BENZENECARBOTHIOCCYCLOPENTA[C] PYRROLE-1,3-DIONE COMPOUNDS AND PROCESS FOR SYNTHESIS THEREOF
20170226057 · 2017-08-10
Inventors
- Dumbala S. Reddy (Pune, IN)
- Satish C. Philkhana (Pune, IN)
- Gorakhnath R. Jachak (Pune, IN)
- Vidya B. Gunjal (Pune, IN)
Cpc classification
C07D409/12
CHEMISTRY; METALLURGY
International classification
Abstract
The present invention relates to a novel analogues of benzenecarbothioccyclopenta[c]pyrrole-1,3-dione of formula (I) useful for treating various viral infections and process for synthesis thereof.
##STR00001##
The present invention provides a novel process for synthesis of nitrosporeusinesA(1) and B(2). More particularly, the present invention provides a synthetic route for synthesis of nitrosporeusinesA(1) and B(2). Said process is simple, industrially scalable, cost effective and eco-friendly.
Claims
1. A compound of formula (I) ##STR00040## wherein, R.sup.1 and R.sup.2 are individually selected from hydrogen, alkyl, alkenyl, aryl, heteroaryl, hydroxyl, alkoxy, heteroaryloxy, carboxy, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, cyano, halo, azide, thioocyano, alkylcarbothioc or arylcarbothioc; or R.sup.1 and R.sup.2 are 3 to 8 membered carbocyclic ring which is optionally be substituted or contain a 1-2 heteroatoms; R.sup.3 is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cylcoalkenyl, aryl, heteroaryl, hydroxyl, alkoxy, heteroaryloxy, alkylcarbonyl, arylcarbonyl, or alkoxycarbonyl; A is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cylcoalkenyl, aryl, heteroaryl, hydroxyl, alkoxy or aryloxy; provided that when R.sup.2 and R.sup.3 are Hydrogen, R.sup.1 is not OH and A is not aryloxy and its derivatives, salts, analogues and isomers.
2. The compound as claimed in claim 1, wherein the compound is selected from a) S-((3aR*,6R*,6aS*)-6-Hydroxy-1,3-dioxohexahydrocyclopenta[c]pyrrol-3a(1 H)-yl) ethanethioate (7); b) S-(3aS*,6R*,6aR*)-6-Hydroxy-1,3-dioxohexahydrocyclopenta[c]pyrrol-3a(1 H)-yl) ethanethioate (8); c) S-((3 aR*,6R*,6aS*)-6-Hydroxy- 1,3 -dioxohexahydrocyclopenta[c]pyrrol-3a(1 H)-y1) 2-phenylethanethioate (9); d) S-((3 aS*,6R*,6aR*)-6-Hydroxy- 1,3 -dioxohexahydrocyclopenta[c]pyrrol-3a(1H)-y1) 2-phenylethanethioate (10); e) S-((3 aS*,6R*,6aR*)-6-Hydroxy- 1,3 -dioxohexahydrocyclopenta[c]pyrrol-3a(1H)-y1) 4-fluorobenzothioate (11) f) S-((3 aS*,6R*,6aR*)-6-Hydroxy- 1,3 -dioxohexahydrocyclopenta[c]pyrrol-3a(1H)-y1) thiophene-2-carbothioate (12) g) S-((3aS*,6S*,6aR*)-6-Hydroxy- 1,3-dioxohexahydrocyclopenta[c]pyrrol-3a(1H)-yl) 2-chlorobenzothioate (13); h) S-((3aS*,6R*,6aR*)-6-Hydroxy- 1,3 -dioxohexahydrocyclopenta[c]pyrrol-3a(1H)-y1) 2-chlorobenzothioate (14); i) S-((3aR*,6R*,6aS*)-6-Hydroxy- 1,3 -dioxohexahydrocyclopenta[c]pyrrol-3a(1H)-y1) benzothioate (15); j) S-((3aS*,6R*,6aR*)-6-Hydroxy-1,3-dioxohexahydrocyclopenta[c]pyrrol-3a(1H)-y1) benzothioate (16); k) S-((3aS*,6R*,6aR*)-6-Hydroxy- 1,3 -dioxohexahydrocyclopenta[c]pyrrol-3a(1H)-y1) 2-hydroxybenzothioate (17); l) S-((3aR*,6aS*)-1,3-Dioxohexahydrocyclopenta[c]pyrrol-3a(1H)-yl) ethanethioate (18); m) S-((3aR*,6aS*)-1,3-Dioxohexahydrocyclopenta[c]pyrrol-3a(1H)-yl) 2-phenylethanethioate (19); n) S-((3aR*,6aS*)-1,3-Dioxohexahydrocyclopenta[c]pyrrol-3a(1H)-yl) 4-fluorobenzothioate (20); o) S-((3aR*,6aS*)-1,3-Dioxohexahydrocyclopenta[c]pyrrol-3a(1H)-yl) 2-chlorobenzothioate (21); p) S-(1,3-Dioxo-2,3,4,5-tetrahydrocyclopenta[c]pyrrol-3a(1H)-yl) 4-fluorobenzothioate (22); q) S,S′-((3aR*,6aR*)-1,3-Dioxohexahydrocyclopenta[c]pyrrole-3a,6(1H)-diyl) bis(4-fluorobenzothioate) (23); r) S-(1,3-Dioxo-1,2,3,4,5,6-hexahydrocyclopenta[c]pyrrol-4-yl) benzothioate (24): s) S,S′-((3aS*,6aS*)-1,3-Dioxohexahydrocyclopenta[c]pyrrole-3a,6(1H)-diyl) dibenzothioate (25); t) S-(1,3-Dioxo-2,3,4,5-tetrahydrocyclopenta[c]pyrrol-3a(1H)-yl)ethanethioate (26) u) S-(1,3-Dioxo-2,3,4,5-tetrahydrocyclopenta[c]pyrrol-3a(1H)-yl) 2-phenylethanethioate (27); v) S,S′-((3aR*,6aR*)-1,3-Dioxohexahydrocyclopenta[c]pyrrole-3a,6(1H)-diyl) diethanethioate (28); w) S-(1,3-Dioxo-1,2,3,4,5,6-hexahydrocyclopenta[c]pyrrol-4-yl)thiophene-2-carbothioate (29); x) (3aS*,6aR*)-1,3-Dioxo-6a-((thiophene-2-carbonyl)thio)octahydrocyclopenta[c]pyrrol-4-yl acetate (30); y) (3aS*,6aR*)-6a-(Acetylthio)-1,3-dioxooctahydrocyclopenta[c]pyrrol-4-yl acetate (31); z) (3aS*,6aR*)-1,3-Dioxo-6a-((2-phenylacetyl)thio)octahydrocyclopenta[c]pyrrol-4-yl acetate (32); aa) (3aS*,6aR*)-6a-((4-Fluorobenzoyl)thio)-1,3-dioxooctahydrocyclopenta[c]pyrrol-4-yl acetate (33); bb) (3aS*,6aR*)-6a-((2-Chlorobenzoyl)thio)-1,3-dioxooctahydrocyclopenta[c]pyrrol-4-yl acetate (34); cc) (3aS*,6aR*)-6a-(Benzoylthio)-1,3-dioxooctahydrocyclopenta[c]pyrrol-4-yl acetate (35).
3. The compound as claimed in claims 1 and 2, wherein said compounds are useful for treating various viral infections.
4. A process for synthesis of compound of formula (I) ##STR00041## wherein, R.sup.1 and R.sup.2 are individually selected from hydrogen, alkyl, alkenyl, aryl, heteroaryl, hydroxyl, alkoxy, heteroaryloxy, carboxy, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, cyano, halo, azide, thioocyano, alkylcarbothioc or arylcarbothioc; or R.sup.1 and R.sup.2 are 3 to 8 membered carbocyclic ring which is optionally be substituted or contain a 1-2 heteroatoms; R.sup.3 is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cylcoalkenyl, aryl, heteroaryl, hydroxyl, alkoxy, heteroaryloxy, alkylcarbonyl, arylcarbonyl, or alkoxycarbonyl; A is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cylcoalkenyl, aryl, heteroaryl, hydroxyl, alkoxy or aryloxy; provided that R.sup.1, R.sup.2 and R.sup.3 are not Hydrogen at the same time; and its derivatives, salts, analogues and isomers. wherein said process comprising the step of: i. Stirring thioacid of formula (b) with compound of formula (a) in solvent at a temperature in the range of 25° C. to 100° C. for period in the range of 2 to 15 hrs followed by extraction to afford compound of formula (I).
