SK5032000A3 - A process for the preparation of aminocarbonyl derivatives of geneseroline having selective brain anticholinesterase activity, pharmaceutical composition containing the same, use thereof and intermediates - Google Patents

A process for the preparation of aminocarbonyl derivatives of geneseroline having selective brain anticholinesterase activity, pharmaceutical composition containing the same, use thereof and intermediates Download PDF

Info

Publication number: SK5032000A3
Authority: SK; Slovakia
Prior art keywords: formula; geneseroline; group; acid; compounds
Prior art date: 1997-10-10

Application number

SK503-2000A

Other languages

English (en)

Slovak (sk)

Inventor

Paolo Chiesi

Paolo Ventura

Vittorino Servadio

Roberto Pighi

Fausto Pivetti

Bluetta Salsi

Maurizio Delcanale

Gabriele Amari

Claudio Pietra

Gino Villetti

Original Assignee

Chiesi Farma Spa

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

1997-10-10

Filing date

1998-10-07

Publication date

2000-10-09

1997-10-10 Priority claimed from IT002300 external-priority patent/IT1295310B1/it

1997-10-10 Priority claimed from IT002299 external-priority patent/IT1295309B1/it

1998-10-07 Application filed by Chiesi Farma Spa filed Critical Chiesi Farma Spa

2000-10-09 Publication of SK5032000A3 publication Critical patent/SK5032000A3/sk

Links

238000000034 method Methods 0.000 title claims abstract description 44
238000002360 preparation method Methods 0.000 title claims abstract description 11
125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 title claims description 13
230000000694 effects Effects 0.000 title claims description 13
239000000543 intermediate Substances 0.000 title claims description 7
239000008194 pharmaceutical composition Substances 0.000 title claims description 4
210000004556 brain Anatomy 0.000 title abstract description 15
239000000544 cholinesterase inhibitor Substances 0.000 title abstract description 8
150000001875 compounds Chemical class 0.000 claims abstract description 68
OPAXVHIAQIXNAM-STQMWFEESA-N (4as,9as)-2,4a,9-trimethyl-4,9a-dihydro-3h-oxazino[6,5-b]indol-6-ol Chemical compound C12=CC(O)=CC=C2N(C)[C@@H]2[C@@]1(C)CCN(C)O2 OPAXVHIAQIXNAM-STQMWFEESA-N 0.000 claims abstract description 37
230000007062 hydrolysis Effects 0.000 claims abstract description 29
238000006460 hydrolysis reaction Methods 0.000 claims abstract description 29
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 15
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 15
MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims abstract description 14
125000000217 alkyl group Chemical group 0.000 claims abstract description 13
PIJVFDBKTWXHHD-UHFFFAOYSA-N Physostigmine Natural products C12=CC(OC(=O)NC)=CC=C2N(C)C2C1(C)CCN2C PIJVFDBKTWXHHD-UHFFFAOYSA-N 0.000 claims abstract description 12
229960001697 physostigmine Drugs 0.000 claims abstract description 12
PIJVFDBKTWXHHD-HIFRSBDPSA-N physostigmine Chemical compound C12=CC(OC(=O)NC)=CC=C2N(C)[C@@H]2[C@@]1(C)CCN2C PIJVFDBKTWXHHD-HIFRSBDPSA-N 0.000 claims abstract description 12
239000012948 isocyanate Substances 0.000 claims abstract description 11
150000002513 isocyanates Chemical class 0.000 claims abstract description 11
150000003839 salts Chemical class 0.000 claims abstract description 11
229910052736 halogen Inorganic materials 0.000 claims abstract description 10
150000002367 halogens Chemical group 0.000 claims abstract description 10
239000003054 catalyst Substances 0.000 claims abstract description 8
125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 7
230000003647 oxidation Effects 0.000 claims abstract description 6
238000007254 oxidation reaction Methods 0.000 claims abstract description 6
238000005917 acylation reaction Methods 0.000 claims abstract description 5
125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract description 4
230000010933 acylation Effects 0.000 claims abstract description 3
-1 2-ethylphenyl Chemical group 0.000 claims description 56
108010022752 Acetylcholinesterase Proteins 0.000 claims description 25
229940022698 acetylcholinesterase Drugs 0.000 claims description 24
QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 23
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 22
DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 15
HKGWQUVGHPDEBZ-OLZOCXBDSA-N eseroline Chemical compound C1=C(O)C=C2[C@]3(C)CCN(C)[C@@H]3N(C)C2=C1 HKGWQUVGHPDEBZ-OLZOCXBDSA-N 0.000 claims description 14
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 13
NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 12
239000000203 mixture Substances 0.000 claims description 12
