CA2271116A1 - Benzothiazo and related heterocyclic group-containing cysteine and serine protease inhibitors - Google Patents

Info

Publication number

CA2271116A1

CA2271116A1 CA002271116A CA2271116A CA2271116A1 CA 2271116 A1 CA2271116 A1 CA 2271116A1 CA 002271116 A CA002271116 A CA 002271116A CA 2271116 A CA2271116 A CA 2271116A CA 2271116 A1 CA2271116 A1 CA 2271116A1

Authority

CA

Canada

Prior art keywords

compound

alkyl

net

optionally substituted

carbons

Prior art date

1996-11-13

Legal status (The legal status 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 status listed.)

Abandoned

Links

• Espacenet
• Global Dossier
• CIPO
• Discuss

• 125000000623 heterocyclic group Chemical group 0.000 title claims abstract description 32
• XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 title abstract description 16
• XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 title abstract description 16
• 235000018417 cysteine Nutrition 0.000 title abstract description 16
• 239000002852 cysteine proteinase inhibitor Substances 0.000 title description 7
• 239000003001 serine protease inhibitor Substances 0.000 title description 7
• 150000001875 compounds Chemical class 0.000 claims description 461
• 125000000217 alkyl group Chemical group 0.000 claims description 119
• 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 74
• 125000003118 aryl group Chemical group 0.000 claims description 58
• 125000001072 heteroaryl group Chemical group 0.000 claims description 46
• 229910052739 hydrogen Inorganic materials 0.000 claims description 41
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 37
• -1 napthyl Chemical group 0.000 claims description 32
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 29
• 229910052736 halogen Inorganic materials 0.000 claims description 25
• 150000002367 halogens Chemical group 0.000 claims description 25
• 239000001257 hydrogen Substances 0.000 claims description 25
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 24
• 125000003710 aryl alkyl group Chemical group 0.000 claims description 23
• 101100079984 Caenorhabditis elegans nhr-9 gene Proteins 0.000 claims description 19
• 125000003545 alkoxy group Chemical group 0.000 claims description 18
• 150000003839 salts Chemical class 0.000 claims description 18
• 229910052799 carbon Inorganic materials 0.000 claims description 17
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 14
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 14
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 14
• 229910052760 oxygen Inorganic materials 0.000 claims description 14
• 125000004429 atom Chemical group 0.000 claims description 13
• 125000005842 heteroatom Chemical group 0.000 claims description 13
• 150000001413 amino acids Chemical class 0.000 claims description 12
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 12
• 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 12
• 101100439665 Arabidopsis thaliana SWI2 gene Proteins 0.000 claims description 11
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 11
• 102000004190 Enzymes Human genes 0.000 claims description 10
• 108090000790 Enzymes Proteins 0.000 claims description 10
• 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 10
• 125000006260 ethylaminocarbonyl group Chemical group [H]N(C(*)=O)C([H])([H])C([H])([H])[H] 0.000 claims description 10
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 10
• 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 9
• 125000003435 aroyl group Chemical group 0.000 claims description 9
• 125000001589 carboacyl group Chemical group 0.000 claims description 9
• 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 9
• 125000001931 aliphatic group Chemical group 0.000 claims description 8
• 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 8
• 229910052801 chlorine Inorganic materials 0.000 claims description 8
• 125000006413 ring segment Chemical group 0.000 claims description 8
• 229910052717 sulfur Inorganic materials 0.000 claims description 8
• 125000004432 carbon atom Chemical group C* 0.000 claims description 6
• 229910052731 fluorine Inorganic materials 0.000 claims description 6
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 6
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 6
• 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 5
• 125000003342 alkenyl group Chemical group 0.000 claims description 5
• 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
• 125000004475 heteroaralkyl group Chemical group 0.000 claims description 5
• QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 claims description 5
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
• OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims description 4
• 125000002723 alicyclic group Chemical group 0.000 claims description 4
• 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 4
• 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 4