5. The process as claimed in claim 4, wherein the compound is selected from a) S-((3aR,6R,6aS)-6-hydroxy-1,3-dioxohexahydrocyclopenta[c]pyrrol-3a(1H)-yl) 4-hydroxybenzothioate (−)1; b) S-((3aS ,6R,6aR)-6-hydroxy-1,3-dioxohexahydrocyclopenta[c]pyrrol-3a(1H)-yl) 4-hydroxybenzothioate (+)2; c) S-((3aS ,6S ,6aR)-6-hydroxy-1,3-dioxohexahydrocyclopenta[c]pyrrol-3a(1H)-yl) 4-hydroxybenzothioate ((+)1); d) S-((3aR,6S ,6aS)-6-hydroxy-1,3-dioxohexahydrocyclopenta[c]pyrrol-3a(1H)-yl) 4-hydroxybenzothioate ((−)2); e) S-((3aR*,6R*,6aS*)-6-Hydroxy- 1,3-dioxohexahydrocyclopenta[c]pyrrol-3a(1H)-y1) ethanethioate (7); f) S-((3aS*,6R*,6aR*)-6-Hydroxy- 1,3-dioxohexahydrocyclopenta[c]pyrrol-3a(1H)-yl) ethanethioate (8); g) S-((3aR*,6R*,6aS*)-6-Hydroxy- 1,3-dioxohexahydrocyclopenta[c]pyrrol-3a(1H)-y1) 2-phenylethanethioate (9); h) S-((3 aS*,6R*,6aR*)-6-Hydroxy- 1,3-dioxohexahydrocyclopenta[c]pyrrol-3a(1H)-y1) 2-phenylethanethioate (10); i) S-((3aS*,6R*,6aR*)-6-Hydroxy- 1,3-dioxohexahydrocyclopenta[c]pyrrol-3a(1H)-y1) 4-fluorobenzothioate (11) j) S-((3 aS*,6R*,6aR*)-6-Hydroxy- 1,3-dioxohexahydrocyclopenta[c]pyrrol-3a(1H)-y1) thiophene-2-carbothioate (12) k) S-((3aS*,6S*,6aR*)-6-Hydroxy- 1,3-dioxohexahydrocyclopenta[c]pyrrol-3a(1H)-yl) 2-chlorobenzothioate (13); l) S -((3aS*,6R*,6aR*)-6-Hydroxy- 1,3-dioxohexahydrocyclopenta[c]pyrrol-3a(1H)-y1) 2-chlorobenzothioate (14); m) S-((3aR*,6R*,6aS*)-6-Hydroxy- 1,3-dioxohexahydrocyclopenta[c]pyrrol-3a(1H)-y1) benzothioate (15); n) S-((3aS*,6R*,6aR*)-6-Hydroxy- 1,3-dioxohexahydrocyclopenta[c]pyrrol-3a(1H) -y1) benzothioate (16); o) S-((3aS*,6R*,6aR*)-6-Hydroxy- 1,3-dioxohexahydrocyclopenta[c]pyrrol-3a(1H)-y1) 2-hydroxybenzothioate (17); p) S-((3aR*,6aS*)-1,3-Dioxohexahydrocyclopenta[c]pyrrol-3a(1H)-yl) ethanethioate (18); q) S-((3aR*,6aS*)-1,3-Dioxohexahydrocyclopenta[c]pyrrol-3a(1H)-yl) 2-phenylethanethioate (19); r) S-((3aR*,6aS*)-1,3-Dioxohexahydrocyclopenta[c]pyrrol-3a(1H)-yl) 4-fluorobenzothioate (20) ; s) S-((3aR*,6aS*)-1,3-Dioxohexahydrocyclopenta[c]pyrrol-3a(1H)-yl) 2-chlorobenzothioate (21); t) S-(1,3-Dioxo-2,3,4,5-tetrahydrocyclopenta[c]pyrrol-3a(1H)-yl) 4-fluorobenzothioate (22); u) S,S′-((3aR*,6aR*)-1,3-Dioxohexahydrocyclopenta[c]pyrrole-3a,6(1H)-diyl) bis(4-fluorobenzothioate) (23); v) S-(1,3-Dioxo-1,2,3,4,5,6-hexahydrocyclopenta[c]pyrrol-4-yl) benzothioate (24): w) S,S′-((3aS*,6aS*)-1,3-Dioxohexahydrocyclopenta[c]pyrrole-3a,6(1H)-diyl) dibenzothioate (25); x) S-(1,3-Dioxo-2,3,4,5-tetrahydrocyclopenta[c]pyrrol-3a(1H)-yl)ethanethioate (26) y) S-(1,3-Dioxo-2,3,4,5-tetrahydrocyclopenta[c]pyrrol-3a(1H)-yl) 2-phenylethanethioate (27); z) S,S′-((3aR*,6aR*)-1,3-Dioxohexahydrocyclopenta[c]pyrrole-3a,6(1H)-diyl) diethanethioate (28); aa) S-(1,3-Dioxo-1,2,3,4,5,6-hexahydrocyclopenta[c]pyrrol-4-yl)thiophene-2-carbothioate (29); bb) (3aS*,6aR*)-1,3-Dioxo-6a-((thiophene-2-carbonyl)thio)octahydrocyclopenta[c]pyrrol-4-yl acetate (30); cc) (3aS*,6aR*)-6a-(Acetylthio)-1,3-dioxooctahydrocyclopenta[c]pyrrol-4-yl acetate (31); dd) (3aS*,6aR*)-1,3-Dioxo-6a-((2-phenylacetyl)thio)octahydrocyclopenta[c]pyrrol-4-yl acetate (32); ee) (3aS*,6aR*)-6a-(4-Fluorobenzoyl)thio)-1,3-dioxooctahydrocyclopenta[c]pyrrol-4-yl acetate (33); ff) (3aS*,6aR*)-6a-(2-Chlorobenzoyl)thio)-1,3-dioxooctahydrocyclopenta[c]pyrrol-4-yl acetate (34); gg) (3aS*,6aR*)-6a-(Benzoylthio)-1,3-dioxooctahydrocyclopenta[c]pyrrol-4-yl acetate (35).
6. The process as claimed in claim 3, wherein said compound of formula (a) is selected from 5,6-dihydrocyclopenta[c]pyrrole-1,3(2H,4H)-dione, 4-hydroxy-5,6-dihydrocyclopenta[c]pyrrole-1,3(2H,4H)-dione (4),4-bromo-5,6-dihydrocyclopenta [c]pyrrole-1,3(2H,4H)-dione,1,3-dioxo-1,2,3,4,5,6-hexahydrocyclopenta[c]pyrrol -4-yl acetate.
7. The process as claimed in claim 3, wherein said compound of formula (b) is selected from ethanethioic S-acid, 2-chlorobenzothioic S-acid, 4-fluorobenzothioic S-acid, benzothioic S-acid, 2-hydroxybenzothioic S-acid, 4-hydroxybenzothioic S-acid (6), thiophene-2-carbothioic S-acid, 2-phenylethanethioic S-acid.
8. The process as claimed in claim 3, wherein said solvent is selected from hydrocarbon solvents, water, alcohols, ethers, esters, cyclic ethers and nitriles such as 1,4-dioxane, tetrahydrofuran, ethanol, methanol or combination thereof.
9. A process for synthesis of compound of formula (1) and (2) as claimed in claims 1 to 8, wherein said process comprising the steps of: a) adding oxidizing agent Selenium dioxide (SeO.sub.2)to a solution of 5,6-dihydrocyclopenta[c]pyrrole-1,3(2H, 4H)-dione (3) at a temp 25° C. in dry solvent; ##STR00042## b) subjecting reaction mixture of step (a) to microwave irradiation at a temperature ranging from 100° C. to 150° C. for period in the range of 30-60 min to afford 4-hydroxy-5,6-dihydroclopenta[c]pyrrole-1,3(2H, 4H)-dione (4); ##STR00043## c) reacting said 4-hydroxy-5,6-dihydroclopenta[c]pyrrole-1,3(2H, 4H)-dione (4) of step (b) with 4-hydroxybenzothioic S-acid (6) in presence of water at a temperature ranging from 25° C. to 100° C. to afford mixture of Nitrosporeusines A(1) & B(2). ##STR00044##
10. The process as claimed in claim 9, wherein said solvent in step (a) is selected from 1,4-dioxane, tetrahydrofuran, ethanol, methanol and like.
11. The process as claimed in claim 9, wherein said reaction is continued for a period of 10 to 24 hours.
12. A pharmaceutical composition comprising compound of formula (I) as claimed in claim 1 and at least one pharmaceutically acceptable carrier useful for treating various viral infections.
Description
BRIEF DESCRIPTION OF ACCOMPANYING DRAWINGS
[0016]
[0017]
[0018]
[0019]
[0020]
[0021]
[0022]
[0023]
[0024]
SUMMARY OF THE INVENTION
[0025] The present invention provides benzenecarbothioccyclopenta[c]pyrrole-1,3-dione compound of formula (I) and process for synthesis thereof which are expected to show better activities against influenza viruses than the existing drugs. Further, the various compounds prepared based on this novel scaffold are expected to show good inhibitory activity not only against influenza viruses but also for treatment of acute renal failure, rhinitis, renal fibrosis and chronic heart failure.
DETAILED DESCRIPTION OF THE INVENTION
[0026] Accordingly, present invention provides benzenecarbothioccyclopenta[c]pyrrole-1,3-dione compound of formula (I).
##STR00002##
[0027] wherein,
[0028] R.sup.1 and R.sup.2 are individually selected from hydrogen, alkyl, alkenyl, aryl, heteroaryl, hydroxyl, alkoxy, heteroaryloxy, carboxy, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, cyano, halo, azide, thioocyano, alkylcarbothioc or arylcarbothioc; or R1 and R2 may form a 3 to 8 membered carbocyclic ring which may optionally be substituted or may contain a 1-2 heteroatoms;
[0029] R.sup.3 is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cylcoalkenyl, aryl, heteroaryl, hydroxyl, alkoxy, heteroaryloxy, alkylcarbonyl, arylcarbonyl, or alkoxycarbonyl; and
[0030] A is selected from alkyl, alkenyl, alkynyl, cycloalkyl, cylcoalkenyl, aryl, heteroaryl, hydroxyl, alkoxy or aryloxy.
[0031] provided that when R.sup.2 and R.sup.3 are Hydrogen, R.sup.1 is not OH and A is not aryloxy and its derivatives, salts, analogues and isomers.