125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 12
AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 10
239000003814 drug Substances 0.000 claims description 10
230000002378 acidificating effect Effects 0.000 claims description 9
230000002401 inhibitory effect Effects 0.000 claims description 9
CNBHDDBNEKKMJH-UHFFFAOYSA-N (2,4a,9-trimethyl-4,9a-dihydro-3h-oxazino[6,5-b]indol-6-yl) n-methylcarbamate Chemical compound O1N(C)CCC2(C)C3=CC(OC(=O)NC)=CC=C3N(C)C21 CNBHDDBNEKKMJH-UHFFFAOYSA-N 0.000 claims description 8
239000002253 acid Substances 0.000 claims description 8
238000004519 manufacturing process Methods 0.000 claims description 8
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
238000006722 reduction reaction Methods 0.000 claims description 7
125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 6
230000002093 peripheral effect Effects 0.000 claims description 6
125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 6
230000001131 transforming effect Effects 0.000 claims description 6
230000002490 cerebral effect Effects 0.000 claims description 5
125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 5
229940098779 methanesulfonic acid Drugs 0.000 claims description 5
150000007522 mineralic acids Chemical class 0.000 claims description 5
150000007524 organic acids Chemical class 0.000 claims description 5
125000000815 N-oxide group Chemical group 0.000 claims description 4
229910000147 aluminium phosphate Inorganic materials 0.000 claims description 4
125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 claims description 4
125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 claims description 4
230000001590 oxidative effect Effects 0.000 claims description 4
239000003444 phase transfer catalyst Substances 0.000 claims description 4
229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
239000002904 solvent Substances 0.000 claims description 4
LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 4
208000024827 Alzheimer disease Diseases 0.000 claims description 3
OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 claims description 3
229960004373 acetylcholine Drugs 0.000 claims description 3
239000002585 base Substances 0.000 claims description 3
150000004649 carbonic acid derivatives Chemical class 0.000 claims description 3
150000004679 hydroxides Chemical class 0.000 claims description 3
150000002475 indoles Chemical class 0.000 claims description 3
238000002955 isolation Methods 0.000 claims description 3
230000001575 pathological effect Effects 0.000 claims description 3
150000004965 peroxy acids Chemical class 0.000 claims description 3
LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 3
230000001603 reducing effect Effects 0.000 claims description 3
JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical group [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 3
NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 claims description 2
108090000371 Esterases Proteins 0.000 claims description 2
230000001476 alcoholic effect Effects 0.000 claims description 2
239000003513 alkali Substances 0.000 claims description 2
125000004183 alkoxy alkyl group Chemical group 0.000 claims description 2
150000005215 alkyl ethers Chemical class 0.000 claims description 2
229940054051 antipsychotic indole derivative Drugs 0.000 claims description 2
125000005843 halogen group Chemical group 0.000 claims description 2
230000003301 hydrolyzing effect Effects 0.000 claims description 2
239000003456 ion exchange resin Substances 0.000 claims description 2
229920003303 ion-exchange polymer Polymers 0.000 claims description 2
150000002978 peroxides Chemical class 0.000 claims description 2
102000012440 Acetylcholinesterase Human genes 0.000 claims 1
239000003937 drug carrier Substances 0.000 claims 1
150000002500 ions Chemical class 0.000 claims 1
239000011347 resin Substances 0.000 claims 1
229920005989 resin Polymers 0.000 claims 1
230000003389 potentiating effect Effects 0.000 abstract description 4
125000000229 (C1-C4)alkoxy group Chemical group 0.000 abstract description 2
125000003545 alkoxy group Chemical group 0.000 abstract description 2
239000003112 inhibitor Substances 0.000 abstract description 2
CNBHDDBNEKKMJH-ZFWWWQNUSA-N Eseridine Chemical compound O1N(C)CC[C@@]2(C)C3=CC(OC(=O)NC)=CC=C3N(C)[C@H]21 CNBHDDBNEKKMJH-ZFWWWQNUSA-N 0.000 abstract 1
229950003340 eseridine Drugs 0.000 abstract 1
230000009466 transformation Effects 0.000 abstract 1
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 30
102100033639 Acetylcholinesterase Human genes 0.000 description 24