• 125000004104 aryloxy group Chemical group 0.000 claims description 4
• 125000000638 benzylaminocarbonyl group Chemical group C(C1=CC=CC=C1)NC(=O)* 0.000 claims description 4
• 125000002795 guanidino group Chemical group C(N)(=N)N* 0.000 claims description 4
• 125000001624 naphthyl group Chemical group 0.000 claims description 4
• 229910052698 phosphorus Inorganic materials 0.000 claims description 4
• 239000011574 phosphorus Substances 0.000 claims description 4
• 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 3
• 125000004471 alkyl aminosulfonyl group Chemical group 0.000 claims description 3
• 125000005141 aryl amino sulfonyl group Chemical group 0.000 claims description 3
• 125000005553 heteroaryloxy group Chemical group 0.000 claims description 3
• 125000005143 heteroarylsulfonyl group Chemical group 0.000 claims description 3
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
• LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims description 2
• 125000006360 carbonyl amino methylene group Chemical group [H]N(C([*:1])=O)C([H])([H])[*:2] 0.000 claims 2
• 238000000034 method Methods 0.000 abstract description 195
• 102000005927 Cysteine Proteases Human genes 0.000 abstract description 26
• 108010005843 Cysteine Proteases Proteins 0.000 abstract description 26
• 102000012479 Serine Proteases Human genes 0.000 abstract description 19
• 108010022999 Serine Proteases Proteins 0.000 abstract description 19
• 239000003112 inhibitor Substances 0.000 abstract description 9
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 198
• 230000015572 biosynthetic process Effects 0.000 description 195
• 238000003786 synthesis reaction Methods 0.000 description 195
• 239000000543 intermediate Substances 0.000 description 115
• 239000000203 mixture Substances 0.000 description 99
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 82
• 239000007787 solid Substances 0.000 description 76
• 235000019439 ethyl acetate Nutrition 0.000 description 67
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 67
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 53
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 51
• 150000001299 aldehydes Chemical class 0.000 description 47
• 239000000741 silica gel Substances 0.000 description 46
• 229910002027 silica gel Inorganic materials 0.000 description 46
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 45
• 239000000243 solution Substances 0.000 description 44
• FZRKAZHKEDOPNN-UHFFFAOYSA-N Nitric oxide anion Chemical compound O=[N-] FZRKAZHKEDOPNN-UHFFFAOYSA-N 0.000 description 39
• 238000005481 NMR spectroscopy Methods 0.000 description 38
• 238000003818 flash chromatography Methods 0.000 description 33
• 239000012267 brine Substances 0.000 description 29
• 239000011734 sodium Substances 0.000 description 29
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 29
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 24
• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 24
• 239000000460 chlorine Substances 0.000 description 22
• 239000012074 organic phase Substances 0.000 description 22
• KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 21
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 18
• SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 18
• 239000012043 crude product Substances 0.000 description 18
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 17
• 238000006243 chemical reaction Methods 0.000 description 17
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 16
• 238000010992 reflux Methods 0.000 description 16
• 239000000047 product Substances 0.000 description 15
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
• 238000012746 preparative thin layer chromatography Methods 0.000 description 14
• WTDRDQBEARUVNC-LURJTMIESA-N L-DOPA Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-LURJTMIESA-N 0.000 description 13
• WTDRDQBEARUVNC-UHFFFAOYSA-N L-Dopa Natural products OC(=O)C(N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-UHFFFAOYSA-N 0.000 description 13
• 208000035475 disorder Diseases 0.000 description 13
• 238000000746 purification Methods 0.000 description 13
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
• 239000005457 ice water Substances 0.000 description 12
• 239000002244 precipitate Substances 0.000 description 12
• 238000003756 stirring Methods 0.000 description 12
• 102000035195 Peptidases Human genes 0.000 description 11
• 108091005804 Peptidases Proteins 0.000 description 11
• 239000004365 Protease Substances 0.000 description 11
• 108010032088 Calpain Proteins 0.000 description 10
• 102000007590 Calpain Human genes 0.000 description 10
• 229940024606 amino acid Drugs 0.000 description 10
• NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 10
• 230000002401 inhibitory effect Effects 0.000 description 10
• 230000005764 inhibitory process Effects 0.000 description 10
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
