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WO2002058703A2 - Traitement de troubles sexuels et de maladie cardio-vasculaire avec des enantiomeres quinolinone - Google Patents

Traitement de troubles sexuels et de maladie cardio-vasculaire avec des enantiomeres quinolinone Download PDF

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Publication number
WO2002058703A2
WO2002058703A2 PCT/US2002/002357 US0202357W WO02058703A2 WO 2002058703 A2 WO2002058703 A2 WO 2002058703A2 US 0202357 W US0202357 W US 0202357W WO 02058703 A2 WO02058703 A2 WO 02058703A2
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WO
WIPO (PCT)
Prior art keywords
flosequinan
enantiomer
enantiomers
patient
symptoms
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PCT/US2002/002357
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English (en)
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WO2002058703A3 (fr
Inventor
Neal R. Cutler
John Sramek
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RT Alamo Ventures I LLC
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RT Alamo Ventures I LLC
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Publication date
Priority claimed from US09/770,704 external-priority patent/US20020147217A1/en
Priority claimed from US09/771,104 external-priority patent/US6562838B2/en
Application filed by RT Alamo Ventures I LLC filed Critical RT Alamo Ventures I LLC
Priority to JP2002559037A priority Critical patent/JP2005503995A/ja
Priority to CA002435876A priority patent/CA2435876A1/fr
Priority to EP02709191A priority patent/EP1355647A2/fr
Publication of WO2002058703A2 publication Critical patent/WO2002058703A2/fr
Anticipated expiration legal-status Critical
Publication of WO2002058703A3 publication Critical patent/WO2002058703A3/fr
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the present invention relates to methods for the treatment of sexual dysfunction in males and females (including but not limited to erectile dysfunction in males) in particular treatment groups.
  • the methods of the present invention comprise the utilization of pharmaceutical compounds and compositions to patients who are free of symptoms of cardiac disease and who have not been treated with drugs which cause hypotensive effects, such as nitrites and nitrates.
  • the present invention also relates to compositions and methods for the treatment of cardiovascular disease.
  • Impotence or erectile insufficiency is a widespread disorder that is thought to affect about twelve percent of adult men under age forty-five, about twenty percent of men at age sixty, and about fifty-five percent of men at age seventy-five.
  • erectile dysfunction can be psychological, resulting from anxiety or depression, with no apparent somatic or organic impairment.
  • erectile dysfunction which is referred to as "psychogenic” is responsible for about fifteen to twenty percent of cases of impotence.
  • the erectile dysfunction is associated with atherosclerosis of the arteries supplying blood to the penis; such dysfunction is referred to as "arteriogenic" or "atherosclerotic.”
  • arteriogenic or "atherosclerotic.
  • About forty to sixty percent of cases of impotence are arteriogenic in origin.
  • Erectile dysfunction in diabetics is often classified as "diabetogenic," although the underlying dysfunction is usually neurogenic associated with neuropathy, but may be arteriogenic or neurogenic and arteriogenic. About half of diabetic males suffer from erectile insufficiency, and about half of the cases of neurogenic impotence are in diabetics. Additionally, erectile insufficiency is sometimes a side effect of certain drugs, such as beta-blockers that are administered to reduce blood pressure in persons suffering from hypertension, or drugs administered to treat depression or anxiety. Excessive alcohol consumption has also been linked to erectile insufficiency.
  • Circumcision in males which removes highly sensitive penile tissue and subjects the glans of the penis to desensitization through keratinization of the remaining tissue, is also believed to be a contributmg factor to some forms of erectile insufficiency.
  • These forms of erectile insufficiency may be regarded as a subset of neurogenic or psychogenic insufficiency.
  • insufficiency is physical because of venous leakage
  • surgery can usually be employed to repair the venous lesion and thereby either cure the insufficiency or, if there remains an erectile insufficiency after repair of the venous lesion, render the insufficiency amenable to treatment by pharmacological methods.
  • penile implants which provide a mechanical means to produce an erection sufficient for vaginal penetration, are widely used to treat impotence.
  • implants have been employed, especially in cases where pharmacological intervention is ineffective, which are usually cases of severe atherogenic impotence. Treatment of impotence with penile implants, however, entails serious disadvantages. Such treatment requires surgery and necessitates total destruction of the erectile tissues of the penis, forever precluding normal erection.
  • Papaverine is now widely used to treat impotence, although papaverine is ineffective in overcoming impotence due, at least in part, to severe atherosclerosis.
  • Papaverine is effective in cases where the dysfunction is psychogenic or neurogenic and severe atherosclerosis is not involved. Injection of papaverine, a smooth muscle relaxant, or phenoxybenzamine, a non-specific blocker and hypotensive, into a corpus cavernosum has been found to cause an erection sufficient for vaginal penetration. Also, in cases where severe atherosclerosis is not a cause of the dysfunction, intracavernosal injection of phentolamine, an ⁇ -adrenergic blocker, causes an erection sufficient for vaginal penetration. The resulting erection is one of significantly shorter duration than that induced by intracavernosal injection of papaverine or phenoxybenzamine and is of such short duration that satisfactory sexual relations are difficult or impossible.
  • priapism Treatment of impotence with papaverine or phenoxybenzamine often results in priapism, a locking-up of an erection for a long period of time, typically a few hours and sometimes longer than twenty-four hours.
  • Priapism is a serious, deleterious side effect of treatment of erectile insufficiency with these drugs. Beyond the embarrassment that may be caused for some men, priapism is usually painful, irreversibly damages erectile tissue, and, to be relieved, requires bleeding or pharmacological intervention, such as injection of a sympathomimetic drug, such as adrenaline.
  • impotence is a ubiquitous problem, there are few satisfactory methods available for treating this disorder. Because of the relatively invasive intervention involved and the high failure rate of penile prostheses, surgical approaches provide unattractive alternatives. A safe pharmacological approach to the treatment of impotence is still to be achieved.
  • Cardiovascular disease is the number one cause of death in the United States. Medical Sciences Bulletin, No. 238; p. 1 (1997). While cardiovascular disease presents many different clinical manifestations, hypertension and congestive heart failure (CHF) are major components of this disease state. Uncontrolled hypertension can result in myocardial infarction and stroke. Congestive heart failure, if untreated, is an ultimately fatal disease that kills more than half its victims within five years of initial diagnosis. CHF affects about 3 million people in the United States and about 15 million worldwide. Currently, an estimated 400,000 new cases are diagnosed in the United States each year, and CHF is responsible for about 900,000 hospitalizations a year.
  • anti-hypertensive compounds such as: beta-blockers, calcium channel blockers (especially dihydropyrimidines), angiotensin-converting enzyme (ACE) inhibitors, diuretics, and alpha-blockers.
  • beta-blockers calcium channel blockers (especially dihydropyrimidines), angiotensin-converting enzyme (ACE) inhibitors, diuretics, and alpha-blockers.
  • ACE angiotensin-converting enzyme
  • What is needed is a pharmaceutical that is effective in the treatment of sexual disfunction in males and females but lacking in significant side effects. Additionally, what is needed is a pharmacological intervention for cardiovascular disease (including, but limited to, hypertension and CHF) that is less disruptive to the patient and is be better tolerated in comparison to existing treatment modalities.
  • cardiovascular disease including, but limited to, hypertension and CHF
  • the present invention relates to methods for the treatment of sexual dysfunction in males and females (including but not limited to erectile dysfunction in males) in particular treatment groups. Additionally, the present invention relates to compositions and methods and for the treatment of cardiovascular disease.
  • the methods of the present invention comprise the utilization of pharmaceutical compounds and compositions to patients who suffer from symptoms of sexual dysfunction and are free of symptoms of cardiac disease and who have not been treated with drugs which cause hypotensive effects, such as nitrites and nitrates.
  • the compositions comprise purified enantiomers of flosequinan, including derivatives thereof.
  • said purified enantiomer of flosequinan is a (+) enantiomer.
  • said composition is substantially free of the (-) enantiomer of flosequinan.
  • the method comprises a) providing: i) a patient (whether male or female) suffering from one or more symptoms of sexual dysfunction; and ii) a pharmaceutical composition comprising a purified enantiomer of flosequinan, or a pharmaceutically acceptable salt thereof; and b) administering said pharmaceutical composition to the patient such that at least one of said one or more symptoms are reduced.
  • a variety of such symptoms are contemplated, including but not limited to, poor blood flow to the sexual organs and/or failure to achieve orgasm.
  • the present invention contemplates administering said flosequinan to said male or female under conditions such that blood flow to the sexual organs of said male or female is improved.
  • the methods of the present invention be limited to a patient who is free from cardiac disease.
  • the patient is free from cardiac disease.
  • said patient is not free from cardiac disease.
  • the patient is male.
  • the patient is female.
  • said administering step is selected from the group consisting of intranasal and respiratory inhalation. It is not intended that the methods of the present invention be limited to a patient who has been, or is being, treated with a drug that causes hypotensive effects.
  • the method comprises a) providing: i) a patient (whether male or female) suffering from one or more symptoms of sexual dysfunction who is not being treated with a drug that causes hypotensive effects, and ii) a pharmaceutical composition comprising a purified enantiomer of flosequinan, or a pharmaceutically acceptable salt thereof; and b) administering flosequinan to the patient such that such at least one of said one or more symptoms are reduced.
  • a variety of such symptoms are contemplated, including but not limited to, poor blood flow to the sexual organs and or failure to achieve orgasm.
  • the present invention contemplates administering said flosequinan to said male or female under conditions such that blood flow to the sexual organs of said male or female is improved.
  • the patient is free from cardiac disease.
  • the patient is male.
  • the patient is female.
  • said administering step is selected from the group consisting of intranasal and respiratory inhalation.
  • said patient is being, or has been, treated in the past with a drug that causes hypotensive effects.
  • the method comprises a) providing: i) a patient (whether male or female) suffering from symptoms of sexual dysfunction who. is not being treated with a nitrite or nitrate, and ii) a pharmaceutical composition comprising a purified enantiomer of flosequinan, or a pharmaceutically acceptable salt thereof; and b) introducing flosequinan to the patient such that such symptoms (or a subset thereof) are reduced.
  • a variety of such symptoms are contemplated, including but not limited to, poor blood flow to the sexual organs and/or failure to achieve orgasm.
  • the present invention contemplates administering said flosequinan to said male or female under conditions such that blood flow to the sexual organs of said male or female is improved.
  • the patient is free from cardiac disease.
