WO2008057402A2 - N-aryl-isoxazolopyrimidin-4-amines et composés associés servant d'activateurs de caspases et d'inducteurs d'apoptose et leur utilisation - Google Patents

N-aryl-isoxazolopyrimidin-4-amines et composés associés servant d'activateurs de caspases et d'inducteurs d'apoptose et leur utilisation Download PDF

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WO2008057402A2
WO2008057402A2 PCT/US2007/023109 US2007023109W WO2008057402A2 WO 2008057402 A2 WO2008057402 A2 WO 2008057402A2 US 2007023109 W US2007023109 W US 2007023109W WO 2008057402 A2 WO2008057402 A2 WO 2008057402A2
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optionally substituted
amine
pyrimidin
alkyl
compound
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PCT/US2007/023109
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WO2008057402A3 (fr
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Sui Xiong Cai
William E. Kemnitzer
Nilantha Sudath Sirisoma
Han-Zhong Zhang
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Cytovia, Inc.
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    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings

Definitions

  • This invention is in the field of medicinal chemistry.
  • the invention relates to /V-aryl-isoxazolopyrimidin-4-amines and related compounds, 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 7(5:419-437 (1965); Ellis, el al, Dev. 772:591-603 (1991); Vaux, el ai, Cell 76:111-119 (1994)).
  • Apoptosis regulates cell number, facilitates morphogenesis, removes harmful or otherwise abnormal cells and eliminates cells that have already performed their function. Additionally, apoptosis occurs in response to various physiological stresses, such as hypoxia or ischemia (PCT published application WO96/20721).
  • 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 ai, Int. Rev. Cyt. (55/251 (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. Because of this clearance mechanism, inflammation is not induced despite the clearance of great numbers of cells (Orrenius, S., J. Internal Medicine 237:529-536 (1995)).
  • 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 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 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 ai, Blood 90:3118-3129 (1997); Friesen, et ai., Nat. Med. 2:51 '4 (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 te ⁇ ned G 0 .
  • S DNA synthesis occurs
  • M cell division, or mitosis occurs, in a phase called M.
  • 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, for example 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., Goodman and Gilman's The Pharmacological Basis of Therapeutics, Ninth Edition, McGraw-Hill, New York (1996), pp. 1225-1287).
  • the possibility exists for the activation of the caspase cascade although the exact mechanisms for doing so are not clear at this point. It is equally - A -
  • caspase cascade activators and inducers of apoptosis are implicated in various types of cancer.
  • the development of caspase cascade activators and inducers of apoptosis is a highly desirable goal in the development of therapeutically effective antineoplastic agents.
  • therapeutic treatment for these diseases could also involve the enhancement of the apoptotic process through the administration of appropriate caspase cascade activators and inducers of apoptosis.
  • R alkyl, aryl, heterocyclyl, etc.
  • Q aryl, arylalkyl, cycloalkyl, etc.
  • WO2005117890 discloses the preparation of thiazolopyrimidines and thienopyrimidines as antagonists of CCR2b receptors for the treatment of chemokine-mediated diseases:
  • Compound II is one of the specific examples.
  • WO2005095419 discloses the preparation of thiazolo[5,4-(f]pyrimidine derivatives as growth factor receptor tyrosine kinase inhibitors:
  • A represents optionally substituted aryl or optionally substituted heteroaryl
  • Ri represents a group bonded through carbon
  • R 2 represents hydrogen or an aliphalic hydrocarbon group
  • X represents -NR 3 -, -O-, -S-, -SO-, -SO 2 -, or -CHR 3 -, wherein R 3 represents hydrogen or an aliphalic hydrocarbon group.
  • JP06001793 discloses the preparation of thiazolo[5,4- ⁇ i]pyrimidines as agrochemical microbicides:
  • R (halo)alkyl, benzyl, Ph, alkenyl, cycloalkyl, alkoxycarbonylalkyl, alkoxyalkyl, phenylalkyl;
  • X H, halo, (halo)alkyl, alkoxy, Ph, anilino, (halo-, alkyl-, or alkoxy-substituted) phenoxy;
  • Y H, halo, alkyl, alkoxy, Ph, phenoxy, anilino;
  • n 1, 2.
  • WO2004005291 discloses the preparation of imidazotriazines as selective phosphodiesterase- 10a inhibitors for the treatment of cancer and neurodegenerative diseases: I I
  • (un)substituted heteroaryl
  • R 2 alkyl, cycloalkyl
  • R 3 Me
  • A 0, NH
  • R 4 (un)substituted aryl, e.g., halo, CHO, C02H, etc.
  • Compounds II and III are two of the specific examples.
  • WO2003000693 discloses the preparation of imidazotriazines as phosphodiesterase 1OA inhibitors for the treatment of neurodegenerative diseases:
  • WO2005082908 discloses the preparation of pyrazolotriazines as kinase inhibitors for treating cancer and other diseases associated with a kinase:
  • Ri is H, optionally substituted alkyl, aryl, heteroaryl, heteroarylalkyl, arylalkyl, NR 6 R 7 , cycloalkyl and cycloalkylalkyl;
  • R 2 is alkyl, cycloalkyl, alkenyl, alkynyl, trifluoromethyl, OR 7 , SR 7 , hydroxyalkyl, haloalkyl, aryl, heteroaryl, halo, CN, formyl, nitro, alkylcarbonyl, aralkylcarbonyl, heteroaralkyicarbonyl, or alkylene-N(R 8 Rc)), wherein R 8 and R 9 represent H or alkyl, or R 8 and Rg taken together with the nitrogen in -N(R 8 Rg) form a five- to seven-membered heterocycle;
  • R 3 is -NR4R 5 , substituted heterocycle, H, alkyl, alkylthio, a
  • WO2004069837 discloses the preparation of pyrazolotriazines as cannabinoid CBl receptor antagonists:
  • R 3 H, alkyl, haloalkyl, alkoxy
  • R 4 Qi, Q 2
  • R41 H, alkyl
  • R 42 , R 43 H, cyano, OH, amino, H 2 NCO, (substituted) alkyl, alkoxy, acyloxy, acyl, aryl, heteroaryl, etc.
