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WO2002092083A1 - 4h-chromene condense en 7,8 et composes analogues employes comme activateurs de caspases et inducteurs de l'apoptose, et leur utilisation - Google Patents

4h-chromene condense en 7,8 et composes analogues employes comme activateurs de caspases et inducteurs de l'apoptose, et leur utilisation Download PDF

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WO2002092083A1
WO2002092083A1 PCT/US2002/015398 US0215398W WO02092083A1 WO 2002092083 A1 WO2002092083 A1 WO 2002092083A1 US 0215398 W US0215398 W US 0215398W WO 02092083 A1 WO02092083 A1 WO 02092083A1
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amino
cyano
chromene
dimethoxyphenyl
bromo
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Sui Xiong Cai
Lifen Xu
Richard Storer
Giorgio Attardo
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Cytovia Therapeutics LLC
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Cytovia Inc
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    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
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    • A61K31/4196—1,2,4-Triazoles
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    • A61K31/42—Oxazoles
    • A61K31/424—Oxazoles condensed with heterocyclic ring systems, e.g. clavulanic acid
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
    • A—HUMAN NECESSITIES
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • This invention is in the field of medicinal chemistry.
  • the invention relates to 7,8-fused 4H-chromene and analogs, and the discovery that these compounds are activators of caspases and inducers of apoptosis.
  • the invention also relates to the use of these compounds as therapeutically effective anti-cancer agents.
  • Organisms eliminate unwanted cells by a process variously known as regulated cell death, programmed cell death, or apoptosis. Such cell death occurs as a normal aspect of animal development as well as in tissue homeostasis and aging (Glucksmann, A., Biol. Rev. Cambridge Philos. Soc. 26:59-86 (1951); Glucksmann, A., Archives de Biologie 76:419-431 (1965);
  • Apoptosis is achieved through an endogenous mechanism of cellular suicide (Wyllie, A. ⁇ ., in Cell Death in Biology and Pathology, Bowen and Lockshin, eds., Chapman and Hall (1981), pp. 9-34).
  • a cell activates its internally encoded suicide program as a result of either internal or external signals.
  • the suicide program is executed through the activation of a carefully regulated genetic program (Wyllie, et al, Int. Rev. Cyt. 68:251 (1980); Ellis, et al, Ann. Rev. Cell Bio. 7:663 (1991)).
  • Apoptotic cells and bodies are usually recognized and cleared by neighboring cells or macrophages before lysis.
  • CED-3 is homologous to interleukin 1 beta-converting enzyme, a cysteine protease, which is now called caspase-1.
  • caspase-1 interleukin 1 beta-converting enzyme
  • the mammalian apoptosis system appears to involve a cascade of caspases, or a system that behaves like a cascade of caspases.
  • the caspase family of cysteine proteases comprises 14 different members, and more may be discovered in the future. All known caspases are synthesized as zymogens that require cleavage at an aspartyl residue prior to forming the active enzyme. Thus, caspases are capable of activating other caspases, in the manner of an amplifying cascade.
  • Apoptosis and caspases are thought to be crucial in the development of cancer (Apoptosis and Cancer Chemotherapy, Hickman and Dive, eds., Humana Press (1999)).
  • cancer cells while containing caspases, lack parts of the molecular machinery that activates the caspase cascade. This makes the cancer cells lose their capacity to undergo cellular suicide and the cells become immortal and cancerous.
  • control points are known to exist that represent points for intervention leading to activation.
  • CED- 9-BCL-like and CED-3 -ICE-like gene family products which are intrinsic proteins regulating the decision of a cell to survive or die and executing part of the cell death process itself, respectively (see, Schmitt, et al. , Biochem. Cell. Biol. 75:301-314 (1997)).
  • BCL-like proteins include BCL-xL and BAX- alpha, which appear to function upstream of caspase activation.
  • BCL-xL appears to prevent activation of the apoptotic protease cascade, whereas BAX- alpha accelerates activation of the apoptotic protease cascade.
  • chemotherapeutic drugs can trigger cancer cells to undergo suicide by activating the dormant caspase cascade. This may be a crucial aspect of the mode of action of most, if not all, known anticancer drugs (Los, et al, Blood (9:3118-3129 (1997); Friesen, et al, Nat. Med. 2:514 (1996)).
  • the mechanism of action of current antineoplastic drugs frequently involves an attack at specific phases of the cell cycle.
  • the cell cycle refers to the stages through which cells normally progress during their lifetime. Normally, cells exist in a resting phase termed G 0 . During multiplication, cells progress to a stage in which DNA synthesis occurs, termed S.
  • Antineoplastic drugs such as cytosine arabinoside, hydroxyurea, 6-mercaptopurine, and methotrexate are S phase specific, whereas antineoplastic drugs, such as vincristine, vinblastine, and paclitaxel are M phase specific.
  • Many slow growing tumors e.g., colon cancers, exist primarily in the G 0 phase, whereas rapidly proliferating normal tissues, e.g., bone marrow, exist primarily in the S or M phase.
  • a drug like 6- mercaptopurine can cause bone marrow toxicity while remaining ineffective for a slow growing tumor.
