WO2002053155A1 - Inhibiteur de telomerase - Google Patents

Inhibiteur de telomerase Download PDF

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Publication number
WO2002053155A1
WO2002053155A1 PCT/US2001/050042 US0150042W WO02053155A1 WO 2002053155 A1 WO2002053155 A1 WO 2002053155A1 US 0150042 W US0150042 W US 0150042W WO 02053155 A1 WO02053155 A1 WO 02053155A1
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substituted
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compound
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PCT/US2001/050042
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Daisuke Machii
Koji Hagihara
Akira Asai
Hitoshi Arai
Yoshinori Yamashita
Allison C. Chin
Mieczyslaw A PIATYSZEK
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Geron Corporation
Kyowa Hakko Kogyo Co.,Ltd.
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Publication of WO2002053155A1 publication Critical patent/WO2002053155A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • A61K31/41—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
    • A61K31/4166—1,3-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
    • 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
    • A61K31/41—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
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/96—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention relates to telomerase inhibitors and antitumor agents containing a 4-oxo-2-thioxoimidazolidine derivative (i.e., thiohydantoin derivative) or a pharmaceutically acceptable salt thereof.
  • telomerase inhibitors and antitumor agents can be used for the treatment of diseases related to telomerase activity, e.g., malignant tumors.
  • the present invention also relates to thiohydantoin derivatives or pharmaceutically acceptable salts thereof.
  • telomeres are present at the termini of eukaryotic chromosomes and are believed to be essential to the stabilization of chromosomes. In humans, the telomere sequence consists of repetitions of TTAGGG from the 5' end. Although there are few exceptions, telomeres in normal cells usually undergo a gradual reduction in length as the cell divides. The cell becomes an aged cell (Ml phase) and ceases to divide when the telomeres are shortened to a certain length.
  • telomeres when there is mutation in a cancer suppressor gene, e.g., p53 gene, the cell keeps dividing until the telomeres are reduced to extremely short lengths resulting in instability of the chromosomes and the cell death (M2 phase). See, for example, Proc. Natl. Acad. Sci. USA, vol. 89, pp. 10114-10118 (1992) and Trends in Cell Biology, vol. 5, pp. 293-297 (1995). [04] In addition, it is believed that 80% or more cancer cells express an enzyme called telomerase, which extends telomeres. Journal of the NCI, vol. 87, pp. 884-894 (1995).
  • Telomerase is a reverse transcription enzyme that extends telomeres using RNA as a template. Telomerase is composed of a template RNA (hTR) and a catalytic subunit protein (hTERT). It is believed that the telomerase in cancer cells suppresses or prevents shortening of the telomeres, thereby rendering the cancer cells immortal, i.e., indefinitely growing by maintaining the length of the telomeres. This theory, often referred to as the "telomere hypothesis", was proposed in 1992 by Cal Harley et al. Proc. Natl. Acad. Sci. USA, vol. 89, pp. 10114-10118 (1992). The telomere hypothesis has been supported experimentally.
  • telomere reduction and cancer cell death For example, administration of an antisense agent against hTR results in telemere reduction and cancer cell death. Science, vol. 269, pp. 1236-1240 (1995). In addition, expression of a dominant-negative mutant hTERT which inhibits wild type telomerase also results in telomere reduction and cancer cell death. Genes & Development, vol. 13, pp. 2388-2399 (1999) and Nature Medicine, vol. 5, pp. 1164-1170 (1999). Therefore, it is believed that compounds that specifically inhibit telomerase may be used as a new type of antitumor agents by inducing a telomere reduction and limiting the life span of cancer cells. Such compounds are expected to be low-toxicity antitumor agents with minimal affect on normal tissues, because the telomerase is expressed only in cancer cells with few exceptions, such as reproductive cells,, etc.
  • Examples of known low molecular weight compounds that inhibit telomerase in vitro include: nucleic acid analogs, e.g., AZTTP, ddGTP [Mol. Cell. Biol., vol. 16, pp. 53- 65 (1996)], and 7-deaza-dGTP [Biochemistry, vol. 35, pp. 15611-15617 (1996)]; hetero 5- membered ring fused pyridine derivatives [U.S. Patent Nos. 5,656,638 and 5,760,062]; benzothiophene derivatives [U.S. Patent No. 5,703,116]; pyridine derivatives [U.S. Patent Nos.
  • telomere inhibitory activity and reduction of telomere in cancer cells have been associated with catechins, which are present in green teas. Biochem. Biophys. Res. Commun., vol. 249, pp. 391-396 (1998).
  • telomerase inhibitors include TMPyP4, a porphyrin having positive charge. J. Am. Chem. Soc, vol. 120, pp. 3261- 3262 (1998) and WO98/33503.
  • Thiohydantoin derivatives have been reported to have a variety of pharmaceutical activities, such as anti-allergic and anti-inflammatory [e.g., WO97/28147 and Japanese Laid-Open Patent Publication No. 2-62864]; anti-ulcer [Japanese Laid-Open Patent Publication No. 8-225537]; blood sugar level reduction [Arzneim. Forsch., vol. 50, pp. 626- 630 (2000)]; aldose reductase inhibition [Farmaco, vol.
  • thiohydantoin derivatives are known to be effective in preventing and have therapeutic effects on tissue damage associated with lipid peroxide [Japanese Laid-Open Patent Publication No. 5-331148]. Moreover, thiohydantoin derivatives are reported to be useful in optic materials [e.g., Japanese Laid-Open Patent Publication No. 6-128234]. However, no telomerase inhibiting activity of thiohydantoin derivatives has been reported to date.
  • Some aspects of the present invention provide telomerase inhibitors, antitumor agents, and novel thiohydantoin derivatives having excellent telomerase inhibitory activity and antitumor activity.