  • the patient is male.
  • the patient is female.
  • said administering step is selected from the group consisting of intranasal and respiratory inhalation.
  • said patient has been, or is being, treated with a nitrite or nitrate.
  • said nitrate is selected from the group consisting of glyceryl trinitrate, isosorbide dinitrate, isosorbide-5'- mononitrate, and erythrityl tetranitrate.
  • the method comprises providing: i) a male or female subject with erectile dysfunction, and ii) a purified enantiomer of flosequinan, or a pharmaceutically acceptable salt thereof; and introducing flosequinan to the male or female subject such that an erection (i.e. penile or clitoral) is produced.
  • an erection i.e. penile or clitoral
  • the method comprises providing: i) a male or female subject with erectile dysfunction, and ii) a pharmaceutical composition comprising a purified enantiomer of flosequinan, or a pharmaceutically acceptable salt thereof; and introducing the pharmaceutical composition to the male or female subject such that an erection (i.e. penile or clitoral) is produced.
  • an erection i.e. penile or clitoral
  • the present invention be limited by the method of introduction of a purified enantiomer of flosequinan, or a pharmaceutically acceptable salt thereof.
  • the enantiomer of flosequinan is introduced into the male or female orally. It is believed that an oral dosage up to approximately 200 milligrams of a racemic mixture of flosequinan is an effective oral dosage. It is also believed that the oral administration of a purified of enantiomer of flosequinan is effective at even lower dosages (e.g. less than 200 mg).
  • the male or female is an adult human and the oral dosage of a purified enantiomer of flosequinan is in a single dose per day of up to approximately two hundred milligrams, more preferably, between approximately fifty to approximately seventy-five milligrams.
  • a purified enantiomer of flosequinan is administered in a single oral dose per day of between approximately twenty and approximately fifty, and even more preferably, between approximately ten and approximately twenty milligrams per day.
  • the administration of multiple dosages of a purified enantiomer of flosequinan are also contemplated.
  • enantiomers of flosequinan are introduced cutaneously, transurethrally, by standard injection, intracavernosally, intranasally or through respiratory inhalation.
  • pharmaceutical compositions comprising a purified enantiomer of flosequinan, or a pharmaceutically acceptable salt thereof, is introduced cutaneously, transurethrally, by standard injection, intracavernosally, intranasally or through respiratory inhalation.
  • the present invention is not limited by the degree of response by the male subject. In one embodiment, the erection induced is sufficient for vaginal penetration. Likewise, the present invention also contemplates the use of sexual stimulation in addition to the application of a pharmaceutical composition.
  • one embodiment comprises a) providing: i) a male, having a penis, with erectile dysfunction, ii) a purified enantiomer of flosequinan, or a pharmaceutically acceptable salt thereof, and iii) sexual stimulation; and b) introducing said flosequinan and sexual stimulation to the male such that an erection is produced.
  • the method comprises a) providing: i) a male, having a penis, with erectile dysfunction, ii) a pharmaceutical composition comprising a purified enantiomer of flosequinan, or a pharmaceutically acceptable salt thereof, and iii) sexual stimulation; and b) introducing said pharmaceutical composition and sexual stimulation to the male such that an erection is produced.
  • the present invention also contemplates the use of sexual stimulation in addition to the application of a pharmaceutical composition.
  • one embodiment comprises a) providing: i) a female, having a clitoris, with erectile dysfunction, ii) a purified enantiomer of flosequinan, or a pharmaceutically acceptable salt thereof, and iii) sexual stimulation; and b) introducing said flosequinan and sexual stimulation to the female such that an erection is produced.
  • the method comprises a) providing: i) a female, having a clitoris, with erectile dysfunction, ii) a pharmaceutical composition comprising a purified enantiomer of flosequinan, or a pharmaceutically acceptable salt thereof, and iii) sexual stimulation; and b) introducing said pharmaceutical composition and sexual stimulation to the female such that an erection is produced.
  • the present invention is not limited by the nature of the sexual stimulation.
  • the sexual stimulation is sexually explicit media.
  • the sexual stimulation involves manipulation of the penis, such as with vibration.
  • the sexual stimulation involves manipulation of the clitoris, such as with vibration or digital stimulation.
  • the present invention contemplates a formulation comprising a purified enantiomer of flosequinan, or derivative thereof, in a mixture comprising lactose.
  • the present invention provides compositions and methods for the treatment of cardiovascular disease.
  • the present invention is particularly suited to the treatment of CHF.
  • the methods of the present invention comprise the administration of pharmaceutical compositions to subjects who, in a preferred embodiment, are not concurrently administered nitrites and nitrates.
  • the compositions of the present invention comprise quinolinones, including derivatives thereof.
  • Quinolinones are also known as quinolones and oxo- quinolines.
  • the present invention contemplates halogenated quinolinones (e.g., fluoroquinolinone).
  • the quinolinone is a thioquinolinone or a sulphinyl or suphonyl derivatives thereof.
  • the halogenated quinolinone is flosequinan [(+-)-7-fluoro-l-methyl-3-(methyl- sulphinyl)-4(lH)-quinolinone]; [7-Fluoro-l-methyl-3-(methylsufinyl)-4(lH)-quinolone].
  • an enantiomer [either (+) or (-)] of flosequinan is used.
  • the present invention contemplates a method, comprising: a) providing: i) a patient presenting at least one symptom of cardiovascular disease, and ii) a purified enantiomer preparation of flosequinan; and b) administering said preparation to said patient (e.g. such that said symptom is reduced).
  • a variety of such symptoms of cardiovascular disease are contemplated. It is not intended that the present invention be limited to the reduction of a particular symptom of cardiovascular disease. In a preferred embodiment, the a symptom of hypertension is reduced.
  • Hypertension is an abnormal increase of blood pressure in the arteries continuing over a period of time. It occurs when the arterioles, the small blood vessels that branch off from the arteries, become constricted. This constriction of the arterioles makes it difficult for blood to flow which increases pressure against the artery walls.
  • a blood pressure reading of approximately 110/60 to 140/90 is considered to be in the normal range.
  • the first number (110) is the systolic pressure which measures the blood pressure in the arteries when the heart is contracting and pumping blood.
  • the second number (60) is the diastolic pressure which measures the blood pressure in the arteries when the heart is at rest.
  • Hypertension adds to the workload of the heart and arteries. Over time, this can lead to heart and blood vessel damage which causes hardening of the arteries, heart failure, stroke, kidneys problems, blindness, and brain damage.
  • a symptom of cardiovascular disease comprises a measured blood pressure of approximately 140/90 or higher.
  • the diagnosis of said hypertensive blood pressure e.g.
  • the present invention contemplates compositions and methods to reduce the symptoms of CHF (also referred to as 'heart failure').
  • CHF is characterized by an inadequacy of the heart so that, as a pump, it fails to maintain the circulation of blood, such that congestion and edema develop in the tissues of the heart are reduced.
  • Symptoms of CHF include, but are not limited to, shortness of breath, pitting edema, an enlarged and tender liver, engorged neck veins, and pulmonary rales in various combinations.
  • CHF may be diagnosed based on a medical history and complete physical examination, which may include a blood pressure check, listening to the subject's heart through a stethoscope and taking the subject's pulse. At physical exam.
  • a Health Care Provider including, but not limited to, Physicians, Nurse Practitioners, or Physician's Assistants may look for the symptoms of CHF (as listed above).
  • a Health Care Provider may order further tests. These test include, but are not limited to, blood tests to assess for anemia and thyroid function, urine tests to measure sugar, an Electrocardiogram (EKG), an exercise stress test, an Echocardiogram, a stress echocardiogram, radionuclide imaging tests (such as a radionuclide ventriculogram).
  • More invasive exploratory tests may also be ordered in conjunction with, or instead of the above. These tests include a coronary angiogram, in which a contrast dye is delivered by catheter to the coronary arteries to visualize the blood vessels and identify heart damage or dysfunction.
  • the present invention is not limited by the degree of response by the subject. It is expected that the administration of quinolinone enantiomers will reduce the symptoms associated with cardiovascular diseases including, but not limited to, angina pectoris, myocardial infarction, congestive heart failure, cardiomyopathy, hypertension, arterial stenosis, and venous stenosis.
  • the enantiomers of flosequinan are administered to reduce the symptoms associated with hypertension.
  • the enantiomers of flosequinan are administered to reduce the symptoms of CHF.
  • the symptoms of CHF include, but are not limited to, shortness of breath, pitting edema, an enlarged and tender liver, engorged neck veins, and pulmonary rales in various combinations.
  • Symptoms are "reduced” when the magnitude (e.g. intensity) or frequency of symptoms is reduced. It is not intended that the present invention be limited only to cases where the symptoms are eliminated. The present invention specifically contemplates treatment such that symptoms are reduced (and the condition of the subject is thereby “improved"), albeit not completely eliminated. Moreover, it is sufficient if one or more (e.g., a subset) of symptoms are reduced.
  • the subject is a human and the oral dosage of either the (+) or (-) enantiomer of flosequinan is in a single dose per day of up to approximately two hundred milligrams. In another embodiment said dosage is between approximately twenty-five to approximately seventy-five milligrams. In another embodiment, the (+) or the (-) enantiomer is administered in a single oral dose per day of between approximately one hundred and twenty-five and approximately two hundred milligrams. In another embodiment, the administration of said enantiomers of flosequinan comprises three daily doses, before meals, each dose of up to approximately two hundred milligrams per dose. In another embodiment, said daily doses comprise between approximately twenty-five to approximately seventy-five milligrams per dose. In another embodiment, said daily doses comprise between approximately one hundred and twenty-five and approximately two hundred milhgrams per dose.
  • said enantiomers of flosequinan are introduced orally, cutaneously, by standard injection (e.g. intravenously), or intranasally.
  • the method comprises a) providing: i) a patient suffering from symptoms of cardiac disease who is not being administered nitrates or nitrites; and ii) an enantiomer of flosequinan; and b) introducing said enantiomer of flosequinan to said patient such that said symptoms of cardiac disease are reduced.
  • said substantially purified enantiomer of flosequinan is a (+) enantiomer.
  • said composition is substantially free of the (-) enantiomer of flosequinan.
  • the method comprises a) providing: i) a subject suffering from symptoms of cardiovascular disease; and ii) a purified enantiomer preparation of flosequinan, or a pharmaceutically acceptable salt thereof; and b) administering said preparation to the subject such that symptoms are reduced.
