Cholinergic enhancers with improved blood-brain barrier permeability for the treatment of diseases accompanied by cognitive impairment

Abstract

The present invention refers to compounds that, in addition to enhancing the sensitivity to acetylcholine and choline, and their exogenous agonists, of neuronal cholinergic receptors and/or acting as cholinesterase inhibitors and/or neuroprotective agents, have enhanced blood-brain barrier permeability in comparison to their parent compounds. The compounds are derived (either formally by their chemical structure or directly by chemical synthesis) from natural compounds belonging to the class of amaryllidaceae alkaloids e.g., galantamine, narwedine and lycoramine, or from metabolites of said compounds. The compounds of the present invention can either interact as such with their target molecules, or they can act as “pro-drugs”, in the sense that after reaching their target regions in the body they are converted by hydrolysis or enzymatic attack to the original parent compound and react as such with their target molecules, or both. The compounds of this invention may be used as medicaments.

1 . A compound of formula (III): 
     
       
         
         
             
             
         
       
       wherein the bond <1> to >2> is a single or a double bond and the bond between <3> and R1 is a single or a double bond and bond <10> to <11> is a single or no bond and residues are
 R1: OH, OCO-(3-pyridyl)(=nicotinic acid residue), OCO-(3-methyl-3-pyridyl), OCO—(C 1 -C 6  alkyl), OCO—(C 1 -C 2 , alkenyl), OCO—NH—(C 1 -C 6  alkyl), OCO—(CH 2 ) x —NH—COO—(C 1 -C 6  alkyl), O—CH 2 —O—(C 1 -C 6  alkyl), O—(CH 2 ) x —OCO—(C 1 -C 6  alkyl), O—(CH 2 ) x —OCO—(CH 2 ) x —N—COO—(C 1 -C 6  alkyl), O—(CH 2 ) x —OCO—(CH 2 ) y -aryl, OCOO—(C 1 -C 6  aminalkyl), OCOO—(CH 2 ) x -tetrahydrofuranyl, or a sugar, preferably glucuronic acid residue, wherein x=1,2, 3 or 4 and y=0, 1, 2, 3 or 4;
 wherein if bond <3> to R1 is a double bond, then R1=O, NH, NOH, NOR6, N—CO—NH 2 , N—CS—NH 2 , N—C(═NH)—NH 2 , N—NH-phenyl, N—NHR6, N—N(R6) 2 , N—N═(CH 2 ) n , with R6=C 1 -C 5  unbranched or branched, saturated or unsaturated (ar)alkyl, phenyl or benzyl and n=2-8; and 
 wherein if bond <3> to R1 is a single bond, then R1=OH, SH, NH 2 , NHR6, N(R6) 2 , OR7, O—CR8R9-O—CO—CHR10-NR11R12, or O—CO—R14, 
 with R7=C 1 -C 22  unbranched or branched, (poly-)unsaturated or saturated alkyl, optionally containing an additional (ar)alkoxy or di(ar)alkylamino group, a sugar or sugar derivative residue, preferably glucuronic acid residue, a phosphoryl, alkylphosphoryl or arylphosphoryl group, a sulfatyl or alkylsufatyl group, or COR13, 
 where R13=R6 or R7 or pyridyl or dihydropyridyl or OR6 preferably methyl, 3-pyridyl, 4-pyridyl, 3-dihydropyridyl, 4-dihydropyridyl 
 R8 and R9 are the same or different and any of H, Me, Ph or they together form a spiro-ring —(CH 2 )n- with n=4-6 
 R10=H or the side chain of a natural amino acid including R10, R11 together are forming a proline or hydroxy-proline derivative 
 R11 either is together with R10 forming a proline or hydroxy-proline derivative or is H 
 R12 is a carbamate protecting group including t-butoxycarbonyl, benzyloxycarbonyl and other N-protecting groups; 
 R14 is an aromatic or heteroaromatic 5- or 6-membered ring, selected from substituted benzene with the proviso that it is not 2-fluorobenzene or 3-nitro-4-fluorobenzene, optionally substituted naphthaline, thiophene, pyrrole, imidazole, pyrazole, oxazole, thiazole; or CH(C 2 H 5 )CH 3 , CH 2 —C(CH 3 ) 3 , or cyclopropane; 
 