  • the present invention provides a compound having a telomerase inhibitory activity, wherein the compound comprises a 4-oxo-2-thioxoimidazolidine skeleton.
  • the present invention provides an antitumor agent comprising as an active ingredient a compound having a 4-oxo-2-thioxoimidazolidine skeleton and having a telomerase inhibitory activity.
  • telomerase inhibitor comprising a compound of the formula:
  • Q 1 is hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted arylalkenyl, substituted or unsubstituted heteroarylalkenyl, substituted or unsubstituted arylalkynyl, substituted or unsubstituted heteroarylalkynyl, substituted or unsubstituted lower alkanoyl, substituted or unsubstituted lower alkenoyl, substituted or unsubstituted lower alkynoyl, substituted or unsubstituted arylalkanoyl, substituted or unsubstituted lower
  • R 1 is hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted arylalkenyl, substituted or unsubstituted heteroarylalkenyl, substituted or unsubstituted arylalkynyl, or substituted or unsubstituted heteroarylalkynyl;
  • R and R are hydrogen, and the other is a moiety of the formula:
  • each Z 1 to Z 5 is independ -e x ntly hydro-gen, substituted or unsubstituted lower alkyl, unsubstituted lower alkoxy having no asymmetric carbon atom, substituted lower alkoxy, unsubstituted lower alkylthio having no asymmetric carbon atom, substituted lower alkylthio, NR 4 R 5 (wherein R 4 and R 5 are the same or different, and each represents hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, aroyl, heteroaroyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroarylalkyl, or a moiety of the formula
  • R 4 and R 5 together with the nitrogen atom to which they are attached to form a substituted or unsubstituted heterocyclic group), nitro, cyano, aryl, heteroaryl, aryloxy, heteroaryloxy, aralkyloxy, heteroarylalkyloxy or halogen, or two of the substituents Z 1 to Z 5 that are attached to the adjacent carbon atoms on the benzene ring together form a moiety of the formula -O-(CH 2 ) n -O- (wherein n represents an integer of 1 or 2)],
  • R 6 has the same meaning as the aforementioned R 1 ;
  • each of R 7 and R 8 is independently hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, or substituted or unsubstituted heteroarylalkyl, or R 7 and R 8 together with the nitrogen atom to which they are attached to form a substituted or unsubstituted heterocyclic group;
  • R 6 , R 7 and R 8 are those defined above, R 1 is the above-mentioned substituent other than hydrogen and substituted or unsubstituted methyl.
  • Still another aspect of the present invention provides a telomerase inhibitor comprising the Compound of Formula la above or a pharmaceutically acceptable salt thereof, as an active ingredient.
  • Another aspect of the present invention provides an antitumor agent comprising the Compound of Formula la above or a pharmaceutically acceptable salt thereof, as an active ingredient.
  • an antitumor agent comprising the Compound of Formula la above or a pharmaceutically acceptable salt thereof, as an active ingredient.
  • a medicament comprising the Compound of Formula la above or a pharmaceutically acceptable salt thereof, as an active ingredient.
  • the Compound having a 4-oxo-2-thioxoimidazolidine skeleton and having telomerase inhibitory activity according to the present invention is preferably the Compound of Formula I above, and more preferably the Compound of Formula la above. However, it should be appreciated that the compounds of the present invention are not limited to such.
  • Compound of Formula (I) or (la) may be denoted as Compound (I) or (la), respectively. Similar notations apply to compounds of formulae with other numerals.
  • “Lower alkyl” refers to a linear or branched saturated monovalent hydrocarbon moiety of 1 to 6 carbon atoms, e.g., methyl, ethyl, propyl, isopropyl, butyl, tert- butyl, isobutyl, pentyl, and hexyl.
  • “Lower alkenyl” refers to a linear or branched monovalent hydrocarbon moiety of 2 to 10 carbon atoms having one or more carbon-carbon double bonds, e.g., vinyl, propenyl, methacryl, prenyl, butenyl, pentenyl, hexenyl, and geranyl.
  • “Lower alkynyl” refers to a linear or branched monovalent hydrocarbon moiety of 2 to 6 carbon atoms having one or more carbon-carbon triple bonds, e.g., ethynyl, propynyl, butynyl, pentynyl, and hexynyl.
  • Aryl refers to monocyclic, bicyclic, or tricyclic aromatic rings, e.g., phenyl, naphthyl, anthryl, and the like.
  • Heteroaryl refers to monocyclic, bicyclic, or tricyclic aromatic heterocyclic rings, e.g., pyridyl, thienyl, furyl, pyrrolyl, imidazolyl, pyrimidinyl, oxazolyl, thiazolyl, pyrazolyl, quinolyl, quinoxalinyl, quinazolyl, benzopyranyl, benzothienyl, benzofuryl, indolyl, benzimidazolyl, benzothiazolyl, indazolyl, benzodioxanyl, benzoxazolyl, and the like.
  • Alkylene alkenylene and alkynylene refer to the corresponding divalent form of lower alkyl, lower alkenyl and lower alkynyl, respectively.
  • Alkyl or “heteroarylalkyl” refers to a moiety of the formula -R'-R", where R' is alkylene and R" is aryl or heteroaryl, respectively, as defined herein.
  • Arylalkenyl or “heteroarylalkenyl” refers to a moiety of the formula -R'-
  • R where R' is alkenylene and R" is aryl or heteroaryl, respectively, as defined herein.
  • R' alkenylene and R" is aryl or heteroaryl, respectively, as defined herein.
  • R" where R' is alkynylene and R" is aryl or heteroaryl, respectively, as defined herein.