  • Further aspects of the chemotherapy of neoplastic diseases are known to those skilled in the art (see, e.g., Hardman, et al., eds.,
  • EP537949 discloses derivatives of 4H-naphtho[l,2-b]pyran as antiproliferatives :
  • each R 1 is independently halo, trifluoromethyl, C 1-4 alkoxy, hydroxy, nitro,
  • R 2 is phenyl, napthyl or heteroaryl selected from thienyl, pyridyl, benzothienyl, quinolinyl, benzofuranyl or benzimidazolyl, wherein said phenyl, napthyl and heteroaryl groups are optionally substituted, or R 2 is furanyl optionally substituted with C 1-4 alkyl;
  • R 3 is nitrile, carboxy, -COOR 8 where R is an ester group, -CONR 9 R where
  • R 9 and R 10 are each hydrogen or C ⁇ -4 alkyl or R ⁇ SO 2 where R n is C 1- alkyl or optionally substituted phenyl;
  • R 13 are each hydrogen or C 1- alkyl optionally substituted with carboxy, or R is
  • X is C 2-4 alkylene, or R 4 is -NHSO 2 R 14 where R 14 is C alkyl or optionally substituted phenyl; and n is 0-2.
  • R 1 is C ⁇ -4 alkoxy, OH or COOH
  • R is optionally substituted phenyl
  • R is nitrile, or R is carboxy or -COOR when R is phenyl substituted with
  • R are each H or C ]- alkyl; and n is 0-2.
  • EP599514 discloses the preparation of pyranoquinoline derivatives as inhibitors of cell proliferation:
  • R 1 is optionally substituted phenyl or optionally substituted heteroaryl selected from thienyl, pyridyl, benzothienyl, quinolinyl, benzofuranyl or benzimidazolyl, or R 1 is furanyl optionally substituted with C ⁇ -4 alkyl;
  • R 2 is nitrile, carboxy, -CO 2 R 4 wherein R 4 is an ester group, -CON(R 5 )R 6 where R 5 and R are independently H or C 1- alkyl, or R 7 SO 2 where R 7 is
  • X is C 2- alkylene
  • ring P represents a pyridine fused to the benzopyran nucleus
  • EP618206 discloses the preparation of naphthopyran and pyranoquinoline as immunosuppressants and cell proliferation inliibitors:
  • R 2 is phenyl, napthyl or heteroaryl selected from thienyl, pyridyl, benzothienyl, quinolinyl, benzofuranyl or benzimidazolyl, wherein said phenyl, napthyl and heteroaryl groups are optionally substituted, or R 2 is furanyl optionally substituted with C ⁇ - alkyl;
  • R 3 is nitrile, carboxy, -COOR 8 where R 8 is an ester group, -CONR 9 R 10 where R 9 and R 10 are each hydrogen or C ]- alkyl, or -S0 2 R n where R 11 is Cj -4 alkyl or optionally substituted phenyl ⁇ d -4 alkyl;
  • R 4 is 1-pyrrolyl, 1-imidazolyl or 1-pyrazolyl, each of which is optionally substituted by one or two C ⁇ - alkyl, carboxyl, hydroxyl-C ⁇ -4 alkyl or -CHO groups, or R 4 is l-(l,2,4-triazolyl), l-(l,3,4-triazolyl) or 2-(l,2,3-triazolyl), each of which is optionally substituted by a Cj -4 alkyl or C ⁇ -4 perfluoroalkyl group, or R 4 is 1-tetrazolyl optionally substituted by C ⁇ -4 alkyl; X is a pyridine or a benzene ring; and n is 0-2.
  • EP619314 discloses the preparation of 4-phenyl-4H-naphtho(2,l-b)- pyran derivatives:
  • Ri and R 2 are independently halo, trifluoromethyl, - alkoxy, hydroxy, nitro, C ⁇ -C alkyl, Cj-C alkylthio, hydroxy-C ⁇ -C 4 alkyl, hydroxy-Ci-
  • R 3 is nitrile, carboxy or -CO2R 11 wherein Ri 1 is an ester group;
  • Ri 3 are each hydrogen or C] -4 alkyl, or R 4 is
  • X is C 2 -C 4 alkylene, or R_ t is optionally substituted 1-pyrrolyl; and m and n are each independently 0-2.
  • the compounds are said to be useful for the treatment of restenosis, immune disease, and diabetic complications.
  • LY290181 an inhibitor of diabetes-induced vascular dysfunction, blocks protein kinase C- stimulated transcriptional activation through inhibition of transcription factor binding to a phorbol response element.
  • the present invention is related to the discovery that 7,8-fused 4H- chromene and analogs, as represented in Formula I, are activators of the caspase cascade and inducers of apoptosis.
  • an aspect of the present invention is directed to the use of compounds of Formula I as inducers of apoptosis.
  • a second aspect of the present invention is to provide a method for treating, preventing or ameliorating neoplasia and cancer by administering a compound of Formula I to a mammal in need of such treatment.
  • Many of the compounds within the scope of the present invention are novel compounds. Therefore, a third aspect of the present invention is to provide novel compounds of Formula I, and to also provide for the use of these novel compounds for treating, preventing or ameliorating neoplasia and cancer.
  • a fourth aspect of the present invention is to provide a pharmaceutical composition useful for treating disorders responsive to the induction of apoptosis, containing an effective amount of a compound of Formula I in admixture with one or more pharmaceutically acceptable carriers or diluents.
  • a fifth aspect of the present invention is directed to methods for the preparation of novel compounds of Formula I.
  • the present invention arises out of the discovery that 7,8-fused 4H- chromene and analogs, as represented in Formula I, are potent and highly efficacious activators of the caspase cascade and inducers of apoptosis. Therefore, compounds of Formula I are useful for treating disorders responsive to induction of apoptosis.
