WO1995010270A1 - Procedes de traitement de l'incontinence urinaire a l'aide de terodiline optiquement pure - Google Patents

Procedes de traitement de l'incontinence urinaire a l'aide de terodiline optiquement pure Download PDF

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Publication number
WO1995010270A1
WO1995010270A1 PCT/US1994/011420 US9411420W WO9510270A1 WO 1995010270 A1 WO1995010270 A1 WO 1995010270A1 US 9411420 W US9411420 W US 9411420W WO 9510270 A1 WO9510270 A1 WO 9510270A1
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butylamine
tert
terodiline
butyl
diphenyl
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PCT/US1994/011420
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English (en)
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Nancy M. Gray
James W. Young
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Sepracor, Inc.
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Priority to AU79713/94A priority Critical patent/AU7971394A/en
Publication of WO1995010270A1 publication Critical patent/WO1995010270A1/fr

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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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline

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  • This invention relates to novel compositions of matter containing optically pure S-terodiline or a hydroxylated derivative of S-terodiline selected from the group consisting of 2S-N-tert-butyl-4-(4- hydroxyphenyl) -4-pheny1-2-butylamine, S-N-tert-butyl- 4,4-diphenyl-4-hydroxy-2-butylamine and S-N-(2- hydroxy ethy1-2-propy1) - ,4-dipheny1-2-butylamine.
  • These compositions of matter possess potent activity in treating disorders such as urinary incontinence, obstructive pulmonary disease, angina, sickle cell anemia and soft tissue necrosis after surgery.
  • compositions of matter possess potent activity in treating these disorders while substantially reducing the adverse effects including but not limited to cardiac arrhythmias, headache, dry mouth, constipation, heartburn, blurred vision, nausea, tremor, dizziness, confusion, rash, muscular weakness, sweating, insomnia, weight change and paralytic ileus which are associated with the administration of the racemic mixture of terodiline.
  • the present invention encompasses methods for treating the above-identified conditions in a human by administering to a human in need of such therapy, optically pure or substantially optically pure S-terodiline, or an optically pure or substantially optically pure hydroxylated derivative of S-terodiline selected from the group consisting of 2S-N-tert-butyl-4-(4-hydroxyphenyl) -4-phenyl-2- butylamine, S-N-(2-hydroxymethyl-2-propyl) -4,4- dipheny1-2-butylamine, and S-N-tert-butyl-4, 4- diphenyl-4-hydroxy-2-butylamine.
  • Stereochemical purity is of importance in the field of pharmaceuticals, where 12 of the 20 most prescribed drugs exhibit chirality.
  • a case in point is provided by the L-form of the ⁇ -adrenergic blocking agent, propranolol, which is known to be 100 times more potent than the D-enantiomer.
  • optical purity is important since certain isomers may actually be deleterious rather than simply inert.
  • the D-enantiomer of thalidomide is a safe and effective sedative when prescribed for the control of morning sickness during pregnancy, while the corresponding L-enantiomer has been thought to be a potent teratogen.
  • the active compounds of the present compositions and methods include the optically pure S- isomers of the compound terodiline and of the 5 optically pure hydroxylated derivatives of terodiline, selected from the group consisting of 2S-N-tert-butyl- 4-(4-hydroxyphenyl) -4-pheny1-2-butylamine, S-N-tert- buty1-4,4-dipheny1-4-hydroxy-2-butylamine and S-N-(2- hydroxymethyl-2-propyl) -4,4-diphenyl-2-butylamine.
  • the optical isomer of terodiline which is part of the present invention is S(-)N-tert- butyl-4,4-diphenyl-2-butylamine or S(-)N-tert-butyl-l- methyl-3, 3-diphenylpropylamine.
  • 2S-N-tert-butyl-4-(4-hydroxyphenyl) -4- phenyl-2-butylamine is meant to include both diastereoisomers 2S,4R-N-tert-butyl-4-(4- hydroxypheny1) -4-phenyl-2-butylamine and 2S,4S-N-tert- butyl-4-(4-hydroxyphenyl) -4-phenyl-2-butylamine, i.e. , compounds where the absolute configuration at the carbon 2 position is S.
  • Terodiline has been administered as a hydrochloride salt; however, terodiline is no longer commercially available.
  • the hydroxylated derivatives described herein are also not available commercially, either as racemates or as optically pure compounds.
  • the racemic mixture of terodiline was used primarily as an agent to treat urinary incontinence.
