Europäisches Patentamt *EP001251131A2* (19) European Patent Office Office européen des brevets (11) EP 1 251 131 A2 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.7: C07D 495/04, A61K 31/40 23.10.2002 Bulletin 2002/43 // (C07D495/04, 333:00, 209:00) (21) Application number: 02013799.8 (22) Date of filing: 28.08.1992 (84) Designated Contracting States: • He, Xiao-Shu AT BE CH DE DK ES FR GB GR IE IT LI LU MC NL Rockville, MD 20852 (US) SE • Rapoport, Stanley I. NW, Washington, DC 20016 (US) (30) Priority: 26.09.1991 US 765766 • Greig, Nigel H. 03.03.1992 US 845081 Silver Spring, MD 20906 (US) • Brzostowska, Malgarzota (62) Document number(s) of the earlier application(s) in 60-518 Poznan (PL) accordance with Art. 76 EPC: 92919058.5 / 0 605 474 (74) Representative: Wallace, Sheila Jane et al Lloyd Wise, Tregear & Co., (71) Applicant: The Government of the United States Commonwealth House, of America, as represented by the Secretary, 1-19 New Oxford Street Department of Health and Human Services London WC1A 1LW (GB) Washington, D.C. 20201 (US) Remarks: (72) Inventors: This application was filed on 21 - 06 - 2002 as a • Brossi, Arnold divisional application to the application mentioned Bethesda, ND 20817 (US) under INID code 62. (54) Carbamate analogs of thiaphysovenine, pharmaceutical compositions, and method for inhibiting cholinesterases (57) This invention relates to certain carbamate analogs of thiaphysovenine of the formula wherein 1 2 R is H and R is C4 - C10 alkyl; 1 2 R and R are independently C1 -C10 alkyl; or R1 is H and R2 is a group of the formula EP 1 251 131 A2 Printed by Jouve, 75001 PARIS (FR) (Cont. next page) EP 1 251 131 A2 wherein R3 is H and R4 is an isopropyl group; including optical isomers of the 3aS series, racemic compounds of this type and processes for their preparation. Pharmaceutical compositions containing such compounds are also provided. Such compounds and compositions are useful as cholinesterase inhibitors, especially butyrylcholinesterase inhibitors. 2 EP 1 251 131 A2 Description [0001] This application is a Continuation-in-Part of U.S. patent application 07/765,766, filed September 26, 1991. 5 Technical Field [0002] The present invention relates to inhibitors of cholinesterases, pharmaceutical compositions and method of use thereof. More particular, the invention relates to thiaphysovenine and carbamate analogs and a method of using these potent inhibitors of cholinesterases. 10 Background Art [0003] Physostigmine, also called eserine, and particular derivatives of physostigmine are anticholinesterase inhib- itors which are well known. Such well known compounds are also useful in the treatment of glaucoma, Myasthenia 15 Gravis, Alzheimer's disease and as antidotes against poisoning with organophosphates. [0004] It has been discovered that the natural isomer of physostigmine has blocking properties as well as agonist properties at the neuromuscular AChR. By contrast (+)-physostigmine shows only negligible inhibition of cholinesterase (ChE). See Brossi et al., FEBS Lett., Vol. 201, pages 190-192 (1986). [0005] Even though (+)-physostigmine has only negligible ChE inhibitory activity, it is as effective as a protective 20 pretreatment drug against multiple lethal doses of sarin, see Albuquerque et al, Fundam. Appl. Caltoxicol., Vol. 5, pages 182-203 (1985). The observed beneficial protection appears to be due to direct interactions of the carbamates with the postsynaptic nicotinic AChR. The protective effectiveness of the carbamates against organophosphates ap- pears to be related to the direct ability of the carbamates to decrease the hyperactivation caused by accumulation of the neurotransmitter. 25 [0006] The above information, available due to the research in this field, is important in the evaluation of potential new pharmacological agents for treating cholinergic disorders, for example, Myasthenia Gravis and Alzheimer's dis- ease. Potential agents can be evaluated for potency in vitro by testing the agents against electric eel acetylcholineste- rase (AChE) and human plasma butyrylcholinesterase (BChE). [0007] Of the two enzymes known to hydrolyze acetylcholine (ACh) in vivo, AChE, which is found in red blood cells, 30 in the brain and in nerve tissues, seems to be more specific than BChE which is found in serum, pancreas and in the liver. It, however, has not previously been shown in the art that compounds which selectively inhibit one of the two enzymes more than the other would offer a medical advantage. The natural alkaloid (-)-physostigmine, its potential metabolite (-)-(Nl)-norphysostigmine, and the natural alkaloid physovenine which are used as biological standards in this art area, inhibit AChE and BChE in vitro similarly at similar concentrations. 