  • X is O, S or NR 6 , wherein R 6 is hydrogen or optionally substituted alkyl;
  • Y is CN, COR 7 , CO 2 R 7 or CONR x R y , wherein R 7 , R x and R y are independently hydrogen, Ci-io alkyl, haloalkyl, aryl, fused aryl, carbocyclic, a heterocyclic group, a heteroaryl group, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, carbocycloalkyl, heterocycloalkyl, hydroxyalkyl or aminoalkyl; or R x and R y are talcen together with the nitrogen to which they are attached to form a heterocycle;
  • R 5 is hydrogen or C M O alkyl
  • A is optionally substituted and is aryl, heteroaryl, saturted carbocyclic, partially saturated carbocylic, saturated heterocyclic, partially saturated heterocyclic, arylalkyl or heteroarylalkyl; and B is optionally substituted and is a fused thiazole, oxazole, 2-imino-imidazole,
  • Preferred compounds of Formula I include compounds wherein A is phenyl, naphthyl, pyridyl, quinolyl, isoquinolyl, thienyl, furyl, pyrrolyl, 2-phenylethyl or cyclohexyl, any of which is optionally substituted.
  • Other preferred compounds are wherein A is
  • R ⁇ 0 -R ⁇ are independently hydrogen, halo, haloalkyl, aryl, fused aryl, carbocyclic, a heterocyclic group, a heteroaryl group, C ⁇ -10 alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, carbocycloalkyl, heterocycloalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, nitro, amino, cyano, acylamido, hydroxy, thiol, acyloxy, azido, alkoxy, carboxy, methylenedioxy, carbonylamido or alkylthiol; or
  • Rio and R 11 ⁇ or R ⁇ and R 12 taken together with the atoms to which they are attached, form an aryl, heteroaryl, optionally substituted carbocyclic or optionally substituted heterocyclic group, wherein said group is optionally substituted.
  • R ] 0 and R 11? or Ru and R 12 may be taken together to form a structure selected from the group consisting of -OCH 2 O-, -(CH 2 ) 3 - -(CH 2 ) - - CH2CH2O-, -CH2N(R)CH 2 --CH 2 CH 2 N(R)CH 2 -,
  • R is hydrogen, C O alkyl, haloalkyl, aryl, fused aryl, carbocyclic, a heterocyclic group, a heteroaryl group, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, carbocycloalkyl, heterocycloalkyl, hydroxyalkyl or aminoalkyl.
  • R 5 is hydrogen.
  • X is O or S. Most preferably, X is O.
  • Z is NH 2 .
  • Y is CN.
  • Optional substituents on B include alkyl, cycloalkylalkyl, hydroxylalkyl, epoxyalkyl, alkoxyalkyl, aminoalkyl and haloalkyl.
  • Preferred optional substitutents on B include methyl, hydroxymethyl, cyclopropylmethyl, and 2-N,N-diethylaminoethyl.
  • B is N-methyl- oxazol-2-one.
  • Such compounds include substituted benzothiazopyrans, benzoxazolepyrans, benzo-(l,2-dihydro-imidazole)pyrans, benzo-(l,2- dihydro-thiazole)pyrans, benzo-(l ,2-dihydro-oxazole)pyrans benzo-(l ,2- dihydro-2-oxo-imidazole)pyrans, benzo-(l,2-dihydro-2-oxo-thiazole)pyrans, benzo-2-oxo-oxazolepyrans, benzo-( 1 ,2-dihydro-2-thioxo-imidazole)pyrans, benzo-(l ,2-dihydro-2-imino-imidazole)pyrans, benzo-(l ,3-dihydro-2-oxo- 2,l,3-thiadiazole)pyrans, and benzotriazolepyrans.
  • R ⁇ -R 2 are hydrogen.
  • R 5 is hydrogen;
  • X is O;
  • Z is NH 2 and
  • Y is CN.
  • A is optionally substituted phenyl, naphthyl, pyridyl, quinolyl, isoquinolyl, thienyl, furyl, pyrrolyl, 2-phenylethyl or cyclohexyl.
  • R_, R 2 , R 5 , X, Y, Z and A are as defined previously with respect to Formula I; and D, E, F, and G are CR J S R KJ , CO, N, O, or S, wherein R ⁇ 5 and R[ 6 are defined above, provided that at least two of D, E, F, and G are hetero atoms and the ring comprising D, E, F and G is not a 1 ,4-dioxolane, pyrazine or 1,4-dihydro- 2,3-dioxopyrazine ring; and the dashed lines represent a single bond or a double bond.
  • Such compounds include substituted benzoxazinepyrans and benzo- 2,3-dioxo-oxazinepyrans.
  • Preferred compounds falling within the scope of Formula III include compounds wherein Rj-R 2 are hydrogen.
  • R 5 is hydrogen.
  • Exemplary preferred compounds that may be employed in the method of the invention include, without limitation: 2-Amino-3-cyano-4-(3-bromo-4,5-dimethoxyphenyl)-8-thioxo-4,7,8,9- tetrahydro-imidazo[4,5-b]chromene;
  • Useful alkyl groups include straight-chained and branched CM O alkyl groups, more preferably C ⁇ -6 alkyl groups.
  • Typical C ⁇ . ⁇ 0 alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, .sec-butyl, tert-butyl, 3-pentyl, hexyl and octyl groups, which can be optionally substituted.
  • Useful alkoxy groups include oxygen substituted by one of the Cj.io alkyl groups mentioned above, which can be optionally substituted.
  • Useful alkylthio groups include sulphur substituted by one of the C M O alkyl groups mentioned above, which can be optionally substituted. Also included are the sulfoxides and sulfones of such alkylthio groups.
  • Useful amino groups include — NH 2 , -NHRj 5 and -NRisRi ⁇ , wherein
  • R ⁇ _ and R ⁇ 6 are C ⁇ _ 10 alkyl or cycloalkyl groups, or Rj and R ⁇ 6 are combined with the N to form a ring structure, such as a piperidine, or R ⁇ 5 and R ⁇ 6 are combined with the N and other group to form a ring, such as a piperazine.
