 50 who have experienced loss. Over 65 years old It is estimated that 25-50% of people above have this disorder.

Many calcium channel antagonists cause serious side effects. These side products Causes include, but are not limited to, tachycardia, orthostatic hypotension, and fluid retention. do not have.

In addition, administering racemic mixtures of felodipine to humans may cause side effects other than those listed above. It was discovered that it causes These side effects include edema of the extremities, including peripheral edema, Pain, facial flushing, fatigue, glare, muscle spasms (convulsions, cramps) and dizziness Including, but not limited to:

Therefore, it is a compound that has the advantages of racemic felodipine and has significant adverse side effects. to find something that does not have the above-mentioned disadvantages of use and is useful for treating other conditions. is particularly desirable.

2. Outline of the invention The optically pure S(-) isomer of felodipine is active during both systole and diastole. Effective against high blood pressure, especially in mild to moderate diseases and angina pectoris. is an antihypertensive agent and is associated with the administration of a racemic mixture of felodipine. Avoid side effects including but not limited to limb edema, headache and dizziness It was discovered that. In addition, it contains optically pure S(-)ferodibin. These novel compositions utilize 5(-)feed as a calcium channel antagonist. It may also be helpful in treating other conditions that may be related to Lodibin activity. At the same time, it avoids the above-mentioned side effects associated with the administration of racemic mixtures of felodipine. It was discovered that. Other symptoms include, but are not limited to: stomach. Namely, cerebral ischemia, brain damage, arrhythmia, cardiac hypertrophy, coronary vasospasm, myocardial infarction, and gastric damage. wound, and acute renal failure. The present invention also provides methods for treating the above-mentioned conditions in humans. method, wherein the 5(-) isomer of phelodibin is administered to the human at the same time. including ways to avoid the side effects associated with racemic mixtures of felodipine.

3. Detailed description of the invention The present invention provides a method for treating hypertension in humans 1 and simultaneously administering racemic felodipine. methods that avoid the attendant disadvantages of side effects associated with. This method is , substantially the R(+) stereoisomer in said human in need of such antihypertensive therapy. administering an amount of 5(-) felodipine or a pharmaceutically acceptable salt thereof that does not contain an amount sufficient to reduce the hypertension; An amount insufficient to cause the side effects associated with the administration of racemic lodipine. .

The present invention also provides antihypertensive compositions for treating humans in need of antihypertensive therapy. include. The composition is substantially free of the R(+) stereoisomer. containing an amount of lodipine or a pharmaceutically acceptable salt thereof, where the amount is Although sufficient to reduce pressure symptoms, side effects associated with administration of felodibin racemic An amount insufficient to cause symptoms.

The present invention further provides a method for treating angina pectoris in humans, while at the same time avoiding the attendant disadvantages of side effects. Includes ways to avoid this. This method provides for the human in need of anti-anginal therapy to 5(-) felogibine substantially free of the R(+) stereoisomer or pharmaceutically acceptable administration of a certain amount of the salt to be administered, where the certain amount is the amount that relieves the angina. is sufficient to induce the side effects associated with racemic administration of felodipine. It refers to a phoenix that is insufficient for scrubbing.

Additionally, the present invention encompasses antianginal compositions for treating humans with angina.

The composition is substantially free of the R(+) stereoisomer or 5(-) ferodibin. or a pharmaceutically acceptable salt thereof, where a certain amount is said to reduce the angina. but not enough to cause the side effects of racemic felodipine. Refers to quantity.

Yet another aspect of the invention provides that by excess calcium influx in human cells, To treat the symptoms caused and at the same time avoid the attendant disadvantages of side effects. This includes methods for This method is useful for patients who need to reduce excessive calcium influx. 5(-) felodipine or pharmaceutical drug substantially free of the R(+) stereoisomer Its salts, which are acceptable to the public, are sufficient to alleviate the symptoms, but felodibine la Avoid administering the semiform in an insufficient amount to cause side effects associated with administration. Ru. Symptoms caused by excessive calcium influx in human cells include: These include, but are not limited to, those listed below. Namely, cerebral ischemia, Alzheimer's Cerebral disorders such as cognitive impairment including but not limited to Immer's disease and memory impairment harm, arrhythmia, cardiac hypertrophy, congestive heart failure, coronary vasospasm, migraine, prebronchial and and asthma, Raynaud's phenomenon, myocardial infarction, renal damage, and acute renal failure.

