Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D497/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having oxygen and sulfur atoms as the only ring hetero atoms
  • C07D497/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having oxygen and sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
  • C07D497/10—Spiro-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/02—Antineoplastic agents specific for leukemia

Definitions

• ⁇ -lapachone (3,4-dihydro-2,2-dimethyl-2H-naphliio[l,2-b]pyran-5,6-dione), a quinone, is derived from lapachol (a naphthoquinone) which can be isolated from the lapacho tree (Tabebnia avellanedae), a member of the catalpa family (Bignoniaceae).
• Lapachol and ⁇ -lapachone (with numbering) have the following chemical structures:
• ⁇ -lapachone as well as its intermediates, derivatives and analogs thereof, are described in Li, CJ. et al, (1993) /. Biol. Chenu, 268(30): 22463-22468. As a single agent, ⁇ -lapachone has demonstrated significant antineoplastic activity against human cancer cell lines at concentrations typically in the range of 1-10 ⁇ M (IC 50 ).
• pancreatic Li, Y., et al, (2000) MoI Med, 6: 1008-1015; Li, Y., (1999) MoI Med, 5: 232- 239), and multiple myeloma cell lines, including drug-resistant lines (Li, Y., (2000) MoI Med, 6: 1008-1015).
• drug-resistant lines Li, Y., (2000) MoI Med, 6: 1008-1015.
• No cytotoxic effects were observed on normal fresh or proliferating human PBMC (Li, Y., (2000) MoI Med, 6: 1008-1015).
• ⁇ -lapachone appears to work by activating DNA damage response/checkpoint pathways, which may involve unscheduled expression of checkpoint molecules, e.g.
• E2F1 independent of DNA damage and cell cycle stages.
• ⁇ -lapachone activates checkpoint pathways and induces cell death in cancer cells from a variety of tissues without cell death of normal cells from these tissues.
• normal cells with their intact regulatory mechanisms such an imposed expression of a checkpoint molecule results in a transient expression pattern and causes little consequence.
• cancer and pre-cancer cells have defective mechanisms, which result in unchecked and persistent expression of unscheduled checkpoint molecules, e.g. E2F1, leading to selective cell death in cancer and pre-cancer cells.
• the present invention provides a compound of Formula I:
• R 1 , R 2 , R 3 , and R 4 are each, independently, H, OH, F, Cl, Br, I, CH 3 , CF 3 , C 2 -C 6 straight chain alkyl, substituted Ci-C 6 straight chain alkyl, C 3 -C 6 branched alkyl, C 3 -C 8 cycloalkyl, allyl, C 2 -C 6 straight chain alkenyl, substituted C 2 -C 6 straight chain alkenyl, C 3 -C 6 branched alkenyl, C 5- C 8 cycloalkenyl, C 2 -C 6 alkynyl, NO 2 , CN, NH 2 , alkylamine, substituted alkylamine, dialkylamine, arylamine, C(O)NHR 14 , NHC(O)R 15 , carbamoyl, aminesulfoxide, sulfonamide, sulfamoyl, sulfonic acid, phenyl
• J 1 is -(CR 5 R 6 )H-(CR 7 Rs) 1n -Y, -S(O) 0 -Z, amidine, substituted amidine, heterocyclyl, substituted heterocyclyl, 3,4-dioxo-3,4-dihydronaphrlialenyl, heteroaryl, substituted heteroaryl,
• R 7 and R 8 are each, independently, H, F, Cl, Br, I, OH, CH 3 , C 2 -C 6 straight chain alkyl, CF 3 , C 3 -C 6 branched alkyl, C 3 -C 8 cycloalkyl, C 2 -C 6 alkoxy, allyl, C 2 -C 6 straight chain alkenyl, C 3 -C 6 branched alkenyl, C 5 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, NO 2 , CN, amine, alkylamine, dialkylamine, arylamine, carbamoyl, aminesulfoxide, sulfonamide, sulfonic acid, phenyl, C 5 -C 8 aryl, heteroaryl, heterocyclyl, OCH 3 , OCF 3 , alkoxycarbonyl, carboxyacid, carbonylalkoxy, SH, thioalkyl, tl
• W is C 2 -C 6 straight chain alkyl, substituted C r C 6 straight chain alkyl, OCH 3 , C 2 -C 6 alkoxy, alkylthioalkyl, substituted alkylthioalkyl, C 3 -C 8 cycloalkyl, substituted C 3 -C 8 cycloalkyl, C 5 -C 8 aryl, substituted aryl, phenyl, substituted phenyl, alkylthio, benzyl, substituted benzyl, heterocyclyl, substituted heterocyclyl, phenoxy, aryloxy, substituted aryloxy, benzyloxy, heteroaryloxy, substituted heteroaryloxy, amine, substituted amine, arylamine, substituted arylamine, phenylamine, substituted phenylamine, substituted phenylamine, CH 3 , CF 3 , C 3 -C 5 branched alkyl, C 5 -C 8 cycl
• Z is CH 3 , CF 3 , C 2 -C 6 straight chain alkyl, heteroaryl, substituted heteroaryl, phenyl, substituted phenyl, C 5 -C 8 aryl, substituted C 5 -C 8 aryl, C 3 -C 6 branched alkyl, C 3 -C 8 cycloallcyl, C 5 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, amine, alkylamine, dialkylamine, arylamine, benzyl, heteroaryloxy, heterocyclyl, CH 2 -heterocycle, OCH 3 , OCF 3 , C 2 -C 6 alkoxy, allcenoxy, phenoxy, aryloxy or benzyloxy;
• R 9 is H, CH 3 , C 2 -C 6 straight chain alkyl, or C 3 -C 6 branched alkyl;
• Rio, Rn, Ri 2 , and Ri 3 are each, independently, H, phenyl, C 5 -C 8 aryl, CH 1 , CF 3 , C 2 -C 6 straight chain alkyl, C 3 -C 8 cycloalkyl, heteroaryl, or heterocyclyl;
• Ri 4 and Ri 5 are each, independently H, C 2 -C 6 straight alkyl, C 3 -C 6 branched alkyl, C 3 -C 8 cycloalkyl, allyl, C 2 -C 6 straight alkenyl, branched alkenyl, C 5 -C 8 cycloalkenyl, phenyl, C 5 -C 8 aryl, benzyl, CH 2 C(OCH 3 ) 2 , heteroaryl, or heterocyclyl; and,
• Ri 6 is C 3 -C 6 branched alkyl, C 5 -C 8 aryl, substituted C 5 -C 8 aryl, heteroaryl, phenyl, substituted phenyl, CH 2 -aryl, benzyl, H, CH 3 , CF 3 , C 2 -C 6 straight chain allcyl, C 3 -C 8 cycloalkyl, heterocyclyl, or CH 2 -heteroaryl.
• Rj 7 , RiS, Ri9, and R 20 are each, independently, H, phenyl, C 5 -C 8 aryl, CH 3 , CF 3 , C 2 -C 6 straight chain alkyl, C 3 -C 8 cycloalkyl, heteroaryl, or lieterocyclyl;
• R 2 i is H, C 2 -C 6 straight alkyl, C 3 -C 6 branched alkyl, C 3 -C 8 cycloalkyl, allyl, C 2 -C 6 straight alkenyl, branched alkenyl, C 5 -C 8 cycloalkenyl, phenyl, C 5 -C 8 aryl, benzyl, CH 2 C(OCH 3 ) 2 , heteroaryl, or heterocyclyl.
• R t , R 2 , R 3 , and R 4 are each, independently, H, OH, F, Cl, Br, I, CH 3 , CF 3 , OCH 3 , C 2 -C 6 alkoxy, C 2 -C 6 straight chain alkyl, substituted C 2 -C 6 straight chain alkyl, phenyl, C 5 -C 8 aryl, NO 2 , CN, C(O)NHR 14 OrNHC(O)Ri 5 .
• R 1 , R 2 , R 3 , and R 4 are each, independently, H, OH, F, Cl, Br, I, CH 3 , CF 3 , OCH 3 , C 2 -C 6 alkoxy.
• R 1 , R 2 , R 3 , and R 4 are each, independently, H or OCH 3 .
• R 7 and R 8 are each, independently, H, F, Cl, Br, I, OH, CH 3 , C 2 -C 6 straight chain alkyl, CF 3 , C 3 -C 6 branched alkyl, C 3 -C 8 cycloalkyl, or C 2 -C 6 alkoxy.
• R 7 and R 8 are each, independently, H or OH.
• Y is CH 2 OR 16 , phenyl, substituted C 5 -C 8 aryl or benzyl.
• R 5 and R 6 are each H.
• Y is substituted or unsiibstiruted C 5 -C 8 aryl.
• the substituted C 5 -C 8 aryl is substituted with from 1 to 5 substituents each of which is independently CN, Cl or F.
• R 5 and R 6 are each H and R 7 and R 8 are each, independently, H or OH.
• Y is CH 2 OR 16 .
• R] 6 is substituted or unsubstituted C 5 - C 8 aryl.
• the substituted C 5 -C 8 aryl is substituted with from 1 to 5 substituents each of which is independently C 3 -C 6 branched alkyl, Cl, or F.
• J 1 is -S(O) 0 -Z.
• Z is CH 3 , CF 3 , C 2 -C 6 straight chain alkyl, heteroaryl, substituted heteroaryl, phenyl, substituted phenyl, C 5 -C 8 aryl, or substituted C 5 -C 8 aryl.
• J is .
• 1 1.
• W is substituted aryl, phenyl, phenoxy, aryloxy and substituted aryloxy.
• the aryl and aryloxy is substituted with from 1 to 5 substituents each of which is independently CF3 or F.
• R 9 is H.
• R] 0 and Rn are both H.
• Ri 2 and R] 3 are both H.
• Rj 2 is H and Ri 3 is phenyl.
• R 16 is C 3 -C 6 branched alkyl, C 5 -C 8 aryl, substituted C 5 -C 8 aryl, heteroaryl, phenyl, substituted phenyl, CH 2 -aryl, or benzyl.
• the compound of the present invention is selected from the following compounds, or a pharmaceutically acceptable salt and/or an individual diastereomer thereof: 1 ⁇ -(3-chlorobenzoyl)spiro [naphtho [ 1 ,2-b] [ 1 ,4]oxathiine-2 ,4'-piperidine] -5 ,6-dione
• the present invention also provides a pharmaceutical composition that comprises a compound of Formula I in combination with a pharmaceutically acceptable carrier or excipient.
• the pharmaceutical composition further comprises a second chemotherapeutic agent.
• said second chemotherapeutic agent is selected from the group consisting of tamoxifen, raloxifene, anastrozole, exemestane, letrozole, cisplatiii, carboplatin, paclitaxel, cyclophosphamide, lovastatin, minosine, gemcitabine, araC, 5-fluorouracil, methotrexate, docetaxel, goserelin, vincristin, vinblastin, nocodazole, teniposide, etoposide, epothilone, navelbine, camptothecin, daunonibicin, dactinomycin, mitoxantrone, amsacrine, doxorubicin, epirubicin
• the present invention further provides a method of treating a cell proliferative disorder.