  • the alkyl group can be optionally substituted.
  • Optional substituents on the alkyl groups include one or more halo, hydroxy, carboxyl, amino, nitro, cyano, C ⁇ -C 6 acylamino, C ⁇ -C 6 acyloxy, C ⁇ -C 6 alkoxy, aryloxy, alkylthio, C 6 -C ⁇ o aryl, C 4 -C cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 6 -C ⁇ o aryl(C 2 -C6)alkenyl, C 6 -C ⁇ o aryl(C2-C 6 )alkynyl, saturated and unsaturated heterocyclic or heteroaryl.
  • Optional substituents on the aryl, aralkyl and heteroaryl groups include one or more halo, C ⁇ -C 6 haloalkyl,
  • Useful aryl groups include C 6- ⁇ aryl, preferably C 6 - I Q aryl. Typical
  • C 6- ⁇ aryl groups include phenyl, naphthyl, phenanthrenyl, anthracenyl, indenyl, azulenyl, biphenyl, biphenylenyl and fluorenyl groups.
  • Useful cycloalkyl groups are C 3-8 cycloalkyl.
  • Typical cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • Useful saturated or partially saturated carbocyclic groups are cycloalkyl groups as described above, as well as cycloalkenyl groups, such as cyclopentenyl, cycloheptenyl and cyclooctenyl.
  • Useful halo or halogen groups include fluorine, chlorine, bromine and iodine.
  • Useful arylalkyl groups include any of the above-mentioned C M O alkyl groups substituted by any of the above-mentioned C 6- ⁇ 4 aryl groups.
  • the arylalkyl group is benzyl, phenethyl or naphthylmethyl.
  • Useful haloalkyl groups include C M O alkyl groups substituted by one or more fluorine, chlorine, bromine or iodine atoms, e.g., fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 1,1-difluoroethyl, chloromethyl, chlorofluoromethyl and trichloromethyl groups.
  • Useful acylamino (acylamido) groups are any C ⁇ -6 acyl (alkanoyl) attached to an amino nitrogen, e.g., acetamido, chloroacetamido, propionamido, butanoylamido, pentanoylamido and hexanoylamido, as well as aryl-substituted C__ 6 acylamino groups, e.g., benzoylamido, and pentafluoro- benzoylamido.
  • Useful acyloxy groups are any C 1-6 acyl (alkanoyl) attached to an oxy
  • (— O-) group e.g., formyloxy, acetoxy, propionoyloxy, butanoyloxy, pentanoyloxy and hexanoyloxy.
  • Useful saturated or partially saturated heterocyclic groups include tetrahydrofuranyl, pyranyl, piperidinyl, piperazinyl, pyrrolidinyl, imidazolidinyl, imidazolinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, isochromanyl, chromanyl, pyrazolidinyl pyrazolinyl, tetronoyl and tetramoyl groups.
  • Useful heteroaryl groups include thienyl, benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl, pyranyl, isobenzofuranyl, chro enyl, xanthenyl, phenoxanthiinyl, 2H-pyrrolyl, pyrrolyl, oxazolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl, phthalzinyl, naphthyridinyl, quinozalinyl, cinnolinyl, pteridinyl, carbazolyl,
  • heteroaryl group contains a nitrogen atom in a ring, such nitrogen atom may be in the form of an N-oxide, e.g., a pyridyl N-oxide, pyrazinyl N-oxide and pyrimidinyl N-oxide.
  • Certain of the compounds of the present invention may exist as stereoisomers including optical isomers.
  • the invention includes all stereoisomers and both the racemic mixtures of such stereoisomers as well as the individual enantiomers that may be separated according to methods that are well known to those of ordinary skill in the art.
  • addition salts include inorganic and organic acid addition salts, such as hydrochloride, hydrobromide, phosphate, sulphate, citrate, lactate, tartrate, maleate, fumarate, mandelate and oxalate; and inorganic and organic base addition salts with bases such as sodium hydroxy, Tris(hydroxymethyl)aminomethane (TRIS, tromethane) and N-methyl-glucamine.
  • inorganic and organic acid addition salts such as hydrochloride, hydrobromide, phosphate, sulphate, citrate, lactate, tartrate, maleate, fumarate, mandelate and oxalate
  • bases such as sodium hydroxy, Tris(hydroxymethyl)aminomethane (TRIS, tromethane) and N-methyl-glucamine.
  • prodrugs of the compounds of the invention include the simple esters of carboxylic acid containing compounds (e.g., those obtained by condensation with a Cj- alcohol according to methods known in the art); esters of hydroxy containing compounds (e.g., those obtained by condensation with a Cj -4 carboxylic acid, C 3-6 dioic acid or anhydride thereof, such as succinic and fumaric anhydrides according to methods known in the art); imines of amino containing compounds (e.g., those obtained by condensation with a C ⁇ aldehyde or ketone according to methods known in the art); carbamate of amino containing compounds, such as those described by Leu, et. al, (J. Med. Chem.
  • the compounds of this invention may be prepared using methods known to those skilled in the art, or the novel methods of this invention.
  • the compounds of this invention with Formulae I-III can be prepared as illustrated by exemplary reaction in Scheme 1.
  • Reaction of a 2,3- disubstituted phenol, such as 2,3-diaminophenol with a substituted benzaldehyde, such as 3-methoxybenzaldehyde and malononitrile in the presence a base, such as piperidine or NN-diisopropylethylamine produced the 7,8-diamino chromene, which can then cyclize under different conditions to produce the 7,8-fused chromenes.