[0032] Accordingly, the present invention encompasses the following exemplary compounds of formula I. [0033] a) S-((3aR,6R,6aS)-6-hydroxy-1,3-dioxohexahydrocyclopenta[c]pyrrol-3a(1H)-yl) 4-hydroxybenzothioate (−)1; [0034] b) S-((3aS,6R,6aR)-6-hydroxy-1,3-dioxohexahydrocyclopenta[c]pyrrol-3a(1H)-yl) 4-hydroxybenzothioate (+)2; [0035] c) S-((3aS,6S,6aR)-6-hydroxy-1,3-dioxohexahydrocyclopenta[c]pyrrol-3a(1H)-yl) 4-hydroxybenzothioate ((+)1) ; [0036] d) S-((3aR,6S,6aS)-6-hydroxy-1,3-dioxohexahydrocyclopenta[c]pyrrol-3a(1H)-yl) 4-hydroxybenzothioate ((−)2); [0037] e) S-(3aR*,6R*,6aS*)-6-Hydroxy-1,3-dioxohexahydrocyclopenta[c]pyrrol-3a(1H)-y1) ethanethioate (7); [0038] f) S-(3aS*,6R*,6aR*)-6-Hydroxy-1,3-dioxohexahydrocyclopenta[c]pyrrol-3a(1H)-y1) ethanethioate (8) ; [0039] g) S-(3aR*,6R*,6aS*)-6-Hydroxy-1,3-dioxohexahydrocyclopenta[c]pyrrol-3a(1H)-yl) 2-phenylethanethioate (9) ; [0040] h) S-(3aS*,6R*,6aR*)-6-Hydroxy-1,3-dioxohexahydrocyclopenta[c]pyrrol-3a(1H)-y1) 2-phenylethanethioate (10) ; [0041] i) S-(3aS*,6R*,6aR*)-6-Hydroxy-1,3-dioxohexahydrocyclopenta[c]pyrrol-3a(1H)-y1) 4-fluorobenzothioate (11) [0042] j) S-(3aS*,6R*,6aR*)-6-Hydroxy-1,3-dioxohexahydrocyclopenta[c]pyrrol-3a(1H)-yl)thiophene-2-carbothioate (12) [0043] k) S-((3aS*,6S*,6aR*)-6-Hydroxy-1,3-dioxohexahydrocyclopenta[c]pyrrol-3a(1H)-y1) 2-chlorobenzothioate (13) ; [0044] 1) S-(3aS*,6R*,6aR*)-6-Hydroxy-1,3-dioxohexahydrocyclopenta[c]pyrrol-3a(1 H)-yl) 2-chlorobenzothioate (14) ; [0045] m) S-((3aR*,6R*,6aS*)-6-Hydroxy-1,3-dioxohexahydrocyclopenta[c]pyrrol-3a(1 H)-yl) benzothioate (15) ; [0046] n) S-(3aS*,6R*,6aR*)-6-Hydroxy-1,3-dioxohexahydrocyclopenta[c]pyrrol-3a(1 H)-yl) benzothioate (16) ; [0047] o) S-(3aS*,6R*,6aR*)-6-Hydroxy-1,3-dioxohexahydrocyclopenta[c]pyrrol-3a(1 H)-yl) 2-hydroxybenzothioate (17) ; [0048] p) S-((3aR*,6aS*)-1,3-Dioxohexahydrocyclopenta[c]pyrrol-3a(1H)-yl) ethanethioate (18); [0049] q) S-((3aR*,6aS*)-1,3-Dioxohexahydrocyclopenta[c]pyrrol-3a(1H)-yl) 2-phenylethanethioate (19) ; [0050] r) S-((3aR*,6aS*)-1,3-Dioxohexahydrocyclopenta[c]pyrrol-3a(1H)-yl) 4-fluorobenzothioate (20) ; [0051] s) S-((3aR*,6aS*)-1,3-Dioxohexahydrocyclopenta[c]pyrrol-3a(1H)-yl) 2-chlorobenzothioate (21) ; [0052] t) S-(1,3-Dioxo-2,3,4,5-tetrahydrocyclopenta[c]pyrrol-3a(1H)-yl) 4-fluorobenzothioate (22); [0053] u) S,S′-((3aR*,6aR*)-1,3-Dioxohexahydrocyclopenta[c]pyrrole-3a,6(1H)-diyl) bis(4-fluorobenzothioate) (23); [0054] v) S-(1,3-Dioxo-1,2,3,4,5,6-hexahydrocyclopenta[c]pyrrol-4-yl) benzothioate (24): [0055] w) S,S′-((3aS*,6aS*)-1,3-Dioxohexahydrocyclopenta[c]pyrrole-3a,6(1H)-diyl) dibenzothioate (25); [0056] x) S-(1,3-Dioxo-2,3,4,5-tetrahydrocyclopenta[c]pyrrol-3a(1H)-yl)ethanethioate (26) [0057] y) S-(1,3-Dioxo-2,3,4,5-tetrahydrocyclopenta[c]pyrrol-3a(1H)-yl) 2-phenylethanethioate (27); [0058] z) S,S′-((3aR*,6aR*)-1,3-Dioxohexahydrocyclopenta[c]pyrrole-3a,6(1H)-diyl) diethanethioate (28); [0059] aa) S-(1,3-Dioxo-1,2,3,4,5,6-hexahydrocyclopenta[c]pyrrol-4-yl)thiophene-2-carbothioate (29); [0060] bb) (3aS*,6aR*)-1,3-Dioxo-6a-((thiophene-2-carbonyl)thio)octahydrocyclopenta[c]pyrrol-4-yl acetate (30) ; [0061] cc) (3aS*,6aR*)-6a-(Acetylthio)-1,3 -dioxooctahydrocyclopenta[c]pyrrol-4-yl acetate (31); [0062] dd) (3aS*,6aR*)-1,3 -Dioxo-6a-(2-phenylacetyl)thio)octahydrocyclopenta[c]pyrrol-4-yl acetate (32); [0063] ee) (3aS*,6aR*)-6a-((4-Fluorobenzoyl)thio)-1,3-dioxooctahydrocyclopenta[c]pyrrol-4-yl acetate (33) ; [0064] ff) (3aS*,6aR*)-6a-((2-Chlorobenzoyl)thio)-1,3-dioxooctahydrocyclopenta[c]pyrrol-4-yl acetate (34); [0065] gg) (3aS*,6aR*)-6a-(Benzoylthio)-1,3-dioxooctahydrocyclopenta[c]pyrrol-4-yl acetate (35).
[0066] In an embodiment, present invention provides a process for synthesis of compound of formula (I) comprises reacting thioacid of formula (b) with compound of formula (a) in suitable solvent followed by extraction to afford compound of formula (I). The above process is shown in
[0067] In another embodiment of the present invention, the reaction mixture is stirred vigorously at a temperature ranging from 25° C. to 100° C. ambient temperature to reflux temperature of the solvent used.
[0068] In another embodiment of the present invention, the reaction mixture is stirred at room temperature for 2 to 15 hrs.
[0069] In another embodiment of the present invention, the solvent may be selected from the group consisting of hydrocarbon solvents, water, alcohols, ethers, esters, cyclic ethers and nitriles or combination thereof.
[0070] In another embodiment of the present invention, the compound of formula (a) is selected from 5,6-dihydrocyclopenta[c]pyrrole-1,3(2H,4H)-dione; 4-hydroxy-5,6-dihydrocyclopenta[c]pyrrole-1,3(2H,4H)-dione; 4-bromo-5,6-dihydrocyclopenta[c]pyrrole-1,3(2H,4H)-dione; 1,3-dioxo-1,2,3,4,5,6-hexahydrocyclopenta[c]pyrrol-4-yl acetate.
[0071] In another embodiment of the present invention, the compound of formula (b) may be selected from ethanethioic S-acid; 2-chlorobenzothioic S-acid ; 4-fluorobenzothioic S-acid; benzothioic S-acid; 2-hydroxybenzothioic S-acid; 4-hydroxybenzothioic S-acid; thiophene-2-carbothioic S-acid; 2-phenylethanethioic S-acid.
[0072] In another embodiment of the present invention, the present invention provides a process for synthesis of nitrosporeusines A (1) and B (2) comprising the steps of: [0073] a) adding oxidizing agent to a solution of 5, 6-dihydroclopenta[c]pyrrole-1, 3 (2H, 4H)-dione (3) at a temperature 25° C. in dry solvent;
##STR00003## [0074] b) subjecting reaction mixture of step (a) to microwave irradiation to afford 4-hydroxy-5,6-dihydroclopenta[c]pyrrole-1, 3 (2H, 4H)-dione (4);
##STR00004## [0075] c) reacting 4-hydroxy-5,6-dihydroclopenta[c]pyrrole-1, 3 (2H, 4H)-dione (4) of step (b) with thiobenzoic acid in presence of water to afford mixture of Nitrosporeusines A (1) & B(2).
##STR00005##
[0076] The above process is shown in
[0077] In another embodiment of the present invention, the microwave irradiation of reaction mixture of step (b) may be carried out at a temperature ranging from 100° C. to 150° C., preferably at 110° C. for 30 min to lhr to afford said compound (4). Said compound (4) is isolated by evaporation of solvent and purified by chromatographic methods.
[0078] In another embodiment of the present invention, the step (c) may be carried out at a temperature ranging from ambient temperature to reflux temperature of the solvent. Preferably the reaction may be carried out at a temperature ranging from 30° C. to 100° C. The reaction may be continued for a period of 10 to 24 hrs by monitoring the progress of the reaction. Once the reaction is completed, the reaction mixture is extracted with suitable organic solvent to isolate the Nitrosporeusines A (1) & B (2) as a mixture, which can be separated by subjecting the mixture to column chromatography.
[0079] In another embodiment of the present invention, the oxidizing agent is selected from Selenium dioxide (SeO.sub.2).
[0080] In another embodiment of the present invention, the solvent is selected from 1,4-dioxane, tetrahydrofuran, ethanol, methanol and like.
[0081] In another embodiment of the present invention, the thiobenzoic acid used is 4-hydroxybenzothioic S-acid.
[0082] In another embodiment, present invention provides a pharmaceutical composition comprising a compound of formula (I), or a stereoisomer, or ester or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.
[0083] The synthesized compounds are analogues of parent compounds nitrosporeusines A and B which are known to possess anti-viral activities, especially against H1N1 influenza virus. The anti-inflamatory activity is being analysed with respect to Nitrogen oxide inhibition
[0084] The pharmaceutical compositions of the invention can be prepared by combining a compound of the invention with an appropriate pharmaceutically acceptable carrier, diluent or excipient, and may be formulated into preparations in solid, semi-solid, liquid or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, injections, gels and microspheres,
[0085] The present invention relates to administering ‘an effective amount’ of the ‘composition of invention ’ to the subject suffering from said disease. Accordingly, compound of formula I and pharmaceutical compositions containing them may be administered using any amount, any form of pharmaceutical composition via any route of administration effective for treating the disease. Typical routes of administering such pharmaceutical compositions include, without limitation, oral, topical, transdermal, inhalation, parenteral, sublingual, buccal, rectal, vaginal, and intranasal.
[0086] Pharmaceutical compositions of the invention are formulated so as to allow the active ingredients contained therein to be bioavailable upon administration of the composition to a patient. Compositions that will be administered to a subject or patient may take the form of one or more dosage units. The dosage forms can also be prepared as sustained, controlled, modified and immediate dosage forms.
EXAMPLES
[0087] Following examples are given by way of illustration and therefore should not be construed to limit the scope of the invention.