• the method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of formula I as defined in claim 1, or a pharmaceutically acceptable salt thereof, or a prodrug or metabolite thereof, in combination with a pharmaceutically acceptable carrier, wherein said cell proliferative disorder is treated.
• the cell proliferative disorder is a precancerous condition.
• the cell proliferative disorder is a cancer.
• the cancer is adenocarcinoma, squamous carcinoma, sarcoma, lymphoma, multiple myeloma, or leukemia.
• the cancer is lung cancer, colon cancer, breast cancer, pancreatic cancer, prostate cancer, acute leukemia, chronic leukemia, multiple melanoma, ovarian cancer, malignant glioma, leiomyosarcoma, hepatoma, or head and neck cancer.
• the compound of formula I or a pharmaceutically acceptable salt thereof, or a prodrug or metabolite thereof is administered in combination with a second chemotherapeutic agent.
• the second chemotherapeutic agent is selected from the group consisting of tamoxifen, raloxifene, anastrozole, exemestane, letrozole, cisplatin, carboplatin, paclitaxel, cyclophosphamide, lovastatin, minosine, gemcitabine, araC, 5-fluorouracil, methotrexate, docetaxel, goserelin, vincristiii, vinblastin, nocodazole, teniposide, etoposide, epothilone, navelbine, camptothecin, daunonibicin, dactinomycin, mitoxantrone, amsacrine, doxorubicin, epirabicin, idarubicin imatanib, gef ⁇ tinib, erlotinib, sorafenib, sunitinib malate, trastuzumab,
• the treating cancer comprises a reduction in tumor size, a delay of tumor growth, an improvement in the survival of patients, or an improvement in the quality of patient life, or at least two of the above.
• the cancer is primary cancer or metastatic cancer, or both.
• Figure 1 shows that the treatments with the test compounds reduced the mean tumor volume of human colon cancer xenograft.
• Figure IA shows the treatment with Compound 184
• Figure IB shows the treatments with Compound 186 and Compound 187
• FIG. 1C shows the treatment with Compound 182
• Figure ID shows the treatments with Compound 180 and Compound 125
• the present invention provides novel tricyclic spiro-oxathiine naphthoquinone derivatives, a synthetic method for making the derivatives, and the use of the derivatives to inhibit proliferation and/or inducing cell death of neoplastic cells.
• the naphthoquinone derivatives of the present invention are related to the compounds known as ⁇ -lapachone (3,4-dihydro-2,2-dimethyl-2H- naphtho(l,2-b)pyran-5,6-dione). The structure of ⁇ -lapachone is described above.
• the ⁇ -lapachone analogs of the present invention include spiro-oxathiine hetero-rings.
• the present invention provides the compounds of Formula I:
• Ri, R 2 , R 3 , and R 4 are each, independently, H, OH, F, Cl, Br, I, CH 3 , CF 3 , C 2 -C 6 straight chain alkyl, substituted C r C fi straight chain alkyl, C 3 -C 6 branched alkyl, C 3 -C 8 cycloalkyl, allyl, C 2 -C 6 straight chain alkenyl, substituted C 2 -C 6 straight chain alkenyl, C 3 -C 6 branched alkenyl, C 5- C 8 cycloalkenyl, C 2 -C 6 alkynyl, NO 2 , CN, NH 2 , alkylamine, substituted alkylamine, dialkylamine, arylamine, C(O)NHRi 4 , NHC(O)Ri 5 , carbamoyl, aminesulfoxide, sulfonamide, sulfamoyl, sulfonic acid, pheny
• OCR 12 CHR 13 , C 2 -C 6 alkynyl, amine, dialkylamine, arylamine, amide, carbamoyl, aminesulfoxide, sulfamide, sulfamoyl, sulfonic acid, heteroaryloxy, OCH 3 , OCF 3 , C 2 -C 6 allcoxy, alkenoxy, phenoxy, benzyloxy, alkoxycarbonyl, carboxyacid, carboxyalkoxy, carboiiylalkyl, thio, alkylthio,
• RH and Ri5 ai-e each, independently H, C 2 -Ce straight alkyl, C 3 -C 6 branched alkyl, C 3 -C 8 cycloalkyl, allyl, C 2 -C 6 straight alkenyl, branched alkenyl, C 5 -C 8 cycloalkenyl, phenyl, C 5 -C 8 aryl, benzyl, CH 2 C(OCH 3 ) 2 , heteroaryl, or heterocyclyl; and,
• Ri 6 is C 3 -C 6 branched alkyl, Cs-C 8 aryl, substituted C 5 -C 8 aryl, heteroaryl, phenyl, substituted phenyl, CH 2 -aryl, benzyl, H, CH 3 , CF 3 , C 2 -C 5 straight chain alkyl, C 3 -C 8 cycloalkyl, heterocyclyl, or CH 2 -heteroaryl.
• J 2 J 3
• J 2 is not OH, NH 2 , SH, or NO 2
• J 2 and J 3 can form a 4, 5; 6, 7, 8 membered spiro ring containing O, 1, or 2 heteroatoms such as O, N, S;
• R 17 , R 18 , R 19 , and R 20 are each, independently, H, phenyl, C 5 -C 8 aryl, CH 3 , CF 3 , C 2 -C 6 straight chain alkyl, C 3 -C 8 cycloalkyl, heteroaryl, or heterocyclyl;
• R 2 i is H, C 2 -C 6 straiglit alkyl, C 3 -C 6 branched alkyl, C 3 -C 8 cycloalkyl, allyl, C 2 -C 6 straight alkenyl, branched alkenyl, C 5 -C 8 cycloalkenyl, phenyl, C 5 -C 8 aryl, benzyl, CH 2 C(OCH 3 ) 2 , heteroaryl, or heterocyclyl.
• p is O and q is 1 and the compound of Formula I has the structure of Formula A:
• p is 2 and q is 1 and the compound of Formula I has the structure of Fo ⁇ nula F:
• Compounds of Formula Ia include those in which Ri, R 2 , R 3 , and R 4 are each, independently, H, OH, F, Cl, Br, I, CFl 3 , CF 3 , OCFI 3 , C 2 -C 6 alkoxy, C 2 -C 6 straight chain alkyl, substituted C 2 -C 6 straight chain alkyl, phenyl, C 5 -C 8 aryl, NO 2 , CN, C(O)NHR 14 or NHC(O)Ri 5 .
• R, , R 2 , R 3 , and R 4 are each, independently, H, OH, F, Cl, Br, I, CH 3 , CF 3 , OCH 3 , C 2 -C 6 alkoxy.
• Ri, R 2 , R 3 , and R 4 are each, independently, H or OCH 3 .
• R ]5 R 2 and R 4 are each H and R 3 is OCH 3 .
• Compounds of Formula Ia include those in which Jj is -(CR 5 R 6 ) J1 -(CR 7 Rg) 111 -Y.
• Compounds of Formula Ia include those in which R 5 and R 6 are each, independently, H or
• R 5 and R 6 are each H.
• Compounds of Formula Ia include those in which R 7 and R 8 are each, independently, H, F, Cl, Br, I, OH, CH 3 , C 2 -C 6 straight chain alkyl, CF 3 , C 3 -C 6 branched alkyl, C 3 -C 8 cycloalkyl, or C 2 -C 6 alkoxy.
• R 7 and R 8 are each, independently, H or OH.
• Compounds of Formula Ia include those in which R 5 and R 5 are each H and R 7 and R 8 are each, independently, H or OH.
• Compounds of Formula Ia include those in which Y is CH 2 OR 16 , phenyl, substituted C 5 -C 8 aryl or benzyl.
• Y is CH 2 OR 16 .
• Y is substituted or unsubstituted C 5 - C 8 aryl.
• the substituted C 5 -C 8 aryl is substituted with from 1 to 5 substituents each of which is independently CN, Cl or F.
• Ri 6 is substituted or unsubstituted C 5 -C 8 aryl: hi another embodiment, the substituted C 5 -C 8 aryl is substituted with from 1 to 5 substituents each of which is independently C 3 -C 6 branched alkyl, Cl, or F.
• Compounds of Formula Ia include those in which Ji is -S(O) 0 -Z.
• Z is CH 3 , CF 3 , C 2 -C 6 straight chain alkyl, heteroaryl, substituted heteroaryl, phenyl, substituted phenyl, C 5 -C 8 aryl, or substituted C 5 -C 8 aryl.
• Compounds of Formula Ia include those in which Ji is N / * .
• W is substituted aryl, phenyl, phenoxy, aryloxy and substituted aryloxy.
• the aryl and aryloxy is substituted with from 1 to 5 substituents each of which is independently CF 3 or F.
• t 2 and W is C 2 -C 6 alkoxy. Additional compounds of Formula Ia include those in which R 9 is H; R] 0 and Rj 1 are both H;
• R 12 and Rj 3 are both H;
• Ri 6 is C 3 -C 6 branched alkyl, C 5 -C 8 aryl, substituted C 5 -C 8 aryl, heteroaryl, phenyl, substituted phenyl, CH 2 -aryl, or benzyl, hi one embodiment,
• R t2 is H and R [3 is phenyl.
• alkyl includes saturated aliphatic groups, including straight-chain alkyl groups (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl), branched- chain alkyl groups (e.g., isopropyl, tert-butyl, isobutyl).
• alkyl' further includes alkyl groups that have oxygen, nitrogen, or sulfur atoms replacing one or more hydrocarbon backbone carbon atoms.
• a straight chain or branched alkyl has six or fewer carbon atoms in its backbone (e.g., C]-C 6 for straight chain, C 3 -C 6 for branched chain), and more preferably four or fewer.
• alkyl also includes both "unsubstituted” and “substituted alkyls", the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbon of the hydrocarbon backbone.
• substitutents can include, for example, alkyl, alkenyl, alkynyl, hydroxyl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, carboxyacid, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, ary
• alkylaryl or aralkyl moiety is an alkyl moiety substituted with an aryl (e.g., methylphenyl (benzyl)).
• aryl e.g., methylphenyl (benzyl)
• Alkyl also includes the side chains of natural and unnatural amino acids.
• Aryl includes groups with aromaticity, including 5- and 6-membered “unconjugated", or single-ring aromatic groups that may include from one to four heteroatoms, as well as " • conjugated", or multicyclic systems with at least one aromatic ring.
• aryl groups include phenyl, pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, pyridine, pyrazine, pyridazine, and pyriinidine, and the like.
• aryl includes mnlticyclic groups, e.g., tricyclic, bicyclic, e.g., naphthalene, benzoxazole, benzodioxazole, benzothizole, benzoimidazole, benzothiophene, methylenedioxyphenyl, quinoline, isoquinoline, napthridine, indole, benzofuran, purine, benzofuran, deazapureine, or indolizine.
• aryl heterocycles e.g., tricyclic, bicyclic, e.g., naphthalene, benzoxazole, benzodioxazole, benzothizole, benzoimidazole, benzothiophene, methylenedioxyphenyl, quinoline, isoquinoline, napthridine, indole, benzofuran, purine, benzofuran, deazapureine, or indolizine.
• heterocycles e.g., pyridine, pyrazole, pyrimidine, fliran, isoxazole, imidazole[2,l,b]thiazole, triazole, pyrazine, benzothiophene, imidazole, or thiophene.
