WO2005063759A1 - PROCESS FOR PREPARING PYRROLO[2, 1-c] [1, 4] BENZODIAZEPINE HYBRIDS - Google Patents

PROCESS FOR PREPARING PYRROLO[2, 1-c] [1, 4] BENZODIAZEPINE HYBRIDS Download PDF

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WO2005063759A1
WO2005063759A1 PCT/IN2003/000462 IN0300462W WO2005063759A1 WO 2005063759 A1 WO2005063759 A1 WO 2005063759A1 IN 0300462 W IN0300462 W IN 0300462W WO 2005063759 A1 WO2005063759 A1 WO 2005063759A1
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formula
pyrrolo
benzo
imidazol
compound
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PCT/IN2003/000462
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French (fr)
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Ahmed Kamal
Poddutoori Ramulu
Olepu Srinivas
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Council Of Scientific And Industrial Research
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Priority to AU2003300718A priority Critical patent/AU2003300718A1/en
Priority to JP2005512761A priority patent/JP4520411B2/en
Priority to PCT/IN2003/000462 priority patent/WO2005063759A1/en
Priority to GB0614750A priority patent/GB2424883B/en
Publication of WO2005063759A1 publication Critical patent/WO2005063759A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • A61K31/5517—1,4-Benzodiazepines, e.g. diazepam or clozapine condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to novel pyrrolo[2, 1-c] [ 1,4] benzodiazepine hybrids as well as processes for the preparation of novel pyrrolo[2, 1-c] [ 1,4] benzodiazepine hybrids. More particularly, present invention relates to a process for the preparation of novel pyrrolo[2, 1-c] [ 1,4] benzodiazepine hybrids as DNA sequence selective agents which are useful as potential antitumour agents. In particular, the present invention relates to a process for the preparation of new pyrrolo [2,1- c] [ 1,4] benzodiazepine hybrids as potential antitumour agents.
  • the present invention also provides a process for the preparation of 7-methoxy- 8- ⁇ n-[41H- benzo [d] imidazolo - 2 yl phenoxy] alkyl ⁇ - oxy (llaS) 1,2,3,-11 a tetrahydro- 5H- pyrrolo [ 2,1- c] 1, 4] benzodiazepin- 5 one V, 7- methoxy- 8- (n - ⁇ 4-[6- (4-methyl hexahydro- 1- pyrainyl)- 1 H- benzo [d] imidazol- 2 yl] phenoxy ⁇ alkyl)- oxy- (l laS) - 1,2,3, 11a - tetrahydro - 5 H- pyrrolo 1 H- benzodiazepin 5 one V, 7- methoxy- 8 (n- ⁇ 4- [6-4 methyl hexahydro-1 prazinyl)- lH-benzo [d] imidazol
  • the present process provides a process for preparation of pyrrolo [ 2,1-c] 1, 4] benzodiazepine hybrids of formula V
  • n 3 to 5 by known methods, reacting the said amino compound of formula IV with conventional deprotecting agents in to produce pyrrolo [ 2,1-c] 1, 4] benzodiazepine hybrids of formula V, wherein "n" is as defined above.
  • the present invention provides a process for preparation of pyrrolo [ 2,1-c] 1, 4] benzodiazepine hybrids of formula IX
  • the present invention provides a process for preparation of pyrrolo [ 2,1-c] 1, 4] benzodiazepine hybrids of formula XTII
  • Example 1 Compound 4-[lH-benzo [d] imidazol-2-yl] phenol I (210 mg, 1 mmol) and (2S)-N-4-(3-bromobutyloxy)-5-methoxy-2-nitrobenzoyl] pyrrolidin-2-carboxaldehyde diethyl thioacetal of formula II (521 mg, 1 mmol) was taken in dry DMF (lOmL). K2CO3 (690mg, 5mmol) was added and the mixture was stirred for 12 to 24hrs.
  • Example 2 Compound 4-[lH-benzo [d] imidazol-2-yl] phenol I (210 mg, 5 mmol) and (2S)-N-[4-(4-bromobutyloxy)-5-methoxy-2-nitrobenzoyl] pyrrolidin-2-carboxaldehyde diethyl thioacetal of formula II (535 mg, 1 mmol) was taken in dry DMF (lOmL). K 2 CO 3 (690 mg, 5 mmol) was added and the mixture was stirred for 12 to 24hrs. The reaction mixture was poured in to ice-water then solid was formed and it was filtered and aqueous media was extracted with EtOAc and CHC1 3 (50 mL).
  • Example 3 Compound 4-[lH-benzo [d] imidazol-2-yl] phenol I (210 mg, 1 mmol) and (2S)-N-[4-(5-bromobutyloxy)-5-methoxy-2-nitrobenzoyl] pyrrolidin-2-carboxaldehyde diethyl thioacetal of formula II (549 mg, 5 mmol) was taken in dry DMF (lOmL), K 2 CO 3 (690 mg, 5 mmol) was added and the mixture was stirred for 12-24 th . The reaction mixture was poured in to ice-water then solid was formed and it was filtered and aqueous media was extracted with EtOAc and CHC1 3 (50 mL).
  • Example 4 Compound 4-[6-(4-methylhexahydro-l-pyrazinyl)-lH-benzo [d] imidazol-2-yl] phenol VI (328 mg, 1 mmol) and (2S)-N-[4-(3-bromobutyloxy)-5-methoxy-2- nitrobenzoyl] pyrrolidin-2-carboxaldehyde diethyl thioacetal of formula II (521 mg, 1 mmol) was taken in dry DMF (lOmL). K 2 CO 3 (690 mg, 5 mmol) was added and the mixture was stirred for 12-24*.
  • reaction mixture was poured in to ice-water then solid was formed and it was filtered and aqueous media was extracted with EtOAc and CHC1 3 (50 mL), then the extracted solution was evaporated in vacuum to obtain the solid compound. Two solids were combined and the crude material was.
  • reaction mixture was diluted with EtOAc (30mL) and filtered through a celite bed.
  • the clear brown organic supernatant was extracted with saturated 5% NaHCO 3 (20mL), brine (20mL) and the combined organic phase was dried (Na2SO4).
  • Example 5 Compound 4-[6-(4-methylhexahydro-l-pyrazonyl)-lH-zenzo [d] imidazol-2-yl] phenol VI (328 g, 1 mmol) and (2S)-N-4-(4-bromobutyloxy)-5-methoxy-2- nitrobenzoyl] pyrrolidin-2-carboxaldehyde diethyl thioacetal of formula II (535 mg, 1 mmol) was stirred for 12-24 .
  • reaction mixture was then adjusted to pH 8 caref lly with saturated NaHCO 3 solution, diluted with ethyl acetate, filtered through celite and extracted.
  • the combined organic phase was dried over Na 2 SO 4 , and evaporated under vacuum to afford the crude compound (2S) -N- ⁇ 4-(4-[6-(4- methylhexahy dro- 1 -pyraziny 1 )- 1 H-benzo [d]imidazol-2-yl] imidazol-2- yl]phenoxy)propoxy-5-metJ ⁇ oxy-2-aminobenzoyl ⁇ pyrrolidine-2-carboxaldehyde diethyl thioacetal VIII.
  • reaction mixture was diluted with EtOAc (30mL) and filtered through a celite bed.
  • the clear brown organic supernatant was extracted with saturated 5% NaHCO 3 (20mL), brine (20mL) and the combined organic phase was dried ( a2SO ).
  • Example 6 Compound 4-[6-(4-methylhexahydro-l-pyrazonyl)-lH-zenzo [d] imidazol-2-yl] phenol VI (328 g, 5 mmol) and (2S)-N-4-(5-bromobutyloxy)-5-methoxy-2- nitrobenzoyl] pyrrolidin-2-carboxaldehyde diethyl thioacetal of formula II (549 mg, 1 mmol) was taken in dry DMF (lO L). K2CO3 (690mg, 5 mmol) was added and the
  • reaction mixture was diluted with EtOAc (30mL) and filtered through a celite bed.
  • the clear brown organic supernatant was extracted with saturated 5% NaHCO 3 (20mL), brine (20mL) and the combined organic phase was dried (Na2SO 4 ).
  • Example 7 • Compound 4-[6-(4-methylhexahydro-l-pyrazonyl)-lH-zenzo [d] imidazol-2-yl] phenol X (342 g, 5 mmol) and (2S)-N-4-(3-bromobutyloxy)-5-methoxy-2- nitrobenzoyl] pyrrolidin-2-carboxaldehyde diethyl thioacetal of formula II (521 mg, 1 mmol) was taken in dry DMF (lOmL). K 2 CO 3 (690mg, 5 mmol) was added and the mixture was stirred for 12-24*.
  • reaction mixture was poured in to ice-water then solid was formed and it was filtered and aqueous media was extracted with EtOAc and C ⁇ C1 3 (50 mL), then the extracted solution was evaporated in vacuum to obtain the solid compound. Two solids were combined and the crude material was.