  • reaction of the 7,8-diamino chromene with l,l'-carbonyldiimidazole (CDI) will produce the 2-oxo- imidazole-chromene compound.
  • Another important aspect of the present invention is the discovery that compounds having Formulae I-III are potent and highly efficacious activators of caspases and inducers of apoptosis in drug resistant cancer cells, such as breast and prostate cancer cells, which enables these compounds to kill these drug resistant cancer cells.
  • drug resistant cancer cells such as breast and prostate cancer cells
  • compounds of this invention are expected to be useful for the treatment of drug resistant cancer in animals.
  • the present invention includes a therapeutic method useful to modulate in vivo apoptosis or in vivo neoplastic disease, comprising administering to a subject in need of such treatment an effective amount of a compound, or a pharmaceutically acceptable salt or prodrag of the compound of Formulae I-III, which functions as a caspase cascade activator and inducer of apoptosis.
  • the present invention also include a therapeutic method comprising administering to an animal an effective amount of a compound, or a pharmaceutically acceptable salt or prodrug of said compound of Formulae I-
  • cancer which is a group of diseases characterized by the uncontrolled growth and spread of abnormal cells.
  • diseases include, but are not limited to, Hodgkin's disease, non- Hodgkin's lymphomas, acute and chronic lymphocytic leukemias, multiple myeloma, neuroblastoma, breast carcinomas, ovarian carcinomas, lung carcinomas, Wilms' tumor, cervical carcinomas, testicular carcinomas, soft- tissue sarcomas, chronic lymphocytic leukemia, primary macroglobulinemia, bladder carcinomas, chronic granulocytic leukemia, primary brain carcinomas, malignant melanoma, small-cell lung carcinomas, stomach carcinomas, colon carcinomas, malignant pancreatic insulinoma, malignant carcinoid carcinomas, malignant melanomas, choriocarcinomas, mycosis fungoides, head and neck carcinomas, osteogenic sarcoma, pancreatic carcinomas, acute gran
  • compositions containing therapeutically effective concentrations of the compounds formulated for oral, intravenous, local and topical application, for the treatment of neoplastic diseases and other diseases in which caspase cascade mediated physiological responses are implicated are administered to an individual exhibiting the symptoms of one or more of these disorders.
  • the amounts are effective to ameliorate or eliminate one or more symptoms of the disorders.
  • An effective amount of a compound for treating a particular disease is an amount that is sufficient to ameliorate, or in some manner reduce, the symptoms associated with the disease. Such amount may be administered as a single dosage or may be administered according to a regimen, whereby it is effective.
  • the amount may cure the disease but, typically, is administered in order to ameliorate the disease.
  • a pharmaceutical composition comprising a compound, or a pharmaceutically acceptable salt of said compound of Formulae I-III, which functions as a caspase cascade activator and inducer of apoptosis in combination with a pharmaceutically acceptable vehicle.
  • Another embodiment of the present invention is directed to a composition effective to inhibit neoplasia comprising a compound, or a pharmaceutically acceptable salt or prodrug of said compound of Formulae I- III, which functions as a caspase cascade activator and inducer of apoptosis, in combination with at least one known cancer chemotherapeutic agent, or a pharmaceutically acceptable salt of said agent.
  • alkylating agents such as busulfan, cis-platin, mitomycin C, and carboplatin
  • antimitotic agents such as colchicine, vinblastine, paclitaxel, and docet
  • the compound of the invention may be administered together with at least one known chemotherapeutic agent as part of a unitary pharmaceutical composition.
  • the compound of the invention may be administered apart from the at least one known cancer chemotherapeutic agent.
  • the compound of the invention and the at least one known cancer chemotherapeutic agent are administered substantially simultaneously, i.e. the compounds are administered at the same time or one after the other, so long as the compounds reach therapeutic levels in the blood at the same time.
  • the compound of the invention and the at least one known cancer chemotherapeutic agent are administered according to their individual dose schedule, so long as the compounds reach therapeutic levels in the blood.
  • Another embodiment of the present invention is directed to a composition effective to inliibit neoplasia comprising a bioconjugates of said compound of Formulae I-III, which functions as a caspase cascade activator and inducer of apoptosis, in bioconjugation with at least one known therapeutically useful antibodies, such as Herceptin ' or Rituxan ' ; growth factors, such as DGF, NGF; cytokines, such as IL-2, IL-4; or any molecule that binds to cell surface.
  • the antibodies and other molecules will deliver compound of Formulae I-III to its targets and make them effective anticancer agents.
  • the bioconjugates also could enhance the anticancer effect of therapeutically useful antibodies, such as Herceptin ® or Rituxan ® .
  • another embodiment of the' present invention is directed to a composition effective to inhibit neoplasia comprising a compound or a pharmaceutically acceptable salt or prodrag of said compound of Formulae I-
  • the compound of the invention may be administered at the same time as the radiation therapy is administered or at a different time.
  • a composition effective for post-surgical treatment of cancer comprising a compound, or a pharmaceutically acceptable salt or prodrug of said compound of Formulae I-III, which functions as a caspase cascade activator and inducer of apoptosis.
  • the invention also relates to a method of treating cancer by surgically removing the cancer and then treating the animal with one of the pharmaceutical compositions described herein.