Additionally, the present invention provides an amount of 5(-) felodibin or a pharmaceutically acceptable thereof. Excess calcium human cells containing salts and substantially free of the R(+) stereoisomer. A composition for treating symptoms caused by intravesicular influx, the composition comprising: sufficient to alleviate the symptoms, but the side effects associated with the administration of racemic felodibin Includes compositions that are in an insufficient amount to cause an effect.

Racemic mixtures of commercially available felodipine (e.g., l:l racemic mixtures of two enantiomers) mixture) elicits antihypertensive and antianginal effects. However, this Racemic mixtures exhibit their expected efficacy and at the same time cause side effects. centre Using the 5(-) isomer of elodipine, the relationship between efficacy and dose becomes clearer. , the side effects are surprisingly reduced, thereby improving the therapeutic index. therefore , it is more desirable to use the S(-) isomer of phelogibine.

The term "side effects" refers to cardiovascular effects (including tachycardia and decreased cardiac contractility), Limb edema, headache, atypical dizziness, flushing ng), fatigue, typical dizziness (vertigo), and muscle spasms, including It is not limited to these.

As used herein, the term "substantially free of R(+) stereoisomer" means The composition may have a greater proportion or is the percentage of Felodipine (the percentage is based on the total amount of Felodipine) It is meant to include the 5(-) isomer of pin. In a preferred embodiment, [substantially The term "free of the (+) stereoisomer" means that the composition is at least 90 % by weight of 5(-) felodipine, and not more than 10% by weight of R(+) felodipine. It means to include. In the most preferred embodiment, "substantially R(+) stereoisomerism" The term body-free means that the composition contains at least 99% by weight of 5(=) Contains elodipine, meaning it contains 1% by weight or less of R(+) felodipine . In other preferred embodiments, as used herein, [substantially R(+) stereoisomer] The term ``free of 5(-) ferrogins'' means that the composition contains 100% by weight of 5(-) ferrodites. Means to include pins. [Substantially optically pure 5(-) of felodipine isomer" and "optically pure 5(-) isomer J of felodipine. It is encompassed within the above meaning.

As used herein, the term ``to treat high blood pressure'' refers to By normalizing systolic and/or diastolic blood pressure, Any possible symptoms caused by elevation or other hemodynamic It means to reduce the effect.

As used herein, the term ``methods of treating angina'' refers to anterior chest tightness, discomfort, or radiating sensation that may be accompanied by changes in blood pressure and including, but not limited to, episodes of severe, intense, and definitive pain that may occur Not meant to alleviate myocardial ischemic symptoms.

The term "symptoms caused by excessive calcium influx into human cells" is Calcium, which may be present in smooth muscle, heart, and other tissues, including lungs and brain including, but not limited to, symptoms associated with the influx of human cells into human cells. this These symptoms are associated with cerebral ischemia, Alzheimer's dementia, and cognitive impairment including memory impairment. Cerebral disorders such as arrhythmia, cardiac hypertrophy, congestive heart failure, coronary vascular spasm, migraine, Pre-bronchial and asthma, Raynaud phenomenon, myocardial infarction, renal damage, and acute renal failure. Including, but not limited to. Symptoms associated with these disorders may be Symptoms of chest discomfort or pain, headache, fatigue, decreased exercise tolerance, fainting, shortness of breath , nausea, dizziness (lightheadedness), edema, pulmonary artery congestion, including arrhythmia or palpitations, azotemia, and/or hypouria It is not limited to.

Preparation of optically pure 5(-)felodipine is carried out by L. amm, B,, and 5inunonsson, R,, Tett, L etters.