  • Substituted aryl, substituted heteroaryl, substituted aralkyl, substituted heteroarylalkyl, substituted arylalkenyl, substituted heteroarylalkenyl, substituted arylalkynyl, substituted heteroarylalkynyl, substituted arylalkanoyl, substituted heteroarylalkanoyl, substituted arylalkenoyl, substituted heteroarylalkenoyl, substituted arylalkynoyl, and substituted heteroarylalkynoyl may include one or more, up to the substitutable number of, substituents; preferably 1 to 5 substituents. Examples of such substituents include: [39] substituted or unsubstituted lower alkyl;
  • aralkyl [48] substituted aralkyl ⁇ where substituent(s) for the aralkyl may be the same or different, and include one or more, up to the substitutable number of, substituents; preferably 1 to 5 substituents, such as lower alkyl, trifluoromethyl, hydroxy, lower alkoxy, trifluoromethoxy, mercapto, lower alkylthio, aryl, NR 9 R 10 (where R 9 and R 10 may be the same or different and represent hydrogen or lower alkyl), nitro, cyano, CO R u (where R 11 represents hydrogen or lower alkyl), CONR R [where R and R may be the same or different and represent hydrogen, lower alkyl, aryl, heteroaryl, aralkyl, or heteroarylalkyl; or alternatively, R 12 and R 13 together with the nitrogen atom to which they are attached to form a substituted or unsubstituted heterocyclic group], arylsulfonylmethyl
  • substituted heteroarylalkyl [where substituent(s) for the heteroarylalkyl may be the same or different, and include one or more, up to the substitutable number of, substituents; preferably 1 to 5 substituents, such as lower alkyl, trifluoromethyl, hydroxy, lower alkoxy, trifluoromethoxy, mercapto, lower alkylthio, aryl, NR 9a R 10a (where R 9a and R 10a are same as R 9 and R 10 , respectively), nitro, cyano, CO 2 R' la (where R 1 la is same as R 1 '), CONR 12a R l3a (where R 12a and R I3a are same as R 12 and R 13 , respectively), arylsulfonylmethyl, methylenedioxy, propylenedioxy, and halogen]; [52] heteroarylalkyloxy;
  • substituted arylalkenyl [where substituent(s) for the arylalkenyl may be the same or different, and include one or more, up to the substitutable number of, substituents; preferably 1 to 5 substituents, such as lower alkyl, trifluoromethyl, hydroxy, lower alkoxy, trifluoromethoxy, mercapto, lower alkylthio, aryl, NR 9A R 10 ⁇ (where R 9A and R 10A are same as R 9 and R 10 , respectively), nitro, cyano, CO 2 R 1 1A (where R 11A is same as R 1 1 ), CONR 12A R 13A
  • R and R are same as R and R , respectively), arylsulfonylmethyl, methylenedioxy, propylenedioxy, and halogen]; [55] heteroarylalkenyl; [56] substituted heteroarylalkenyl [where substituent(s) for the heteroarylalkenyl may be the same or different, and include one or more, up to the substitutable number of, substituents; preferably 1 to 5 substituents, such as lower alkyl, trifluoromethyl, hydroxy, lower alkoxy, trifluoromethoxy, mercapto, lower alkylthio, aryl, NR 9Aa R 10Aa (where R 9Aa and R 10Aa are same as R 9 and R 10 , respectively), nitro, cyano, CO 2 R' ' Aa (where R 1 1Aa is same as R 1 '), CONR 12Aa R 13Aa (where R l2Aa and R ,3Aa are same as R 12 and R
  • substituted arylalkynyl [where substituent(s) for the arylalkynyl may be the same or different, and include one or more, up to the substitutable number of, substituents; preferably 1 to 5 substituents, such as lower alkyl, trifluoromethyl, hydroxy, lower alkoxy, trifluoromethoxy, mercapto, lower alkylthio, aryl, NR 9B R 10B (where R 9B and R 10B are same as R 9 and R 10 , respectively), nitro, cyano, CO 2 R 11B (where R 1 1 B is same as R ⁇ ), CONR 12B R , 3B (where R 12B and R 13B are same as R 12 and R 13 , respectively), arylsulfonylmethyl, methylenedioxy, propylenedioxy, and halogen]; [59] heteroarylalkynyl;
  • substituted heteroarylalkynyl [where substituent(s) for the heteroarylalkynyl may be the same or different, and include one or more, up to the substitutable number of, substituents; preferably 1 to 5 substituents, such as lower alkyl, trifluoromethyl, hydroxy, lower alkoxy, trifluoromethoxy, mercapto, lower alkylthio, aryl, R 9Ba R 10Ba (where R 9Ba and R 10Ba are same as R 9 and R 10 , respectively), nitro, cyano, CO 2 R' 1Ba (where R 1 1 Ba is same as R 11 ), CONR 12Ba R 13Ba (where R 12Ba and R 13Ba are same as R 12 and R 13 , respectively), arylsulfonylmethyl, methylenedioxy, propylenedioxy, and halogen]; [61] lower alkanoyl ; [62] lower alkanoyloxy;
  • NR 14 R 15 is independently hydrogen, lower alkyl, lower alkanoyl, aroyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, substituted aryl [where substituent(s) for the aryl include one or more, up to the substitutable number of, substituents; preferably 1 to 5 substituents, such as lower alkyl, hydroxy, lower alkoxy, lower alkanoyl, lower alkanoyloxy, mercapto, lower alkylthio, NR 16 R 17 (where R 16 and R 17 are same as R 9 and R 10 , respectively), nitro, cyano, CO 2 R 18 (where R 18 is same as R 1 1 ), CONR 19 R 20 (where R 19 and R 20 are same as R 12 and R 13 , respectively), 4-oxo-2-thioxoimidazolidin-5- ylidenemethyl and halogen], substituted heteroaryl [where substituent(s)
  • each of R 22 and R 23 is independently hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, substituted aryl [where substituent(s) for the aryl include one or more, up to the substitutable number of, substituents; preferably 1 to 5 substituents, such as lower alkyl, trifluoromethyl, hydroxy, lower alkoxy, trifluoromethoxy, lower alkanoyl, lower alkanoyloxy, mercapto, lower alkylthio, aryl, NR 16A R , 7A (where R 16A and R 17A are same as R 9 and R 10 , respectively), nitro, cyano, CO 2 R 18A (where R 18A is same as R 1 1 ), CONR 19A R 20A (where R 19A and R 20A are same as R 12 and R 13 ,
  • Aryl bears the same definition as the aforementioned aryl in the definition of formula (I).
