accordingly , the present invention provides pyrrolo [ 2 , 1 - c ][ 1 , 4 ] benzodiazepine compounds of general formula v , one embodiment of the invention provides pyrrolobenzodiazepine having structural formula shown below where r = r 1 = h and n = 3 . one embodiment of the invention provides pyrrolobenzodiazepine having structural formula shown below , where r = r 1 = h and n = 4 . one more embodiment of the invention provides pyrrolobenzodiazepine having structural formula shown below , where r = r 1 = h and n = 5 . still another embodiment of the invention provides pyrrolobenzodiazepine having structural formula shown below where r = oh , r 1 = h and n = 3 . another embodiment of the invention provides pyrrolobenzodiazepine having structural formula shown below , where r = oh , r 1 = h and n = 4 . still another embodiment of the invention provides pyrrolobenzodiazepine having structural formula shown below , where r = oh , r 1 = h and n = 5 . in another embodiment , the invention provides a pyrrolobenzodiazepine compound having structural formula shown below , where r = h , r 1 = oh and n = 3 . in another embodiment , the invention provides a pyrrolobenzodiazepine compound having structural formula shown below , where r = h , r 1 = oh and n = 4 . in another embodiment , the invention provides a pyrrolobenzodiazepine compound having structural formula shown below , where r = h , r 1 = oh and n = 5 . another embodiment of the invention relates to the activity of the pyrrolo [ 2 , 1 - c ][ 1 , 4 ] benzodiazepine of formula v against human tumor cell lines . still another embodiment of the invention provides growth inhibition activity of these compounds against various types of cancer cells like leukemia , non - small - cell lung , colon , cns , melanoma , ovarian , prostate and breast cancer . one more embodiment of the invention relates to a process for the preparation of compounds , the said process comprising steps of : a ) reacting a compound of formula ( 1 ) with formula ( ii ) in presence of mild base in water miscible aprotic organic solvent at reflux temperature for a period of 16 h to 48 h , b ) pouring the reaction mixture of step ( a ) into water , extracting with ethyl acetate separating organic layer and discarding aqueous layer , c ) evaporating the organic layer of step ( b ) to obtain a residue which is purified to get compound of formula ( iii ), d ) reducing the nitro compound of formula ( iii ) in halogenated solvent , adding stannous chloride dihydrate , refluxing for a period of 0 . 5 h to 2 h , e ) adjusting the ph of the reaction mixture of step ( d ) to 8 . 0 using alkali bicarbonate solution , f ) extracting the step ( e ) solution with ethylacetate , evaporating the ethylacetate extract under reduced pressure to obtain crude compound of formula ( iv ), g ) providing a solution of compound of formula ( iv ) in a mixture of acetonitrile / h 2 o adding mercuric chloride , calcium carbonate , stirring at room temperature for 6 h to 12 h , h ) filtering and evaporating the organic layer under reduced pressure to obtain a residue which is diluted with ethyl acetate , i ) adding saturated solution of sodium bicarbonate to ethylacetate solution of step ( h ) at room temperature , j ) filtering the solution of step ( i ) through celite bed , evaporating the filtrate to obtain a residue containing crude compound of formula v , and k ) purifying crude compound of step ( j ) using silica gel as an adsorbent to obtain pure compound of formula ( v ) wherein r and r 1 are as defined earlier . still another embodiment , wherein the aprotic organic solvent used in step ( a ) is selected from a group consisting of tetrahydrofuran , acetone or dimethyl formamide . yet another embodiment , the mild base used in step ( a ) is selected from a group of sodium carbonate , potassium carbonate , lithium carbonate , barium carbonate and cesium carbonate . yet another embodiment , in step ( d ) the halogenated solvent used is selected from a group consisting of carbon tetra chloride , chloroform and dichloromethane , preferably dichloromethane . still another embodiment of the invention relates to the process , wherein in step ( c ) the alkali carbonate solution used is selected from a solution of sodium bicarbonate potassium bicarbonate or lithium bicarbonate . one more embodiment of the invention provide pharmaceutical composition effective against human cancer cell lines , said composition comprising effective amount of compound pyrrolo [ 2 , 1 - c ][ 1 , 4 ] benzodiazepine of general formula v , where r and r 1 is h and / or oh ; and n is 3 to 5 , along with pharmaceutically acceptable additives . the composition is administered to mammals including human beings . the composition is administered orally , systemically or by any other conventional methods . the pharmaceutically acceptable additives are selected from a group consisting of carriers , diluents , solvents , filler , lubricants , excipients , binders and stabilizers . another embodiment of the invention , the said composition inhibits the growth of cancer cells . still another embodiment , the said composition inhibits the growth of the cancer cells such as leukemia , non - small - cell lung , colon , cns , melanoma , ovarian , prostate