• the aromatic ring can be substituted at one or more ring positions with such substituents as described above, as for example, halogen, hydroxyl, alkyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, carboxyacid, alkylcarbonyl, allcylaminocarbonyl, arallcylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkyltliiocarbonyl, carboxyalkyl, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl
• Aryl groups can also be fused or bridged with alicyclic or heterocyclic rings, which are not aromatic so as to form a multicyclic system (e.g., tetralin, methylenedioxyphenyl).
• alkenyl includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double bond.
• alkenyl includes straight-chain alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl), branched-chain alkenyl groups, cycloalkenyl (e.g., alicyclic) groups (e.g., cyclopropenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl), allcyl or alkenyl substituted cycloalkenyl groups, and cycloalkyl or cycloalkenyl substituted alkenyl groups.
• alkenyl includes straight-chain alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, oc
• alkenyl further includes alkenyl groups, which include oxygen, nitrogen, or sulfur replacing one or more hydrocarbon backbone carbons.
• a straight chain or branched chain alkenyl group has six or fewer carbon atoms in its backbone (e.g., C 2 -C 6 for straight chain, C 3 -C 6 for branched chain.)
• cycloalkenyl groups may have from three to eight carbon atoms in their ring structure, and more preferably have five or six carbons in the ring structure.
• C 2 -C 6 includes alkenyl groups containing two to six carbon atoms.
• alkenyl also includes both “unsubstituted alkenyls” and “substituted alkenyls”, the latter of which refers to alkenyl moieties having substituents replacing a hydrogen on one or more hydrocarbon backbone carbon atoms.
• substituents can include, for example, alkyl groups, alkenyl groups, alkynyl groups, halogens, hydroxyl, alkylcarboiryloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, carboxyacid, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarboiiyl, dialkylaminocarbonyl, alkyltliiocarbonyl, alkoxyl, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and allcylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfliydryl, alkylthio, arylthio, thi
• Alkynyl includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one triple bond.
• alkynyl includes straight chain alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, lieptynyl, octynyl, nonynyl, decynyl), branched chain allcynyl groups, and cycloalkyl or cycloalkenyl substituted alkynyl groups.
• alkynyl further Includes alkynyl groups having oxygen, nitrogen, sulfur or phosphorous atoms replacing one or more hydrocarbon backbone carbons.
• a straight chain or branched chain alkynyl group has six or fewer carbon atoms in its backbone (e.g., C 2 -C 6 for straight chain, C 3 -C 6 for branched chain).
• C 2 -C 6 includes alkynyl groups containing two to six carbon atoms.
• alkynyl also includes botiV'unsubstituted alkynyls" and “substituted alkynyls”, the latter of which refers to alkynyl moieties having substituents replacing a hydrogen on one or more hydrocarbon backbone carbon atoms.
• substituents can include, for example, alkyl groups, alkenyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, carboxyacid, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfliydryl, alkylthio, arylthio, thiocarboxylate, sulf
• lower alkyl includes an alkyl group, as defined above, but having from one to ten, more preferably from one to six, carbon atoms in its backbone structure.
• Lower alkenyl and “lower alkynyl” have chain lengths of, for example, 2-5 carbon atoms.
• amine or “amino” includes compounds where a nitrogen atom is covalently bonded to at least one carbon or heteroatom.
• Alkylamino includes groups of compounds wherein nitrogen is bound to at least one additional alkyl group. Examples of alkylamino groups include benzylamino, methylamino, ethylamino, and phenethylamino.
• Dialkylamino includes groups wherein the nitrogen atom is bound to at least two additional alkyl groups. Examples of dialkylamino groups include dimethylamino and diethylamino.
• Arylamino and “diarylamino” include groups wherein the nitrogen is bound to at least one or two aryl groups, respectively.
• Alkylarylamino refers to an amino group which is bound to at least one alkyl group and at least one aryl group.
• Alkaminoalkyl refers to an alkyl, alkenyl, or alkynyl group bound to a nitrogen atom which is also bound to an alkyl group.
• amide or “aminocarboxy” includes compounds or moieties that contain a nitrogen atom that is bound to the carbon of a carboiiyl or a thiocarbonyl group.
• alkaminocarboxy groups that include alkyl, allcenyl, or alkynyl giOups bound to an amino group bound to a carboxy group. It includes arylaminocarboxy groups that include aryl or heteroaryl moieties bound to an amino group that is bound to the carbon of a carbonyl or thiocarbonyl group.
• alkylaminocarboxy alkenylaminocarboxy
• alkynylaminocarboxy arylaminocarboxy
• arylaminocarboxy moieties wherein alkyl, allcenyl, alkynyl and aryl moieties, respectively, are bound to a nitrogen atom which is in turn bound to the carbon of a carbonyl group.
• Amides can be substituted with substituents such as straight chain alkyl, branched alkyl, cycloalkyl, aryl, heteroaryl, or heterocycle. Substituents on amide groups may be further substituted.
• Acyl includes compounds and moieties that contain the acy] radical (CH 3 CO-) or a carbonyl group.
• Substituted acyl includes acyl groups where one or more of the hydrogen atoms are replaced by for example, alkyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, carboxyacid, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and
• Acylamino includes moieties wherein an acyl moiety is bonded to an amino group.
• the term includes alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido groups.
• alkoxy or “alkoxyl” includes substituted and unsubstituted alkyl, alkenyl, and alkynyl groups covalently linked to an oxygen atom. Examples of alkoxy groups (or alkoxyl radicals) include metlioxy, ethoxy, isopropyloxy, propoxy, butoxy, and pentoxy groups. Examples of substituted alkoxy groups include halogenated alkoxy groups.
• the alkoxy groups can be substituted with groups such as alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, carboxyacid, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfliydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alky
• halogen substituted alkoxy groups include, but are not limited to, fluoromethoxy, difiuoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, and trichloromethoxy.
• cycloalkyl includes saturated acyclic groups (e.g., cyclopropyl, cyclopentyl, cyclohexyl, cyclohexyl, cycloheptyl, cyclooctyl).
• Preferred cycloalkyls have from three to eight carbon atoms in their ring structure, and more preferably have five or six carbon atoms in the ring structure.
• Cycloalkyls includes both "unsubstituted cycloalkyls" and “substituted cycloalkyls", the latter of which refers to replacing a hydrogen on one or more of the carbons in the ring structure.
• substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, carboxyacid, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aininocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamiiio, and alkylarylamino), acylamino (including alkylcarbony
• heterocyclyl or “heterocyclic group” include closed ring structures, e.g., 3- to 10- , or 4- to 7-membered rings, which include one or more heteroatoms.
• ⁇ eteroatom includes atoms of any element other than carbon or hydrogen. Examples of heteroatoms include nitrogen, oxygen, or sulfur.
• Heterocyclyl groups can be saturated or unsaturated and include pyrrolidine, pyrazine, pyrimidine, oxolane, 1,3-dioxolane, thiolane, tetrahydrofuran, tetrahydropyran, piperidine, piperazine, pyrrolidine, morpholine, lactones, lactams such as azetidinones and pyrrolidinones, sultams, and sultones.
• Heterocyclic groups such as pyrrole and furan can have aromatic character. They include fused ring structures such as quinoline and isoquinoline. Other examples of heterocyclic groups include pyridine and purine.
• the heterocyclic ring can be substituted at one or more positions with such substituents as described above, as for example, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, carboxyacid, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxyl, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, sulfonate), sulfamoyl, sulfonamido,
• Heterocyclic groups can also be substituted at one or more constituent atoms with, for example, a lower alkyl, a lower alkenyl, a lower alkoxy, a lower alkylthio, a lower alkylamino, a lower alkylcarboxyl, a nitro, a hydroxyl, -CF 3 , or - CN, or the like.
• thioalkyl includes compounds or moieties which contain an alkyl group connected with a sulfur atom.
• the thioalkyl groups can be substituted with groups such as alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, carboxyacid, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, s
• carbonyl or “carboxy” includes compounds and moieties which contain a carbon connected with a double bond to an oxygen atom.
• moieties containing a carbonyl include, but are not limited to, aldehydes, ketones, carboxylic acids, amides, esters, anhydrides, etc.
• thiocarbonyl or "thiocarboxy” includes compounds and moieties which contain a carbon connected with a double bond to a sulfur atom.
• hydroxy or "hydroxy! includes groups with an -OH or -0 ⁇
• halogen includes fluorine, bromine, chlorine, iodine, etc.
• perhalogenated generally refers to a moiety wherein all hydrogens are replaced by halogen atoms.
• C1-C6 includes one to six carbon atoms (Cl, C2, C3, C4, C5 or C6).
• C2-C6 includes two to six carbon atoms (C2, C3, C4, C5 or C6).
• C3-C6 includes three to six carbon atoms (C3, C4, C5 or C6).
• C3-C8 includes two to eight carbon atoms (C3, C4, C5, C6, C7 or C8).
• €5-08 includes five to eight carbon atoms (C5, C6, C7 or C8).
• any heteroatom or carbon atom with unsatisfied valences is assumed to have the hydrogen atom to satisfy the valences.
• the compounds described herein may have asymmetric centers.
• Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. All chiral, diastereomeric, racemic, and geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated. All tautomers of shown or described compounds are also considered to be part of the present invention.
• substituted means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound.
• 2 hydrogens on the atom are replaced.
• Keto substituents are not present on aromatic moieties.
• “Stable compound” and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
• a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom in the ring.
• a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent.
• Combinations of substituents and/or variables are permissible, but only if such combinations result in stable compounds.
• the present invention also provides methods for the synthesis of the compounds of Formula I.
• the present invention provides a method for the synthesis of compounds according to the following schemes, and the protocols shown in the Examples.
• compositions are described as having, including, or comprising specific components, it is contemplated that compositions also consist essentially ; of, or consist of, the recited components.
• methods or processes are described as having, including, or comprising specific process steps, the processes also consist essentially of, or consist of, the recited processing steps.
• steps or order for performing certain actions is immaterial so long as the invention remains operable.
• two or more steps or actions can be conducted simultaneously.
• the synthetic processes of the invention can tolerate a wide variety of functional groups, therefore various substituted starting materials can be used.
• the processes generally provide the desired final compound at or near the end of the overall process, although it may be desirable in certain instances to further convert the compound to a pharmaceutically acceptable salt, ester, or prodrug thereof.
• the compounds of the present invention can be prepared from the reaction of spiro-1,2- quinone (Ia) and appropriate intermediate/commercial reagents. (Scheme 9)
• Epoxide compounds such as formula (IV) may be conveniently prepared from ketones of formula (III) where Ji is a protecting group such as tert-butyl carbamate (t-BOC).
• Trimethylsulfoxonium ylide is prepared by treating trimethylsulfoxonium iodide with bases such as sodium hydride in a polar solvent such as anhydrous dimethylsulfoxide.
• bases such as potassium t-butoxide may also be used instead of sodium hydride.
• epoxide (IV) The trimethylsulfoxonium ylide is treated with ketone of formula (III) at O 0 C initially and the reaction warmed to room temperature for 4-24 hours to provide epoxide (IV).
