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  • C07C225/00—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones
  • C07C225/22—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
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  • C07C225/00—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones
  • C07C225/20—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of the carbon skeleton
• • 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
  • A61K31/12—Ketones
• • 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
  • A61K31/12—Ketones
  • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
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  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
  • C07C49/527—Unsaturated compounds containing keto groups bound to rings other than six-membered aromatic rings
  • C07C49/543—Unsaturated compounds containing keto groups bound to rings other than six-membered aromatic rings to a six-membered ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
  • C07C49/527—Unsaturated compounds containing keto groups bound to rings other than six-membered aromatic rings
  • C07C49/557—Unsaturated compounds containing keto groups bound to rings other than six-membered aromatic rings having unsaturation outside the rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
  • C07D209/04—Indoles; Hydrogenated indoles
  • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
  • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
  • C07D209/04—Indoles; Hydrogenated indoles
  • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
  • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
  • C07D209/16—Tryptamines
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
  • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
  • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
  • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
  • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
  • C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2601/00—Systems containing only non-condensed rings
  • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
  • C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated

Definitions

• C ⁇ C g alkyl optionally substituted with one or more halogen, R5R5, OR5, aryl or heteroaryl;
• R 3 is hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, or the like. In certain embodiments, R 3 is methyl.
• R 4 is hydrogen.
• each of R, and R 1 independently is a hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, or the like, optionally substituted with one or more halogen, R5R6, OR 5 , aryl or heteroaryl.
• the compounds disclosed herein are useful for treating or reducing the risk of liver cancer in a subject, especially in view of their unexpected benefit in inhibition of liver cancer cells in comparison with their respective 3-hydroxyl analogs.
• R 2 , and R 3 independently is a hydrogen, optionally substituted methyl or
• R 7 is a C r C 8 alkyl, OR 5 or R5R5.
• R is a hydrogen (H), methyl, ethyl, propyl, butyl, pentyl, hexyl, or the like, optionally substituted with one or more halogen, R5R5, OR5, C6-Cioaryl or C4-Cioheteroaryl.
• R is H, or C ⁇ C g alkyl.
• R 1 is hydrogen (H). In certain embodiments, R 1 is hydrogen, C x -
• Cioheteroaryl In certain embodiments, C6-Cioaryl is phenyl. In certain embodiments, C 4 - Cioheteroaryl is pyridyl, thiophenyl, or indolyl. In certain embodiments, R 1 is hydrogen, or C x -
• R 1 is H, C ⁇ C g alkyl, or C ⁇ C g alkyl substituted with one or more R5R5, or C4-Cioheteroaryl.
• R 1 is a hydrogen (H), methyl, ethyl, propyl, butyl, pentyl, hexyl, or the like, optionally substituted with one or more halogen, R5R6, OR5, C6-Cioaryl or C4-Cioheteroaryl.
• R 1 is hydrogen, methyl, ethyl, propyl, butyl, optionally substituted with R5R5, OR5, C6-Cioaryl or C4-Cioheteroaryl.
• R 1 is hydrogen, methyl, methyl substituted with C4-Cioheteroaryl such as thiophenyl, ethyl substituted with OR5 such as OH, ethyl substituted with C4-Cioheteroaryl such as indolyl, propyl substituted with R5R5 such as H 2 .
• R 1 is hydrogen, methyl, methyl substituted with C4-Cioheteroaryl such as thiophenyl, or propyl substituted with R5R5 such as H 2 .
• R is C ⁇ C g alkyl and R 1 is C ⁇ C g alk l.
• R is hydrogen, and R 1 is hydrogen, C ⁇ C g alk l, or C ⁇ C g alkyl substituted with one or more halogen,
• NR5R5, OR5, C6-Cioaryl or C 4 -C 10 heteroaryl is hydrogen
• R 1 is hydrogen, methyl, ethyl, propyl, butyl, optionally substituted with NR5R5, OR5, C 6 -Cioaryl or C 4 - Cioheteroaryl.