and breast cancer . the present process provides a process for preparation of pyrrolo [ 2 , 1 - c ][ 1 , 4 ] benzodiazepines of formula v of the drawing accompanying the specification wherein r is h , oh , r 1 is h , oh and n is 3 to 5 which comprises : ( 2s )- n -[ 4 -( n - bromoalkoxy )- 5 - methoxy - 2 - nitrobenzoyl ] pyrrolidine - 2 - carboxaldehyde diethyl thioacetal wherein r 1 is h , oh and n is 3 - 5 compounds of formula i with secondary amine of formula ii wherein r is h and oh in presence of an inorganic mild bases like k 2 co 3 , csco 3 and baco 3 in presence of aprotic water miscible organic solvents like acetone , thf , and dmf upto refluxing temperature for a period upto 12 - 48 hours isolating ( 2s )- n -{ 4 -[ n -( 7 - methoxy -( 11as )- 1 , 2 , 3 , 10 , 11 , 11a - hexahydro - 5h - pyrrolo [ 2 , 1 - c ][ 1 , 4 ] benzodiazepine - 5 - one - 8 - yloxy ) alkyloxy ]- 5 - methoxy - 2 - nitrobenzoyl }- pyrrolidine - 2 - carboxaldehyde diethyl thioacetal and iii wherein r is h , oh , r 1 is h , oh and n is 3 to 5 by conventional methods , reducing the above nitro compounds of formula iii with sncl 2 . 2h 2 o in presence of organic solvent up to a reflux temperature , isolating the ( 2s )- n -{ 4 -[ n -( 7 - methoxy -( 1 as )- 1 , 2 , 3 , 10 , 11 , 11a - hexahydro - 5h - pyrrolo [ 2 , 1 - c ][ 1 , 4 ] benzodi - azepine - 5 - one - 8 - loxy ) alkoxy ]- 5 - methoxy - 2 - aminobenzoyl } pyrrolidine - 2 - carboxaldehyde diethyl thioacetal of formula iv wherein r is h , oh , r 1 is h , oh and n is 3 to 5 by known methods , reacting the above said amino compound of formula iv with known deprotecting agents in a conventional manner to give novel pyrrolo [ 2 , 1 - c ][ 1 , 4 ] benzodiazepines of formula v wherein r is h , oh , r 1 is h , oh and n is 3 to 5 . the precursors , ( 2s )- n -[ 4 -( n - bromoalkoxy )- 5 - methoxy - 2 - nitrobenzoyl ] pyrrolidine - 2 - carboxaldehyde diethyl thioacetal of formula i prepared by literature methods ( ref : kamal , a . ; laxman , n . ; ramesh , g . ; nileema , k . ; kondapi , a . k . chem . commun . 2001 , 437 ) and 8 - hydroxy 7 - methoxy -( 11as )- 1 , 2 , 3 , 10 , 11 , 11a - hexahydro - 5h - pyrrolo [ 2 , 1 - c ][ 1 , 4 ] benzodiazepine - 5 - one of formula ii prepared by literature method ( ref : kamal , a . ; howard , p . w . ; reddy , b . s . n . ; reddy , b . s . p . ; thurston , d . e . tetrahedron 1997 , 53 , 3223 - 3230 ). some representative compounds of formula v present invention are given below the process of preparation of new pyrrolo [ 2 , 1 - c ][ 1 , 4 ] benzodiazepines is disclosed and claimed in applicants co pending application ser . no . ______ these new analogues of pyrrolo [ 2 , 1 - c ][ 1 , 4 ] benzodiazepines linked at c - 8 position have shown promising anticancer activity in various cell lines . the molecules synthesized are of immense biological significance with potential sequence selective dna - binding property . this resulted in design and synthesis of new congeners as illustrated in scheme - 1 , which comprise : 1 . the ether linkage at c - 8 position of dc - 81 intermediates with secondary amine . 4 . purification by column chromatography using different solvents like ethylacetate , hexane and methanol . the following examples are given by way of illustrations and therefore should not be constructed to the present limit of the scope of invention . [ 0066 ] fig1 represents schematic diagram of preparing compound of general formula v . a solution of ( 2s )- n -[ 4 -( 3 - bromopropoxy )- 5 - methoxy - 2 - nitrobenzoyl ] pyrrolidine - 2 - carboxaldehyde diethyl thioacetal of formula i ( 521 mg , 1 mmol ), 8 - hydroxy - 7 - methoxy -( 11as )- 1 , 2 , 3 , 10 , 11 , 11a - hexahydro - 5h - pyrrolo [ 2 , 1 - c ][ 1 , 4 ] benzodiazepine - 5 - one ( 248 mg , 1 mmol ) of the formula ii and k 2 co 3 ( 414 mg , 3 mmol ) in dry acetone ( 20 ml ) was refluxed for 48 h . after the completion of reaction as indicated by tlc , etoac , the reaction mixture was poured on to the water and then extracted with ethylacetate . evaporation of the organic layer gave the crude product , which was further purified by column chromatography on silica gel eluting with etoac : hexane ( 8 : 2 ) gave the pure ( 2s )- n -{ 4 -[ 3 -( 7 - methoxy -( 11as )- 1 , 2 , 3 , 10 , 11 , 11a - hexahydro - 5h - pyrrolo [ 2 , 1 -][ 1 , 4 ] benzodiazepine - 5 - one - 8 - yloxy ) propoxy ]- 5 - methoxy - 2 - nitrobenzoyl } pyrrolidine - 2 - carboxaldehyde diethyl thioacetal iii . [ 0068 ] 1 h nmr ( cdcl 3 ) γ 1 . 35 - 1 . 45 ( m , 6h ), 1 . 70 - 2 . 45 ( m , 10h ), 2 . 72 - 2 . 90 ( m , 4h ), 3 . 20 - 3 . 28 ( m , 3h ), 3 . 50 - 3 . 58 ( m , 1h ), 3 . 62 - 3 . 75 ( m , 1h ) 3 . 80 - 3 . 90 ( m , 4h ), 4 . 20 ( t , 2h ), 4 . 35 ( t , 2h ), 4 . 65 - 4 . 75 ( m , 1h ), 4 . 85 ( d , 1h , j = 4 . 28 hz ), 6 . 25 ( s , 1h ), 6 . 82 ( s , 1h ) 7 . 48 ( s , 1h ), 7 . 72 ( s , 1h ); ms ( fab ) 689 [ m + h ] + . the ( 2s )- n -{ 4 -[ 3 -( 7 - methoxy -( 11as )- 1 , 2 , 3 , 10 , 11 , 11a - hexahydro - 5h - pyrrolo [ 2 , 1 - c ][ 1 , 4 ] benzodiazepine - 5 - one - 8 - yloxy ) propoxy ]- 5 - methoxy - 2 - nitrobenzoyl } pyrrolidine - 2 - carboxaldehyde diethyl thioacetal iii ( 688 mg , 1 . 0 mmol ) was dissolved in dichloromethane ( 5 ml ), methanol ( 10 ml ) and added sncl 2 . 2h 2 o ( 1 . 