Pharmaceutical salts

Abstract

The invention relates to pharmaceutical salts comprised of a pharmaceutical active substance and of a least one sugar substitute, to medicaments containing these salts, and to the use of these salts for producing medicaments.

1 . A pharmaceutical salt of a pharmaceutical active compound and at least one sugar substitute with the exception of the respective pharmaceutical salt of a sugar substitute and tramadol, (+)-tramadol, (−)-tramadol, (+)-demethyltramadol and (−)-demethyltramadol.  
     
     
         2 . The pharmaceutical salt as claimed in  claim 1 , characterized in that the solubility of the salt in water is ≦250 mg/ml of water, preferably ≦200 mg/ml, particularly preferably ≦150 mg/ml, very particularly preferably ≦100 mg/ml.  
     
     
         3 . The pharmaceutical salt as claimed in  claim 1 , characterized in that the salt-forming sugar substitute is saccharin, cyclamate or acesulfam, preferably saccharin.  
     
     
         4 . The pharmaceutical salt as claimed in  claim 1 , characterized in that the salt-forming active compound is selected from the group consisting of the salt-forming analgesics, antiobesity agents, analeptics, antihypoxemics, antirheumatics, opioid antagonists, anthelmintics, antiallergics, antiarrhythmics, antibiotics, anti-dementives (nootropics), antidiabetics, anti-emetics, antivertiginous agents, antiepileptics, antihypertensives, antihypotensives, antimycotics, antiinflammatories, antitussives, expectorants, arteriosclerosis agents, β-receptor blockers, calcium channel blockers, broncholytics, anti-asthmatics, cholinergics, diuretics, circulation-promoting agents, weaning agents, geriatrics, hypnotics, sedatives, immunomodulators, oral therapeutics, pharyngeal therapeutics, coronary agents, hypolipidemics, local anesthetics, neural therapeutics, gastric agents, intestinal agents, migraine agents, muscle relaxants, anesthetics, neuropathy preparations, ophthalmologicals, otologicals, Parkinson agents, psychopharmaceuticals, rhinologicals, sinusitis agents, spasmolytics, platelet aggregation inhibitors, tuberculosis agents, urologicals and cytostatics.  
     
     
         5 . The pharmaceutical salt as claimed in  claim 4 , characterized in that the active compound is selected from the group consisting of the salt-forming analgesics, analeptics, antihypoxemics, antiallergics, antiarrhythmics, antiemetics, antivertiginous agents, antihypertensives, antihypotensives, antitussives, expectorants, β-receptor blockers, calcium channel blockers, ophthalmologicals, otologicals, spasmolytics and urologicals, preferably from the group consisting of the salt-forming analgesics.  
     
     
         6 . The pharmaceutical salt as claimed in  claim 4 , characterized in that the salt-forming analgesic is selected from the group consisting of the salt-forming opioids, the salt-forming opiod analogs, ephdrine, chloroquine lidocaine, ethaverine, preglumetacin and triflupromazine.  
     
     
         7 . The pharmaceutical salt as claimed in  claim 6 , characterized in that the salt-forming opioid or opioid analog is selected from the group consisting of morphine, codeine, ethylmorphine, diacetylmorphine, dihydrocodeine, etorphine, hydrocodone, hydromorphone, levorphanol, oxycodone, oxymorphone, pethidine, ketobemidone, fentanyl, alfentanil, remifentanil, sufentanil, levomethadone, levomethadyl, dextromoramide, dextropropoxyphene, diphenoxylate, piritramide, tilidine, buprenorphine, butorphanol, dezozine, nalbuphine, nalorphine, pentazocine, nefopam, flupirtin and meptazinol.  
     
     
         8 . The pharmaceutical salt as claimed in  claim 7 , characterized in that the salt-forming opioid is selected from the group consisting of morphine, codeine, hydrocodone, hydromorphone, oxycodone, tilidine, fentanyl and buprenorphine.  
     