 R2: R7, or O—CR8R9-O—CO—CHR10-NR11R12 with the same definitions of R7-R12 as above, H, CH 3 , CO—(C 1 -C 6  alkyl), CH 2 —OCO—(CH 2 ) x -aryl, or a sugar, preferably glucuronic acid residue; 
 R3: H, F, Cl, Br, I, NH 2 , NO 2 , CN, CH 3 ; 
 R4: H, C 1 -C 6  alkyl, preferably CH 3 , CO—(C 1 -C 6  alkyl), CO-(3-pyridyl)(=nicotinic acid residue), CO-(3-methyl-3-pyridyl), CO—(CH-mercaptoalkyl)-(CH 2 ) x -aryl, (CH 2 ) x —OCO—(CH 2 ) x —N—COO—(C 1 -C 6  alkyl), (CH 2 ) x —OCO—(CH-arylalkyl)-N—COO—(C 1 -C 6  alkyl), wherein x=1, 2, 3 or 4; 
 R5: if R4=H, then R5 is an electron pair;
 if R4=CH 3  then R5 is either hydrogen or a C 1 -C 5  (ar)alkyl group, CH 2 —O—CH 3 , CH 2 —O—CO—R6, CH 2 —O—CR8R9-O—CO—CHR10-NR11R12 with the same definitions of R6 and R8-R12 as above, whereby in all the latter cases the nitrogen has an additional positive charge as well as a counterion, selected from chloride, bromide, iodide, sulphate, nitrate, hydrogensulfate, phosphate, methanesulphonate, tosylate or any other pharmaceutically acceptable anion, with the proviso that the resulting compound is not Galantamine, Norgalantamine, Sanguinine, Norsanguinine, Lycoramine, Norlycoramine, Lycoraminone, Narwedine, Nornarwedine,3-Amino-3-deoxy-galantamine or 3-amino-3-deoxy-1,2-dihydro-galantamine;
 or R5=(CH 2 ) x —O—(C 1 -C 6  alkyl), (CH 2 ) x —OCO—(C 1 -C 6  alkyl), (CH 2 ) x —OCO—(CH 2 ) x -aryl, (CH 2 ) x —OCO—(CH 2 ) x —N—COO—(C 1 -C 6  alkyl), wherein x=1, 2, 3 or 4; in case that bond <10> to <11> is a single bond the nitrogen has a positive charge and the counterion is chloride, with the proviso that the compound is not Galantamine, Norgalantamine, Sanguinine, Norsanguinine, Lycoramine, Norlycoramine, Lycoraminone, Narwedine, Nomarwedine,3-Amino-3-deoxy-galantamine or 3-amino-3-deoxy-1,2-dihydro-galantamine as a pro-drug or medicament with improved blood-brain barrier permeability compared to Galantamine. 
 
 
 
     
   
   
       2 . A pharmaceutical composition comprising a compound according to  claim 1  or a pharmaceutically acceptable salt thereof. 
   
   
       3 . A pharmaceutical composition according to  claim 2 , further comprising a pharmaceutically acceptable carrier. 
   
   
       4 . A method for the treatment of a neurodegenerative or psychiatric or neurological disease associated with a cholinergic deficit comprising administering the pharmaceutical composition of  claim 2  to a patient in need thereof. 
   
   
       5 . The method of  claim 4 , wherein the disease is selected from Alzheimer's and Parkinson's disease, other types of dementia, schizophrenia, epilepsy, stroke, poliomyelitis, neuritis, myopathy, oxygen and nutrient deficiencies in the brain after hypoxia, anoxia, asphyxia, cardiac arrest, chronic fatigue syndrome, various types of poisoning, anesthesia, particularly neuroleptic anesthesia, spinal cord disorders, inflammation, particularly central inflammatory disorders, postoperative delirium and/or subsyndronal postoperative delirium, neuropathic pain, subsequences of the abuse of alcohol and drugs, addictive alcohol and nicotine craving, and subsequences of radiotherapy. 
   
   
       6 . A method for improvement of blood-brain barrier permeability and/or brain-to-plasma distribution ratio of a cholinergic enhancer molecule, whether a cholinergic agonist or APL and/or a cholinesterase inhibitor and/or a neuroprotective agent, by modification of at least one of the residues R1, R2, R3, R4 and/or R5 of the compound of formula (III) according to  claim 1  so as to enhance transport into the brain and compound concentration therein. 
   
