GB2373499A - Benzo[a]phenazin-11-carboxamide derivatives and their use as joint inhibitors of topomerase I and II - Google Patents

Benzo[a]phenazin-11-carboxamide derivatives and their use as joint inhibitors of topomerase I and II Download PDF

Info

Publication number
GB2373499A
GB2373499A GB0215275A GB0215275A GB2373499A GB 2373499 A GB2373499 A GB 2373499A GB 0215275 A GB0215275 A GB 0215275A GB 0215275 A GB0215275 A GB 0215275A GB 2373499 A GB2373499 A GB 2373499A
Authority
GB
United Kingdom
Prior art keywords
unsubstituted
substituted
alkyl
hydrogen
different
Prior art date
Legal status (The legal status 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 status listed.)
Granted
Application number
GB0215275A
Other versions
GB0215275D0 (en
GB2373499B (en
Inventor
John Milton
Nigel Vicker
Adrian John Folkes
Shouming Wang
William Alexander Denny
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Xenova Ltd
Original Assignee
Xenova Ltd
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 Xenova Ltd filed Critical Xenova Ltd
Publication of GB0215275D0 publication Critical patent/GB0215275D0/en
Publication of GB2373499A publication Critical patent/GB2373499A/en
Application granted granted Critical
Publication of GB2373499B publication Critical patent/GB2373499B/en
Anticipated expiration legal-status Critical
Expired - Fee Related legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
    • C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
    • C07D241/46—Phenazines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Epidemiology (AREA)
  • Virology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

A compound which is a benzo[a]phenazine-11-carboxamide derivative of formula (I) wherein each of R<SP>1</SP> to R<SP>4</SP>, which are the same or different, is selected from hydrogen, halogen, hydroxyl, C<SB>1</SB>-C<SB>6</SB> alkoxy which is unsubstituted or substituted, heteroaryloxy, C<SB>1</SB>-C<SB>6</SB> alkyl which is unsubstituted or substituted, nitro, cyano, azido, amidoxime, CO<SB>2</SB>R<SP>10</SP>, CON(R<SP>12</SP>)<SB>2</SB>, OCON(R<SP>12</SP>), SR<SP>10</SP>, SOR<SP>11</SP>, SO<SB>2</SB>(R<SB>11</SB>), SO<SB>2</SB>N(R<SP>12</SP>)<SB>2</SB>, N(R<SP>12</SP>)<SB>2</SB>, NR<SP>10</SP>SO<SB>2</SB>R<SP>11</SP>, N(SO<SB>2</SB>R<SP>11</SP>)<SB>2</SB>, NR<SP>10</SP>(CH<SB>2</SB>)<SB>n</SB>CN, NR<SP>10</SP>COR<SP>11</SP>, OCOR<SP>11</SP> or COR<SP>10</SP>; each of R<SP>5</SP> to R<SP>7</SP>, which are the same or different, is selected from hydrogen, halogen, hydroxy, C<SB>1</SB>-C<SB>6</SB> alkoxy, C<SB>1</SB>-C<SB>6</SB> alkyl, SR<SP>10</SP> and N(R<SP>12</SP>)<SB>2</SB>; Q is C<SB>1</SB>-C<SB>6</SB> alkylene which is unsubstituted or substituted by (i) C<SB>1</SB>-C<SB>6</SB> alkyl which is unsubstituted or substituted, (ii) hydroxy, provided that the hydroxy group is not a to either of the N atoms adjacent to Q in formula (I), (iii) CO<SB>2</SB>R<SP>10</SP>, or (iv) CON(R<SP>12</SP>); R<SP>8</SP> and R<SP>9</SP>, which are the same or different, are each hydrogen or C<SB>1</SB>-C<SB>6</SB> alkyl, or R<SP>8</SP> and R<SP>9</SP> together with the nitrogen atom to which they are attached form a saturated 5- or 6-membered N-containing heterocyclic ring which may include one additional heteroatom selected from O, N and S, or one of R<SP>8</SP> and R<SP>9</SP> is an alkylene chain optionally interrupted by O, N or S, which is attached to a carbon atom on the alkylene chain represented by Q to complete a saturated 5- or 6-membered N-containing heterocyclic ring as defined above; or a pharmaceutically acceptable salt thereof; with the proviso that at least one R<SP>1</SP> to R<SP>4</SP> is other than hydrogen. These compounds are inhibitors of topoisomerase I and/or topoisomerase II and can be used to treat tumours, including tumours which express MDR.