  • the aryl moiety of an aralkyl bears the same definition as the aforementioned aryl in the definition of formula (I).
  • the alkylene moiety of an aralkyl represents the lower alkyl as defined above in the definition of formula (I) less one hydrogen atom.
  • Heteroaryl bears the same definition as the aforementioned heteroaryl in the definition of formula (I).
  • the heteroaryl moiety of a heteroarylalkyl bears the same definition as the aforementioned heteroaryl in the definition of formula (I).
  • the alkylene moiety of a heteroarylalkyl represents the lower alkyl as defined above in the definition of formula (I) less one hydrogen atom.
  • the aryl moiety of an arylsulfonylmethyl bears the same definition as the aforementioned aryl in the definition of formula (I).
  • the aryl moiety of an arylalkenyl bears the same definition as the aforementioned aryl in the definition of formula (I).
  • the alkenylene moiety of an arylalkenyl represents the lower alkenyl as defined above in the definition of formula (I) less one hydrogen atom.
  • the heteroaryl moiety of a heteroarylalkenyl bears the same definition as the aforementioned heteroaryl in the definition of formula (I).
  • the alkenylene moiety of a heteroarylalkenyl represents the lower alkenyl as defined above in the definition of formula (I) less one hydrogen atom.
  • the aryl moiety of an arylalkynyl bears the same definition as the aforementioned aryl in the definition of formula (I).
  • the alkynylene moiety of an arylalkynyl represents the lower alkynyl as defined above in the definition of formula (I) less one hydrogen atom.
  • the heteroaryl moiety of a heteroarylalkynyl bears the same definition as the aforementioned heteroaryl in the definition of formula (I).
  • the alkynylene moiety of a heteroarylalkynyl represents the lower alkynyl as defined above in the definition of formula (I) less one hydrogen atom.
  • Halogen means an iodine, bromine, chlorine, or fluorine atom.
  • heterocyclic groups which may be formed together with the adjoining nitrogen atom include pyrrolidinyl, piperidino, piperazinyl, morpholino, thiomorpholino, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3,6- tetrahydropyridyl, 1,2,3,4-tetrahydroisoquinolynyl, and the like.
  • Substituents for a heterocyclic group which may be formed together with the adjoining nitrogen atom are: lower alkyl, aralkyl, lower alkanoyl (where the lower alkyl moiety of the lower alkanoyl bears the same definition as above), aroyl, heteroaroyl, and substituted or unsubstituted aryl (where a substituent for the substituted aryl is lower alkyl, lower alkoxy, or halogen).
  • substituents for substituted lower alkyl, substituted lower alkenyl, substituted lower alkynyl, substituted lower alkoxy, substituted lower alkanoyl, substituted lower alkenoyl, substituted lower alkynoyl, or substituted lower alkylthio include one or more, up to the substitutable number of, substituents; preferably 1 to 5 substituents; and more preferably 1 to 3 substituents, such as lower alkyl, lower alkenyl, lower alkynyl, hydroxy, lower alkoxy, lower alkoxy lower alkoxy, lower alkanoyl, lower alkanoyloxy, mercapto, lower alkylthio, cycloalkyl, cycloalkenyl, NR 24a R 25 (where R 24 and R 25 are same as R 9 and R 10 ), nitro, cyano, CO 2 R 26 (where R 26 is same as R 1 1 ), CONR 27 R 28 (where R 27 and R 28 are same as R
  • lower alkyl bears the same definition as above; and the lower alkyl moiety of lower alkoxy, lower alkanoyl, lower alkanoyloxy, or lower alkylthio bears the same definition as the aforementioned lower alkyl.
  • Lower alkenyl and lower alkynyl bear the same definitions as lower alkenyl and lower alkyl as defined above, respectively.
  • Cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like, having 3 to ' 8 carbons.
  • Cycloalkenyl includes cyclopentenyl, cyclohexenyl, and the like, having 5 to 8 carbons.
  • Lower alkoxy lower alkoxy means a lower alkoxy which has been substituted with lower alkoxy. Examples of alicyclic heterocyclic groups include tetrahydrofiiranyl, tetrahydropyranyl, 2-pyrrolidon-l-yl, and the like.
  • Aryl bears the same definition as the aforementioned aryl in the definition of formula (I).
  • Heteroaryl bears the same definition as the aforementioned heteroaryl in the definition of formula (I).
  • the aryl moiety of the arylsulfonyl bears the same definition as the aforementioned aryl in the definition of formula (I).
  • Halogen bears the same definition as above.
  • lower alkyl examples include those which have 1 to 6 carbons and which are in a straight chain or branched form, e.g., methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, pentyl, and hexyl.
  • lower alkenyl examples include those which have 2 to 10 carbons and which are in a straight chain or branched form, e.g., vinyl, propenyl, methacryl, prenyl, butenyl, pentenyl, hexenyl, and geranyl.
  • lower alkynyl examples include those which have 2 to 6 carbons and which are in a straight chain or branched form, e.g., ethynyl, propynyl, butynyl, pentynyl, and hexynyl.