  • the detrusor muscle which provides the propulsive force for emptying the bladder, consists of interlacing fibers of smooth muscle that are under control by pelvic nerves from the spinal cord. Contractions of the detrusor muscle are synergistic and are stimulated by both acetyl choline and calcium. Involuntary contraction of the detrusor muscle is the cause of urinary incontinence; therefore, agents which block the actions of acetyl choline or calcium on the detrusor muscle serve as therapeutic agents for the treatment of urinary incontinence.
  • racemic terodiline possesses anticholinergic activity and inhibits carbachol- induced muscle contractions.
  • the racemic mixture of terodiline also showed specific calcium antagonism in the bladder.
  • the local anaesthetic and spasmolytic activities of racemic terodiline may also contribute to its activity. See Langtry et al., Drugs , 40(5) :748-761 (1990) ; Bogentoft et al., Supplement to Urology, Vol. XXXVI, 4:58-62 (1990) ; Andersson, Scand . J . Urol . Nephrol . Supp . , 87:13-20 (1984) .
  • the racemic mixture of terodiline is also useful to treat angina.
  • United States Patent No. 3,371,014 reports that the dilation of the coronary vessels and diminished spasmolytic activity of the racemic mixture of terodiline contributes to its vasodilating activity.
  • terodiline also blocks the influx of Ca +2 into the cardiac muscle to alleviate angina.
  • terodiline can be useful for treating obstructive pulmonary disease. Because of its activity as an anticholinergic agent, terodiline is responsible for decreases in the volume of bronchial secretion and thereby alleviates the obstruction of airflow in the lungs. See Castenfors et al., Eur . J . Clin . Pharmacol . , 8:197-200 (1975) .
  • terodiline can be useful to treat sickle cell anemia.
  • United States Patent No. 4,851,404 teaches that terodiline can be used for the treatment of sickle cell anemia due to its calcium channel blocking activity which normalizes the deformity of sickle cells.
  • racemic mixture of terodiline can be used to treat soft tissue necrosis which occurs after surgery.
  • the calcium channel blocking ability of terodiline improves the vascular blood flow at the site of the wound, thus reducing the tissue necrosis. See U.S. Patent No. 4,599,340.
  • racemic mixture of terodiline has the foregoing advantages, it also has disadvantages, such as causing adverse effects, including but not limited to cardiac arrhythmias (especially torsades de pointes) , headache, dry mouth, constipation, heartburn, blurred vision, tremor, nausea, dizziness, confusion, rash, muscular weakness, sweating, insomnia, weight change and paralytic ileus.
  • cardiac arrhythmias especially torsades de pointes
  • tremor nausea, dizziness, confusion, rash, muscular weakness, sweating, insomnia, weight change and paralytic ileus.
  • optically pure S-isomers of terodiline, and of the hydroxylated derivatives of terodiline are effective agents for treating disorders in a human, such as urinary incontinence, obstructive pulmonary disease, angina, sickle cell anemia and soft tissue necrosis.
  • the invention encompasses novel compositions of matter containing optically pure S-terodiline or a hydroxylated derivative thereof as the active ingredient. These compositions of matter are effective for treating urinary incontinence while substantially reducing adverse effects including but not limited to cardiac arrhythmias, headache, dry mouth, constipation, heartburn, blurred vision, tremor, dizziness, confusion, rash, and muscular weakness, sweating, insomnia, weight change and paralytic ileus which are associated with the administration of the racemic mixture of terodiline. Additionally, the novel compositions of matter of the present invention are useful for treating angina in a human while substantially reducing adverse effects associated with the administration of the racemic mixture of terodiline.
  • novel compositions of matter containing S-terodiline, or one of the hydroxylated derivatives thereof are useful for treating obstructive pulmonary disease while substantially reducing adverse effects associated with the administration of racemic terodiline.
  • novel compositions of matter containing S-terodiline or a hydroxylated derivative thereof are useful for treating soft tissue necrosis caused by surgery while substantially reducing adverse effects associated with the administration of the racemic mixture of terodiline.
  • the present invention also encompasses methods for treating the above-described disorders in a human while substantially reducing adverse effects associated with the administration of racemic terodiline, comprising administering an effective amount of the optically pure S-isomer of terodiline to a human.
  • the present invention also encompasses methods for treating the above-described conditions in a human, comprising administering an effective amount of the optically pure S-isomer of a hydroxylated derivative of terodiline to a human.