Description

1,UK Patent Application 1g,GB 1.'2 373 499, ,A (43) Date of Printing by UK
Office 25.09.2002 (21) Application No 0215275.9 (51) INT CL7 C07D 241/46, A61K 31/498, A61P 35/00, C07D 403/12
(22) Date of Filing 01.12.2000 (52) UK CL (Edition T) (30) Priority Data C2C CAA (31) 9928542 (32) 02.12.1999 (33) GB U1S S1313
(86) International Application Data (56) Documents Cited by ISA PCT/GB2000/004609 En 01.12.2000 WO 1998/045272 A WO 1998/012181 A (87) International Publication Data Journal of Medicinal Chemistry Vol. 30, No. 5,1987, WO2001/046157 En 28.06.2001 G W Rewcastle et al., "Potential antitumor agents. 51.
Synthesis and antitumor activity of substtuted phenazine-1<arboxamides", pages 843 851 (71) Applicant(s) Xenova Limited (58) Field of Search by ISA
llncorporated in the United Kingdom) INT CL7 A61K, C07D 957 Buckingham Avenue, SLOUGH, Berkshire, SL1 4NL, United Kingdom (74) Agent and/or Address for Service (72) Inventor(s) J A Kemp & Co. John Milton 14 South Square, Gray's Inn, LONDON, WC1R 5JJ, Nigel Vicker United Kingdom Adrian John Folkes Shouming Wang William Alexander Denny (54) Abstract Title Benzolalphenazin-1 1-carboxamide derivatives and their use as joint inhibitors of topomerase I and 11 (57) A compound which is a benzo[a] phenazine-1 1-carboxamide derivative of formula {I) wherein each of R' to R4, which are the same or different, is selected from hydrogen, halogen, hydroxyl, C'-C6 alkoxy which is unsubstituted or substituted, heteroaryloxy, C'-C6 alkyl which is unsubstituted or substituted, nitro, cyano, azido, amidoxime, CO2R' , CONIR,2)', OCONfRi2), SR3 , SOR3', SO7tR7), SO2NIR32)2, N{R32)2, NR7 SO2R'', N(SO2R'3)2, NR' (CH2)nCN, NR3 COR ', OCORi' or COR' ; each of R to R7, which are the same or different, is selected from hydrogen, halogen, hydroxy, C'-C6 alkoxy, C'C6 alkyl, SR, and NfR'2)2; Q is C,-C6 alkylene which is unsubstituted or substituted by li) C'-C6 alkyl which is unsubstituted or substituted, (ii) hydroxy, provided that the hydroxy group is not a to either of the N atoms adjacent to Q in formula 11), (iii) CO2R3 , or (iv) CONIR,2); R8 and R9, which are the same or different, are each hydrogen or C'-C6 alkyl, or R8 and R9 together with the nitrogen atom to which they are attached form a saturated 5- or 6-membered N-containing heterocyclic ring which may include one additional heteroatom selected from O. N and S. or one of R8 and R9 is an alkylene chain optionally interrupted by O. N or S. which is attached to a carbon atom on the alkylene chain represented by Q to complete a saturated 5- or 6-membered N-containing heterocyclic ring as defined above; or a pharmaceutically acceptable salt thereof; with the proviso that at least one R' to R4 is other than hydrogen. These compounds are inhibitors of topoisomerase I and/or topoisomerase 11 and can be used to treat tumours, including tumours which express MDR.
S W N;:6 R'J: 1 X -N(R)(R)
R2 C,0
D
GB0215275A 1999-12-02 2000-12-01 Pharmaceutical compounds Expired - Fee Related GB2373499B (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB9928542.1A GB9928542D0 (en) 1999-12-02 1999-12-02 Pharmaceutical compounds
PCT/GB2000/004609 WO2001046157A1 (en) 1999-12-02 2000-12-01 Benzo[a]phenazin-11-carboxamide derivatives and their use as joint inhibitors of topomerase i and ii