124 g , 5 . 0 mmol ) was refluxed for 1 . 5 h . the reaction mixture was then carefully adjusted to ph 8 with saturated nahco 3 solution and then extracted with ethyl acetate ( 3 × 20 ml ). the combined organic phase was dried over na 2 so 4 and evaporated under vacuum to afford the crude ( 2s )- n -{ 4 -[ 3 -( 7 - methoxy -( 11as )- 1 , 2 , 3 , 10 , 11 , 11a - hexahydro - 5h - pyrrolo [ 2 , 1 - c ][ 1 , 4 ] benzodiazepine - 5 - one - 8 - yloxy ) propoxy ]- 5 - methoxy - 2 - aminobenzoyl } pyrrolidine - 2 - carboxaldehyde diethyl thioacetal iv a solution of the ( 2s )- n -{ 4 -[ 3 -( 7 - methoxy -( 11as )- 1 , 2 , 3 , 10 , 11 , 11a - hexahydro - 5h - pyrrolo [ 2 , 1 - c ][ 1 , 4 ] benzodiazepine - 5 - one - 8 - yloxy ) propoxy ]- 5 - methoxy - 2 - aminobenzoyl } pyrrolidine - 2 - carboxaldehyde diethyl thioacetal iv ( 658 mg , 1 mmol ), hgcl 2 ( 794 mg , 2 . 93 mmol ) and caco 3 ( 300 mg , 3 mmol ) in ch 3 cn / h 2 o ( 4 : 1 , 15 ml ) was stirred at room temperature for 12 h until tlc ( etoac ), indicates complete loss of starting material . then organic layer is evaporated in vacuum and the residue is diluted with etoac . to this saturated nahco 3 was added slowly at room temperature and the mixture is filtered through celite and washed with ethylacetate . the filterate is evaporated in vacuum to get crude 7 - methoxy - 8 -{ 3 -[ 7 - methoxy -( 11as )- 1 , 2 , 3 , 10 , 11 , 11a - hexahydro - 5h - pyrrolo [ 2 , 1 - c ][ 1 , 4 ] benzodiazepine - 5 - one - 8 - yloxy ] propoxy }-( 11as )- 1 , 2 , 3 , 11a - tetrahydro - 5h - pyrrolo [ 2 , 1 - c ][ 1 , 4 ] benzodiazepine - 5 - one of formula v , which was further purified by column chromatography on silica gel eluting with methanol : etoac ( 2 : 8 ). [ 0071 ] 1 h nmr ( cdcl 3 ) γ 1 . 65 - 2 . 45 ( m , 10h ), 3 . 15 - 3 . 25 ( m , 2h ), 3 . 48 - 3 . 75 ( m , 4h ), 3 . 78 - 3 . 88 ( m , 4h ), 3 . 90 ( s , 3h ), 4 . 25 - 4 . 35 ( m , 5h ), 6 . 18 ( s , 1h ), 6 . 82 ( s , 1h ), 7 . 48 ( s , 1h ), 7 . 52 ( s , 1h ), 7 . 65 ( d , 1h , j = 4 . 8 hz ); ms ( fab ) 535 [ m + h ] + a solution of ( 2s )- n -[ 4 -( 4 - bromobutoxy )- 5 - methoxy - 2 - nitrobenzoyl ] pyrrolidine - 2 - carboxaldehyde diethyl thioacetal of formula i ( 535 mg , 1 mmol ), 8 - hydroxy - 7 - methoxy -( 11as )- 1 , 2 , 3 , 10 , 11 , 11a - hexahydro - 5h - pyrrol [ 2 , 1 - c ][ 1 , 4 ] benzodiazepine - 5 - one ( 248 mg , 1 mmol ) of the formula ii and k 2 co 3 ( 414 mg , 3 mmol ) in dry acetone ( 20 ml ) was refluxed for 48 h . after the completion of reaction as indicated by tlc , etoac , the reaction mixture was poured on to the water and then extracted with ethylacetate . evaporation of the organic layer gave the crude product , which was further purified by column chromatography on silica gel eluting with etoac : hexane ( 8 : 2 ) gave the pure ( 2s )- n -{ 4 -[ 4 -( 7 - methoxy -( 11as )- 1 , 2 , 3 , 10 , 11 , 11a - hexahydro - 5h - pyrrolo [ 2 , 1 - c ][ 1 , 4 ] benzodiazepine - 5 - one - 8 - yloxy ) butoxy ]- 5 - methoxy - 2 - nitrobenzoyl } pyrrolidine - 2 - carboxaldehyde diethyl thioacetal iii . [ 0073 ] 1 h nmr ( cdcl 3 ) γ 1 . 35 - 1 . 45 ( m , 6h ), 1 . 70 - 2 . 45 ( m , 12h ), 2 . 72 - 2 . 90 ( m , 4h ), 3 . 20 - 3 . 28 ( m , 3h ), 3 . 50 - 3 . 58 ( m , 1h ), 3 . 62 - 3 . 75 ( m , 1h ) 3 . 80 - 3 . 90 ( m , 4h ), 4 . 20 ( t , 2h ), 4 . 35 ( t , 2h ), 4 . 65 - 4 . 75 ( m , 1h ), 4 . 85 ( d , 1h , j = 4 . 28 hz ), 6 . 25 ( s , 1h ), 6 . 82 ( s , 1h ), 7 . 48 ( s , 1h ), 7 . 72 ( s , 1h ); ms ( fab ) 703 [ m + h ] + . the ( 2s )- n -{ 4 -[ 4 -( 7 - methoxy -( 11as )- 1 , 2 , 3 , 10 , 11 , 11a - hexahydro - 5h - pyrrolo [ 2 , 1 - c ][ 1 , 4 ] benzodiazepine - 5 - one - 8 - yloxy ) butoxy ]- 5 - methoxy - 2 - nitrobenzoyl } pyrrolidine - 2 - carboxaldehyde diethyl thioacetal ( 702 mg , 1 . 0 mmol ) of the formula iii was dissolved in dichloromethane ( 5 ml ), methanol ( 10 ml ) and added sncl 2 . 2h 2 o ( 1 . 124 g , 5 . 0 mmol ) was refluxed for 1 . 5 h . the reaction mixture was then carefully adjusted to ph 8 with saturated nahco 3 solution and then extracted with ethylacetate ( 3 × 20 ml ). the combined organic phase was dried over na 2 so 4 and evaporated under vacuum to afford the crude ( 2s )- n -{ 4 -[ 4 -( 7 - methoxy -( 11as )- 1 , 2 , 3 , 10 , 11 , 11a - hexahydro - 5h - pyrrolo [ 2 , 1 - c ] [ 1 , 4 ] benzodiazepine - 5 - one - 8 - yloxy ) butoxy ]- 5 - methoxy - 2 - aminobenzoyl } pyrrolidine - 2 - carboxaldehyde diethyl thioacetal iv . a solution of the ( 2s )- n -{ 4 -[ 4 -( 7 - methoxy -( 11as )- i , 2 , 3 , 10 , 11 , 11a - hexahydro - 5h - pyrrolo [ 2 , 1 - c ][ 1 , 4 ] benzodiazepine - 5 - one - 8 - yloxy ) butoxy ]- 5 - methoxy - 2 - aminobenzoyl } pyrrolidine - 2 - carboxaldehyde diethyl thioacetal of formula iv . ( 672 mg , 1 mmol ), hgcl 2 ( 794 mg , 2 . 93 mmol ) and caco 3 ( 300 mg , 3 mmol ) in ch 3 cn / h 2 o ( 4 : 1 , 15 ml ) was stirred at room temperature for 12 h until tlc ( etoac ), indicates complete loss of starting material . then organic layer is evaporated in vacuum and the residue is diluted with etoac . to this saturated nahco 3 was added slowly at room temperature and the mixture is filtered through celite and washed with ethylacetate . the filterate is evaporated in vacuum to get crude 7 - methoxy - 8 -{ 4 -[ 7 - methoxy -( 11as )- 1 , 2 , 3 , 10 , 11 , 11a - hexahydro - 5h - pyrrolo [ 2 , 1 - c ][ 1 , 4 ] benzodiazepine - 5 - one - 8 - yloxy ] butoxy }-( 11as )- 1 , 2 , 3 , 11a - tetrahy - dro - 5h - pyrrolo [ 2 , 1 - c ][ 1 , 4 ] benzodiazepine - 5 - one of formula v , which was further purified by column chromatography on silica gel eluting with methanol : etoac ( 2 : 8 ). [ 0076 ] 1 h nmr ( cdcl 3 ) γ 1 . 