• R is hydrogen
• R 1 is hydrogen, methyl, methyl substituted with C 4 -Cioheteroaryl such as thiophenyl, ethyl substituted with OR5 such as OH, ethyl substituted with C 4 -Cioheteroaryl such as indolyl, or propyl substituted with NR5R5 such as NH 2 .
• R is hydrogen or methyl
• R 1 is hydrogen, methyl, methyl substituted with C 4 -Cioheteroaryl such as thiophenyl, or propyl substituted with NR5R5 such as NH 2 .
• alkyl as used herein, means a straight, branched chain, or cyclic (in this case, it would also be known as “cycloalkyl”) hydrocarbon containing from 1-10 carbon atoms.
• alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2- dimethylpentyl, 2,3-dimethylhexyl, n-heptyl, n-octyl, n-nonyl, and n-decyl.
• Ci-Calkyl as used herein, means a straight, branched chain, or cyclic (in this case, it would also be known as “cycloalkyl”) hydrocarbon containing from 1-8 carbon atoms.
• alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso- propyl, cyclopyl, n-butyl, sec-butyl, tert-butyl, cyclobutyl, n-pentyl, isopentyl, neopentyl, cyclopentyl, and n-hexyl.
• halo or halogen as used herein, means a -CI, -Br, -I or -F.
• aryl refers to an aromatic ring wherein each of the atoms forming the ring is a carbon atom.
• Aryl rings are formed by five, six, seven, eight, nine, or more than nine carbon atoms.
• Aryl groups are optionally substituted.
• an aryl is a phenyl or a naphthalenyl.
• an aryl is a phenyl.
• an aryl is a C6-Cioaryl.
• an aryl group can be a monoradical or a diradical (i.e., an arylene group).
• an arylene is a C 6 -Cio arylene.
• Examplary arylenes include, but are not limited to, phenyl -1,2-ene, phenyl- 1, 3 -ene, and phenyl- 1,4-ene.
• heteroaryl or “C4-Cioheteroaryl” employed alone or in combination with other terms, refers to a monocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings) aromatic hydrocarbon moiety, having one or more heteroatom ring members selected from nitrogen, sulfur and oxygen, and having 4 to 10 carbon atoms.
• the heteroaryl group has 1, 2, 3, or 4 heteroatoms.
• the heteroaryl group has 1, 2, or 3 heteroatoms.
• the heteroaryl group has 1 or 2 heteroatoms.
• the heteroaryl group has 1 heteroatom. When the heteroaryl group contains more than one heteroatom ring member, the heteroatoms may be the same or different.
• Example heteroaryl groups include, but are not limited to, pyrrolyl, azolyl, oxazolyl, thiazolyl, imidazolyl, furyl, thienyl, quinolinyl, isoquinolinyl, indolyl, benzothienyl, benzofuranyl, benzisoxazolyl, imidazo[l,2-b]thiazolyl or the like.
• the heteroaryl group has 5 to 10 carbon atoms.
• the term "optionally substituted” or “substituted” means that the referenced group may be substituted with one or more additional group(s) indicated thereof.
• the group(s) may be individually and independently selected from alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfoxide, aryl sulfoxide, alkylsulfone, arylsulfone, cyano, halo, nitro, haloalkyl, fluoroalkyl, fluoroalkoxy, and amino, including mono- and di -substituted amino groups, and the protected derivatives thereof.
• substituents are selected from halogen, -CN, -NH 2 , -OH, -N(CH 3 ) 2 , alkyl, fluoroalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone.
• an optional substituent is selected from halogen, -CN, -NH 2 , -OH, -NH(CH 3 ), -N(CH 3 ) 2 , -CH 3 , -CH 2 CH 3 , -CF 3 , -OCH 3 , and -OCF 3 .
• substituted groups are substituted with one or two of the preceding groups.
• substituted groups are substituted with one of the preceding groups.
• alkylene refers to a divalent alkyl radical. Any of the above mentioned monovalent alkyl groups may be an alkylene by abstraction of a second hydrogen atom from the alkyl. In one aspect, an alkelene is a Ci-C 6 alkylene. In another apsect, an alkylene is a Ci- C 4 alkylene.