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238000006243 chemical reaction Methods 0.000 description 16
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 14
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 13
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
230000015572 biosynthetic process Effects 0.000 description 11
238000003756 stirring Methods 0.000 description 11
238000003786 synthesis reaction Methods 0.000 description 11
238000004128 high performance liquid chromatography Methods 0.000 description 10
230000005764 inhibitory process Effects 0.000 description 10
239000000047 product Substances 0.000 description 10
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
235000011149 sulphuric acid Nutrition 0.000 description 9
239000000725 suspension Substances 0.000 description 9
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
150000002170 ethers Chemical class 0.000 description 8
239000011780 sodium chloride Substances 0.000 description 7
102000004190 Enzymes Human genes 0.000 description 6
108090000790 Enzymes Proteins 0.000 description 6
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
239000012043 crude product Substances 0.000 description 6
229940088598 enzyme Drugs 0.000 description 6
235000011007 phosphoric acid Nutrition 0.000 description 6
239000007787 solid Substances 0.000 description 6
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238000001816 cooling Methods 0.000 description 5
230000002255 enzymatic effect Effects 0.000 description 5
239000012074 organic phase Substances 0.000 description 5
GWHQHAUAXRMMOT-MBANBULQSA-N rivastigmine tartrate Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.CCN(C)C(=O)OC1=CC=CC([C@H](C)N(C)C)=C1 GWHQHAUAXRMMOT-MBANBULQSA-N 0.000 description 5
150000007513 acids Chemical class 0.000 description 4
125000003118 aryl group Chemical group 0.000 description 4
210000005013 brain tissue Anatomy 0.000 description 4
125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 4
238000012360 testing method Methods 0.000 description 4
241001465754 Metazoa Species 0.000 description 3
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 3
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
239000004480 active ingredient Substances 0.000 description 3
238000001035 drying Methods 0.000 description 3
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235000011181 potassium carbonates Nutrition 0.000 description 3
125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
239000007858 starting material Substances 0.000 description 3
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ZVFNUQWYLXXSJM-UHFFFAOYSA-N 1-ethyl-2-isocyanatobenzene Chemical compound CCC1=CC=CC=C1N=C=O ZVFNUQWYLXXSJM-UHFFFAOYSA-N 0.000 description 2
RFXBSYPBSRSQDU-UHFFFAOYSA-N 1-isocyanatoheptane Chemical compound CCCCCCCN=C=O RFXBSYPBSRSQDU-UHFFFAOYSA-N 0.000 description 2
HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 2
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VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
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IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
239000002841 Lewis acid Substances 0.000 description 2
KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 2
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239000000908 ammonium hydroxide Substances 0.000 description 2
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239000003795 chemical substances by application Substances 0.000 description 2
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125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
238000001704 evaporation Methods 0.000 description 2
230000008020 evaporation Effects 0.000 description 2
238000002474 experimental method Methods 0.000 description 2
238000009472 formulation Methods 0.000 description 2
238000010438 heat treatment Methods 0.000 description 2
RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 2
238000000338 in vitro Methods 0.000 description 2
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TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 2
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YLJREFDVOIBQDA-UHFFFAOYSA-N tacrine Chemical compound C1=CC=C2C(N)=C(CCCC3)C3=NC2=C1 YLJREFDVOIBQDA-UHFFFAOYSA-N 0.000 description 2
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GLVYLTSKTCWWJR-UHFFFAOYSA-N 2-carbonoperoxoylbenzoic acid Chemical compound OOC(=O)C1=CC=CC=C1C(O)=O GLVYLTSKTCWWJR-UHFFFAOYSA-N 0.000 description 1
125000006282 2-chlorobenzyl group Chemical group [H]C1=C([H])C(Cl)=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