65 - 2 . 45 ( m , 10h ), 3 . 15 - 3 . 25 ( m , 2h ), 3 . 48 - 3 . 75 ( m , 4h ), 3 . 78 - 3 . 88 ( m , 4h ), 3 . 90 ( s , 3h ), 4 . 25 - 4 . 35 ( m , 5h ), 6 . 18 ( s , 1h ), 6 . 82 ( s , 1h ), 7 . 48 ( s , 1h ), 7 . 52 ( s , 1h ), 7 . 65 ( d , 1h , j = 4 . 8 hz ); ms ( fab ) 549 [ m + h ] + . a solution of ( 2s )- n -[ 4 -( 5 - bromopentyloxy )- 5 - methoxy - 2 - nitrobenzoyl ] pyrrolidine - 2 - carboxaldehyde diethyl thioacetal of formula i . ( 549 mg , 1 mmol ), 8 - hydroxy - 7 - methoxy -( 11as )- 1 , 2 , 3 , 10 , 11 , 11a - hexahydro - 5h - pyrrolo [ 2 , 1 - c ][ 1 , 4 ] benzodiazepine - 5 - one ( 248 mg , 1 mmol ) ii and k 2 co 3 ( 414 mg , 3 mmol ) in dry acetone ( 20 ml ) was refluxed for 48 h . after the completion of reaction as indicated by tlc , etoac , the reaction mixture was poured on to the water and then extracted with ethylacetate . evaporation of the organic layer gave the crude product , which was further purified by column chromatography on silica gel eluting with etoac : hexane ( 8 : 2 ) gave the pure ( 2s )- n -{ 4 -[ 5 -( 7 - methoxy -( 11as )- 1 , 2 , 3 , 10 , 11 , 11a - hexahydro - 5h - pyrrolo [ 2 , 1 - c ][ 1 , 4 ] benzodiazepine - 5 - one - 8 - yloxy ) pentyloxy ]- 5 - methoxy - 2 - nitrobenzoyl } pyrrolidine - 2 - carboxaldehyde diethyl thioacetal iii . [ 0078 ] 1 h nmr ( cdcl 3 ) γ 1 . 30 - 1 . 40 ( m , 6h ), 1 . 65 - 2 . 35 ( m , 14h ), 2 . 65 - 2 . 75 ( m , 4h ), 3 . 18 - 3 . 32 ( m , 3h ), 3 . 45 - 3 . 75 ( m , 2h ), 3 . 80 - 3 . 85 ( s 4h ), 3 . 85 - 4 . 0 ( m , 5h ), 4 . 65 - 4 . 72 ( m , 1h ), 4 . 85 ( d , 1h , j = 4 . 38 hz ), 6 . 0 ( s , 1h ), 6 . 78 ( s , 1h ) 7 . 52 ( s , 1h ), 7 . 65 ( s , 1h ); ms ( fab ) 717 [ m + h ] + . the ( 2s )- n -{ 4 -[ 5 -( 7 - methoxy -( 11as )- 1 , 2 , 3 , 10 , 11 , 11a - hexahydro - 5h - pyrrolo [ 2 , 1 - c ][ 1 , 4 ]- benzodiazepine - 5 - one - 8 - yloxy ) pentyloxy ]- 5 - methoxy - 2 - nitrobenzoyl } pyrrolidine - 2 - carboxaldehyde diethyl thioacetal iii ( 716 mg , 1 . 0 mmol ) was dissolved in dichloromethane ( 5 ml ), methanol ( 10 ml ) and added sncl 2 . 2h 2 o ( 1 . 124 g , 5 . 0 mmol ) was refluxed for 1 . 5 h . the reaction mixture was then carefully adjusted to ph 8 with saturated nahco 3 solution and then extracted with ethyl acetate ( 3 × 20 ml ). the combined organic phase was dried over na 2 so 4 and evaporated under vacuum to afford the crude ( 2s )- n -{ 4 -[ 5 -( 7 - methoxy -( 11as )- 1 , 2 , 3 , 10 , 11 , 11a - hexahydro - 5h - pyrrolo [ 2 , 1 - c ][ 1 , 4 ] benzodiazepine - 5 - one - 8 - yloxy ) pentyloxy ]- 5 - methoxy - 2 - aminobenzoyl ] pyrrolidine - 2 - carboxaldehyde diethyl thioacetal of formula iv . a solution of ( 2s )- n -{ 4 -[ 5 -( 7 - methoxy -( 11as )- 1 , 2 , 3 , 10 , 11 , 11a - hexahydro - 5h - pyrrolo -[ 2 , 1 - c ][ 1 , 4 ] benzodiazepine - 5 - one - 8 - yloxy ) pentyloxy ]- 5 - methoxy - 2 - aminobenzoyl } pyrrolidine - 2 - carboxaldehyde diethyl thioacetal iv . ( 686 mg , 1 mmol ), hgcl 2 ( 794 mg , 2 . 93 mmol ) and caco 3 ( 300 mg , 3 mmol ) in ch 3 cn / h 2 o ( 4 : 1 , 15 ml ) was stirred at room temperature for 12 h until tlc ( etoac ), indicates complete loss of starting material . then organic layer is evaporated in vacuum and the residue is diluted with etoac . to this saturated nahco 3 was added slowly at room temperature and the mixture is filtered thorough celite and washed with ethylacetate . the filterate is evaporated in vacuum to get crude 7 - methoxy - 8 -{ 5 -[ 7 - methoxy -( 11as )- 1 , 2 , 3 , 10 , 11 , 11a - hexahydro - 5h - pyrrolo [ 2 , 1 - c ]-[ 1 , 4 ] benzodiazepine - 5 - one - 8 - yloxy ] butoxy }-( 11as )- 1 , 2 , 3 , 11a - tetrahydro - 5h - pyrrolo [ 2 , 1 - c ][ 1 , 4 ] benzodiazepine - 5 - one of formula v , which was further purified by column chromatography on silica gel eluting with methanol : etoac ( 2 : 8 ). [ 0081 ] 1 h nmr ( cdcl 3 ) γ 1 . 20 - 2 . 45 ( m , 14h ), 3 . 10 - 3 . 20 ( m , 2h ), 3 . 20 - 3 . 28 ( m , 1h ), 3 . 40 - 3 . 78 ( m , 5h ), 3 . 80 ( s , 3h ), 3 . 98 ( s , 3h ), 4 . 10 - 4 . 22 ( m , 4h ), 6 . 0 ( s , 1h ), 7 . 02 ( s , 1h ); 7 . 50 ( s , 1h ), 7 . 55 ( s , 1h ), 7 . 65 ( d , 1h , j = 5 . 1 hz ); ms ( fab ) 563 [ m + h ] + . a solution of ( 2s )- n -[ 4 -( 3 - bromopropoxy )- 5 - methoxy - 2 - nitrobenzoyl ] pyrrolidine - 2 - carboxaldehyde diethyl thioacetal of formula i ( 521 mg , 1 mmol ), 8 - hydroxy - 7 - methoxy -( 2r )- hydroxy -( 11as )- 1 , 2 , 3 , 10 , 11 , 11a - hexahydro - 5h - pyrrolo [ 2 , 1 - c ][ 1 , 4 ] benzodiazepine - 5 - one ( 264 mg , 1 mmol ) of the formula ii and k 2 co 3 ( 414 mg , 3 mmol ) in dry acetone ( 20 ml ) was refluxed for 24 - 48 h . after the completion of reaction as indicated by tlc , etoac , the reaction mixture was poured on to the water and then extracted with ethylacetate . evaporation of the organic layer gave the crude product , which was further purified by column chromatography on silica gel eluting with etoac gave the pure ( 2s )- n -{ 4 -[ 3 -( 7 - methoxy -( 2r )- hydroxy -( 11as )- 1 , 2 , 3 , 10 , 11 , 11a - hexahydro - 5h - pyrrolo [ 2 , 1 ] [ 1 , 4 ] benzodiazepine - 5 - one - 8 - yloxy ) propoxy ]- 5 - methoxy - 2 - nitrobenzoyl } pyrrolidine - 2 - carboxaldehyde diethyl thioacetal iii . the ( 2s )- n -{ 4 -[ 3 -( 7 - methoxy -( 2r )- hydroxy -( 11as )- 1 , 2 , 3 , 10 , 11 , 11a - hexahydro - 5h - pyrro lo [ 2 , 1 - c ][ 1 , 4 ] benzodiazepine - 5 - one - 8 - yloxy ) propoxy ]- 5 - methoxy - 2 - nitrobenzoyl } pyrrolidine - 2 - carboxaldehyde diethyl thioacetal iii ( 704 mg , 1 . 