NZ503130A - Pyrrolopyrrolone derivatives as inhibitors of neutrophil elastase - Google Patents

Info

Publication number

NZ503130A

NZ503130A NZ503130A NZ50313098A NZ503130A NZ 503130 A NZ503130 A NZ 503130A NZ 503130 A NZ503130 A NZ 503130A NZ 50313098 A NZ50313098 A NZ 50313098A NZ 503130 A NZ503130 A NZ 503130A

Authority

NZ

New Zealand

Prior art keywords

hexahydro

carbonyl

methanesulfonyl

rel

pyrrolo

Prior art date

1997-09-09

Links

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• Global Dossier
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• 108010028275 Leukocyte Elastase Proteins 0.000 title description 7
• 102000016799 Leukocyte elastase Human genes 0.000 title description 7
• 239000003112 inhibitor Substances 0.000 title description 7
• ACJSMQZKXAMMRA-UHFFFAOYSA-N 1h-pyrrolo[3,2-b]pyrrol-5-one Chemical class N1C=CC2=NC(=O)C=C21 ACJSMQZKXAMMRA-UHFFFAOYSA-N 0.000 title description 2
• 150000001875 compounds Chemical class 0.000 claims abstract description 234
• 238000011282 treatment Methods 0.000 claims abstract description 31
• 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 19
• 229910052736 halogen Inorganic materials 0.000 claims abstract description 15
• 150000002367 halogens Chemical class 0.000 claims abstract description 14
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 14
• 229910052799 carbon Inorganic materials 0.000 claims abstract description 8
• 125000000719 pyrrolidinyl group Chemical group 0.000 claims abstract description 8
• 125000003386 piperidinyl group Chemical group 0.000 claims abstract description 7
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 6
• 125000002757 morpholinyl group Chemical group 0.000 claims abstract description 6
• 125000004193 piperazinyl group Chemical group 0.000 claims abstract description 6
• 125000003118 aryl group Chemical group 0.000 claims abstract description 5
• 125000002619 bicyclic group Chemical group 0.000 claims abstract description 5
• 125000005842 heteroatom Chemical group 0.000 claims abstract description 5
• 229910052760 oxygen Inorganic materials 0.000 claims abstract description 5
• 229910052717 sulfur Inorganic materials 0.000 claims abstract description 5
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 4
• 125000005843 halogen group Chemical group 0.000 claims abstract description 4
• 125000002785 azepinyl group Chemical group 0.000 claims abstract description 3
• 125000002393 azetidinyl group Chemical group 0.000 claims abstract description 3
• 125000002950 monocyclic group Chemical group 0.000 claims abstract description 3
• 235000011468 Albizia julibrissin Nutrition 0.000 claims description 106
• 241001070944 Mimosa Species 0.000 claims description 106
• -1 pyrrole-2-carbonyl Chemical group 0.000 claims description 72
• 239000000203 mixture Substances 0.000 claims description 57
• 238000006243 chemical reaction Methods 0.000 claims description 52
• 150000003839 salts Chemical class 0.000 claims description 24
• 238000002360 preparation method Methods 0.000 claims description 18
• 239000002253 acid Substances 0.000 claims description 17
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 14
• 229910052739 hydrogen Inorganic materials 0.000 claims description 12
• 239000001257 hydrogen Substances 0.000 claims description 12
• 239000012453 solvate Substances 0.000 claims description 12
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 11
• 206010006451 bronchitis Diseases 0.000 claims description 11
• WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 9
• 206010006458 Bronchitis chronic Diseases 0.000 claims description 8
• 208000007451 chronic bronchitis Diseases 0.000 claims description 8
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 8
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 8
• 239000008194 pharmaceutical composition Substances 0.000 claims description 8
• VIXWGKYSYIBATJ-UHFFFAOYSA-N pyrrol-2-one Chemical compound O=C1C=CC=N1 VIXWGKYSYIBATJ-UHFFFAOYSA-N 0.000 claims description 8
• 239000003814 drug Substances 0.000 claims description 7
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 6
• 229930040373 Paraformaldehyde Natural products 0.000 claims description 6
• 239000000460 chlorine Substances 0.000 claims description 6
• 229910052801 chlorine Inorganic materials 0.000 claims description 6
• 150000002148 esters Chemical class 0.000 claims description 6
• 238000007254 oxidation reaction Methods 0.000 claims description 6
• 229920002866 paraformaldehyde Polymers 0.000 claims description 6
• 238000004519 manufacturing process Methods 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
• 125000003373 pyrazinyl group Chemical group 0.000 claims description 5
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 4