  • the present invention encompasses a method of treating urinary incontinence in a human while substantially reducing the adverse effects associated with the administration of racemic terodiline, which comprises administering to a human in need of such therapy an effective amount of S-terodiline, or a pharmaceutically acceptable salt thereof, substantially free of its R-stereoisomer, said effective amount being sufficient to alleviate urinary incontinence but insufficient to cause adverse effects associated with racemic terodiline.
  • the invention also encompasses a method for treating urinary incontinence in a human while substantially reducing adverse effects associated with the administration of racemic terodiline, which comprises administering to a human in need of such therapy an effective amount of a compound selected from the group consisting of 2S-N-tert-butyl-4-(4- hydroxyphenyl)-4-phenyl-2-butylamine, S-N-(2- hydroxymethyl-2-propyl)-4,4-diphenyl-2-butylamine, and S-N-tert-butyl-4,4-dipheny1-4-hydroxy-2-butylamine or a pharmaceutically acceptable salt thereof, substantially free of the 2R-stereoisomer, said effective amount being sufficient to alleviate urinary incontinence but insufficient to cause adverse effects associated with the administration of racemic terodiline.
  • the present invention further comprises a method of treating urinary incontinence in a human comprising administering to a human in need of such therapy an effective amount of a compound selected from the group-consisting of 2S-N-tert-butyl-4-(4- hydroxyphenyl)-4-phenyl-2-butylamine, S-N-tert-butyl- 4,4-diphenyl-4-hydroxy-2-butylamine and S-N-(2- hydroxymethyl-2-propyl)-4,4-diphenyl-2-butylamine, or pharmaceutically acceptable salts thereof, substantially free of its 2R-stereoisomer, said effective amount being sufficient to alleviate urinary incontinence.
  • the present invention also encompasses a pharmaceutical composition for the treatment of urinary incontinence in a human, which comprises an effective amount of a compound selected from the group consisting of S-terodiline, 2S-N-tert-butyl-4-(4- hydroxypheny1) -4-pheny1-2-butylamine, S-N-tert-butyl- 4,4-diphenyl-4-hydroxy-2-butylamine, and S-N-(2- hydroxymethyl-2-propyl)-4,4-diphenyl-2-butylamine or pharmaceutically acceptable salts thereof, wherein said compound is substantially free of its 2R- stereoisomer, said effective amount being sufficient to alleviate urinary incontinence but insufficient to cause adverse effects associated with the administration of racemic terodiline; and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition for the treatment of urinary incontinence in a human which comprises an effective amount of a compound selected from the group consisting of S-terodiline, 2
  • the present invention encompasses a method of treating obstructive pulmonary disease in a human while substantially reducing adverse effects associated with the administration of racemic terodiline, comprising administering to a human in need of such therapy an effective amount of S-terodiline, or a pharmaceutically acceptable salt thereof, substantially free of its R-stereoisomer, said effective amount being sufficient to alleviate obstructive pulmonary disease but insufficient to cause adverse effects associated with the administration of racemic terodiline.
  • the present invention also encompasses a method of treating obstructive pulmonary disease in a human while substantially reducing adverse effects associated with the administration of racemic terodiline, comprising administering to a human in need of such therapy an effective amount of a compound selected from the group consisting of 2S-N-tert-butyl- 4-(4-hydroxyphenyl) -4-phenyl-2-butylamine, S-N-tert- buty1-4,4-dipheny1-4-hydroxy-2-butylamine and S-N-(2- hydroxymethyl-2-propyl) -4,4-dipheny1-2-butylamine, or a pharmaceutically acceptable salt thereof, substantially free of its 2R-stereoisomer, said effective amount being sufficient to alleviate obstructive pulmonary disease but insufficient to cause adverse effects associated with the administration of racemic terodiline.
  • the present invention further comprises a method of treating obstructive pulmonary disease in a human comprising administering to a human in need of such therapy an effective amount of a compound selected from the group consisting of 2S-N-tert-butyl- 4-(4-hydroxyphenyl) -4-pheny1-2-butylamine, S-N-tert- butyl-4,4-diphenyl-4-hydroxy-2-butylamine and S-N-(2- hydroxymethyl-2-propyl) -4,4-diphenyl-2-butylamine, or pharmaceutically acceptable salts thereof, substantially free of its 2S-stereoisomer, said effective amount being sufficient to alleviate obstructive pulmonary disease.
