Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Reexamination Certificate
1998-12-23
2001-03-27
Killos, Paul J. (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
C564S171000, C514S534000, C514S617000, C514S622000, C568S329000
Reexamination Certificate
active
06207852
ABSTRACT:
This application is a 371 of PCT/US97/11310 filed Jun. 30, 1997.
FIELD OF INVENTION
The present invention relates to smooth muscle spasmolytic agents, pharmaceutical compositions containing them and method of using said compounds and compositions for the treatment of urinary incontinence, gastric hyperactivity (ex. Irritable Bowel Syndrome) and other smooth muscle contractile conditions.
More particularly, the present invention relates to certain substituted esters, amides and ketones having smooth muscle relaxing properties while avoiding, on administration to a mammal, adverse side effects such as prominent antimuscarinic, arrhythmogenic and cardiodepressive effects.
REPORTED DEVELOPMENT
Racemic oxybutynin (OXY) is the leading drug for urinary incontinence and is also being used for the treatment in intestinal disorders, such as Irritable Bowel Syndrome (IBS). OXY is specifically used in the treatment of urinary urge incontinence. Urge incontinence is believed to be due to instability of the smooth muscle of the bladder (detrusor muscle). OXY exerts a direct antispasmodic effect on various forms of smooth muscle, mainly by inhibiting the action of acetylcholine on smooth muscle (anticholinergic activity). OXY is selective for muscarinic (acetylcholine) receptors over nicotinic (acetylcholine) receptors and as a result, no blocking effects are observed at skeletal neuromuscular junctions.
OXY relaxes urinary bladder smooth muscle and in patients with conditions characterized by involuntary bladder contractions, cystometric studies have demonstrated that OXY increases vesicle capacity, diminishes the frequency of involuntary contractions of the detrusor muscle, and delays the initial desire to void. There may be different reasons for urinary urge incontinence between patients. Thus involuntary bladder contractions may be caused by cholinergic or non-cholinergic mechanisms. The efficacy of OXY in the bladder has been attributed to a combination of antimuscarinic, direct spasmolytic and local anesthetic effects on the detrusor muscle. The racemic drug causes side effects such as drowsiness, impotence, diarrhea, mydriasis (dilated pupils), xerostomia (dry mouth) and tachycardia (fast heart beats). In fact, at least one researcher has referred to the “inevitable symptoms of mydriasis, xerostomia, tachycardia, etc.” that accompany the administration of racemic oxybutynin (Lish et al. Arch. Int. Pharmacodyn. 156, 467-488 (1965), 481). Since cholinergic mechanisms are involved in the memory functions of the brain and the control of heart rate, anticholinergic drugs may be contraindicated in many patients, particularly in older patients. Other, clinically less serious anticholinergic side effects of oxybutynin are dry mouth (xerostomia), mydriasis and blurry vision. The high incidence of anticholinergic side effects by oxybutynin among patients with urinary incontinence, often results in reduction of the dosage or discontinuation of the therapy. Oxybutynin was originally developed as a membrane stabilizer (local anesthetic) and has therefore cardiac depressive effects that may limit its use in the elderly or in patients with cardiac disorders. In racemic oxybutynin, the cardiac depressive effects of the molecule are partly counteracted by the cardiac anticholinergic activity of the R-isomer, while that is not the case when the single S-isomer of oxybutynin is used for therapeutic purposes.
Previous pharmacological studies of the individual enantiomers of OXY have suggested that the R-enantiomer is the therapeutically active enantiomer. Thus, Noronha-Blob et al. (J. Pharmacol. Exp. Ther. 256, 562-567 (1991)) concluded that the cholinergic antagonism of racemic oxybutynin (measured in vitro by its affinity for muscarinic receptor subtypes and in vivo for diverse physiological responses) could be attributed mainly to the activity of the R-enantiomer. For all muscarinic responses they found the rank order of potency of racemic oxybutynin and its enantiomers to be: (R)-oxybutynin (R-OXY) greater or equal to OXY, which was much greater than (S)-oxybutynin (S-OXY), with S-OXY being 1 to 2 orders of magnitude less potent than R-OXY as an antimuscarinic agent.