  • said cardiovascular disease is selected from the group consisting of hypertension, angina pectoris, myocardial infarction, and congestive heart failure.
  • Said administering step is selected from the routes consisting of intranasal and respiratory inhalation.
  • the method comprises a) providing: i) a subject suffering from symptoms of cardiovascular disease who is not being treated with a drug that causes hypotensive effects, and ii) a purified enantiomer preparation of flosequinan, or a pharmaceutically acceptable salt thereof; and b) administering said preparation to the subject such that such symptoms are reduced.
  • the method comprises a) providing: i) a subject suffering from symptoms of cardiovascular disease who is not being treated with a nitrite or nitrate, and ii) a purified enantiomer preparation of flosequinan, or a pharmaceutically acceptable salt thereof; and b) introducing said preparation to the subject such that such symptoms are reduced.
  • Said nitrate is selected from the group consisting of glyceryl trinitrate, isosorbide dinitrate, isosorbide-5'-mononitrate, and erythrityl tetranitrate.
  • the present invention be limited by the method of introduction of a purified enantiomer preparation of flosequinan, or a pharmaceutically acceptable salt thereof.
  • the enantiomer of flosequinan is introduced orally.
  • an adult human is provided an oral dosage as a single dose per day of 10 to 200 milligrams.
  • enantiomers of flosequinan are introduced cutaneously, by standard injection, intranasally, or through respiratory inhalation.
  • the present invention is not limited by the degree of response by the subject. In one embodiment, relief of pain from angina pectoris is sufficient.
  • the present invention contemplates a mixture of a purified enantiomer of flosequinan and a carrier, i.e. a mixture comprising lactose.
  • the enantiomers recited in the present invention are introduced into said subject by oral administration or cutaneous administration.
  • said subject is an adult human and said oral administration comprises up to approximately 200 milligrams of flosequinan.
  • the enantiomers of flosequinan recited in the present invention are administered to a subject who has not been treated in the past with a drug that causes hypotensive effects.
  • the enantiomers of flosequinan recited in the present invention are administered to a subject who is not being treated with a nitrite or nitrate.
  • said nitrate is selected from the group consisting of glyceryl trinitrate, isosorbide dinitrate, isosorbide-5-mononitrate and erythrityl tetranitrate.
  • the present invention also contemplates a method, comprising: a) providing: i) a subject suffering from a symptom of a cardiovascular disease selected from the group of hypertension and congestive heart failure and; ii) a purified enantiomer preparation of flosequinan and; b) administering said preparation to said subject under conditions such that said symptom is reduced.
  • said purified enantiomer of flosequinan is the (+) enantiomer.
  • said purified enantiomer of flosequinan is the (-) enantiomer.
  • the enantiomer preparation introduced into said subject by oral or cutaneous administration comprises up to approximately 200 milligrams of flosequinan.
  • the present invention also contemplates a purified flosequinan enantiomer preparation comprising a carrier.
  • Figure 1 depicts the respective HPLC column retention times and optical rotations of the enantiomers of flosequinan separated by the method provided in Example 2.
  • Figure 2 depicts the chemical structure of a quinolinone (top) and 16 C-7 substituents (bottom).
  • enantiomer refers to stereoisomers of molecules that are non-superimposable mirror images of each other. Enantiomers have identical physical properties, such as melting points and boiling points, and also have identical spectroscopic properties. Enantiomers differ from each other with respect to their interaction with plane-polarized light and with respect to biological activity.
  • stereoisomer refers to compounds that have their atoms connected in the same order but differ in the arrangement of their atoms in space, (e.g. cw-2-butane and tr r ⁇ -2-butane).
  • diastereoisomers refers to stereoisomers that are not mirror images of each other.
  • quinolinone refers to chemical compositions comprising quinolinone as set forth in the following structure (2-quinolone):
  • quinolinone e.g., isoquinolone
  • derivatives of quinolinone refers to chemical compositions comprising quinolinone with a chemical group attached, including (but not limited to) halogenated quinolinones.
  • methylsulphmyl derivatives of quinolinone refers to chemical compositions comprising quinolinone with a methylsulphmyl group
  • flosequinan (7-fluoro-l-methyl-3-(methylsulphinyl)-4(lH)- quinolone; 7-fluoro-l-methyl-3-(methylsufinyl)-4(lH)-quinolinone):
  • purified enantiomer and “purified enantiomer preparation” are meant to indicate a preparation (e.g. derived from a racemic mixture or synthesized de novo) wherein one enantiomer has been enriched over the other, and more preferably, wherein the other enantiomer represents less than 10%, and more preferably less than 5%, and still more preferably, less than 2% of the preparation.
  • racemic mixture refers to a mixture of the two enantiomers of one compound.
  • An ideal racemic mixture is one wherem there is a 50:50 mixture of both enantiomers of a compound such that the optical rotation of the (+) enantiomer cancels out the optical rotation of the (-) enantiomer.
  • salts or “a pharmaceutically acceptable salt thereof refer to salts prepared from pharmaceutically acceptable non-toxic acids or bases including inorganic acids and bases and organic acids and bases. Since the compound of the present invention is basic, salts may be prepared from pharmaceutically acceptable non-toxic acids.
  • a patient who is "free from cardiac disease” and a patient who is “free from symptoms of cardiac disease” indicate that the patient has not been diagnosed with angina, myocardial infarction, congestive heart failure and that symptoms of angina, ischemia, myocardial infarction, and/or congestive heart failure have not been detected.
  • symptoms of cardiovascular disease refers to any clinical manifestation of a disease state associated with the heart and vasculature.
  • said clinical manifestation include: angina pectoris, myocardial infarction, congestive heart failure, cardiomyopathy, hypertension, arterial stenosis, and venous stenosis.
  • the present invention specifically contemplates treatment such that symptoms are reduced (and the condition of the subject is thereby "improved"), albeit not completely eliminated.
  • “congestive heart failure” is a specific cardiovascular disease which is characterized, but not limited to, the following symptoms: shortness of breath, pitting edema, an enlarged and tender liver, engorged neck veins, and pulmonary rales in various combinations.
  • the terms “lower alkyl”, “lower alkoxy”, “lower alkanoyl”, and “lower alkythio” denote such groups containing 1-8 carbon atoms, especially 2-4 carbon atoms for lower alkanoyl and 1-4 carbon atoms for the other groups.
  • Examples of such groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-heptyl, n-octyl, methoxy, ethoxy, propoxy, n-butoxy, isobutoxy, acetyl, propionyl, butyryl, methylthio, ethylthio, propylthio and n-butylthio.
  • active compound denotes a pyridinone compound of general formula I (as illustrated and described below in the section entitled “Other Compounds Useful In The Treatment of Cardiovascular Disease”), or a quinolinone or quinolinone derivative as illustrated and described above.
  • drug that have hypotensive effects are those drugs which, when administered, cause the patient's end-diastolic blood pressure to be reduced. Nitrates are commonly used drugs which have hypotensive effects.
  • Nitrates are compounds that contain the -NO 3 - moiety. Nitrates typically used in the clinic are shown in Table 1.
  • Nitrites are compounds that contain the -NO 2 - moiety. Nitrites typically used in the clinic are shown in Table 1.
  • erectile dysfunction refers to certain disorders of the cavernous tissue of the penis and the associated facia which produce impotence, the inability to attain a sexually functional erection.
  • symptoms of erectile dysfunction refers to any two of the following symptoms: penile flaccidity, lack of penile tumescence, lack of penile rigidity, and inability to produce an erection sufficient for vaginal penetration. Symptoms are "reduced” when the magnitude (e.g. intensity) or frequency of symptoms is reduced. It is not intended that the present invention be limited only to cases where the symptoms are eliminated. The present invention specifically contemplates treatment such that one or more symptoms are reduced (and the condition of the patient is thereby "improved"), albeit not completely eliminated.
  • symptoms of sexual dysfunction includes, but is not limited to, poor blood flow to the sexual organs and/or failure to achieve orgasm. Symptoms are "reduced” when the magnitude (e.g. intensity) or frequency of symptoms is reduced. It is not intended that the present invention be limited only to cases where the symptoms are eliminated. The present invention specifically contemplates treatment such that one or more symptoms are reduced (and the condition of the patient is thereby “improved"), albeit not completely eliminated.
  • an “erection” refers to the condition of a penis whereby it is at least semi-rigid as opposed to being in a flaccid state.
  • the term "subject” refers to both humans and animals.
  • standard injection refers to the placement of a pharmaceutical composition into a subject (e.g., with a hypodermic needle). For example, such TABLE 1
  • injection can be made subcutaneously, intravenously, intramuscularly, intracavernosally, etc.
  • intracavernosal injection is injection into the corpus cavernosum of the penis.
  • intranasally refers to the introduction of a pharmaceutical composition within the nasal cavity.
  • respiratory inhalation refers to the introduction of a pharmaceutical composition within the respiratory tract.
  • oral administration refers to the introduction of a pharmaceutical composition into a subject by way of the oral cavity (e.g., in aqueous liquid or solid form).
  • cutaneously refers to the introduction of a pharmaceutical composition into a subject by application to the surface of the skin such that the composition is absorbed into the subject.
  • transurethrally refers to the introduction of a pharmaceutical composition to the urethra of a subject such that the composition is absorbed into the subject.
  • intranasally refers to the introduction of a pharmaceutical composition within the nasal cavity.
  • respiratory inhalation refers to the introduction of a pharmaceutical composition within the respiratory tract.
  • vaginal penetration refers to the state of an erection such that the penis is capable of entering a vagina without manual manipulation.
  • sexual stimulation refers to activity that would induce an erection in a male without erectile dysfunction (e.g., sexually explicit media, manual manipulation, vibration, live erotic entertainment, etc.)
  • single dosage refers to a pharmaceutical composition of a formulation that is capable of achieving its intended effect in a single administration or application.
  • the present invention relates to methods for the treatment of sexual dysfunction in males and females (including but not limited to erectile dysfunction in males) in particular treatment groups. This will be reviewed in section (A) below.
  • the present invention also relates to the treatment of cardiovascular disease. This will be reviewed in section (B) below.
  • the present invention relates to methods for the treatment of sexual dysfunction in males and females (including but not limited to erectile dysfunction in males) in particular treatment groups.
  • the methods of the present invention comprise the utilization of pharmaceutical compounds and compositions to patients who are free of symptoms of cardiac disease and who have not been treated with drugs which cause hypotensive effects, such as nitrites and nitrates.