  • R 44 , R 45 H, cyano, OH, amino, H 2 NCO, (substituted) alkyl, aryl, heteroaryl, heterocyclyl, etc.
  • pairs Of R 4I -R 45 may form bonds, methylene, ethylene bridges
  • X bond, CH 2 CH 2 , etc.
  • Y O, S, CO, etc.
  • Z bond, CH 2 CH 2 , etc.
  • WO2004072078 discloses the preparation of pyrazolotriazines I, exemplified by compounds II and III, as cyclic nucleotide phosphodiesterase, in particular PDE4 inhibitors, for treating inflammations.
  • WO2004011464 discloses new substituted pyrazolo[l,5- ⁇ ]-l,3,5- triazines and their analogs, pharmaceutical compositions containing them, their use as drugs (particularly as neurotrophic factor production stimulants), and process for their preparation.
  • R 2 , R 3 H, halo, NO 2 , alkyl, carboxyalkyl, trifluoroalkyl, cycloalkyl, acyl, alkenyl, alkynyl, aryl, etc.
  • R 4 H, alkyl, cycloalkyl, aryl, arylalkyl, alkylaryl, heterocyclyl, NH 2 or derivatives;
  • Y halo, alkyl, alkenyl, alkynyl, Ph, OH or derivatives., SH or derivatives., NH 2 or derivatives, exemplified by specific compounds IV.
  • WO2002050079 discloses pyrazolo[l,5- ⁇ ]-l,3,5-triazine derivatives with activity as cyclin-dependent kinase (CDK) and glycogen synthase kinase- 3 (GSK-3) inhibitors, and their preparation, pharmaceutical compositions, and use as, e.g., antiproliferative agents.
  • CDK cyclin-dependent kinase
  • GSK-3 glycogen synthase kinase- 3
  • WO9967247 discloses the preparation of pyrazolo[l ,5- ⁇ ]triazine corticotropin releasing factor antagonists.
  • X N, CH, CR 5 ;
  • R 1 H, alkyl, alkenyl, etc.;
  • R 2 H, alkyl, cycloalkyl, etc.;
  • R 3 (un)substituted Ci -I0 alkyl, C 2 -I 0 alkenyl, C 2- Io alkynyl, etc.;
  • R 4 H, alkyl, allyl, propargyl;
  • R 5 alkyl, alkenyl, alkynyl, etc.;
  • the present invention is related to the discovery that /V-aryl- isoxazolopyrimidin-4-amines and related compounds, as represented in Formulae I-XI, are activators of the caspase cascade and inducers of apoptosis.
  • an aspect of the present invention is directed to the use of compounds of Formulae I-XI 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 one of the Formulae I-XI to a mammal in need of such treatment.
  • a third aspect of the present invention is to provide novel compounds of Formulae I-XI, 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 one of the Formulae I-XI 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 Formulae I-XI.
  • the present invention arises out of the discovery that ⁇ /-aryl- isoxazolopyrimidin-4-amines and related compounds, as represented in Formulae I-XI, are potent and highly efficacious activators of the caspase cascade and inducers of apoptosis. Therefore, compounds of Formulae I-XI are useful for treating disorders responsive to induction of apoptosis.
  • Ar is optionally substituted aryl or optionally substituted heteroaryl
  • A, B and D are independently carbon, nitrogen, oxygen or sulfur, wherein when A, B or D are nitrogen, oxygen or sulfur, then there is no substituent at the nitrogen, oxygen or sulfur; with the proviso that when one of A or D is sulfur, then the other of A or D is not carbon;
  • E and F are independently carbon or nitrogen
  • H is an aromatic ring, and the line between A and B, B and D, D and E, E and F, E and A can be a single bond or a double bond.
  • Ri is hydrogen, halo, optionally substituted amino, optionally substituted alkoxy, optionally substituted Ci-io alkyl, haloalkyl, aryl, carbocyclic, a heterocyclic group, a heteroaryl group, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, carbocycloalkyl, heterocycloalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, nitro, cyano, acylamido, hydroxy, thiol, sulfone, sulfoxide, acyloxy, azido, carboxy, carbonylamido or optionally substituted alkylthiol;
  • R 2 is hydrogen or optionally substituted alkyl
  • R 3 -R 5 independently are hydrogen, halo, amino, alkoxy, Ci -1 0 alkyl, haloalkyl, aryl, carbocyclic, a heterocyclic group, a heteroaryl group, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, carbocycloalkyl, heterocycloalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, nitro, cyano, acylamido, hydroxy, thiol, sulfone, sulfoxide, acyloxy, azido, carboxy, carbonylamido, alkylthiol, or any two adjacent substituents form methylenedioxy.
  • Preferred compounds of Formula I include compounds wherein Ar is phenyl, naphthyl, pyridyl, quinolyl, isoquinolyl, isoxazolyl, pyrazolyl, imidazolyl, thienyl, furyl or pyrrolyl, each of which is optionally substituted. More preferably, Ar is phenyl or pyridyl.