General Example
Synthesis of Compound of formula I through Michael Addition Reaction
[0088] In a round-bottomed flask equipped with a magnetic stirrer, thioacid (b) (1.1 eq.), substituted imide (a) (1 eq.), and THF: water (1:1, 2 mL) were charged. The reaction mixture was stirred vigorously at room temperature for 2 to 15 h, then it was diluted with ethyl acetate and extracted twice (2×3 ml). The combined organic layer was washed with saturated aqueous NaHCO.sub.3 solution followed by brine solution and concentrated under vacuum to obtain a crude mixture which was purified by column chromatography (silica gel; ethyl acetate : petroleum ether) to obtain the desired nitrosporeusine compound of formula I.
Example 1
Synthesis of 4-hydroxy-5, 6-dihydroclopenta[c]pyrrole-1, 3 (2H, 4H)-dione (4)
[0089] ##STR00006##
[0090] To a solution of compound 3 (0.10 g, 0.73 mmol) in dry 1, 4-Dioxane (1.5 mL) was added SeO.sub.2 (0.32 g, 2.91 mmol) and was subjected to microwave irradiation at 110° C. for 30 min. (Antonpaarmonowave 300 instrument). The reaction mixture was evaporated to dryness and the crude obtained was purified by silica gel column chromatography with elution of 50-70% EtOAc: Pet Ether to obtain product 4 (30 mg) in 61% yield (based on recovered starting material). Unreacted starting material was recovered (54mg).
[0091] .sup.1H NMR: (6 ppm, 400 MHz) D.sub.2O: 2.60-2.64 (m, 1H), 2.99-3.12 (m, 1H), 3.18 (m, 2H), 5.53-5.56 (m, 1H); .sup.13C NMR: (δ ppm, 100 MHz) D.sub.2O: 24.0, 37.3, 69.8, 152.0, 152.9 , 169.0, 169.7
[0092] The racemic alcohol (4) obtained above has been subjected to enzymatic resolution with amano lipase PS and vinyl acetate which gave (+) 4-hydroxy-5,6-dihydroclopenta[c]pyrrole-1,3 (2H, 4H)-dione as single enantiomer with 98% enantiomeric excess as shown in example 2.
Example 2
[0093] Synthesis of (S)-4-Hydroxy-5,6-dihydrocyclopenta[c]pyrrole-1,3(2H,4H)-dione ((+)-4)
##STR00007##
[0094] To a solution of alcohol 4 (1.12 g, 7.32 mmol) in dry THF was added Amano PS lipase (1.0 g) followed by addition of vinyl acetate (3.3 mL, 36.6 mmol) and stirred at room temperature for 10h. The reaction was monitored by chiral HPLC analysis (Chiralpak IB column,) and upon 50% conversion, the reaction mixture was filtered through celite bed, concentrated and was added with 10 mL of water. The aqueous layer was extracted thrice with EtOAc (3×10 mL) and combined organic layer was washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated in vacuo to obtain crude mixture of alcohol and acetate which on chromatographic separation yielded (R)-1,3-dioxo-1,2,3,4,5,6-hexahydrocyclopenta[c]pyrrol-4-yl (−)-5 (0.538 g)in 38% yield as white solid and (+)-(S)-4-hydroxy-5,6-dihydrocyclopenta[c]pyrrole-1,3(2H,4H)-dione (+)-4 (0.518 g) with 98%ee in 47% yield as white solid. HPLC conditions: Chiralpak IB column, Petroleum ether/2-propanol =95: 5, flow rate =1 mL/min, 230nm UV detector, t.sub.i =46.2 min (minor) and t.sub.2 =51.9 min (major).
[0095] (−)-2[α].sub.D.sup.26−38.3 (c 0.77 in CHCl.sub.3), .sup.1H NMR (200 MHz, CDCl.sub.3); δ7.43 (br s, 1H), 5.96-5.91 (m, 1H), 2.92-2.64 (m, 3H), 2.32-2.27 (m, 1H), 2.02 (s, 3H); .sup.13C NMR (100 MHz, CDCl.sub.3): 6 170.1, 165.7, 165.6, 164.8, 159.2, 149.8, 72.0, 36.1, 25.1, 20.9.
[0096] (+)-4 [α].sub.D.sup.26+56.1 (c 1.07 in MeOH), .sup.1H NMR (200 MHz, D.sub.2O); δ5.21-5.10 (m, 1 H), 2.91-2.67 (m, 2H), 2.65-2.47 (m, 1H), 2.31-2.13 (m, 1H).
Example 3
Synthesis of (R)-4-Hydroxy-5,6-dihydrocyclopenta[c]pyrrole-1,3(2H,4H)-dione ((−)-4)
[0097] ##STR00008##
[0098] To a solution of acetate (−)-5 (0.10 g, 0.50 mmol) in acetone was added Amano PS lipase (0.08 g) and phosphate buffer (10 mL) of pH 7 and warmed at 40° C. for 3h. The reaction mixture was then concentrated in vacuoto remove acetone and extracted twice with EtOAc (2×4 mL). The combined organic layer was washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated to obtain crude residue which was subjected to chromatographic separation to yield (−)-4 (0.072g) as white solid with 99% ee in 92% yield. [α].sub.D.sup.25−53.41 (c 1.34 in MeOH), .sup.1H NMR (200 MHz, D.sub.2O): δ5.22-5.08 (m, 1H), 2.92-2.66 (m, 2H), 2.65-2.48 (m, 1H), 2.31-2.13 (m, 1H); HPLC condition: Chiralpak IB column, Petroleum ether/2-propanol=95:5, 1 mL/min, 230 nm UV detector, t.sub.1=46.2 min (major) and t.sub.2=51.9 min (minor).
Example 4
Synthesis of (R)-1,3-Dioxo-1,2,3,4,5,6-hexahydrocyclopenta[c]pyrrol-4-yl acetate ((+)-.SUP.5.)
[0099] ##STR00009##
[0100] To a solution of alcohol (+)-4 (0.10 g, 0.65 mmol) in dry CH.sub.2Cl.sub.2 (3.0 mL) was added pyridine (0.102 mL, 1.300 mmol) and Ac.sub.2O (0.066 mL, 0.65 mmol). The reaction mixture was stirred at room temperature for 10h. Then the reaction mixture was diluted with water (3.0 mL) and extracted with CH.sub.2Cl.sub.2 (3×3 mL). The combined organic layer was washed with 1N HCl and then with brine solution, dried over anhydrous Na.sub.2SO.sub.4 and concentrated in vacuo to obtain crude residue which was subjected to chromatographic separation (30% EtOAc : Petroleum ether) to yield (+)-5 (0.105 g) as white solid with 82% yield. [α].sub.D.sup.26+40.1 (c 0.54 in CHCl.sub.3), .sup.1H NMR (200 MHz, CDCl.sub.3): 67.43 (br s, 1H), 5.96-5.91 (m, 1H), 2.92-2.64 (m, 3H), 2.32-2.27 (m, 1H), 2.02 (s, 3H); .sup.13C NMR (100 MHz, CDCl.sub.3): δ170.1, 165.7, 165.6, 164.8, 159.2, 149.8, 72.0, 36.1, 25.1, 20.9.
Example 5
Synthesis of 4-hydroxybenzothioic S-acid (6)
[0101] ##STR00010##
[0102] To a solution of 4-hydroxy benzoic acid(0.50 g, 3.62 mmol) in dry acetonitrile (5 mL) was added Lawesson's reagent(0.73 g, 1.81 mmol) and was subjected to microwave irradiation at 100° C. for 15 min. (Antonpaarmonowave 300 instrument). The reaction mixture was evaporated to dryness to obtain crude compound which was washed several times with 1N HCl, then with brine solution and dried over anhydrous sodium sulphate. The combined organic layer was concentrated in vacuo and purified by silica gel column chromatography with elution of 20-30% EtOAc: Petroleum Ether to obtain the 4-hydroxybenzothioic S-acid (6) (300 mg) in 53% yield. .sup.1H NMR: (δ ppm, 200MHz) CDCl.sub.3:3.58 (br. s, 1H), 6.88 (d, J=8Hz, 2H), 7.85 (d, J=8Hz, 2H)
Example 6
Synthesis of S-((3a5*,65*,6aR*)-6-hydroxy-1,3-dioxohexahydrocyclopenta[c]pyrrol-3a(1H)-yl) 4-hydroxybenzothioate (Nitrosporeusine A (1)) and
S-((3aS*,6R*,6aR*)-6-hydroxy-1,3-dioxohexahydrocyclopenta[c]pyrrol-3a(1H)-yl) 4-hydroxybenzothioate (Nitrosporeusine B (2))
[0103] A round-bottomed flask equipped with a magnetic stirrer, was charged with 4-hydroxybenzothoic S-acid (6)(0.10 g, 0.57 mmol), compound (4) (0.08 g, 0.52 mmol), and water (2.0 mL). The reaction mixture was stirred vigorously at room temperature i.e. 25° C. for 12 h. The progress of reaction was monitored by TLC analysis, which was then diluted with ethyl acetate and extracted thrice (3×2 mL). The combined organic layer was washed with saturated aqueous NaHCO.sub.3 followed by brine solution and dried over anhydrous Na.sub.2SO.sub.4. The crude compound obtained was subjected to column chromatography (60-70% EtOAc: petroleum ether) to give a 3:1 diastereomeric mixture of compound 2 (100 mg) and compound 1 (30mg), respectively, as white solids in 65% overall yield.
[0104] Compound (1): .sup.1H NMR: (δ ppm, 400MHz) DMSO-D.sub.6: 11.28 (br. s., 1H), 7.74 (d, J=8.02 Hz, 2 H), 6.85 (d, J=8.02 Hz, 2 H), 5.30-5.31 (m, 1H), 4.47 (br. s., 1H), 3.25 (d, J=7.3 Hz, 1H), 2.20-2.28 (m, 2H), 1.90-1.92 (m, 2H), 1.69-1.71 (m, 2H); .sup.13C NMR: (δ ppm, 100 MHz) DMSO-D.sub.6: 190.0, 179.1, 175.2, 163.6, 130.0, 127.0, 116.2, 72.3, 60.2, 59.2, 35.06, 32.8
[0105] Compound (2) .sup.1H NMR: (6 ppm, 400MHz) DMSO-D.sub.6: 11.54 (s, 1 H), 10.65 (s, 1 H), 7.74 (d, J=8.02 Hz, 2 H), 6.88 (d, J=8.02 Hz, 2 H), 5.30-5.26 (m, 1 H), 4.38-4.39 (m, 1 H), 3.11 (br. s, 1 H), 2.22 - 2.17 (m, 2 H), 1.83-1.78 (m, 1 H), 1.62-1.56 (m, 1 H); .sup.13C NMR: (δ ppm, 100MHz) DMSO D.sub.6: 190.4, 179.3, 176.9, 163.7, 130.0, 126.8, 116.2, 74.5, 63.9, 58.1, 33.8, 32.4.
