Patent EA-001437-B1 (EA)
Title: Pyrrolopyrrolone derivatives as inhibitors of neutrophil elastase
Inventor: DOWLE MICHAEL DENNIS
IPC: A61P13/12
Filed: 1997-03-26
Abstract: 1. A compound of the general formula (I)   wherein: R1 represents C1-6 alkyl; C2-6 alkenyl; aryl, aryl-C1-4 alkyl, aryl-C2-4 alkenyl, heteroaryl, heteroaryl-C1-4 alkyl, or heteroaryl-C2-4 alkenyl, or a group wherein the aryl or heteroaryl moiety is substituted by one or more C1-4 alkyl, halo, tetrazolyl, trifluoromethylsulphonamide, NR9CO-C1-8 alkyl, -(CH2)m-NR4R5, -CN, -COOR9, -CONR9R10, -NO2, -SO2-C1-6 alkyl, -CF3 or C1-6 alkoxy groups; -(CH2)n-NR4R5 ; C2-8 alkenyl-NR4R5 ; -(CH2)nCONR4R5; -(CH2)nNR9CO-C1-6alkyl; C2-8 alkenyl-COOR9; (CH2)nCOOR9 ; and C2-8 alkenyl-CONR4R5; X represents  (where carbonyl is bound to the ring nitrogen); R2 represents C2-4 alkyl, C2-4 alkenyl, C1-3 alkoxy or C1-3 alkylthio; R3 represents C1-6 alkyl; -CH2(CF2)0-4CF3 ; aryl or heteroaryl, which aryl or heteroaryl are monocyclic, or have two fused rings one of which may be saturated, and which aryl and heteroaryl groups may be substituted by one or more C1-4 alkyl, halo, -NR7R8, -SO2NR7R8, -CONR7R8, -C1-6 alkyl ester, -CN, -CH2OH, -O-C1-6 alkyl, -CF3, or nitro groups; aryl-C1-4 alkyl, aryl-C1-4 alkyl-NH- or aryl-C2-4 alkenyl, or such groups wherein aryl is substituted by one or more C1-4 alkyl or halo groups; R4 and R5 independently represent hydrogen, C1-4 alkyl, C1-4 alkoxy, -(CH2)1-4CONR11R12, -CO-C1-4 alkyl or phenyl optionally substituted by one or more C1-4 alkyl or halogen groups or R4 and R5 may be joined such that NR4R5 represents a mono, bi- or tri-cyclic ring system containing 4-15 ring carbon atoms, wherein one or more rings may be optionally interrupted by one or more heteroatoms selected from O, N and S and wherein one or more ring carbon atoms may have carbonyl functionality, or -(CH2)n-NR4R5 may represent a group of formula 1a   wherein R6 is hydrogen or a carboxy C1-6 alkyl ester, n<1> is 0-6 and a and b independently represent an integer 0-3 provided that a+b is in the range 3-5; R7, R8, R9, R10, R11, R12 independently represent hydrogen or C1-4 alkyl; alkyl represents branched and normal alkyl and also may represent cycloalkyl when three or more carbon atoms are present; aryl represents phenyl, naphtyl, or tetrahydronaphtyl; heteroaryl represents aromatic 5- or 6-membered monocyclic heterocycle, comprising one or more heteroatom of sulfur, nitrogen or oxygen, or a condensed bicyclic system, consisting of two 5- and 6-membered rings, comprising one or more said heteroatom, of which one ring is optionally saturated; m represents an integer 0 to 8; n represents an integer 1 to 9; or salts and solvates thereof. 