  • Another group of preferred compounds of Formula I include compounds wherein Ri is hydrogen, halo, optionally substituted amino, optionally substituted alkoxy, optionally substituted alkylthiol, or optionally substituted CM O alkyl.
  • Another group of preferred compounds of Formula I include compounds wherein R 2 is hydrogen.
  • Another group of preferred compounds of Formula I include compounds wherein R 2 is methyl or ethyl. Another group of preferred compounds include compounds wherein A, E and F are carbon, B is nitrogen and D is oxygen. Another group of preferred compounds include compounds wherein B, E and F are carbon, A is nitrogen and D is oxygen. Another group of preferred compounds include compounds wherein B, E and F are carbon, A is nitrogen and D is sulfur. Another group of preferred compounds include compounds wherein A, D and F are carbon, B and E are nitrogen. Another group of preferred compounds include compounds wherein B, D and E are carbon, A and F are nitrogen. One group of preferred compounds of the present invention are represented by Formulae H-VI:
  • Ri is hydrogen, halo, optionally substituted amino, optionally substituted alkoxy, optionally substituted C 1 -1 O alkyl, haloalkyl, aryl, carbocyclic, a heterocyclic group, a heteroaryl group, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, carbocycloalkyl, heterocycloalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, nitro, cyano, acylamido, hydroxy, thiol, sulfone, sulfoxide, acyloxy, azido, carboxy, carbonylamido or optionally substituted alkylthiol;
  • R 2 is hydrogen or optionally substituted alkyl
  • R 3 -R 5 independently are hydrogen, halo, amino, alkoxy, C M 0 alkyl, haloalkyl, aryl, carbocyclic, a heterocyclic group, a heteroaryl group, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, carbocycloalkyl, heterocycloalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, nitro, cyano, acylamido, hydroxy, thiol, sulfone, sulfoxide, acyloxy, azido, carboxy, carbonylamido, alkylthiol, or any two adjacent substituents form methylenedioxy.
  • Preferred compounds of Formulae II-VI include compounds wherein
  • Ar is phenyl, naphthyl, pyridyl, quinolyl, isoquinolyl, isoxazolyl, pyrazolyl, imidazolyl, thienyl, furyl or pyrrolyl, each of which is optionally substituted. More preferably, Ar is optionally substituted phenyl or pyridyl.
  • Another gro ⁇ p of preferred compounds of Formulae II- VI include compounds wherein Ri is hydrogen, halo, optionally substituted amino, optionally substituted alkoxy, optionally substituted alkylthiol, or optionally substituted Ci -I 0 alkyl.
  • Another group of preferred compounds of Formulae II-VI include compounds wherein R 2 is hydrogen.
  • Another group of preferred compounds of Formulae II-VI include compounds wherein R 2 is methyl or ethyl.
  • Another group of preferred compounds of the present invention are represented by Formulae VII-XI:
  • R ⁇ is hydrogen, halo, optionally substituted amino, optionally substituted alkoxy, optionally substituted C M 0 alkyl, haloalkyl, aryl, carbocyclic, a heterocyclic group, a heteroaryl group, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroaryl alkenyl, heteroarylalkynyl, carbocycloalkyl, heterocycloalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, nitro, cyano, acylamido, hydroxy, thiol, sulfone, sulfoxide, acyloxy, azido, carboxy, carbonylamido or optionally substituted alkylthiol;
  • R 2 is hydrogen or optionally substituted alkyl
  • R 3 -R 10 independently are hydrogen, halo, amino, alkoxy, Ci. 10 alkyl, haloalkyl, aryl, carbocyclic, a heterocyclic group, a heteroaryl group, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, carbocycloalkyl, heterocycloalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, nitro, cyano, acylamido, hydroxy, thiol, sulfone, sulfoxide, acyloxy, azido, carboxy, carbonylamido, alkylthiol, or any two adjacent substituents form methylenedioxy.
  • Preferred compounds of Formulae VII-XI include compounds wherein
  • Ar is phenyl, naphthyl, pyridyl, quinolyl, isoquinolyl, isoxazolyl, pyrazolyl, imidazolyl, thienyl, furyl or pyrrolyl, each of which is optionally substituted. More preferably, Ar is optionally substituted phenyl or pyridyl.
  • Another group of preferred compounds of Formulae VII-XI include compounds wherein Ri is hydrogen, halo, optionally substituted amino, optionally substituted alkoxy, optionally substituted alkylthiol, or optionally substituted Ci-io alkyl.
  • Another group of preferred compounds of Formulae VII-XI include compounds wherein R. 2 is hydrogen.
  • Another group of preferred compounds of Formulae VlI-XI include compounds wherein R 2 is methyl or ethyl.
  • Exemplary preferred compounds of Formulae I-XI that may be employed in the method of the invention include, without limitation:
  • the present invention is also directed to novel compounds within the scope of Formulae I-XI.
  • Exemplary preferred compounds that may be employed in this invention include, without limitation:
  • alkyl as employed herein by itself or as part of another group refers to both straight and branched chain radicals of up to ten carbons.
  • Useful alkyl groups include straight-chained and branched C M O alkyl groups, more preferably Ci -6 alkyl groups.
  • Typical C M0 alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, ter ⁇ -butyl, 3-pentyl, hexyl and octyl groups, which may be optionally substituted.
  • alkenyl as employed herein by itself or as part of another group means a straight or branched chain radical of 2-10 carbon atoms, unless the chain length is limited thereto, including at least one double bond between two of the carbon atoms in the chain.
  • Typical alkenyl groups include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-l-propenyl, 1-butenyl and 2-butenyl.