Example 7
Synthesis of S-((3aS,6S,6aR)-6-hydroxy-1,3-dioxohexahydrocyclopenta[c]pyrrol-3a(1H)-yl) 4-hydroxybenzothioate ((+)1) and S-((3aR,6S,6aS)-6-hydroxy-1,3-dioxohexahydrocyclopenta[c]pyrrol-3a(1H)-yl) 4-hydroxybenzothioate ((−)2)
[0106] Nitrosporeusine A (+)1[α].sub.D.sup.27+49.3 (c 0.51, MeOH);.sup.1H NMR (500 MHz, CD.sub.3OD): 7.81 (d, J=8.9 Hz, 2H), 6.87 (d, J=8.9 Hz, 2H), 4.65-4.63 (m, 1H), 3.40 (d, J=7.6 Hz, 1H), 2.42-2.40 (m, 1H), 2.12-2.05 (m, 2H), 1.87-1.85 (m, 1H); .sup.13C NMR (125 MHz, CD.sub.3OD): δ191.0, 181.5, 177.3, 164.9, 130.9, 128.8, 116.7, 73.9, 61.3, 60.4, 35.2, 33.7.
[0107] Nitrosporeusine B(−)2 [α].sub.D .sup.27−121.8 (c 0.61, MeOH);.sup.1H NMR (500 MHz, CD.sub.3OD): δ7.81 (d, J=8.9 Hz, 2H), 6.86 (d, J=8.9 Hz, 2H), 4.57-4.55 (m, 1H), 3.27 (brs, 1H), 2.38-2.30 (m, 2H), 1.95-1.94 (m, 1H), 1.77-1.74 (m, 1H); .sup.13C NMR (125 MHz, CD.sub.3OD): δ192.4, 181.6, 178.5, 164.9, 130.9, 128.8, 116.7, 76.4, 65.5, 59.6, 34.7, 33.4.
Example 8
Synthesis of S-((3aR,6R,6aS)-6-hydroxy-1,3-dioxohexahydrocyclopenta[c]pyrrol-3a(1H)-yl) 4-hydroxybenzothioate ((−)1) and S-((3aS,6R,6aR)-6-hydroxy-1,3-dioxohexahydrocyclopenta[c]pyrrol-3a(1H)-yl) 4-hydroxybenzothioate ((+)2)
[0108] Nitrosporeusine A (−)1:[α].sub.D.sup.27−56.5 (c 0.25 in MeOH);.sup.1H NMR (500 MHz, CD.sub.3OD): δ7.81 (d, J =8.9 Hz, 2H), 6.87 (d, J=8.9 Hz, 2H), 4.65-4.63 (m, 1H), 3.40 (d, J=7.6 Hz, 1H), 2.42-2.40 (m, 1H), 2.12-2.05 (m, 2H), 1.87-1.85 (m, 1H); .sup.13C NMR (125 MHz, CD.sub.3OD): δ191.0, 181.5, 177.3, 164.9, 130.9, 128.8, 116.7, 73.9, 61.3, 60.4, 35.2, 33.7.
[0109] Nitrosporeusine B(+)2: [α].sub.D.sup.27+125.2 (c 0.31 in MeOH);.sup.1H NMR (500 MHz, CD.sub.3OD): δ7.81 (d, J=8.9 Hz, 2H), 6.86 (d, J=8.9 Hz, 2H), 4.57-4.55 (m, 1H), 3.27 (br s, 1H), 2.38-2.30 (m, 2H), 1.95-1.94 (m, 1H), 1.77-1.74 (m, 1H); .sup.13C NMR (125 MHz, CD.sub.3OD): δ192.4, 181.6, 178.5, 164.9, 130.9, 128.8, 116.7, 76.4, 65.5, 59.6, 34.7, 33.4.
Example 9
Synthesis of S-((3aR*,6R*,6aS*)-6-Hydroxy-1,3-dioxohexahydrocyclopenta[c] pyrrol-3a(1H)-yl) ethanethioate (7)
[0110] ##STR00011##
[0111] 20 mg obtained as white solid. IR (neat) v.sub.max 3809, 1708, 1692, 1515 cm.sup.−1;.sup.1H NMR (400 MHz, CD.sub.3OD): 8 4.60-4.56 (m, 1H), 3.34-3.30 (d, 1H), 2.33 (s, 3H), 2.31-2.28 (m, 1H) 2.02-1.89 (m, 1H), 1.88-1.81 (m, 1H), 1.79-1.77 (m, 1H);.sup.13C NMR (100 MHz, CD.sub.3OD): 8198.0, 181.0, 177.1, 73.9, 61.0, 60.7, 35.2, 33.4, 29.8; HRMS (ESI):m/z calculated for C.sub.9H.sub.11NO.sub.4S[M+Na].sup.+252.0301, found 252.0299.
Example 10
Synthesis of S-((3aS*,6R*,6aR*)-6-Hydroxy-1,3-dioxohexahydrocyclopenta[c] pyrrol-3a(1H)-yl) ethanethioate (8)
[0112] ##STR00012##
[0113] 57 mg obtained as white solid. mp 120-129° C.; IR (neat) v.sub.max 3809, 1708, 1692, 1515 cm.sup.−1;.sup.1H NMR (400 MHz, CD.sub.3OD): δ4.53-4.51 (m, 1H), 3.17-3.15 (d, 1H), 2.31 (s, 3H), 2.23-2.19 (m, 2H), 1.89-1.88 (m, 1H), 1.70-1.65 (m, 1H); .sup.13C NMR (100 MHz, CD.sub.3OD): δ196.9, 179.6, 176.7, 74.8, 63.6, 58.3, 32.9, 31.7, 28.0; HRMS (ESI):m/z calculated for C.sub.9H.sub.11NO.sub.4S[M+Na].sup.+252.0301, found 252.0299.
Example 11
Synthesis of S-((3aR*,6R*,6aS*)-6-Hydroxy-1,3-dioxohexahydrocyclopenta[c] pyrrol-3a(1H)-yl) 2-phenylethanethioate (9)
[0114] ##STR00013##
[0115] 25 mg obtained as yellow solid..sup.1H NMR (400 MHz, CD.sub.3OD): δ7.36 -7.28 (m, 5H), 4.55-4.53 (m, 1H), 3.84 (s, 2H), 3.25-3.23 (d, J=7.6 Hz, 1H), 2.31-2.27 (m, 1H), 1.99-1.87 (m, 1H), 1.85-1.75 (m, 2H); .sup.13C NMR (125 MHz, CD.sub.3OD): δ199.9, 181.0, 177.1, 134.5, 131.0, 129.9, 128.8, 73.9, 61.0, 50.3, 49.7, 35.2, 33.5; HRMS (ESI):m/z calculated for C.sub.15H.sub.15NO.sub.4S[M+Na].sup.+328.0614, found 328.0601.
Example 12
Synthesis of S-((3aS*,6R*,6aR*)-6-Hydroxy-1,3-dioxohexahydrocyclopenta[c] pyrrol-3a(1H)-yl) 2-phenylethanethioate (10)
[0116] ##STR00014##
[0117] 35 mg obtained as white solid. .sup.1H NMR (500 MHz, CD.sub.3OD): δ7.35-7.30 (m, 5H), 4.52-4.51 (m, 1H), 3.86 (s, 2H), 3.13 (s, 1H), 2.21-2.18 (m, 2H), 1.91-1.87 (m, 1H), 1.69-1.66 (m, 1H); .sup.13C NMR (125 MHz, CD.sub.3OD): δ198.9, 179.6, 176.7, 133.0, 129.5, 128.3, 127.2, 74.8, 63.6, 58.4, 48.6, 33.0, 31.7; □HRMS (ESI): m/z calculated for C.sub.15H.sub.15NO.sub.4S[M+Na].sup.+328.0614, found 328.0601.
Example 13
Synthesis of S-((3aS*,6R*,6aR*)-6-Hydroxy-1,3-dioxohexahydrocyclopenta[c] pyrrol-3a(1H)-yl) 4-fluorobenzothioate (11)
[0118] ##STR00015##
[0119] 50 mg obtained as brown solid,mp 184-186° C.;IR (neat) v.sub.max 3314, 2934, 1798, 1024 cm.sup.−1;.sup.1H NMR (400 MHz, CD.sub.3OD): δ8.02-7.98 (m, 2H), 7.29-7.24 (m, 2H), 4.59-4.58 (m, 1H), 3.34-3.28 (m, 1H), 2.40-2.33 (m, 2H), 1.98-1.95 (m, 1H), 1.84-1.69 (m, 1H); .sup.13C NMR (100 MHz, CD.sub.3OD): δ91.1, 179.5, 176.7, 167.6, 132.2, 132.2, 129.8, 129.7, 115.8, 115.6, 74.8, 63.7, 58.3, 33.2, 31.8;HRMS (ESI):m/z calculated for C.sub.14H.sub.12NO.sub.4SF[M+Na].sup.+332.0363 found 332.0361.
Example 14
Synthesis of S-((3aS*,6R*,6aR*)-6-Hydroxy-1,3-dioxohexahydrocyclopenta[c] pyrrol-3a(1H)-yl) thiophene-2-carbothioate (12)
[0120] ##STR00016##
[0121] 70 mg obtained as white solid. IR (neat) v.sub.max 3808, 1741, 1706, 1693, 1515 cm.sup.−1;.sup.1H NMR (400 MHz, CD.sub.3OD): δ7.91-7.87 (m, 2H), 7.23-7.20 (dd, J=4.8, 4.0 Hz, 1H), 4.58-4.57 (m, 1H), 3.31-3.30(d, 1H), 2.36-2.30 (m, 2H), 1.95-1.94 (m, 1H), 1.76-1.73 (m, 1H); .sup.13C NMR (100 MHz, CD.sub.3OD): δ182.8, 177.9, 175.1, 138.5, 132.7, 130.7, 126.7, 73.4, 62.3, 56.9, 31.7, 30.3; HRMS (ESI):m/z calculated for C.sub.12H.sub.11NO.sub.4S.sub.2 [M+Na].sup.+320.0002, found 320.0008.