   
       7 . A compound of formula (III) 
     
       
         
         
             
             
         
       
       wherein the bond <1> to >2> is a double bond and the bond between <3> and R1 is a single bond and bond <10> to <11> is a single or no bond and residues are 
       R1=OH, OCO-(3-pyridyl)(=nicotinic acid residue), OCO-(3-methyl-3-pyridyl), OCO—(C 1 -C 6  alkyl), OCO—(C 1 -C 21  alkenyl), OCO—NH—(C 1 -C 6  alkyl), OCO—(CH 2 ) x —NH—COO—(C 1 -C 6  alkyl), O—CH 2 —O—(C 1 -C 6  alkyl), O—(CH 2 ) x —OCO—(C 1 -C 6  alkyl) X O—(CH 2 ) x —OCO—(CH 2 ) x —N—COO—(C 1 -C 6  alkyl), O—(CH 2 ) x —OCO—(CH 2 ) y -aryl, OCOO—(C 1 -C 6  aminalkyl), OCOO—(CH 2 ) X -tetrahydrofuranyl, or a sugar, preferably glucuronic acid residue, wherein x=1, 2, 3 or 4 and y=0, 1, 2, 3 or 4; 
       R2=H, CH 3 , CO—(C 1 -C 6  alkyl), CH 2 —OCO—(CH 2 ) x -aryl, or a sugar, preferably glucuronic acid residue; 
       R3=H, F or Br; 
       R4=H, C 1 -C 6  alkyl, preferably CH 3 , CO—(C 1 -C 6  alkyl), CO-(3-pyridyl)(=nicotinic acid residue), CO-(3-methyl-3-pyridyl), CO—(CH-mercaptoalkyl)-(CH 2 ) x -aryl, (CH 2 ) x OCO—(CH 2 ) x —N—COO—(C 1 -C 6  alkyl), (CH 2 ) x —OCO—(CH-arylalkyl)-N—COO—(C 1 -C 6  alkyl), wherein x=1, 2, 3 or 4; 
       R5=an electron pair or (CH 2 ) x —O—(C 1 -C 6  alkyl), (CH 2 ) x —OCO—(C 1 -C 6  alkyl), (CH 2 ) x —OCO—(CH 2 ) x -aryl, (CH 2 ) x —OCO—(CH 2 ) x —N—COO—(C 1 -C 6  alkyl), wherein x=1, 2, 3 or 4; in case that bond <10> to <11> is a single bond the nitrogen has a positive charge and the counterion is chloride; 
       with the proviso that the compound is not Galantamine, Norgalantamine, Sanguinine, Norsanguinine, Lycoramine, Norlycoramine, Lycoraminone, Narwedine, Nomarwedine,3-Amino-3-deoxy-galantamine or 3-amino-3-deoxy-1,2-dihydro-galantamine as a pro-drug or medicament with improved blood-brain barrier permeability compared to Galantamine. 
     
   
   
       8 . A compound according to  claim 7 , whereby the derivative is selected from the group provided in Table 4. 
   
   
       9 . A pharmaceutical composition comprising a compound according to  claim 7  or a pharmaceutically acceptable salt thereof. 
   
   
       10 . A pharmaceutical composition according to  claim 9 , further comprising a pharmaceutically acceptable carrier. 
   
   
       11 . A method for the treatment of a neurodegenerative or psychiatric or neurological disease associated with a cholinergic deficit comprising administering the pharmaceutical composition of  claim 9  to a patient in need thereof. 
   
   
       12 . The method of  claim 11 , wherein the disease is selected from Alzheimer's and Parkinson's disease, other types of dementia, schizophrenia, epilepsy, stroke, poliomyelitis, neuritis, myopathy, oxygen and nutrient deficiencies in the brain after hypoxia, anoxia, asphyxia, cardiac arrest, chronic fatigue syndrome, various types of poisoning, anesthesia, particularly neuroleptic anesthesia, spinal cord disorders, inflammation, particularly central inflammatory disorders, postoperative delirium and/or subsyndronal postoperative delirium, neuropathic pain, subsequences of the abuse of alcohol and drugs, addictive alcohol and nicotine craving, and subsequences of radiotherapy. 
   