• ketone of formula (III) is treated with ketone of formula (III) at O 0 C initially and the reaction warmed to room temperature for 4-24 hours to provide epoxide (IV).
• ketone of formula (III) at O 0 C initially and the reaction warmed to room temperature for 4-24 hours to provide epoxide (IV).
• ketones are commercially available or readily prepared from ketones (III) by methods described in the literature [Abell A. et al, Organophosphorus Reagents, 2004, 99; Lawrence N. et al, Preparation of Alkenes, 1996, 19; Edmonds M. et al, Modem Carbonyl Olefmation 2004,1] and known to those skilled in art.
• the epoxides (IV) are used to prepare tliioalcohol compounds of formula (VT). These can be conveniently prepared by a variety of methods familiar to those skilled in the art.
• the epoxide (IV) is treated with a pretreated mixture of sodium sulfide and acids such as p-toluene sulfonic acid in polar protic solvent such as methanol for 0.5-4 hours at a temperature of 0-25 0 C to provide the tliioalcohol (VI).
• thialcoliols VI
• Another common route to prepare thialcoliols (VI) is by treating epoxide (IV) with triphenylsilane thiol, tertiary amine bases such as triethyl amine and in polar protic solvent such as methanol for 0.5-4 hours at ambient temperatures (Brittain J. et al, Tetrahedron Letters, 1993, 34(21), 3363).
• the thioalcohols (VI) are used to prepare 1,2-quinone alcohol compounds of formula (VHI). These can be conveniently prepared by methods familiar to those skilled in the art.
• the tliioalcohol (VI) is treated with 1,2-quinones (VII), bases such as potassium carbonate and solvents such as tetrahydrofuran for 0.5-4 hours at ambient temperatures to provide the 1,2-quinone alcohols with formula (VIII).
• bases such as triethylamine, sodium carbonate, cesium carbonate and solvents such as acetonitrile dichloromethane can also be utilized.
• 1,2-Quinone alcohols (VIII) are used to prepare spiro-l,2-quionone compounds with formula
• the resulting crude spiro-1 ,2-quionone compounds (II) are treated with ⁇ i-tert-buty ⁇ dicarbonate in bases such as aqueous sodium bicarbonate, solvent such as dichloromethane for 0.25-4 hours at ambient temperature to provide the t-butoxycarbamte (t-BOC) protected spiro-1 ,2-quionones compounds with formula (Ia).
• bases such as aqueous sodium bicarbonate, solvent such as dichloromethane
• Spiro-1,2- quionones (II) can be prepared by treating spiro-l,2-quionones (Ia) where Ji is a protecting group such as tert-butyl carbamate (t-BOC) with acids such as trifiuoroacetic acid in solvents such as dichloromethane or solution of hydrogen chloride gas in solvents such as ethyl acetate, 1,2-dioxane, diethyl ether at ambient temperature for 1-24 hours.
• the product spiro-l,2-quionones (II) can be isolated as free base, hydrochloride or trifiuoroacetic acid salt. To obtain the free base an aqueous workup with sodium bicarbonate is carried out on either acid salt.
• the above condition also describes a method to remove the protecting group tert-butyl carbamte (t-BOC) group from amines.
• Scheme 9 illustrates a variety of chemical transformation of spiro-l,2-quinone (II) to provide compounds (XII-XXI).
• the following methods are provided by way of exemplification. Alternative methods may be employed and are described in reference text's such as Comprehensive Organic Transformations, Richard C. Larock, Second Edition, Wiley- VCH, 1999; Protective Groups in Organic Synthesis, Third Edition, Theodora W. Greene and Peter M. Wuts, Wiley Interscience, 1999; The Practice of Peptide Synthesis, M. Bodanszky and A. Bodanzsky, Springer- Verlag, 1984.
• the spiro-l,2-quinone amide (XII) can be conveniently prepared by treating spiro-1,2- quinone (II) with acid chlorides such as m-trifluoromethylbenzoyl chloride in presence of tertiary amine bases such as triethylamine, diisopropylethyl amine and solvents such as dichloromethane at ambient temperature for 1-12 hours.
• acid chlorides such as m-trifluoromethylbenzoyl chloride in presence of tertiary amine bases such as triethylamine, diisopropylethyl amine and solvents such as dichloromethane at ambient temperature for 1-12 hours.
• acid chlorides are commercially available or readily prepared by methods described in the literature and known to those skilled in art.
• spiro-l,2-quinone amide (XII) can be conveniently prepared by treating spiro- 1,2 -quinone (II) with the corresponding carboxylic acid in presence of amide coupling agents such as HBTU (O-(benzotriazo-l-yl)-N,N,N',N'-tetrametliyluroniumhexafluorophosphate), tertiary amine bases such as dimethylaminopyridine and solvents such as dimethylformamide at ambient temperature for 4-24 hours.
• amide coupling agents such as HBTU (O-(benzotriazo-l-yl)-N,N,N',N'-tetrametliyluroniumhexafluorophosphate)
• tertiary amine bases such as dimethylaminopyridine
• solvents such as dimethylformamide at ambient temperature for 4-24 hours.
• amide coupling agents such as DCC (dicylcohexycarbodiimide), BOP ((benzotriazo-l-yloxy)tris(dimethylamino) phosphonium hexafluorophosphate, EDCI.HC1 (l-(3- Dimethyl aminopropyl)-3-ethylcarbodiimide hydrochloride), DMC (2-chloro-l ,3- dimethylimidazolinium chloride) and tertiary amines bases such as triethylamine, diisopropylethyl amine can also be used.
• DCC dicylcohexycarbodiimide
• BOP ((benzotriazo-l-yloxy)tris(dimethylamino) phosphonium hexafluorophosphate
• EDCI.HC1 l-(3- Dimethyl aminopropyl)-3-ethylcarbodiimide hydrochloride
• DMC (2-ch
• Spiro-l,2-quinone sulfonamide (XIII) can be conveniently prepared by treating spiro-1, 2- quinone (II) with sulfonyl chlorides such as methanesulfonyl chloride in presence of tertiary amine bases such as triethylamine and solvents such as dichlorometliane at ambient temperature for 1-12 hours. Alternatively tertiary amines bases such as diisopropylethyl amine can also be used. Many sulfonyl chlorides are commercially available or readily prepared by methods described in the literature and known to those skilled in art.
• Spiro-l,2-quinone amino alcohol (XIV) can be conveniently prepared by treating spiro-1, 2- quinone (II) with epoxides such as (2S)-2-[(4-t-butyl-phenoxy)methyl]oxirane in solvents such as acetonitrile, ethanol and with or without lithium perchlorate at 50-100 0 C for 1-12 hours.
• epoxides such as (2S)-2-[(4-t-butyl-phenoxy)methyl]oxirane in solvents such as acetonitrile, ethanol and with or without lithium perchlorate at 50-100 0 C for 1-12 hours.
• solvents such as acetonitrile, ethanol and with or without lithium perchlorate at 50-100 0 C for 1-12 hours.
• solvents such as acetonitrile, ethanol and with or without lithium perchlorate at 50-100 0 C for 1-12 hours.
• the above conditions can be used with both
• Spiro-l,2-quinone urea can be conveniently prepared by treating spiro-l,2-quinone (II) with isocyanates such as phenylisocyanante in solvents such as dichloromethane at ambient temperature for 1-12 hours.
• isocyanates are commercially available or readily prepared by methods described in the literature and known to those skilled in art.
• Isocyantes can also be prepared in situ from carboxylic acids by a variety of methods familiar to those skilled in the art.
• Carboxylic acids are treated with diphenyl phosphoryl azide in solvents such as toluene at reflux for 1-5 hours.
• the isocyanates are used in situ as solution to react with the spiro-l,2-quinones (II) to prepare spiro- 1,2 -quinone ureas (XV) as described above.
• Spiro-l,2-quinone carbamate can be conveniently prepared by treating spiro-1,2- quinone (II) with carbamoyl chlorides such as pheiiylchlorido carbonate, bases such as triethylamine, diisopropylethyl amine, aqueous sodium carbonate in solvents such as ethyl acetate, dichloromethane at ambient temperature for 1-12 hours.
• carbamoyl chlorides such as pheiiylchlorido carbonate
• bases such as triethylamine, diisopropylethyl amine, aqueous sodium carbonate in solvents such as ethyl acetate, dichloromethane at ambient temperature for 1-12 hours.
• carbamates are commercially available or readily prepared by methods described in the literature and known to those skilled in art.
• Carbamoyl chlorides can also be prepared in situ from carboxylic acids by a variety of methods familiar to those skilled
• Carboxylic acids are treated with oxalyl chloride, triphosgenes in solvents such as dichloromethane at 0 0 C to ambient temperature for 1-5 hours.
• the resulting carbamoyl are used in situ as solution to react with the spiro-l,2-quinones (II) to prepare spiro-l,2-quinone carbamates with formula (XVI) as described above.
• Spiro-1, 2 -quinone sulfonyl urea where X is nitrogen can be conveniently prepared by treating spiro-1, 2 -quinone (II) with sulfonyl isocyanates such as phenylsulfonyl isocyanate (XVIII) in solvents such as dichlorometliane at 0 0 C to ambient temperature for 1-12 hours.
• sulfonyl isocyanates such as phenylsulfonyl isocyanate (XVIII) in solvents such as dichlorometliane at 0 0 C to ambient temperature for 1-12 hours.
• solvents such as dichlorometliane at 0 0 C to ambient temperature for 1-12 hours.
• Many sulfonyl isocyanates are commercially available or readily prepared by methods described in the literature and known to those skilled in art.
• Spiro-1, 2 -quinone guanidine with fo ⁇ mila can be conveniently prepared by treating spiro-l,2-quinone (II) with pyrazole carboxamidine hydrochloride, tertiary amine bases such as triethylamine, diisopropylethyl amine and in solvents such as dimethylformamide at 50-90 0 C for 1-12 hours.
• the crude spiro-l,2-quinone guanidines (XVIII) are titurated with diethyl ether to provide pure spiro-l,2-quinone guanidines (XVIII) isolated as HCl salts.
• alkyl substituted spiro-1 ,2-quinone guanidines can be conveniently prepared by treating spiro-1 ,2-quinone (II) with bis(ter/-butoxycarbonyl)- 1 S r -methylisotliio ⁇ u-ea, mercuric (II) chloride, tertiary amine bases such as triethylamine, diisopropylethyl amine and in solvents such as dimethylformamide at 50-90 0 C for 1-12 hours.
• spiro-1 ,2-quinone (II) with bis(ter/-butoxycarbonyl)- 1 S r -methylisotliio ⁇ u-ea, mercuric (II) chloride, tertiary amine bases such as triethylamine, diisopropylethyl amine and in solvents such as dimethylformamide at 50-90 0 C for 1-12 hours.
• the resulting bis(fert-butoxycarbonyl) protected guanidine can be treated with benzyl bromide or other alkyl halides in presence of phase transfer catalyst such as tert-butyl ammonium iodide, bases such as potassium hydroxide in water and organic solvent such as toluene at 40-70 0 C for 1-8 hours to provide allcyl substituted bis(t ⁇ Y-butoxycarbonyl) protected guanidine.