30(46): 6423-6426 (1989), and Hltze, M. , et al., Chirality 2: 233 (1990). This can be achieved by the following methods.

Prophylactic or therapeutic use of 5(-)phelodibin in the treatment of acute or chronic diseases The extent of administration will vary depending on the severity of the disease being treated and the route of administration.

Dosage and perhaps frequency of administration will depend on each patient's age, weight, and response. It will probably change.

Generally, for the diseases described herein, the total daily dose range is about 0.01 to 100 ．． It is 0 mg. Preferably, the daily dose range is about 0.5-20.0 mg but most preferably should be about 0.5 to tomg. when treating a patient to start treatment at a relatively low dose (perhaps about 0.025-2.5 mg), The dose should be increased to approximately 20 mg or more depending on the patient's overall response. Ru. Additionally, children, patients over 65 years of age, and those with impaired kidney or liver function Patients receive a lower dose initially and then receive a lower dose based on overall response and blood levels. It is recommended to determine the dose of Dosages outside these ranges may be used in some cases. You may need to be there.

Some expressions, ``an amount sufficient to reduce high blood pressure, but cause the side effects.'' ``An amount insufficient to relieve the symptoms, but an amount insufficient to alleviate the symptoms, but not enough to cause the side effects.'' "insufficient amount to cause" (here, the symptom refers to angina pectoris), and r-sedatives. An amount sufficient to reduce spasticity, but insufficient to cause the severe effect. (Here, the symptoms include cerebral ischemia, cerebral damage, arrhythmia, cardiac hypertrophy, coronary vasospasm, including but not limited to myocardial infarction, renal impairment and acute renal failure) included in the dosage and frequency schedules set forth below.

What is the appropriate route of administration for administering an effective amount of S(-)phelogibine to a patient? can also be used. For example, oral, rectal, parenteral, transdermal, subcutaneous, intramuscular, etc. be done. Dosage forms include tablets, troches, dispersions, suspensions, solutions, and capsules. agents, patches, etc.

The pharmaceutical composition of the present invention contains S(-)felodipine or its pharmaceutical composition as an active ingredient. containing an acceptable salt and a pharmaceutically acceptable carrier and optionally other treatments. It may contain ingredients for use.

The term "pharmaceutically acceptable salts" refers to pharmaceutically acceptable salts, including inorganic and organic acids. Refers to salts prepared from compatible non-toxic acids.

Since the compounds of the present invention are basic, pharmaceutically acceptable compounds, including inorganic and organic acids, Salts can be prepared from non-toxic acids.

Such acids include acetic acid, benzenesulfonic acid (besylate), e)), benzoic acid, camphorsulfonic acid, citric acid, ethenesulfonic acid, Malic acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, Maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucilage acid, nitric acid, pamoi phosphoric acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p~toluenesulfone There are acids, etc. Particularly preferred are besylate, hydrobromic acid, hydrochloric acid, phosphoric acid and sulfuric acid. (See U.S. Pat. No. 4.806.557 to Campbell, S. F., et al. I want to be illuminated).

The composition can be administered orally, rectally, and parenterally (including subcutaneously, intramuscularly, and intravenously). The most suitable route in each case depends on the route being treated. This will depend on the nature and severity of the disease. The optimal route of administration for the present invention is oral. be. Preferably, the compositions are provided in unit dosage form and are well-known in the art of formulation. Prepared by method.

When using oral compositions, a suitable dosage range is a total daily dose of about 0.01 to 100 ．． 0 mg, which can be administered once a day or, if necessary, for example twice a day. It may also be administered in divided doses.

In one embodiment of the invention, 5(-)felodibin is administered as a tablet twice a day. or administered as a sustained release formulation allowing for a once-daily dosing schedule. good Preferably, about 0. Administer a dose range of 5 to 20.0 mg once a day or Administer in divided doses as needed. Most preferably about 0.5 to IO, Omg The dosage range is administered once daily or in divided doses as needed.