  • the present invention encompasses a pharmaceutical composition for the treatment of obstructive pulmonary disease in a human, which comprises an effective amount of a compound selected from the group consisting of S-terodiline, 2S-N-tert- butyl-4-(4-hydroxyphenyl) -4-pheny1-2-butylamine, S-N- tert-butyl-4,4-diphenyl-4-hydroxy-2-butylamine, and S- N-(2-hydroxymethyl-2-propyl) -4,4-dipheny1-2- butylamine, or pharmaceutically acceptable salts thereof, wherein said compound is substantially free of its 2R-stereoisomer, said effective amount being sufficient to alleviate obstructive pulmonary disease but insufficient to cause adverse effects of racemic terodiline; and a pharmaceutically acceptable carrier.
  • the present invention encompasses a method of treating angina in a human while substantially reducing adverse effects associated with the administration of racemic terodiline, which comprises administering to a human in need of such therapy an effective amount ' of S-terodiline, or a pharmaceutically acceptable salt thereof, substantially free of its R-stereoisomer, said effective amount being sufficient to alleviate angina but insufficient to cause said adverse effects associated with the administration of racemic terodiline.
  • the present invention also encompasses a method for treating angina in a human while substantially reducing adverse effects associated with the administration of racemic terodiline, comprising administering to a human in need of such therapy an effective amount of a compound selected from the group consisting of 2S-N-tert-butyl-4-(4-hydroxyphenyl) -4- pheny1-2-butylamine, S-N-tert-butvl-4,4-diphenyl-4- hydroxy-2-butylamine, and S-N-(2-hydroxymethyl-2- propyl) -4,4-diphenyl-2-butylamine, or a pharmaceutically acceptable salt thereof, substantially free of its 2R-stereoisomer, said effective amount being sufficient to alleviate angina but being insufficient to cause adverse effects associated with the administration of racemic terodiline.
  • the present invention encompasses a pharmaceutical composition for the treatment of angina in a human, which comprises an effective amount of a compound selected from the group consisting of S-terodiline, 2S-N-tert-butyl-4-(4- hydroxyphenyl) -4-phenyl-2-butylamine, S-N-tert-butyl- 4,4-dipheny1-4-hydroxy-2-butylamine, and S-N-(2- hydroxymethyl-2-propyl) -4,4-dipheny1-2-butylamine, or pharmaceutically acceptable salts thereof, wherein said compound is substantially free of its 2R- stereoisomer, said effective amount being sufficient to alleviate angina but insufficient to cause said adverse effects of racemic terodiline; and a pharmaceutically acceptable carrier.
  • the present invention encompasses a method of treating sickle cell anemia in a human while substantially reducing adverse effects associated with the administration of racemic terodiline, comprising administering to a human in need of such therapy an effective amount of S-terodiline or a pharmaceutically acceptable salt thereof, substantially free of its R- stereoisomer, said effective amount being sufficient to alleviate sickle cell anemia but insufficient to cause said adverse effects associated with the administration of racemic terodiline.
  • the present invention encompasses a method of treating sickle cell anemia in a human while substantially reducing adverse effects associated with the administration of racemic terodiline, comprising administering to a human in need of such therapy an effective amount of a compound selected from the group consisting of 2S-N-tert-butyl-4-(4-hydroxyphenyl) -4- phenyl-2-butylamine, S-N-tert-butyl-4,4-diphenyl-4- hydroxy-2-butylamine, and S-N-(2-hydroxymethyl-2- propyl) - ,4-diphenyl-2-butylamine, or a pharmaceutically acceptable salt thereof, substantially free of its 2R-stereoisomer, said effective amount being sufficient to alleviate sickle cell anemia but being insufficient to cause adverse effects associated with the administration of racemic terodiline.
  • the present invention also encompasses a pharmaceutical composition for the treatment of sickle cell anemia in a human, which comprises an effective amount of a compound selected from the group consisting of S-terodiline, 2S-N-tert-butyl-4-(4- hydroxyphenyl) -4-pheny1-2-butylamine, S-N-tert-butyl- 4,4-diphenyl-4-hyd oxy-2-butylamine, and S-N-(2- hydroxymethyl-2-propyl) -4, 4-dipheny1-2-butylamine, or pharmaceutically acceptable salts thereof, wherein said compound is substantially free of its 2R- stereoisomer, said effective amount being sufficient to alleviate sickle cell anemia but insufficient to cause adverse effects associated with the administration of racemic terodiline; and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition for the treatment of sickle cell anemia in a human which comprises an effective amount of a compound selected from the group consisting of S-terodiline
  • the present invention encompasses a method of treating soft tissue necrosis after surgery in a human while substantially reducing adverse effects associated with the administration of racemic terodiline, which comprises administering to a human in need of such therapy an effective amount of S-terodiline or a pharmaceutically acceptable salt thereof, substantially free of its R-stereoisomer, said effective amount being sufficient to alleviate soft tissue necrosis but insufficient to cause said adverse effects associated with the administration of racemic terodiline.