     
         9 . The pharmaceutical salt as claimed in  claim 1 , characterized in that the salt-forming active compound is a salt-forming compound of 1-phenyl-3-dimethylaminopropane compounds of the general formula I  
       
         
           
           
               
               
           
         
       
       in which 
 X is OH, F, Cl, H or an OCOR 6  group,  
 R 1  is a C 1-4 -alkyl group,  
 R 2  is H or a C 1-4 -alkyl group and R 3  is H or a straight-chain C 1-4 -alkyl group or the radicals R 2  and R 3  together form a C 4-7 -cycloalkyl radical, and  
 if R 5  is H, R 4  is meta-O-Z where Z is H, C 1-3 -alkyl, PO(O—C 1-4 -alkyl) 2 , CO(OC 1-5 -alkyl), CONH—C 6 H 4 —(C 1-3 -alkyl), CO—C 6 H 4 —R 7 , where R 7  is ortho-OCOC 1-3 -alkyl or meta- or para-CH 2 N(R 8 ) 2  where R 8  is C 1-4 -alkyl or 4-morpholino, or R 4  is meta-S—C 1-3 -alkyl, meta-Cl, meta-F, meta-CR 9 R 10 R 11  where R 9 , R 10 , R 11  are H or F, ortho-OH, ortho-O—C 2-3 -alkyl, para-F or para-CR 9 R 10 R 11  where R 9 , R 10 , R 11  are H or F, or if R 5  is para-Cl, —F, —OH or —O—C 13 -alkyl, R 4  is meta-Cl, —F, —OH or —O—C 1-3 -alkyl, or  
 R 4  and R 5  together are 3,4-OCH═CH— or 3,4-OCH═CHO—,  
 R 6  is C 1-3 -alkyl,  
 in the form of their possible stereoisomers as racemates or diastereomerically pure enantiomers or in the form of mixtures of enantiomers, in which the respective enantiomers are present in nonequimolar amounts.  
 
     
     
         10 . The pharmaceutical salt as claimed in  claim 9 , characterized in that X is OH, F, Cl or H, R 1  is a C 1-4 -alkyl group, R 2  is H or CH 3  and R 3  is H or CH 3  and if R 5  is H, R 4  is meta-O—C 1-3 -alkyl, meta-OH, meta-S—C 1-3 -alkyl, meta-F, meta-Cl, meta-CH 3 , meta-CF 2 H, meta-CF 3  or para-CF 3  or if R 5  is a para-Cl or —F, R 4  is meta-Cl or —F, or R 4  and R 5  together are 3,4-OCH═CH—.  
     
     
         11 . The pharmaceutical salt as claimed in  claim 9 , characterized in that the radicals R 2  and R 3  have different meanings and the compounds of the general formula I as claimed in  claim 9  are present in the form of their diastereomers having the configuration Ia  
       
         
           
           
               
               
           
         
       
     
     
         12 . The pharmaceutical salt as claimed in  claim 9 , characterized in that the salt-forming 1-phenyl-3-dimethylaminopropane compound is selected from the group consisting of 
 (1RS,2RS)-3-(3-dimethylamino-1-hydroxy-1,2-dimethylpropyl)phenol,    (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)phenol,    (+)-(1S,2S)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)phenol,    (2RS,3RS)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol,    (−)-(1S,2S)-3-(3-dimethylamino-1-ethyl-1-fluoro-2-methylpropyl)phenol,    (+)-(1R,2R)-3-(3-dimethylamino-1-hydroxy-1,2-dimethylpropyl)phenol,    (+)-(2R,3R)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol and    (−)-(2S,3S)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol.    
     
     
         13 . The pharmaceutical salt as claimed in  claim 1 , characterized in that the salt-forming active compound is a salt-forming compound of 6-dimethylaminomethyl-1-phenylcyclohexane compounds of the general formula II,  
       
         
           
           
               
               
           
         
       
       in which 
 R 1′  is H, OH, Cl or F,  
 R 2′  and R 3′  are identical or different and are H, C 1-4 -alkyl, benzyl, CF 3 , OH, OCH 2 —C 6 H 5 , O—C 1-4 -alkyl, Cl or F with the proviso that at least one of the radicals R 2′  or R 3′  is H,  
 R 4  is H, CH 3 , PO(O—C 1-4 -alkyl) 2 , CO(O—C 1-5 -alkyl), CO—NH—C 6 H 4 —C 1-3 -alkyl, CO—C 6 H 4 —R 5 , CO—C 1-5 -alkyl, CO—CHR 6′ —NHR 7′  or an unsubstituted or substituted pyridyl, thienyl, thiazoyl [sic] or phenyl group,  
 R 5′  is OC(O)C 1-3 -alkyl in the ortho-position or CH 2 —N(R 8′ ) 2  in the meta- or para-position, where R 8′  is C 1-4 -alkyl or both radicals R 8′  together with N are the 4-morpholino radical, and  
 R 6′  and R 7′  are identical or different and are H or C 1-6 -alkyl,  
 with the proviso that if both radicals R 2′  and R 3′  are H, R 4′  is not CH 3  if R 1′  is H, OH or Cl or R 4′  is not H if R 1′  is OH,  
 in the form of their possible stereoisomers as racemates or diastereomerically pure enantiomers or in the form of mixtures of enantiomers, in which the respective enantiomers are present in nonequimolar amounts.  
 
