CZ184194A3 - Aspartylprotease inhibitor and method of identifying thereof - Google Patents

Info

Publication number

CZ184194A3

CZ184194A3 CZ941841A CZ184194A CZ184194A3 CZ 184194 A3 CZ184194 A3 CZ 184194A3 CZ 941841 A CZ941841 A CZ 941841A CZ 184194 A CZ184194 A CZ 184194A CZ 184194 A3 CZ184194 A3 CZ 184194A3

Authority

CZ

Czechia

Prior art keywords

group

carbon atoms

alkyl

reaction

amino

Prior art date

1993-08-09

Links

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• 239000003696 aspartic proteinase inhibitor Substances 0.000 title claims abstract description 42
• 238000000034 method Methods 0.000 title claims description 58
• 101710110426 Aspartyl protease inhibitor Proteins 0.000 title claims description 38
• 150000001875 compounds Chemical class 0.000 claims abstract description 134
• 238000004519 manufacturing process Methods 0.000 claims abstract description 64
• 238000012360 testing method Methods 0.000 claims abstract description 60
• 230000002401 inhibitory effect Effects 0.000 claims abstract description 30
• 239000003112 inhibitor Substances 0.000 claims abstract description 28
• 230000000694 effects Effects 0.000 claims abstract description 26
• 102000004580 Aspartic Acid Proteases Human genes 0.000 claims abstract description 20
• 108010017640 Aspartic Acid Proteases Proteins 0.000 claims abstract description 20
• DZHSAHHDTRWUTF-SIQRNXPUSA-N amyloid-beta polypeptide 42 Chemical compound C([C@@H](C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)NCC(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(O)=O)[C@@H](C)CC)C(C)C)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC(O)=O)C(C)C)C(C)C)C1=CC=CC=C1 DZHSAHHDTRWUTF-SIQRNXPUSA-N 0.000 claims abstract description 19
• 238000003556 assay Methods 0.000 claims abstract description 18
• -1 C 2 -C 6 alkanoyl Chemical group 0.000 claims description 96
• 125000004432 carbon atom Chemical group C* 0.000 claims description 87
• 125000000217 alkyl group Chemical group 0.000 claims description 62
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 61
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 50
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 39
• 108090000765 processed proteins & peptides Proteins 0.000 claims description 37
• 125000000623 heterocyclic group Chemical group 0.000 claims description 30
• 125000003118 aryl group Chemical group 0.000 claims description 25
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 24
• 229910052757 nitrogen Inorganic materials 0.000 claims description 23
• 201000010099 disease Diseases 0.000 claims description 22
• 230000001413 cellular effect Effects 0.000 claims description 19
• 150000003839 salts Chemical class 0.000 claims description 17
• 208000024827 Alzheimer disease Diseases 0.000 claims description 15
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 15
• 229940121710 HMGCoA reductase inhibitor Drugs 0.000 claims description 13
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 13
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 11
• 229910052799 carbon Inorganic materials 0.000 claims description 10
• 239000001257 hydrogen Substances 0.000 claims description 10
• 229910052739 hydrogen Inorganic materials 0.000 claims description 10
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 9
• 241001465754 Metazoa Species 0.000 claims description 8
• 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 8
• 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 7
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 7
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
• 125000000539 amino acid group Chemical group 0.000 claims description 6
• 125000003710 aryl alkyl group Chemical group 0.000 claims description 6
• 210000001124 body fluid Anatomy 0.000 claims description 6
• 239000010839 body fluid Substances 0.000 claims description 6
• 125000003282 alkyl amino group Chemical group 0.000 claims description 5
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 5
• 125000004414 alkyl thio group Chemical group 0.000 claims description 4
• 229910052736 halogen Inorganic materials 0.000 claims description 4
• 150000002367 halogens Chemical class 0.000 claims description 4
• 239000000137 peptide hydrolase inhibitor Substances 0.000 claims description 4
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
• 125000000304 alkynyl group Chemical group 0.000 claims description 3
• 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 3
• 229940124158 Protease/peptidase inhibitor Drugs 0.000 claims description 2
• 125000001589 carboacyl group Chemical group 0.000 claims description 2
• 150000002431 hydrogen Chemical class 0.000 claims 5
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 2
• 125000003275 alpha amino acid group Chemical group 0.000 claims 2
• 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims 1
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 1
• 125000002853 C1-C4 hydroxyalkyl group Chemical group 0.000 claims 1
• 229940123363 Cathepsin D inhibitor Drugs 0.000 claims 1
• 101100113485 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) chs-3 gene Proteins 0.000 claims 1
• 101000959886 Solanum tuberosum Aspartic protease inhibitor 2 Proteins 0.000 claims 1
• 101000959868 Solanum tuberosum Aspartic protease inhibitor 8 Proteins 0.000 claims 1
• 125000003342 alkenyl group Chemical group 0.000 claims 1
• 230000005764 inhibitory process Effects 0.000 abstract description 20
• 108091005804 Peptidases Proteins 0.000 abstract description 19
• 239000004365 Protease Substances 0.000 abstract description 19
• 102000035195 Peptidases Human genes 0.000 abstract description 18
• 239000008194 pharmaceutical composition Substances 0.000 abstract description 11
• 102000013455 Amyloid beta-Peptides Human genes 0.000 abstract description 9
• 108010090849 Amyloid beta-Peptides Proteins 0.000 abstract description 9
• 238000000338 in vitro Methods 0.000 abstract description 6
• 102000003908 Cathepsin D Human genes 0.000 abstract description 5
• 108090000258 Cathepsin D Proteins 0.000 abstract description 5
• 238000000423 cell based assay Methods 0.000 abstract description 4
• 238000004113 cell culture Methods 0.000 abstract description 3
• 230000003834 intracellular effect Effects 0.000 abstract description 3
• 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 abstract 1
• 238000001727 in vivo Methods 0.000 abstract 1
• 238000006243 chemical reaction Methods 0.000 description 198
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 98
