Treatment of faecal incontinence and other conditions with 1r,2s-methoxamine

Abstract

1R,2S-Methoxamine may be used topically for effective treatment of faecal incontinence at low doses without local or systemic side effects, for example, without affecting blood pressure. 1R,2S-Methoxamine may be used to treat other disturbances and disorders of the gastro-intestinal, as a pressor agent, as a nasal decongestant and in ophthalomology, at low doses and without significant side effects.

1 . A pharmaceutical composition comprising 1R,2S-methoxamine or a physiologically tolerable salt thereof in admixture or conjunction with a pharmaceutically suitable carrier.  
     
     
         2 . A pharmaceutical composition as claimed in  claim 1 , in a form suitable for systemic administration.  
     
     
         3 . A pharmaceutical composition as claimed in  claim 1 , in a form suitable for topical administration to all or part of the area comprising the anus, the anal canal, and the area around the anus.  
     
     
         4 . A pharmaceutical composition as claimed in  claim 3 , in the form of a gel, cream, ointment, paste, foam or adhesive patch.  
     
     
         5 . A pharmaceutical composition as claimed in  claim 1 , in a form suitable for oral, rectal or parenteral administration.  
     
     
         6 . A pharmaceutical composition as claimed in  claim 5 , in the form of a delayed release oral composition.  
     
     
         7 . A pharmaceutical composition as claimed in  claim 6 , wherein the delayed release oral composition has release targeted to the colon.  
     
     
         8 . A pharmaceutical composition as claimed in  claim 7 , wherein the composition is a time-delayed release composition, a composition that releases the active substance at the pH of the colon, or a composition that comprises a coating susceptible to degradation by colonic bacteria.  
     
     
         9 . A pharmaceutical composition as claimed in  claim 1 , in a form suitable for administration to the nasal mucosa.  
     
     
         10 . A pharmaceutical composition as claimed in  claim 9 , in the form of drops, a spray or an aerosol.  
     
     
         11 . A pharmaceutical composition as claimed in  claim 1 , in a form suitable for administration to the surface of the eye.  
     
     
         12 . A pharmaceutical composition as claimed in  claim 11 , in the form of drops, a cream or an ointment.  
     
     
         13 . A pharmaceutical composition as claimed in  claim 1 , in a form suitable for administration by injection or infusion.  
     
     
         14 . A pharmaceutical composition as claimed in  claim 1 , in unit dosage form.  
     
     
         15 . A pharmaceutical composition as claimed in  claim 1 , which comprises up to and including 10% by weight of 1R,2S-methoxamine or said physiologically tolerable salt thereof.  
     
     
         16 . A pharmaceutical composition as claimed in  claim 3 , which comprises up to and including 10% by weight of 1R,2S-methoxamine or said physiologically tolerable salt thereof.  
     
     
         17 . A pharmaceutical composition as claimed in  claim 16 , which comprises up to and including 8% by weight of 1R,2S-methoxamine or said physiologically tolerable salt thereof.  
     
     
         18 . A pharmaceutical composition as claimed in  claim 17 , which comprises up to and including 5% by weight of 1R,2S-methoxamine or said physiologically tolerable salt thereof.  
     
     
         19 . A pharmaceutical composition as claimed in  claim 18 , which comprises up to and including 4% by weight of 1R,2S-methoxamine or said physiologically tolerable salt thereof.  
     
     
         20 . A pharmaceutical composition as claimed in  claim 19 , which comprises up to and including 3% by weight of 1R,2S-methoxamine or said physiologically tolerable salt thereof.  
     
     
         21 . A pharmaceutical composition as claimed in  claim 20 , which comprises up to and including 1% by weight of 1R,2S-methoxamine or said physiologically tolerable salt thereof.  
     
     
         22 . A pharmaceutical composition as claimed in  claim 21 , which comprises up to and including 0.5% by weight of 1R,2S-methoxamine or said physiologically tolerable salt thereof.  
     
     
         23 . A pharmaceutical composition as claimed in  claim 22 , which comprises up to and including 0.3% by weight of 1R,2S-methoxamine or said physiologically tolerable salt thereof.  
     
     
         24 . A pharmaceutical composition as claimed in  claim 23 , which comprises up to and including 0.1% by weight of 1R,2S-methoxamine or said physiologically tolerable salt thereof.  
     