35 [0008] Accordingly, there is need in the art for highly selective agents active against one of AChE and BChE while not being potent against the other so as to lead to better treatment of a particular cholinergic disorder and minimize negative side effects. Such compounds would be of great medical importance in the treatment of cholinergic disorders. Summary of the Invention 40 [0009] It is an object of the present invention to provide highly potent and selective cholinergic agonist and blocking compounds. [0010] It is a further object of the present invention to provide improvements in therapy relative to cholinergic diseases such as glaucoma, Myasthenia Gravis, Alzheimer's disease, and organophosphate poisoning. 45 [0011] It is a still further object of the present invention to provide compounds with selective acetylcholinesterase and butyrylcholinesterase activity. [0012] It is an even further object of the present invention to provide (3aS-cis) isomer compounds with absolute configuration identical to that of natural physostigmine, which is a compound of the formula 50 55 3 EP 1 251 131 A2 5 10 1 2 wherein R is H or a linear or branched chain C1 - C10 alkyl group; and R is selected from the group consisting of 3 4 wherein R and R are independently selected from the group consisting of H and a linear or branched chain C1 -C10 15 - alkyl group; and with the proviso that when one of R1 or R2 is a H or a methyl group, the other of R1 or R2 is not H; including optical isomers. Brief Description of the Figures 20 [0013] Figure 1 illustrates the in vivo inhibiton rates and duration of activity for inhibiting the enzyme acetylcholinesterase (AChE) by Tacrine (THA), (-)-Physostigmine, and (-)-Thiaphysovenine. 25 Figure 2 compares the in vivo inhibition rates and duration of activity for thiaphysovenine and thiaphysovenol phenylcarbamates in inhibiting AChE. Description of Preferred Embodiments 30 [0014] In accordance with this invention there are disclosed compounds of the formula I 35 40 1 2 wherein R is H or a linear or branched chain C1 - C10 alkyl aroup; and R is selected from the group consisting of 45 a linear or branched chain -C1 - C10 alkyl group, or 50 3 4 wherein R and R are independently selected from the group consisting of H and a linear or branched chain C1 -C10 55 - alkyl group; and with the proviso that when one of R1 or R2 is a H or a methyl group, the other of R1 or R2 is not H; including optical isomers. [0015] Preferred are compounds wherein 4 EP 1 251 131 A2 1 2 R is H and R is C4 - C10 alkyl; 1 2 R and R are independently C1 -C10 alkyl; or R1 is H and R2 is a group of the formula 5 10 wherein 3 4 R and R are both H or a -CH3 group; 15 R3 is selected from the group consisting of a methyl, ethyl, or isopropyl group and R4 is H; or R3 is H and R4 is an isopropyl group.and R2 is a structure of the formula wherein 3 4 R is independently H or a -C1-C5-alkyl group and R is independently H or a -C1-C5-alkyl group. Even more preferred 3 are compounds wherein R is selected from the group of radicals consisting of H, -CH3,-CH2-CH3,-CH2-CH2-CH3, 20 4 and -CH(-CH3)2, and R is H, -CH3, or -CH(-CH3)2. [0016] The. above compounds are thiaphysovenol carbamic acid derivatives having high potency in the inhibition of acetylcholinesterase and butyrylcholinesterase. Some of the carbamates were more specific for AChE whereas others were more highly specific for BChE. [0017] Other cholinesterase inhibitors are known in the prior art. Physostigmine and physovenine are optically active 25 alkaloids with a (3aS)-absolute configuration at the chiral carbon atom C(3a). Both of these compounds are potent inhibitors of cholinesterases in vitro and in vivo, blocking the conversion of acetylcholine into choline reversibly. Phys- ostigmine has been found to have useful medical applications in disorders which result to a malfunction of this process. [0018] Surprisingly, the thiaphysovenol carbamates according to the present invention have shown high potency. Thus, carbamates with longer aliphatic side chains are long acting and appear to be less toxic than carbamate analogs 30 of physovenine and physostigmine. Accordingly, the present compounds represent a significant advancement in the prior art. [0019] Compositions within the scope of the invention include compositions wherein the active ingredient is contained in an effective amount to achieve its intended purpose. The compounds can be administered in any pharmaceutically acceptable amount, for example, in amounts ranging from 0.001 gram to about 1 gram per kilogram of body weight. 35 Based on the information which is presented herein, the determination of effective amounts is well within the skill of the ordinary practitioner in the art. The compounds are generally useed in pharmaceutical compositions (wt%) con- taining the active ingredient with a carrier or vehicle in the composition in an amount of about 0.1 to 99 wt% and preferably about 25-85 wt%.