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WO2005063759A1 - Procede servant a preparer des hybrides de pyrrolo[2, 1-c] [1, 4] benzodiazepine - Google Patents

Procede servant a preparer des hybrides de pyrrolo[2, 1-c] [1, 4] benzodiazepine Download PDF

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Publication number
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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WO
WIPO (PCT)
Prior art keywords
formula
pyrrolo
benzo
imidazol
compound
Prior art date
Application number
PCT/IN2003/000462
Other languages
English (en)
Inventor
Ahmed Kamal
Poddutoori Ramulu
Olepu Srinivas
Original Assignee
Council Of Scientific And Industrial Research
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Council Of Scientific And Industrial Research filed Critical Council Of Scientific And Industrial Research
Priority to GB0614750A priority Critical patent/GB2424883B/en
Priority to JP2005512761A priority patent/JP4520411B2/ja
Priority to PCT/IN2003/000462 priority patent/WO2005063759A1/fr
Priority to AU2003300718A priority patent/AU2003300718A1/en
Publication of WO2005063759A1 publication Critical patent/WO2005063759A1/fr

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Classifications

    • 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
    • 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
    • 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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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des nouveaux hybrides de pyrrolo[2, 1-c] [1, 4] benzodiazepine, ainsi que des procédés servant à préparer ces nouveaux hybrides. Elle concerne, plus particulièrement, un procédé servant à préparer de nouveaux hybrides de pyrrolo [2, 1-c] [1, 4] benzodiazepine en tant qu'agents sélectifs de séquences d'ADN utiles en tant qu'agents antitumoraux potentiels. Elle concerne, en particulier, un procédé servant à préparer de nouveaux hybrides de pyrrolo [2, 1-c] [1, 4] benzodiazepine en tant qu'agents antitumoraux potentiels. Ces composés sont représentés par la formule (XIV).
PCT/IN2003/000462 2003-12-31 2003-12-31 Procede servant a preparer des hybrides de pyrrolo[2, 1-c] [1, 4] benzodiazepine WO2005063759A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
GB0614750A GB2424883B (en) 2003-12-31 2003-12-31 Process for preparing pyrrolo[2, 1-c] [1,4] benzodiazepine hybrids
JP2005512761A JP4520411B2 (ja) 2003-12-31 2003-12-31 ピロロ［２，１−ｃ］［１，４］ベンゾジアゼピン・ハイブリッドの調製方法
PCT/IN2003/000462 WO2005063759A1 (fr) 2003-12-31 2003-12-31 Procede servant a preparer des hybrides de pyrrolo[2, 1-c] [1, 4] benzodiazepine
AU2003300718A AU2003300718A1 (en) 2003-12-31 2003-12-31 Process for preparing pyrrolo(2, 1-c) (1, 4) benzodiazepine hybrids

Applications Claiming Priority (1)

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PCT/IN2003/000462 WO2005063759A1 (fr) 2003-12-31 2003-12-31 Procede servant a preparer des hybrides de pyrrolo[2, 1-c] [1, 4] benzodiazepine

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WO2005063759A1 true WO2005063759A1 (fr) 2005-07-14

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WO (1) WO2005063759A1 (fr)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008099416A2 (fr) * 2007-02-13 2008-08-21 Council Of Scientific & Industrial Research Nouveaux hybrides de pyrrolo[2,1-c][1,4]benzodiazépine liée à un benzothiazole et un benzoxazole en tant que nouveaux agents antitumoraux et leur procédé de préparation
JP2009515870A (ja) * 2005-11-10 2009-04-16 カウンスィル オブ サイエンティフィック アンド インダストリアル リサーチ 新規なピロロ［２，１−ｃ］［１，４］ベンゾジアゼピンハイブリッドおよびその調製のための方法
WO2009110000A1 (fr) * 2008-03-05 2009-09-11 Council Of Scientific & Industrial Research Nouveaux hybrides de naphtalimide-benzimidazole comme agents antitumoraux potentiels et leur procédé de préparation
WO2009113085A1 (fr) * 2008-03-11 2009-09-17 Council Of Scientific & Industrial Research Nouveaux hybrides de pyrrolo[2,1-q[1,4] benzodiazépine liés au un cycle benzimidazole en tant qu’agents anti-tumoraux et leurs procédés de préparation
WO2009118748A1 (fr) * 2008-03-26 2009-10-01 Council Of Scientific & Industrial Research Hybrides de pyrrolo[2,1-q[1.^benzodiazépine liés à l'isoxazoline en tant qu'agents anti-cancéreux potentiels et leurs procédés de fabrication
WO2010058414A1 (fr) * 2008-11-19 2010-05-27 Council Of Scientific & Industrial Research Nouveaux dérivés de pyrrolo[2,1-c][1,4]benzodiazépine possédant des chaînes latérales dithiocarbamate et leur procédé de préparation
US10787463B2 (en) 2015-07-21 2020-09-29 Immunogen, Inc. Methods of preparing cytotoxic benzodiazepine derivatives

Citations (1)

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WO2000012508A2 (fr) * 1998-08-27 2000-03-09 Spirogen Limited Composes

Patent Citations (1)

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WO2000012508A2 (fr) * 1998-08-27 2000-03-09 Spirogen Limited Composes