  • the alkylene moieties of aralkyl or heteroarylalkyl represents the aforementioned lower alkyl less one hydrogen atom.
  • the alkenylene moiety of arylalkenyl or heteroarylalkenyl represents the aforementioned lower alkenyl less one hydrogen atom.
  • the alkynylene moiety of arylalkynyl or heteroarylalkynyl represents the aforementioned lower alkynyl less one hydrogen atom.
  • the lower alkyl moiety of lower alkoxy, lower alkylthio, or lower alkanoyl bears the same definition as the aforementioned lower alkyl.
  • "Halogen" means iodine, bromine, chlorine, or fluorine.
  • aryl examples include phenyl, naphthyl, and the like.
  • heteroaryl examples include pyridyl, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, pyrimidinyl, oxazolyl, thiazolyl, indolyl, and the like.
  • the aryl moiety of aralkyl, arylalkenyl, arylalkynyl, aryloxy, and aralkyloxy bears the same definition as the aforementioned aryl in the definition of formula (la).
  • heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heteroaryloxy, and heteroarylalkyloxy bears the same definition as the heteroaryl in the definition of formula (la).
  • exemplary heterocyclic groups which may be formed together with the adjoining nitrogen atom include pyrrolidinyl, piperidino, piperazinyl, morpholino, thiomorpholino, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3,6-tetrahydropyridyl, 1,2,3,4- tetrahydroisoquinolynyl, and the like.
  • Substituents for a substituted heterocyclic group which may be formed together with the adjoining nitrogen atom include: lower alkyl, aralkyl, lower alkanoyl, aroyl, heteroaroyl, and substituted or unsubstituted aryl (where a substituent for substituted aryl is lower alkyl, lower alkoxy, or halogen).
  • lower alkyl and aralkyl bear the same definitions as the lower alkyl and aralkyl in the definition of formula (la), respectively.
  • the lower alkyl moiety of the lower alkanoyl bears the same definition as the lower alkyl in the definition of formula (la).
  • the aryl moiety of aroyl bears the same definition as aryl in the definition of formula (la).
  • the heteroaryl moiety of heteroaroyl bears the same definition as heteroaryl in the definition of formula (la).
  • Aryl bears the same definition as aryl in the definition of formula (la).
  • Lower alkoxy and halogen bear the same definition as the lower alkyl and halogen in the definition of formula (la).
  • substituents for substituted aryl, substituted naphthyl, substituted heteroaryl, substituted aralkyl, substituted heteroarylalkyl, substituted arylalkenyl, substituted heteroarylalkenyl, substituted arylalkynyl, or substituted heteroarylalkynyl may be the same or different, and include one or more, up to the substitutable number of, substituents; preferably 1 to 3 substituents, such as lower alkyl, trifluoromethyl, hydroxy, lower alkoxy, trifluoromethoxy, mercapto, lower alkylthio, aryl, NR 29 R 30 (where R 29 and R 30 may be the same or different and respectively bear the same definitions as the aforementioned R 9 and R 10 ), nitro, cyano, CO 2 R 31 (where R 31 bears the same definitions as the aforementioned R u ), CONR 32 R 33 (where R 32 and R 33 may be the same or different and respectively
  • lower alkyl bears the same definition as the lower alkyl in the definition of formula (la).
  • the lower alkyl moiety of lower alkoxy or lower alkylthio bears the same definition as the lower alkyl in the definition of formula (la).
  • Aryl bears the same definition as the aryl in the definition of formula (la).
  • the aryl moiety of arylsulfonylmethyl bears the same definition as the aryl in the definition of formula (la).
  • Halogen bears the same definition as the halogen in the definition of formula (la).
  • substituents for substituted lower alkyl, substituted lower alkenyl, substituted lower alkynyl, substituted lower alkoxy, or substituted lower alkylthio may be the same or different, and include one or more, up to the substitutable number of, substituents; preferably 1 to 3 substituents, such as lower alkyl, lower alkenyl, lower alkynyl, hydroxy, lower alkoxy, lower alkoxy lower alkoxy, mercapto, lower alkylthio, cycloalkyl, cycloalkenyl, NR 34 R 35 (where R 34 and R 35 are same as R 9 and R 10 , respectively), nitro, cyano, CO 2 R 36 (where R 36 is same as R ), aryl, heteroaryl, arylsulfonyl, alicyclic heterocyclic group and halogen.
  • lower alkyl, lower alkenyl, and lower alkynyl bear the same definitions as the lower alkyl, lower alkenyl, and lower alkynyl in the definition of formula (la), respectively.
  • the lower alkyl moiety of lower alkoxy and lower alkylthio bears the same definition as the lower alkyl in the definition of formula (la).
  • Cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like, having 3 to 8 carbons.
  • Cycloalkenyl includes cyclopentenyl, cyclohexenyl, and the like, having 5 to 8 carbons.
  • Lower alkoxy lower alkoxy means a lower alkoxy group which is substituted with lower alkoxy.
  • Aryl bears the same definition as aryl in the definition of formula (la).
  • Heteroaryl bears the same definition as heteroaryl in the definition of formula (la).
  • aryl moiety of arylsulfonyl bears the same definition as aryl in the definition of formula (la).
  • alicyclic heterocyclic groups include tetrahydrofiiranyl, tetrahydropyranyl, 2-pyrrolidon-l-yl, and the like.
  • Halogen bears the same definition as halogen in the definition of formula (la).
  • Exemplary pharmaceutically acceptable salts of Compound (I) include pharmaceutically acceptable acid addition salts or base addition salts, such as: inorganic acid salts, e.g., hydrochlorides, hydrobromides, sulfates, and phosphates; organic acid salts, e.g., methanesulfonates, oxalates, acetates, malonates, succinates, fumarates, maleates, tartrates, and citrates; and base addition salts, e.g., sodium salts, potassium salts, and calcium salts.
