Trigonelline based compounds

Abstract

The present invention provides novel compounds with improved solubility and altered pharmacokinetic properties. The compounds of the present invention may be represented by Formula I as below:

1 . A compound according to formula I with improved solubility and altered pharmacokinetic properties 
       
         
           
           
               
               
           
         
         wherein DX- is an active pharmaceutical ingredient (API) or a drug substance and; 
         X is either O, or NR; 
         Z is selected from Cl—, Br—, I—, mesylate, tosylate, tetrafluoroborate, carbonate or phosphate. 
         R is H, CH 3 , lower straight chain or branched chain alkyl, alternatively X can also be part of a 3-7 membered ring when there is a bond present between R and another atom on D. 
       
     
     
         2 . The compound of  claim 1 , wherein the active pharmaceutical ingredient (API) is selected from the group comprising analgesic agents; anesthetic agents; antiarthritic agents; respiratory drugs, including antiasthmatic agents; anticancer agents, including antineoplastic agents; anticholinergics; anticonvulsants; antidepressants; antidiabetic agents; antidiarrheals; antihelminthics; antihistamines; antihyperlipidemic agents; antihypertensive agents; anti-infective agents such as antibiotics and antiviral agents; antiinflammatory agents; antimigraine preparations; antinauseants; antiparkinsonism drugs; antipruritics; antipyretics; antispasmodics; antitubercular agents; antiulcer agents; antiviral agents; anxiolytics; appetite suppressants; attention deficit disorder (ADD) and attention deficit hyperactivity disorder (ADHD) drugs; cardiovascular preparations including calcium channel blockers, CNS agents; beta-blockers and antiarrhythmic agents; alpha adrenergic antagonists or agonists; cough and cold preparations, including decongestants; antitussives; diuretics; gastrointestinal (GI) motility agents; hormones; hormonolytics; hypnotics; hypoglycemic agents; immunosuppressive agents; leukotriene inhibitors; mitotic inhibitors; phosphodiesterase inhibitors; muscle relaxants; narcotic antagonists; opiod modulators; nicotine; nictone/acetylcholine antagonists or agonists; psychostimulants; sedatives; steroids; tranquilizers; and vasodilators including general coronary, peripheral and cerebral, preferably selected from the group of anticancer compounds such as paclitaxel, docetaxel and cabazitaxel; phosphodiestrase 5 inhibitors such as tadafil; vasodilators such as dopamine; narcotic antagonists; opiod modulators; nicotine; nictone/acetylcholine antagonists or agonists; most preferably the active pharmaceutical ingredient is an anticancer compound. 
     
     
         3 . The compound of  claim 1 , having Formula (II) and Formula (III) 
       
         
           
           
               
               
           
         
       
     
     
         4 . The compound of  claim 1 , wherein the compound is
 i. 3-((((1R,2R)-1-benzamido-3-(((2aR,4S,6R,9S,11S,12S,12bS)-6,12b-diacetoxy-12-(benzoyloxy)-4,11-dihydroxy-4a,8,13,13-tetramethyl-5-oxo-2a,3,4,4a,5,6,9,10,11,12,12a,12b-dodecahydro-1H-7,11-methanocyclodeca[3,4]benzo[1,2-b]oxet-9-yl)oxy)-3-oxo-1-phenylpropan-2-yl)oxy)carbonyl)-1-methylpyridin-1-ium iodide;   ii. 3-((((1R,2R)-1-benzamido-3-(((2aR,4S,6R,9S,11S,12S,12bS)-6,12b-diacetoxy-12-(benzoyloxy)-4,11-dihydroxy-4a,8,13,13-tetramethyl-5-oxo-2a,3,4,4a,5,6,9,10,11,12,12a,12b-dodecahydro-1H-7,11-methanocyclodeca[3,4]benzo[1,2-b]oxet-9-yl)oxy)-3-oxo-1-phenylpropan-2-yl)oxy)carbonyl)-1-methylpyridin-1-ium Mesylate;   iii. 3-((((1R,2R)-1-benzamido-3-(((2aR,4S,6R,9S,11S,12S,12bS)-6,12b-diacetoxy-12-(benzoyloxy)-4,11-dihydroxy-4a,8,13,13-tetramethyl-5-oxo-2a,3,4,4a,5,6,9,10,11,12,12a,12b-dodecahydro-1H-7,11-methanocyclodeca[3,4]benzo[1,2-b]oxet-9-yl)oxy)-3-oxo-1-phenylpropan-2-yl)oxy)carbonyl)-1-methylpyridin-1-ium Tetrafluoroborate;   iv. 3-((((1R,2R)-1-benzamido-3-(((2aR,4S,6R,9S,11S,12S,12bS)-6,12b-diacetoxy-12-(benzoyloxy)-4,11-dihydroxy-4a,8,13,13-tetramethyl-5-oxo-2a,3,4,4a,5,6,9,10,11,12,12a,12b-dodecahydro-1H-7,11-methanocyclodeca[3,4]benzo[1,2-b]oxet-9-yl)oxy)-3-oxo-1-phenylpropan-2-yl)oxy)carbonyl)-1-methylpyridin-1-ium Tosylate;   v. 3-((6R,12aR)-6-(benzo[d][1,3]dioxol-5-yl)-2-methyl-1,4-dioxo-1,2,3,4,6,7,12,12a-octahydropyrazino[1′,2′:1,6]pyrido[3,4-b]indole-7-carbonyl)-1-methylpyridin-1-ium iodide;   vi. 3-((4-((1E,4Z,6E)-5-hydroxy-7-(4-hydroxy-3-methoxyphenyl)-3-oxohepta-1,4,6-trien-1-yl)-2-methoxyphenoxy)carbonyl)-1-methylpyridin-1-ium iodide;   vii. 3,3′-(((((1E,3Z,6E)-3-hydroxy-5-oxohepta-1,3,6-triene-1,7-diyl)bis(2-methoxy-4,1-phenylene))bis(oxy))bis(carbonyl))bis(1-methylpyridin-1-ium) iodide;   viii. 3-((((2R,3S)-1-(((2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-12b-acetoxy-12-(benzoyloxy)-4,6,11-trihydroxy-4a,8,13,13-tetramethyl-5-oxo-2a,3,4,4a,5,6,9,10,11,12,12a,12b-dodecahydro-1H-7,11-methanocyclodeca[3,4]benzo[1,2-b]oxet-9-yl)oxy)-3-((tert-butoxycarbonyl)amino)-1-oxo-3-phenylpropan-2-yl)oxy)carbonyl)-1-methylpyridin-1-ium iodide;   ix. 3-((1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)-1-methylpyridin-1-ium iodide;   x. 3-((((2R,3R,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-4,4-difluoro-2-(hydroxymethyl)tetrahydrofuran-3-yl)oxy)carbonyl)-1-methylpyridin-1-ium iodide.   xi. 3-((R)-2-((S)-(2,8-bis(trifluoromethyl)quinolin-4-yl)(hydroxy)methyl)piperidine-1-carbonyl)-1-methylpyridin-1-ium;   xii. (R)-3-(((1-(4-((2-(5-chloro-2-fluorophenyl)-5-isopropylpyrimidin-4-yl)amino)nicotinamido)propan-2-yl)oxy)carbonyl)-1-methylpyrin-1-ium;   xiii. (S)-3-(((1-(4-((2-(5-chloro-2-fluorophenyl)-5-isopropylpyrimidin-4-yl)amino)nicotinamido)propan-2-yl)oxy)carbonyl)-1-methylpyrin-1-ium iodide   
     