  • the compositions comprise enantiomers of flosequinan, including derivatives thereof.
  • a purified enantiomer of flosequinan is administered.
  • flosequinan enantiomers may potentiate the hypotensive effects of nitrates, and its administration to patients who are concurrently using organic nitrates in any form may be contraindicated.
  • an enantiomer of flosequinan be administered cutaneously, transurethrally, by standard injection, intracavernosally, intranasally or through respiratory inhalation, although it is not intended that the methods of the present invention be limited to the mode of administration of an enantiomer of flosequinan.
  • a pharmaceutical composition comprising a purified enantiomer of flosequinan is administered. It is contemplated that said pharmaceutical composition be administered cutaneously, transurethrally, by standard injection, intracavernosally, intranasally or through respiratory inhalation, although it is not intended that the methods of the present invention be limited to the mode of administration of said pharmaceutical composition.
  • the present invention contemplates the use of compositions that are effective to induce an erection in a human male suffering from impotence of any origin, other than anatomical deficiencies (i.e., lacking a penis or a significant portion thereof) that preclude an erection sufficient for vaginal penetration.
  • these compositions may be used to induce an erection in a male suffering from impotence caused by severe atherosclerosis, and also impotence that is neurogenic or psychogenic in origin.
  • the compositions utilized in the methods of the present invention comprise purified enantiomers of flosequinan, including derivatives thereof.
  • the present invention contemplates the resolution of the (+) and (-) enantiomers of flosequinan.
  • Many organic compounds, including flosequinan exist in optically active forms (i.e., they have the ability to rotate the plane of plane-polarized light).
  • the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center(s).
  • the prefixes d and 1 or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or 1 meaning that the compound is levorotatory (rotates to the left).
  • a compound prefixed with (+) or d is dextrorotatory (rotates to the right).
  • stereoisomers are identical except that they are mirror images of one another.
  • a specific stereoisomer may also be referred to as an "enantiomer.
  • Stereochemical purity is of importance in the field of pharmaceuticals, where
  • the present invention is not limited by any specific means of resolving the (+) and (-) enantiomers of flosequinan to obtain a purified enantiomer of flosequinan.
  • said enantiomers are resolved as follows. A racemic mixture of flosequinan is subjected to high-performance liquid chromatography (HPLC) over a Chiracel OD column (Chiral Technologies, Exton, PA) at a flow rate of 1.0 ml/minute. A mobile phase comprising methanol is utilized, resulting in the resolution of a distinct peak for each enantiomer. The resolved (+) and (-) enantiomers of flosequinan are eluted with methanol with an optical purity greater than 99%.
  • flosequinan has been reported to be a selective inhibitor of phosphodiesterase III (PDE3).
  • PDE3 phosphodiesterase III
  • Shiraishi et al "Effect of cilostazol, a phosphodiesterase type III inhibitor, on histamine-induced increase in [Ca 2+ ]i and force in middle cerebral artery of the rabbit," Br. J. Pharmacol, 123: 869-878 (1998)).
  • the present invention be limited to any particular mechanism to reduce symptoms of sexual dysfunction.
  • the (+) and (-) enantiomers of flosequinan were subjected to biochemical assays to determine their respective percent inhibition of PDE3. In one embodiment, it was shown that the
  • (+) enantiomer of flosequinan has an eight- fold increase in PDE3 inhibition as compared to that of the (-) enantiomer of flosequinan at the same molar concentration. Moreover, in the same embodiment, the (+) enantiomer of flosequinan exhibited greater inhibition of PDE3 than a racemic mixture of flosequinan at the same molar concentration.
  • a human male suffering from impotence that is substantially only neurogenic or psychogenic is readily made by a person skilled in the art using a number of readily available diagnostic procedures.
  • a male suffering from impotence can first be given a physical examination with particular attention to possible penile and scrotal pathology, whereby any anatomical deficiency precluding an erection sufficient for vaginal penetration can be detected.
  • the male can be subjected to tests, whereby penile venous leakage or severe or untreatable atherosclerosis can be detected.
  • Such tests include determination of the penobrachial blood pressure index (PBPI), doppler investigation of the penile arteries, and a papaverine test.
  • PBPI penobrachial blood pressure index
  • the PBPI is the penile systolic blood pressure divided by the systolic blood pressure determined at one of the arms. These blood pressures can be determined by any number of standard techniques.
  • the penile systolic blood pressure can be determined by i) placing an inflatable cuff around the base of the free part of the penis in the flaccid state which is capable of being used to apply variable pressure, readable from a gauge, to an object around which the cuff is placed, ii) localizing the penile arteries with a Doppler ultrasound probe (e.g., 8 MHz probe, such as the Mini Doplex D500 available from
  • the pressure at which the Doppler sound reappears is the penile systolic blood pressure.
  • a male's penile blood pressure is regarded as normal if his PBPI is >0.80.
  • each of the two penile cavernous arteries is investigated distal to the aforementioned cuff using the Doppler ultrasound problem.
  • the function of each of the two arteries is assessed by Doppler ultrasound using an arbitrary scale of 0, 1, 2 or 3, where 0 means that the function is so deficient that the artery cannot be located and 3 means that the artery is well enough that maximal Doppler sound is observed.
  • a tourniquet is placed at the base of the free part of the penis and tightened and then, with the patient seated, 30 mg of papaverine in 1 ml of a physiologically acceptable fluid (e.g., physiological saline or phosphate-buffered saline) is injected into the penile cavernous body.
  • a physiologically acceptable fluid e.g., physiological saline or phosphate-buffered saline
  • An impotent male who does not have an anatomical deficiency that would preclude having an erection sufficient for vaginal penetration, who has a PBPI >0.80, who has scores of 2 or 3 in Doppler ultrasound investigations of both of the cavernous arteries of the penis, after papaverine injection as described above, and who has a fully rigid erection after papaverme injection and vibration as described above, is suffering from impotence that is "substantially only neurogenic or psychogenic" in origin.
  • Atherosclerosis or venous leakage contributes to such impotence, and atherosclerosis likely does contribute if the score is less than 3 in the
  • a male who is diagnosed in accordance with the present specification as suffering from impotence that is "substantially only neurogenic or psychogenic” in origin is suffering from impotence that is substantially only neurogenic, psychogemc or neurogenic and psychogenic in origin, even though an underlying cause of the impotence has been identified as a side-effect of a drug, alcoholism or excessive consumption of alcohol.
  • a male with a PBPI less than about 0.60 with scores of 0 in Doppler investigations of both penile cavernous arteries (after papaverme injection as described above), and with a less than fully rigid erection after papaverine injection and vibration will have impotence caused by "untreatable" atherosclerosis.
  • Methods are available to ascertain whether impotence is untreatable because of venous leakage.
  • One method of ascertaining whether untreatable venous leakage is a cause of impotence is by cavernosometry, optionally supplemented with cavernosography. (See, e.g., Delcour et al, Radiology 161: 799 (1986); Porst et al, J. Urol. 137: 1163 (1987); Lue et al, J. Urol. 37: 829 (1987)).
  • Cavernosometry can be done using, both before and after intracavernosal injection of 60 mg of papaverine (in 1 ml of physiological saline), infusion of physiological saline through a 19-gauge needle into one corpus cavernosum with a 21 -gauge needle inserted into the other corpus cavemosum for measurement of intracorporal pressure (which is recorded on a plotter).
  • the infusion rates needed to induce and maintain an erection are measured. If the infusion rate needed to maintain an erection is greater than 50 ml/min before administration of the papaverine and greater than 15 ml/min after administration of the papaverine, untreatable venous leakage is present.
  • the penis is X-rayed, both before and after intracavernosal injection of 60 mg papaverine (in 1 ml of physiological saline), while infusing contrast medium into the corpus cavernosum (e.g., through a 19-gauge needle) at a flow rate that maintains an erection during the X-ray.
  • contrast media suitable for the procedure are available in the art; these are typically aqueous solutions of iodinated compounds that provide between about 180 mg/ml and about 360 mg/ml of iodine.
  • Examples are a solution of iohexol providing 240 mg/ml of iodine sold by Winthrop Pharmaceuticals, New York, N.Y., USA, and a solution of iopamidol providing 300 mg/ml iodine sold by Astra Meditec, Goteborg, Sweden.
  • 50-100 ml of the contrast medium will be employed for each x-ray (i.e., before and then after the injection of papaverine).
  • 30 mg papaverine in 1 ml physiological saline
  • stimulation by vibration can be employed in place of 60 mg papaverine (in 1 ml physiological saline).
  • the clitoris is the homologue of the penis. It is a cylindrical, erectile organ composed of the glans, corporal body and the crura. The corporal body is surrounded by a fibrous sheath, tunica albuginea, which encases cavernosal tissue consisting of sinusoids and surrounding smooth muscle. The clitoris responds to sexual excitement by tumescence and erection, although this does not occur with the degree of pressure elevation as found during penile erection. The characteristics of the clitoral blood flow, however, approximately parallel those of the male. See K. Park et al, "Vasculogenic female sexual dysfunction: The hemodynamic basis for vaginal engorgement insufficiency and clitoral erectile insufficiency," fnt. J. Impotence Res.
  • Post-menopausal women and women with a history of vascular risk factors have been shown to have significantly more complaints of self-reported female vaginal and clitoral dysfunctions than pre-menopausal women or women without vascular risk factors.
  • Such problems include, but are not limited to, atherosclerosis-induced vaginal engorgement insufficiency and clitoral erectile insufficiency syndromes.
  • a human female is suffering from poor blood flow or supply is readily made by a person skilled in the art using a number of readily available diagnostic procedures.
  • the human vagina receives arterial blood supply from the vaginal artery, the vaginal branch of the uterine artery, the internal pudendal artery, and the vaginal branches of the middle rectal artery. Blood flow in these areas can readily be assessed by a number of techniques. Arterial blood can be obtained and the blood levels of cholesterol and triglycerides can be analyzed as a first step. However, the preferred method is imaging.
  • vaginal wall blood flow can be measured by laser Doppler flow probes placed into the vaginal muscularis layer within the spongy region of blood-filled spaces and vascular smooth muscle.
  • Clitoral intracavernosal erectile tissue blood flow can be measured with a similar laser Doppler flow probe placed into the corporal bodies.
  • the flow probes are connected to a laser Doppler flowmeter (Transonic Systems, Inc.) which is calibrated against an internal standard reading flow in units of ml/min/ 100 gm of tissue.