• Typical alkylene groups include, but are not limited to, -CH 2 -, -CH(CH 3 )-, -C(CH 3 ) 2 - , -CH2CH2-, -CH 2 CH(CH 3 )-, -CH 2 C(CH 3 ) 2 -, -CH 2 CH 2 CH 2 -, -CH2CH2CH2CH2-, and the like.
• alkenyl refers to an unsaturated aliphatic group having at least one carbon- carbon double bond. In some embodiments, C 2 -C 8 alkenyl has at least two carbons and up to 8 carbons in said unsaturated aliphatic group.
• alkynyl refers to an unsaturated aliphatic group having at least one carbon- carbon triple bond. In some embodiments, C 2 -C 8 alkynyl has at least two carbons and up to 8 carbons in said unsaturated aliphatic group.
• Example 1 Preparation of exemplary amine derivative anticancer agents.
• Exemplary anticancer agents were prepared according to Scheme 1 from 4-hydroxy-2,3- dimethoxy-6-methyl-5-(3,7, l l-trimethyldodeca-2,6, 10-trienyl)cyclohex-2-enone (100 mg, 0256 mmol) with a suitable amine reagent.
• non exclusive exemplary compounds are prepared accordingly.
• the MTT (3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) cell viability assay is a colorimetric assay system, which measures the reduction of a tetrazolium component (MTT) into an insoluble blue/purple colored formazan product by succinate tetrazolium reductase in mitochondria of viable cells. The absorbance of the complex is read
• Formazan formation can therefore be used to assess and determine the survival rate of cells.
• HepG2 Human hepatoma cell lines
• Example 3 Efficacy test of exemplary Compound 1 on liver cancer xenograft model
• Thymic nude mice National Laboratory Animal Center
• Human HCC Mahlavu cells (1 x 10 6 cells) carrying luciferase gene were re-suspended in 20 ⁇ of PBS containing 50% matrigel (BD Biosciences, MA) and injected into the left lateral liver lobe of athymic nude mice (National Laboratory Animal Center) with 27-gauge needle by sterile techniques (Lu et al., 2007).
• the animals were injected with the luciferase substrate D-luciferin at a dose of 150 mg/kg in 0.2 mL sterile isotonic saline.
• Tumor growth and metastatic status was monitored using the Xenogen International Veterinary Information Service (IVIS) imaging system every two weeks. All images were obtained after intraperitoneal injection of luciferin (100 mg/kg body weight; Synchem, Elk Grove Village, IL, United States). Ten minutes after injection of luciferin, nude mice were placed onto the Xenogen IVIS imaging stage and were continuously sedated during image acquisition. Image analysis and bioluminescence quantification were performed using Living Image software (Caliper Life Sciences, Hopkinton, MA, United States). BLI is based on the detection of light emitted by living cells expressing a luciferase gene. The tumor-bearing mice were treated with vehicle (olive oil) or Compound 1 at 120 mg/kg by oral gavage twice per day and 5 days per week for 4 weeks. The body weight was measured twice weekly.
• vehicle olive oil
• Compound 1 Compound 1 at 120 mg/kg by oral gavage twice per day and 5 days per week for 4 weeks. The body weight was measured twice weekly.
• FIG. 1 shows decrease of the tumor size of TUP- 1 xenograft mice treated with the exemplary test compound.
• the tumor-bearing mice were treated with vehicle (olive oil) or Compound 1 at 120 mg/kg by oral gavage twice per day and 5 days per week for 4 weeks.
• the tumor volume was measured twice weekly. ** ⁇ 0.005 compared to vehicle control.
• FIG. 2 shows the decrease tumor mass weight at the end point of THP-1 xenograft mice treated with test compound. At the end of week 12, tumor mass of the mice treated with
• Compound 1 descrease at least 4 folds compared with one without treatment (the control).
• FIG. 3 shows the results of body weight changes of TUP- 1 xenograft mice treated with or without test compound. The almost no change of body weight indicates the test compound did not cause any serious side effects.

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