• phase transfer catalyst such as tert-butyl ammonium iodide
• bases such as potassium hydroxide in water
• organic solvent such as toluene
• alkyl substituted bis(terZ-butoxycarbonyl) protected guanidine Treatment of the alkyl substituted bis(terZ-butoxycarbonyl) protected guanidine with acids such as trifluoroacetic acid in solvents such as dichloromethane or solution of hydrogen chloride gas in solvents such as ethyl acetate, 1,2-dioxane, diethyl ether at ambient temperature for 1- 24 hours provided alkyl substituted guanidine as hydrochloride salt.
• alkyl halides such as allcyl chloride, bromide and iodides are commercially available or readily prepared by methods described in the literature and known to those skilled in
• S ⁇ iro-1, 2-quinone allcyl amines can be conveniently prepared by treating spiro-1,2- quinone (II) with alkyl halides such as 2-bromopropane, bases such as potassium carbonate, cesium carbonate, triethylamine, diisopropylethyl amies in solvent such as acetonitrile, dimethylformamide at 70-90 0 C for 1-12 hours.
• alkyl chloride can be treated with the spiro-1, 2-quinone (II) in presence of sodium iodide (to in situ prepare alkyl iodide) to provide spiro-1 ,2-quinone alkyl amines (XIX).
• alkyl chlorides such as 2-bromopropane
• bases such as potassium carbonate, cesium carbonate
• triethylamine diisopropylethyl amies
• solvent such as acetonitrile
• dimethylformamide dimethylformamide
• Spiro-1, 2 -quinone amine heterocycle (XX) can be conveniently prepared by treating spiro- 1, 2-quinone (II) with heterocyclic halides such as 2-chloropyrazine, tertiary amine bases such as triethylamine, diisopropylethyl amies in polar aprotic solvent such as dimethylsulfoxide, dimethylformamide at 80-110 0 C for 1-12 hours.
• heterocyclic halides such as 2-chloropyrazine, tertiary amine bases such as triethylamine, diisopropylethyl amies in polar aprotic solvent such as dimethylsulfoxide, dimethylformamide at 80-110 0 C for 1-12 hours.
• heterocyclic halides such as 2-chloropyrazine, tertiary amine bases such as triethylamine, diisopropylethyl amies in polar aprotic solvent such
• Spiro-1, 2-quinone amide acids can be conveniently prepared by treating spiro-1, 2- quinone (II) with anhydrides such as dihydrofuran-2,5-dione in solvent such as acetonitrile, dimethylsulfoxide at 70-90 0 C for 1-12 hours.
• anhydrides such as dihydrofuran-2,5-dione in solvent such as acetonitrile, dimethylsulfoxide at 70-90 0 C for 1-12 hours.
• solvent such as acetonitrile, dimethylsulfoxide
• phenyl spiro-l,2-quinones where J, is a protecting group such as tert-butyl carbamate (t-BOC) can be conveniently prepared by treating tert-butoxy carbamate protected bromo-spiro-l,2-quinone amine (XXII) with boroiiic acids such as phenyl boronic acid, Pd(O) catalyst such as Pd(Ph 3 P) 4 , bases such as sodium bicarbonate, cesium carbonate in solvent such as ethanol, toluene at 70-100 0 C for 1-12 hours.
• Pd(O) catalyst such as Pd(Ph 3 P) 4
• bases such as sodium bicarbonate, cesium carbonate in solvent such as ethanol, toluene at 70-100 0 C for 1-12 hours.
• aromatic boronic acids are commercially available or readily prepared by methods described in the literature and known to those skilled in art. (Prieto M. et al, JOC, 2004, 69(
• phenyl amino substituted spiro-l,2-quinones where Ji is a protecting group such as tert-butyl carbamate (t-BOC) can be conveniently prepared by treating tert- butoxy carbamate protected bromo-spiro-l,2-quinone amine (XXII) with amines such as piperidine, Pd(O) catalyst such as bis(tri-fert-butyl phosphine)palladium(O), bases such as cesium carbonate, sodium bicarbonate in solvent such as dioxane at 70-130 0 C for 1-12 hours.
• Pd(O) catalyst such as bis(tri-fert-butyl phosphine)palladium(O
• bases such as cesium carbonate, sodium bicarbonate in solvent such as dioxane at 70-130 0 C for 1-12 hours.
• bases such as cesium carbonate, sodium bicarbonate in solvent such as dioxane at 70-130 0 C for 1-12 hours.
• s ⁇ iro-l,2-quinone amino alcohol esters can be conveniently prepared by treating spiro-l,2-qninone amino alcohols (XIV) with anhydride such as acetic anhydride, tertiary amine base such as dimethylamino pyridine, triethylamine, diisopropylethylamine in solvent such as dichloromethane at O 0 C to ambient temperatures for 1-12 hours.
• anhydride such as acetic anhydride, tertiary amine base such as dimethylamino pyridine, triethylamine, diisopropylethylamine in solvent such as dichloromethane at O 0 C to ambient temperatures for 1-12 hours.
• anhydrides are commercially available or readily prepared by methods described in the literature and known to those skilled in art.
• the spiro-l,2-quinone amino alcohol esters with formula (XXVI) can be conveniently prepared by treating spiro-l,2-quinone amino alcohols (XIV) withcarboxylic acds such as N-(tert-butoxycarbonyl)glycine, in presence of ester coupling agents such as HBTU (O- (benzotiiazo-l-yl)- ⁇ , ⁇ , ⁇ ', ⁇ '-tetramethyluroniumhexafluorophosphate), tertiary amine bases such as dimethylaminopyridine, solvents such as dimethylformamide at ambient temperatures for 4-24 hours.
• ester coupling agents such as HBTU (O- (benzotiiazo-l-yl)- ⁇ , ⁇ , ⁇ ', ⁇ '-tetramethyluroniumhexafluorophosphate)
• tertiary amine bases such as dimethylaminopyridine
• solvents such as dimethylformamide at ambient temperatures for 4
• spiro-l,2-quinone acid (XXVIII) can be conveniently prepared by treating spiro-l,2-quinone benzyl ester (XXVII) with Pd (O) on carbon, in an atmosphere of hydrogen and with solvents such as ethyl acetate at ambient temperatures for 4-24 hours.
• the compounds of the present invention having the formula (Ic and Id) where X is oxygen and sulfur can be conveniently prepared as shown in Scheme 14.
• Epoxide compounds (XXX) where X is oxygen and sulfur may be conveniently prepared from ketones (XXIX) where X is oxygen and sulfur.
• Trimethylsulfoxonium ylide is prepared by treating trimethylsulfoxonium iodide with bases such as sodium hydride in a polar solvent such as anhydrous dimethylsulfoxide. Other bases such as potassium t-butoxide may also be used instead of sodium hydride.
• epoxide XXX
• XXX epoxide
• Many ketones are commercially available or readily prepared by methods described in the literature and known to those skilled in art.
• the epoxide (XXX) where X is oxygen or sulfur substituted with phenyl can also be conveniently prepared from alkenes (XXXI) by treatment with peroxy acids such m-chloroperoxybezoic acid.
• Many alkenes are commercially available or readily prepared from ketones (XXIX) by methods described in the literature (such as wittig reaction) and known to those skilled in art.
• the epoxides (XXX) are used to prepare thioalcohol compounds of formula (XXXII). These can be conveniently prepared by a variety of methods familiar to those skilled in the art.
• the epoxide (XXX) is treated with a pretreated mixture of sodium sulfide and acids such as p-toluene sulfonic acid in polar protic solvent such as methanol for 0.5-4 hours at a temperature of 0-25 0 C to provide the thioalcohol (XXXII).
• thioalcohols XXXII
• triphenylsilane thiol, tertiary amine bases such as triethyl amine and in polar protic solvent such as methanol for 0.5-4 hours at ambient temperatures.
• Thioalcohols are used to prepare 1,2-quinone alcohol (XXXIII). These can be conveniently prepared by methods familiar to those skilled in the art. Thioalcohol (XXXH) is treated with 1 ,2-quinones (VII), bases such as potassium carbonate and solvents such as tetrahydrofuran for 0.5-4 hours at ambient temperatures to provide the 1,2-quinone alcohols with formula (XXXIII). Alternatively bases such as triethylamine, sodium carbonate, cesium carbonate and solvents such as acetonitrile dichloromethane can also be utilized.
• bases such as triethylamine, sodium carbonate, cesium carbonate and solvents such as acetonitrile dichloromethane can also be utilized.
• 1,2-Quinone alcohols (XXXIII) are used to prepare spiro-l,2-quionone compounds with formula (XXXIV). These can be conveniently prepared by methods familiar to those skilled in the art. 1,2-Quinone alcohols with formula (XXXIII) are treated with acid such as trifluoroacetic acid and solvents such as dichloromethane in open air at ambient temperature for 24-96 hours. Alternatively acids such as p-toluenesulfonic acid can also be used and air or oxygen can also be bubbled through the reaction.
• acid such as trifluoroacetic acid and solvents such as dichloromethane
• solvents such as dichloromethane
• acids such as p-toluenesulfonic acid can also be used and air or oxygen can also be bubbled through the reaction.
• the compounds of the present invention having the fomiula (Ib) where J 2 and J 3 can be protecting group such as dioxolane ring, ketone or when J 2 is hydrogen, J 3 is phenyl or N-Ji and J 1 is a protecting group such as tert-butyl carbamate (t-BOC) or selected from additional groups described in the detailed description of the invention, can be conveniently prepared as shown in Scheme 9 and 15.
• Epoxide compounds may be conveniently prepared from ketones (XXXV).
• Trimethylsulfoxonium ylide is prepared by treating trimethylsi ⁇ foxoimmi iodide with bases such as sodium hydride in a polar solvent such as anhydrous dimethylsulfoxide. Other bases such as potassium t-butoxide may also be used instead of sodium hydride.
• the trimethylsulfoxonium ylide is treated with ketone (XXXV) at O 0 C initially and the reaction warmed to room temperature for 4-24 hours to provide epoxide (XXXVI).
• ketone XXXV
• Many ketones are commercially available or readily prepared by methods described in the literature and known to those skilled in art. Alternatively, the epoxide
• XXXVI can also be conveniently prepared from alkenes (XXXVII) by treatment with peroxy acids such 7W-chloro ⁇ eroxybezoic acid.
• alkenes are commercially available or readily prepared from ketone (XXXV) by methods described in the literature (such as wittig reaction) and known to those skilled in art.
• the epoxides (XXXVI) are used to prepare thioalcohol compounds of formula (XXXVTH).
• epoxide (XXXVI) is treated with a pretreated mixture of sodium sulfide and acids such as p-toluene sulfonic acid in polar protic solvent such as methanol for 0.5-4 hours at a temperature of 0-25 0 C to provide the thioalcohol (XXXVIII).
• a preferred common route to prepare thiolcohols (XXXVIII) where J 2 and J 3 are a part of the dioxolane ring, which is an acid sensitive moiety is by treating epoxide (XXXVI) with triphenylsilane thiol, tertiary amine bases such as triethyl amine and in polar protic solvent such as methanol for 0.5-4 hours at ambient temperatures.