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125000006181 4-methyl benzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])C([H])([H])* 0.000 description 1
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XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
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238000004458 analytical method Methods 0.000 description 1
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150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
244000309464 bull Species 0.000 description 1
125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
239000006227 byproduct Substances 0.000 description 1
239000002775 capsule Substances 0.000 description 1
239000004202 carbamide Substances 0.000 description 1
239000000969 carrier Substances 0.000 description 1
210000003169 central nervous system Anatomy 0.000 description 1
238000005119 centrifugation Methods 0.000 description 1
229920001429 chelating resin Polymers 0.000 description 1
239000003638 chemical reducing agent Substances 0.000 description 1
210000002932 cholinergic neuron Anatomy 0.000 description 1
230000000052 comparative effect Effects 0.000 description 1
238000007796 conventional method Methods 0.000 description 1
229920001577 copolymer Chemical group 0.000 description 1
238000002425 crystallisation Methods 0.000 description 1
230000008025 crystallization Effects 0.000 description 1
239000012380 dealkylating agent Substances 0.000 description 1
239000003405 delayed action preparation Substances 0.000 description 1
201000010099 disease Diseases 0.000 description 1
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
239000002552 dosage form Substances 0.000 description 1
239000000839 emulsion Substances 0.000 description 1
210000003743 erythrocyte Anatomy 0.000 description 1
238000011156 evaluation Methods 0.000 description 1
229940108366 exelon Drugs 0.000 description 1
239000012467 final product Substances 0.000 description 1
239000012458 free base Substances 0.000 description 1
150000008282 halocarbons Chemical class 0.000 description 1
231100001261 hazardous Toxicity 0.000 description 1
125000000623 heterocyclic group Chemical group 0.000 description 1
238000009776 industrial production Methods 0.000 description 1
239000012442 inert solvent Substances 0.000 description 1
238000002329 infrared spectrum Methods 0.000 description 1
231100000636 lethal dose Toxicity 0.000 description 1
239000007788 liquid Substances 0.000 description 1
210000004185 liver Anatomy 0.000 description 1
230000007774 longterm Effects 0.000 description 1
238000001819 mass spectrum Methods 0.000 description 1
210000000274 microglia Anatomy 0.000 description 1
125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
229930014626 natural product Natural products 0.000 description 1
230000000626 neurodegenerative effect Effects 0.000 description 1
230000007935 neutral effect Effects 0.000 description 1
229910052757 nitrogen Inorganic materials 0.000 description 1
239000012299 nitrogen atmosphere Substances 0.000 description 1
238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
210000000056 organ Anatomy 0.000 description 1
150000001451 organic peroxides Chemical class 0.000 description 1
125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
239000000546 pharmaceutical excipient Substances 0.000 description 1
239000000825 pharmaceutical preparation Substances 0.000 description 1
239000008363 phosphate buffer Substances 0.000 description 1
229940086066 potassium hydrogencarbonate Drugs 0.000 description 1
239000000843 powder Substances 0.000 description 1
125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
238000000746 purification Methods 0.000 description 1
238000011160 research Methods 0.000 description 1
239000013557 residual solvent Substances 0.000 description 1
229920006395 saturated elastomer Polymers 0.000 description 1
238000000926 separation method Methods 0.000 description 1
239000011734 sodium Substances 0.000 description 1
229910052938 sodium sulfate Inorganic materials 0.000 description 1
235000011152 sodium sulphate Nutrition 0.000 description 1
239000006228 supernatant Substances 0.000 description 1
238000002636 symptomatic treatment Methods 0.000 description 1
239000006188 syrup Substances 0.000 description 1
235000020357 syrup Nutrition 0.000 description 1
239000003826 tablet Substances 0.000 description 1
239000011273 tar residue Substances 0.000 description 1
GPRLSGONYQIRFK-MNYXATJNSA-N triton Chemical compound [3H+] GPRLSGONYQIRFK-MNYXATJNSA-N 0.000 description 1
238000005406 washing Methods 0.000 description 1
238000005303 weighing Methods 0.000 description 1