  • alkynyl is used herein to mean a straight or branched chain radical of 2-10 carbon atoms, unless the chain length is limited thereto, wherein there is at least one triple bond between two of the carbon atoms in the chain.
  • Typical alkynyl groups include ethynyl, 1-propynyl, l-methyl-2- propynyl, 2-propynyl, 1-butynyl and 2-butynyl.
  • Useful alkoxy groups include oxygen substituted by one of the C M 0 alkyl groups mentioned above, which may be optionally substituted.
  • Alkoxy substituents include, without limitation, halo, morpholino, amino including alkylamino and dialkylamino, and carboxy including esters thereof.
  • Useful alkylthio groups include sulfur substituted by one of the C M O alkyl groups mentioned above, which may be optionally substituted. Also included are the sulfoxides and sulfones of such alkylthio groups.
  • Useful amino and optionally substituted amino groups include -NH 2 , -
  • NHRi 5 and -NRi 5 Ri 6 wherein Ri 5 and Ri 6 are CM O alkyl or cycloalkyl groups, or R] 5 and Ri 6 are combined with the N to form a ring structure, such as a piperidine, or Ri 5 and Ri 6 are combined with the N and other group to form a ring, such as a piperazine.
  • the alkyl group may be optionally substituted.
  • Optional substituents on the alkyl, alkoxy, alkylthio, alkenyl, alkynyl, cycloalkyl, carbocyclic and heterocyclic groups include one or more halo, hydroxy, carboxyl, amino, nitro, cyano, Ci-C 6 acylamino, Ci-C 6 acyloxy, Ci-C 6 alkoxy, aryloxy, alkylthio, C 6 -Ci O aryl, C4-C7 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 6 -Ci 0 aryl(C 2 -C 6 )alkenyl, C 6 -Ci O aryl(C 2 -C 6 )alkynyl, saturated and unsaturated heterocyclic or heteroaryl.
  • Optional substituents on the aryl, arylalkyl, arylalkenyl, arylalkynyl and heteroaryl and heteroarylalkyl groups include one or more halo, C]-C 6 haloalkyl, C 6 -Ci 0 aryl, C 4 -C 7 cycloalkyl, CpC 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 6 -C 0 aryl(C,-C 6 )alkyl, C 6 -C 10 aryl(C 2 -C 6 )alkenyl, C 6 -C 10 aryl(C 2 -C 6 )alkynyl, Ci-C 6 hydroxyalkyl, nitro, amino, ureido, cyano, C]-C 6 acylamino, hydroxy, thiol, sulfone, sulfoxide, Ci-C 6
  • aryl as employed herein by itself or as part of another group refers to monocyclic, bicyclic or tricyclic aromatic groups containing from 6 to 14 carbons in the ring portion.
  • Useful aryl groups include C 6 -H aryl, preferably C 6 -Io aryl. Typical
  • C ⁇ 5 -i 4 aryl groups include phenyl, naphthyl, phenanthrenyl, anthracenyl, indenyl, azulenyl, biphenyl, biphenylenyl and fluorenyl groups.
  • Carbocycle as employed herein include cycloalkyl and partially saturated carbocyclic 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.
  • arylalkyl is used herein to mean any of the above- mentioned C]- I0 alkyl groups substituted by any of the above-mentioned C 6 - M aryl groups.
  • the arylalkyl group is benzyl, phenethyl or naphthylmethyl.
  • arylalkenyl is used herein to mean any of the above- mentioned C 2 - I0 alkenyl groups substituted by any of the above-mentioned C 6 .
  • arylalkynyl is used herein to mean any of the above- mentioned C 2 - 10 alkynyl groups substituted by any of the above-mentioned C 6 -H aryl groups.
  • aryloxy is used herein to mean oxygen substituted by one
  • aryl groups which may be optionally substituted.
  • Useful aryloxy groups include phenoxy and 4-methylphenoxy.
  • arylalkoxy is used herein to mean any of the above mentioned Ci. 10 alkoxy groups substituted by any of the above-mentioned aryl groups, which may be optionally substituted.
  • Useful arylalkoxy groups include benzyloxy and phenethyloxy.
  • Useful haloalkyl groups include C M 0 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.
  • acylamino (acylamido) groups are any Ci -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 pentafluorobenzoylamido.
  • Useful acyloxy groups are any Ci -6 acyl (alkanoyl) attached to an oxy
  • (-O-) group e.g., formyloxy, acetoxy, propionoyloxy, butanoyloxy, pentanoyloxy and hexanoyloxy.
  • heterocycle is used herein to mean a saturated or partially saturated 3-7 membered monocyclic, or 7-10 membered bicyclic ring system, which consists of carbon atoms and from one to four heteroatoms independently selected from the group consisting of O, N, and S, wherein the nitrogen and sulfur heteroatoms can be optionally oxidized, the nitrogen can be optionally quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring, and wherein the heterocyclic ring can be substituted on carbon or on a nitrogen atom if the resulting compound is stable.
  • Useful saturated or partially saturated heterocyclic groups include tetrahydrofuranyl, pyranyl, piperidinyl, piperazinyl, pyrrolidinyl, imidazolidinyl, imidazolinyl, indolinyl, isoindolinyl, quinuclidinyl, mo ⁇ holinyl, isochromanyl, chromanyl, pyrazolidinyl pyrazolinyl, tetronoyl and tetramoyl groups.