The patient should increase the dose from below this dose range to within the range, and adjust the symptoms and blood pressure accordingly. can be controlled.

Practically speaking, S<->felodipine as an active ingredient can be used in conventional formulation techniques. Therefore, they may be combined by homogeneously mixing with a pharmaceutical carrier. carrier is hope the dosage form of the preparation, e.g. oral or parenteral (including intravenous injection or infusion) It can take many different forms depending on the situation. To prepare compositions for oral dosage forms , any conventional pharmaceutical vehicle may be used. As a conventional pharmaceutical vehicle, For example, for oral liquid preparations (e.g. suspensions, solutions and elixirs) Water, glycol, oil, alcohol, flavoring agents, preservatives, coloring agents, etc.; aerosol agents ; or in the case of oral solid formulations (e.g. powders, capsules and tablets) Punch, sugar, microcrystalline cellulose, diluent, granulating agent, lubricant, binder, disintegrant, etc. Which carriers can be mentioned, oral solid formulations are preferred over oral liquid formulations . The most preferred oral solid formulation is a tablet.

Tablets and capsules represent the most advantageous oral unit dosage form because they are easy to swallow; In this case, a solid pharmaceutical carrier is used. If desired, tablets can be prepared in standard aqueous or may be coated by non-aqueous techniques.

In addition to the common dosage forms described above, the compositions of the present invention may also be used in U.S. Pat. ．． No. 770; No. 3.916.899; No. 3.536.809; No. 3. No. 598.123; No. 4.008.719; European Patent Application No. 0274176; 0317780, 51015.479; and 4,803,031 < Controlled release, as described in (these disclosures are incorporated herein by reference) and may be administered by sustained release devices and/or delivery devices.

Pharmaceutical compositions of the present invention suitable for oral administration each contain a predetermined active ingredient. as separate units such as capsules, cachets, tablets or aerosol sprays. It can be used as a powder or granule, or in aqueous liquids, non-aqueous liquids, or oil-in-water formulations. Presented as a solution or suspension in an emulsion or water-in-oil emulsion can do. Such compositions may be prepared by any formulation technique. may also be used, but all methods constitute one or more necessary ingredients. including the step of bringing into association the carrier and the active ingredient. Generally, the composition includes active ingredients homogeneously with a liquid carrier or a finely divided solid carrier or both and Mix thoroughly and then, if necessary, shape the product into the desired presentation form. Therefore, it is prepared.

For example, tablets can be compressed or molded, optionally with one or more accessory ingredients. It can be prepared by shaping. Compressed tablets are powder or granule-like The active ingredient in free-flowing form, optionally with binders, lubricants, inert diluents, and / or mixed with a surfactant or dispersant and compressed with a suitable machine. It can be prepared more easily. Molded tablets are prepared by mixing the compound in powder form moistened with an inert liquid diluent. It can be made by molding the compound in a suitable machine. Preferably each tablet is about 0. Contains from 1 to about 50 active ingredients, and each cachet or cap The cell agent contains about 0.5+ng to about 50mg of the active ingredient S (-) Including pin. Most preferably, the tablets, cachets or capsules are (preferred) Dosage forms (as scored tablets) 0.5■, 2.5■ and 5°0 ■ Contains any of three doses of the active ingredient.

See the Examples below which describe in detail the testing and preparation of compositions of the invention. The present invention will now be described in further detail.

Many improvements, both in materials and methods, have departed from the purpose and subject matter of this invention. It will be clear to those skilled in the art that other modifications may be made.