  • the laser Doppler probe uses the Doppler shift of a projected beam of laser light that registers on a photodetector. Static tissues will produce no Doppler shift in wavelength but moving red blood cells will produce a shift proportional to the red cell velocity.
  • the (+) enantiomer of flosequinan is provided together with physiologically tolerable liquid, gel or solid carriers, diluents, adjuvants and excipients.
  • enantiomers of flosequinan may be used together with other chemotherapeutic agents.
  • formulations may also contain such normally employed additives as binders, fillers, carriers, preservatives, stabilizing agents, emulsifiers, buffers and excipients as, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and the like.
  • compositions typically contain l%-95% of active ingredient, preferably 2%-70%.
  • the present invention is not limited by the method of introduction of the therapeutic compound to the body.
  • the present invention contemplates administering cutaneously, orally, intracavernosally, transurethrally, by standard injection (e.g. intravenous or intramuscular), intranasally or through respiratory inhalation. It is believed that oral administration of the (+) flosequinan enantiomer and pharmaceutical compositions comprising the (+) enantiomer of flosequinan is an effective mode of administration.
  • Peak plasma concentrations of flosequinan (+) enantiomer are observed 1-2 hours following oral administration, while peak metabolite plasma levels are observed about seven hours following oral dosage.
  • the enantiomer of flosequinan is introduced into the male or female orally. It is believed that an oral dosage up to approximately 200 milligrams of a racemic mixture of flosequinan is an effective oral dosage. It is also believed that the oral administration of a purified of enantiomer of flosequinan is effective at even lower dosages (e.g. less than 200 mg).
  • the male or female is an adult human and the oral dosage of a purified enantiomer of flosequinan is in a single dose per day of up to approximately two hundred milligrams, more preferably, between approximately fifty to approximately seventy-five milligrams.
  • a purified enantiomer of flosequinan is administered in a single oral dose per day of between approximately twenty and approximately fifty, and even more preferably, between approximately ten and approximately twenty milligrams per day.
  • Flosequinan enantiomers and pharmaceutical compositions comprising flosequinan enantiomers may also be administered cutaneously in a carrier adapted for topical administration.
  • a carrier include creams, ointments, lotions, pastes, jellies, sprays, aerosols, bath oils, or other pharmaceutical carriers which accomplish direct contact between flosequinan and the pore of the skin.
  • pharmaceutical preparations may comprise from about 0.001% to about 10%, and preferably from about 0.01 to 5% by w/w of the active compound (e.g., flosequinan) in a suitable carrier.
  • the flosequinan enantiomer or pharmaceutical compositions comprising a flosequinan enantiomer in an appropriate solvent such as ethanol or DMSO (dimethylsulfoxide), and the like, to facilitate incorporation into a pharmaceutical preparation.
  • an appropriate solvent such as ethanol or DMSO (dimethylsulfoxide), and the like.
  • the present invention can be incorporated in other products associated with sexual activity.
  • a coated, erection inducing condom as disclosed in U.S. Pat. No. 4,829,991, hereby incorporated by reference, can be utilized with flosequinan enantiomers or pharmaceutical compositions comprising flosequinan enantiomers.
  • injection of flosequinan enantiomers, or a pharmaceutical composition thereof can be carried out by any conventional injection means (e.g., employing an hypodermic syringe and needle or a similar device such as the NovolinPen. sold by Squibb-Novo, Inc.,
  • flosequinan enantiomers are introduced intracavernously as described in U.S. Patent No. 5,447,912 to Gerstenberg et al, hereby incorporated by reference.
  • Flosequinan enantiomers and pharmaceutical compositions comprising flosequinan enantiomers can be introduced intracavernosally in a physiologically acceptable composition.
  • Such compositions are aqueous solutions that are physiologically acceptable for administration by intracavernosal injection into the penis.
  • the physiologically acceptable carrier is selected such that it is not painful or irritating upon intracavernosal injection.
  • the physiologically acceptable compositions will preferably be sterile at the time of administration by intracavernosal injection.
  • physiologically acceptable compositions for use in the methods is physiological saline or phosphate buffered saline, in which flosequinan enantiomers or a pharmaceutical composition comprising enantiomers of flosequinan, is dissolved or suspended, such that the resulting composition is suitable for intracavernosal injection.
  • a physiologically acceptable composition can also include a non-irritant preservative, such as, e.g., benzalkonium chloride at 0.05% (w/v) to'0./2% (w/v).
  • non-toxic salts of VIP, PHM and ⁇ -adrenergic blockers that can be employed in a physiologically acceptable composition for use in the methods herein, including, among others, the chloride, bromide, acetate, sulfate, and mesylate salts.
  • the penis is constricted near the base thereof and between the base and the point at which the injection into a corpus cavernosum occurs, in order to limit loss of injected fluid from the corpus cavernosum before the ingredients in the fluid, that are active in inducing erection, have been able to have erection-inducing effects.
  • the constriction can be effected by any means known in the art, such as with a tourniquet, cuff, rubber band or the like, or even manually, in order to slow the release of the injected fluid and the pharmacologically active substance(s) therein into the general circulation.
  • the present invention is not limited by a particular method for introducing flosequinan enantiomers or a pharmaceutical composition comprising enantiomers of flosequinan transurethrally.
  • the (+) flosequinan enantiomer, or a pharmaceutical composition thereof is introduced to the urethra in a carrier as described for cutaneous administration.
  • Devices and methods for transurethral introduction of pharmaceutical compositions is described in U.S. Patent No. 5,474,535 to Place et al; Noss, U.S. Pat. No. 4,801,587 and Kock, EPA 0357581, all hereby incorporated by reference.
  • Additional methods of the transurethral introduction of flosequinan enantiomers, or pharmaceutical compositions thereof, include the use of medicated catheters, such as those used to prevent or treat localized infections and irritation of the urethra and bladder (See U.S. Pat. No. 4,640,912, hereby incorporated by reference).
  • transurethral administration of pharmaceutical compositions is presented in U.S. Pat. Nos. 4,478,822, 4,610,868, 4,640,912 and 4,746,508, all hereby incorporated by reference, and medicated urethral suppositories, inserts or plugs, typically containing anti-infective agents or spermicide are disclosed in U.S. Pat. Nos.
  • flosequinan or a pharmaceutical composition comprising flosequinan is injected with a standard syringe.
  • flosequinan or a pharmaceutical composition comprising flosequinan is injected with a carrier as described for intracavernosal injection.
  • Flosequinan enantiomers and pharmaceutical compositions comprising flosequinan enantiomers may also be administered intranasally.
  • Formulations suitable for intranasal administration include ointments, creams, lotions, pastes, gels, sprays, aerosols, oils and other pharmaceutical carriers which accomplish direct contact between flosequinan or a pharmaceutical composition comprising flosequinan and the nasal cavity.
  • Examples of pharmaceutical compositions administered intranasally are described in U.S. Patents Nos. 5,393,773 and 5,554,639 to Craig et al; and 5,801,161 to Merkus, all hereby incorporated by reference.
  • Flosequinan enantiomers and pharmaceutical compositions comprising flosequinan enantiomers may also be administered through respiratory inhalation.
  • Formulations suitable for respiratory inhalation include ointments, creams, lotions, pastes, gels, sprays, aerosols, oils and other pharmaceutical carriers which accomplish direct contact between flosequinan enantiomers or a pharmaceutical composition comprising flosequinan enantiomers and the respiratory tract.
  • Examples of pharmaceutical compositions administered through respiratory inhalation are described in U.S. Patent 4,552,891 to Hu et al; 5,869,479 to Kreutner et al, and 5,864,037 to
  • intranasal administration and respiratory inhalation are the preferred modes of administration due to the ease of administration and faster onset of therapeutic activity. It is contemplated that intranasal administration and respiratory inhalation are advantageous as they may allow a smaller effective dosage to be administered than would be possible with the oral route of administration.
  • a preferred mode of administration comprises administration to the lung. Intrapulmonary delivery of pharmacologic agents to patients can be accomplished via aerosolization. Alternatively, the agent may be administered to the lung through a bronchoscope. Of course, the therapeutic agents may be investigated for their efficacy via other routes of administration, including parenteral administration.
  • the administration of the compositions of the present invention is accompanied by sexual stimulation to induce an erection.
  • the sexual stimulation can v begin before or after the introduction of flosequinan or a pharmaceutical composition comprising flosequinan. If the stimulation begins after the injection, it is preferably begun within 5 to 10 minutes to insure that there is significant overlap of the pharmacological effects of the pharmaceutical composition administered and the stimulative effects of the sexual stimulation. Whether the stimulation begins before or after the injection, it will continue preferably at least until an erection sufficient for vaginal penetration is achieved.
  • Sexual stimulation as prescribed by these methods includes any form of sexual stimulation that would induce an erection in a normal male who is not suffering from erectile insufficiency.
  • the sexual stimulation can be that which occurs in the course of sexual relations between the subject and another person or can be outside sexual relations with another person.
  • Examples of methods of sexual stimulation include, alone or in combination, touching or erotically manipulating erogenous areas of the genital organs or other erogenous parts of the body; providing visual stimulation, as with a sexually explicit media (e.g., pornographic film) or other form of sexually stimulative show or display. Additionally, providing vibratory stimulation to the penis, at between about 30 Hz and about 100 Hz with an amplitude of about 1 mm to about
  • 5 ram as can be provided, for example, by resting the penis on the table of a vibrating apparatus such as that of a Vibrector system (Multicept, Genofte, Denmark).
  • a Vibrector system Multicept, Genofte, Denmark.
  • a preferred method of sexual stimulation includes providing visual stimulation, as with a pornographic film, simultaneously with vibratory stimulation of the penis, as with a Vibrector system set to between about 30 Hz and about 60 Hz (usually about 50 Hz)in frequency and between about 1 mm and about 2.5 mm (usually about 2.2 mm) in amplitude.
  • sexual dysfunction e.g. erectile dysfunction
  • pharmaceutical agents e.g. flosequinan enantiomers, or pharmaceutical compositions comprising flosequinan enantiomers, are administered therapeutically to patients having such dysfunction.
  • the present invention relates to methods for the treatment of cardiovascular disease.
  • the present invention contemplates compositions and methods for the treatment of CHF and hypertension.
  • These compositions comprise quinolinones, including derivatives and enantiomers thereof.
  • a variety of quinolinone derivatives are shown in Figure 2.