  • a wide range of immune mechanisms operate rapidly following exposure to an infectious agent. Depending on the type of infection, rapid clonal expansion of the T and B lymphocytes occurs to combat the infection. The elimination of the effector cells following an infection is one of the major mechanisms maintaining immune homeostasis. This deletion of reactive cells has been shown to be regulated by a phenomenon known as apoptosis. Autoimmune diseases have been lately identified as a consequence of deregulated cell death. In certain autoimmune diseases, the immune system directs its powerful cytotoxic effector mechanisms against specialized cells, such as oligodendrocytes in multiple sclerosis, the beta cells of the pancreas in diabetes mellitus, and thyrocytes in Hashimoto's thyroiditis (Ohsako, S.
  • lymphocyte apoptosis receptor Fas/APO-l/CD95 Mutations of the gene encoding the lymphocyte apoptosis receptor Fas/APO-l/CD95 are reported to be associated with defective lymphocyte apoptosis and autoimmune lymphoproliferative syndrome (ALPS), which is characterized by chronic, histologically benign splenomegaly and generalized lymphadenopathy, hypergammaglobulinemia, and autoantibody formation.
  • APS autoimmune lymphoproliferative syndrome
  • Fas-Fas ligand (FasL) interaction is known to be required for the maintenance of immune homeostasis.
  • Experimental autoimmune thyroiditis (EAT) characterized by autoreactive T and B cell responses and a marked lymphocytic infiltration of the thyroid, is a good model to study the therapeutic effects of FasL. Batteux, F., et al, (J. Immunol 7(52:603-608 (1999)) reported that by direct injection of DNA expression vectors encoding FasL into the inflammed thyroid, the development of lymphocytic infiltration of the thyroid was inhibited and induction of infiltrating T cells death was observed.
  • FasL expression on thyrocytes may have a curative effect on ongoing EAT by inducing death of pathogenic autoreactive infiltrating T lymphocytes.
  • Bisindolylmaleimide VIII is known to potentiate Fas-mediated apoptosis in human astrocytoma 1321N1 cells and in Mo lt-4T cells, both of which were resistant to apoptosis induced by anti-Fas antibody in the absence of bisindolylmaleimide VIII.
  • Potentiation of Fas-mediated apoptosis by bisindolylmaleimide VIII was reported to be selective for activated, rather than non-activated, T cells, and was Fas-dependent. Zhou T., et al, (Nat.
  • Psoriasis is a chronic skin disease that is characterized by scaly red patches.
  • Psoralen plus ultraviolet A (PUVA) is a widely used and effective treatment for psoriasis vulgaris and Coven, et al, Photodermatol Photoimmunol. Photomed. 15:22-21 (1999), reported that lymphocytes treated with psoralen 8 -MOP or TMP plus UVA displayed DNA degradation patterns typical of apoptotic cell death.
  • Ozawa, et al, J. Exp. Med. 189:111-118 (1999) reported that induction of T cell apoptosis could be the main mechanism by which 312-nm UVB resolves psoriasis skin lesions.
  • methotrexate Low doses of methotrexate may be used to treat psoriasis to restore a clinically normal skin. Heenen, et al, Arch. Dermatol Res. 290:240-245 (1998), reported that low doses of methotrexate may induce apoptosis and this mode of action could explain the reduction in epidermal hyperplasia during treatment of psoriasis with methotrexate. Therefore, an effective amount of a compound, or a pharmaceutically acceptable salt or prodrug of the compound of Formulae I- III, which functions as a caspase cascade activator and inducer of apoptosis, should be an effective treatment for hyperproliferative skin diseases, such as psoriasis.
  • Synovial cell hyperplasia is a characteristic of patients with rheumatoid arthritis (RA). Excessive proliferation of RA synovial cells, as well as defective in synovial cell death, might be responsible for the synovial cell hyperplasia. Wakisaka, et al, Clin. Exp. Immunol.
  • an effective amount of a compound, or a pharmaceutically acceptable salt or prodrug of the compound of Formulae I- III, which functions as a caspase cascade activator and inducer of apoptosis, should be an effective treatment for rheumatoid arthritis.
  • Neutrophils are constitutively programmed to undergo apoptosis, thus limiting their pro-inflammatory potential and leading to rapid, specific, and non- phlogistic recognition by macrophages and semi-professional phagocytes (Savill, J., J. Leukoc. Biol. 61:315-380 (1997)).
  • Boirivant, et al, Gastroenterology 116:551-565 (1999) reported that lamina intestinal T cells isolated from areas of inflammation in Crohn's disease, ulcerative colitis, and other inflammatory states manifest decreased CD2 pathway-induced apoptosis, and that studies of cells from inflamed Crohn's disease tissue indicate that this defect is accompanied by elevated Bcl-2 levels.
  • compositions within the scope of this invention include all compositions wherein the compounds of the present invention are contained in an amount that is effective to achieve its intended purpose. While individual needs vary, determination of optimal ranges of effective amounts of each component is within the skill of the art.
  • the compounds may be administered to mammals, e.g., humans, orally at a dose of 0.0025 to 50 mg/kg, or an equivalent amount of the pharmaceutically acceptable salt thereof, per day, of the body weight of the mammal being treated for apoptosis-mediated disorders.
  • approximately 0.01 to approximately 10 mg/kg is orally administered to treat or prevent such disorders.
  • the dose is generally approximately one-half of the oral dose.
  • a suitable intramuscular dose would be approximately 0.0025 to approximately 25 mg/kg, and most preferably, from approximately 0.01 to approximately 5 mg/kg.
  • a known cancer chemotherapeutic agent is also administered, it is administered in an amount with is effective to achieve its intended purpose. The amounts of such known cancer chemotherapeutic agents effective for cancer are well known to those of skill in the art.
  • the unit oral dose may be comprised of approximately 0.01 to approximately 50 mg, preferably approximately 0.1 to approximately 10 mg of the compound of the invention.