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Landscapes

Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Health & Medical Sciences (AREA)
Engineering & Computer Science (AREA)
Bioinformatics & Cheminformatics (AREA)
Biomedical Technology (AREA)
Neurology (AREA)
Neurosurgery (AREA)
General Chemical & Material Sciences (AREA)
Life Sciences & Earth Sciences (AREA)
Veterinary Medicine (AREA)
Medicinal Chemistry (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Public Health (AREA)
Pharmacology & Pharmacy (AREA)
Chemical Kinetics & Catalysis (AREA)
Animal Behavior & Ethology (AREA)
General Health & Medical Sciences (AREA)
Hospice & Palliative Care (AREA)
Psychiatry (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

SK503-2000A 1997-10-10 1998-10-07 A process for the preparation of aminocarbonyl derivatives of geneseroline having selective brain anticholinesterase activity, pharmaceutical composition containing the same, use thereof and intermediates SK5032000A3 (en)

Applications Claiming Priority (3)

Application Number	Priority Date	Filing Date	Title
IT002300 IT1295310B1 (it)	1997-10-10	1997-10-10	Amminocarbonil derivati di geneserolina ad attivita' anticolinesterasica selettiva a livello cerebrale
IT002299 IT1295309B1 (it)	1997-10-10	1997-10-10	Procedimento per la preparazione di amminocarbonil derivati di geneserolina
PCT/EP1998/006377 WO1999019329A1 (fr)	1997-10-10	1998-10-07	Procede de preparation de derives aminocarbonyle de geneseroline ayant une activite anticolinesterase selective dans le cerveau

Publications (1)

Publication Number	Publication Date
SK5032000A3 true SK5032000A3 (en)	2000-10-09

Family

ID=26331547

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
SK503-2000A SK5032000A3 (en)	1997-10-10	1998-10-07	A process for the preparation of aminocarbonyl derivatives of geneseroline having selective brain anticholinesterase activity, pharmaceutical composition containing the same, use thereof and intermediates

Country Status (17)

Country	Link
US (1)	US6297237B1 (fr)
EP (1)	EP1023297A1 (fr)
KR (1)	KR20010015714A (fr)
CN (1)	CN1278264A (fr)
AR (1)	AR018511A1 (fr)
AU (1)	AU750964B2 (fr)
BR (1)	BR9815237A (fr)
CA (1)	CA2274658A1 (fr)
EA (1)	EA003192B1 (fr)
HU (1)	HUP0003747A3 (fr)
IL (1)	IL135399A0 (fr)
NZ (1)	NZ503773A (fr)
PL (1)	PL339761A1 (fr)
SK (1)	SK5032000A3 (fr)
TR (1)	TR200000951T2 (fr)
TW (1)	TW490467B (fr)
WO (1)	WO1999019329A1 (fr)

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
IT1109003B (it) *	1977-09-20	1985-12-16	Univ Firenze	Derivati dell 1 2 3 8 3 a 8 a esai dropirrolo 23 b indolo
US4791107A (en) *	1986-07-16	1988-12-13	Hoechst-Roussel Pharmaceuticals, Inc.	Memory enhancing and analgesic 1,2,3,3A,8,8A-hexahydro-3A,8 (and) 1,3A,8)-di(and tri)methylpyrrolo(2,3-B)indoles, compositions and use
IT1251166B (it) *	1991-08-09	1995-05-04	Chiesi Farma Spa	Derivati di geneserina,loro preparazione e composizioni farmaceutiche che li contengono
US5571929A (en)	1994-12-07	1996-11-05	The United States Of America As Represented By The Department Of Health And Human Services	Resolution and reduction of physostigmine intermediates and derivatives
US5677457A (en) *	1996-12-19	1997-10-14	Hoechst Marion Roussel, Inc.	Method of preparation of physostigmine carbamate derivatives from eseroline ethers

1998
- 1998-10-07 CN CN98810683A patent/CN1278264A/zh active Pending
- 1998-10-07 KR KR1020007003805A patent/KR20010015714A/ko not_active Withdrawn
- 1998-10-07 WO PCT/EP1998/006377 patent/WO1999019329A1/fr not_active Ceased
- 1998-10-07 EP EP98954370A patent/EP1023297A1/fr not_active Withdrawn
- 1998-10-07 TR TR2000/00951T patent/TR200000951T2/xx unknown
- 1998-10-07 AU AU11516/99A patent/AU750964B2/en not_active Ceased
- 1998-10-07 BR BR9815237-8A patent/BR9815237A/pt not_active IP Right Cessation
- 1998-10-07 NZ NZ503773A patent/NZ503773A/en unknown
- 1998-10-07 IL IL13539998A patent/IL135399A0/xx unknown
- 1998-10-07 US US09/319,693 patent/US6297237B1/en not_active Expired - Fee Related
- 1998-10-07 HU HU0003747A patent/HUP0003747A3/hu unknown
- 1998-10-07 PL PL98339761A patent/PL339761A1/xx unknown
- 1998-10-07 SK SK503-2000A patent/SK5032000A3/sk unknown
- 1998-10-07 EA EA200000300A patent/EA003192B1/ru not_active IP Right Cessation
- 1998-10-07 CA CA002274658A patent/CA2274658A1/fr not_active Abandoned
- 1998-10-09 AR ARP980105062A patent/AR018511A1/es unknown
- 1998-10-23 TW TW087117571A patent/TW490467B/zh active