  • the present invention also encompasses a method of treating soft tissue necrosis in a human after surgery while substantially reducing adverse effects associated with the administration of racemic terodiline, comprising administering to a human in need of such therapy an effective amount of a compound selected from the group consisting of 2S-N-tert-butyl- 4-(4-hydroxyphenyl) -4-phenyl-2-butylamine, S-N-tert- butyl-4,4-diphenyl-4-hydroxy-2-butylamine, and S-N-(2- hydroxymethyl-2-propyl) -4, 4-diphenyl-2-butylamine or a pharmaceutically acceptable salt thereof, substantially free of its 2R-stereoisomer, said effective amount being sufficient to alleviate soft tissue necrosis but being insufficient to cause adverse effects associated with the administration of racemic terodiline.
  • the present invention also encompasses a pharmaceutical composition for the treatment of soft tissue necrosis after surgery in a human, which comprises an effective amount of a compound selected from the group consisting of S-terodiline, 2S-N-tert- butyl-4-(4-hydroxyphenyl) -4-pheny1-2-butylamine, S-N- tert-butyl-4 ,4-diphenyl-4-hydroxy-2-butylamine, and S- N-(2-hydroxymethyl-2-propyl) -4,4-diphenyl-2- butylamine, or pharmaceutically acceptable salts thereof, wherein said compound is substantially free of its 2R-stereoisomer, said effective amount being sufficient to alleviate soft tissue necrosis but insufficient to cause adverse effects associated with the administration of racemic terodiline; and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition for the treatment of soft tissue necrosis after surgery in a human which comprises an effective amount of a compound selected from the group consisting of S-ter
  • the racemic mixture of terodiline (e.g. , a 1:1 racemic mixture of the R- and S-enantiomers) exhibits anticholinergic and calcium antagonist activity, and provides therapy and/or a reduction of symptoms in a variety of conditions and disorders.
  • the racemic mixture while offering the expectation of efficacy, causes adverse effects.
  • Utilizing the optically pure or substantially optically pure S-isomer of terodiline or of a hydroxylated derivative of terodiline results in clearer dose related definitions of efficacy, diminished adverse effects, and accordingly, an improved therapeutic index.
  • terodiline S-isomer of terodiline or of one of the hydroxylated derivatives of terodiline than to use racemic terodiline.
  • adverse effects includes ' , but is not limited to cardiac arrhythmias, headache, dry mouth, constipation, heartburn, blurred vision, nausea, tremor, dizziness, confusion, rash, muscular weakness, sweating, insomnia, weight change, and paralytic ileus.
  • cardiac arrhythmias includes, but is not limited to ventricular tachyarrhythmias, torsades de pointes and ventricular fibrillation.
  • substantially free of its R- stereoisomer and “substantially free of its 2R- stereoisomer” as used herein, relates to the proportion of the S-isomer of terodiline to that of the R-isomer, or relates to the proportion of the 2S- isomer of the hydroxylated derivative in relation to the 2R-isomer.
  • the 2S-isomer is meant to include both diastereoisomers of the compounds with two chiral centers, i.e. , the two compounds with the absolute configuration being S at the carbon 2 position, e.g. ,
  • the term "substantially free of its R-stereoisomer” or “substantially free of its 2R-stereoisomer” as used herein means that ' the composition contains at least
  • the terms "substantially free of the R-stereoisomer” or “substantially free of its 2R-stereoisomer” mean that the composition contains at least 99% by weight of the
  • the terms "substantially free of its R-stereoisomer” or “substantially free of its 2R- stereoisomer” as used herein mean that the composition contains greater than 99% by weight of the S-isomer. The above percentages are based on the total amount of terodiline or the total amount of hydroxylated derivative of terodiline present in the composition.
  • optically pure or substantially optically pure S-isomer of terodiline and “optically pure or substantially optically pure hydroxylated derivatives of terodiline” are also encompassed by the above-described amounts.
  • a method of treating urinary incontinence means the treatment of premature urination due to conditions including, but not limited to, neurogenic bladder dysfunction, nocturnal enuresis, irritative bladder, chronic cystitis or prostatitis, psychosomatic bladder, nervous pollakiuria, and stress or motor urge incontinence.
  • a method of treating obstructive pulmonary disease means the treatment of bronchial obstruction due to conditions such as bronchial asthma, bronchitis or emphysema.