  • Some species of Compound (I) according to the present invention may have various stereoisomers, regioisomers, tautomers, and the like.
  • Compound (I) may in itself be commercially available. Any species thereof which are not commercially available or are novel can be synthesized in a method similar to the following method for producing Compound (la) or methods individually described in Examples, etc. [94] If any of the defined groups are susceptible to unwanted modification under the described conditions or otherwise unsuitable for practicing the production method described below, it is possible to adopt a method commonly used in synthetic organic chemistry, e.g., protection and deprotection of functional groups to facilitate production [see Protective Groups in Organic Synthesis, T.W. Greene, John Wiley & Sons, Inc. (1981), etc.]. The order of reaction steps, such as introduction of substituents, may be altered if necessary. [95] Compound (la) can be produced through the following reaction step.
  • Compound (la) can be obtained by reacting a 4-oxo-2-thioxoimidazolidine derivative (II), as commercially available or obtained by the method described later, with a carbonyl Compound (III), as commercially available or obtained by the method described later.
  • the reaction can be carried out in the presence of a base catalyst, in a solvent if necessary.
  • a base catalyst include piperidine, piperidinium acetate, di ethylamine, pyridine, sodium acetate, potassium carbonate, sodium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like.
  • Such base catalysts may be used in 0.1 to 1 equivalent of Compound (III).
  • Suitable solvents include alcohols, such as methanol, ethanol, propanol; ethers, such as diethyl ether, tetrahydrofuran, dioxane; hydrocarbons, such as benzene, toluene, xylene; N,N-dimethylformamide; N-methyl- pyrrolidinone and a combination thereof.
  • Compound (II) and Compound (III) may be used in equivalent molar amounts, although in some cases Compound (III) may be used in 0.5 to 2 equivalents of Compound (II).
  • the reaction is carried out at a temperature range from room temperature to the boiling point of the solvent, preferably from room temperature to 100 °C.
  • the reaction time is typically from 1 to 50 hours.
  • Compound (Iaa) can be obtained by reacting Compound (Ilia) with 2 to 4 equivalents of Compound (II) in a manner similar to obtaining Compound (la) from Compound (II) and Compound (III).
  • R l a represents a group according to the definition of aforementioned R 1 other than hydrogen; and X represents chlorine, bromine, iodine, p-toluenesulfonyloxy or methanesulfonyloxy.
  • Compound (V) can be produced in a method similar to that disclosed in Tetrahedron Letters, vol. 38, pp. 5831-5834 (1997). Briefly, in an ether solvent such as diethyl ether, tetrahydrofuran, or dioxane, or in an aromatic hydrocarbon solvent such as benzene, toluene, or xylene, Compound (IV) is allowed to react with R la OH (where R l a is that defined above) for 1 to 24 hours at a temperature range of from room temperature to the boiling point of the solvent in the presence of triphenylphosphine or the like, and diethyl azodicarboxylate, diisopropyl azodicarboxylate, or the like.
  • ether solvent such as diethyl ether, tetrahydrofuran, or dioxane
  • aromatic hydrocarbon solvent such as benzene, toluene, or xylene
  • R la X (where R la and X are those defined above) for 1 to 24 hours at a temperature range of from room temperature to the boiling point of the solvent in the presence of a base, such as potassium carbonate, sodium carbonate, sodium hydride, sodium ethoxide or potassium tert-butoxide.
  • the Compound (V) and benzoyl isothiocyanate are allowed to react for 1 to 24 hours at a temperature range of from room temperature to the boiling point of the solvent, e.g., halomethane solvent, such as methylene chloride or chloroform; or ether solvent, such as diethyl ether, tetrahydrofuran or dioxane.
  • the solvent e.g., halomethane solvent, such as methylene chloride or chloroform
  • ether solvent such as diethyl ether, tetrahydrofuran or dioxane.
  • a treatment is performed as to the product for 1 to 24 hours at a temperature in the range from room temperature to the boiling point of the solvent in a halomethane solvent such as methylene chloride or chloroform, or in an ether solvent such as ether, tetrahydrofuran, or dioxane, thereby effecting cyclization reaction and deprotection of the benzoyl group after cyclization.
  • a halomethane solvent such as methylene chloride or chloroform
  • an ether solvent such as ether, tetrahydrofuran, or dioxane
  • Compound (V) and sodium thiocyanate, potassium thiocyanate or the like are allowed to react for 1 to 24 hours at a temperature in the range from room temperature to the boiling point of the solvent in an alcohol solvent such as methanol, ethanol, or propanol, or in a mixed solvent containing the same and water, if necessary with pH adjustment using acetic acid or the like.
  • an alcohol solvent such as methanol, ethanol, or propanol
  • a mixed solvent containing the same and water if necessary with pH adjustment using acetic acid or the like.
  • an organic lithium reagent such as n-butyl lithium or methyl lithium
  • an ether solvent such as diethyl ether, tetrahydrofuran, or dioxane
  • a formylating reagent such as N,N-dimethylformamide is allowed to react with the product for 30 minutes to 24 hours at a temperature in the range from -78°C to room temperature, whereby Compound (VII) can be produced.
  • Compound (VIII) can be produced by adding an organic acid such as trifluoroacetic acid or a mineral acid such as hydrogen chloride or hydrogen bromide to Compound (VII) in a halomethane solvent such as methylene chloride or chloroform, or in an ether solvent such as ether, tetrahydrofuran, or dioxane, and carrying out a treatment of the mixture at a temperature range of from 0°C to the boiling point of the solvent for 1 to 24 hours.