• thioalcohols are used to prepare 1,2-quinone alcohol compounds of formula (XXXrX). These can be conveniently prepared by methods familiar to those skilled in the art.
• Thioalcohol (XXXVIII) is treated with 1,2-quinones (VII), bases such as potassium carbonate and solvents such as tetrahydrofuran for 0.5-4 hours at ambient temperatures to provide the 1,2-quinone alcohols with formula (XXXIX).
• bases such as triethylamine, sodium carbonate, cesium carbonate and solvents such as acetonitrile dichloromethane can also be utilized.
• 1,2-Quinone alcohols are used to prepare spiro-l,2-quionone compounds (XXXX). These can be conveniently prepared by methods familiar to those skilled in the art. 1,2-Quinone alcohols (XXXIX) are treated with, acid such as trifluoroacetic acid and solvents such as dichloromethane in open air at ambient temperature for 24-96 hours to prepare spiro-l,2-quinone (XXXX). Alternatively acids such as p-toluenesulfonic acid can also be used and air or oxygen can also be bubbled through the reaction.
• spiro-l,2-quinone alcohol (XXXXI) can be conveniently prepared by treating spiro-l,2-quinone ketone (XXXX) with reducing agents such as sodium borohydride in solvents such as methanol at ambient temperatures for 4-24 hours.
• reducing agents such as sodium borohydride in solvents such as methanol at ambient temperatures for 4-24 hours.
• reducing agents such as sodium triacetoxyborohydride in solvents such as tetrahydrofuran, dichloromethane can also be used to prepare spiro-l,2-quinone alcohol with formula (XXXXI)
• XXXXII Compounds of formula (XXXXII) can be prepared as shown in Scheme 17.
• Spiro-1,2- quionones (XXXII) can be prepared by treating s ⁇ iro-l,2-quionones (XXXX) where and J 1 is a protecting group such as t-butyl carbamate (t-BOC) with acids such as a solution of hydrogen chloride gas in solvents such as ethyl acetate, 1,2-dioxane, diethyl ether at ambient temperature for 1-24 hours to give the product as an hydrochloride salt.
• solvents such as ethyl acetate, 1,2-dioxane, diethyl ether
• trifluoroacetic acid in solvents such as dichloromethane can also be used in the above reaction.
• the product spiro-l,2-quionones can be isolated as free base, hydrochloride or trifluoroacetic acid salt.
• an aqueous workup with sodium bicarbonate is carried out on either acid salt.
• the above condition also describes the method to deprotect amines protected with t-butoxycarbamoyl (t-BOC) group.
• Scheme 18 illustrates a variety of chemical transformation of spiro-l,2-quinone (XXXXI) to provide compounds (XXXXII-XXXXIII).
• XXXXI spiro-l,2-quinone
• Scheme 18 illustrates a variety of chemical transformation of spiro-l,2-quinone (XXXXI) to provide compounds (XXXXII-XXXXIII).
• the following methods are provided by way of exemplification.
• the s ⁇ iro-1 ,2-quinone (XXXXII) can also be functionalized to prepare compounds with functional groups in an analogous fashion as illustrated in Scheme 9.
• Alternative methods may be employed and are described in reference text's such as Comprehensive Organic Transformations, Richard C. Larock, Second Edition, Wiley- VCH, 1999; Protective Groups in Organic Synthesis, Third Edition, Theodora W. Greene and Peter M. Wuts, Wiley Interscience, 1999; The Practice of Peptide Synthesis,
• the spiro-l,2-quinone amides can be conveniently prepared by treating spiro-1,2- quinone (XXXXI) with acid chlorides such as /n-nifluoromethylbenzoyl chlorides in presence of tertiary amine bases such as triethylamine, diisopropylethyl amine and solvents such as dichloromethane at ambient temperature for 1-12 hours.
• acid chlorides such as /n-nifluoromethylbenzoyl chlorides in presence of tertiary amine bases such as triethylamine, diisopropylethyl amine and solvents such as dichloromethane at ambient temperature for 1-12 hours.
• acid chlorides are commercially available or readily prepared by methods described in the literature and known to those skilled in art.
• spiro-l,2-quinone amides (XXXXIII) can be conveniently prepared by treating spiro-l,2-quinone (XXXXII) with carboxylic acids with formula in presence of amide coupling agents such as HBTU (O-(benzotriazo-l-yl)-N,N,N',N'-tetrametliyliuOniumhexafluorophosphate), tertiary amine bases such as dimethylaminopyridine and solvents such as dimethylformamide at ambient temperature for 4-24 hours.
• amide coupling agents such as DCC
• Spiro-1 ,2-quinone carbamates can be conveniently prepared by treating spiro-1 ,2- qninone (XXXXII) with carbamoyl chlorides such as 3-(trifluoromethyl) phenyl chloroformate, bases such as triethylamine, diisopropylethyl amine, aqueous sodium carbonate in solvents such as ethyl acetate, dichloromethane at ambient temperature for 1-12 hours.
• carbamoyl chlorides such as 3-(trifluoromethyl) phenyl chloroformate
• bases such as triethylamine, diisopropylethyl amine, aqueous sodium carbonate in solvents such as ethyl acetate, dichloromethane at ambient temperature for 1-12 hours.
• solvents such as ethyl acetate, dichloromethane at ambient temperature for 1-12 hours.
• carbamates are commercially available or readily prepared by methods described in the literature
• the present invention further provides a compound prepared by one of the synthetic processes disclosed herein, such as those disclosed in the Examples.
• the present invention also provides a method for the treatment of a cell proliferative disorder in a mammal comprising administering to a mammal in need of such treatment, a therapeutically effective amount of a compound of Formula I.
• the invention further provides the use of a compound of Formula I for the preparation of a medicament useful for the treatment of a cell proliferative disorder.
• the invention provides for the treatment of cancer or precancerous conditions in a mammal comprising administering to a mammal in need of such treatment, a therapeutically effective amount of a compound of Formula I.
• the mammal can be e.g., any mammal, e.g., a human, a primate, mouse, rat, dog, cat, cow, horse, pig.
• the mammal is a human.
• An effective amount of a compound of Formula I is used in a method to treat a cell proliferative disorder in a mammal without affecting normal cells of the mammal.
• a therapeutically effective amount of a compound of Formula I is used in a method for treating cancer in a mammal by inducing cell death in cancer cells without affecting normal cells in the mammal. Cell death can occur by either apoptosis or necrosis mechanisms.
• administration of a therapeutically effective amount of a compound of Formula I induces sustained (non-transient) ⁇ activity (e.g.
• administration of a therapeutically effective amount of a compound of Formula I induces activation of E2F1 checkpoint pathway in abnormally proliferating cells without significantly affecting normal cells.
• administration induces sustained E2F pathway activity (e.g. elevation of E2F levels) in cancer cells without affecting E2F pathway activity (e.g. E2F levels) in normal cells. Methods of measuring induction of E2F activity and elevation of E2F levels are as shown in Li et al., (2003) Proc Natl Acad Sd USA. 100(5): 2674-8.
• administration of a therapeutically effective amount of a compound of Formula I induces cell death in abnormally proliferating cells without inducing cell death in normal cells.
• the invention also provides a method of protecting against a cell proliferative disorder in a mammal by administering a therapeutically effective amount of a compound of Formula I to a mammal.
• the invention also provides the use of a compound of Formula I for the preparation of a medicament useful for the prevention of a cell proliferative disorder.
• the invention provides for the prevention of cancer in a mammal comprising administering to a mammal in need of such treatment, a therapeutically effective amount of a compound of Formula I.
• a "subject" can be any mammal, e.g., a human, a primate, mouse, rat, dog, cat, cow, horse, pig, sheep, goat, camel. In a preferred aspect, the subject is a human.
• a "subject in need thereof is a subject having a cell proliferative disorder, or a subject having an increased risk of developing a cell proliferative disorder relative to the population at large.
• a subject in need thereof has a precancerous condition, hi a preferred aspect, a subject in need thereof has cancer.
• the term "cell proliferative disorder” refers to conditions in which the unregulated and/or abnormal growth of cells can lead to the development of an unwanted condition or disease, which can be cancerous or non-cancerous, for example a psoriatic condition.
• psoriatic condition refers to disorders involving keratinocyte hyperproliferation, inflammatory cell infiltration, and cytokine alteration.
• the cell proliferation disorder is cancer.
• cancer includes solid tumors, such as lung, breast, colon, ovarian, prostate, malignant melanoma, non-melanoma skin cancers, as well as hematologic tumors and/or malignancies, such as childhood leukemia and lymphomas, multiple myeloma, Hodgkin's disease, lymphomas of lymphocytic and cutaneous origin, acute and chronic leukemia such as acute lymphoblastic, acute myelocytic or chronic myelocytic leukemia, plasma cell neoplasm, lymphoid neoplasm and cancers associated with AIDS.
• solid tumors such as lung, breast, colon, ovarian, prostate, malignant melanoma, non-melanoma skin cancers, as well as hematologic tumors and/or malignancies, such as childhood leukemia and lymphomas, multiple myeloma, Hodgkin's disease, lymphomas of lymphocytic and cutaneous origin, acute and chronic leukemia such as acute
• Hie types of proliferative diseases which may be treated using the compositions of the present invention are epidermic and dermoid cysts, lipomas, adenomas, capillary and cutaneous hemangiomas, lymphangiomas, nevi lesions, teratomas, nephromas, myof ⁇ bromatosis, osteoplastic tumors, and other dysplastic masses and the like, hi one embodiment, proliferative diseases include dysplasias and disorders of the like.
• monotherapy refers to administration of a single active or therapeutic compound to a subject in need thereof.
• monotherapy will involve administration of a therapeutically effective amount of an active compound.
• cancer monotherapy with one of the compound of the present invention, or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof, to a subject in need of treatment of cancer.
• Monotherapy may be contrasted with combination therapy, in which a combination of multiple active compounds is administered, preferably with each component of the combination present in a therapeutically effective amount.
• montherapy with a compound of the present invention is more effective than combination therapy in inducing a desired biological effect.
• treating describes the management and care of a patient for the purpose of combating a disease, condition, or disorder and includes the administration of a compound of the present invention to prevent the onset of the symptoms or complications, alleviating the symptoms or complications, or eliminating the disease, condition or disorder.
• treating cancer results in a reduction in size of a tumor. In another aspect, treating cancer results in a reduction in tumor volume. In another aspect, treating cancer results in a decrease in number of tumors. In another aspect, treating cancer results in a decrease in number of metastatic lesions in other tissues or organs distant from the primary tumor site, hi another aspect, treating cancer results in an increase in average survival time of a population of treated subjects in comparison to a population receiving carrier alone. In another aspect, treating cancer results in an increase in average survival time of a population of treated subjects in comparison to a population of untreated subjects.
• treating cancer results in increase in average survival time of a population of treated subjects in comparison to a population receiving monotherapy with a drug that is not a compound of the present invention, or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof, hi another aspect, treating cancer results in a decrease in the mortality rate of a population of treated subjects in comparison to a population receiving carrier alone, hi another aspect, treating cancer results in a decrease in the mortality rate of a population of treated subjects in comparison to an untreated population.