  • heteroaryl refers to groups having 5 to
  • Useful heteroaryl groups include thienyl (thiophenyl), benzo[6]thienyl, naphtho[2,3-6]thienyl, thianthrenyl, furyl (furanyl), pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxanthiinyl, pyrrolyl, including without limitation 2//-pyrrolyl, imidazolyl, pyrazolyl, pyridyl (pyridinyl), including without limitation 2-pyridyl, 3-pyridyl, and 4-pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, 4//-q ⁇ inolizinyl, isoquinolyl, quinolyl, phthalzinyl
  • heteroaryl group contains a nitrogen atom in a ring
  • nitrogen atom may be in the form of an iV-oxide, e.g., a pyridyl TV-oxide, pyrazinyl TV-oxide and pyrimidinyl TV-oxide.
  • heteroaryloxy is used herein to mean oxygen substituted by one of the above-mentioned heteroaryl groups, which may be optionally substituted.
  • Useful heteroaryloxy groups include pyridyloxy, pyrazinyloxy, pyrrolyloxy, pyrazolyloxy, imidazolyloxy and thiophenyloxy.
  • heteroarylalkoxy is used herein to mean any of the above- mentioned Ci-io alkoxy groups substituted by any of the above-mentioned heteroaryl groups, which may be optionally substituted.
  • Some 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.
  • Examples of pharmaceutically acceptable 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.
  • Examples of prodrugs of the compounds of the invention include the simple esters of carboxylic acid containing compounds (e.g., those obtained by condensation with a C M alcohol according to methods known in the art); esters of hydroxy containing compounds (e.g., those obtained by condensation with a Ci -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 Ci -4 aldehyde or ketone according to methods known in the art); carbamate of amino containing compounds, such as those described by Leu, et. ai, (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. Specifically, the compounds of this invention with Formulae I-II and VII could be prepared as illustrated by the exemplary reaction in Scheme 1. Reaction of 5-amino-3-methylisoxazole-4-carbonitrile with phosphorous oxychloride and N,N-dimethyl acetamide produced 4-chloro-3,6- dimethylisoxazolo[5,4-(/]pyrimidine.
  • VIII could be prepared as illustrated by the exemplary reaction in Scheme 7.
  • Reaction of 7-chloro-2,5-dimethyloxazolo[5,4-d]pyrimidine with a substituted aniline such as iV-methyl-4-methoxyaniline in the presence of a base such as sodium acetate in solvents such as THF and water produced N-(4- Methoxyphenyl)-N,2,5-trimethyloxazolo[5,4-cT]pyrimidin-7-amine.
  • An important aspect of the present invention is the discovery that compounds having Formulae I-XI are activators of caspases and inducers of apoptosis. Therefore, these compounds are useful in a variety of clinical conditions in which there is uncontrolled cell growth and spread of abnormal cells, such as in the case of cancer.
  • Another important aspect of the present invention is the discovery that compounds having Formulae I-XI 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
  • most standard anti-cancer drugs are not effective in killing drug resistant cancer cells under the same conditions. Therefore, compounds of this invention are useful for the treatment of drug resistant cancer, such as breast 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 prodrug of the compound of Formulae I-XI, which functions as a caspase cascade activator and inducer of apoptosis.
  • the present invention also includes 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- XI, wherein said therapeutic method is useful to treat cancer, which is a group of diseases characterized by the uncontrolled growth and spread of abnormal cells.
  • Such diseases include, but are not limited to, Hodgkin's disease, non- Hodgkin's lymphoma, acute lymphocytic leukemia, chronic lymphocytic leukemia, multiple myeloma, neuroblastoma, breast carcinoma, ovarian carcinoma, lung carcinoma, Wilms' tumor, cervical carcinoma, testicular carcinoma, soft-tissue sarcoma, primary macroglobulinemia, bladder carcinoma, chronic granulocytic leukemia, primary brain carcinoma, malignant melanoma, small-cell lung carcinoma, stomach carcinoma, colon carcinoma, malignant pancreatic insulinoma, malignant carcinoid carcinoma, choriocarcinoma, mycosis fungoides, head or neck carcinoma, osteogenic sarcoma, pancreatic carcinoma, acute granulocytic leukemia, hairy cell leukemia, neuroblastoma, rhabdomyosarcoma, Kaposi's sarcoma, genitourinary carcinoma, thyroid carcinoma,
  • 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 symptoms of the disease. Typically, repeated administration is required to achieve the desired amelioration of symptoms.
  • a pharmaceutical composition comprising a compound, or a pharmaceutically acceptable salt of said compound of Formulae I-XI, which functions as a caspase cascade activator and inducer of apoptosis in combination with a pharmaceutically acceptable vehicle is provided.
  • 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- XI, 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.
  • cancer chemotherapeutic agents which may be used for combination therapy include, but not are limited to alkylating agents, such as busulfan, cis-platin, mitomycin C, and carboplatin; antimitotic agents, such as colchicine, vinblastine, paclitaxel, and docetaxel; topo I inhibitors, such as camptothecin and topotecan; topo II inhibitors, such as doxorubicin and etoposide; RNA/DNA antimetabolites, such as 5-azacytidine, 5-fluorouracil and methotrexate; DNA antimetabolites, such as 5-fluoro-2'-deoxy-uridine, ara-C, hydroxyurea and thioguanine; antibodies, such as campath, Herceptin® or Rituxan®.
  • alkylating agents such as busulfan, cis-platin, mitomycin C, and carboplatin
  • antimitotic agents such as colchicine, vinblastine, paclitaxel
  • cancer chemotherapeutic agents which may be used for combination therapy include melphalan, chlorambucil, cyclophosamide, ifosfamide, vincristine, mitoguazone, epirubicin, aclarubicin, bleomycin, mitoxantrone, elliptinium, fludarabine, octreotide, retinoic acid, tamoxifen, Gleevec® and alanosine.