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Title
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KELLY D P ET AL: "DNA BINDING COMPOUNDS. VI SYNTHESIS AND CHARACTERIZATION OF 2,5'-DISUBSTITUTED BIBENZIMIDAZOLES RELATED TO THE DNA MINOR GROOVEBINDER HOECHST 33258", AUSTRALIAN JOURNAL OF CHEMISTRY, XX, XX, vol. 47, no. 9, 1994, pages 1751 - 1769, XP000826532, ISSN: 0004-9425 *
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TAWAR U. ET AL.: "Influence on phenyl ring disubstitution on bisbenzimidazole and terbenzimidazole cytotoxicity: Synthesis and biological evaluation as radioprotectors", J. MED. CHEM., vol. 46, no. 18, 28 August 2003 (2003-08-28), pages 3785 - 3792, XP002288100 *
THURSTON D E ET AL: "SYNTHESIS OF DNA-INTERACTIVE PYRROLO2,1-C1,4BENZODIAZEPINES", CHEMICAL REVIEWS, AMERICAN CHEMICAL SOCIETY. EASTON, US, vol. 94, 1994, pages 433 - 465, XP001026336, ISSN: 0009-2665 *
THURSTON D E ET AL: "Synthesis of Sequence-Selective C8-Linked Pyrrolo(2,1-c)(1,4)benzodia zepine DNA Interstrand Cross-Linking Agents", JOURNAL OF ORGANIC CHEMISTRY, AMERICAN CHEMICAL SOCIETY. EASTON, US, vol. 61, no. 23, 1996, pages 8141 - 8147, XP002272010, ISSN: 0022-3263 *
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Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2009515870A (ja) * 2005-11-10 2009-04-16 カウンスィル オブ サイエンティフィック アンド インダストリアル リサーチ 新規なピロロ［２，１−ｃ］［１，４］ベンゾジアゼピンハイブリッドおよびその調製のための方法
GB2459808B (en) * 2007-02-13 2011-09-14 Council Scient Ind Res Benzothiazole and benzoxazole linked pyrrolo [2,1-C] [1,4] benzodiazepine hybrids as novel antitumour agents and process for the preparation thereof
WO2008099416A3 (fr) * 2007-02-13 2008-10-16 Council Scient Ind Res Nouveaux hybrides de pyrrolo[2,1-c][1,4]benzodiazépine liée à un benzothiazole et un benzoxazole en tant que nouveaux agents antitumoraux et leur procédé de préparation
WO2008099416A2 (fr) * 2007-02-13 2008-08-21 Council Of Scientific & Industrial Research Nouveaux hybrides de pyrrolo[2,1-c][1,4]benzodiazépine liée à un benzothiazole et un benzoxazole en tant que nouveaux agents antitumoraux et leur procédé de préparation
GB2459808A (en) * 2007-02-13 2009-11-11 Council Scient Ind Res Novel benzothiazole and benzoxazole linked pyrrolo (2,1-C) (1,4) benzodiazepine hybrids as novel antitumour agents and process for the preparation thereof
US8063204B2 (en) 2007-02-13 2011-11-22 Council Of Scientific & Industrial Research Benzothiazole and benzoxazole linked pyrrolo[2,1-c] [1, 4] benzodiazepine hybrids as novel antitumour agents and process for the preparation thereof
WO2009110000A1 (fr) * 2008-03-05 2009-09-11 Council Of Scientific & Industrial Research Nouveaux hybrides de naphtalimide-benzimidazole comme agents antitumoraux potentiels et leur procédé de préparation
GB2469980B (en) * 2008-03-05 2012-02-22 Council Scient Ind Res Naphthalimide-benzimidazole hybrids as potential antitumour agents and process for the preparation thereof
GB2469980A (en) * 2008-03-05 2010-11-03 Council Scient Ind Res Novel napthalimide-benzimidazole hybrids as potential antitumour agents and process for the preparation thereof
WO2009113085A1 (fr) * 2008-03-11 2009-09-17 Council Of Scientific & Industrial Research Nouveaux hybrides de pyrrolo[2,1-q[1,4] benzodiazépine liés au un cycle benzimidazole en tant qu’agents anti-tumoraux et leurs procédés de préparation
US8835421B2 (en) 2008-03-11 2014-09-16 Council Of Scientific And Industrial Research Benzimidazole linked pyrrolo[2,1-c[1,4] benzodiazepine hybrids as potential antitumour agents and process for the preparation thereof
WO2009118748A1 (fr) * 2008-03-26 2009-10-01 Council Of Scientific & Industrial Research Hybrides de pyrrolo[2,1-q[1.^benzodiazépine liés à l'isoxazoline en tant qu'agents anti-cancéreux potentiels et leurs procédés de fabrication
US8372831B2 (en) 2008-03-26 2013-02-12 Council Of Scientific & Industrial Research Isoxazoline linked pyrrolo[2,1-c][1,4]benzodiazepine hybrids as potential anticancer agents and the process for preparation thereof
WO2010058414A1 (fr) * 2008-11-19 2010-05-27 Council Of Scientific & Industrial Research Nouveaux dérivés de pyrrolo[2,1-c][1,4]benzodiazépine possédant des chaînes latérales dithiocarbamate et leur procédé de préparation
US8592407B2 (en) 2008-11-19 2013-11-26 Council Of Scientific & Industrial Research Pyrrolo[2,1-c][1,4] benzodiazepine derivatives with dithiocarbamate side chains and process for the preparation thereof
US10787463B2 (en) 2015-07-21 2020-09-29 Immunogen, Inc. Methods of preparing cytotoxic benzodiazepine derivatives
US10899775B2 (en) 2015-07-21 2021-01-26 Immunogen, Inc. Methods of preparing cytotoxic benzodiazepine derivatives
US11420982B2 (en) 2015-07-21 2022-08-23 Immunogen, Inc. Methods of preparing cytotoxic benzodiazepine derivatives

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GB2424883A (en) 2006-10-11
JP2007528343A (ja) 2007-10-11
JP4520411B2 (ja) 2010-08-04
GB2424883B (en) 2008-10-22
AU2003300718A1 (en) 2005-07-21
GB0614750D0 (en) 2006-09-06

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