   
       13 . A method for improvement of blood-brain barrier permeability and/or brain-to-plasma distribution ratio of a cholinergic enhancer molecule, whether a cholinergic agonist or APL and/or a cholinesterase inhibitor and/or a neuroprotective agent, by modification of at least one of the residues R1, R2, R3, R4 and/or R5 of the base structure(s) of formula (III) so as to enhance transport into the brain and compound concentration therein: 
     
       
         
         
             
             
         
       
       wherein the bond between positions <1> and <2> denotes a single- or double bond and the bonds <1> to <2> and <11> to <12> can be either a single or a double bond, and the bond between <10> and <11> is either a single bond or no bond, wherein the modified residues R1-R5 are defined as follows: 
       R1:
 a) if bond <3> to R1 is a double bond, then 
 R1=O, NH, NOH, NOR6, N—CO—NH 2 , N—CS—NH 2 , N—C(═NH)—NH 2 , N—NH-phenyl, N—NHR6, N—N(R6) 2 , N—N═(CH 2 ) n , 
 with R6=C 1 -C 5  unbranched or branched, saturated or unsaturated (ar)alkyl, phenyl or benzyl and n=2-8; 
 b) if bond <3> to R1 is a single bond, then 
 R1=OH, SH, NH 2 , NHR6, N(R6) 2 , OR7, O—CR8R9-O—CO—CHR10-NR11R12, with R7=C 1 -C 22  unbranched or branched, (poly-)unsaturated or saturated alkyl, optionally containing an additional (ar)alkoxy or di(ar)alkylamino group, a sugar or sugar derivative residue, preferably glucuronic acid residue, a phosphoryl, alkylphosphoryl or arylphosphoryl group, a sulfatyl or alkylsufatyl group, or COR13,
 where 
 R13=R6 or R7 or pyridyl or dihydropyridyl or OR6, preferably methyl, 3-pyridyl, 4-pyridyl, 3-dihydropyridyl, 4-dihydropyridyl, R8 and R9 are the same or different and any of H, Me, Ph or they together form a spiro-ring —(CH 2 )n- with n=4-6, 
 R10=H or the side chain of a natural amino acid including R10,R11 together are forming a proline or hydroxy-proline derivative, 
 R11 either is together with R10 forming a proline or hydroxy-proline derivative or is H, 
 R12 is a carbamate protecting group including t-butoxycarbonyl, benzyloxycarbonyl and other N-protecting groups; 
 
 
       R2: H, R7, or O—CR8R9-O—CO—CHR10-NR11R12 with the same definitions of R7-R12 as above; 
       R3: H, F, Cl, Br, I, NH 2 , NO 2 , CN, CH 3 ; 
       R4: H or CH 3 ; 
       R5: If R4=H, then R5 is an electron pair, 
       if R4=CH 3 , then R5 is either hydrogen or a C 1 -C 5  (ar)alkyl group, CH 2 —O—CH 3 , CH 2 —O—CO—R6, CH 2 —O—CR8R9-O—CO—CHR10-NR11R12 with the same definitions of R6 and R8-R12 as above, whereby in all the latter cases the nitrogen has an additional positive charge as well as a counterion, selected from chloride, bromide, iodide, sulphate, nitrate, hydrogensulfate, phosphate, methanesulphonate, tosylate or any other pharmaceutically acceptable anion, 
       with the proviso that the resulting compound is not Galantamine, Norgalantamine, Sanguinine, Norsanguinine, Lycoramine, Norlycoramine, Lycoraminone, Narwedine, Nomarwedine,3-Amino-3-deoxy-galantamine or 3-amino-3-deoxy-1,2-dihydro-galantamine. 
     