Optically pure 5(-) fluoride as a calcium channel antagonist and negative inotrope The relative potency of elodipine and felodipine racemate was determined by pharmacological tests. Bell. Evaluation of these and other compounds in in vitro test systems provides some results that make it difficult to assess the vascular selectivity of a particular compound. I can do it. Calcium channel antagonist activity of compounds as a function of molar concentration rebs-Hensele containing 45mM but without Ca2+ Calcium-induced contraction of rat aortic strips immersed in a bath of IT buffer. This can be evaluated by measuring their inhibition. Antagonist at various concentrations In the presence of calcium chloride, shrinkage of isolated tissue pieces is suppressed in response to the addition of calcium chloride. will be done. An antagonist is a molar concentration of a compound that inhibits calcium-induced contractions by 50%. Comparisons can be made by testing the degree of

As an indicator of cardiac decline, negative inotropic activity was detected in cardiac specimens isolated from adult rats. By using it, it can be evaluated relatively. Tissues were prepared and Krebs-Hens Perfuse in vitro with eleit buffer. And calcium chun The activity of Nell antagonists is evaluated as a function of their concentration. Compounds that alter heart contractions test for competency.

Relative potency is the compound's ICt-value, i.e., the value needed to inhibit contraction by 25%. Calculate from the concentration.

Rat or guinea pig hind leg skeletal muscle is cut into small pieces and homogenized. filtration and After continuous centrifugation, the pellet was homogenized to a protein concentration of 1-3 mg. Dilute in Tris buffer to 1/ml. Contains 3-IOμg of protein of this suspension was added to a constant concentration of (+)-[”H]-i from 0.2 to 0.5 nM. with sradipine or a similar radioactive ligand and progressively Increasing concentrations of racemic felodipine, 5(-) felodipine, or R(+) Incubate in the presence of felodipine. After 1 hour incubation, Bound and free radioactivity was measured using a scintillation counter, and test compound Measures the affinity of a substance for its receptor.

4.3 Example 3 Effect on coronary vascular tolerance in guinea pig Langenodorf heart preparations Male guinea pigs weighing 400 to 450 g are sacrificed by cervical dislocation. heart by retrograde cannulation into the aorta within a Langenodorf device. Therefore, under constant pressure (60 cm water), Krebs-Henserite (Krebs-H enseleit) solution. 118.0mM NaCl, 4.7 mM KCI, 5.5 mM CaCl*, 1.2 mM Mg5O+.

Krebs-25, consisting of OmM NaHCOs, and 5.0mM glucose. The Henselite solution was prewarmed to 37°C and placed in an atmosphere of 95% oxygen and 15% carbon dioxide. Supply mixed gas. A balloon catheter connected to a pressure transducer is passed through the left atrium. into the left ventricle and prepressurize to 40 mmHg. Continuous coronary perfusion changes in heart rate and left ventricular contractility are also continuously monitored.

Each test consisted of a 30 minute equilibration period during which the return flow rate was 9-12 m1/min. stable. After this period, apply vasoconstrictor to the aortic cannula 3 times at 40 minute intervals. Insert twice. This U-46619 (9, l l-me 9J epoxy'/PGH2) administration reduces coronary flow by approximately 75% within 30-40 seconds, and this effect is similar to that of 20-2 Full recovery occurs after 5 minutes of continuous perfusion. Dissolved in dimethyl sulfoxide or vehicle Racemic felodipine, 5(-) felodipine, or R(+) felodipine Increasing concentrations of U-46619 are administered prior to further U-46619 administration.

Coronary flow rates obtained with three consecutive administrations of U-46619 in the absence of test compound. This in the presence of increasing concentrations of test drug, taking the average reduction as 100%. Calculate the percent inhibition of the effect. Complete response to each test drug in 5 hearts A dose-response curve was obtained, with half-maximal anti-vasoconstrictor effects (IDs=) The dose can be calculated.

Insert an ethylene catheter through the femoral artery into the abdominal aorta and through the femoral vein into the abdomen. Implant into the vena cava. The arterial catheter is connected to an intraflow device (intraflow device). device) to a pressure transducer, and flush the catheter at 3 ml/hr. Rush. The mean arterial pressure is determined electronically from the blood pressure wave. Treatment of mean arterial pressure The average value before treatment is in the range 160-160-22O. racemic felodipine, Administration of 5(-) felodibin or R(+) felodipine or solvent vehicle. Inject the dose into the intravenous catheter. Mean arterial pressure for each drug and solvent The response is recorded and the relative potency of the test compound is calculated.