0 mmol ) was dissolved in dichloromethane ( 5 ml ), methanol ( 10 ml ) and added sncl 2 . 2h 2 o ( 1 . 124 g , 5 . 0 mmol ), was refluxed for 1 . 5 h . the reaction mixture was then carefully adjusted to ph 8 with saturated nahco 3 solution and then extracted with ethyl acetate ( 3 × 20 ml ). the combined organic phase was dried over na 2 so 4 and evaporated under vacuum to afford the crude ( 2s )- n -{ 4 -[ 3 -( 7 - methoxy -( 2r )- hydroxy -( 11as )- 1 , 2 , 3 , 10 , 11 , 11a - hexahydro - 5h - pyrrolo [ 2 , 1 - c ][ 1 , 4 ] benzodiazepine - 5 - one - 8 - yloxy ) propoxy ]- 5 - methoxy - 2 - aminobenzoyl } pyrrolidine - 2 - carboxaldehyde diethyl thioacetal iv a solution of the ( 2s )- n -{ 4 -[ 3 -( 7 - methoxy -( 2r )- hydroxy -( 11as )- 1 , 2 , 3 , 10 , 11 , 11a - hexahydro - 5h - pyrrolo [ 2 , 1 - c ][ 1 , 4 ] benzodiazepine - 5 - one - 8 - yloxy ) propoxy ]- 5 - methoxy - 2 - aminobenzoyl } pyrrolidine - 2 - carboxaldehyde diethyl thioacetal iv ( 674 mg , 1 mmol ), hgcl 2 ( 794mg , 2 . 93 mmol ) and caco 3 ( 300 mg , 3 mmol ) in ch 3 cn / h 2 o ( 4 : 1 , 15 ml ) was stirred at room temperature for 12 h until tlc ( etoac ), indicates complete loss of starting material . then organic layer is evaporated in vacuum and the residue is diluted with etoac . to this saturated nahco 3 was added slowly at room temperature and the mixture is filtered through celite and washed with ethylacetate . the filterate is evaporated in vacuum to get crude 7 - methoxy - 8 -{ 3 -[ 7 - methoxy -( 11as )- 1 , 2 , 3 , 10 , 11 , 11a - hexahydro - 5h - pyrrolo [ 2 , 1 - c ][ 1 , 4 ] benzodiazepine - 5 - one - 8 - yloxy ] propoxy }-( 11as )- 1 , 2 , 3 , 11a - tetrahydro5h - pyrrolo [ 2 , 1 - c ][ 1 , 4 ] benzodiazepine - 5 - one of formula v , which was further purified by column chromatography on silica gel eluting with methanol : etoac ( 3 : 7 ). a solution of ( 2s )- n -[ 4 -( 4 - bromobutoxy )- 5 - methoxy - 2 - nitrobenzoyl ] pyrrolidine - 2 - carboxaldehyde diethyl thioacetal of formula i ( 535 mg , 1 mmol ), 8 - hydroxy - 7 - methoxy -( 2r )- hydroxy -( 11as )- 1 , 2 , 3 , 10 , 11 , 11a - hexahydro - 5h - pyrrol [ 2 , 1 - c ][ 1 , 4 ] benzodiazepine - 5 - one ( 264 mg , 1 mmol ) of the formula ii and k 2 co 3 ( 414 mg , 3 mmol ) in dry acetone ( 20 ml ) was refluxed for 48 h . after the completion of reaction as indicated by tlc , etoac , the reaction mixture was poured on to the water and then extracted with ethylacetate . evaporation of the organic layer gave the crude product , which was further purified by column chromatography on silica gel eluting with etoac gave the pure ( 2s )- n -{ 4 -[ 4 -( 7 - methoxy -( 2r )- hydroxy -( 11as )- 1 , 2 , 3 , 10 , 11 , 11a - hexahydro - 5h - pyrrolo -[ 2 , 1 - c ][ 1 , 4 ] benzodiazepine - 5 - one - 8 - yloxy ) butoxy ]- 5 - methoxy - 2 - nitrobenzoyl } pyrrolidine - 2 - carboxaldehyde diethyl thioacetal iii . the ( 2s )- n -{ 4 -[ 4 -( 7 - methoxy -( 2r )- hydroxy -( 11as )- 1 , 2 , 3 , 10 , 11 , 11a - hexahydro - 5h - pyrrolo [ 2 , 1 - c ][ 1 , 4 ] benzodiazepine - 5 - one - 8 - yloxy ) butoxy ]- 5 - methoxy - 2 - nitrobenzoyl } pyrrolidine - 2 - carboxaldehyde diethyl thioacetal ( 718 mg , 1 . 0 mmol ) of the formula iii was dissolved in dichloromethane ( 5 ml ), methanol ( 10 ml ) and added sncl 2 . 2h 2 o ( 1 . 124 g , 5 . 0 mmol ) was refluxed for 1 . 5 h . the reaction mixture was then carefully adjusted to ph 8 with saturated nahco 3 solution and then extracted with ethyl acetate ( 3 × 20 ml ). the combined organic phase was dried over na 2 so 4 and evaporated under vacuum to afford the crude ( 2s )- n -{ 4 -[ 4 -( 7 - methoxy -( 2r )- hydroxy -( 11as )- 1 , 2 , 3 , 10 , 11 , 11a - hexahydro - 5h - pyrrolo [ 2 , 1 - c ][ 1 , 4 ] benzodiazepine - 5 - one - 8 - yloxy ) butoxy ]- 5 - methoxy - 2 - aminobenzoyl }- pyrrolidine - 2 - carboxaldehyde diethyl thioacetal iv . a solution of the ( 2s )- n -{ 4 -[ 4 -( 7 - methoxy -( 2r )- hydroxy -( 11as )- 1 , 2 , 3 , 10 , 11 , 11a - hexahydro - 5h - pyrrolo [ 2 , 1 - c ][ 1 , 4 ] benzodiazepine - 5 - one - 8 - yloxy ) butoxy ]- 5 - methoxy - 2 - aminobenzoyl } pyrrolidine - 2 - carboxaldehyde diethyl thioacetal of formula iv . ( 688 mg , 1 mmol ), hgcl 2 ( 794 mg , 2 . 