   
   
       14 . A method according to  claim 13  wherein the bond <1> to >2> is a double bond and the bond between <3> and R1 is a single bond and bond <10> to <11> is a single or no bond and residues are
 R1=OH, OCO-(3-pyridyl)(=nicotinic acid residue), OCO-(3-methyl-3-pyridyl), OCO—(C 1 -C 6  alkyl), OCO—(C 1 -C 2 , alkenyl), OCO—NH—(C 1 -C 6  alkyl), OCO—(CH 2 ) x —NH—COO—(C 1 -C 6  alkyl), O—CH 2 —O—(C 1 -C 6  alkyl), O—(CH 2 ) x —OCO—(C 1 -C 6  alkyl), O—(CH 2 ) x —OCO—(CH 2 ) x —N—COO—(C 1 -C 6  alkyl), O—(CH 2 ) x —OCO—(CH 2 ) y -aryl, OCOO—(C 1 -C 6  aminalkyl), OCOO—(CH 2 ) X -tetrahydrofuranyl, or a sugar, preferably glucuronic acid residue, wherein x=1, 2, 3 or 4 and y=0, 1, 2, 3 or 4;   R2=H, CH 3 , CO—(C 1 -C 6  alkyl), CH 2 —OCO—(CH 2 ) X -aryl, or a sugar, preferably glucuronic acid residue;   R3=H, F or Br;   R4=H, C 1 -C 6  alkyl, preferably CH 3 , CO—(C 1 -C 6  alkyl), CO-(3-pyridyl)(=nicotinic acid residue), CO-(3-methyl-3-pyridyl), CO—(CH-mercaptoalkyl)-(CH 2 ) x -aryl, (CH 2 ) x —OCO—(CH 2 ) x —N—COO—(C 1 -C 6  alkyl), (CH 2 ) x —OCO—(CH-arylalkyl)-N—COO—(C 1 -C 6  alkyl), wherein x=1, 2, 3 or 4;   R5=an electron pair or (CH 2 ) x —O—(C 1 -C 6  alkyl), (CH 2 ) x —OCO—(C 1 -C 6  alkyl), (CH 2 ) x —OCO—(CH 2 ) X -aryl, (CH 2 ) x —OCO—(CH 2 ) x —N—COO—(C 1 -C 6  alkyl), wherein x=1, 2, 3 or 4; in case that bond <10> to <11> is a single bond the nitrogen has a positive charge and the counterion is chloride.   
   
   
       15 . A compound according to formula V 
     
       
         
         
             
             
         
       
       wherein R1=aromatic or heteroaromatic 5- or 6-membered ring, selected from benzene, substituted benzene with the proviso that it is not 2-fluorobenzene or 3-nitro-4-fluorobenzene, optionally substituted naphthaline, thiophene, pyrrole, imidazole, pyrazole, oxazole, thiazole; or CH(C 2 H 5 )CH 3 , CH 2 —C(CH 3 ) 3 , or cyclopropane. 
     
   
   
       16 . Compound according to  claim 15 , selected from 
     
       
         
         
             
             
         
       
       wherein R2-R6 comprising any substituent selected from H, halogen, optionally substituted C 1 -C 3  alkyl or cyclopropyl, OH, O-alkyl, SH, S-alkyl, NH 2 , NH-alkyl, N-dialkyl, optionally substituted aryl or heteroaryl, whereby neighbouring substitutents can cooperate to form an additional ring, with the proviso that not all of R2 to R6 are H and substituted benzene is not 2-fluorobenzene or 3-nitro-4-fluorobenzene. 
     
   
   
       17 . A compound according to  claim 15  selected from the group consisting of the compounds shown in Table 4. 
   
   
       18 . A compound according to  claim 15  for use as a pro-drug or medicament. 
   
   
       19 . A pharmaceutical composition comprising a compound according to  claim 15 . 
   
   
       20 . A compound or pharmaceutical composition according to  claim 15 , wherein R1 further can be non-substituted benzene or 2-fluorobenzene or 3-nitro-4-fluorobenzene for the treatment of a neurodegenerative or psychiatric or neurological disease associated with a cholinergic deficit. 
   
   
       21 . A compound or pharmaceutical composition according to  claim 20  wherein the disease is selected from Alzheimer's and Parkinson's disease, other types of dementia, schizophrenia, epilepsy, oxygen and nutrient deficiencies in the brain after hypoxia, anoxia, asphyxia, cardiac arrest, various types of poisoning, anesthesia, particularly neuroleptic anesthesia, autism, postoperative delirium and/or subsyndronal postoperative delirium, subsequences of the abuse of alcohol and drugs, addictive alcohol and nicotine craving, and subsequences of radiotherapy. 
   
   
       22 . A compound or pharmaceutical composition according to  claim 21 , wherein the neurodegenerative disease is selected from Alzheimer's and Parkinson's disease.