     
     
         14 . The pharmaceutical salt as claimed in  claim 13 , characterized in that R 1′  is H, OH or F.  
     
     
         15 . The pharmaceutical salt as claimed in  claim 13 , characterized in that the compounds of the general formula II have a configuration in which the phenyl ring and the dimethylaminomethyl group are in each case arranged in an equatorial position to one another.  
     
     
         16 . The pharmaceutical salt as claimed in  claim 13 , characterized in that the salt-forming 6-dimethylaminomethyl-1-phenylcyclohexane compound is selected from the group consisting of 
 (−)-(1R,2R)-3-(2-dimethylaminomethylcyclohexyl)phenol,    (1RS,3RS,6RS)-6-(dimethylaminomethyl)-1-(3-methoxyphenyl)cyclohexane-1,3-diol and    (1RS,3RS,6RS)-6-(dimethylaminomethyl)-1-(3-hydroxyphenyl)cyclohexane-1,3-diol.    
     
     
         17 . The pharmaceutical salt as claimed in  claim 1 , characterized in that the salt-forming active compound is a salt-forming compound of 1-phenyl-2-dimethylaminomethylcyclohexan-1-ol compounds of the general formula III,  
       
         
           
           
               
               
           
         
       
       in which in each case 
 A is O or S,  
 R 1″  is H, C 1-6 -alkyl, C 2-6 -alkenyl, C 5-7 -cycloalkyl or halogenated C 1-6 -alkyl,  
 the group  
                     
 R 2′″  is C 1-6 -alkyl, C 2-6 -alkenyl, C 5-7 -cycloalkyl-methyl, substituted or unsubstituted phenyl or substituted or unsubstituted benzyl,  
 in the form of their possible stereoisomers as racemates or diastereomerically pure enantiomers or in the form of mixtures of enantiomers, in which the respective enantiomers are present in nonequimolar amounts.  
 
     
     
         18 . The pharmaceutical salt as claimed in  claim 17 , characterized in that R 1″  is H, C 1-4 -alkyl, 2′-methyl-2′-propenyl, cyclopentyl or fluoroethyl, with the proviso that R 1″  is C 1-4 -alkyl if A is S, 
 R 2″  is C 1-4 -alkyl, C 2-4 -alkenyl, cyclopentylmethyl, phenyl, C 1-4 -alkoxyphenyl, benzyl, C 1-4 -alkylbenzyl, mono- or dihalogenated phenyl or mono- or dihalogenated benzyl.    
     
     
         19 . The pharmaceutical salt as claimed in  claim 17 , characterized in that R 1″  is H, methyl, ethyl, isopropyl, 2′-methyl-2′-propenyl, cyclopentyl or fluoroethyl, with the proviso that R 1″  is methyl if A is S, 
 R 2″  is methyl, propyl, 2′-methylpropyl, allyl, 2′-methyl-2′-propenyl, cyclopentylmethyl, phenyl, 3-methoxyphenyl, benzyl, 4-tert-butylbenzyl, 4-chlorobenzyl, 4-fluorobenzyl or 3,4-dichlorobenzyl.    
     
     
         20 . The pharmaceutical salt as claimed in  claim 17 , characterized in that the compounds of the general formula III have a configuration in which the phenyl ring and the dimethylaminomethyl group are in each case arranged in an equatorial position to one another.  
     
     
         21 . The pharmaceutical salt as claimed in  claim 17 , characterized in that the salt-forming 1-phenyl-2-dimethylaminomethylcyclohexan-1-ol compound of the general formula III is selected from the group consisting of 
 (+)-(1R,2R,4S)-2-(dimethylaminomethyl)-4-(4-fluorobenzyloxy)-1-(3-methoxyphenyl)cyclohexanol,    (+)-(1R,2R,4S)-2-dimethylaminomethyl-4-(4-chloro-benzyloxy)-1-(3-methoxyphenyl)cyclohexanol and    (+)-(1R,2R,4S)-3-[2-dimethylaminomethyl-4-(4-fluorobenzyloxy)-1-hydroxycyclohexyl]phenol.    
     