  • the unit dose may be administered one or more times daily as one or more tablets, each containing from approximately 0.1 to approximately 10, conveniently approximately 0.25 to 50 mg of the compound or its solvates.
  • the compound may be present at a concentration of approximately 0.01 to 100 mg per gram of carrier.
  • the compounds of the invention may be administered as part of a pharmaceutical preparation containing suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the compounds into preparations that can be used pharmaceutically.
  • suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the compounds into preparations that can be used pharmaceutically.
  • the preparations particularly those preparations which can be administered orally and which can be used for the preferred type of administration, such as tablets, dragees, and capsules, and also preparations which can be administered rectally, such as suppositories, as well as suitable solutions for administration by injection or orally, contain from approximately 0.01 to 99 percent, preferably from approximately 0.25 to 75 percent of active compound(s), together with the excipient.
  • non- toxic pharmaceutically acceptable salts of the compounds of the present invention are included within the scope of the present invention.
  • Acid addition salts are formed by mixing a solution of the particular apoptosis inducers of the present invention with a solution of a pharmaceutically acceptable non-toxic acid, such as hydrochloric acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid, oxalic acid, and the like.
  • Basic salts are formed by mixing a solution of the particular apoptosis inducers of the present invention with a solution of a pharmaceutically acceptable non-toxic base, such as sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, Tris, N-methyl-glucamine, and the like.
  • a pharmaceutically acceptable non-toxic base such as sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, Tris, N-methyl-glucamine, and the like.
  • compositions of the invention may be administered to any animal which may experience the beneficial effects of the compounds of the invention.
  • animals are mammals, e.g., humans and veterinary animals, although the invention is not intended to be so limited.
  • compositions of the present invention may be administered by any means that achieve their intended purpose.
  • administration may be by parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, buccal, intrathecal, intracranial, intranasal or topical routes.
  • Administration alternatively, or concurrently, may be by the oral route.
  • the dosage administered will be dependent upon the age, health, and weight of the recipient, kind of concurrent treatment, if any, frequency of treatment, and the nature of the effect desired.
  • the pharmaceutical preparations of the present invention are manufactured in a manner which is itself known, e.g., by means of conventional mixing, granulating, dragee-making, dissolving, or lyophilizing processes.
  • compositions for oral use can be obtained by combining the active compounds with solid excipients, optionally grinding the resulting mixture and processing the mixture of granules, after adding suitable auxiliaries, if desired or necessary, to obtain tablets or dragee cores.
  • Suitable excipients are, in particular, fillers, such as saccharides, e.g., lactose or sucrose, mannitol or sorbitol; cellulose preparations and/or calcium phosphates, e.g., tricalcium phosphate or calcium hydrogen phosphate, as well as binders, such as starch paste, using, e.g., maize starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and/or polyvinyl pyrrolidone.
  • fillers such as saccharides, e.g., lactose or sucrose, mannitol or sorbitol
  • cellulose preparations and/or calcium phosphates e.g., tricalcium phosphate or calcium hydrogen phosphate
  • binders such as starch paste, using, e.g., maize starch, wheat starch, rice
  • disintegrating agents may be added such as the above-mentioned starches and also carboxymethyl-starch, cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate.
  • Auxiliaries are, above all, flow-regulating agents and lubricants, for example, silica, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate, and/or polyethylene glycol.
  • Dragee cores are provided with suitable coatings which, if desired, are resistant to gastric juices.
  • concentrated saccharide solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures.
  • suitable cellulose preparations such as acetylcellulose phthalate or hydroxypropymethyl-cellulose phthalate, are used.
  • Dye stuffs or pigments may be added to the tablets or dragee coatings, e.g., for identification or in order to characterize combinations of active compound doses.
  • Other pharmaceutical preparations which can be used orally, include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules can contain the active compounds in the form of granules, which may be mixed with fillers, such as lactose; binders, such as starches, and/or lubricants, such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds are preferably dissolved or suspended in suitable liquids, such as fatty oils, or liquid paraffin.
  • suitable liquids such as fatty oils, or liquid paraffin.
  • stabilizers may be added.
  • Possible pharmaceutical preparations which can be used rectally include, e.g., suppositories, which consist of a combination of one or more of the active compounds with a suppository base.
  • Suitable suppository bases are, e.g., natural or synthetic triglycerides, or paraffin hydrocarbons.
  • gelatin rectal capsules which consist of a combination of the active compounds with a base.
  • Possible base materials include, e.g., liquid triglycerides, polyethylene glycols, or paraffin hydrocarbons.
  • Suitable formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form, e.g., water-soluble salts and alkaline solutions.
  • suspensions of the active compounds as appropriate oily injection suspensions may be administered.
  • Suitable lipophilic solvents or vehicles include fatty oils, e.g., sesame oil, or synthetic fatty acid esters, e.g., ethyl oleate or triglycerides or polyethylene glycol-400 (the compounds are soluble in PEG-400) cremophor, or cyclodextrins.
  • Aqueous injection suspensions may contain substances, which increase the viscosity of the suspension include, e.g., sodium carboxymethyl cellulose, sorbitol, and/or dextran.
  • the suspension may also contain stabilizers.
  • compounds of the invention are employed in topical and parenteral formulations and are used for the treatment of skin cancer.
  • the topical compositions of this invention are formulated preferably as oils, creams, lotions, ointments and the like by choice of appropriate carriers.
  • Suitable carriers include vegetable or mineral oils, white petrolatum (white soft paraffin), branched chain fats or oils, animal fats and high molecular weight alcohol (greater than C 12 ).