• 239000005864 Sulphur Substances 0.000 claims description 4
• 230000003647 oxidation Effects 0.000 claims description 4
• 125000000335 thiazolyl group Chemical group 0.000 claims description 4
• NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 claims description 3
• 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 3
• 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 claims description 3
• 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 3
• 150000008065 acid anhydrides Chemical class 0.000 claims description 3
• 230000002378 acidificating effect Effects 0.000 claims description 3
• 150000008064 anhydrides Chemical class 0.000 claims description 3
• 238000009833 condensation Methods 0.000 claims description 3
• 230000005494 condensation Effects 0.000 claims description 3
• 239000012458 free base Substances 0.000 claims description 3
• 125000000842 isoxazolyl group Chemical group 0.000 claims description 3
• 125000003226 pyrazolyl group Chemical group 0.000 claims description 3
• 230000009467 reduction Effects 0.000 claims description 3
• 208000006673 asthma Diseases 0.000 claims description 2
• 239000000969 carrier Substances 0.000 claims description 2
• 239000003085 diluting agent Substances 0.000 claims description 2
• 125000002971 oxazolyl group Chemical group 0.000 claims description 2
• XKEFTOLYQVJIJM-UHFFFAOYSA-N 4-methylsulfonyl-1,2,3,3a,6,6a-hexahydropyrrolo[3,2-b]pyrrol-5-one Chemical compound C1CNC2CC(=O)N(S(=O)(=O)C)C21 XKEFTOLYQVJIJM-UHFFFAOYSA-N 0.000 claims 4
• BDCHCJSIJYFPJO-UHFFFAOYSA-N 4-methylsulfonyl-6-propan-2-yl-1,2,3,3a,6,6a-hexahydropyrrolo[3,2-b]pyrrol-5-one Chemical compound N1CCC2N(S(C)(=O)=O)C(=O)C(C(C)C)C21 BDCHCJSIJYFPJO-UHFFFAOYSA-N 0.000 claims 2
• 125000003262 carboxylic acid ester group Chemical class [H]C([H])([*:2])OC(=O)C([H])([H])[*:1] 0.000 claims 2
• TZSPKNFWFIBCTO-IXDOHACOSA-N (3ar,6s,6as)-1-[5-[(cyclopropylamino)methyl]pyrazine-2-carbonyl]-4-methylsulfonyl-6-propan-2-yl-3,3a,6,6a-tetrahydro-2h-pyrrolo[3,2-b]pyrrol-5-one Chemical compound C([C@@H]1[C@@H]2[C@@H](C(N1S(C)(=O)=O)=O)C(C)C)CN2C(=O)C(N=C1)=CN=C1CNC1CC1 TZSPKNFWFIBCTO-IXDOHACOSA-N 0.000 claims 1
• 125000000217 alkyl group Chemical group 0.000 abstract description 9
• 208000027866 inflammatory disease Diseases 0.000 abstract description 4
• 210000002345 respiratory system Anatomy 0.000 abstract description 2
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 abstract 5
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 2
• 125000004209 (C1-C8) alkyl group Chemical group 0.000 abstract 1
• 125000006656 (C2-C4) alkenyl group Chemical group 0.000 abstract 1
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 420
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 229
• 239000000543 intermediate Substances 0.000 description 163
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 157
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 157
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 152
• 239000007787 solid Substances 0.000 description 130
• 238000004949 mass spectrometry Methods 0.000 description 125
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 110
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 87
• 239000002904 solvent Substances 0.000 description 83
• 239000000243 solution Substances 0.000 description 81
• 229940093499 ethyl acetate Drugs 0.000 description 74
• 235000019439 ethyl acetate Nutrition 0.000 description 74
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 68
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 68
• QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 58
• 235000019441 ethanol Nutrition 0.000 description 54
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 48
• 239000000843 powder Substances 0.000 description 45
• 239000011541 reaction mixture Substances 0.000 description 40
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 39
• 239000006071 cream Substances 0.000 description 36
• 238000002844 melting Methods 0.000 description 36
• 230000008018 melting Effects 0.000 description 36
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 31
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 30
• 239000000377 silicon dioxide Substances 0.000 description 30
• 229910021529 ammonia Inorganic materials 0.000 description 29
• 238000000034 method Methods 0.000 description 27
• 238000003756 stirring Methods 0.000 description 27
• CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 26
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 26
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 25
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
• 239000003921 oil Substances 0.000 description 24
• 235000019198 oils Nutrition 0.000 description 24