• 238000000967 suction filtration Methods 0.000 description 10
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 9
• NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 9
• 230000007062 hydrolysis Effects 0.000 description 9
• 238000006460 hydrolysis reaction Methods 0.000 description 9
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
• 235000001014 amino acid Nutrition 0.000 description 8
• 229940088598 enzyme Drugs 0.000 description 8
• 230000004048 modification Effects 0.000 description 8
• 238000012986 modification Methods 0.000 description 8
• 239000003921 oil Substances 0.000 description 8
• 239000000843 powder Substances 0.000 description 8
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 8
• 238000004458 analytical method Methods 0.000 description 7
• 229920006395 saturated elastomer Polymers 0.000 description 7
• 238000000926 separation method Methods 0.000 description 7
• 239000002002 slurry Substances 0.000 description 7
• 239000002904 solvent Substances 0.000 description 7
• 239000007858 starting material Substances 0.000 description 7
• KEQGZUUPPQEDPF-UHFFFAOYSA-N 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione Chemical compound CC1(C)N(Cl)C(=O)N(Cl)C1=O KEQGZUUPPQEDPF-UHFFFAOYSA-N 0.000 description 6
• 238000006646 Dess-Martin oxidation reaction Methods 0.000 description 6
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
• XTHPWXDJESJLNJ-UHFFFAOYSA-N chlorosulfonic acid Substances OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 description 6
• 238000001914 filtration Methods 0.000 description 6
• 238000009472 formulation Methods 0.000 description 6
• OFIJLSUAGOAQOM-UHFFFAOYSA-N n,n-dimethylformamide;4-methylmorpholine Chemical compound CN(C)C=O.CN1CCOCC1 OFIJLSUAGOAQOM-UHFFFAOYSA-N 0.000 description 6
• 229910000027 potassium carbonate Inorganic materials 0.000 description 6
• 239000011541 reaction mixture Substances 0.000 description 6
• 238000001953 recrystallisation Methods 0.000 description 6
• YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 5
• VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 5
• YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 5
• 125000004122 cyclic group Chemical group 0.000 description 5
• 230000000694 effects Effects 0.000 description 5
• 238000001704 evaporation Methods 0.000 description 5
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• 239000000546 pharmaceutical excipient Substances 0.000 description 5
• AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 5
• 235000019345 sodium thiosulphate Nutrition 0.000 description 5
• XHVNXVGEFJHTMY-VIFPVBQESA-N (2s)-2-amino-4-(3-chlorophenyl)butanoic acid Chemical compound OC(=O)[C@@H](N)CCC1=CC=CC(Cl)=C1 XHVNXVGEFJHTMY-VIFPVBQESA-N 0.000 description 4
• KYUNTDRHCPSMOG-UHFFFAOYSA-N 2h-1,3-benzothiazole-3-carboxylic acid Chemical class C1=CC=C2N(C(=O)O)CSC2=C1 KYUNTDRHCPSMOG-UHFFFAOYSA-N 0.000 description 4
• ANMVTYAYYHHSTF-UHFFFAOYSA-N 4-(4-ethylpiperazin-1-yl)-N-[6-(2-fluoro-3-methoxyphenyl)-1H-indazol-3-yl]benzamide Chemical compound CCN1CCN(CC1)c1ccc(cc1)C(=O)Nc1n[nH]c2cc(ccc12)-c1cccc(OC)c1F ANMVTYAYYHHSTF-UHFFFAOYSA-N 0.000 description 4
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• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
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• MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
• 230000002159 abnormal effect Effects 0.000 description 4
• 239000002585 base Substances 0.000 description 4
• 230000000903 blocking effect Effects 0.000 description 4
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 4
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 4
• 238000007911 parenteral administration Methods 0.000 description 4
• QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 description 4
• 125000006239 protecting group Chemical group 0.000 description 4
• 230000002829 reductive effect Effects 0.000 description 4
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• 210000001519 tissue Anatomy 0.000 description 4
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• DHKHKXVYLBGOIT-UHFFFAOYSA-N 1,1-Diethoxyethane Chemical compound CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 3
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• XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 3
• DEGMIFWLGSEDAA-UHFFFAOYSA-N 4,5-dihydro-1,2-benzothiazepine-3-carboxylic acid Chemical class C1CC(C(=O)O)=NSC2=CC=CC=C21 DEGMIFWLGSEDAA-UHFFFAOYSA-N 0.000 description 3
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• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
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• 125000002962 imidazol-1-yl group Chemical group [*]N1C([H])=NC([H])=C1[H] 0.000 description 3
• 230000004054 inflammatory process Effects 0.000 description 3
• UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 3
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