2. A compound according to claim 1, wherein R2 represents n-propyl or isopropyl. 3. A compound according to claim 2, wherein R2 represents isopropyl. 4. A compound according to any of claims 1-3, wherein R3 represents C1-6 alkyl. 5. A compound according to claim 4 wherein R3 represents methyl. 6. A compound according to any of claims 1-5, wherein X represents -CO- or -SO2. 7. A compound according to claim 6, wherein X represents -CO-. 8. A compound according to any of claims 1-7, wherein R1 represents C2-8 alkenyl-NR4R5. 9. A compound according to claim 8, wherein R1 represents -CH=CH-CH2-NR4R5. 10. A compound according to any of claims 1-7, wherein R1 represents phenyl, furanyl, thiophenyl or pyrrolyl substituted by the group -(CH2)n`-NR4R5 and n` represents an integer 1 to 5. 11. A compound according to claim 10, wherein n` represents an integer 1 to 3. 12. A compound according to any of claims 8-11, wherein -NR4R5 together represents morpholine, pyrrolidine, piperidine, azepine, piperazine or 4-methylpiperazine or one or both of R4 and R5 represents C1-4 alkyl and the other (if it does not represent C1-4 alkyl) represents hydrogen. 13. A compound according to any of claims 1-7 wherein R1 represents phenyl substituted by -NHCO-C1-8 alkyl. 14. A compound according to claim 13 wherein R1 represents phenyl substituted by -NHCOMe. 15. A compound according to claim 1 which is: (3R<(,>3aR<(>,6aS<(>)-1-methanesulfonyl-4-(4-piperidin-1-yl-but-2-(E)-enoyl-3-propyl-hexahydro-pyrrolo[3,2-b]pyrrol-2-one; (3R<(>,3aR<(>,6aS<(>)-4-(6-azepin-1-yl-hexanoyl-3-isopropyl-1-methanesulfonyl-hexahydro-pyrrolo[3,2-b]pyrrol-2-one; (3R<(>,3aR<(>,6aS<(>)-3-isopropyl-1-methanesulfonyl-4-(3-piperidin-1yl-propionyl)-hexahydro-pyrrolo[3,2-b]pyrrol-2-one; (3R<(>,3aR<(>,6aS<(>)-1-methanesulfonyl-4-(4-piperidin-1-ylmethyl-benzoyl)-3-propyl-hexahydro-pyrrolo[3,2-b]pyrrol-2-one; N-[4-(4-methanesulfonyl-5-oxo-6R<(>-propyl-hexahydro-(3aS<(>,6aR<(>)-pyrrolo[3,2-b]pyrrole-1-sulfonyl)phenyl]-acetamide; (3R*,3aR*,6aS*)-1-methanesulfonyl-4-[(methyl-phenyl-amino)-acetyl]-3-propyl-hexahydro-pyrrolo[3,2-b]pyrrol-2-one; N-[4-(4-methanesulfonyl-5-oxo-6R*-propyl-hexahydro-(3aS*,6aR*)-pyrrolo[3,2-b]pyrrole-1-carbonyl)-phenyl]-acetamide; 