Publications (3)

Publication Number Publication Date
GB0215275D0 GB0215275D0 (en) 2002-08-14
GB2373499A true GB2373499A (en) 2002-09-25
GB2373499B GB2373499B (en) 2004-11-17

Family

ID=10865607

Family Applications (2)

Application Number Title Priority Date Filing Date
GBGB9928542.1A Ceased GB9928542D0 (en) 1999-12-02 1999-12-02 Pharmaceutical compounds
GB0215275A Expired - Fee Related GB2373499B (en) 1999-12-02 2000-12-01 Pharmaceutical compounds

Family Applications Before (1)

Application Number Title Priority Date Filing Date
GBGB9928542.1A Ceased GB9928542D0 (en) 1999-12-02 1999-12-02 Pharmaceutical compounds

Country Status (16)

Country Link
EP (1) EP1240148A1 (en)
JP (1) JP2003518103A (en)
KR (1) KR100767613B1 (en)
CN (1) CN1304380C (en)
AU (1) AU784397B2 (en)
BR (1) BR0016093A (en)
CA (1) CA2392873A1 (en)
GB (2) GB9928542D0 (en)
HK (1) HK1046133B (en)
HU (1) HUP0300392A3 (en)
MX (1) MXPA02005476A (en)
MY (1) MY136029A (en)
PL (1) PL356482A1 (en)
TW (1) TWI280242B (en)
WO (1) WO2001046157A1 (en)
ZA (1) ZA200204296B (en)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2433071A (en) * 2005-12-05 2007-06-13 Kontrakt Technology Ltd Organic acids comprising planar conjugated heterocyclic molecular system, & photoelectric layer thereof with rodlike supramolecules for use in solar cell
CN102898388B (en) * 2012-09-26 2014-12-03 浙江工业大学 Method for synthesizing substituted benzo[alpha]phenazine compound
CN103360329B (en) * 2013-07-18 2015-11-18 中国科学院南海海洋研究所 One class compound phenazine and preparing the application in antitumor drug
CN106554321B (en) * 2015-09-25 2019-05-28 陆源 A kind of azophenlyene substance, preparation method and its application
CN113461623A (en) * 2021-07-14 2021-10-01 长江大学 Antiviral compound and preparation method and application thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993024096A2 (en) * 1992-05-28 1993-12-09 Xenova Limited Use of n-(2-(dimethylamino)ethyl)acridine-4-carboxamide and its analogues for cancer treatment
WO1998012181A1 (en) * 1996-09-23 1998-03-26 Rutgers, The State University Of New Jersey Substituted heterocycles as anti-tumor agents
WO1998045272A1 (en) * 1997-04-07 1998-10-15 Latrobe University Topoisomerase inhibitors

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5696131A (en) * 1993-01-22 1997-12-09 Xenova Limited Treatment of cancers

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993024096A2 (en) * 1992-05-28 1993-12-09 Xenova Limited Use of n-(2-(dimethylamino)ethyl)acridine-4-carboxamide and its analogues for cancer treatment
WO1998012181A1 (en) * 1996-09-23 1998-03-26 Rutgers, The State University Of New Jersey Substituted heterocycles as anti-tumor agents
WO1998045272A1 (en) * 1997-04-07 1998-10-15 Latrobe University Topoisomerase inhibitors

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Journal of Medicinal Chemistry Vol. 30, No. 5, 1987, G W Rewcastle et al., "Potential antitumor agents. 51. Synthesis and antitumor activity of substtuted phenazine-1-carboxamides", pages 843-851 *