  • reaction mixture was diluted with EtOAc (30mL) and filtered through a celite bed.
  • the clear brown organic supernatant was extracted with saturated 5% NaHCO 3 (20mL), brine (20mL) and the combined organic phase was dried (Na 2 SO 4 ).
  • Example 8 Compound 4-[6-(4-methylhexahydro-l-pyrazonyl)-lH ⁇ zenzo [d] imidazol-2-yl] phenol X (342 g, 5 mmol) and (2S)-N-4-(4-bromobutyloxy)-5-methoxy-2- nitrobenzoyl] pyrrolidin-2-carboxaldehyde diethyl thioacetal of formula II (535 mg, 1 mmol) was taken in dry DMF (lOmL). K 2 CO 3 (690mg, 5 mmol) was added and the mixture was stirred for 12-24*.
  • reaction mixture was poured in to ice-water then solid was formed and it was filtered and aqueous media was extracted with EtOAc and CHC1 3 (50 mL), then the extracted solution was evaporated in vacuum to obtain the solid compound. Two solids were combined and the crude material was.
  • reaction mixture was diluted with EtOAc (30mL) and filtered through a celite bed.
  • the clear brown organic supernatant was extracted with saturated 5% NaHCO 3 (20mL), brine (20mL) and the combined organic phase was dried (Na 2 SO ).
  • Example 9 Compound 4-[6-(4-methylhexahydro-l-pyrazonyl)-lH-zenzo [d] imidazol-2-yl] phenol X (342 g, 1 mmol) and (2S)-N-4-(5-bromobutyloxy)-5-methoxy-2- nitrobenzoyl] pyrrolidin-2-carboxaldehyde diethyl thioacetal of formula II (549 mg, 5 mmol) was taken in dry DMF (lOmL). K 2 CO 3 (690mg, S mmol) was added and the mixture was stirred for 12-24*.
  • reaction mixture was poured in to ice-water then solid was formed and it was filtered and aqueous media was extracted with EtOAc and CHC1 3 (50 mL), then the extracted solution was evaporated in vacuum to obtain the solid compound. Two solids were combined and the crude material was.
  • Cytotoxicity Compound IX was evaluated for the primary anti-cancer activity (Table- 1) and 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 control was calculated.
  • SRB sulforhodamine B
  • the mean graph midpoint values of loglO TGI and loglO LC50 as well as log 10 GI50 for VI are listed in Table 2. As demonstrated by mean graph pattern, compound IV exhibits an interesting profile of activity and selectivity for various cell lines. The mean graph mid point of loglO TGI and loglO LC50 showed similar pattern to the loglO Gl 50 mean graph mid points. Table 1 : in vitro one dose primary anticancer assay a of PBD hybrid formula IX as representative compound.
  • Table 2. loglO GI50 loglO TGI and LC50 mean graphs midpoints (MG_MID) of in vitro cytotoxicity data for the compound IX as representative compound against human tumour cell lines.
  • Each cancer type represents the average of six to nine different cancer cell lines.

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Abstract

Novel pyrrolo[2, 1-c] [1, 4] benzodiazepine hybrids as well as processes for the proepartion of novel pyrrolo [2, 1-c] [1, 4] benzodiazepine hybrids are disclosed. More particularly, present invention relates to a process for the preparation of novel pyrrolo [2, 1-c] [1, 4] benzodiazepine hybrids as DNA sequence selective agents which are useful as potential antitumour agents. In particular, the present invention relates to a process for the preparation of new pyrrolo [2, 1-c] [1, 4] benzodiazepine hybrids as potential antitumour agents. These compounds have the formula (XIV).

Description

PROCESS FOR PREPARING PYRROLO [2, 1-c] [1,4] BENZODIAZEPINE
HYBRIDS
Field of the invention The present invention relates to novel pyrrolo[2, 1-c] [ 1,4] benzodiazepine hybrids as well as processes for the preparation of novel pyrrolo[2, 1-c] [ 1,4] benzodiazepine hybrids. More particularly, present invention relates to a process for the preparation of novel pyrrolo[2, 1-c] [ 1,4] benzodiazepine hybrids as DNA sequence selective agents which are useful as potential antitumour agents. In particular, the present invention relates to a process for the preparation of new pyrrolo [2,1- c] [ 1,4] benzodiazepine hybrids as potential antitumour agents. Background of the invention Pyrrolo [2, 1-c] [1,4] benzodiazepine antitumour antibiotics are commonly known as anthramycin class of compounds. In the last few years, a growing interest has been shown in the development of new pyrrolo [2,1-c] benzodiazepines (PBDs). These antibiotics react covalently with DNA to form, an N2- guanine adduct that lies within the minor groove of duplex DNA via an acid-labile aminal bond to the electrophilic imine at the N10-C11 position (Kunimoto, S.; Masuda, T.; Kanbayashi, N. ; Hamada, M.; Naganawa, H.; Miyamoto, M.; Takeuchi, T.; and Unnezawa, H. J. Antibiot, 1980, 33, 665.; Kohn, K. w. and Speous, C. L. J. Mol., Biol., 1970, 51,551.; Hurley, L. H.; Gairpla, c. and Zmijewski, M. Biochem, Biophys. Acta., 1977, 475, 521,; Kaplan, D. J. and Hurley, L. H. biochmestry, 1981, 20, 7572). The molecules have a right - handed twist, which allows them to follow the curvature of the minor groove of B-form double-
" stranded DNA spanning three base pairs. Recently, PBD dimmers have been developed that comprises two C2- exo-methylene substituted DC-81 subunits tethered through their C-8 position I an inert propanedioxy linker (Gregson, S. J.; Howard, P. W; Hartely, J. A.; Brooks, N.a.; Adams, L.J.; Jenkins, T.C.; Kelland, L.R. and Thurston, D.E. J. Med Chem. 2001, 44, 737). A recent development has been the linking of two PBD units through their C-8 positions to give bisfunctional alkylating agents capable of cross- linking DNA (Thurston D. E.; Bose, D.S.; Thomson, a, S; Howard, P. W.; Leoni, A; Croker, S. J; Jenkins, T. C; Neidle, S. and Hurley, L. H. J. Org. Chem., 1996, 61, 8141). Recently, a noncross linking mixed inmin'e-amide PBD dimmers have been synthesized that have significant DNA binding ability and potent anti tumour activity. (Kamal, A,; Ramesh, G.; Laxman, N; Ramulu, P,; Srinicas, O.; Neelima, K.; Kondapi, A. K.; Srinu, V. B,; Nagarajaram, H. M. J. Med. Chem. 2002, 45, 4679). These imine-amide PBD dimers have the structures shown below:
Figure imgf000003_0001
DC-SI dimeis (n = 3-5); DSB-120 m = 3)
Figure imgf000003_0002
imine-amide PBD dimers; n = 3 - 5 Naturally occurring pyrrolo [ 2, 1-c] [ 1,4] benzodiazepines belong to a group of antitumour antibiotics derived from Streptomyces Species. Recently, there is much impetus for the PBD system as they can recognize and bind to specific sequence of DNA. Examples of naturally occurring PBDs include anthramycin, DC-81, tomaymycin, sibiromycin and neothramycin. However, the clinical efficacy for these antibiotics is hindered by several limitations, such as poor water solubility, cardiotoxicity, development of drag resistance and metabolic inactivation. There is therefore, a urgent need for such κ antibiotics which do have the disadvantages of the prior art. Objects of the invention ■• It is therefore am important object of the present invention is to provide a new pyrrolo [2, 1-c] [1, 4]- benzodiazepine hybrids useful as antitumour agents. Another object of the present invention is to provide a process for the preparation of novel pyrrolo [2, 1-c] 1,4]- benzodiazepine hybrids useful as antitumour agents. Summary of the invention The above and othe objects of the present invention'are achieved by providing a novel pyrrolo [ 2, 1-c] [1,4] benzodiazepine hybrid compound. The present invention also provides a process for the preparation of 7-methoxy- 8-{n-[41H- benzo [d] imidazolo - 2 yl phenoxy] alkyl } - oxy (llaS) 1,2,3,-11 a tetrahydro- 5H- pyrrolo [ 2,1- c] 1, 4] benzodiazepin- 5 one V, 7- methoxy- 8- (n -{ 4-[6- (4-methyl hexahydro- 1- pyrainyl)- 1 H- benzo [d] imidazol- 2 yl] phenoxy } alkyl)- oxy- (l laS) - 1,2,3, 11a - tetrahydro - 5 H- pyrrolo 1 H- benzodiazepin 5 one V, 7- methoxy- 8 (n- {4- [6-4 methyl hexahydro-1 prazinyl)- lH-benzo [d] imidazol- 2- yl [ phenoxy} alkyl ) oxy- (l laS)- 1,2,3, -11 a- tetrahydro-5H-pyrrolo [2,1-c) [ 1,4] benzodiazepin -5 one IX and 7- methoxy-8 (n- {4-[ 6-4-ethylhexahydro-l- pyraziny)- 1H- benzo [d] imidazol-2- yl] phenoxy} alkyl ) - oxy- (l laS) - 1,2,3, -lla-tetra hydro 5H-pyrrolo [ 2,1-c) [1,4] bebzidiazepin- 5 one with aliphatic chain lenth variation of these compounds. These novel compounds also show DNA binding and anticancer (antitumour) activity. These novel pyrrolo [ 2,1,-c] [1,4] benzodiazepines have the general Formula XIV shown below:
Figure imgf000004_0001
n = 3 - 5 R = H,
Figure imgf000004_0002
In a preferred embdodiment, present invention provides a process^ for the preparation of a novel pyrrolo [ 2,1-c] [1,4] benzodiazepine hybrids selected from the compounds of formulae V, IX and XIII wherein R= H, N- methylpypazine, N- ' ethylpyperazine and "n" is 3 to.5,
Figure imgf000004_0003
n = 3 - 5
Figure imgf000004_0004
Figure imgf000005_0001
Accordingly the present process provides a process for preparation of pyrrolo [ 2,1-c] 1, 4] benzodiazepine hybrids of formula V
Figure imgf000005_0002
n = 3 - 5 V
which comprises reacting a 4- (ItY- benzo[d] imidazol-2-yl) phenol of the formula I,
Figure imgf000005_0003
with N- [4-(n- bromoalkyloxy)-5- methoxyy-2- nitrobenzo-yl] pyrrolidine- 2- carboxaldehyde diethyl thio acetal of formula II
Figure imgf000005_0004
in the presence of K2 CO3 in organic solvent for a period of 12 to 24 hrs, isolating (2S)- N- {4r (liA benoz [d] imidazolo- 2 yl) phenoxy] alkyl - oxy- 5 methoxy- 2- nitrobenzoyl} pyrrolidine-2- carboxaldehyde diethyl thioacetal III
Figure imgf000005_0005
where "n" is 3 to 5, reducing said compound of formula III with SnCl2. 2H2O in the presence of organic solvent up to a reflux temperature, isolating the (2S) -N- {n- 4- (1 H- benzo [d] imidazolo- 2 yl) phenoxy] alkyl]-oxy- 5- methoxy- 2- aminobenzoyly} pyrrolidine- 2- cstrboxaldehyde diethyl thioacetal of the formula IV
Figure imgf000006_0001
where n is 3 to 5 by known methods, reacting the said amino compound of formula IV with conventional deprotecting agents in to produce pyrrolo [ 2,1-c] 1, 4] benzodiazepine hybrids of formula V, wherein "n" is as defined above. In another embodiment, the present invention provides a process for preparation of pyrrolo [ 2,1-c] 1, 4] benzodiazepine hybrids of formula IX
Figure imgf000006_0002
which comprises reacting a 4- [6-4- methylhexahydro- 1- pyrazinyl)- 1H - benzo[ imidazol- 2- yl] phenol VI
Figure imgf000006_0003
with .N- [4-(n- bromoalkyloxy)-5- methoxyy-2- nitrobenzo-yl] pyrrolidine- 2- carboxaldehyde diethyl thio acetal of formula II
Figure imgf000006_0004
in the presence of K2 CO3 in organic solvent for a period of 12 to 24 hrs, isolating (2S)- N- (n- (4- [6-4- methylhexahydro- 1- pyraxinzyl)- 1H- benzo [d] imidazol- 2-yl] phenoxy] alkyl-oxy- 5- methoχy-2- nitrobenzoy pyrrolidine-2- carboxaldehyde diethyl thioacetal VII
Figure imgf000007_0001
where "n" is 3 to 5, reducing said compound of formula VII with SnCl_. 2H2O in the presence of organic solvent up to a reflux temperature, isolating (2S)-N- {n- (4- [6-(4- methylhexahydro- 1- pyrazinyl )- IH- benzo [d] imidazol-2- yl] phenoxy] alkyl)-o xy- 5- methoxy -2- aminobenzoy} pyrrolidine-2- carboxaldehyde diethyl thioacetal VIII
Figure imgf000007_0002
and reacting the said amino compound of formula VIII with conventional deprotecting agents in to produce pyrrolo [ 2,1-c] 1, 4] benzodiazepine hybrids of formula IX. wherein "n" In yet another embodiment, the present invention provides a process for preparation of pyrrolo [ 2,1-c] 1, 4] benzodiazepine hybrids of formula XTII
Figure imgf000007_0003
which comprises reacting a 4- [6-(4- ehtylhexahydro- I- pyrazinyl)- \H- benzo [d] imidazol-2- yl] phenol X
Figure imgf000007_0004
with N- [4-(n- bromoalkyloxy)-5- methoxyy-2- nitrobenzo-yl] pyrrolidine- 2- carboxaldehyde diethyl thio acetal'of formula II
Figure imgf000008_0001
in the presence of K2 CO3 in organic solvent for a period of 12 to 24 hrs, isolating (2S)- N- {n- (4- [6-4- ehtyhexahydro-1- pyrazinyl)- H- benzo [d] imidazol-2- yl] phenoxy ] alkyll] - oxy- 5- methoxyr 2- nitrobenzoyl} pyrrolidine- 2- carboxaldehyde diethyl thioacetal XI
Figure imgf000008_0002
XI
where "n" is 3 to 5, reducing said compound of formula XI with SnCk. 2H2O in the presence of organic solvent up to a reflux temperature, isolating (2S)-N- {n-(4-[6-(4- ehtylhexahydro-1- pyrazinyl)-lH - beι»zo[d] imidazol-2- yl] phenoxy] alkyl)- oxy-5- methoxy-2- aminobenzoyl} pyrrolidine- 2- carboxaldehyde diethyl thioacetal XII where n is 3 to 5
Figure imgf000008_0003
and reacting' the said amino compound of formula XII with conventional deprotecting agents to produce pyrrolo [ 2,1-c] 1, 4] benzodiazepine hybrids of formula XIII wherein "n" is as defined above.. Detailed Description The precursors, 4- (IH- benzo [d] imidazo 1-2-yl) phenol 1, 4- [6- (4- methylhexadhyro-1- pyrazinyl)- IH- benzo [d] imidazo 1-2- yl] phenol VI and 4- [6-(4 ehtylhexahydro-1- pyrazinyl)- IH- benzo[d] dimidazol-2-,'yl] phenol X (Ji, Yu,; Hasler , W,; Schmitt, V. R.; Dora, A.; Baily C; Waring, M.J.; Hochstrasser, R.; Keupin, W. Bioorg Med Chem Lett. 2001, 9, 2905) and (2S)-N- [4-(b- bromoalkyloxy)- 5- methoxy- 2- nitrobenzo- yl] pyrrolidine-2-carboxaldehyde diethyl thioacetal II ( amal, A.; Ramesh, G.; Laxman, N.; Ramulu, P.; Srinivas, O,; Neelima, K.; Kondapi, A. K.; Srinu, V. B.; Nagarajaram H. M. J. Med. Chem. 2002, 45,4679) have been prepared by literature methods. Some representative compound of formulae V/IX/XIII of present invention are given below 1. 7-Methoxy -8- n{3-[4- (1 H- benzo [d] imidazolo- 2 yl) phenoxyl ] propoxy} - (l laS) 1,2,3- l la -tetrahydro- 5H- pyrrolo [ 2,1-c] 01,4] benzodiazepin- 5- one. 1
2. 7-Methoxy -8- {4- [4- )lH-benzo [d] imidazolo- 2yl phenoxy] butoxy} - (1 laS) 1,2,3-1 la-tetrahydro- 5H- pyrrolo[ 2,1- c] [1,4] benzodiazepin -5- one
3. 7- Methoxy- 8- {5 - [4-(lH- benzo [d] imidazolo - 2yl) phenoxyl] pentyloxy} - (l laS) 1,2,3,-1 la-tetrahydro-5H- pyrrolo {2, 1-c] [1, 4] benzodiazepin-5- one 4. 7- methoxy -8- (3-{4-[6-(4- methylhexahydro- 1- pyrazinyl)- IH- benzol [d] imidazol-2- yl] phexnoxy} propoxy ) - (llaS)- 1,2,3-11 a- tetrahydro- 5 H- pyrrolo [2,1-c] 5. 7-methoxy-8- (4-{4-[6-(4- methylhexaydro-1- pyrazinyl)- IH- benzol [ d] imidazol-2- yl] phenoxy} butoxy)- (llaS) -1,2,3,-11 a- tetrahydro-5 H- pyrrolo [2,1-c] [1,4] benzodiazepin- 5- one 6. 7- methoxy- 8- (5- {4-[6- (4- methylhexahydro- 1 - pyrazinyl)- 1 H- benzo[d] imidazol-2- yl] phenoxy} pentyloxy)- (llaS)- 1,2,3- 11a- tetrahydro-5- pyrrolo [2,1-c) [1,4] benzodiazepin -5- one A 7-methoxy-8- (3-{4-[6-(4- ethyexahydro-1- pyrazinyl)- IH- benzofd] imidazol- 2- yl] phenoxy)- (llaS)- 1,2,3,-11 a- tetrahydro- 5H- pyrrolo [2, 1- c] . [l,4]benzodiazepin- 5 - one 8. 7- methoxy-8- (4-{4-[6-(4- ethylhexahydro-1- pyrazinyl)- 1 H- benzo [d] imidazol-2- yl] phenoxy } butoxy- (l laS)- 1,2,3-1 la- tetrahydro- 5H- pyrrolo [2,1-c] [1,4] benzodiazepin -5- one 9. 7- methoxy-8- (5-{4-[6-(4- ethylhexahydro-1- pyrazinyl)- 1 H- benzo [d] imidazol-2- yl] phenoxy } pentyloxy- (llaS)- 1,2,3-1 la- tetrahydro- 5H- pyrrolo [2,1-c] [1,4] benzodiazepin-5- one These new analogues of pyrrolo [2,1-c] [1,4] benzodiazepin hybrids linked at C-
8 position have shown promising DNA binding 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 the following reaction Schemes which comprise:
1. The either linkage at C-8 position of DC-81 intermediates with substituted 2- phenoxy benzimadazole moiety.
2. Up to refluxing the reaction mixture for 12-48 h.
3. Synthesis of C-8 linked PBD antitumour antibiotic hybrid i ines. 4. Purification by column chromatography using different solvents like ethyl acetate hexane, dichloromethane, chlorform and methanol.
Reaction Schemes
Figure imgf000011_0001
Figure imgf000012_0001
VIII
Figure imgf000012_0002
Figure imgf000013_0001
XI
Figure imgf000013_0002
n = 3 • 5 XIII The invention will now be described with reference to the following example, which are given by way of illustration and therefore should not be construed to the present limit of the scope of invention. Example 1 Compound 4-[lH-benzo [d] imidazol-2-yl] phenol I (210 mg, 1 mmol) and (2S)-N-4-(3-bromobutyloxy)-5-methoxy-2-nitrobenzoyl] pyrrolidin-2-carboxaldehyde diethyl thioacetal of formula II (521 mg, 1 mmol) was taken in dry DMF (lOmL). K2CO3 (690mg, 5mmol) was added and the mixture was stirred for 12 to 24hrs. The reaction mixture was poured in to ice-water then solid was formed and it was filtered and aqueous media was extracted with EtOAc and CHC13 (50 mL), then the extracted solution was evaporated in vacuum to obtain the solid compound. Two solids were combined and the crude material was. chromatographed over silica gel using chloroform / methanol (8:2) solvent to give compound (2S)-N-{3-(4-(lH-benzo[d] imidazol-2-yl] phenoxy) propoxy-5-method-2-nitrobenzoyl} pyrrolidine-2- carboxaldehyde diethyl thioacetal VII as a sticky solid. The compound (2S)-N-{3-(4-(li/-benzo[d] imidazol-2-yl] phenoxy) propoxy- 5-method-2-nitrobenzoyl} pyrrolidine-2-carboxaldehyde diethyl thioacetal III (0.649 mg, 1 mmol) was dissolved in methanol (15 ml) and added SnCl2.2H2O (1.13 g, 5 mmol) was refluxed fro 2-5 h or until the TLC indicated that reaction was completed. The reaction mixture was then adjusted to pH 8 carefully with saturated NaHCO3 solution, diluted with ethyl acetate, filtered through celite and extracted. The combined organic phase was dried over Na2SO4, and evaporated under vacuum to afford the crude v compound (2S)-N-{3-(4-(lH-benzo[d] imidazolo-2-yl] phenoxy) propoxy-5-method-2- aminobenzoy!} pyrrolidine-2-carboxaldehyde diethyl thioacetal VIII. • A solution of compound (2S)-N-{3-(4-(lH-benzo[d] imidazolo-2-yl] phenoxy) propoxy-5-method-2-aminobenzoyl} pyrrolidine-2-carboxaldehyde diethyl thioacetal IV (619 mg, 1 mmol), HgCl2 (613 mg, 2.26 mmol) and CaCO3 (246 mg, 2.46 mmol) in MeCN-water (4:1) was stirred slowly at room temperature until TLC indicates completed loss of starting material. The reaction mixture was diluted with EtOAc (30mL) and filtered through a celite bed. The clear brown organic supernatant was extracted with saturated 5% NaHCO3 (20mL), brine (20mL) and the combined organic phase was dried (Na2SO ). The organic layer was evaporated in vacuum and purified by column chromatography (95% CH2Cl2-MeOH) to give compound 7-methoxy-8-(3- [4-[lH-benzo[d] imidazol-2-yl] phenoxy} protoxy)-(l laS)-l, 2, 3, - l la-tetrahydro- 5H-pyrrolo[2,l-c] [1,4] benzodiazepin-5-one.
1HNMR (CDC13) & 1.90-2.10 (m,2H), 2.20-2.39 (m, 4H), 3.90 (s, 3H), 3.90 (m,3H), 4.10-4.30 (m, 4H), 6.80-6.98 (3s,3H), 7.10-7.30 (m, 2H), 7.45 (s,lH), 7.5-7.65 (m, 3H), 7.85-7-.90 (d, 2H); MS (TAB) 497 [M+H]+. Example 2 Compound 4-[lH-benzo [d] imidazol-2-yl] phenol I (210 mg, 5 mmol) and (2S)-N-[4-(4-bromobutyloxy)-5-methoxy-2-nitrobenzoyl] pyrrolidin-2-carboxaldehyde diethyl thioacetal of formula II (535 mg, 1 mmol) was taken in dry DMF (lOmL). K2CO3 (690 mg, 5 mmol) was added and the mixture was stirred for 12 to 24hrs. The reaction mixture was poured in to ice-water then solid was formed and it was filtered and aqueous media was extracted with EtOAc and CHC13 (50 mL). Then the extracted solution was evaporated in vacuum to obtain the solid compound. Two solids were combined and the crude material was chromatographed over silica gel using chloroform /'methanol (8:2) solvent to give compound (2S)-N-{3-(4-(lH-benzo[d] imidazol-2-yl] phenoxy) propoxy] butoxy-5-method-2-nitrobenzoyl} pyrrolidine-2-carboxaldehyde diethyl thioacetal III as a sticky solid. The compound (2S)-N-{4-(4-(lH-benzo[d] imidazol-2-yl] phenoxy)-5- methoxy-2-nitrobenzoyl} pyrrolidine-2-carboxaldehyde diethyl thioacetal III (633 mg, 1 mmol) was dissolved in methanol (15 ml) and added with SnCl2.2H2O (1.12 g, 5 mmol) and was refluxed for 2-5 h or until the TLC indicated that reaction was completed. The reaction mixture was then adjusted to pH 8 .carefully with saturated NaHCO3 solution,
'diluted with ethyl acetate, filtered through celite and extracted. The combined organic phase was dried over Na2SO4, and evaporated under vacuum to afford the crude compound (2S)-N-{3-(4-(lH-benzo[d] imidazolo-2-yl]phenoxy] butoxy-5 -methoxy -2- aminobenzoyl} pyrrolidine-2-carboxaldehyde diethyl thioacetal IV. A solution of compound (2S)-N-{4-(4-(lH-benzo[d] imidazolo-2-yl] phenoxy) butoxy-5-method-2-aminobenzoyl} pyrrolidine-2-carboxaldehyde diethyl thioacetal IV (603 mg, 1 mmol), ΗgCl2 (613 mg, 2.26 mmol) and CaCO3 (246 mg, 2.46 mmol) in MeCN-water (4:1) was stirred slowly at room temperature until TLC indicates completed loss of starting material. The reaction mixture was diluted with EtOAc (30mL) and filtered through a celite bed. The clear brown organic supernatant was extracted with saturated 5% NaHCO3 (20mL), brine (20mL) and the combined organic phase was dried (Na2SO ). The organic layer was evaporated in vacuum and purified by column chromatography (95% CH2Cl2-MeOH) to give compound 7-methoxy-8-(3-[4- [lH-benzo[d] imidazol-2-yl] phenoxy} butoxy)-(llaS)-l,2,3,-lla-tetrahydro-5H- pyrrolo[2,l-c] [1,4] benzodiazepin-5-one.