  • Methods for producing antibiotic derivatives of a particular quinolone carboxylic acid skeleton are provided in U.S. Patent No. 4,623,650 to Gilligan et al, hereby incorporated by reference.
  • the present invention encompasses the use of a variety of quinolinone derivatives (e.g., 5-bromoquinoline, 5-nitroisoquinoline, 8-nitroisoquinoline and 1- methylisoquinoline).
  • quinolinone derivatives e.g., 5-bromoquinoline, 5-nitroisoquinoline, 8-nitroisoquinoline and 1- methylisoquinoline.
  • One skilled in the art can readily produce such derivatives as set forth in McMurry, Organic Chemistry. 2nd Ed., Brooks/Cole Publishing, Belmont, CA (1988), pages 1044-1045 and 1076.
  • the present invention contemplates the use of methylthio and methylsulphmyl derivatives of quinolinone.
  • the methylsulphmyl derivative is flosequinan (whether as a racemic mixture or as a purified enantiomer).
  • the present invention contemplates compositions and methods for the treatment of CHF and hypertension in subjects who are not concurrently being treated with nitrites or nitrates.
  • the present invention contemplates the administration of the enantiomers of flosequinan as a methods of treating CHF and hypertension.
  • the optically active derivatives and metabolites of flosequinan are also contemplated.
  • a purified enantiomer. preparation of flosequinan is administered. It is contemplated that an enantiomer of flosequinan be administered cutaneously, by standard injection, intranasally, or through respiratory inhalation. It is not intended that the methods of the present invention be limited to the mode of administration of an enantiomer of flosequinan.
  • Suitable animal models include, but are not limited to, species including rodents, non-human primates, ovines, bovines, ruminants, lagomorphs, porcines, caprines, equines, canines, felines, and aves.
  • female rats (weight range 180-240 g) of the Aoki-Okamoto strain of spontaneously hypertensive can be used.
  • the rats are divided into groups of four and will be fasted overnight before administration of either the (+) or (-) enantiomer of flosequinan.
  • Blood pressure will be determined in the following way.
  • the rats are placed in a restraining cage, maintained at 38°C, with their tails protruding through holes in the cage. After 30 minutes in the cage, blood pressure will be measured using an inflatable cuff placed round the base of the tail and arterial pulsations will be monitored with a pneumatic pulse transducer.
  • a limb or a phalanx as a site to monitor blood pressure.
  • a pressure, greater than the expected blood pressure, will be applied to the cuff and this pressure will be slowly reduced.
  • the pressure in the cuff at which arterial pulsations reappears will be recorded as the blood pressure.
  • the rats will be removed from the cage and each group will be orally administered a given dose of either the (+) or (-) enantiomer of flosequinan.
  • blood pressure will be measured at 1.5 and 5.0 hours after dosing.
  • a effective dosage will be defined as follows.
  • a threshold antihypertensive dose dose giving a reduction of blood pressure of between 5 and 15% after correction
  • Compounds which are inactive at a particular dose level and which produce a reduction of blood pressure equal to or greater than 15% after correction at the next highest dose level will be designated as having a threshold antihypertensive dose within the range covered by the two dose levels.
  • the above described protocol is suited it a variety of hypertensive and normotensive animal models.
  • a normotensive marmoset monkey will be used.
  • Mature M. fascicularis primates will be premedicated with ketamine hydrochloride (15 mg/kg im) and glycopyrrolate (0.01 mg/kg i ). Following intubation, anesthesia will be maintained with 0.5% to 1% isoflurane. A left thoracotomy, including removal of the fourth or fifth rib, will be performed under sterile conditions and the pericardium will be opened and reflected to expose the heart. Silastic catheters attached to subcutaneous vascular access ports (VAPs; Access Technology) will be inserted into the descending thoracic aorta and into the right atrium via the atrial appendage.
  • VAPs subcutaneous vascular access ports
  • a solid-state micromanometer (Konigsberg Instruments) will be introduced via a stab wound in the ventricular apex and secured with a purse-string suture.
  • a unipolar pacing lead will be sutured to the posterior wall of the LV and connected to a programmable pacemaker (Medtronic, Model Minix 8340) that will be situated subcutaneously over the left chest wall.
  • a programmable pacemaker Medtronic, Model Minix 8340
  • Internal electrocardiogram (ECG) leads will be sutured to the chest wall. All catheters and wires will be tunneled subcutaneously to the dorsal midline below the scapula.
  • Transdermal titanium skin buttons (Konigsberg Instruments) attached to the wires from the LV pressure transducer and ECG leads will be secured along the midline, while the catheter VAPs will be situated in subcutaneous pockets. The chest will be closed in layers and negative intrapleural pressure restored via a temporary chest tube.
  • Antibiotics (Cefazolin, 30 mg/kg) will be administered subcutaneously prior to surgery and postoperatively for 10 days (30 mg/kg bid).
  • Buprenorphine (0.01 mg/kg sq) will be administered for analgesia immediately after surgery and as needed the first postoperative week. All monkeys will be allowed to recover for a minimum of 2 weeks after surgery and were conditioned to sit in upright/reclining primate restraint chairs prior to commencement of experimental investigations.
  • Arterial blood pressure will be measured by inserting into the aortic VAP a saline-filled needle-tipped catheter, the other end of which was connected to a Statham P23 XL pressure transducer.
  • Intravenous agents will be delivered via a similar catheter extension set inserted into the right atrial VAP.
  • Left ventricular pressure (LVP) will be measured via the Konigsberg micromanometer and will be cross- calibrated with the aortic pressure signal, and the transthoracic ECG will be measured using a Gould ECG/Biotach amplifier (Gould Instrument Systems).
  • All physiological signals will be sampled at 500 Hz using a computerized digital data acquisition system (Po-Ne-Mah, Gould Instrument Systems), while being simultaneously recorded on digital audio tape (Model RD HIT, Teac) and displayed on an MT 95000 eight- channel thermal-array recorder (Astro-Med).
  • HR heart rate
  • MAP mean arterial blood pressure
  • LVSP left ventricular systolic and end-diastolic blood pressures
  • LVEDP peak positive rate of change in LVP (+dP/dt max ) will derived using algorithm-based analyses of the digitized waveforms.
  • LV dimensions will be recorded with the primates under ketamine sedation using M-mode echocardiographic imaging (Hewlett Packard Sons 100CF) of the LV via a left transthoracic approach. Images will be recorded on VHS tape for subsequent calculation of LV fractional shortening and wall thickening percentage (WT) from the short axis and wall thickness dimensions.
  • WT wall thickening percentage
  • end-diastolic dimensions will be defined as occurring at the peak of the R-wave, while end-systole will be associated with the peak of the T-wave.
  • Systolic WT will be then calculated as the difference between end-systolic and end-diastolic dimensions and is expressed as percent change from end-diastolic thickness [(EST - EDT)/EDT] x 100.
  • the present invention be limited by the species of the animal model used to evaluate the efficacy of a given compound as potential CHF therapeutic.
  • the above described protocol is suited it a variety of hypertensive and normotensive animal models.
  • a normotensive marmoset monkey will be used.
  • compositions utilized in the methods of the present invention comprise purified enantiomers of flosequinan, including derivatives thereof.
  • the present invention is not limited by a specific means of producing enantiomers of flosequinan, methods of producing a racemic mixture of flosequinan (and methylsuphinyl / methylthio derivatives of quinolinone) are set forth in U.S. Patent Nos. 5,079,264 and 5,011,931 to MacLean et al, hereby incorporated by reference.
  • a means of resolving the enantiomers of flosequinan is set forth in Morita et al, "Synthesis and
  • the present invention contemplates the administration of a purified enantiomer of flosequinan.
  • Many organic compounds, including flosequinan exist in optically active forms (i.e., they have the ability to rotate the plane of plane-polarized light).
  • the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center(s).
  • the prefixes d and 1 or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or 1 meaning that the compound is levorotatory (rotates to the left).
  • a compound prefixed with (+) or d is dextrorotatory (rotates to the right).
  • the present invention is not limited by any specific means of resolving the (+) and (-) enantiomers of flosequinan to obtain a substantially purified enantiomer of flosequinan.
  • the enantiomers were resolved according to the methods in Example 2.
  • the enantiomers of flosequinan can function as a vasodilator. This vasodilation decreases the total peripheral resistance offered by the vasculature, thereby, decreasing blood pressure.
  • Flosequinan has also been reported to be a selective inhibitor of phosphodiesterase III (PDE3). (See Gristwood et al, Br. J. Pharmacol, 105: 985 (1992); Frodsham et al, Eur. J. Pharmacol. 211: 383 (1992)). Inhibitors of PDE3 cause vasodilation leading to a concomitant reduction in arterial blood pressure. See Shiraishi et al, Br. J.
  • (+) enantiomer of flosequinan has an eight-fold increase in PDE3 inhibition as compared to that of the (-) enantiomer of flosequinan at the same molar concentration. Moreover, in the same embodiment, the (+) enantiomer of flosequinan exhibited greater inhibition of PDE3 than a racemic mixture of flosequinan at the same molar concentration. Further data concerning this is provided in Example 3.
  • a 100 ⁇ M mixture of the (+) and (-) enantiomers of flosequinan were subjected to biochemical assays to determine their respective percent inhibition of PDE6 as compared to that of sildenafil citrate at a concentration of 1 ⁇ M.
  • the mixture of the (+) and (-) enantiomers of flosequinan exhibited approximately half as much inhibition of PDE6 as compared to that of a 100-fold lower molar concentration of sildenafil citrate. Further data concerning this is provided in Example 1.
  • an adult human suffering from cardiovascular disease is readily made by a person skilled in the art using a number of readily available diagnostic procedures.
  • an adult human suffering from cardiovascular disease can first be given a physical examination with particular attention to possible blood pressure or heart rhythm pathology, whereby many anatomical electrophysiological cardiovascular abnormalities can be detected.
  • Tests to determine hypertension may be performed by doppler investigation of the venous blood return system sufficiency. Blood pressures can be determined by a number of standard techniques.
  • Tests to determine myocardial infarction include detecting aberrations in blood enzymes. Following a myocardial infarction the damaged heart cells release of lactate dehydrogenase (LDH) subtypes result in circulating ratios that are not normally observed in a healthy person.
  • LDH lactate dehydrogenase
  • Test to determine angina pectoris include testing procedures as with myocardial infarction, only with the appearance of normal LDH subtype ratios.