The S-isomer of oxybutynin has been suggested as a drug for urge incontinence (Aberg et al. U.S. Pat. No. 5,532,274). The present invention is concerned with compounds that have significantly less membrane stabilizing (cardiac depressant) activity than S-OXY (see above) and compounds that also have longer duration than S-OXY. The S-isomers of the compounds of the present invention are useful in the treatment of such types of urinary incontinence and other spasmogenic malfunctions, such as for example dysmenorrhea and certain types of irritable bowel syndrome, that are not caused by muscarinic mechanisms, while avoiding the side effects that reside in the corresponding R-isomers.
The R-isomers of the compounds of the present invention will be useful in the treatment of such types of urinary incontinence and other spasmogenic malfunctions that are caused by muscarinic mechanisms, while avoiding the side effects that reside in the corresponding S-isomers.
SUMMARY OF THE INVENTION
It has now been found that compounds with certain substituents (Table I) on the nitrogen atom of oxybutynin, have anticholinergic and/or calcium antagonistic activities, superior to those of oxybutynin. It has also been found that in certain cases, the (S)-isomers of said compounds have calcium antagonistic activities that are similar to the corresponding racemates and (R)-isomers. Most of the anticholinergic activity resides in the (R)-isomers of these compounds and the (S)-isomers have significantly less antimuscarinic activity than both the (R)-isomers and the racemates. Thus, practically all of the anti-cholinergic side effects of the racemic compounds (tachycardia, memory impairment, dry mouth, blurry vision etc.) reside in the (R)-isomer. However, the side effect of membrane stabilization that causes cardiac depressant effects in vivo, resides in both the (R)- and the (S)-isomers of these compounds. It has now been found that certain molecules have less membrane stabilizing activity and have therefore less cardiodepressant effects than OXY or S-OXY. Molecules have also been found that offer significantly longer durations of action in vivo than OXY or S-OXY, while the beneficial ratio between calcium antagonistic activity and anticholinergic activities, seen in S-OXY, were surprisingly well maintained, or even improved. Thus, the S-isomers of certain amides and ketoness of the present invention offered less anticholinergic side effects than OXY and R-OXY, less cardiodepressive side effects than OXY, R-OXY and S-OXY and longer duration of activity than OXY, R-OXY and S-OXY.
It has now been found the optically pure (S)-4-dimethylamino-2-butyn-1-yl cyclohexylphenylglycolate, herein also called S-dimethyloxybutynin (S-DIMEO), provides medical treatment for urinary incontinence, while avoiding the strong anticholinergic side effects of racemic 4-dimethyl-amino-2-butyn-1-yl cyclohexyl-phenylglycolate, herein also called dimethyloxybutynin (DIMEO) and of (R)-4-dimethyl-amino-2-butyn-1-yl cyclohexylphenylglycolate, herein also called R-dimethyloxybutynin (R-DIMEO). Furthermore, analogs to S-DIMEO where the ester bridge was replaced by an amide (Examples 4 and 5) or an keto link (Examples 6 and 7), offered a longer duration of activity, while still avoiding the anticholinergic and the membrane stabilizing side effects, mentioned above.
S-DIMEO and the aforementioned S-DIMEO analogs are particularly useful in patients where urinary incontinence is caused by non-cholinergic mechanisms, which is believed to be the majority of all patients suffering from urinary urge incontinence. Compounds of this type are also useful for the treatment of various other spasmodic conditions, such as for example dysmenorrhea and certain types of irritable bowel syndrome. Non-cholinergic mechanisms causing irregular contractions of smooth muscles, include but are not limited to scars (i.e.
Aberg A. K. Gunnar
Chen Jan L.
Wright George E.
Bridge Pharma, Inc.
Killos Paul J.
Nields & Lemack
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