  • 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 at least one known cancer chemotherapeutic agent.
  • the compound of the invention and 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 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.
  • alpha- 1 -adrenoceptor antagonists such as doxazosin, terazosin, and tamsulosin can inhibit the growth of prostate cancer cell via induction of apoptosis (Kyprianou, N., et al., Cancer Res 60:4550- 4555, (2000)).
  • 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 a compound described herein, which functions as a caspase cascade activator and inducer of apoptosis, in combination with at least one known alpha- 1 -adrenoceptor antagonists, or a pharmaceutically acceptable salt of said agent.
  • known alpha- 1 -adrenoceptor antagonists which can be used for combination therapy include, but are not limited to, doxazosin, terazosin, and tamsulosin.
  • sigma-2 receptors are expressed in high densities in a variety of tumor cell types (Vilner, B. J., et al., Cancer Res. 55: 408-413 (1995)) and that sigma-2 receptor agonists, such as CB-64D, CB- 184 and haloperidol activate a novel apoptotic pathway and potentiate antineoplastic drugs in breast tumor cell lines. (Kyprianou, N., et al., Cancer Res. (52:313-322 (2002)).
  • 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 a compound described herein, which functions as a caspase cascade activator and inducer of apoptosis, in combination with at least one known sigma-2 receptor agonist, or a pharmaceutically acceptable salt of said agonist.
  • known sigma-2 receptor agonists that can be used for combination therapy include, but are not limited to, CB-64D, CB- 184 and haloperidol.
  • 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 a compound described herein, which functions as a caspase cascade activator and inducer of apoptosis, in combination with at least one known HMG-CoA reductase inhibitor, or a pharmaceutically acceptable salt of said agent.
  • HMG-CoA reductase inhibitors which can be used for combination therapy include, but are not limited to, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin and cerivastatin.
  • 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 a compound described herein, which functions as a caspase cascade activator and inducer of apoptosis, in combination with at least one known HIV protease inhibitor, or a pharmaceutically acceptable salt of said agent.
  • HIV protease inhibitors which can be used for combination therapy include, but are not limited to, amprenavir, abacavir, CGP-73547, CGP-61755, DMP-450, indinavir, nelfmavir, tipranavir, ritonavir, saquinavir, ABT-378, AG 1776, and BMS-232,632.
  • retinoids such as fenretinide (N-(A- hydroxyphenyl)retinamide, 4HPR)
  • fenretinide N-(A- hydroxyphenyl)retinamide, 4HPR
  • 4HPR also was reported to have good activity in combination with gamma-radiation on bladder cancer cell lines (Zou, C, et al, Int. J. Oncol. 73: 1037-1041 (1998)).
  • 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 a compound described herein, which functions as a caspase cascade activator and inducer of apoptosis, in combination with at least one known retinoid and synthetic retinoid, or a pharmaceutically acceptable salt of said agent.
  • retinoids and synthetic retinoids which can be used for combination therapy include, but are not limited to, bexarotene, tretinoin, 13-cis-retinoic acid, 9-cis-retinoic acid, ⁇ -difluoromethylomithine, ILX23-7553, fenretinide, and iV-4-carboxyphenyl retinamide.
  • proteasome inhibitors such as lactacystin
  • lactacystin exert anti-tumor activity in vivo and in tumor cells in vitro, including those resistant to conventional chemotherapeutic agents.
  • proteasome inhibitors may also prevent angiogenesis and metastasis in vivo and further increase the sensitivity of cancer cells to apoptosis (Almond, J. B., et al., Leukemia 7(5:433-443 (2002)).
  • 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 a compound described herein, which functions as a caspase cascade activator and inducer of apoptosis, in combination with at least one known proteasome inhibitor, or a pharmaceutically acceptable salt of said agent.
  • known proteasome inhibitors which can be used for combination therapy include, but are not limited to, lactacystin, MG- 132, and PS-341.
  • 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 a compound described herein, which functions as a caspase cascade activator and inducer of apoptosis, in combination with at least one known tyrosine kinase inhibitor, or a pharmaceutically acceptable salt of said agent.
  • tyrosine kinase inhibitors which can be used for combination therapy include, but are not limited to, Gleevec®, ZD 1839 (Iressa), SH268, genistein, CEP2563, SU6668, SUl 1248, and EMD121974.
  • prenyl-protein transferase inhibitors such as farnesyl protein transferase inhibitor Rl 15777
  • Rl 15777 preclinical antitumor activity against human breast cancer
  • Synergy of the protein farnesyltransferase inhibitor SCH66336 and cisplatin in human cancer cell lines also has been reported (Adjei, A. A., et al, Clin. Cancer. Res. 7:1438-1445 (2001)).
  • 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 a compound described herein, which functions as a caspase cascade activator and inducer of apoptosis, in combination with at least one known prenyl-protein transferase inhibitor, including farnesyl protein transferase inhibitor, inhibitors of geranylgeranyl-protein transferase type I (GGPTase-I) and geranylgeranyl-protein transferase type- II, or a pharmaceutically acceptable salt of said agent.
  • known prenyl- protein transferase inhibitors which can be used for combination therapy include, but are not limited to, Rl 15777, SCH66336, L-778,123, BAL9611 and TAN-1813.
  • CDK cyclin-dependent kinase
  • 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 a compound described herein, which functions as a caspase cascade activator and inducer of apoptosis, in combination with at least one known cyclin-dependent kinase inhibitor, or a pharmaceutically acceptable salt of said agent.