  • a method of treating angina means treating the substernal or chest pains which are associated with ischemic heart disease.
  • the forms of angina include, but are not limited to, variant angina, exertional angina and unstable angina.
  • a method of treating sickle cell anemia means treating the symptoms of sickle cell anemia in humans afflicted with said disorder.
  • a method of treating soft tissue necrosis caused by surgery means treating a human, after surgery, with the compositions contained herein to prevent or minimize tissue necrosis at the site of the surgical wound.
  • the separation of the enantiomeric pairs of terodiline metabolites and preparation of the enantiomers of terodiline is disclosed in Enquist et al., J . Chromatog. , 519:285-298 (1990), Helander et al., Acta Chem . Scand . Ser . B Org . Chem . Biochem . ,
  • Examples of such chiral reducing agents are (+) beta- chlorodiisopinoca phenylborane, (-) beta- chlorodiisopinocamphenylborane, R,R, -N,N' -bis (mono- isopinocamphenylborane) -N,N,N' ,N'- tetramethylenediamine or other such reagents familiar to those skilled in the art.
  • the magnitude of a prophylactic or therapeutic dose of the S-isomers of terodiline or of the hydroxylated derivatives of terodiline in the acute or chronic management of disease will vary with the severity of the condition to be treated, and the route of administration.
  • the dose, and perhaps the dose frequency, will also vary according to the age, body weight, response, and past medical history of the individual patient.
  • the recommended daily dose ranges, for the conditions described herein lie within the range of from about 5 mg to about 100 mg per day given as a once daily administration or in divided doses, if required.
  • a daily dose range should be between about 10 mg to about 75 mg per day, given as a once daily administration or in divided doses, if required; and most preferably, a daily dose range should be between about 10 mg to about 50 mg per day, given as a once daily administration or in divided doses, if required.
  • the therapy should be initiated at a lower dose, perhaps about 15 mg to about 25 mg and increased if necessary up to about 50 mg or higher depending on the patient's global response. It is further recommend that children, and patients aged over 65 years, and those with impaired renal or hepatic function, initially receive low doses, and that they be titrated based on global response and blood level. It may be necessary to use dosages outside these ranges in some cases.
  • an amount being sufficient to alleviate said urinary incontinence but insufficient to cause adverse effects is encompassed by the above described dosage amounts and dose frequency schedule.
  • compositions of the present invention contain the S-isomers of terodiline or of the hydroxylated derivatives of terodiline, selected from the group consisting of 2S-N-tert-butyl- 4-(4-hydroxyphenyl) -4-pheny1-2-butylamine, S-N-tert- buty1-4,4-dipheny1-4-hydroxy-2-butylamine, and S-N-(2- hydroxymethyl-2-propyl) -4,4-diphenyl-2-butylamine as active ingredients, or pharmaceutically acceptable salts thereof, and may also contain a pharmaceutically acceptable carrier and, optionally, other therapeutic ingredients known to those skilled in the art.
  • the term "pharmaceutically acceptable salts” refers to salts prepared from pharmaceutically acceptable non-toxic acids including inorganic acids and organic acids.
  • Such acids include acetic, benzenesulfonic (besylate) , benzoic, ca phorsulfonic, citric, ethenesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, ucic, nitric, pyemic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic, and the like.
  • Particularly preferred are besylate, hydrobromic, hydrochloric, phosphoric and sulfuric acids.
  • any suitable route of administration may be employed for providing the patient with an effective dosage of the S-isomers of terodiline or of the hydroxylated derivatives of terodiline.
  • oral, rectal, parenteral e.g. , intravenous or intramuscular
  • transdermal, subcutaneous, topical, and the like may be employed.
  • Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, patches, creams, aerosols and the like.
  • the most preferred route of the present invention is the oral route.
  • the compositions may be conveniently presented in unit dosage form, and prepared by any of the methods well known in the art of pharmacy.
  • a suitable dosage range for use is from about 5 mg to about 100 mg total daily dose, given as a once daily administration or in divided doses if required.
  • a dose range of from about 10 mg to about 75 mg is given as a once daily administration or in divided doses if required, and most preferably a dose range of from about 10 mg to about 50 mg is given as a once daily administration or in divided doses if required.