  • Test to determine congestive heart failure include comparisons of blood pressures, cardiac output and stroke volume measurement. Congestive heart failure is a debilitating progressive condition that is fatal if immediate action is not taken.
  • the (+) enantiomer of flosequinan is provided together with physiologically tolerable liquid, gel or solid carriers, diluents, adjutants and excipients.
  • enantiomers of flosequinan may be used together with other chemotherapeutic agents.
  • formulations may also contain such normally employed additives as binders, fillers, carriers, preservatives, stabilizing agents, emulsifiers, buffers and excipients as, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and the like. These compositions typically contain l%-95% of active ingredient, preferably 2%-70%.
  • the present invention is not limited by the method of introduction of the compound to the body.
  • the present invention contemplates administering cutaneously, orally, or by standard injection (e.g. intravenous).
  • the present invention also contemplates administering the enantiomers of flosequinan to the subject intranasally or through respiratory inhalation.
  • Formulations suitable for intranasal administration include ointments, creams, lotions, pastes, gels, sprays, aerosols, oils and other pharmaceutical carriers which accomplish direct contact between an enantiomer of flosequinan or a pharmaceutical composition comprising an enantiomer of flosequinan and the nasal cavity. Examples of pharmaceutical compositions administered intranasally are described in U.S.
  • Formulations suitable for respiratory inhalation include ointments, creams, lotions, pastes, gels, sprays, aerosols, oils and other pharmaceutical carriers which accomplish direct contact between an enantiomer of flosequinan or a pharmaceutical composition comprising an enantiomer of flosequinan and the respiratory tract.
  • Examples of pharmaceutical compositions administered through respiratory inhalation are described in U.S. Patent 4,552,891 to Hu et al; 5,869,479 to Kreutner et al, and 5,864,037 to Chasis et al, all hereby incorporated by reference.
  • intranasal admimstration and respiratory inhalation are the preferred modes of administration due to the ease of administration and faster onset of therapeutic activity. It is contemplated that intranasal administration and respiratory inhalation are advantageous as they may allow a smaller effective dosage to be administered than would be possible with the oral route of administration.
  • a prefe ⁇ ed mode of administration comprises administration to the lung. Intrapulmonary delivery of pharmacologic agents to subjects can be accomplished via aerosolization. Alternatively, the agent may be administered to the lung through a bronchoscope. Of course, the therapeutic agents may be investigated for their efficacy via other routes of admimstration, including parenteral administration.
  • Oral administration of an enantiomer of flosequinan is an effective mode of administration, with a mean absolute bioavailability of 72% following a single dose of fifty milligrams. Peak plasma concentrations of an enantiomer of flosequinan are observed 1-2 hours following oral admimstration, while peak metabolite plasma levels are observed about seven hours following oral dosage.
  • the dosage is a single dosage per day of 10 milligrams, while in another prefe ⁇ ed embodiment the dosage is a single dosage per day of 25 milligrams, while in another prefe ⁇ ed embodiment the dosage is a single dosage per day of 50 milligrams, while in yet another prefe ⁇ ed embodiment the dosage is a single dosage per day of 75 milligrams. In another prefe ⁇ ed embodiment, the dosage is a single dosage per day of approximately 125 milligrams and in another prefe ⁇ ed embodiment, the dosage is a single dosage per day of approximately 150 milligrams. In another prefe ⁇ ed embodiment, the dosage is a single dosage per day of approximately 200 milligrams. Multiple dosage is also contemplated.
  • Flosequinan and its enantiomers are water soluble and soluble in many organic solvents.
  • aqueous and organic solution of an enantiomer of flosequinan for oral administration is contemplated.
  • an enantiomer of flosequinan can be associated with a solid pharmaceutical carrier for solid oral administration (i.e., in pill form).
  • the inactive ingredients include croscarmellose sodium, hydroxypropyl methylcellulose, lactose, magnesium stearate, methocel E5, microcrystalline cellulose, povidine, propylene glycol and titanium dioxide.
  • the enantiomers of flosequinan may also be administered cutaneously in a ca ⁇ ier adapted for topical administration.
  • ca ⁇ iers include creams, ointments, lotions, pastes, jellies, sprays, aerosols, bath oils, or other pharmaceutical carriers which accomplish direct contact between an enantiomer of flosequinan and the pore of the skin.
  • pharmaceutical preparations may comprise from about 0.001% to about 10%, and preferably from about 0.01 to 5% by w/w of the active compound
  • an enantiomer of flosequinan in a suitable carrier.
  • an appropriate solvent such as ethanol or DMSO (dimethylsulfoxide), and the like.
  • injection of an enantiomer of flosequinan can be carried out by any conventional injection means (e.g., employing an hypodermic syringe and needle or a similar device such as the NovolinPen. sold by Squibb-Novo, Inc., Princeton, N.J.,
  • Flosequinan and its enantiomers can be introduced by injection in a physiologically acceptable composition.
  • Such compositions are aqueous solutions that are physiologically acceptable for administration by injection.
  • the physiologically acceptable carrier is selected such that it is not painful or i ⁇ itating upon injection.
  • the physiologically acceptable compositions will preferably be sterile at the time of administration by injection.
  • physiologically acceptable compositions for use in the methods is physiological saline or phosphate buffered saline, n which the enantiomers of flosequinan are dissolved or suspended, such that the resulting composition is suitable for injection.
  • a physiologically acceptable composition can also include a non-i ⁇ itant preservative, such as, e.g., benzalkomum chloride at 0.05% (w/v) to 0./2% (w/v).
  • non-toxic salts of VIP, PHM and ⁇ -adrenergic blockers that can be employed in a physiologically acceptable composition for use in the methods herein, including, among others, the chloride, bromide, acetate, sulfate, and mesylate salts.
  • the present invention is not limited to the method of injecting the enantiomers of flosequinan, in the prefe ⁇ ed embodiment, it is injected with a standard syringe.
  • One skilled in the art would be capable of injecting the enantiomers of flosequinan with a carrier as described above.
  • the present invention provides methods for the treatment human cardiovascular disease with the enantiomers of flosequinan (or a formulation comprising the enantiomers of flosequinan). 6.
  • R j is hydrogen, lower alkyl optionally substituted by hydroxy or C M alkoxycarbonyl, allyl, propynyl or phenyl-lower alkyl in which the phenyl ring is optionally substituted by 1 or 2 C M alkoxy groups;
  • R 2 is hydrogen or lower alkyl;
  • R 3 is (X) m -S(O) n R 4 , COR 5 , SRg, or S(OH) (O)NR 7 , wherem m is 0 or 1, n is 0, 1, or 2, X is oxygen or lower alkylene, R 4 is C,. 4 alkyl, R 5 is hydroxyl, lower alkyl carbonyl, amino, or lower alkyl amino, and Rg and R 7 are lower alkyl; and ring A represents an optionally substituted phenyl ring of the formula:
  • R 8 , R ⁇ , and R 10 which may be the same or different, are hydrogen, lower alkyl, lower alkoxy, lower alkanoyl, halo, tri-fluoromethyl, lower alkylthio, lower alkylsulphinyl, lower alkylsulphonyl, halogenated lower alkyl, halogenated lower alkoxy, cyano, phenyl, or phenyl substituted by 1 to 3 groups independently selected from lower alkyl, lower alkoxy and trifluoromethyl; or ring A represents an optionally substituted thiophene ring of the formula:
  • R ⁇ is hydrogen, lower alkyl, lower alkoxy, lower alkanoyl, halo, trifluoromethyl, lower alkylthio, phenyl, or phenyl substituted by halogen, or a pharmaceutically acceptable salt thereof.
  • the compounds of the general formula I have been found to have antihypertensive activity and cardiac activity in warm-blooded animals.
  • the compounds, methods of making the compounds, antihypertensive and cardiac therapeutic compositions of the compounds, and methods for treating hypertension and heart failure using the compounds are described in US Patent 4,302,460, US Patent 4,522,884, US Patent 4,855,291, US Patent 4,877,793, US Patent 4,710,506, US Patent 4,772,614 and US Patent 4,997,840, the disclosures of which patents are expressly incorporated herein, in their entirety, by reference.
  • the invention provides pharmaceutical compositions comprising compounds of the general formula I, and methods of using the compositions to treat subjects with symptoms of cardiovascular disease, such that said symptoms are reduced.
  • the invention is not limited by the particular nature of the pharmaceutical composition, or by the method of introduction of the active or therapeutic compound to the body. All of the treatment methods and compositions contemplated above are also contemplated here for compounds of formula I.
  • the active ingredient in the compositions is preferably administered in unit dosage form.
  • tablets and capsules may conveniently contain a unit dosage of the active compound of 1-500 mg kg, more preferably 5-100 mg/kg and still more preferably 5-50 mg/kg.
  • the compounds of formula I may contain one or more asymmetric centers and, therefore, can exist as enantiomers or diastereoisomers. Furthermore, certain compounds of formula I containing alkenyl groups may exist as cis-isomers or trans- isomers. In each case, the invention includes both mixtures and separate individual isomers. The compounds of formula I may also exist in tautomeric forms and the invention includes both mixtures and separate individual tautomers.
  • R 3 is (X) m -S(O) n R 4) COR 5 , SRg, or S(OH) (O)NR 7 ;
  • R 10 is hydrogen and Rt, is 6-lower alkoxy, 8-lower alkoxy, 5-halo or 6-halo;
  • R 10 is halo, lower alkoxy or lower alkyl and g is 6-lower alkyl, 6-lower alkoxy or 6-halo of a different value from R 10 ; or
  • R 9 and R 10 are hydrogen.
  • Preferred embodiments include compounds of formula IIA wherein R j and R 2 are methyl, Re, is hydrogen and R 10 is halo, lower alkyl or trifluoromethyl. More preferably, R 10 is halo or C,-C 4 alkyl. In yet another prefe ⁇ ed embodiment, Rg is 6- lower alkoxy and R 10 is halo or lower alkoxy. In a further prefe ⁇ ed embodiment, R p is 6-halo and R 10 is lower alkoxy. In another prefe ⁇ ed embodiment, R 10 is C r C 4 alkyl. Thus, prefe ⁇ ed embodiments include compounds of formula IIB, IIC, IID, HE,
  • Prefe ⁇ ed compounds of formula IIB are those in which m is 1, n is 2, and X is oxygen.
  • Preferred compounds of formula IIC include those in which m is 0, n is 1 or 2, and R 4 is methyl.