Also Published As

Publication number Publication date
ZA200204296B (en) 2003-05-29
AU1718401A (en) 2001-07-03
KR100767613B1 (en) 2007-10-19
WO2001046157A1 (en) 2001-06-28
HUP0300392A2 (en) 2003-07-28
CA2392873A1 (en) 2001-06-28
CN1304380C (en) 2007-03-14
MY136029A (en) 2008-07-31
AU784397B2 (en) 2006-03-23
JP2003518103A (en) 2003-06-03
GB0215275D0 (en) 2002-08-14
GB2373499B (en) 2004-11-17
KR20020070305A (en) 2002-09-05
GB9928542D0 (en) 2000-02-02
CN1433406A (en) 2003-07-30
BR0016093A (en) 2002-08-20
HK1046133B (en) 2005-04-15
TWI280242B (en) 2007-05-01
HUP0300392A3 (en) 2003-09-29
HK1046133A1 (en) 2002-12-27
EP1240148A1 (en) 2002-09-18
PL356482A1 (en) 2004-06-28
MXPA02005476A (en) 2003-09-22

Similar Documents

Publication Publication Date Title
DE69706407D1 (en) META-SUBSTITUTED PHENYLENE DERIVATIVES AND THEIR USE AS ALPHAvBETA3 INTERGRIN ANTAGONISTS OR INHIBITORS
CA2423103A1 (en) N-acylsulfonamide apoptosis promoters
TR199802202T2 (en) �substituted indezole derivatives; tumor necrosis factor (TNF) production.
BR0315405A (en) Tricyclically pre-organized integrase inhibitor compounds
BRPI0407082A (en) Compound, prodrug, pharmaceutical, method of antagonizing gonadotropin-releasing hormone, and use of the compound
BR0306208A (en) Dibenzylamine compounds and their pharmaceutical use
ATE232520T1 (en) IMIDAZOLIDIN-4-ONE DERIVATIVES USABLE AS ANTICANCER AGENT
BRPI0517461A (en) pharmaceutical compounds
CA2280905A1 (en) Highly lipophilic camptothecin derivatives
EE200200148A (en) Quinazoline derivatives, methods for their preparation and their use
RU93005332A (en) DERIVATIVES 4,1-BENZOXAZEPINA, PHARMACEUTICAL COMPOSITION, METHOD OF TREATMENT
KR950000693A (en) Propenoic acid derivatives
ATE34976T1 (en) ARYLCYCLOBUTYLALKYLAMINES AND THEIR USE AS ANTIDEPRESSIVE DRUGS.
RU2008108903A (en) PENTACYCLIC KINASE INHIBITOR
ATE268330T1 (en) AZAIDOLE WITH SEROTONIN RECEPTOR AFFINITY
WO2002008193A3 (en) Therapeutic acridone and acridine compounds
GB2373499A (en) Benzo[a]phenazin-11-carboxamide derivatives and their use as joint inhibitors of topomerase I and II
ES8608503A1 (en) Coumarin derivatives, pharmaceutical compositions containing the same, and the use thereof in the treatment of cancer.
KR910014119A (en) Thiazolidine derivatives having anti-hypertensive activity and therapeutic uses thereof
CA2016665A1 (en) Rhodanine derivatives and pharmaceutical compositions
CO5080785A1 (en) HETEROCICLIC DERIVATIVES
GR75618B (en)
RU99113432A (en) NEW DERIVATIVES OF PHENANTRIDINIA
AR008920A1 (en) PROCESS FOR THE PREPARATION OF THE DERIVATIVES OF 2-AMINO-2-IMIDAXOLINE, GUANIDINE, AND 2-AMINO-3,4,5,6-TETRAHYDROPYRIDIMINE
ATE240329T1 (en) CYTOTOXIC PYRIDO(2,3,4-KL)ACRIDINE DERIVATIVES, THEIR PREPARATION AND THERAPEUTIC USE

Legal Events

Date Code Title Description
REG Reference to a national code

Ref country code: HK

Ref legal event code: GR

Ref document number: 1046133

Country of ref document: HK

PCNP Patent ceased through non-payment of renewal fee

Effective date: 20081201