Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing compound doai
Reexamination Certificate
1999-01-11
2001-10-30
Bawa, Raj (Department: 1619)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing compound doai
C424S045000, C424S436000, C424S443000, C424S449000, C424S464000, C424S489000, C564S315000, C564S316000
Reexamination Certificate
active
06310103
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to a compound named S(−)-tolterodine and having the formula:
Specifically, the invention relates to processes for preparing S-tolterodine, to a method for treating urinary disorders, including urinary incontinence and a method for treating gastrointestinal disorders, including gastrointestinal hyperactivity, using the compound S-tolterodine and to pharmaceutical compositions containing S-tolterodine.
The generic name TOLTERODINE (CAS-124937-51-1; INN) refers to the R-enantiomer of the drug. In this document, the racemate and the optically active isomers of the compound are referred to as RS-tolterodine (or RS-TOL), S-tolterodine (or S-TOL), and R-tolterodine (or R-TOL).
BACKGROUND OF THE INVENTION
R-tolterodine has been shown to reduce bladder pressure in cats and is presently undergoing clinical testing for inhibitory activity in patients suffering from detrusor overactivity (urinary incontinence). R-TOL exerts a spasmolytic effect on bladder smooth muscle by inhibiting the action of acetylcholine on smooth muscle. R-TOL is selective for muscarinic receptors over nicotinic receptors and as a result, no blocking effects are observed at skeletal neuromuscular junctions. Like all other antimuscarinic compounds, R-TOL causes dry mouth, blurry vision, tachycardia and possibly also memory impairment.
R-TOL relaxes urinary bladder smooth muscle and in animals with conditions characterized by increased bladder contractions, cystometric studies have demonstrated that R-TOL has beneficial effects. R-TOL may therefore be useful in the treatment and prevention of incontinency and frequent voluntary urination in patients. The efficacy of R-TOL in the bladder has been attributed to its antimuscarinic effects on the detrusor muscle. Because of its antimuscarinic activity, mydriasis (dilated pupils), xerostomia (dry mouth), tachycardia (fast heart beats) and impaired normal urinary voiding, which mechanisms all involve muscarinic cholinergic receptors, are obvious and reported side effects for R-TOL (Ekström et al., J. Urol. 1995, Suppl.4: 394A and Stahl et al. 1995. Neurourol Urodyn 14:647-655).
Pharmacological studies of the individual enantiomers of tolterodine have now been performed and have suggested that the R-TOL indeed is the efficacious enantiomer on muscarinic receptors. Thus, it was concluded that the cholinergic antagonism of racemic tolterodine (RS-TOL) could be attributed mainly to the activity of R-TOL. The rank order of potency of racemic tolterodine and its enantiomers for antimuscarinic activity is: R-TOL was greater or equal to RS-TOL, which was much greater than S-TOL, with S-TOL being approximately one or more orders of magnitude less potent than R-TOL.
SUMMARY OF THE INVENTION
lt has now unexpectedly been found that S-TOL has outstanding non-cholinergic spasmolytic activities, while being practically devoid of anticholinergic activity. It has furthermore unexpectedly been found that S-TOL provides weak sedative effects. S-TOL therefore will offer superior treatment for urinary disorders, including urinary incontinence and for gastrointestinal disorders, including gastrointestinal hyperactivity, while being devoid of the anticholinergic side effects that reside in R-TOL.
While the optically pure R-TOL provides medical treatment in patients with urinary incontinence that arises from one single cause, namely muscarinic hyperactivity, it was found that the optically pure S-TOL provides spasmolytic activity against urinary and intestinal spasms that arise from various mechanisms. S-TOL is particularly useful in patients where urinary incontinence is caused by non-cholinergic mechanisms or in patients, where antimuscarinic side effects are not acceptable (for example in the elderly, where antimuscarinic side effects have unacceptable effects on memory). Non-cholinergic spasmogenic mechanisms include but are not limited to scars (i.e. from childberth or surgical interventions) causing detrusor pacemaker activity, release of thromboxane, release of platelet activating factor and other non-muscarinic spasmogens.
Chemically, S-TOL is S(−)-2-[&agr;[2-(diisopropylamino)ethyl] benzyl]-p-cresol.
The active compound of this invention is S-TOL. The synthetic preparation is described in European Pat. Appl. EP 325571 A1, the disclosures of which are hereby incorporated by reference.
Alternatively, S-TOL can be prepared by stereoselective synthesis, using (other) chiral templates.
Alternatively, S-TOL can be obtained by the resolution of RS-TOL using conventional means such as fractional crystallization of diastereomeric salts with chiral acids. Other standard methods of resolution known to those skilled in the art, include, but are not limited to, crystallization and chromatography on a chiral substrate and can also be used.
The magnitude of a prophylactic or therapeutic dose of S-TOL in the acute or chronic management of disease will vary with the severity and nature of the condition to be treated and the route of administration. The dose and the frequency of the dosing will also vary according to the age, body weight and response of the individual patient. In general, the total daily dose range for S-TOL for the conditions described herein is from about 0.5 mg to about 100 mg in single or divided doses, preferably in divided doses. In managing the patient, the therapy should be initiated at a lower dose, perhaps at about 0.5 mg to about 25 mg, and may be increased up to about 200 mg depending on the patient's global response. It is further recommended that patients over 65 years and those with impaired renal or hepatic function initially receive low doses and that they be titrated based on individual response(s) and plasma drug level(s). It may be necessary to use dosages outside these ranges in some cases, as will be apparent to those skilled in the art. Further, it is noted that the clinician or treating physician will know how and when to interrupt, adjust, or terminate therapy in conjunction with individual patient response. The terms “a therapeutically effective amount” and “an amount sufficient to treat the disorder but insufficient to cause adverse effects” are encompassed by the above-described dosage amounts and dose frequency schedule.
Any suitable route of administration may be employed for providing the patient with an effective dosage of S-TOL. For example, oral, sublingual, parental (i.e. subcutaneous, intramuscular, intravenous, etc.), transdermal, vaginal, aerosol and like forms of administration may be employed. Additionally, the drug may be administered directly into the bladder, as described for oxybutynin by Massad et al. [
J. Urol
148. 595-597 (1992)] or rectally directly into the gastrointestinal canal as known in the art. Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, suppositories, microencapsulated systems, slowrelease and controlled release systems, transdermal delivery systems, and the like.
The pharmaceutical compositions of the present invention comprise of S-TOL as the active ingredient, or a pharmaceutically acceptable salt thereof, and may also contain a pharmaceutically acceptable carrier, and optionally, other therapeutic ingredients.
The terms “pharmaceutically acceptable salts” or “a pharmaceutically acceptable salt thereof” refer to salts prepared from pharmaceutically acceptable non-toxic acids. Suitable pharmaceutically acceptable acid addition salts for the compound of the present invention include acetic, benzenesulfonic (besylate), benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pathothenic, phosphoric, p-toluenesulfonic, succinic, sulfuric, tartaric, and the like. The hydrochloride is particularly preferred.
The compositions of the present invention include suspensions, solutions, elixirs or solid dosage forms. Carriers such as starches, sugars, and microcrystalline cel
Bawa Raj
Bridge Pharma, Inc.
Nields & Lemack
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