• 239000000243 solution Substances 0.000 description 91
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 79
• 238000002360 preparation method Methods 0.000 description 65
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 54
• 239000002253 acid Substances 0.000 description 54
• 239000000047 product Substances 0.000 description 53
• 238000004458 analytical method Methods 0.000 description 51
• 238000005481 NMR spectroscopy Methods 0.000 description 47
• 210000004027 cell Anatomy 0.000 description 47
• 239000011541 reaction mixture Substances 0.000 description 44
• 230000002829 reductive effect Effects 0.000 description 43
• 229940024606 amino acid Drugs 0.000 description 40
• 239000000203 mixture Substances 0.000 description 40
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 39
• 239000000543 intermediate Substances 0.000 description 38
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 35
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 30
• 239000002904 solvent Substances 0.000 description 30
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 29
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 28
• 150000001413 amino acids Chemical class 0.000 description 28
• 239000006260 foam Substances 0.000 description 26
• 239000007787 solid Substances 0.000 description 25
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 24
• SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 24
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 24
• 239000011347 resin Substances 0.000 description 22
• 229920005989 resin Polymers 0.000 description 22
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
• 239000010410 layer Substances 0.000 description 21
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 20
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 20
• 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 19
• 239000012044 organic layer Substances 0.000 description 19
• 238000005859 coupling reaction Methods 0.000 description 18
• 230000035772 mutation Effects 0.000 description 18
• 239000000758 substrate Substances 0.000 description 18
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 17
• 241000282414 Homo sapiens Species 0.000 description 17
• 125000003277 amino group Chemical group 0.000 description 17
• 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 17
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 16
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 16
• PRNUISXJAASHJM-UHFFFAOYSA-N 2-heptylbenzamide Chemical compound CCCCCCCC1=CC=CC=C1C(N)=O PRNUISXJAASHJM-UHFFFAOYSA-N 0.000 description 15
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 15
• 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 15
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 15
• 238000011282 treatment Methods 0.000 description 15
• 125000000979 2-amino-2-oxoethyl group Chemical group [H]C([*])([H])C(=O)N([H])[H] 0.000 description 14
• 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 14
• 238000010168 coupling process Methods 0.000 description 14
• 102000005600 Cathepsins Human genes 0.000 description 13
• 108010084457 Cathepsins Proteins 0.000 description 13
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 13
• 230000008878 coupling Effects 0.000 description 13
• 239000003480 eluent Substances 0.000 description 13
• 239000003921 oil Substances 0.000 description 13
• UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 13
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 13
• KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 12
• 150000001412 amines Chemical class 0.000 description 12
• 239000012267 brine Substances 0.000 description 12
• 229910052938 sodium sulfate Inorganic materials 0.000 description 12
• 235000011152 sodium sulphate Nutrition 0.000 description 12
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 12
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 11
• 150000001408 amides Chemical class 0.000 description 11
• 239000002609 medium Substances 0.000 description 11
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 10
• 125000004429 atom Chemical group 0.000 description 10
• 239000011230 binding agent Substances 0.000 description 10
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• 125000006239 protecting group Chemical group 0.000 description 10
• 238000004809 thin layer chromatography Methods 0.000 description 10
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 9
• QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 9
• 102000004190 Enzymes Human genes 0.000 description 9
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• WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 9
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• 210000004556 brain Anatomy 0.000 description 9
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• 238000002474 experimental method Methods 0.000 description 9
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• YYRFAGCHLGXHTC-UHFFFAOYSA-N 2-decylbenzamide Chemical compound CCCCCCCCCCC1=CC=CC=C1C(N)=O YYRFAGCHLGXHTC-UHFFFAOYSA-N 0.000 description 8
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• ZJSQZQMVXKZAGW-UHFFFAOYSA-N 2H-benzotriazol-4-ol hydrate Chemical compound O.OC1=CC=CC2=C1N=NN2 ZJSQZQMVXKZAGW-UHFFFAOYSA-N 0.000 description 7
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• 125000003545 alkoxy group Chemical group 0.000 description 6
• 125000004453 alkoxycarbonyl group Chemical group 0.000 description 6
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• 229910052708 sodium Inorganic materials 0.000 description 6
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• QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 5
• VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 5
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• 230000008021 deposition Effects 0.000 description 4
• 150000002170 ethers Chemical class 0.000 description 4
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
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• GSYSFVSGPABNNL-UHFFFAOYSA-N methyl 2-dimethoxyphosphoryl-2-(phenylmethoxycarbonylamino)acetate Chemical group COC(=O)C(P(=O)(OC)OC)NC(=O)OCC1=CC=CC=C1 GSYSFVSGPABNNL-UHFFFAOYSA-N 0.000 description 4
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• 239000003415 peat Substances 0.000 description 4
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• FSYKKLYZXJSNPZ-UHFFFAOYSA-N sarcosine Chemical compound C[NH2+]CC([O-])=O FSYKKLYZXJSNPZ-UHFFFAOYSA-N 0.000 description 4
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