Example 15
Synthesis of S-((3aS*,6S*,6aR*)-6-Hydroxy-1,3-dioxohexahydrocyclopenta[c] pyrrol-3a(1H)-yl) 2-chlorobenzothioate (13)
[0122] ##STR00017##
[0123] 26 mg obtained as white solid, mp 173-174° C.;IR (neat) v.sub.max 3743, 2925, 2320, 1707, 1515 cm.sup.−1; .sup.1H NMR (400 MHz, CD.sub.3OD): δ7.72-7.69 (m, 1H), 7.55-7.53 (m, 2H), 7.45-7.43 (m, 1H), 4.67-4.63 (m, 1H), 3.47-3.45 (d, J=7.6 Hz, 1H), 2.43-2.39 (m, 1H), 2.08-1.99 (m, 2H), 1.86-1.83 (m, 1H); .sup.13C NMR (100 MHz, CD.sub.3OD): δ196.0, 183.0, 179.3, 139.7, 136.9, 134.6, 134.3, 133.0, 130.9, 76.3, 64.0, 63.3, 37.7, 35.9; HRMS (ESI):m/z calculated for C.sub.14H.sub.12NO.sub.4ClS[M+Na].sup.+348.0068, found 348.0061.
Example 16
Synthesis of S-((3aS*,6R*,6aR*)-6-Hydroxy-1,3-dioxohexahydrocyclopenta[c] pyrrol-3a(1H)-yl) 2-chlorobenzothioate (14)
[0124] ##STR00018##
[0125] 82 mg obtained as white solid.mp 154-158° C.; IR (neat) v.sub.max 3743, 2925, 2320, 1707, 1515 cm.sup.−1;.sup.1H NMR (200 MHz, CD.sub.3OD): δ7.78-7.76 (m, 1H), 7.58-7.50 (m, 3H), 4.63-4.60 (td, J=3.7, 1.2 Hz, 1H), 2.39-2.31 (m, 2H), 1.97-1.95 (m, 1H), 1.82-1.80 (m, 1H); .sup.13C NMR (100 MHz, CDCl.sub.3): δ192.6, 178.3, 176.1, 135.0, 133.2, 131.3, 131.1, 129.9, 126.9, 75.4, 63.7, 59.2, 33.2, 32.5; HRMS (ESI):m/z calculated for C.sub.14H.sub.12NO.sub.4ClS[M+Na].sup.+348.0068, found 348.0061.
Example 17
Synthesis of S-((3aR*,6R*,6aS*)-6-Hydroxy-1,3-dioxohexahydrocyclopenta[c] pyrrol-3a(1H)-yl) benzothioate (15)
[0126] ##STR00019##
[0127] 26 mg as white solid.mp 185-186 ° C.; IR (neat) v.sub.max 3743, 2927, 2320, 1741, 1706, 1531 cm.sup.−1; .sup.1H NMR (400 MHz, CD.sub.3OD): δ7.91-7.89 (dd, J=8.4, 1.1 Hz, 2H), 7.66-7.64 (m, 1H), 7.53-7.49 (m, 2H), 4.62-4.59 (m, 1H), 3.42 (d, J=7.6 Hz, 1H), 2.42-2.39 (dd, J=13.2, 7.1 Hz, 1H), 2.08-2.02 (m, 2H), 1.84-1.82 (m, 1H); .sup.13C NMR (100 MHz, CD.sub.3OD): δ193.6, 181.1, 177.2, 137.4, 135.6, 130.3, 128.4, 73.9, 61.1, 60.6, 35.3, 33.7; HRMS (ESI):m/z calculated for C.sub.14H.sub.13NO.sub.4S[M+Na].sup.+314.0457, found 314.0456.
Example 18
Synthesis of S-((3a5*,6R*,6aR*)-6-Hydroxy-1,3-dioxohexahydrocyclopenta[c] pyrrol-3a(1H)-yl) benzothioate (16)
[0128] ##STR00020##
[0129] 36 mg as white solid.mp 180-182° C.; IR (neat) v.sub.max 3743, 2927, 2320, 1741, 1706, 1531 cm.sup.−1;.sup.1H NMR (400 MHz, CD.sub.3OD): δ7.94-7.91 (m, 2H), 7.69-7.66 (m, 1H), 7.54-7.51 (m, 2H), 4.59-4.58 (m, 1H), 3.34-3.42 (m, 1H), 2.40-2.33 (m, 2H), 1.96-1.95 (m, 1H), 1.78-1.77 (m, 1H); .sup.13C NMR (100 MHz, CD.sub.3OD): δ191.1, 178.1, 175.27, 134.21, 132.54, 127.23, 125.36, 73.36, 62.28, 56.75, 31.75, 30.32; HRMS (ESI):m/z calculated for C.sub.14H.sub.13NO.sub.4S[M+Na].sup.+314.0457, found 314.0456.
Example 19
Synthesis of S-((3aS*,6R*,6aR*)-6-Hydroxy-1,3-dioxohexahydrocyclopenta[c] pyrrol-3a(1H)-yl) 2-hydroxybenzothioate (17)
[0130] ##STR00021##
[0131] 23 mg obtained as white solid, mp 213-216° C.; IR (neat) v.sub.max 2935, 2827, 1823, 1448, 1023 cm.sup.−1;.sup.1H NMR (400 MHz, CD.sub.3OD): δ7.85-7.84 (m, 1H), 7.55-7.51 (m, 1H), 6.98-6.95 (m, 2H), 4.59 (m, 1H), 3.34-3.32 (d, 1H), 2.41-2.33 (m, 2H), 2.00-1.96 (m, 1H), 1.78-1.75(m,1H);
[0132] .sup.13C NMR (100 MHz,CD.sub.3OD): δ196.0, 179.6, 176.6, 158.9, 136.1, 128.8, 119.7, 119.3, 117.6, 75.0, 63.7, 58.26, 33.1, 31.7; HRMS (ESI):m/z calculated for C.sub.14H.sub.13NO.sub.5S[M+Na].sup.+330.0407, found 330.0405.
Example 20
Synthesis of S-((3aR*,6aS*)-1,3-Dioxohexahydrocyclopenta[c]pyrrol-3a(1H)-yl) ethanethioate (18)
[0133] ##STR00022##
[0134] 71 mg obtained as white solid, mp 120-122° C.; .sup.1H NMR (400 MHz, CDCl.sub.3): δ8.96 (br s, 1H), 3.27-3.24 (d, J=8.8 Hz, 1H), 2.34 (s, 3H), 2.32-2.24 (m, 2H), 1.83-1.54 (m, 4H); .sup.13C NMR (100 MHz, CDCl.sub.3): δ196.3, 178.2, 178.2, 59.5, 54.7, 36.2, 29.7, 29.6, 24.3;HRMS (ESI):m/z calculated for C.sub.9H.sub.11NO.sub.3S[M+Na].sup.+236.0348, found 236.0352.
Example 21
Synthesis of S-43aR*,6aS*)-1,3-Dioxohexahydrocyclopenta[c]pyrrol-3a(1H)-yl) 2-phenylethanethioate (19)
[0135] ##STR00023##
[0136] 80 mg obtained as sticky liquid. .sup.1H NMR (400 MHz, CDCl.sub.3): δ8.50 (br s, 1H), 7.96-7.89(m, 2 H), 7.18-7.09 (m, 2H), 3.39-3.35 (dd, J=8.8, 0.6 Hz, 1H), 2.42-2.27 (m, 2H), 2.09-1.95 (m, 4H), 1.91-1.56 (m, 2H); .sup.13C NMR (100 MHz, CDCl.sub.3): δ198.3, 178.1, 178.1, 132.4, 129.7, 128.9, 127.8, 59.6, 54.8, 49.5, 36.3, 29.8, 24.3; HRMS (ESI):m/z calculated for C.sub.15H.sub.15NO.sub.3S[M+Na].sup.+312.0665, found 312.0657.
Example 22
Synthesis of S-43aR*,6aS*)-1,3-Dioxohexahydrocyclopenta[c]pyrrol-3a(1H)-yl) 4-fluorobenzothioate (20)
[0137] ##STR00024##
[0138] 40 mg as white solid, mp 186-187° C.; IR (neat) v.sub.max 3744, 2922, 1770, 1647 cm.sup.−1; .sup.1H NMR (400 MHz, CDCl.sub.3): δ8.40 (br s, 1H) 7.96-7.89 (m, 2H), 7.18-7.08 (m, 2H), 3.39-3.35 (m, 1H), 2.48-2.28 (m, 2H), 2.09-1.91 (m, 2H), 1.64-1.59(m, 2H); .sup.13C NMR (100 MHz, CDCl.sub.3): δ190.6. 178.3, 178.2, 167.6, 165.1, 131.9, 130.1, 130.0, 116.1, 116.0, 59.5, 55.0, 36.5, 29.8, 29.8, 24.5; HRMS (ESI):m/z calculated for C.sub.14H.sub.12NO.sub.3FS[M+Na].sup.+316.0414, found 316.0408.
Example 23
Synthesis of S-43aR*,6aS*)-1,3-Dioxohexahydrocyclopenta[c]pyrrol-3a(1H)-yl) 2-chlorobenzothioate (21)
[0139] ##STR00025##
[0140] 31 mg obtained as white solid, mp 188-190° C.;IR (neat) v.sub.max 3229, 1707, 1675, 1547 cm.sup.−1; .sup.1H NMR (400 MHz, CDCl.sub.3): δ8.88 (br s, 1H), 7.72-7.70 (d, J=7.8 Hz, 1H), 7.44-7.43 (m, 2H), 7.35-7.33 (m, 1H), 3.44-3.42 (d, J=8.8 Hz, 1H), 2.41-2.38 (m, 1H), 2.31-2.30 (m, 1H), 1.95-1.93 (m, 1H), 1.92-1.90 (m, 2H), 1.63-1.61 (m, 1H); .sup.13C NMR (100 MHz, CDCl.sub.3): δ191.9, 178.1, 177.9, 135.3, 133.1, 131.4, 131.1, 129.7, 126.7, 60.3, 54.8, 36.4, 29.8, 24.5; HRMS (ESI):m/z calculated for C.sub.14H.sub.12NO.sub.3ClS[M+Na].sup.+332.0109, found 332.0119.