  • a halomethane solvent such as methylene chloride or chloroform
  • an ether solvent such as ether, tetrahydrofuran, or dioxane
  • Compound (Ilia) can be produced by allowing Compound (VIII) to react with
  • R 4 X (where R 4 and X are those defined above) at a temperature range of from room temperature to the boiling point of the solvent for 1 to 24 hours in an ether solvent such as ether, tetrahydrofuran, or dioxane, or in a solvent such as N,N-dimethylformamide or N- methylpyrrolidinone, in the presence of a base such as sodium hydride, potassium hydride, or potassium tert-butoxide.
  • ether solvent such as ether, tetrahydrofuran, or dioxane
  • a solvent such as N,N-dimethylformamide or N- methylpyrrolidinone
  • R 7 and R 8 are those defined above.
  • Compound (Illba) can be produced by allowing Compound (IX) (J. Org.
  • Compound (Illba) can also be produced by allowing an acid halide - which can be produced by halogenating Compound (X) in an inert solvent such as methylene chloride by employing 1 equivalent to the solvent amount, preferably 1 to 2 equivalents, of a halogenating agent such as thionyl chloride, at a temperature range of from 0 °C to the boiling point of the solvent, preferably at a temperature range of from room temperature to the boiling point of the solvent, for 1 to 72 hours, preferably 1 to 5 hours - to react with 1 to 4 equivalents, preferably 1 to 2 equivalents, of a primary or secondary amine at a temperature range of from 0 °C to the boiling point of the solvent, preferably at a temperature range of from room temperature to the boiling point of the solvent, for 1 to 72 hours, preferably 1 to 24 hours, in a solvent such as methylene chloride, chloroform, N,N-dimethylformamide, tetrahydrofuran, 1,2-
  • R 6a , R 7 , R 8 and X are those defined above.
  • Compound (Illbb) can be produced by allowing Compound (Illba) and 1 to 4 equivalents, preferably 1 to 2 equivalents of a compound represented as R 6a -X (where R 6a and X are those defined above) to react at a temperature range of from 0 °C to the boiling point of the solvent, preferably at a temperature range of from room temperature to the boiling point of the solvent, for 1 to 72 hours, preferably 1 to 48 hours, in a inert solvent such as N,N- dimethylformamide, tetrahydrofuran, dimethoxyethane, or 1,4-dioxane, in the presence of an organic base such as 1 to 4 equivalents, preferably 1 to 2 equivalents of sodium carbonate, cesium carbonate, sodium hydride or potassium tert-butoxide, or 1 to 4 equivalents, preferably 1 to 1.5 equivalents of 2-(tert-butylimino)-2-diethylamino- 1, 3-dimethylperhydro- 1,
  • R 6a , R 7 and R 8 are those defined above.
  • Compound (XI) can be produced from a compound represented by R 6a NH 2 (where R 6a is that defined above) and 2,5-dimethoxytetrahydrofuran, according to a method similar to that described in literature [J. Org. Chem., vol. 63, pp. 6715-6718 (1998)].
  • Compound (XII) can be produced from Compound (XI) and trichloroacetyl chloride in a method similar to that described in literature [J. Org. Chem., vol. 43, pp. 4849-
  • Compound (XIII) can be produced by subjecting Compound (XII) to formylation in a method similar to that described in literature [J. Org. Chem., vol. 43, pp.
  • Compound (Illbb) can be produced from Compound (XIII) and a compound represented by R 7 R 8 NH in a method similar to that for obtaining Compound (Illba) from Compound (IX).
  • Compound (Illbb) can also be produced through the following reaction steps.
  • Compound (XV) can be produced from Compound (XIV) in a method similar to that for obtaining Compound (Illbb) from Compound (Illba).
  • Compound (XV) can be produced by allowing Compound (XIII) and 1 to 4 equivalents, preferably 1 to 2 equivalents of sodium methoxide to react in methanol at a temperature range of from 0 °C to the boiling point of the solvent, preferably at a temperature range of from room temperature to the boiling point of the solvent, for 1 to 72 hours, preferably 1 to 48 hours.
  • Compound (XVI) can be produced by hydrolyzing Compound (XV) in a solvent such as methanol or ethanol, in the presence of 1 to 4 equivalents, preferably 1 to 2 equivalents of an aqueous solution of sodium hydroxide, an aqueous solution of potassium hydroxide, an aqueous solution of lithium hydroxide or the like, at a temperature range of from 0 °C to the boiling point of the solvent, preferably at a temperature range of from room temperature to the boiling point of the solvent, for 1 to 72 hours, preferably 1 to 48 hours.
  • Compound (Illbb) can be produced from Compound (XVI) in a method similar to that for producing Compound (Illba) from Compound (X).
  • a desired compound according to each of the above-described production method may be isolated and purified by a purification method which is commonly used in synthetic organic chemistry, e.g., filtration, extraction, washing, drying, concentration, recrystallization, and/or various chromatography techniques. Furthermore, the desired compound may be purified by a purification method which is commonly used in general parallel synthesis methods, e.g., methods using scavenger resin and/or ion exchange resin techniques.
  • a salt of Compound (I) can be obtained from a free form of Compound (I) by forming a salt by usual methods.
  • Compound (I) can be dissolved or suspended in an appropriate solvent and a predetermined acid or base can be added. The resulting salt can then be isolated and/or purified.
  • a salt of Compound (I) can be obtained directly from the reaction and optionally be purified.
  • Compound (I) or a pharmaceutically acceptable salt thereof may be in the form of an adduct with water or various solvents. Such adducts are also encompassed within the present invention.
  • Compound (I) or a pharmaceutically acceptable salt thereof may be used as such or in various forms of pharmaceutical formulations depending on the pharmacological effects and purpose of administration thereof.