  • Patients should be upwardly titrated from below to within this dose range to a satisfactory control of symptoms or blood pressure, as appropriate.
  • the S-isomers of terodiline or of the hydroxylated derivatives of terodiline can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
  • the carrier may take a wide variety of forms depending on the form of the preparation desired for administration, e . g . , oral or parenteral
  • any of the usual pharmaceutical media may be employed, such as carriers.
  • suitable carriers include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like.
  • suitable carriers include starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Oral solid preparations are preferred over oral liquid preparations. The most preferred oral solid preparation is tablets.
  • tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are employed. If desired, tablets may be coated by standard aqueous or nonaqueous techniques.
  • the compounds of the present invention may also be administered by controlled release means and/or delivery devices such as those described in United States Patent Nos.: 3,845,770; 3,916,899; 3,536,809; 3,598,123; 3,632,200; 4,008,719, 4,687,660; 4,769,027, the disclosures of which are incorporated herein by reference.
  • compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets, or tablets, or aerosol sprays, each containing a predetermined amount of the active ingredient, as a powder or granules, or as a solution or a suspension in an aqueous liquid, a non-aqueous liquid, an oil-in- water emulsion, or a water-in-oil liquid emulsion.
  • Such pharmaceutical compositions may be prepared by any of the methods of pharmacy, but all methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more necessary ingredients.
  • the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation.
  • a tablet may be prepared by compression or molding, optionally, with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, and/or surface active or dispersing agent.
  • Molded tablets may be made by molding, in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.
  • each tablet contain from about 5 mg to about 100 mg of the active ingredient
  • each cachet or capsule contain from about 5 mg to about 100 mg of the active ingredient, the S-isomers of terodiline or of the hydroxylated derivatives of terodiline.
  • the tablet, cachet or capsule contains either one of three dosages, e . g . about 15 mg, about 25 mg and about 50 mg of the active ingredient.
  • Example l The potential for promoting arrhythmia is evaluated by examining the effects of the optically pure isomers of terodiline and of the hydroxylated derivatives thereof on cardiac action potential and contractility in human and canine hearts.
  • Torsades de pointes is a well known side effect of antiarrhythmic drugs, such as quinidine, sotalol and acetyl-procainamide, which cause a prolongation of cardiac repolarization. All of these drugs have in common the ability to block a cellular potassium channel called the delayed rectifier (I k ) , and it is generally assumed that this is mechanistically linked to their ability to induce the syndrome of torsades de pointes. [See Zehender et al., Cardiovascular Drugs Ther . , 5:515-530 (1991) .] A.
  • the hearts are perfused with an oxygenated Tyrode's solution, containing 0.0; 1.0; 5.0 or 10.0 ⁇ M of the test compound.
  • QT duration and action potential duration are measured from cardiac electrodes. APD is measured at 50% (APD-50) and 90% (APD-90) .
  • test compounds include racemic terodiline, R-terodiline, S-terodiline as well as the racemates, R- and S- isomers of the hydroxylated derivatives of terodiline: 2-N-tert-butyl-4-(4- hydroxyphenyl) -4-pheny1-2-butylamine, N-tert-butyl- 4,4-diphenyl-4-hydroxy-2-butylamine and N-(2- hydroxymethyl-2-propyl) -4,4-dipheny1-2-butylamine. According to the studies of Zehender et al. , these results are indicative of a potential arrhythmogenic effect of the test compounds in vivo.
  • the active ingredient is sieved and blended with the excipients.
  • the mixture is filled into suitably sized two-piece hard gelatin capsules using suitable machinery.
  • Other doses may be prepared by altering the fill weight and if necessary, changing the capsule size to suit.
  • the active ingredient is sieved through a suitable sieve and blended with the lactose, starch, and pregelatinized maize starch. Suitable volumes of purified water are added and the powders are granulated. After drying, the granules are screened and blended with the magnesium stearate. The granules are compressed into tablets of desired shape, thickness, hardness, and disintegration. If desired, tablets may be coated by standard aqueous or nonaqueou ⁇ techniques. Other doses may be prepared by altering the ratio of the active ingredient to the lactose, or by changing the compression weight and, if necessary, the size or shape of the tablet to suit.