Example 24
Synthesis of S-(1,3-Dioxo-2,3,4,5-tetrahydrocyclopenta[c]pyrrol-3a(1H)-yl) 4-fluorobenzothioate (22)
[0141] ##STR00026##
[0142] 35 mg obtained as white solid, mp 191-192° C.; IR (neat) v.sub.max 3159, 2979, 1714, 1661, 1594, 1200 cm.sup.−1; .sup.1H NMR (200 MHz, CDCl.sub.3): δ7.97-7.89 (m, 3H), 7.17-7.09 (m, 2H), 6.92-6.89 (dd, J=4.0, 2.0 Hz, 1H), 3.23-3.14 (m, 1H), 2.87-2.85 (m, 1H), 2.59-2.56 (m, 2H); .sup.13C NMR (100 MHz, CDCl.sub.3): δ188.9. 173.1, 163.3, 140.5, 132.4, 130.2, 130.1, 116.1, 115.9, 63.6, 37.2, 36.0; HRMS (ESI):m/z calculated for C.sub.14H.sub.10NO.sub.3FS[M+Na].sup.+314.0258, found 314.0250.
Example 25
Synthesis of S,S′-((3aR*,6aR*)-1,3-Dioxohexahydrocyclopenta[c]pyrrole-3a,6(1H)-diyl) bis(4-fluorobenzothioate) (23)
[0143] ##STR00027##
[0144] 35 mg obtained as sticky liquid. .sup.1H NMR (200 MHz, CDCl.sub.3): δ8.35 (br s, 1H), 7.98-7.92 (m, 4H), 7.19-7.09 (m, 4H), 4.62-4.60 (m, 1H), 3.53-3.52 (t, J=1.4 Hz, 1H), 2.50-2.29 (m, 1H), 2.29-2.01 (m, 4H); .sup.13C NMR (100 MHz, CDCl.sub.3): δ190.5, 188.4, 177.2, 174.8, 167.8, 167.4, 165.2, 164.9, 132.7, 131.7, 131.6, 130.3, 130.2, 130.0, 129.9, 116.2, 116.1, 115.8, 60.7, 58.7, 46.7, 34.6, 31.5, 29.7;HRMS (ESI):m/z calculated for C.sub.21H.sub.15NO.sub.4F.sub.2S.sub.2[M+Na].sup.+470.0285, found 470.0293.
Example 26
Synthesis of S-(1,3-Dioxo-1,2,3,4,5,6-hexahydrocyclopenta[c]pyrrol-4-yl) benzothioate (24)
[0145] ##STR00028##
[0146] 30 mg obtained as white solid, mp 149-151° C.; IR (neat) v.sub.max 3806, 2922, 1707, 1676, 1532 cm.sup.−1;.sup.1H NMR (200 MHz, CDCl.sub.3): δ7.94 (dd, J=8.4, 1.3 Hz, 2H), 7.64-7.43 (m, 3H), 7.23 (br s, 1H), 5.09-5.02 (m, 1H), 3.28-3.21 (m, 1H), 2.8-2.80 (m, 2H), 2.61-2.50 (m, 1H); .sup.13C NMR (100 MHz, CDCl.sub.3): δ190.2, 165.5, 164.7, 156.5, 151.4, 136.2, 133.9, 128.8, 127.4, 41.5, 38.3, 25.7;HRMS (ESI):m/z calculated for C.sub.14H.sub.11NO.sub.3S[M+Na].sup.+296.0352, found 296.0345.
Example 27
Synthesis of S,S′-((3aS*,6aS*)-1,3-Dioxohexahydrocyclopenta[c]pyrrole-3a,6(1H)-diyl) dibenzothioate (25)
[0147] ##STR00029##
[0148] 35 mg obtained as sticky liquid. .sup.1H NMR (200 MHz, CDCl.sub.3): δ8.45 (br s, 1H), 7.98-7.87 (m, 4H), 7.50-7.47 (m, 2H), 7.46-7.41 (dd, J=7.5, 1.7 Hz, 4H), 4.63-4.61 (m, 1H), 3.53 (s, 1H), 2.51-2.14 (m, 4H);.sup.13C NMR (100 MHz, CDCl.sub.3): δ192.1, 190.0, 177.4, 174.9, 136.4, 135.3, 134.4, 133.8, 128.9, 128.7, 127.6, 127.5, 60.7, 58.6, 46.6, 34.6, 31.6.
Example 28
Synthesis of S-(1,3-Dioxo-2,3,4,5-tetrahydrocyclopenta[c]pyrrol-3a(1H)-yl)pethanethioate (26)
[0149] ##STR00030##
[0150] 40 mg obtained as white solid, mp 170-172° C.; IR (neat) v.sub.max 3744, 2924, 2854, 1707, 1515, 1462 cm.sup.−1; .sup.1H NMR (400 MHz, CDCl.sub.3): δ8.18 (br s, 1H), 6.85 (dd, J=4.2, 2.0 Hz, 1H), 3.16-3.13 (m, 1H), 2.80-2.75 (m, 1H), 2.48-2.37 (m, 2H), 2.32 (s, 3H); .sup.13C NMR (100 MHz, CDCl.sub.3): δ194.5, 173.1, 163.1, 140.4, 140.3, 63.8, 36.8, 35.9, 30.4; HRMS (ESI):m/z calculated for C.sub.9H.sub.9NO.sub.3S[M+Na].sup.+234.0195, found 234.0194.
Example 29
Synthesis of S-(1,3-Dioxo-2,3,4,5-tetrahydrocyclopenta[c]pyrrol-3a(1H)-yl) 2-phenylethanethioate (27)
[0151] ##STR00031##
[0152] 30 mg obtained as white solid, mp 155-158° C.; IR (neat) v.sub.max 3200, 2923, 1764, 1693, 1267 cm.sup.−1; .sup.1H NMR (200 MHz, CDCl.sub.3): δ7.86 (br s, 1H),7.36-7.24 (m, H), 6.84-6.82 (m, 1H), 3.81 (s, 2H), 3.14-3.00 (m, 1H), 2.82-2.67 (m, 1H), 2.47-2.36 (m, 2H); .sup.13C NMR (125 MHz, CDCl.sub.3): M96.1, 173.2, 163.4, 140.5, 140.4, 132.3, 129.8, 128.8, 127.8, 63.8, 50.2, 36.8, 35.9; HRMS (ESI): m/z calculated for C.sub.15H.sub.13NO.sub.3S[M+Na].sup.+310.0508, found 310.0501.
Example 30
Synthesis of S,S′-((3aR*,6aR*)-1,3-Dioxohexahydrocyclopenta[c]pyrrole-3a,6(1H)-diyl) diethanethioate (28)
[0153] ##STR00032##
[0154] 30mg of compound as sticky solid..sup.1H NMR (200 MHz, CDCl.sub.3): 68.8 (br s, 1H), 4.37-4.35 (m, 1H), 3.27 (s, 1H), 2.34 (s, 3H), 2.32 (s, 1H), 2.10 (m, 4H); .sup.13CNMR (100 MHz, CDCl.sub.3):
[0155] δ196.3, 193.3, 177.22, 174.7, 60.2, 58.7, 46.3, 34.1, 31.6, 30.7, 29.6 HRMS (ESI):m/z calculated for C.sub.11H.sub.13NO.sub.4S.sub.2[M+Na].sup.+310.0178, found 310.0171.
Example 31
Synthesis of S-(1,3-Dioxo-1,2,3,4,5,6-hexahydrocyclopenta[c]pyrrol-4-yl) thiophene-2-carbothioate (29)
[0156] ##STR00033##
[0157] 38 mg obtained as white solid, mp 138-139° C.; IR (neat) v.sub.max 2921, 2853, 1709, 1647, 1461 cm.sup.−1;.sup.1H NMR (200 MHz, CDCl.sub.3): δ7.79 (d, J=3.9 Hz, 1H), 7.69-7.65 (m, 1H), 7.16-7.11 (m, 2H), 5.03-4.96 (m, 1H), 3.30-3.16 (m, 1H), 2.85-2.79 (m, 2H), 2.76-2.51 (m, 1H); .sup.13C NMR (100 MHz, CDCl.sub.3): 6182.1, 165.5, 164.8, 156.6, 151.1, 141.0, 133.5, 131.8, 128.1, 41.7, 38.3, 25.8; HRMS (ESI):m/z calculated for C.sub.12H.sub.9NO.sub.3S.sub.2[M+Na].sup.+301.9916, found 301.9910.
Example 32
Synthesis of 1(3aS*,6aR*)-1,3-Dioxo-6a-((thiophene-2-carbonyl)thio) octahydrocyclopenta[c]pyrrol-4-yl acetate (30)
[0158] ##STR00034##
[0159] 49 mg obtained as solid. mp 140-141° C.; IR (neat) v.sub.max 3830, 2922, 2853, 1737, 1707, 1646, 1514, 1210 cm.sup.−1;.sup.1H NMR (400 MHz, CDCl.sub.3): δ8.78 (br s, 1H), 7.80-7.69 (d, J=3.9 Hz, 1H), 7.70-7.69 (d, J=4.9 Hz, 1H), 7.15-7.12 (m, 1H), 5.53-5.52 (d, J=3.9 Hz, 1H), 3.56-3.49 (m, 1H), 2.49-2.43 (m, 1H), 2.26-2.24 (m, 1H), 2.11-2.10 (m, 4H), 2.07-2.06 (m, 1H); .sup.13C NMR (100 MHz, CDCl.sub.3): M83.8, 177.3, 173.6, 169.8, 140.0, 134.4, 134.3, 132.5, 128.3, 61.0, 58.5, 55.6, 33.6, 30.4, 30.1, 29.7, 21.1;HRMS (ESI):m/z calculated for C.sub.14H.sub.13NO.sub.5S2[M+Na].sup.+340.0302, found 340.0308.