  • an effective amount of Compound (I) or a pharmaceutically acceptable salt thereof may be uniformly mixed with a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable carrier may be in a wide range of forms depending on the particular formulation desired for administration.
  • Such a drug composition is preferably in a unit dosage form appropriate for oral or parenteral administration (e.g., via injection).
  • Tablets can be formulated using any of the conventional methods known to one skill in the art and can include an excipient, a disintegrator, a lubricant, a binder and/or a surfactant.
  • Exemplary excipients include lactose, glucose, sucrose, mannitol, methyl cellulose, and the like.
  • Exemplary disintegrators include starch, sodium alginate, carboxymethyl cellulose calcium, crystalline cellulose, and the like.
  • Exemplary lubricants include magnesium stearate, talc, and the like.
  • Exemplary binders include gelatin, polyvinylalcohol, polyvinylpyrrolidone, hydroxypropyl cellulose, methyl cellulose, and the like.
  • Exemplary surfactants include sucrose fatty acid esters, sorbitan fatty acid esters, and the like. Such tablets preferably contain 1 to 300 mg of an active ingredient per tablet.
  • Granules can be prepared using any of the conventional methods known to one skilled in the art by adding suitable components, e.g., excipients such as lactose or sucrose; disintegrators such as starch; and/or binders such as gelatin.
  • powder forms can be prepared using any of the conventional methods known to one skilled in the art by adding suitable components, for example, an excipient, such as lactose or mannitol.
  • Capsule formulation can include gelatin, water, sucrose, gum Arabic, sorbitol, glycerin, crystalline cellulose, magnesium stearate talc, and/or the like. Such capsules preferably contain 1 to 300 mg of an active ingredient per capsule.
  • Injectable form can include a solvent, such as water, saline, vegetable oils
  • Compound (I) or a pharmaceutically acceptable salt thereof can be orally or parenterally (e.g., via injection) administered.
  • the effective dose and administration frequency may vary depending on the mode of administration, the age, weight, and/or symptoms of each patient and/or the like, it is generally preferable to administer 0.01 to 20 mg/kg of Compound (I) or a pharmaceutically acceptable salt thereof, over one to four times per day.
  • Compound (I) are shown in Tables 1 to 3 below. However, it should be appreciated that the scope of the present invention is not limited to such specific examples.

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Abstract

La présente invention concerne un inhibiteur de télomérase contenant comme ingrédient actif un composé qui a le squelette 4-oxo-2-thioxoimidazolidine et qui présente une activité inhibitrice de la télomérase.
PCT/US2001/050042 2000-12-30 2001-12-28 Inhibiteur de telomerase WO2002053155A1 (fr)

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JP2006521377A (ja) * 2003-03-27 2006-09-21 ランケナー インスティテュート フォー メディカル リサーチ 新型ｉｄｏ阻害剤とその使用方法
US8034548B2 (en) 2003-12-19 2011-10-11 The Regents Of The University Of California Methods and materials for assessing prostate cancer therapies
US7718684B2 (en) 2004-02-24 2010-05-18 The Regents Of The University Of California Methods and materials for assessing prostate cancer therapies and compounds
EP1568698A1 (fr) * 2004-02-27 2005-08-31 Aventis Pharma Deutschland GmbH Dérivés de pyrrole en tant qu'inhibiteurs du facteur xa
US7465806B2 (en) 2004-02-27 2008-12-16 Sanofi-Aventis Deutschland Gmbh Pyrrole-derivatives as factor Xa inhibitors
US9126941B2 (en) 2005-05-13 2015-09-08 The Regents Of The University Of California Treatment of hyperproliferative disorders with diarylhydantoin compounds
US7709517B2 (en) 2005-05-13 2010-05-04 The Regents Of The University Of California Diarylhydantoin compounds
US8802689B2 (en) 2006-03-27 2014-08-12 The Regents Of The University Of California Androgen receptor modulator for the treatment of prostate cancer and androgen receptor-associated diseases
US10857139B2 (en) 2006-03-27 2020-12-08 The Regents Of The University Of California Substituted diazaspiroalkanes as androgen receptor modulators
US8445507B2 (en) 2006-03-27 2013-05-21 The Regents Of The University Of California Androgen receptor modulator for the treatment of prostate cancer and androgen receptor-associated diseases
US11771687B2 (en) 2006-03-27 2023-10-03 The Regents Of The University Of California Substituted diazaspiroalkanes as androgen receptor modulators
US9388159B2 (en) 2006-03-27 2016-07-12 The Regents Of The University Of California Substituted diazaspiroalkanes as androgen receptor modulators
US9987261B2 (en) 2006-03-27 2018-06-05 The Regents Of The University Of California Substituted diazaspiroalkanes as androgen receptor modulators
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US9896437B2 (en) 2007-10-26 2018-02-20 The Regents Of The University Of California Diarylhydantoin compounds
US9108944B2 (en) 2010-02-16 2015-08-18 Aragon Pharmaceuticals, Inc. Androgen receptor modulators and uses thereof
US9481664B2 (en) 2010-02-16 2016-11-01 Aragon Pharmaceuticals, Inc. Androgen receptor modulators and uses thereof
US10023556B2 (en) 2010-02-16 2018-07-17 Aragon Pharmaceuticals, Inc. Androgen receptor modulators and uses thereof
US9884054B2 (en) 2012-09-26 2018-02-06 Aragon Pharmaceuticals, Inc. Anti-androgens for the treatment of non-metastatic castrate-resistant prostate cancer
US10799489B2 (en) 2012-09-26 2020-10-13 Aragon Pharmaceuticals, Inc. Anti-androgens for the treatment of non-metastatic castrate-resistant prostate cancer
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