Also Published As

Publication number	Publication date
TW490467B (en)	2002-06-11
NZ503773A (en)	2002-05-31
HUP0003747A2 (hu)	2001-10-28
TR200000951T2 (tr)	2000-07-21
AU1151699A (en)	1999-05-03
EP1023297A1 (fr)	2000-08-02
BR9815237A (pt)	2000-10-31
IL135399A0 (en)	2001-05-20
AR018511A1 (es)	2001-11-28
US6297237B1 (en)	2001-10-02
CN1278264A (zh)	2000-12-27
EA003192B1 (ru)	2003-02-27
AU750964B2 (en)	2002-08-01
CA2274658A1 (fr)	1999-04-22
PL339761A1 (en)	2001-01-02
EA200000300A1 (ru)	2000-12-25
KR20010015714A (ko)	2001-02-26
HUP0003747A3 (en)	2001-12-28
WO1999019329A1 (fr)	1999-04-22

Publication	Publication Date	Title
US20040176353A1 (en)	2004-09-09	Derivatives of pyrimido[6,1-a]isoquinolin-4-one
JPH0529399B2 (fr)	1993-04-30
KR100225927B1 (ko)	1999-10-15	콜린에스테라제 저해제로서의 제네세린 유도체
CH663023A5 (fr)	1987-11-13	Derives de la furo-(3,4-c)-pyridine substitues en position 6, un procede pour leur preparation et compositions therapeutiques a base de ces derives.
EP0521768B1 (fr)	1994-02-02	Nouveaux dérivés de triazolopyrimidine antagonistes des récepteurs à l'angiotensine II; leurs procédés de préparation, compositions pharmaceutiques les contenant
US5679677A (en)	1997-10-21	Heterocyclic carbamates, process for their preparation and medicaments
IE49541B1 (en)	1985-10-30	4,5-dihydro-1-(3-mercapto-1-oxopropyl)-3-phenyl-1h-pyrazole-5-carboxylic acid and derivatives thereof
EP0136198B1 (fr)	1988-02-10	Dérivés de triazolo pyrimidine, leur procédé de préparation et leur application thérapeutique en tant que toni-cardiaques
EP0077427B1 (fr)	1985-05-22	Dérivés de pipéridine, leur procédé de préparation et leur application en thérapeutique
NZ208896A (en)	1988-03-30	Benzazepine and benzoxazepine derivatives and pharmaceutical compositions
US6297237B1 (en)	2001-10-02	Process for the preparation of aminocarbonyl derivatives of geneseroline having selective brain anticholinesterase activity
FR2470770A1 (fr)	1981-06-12	Nouveaux ethers de b-imidazolylethyle de quinoleine-2 ou 4-methanols, utiles notamment comme antimicrobiens, et leur procede de preparation
US4438121A (en)	1984-03-20	Isoquinoline amidoxime derivatives
FI90417C (fi)	1994-02-10	Menetelmä terapeuttisesti aktiivisten hydroksi-1,2,3,4-tetrahydroaminoakridiinien valmistamiseksi
FI57589C (fi)	1980-09-10	Foerfarande foer framstaellning av blodtrycket saenkande 6-substituerade 3-karbetoksihydrazinopyridaziner
KR860001583B1 (ko)	1986-10-10	6-아닐리노-5,8-퀴녹살린 디온의 제조방법
EP0233800A1 (fr)	1987-08-26	Dérivés d'imidazo[1,2-a]quinoléines, leur préparation et leur application en thérapeutique
CZ20001294A3 (cs)	2000-10-11	Způsob výroby aminokarbonylových derivátů geneserolinu
EP0231138B1 (fr)	1990-04-18	Dérivés d'acylaminométhyl-1imidazo [1,2-a] quinoléines, leur préparation et leur application en thérapeutique
EP0581767B1 (fr)	1997-09-03	5H-DIBENZO(a,d)CYCLOHEPTENES UTILISES COMME ANTAGONISTES DE RECEPTEURS MUSCARINIQUES
KR880001659B1 (ko)	1988-09-05	1,7-디하이드로-피롤로[3,4-e][1,4]디아제핀-2-(1H)-온 유도체 및 이의 중간체의 제조방법
CA2086440A1 (fr)	1993-07-01	Derives eseroline a activite anticholinesterase, procede pour leur preparation et compositions pharmaceutiques en contenant
FR2640975A1 (fr)	1990-06-29
FR2481285A1 (fr)	1981-10-30	Nouvelles pyrazolo(1,2-a)(1,2,4)benzotriazines, utiles notamment comme agents anti-inflammatoires, et leur procede de preparation
ITMI972299A1 (it)	1999-04-10	Procedimento per la preparazione di amminocarbonil derivati di geneserolina