93 mmol ) and caco 3 ( 300 mg , 3 mmol ) in ch 3 cn / h 2 o ( 4 : 1 , 15 ml ) was stirred at room temperature for 12 h until tlc ( etoac ), indicates complete loss of starting material . then organic layer is evaporated in vacuum and the residue is diluted with etoac . to this saturated nahco 3 was added slowly at room temperature and the mixture is filtered through celite and washed with ethylacetate . the filterate is evaporated in vacuum to get crude 7 - methoxy - 8 -{ 4 -[ 7 - methoxy -( 2r )- hydroxy -( 11as )- 1 , 2 , 3 , 10 , 11 , 11 a - hexahydro - 5h - pyrrolo [ 2 , 1 - c ][ 1 , 4 ] benzodiazepine - 5 - one - 8 - yloxy ] butoxy } ( 11as )- 1 , 2 , 3 , 11a - tetrahy - dro - 5h - pyrrolo [ 2 , 1 - c ][ 1 , 4 ] benzodiazepine - 5 - one of formula v , which was further purified by column chromatography on silica gel eluting with methanol : etoac ( 3 : 7 ). a solution of ( 2s )- n -[ 4 -( 5 - bromopentyloxy )- 5 - methoxy - 2 - nitrobenzoyl ] pyrrolidine - 2 - carboxaldehyde diethyl thioacetal of formula i . ( 549 mg , 1 mmol ), 8 - hydroxy - 7 - methoxy -( 2r )- hydroxy -( 11as )- 1 , 2 , 3 , 10 , 11 , 11a - hexahydro - 5h - pyrrolo [ 2 , 1 - c ][ 1 , 4 ] benzodiazepine - 5 - one ( 264 mg , 1 mmol ) ii and k 2 co 3 ( 414 mg , 3 mmol ) in dry acetone ( 20 ml ) was refluxed for 48 h . after the completion of reaction as indicated by tlc , etoac , the reaction mixture was poured on to the water and then extracted with ethylacetate . evaporation of the organic layer gave the crude product , which was further purified by column chromatography on silica gel eluting with etoac gave the pure ( 2s )- n -{ 4 -[ 5 -( 7 - methoxy -( 2r )- hydroxy -( 11as )- 1 , 2 , 3 , 10 , 11 , 11a - hexahydro - 5h - pyrrolo -[ 2 , 1 - c ][ 1 , 4 ] benzodiazepine - 5 - one - 8 - yloxy ) pentyloxy ]- 5 - methoxy - 2 - nitrobenzoyl } pyrrolidine - 2 - carboxaldehyde diethyl thioacetal iii . the ( 2s )- n -{ 4 -[ 5 -( 7 - methoxy -( 2r )- hydroxy -( 11as )- 1 , 2 , 3 , 10 , 11 , 11a - hexahydro - 5h - pyrrolo [ 2 , 1 - c ][ 1 , 4 ] benzodiazepine - 5 - one - 8 - yloxy ) pentyloxy ]- 5 - methoxy - 2 - nitrobenzoyl } pyrrolidine - 2 - carboxaldehyde diethyl thioacetal iii ( 732 mg , 1 . 0 mmol ) was dissolved in dichloromethane ( 5 ml ), methanol ( 10 ml ) and added sncl 2 . 2h 2 o ( 1 . 124 g , 5 . 0 mmol ) was refluxed for 1 . 5 h . the reaction mixture was then carefully adjusted to ph 8 with saturated nahco 3 solution and then extracted with ethylacetate ( 3 × 20 ml ). the combined organic phase was dried over na 2 so 4 and evaporated under vacuum to afford the crude ( 2s )- n -{ 4 -[ 5 -( 7 - methoxy -( 2r )- hydroxy -( 11as )- 1 , 2 , 3 , 10 , 11 , 11a - hexahydro - 5h - pyrrolo [ 2 , 1 - c ][ 1 , 4 ] benzodiazepine - 5 - one - 8 - yloxy ) pentyloxy ]- 5 - methoxy - 2 - aminobenzoyl ] pyrrolidine - 2 - carboxaldehyde diethyl thioacetal of formula iv . a solution of ( 2s )- n -{ 4 -[ 5 -( 7 - methoxy -( 2r )- hydroxy -( 11as )- 1 , 2 , 3 , 10 , 11 , 11a - hexahydro - 5h - pyrrolo [ 2 , 1 - c ][ 1 , 4 ] benzodiazepine - 5 - one - 8 - yloxy ) pentyloxy ]- 5 - methoxy - 2 - aminoben zoyl } pyrrolidine - 2 - carboxaldehyde diethyl thioacetal iv . ( 702 mg , 1 mmol ), hgcl 2 ( 794 mg , 2 . 93 mmol ) and caco 3 ( 300 mg , 3 mmol ) in ch 3 cn / h 2 o ( 4 : 1 , 15 ml ) was stirred at room temperature for 12 h until tlc ( etoac : methanol ), indicates complete loss of starting material . then organic layer is evaporated in vacuum and the residue is diluted with etoac . to this saturated nahco 3 was added slowly at room temperature and the mixture is filtered thorough celite and washed with ethylacetate . the filterate is evaporated in vacuum to get crude 7 - methoxy - 8 -{ 5 -[ 7 - methoxy -( 2r )- hydroxy -( 11as )- 1 , 2 , 3 , 10 , 11 , 11a - hexahydro - 5h - pyrrolo [ 2 , 1 - c ][ 1 , 4 ] benzodiazepine - 5 - one - 8 - yloxy ] butoxy } ( 11as )- 1 , 2 , 3 , 11a - tetrahydro - 5h - pyrrolo [ 2 , 1 - c ][ 1 , 4 ] benzodiazepine - 5 - one of formula v , which was further purified by column chromatography on silica gel eluting with methanol : etoac ( 3 : 7 ). a solution of ( 4r )- hydroxy -( 2s )- n -[ 4 -( 3 - bromopropoxy )- 5 - methoxy - 2 - nitrobenzoyl ]- pyrrolidine - 2 - carboxaldehyde diethyl thioacetal of formula i ( 537 mg , 1 mmol ), 8 - hydroxy - 7 - methoxy -( 11as )- 1 , 2 , 3 , 10 , 11 , 11a - hexahydro - 5h - pyrrolo [ 2 , 1 - c ][ 1 , 4 ] benzodiaze pine - 5 - one ( 248 mg , 1 mmol ) of the formula ii and k 2 co 3 ( 414 mg , 3 mmol ) in dry acetone ( 20 ml ) was refluxed for 48 h . after the completion of reaction as indicated by tlc , etoac , the reaction mixture was poured on to the water and then extracted with ethylacetate . evaporation of the organic layer gave the crude product , which was further purified by column chromatography on silica gel eluting with etoac gave the pure ( 4r )- hydroxy -( 2s )- n -{ 4 -[ 3 -( 7 - methoxy -( 11as )- 1 , 2 , 3 , 10 , 11 , 11a - hexahydro - 5h - pyrrolo [ 2 , 1 - c ] [ 1 , 4 ] benzodiazepine - 5 - one - 8 - yloxy ) propoxy ]- 5 - methoxy - 2 - nitrobenzoyl } pyrrolidine - 2 - carboxaldehyde diethyl thioacetal iii . the ( 4r )- hydroxy -( 2s )- n -{ 4 -[ 3 -( 7 - methoxy -( 11as )- 1 , 2 , 3 , 10 , 11 , 11a - hexahydro - 5h - pyrrolo [ 2 , 1 - c ][ 1 , 4 ] benzodiazepine - 5 - one - 8 - yloxy ) propoxy ]- 5 - methoxy - 2 - nitrobenzoyl } pyrrolidine - 2 - carboxaldehyde diethyl thioacetal iii ( 704 mg , 1 . 0 mmol ) was dissolved in dichloromethane ( 5 ml ), methanol ( 10 ml ) and added sncl 2 . 2h 2 o ( 1 . 124 g , 5 . 0 mmol ) was refluxed for 1 . 