(Leaving space below) 4.5 Example 5 Calcium antagonistic 9 guinea pig ileum (in vitro): Ca-free at 37°C Calcium was applied to isolated guinea pig ileum fragments that had been polarized in saline solution. When calcium (calcium chloride 20 μg/ml) was added, calcium antagonist activity was observed. shows.

Reference drug (ED,..., μg/ff1l) 4.6 Example 6 Research on insulin resistance Insulin is a hormone that activates various biochemical processes in the body. Promotion of glucose transport to the cell membrane and activation of cell growth are the most well-known It is. The development of insulin resistance is common in both diabetic and non-diabetic patients. However, resistance to insulin occurs only in the glucose transport system. It is. To compensate for impaired glucose transport, the normal body produces more insulin. produces insulin, and diabetics must take high doses of insulin. stomach. Insulin is also a growth hormone, so increasing insulin levels can cause Promotes growth of telosclerotic areas and increases cardiovascular morbidity and mortality Induce danger.

This study focused on the naturally occurring high-intensity disease in old age, which is known to cause insulin resistance. Performed in blood pressure rats (SHR). Racemic felodibin, 5(-) felodibin or Glucose transport, insulin blood concentration, and and their effects on arterial blood pressure.

Prior to administering vehicle or test compound, the following parameters should be established: Perform measurements: (1) Systolic blood pressure (measured by tail cuff occlusion); (2) Plasma blood pressure loss levels of insulin and triglycerides; and (3) glucose tolerance nce.

SHR was given vehicle or test compound by oral gavage once or twice daily. , given over 2 or 4 weeks. Blood pressure, circulating insulin and trigs Measurements of lyceride and glucose clearance should be performed for 2 (to 4) weeks after drug administration. Do it after giving. Any change in insulin resistance resulting from drug administration may as a change in the ratio of course/plasma insulin levels, and glucose tolerance It is clear from the performance tests.

Capsule: Prescription Amount per capsule (mg) Active ingredient 0.5 2.5 5.0 S (-) Felodipine Lactose 83.5 81.5 79.0 Cornstarch 15. OL5.0 15.0 Magnesium stearate 1.0 1.0 1.0 Compressed weight 10 0.0 100.0 100.0 Effective acid content 5(-) felodipine, lacto Stearate and corn starch are mixed until homogeneous, then the stearate macerate is mixed. Mix gnesium to obtain powder. Pour the resulting mixture into two pieces of suitable size. Fill into hard gelatin capsules.

4.8 Example 8 Capsule: Active ingredient 0.5 2.5 5.0 8(-) ferodibin Lactose B P 183.0 181.5 178.5 Starch B P 15 ．． 0 15.0 15.0 Pregelatinized corn starch BP stearin Magnesium acid 1.0 1.5 1.5 Compressed weight 200.0 200.0 S(-)phelogibine, which has an effective acid content of 200.0, was passed through a suitable sieve to remove lactose. mixture with starch, starch, and pregelatinized corn starch. appropriate amount Add purified water and granulate the powder. After drying, sieve the granules and add stearic acid magnesium. Mix with Cium. The granules are compressed into tablets using a 7 mm diameter punch.

Tablets of other concentrations may vary depending on the ratio of active ingredient to lactose, as well as compressed weight and It can be prepared by appropriately changing the punch used.

Continuation of front page (51) Int, C1,' Identification symbol Internal office reference number A61K 31/44 ABS 9454-4CACD 9454-4C ACV 9454-4C (81) Designated countries EP (AT, BE, CH, DE.

DK, ES, FR, GB, GR, IE, IT, LU, MC, NL, PT, S E), 0A (BF, BJ, CF, CG, CI, CM, GA, GN, M L, MR, SN, TD.