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Abstract

Procédés et compositions dans lesquels on emploie les S-isomères optiquement purs de térodiline ou ceux des dérivés hydroxylés de térodiline. Ces composés sont des médicaments puissants utilisés pour traiter l'incontinence urinaire, le syndrome respiratoire obstructif et les autres pathologies liées à l'activité de ces composés employés comme agents anticholinergiques. En outre les S-isomères optiquement purs de térodiline ou ceux des dérivés hydroxylés de térodiline sont utiles pour traiter l'angine et les autres pathologies liées à l'activité de ces composés utilisés comme antagonistes du calcium.
PCT/US1994/011420 1993-10-08 1994-10-07 Procedes de traitement de l'incontinence urinaire a l'aide de terodiline optiquement pure WO1995010270A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU79713/94A AU7971394A (en) 1993-10-08 1994-10-07 Method for treating urinary incontinence using optically pure s-terodiline

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US13432493A 1993-10-08 1993-10-08
US08/134,324 1993-10-08

Publications (1)

Publication Number Publication Date
WO1995010270A1 true WO1995010270A1 (fr) 1995-04-20

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PCT/US1994/011420 WO1995010270A1 (fr) 1993-10-08 1994-10-07 Procedes de traitement de l'incontinence urinaire a l'aide de terodiline optiquement pure

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Country Link
AU (1) AU7971394A (fr)
WO (1) WO1995010270A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998000011A1 (fr) * 1996-07-01 1998-01-08 Sepracor, Inc. Procedes et compositions de traitement de l'incontinence urinaire par (r)-tridihexethyle enrichi en enantiomere
US6890920B2 (en) 2001-10-26 2005-05-10 Pharmacia & Upjohn Company Quaternary ammonium compounds

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
EUROPEAN J. CLIN. PHARMACOLOGY, Volume 8, issued 1975, (Stockholm, Sweden), CASTENFORS et al., "Pilot Study of the Effect of Terodiline Chloride (Bicor) in Obstructive Pulmonary Disease", pages 197-200. *
PHARMACOLOGY & TOXICOLOGY, Volume 63, issued 1988, (Lund, Sweden), K.E. ANDERSSON et al., "Actions of Terodiline, Its Isomers and Main Metabolite on Isolated Detrusor Muscle from Rabbit and Man", pages 390-395. *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998000011A1 (fr) * 1996-07-01 1998-01-08 Sepracor, Inc. Procedes et compositions de traitement de l'incontinence urinaire par (r)-tridihexethyle enrichi en enantiomere
US6890920B2 (en) 2001-10-26 2005-05-10 Pharmacia & Upjohn Company Quaternary ammonium compounds
US7439397B2 (en) 2001-10-26 2008-10-21 Pfizer Inc Phenol derivative

Also Published As

Publication number Publication date
AU7971394A (en) 1995-05-04

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