  • known cyclin-dependent kinase inhibitor which can be used for combination therapy include, but are not limited to, flavopiridol, UCN-01 , roscovitine and olomoucine.
  • 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 a compound described herein, which functions as a caspase cascade activator and inducer of apoptosis, in combination with at least one known COX-2 inhibitor, or a pharmaceutically acceptable salt of said inhibitor.
  • known COX-2 inhibitors that can be used for combination therapy include, but are not limited to, celecoxib, valecoxib, and rofecoxib.
  • Another embodiment of the present invention is directed to a composition effective to inhibit neoplasia comprising a bioconjugate of a compound described herein, which functions as a caspase cascade activator and inducer of apoptosis, in bioco ⁇ jugation with at least one known therapeutically useful antibody, such as Herceptin ® or Rituxan ® , growth factors, such as DGF, NGF; cytokines, such as IL-2, IL-4, or any molecule that binds to the cell surface.
  • the antibodies and other molecules will deliver a compound described herein to its targets and make it an effective anticancer agent.
  • the bioconjugates could also 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 prodrug of a compound described herein, which functions as a caspase cascade activator and inducer of apoptosis, in combination with radiation therapy.
  • the compound of the invention may be administered at the same time as the radiation therapy is administered or at a different time.
  • Yet another embodiment of the present invention is directed to a composition effective for post-surgical treatment of cancer, comprising a compound, or a pharmaceutically acceptable salt or prodrug of a compound described herein, 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 operates 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 for maintaining immune homeostasis.
  • the elimination of the effector cells is regulated by apoptosis.
  • Autoimmune diseases have lately been determined to occur as a consequence of deregulated cell death.
  • 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, 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 inflamed thyroid, the development of lymphocytic infiltration of the thyroid was inhibited and induction of infiltrating T cells death was observed. These results show that FasL expression on thyrocytes may have a curative effect on ongoing EAT by inducing death of pathogenic autoreactive infiltrating T lymphocytes.
  • Bisindolylmaleimide VIlI is known to potentiate Fas-mediated apoptosis in human astrocytoma 1321N1 cells and in Molt-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. Med.
  • 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.
  • an effective amount of a compound, or a pharmaceutically acceptable salt or prodrug of the compound of Formulae I-XI, which functions as a caspase cascade activator and inducer of apoptosis is an effective treatment for hyperproliferative skin diseases, such as psoriasis.
  • Synovial cell hyperplasia is a characteristic of patients with rheumatoid arthritis (RA). It is believed that excessive proliferation of RA synovial cells, as well as defects in synovial cell death, may be responsible for synovial cell hyperplasia. Wakisaka, et al., CHn. Exp. Immunol. 114: ⁇ 19-128 (1998), found that although RA synovial cells could die via apoptosis through a Fas/FasL pathway, apoptosis of synovial cells was inhibited by proinflammatory cytokines present within the synovium. Wakisaka, et al.
  • an effective amount of a compound, or a pharmaceutically acceptable salt or prodrug of the compound of Formulae I-Xl, which functions as a caspase cascade activator and inducer of apoptosis is an effective treatment for rheumatoid arthritis.
  • an effective amount of a compound, or a pharmaceutically acceptable salt or prodrug of the compound of Formulae I-XI, which functions as a caspase cascade activator and inducer of apoptosis, is an effective treatment for inflammation.
  • Caspase cascade activators and inducers of apoptosis may also be a desirable therapy in the elimination of pathogens, such as HIV, Hepatitis C and other viral pathogens.
  • pathogens such as HIV, Hepatitis C and other viral pathogens.
  • the long lasting quiecence, followed by disease progression, may be explained by an anti-apoptotic mechanism of these pathogens leading to persistent cellular reservoirs of the virions. It has been reported that HIV- 1 infected T leukemia cells or peripheral blood mononuclear cells (PBMCs) underwent enhanced viral replication in the presence of the caspase inhibitor Z-VAD-fmk.
  • PBMCs peripheral blood mononuclear cells
  • Z-VAD-fmk also stimulated endogenous virus production in activated PBMCs derived from HIV-I- infected asymptomatic individuals (Chinnaiyan, A., et al., Nat. Med. 3:333 (1997)). Therefore, apoptosis serves as a beneficial host mechanism to limit the spread of HIV and new therapeutics using caspase/apoptosis activators are useful to clear viral reservoirs from the infected individuals.
  • HCV infection also triggers anti-apoptotic mechanisms to evade the host's immune surveillance leading to viral persistence and hepatocarcinogenesis (Tai, D. I., et al. Hepatology 3:656-64 (2000)). Therefore, apoptosis inducers are useful as therapeutics for HIV and other infectious disease.
  • Stent implantation has become the new standard angioplasty procedure.
  • in-stent restenosis remains the major limitation of coronary stenting.
  • New approaches have been developed to target pharmacological modulation of local vascular biology by local administration of drugs. This allows for drug applications at the precise site and time of vessel injury.
  • Numerous pharmacological agents with antiproliferative properties are currently under clinical investigation, including actinomycin D, rapamycin or paclitaxel coated stents (Regar E., et al., Br. Med. Bull. 59:227- 248 (2001)). Therefore, apoptosis inducers, which are antiproliferative, are useful as therapeutics for the prevention or reduction of in-stent restenosis.
  • 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 animals, e.g., mammals, orally at a dose of 0.0025 to 50 mg/kg of body weight, per day, or an equivalent amount of the pharmaceutically acceptable salt thereof, to a mammal being treated. Preferably, approximately 0.01 to approximately 10 mg/kg of body weight is orally administered.