1H NMR (CDC13) & 1.80-2.20 (m,6H), 2.21-2.42 (m, 2H), 3.50-3.95 (m, 6H), 4.05- 4.30 (m,4H), 6.70-682 (m, 3H), 7.19-7.21 (m, 2H), 7.3 (s, IH), 7.59-7.70 (m, 3H), 7.80-7.70 (m, 3H), 7.80-7.90 (d, 2H); MS (FAB) 511[M+H]+. Example 3 Compound 4-[lH-benzo [d] imidazol-2-yl] phenol I (210 mg, 1 mmol) and (2S)-N-[4-(5-bromobutyloxy)-5-methoxy-2-nitrobenzoyl] pyrrolidin-2-carboxaldehyde diethyl thioacetal of formula II (549 mg, 5 mmol) was taken in dry DMF (lOmL), K2CO3 (690 mg, 5 mmol) was added and the mixture was stirred for 12-24th. The reaction mixture was poured in to ice-water then solid was formed and it was filtered and aqueous media was extracted with EtOAc and CHC13 (50 mL). Then the extracted solution was evaporated in vacuum to obtain the solid compound. Two solids were combined and the crude material was. chromatographed over silica gel using chloroform / methanol (9:1) solvent to give compound (2S)-N-{5-(4-(lH-benzo-[d] imidazol-2-yl] phenoxy) pentyloxy-5-method-2-nitrobenzoyl} pyrrolidine-2- carboxaldehyde diethyl thioacetal III as a sticky solid. The compound (2S)-N-{5-(4-(lH-benzo[d] imidazol-2-yl] phenoxy) pentyloxy- 5-methoxy-2-nitrobenzoyl} pyrrolidine-2-carboxaldehyde diethyl thioacetal III (0.647 g, 1 mmol) was dissolved in methanol (15 ml) and added SnCl2.2H2O (1.12 g, 5 mmol) was refluxed fro 2-5 h or until the TLC indicated that reaction was completed. The
'reaction mixture was then adjusted to pH 8 carefully with saturated NaHCO3 solution, diluted with thyl acetate, filtered through celite and extracted. The combined organic phase was dried over Na2SO4, and evaporated under vacuum to afford the crude compound (2S)-N-{5-(4-(lH-benzo[d] imidazolo-2-yl]phenoxy] pentyloxy-5-methoxy -2-aminobenzoyl} pyrrolidine-2-carboxaldehyde diethyl thioacetal IV. A solution of compound (2S)-N-{5-(4-(lH-benzo[d] imidazolo-2-yl] phenoxy) pentyloxy-5-method-2-aminobenzoyl} pyrrolidine-2-carboxaldehyde diethyl thioacetal III (617 mg, 1 mmol), HgCl2 (613 mg, 2.26 mmol) and CaCO3 (246 mg, 2.46 mmol) in MeCN-water (4:1) was stirred slowly at room temperature until TLC indicates completed loss of starting material. The reaction mixture was diluted with EtOAc (30mL) and filtered through a celite bed. The clear brown organic supernatant was extracted with saturated 5% NaHCO3 (20mL), brine (20mL) and the combined organic phase was dried (Na2SO4). The organic layer was evaporated in vacuum and purified by column chromatography (95% CH2Cl2-MeOH) to give compound 7-methoxy-8-(5-[4- [lH-benzo[d] imidazol-2-yl] phenoxy} pentyloxy)-(llaS)-l,2,3,-l la-tetrahydro-5H- pyrrolo[2,l-c] [1,4] benzodiazepin-5-one. 1H NMR (CDC13) & 1.60-2.19 (m, 8H), 2.25-2.39 (m, 2H), 3.60-4.20 (m, lOH), 6.70- 6.90 (m,3H), 7.19-7.30 (m, 2H), 7.50 (s, IH), 7-.65-7.78 (m, 3H), 7.90-8.01 (d, 2H); MS (FAB) 525[M+H]+. Example 4 Compound 4-[6-(4-methylhexahydro-l-pyrazinyl)-lH-benzo [d] imidazol-2-yl] phenol VI (328 mg, 1 mmol) and (2S)-N-[4-(3-bromobutyloxy)-5-methoxy-2- nitrobenzoyl] pyrrolidin-2-carboxaldehyde diethyl thioacetal of formula II (521 mg, 1 mmol) was taken in dry DMF (lOmL). K2CO3 (690 mg, 5 mmol) was added and the mixture was stirred for 12-24*. The reaction mixture was poured in to ice-water then solid was formed and it was filtered and aqueous media was extracted with EtOAc and CHC13 (50 mL), then the extracted solution was evaporated in vacuum to obtain the solid compound. Two solids were combined and the crude material was. chromatographed over silica gel using chloroform / methanol (9:1) solvent to give compound (2S)-N-{3-(4-(6(4-Methylhexahydro-l-pyrazinyl)-lH-benzo [d] imidazol- 2-yl] phenoxy) propoxy-5-methoxy-2-nitrobenzoyl} pyrrolidine-2-carboxaldehyde diethyl thioacetal VII as a stick solid. The compound (2S) -N-{3-(4-[6-(4-methylhexahydro-l-pyrazinyl)-lH-benzo [d] imidazol-2-yl] phenoxy) propoxy-5-methoxy-2-nitrobenzoyll} pyrrolidine-2- 'carbόxaldehyde diethyl thioacetal VII (0.767 g, 1 mmol) was dissolved in methanol (15 ml) and added SnCl2.2H2O (1.12 g, 5 mmol) was refluxed fro 5-7 h or until the TLC indicated that reaction was completed. The reaction mixture was then adjusted to pH 8 carefully with saturated NaHCO3 solution, diluted with ethyl acetate, filtered through celite and extracted. The combined organic phase was dried over Na2SO , and evaporated under vacuum to afford the crude compound (2S) -N-{3-(4-[6-(4- methylhexahydro-l-pyrazinyl)-lH-benzo[d]imidazol-2-yl] imidazol-2- yl]phenoxy)propoxy-5-methoxy-2-aminobenzoyl}pyrrolidine-2-carboxaldehyde diethyl thioacetal VIII. A solution of compound (2S) -N-{3-(4-[6-(4-methylhexahydro-l-pyrazinyl)- lH-benzo[d]imidazol-2-yl] imidazol-2-yl]phenoxy)propoxy-5-methoxy-2- aminobenzoyl}pyrrolidine-2-carboxaldehyde diethyl thioacetal VIII (637 mg, 1 mmol), HgCl2 (613 mg, 2.26 mmol) and CaCO3 (246 mg, 2.46 mmol) in MeCN-water (4:1) was stirred slowly at room temperature until TLC indicates completed loss of starting material. The reaction mixture was diluted with EtOAc (30mL) and filtered through a celite bed. The clear brown organic supernatant was extracted with saturated 5% NaHCO3 (20mL), brine (20mL) and the combined organic phase was dried (Na2SO4). The organic layer was evaporated in vacuum and purified by column chromatography (80% CH2Cl2-MeOH) to give compound 7-methoxy-8-(3-[4-[6-(4-methyllιexahydro- l-pyraziny)-lH-benzo[d] imidazol-2-yl] phenoxy} propoxy)-(llaS)-l, 2, 3, - 11a- tetrahydro-5H-pyrrolo[2,l-c] [1,4] benzodiazepin-5-one. IH NMR (CDC13) & 1.90-2.15 (m,3H), 2.20-2.30 (m, 3H), 2.40 (s, 3H), 2.60-2.75 (m,4H), 3.10-3.20 (m, 3H), 3.90 (s,3H), 4.10-4.35 (m, 4H), 6.75 (s, IH), 6.80-7.1 (m, 5H), 7.60-7.70 (d, IH, J=4.4 Hz), 7.90-8.10 (d, 2H): MS (FAB) 595 [M+H]+. Example 5 ' Compound 4-[6-(4-methylhexahydro-l-pyrazonyl)-lH-zenzo [d] imidazol-2-yl] phenol VI (328 g, 1 mmol) and (2S)-N-4-(4-bromobutyloxy)-5-methoxy-2- nitrobenzoyl] pyrrolidin-2-carboxaldehyde diethyl thioacetal of formula II (535 mg, 1 mmol) was stirred for 12-24 . The reaction mixture was poured in to ice-water then solid was formed and it was filtered and aqueous media was extracted with EtOAc and CHC13 (50 mL), then the extracted solution was evaporated in vacuum to obtain the solid compound. Two solids were combined and the crude material was. Ghromatographed over silica gel using chloroform / methanol (8:2) solvent to give compound (2S)-N-{4-(4-[6-(4-methylhexahydro-l-pyrazinyl)-lH-benzo[d] imidazol-