  • the preferred carriers are those in which the active ingredient is soluble.
  • Emulsifiers, stabilizers, humectants and antioxidants may also be included, as well as agents imparting color or fragrance, if desired.
  • transdermal penetration enhancers can be employed in these topical formulations. Examples of such enhancers can be found in U.S. Patent Nos. 3,989,816 and 4,444,762.
  • Creams are preferably formulated from a mixture of mineral oil, self- emulsifying beeswax and water in which mixture the active ingredient, dissolved in a small amount of an oil such as almond oil, is admixed.
  • a typical example of such a cream is one which includes approximately 40 pails water, approximately 20 parts beeswax, approximately 40 parts mineral oil and approximately 1 part almond oil.
  • Ointments may be formulated by mixing a solution of the active ingredient in a vegetable oil, such as almond oil with warm soft paraffin and allowing the mixture to cool.
  • a typical example of such an ointment is one which includes approximately 30% almond oil and approximately 70% white soft paraffin by weight.
  • the product was isolated by Biotage flash chromatography (cartridge 12S, SiO 2 ) using approximately 0 %, 2 % and 4 % methanol solutions in dichloromethane as eluant to yield 13.5 mg of a yellow oily solid. NMR showed impurities in the aliphatic region. The product was re-crystallized in a minimum of methanol. The crystals were washed with diethyl ether to yield 4.6 mg (15 %) of the title compound as a yellow solid.
  • Human breast cancer cell lines T-47D and ZR-75-1 were grown according to media component mixtures designated by American Type
  • T-47D and ZR-75- 1 cells were maintained at a cell density between 30 and 80 % confluency at a cell density of 0.1 to 0.6 x 10 6 cells/mL.
  • Cells were harvested at approximately 600 x g and resuspended at approximately 0.65 x 10 6 cells/mL into appropriate media plus approximately 10 % FCS.
  • the Relative Fluorescence Unit values were used to calculate the sample readings as follows:
  • the activity of caspase cascade activation was determined by the ratio of the net RFU value for the test compounds to that of control samples.
  • the EC 50 (nM) was determined by a sigmoidal dose-response calculation (Prism 2.0, GraphPad Software Inc.).
  • the caspase activity (Ratio) and potency (EC 50 ) are summarized in Table I:
  • these compounds are identified as potent caspase cascade activators and inducers of apoptosis in solid tumor cells.

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Abstract

La présente invention se rapporte à du 4H-chromène substitué et à des composés analogues représentés par la formule générale (I), ou à des sels pharmaceutiquement acceptables ou des promédicaments dudit composé. Dans la formule (I), A, R1, R2, R5, X, et Z sont tels que définis dans la description, et B est un des composés condensés suivants : du thiazol, de l'oxazole, du 2-imino-imidazole, du 2,1,3-thiadiazo-2-one, du thiazol-2-one, de l'oxazol-2-one, de l'imidazol-2-thione, du thiazol-2-thione, de l'oxazol-2-thione, de l'imidazoline, de l'oxazoline, de la thiazoline, du triazol, de l'oxazine, de l'oxazine-2,3-dione ou un noyau pipérazine. La présente invention a également trait à la découverte selon laquelle les composés de formule (I) activent des caspases et induisent l'apoptose. Ces activateurs de caspases et inducteurs de l'apoptose peuvent par conséquent servir à induire la mort cellulaire dans divers états cliniques marqués par la croissance et l'expansion incontrôlée de cellules anormales.
PCT/US2002/015398 2001-05-16 2002-05-16 4h-chromene condense en 7,8 et composes analogues employes comme activateurs de caspases et inducteurs de l'apoptose, et leur utilisation Ceased WO2002092083A1 (fr)

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EP1620564A4 (fr) * 2003-04-18 2008-03-12 Cytovia Inc Procedes pour traiter des maladies entrainant l'induction d'apoptose et essais de criblage
US7476741B2 (en) 2002-05-16 2009-01-13 Cytovia, Inc. Substituted 4H-chromens, 2H-chromenes, chromans and analogs as activators of caspases and inducers of apoptosis and the use thereof
US7528164B2 (en) 2002-05-16 2009-05-05 Cytovia, Inc. Substituted 4-aryl-4h-pyrrolo[2,3-h]chromenes and analogs as activators of caspases and inducers of apoptosis and the use thereof
WO2012062905A3 (fr) * 2010-11-12 2013-01-03 Deutsches Krebsforschungszentrum (Dkfz) Dérivés de chromène et leurs analogues en tant qu'antagonistes de la voie wnt
CN102924477B (zh) * 2009-02-09 2014-10-29 沈阳药科大学 新噁嗪类化合物及其用途
CN107501281A (zh) * 2017-09-26 2017-12-22 清华大学 式i所示化合物及其应用

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US7507762B2 (en) 1999-11-05 2009-03-24 Cytovia, Inc. Substituted 4H-chromene and analogs as activators of caspases and inducers of apoptosis and the use thereof
US6906203B1 (en) 1999-11-05 2005-06-14 Cytovia, Inc. Substituted 4H-chromene and analogs as activators of caspases and inducers of apoptosis and the use thereof
US7476741B2 (en) 2002-05-16 2009-01-13 Cytovia, Inc. Substituted 4H-chromens, 2H-chromenes, chromans and analogs as activators of caspases and inducers of apoptosis and the use thereof
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CN107501281A (zh) * 2017-09-26 2017-12-22 清华大学 式i所示化合物及其应用
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CN107501281B (zh) * 2017-09-26 2019-11-22 清华大学 式i所示化合物及其应用

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