     
         25 . A pharmaceutical composition as claimed in  claim 1 , in a form suitable for non-systemic administration.  
     
     
         26 . A pharmaceutical composition as claimed in  claim 3 , in a form suitable for administration to the anus.  
     
     
         27 . A pharmaceutical composition as claimed in  claim 1 , in a form suitable for administration to all or part of the area comprising the anoderm, the anal canal, the internal anal sphincter, the area around the anus, and the buttocks.  
     
     
         28 . A pharmaceutical composition as claimed in  claim 1 , wherein said composition comprises 1R,2S-methoxamine.  
     
     
         29 - 41 . (canceled)  
     
     
         42 . A method of treating faecal incontinence, comprising administering 1R,2S-methoxamine, or a physiologically tolerable salt thereof to a mammal in an amount effective to treat faecal incontinence in said mammal.  
     
     
         43 . A method as claimed in  claim 42 , wherein 1R,2S-methoxamine is administered to said mammal.  
     
     
         44 . A method of treating faecal incontinence, comprising administering 1R,2S-methoxamine to a mammal in an amount effective to treat faecal incontinence in said mammal.  
     
     
         45 . A method as claimed in  claim 46 , wherein 1R,2S-methoxamine is administered to said mammal.  
     
     
         46 . A method of treating a mammal in need of treatment with an α-adrenoceptor agonist, which comprises administering a therapeutically effective amount of 1R,2S-methoxamine or a physiologically tolerable salt thereof to said mammal.  
     
     
         47 . A method as claimed in  claim 46 , wherein the 1R,2S-methoxamine or a physiologically tolerable salt thereof is administered systemically or topically.  
     
     
         48 . A method as claimed in  claim 46 , wherein said mammal is in need of treatment for faecal incontinence.  
     
     
         49 . A method as claimed in  claim 48 , wherein the 1R,2S-methoxamine or a physiologically tolerable salt thereof is administered topically to the anal region.  
     
     
         50 . A method as claimed in  claim 48 , wherein the 1R,2S-methoxamine or a physiologically tolerable salt thereof is administered topically to all or part of the area comprising the anus, the internal anal canal, and the area around the anus.  
     
     
         51 . A method as claimed in  claim 48 , wherein the 1R,2S-methoxamine or a physiologically tolerable salt thereof is administered topically to all or part of the area comprising the anoderm, the anal canal, the internal or external anal sphincter, the area around the anus, and the buttocks.  
     
     
         52 . A method as claimed in  claim 48 , wherein the 1R,2S-methoxamine or a physiologically tolerable salt thereof is administered as a gel, cream, ointment, paste, foam or adhesive patch.  
     
     
         53 . A method as claimed in  claim 46 , wherein the 1R,2S-methoxamine or a physiologically tolerable salt thereof is administered by oral, rectal or parenteral administration.  
     
     
         54 . A method as claimed in  claim 53 , wherein the 1R,2S-methoxamine or a physiologically tolerable salt thereof is administered as a delayed release oral composition.  
     
     
         55 . A method as claimed in  claim 54 , wherein the 1R,2S-methoxamine or a physiologically tolerable salt thereof is administered as a delayed release oral composition having release targeted to the colon.  
     
     
         56 . A method as claimed in  claim 55 , wherein the 1R,2S-methoxamine or a physiologically tolerable salt thereof is administered as a time-delayed release composition, a composition that releases the active substance at the pH of the colon, or a composition that comprises a coating susceptible to degradation by colonic bacteria.  
     
     
         57 . A method as claimed in  claim 46 , wherein said mammal is in need of treatment with a vasoconstrictor agent.  
     
     
         58 . A method as claimed in  claim 46 , wherein said mammal is in need of treatment for nasal congestion and wherein said 1R,2S-methoxamine or a physiologically tolerable salt thereof is administered to the nasal mucosa of said mammal.  
     
     
         59 . A method as claimed in  claim 58 , wherein the 1R,2S-methoxamine or a physiologically tolerable salt thereof is administered as drops, a spray or an aerosol suitable for administration to the nasal mucosa.  
     
     
         60 . A method as claimed in  claim 46 , wherein said mammal is in need of treatment for ophthalmological vasoconstriction and wherein said 1R,2S-methoxamine or a physiologically tolerable salt thereof is administered to an eye of said mammal.  
     