4-(4-methanesulfonyl-5-oxo-6R*-propyl-hexahydro-(3aS*,6aR*)-pyrrolo[3,2-b]pyrrole-1-sulfonyl)-N-(2-piperidin-1-yl-ethyl)-benzamide; N-(2-dimethylamino-ethyl)-4-(4-methanesufonyl-5-oxo-6R*-propyl-hexahydro-(3aS*,6aR*)-pyrrolo[3,2-b]pyrrole-1-sulfonyl)-benzamide); (3R*,3aR*,6aS*)-1-methanesulfonyl-4-[4-(4-methyl-piperazine-1-carbonyl)-benzenesulfonyt]-3-propyl-hexahydro-pyrrolo[3,2-b]pyrrol-2-one; (3R*,3aR*,6aS*)-4-(4-methanesulfonyl-5-oxo-6-propyl-hexahydro-pyrrolo[3,2-b]pyrrol-1-yl)-4-oxo-but-2E-enoic acid ethyl ester; 4-(4-methanesulfonyl-5-oxo-6-propyl-hexahydro-(3aS*,6aR*)-pyrrolo[3,2-b]pyrrol-1-yl)-4-oxo-but-2E-enoic acid; (3R*,3aR*,6aS*)-1-(4-methanesufonyl-5-oxo-6-propyl-hexahydro-pyrrolo[3,2-b]pyrrol-1-yl)-4-(4-methyl-piperazin-1-yl)-but-2E-ene-1,4-dione; (3R*,3aR*,6aS*)-4-but-2E-enoyl-1-methanesulfonyl-3-propyl-hexahydro-pyrrolo[3,2-b]pyrrol-2-one; (3R*,3aR*,6aS*)-1-methanesulfonyl-4-{3-[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-(E)-acryloyl}-3-propyl-hexahydro-pyrrolo[3,2-b]pyrrol-2-one; (3R*,3aR*,6aS*)-1-methanesulfonyl-4-[3-(4-piperidin-1-ylmethyl-phenyl)-(E)-acryloyl]-3-propyl-hexahydro-pyrrolo[3,2-b]pyrrol-2-one; N-{4-[3-(4-methanesulfonyl-5-oxo-6R*-propyl-hexahydro-(3aS*,6aR*)-pyrrolo[3,2-b]pyrrol-1-yl)-3-oxo-(E)-propenyl]-phenyl}acetamide; (3R*,3aR*,6aS*)-3-isopropyl-1-methanesulfonyl-4-(4-piperidin-1-yl-but-2E-enoyl)-hexahydro-pyrrolo[3,2-b]pyrrol-2-one; (3R*,3aR*,6aS*)-4-(4-azepin-1-yl-but-2E-enoyl)-3-isopropyl-1-methanesulfonyl-hexahydro-pyrrolo[3,2-b]pyrrol-2-one; (3R*,3aR*,6aS*)-4-(4-cyclopropylamino-but-2E-enoyl)-3-isopropyl-1-methanesulfonyl-hexahydro-pyrrolo[3,2-b]pyrrol-2-one; (3R*,3aR*,6aS*)-4-[4-(4-acetyl-piperazin-1-yl)-but-2E-enoyl]-3-isopropyl-1-methanesulfonyl-hexahydro-pyrrolo[3,2-b]pyrrol-2-one; (3R*,3aR*,6aS*)-4-[4-(2,6-dimethyl-piperidin-1-yl)-but-2E-enoyl]-3-isopropyl-1-methanesulfonyl-hexahydro-pyrrolo[3,2-b]pyrrol-2-one; 1-[4-(6R*-isopropyl-4-methanesulfonyl-5-oxo-hexahydro-(3aS*,6aR*)-pyrrolo[3,2-b]pyrrol-1-yl)-4-oxo-but-2E-enyl]-pyrrolidine-2S-carboxylic acid methyl ester; (3R*,3aR*,6aS*)-3-isopropyl-1-methanesulfonyl-4-[4-(methyl-propyl-amino)-but-2E-enoyl]-hexahydro-pyrrolo[3,2-b]pyrrol-2-one; (3R*,3aR*,6aS*)-3-isopropyl-1-methanesulfonyl-4-(4-morpholin-4-yl-but-2E-enoyl)-hexahydro-pyrrolo[3,2-b]pyrrol-2-one; (3R*,3aR*,6aS*)-3-isopropyl-1-methanesulfonyl-4-[4-(4-methyl-piperazin-1yl)-but-2E-enoyl]-hexahydro-pyrrolo[3,2-b]pyrrol-2-one; (3R*,3aR*,6aS*)-4-(4-diisopropylamino-but-2E-enoyl)-3-isopropyl-1-methanesulfonyl-hexahydro-pyrrolo[3,2-b]pyrrol-2-one; (3R*,3aR*,6aS*)-4-(4-diethylamino-but-2E-enoyl)-3-isopropyl-1-methanesulfonyl-hexahydro-pyrrolo[3,2-b]pyrrol-2-one; (3R*,3aR*,6aS*)-3-isopropyl-1-methanesulfonyl-4-(4-pyrrolidin-1-yl-but-2E-enoyl)-hexahydro-pyrrolo[3,2-b]pyrrol-2-one; (3R*,3aR*,6aS*)-3-isopropyl-1-methanesulfonyl-4-[4-(methoxy-methyl-amino)-but-E2-enoyl]-hexahydro-pyrrolo[3,2-b]pyrrol-2-one; (3R*,3aR*,6aS*)-4-(4-dimethylamino-but-2E-enoyl)-3-isopropyl-1-methanesulfonyl-hexahydro-pyrrolo[3,2-b]pyrrol-2-one; (3R*,3aR*,6aS*)-4-[4-(2,5-dimethyl-pyrrolidin-1-yl)-but-2E-enoyl]-3-isopropyl-1-methanesulfonyl-hexahydro-pyrrolo[3,2-b]pyrrol-2-one; 2-{[4-(6R*-isopropyl-4-methanesulfonyl-5-oxo-hexahydro-(3aS*,6aR*)-pyrrolo[3,2-b]pyrrol-1-yl)-4-oxo-but-2E-enyl]-methyl-amino}-acetamide; (3R*,3aR*,6aS*)-3-isopropyl-4-(4-isopropylamino-but-2E-enoyl)-1-methanesulfonyl-hexahydro-pyrrolo[3,2-b]pyrrol-2-one; 1-[4-(6R*-isopropyl-4-methanesulfonyl-5-oxo-hexahydro-(3aS*,6aR*)-pyrrolo[3,2-b]pyrrol-1-yl)-4-oxo-but-2E-enyl]-piperidine-4-carboxylic acid amide; (3R*,3aR*,6aS*)-4-[4-(5,8-difluoro-1,3,3a,4,9,9a-hexahydro-(3aS*,9aS*)-benzo[f]isoindol-2-yl)-but-2E-enoyl]-3-isopropyl-1-methanesulfonyl-hexahydro-pyrrolo[3,2-b]pyrrol-2-one; (3R,3aR,6aS)-3-isopropyl-1-methanesufonyl-4-(4-piperidin-1-yl-but-2E-enoyl)-hexahydro-pyrrolo[3,2-b]pyrrol-2-one; (3R*,3aR*,6aS*)-3-isopropyl-1-methanesufonyl-4-[3-(4-piperidin-1-ylmethyl-phenyl)-(E)-acryloyl]-hexahydro-pyrrolo[3,2-b]pyrrol-2-one; (3R*,3aR*,6aS*)-4-[3-(4-dimethylaminomethyl-phenyl)-(E)-acryloyl]-3-isopropyl-1-methanesulfonyl-hexahydro-pyrrolo[3,2-b]pyrrol-2-one; (3R*,3aR*,6aS*)-1-ethanesulfonyl-4-(3-piperidin-1-yl-propionyl)-3-propyl-hexahydro-pyrrolo[3,2-b]pyrrol-2-one; (3R*,3aR*,6aS*)-3-isopropyl-1-methanesulfonyl-4-(4-pyrrolidin-1-ylmethyl-benzoyl)-hexahydro-pyrrolo[3,2-b]pyrrol-2-one; (3R*,3aR*,6aS*)-3-isopropyl-1-methanesulfonyl-4-(4-piperidin-1-ylmethyl-benzoyl)-hexahydro-pyrrolo[3-2-b]pyrrol-2-one; (3R*,3aR*,6aS*)-4-(4-dimethylaminomethyl-benzoyl)-3-isopropyl-1-methanesulfonyl-hexahydro-pyrrolo[3,2-b]pyrrol-2-one; (3R*,3aR*,6aS*)-3-isopropyl-1-methanesulfonyl-4-[4-(4-methyl-piperazin-1-ylmethyl)-benzoyl]-hexahydro-pyrrolo[3,2-b]pyrrol-2-one; (3R*,3aR*,6aS*)-3-isopropyl-1-methanesulfonyl-4-(4-morpholin-4-ylmethyl-benzoyl)-hexahydro-pyrrolo[3,2-b]pyrrol-2-one; (3R*,3aR*,6aS*)-4-(4-azepin-1-ylmethyl-benzoyl)-3-isopropyl-1-methanesulfonyl-hexahydro-pyrrolo[3,2-b]pyrrol-2-one; (3R*,3aR*,6aS*)-3-isopropyl-4-[4-(isopropylamino-methyl)-benzoyl]-1-methanesulfonyl-hexahydro-pyrrolo[3,2-b]pyrrol-2-one; (3R*,3aR*,6aS*)-4-(4-cyclopropylaminomethyl-benzoyl)-3-isopropyl-1-methanesulfonyl-hexahydro-pyrrolo[3-2-b]pyrrol-2-one; (3R*,3aR*,6aS*)-3-isopropyl-1-metha