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HU, JP, KR, LK, MG, MN, MW, No, NZ, PL, RO, RU, S.D., D.A. I

Claims (56)

[Claims] 1. while avoiding the attendant tendency for side effects associated with the administration of racemic felodipine. A method of treating hypertension in humans, the method of treating hypertension in humans substantially an amount of S(-) felodipine or its comprising administering a pharmaceutically acceptable salt, the amount of which is sufficient to reduce hypertension. sufficient amount, but not enough to cause the side effects of racemic felodipine. Yes, the above method. 2. S(-)felodipine is administered by intravenous infusion and by transdermal delivery. 2. The method of claim 1, wherein the method is administered orally as a tablet or capsule. 3. 3. The method of claim 2, wherein the dosage is about 0.01-100.0 mg per day. 4. 4. The method of claim 3, wherein the dosage is about 0.5-20 mg. 5. 5. The method of claim 4, wherein the dosage is about 0.5-10.0 mg. 6. The amount of S(-) felodipine or its pharmaceutically acceptable salt is felodipine The method of claim 1, wherein the amount is greater than about 90% by weight of the total amount of. 7. the amount of S(-) felodipine substantially free of the R(+) stereoisomer; or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier. The method described in Section 1. 8. Claims 2, 3, wherein S(-)felodipine is administered as its besylate salt. 4, 5 or 6. 9. An antihypertensive composition for use in the treatment of humans in need of antihypertensive treatment, the composition comprising: an amount of S(-) felodipine or the like that is qualitatively free of the R(+) stereoisomer; containing a pharmaceutically acceptable salt of, the amount being sufficient to reduce hypertension. but in an amount insufficient to cause side effects associated with administration of felodipine racemate. The above composition. 10. 10. The composition of claim 9, wherein said amount is about 0.01-100.0 mg. 11. 11. The composition of claim 10, wherein said composition is administered from 1 to 4 times per day. 12. 12. The composition of claim 11, wherein said composition is administered once a day. 13. 11. The composition according to claim 10, containing S(-)felodipine besylate. 14. 14. The composition of claim 13, wherein said composition is suitable for oral administration. 15. 14. The composition of claim 13, which is suitable for intravenous delivery. 16. 14. The composition of claim 13 for use in transdermal formulations. 17. 17. A composition according to claim 16 for use as a transdermal batch. 18. S(-) felodipine substantially free of R(+) stereoisomer or its 10. The pharmaceutically acceptable salt of claim 9, wherein the pharmaceutically acceptable salt is administered together with a pharmaceutically acceptable carrier. Composition. 19. while avoiding the attendant tendency for side effects associated with the administration of racemic felodipine. , a method for treating angina pectoris in humans, the method comprising: an amount of S(-) felodipine or substantially free of the R(+) stereoisomer; or a pharmaceutically acceptable salt thereof, the amount of which reduces angina pectoris. sufficient to cause the side effects associated with administration of racemic felodipine. In the above method, the amount is insufficient to cause 20. S(-)felodipine is administered by intravenous infusion and transdermal delivery. 20. The method of claim 19, wherein the method is administered orally as a tablet or capsule. 21. 21. The method of claim 20, wherein the dosage is about 0.01-100.0 mg. 22. 22. The method of claim 21, wherein the dosage is about 0.5-20.0 mg. 23. 23. The method of claim 22, wherein the dosage is about 0.5-10.0 mg. 24. The amount of S(-) felodipine or its pharmaceutically acceptable salt is 20. The method of claim 19, wherein the method is greater than about 90% by weight of the total amount of the ingredients. 25. the amount of S(-) ferodipi substantially free of the R(+) stereoisomer; or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier. The method according to claim 19. 26. Claims 20, 21, wherein S(-)felodipine is administered as a besylate salt. , 22, 23 or 24. 27. An antianginal composition for use in the treatment of humans with angina, the composition comprising substantially R( +) an amount of S(-)felodipine or its pharmaceutical form, free of stereoisomers; contains an acceptable salt, the amount being sufficient to alleviate angina, but The above composition is in an amount insufficient to cause the side effects of the dipine racemate. 