     
         22 . The pharmaceutical salt as claimed in  claim 1 , characterized in that the salt-forming active compound is a salt-forming dimethyl-(3-arylbut-3-enyl)amine compound of the general formula IV, in which [sic] 
       
         
           
           
               
               
           
         
         the radical R 1′″  is C 1-5 -alkyl and R 2′″  is H or C 1 - 5 -alkyl or R 1′″  and R 2′″  together are —(CH 2 ) 2-4 —, —(CH 2 ) 2 —CHR 7′″  or —CH 2 —CHR 7′″ —CH 2 —,  
         R 3′″  is H or C 1-5 -alkyl,  
         R 4′″  is H, OH, C 1-4 -alkyl, O—C 1-4 -alkyl, O-benzyl, CF 3 , O—CF 3 , Cl, F or OR 8′″ ,  
         R 5′″  is H, OH, C 1-4 -alkyl, O—C 1-4 -alkyl, O-benzyl, CHF 2 , CF 3 , O—CF 3 , Cl, F or OR 8′″  and  
         R 6′″  is H, OH, C 1-4 -alkyl, O—C 1-4 -alkyl, O-benzyl, CF 3 , O—CF 3 , Cl, F or OR 8′″ ,  
         with the proviso that two of the radicals R 4′″ , R 5′″  or R 6′″  are H, or  
         R 4′″  and R 5′″  together are —CH═C(R 9′″ )—O— or —CH═C(R 9′″ )—S—, with the proviso that R 6′″  is H, or  
         R 5′″  and R 6′″  together are —CH═CH—C(OR 10′″ )═CH—, with the proviso that R 4′″  is H,  
         R 7′″  is C 1-8 -alkyl, C 3-8 -cycloalkyl, O—C 1-4 -alkyl, O-benzyl, CF 3 , Cl or F,  
         R 8′″  is CO—C 1-5 -alkyl, PO(O—C 1-4 -alkyl) 2 , CO—C 6 H 4 —R 11′″ , CO(O—C 1-5 -alkyl), CO—CHR 12′″ —NHR 13 ′″ , CO—NH—C 6 H 3 —(R 14′″ ) 2  or an unsubstituted or substituted pyridyl, thienyl, thiazoyl [sic] or phenyl group,  
         R 9′″  is H or C 1-4 -alkyl,  
         R 10′″  is H or C 1-3 -alkyl,  
         R 11′″  is OC(O)—C 1-3 -alkyl in the ortho-position or CH 2 —N—(R 15′″ ) 2  in the meta- or para-position, where R 15′″  is C 1-4 -alkyl or both radicals R 15′″  together with N form the 4-morpholino radical,  
         R 12′″  and R 13′″  are identical or different and are H, C 1-6 -alkyl or C 3-8 -cycloalkyl or R 12′″  and R 13′″  together are —(CH 2 ) 3-8 —,  
         R 14′″  is H, OH, C 1-7 -alkyl, O—C 1-7 -alkyl, phenyl, O-aryl, CF 3 , Cl or F, with the proviso that the two radicals R 14′″  are identical or different,  
         in the form of their possible stereoisomers as racemates or diastereomerically pure enantiomers or in the form of mixtures of enantiomers, in which the respective enantiomers are present in nonequimolar amounts.  
       
     
     
         23 . The pharmaceutical salt as claimed in  claim 22 , characterized in that R 1′″  is C 1-3 -alkyl and R 2′″  is H or C 1-3 -alkyl, or R 1′″  and R 2′″  together are —(CH 2 ) 2-4 — or —(CH 2 ) 2 —CHR 7′″ , 
 R 3′″  is H or C 1-3 -alkyl,    R 4′″  is H, OH, CF 3 , Cl, F or OR 8′″ ,    R 5′″  is H, OH, C 1-4 -alkyl, O—C 1-4 -alkyl, O-benzyl, CHF 2 , CF 3 , Cl, F or OR 8′″  and    R 6′″  is H, OH, O—C 1-4 -alkyl, O-benzyl, CF 3 , Cl, F or OR 8′″ ,    with the proviso that two of the radicals R 4′″ , R 5′″  or R 6′″  are H, or    R 4′″  and R 5′″  together are —CH═C(R 9′″ )—O— or —CH═C(R 9′″ )—S—, with the proviso that R 6′″  is H, or    R 5′″  and R 6′″  together are —CH═CH—C(OR 10 ′″)═CH—, with the proviso that R 4′   is H, and    R 7′″  is C 1-4 -alkyl, CF 3 , Cl or F.    
     