' 2-yl] phenoxy) butoxy-5-method-2-nitrobenzoyl} pyrrolidine-2-carboxaldehyde diethyl thioacetal VII as a sticky solid. • The compound (2S) -N-{4-(4-[6-(4-methylhexahydro-l-pyrazinyl)-lH-benzo [d] imidazol-2-yl] phenoxy) propoxy-5-methoxy-2-nitrobenzoyll} pyrrolidine-2- carboxaldehyde diethyl thioacetal VII (0.781 g, 1 mmol) was dissolved in methanol (15 ml) and added SnCl2.2Η2O (1.12 g, 5 mmol) was refluxed fro 5-7 h or until the TLC indicated that reaction was completed. The reaction mixture was then adjusted to pH 8 caref lly with saturated NaHCO3 solution, diluted with ethyl acetate, filtered through celite and extracted. The combined organic phase was dried over Na2SO4, and evaporated under vacuum to afford the crude compound (2S) -N-{4-(4-[6-(4- methylhexahy dro- 1 -pyraziny 1 )- 1 H-benzo [d]imidazol-2-yl] imidazol-2- yl]phenoxy)propoxy-5-metJιoxy-2-aminobenzoyl}pyrrolidine-2-carboxaldehyde diethyl thioacetal VIII. A solution of compound (2S) -N-{4~(4-[6-(4-methylhexahydro-l-pyrazinyl)- lH-benzo[d]imidazol-2-yl] imidazol-2-yl]phenoxy)propoxy-5-methoxy-2- aminobenzoyl }pyrrolidine-2-carboxaldehyde diethyl thioacetal VIII (751 mg, 1 mmol), HgCl2 (613 mg, 2.26 mmol) and CaCO3 (246 mg, 2.46 mmol) in MeCN-water (4:1) was stirred slowly at room temperature until TLC indicates completed loss of starting material. The reaction mixture was diluted with EtOAc (30mL) and filtered through a celite bed. The clear brown organic supernatant was extracted with saturated 5% NaHCO3 (20mL), brine (20mL) and the combined organic phase was dried ( a2SO ). The organic layer was evaporated in vacuum and purified by column chromatography (80% CH2Cl2-MeOH) to give compound 7-methoxy-8-(4-[4-[6-(4-methylhexahydro-l- pyraziny)-lH-benzo[d] imidazol-2-yl] phenoxy} butoxy)-(llaS)-l, 2, 3, - 11a- tetrahydro-5H-pyrrolo[2,l-c] [1,4] benzodiazepin-5-one. 1H NMR (CDC13) & 1.80-2.18 (m,3H), 2.35 (m, 3H), 2.60-2.70 (s, 4H), 3.10-3.20
(m,4H), 3.60-3.80 (m, 3H), 3.90 (s,3H), 4.01-4.25 (m, 4H), 6.72 (s, IH), 7.35 (m, 5H), 7.61-7.30 (d, IH, J=3.6 Hz), 7.98-8.03 (d, 2H): MS (FAB) 6.9 [M+H]+. Example 6 1 Compound 4-[6-(4-methylhexahydro-l-pyrazonyl)-lH-zenzo [d] imidazol-2-yl] phenol VI (328 g, 5 mmol) and (2S)-N-4-(5-bromobutyloxy)-5-methoxy-2- nitrobenzoyl] pyrrolidin-2-carboxaldehyde diethyl thioacetal of formula II (549 mg, 1 mmol) was taken in dry DMF (lO L). K2CO3 (690mg, 5 mmol) was added and the
"mixture was stirred for 12-24*. The reaction mixture was poured in to ice-water then 'solid was formed and it was filtered and aqueous media was extracted with EtOAc and CHC13 (50 mL), then the extracted solution was evaporated in vacuum to obtain the solid compound. Two solids were combined and the crude material was. Chromatographed over solica gel using chloroform / methanol (8:2) solvent to give compound (2S) -N-{5-(4-[6-(4-methylhexahydro-l-pyrazinyl)-lH-benzo[d] imidazol- 2-yl] phenoxy) ρentyloxy-5-method-2-nitrobenzoyl} pyrrolidine-2-carboxaldehyde diethyl thioacetal VII as a sticky solid. The compound (2S) -N-{5-(4-[6-(4-methylhexahydro-l-pyrazinyl)-lH-benzo [d] imidazol-2-yl] phenoxy) propoxy-5-methoxy-2-nitrobenzoyll} pyrrolidine-2- carboxaldehyde diethyl thioacetal VII (0.795 g, 1 mmol) was dissolved in methanol (15 ml) and added SnCl2.2H2O (1.12 g, 5 mmol) was refluxed fro 5-7 h or until the TLC indicated that reaction was completed. The reaction mixture was then adjusted to pH 8 carefully with saturated NaHCO3 solution, diluted with ethyl acetate, filtered through celite and extracted. The combined organic phase was dried over Na2SO4, and evaporated under vacuum to afford the crude compound (2S) -N-{5-(4-[6-(4- methylhexahydro-l-pyrazinyl)-lH-benzo[d]imidazol-2-yl] imidazol-2-yl]phenoxy) pentyloxy -5-methoxy-2-aminobenzoy 1 }pyrrolidine-2-carboxaldehyde diethyl thioacetal VIII. A solution of compound (2S) -N-{4-(5-[6-(4-methylhexahydro-l-pyrazinyl)- lH-benzo[d]imidazol-2-yl] imidazol-2-yl]phenoxy)propoxy-5-methoxy-2- aminobenzoyl} pyrrolidine-2-carboxaldehyde diethyl thioacetal (765 mg, 1 mmol), HgCl2 (613 mg, 2.26 mmol) and CaCO3 (246 mg, 2.46 mmol) in MeCN-water (4:1) was stirred slowly at room temperature until TLC indicates completed loss of starting material. The reaction mixture was diluted with EtOAc (30mL) and filtered through a celite bed. The clear brown organic supernatant was extracted with saturated 5% NaHCO3 (20mL), brine (20mL) and the combined organic phase was dried (Na2SO4). The organic layer was evaporated in vacuum and purified by column chromatography (80% CH2Cl2-MeOH) to give compound 7-methoxy-8-(5-[4-[6-(4-methylhexahydro-l- pyraziny)-lH-benzo[d] imidazol-2-yl] phenoxy} butoxy)-(llaS)-l,2,3, - 11a- tetrahydro-5H-pyrrolo[2,l-c] [1,4] benzodiazepin-5-one. 1HNMR (CDC13) & 1.75-2.95 (m,3H), 2.19-2.21 (m, 3H), 2.55-2.61 (m, 4H), 3.10- Ϊ.20 (m,4H), 3.60-3.80 (m, 3H), 3.85 (s,3H), 3.90-4.19 (m, 4H), 6.68 (s, IH), 6.78-6.90 (m, 4H), 6.90 (s, IH) 7.50-7.60 (d, IH, J=4.4 Hz), 7.90-8.09 (d, 2H): MS (FAB) 623 l[M+H]+. Example 7 • Compound 4-[6-(4-methylhexahydro-l-pyrazonyl)-lH-zenzo [d] imidazol-2-yl] phenol X (342 g, 5 mmol) and (2S)-N-4-(3-bromobutyloxy)-5-methoxy-2- nitrobenzoyl] pyrrolidin-2-carboxaldehyde diethyl thioacetal of formula II (521 mg, 1 mmol) was taken in dry DMF (lOmL). K2CO3 (690mg, 5 mmol) was added and the mixture was stirred for 12-24*. The reaction mixture was poured in to ice-water then solid was formed and it was filtered and aqueous media was extracted with EtOAc and CΗC13 (50 mL), then the extracted solution was evaporated in vacuum to obtain the solid compound. Two solids were combined and the crude material was. Chromatographed over solica gel using chloroform / methanol (8:2) solvent to give compound (2S) -N-{3-(4-[6-(4-methylhexahydro-l-pyrazinyl)-lH-benzo[d] imidazol- 2-yl] phenoxy) propoxy-5-method-2-nitrobenzoyl} pyrrolidine-2-carboχaldehyde diethyl thioacetal VII as a sticky solid. The compound (2S) -N-{3-(4-[6-(4-methylhexahydro-l-pyrazinyl)-lH-benzo [d] imidazol-2-yl] phenoxy) propoxy-5-methoxy-2-nitrobenzoyll} pyrrolidine-2- carboxaldehyde diethyl thioacetal XI (0.781 g, 1 mmol) was dissolved in methanol (15 ml) and added SnCl2.2H2O (1.12 g, 5 mmol) was refluxed fro 2-5 h or until the TLC indicated that reaction was completed. The reaction mixture was then adjusted to pH 8 carefully with saturated NaHCO3 solution, diluted with ethyl acetate, filtered through celite and extracted. The combined organic phase was dried over Na2SO4, and evaporated under vacuum to afford the crude compound (2S) -N-{3-(4-[6-(4- methylhexahydro-l-pyrazinyl)-lH-benzo[d]imidazol-2-yl] imidazol-2- yl]phenoxy)proρoxy-5-methoxy-2-aminobenzoyl}pyrrolidine-2-carboxaldehyde diethyl thioacetal XII. A solution of compound (2S) -N-{3-(4-[6-(4-methylhexahydro-l-pyrazinyl)- lH-benzo[d]imidazol-2-yl] imidazol-2-yl]phenoxy)propoxy-5-methoxy-2- aminobenzoyl} pyrrolidine-2-carboxaldehyde diethyl thioacetal (765 mg, 1 mmol), HgCl2 (613 mg, 2.26 mmol) and CaCO3 (246 mg, 2.46 mmol) in MeCN-water (4:1) was stirred slowly at room temperature until TLC indicates completed loss of starting material. The reaction mixture was diluted with EtOAc (30mL) and filtered through a celite bed. The clear brown organic supernatant was extracted with saturated 5% NaHCO3 (20mL), brine (20mL) and the combined organic phase was dried (Na2SO4). The organic layer was evaporated in vacuum and purified by column chromatography (80% CH2Cl2-MeOH) to give compound 7-methoxy-8-(3-[4-[6-(4-methylhexahydro-l- pyraziny)-li?