  • Prefe ⁇ ed compounds of formula IID include those in which R 5 is amino or lower alkyl amino.
  • Prefe ⁇ ed compounds of formula HE include those in which J is methyl.
  • Prefe ⁇ ed compounds of formula IIF include those in which R 7 is methyl.
  • Preferred compounds of formula IIIA include those in which n is 1 and R 4 is methyl.
  • Prefe ⁇ ed compounds of formula MB include those in which R_ is amino or lower alkyl amino.
  • Specific prefe ⁇ ed compounds of these formulae include: 1 -methyl-3 -methylsulphinyl-4-quinolone, 7-fluoro-l-methyl-4-oxo- 1 ,4-dihydro- quinolone-3-carboxamide, 4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6- carboxamide, 4-methyl-6-methylsulphinyl-7(4H)-thieno [3 ,2-b] ⁇ yridinone, 7-chloro-l- methyl-3 -methylsulphamoyl-4-quinolone, l-methyl-4-oxo- 1 ,4-dihydroquinol-3 -yl methanesulphonate, 7-chloro-l-methyl-4-oxo-l,4-dihydroquinolme-3-carboxamide, 7- fluoro-l-methyl-3 -methylsulphonyl-4-quinolone, or 7-fluoro-
  • Example 1 a biochemical assay was performed to test the percentage of phosphodiesterase 6 (PDE6) inhibition of various molar concentrations of sildenafil citrate (Viagra) as compared to that of a 100 ⁇ M concentration of a racemic mixture of flosequinan as follows.
  • PDE6 phosphodiesterase 6
  • PDE6 partially purified from bovine retinal rod and activated by trypsin was used.
  • Viagra at molar concentrations of 0.3 ⁇ M, 1.0 ⁇ M, and 3.0 ⁇ M, and a 100 ⁇ M racemic mixture of flosequinan were incubated with 0.2 ⁇ g/ml active PDE6 and 100 ⁇ M cGMP containing 0.1 ⁇ M [ 3 H]cGMP in Tris buffer pH 7.5 for 20 minutes at 30°C.
  • Each reaction was terminated by raising the temperature to 100°C for 2 minutes.
  • the resulting GMP was converted to guanosine by addition of 10 mg/ml snake venom nucleotidase and further incubated at 30°C for 10 minutes.
  • Unhydrolyzed cGMP was bound to AGI-X2 resin, and [ 3 H] guanosine remaining in the aqueous phase was quantitated by scintillation counting.
  • the enantiomers of flosequinan were resolved by high- performance liquid chromatography (HPLC) as follows.
  • HPLC high- performance liquid chromatography
  • a 5.0 g sample of a racemic mixture of flosequinan was resolved over a 10 cm ID x 50 cm L CHIRALCEL OD HPLC column (Chiral Technologies, Exton, PA) at 25°C and with a flow rate of 1.0 ml/minute such that the column pressure was 37 bar.
  • the mobile phase employed was 100% methanol and the detection of the mixture was performed at 270 nm.
  • the (-) enantiomer had a retention time of 3.13 minutes, while the (+) enantiomer had a retention time of 4.40 minutes.
  • a total of 2.1 g of the (-) enantiomer having an optical purity greater than 99% was produced.
  • a total of 2.3 g of the (+) enantiomer having an optical purity greater than 99% was produced. (See Figure 1).
  • a racemic mixture of flosequinan and the (+) and (-) enantiomers of flosequinan were subjected to biochemical enzyme assays to determine their respective percent inhibition of a variety of phosphodiesterases (PDE1-PDE6).
  • the reaction conditions for each PDE assay were as follows.
  • PDE1 partially purified from bovine heart was used. A racemic mixture of flosequinan, and each enantiomer of flosequinan, all at a molar concentration of 100 ⁇ M, were independently incubated with 13 ⁇ g PDE1 enzyme, 1.0 ⁇ M [ 3 H]cAMP and CaCl 2 /calmodulin in Tris buffer pH 7.5 for 20 minutes at 30°C. The reaction was terminated by boiling for 2 minutes, and the resulting AMP was converted to adenosine by addition of 10 mg/ml snake venom nucleotidase and further incubation at 30°C for 10 minutes.
  • PDE4 PDE4 partially purified from human U-937 pronocytic cells was used.
  • PDE5 partially purified from human platelets was used. A racemic mixture of flosequinan, and each enantiomer of flosequinan, all at a molar concentration of 100 ⁇ M, were independently incubated with 120 ⁇ g PDE5 enzyme and 1 ⁇ M cGMP containing 0.01 ⁇ M [ 3 H]cGMP in Tris buffer pH 7.5 for 20 minutes at 30°C. The reaction was terminated by boiling for 2 minutes, and the resulting GMP was converted to guanosine by addition of 10 mg/ml snake venom nucleotidase and further incubation at 30°C for 10 minutes. Unhydrolyzed cGMP was bound to AGI-X2 resin, and the remaining [ 3 H]guanosine in the aqueous phase was quantitated by scintillation counting.
  • PDE6 PDE6 partially purified from bovine retinal rod and activated by trypsin was used. A racemic mixture of flosequinan, and each enantiomer of flosequinan, all at a molar concentration of 100 ⁇ M, were independently incubated with 0.2 ⁇ g/ml active PDE6 and 100 ⁇ M cGMP containing 0.1 ⁇ M [ 3 H]cGMP in Tris buffer pH 7.5 for 20 minutes at 30°C. Each reaction was terminated by boiling for 2 minutes. The resulting GMP was converted to guanosine by addition of 10 mg/ml snake venom nucleotidase, and further incubated at 30°C for 10 minutes.
  • the solid can be collected, washed with ether, dried and recrystallized from industrial methylated spirit to give the compound ethyl 7- fluoro-l-methyl-4-oxo-l,4- dihydroquinoline-3-carboxylate, m.p. 164°C-166°C.
  • Dimethyl sulphate (3.9 ml) can be added to a sti ⁇ ed solution of ethyl 7-hydroxytMeno[3,2-b]-pyridine-6-carboxylate (4.63 g) and potassium hydroxide (3.5 g) in water (50 ml) at 0°C-5°C. More water (20 ml) can be added and the mixture can be sti ⁇ ed at ambient temperature for 24 hours. The solid product can be collected by filtration, washed with water and dried to give the compound ethyl 4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxylate, m.p.
  • a solution of 3-chloroperbenzoic acid (85%; 1.63 g) in dichloromethane (60 ml) can be added dropwise during 20 minutes to a sti ⁇ ed solution of 4-methyl ⁇ 6-methyltWotWeno[3,2-b]pyrid-7(4H)-one (2.0 g) in dichloromethane (60 ml) at 0°C-5°C. After 4 hours, more 3-chloroperbenzoic acid (0.15 g) in dichloromethane (10 ml) can be added and the mixture stirred overnight at ambient temperature.
  • the residue can be crystallized from industrial methylated spirit to give the compound 7-chloro-l,N-dimethyl-4-oxo-l,4-dihydroquinoline-3-sulphonamide, m.p. 220 °C-223 °C.
  • e. 7-chloro-l-methyl-4-oxo-l,4-dihydroquinoline-3-carboxamide can be prepared as described in Example 4 of US Patent 4,855,291.
  • aqueous ammonia (5.0 g) and aqueous ammonia (specific gravity 0.88, 100 ml) can be sti ⁇ ed and heated on a steam bath for 3.5 hours. More aqueous ammonia (100 ml) can be added and heating continued for a further 21 hours. The mixture can be cooled in ice. The solid product can be collected by filtration and dried to give the compound 7-chloro- l-methyl-4-oxo-l,4-dihydroquinoline-3-carboxamide, m.p. >240°C.

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Abstract

La présente invention concerne des techniques de traitement de groupes de patients spécifiques soignés pour des troubles sexuels. Les techniques de cette invention comprennent l'utilisation d'énantiomères de floséquinan et des compositions pharmaceutiques comprenant des énantiomères de floséquinan, chez des patients exempts de maladies cardiaques, qui n'ont pas été traité avec un médicament hypotenseur et/ou à qui on n'a pas donné de nitrites ou de nitrates organiques. Ces énantiomères de floséquinan et les compositions comprenant ces énantiomères de floséquinan sont administrés aux patients par voie nasale, orale et/ou par inhalation. Cette invention concerne aussi des compositions et des techniques de traitement de maladie cardio-vasculaire. Dans un mode de réalisation préféré, cette invention concerne l'utilisation d'énantiomères de floséquinan (et de préparations comprenant du floséquinan) chez des sujets qui ne sont pas simultanément traités avec des nitrites ou des nitrates.
PCT/US2002/002357 2001-01-26 2002-01-24 Traitement de troubles sexuels et de maladie cardio-vasculaire avec des enantiomeres quinolinone Ceased WO2002058703A2 (fr)

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JP2002559037A JP2005503995A (ja) 2001-01-26 2002-01-24 キノリノン鏡像異性体による性的機能不全および心血管疾患の治療法
CA002435876A CA2435876A1 (fr) 2001-01-26 2002-01-24 Traitement de troubles sexuels et de maladie cardio-vasculaire avec des enantiomeres quinolinone
EP02709191A EP1355647A2 (fr) 2001-01-26 2002-01-24 Traitement de troubles sexuels et de maladie cardio-vasculaire avec des enantiomeres quinolinone

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004037262A3 (fr) * 2002-10-22 2004-08-12 Vivus Inc De formulation pharmaceutique a liberation immediate topique en vue d'ameliorer le desir et la receptivite sexuelle des femmes
EP1446120A4 (fr) * 2001-10-25 2005-01-26 R T Alamo Ventures I Llc Enrichissement stereospecifique d'enantiomeres heterocycliques

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999056666A1 (fr) * 1998-05-01 1999-11-11 Rt Alamo Ventures, Inc. Traitement des troubles de la sexualite chez certains groupes de patients
AU5509099A (en) * 1998-08-03 2000-02-28 Basf Corporation Pyridinones for the treatment of sexual dysfunction

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1446120A4 (fr) * 2001-10-25 2005-01-26 R T Alamo Ventures I Llc Enrichissement stereospecifique d'enantiomeres heterocycliques
WO2004037262A3 (fr) * 2002-10-22 2004-08-12 Vivus Inc De formulation pharmaceutique a liberation immediate topique en vue d'ameliorer le desir et la receptivite sexuelle des femmes

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