  • 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 of body weight, and most preferably, from approximately 0.01 to approximately 5 mg/kg of body weight.
  • a known cancer chemotherapeutic agent is also administered, it is administered in an amount that is effective to achieve its intended purpose.
  • the amounts of such known cancer chemotherapeutic agents effective for cancer are well known to those skilled in the art.
  • the unit oral dose may comprise from 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 mg, conveniently approximately 0.25 to 50 mg of the compound or its solvates.
  • the compound in a topical formulation, 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 may be used pharmaceutically.
  • the preparations particularly those preparations which may be administered orally and that may be used for the preferred type of administration, such as tablets, dragees, and capsules, and also preparations that may 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.
  • nontoxic 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 compounds 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 compounds 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, /V-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, transde ⁇ nal, buccal, intrathecal, intracranial, intranasal or topical routes.
  • administration 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.
  • compositions 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.
  • pharmaceutical preparations for oral use may 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 starch, potato
  • 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, e.g., 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 hydroxy- propylmethyl-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 may 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 may 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 may 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), or 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 Cn).
  • 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 may be employed in these topical formulations. Examples of such enhancers are 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 of the active ingredient, dissolved in a small amount of an oil, such as almond oil, is admixed.
  • An oil such as almond oil
  • a typical example of such a cream is one which includes approximately 40 parts 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 vegetable oil such as almond oil
  • a typical example of such an ointment is one which includes approximately 30 % almond oil and approximately 70 % white soft paraffin by weight.
  • T-47D Human breast cancer cell lines T-47D, human hepatocellular carcinoma cell line SNU398, human colon carcinoma cell line HCTl 16, and human lung cancer cell line H 1299 were grown according to media component mixtures designated by American Type Culture Collection + 10% FCS (Invitrogen Corporation), in a 5 % CO 2 -95 % humidity incubator at 37 0 C.
  • T- 47D and H 1299 cells were maintained at a cell density between 50 and 80 % confluency at a cell density of 0.1 to 0.6 x 10 6 cells/mL.
  • Cells were harvested at 600xg and resuspended at 0.65 x 10 6 cells/mL into appropriate media + 10 % FCS.
  • the samples were mixed by agitation and then incubated at 37 0 C for 24 h or 48 h in a 5 % CO 2 - 95 % humidity incubator. After incubation, the samples were removed from the incubator and 25 ⁇ L of a solution containing 14 ⁇ M of TV-(Ac-DE VO)-N '- ethoxycarbonyl-Rl lO (SEQ ID No.:l) fluorogenic substrate (Cytovia, Inc.; WO99/18856), 20 % sucrose (Sigma), 20 mM DTT (Sigma), 200 mM NaCl (Sigma), 40 mM Na PIPES buffer pH 7.2 (Sigma), and 500 ⁇ g/mL lysolecithin (Calbiochem) was added.
  • a solution containing 14 ⁇ M of TV-(Ac-DE VO)-N '- ethoxycarbonyl-Rl lO (SEQ ID No.:l) fluorogenic substrate (Cytovia,
  • the activity of caspase cascade activation was determined by the ratio of the net RFU value for ⁇ r -(4-methoxyphenyl)-N,3,6-trimethylisoxazolo[5,4- rf]pyrimidin-4-amine (Example 7) or other test compound to that of control samples.
  • the EC 50 (nJVI) was determined by a sigmoidal dose-response calculation (Prism 3.0, GraphPad Software Inc.).
  • Human breast cancer cell lines T-47D, MX-I and MDAMB435, human sarcoma cell line MES-SA and multi-drug resistant (MDR) human sarcoma cell line MES-SA/ ADR, murine leukemia cell line P388 and multidrug resistant (MDR) murine leukemia cell line P388ADR were grown and harvested as in Example 35.
  • Baseline for GI 50 dose for 50% inhibition of cell proliferation
  • GI 50 dose for 50% inhibition of cell proliferation
  • the samples were mixed by agitation and then incubated at 37 0 C for 0.5 h in a 5% C ⁇ 2 -95% humidity incubator. After incubation, the samples were removed from the incubator and 25 ⁇ L of CellTiter-Glo ⁇ reagent (Promega) was added.
  • Example 7 4-amine (Example 7) and related compounds are identified as antineoplastic compound that inhibits cell proliferation. More importantly, N-(4- methoxyphenyl)-N,3,6-trimethylisoxazolo[5,4-c/]pyrimidin-4-amine (Example 7) was found to have similar activity against MES-SA and its corresponding multi-drug resistant cell MES-SA/ ADR, as well as P388 and its corresponding multi-drug resistant cell P388/ADR.

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Abstract

La présente invention concerne des N-aryl-isoxazolopyrimidin-4-amines et leurs composés associés représentés par la formule (I) : Ar, R1-R5, A, B, D, E et H étant tels que définis dans la présente formule. L'invention porte sur la découverte selon laquelle les composés possédant la formule I sont des activateurs de caspsases et des inducteurs de l'apoptose. Dès lors, les activateurs de caspases et les inducteurs de l'apoptose de l'invention peuvent servir à induire une mort cellulaire dans une variété de conditions cliniques au cours desquelles apparaissent une croissance et une propagation incontrôlées de cellules anormales.
PCT/US2007/023109 2006-11-02 2007-11-02 N-aryl-isoxazolopyrimidin-4-amines et composés associés servant d'activateurs de caspases et d'inducteurs d'apoptose et leur utilisation WO2008057402A2 (fr)

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