-benzo[d] imidazol-2-yl] phenoxy} butoxy)-(l laS)-l,2,3,-lla-tetrahydro- 5H-pyrrolo[2,l-c] [1,4] benzodiazepin-5-one. Example 8 Compound 4-[6-(4-methylhexahydro-l-pyrazonyl)-lH~zenzo [d] imidazol-2-yl] phenol X (342 g, 5 mmol) and (2S)-N-4-(4-bromobutyloxy)-5-methoxy-2- nitrobenzoyl] pyrrolidin-2-carboxaldehyde diethyl thioacetal of formula II (535 mg, 1 mmol) was taken in dry DMF (lOmL). K2CO3 (690mg, 5 mmol) was added and the mixture was stirred for 12-24*. The reaction mixture was poured in to ice-water then solid was formed and it was filtered and aqueous media was extracted with EtOAc and CHC13 (50 mL), then the extracted solution was evaporated in vacuum to obtain the solid compound. Two solids were combined and the crude material was. chromatographed over solica gel using chloroform / methanol (8:2) solvent to give compound (2S) -N-{4-(4-[6-(4-methylhexahydro-l-pyrazinyl)-lH-benzo[βTl imidazol- 2-yl] phenoxy) butoxy-5-method-2-nitrobenzoyl} pyrrolidine-2-carboxaldehyde diethyl thioacetal XI as a sticky solid. The compound (2S) -N-{4(4-[6-(4-methylhexahydro-l-pyrazinyl)-lH-benzo
[d] imidazol-2-yl] phenoxy) propoxy-5-methoxy-2-nitrobenzoyll} pyrrolidine-2- carboxaldehyde diethyl thioacetal XI (0.795g, mmol) was dissolved in methanol (15 ml) and added SnCl2.2H2O (1.12 g, 5 mmol) was refluxed fro 2-5 h or until the TLC indicated that reaction was completed. The reaction mixture was then adjusted to pH 8 carefully with saturated NaHCO3 solution, diluted with ethyl acetate, filtered through celite and extracted. The combined organic phase was dried over Na2SO , and evaporated under vacuum to afford the crude compound (2S) -N-{4-(4-[6-(4- methylhexahydro-l-pyrazinyl)-lH-benzo[d]imidazol-2-yl] phenoxy) butoxy-5- methoxy-2-aminobenzoyl}pyrrolidine-2-carboxaldehyde diethyl thioacetal XII. A solution of compound (2S) -N-{4-(4-[6-(4-methylhexahydro-l-pyrazinyl)- lH-benzo[d]imidazol-2-yl] imidazol-2-yl]phenoxy)propoxy-5-methoxy-2- aminobenzoyl} pyrrolidine-2-carboxaldehyde diethyl thioacetal (765 mg, 1 mmol), HgCl2 (613 mg, 2.26 mmol) and CaCO3 (246 mg, 2.46 mmol) in MeCN-water (4:1) was stirred slowly at room temperature until TLC indicates completed loss of starting material. The reaction mixture was diluted with EtOAc (30mL) and filtered through a celite bed. The clear brown organic supernatant was extracted with saturated 5% NaHCO3 (20mL), brine (20mL) and the combined organic phase was dried (Na2SO ). 'The organic layer was evaporated in vacuum and purified by column chromatography (80% CH2Cl2-MeOH) to give compound 7-methoxy-8-(4-[4-[6-(4-methylhexahydro-l- pyraziny)-lH-benzo[d] imidazol-2-yl] phenoxy} butoxy)-(l laS)-l,2,3,-l la-tetrahydro- 5H-pyrrolo[2,l-c] [1,4] benzodiazepin-5-one. Example 9 Compound 4-[6-(4-methylhexahydro-l-pyrazonyl)-lH-zenzo [d] imidazol-2-yl] phenol X (342 g, 1 mmol) and (2S)-N-4-(5-bromobutyloxy)-5-methoxy-2- nitrobenzoyl] pyrrolidin-2-carboxaldehyde diethyl thioacetal of formula II (549 mg, 5 mmol) was taken in dry DMF (lOmL). K2CO3 (690mg, S mmol) was added and the mixture was stirred for 12-24*. The reaction mixture was poured in to ice-water then solid was formed and it was filtered and aqueous media was extracted with EtOAc and CHC13 (50 mL), then the extracted solution was evaporated in vacuum to obtain the solid compound. Two solids were combined and the crude material was. chromatographed over silica gel using chloroform / methanol (8:2) solvent to give compound (2S) -N-{5-(4-[6-(4-methylhexahydro-l-pyrazinyl)-lH-benzo[β ] imidazol- 2-yl] phenoxy) pentyloxy-5-method-2-nitrobenzoyl} pyrrolidine-2-carboxaldehyde diethyl thioacetal XI as a sticky solid. The compound (2S) -N-{5(4-[6-(4-methylhexahydro-l-pyrazinyl)-lH-benzo [d] imidazol-2-yl] phenoxy) pentyloxy -5-methoxy-2-nitrobenzoyll} pyrrolidine-2- carboxaldehyde diethyl thioacetal XI (0.809 g, 1 mmol) was dissolved in methanol (15 ml) and added SnCl2'.2H2O (1.12 g, 5 mmol) was refluxed fro 2-5 h or until the TLC indicated that reaction was completed. The reaction mixture was then adjusted to pH 8 carefully with saturated NaHCO3 solution, diluted with ethyl acetate, filtered through celite and extracted. The combined organic phase was dried over Na2SO4, and evaporated under vacuum to afford the crude compound (2S) -N-{5-(4-[6-(4- etyylhexahydro-l-pyrazinyl)-lH-benzo[d]imidazol-2-yl] phenoxy) pentyloxy-5- methoxy-2-aminobenzoyl} pyrrolidine -2-carboxaldehyde diethyl thioacetal XII. A solution of compound (2S) -N-{5-(4-[6-(4-ethylhexahydro-l-pyrazinyl)-lH- benzb[d]imidazol-2-yl] phenoxy)pentyloxy-5-methoxy-2-aminobenzoy 1 } pyrrolidine- 2-carboxaldehyde diethyl thioacetal XII (779 mg, 1 mmol), HgCl2 (613 mg, 2.26 mmol) and CaCO3 (246 mg, 2.46 mmol) in MeCN-water (4:1) was stirred slowly at room temperature until TLC indicates completed loss of starting material. The reaction mixture was diluted with EtOAc (30mL) and filtered through a celite bed. The clear brown organic supernatant was extracted with saturated 5% NaHCO3 (20mL), brine
" (20mL) and the combined organic phase was dried (Na2SO ). The organic layer was evaporated h vacuum and purified by column chromatography (80% CH2Cl2-MeOH) to give compound 7-methoxy-8-(5-[4-[6-(4-ethylhexahydro-l-pyraziny)-lH-benzo[d] imidazol-2-yl] phenoxy} pentyloxy)-(l laS)-l,2,3,-lla-tetrahydro-5H-pyrrolo[2,l-c] [1,4] benzodiazepin-5-one. Biological activity: in vitro biological activity studies were carried out at National Cancer Institute (USA). Cytotoxicity: Compound IX was evaluated for the primary anti-cancer activity (Table- 1) and 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 control was calculated. The mean graph midpoint values of loglO TGI and loglO LC50 as well as log 10 GI50 for VI are listed in Table 2. As demonstrated by mean graph pattern, compound IV exhibits an interesting profile of activity and selectivity for various cell lines. The mean graph mid point of loglO TGI and loglO LC50 showed similar pattern to the loglO Gl 50 mean graph mid points. Table 1 : in vitro one dose primary anticancer assaya of PBD hybrid formula IX as representative compound.
PBD hybrid Growth Percentages.