     
         5 . The compound of  claim 1 , having Formula V; 
       
         
           
           
               
               
           
         
         wherein R 1  is selected from an cyclic or acyclic or branched alkyl, aryl such as methyl, propyl, isopropyl, n-butyl, t-butyl or aralkyl such as benzyl, hydrogen, tertbutoxycarbonylamino or N-phenylcarbamoyl; 
         R 2  is selected from hydrogen, hydroxyl, acyclic, cyclic or branched alkyl, aryl or an aralkyl group; 
         R 3  and R 4  are independently selected from the group of hydrogen, hydroxyl, lower alkyl, lower alkoxy, acetyl or benzyl. 
       
     
     
         6 . A process for the preparation of compound of formula (I) and intermediates, salts thereof as claimed in  claim 1  comprising the steps of:
 i) reacting an active pharmaceutical ingredient (API) of formula D-XHn with nictotine acid derivative of (100) in the presence of a base and optionally with a catalyst and/or a dehydrating agent to obtain the compound of (200) 
 
       
         
           
           
               
               
           
         
         wherein Y is selected from halides such as F, Cl or Br, and OH and X is selected from O, N, S or P; and, n=0 to 3 depending on the valency of X 
         ii) reacting (200) with alkyl halide and optionally with a catalyst as counter ion to obtain compound of (300) 
       
       
         
           
           
               
               
           
         
         iii) Optionally, reacting an active pharmaceutical ingredient (API) of formula D-XHn with 3,3′-(oxybis(carbony))bis(1-methylpyridin-1-ium)iodide to obtain compound (300); 
       
       
         
           
           
               
               
           
         
         iv) Optionally, converting the iodine counter ion of compound (300) to another counter ion by adding a catalyst and appropriate counter ion to obtain the compound (400); 
       
       
         
           
           
               
               
           
         
         Wherein M ⊖  is any counter ion selected from iodide, chloride, bromide, mesylate, tosylate or tetra fluoroborate or any other pharmaceutically acceptable anion and the counterion is either one or more counter ions to balance the charge. 
       
     
     
         7 . The process as claimed in  claim 6 , wherein the base used in step (I) is selected from the group comprising DIPEA (N, N-Diisopropylethylamine), triethylamine or pyridine, inorganic base such NaH (sodium hydride) or carbonate salt of sodium or potassium and the solvent used in step (I) is selected from the group comprising DCM (dichloromethane), THF (tetrahydrofuran), ACN (acetonitrile), ethyl acetate etc. 
     
     
         8 . The process as claimed in  claim 6 , wherein the catalyst used in step (I) is selected from the group comprising DMAP (4-Dimethylaminopyridine), TBAC (Tert-Butyl Acetate), and the dehydrating agent used in step (I) is selected from the group comprising DCC (N,N′-Dicyclohexylcarbodiimide) or EDC (dichloroethane). 
     
     
         9 . The process as claimed in  claim 6 , wherein the alkyl halide used in step (I) is selected from the group comprising methyl halide, methyl chloride, methyl bromide and the catalyst in step (iv) is selected from the group comprising silver methane sulphonate. 
     
     
         10 . The process as claimed in  claim 6 , wherein the catalyst used in step (II) is selected from the group comprising 18-crown-6, 12crown-4, DMAP (4-dimethylaminopyridine), TBAC (Tert-Butyl Acetate). 
     
     
         11 . The compound of  claim 1 , wherein the compound is not a substrate for CYP450.