28. 28. The composition of claim 27, wherein said amount is about 0.01-100.0 mg. . 29. 29. The composition of claim 28, wherein said composition is administered from 1 to 4 times per day. 30. 30. The composition of claim 29, wherein said composition is administered once a day. 31. 29. The composition of claim 28, containing S(-)felodipine besylate. 32. 32. The composition of claim 31, wherein said composition is suitable for oral administration. 33. 32. The composition of claim 31, which is suitable for intravenous delivery. 34. 32. A composition according to claim 31 for use in a transdermal formulation. 35. 35. A composition according to claim 34 for use as a transdermal batch. 36. S(-) felodipine substantially free of R(+) stereoisomer or its 28. The pharmaceutically acceptable salt is administered together with a pharmaceutically acceptable carrier. Composition of. 37. while avoiding the attendant tendency for side effects associated with the administration of racemic felodipine. , treats symptoms caused by excessive calcium influx into cells in humans. A method of treating a human in need of such treatment that substantially eliminates R(+) stereoisomerism. an amount of S(-)felodipine or its pharmaceutically acceptable form salt in an amount sufficient to alleviate the symptoms, but not amounts that are insufficient to cause side effects associated with administration of elodipine racemate , the above method. 38. Cerebral ischemia is a symptom caused by excessive calcium influx into cells. Cerebral disorders, cognitive disorders, Alzheimer's dementia, memory disorders, arrhythmia, cardiac hypertrophy, cancer Congestive heart failure, coronary vasospasm, migraine, bronchospasm and asthma, Raynaud phenomenon, 38. Selected from the group consisting of myocardial infarction, renal failure and acute renal failure. Method. 39. S(-)felodipine is administered by intravenous infusion and transdermal delivery. 38. The method of claim 37, wherein the method is administered orally as a tablet or capsule. 40. 40. The method of claim 39, wherein the dosage is about 0.01-100.0 mg. 41. 41. The method of claim 40, wherein the dosage is about 0.5-20 mg. 42. 42. The method of claim 41, wherein the dosage is about 0.5-10.0 mg. 43. The amount of S(-) felodipine or its pharmaceutically acceptable salt is 38. The method of claim 37, wherein the method is greater than about 90% by weight of the total amount of the ingredients. 44. the amount of S(-) ferodipi substantially free of the R(+) stereoisomer; or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier. The method according to claim 37. 45. Claims 39, 40, 41, wherein S(-) felodipine besylate is administered. 42 or 43. 46. Symptoms caused by excessive calcium influx into cells in humans 2. A composition for treating a. S(-)felodipine or a pharmaceutically acceptable salt thereof in an amount of in an amount sufficient to alleviate the symptoms, but not associated with the administration of felodipine racemate. said composition in an amount insufficient to cause side effects. 47. Symptoms caused by excessive intracellular influx of calcium in humans Cerebral ischemia, cerebral damage, cognitive impairment, Alzheimer's dementia, memory impairment, arrhythmia, Cardiac hypertrophy, congestive heart failure, coronary vasospasm, migraine, bronchospasm and asthma, A kidney disease selected from the group consisting of Hinault phenomenon, myocardial infarction, renal failure, and acute renal failure. 47. The composition according to claim 46. 48. 47. The composition of claim 46, wherein said amount is about 0.01-100.0 mg. . 49. 49. The composition of claim 48, wherein said composition is administered from 1 to 4 times per day. 50. 50. The composition of claim 49, wherein said composition is administered once a day. 51. 49. The composition of claim 48, comprising S(-) felodipine besylate. 52. 52. The composition of claim 51, wherein said composition is suitable for oral administration. 53. 52. The composition of claim 51, which is suitable for intravenous delivery. 54. 52. A composition according to claim 51 for use in a transdermal formulation. 55. 55. A composition according to claim 54 for use as a transdermal batch. 56. S(-) felodipine substantially free of R(+) stereoisomer or its 47. The pharmaceutically acceptable salt is administered together with a pharmaceutically acceptable carrier. Composition of.