(Lung) (Breast) (CNS) NCI-H460 MCF7 SF-268
IX 0 0 0
AOne dose of IX at 10"4 molar concentration. The novel pyrrolobenzodiazepine hybrid of formula IX has shown to possess 10 nano molar potency (at the LC50 level) against one non-small cell lung caner (NCI-
H522), one CNS cancer (SF-539), three melanoma cancer (SK-MEL-2-SK-MEL-
5,VACC-62), two renal cancer (A-498, RXF 393), and one breast cancer (MDA-MB-
435). The LC 50 values of nine cancer (average of six to nine cancer cell line) of compound IX listed in Table 3. Table 2. loglO GI50 loglO TGI and LC50 mean graphs midpoints (MG_MID) of in vitro cytotoxicity data for the compound IX as representative compound against human tumour cell lines.
Compound LoglO GI50 LoglO TGI Logl0LC50
V -7.97 -6.79 ' -4.57 Table 3. Log LC50 (concentration in mol/L causing 50% lethality) Values for Compounds IX as representative compound.
Cancer Compound
Leukemia >4.0
Non-small-cell lung -4.89
Colon >-4.03
CNS -4.12 .
Melanoma -5.84
Ovarian >-4.23
Renal -4.33
Prostate -4.48
Breast >-4.65
Each cancer type represents the average of six to nine different cancer cell lines.
437NF/03
Figure imgf000026_0001

Claims

Claims.:
1. A novel ρyrrolo[2, 1-c] [ 1,4] benzodiazepine hybrid of the formula
Figure imgf000027_0001
/ — \ /— \ n = 3 - 5 ~ K N~CH3, _N N-CH2CH3
2. A pyrrolo[2, 1-c] [ 1,4] benzodiazepine hybrid as claimed in claim ϊ having the formula
Figure imgf000027_0002
3 A pyrrolo[2, 1-c] [ 1,4] benzodiazepine hybrid as claimed in claim 1 having the formula
Figure imgf000027_0003
4. A pyrrolo[2, 1-c] [ 1,4] benzodiazepine hybrid as claimed in claim 1 having the formula
Figure imgf000027_0004
5. A ρyrrolo[2, 1-c] [ 1,4] benzodiazepine hybrid as claimed in claim 1 having the formula
Figure imgf000028_0001
6. A pyrrolo[2, 1-c] [ 1,4] benzodiazepine hybrid as claimed in claim ϊ having the formula
Figure imgf000028_0002
7. A pyrrolo[2, 1-c] [ 1,4] benzodiazepine hybrid as claimed in claim 1 having the formula
Figure imgf000028_0003
8. A pyrrolo[2, 1-c] [ 1,4] benzodiazepine hybrid as claimed in claim 1 having the formula
Figure imgf000028_0004
9. A pyrrolo[2, 1-c] [ 1,4] benzodiazepine hybrid as claimed in claim 1 having the formula
Figure imgf000029_0001
10. A pyrrolo[2, 1-c] [ 1,4] benzodiazepine hybrid as claimed in claim 1 having the formula
Figure imgf000029_0002
11. A process for the preparation of pyrrolo [ 2,1-c] 1, 4] benzodiazepine hybrids of formula V
Figure imgf000029_0003
n = 3 - 5 V which comprises reacting a 4- (IH- benzα[dj imidazol-2-yl) phenol of the formula I,
(XA>0Η
with N- [4-(n- bromoallcyloxy)-5- methoxyy-2- nitrobenzo-yl] pyrrolidine- 2- O carboxaldehyde diethyl thio acetal of formula II
Figure imgf000029_0004
in the presence of IC2 CO3 in organic solvent for a period of 12 to 24 hrs, isolating (2S)- N- (4- (IH- benoz [d] imidazolo- 2 yl) phenoxy] alkyl - oxy- 5 methoxy- 2- nitrobenzoyl} pyrrolidine-2- carboxaldehyde diethyl thioacetal III
Figure imgf000030_0001
where "n" is 3 to 5, reducing said compound of formula III with SnCl2. 2Η-.Q in the presence of organic solvent up to a reflux temperature, isolating the (2S) ~N- {n- 4- (1
B- benzo [d] imidazolo- 2 yl) phenoxy] allcyl]-oxy- 5- methoxy- 2- aminobenzoyly}
Figure imgf000030_0002
where n is 3 to 5 by known methods, reacting the said amino compound of formula IV with conventional deprotectiug agents in to produce pyrrolo [ 2,1-c] 1, 4] benzodiazepine hybrids of formula V, wherein "n" is as defined above.
12. A process for the preparation of pyrrolo [ 2,1-c] 1, 4] benzodiazepine hybrids of ■formula IX
Figure imgf000030_0003
which comprises reacting a 4- [6-4- methylhexahydro- 1- pyrazinyl)- IH - benzo[ ipαidazol- 2- yl] phenol VI
Figure imgf000030_0004
wiih N- [4-(n- bromoalkyloxy)-5- methoxyy-2- nitrobenzo-yl] pyrrolidine- 2- carboxaldehyde diethyl thio acetal of formula II B,-(CH2)nO γN0ϊ sCH(SE0_ n °
in the presence of K2 C03 in organic solvent for a period of 12 to 24 hrs, isolating (2S)- N- {n- (4- [6-4- methylhexahydro-1- pyraxinzyl)- IH- benzo [d] imidazol- 2-yl] phenoxy] alkyl-oxy- 5- methoxy-2- nitrobenzoy pyrrolidine-2- carboxaldehyde diethyl thioacetal VII
Figure imgf000031_0001
where "n" is 3 to 5, reducing said compound of formula VII with SnCl2. 2H20 in the presence of organic solvent up to a reflux temperature, isolating (2S)-N- {n- (4- [6-(4- methylhexahydro-1- pyrazinyl )- IH- benzo [d] imidazol-2- yl] phenoxy] alkyl)-o xy- 5- methoxy -2- aminobenzoy} pyrrolidine-2- carboxaldehyde diethyl thioacetal VIII
Figure imgf000031_0002
and reacting the said amino compound of formula VIII with conventional deprotectiug agents in to produce pyrrolo [ 2,1-c] 1, 4] benzodiazepine hybrids of formula IX. wherein "n".
13. A process for the preparation of pyrrolo [ 2,1-c] 1, 4] benzodiazepine hybrids of formula XIII
Figure imgf000031_0003
which comprises .reacting a 4- [6-(4- ehtylhexahydro- I- pyrazinyl)- IH- benzo [d] imidazol-2- yl] phenol X
Figure imgf000032_0001
with N- [4-(n- bromoallcyloxy)-5- methoxyy-2- nitrobenzo-yl} pyrrolidine- 2- carboxaldehyde diethyl thio acetal of formula II
Figure imgf000032_0002
in the presence of 2 CQ3 in organic solvent for a period of 12 to 24 hrs, isolating (2S)- N- {n- (4- [6-4- ehtyhexahydro-1- pyrazinyl)- H- benzo [d] imidazol-2- yl] phenoxy ] alkyll] - oxy- 5- methoxy- 2- nitrobenzoyl} pyrrolidine- 2- carboxaldehyde diethyl thioacetal XI
Figure imgf000032_0003
where "n" is 3 to 5, reducing said compound of formula XI with SaCk. 2H2O in the ■presence, of organic solvent up to a reflux temperature, isolating (2S)-N- (n-(4-[6-(4- ehtylhexahydro- 1- pyrazinyl)- IH - benzo[d] imidazol-2- yl] phenoxy] alkyl)- oxy-5- methoxy-2- aminobenzoyl} pyrrolidine- 2- carboxaldehyde diethyl thioacetal XII where n is 3 to 5
Figure imgf000032_0004
and reacting the said amino compound of formula XII wit conventional deprotectiug agents to produce pyrrolo [ 2,1-c] 1, 4] benzodiazepine hybrids of formula XIII wherein "n" is as defined above.
14. Use of a pyrrolo [ 2,1-c] 1, 4] benzodiazepine hybrid compound as claimed in anyone of claims Ito 10 for the preparation of medicament useful for treating tumours.
15. A pharmaceutical composition for use as antitumour agents comprising of an effective amount of a pyrrolo [ 2,1-c] 1, 4] benzodiazepine hybrid compound as claimed in any one of claims 1 to 10.
16. A method of treating a mammal which comprises administering an affective amount of a pyrrolo [ 2,1-c] 1, 4] benzodiazepine hybrid compound as claimed in any one of claims 1 to 10.
17. A method of treating a mammal, which comprises administering an affective amount of a pharmaceutical composition as claimed in claim 15.
PCT/IN2003/000462 2003-12-31 2003-12-31 PROCESS FOR PREPARING PYRROLO[2, 1-c] [1, 4] BENZODIAZEPINE HYBRIDS WO2005063759A1 (en)

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