5 h . the reaction mixture was then carefully adjusted to ph 8 with saturated nahco 3 solution and then extracted with ethyl acetate ( 3 × 20 ml ). the combined organic phase was dried over na 2 so 4 and evaporated under vacuum to afford the crude ( 2s )- n -{ 4 -[ 3 -( 7 - methoxy -( 11as )- 1 , 2 , 3 , 10 , 11 , 11a - hexahydro - 5h - pyrrolo [ 2 , 1 - c ][ 1 , 4 ] benzodiazepine - 5 - one - 8 - yloxy ) propoxy ]- 5 - methoxy - 2 - aminobenzoyl } pyrrolidine - 2 - carboxaldehyde diethyl thioacetal iv a solution of the ( 4r )- hydroxy -( 2s )- n -{ 4 -[ 3 -( 7 - methoxy -( 11as )- 1 , 2 , 3 , 10 , 11 , 11a - hexahydro - 5h - pyrrolo [ 2 , 1 - c ][ 1 , 4 ] benzodiazepine - 5 - one - 8 - yloxy ) propoxy ]- 5 - methoxy - 2 - aminobenzoyl } pyrrolidine - 2 - carboxaldehyde diethyl thioacetal iv ( 674 mg , 1 mmol ), hgcl 2 ( 794 mg , 2 . 93 mmol ) and caco 3 ( 300 mg , 3 mmol ) in ch 3 cn / h 2 o ( 4 : 1 , 15 ml ) was stirred at room temperature for 12 h until tlc ( etoac ), indicates complete loss of starting material . then organic layer is evaporated in vacuum and the residue is diluted with etoac . to this saturated nahco 3 was added slowly at room temperature and the mixture is filtered through celite and washed with ethylacetate . the filterate is evaporated in vacuum to get crude 7 - methoxy - 8 -{ 3 -[ 7 - methoxy -( 11as )- 1 , 2 , 3 , 10 , 11 , 11a - hexahydro - 5h - pyrrolo [ 2 , 1 - c ][ 1 , 4 ] benzodiazepine - 5 - one - 8 - yloxy ] propoxy }-( 4r )- hydroxy -( 11as )- 1 , 2 , 3 , 11a - tetrahydro - 5h - pyrrolo [ 2 , 1 - c ][ 1 , 4 ] benzodiazepine - 5 - one of formula v , which was further purified by column chromatography on silica gel eluting with methanol : etoac ( 3 : 7 ). a solution of ( 4r )- hydroxy -( 2s )- n -[ 4 -( 4 - bromobutoxy )- 5 - methoxy - 2 - nitrobenzoyl ] pyrrolidine - 2 - carboxaldehyde diethyl thioacetal of formula i ( 551 mg , 1 mmol ), 8 - hydroxy - 7 - methoxy -( 11as )- 1 , 2 , 3 , 10 , 11 , 11a - hexahydro - 5h - pyrrol [ 2 , 1 - c ][ 1 , 4 ] benzodiazepine - 5 - one ( 248 mg , 1 mmol ) of the formula ii and k 2 co 3 ( 414 mg , 3 mmol ) in dry acetone ( 20 ml ) was refluxed for 48 h . after the completion of reaction as indicated by tlc , etoac , the reaction mixture was poured on to the water and then extracted with ethylacetate . evaporation of the organic layer gave the crude product , which was further purified by column chromatography on silica gel eluting with etoac gave the pure ( 4r )- hydroxy -( 2s )- n -{ 4 -[ 4 -( 7 - methoxy -( 11as )- 1 , 2 , 3 , 10 , 11 , 11a - hexahydro - 5h - pyrrolo [ 2 , 1 - c ][ 1 , 4 ] benzodiazepine - 5 - one - 8 - yloxy ) butoxy ]- 5 - methoxy - 2 - nitrobenzoyl } pyrrolidine - 2 - carboxaldehyde diethyl thioacetal iii . the ( 4r )- hydroxy -( 2s )- n -{ 4 -[ 4 -( 7 - methoxy -( 11as )- 1 , 2 , 3 , 10 , 11 , 11a - hexahydro - 5h - pyrrolo [ 2 , 1 - c ][ 1 , 4 ] benzodiazepine - 5 - one - 8 - yloxy ) butoxy ]- 5 - methoxy - 2 - nitrobenzoyl } pyrrolidine - 2 - carboxaldehyde diethyl thioacetal ( 718 mg , 1 . 0 mmol ) of the formula iii was dissolved in dichloromethane ( 5 ml ), methanol ( 10 ml ) and added sncl 2 . 2h 2 o ( 1 . 124 g , 5 . 0 mmol ) was refluxed for 1 . 5 h . the reaction mixture was then carefully adjusted to ph 8 with saturated nahco 3 solution and then extracted with ethylacetate ( 3 × 20 ml ). the combined organic phase was dried over na 2 so 4 and evaporated under vacuum to afford the crude ( 2s )- n -{ 4 -[ 4 -( 7 - methoxy -( 11as )- 1 , 2 , 3 , 10 , 11 , 11a - hexahydro - 5h - pyrrolo [ 2 , 1 - c ] [ 1 , 4 ] benzodiazepine - 5 - one - 8 - yloxy ) butoxy ]- 5 - methoxy - 2 - aminobenzoyl } pyrrolidine - 2 - carboxaldehyde diethyl thioacetal iv . a solution of the ( 4r )- hydroxy -( 2s )- n -{ 4 -[ 4 -( 7 - methoxy -( 11as )- 1 , 2 , 3 , 10 , 11 , 11a - hexahydro - 5h - pyrrolo [ 2 , 1 - c ][ 1 , 4 ] benzodiazepine - 5 - one - 8 - yloxy ) butoxy ]- 5 - methoxy - 2 - aminobenzoyl } pyrrolidine - 2 - carboxaldehyde diethyl thioacetal of formula iv . ( 688 mg , 1 mmol ), hgcl 2 ( 794 mg , 2 . 93 mmol ) and caco 3 ( 300 mg , 3 mmol ) in ch 3 cn / h 2 o ( 4 : 1 , 15 ml ) was stirred at room temperature for 12 h until tlc ( etoac ), indicates complete loss of starting material . then organic layer is evaporated in vacuum and the residue is diluted with etoac . to this saturated nahco 3 was added slowly at room temperature and the mixture is filtered through celite and washed with ethylacetate . the filterate is evaporated in vacuum to get crude 7 - methoxy - 8 -{ 4 -[ 7 - methoxy -( 11as )- 1 , 2 , 3 , 10 , 11 , 11a - hexahydro - 5h - pyrrolo [ 2 , 1 - c ][ 1 , 4 ] benzodiazepine - 5 - one - 8 - yloxy ] butoxy }-( 4r )- hydroxy -( 11as )- 1 , 2 , 3 , 11a - tetrahy - dro - 5h - pyrrolo [ 2 , 1 - c ][ 1 , 4 ] benzodiazepine - 5 - one of formula v , which was further purified by column chromatography on silica gel eluting with methanol : etoac ( 2 : 8 ). a solution of ( 4r )- hydroxy -( 2s )- n -[ 4 -( 5 - bromopentyloxy )- 5 - methoxy - 2 - nitrobenzoyl ]- pyrrolidine - 2 - carboxaldehyde diethyl thioacetal of formula i . ( 565 mg , 1 mmol ), 8 - hydroxy - 7 - methoxy -( 11as )- 1 , 2 , 3 , 10 , 11 , 11a - hexahydro - 5h - pyrrolo [ 2 , 1 - c ][ 1 , 4 ] benzodiazepine - 5 - one ( 248 mg , 1 mmol ) ii and k 2 co 3 ( 414 mg , 3 mmol ) in dry acetone ( 20 ml ) was refluxed for 48 h . after the completion of reaction as indicated by tlc , etoac , the reaction mixture was poured on to the water and then extracted with ethylacetate . evaporation of the organic layer gave the crude product , which was further purified by column chromatography on silica gel eluting with etoac gave the pure ( 4r )- hydroxy -( 2s )- n -{ 4 -[ 5 -( 7 - methoxy -( 11as )- 1 , 2 , 3 , 10 , 11 , 11a - hexahydro - 5h - pyrrolo [ 2 , 1 - c ][ 1 , 4 ] benzodiazepine - 5 - one - 8 - yloxy ) pentyloxy ]- 5 - methoxy - 2 - nitrobenzoyl } pyrrolidine - 2 - carboxaldehyde diethyl thioacetal iii . the ( 4r )- hydroxy -( 2s )- n -{ 4 -[ 5 -( 7 - methoxy -( 11as )- 1 , 2 , 3 , 10 , 11 , 11a - hexahydro - 5h - pyrrolo [ 2 , 1 - c ][ 1 , 4 ] benzodiazepine - 5 - one - 8 - yloxy ) pentyloxy ]- 5 - methoxy - 2 - nitrobenzoyl } pyrrolidine - 2 - carboxaldehyde diethyl thioacetal iii ( 732 mg , 1 . 