     
         24 . The pharmaceutical salt as claimed in  claim 22 , characterized in that R 1′″  is CH 3  or C 3 H 7  and R 2′″  is H, CH 3  or CH 2 CH 3 , or R 1′″  and R 2′″  together are —(CH 2 ) 2-3 — or —(CH 2 ) 2 —CHR 7′″ , 
 R 3′″  is H, CH 3  or CH 2 CH 3 ,    R 4′″  is H or OH, R 5′″  is H, OH, OCH 3 , CHF 2  or OR 8′″  and R 6′″  is H, OH or CF 3 , with the proviso that two of the radicals R 4′″ , R 5′″  or R 6′″  are H, or    R 4′″  and R 5′″  together are —CH═C(CH 3 )—S—, with the proviso that R 6′″  is H, or    R 5′″  and R 6′″  together are —CH⊚CH—C (OH)═CH—, with the proviso that R 4′″  is H, and    R 8′″  is CO—C 6 H 4 —R 11′″  where R 11′″  is OC(O)—C 1-3 -alkyl in the ortho-position.    
     
     
         25 . The pharmaceutical salt as claimed in  claim 22 , characterized in that 
 R 1′″  is CH 3  and R 2′″  is H or CH 3  or R 1′″  and R 2′″  together are —(CH 2 ) 2-3 — or —(CH 2 ) 2 —CH(CH 3 )—,    R 3′″  is H or CH 3 ,    R 4′″  is H, R 5′″  is OH or OR 8′″ , R 6′″  is H, and R 8′″  is CO—C 6 H 4 —R 11′″  where R 11′″  is OC(O)—CH 3  in the ortho-position.    
     
     
         26 . The pharmaceutical salt as claimed in  claim 22 , characterized in that the salt-forming dimethyl-(3-arylbut-3-enyl)amine compound present is trans-(−)-(1R)-3-[1-(2-dimethylamino-1-methylethyl)propenyl]phenol.  
     
     
         27 . A medicament comprising at least one pharmaceutical salt as claimed in  claim 1  and, if appropriate, physiologically tolerable excipients.  
     
     
         28 . A medicament comprising at least one pharmaceutical salt as claimed in  claim 6  for the control of pain.  
     
     
         29 . A medicament comprising at least one pharmaceutical salt as claimed in  claim 9  for the control of urinary incontinence.  
     
     
         30 . The medicament as claimed in  claim 27 , characterized in that it are [sic] present formulated in the form of gels, chewing gums, juices, sprays, tablets, chewable tablets, coated tablets, powders, if appropriate filled into capsules, easily reconstitutable dry preparations, preferably in the form of gels, aqueous or oily juices, sublingual sprays, tablets or chewable tablets.  
     
     
         31 . The medicament as claimed in  claim 27 , characterized in that it is present formulated in multiparticulate form, preferably in the form of microtablets, microcapsules, granules, active compound crystals or pellets, particularly preferably in the form of microtablets, granules or pellets, optionally filled into capsules or compressed to give tablets.  
     
     
         32 . The medicament as claimed in  claim 27 , characterized in that the salt is present at least partially in delayed-release form.  
     
     
         33 . The medicament as claimed in  claim 32 , characterized in that delaying of the release is carried out by applying a release-delaying coating, embedding in a release-delaying matrix, binding to an ion-exchange resin or by a combination of at least two of these methods.  
     
     
         34 . The medicament as claimed in  claim 33 , characterized in that the release-delaying coating is based on a water-insoluble, optionally modified natural or synthetic polymer, optionally in combination with a customary plasticizer, or on a natural, semisynthetic or synthetic wax or fat or fatty alcohol or a mixture of at least two of these components.  
     
     
         35 . The medicament as claimed in  claim 33 , characterized in that the matrix is based on a hydrophilic matrix material, preferably hydrophilic polymers, particularly preferably on cellulose ethers, cellulose esters and/or acrylic resins, very particularly preferably on ethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxymethylcellulose, poly(meth)acrylic acid and/or their their salts, amides and/or esters.  
     
     
         36 . The medicament as claimed in  claim 33 , characterized in that the matrix is based on a hydrophobic matrix material, preferably hydrophobic polymers, waxes, fats, long-chain fatty acids, fatty alcohols or appropriate esters or ethers or their mixtures, particularly preferably on mono- or diglycerides of C 12 -C 30  fatty acids and/or C 12 -C 30 -fatty alcohols and/or waxes or their mixtures.  
     
     
         37 . The medicament as claimed in  claim 27 , characterized in that it has a protective coating, preferably an enteric protective coating.  
     
     
         38 . The use of at least one pharmaceutical salt as claimed in  claim 6  for the production of a medicament for the control of pain.  
     
     
         39 . The use of at least one pharmaceutical salt as claimed in  claim 9  for the production of a medicament for the treatment of urinary incontinence.