     
         61 . A method as claimed in  claim 60 , wherein the 1R,2S-methoxamine or a physiologically tolerable salt thereof is administered as drops, a cream or an ointment suitable for administration to the surface of the eye.  
     
     
         62 . A method as claimed in  claim 46 , wherein said mammal is in need of dilating the pupil of an eye and wherein said 1R,2S-methoxamine or a physiologically tolerable salt thereof is administered to an eye of said mammal.  
     
     
         63 . A method as claimed in  claim 62 , wherein the 1R,2S-methoxamine or a physiologically tolerable salt thereof is administered as drops suitable for administration to the surface of the eye.  
     
     
         64 . A method as claimed in  claim 46 , wherein said mammal is in need of treatment or prevention of hypotension.  
     
     
         65 . A method as claimed in  claim 46 , wherein said mammal is in need of maintaining blood pressure during and/or after anaesthesia and wherein said 1R,2S-methoxamine or a physiologically tolerable salt thereof is administered to said mammal during anaesthesia.  
     
     
         66 . A method as claimed in  claim 65 , wherein the 1R,2S-methoxamine or a physiologically tolerable salt thereof administered to said mammal by injection or infusion.  
     
     
         67 . A method as claimed in  claim 46 , wherein said mammal is in need of increasing the tone of smooth muscle of the gastrointestinal tract.  
     
     
         68 . A method as claimed in  claim 46 , wherein said mammal is in need of treatment for a disturbance or disorder resulting from loss of tone of smooth muscle of the gastrointestinal tract.  
     
     
         69 . A method as claimed in  claim 46 , wherein said mammal is in need of increasing the tone of a sphincter of the gastrointestinal tract.  
     
     
         70 . A method as claimed in  claim 46 , wherein said mammal is in need of treatment for a disturbance or disorder resulting from loss of tone of a sphincter of the gastrointestinal tract.  
     
     
         71 . A method as claimed in  claim 70 , wherein said disturbance or disorder is gastrogenous diarrhoea.  
     
     
         72 . A method as claimed in  claim 46 , wherein said mammal is in need of prevention or treatment of disturbances or disorders of cardiac function.  
     
     
         73 . A method as claimed in  claim 72 , wherein said mammal has a disturbance or disorder of cardiac rhythym.  
     
     
         74 . A method as claimed in  claim 46 , wherein said mammal is a human.  
     
     
         75 . A process for the production of 1R,2S-methoxamine, which comprises adding trifluoroacetic acid dropwise to a solution comprising (S)-amino-1-(2,5-dimethoxy-phenyl)-1-propanone, the amino group of which is protected, and dimethylphenylsilane and removing the protecting group from the resulting amino-protected (1R,2S)-2-amino-1-(2,5-dimethoxy-phenyl)-1-propanol.  
     
     
         76 . A process as claimed in  claim 75 , wherein the first step is carried out with cooling.  
     
     
         77 . A process as claimed in  claim 75 , wherein the resulting 1R,2S-methoxamine is converted into a salt thereof.  
     
     
         78 . A process as claimed in  claim 75 , wherein the (S)-amino-1-(2,5-dimethoxy-phenyl)-1-propanone, the amino group of which is protected, is produced by converting (S)-N-alanine dimethylamide, the amino group of which is protected, into the acid chloride and reacting the resulting acid chloride in situ with 1.5 equivalents of n-butyl lithium and 1.5 equivalents of bromo-2,5-dimethoxybenzene.  
     
     
         79 . A process as claimed in  claim 78 , wherein (S)-N-alanine dimethylamide, the amino group of which is protected, is produced by reacting L-analine with methyl chloroformate.  
     
     
         80 . A method for isolating the 1R,2S-isomer of methoxamine from a mixture of methoxamine isomers, which comprises subjecting the mixture of isomers to high pressure liquid chromatography using a chromatography medium that comprises β-cyclodextrin R,S-hydroxypropyl ether, bonded to silica gel.  
     
     
         81 . A method as claimed in  claim 80 , wherein the eluate is subjected to reversed phase chromato-graphy using a chromatography medium comprising a vinyl alcohol copolymer base derivatized by the introduction of octadecyl (C18) groups on the hydroxyl groups of the vinyl alcohol copolymers.