• treating cancer results a decrease in the mortality rate of a population of treated subjects in comparison to a population receiving monotherapy with a drug that is not a compound of the present invention, or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof, hi another aspect, treating cancer results in a decrease in tumor growth rate, hi another aspect, treating cancer results in a decrease in tumor regrowrli. hi another aspect, treating or preventing a cell proliferative disorder results in a reduction in the rate of cellular proliferation. In another aspect, treating or preventing a cell proliferative disorder results in a reduction in the proportion of proliferating cells.
• treating or preventing a cell proliferative disorder results in a decrease in size of an area or zone of cellular proliferation
• treating or preventing a cell proliferative disorder results in a decrease in the number or proportion of cells having an abnormal appearance or morphology.
• ⁇ -lapachone or a pharmaceutically acceptable salt, metabolite, analog or derivative thereof, can be administered in combination with a chemotherapeutic agent.
• chemotherapeutic agents with activity against cell proliferative disorders are known to those of ordinary skill in the art, and may be found in reference texts such as the Physician 's Desk Reference, 59"' Edition, Thomson PDR (2005).
• the chemotherapeutic agent can be a taxane, an aromatase inhibitor, an anthracycline, a microtubule targeting drug, a topoisomerase poison drug, a targeted monoclonal or polyconal antibody, an inhibitor of a molecular target or enzyme (e.g., a kinase inhibitor), or a cytidine analogue drug.
• the chemotherapeutic agent can be, but is not restricted to, tamoxifen, raloxifene, anastrozole, exemestane, letrozole, cisplatin, carboplatin, TAXOL ® (paclitaxel), cyclophosphamide, lovastatin, minosine, GEMZAR ® (gemcitabine HCl), araC, 5-fluorouracil (5-FU), methotrexate (MTX), TAXOTERE ® (docetaxel), ZOLADEX ® (goserelin), vincristin, vinblastin, nocodazole, teniposide, etoposide, epothilone, navelbine, camptothecin, daunonibicin, dactinomycin, mitoxantrone, amsacrine, doxombicin (adrianiycin), epimbicin, idarubicin
• the chemotherapeutic agent can be a cytokine such as G-CSF (granulocyte colony stimulating factor).
• cytokine such as G-CSF (granulocyte colony stimulating factor).
• ⁇ -lapachone, or a pharmaceutically acceptable salt, metabolite, analog or derivative thereof may be administered in combination with radiation therapy.
• ⁇ -lapachone, or a pharmaceutically acceptable salt, metabolite, analog or derivative thereof may be administered in combination with standard chemotherapy combinations such as, but not restricted to, CMF (cyclophosphamide, metliotrexate and 5-fluorouracil), CAF (cyclophosphamide, adriamycin and 5-fluorouracil), AC
• CMFP cyclophosphamide, metliotrexate, 5-fluorouracil and prednisone
• a “pharmaceutically acceptable salt” or “salt” of the disclosed compound is a product of the disclosed compound that contains an ionic bond, and is typically produced by reacting the disclosed compound with either an acid or a base, suitable for administering to a subject.
• Pharmaceutically acceptable salt can include, but is not limited to, acid addition salts including hydrochlorides, hydrobromides, phosphates, sulphates, hydrogen sulphates, alkylsulphonates, arylsulphonates, acetates, benzoates, citrates, maleates, fumarates, succinates, lactates, and tartrates; alkali metal cations such as Na, K, Li, alkali earth metal salts such as Mg or Ca, or organic amine salts.
• a "pharmaceutical composition” is a formulation containing the disclosed compounds in a form suitable for administration to a subject.
• the pharmaceutical composition is in bulk or in unit dosage form.
• the unit dosage form is any of a variety of forms, including, for example, a capsule, an IV bag, a tablet, a single pump on an aerosol inhaler, or a vial.
• the quantity of active ingredient (e.g., a formulation of the disclosed compound or salts thereof) in a unit dose of composition is an effective amount and is varied according to the particular treatment involved.
• active ingredient e.g., a formulation of the disclosed compound or salts thereof
• the dosage will also depend on the route of administration.
• routes including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, intranasal, and the like.
• Dosage forms for the topical or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
• the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that are required.
• the present invention also provides pharmaceutical formulations comprising a compound of Formula I in combination with at least one pharmaceutically acceptable excipient or carrier.
• pharmaceutically acceptable excipient or “pharmaceutically acceptable carrier” is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. Suitable carriers are described in "Remington: The Science and Practice of Pharmacy, Twentieth Edition," Lippincott Williams & Wilkins, Philadelphia, PA., which is incorporated herein by reference.
• Such carriers or diluents include, but are not limited to, water, saline, Ringer' s solutions, dextrose solution, and 5% human serum albumin. Liposomes and non-aqueous vehicles such as fixed oils may also be used.
• the use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the compositions is contemplated. Supplementary active compounds can also be incorporated into the compositions.
• a compound of Formula I is administered in a suitable dosage form prepared by combining a therapeutically effective amount (e.g., an efficacious level sufficient to achieve the desired therapeutic effect through inhibition of tumor growth, killing of tumor cells, treatment or prevention of cell proliferative disorders, etc.) of a compound of Formula I (as an active ingredient) with standard pharmaceutical carriers or diluents according to conventional procedures (i.e., by producing a pharmaceutical composition of the invention). These procedures may involve mixing, granulating, and compressing or dissolving the ingredients as appropriate to attain the desired preparation.
• a therapeutically effective amount of a compound of Formula I is administered in a suitable dosage form without standard pharmaceutical carriers or diluents.
• Pharmaceutically acceptable carriers include solid carriers such as lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like.
• Exemplary liquid carriers include syrup, peanut oil, olive oil, water and the like.
• the carrier or diluent may include time-delay material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or with a wax, ethylcellulose, hydroxypropylmethylcellulose, methylmethacrylate or the like.
• Other fillers, excipients, flavorants, and other additives such as are known in the art may also be included in a pharmaceutical composition according to this invention.
• compositions containing active compounds of the present invention may be manufactured in a manner that is generally known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or lyophilizing processes.
• Pharmaceutical compositions may be formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and/or auxiliaries which facilitate processing of the active compounds into preparations mat can be used pharmaceutically. Of course, the appropriate formulation is dependent upon the route of administration chosen.
• a compound or pharmaceutical composition of the invention can be administered to a subject in many of the well-known methods currently used for chemotherapeutic treatment.
• a compound of the invention may be injected directly into tumors, injected into the blood stream or body cavities or taken orally or applied through the skin with patches.
• systemic administration e.g., oral administration
• topical administration to affected areas of the skin are preferred routes of administration.
• the dose chosen should be sufficient to constitute effective treatment but not so high as to cause unacceptable side effects.
• the state of the disease condition e.g., cancer, psoriasis, and the like
• the health of the patient should be closely monitored during and for a reasonable period after treatment.
• the tert-butyl l-oxa-6-azaspiro[2.5]octane-6-carboxylate (21.2 g, 0.1 mol) was added to the reaction mixture and stirred at 0 0 C for 1 Ii and then at room temperature for 1.5 h.
• Saturated sodium bicarbonate solution 200 mL was added to the reaction, and the methanol was evaporated under reduced pressure.
• To the residue was added water (500 mL) and extracted with EtOAc (1 x 40OmL and 2 x 250 mL), the combined organic layer was washed with brine (250 mL) and dried over sodium sulfate. After concentration, the crude product (26.2 g) was obtained as an oil.
• Compound 5 was synthesized using tert-butyl l-oxa-6-azaspiro[2.6]nonane-6-carboxylate using conditions outlined in procedure C.
• Compound 10 was synthesized using 6-bromo-l-naphthol and conditions outlined in procedure D.
• Compound 11 was synthesized using 6-methoxy-l-naphthol and conditions outlined in procedure D.
• Compound 15 was synthesized using spiro[iiaphmo[l,2-b][l,4]oxamiine-2,4'- ⁇ i ⁇ eridine]-5,6- dione, /r ⁇ 72s-cyclohexane-l,2-dicarboxylic acid and conditions outlined for compound 14. M.p.
• M.p. >300 0 C; 400 MHz 1 HNMR (DMSO-d 6 ) ⁇ : 7.91-7.86 (m, IH), 7.67-7.62 (m, 2H), 3.07 (s, 2H), 2.86-2.77 (m, 4H), 1.93-1.89 (m, 2H), 1.71-1.64 (m, 2H); LCMS: 336 [M+H].
• Compound 25 was synthesized using tert-bntyl 4-[(5,6-dioxo-5,6-dihydro-l'i ⁇ - spirofnaphtliofl ⁇ - ⁇ fl ⁇ oxatlimie ⁇ '-piperidii ⁇ -r-y ⁇ carbonyljpiperidine-l-carboxylate, ethyl acetate as a solvent instead of dichlorometliane and conditions outlined in procedure H. M.p.
• Compoimd 27 was synthesized using tert-butyl 9-mo ⁇ holin-4-yl-5,6-dioxo-5,6-dihydro-l ⁇ - spiro[naphtlio[l,2-b][l,4]oxathiine-2,4'-piperidine]-r-carboxylate and conditions outlined in procedure H. M.p.
• Compound 28 was synthesized using tert-butyl 4-(5,6-dioxo-5,6-dihydro-l'H- spiro[naplitho[l,2-b][l,4]oxatliiine-2,4'-piperidin]-r-yl)piperidine-l-carboxylate, 3.0 M HCl gas as a solution in ethylacetae instead of dioxane, ethyl acetate as a solvent instead of dichloromethane and conditions outlined in procedure H. NLp.
• Compound 31 was synthesized using using tert-bntyl 5,6-dioxo-9-piperidin-l-yl-5,6-dihydro- rH-spuO[naphtho[l,2-b][l,4]oxathiine-2,4'-piperidine]-r-carboxylate and conditions outlined in procedure I. M.p.
• Compound 33 was synthesized using tert-butyl 5,6-dioxo-9-pyridin-4-yl-5,6-dihydro-rH- spiiO[napMio[l,2- ⁇ ][l,4]oxathiine-2,4'-piperidiiie]-r-carboxylate and conditions outlined in procedure J. M.p.
• Compound 34 was synthesized using tert-buty ⁇ 5,6-dioxo-9-pyridin-3-yl-5,6-dihydro-l'i?- spiro[naphtho[l,2- ⁇ ][l,4]oxatliiine-2,4'-piperidine]-r-carboxylate and conditions outlined in procedure J. M.p.
• Compound 36 was synthesized using tert-buty ⁇ 5,6-dioxo-9-[4-(trifluoromethyl)phenyl]-5,6- diliydro-ri7-spiro[napMio[l,2-o][l,4]oxatliiine-2,4'-piperidine]-r-carboxylate and conditions outlined in procedure J. M.p.
• Compound 37 was synthesized using tert-butyl 5,6-dioxo-9-[2-(trifluoromethyl)phenyl]-5,6- dihydro-l'H-spiro[na ⁇ htho[l,2-&][l ,4]oxathiine-2,4'-pipeiidine]-r-carboxylate and conditions outlined in procedure J. M.p.