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 22
• 239000002585 base Substances 0.000 description 21
• 238000003818 flash chromatography Methods 0.000 description 21
• 235000017557 sodium bicarbonate Nutrition 0.000 description 21
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 21
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 21
• 239000000725 suspension Substances 0.000 description 21
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 20
• 239000003480 eluent Substances 0.000 description 20
• 239000000284 extract Substances 0.000 description 20
• IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 20
• 229910000041 hydrogen chloride Inorganic materials 0.000 description 20
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 19
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 19
• 102000016387 Pancreatic elastase Human genes 0.000 description 19
• 108010067372 Pancreatic elastase Proteins 0.000 description 19
• 239000012074 organic phase Substances 0.000 description 19
• 239000000047 product Substances 0.000 description 18
• XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 17
• 239000012267 brine Substances 0.000 description 17
• 230000008569 process Effects 0.000 description 17
• 238000010992 reflux Methods 0.000 description 17
• RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical group C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 16
• 230000000694 effects Effects 0.000 description 16
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 14
• 239000008346 aqueous phase Substances 0.000 description 13
• 229910000029 sodium carbonate Inorganic materials 0.000 description 13
• FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 12
• YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 12
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 11
• 239000006260 foam Substances 0.000 description 11
• 229910000027 potassium carbonate Inorganic materials 0.000 description 11
• 235000011181 potassium carbonates Nutrition 0.000 description 11
• 125000006239 protecting group Chemical group 0.000 description 10
• SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 9
• 210000000440 neutrophil Anatomy 0.000 description 9
• WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 8
• 238000010511 deprotection reaction Methods 0.000 description 8
• 201000010099 disease Diseases 0.000 description 8
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 8
• 238000010828 elution Methods 0.000 description 8
• 239000012442 inert solvent Substances 0.000 description 8
• CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 8
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• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 7
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• 239000010410 layer Substances 0.000 description 7
• 210000004072 lung Anatomy 0.000 description 7
• 239000012321 sodium triacetoxyborohydride Substances 0.000 description 7
• RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 7
• VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 6
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• 230000004054 inflammatory process Effects 0.000 description 6
• 239000012071 phase Substances 0.000 description 6
• 230000002829 reductive effect Effects 0.000 description 6
• FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 6
• 238000003786 synthesis reaction Methods 0.000 description 6
• DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 6
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• ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 4
• 229910015900 BF3 Inorganic materials 0.000 description 4
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• VMVNZNXAVJHNDJ-UHFFFAOYSA-N methyl 2,2,2-trifluoroacetate Chemical compound COC(=O)C(F)(F)F VMVNZNXAVJHNDJ-UHFFFAOYSA-N 0.000 description 4
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• 235000019502 Orange oil Nutrition 0.000 description 3
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• QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
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• LAORHHSYLRWIMN-PWZMFNOBSA-N benzyl (2s,3r)-3-amino-2-(1-ethoxy-3-methyl-1-oxobutan-2-yl)pyrrolidine-1-carboxylate Chemical compound CCOC(=O)C(C(C)C)[C@H]1[C@H](N)CCN1C(=O)OCC1=CC=CC=C1 LAORHHSYLRWIMN-PWZMFNOBSA-N 0.000 description 3
• HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 3
• 210000004369 blood Anatomy 0.000 description 3
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• 238000004296 chiral HPLC Methods 0.000 description 3
• KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
• 238000007796 conventional method Methods 0.000 description 3
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