Example 33
Synthesis of (3aS*,6aR*)-6a-(Acetylthio)-1,3-dioxooctahydrocyclopenta[c]pyrrol-4-yl acetate (31)
[0160] ##STR00035##
[0161] 60 mg obtained as white solid. .sup.1H NMR (200 MHz, CDCl.sub.3): 68.45 (br s, 1 H), 5.53 -5.35 (m, 1H), 3.67-3.43 (m, 1H), 2.39-2.37 (m, 4H), 2.35-2.09 (m, 4H), 1.93-1.82 (m, 2H); .sup.13C NMR (100 MHz, CDCl.sub.3): δ196.6, 196.0, 177.8, 177.7, 174.0, 172.8, 170.5, 169.9, 73.6, 60.7, 58.7, 58.3, 55.1, 33.3, 31.4, 30.3, 29.9, 29.7, 29.6, 29.5, 21.0, 20.8; □HRMS (ESI):m/z calculated for C.sub.11H.sub.13NO.sub.5S[M+Na].sup.+294.0407, found 294.0402.
Example 34
Synthesis of (3aS*,6aR*)-1,3-Dioxo-6a-((2-phenylacetyl)thio) octahydrocyclopenta[c]pyrrol-4-yl acetate (32)
[0162] ##STR00036##
[0163] 45 mg obtained as white solid. .sup.1H NMR (400 MHz, CDCl.sub.3): 68.61-8.53 (br s, 1H), 7.31-7.17 (m, 5H), 5.39-5.23 (m, 1H), 3.72 (s, 2H), 3.51-3.27 (m, 1H), 2.28-2.25 (m, 1H), 2.15 (s, 3H), 2.01-1.94 (m,1H), 1.70-1.68 (m, 2H); .sup.13C NMR (100 MHz, CDCl.sub.3): δ198.4, 197.9, 177.6, 173.7, 172.6, 170.5, 169.8, 132.2, 132.0, 129.8, 129.7, 128.8, 127.8, 73.6, 60.7, 58.7, 58.3, 55.1, 49.5, 49.3, 33.4, 31.5, 30.3, 29.8, 29.7, 21.0, 20.8 HRMS (ESI):m/z calculated for C.sub.17H.sub.17NO.sub.5S[M+Na].sup.+370.0720, found 370.0717.
Example 35
Synthesis of (3aS*,6aR*)-6a-(4-Fluorobenzoyl)thio)-1,3-dioxooctahydrocyclopenta[c]pyrrol-4-yl acetate (33)
[0164] ##STR00037##
[0165] 45 mg obtained as white solid. mp 118-119° C.; IR (neat) v.sub.max 3743, 3057, 2925, 1707, 1649, 1513 cm.sup.−1;.sup.1H NMR (400 MHz, CDCl.sub.3): 68.58-8.40 (br s, 1H), 8.00-7.93 (m, 2H), 7.23-7.14 (m, 2H), 5.58-5.43 (m, 1H), 3.79-3.55 (m, 1H), 2.51-2.32 (m, 2H), 2.20-2.11 (m, 4H), 1.96-1.87 (m, 1H); .sup.13C NMR (100 MHz, CDCl.sub.3): δ190.0, 177.7, 177.6, 174.0, 169.9, 169.4, 165.4, 131.7, 130.2, 130.1, 116.2, 116.0, 73. 6, 60.9,58.6, 58.3, 55.3, 33.6, 31.8, 30.4, 29.9, 29.6, 21.0, 20.8 HRMS (ESI):m/z calculated for C.sub.16H.sub.14NO.sub.5SF[M+Na].sup.+374.0456, found 374.0469.
Example 36
Synthesis of (3aS*,6aR*)-6a-(2-Chlorobenzoyl)thio)-1,3-dioxooctahydrocyclopenta[c]pyrrol-4-yl acetate (34)
[0166] ##STR00038##
[0167] 35 mg obtained as white solid,mp 90-91° C.;IR (neat) v.sub.max 3744, 1771, 1707, 1547, 1626 cm.sup.−1;.sup.1H NMR (400 MHz, CDCl.sub.3): 68.77 (br s, 1H), 7.74-7.73 (d, J=7.6 Hz, 1H), 7.47-7.37 (m, 2H), 7.36-7.33 (m, 1H), 5.55-5.54 (m, 1H), 3.57-3.56 (m, 1H), 2.46-2.43 (m, 1H), 2.26-2.25 (dt, J =13.3, 7.0 Hz, 1H), 2.16-2.13 (dd, J=6.6, 4.7 Hz, 1H), 2.11 (s, 3H), 2.09-1.91 (m, 1H); .sup.13C NMR (100 MHz, CDCl.sub.3): δ191.9, 177.2, 173.6, 169.9, 134.9, 133.3, 131.6, 131.3, 129.9, 126.9, 73.6, 60.8, 59.0, 55.2, 33.4, 31.7, 30.4, 30.0, 21.0, 20.9; HRMS (ESI):m/z calculated for C.sub.16K.sub.4NO.sub.5ClS[M+Na].sup.+390.0173, found 390.0158.
Example 37
Synthesis of (3aS*,6aR*)-6a-(Benzoylthio)-1,3-dioxooctahydrocyclopenta [c]pyrrol-4-yl acetate (35)
[0168] ##STR00039##
[0169] 25 mg obtained as white solid. IR (neat) vmax 3743, 2922, 1737, 1707, 1675, 1546, 1208 cm.sup.−1;.sup.1H NMR (400 MHz, CDCl.sub.3): 69.05 (br s, 1H), 7.92-7.86 (m, 2H), 7.64-7.60 (m, 1H), 7.49-7.45 (m, 2H), 5.55-5.44 (m, 1H), 3.76-3.54(s, 1H), 2.49-2.47 (m, 1H), 2.29-2.14 (dt, J=13.4, 6.9 Hz, 1H), 2.10 (s, 3H), 2.11-2.06 (s, 1H), 1.96-1.93 (m, 2H);.sup.13C NMR (100 MHz, CDCl.sub.3): δ192.2, 177.7, 174.0, 169.9, 135.3, 134.4, 128.9, 127.5, 73.7, 61.0, 58.2, 55.4, 33.6, 31.8, 30.4, 30.1, 29.7, 21.1, 20.8; HRMS (ESI):m/z calculated for C.sub.16H.sub.15NO.sub.5S[M+Na].sup.+356.0553 found 356.0563.
Example 38
Biological Testing Results
[0170] All the synthesized analogues were subjected for biological screening against inhibition of LPS induced NO generation. The cytotoxicity effects of the synthesized analogues were also analysed and all the results were summarized in table 1 below. Compound NDS100652, NDS100653, NDS100656 showed promising inhibitory activity, selectivity index and further studies on these compounds are underway.
TABLE-US-00001 TABLE 1 Cytotoxicity and inhibition of compounds on LPS induced NO generation in RAW 264.7 cells Cytotoxicity (A) NO inhibition (B) Selectivity Compound IC.sub.50 (μM) IC50 (μM) index (A/B) -(−)-4 319.2 121.3 2.631492168 (−)-5 128 866.9 0.147653 (±)-2 433.8 225.3 1.925433 11 473.7 318 1.489623 16 17063 65.2 261.7025 14 717.1 178.3 4.021873 12 10872.1 36.6 297.0519 33 12135.6 34.3 353.8076 27 93.07 30.6 3.041503 26 184.5 20.5 9 28 10007.6 19.8 505.4343 29 26.7 65 0.410769 (−)-2 1383.9 140.5 9.849822 5 616.1 42 14.66905 (+)-1 1015.6 71.8 14.14485 21 834.5 59.8 13.95485 23 210.6 98.3 2.142421 18 674.4 59.2 11.39189 20 383.6 389.8 0.984094 19 425.6 56.9 7.479789 10 773.7 142.8 5.418067 9 834.5 132 6.32197 8 856.7 832.8 1.028698 7 558.5 147.9 3.7762 15 479.4 72.4 6.621547 34 9076.1 101.4 89.50789 35 1912 64.3 29.73561 32 1607.3 68.2 23.56745 6 2914.9 126.8 22.98817 (+)-4 216.7 95.9 2.259645 13 667.7 127.3 5.24509
Example 39
Method for Biological Assays
[0171] Cell Culture
[0172] Mouse macrophage cell line RAW 264.7 was maintained in laboratory at 37° C. in
[0173] RPMI-1640 media supplemented with 10% heat-inactivated fetal bovine serum (FBS) and penicillin/streptomycin.
[0174] Cytotoxicity Assay
[0175] Viability of cultured cells was determined by (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT; Sigma) as described earlier (1). RAW 264.7 was seeded in triplicate at a density of 2×10.sup.4 cells per well on a 96-well plate. After 12 h, cells were treated with varying concentrations (0-100 μM) of all the compounds in a serum free condition for another 24 h. MTT solution (0.5 mg/ml) was then added to each well and incubate for 4 h at 37° C. At the end of the incubation period, the medium was removed and the resulting purple formazan was solubilized with acidic isopropanol (0.1 N HCl in absolute isopropanol), and the absorbance was read at 570 nm using Biorad Microplate reader (Biorad, USA).
[0176] Nitric Oxide (NO) Measurement
[0177] Nitrite, a stable oxidized product of NO, was measured in culture supernatant using Griess reagent (Sigma Aldrich) according to a previously reported method (2). After overnight seeding in 96-well plate (2×10.sup.4 cells/well), RAW 264.7 cell was treated with lipopolysachharide (LPS; Sigma) at a concentration of 1 μg/ml along with different doses of compounds (as determined from cytotoxicity assay) in serum-free culture for 24 h. Following treatment, media was collected and centrifuged at 2,000 rpm for 5 min to remove cellular debris. 50 μl of this media was then reacted with equal volume of Griess reagent for 15 min at room temperature in dark and absorbance was taken at 540 nm using Microplate reader (Biorad, USA). Nitrite concentrations were determined using standard solutions of sodium nitrite prepared in cell culture medium.
Advantages of Invention
[0178] a. Novel compounds which can be potential antivirals or anti-inflammatory agents. [0179] b. Invention provides a synthetic route for synthesis of nitrosporeusinesA (1) and B (2). [0180] c. Process is simple and industrially scalablein view of the limited number of steps. [0181] d. Process is cost-effective and eco-friendly. [0182] e. Raw materials are easily available.