0 mmol ) was dissolved in dichloromethane ( 5 ml ), methanol ( 10 ml ) and added sncl 2 . 2h 2 0 ( 1 . 124 g , 5 . 0 mmol ) was refluxed for 1 . 5 h . the reaction mixture was then carefully adjusted to ph 8 with saturated nahco 3 solution and then extracted with ethyl acetate ( 3 × 20 ml ). the combined organic phase was dried over na 2 so 4 and evaporated under vacuum to afford the crude ( 4r )- hydroxy -( 2s )- n -{ 4 -[ 5 -( 7 - methoxy -( 11as )- 1 , 2 , 3 , 10 , 11 , 11la - hexahydro - 5h - pyrrolo [ 2 , 1 - c ][ 1 , 4 ] benzodiazepine - 5 - one - 8 - yloxy ) pentyloxy ]- 5 - methoxy - 2 - aminobenzoyl ] pyrrolidine - 2 - carboxaldehyde diethyl thioacetal of formula iv . a solution of ( 4r )- hydroxy -( 2s )- n -{ 4 -[ 5 -( 7 - methoxy -( 11as )- 1 , 2 , 3 , 10 , 11 , 11a - hexahydro - 5h - pyrrolo [ 2 , 1 - c ][ 1 , 4 ] benzodiazepine - 5 - one - 8 - yloxy ) pentyloxy ]- 5 - methoxy - 2 - aminobenzoyl } pyrrolidine - 2 - carboxaldehyde diethyl thioacetal iv . ( 702 mg , 1 mmol ), hgcl 2 ( 794 mg , 2 . 93 mmol ) and caco 3 ( 300 mg , 3 mmol ) in ch 3 cn / h 2 o ( 4 : 1 , 15 ml ) was stirred at room temperature for 12 h until tlc ( etoac ), indicates complete loss of starting material . then organic layer is evaporated in vacuum and the residue is diluted with etoac . to this saturated nahco 3 was added slowly at room temperature and the mixture is filtered thorough celite and washed with ethylacetate . the filterate is evaporated in vacuum to get crude 7 - methoxy - 8 -{ 5 -[ 7 - methoxy -( 11as )- 1 , 2 , 3 , 10 , 11 , 11a - hexahydro - 5h - pyrrolo [ 2 , 1 - c ][ 1 , 4 ] benzodiazepine - 5 - one - 8 - yloxy ] butoxy }-( 4r )- hydroxy -( 11as )- 1 , 2 , 3 , 11a - tetrahydro - 5h - pyrrolo [ 2 , 1 - c ][ 1 , 4 ] benzodiazepine - 5 - one of formula v , which was further purified by column chromatography on silica gel eluting with methanol : etoac ( 2 : 8 ). biological activity . in vitro biological activity studies were carried out at national cancer institute ( usa ). cytotoxicity . compounds va and vc were evaluated in vitro against sixty human tumour cells derived from nine cancer types ( leukemia , non - small - cell lung , colon , cns , melanoma , ovarian , prostate , and breast cancer ). for each compound , dose response curves for each cell line were measured at a minimum of five concentrations at 10 fold dilutions . a protocol of 48 h continuous drug exposure was used , and a sulforhodamine b ( srb ) protein assay was used to estimate cell viability or growth . the concentration causing 50 % cell growth inhibition ( gi50 ), total cell growth inhibition ( tgi 0 % growth ) and 50 % cell death ( lc50 , − 50 % growth ) compared with the control was calculated . the mean graph midpoint values of log 10 tgi and log 10 lc50 as well as log 10 gi50 for va and vc are listed in table 1 . as demonstrated by mean graph pattern , compound vic exhibits an interesting profile of activity and selectivity for various cell lines . the mean graph mid point of log 10 tg1 and log 10 lc50 showed similar pattern to the log 10 gi50 mean graph mid points . [ 0102 ] table 2 log lc50 ( concentration in mol / l causing 50 % lethality ) values for compounds va and vc cancer compound va compound vc leukemia − 4 . 08 − 4 . 46 non - small - cell lung − 4 . 41 − 4 . 14 colon − 4 . 59 − 4 . 04 cns − 4 . 49 − 4 . 09 melanoma − 5 . 45 − 4 . 42 ovarian − 4 . 15 − 4 . 01 renal − 4 . 20 − 4 . 02 prostate − 4 . 08 − 4 . 00 breast − 4 . 36 − 4 . 05 each cancer type represents the average of six to eight different cancer cell lines . the anticancer activity for two representative compounds has been given in table 2 . the comparison of the data of table 2 reveals the importance of the alkane spacer . as the alkane spacer increased from 3 - 5 the cytotoxic activity has moderately decreased . the 3 carbon spacer of compound va confers a suitable fit in the minor groove of double helix dna and shows slightly higher activity in this series of compounds va and vc .
the present invention relates to novel pyrrolobenzodiazepines compounds of general formula v as shown below , which are useful as potential antitumour agents and a process of preparing these compounds ; particularly the present invention provides a process for the preparation of 7 - methoxy - 8 -- 1 , 2 , 3 , 10 , 11 , 11a - hexahydro - 5h - pyrroloben - zodiazepine - 5 - one - 8 - yloxy ] alkyloxy }-- 1 , 2 , 3 , 11a - tetrahydro - 5h - pyrrolobenzodiazepin - 5 - one , with varying aliphatic chain length and its 2 - hydroxy derivatives .