• Compound 38 was synthesized using tert-butyl 5,6-dioxo-9-phenyl-5,6-dihydro-l ⁇ - spiiO[napMio[l,2- ⁇ ][l,4]oxathiine-2,4'-piperidine]-r-carboxylate and conditions outlined in procedure J. M.p.
• the combined aqueous layer was then extracted with dichloromethane (25 niL).
• the resulting aqueous layer after dichloromethane extraction contained and _jpzro[naphtha[l,2- ⁇ ][l,4]oxatliiine-2,4'-piperidine]-5,6-dione was stored for further workup.
• the combined dichloromethane extracts were washed with brine (50 mL), dried with sodium sulfate and concentrated under reduced pressure.
• aqueous layer containing jpzro[naphtha[l,2- ⁇ ][l,4]oxati. ⁇ iine-2,4'- piperidine]-5,6-dione was basified to pH 8 using sodium bicarbonate and extracted with dichloromethane (2 x 20 mL). The combined organic extracts were washed with bring (20 mL), dried with sodium sulfate and concentrated under reduced pressure. The presence of spzra[naphtha[l,2- £][l,4]oxathiine-2,4'-piperidme]-5,6-dione (0.034 g, 7%) was identified by LCMS: 302 [M+H].
• Compound 40 was synthesized using spiro[naphtho[l,2-b][l,4]oxathiine-2,4'-piperidine]-5,6- dione, 3,5-dimethylisoxazole-4-carbonyl chloride and conditions outlined in procedure N. M.p.
• Compound 41 was synthesized using spiro[naphtho[l,2-b][l,4]oxatliiine-2,4'-piperidine]-5,6- dione, 2,5-dimethyl-3-furoyl chloride and conditions outlined in procedure N. M.p.
• Compound 42 was synthesized using spiro[iraphtho[l,2-b][l,4]oxafliiine-2,4'-piperidine]-5,6- dione, l,3-dimethyl-li ⁇ -pyrazole-5-carbonyl chloride and conditions outlined in procedure N. M.p.
• Compound 43 was synthesized using spiro[naphmo[l,2-b][l,4]oxatliiine-2,4'-piperidine]-5,6- dione, 3-furoyl chloride and conditions outlined in procedure N. M.p.
• Compound 44 was synthesized using spiro[naphtho[l,2-b][l,4]oxathiine-2,4'-piperidine]-5,6- dione, 4-(lH-pyrazol-l-yl)benzoyl chloride and conditions outlined in procedure N. M. ⁇ .
• Compound 45 was synthesized using spiro[naphmo[l,2-b][l,4]oxathiine-2,4'-piperidine]-5,6- dione, 1,5 -dimethyl- lH-pyrazole-3-carbonyl chloride and conditions outlined in procedure N. M.p.
• Compound 48 was synthesized using spiro[naphtho[l,2-b][l,4]oxathiine-2,4'- ⁇ i ⁇ eridine]-5,6- dione, (phenylthio)acetyl chloride and conditions outlined in procedure N. M.p.
• Compound 51 was synthesized using spuO[naphmo[l,2-b][l,4]oxamiine-2,4'-piperidine]-5,6- dione, l-benzothiophene-2-carbonyl chloride and conditions outlined in procedure N. M.p.
• Compound 52 was synthesized using spiro[iiaphtho[l,2-b][l,4]oxamiine-2,4'-piperidine]-5,6- dione, methyl oxalyl chloride and conditions outlined in procedure N. M.p.
• Compound 53 was synthesized using spiiO[naphtho[l,2-b][l,4]oxathiine-2,4'-piperidine]-5,6- dione, 3,4-dichlorobenzoyl chloride and conditions outlined in procedure N. M.p.
• Compound 58 was synthesized using spiro[naphtho[l,2-b][l,4]oxamiine-2,4'-piperidine]-5,6- dione, 5-metliyl-2-phenyl-2H-l,2,3-triazole-4-carbonyl chloride and conditions outlined in procedure N. M.p.
• Compound 60 was synthesized using spiro[naphmo[l,2-b][l,4]oxathiine-2,4'-pi ⁇ eridine]-5,6- dione, 3-methylbenzoyl chloride and conditions outlined in procedure N. M.p.
• Compound 62 was synthesized using spiro[azepane-4,2'-naphllio[l,2-b][l,4]oxatliiine]-5 l ,6'- dione, 3-chlorobenzoyl chloride and conditions outlined in procedure N. M.p.
• Compound 63 was synthesized using 8-me1hoxyspiro[naphtho[l,2-b][l,4]oxafliiine-2,4'- piperidine]-5,6-dione, 3-chlorobenzoyl chloride and conditions outlined in procedure N. M.p.
• Compound 64 was synthesized using 9-phenylspiiO[naphmo[l,2- ⁇ ][l,4]oxathii ⁇ ie-2,4'- piperidine]-5,6-dione, 3-chlorobenzoyl chloride and conditions outlined in procedure N.
• Compound 65 was synthesized using 9- ⁇ yridin-3-ylspiro[naphtho[l,2- ⁇ ][l,4]oxatliiine-2,4'- piperidine]-5,6-dione, 3-chlorobenzoyl chloride and conditions outlined in procedure N.
• Compound 68 was synthesized using 9-bromospiro[naphtiio[l,2-b][l,4]oxatiiiine-2,4'- piperidine]-5,6-dione, 3-chlorobenzoyl chloride and conditions outlined in procedure N. M.p.
• Compound 69 was synthesized using 9-memoxyspiro[naphtho[l,2- ⁇ ][l,4]oxamiine-2,4'- piperidine]-5,6-dione, 3-chlorobenzoyl chloride and conditions outlined in procedure N.
• Compound 70 was synthesized using 4-aminospiro[cyclohexane-l,2'-naphtlio[l,2- &][l,4]oxathiine]-5',6'-dione hydrochloride, 3-(trifluoiOmethyl)benzoyl chloride, triethylamine to neutralize the hydrochloride and conditions outlined in procedure N. M.p.
• Compound 72 was synthesized using spiro[naphtho[l,2-b][l,4]oxa ⁇ iime-2,4'- ⁇ iperidine]-5,6- dione, [l-(te?t-butoxycai-bonyl)piperidin-4-yl]acetic acid and conditions outlined in procedure O. M.p.
• Compound 73 was synthesized using spiro[naphtho[l,2-b][l,4]oxathiine-2,4'-piperidine]-5,6- dione, 5,6-dihydro-4H-pyi ⁇ olo[3,2,l-ij]quinoline-l-carboxylic acid conditions outlined in procedure O. M.p.
• Compound 74 was synthesized using spiro[naphtho[l,2-b][l,4]oxatliiine-2,4'- ⁇ iperidine]-5,6- dione, lH-beiizimidazole-2-carboxylic acid and conditions outlined in procedure O. M.p.
• Compound 76 was synthesized using spko[naphmo[l,2- ⁇ ][l,4]oxathiine-2,4'-piperidine]-5,6- dione, 3,4-dichlorobenzenesulfonyl chloride and conditions outlined in procedure P. M.p.
• Compound 77 was synthesized using spuO[naphdio[l,2- ⁇ ][l,4]oxatiiime-2,4'- ⁇ iperidine]-5,6- dione, 6-chloroimidazo[2,l- ⁇ ][l,3]thiazole-5-sulfonyl chloride and conditions outlined in procedure P. M.p.
• Compound 78 was synthesized using spiro[naphtlio[l,2- ⁇ ][l,4]oxathiine-2,4'-piperidine]-5,6- dione, thiophene-2-sulfonyl chloride and conditions outlined in procedure P. M.p.
• Compound 80 was synthesized using spiro[naphmo[l,2- ⁇ ][l,4]oxauiime-2,4'- ⁇ iperidine]-5,6- dione, l,3,5-trimemyl-lH-pyrazole-4-sulfonyl chloride and conditions outlined in procedure P. M.p.
• Compound 81 was synthesized using spiro[napMio[l,2- ⁇ ][l,4]oxathiine-2,4'-piperidine]-5,6- dione, 5 -chloro- 1,3 -dimethyl- lH-pyrazole-4-sulfonyl chloride and conditions outlined in procedure P. M.p.
• Compound 82 was synthesized using spiro[naphmo[l,2-Z>][l,4]oxamime-2,4'-piperidine]-5,6- dione, 3-chlorobenzenesulfonyl chloride and conditions outlined in procedure P. M.p.
• Compound 83 was synthesized using spiro[naphilia[l,2- ⁇ ][l,4]oxathiine-2,4'-piperidine]-5,6- dione, dimethylsulfamoyl chloride and conditions outlined in procedure P. M.p.
• Compound 85 was synthesized using spiro[napMio[l,2- ⁇ ][l,4]oxathiine-2,4'-piperidine]-5,6- dione, l-fluoro-4-isocyanatobenzene and conditions outlined in procedure Q. M.p.
• Compound 86 was synthesized using spiro[naphtho[l,2- ⁇ ][l,4]oxatliiine-2,4'-piperidine]-5,6- dione, l-isocyanato-3-(trifluorome1iiyl)benzene and conditions outlined in procedure Q. M.p.
• Compound 87 was synthesized using spiro[naphtho[l,2- ⁇ ][l,4]oxatliiine-2,4'-piperidine]-5,6- dione, l,2-dichloro-4-isocyanatobenzene and conditions outlined in procedure Q. M.p.
• Compound 88 was synthesized using s ⁇ iro[naphtho[l,2- ⁇ ][l,4]oxafliiine-2,4'-piperidine]-5,6- dione, 4-isocyanato-N,N-dimethylaniline and conditions outlined in procedure Q. M.p.
• Compound 91 was synthesized using 6-methylnicotinic acid to synthesize 5-isocyanato-2- methylpyridine [Step (i)] followed by [step (ii)] using spiro[iraphmo[l,2- ⁇ ][l,4]oxathiine-2,4'- piperidine]-5,6-dione as outlined in procedure R. M.p.
• Compound 93 was synthesized using spiro[naph1ho[l,2-b][l,4]oxamiine-2,4'-piperidine]-5,6- dione, isobutyl chloridocarbonate, EtOAc as Hie solvent and conditions outlined in procedure S. M.p.
• Compound 94 was synthesized using spiro[naphmo[l,2-b][l,4]oxathiine-2,4'-piperidine]-5,6- dione, vinyl chloridocarbonate, EtOAc as the solvent and conditions outlined in procedure S. M.p.
• Compound 95 was synthesized using spira[naphmo[l,2-b][l,4]oxaiMne-2,4'-piperidine]-5,6- dione, 2-ethylhexyl chloridocarbonate, EtOAc as the solvent and conditions outlined in procedure S. M.p.
• Compound 96 was synthesized using spiro[naphtho[l,2-b][l,4]oxamiine-2,4'-piperidine]-5,6- dione, 3-(trifluoromethyl)phenyl chloridocarbonate, EtOAc as the solvent and conditions outlined in procedure S. M.p.
• Compound 97 was synthesized using spiro[naphtho[l,2-b][l,4]oxathiine-2,4'-piperidine]-5,6- dione, 4-fluorophenyl chloridocarboiiate, EtOAc as the solvent and conditions outlined in procedure S. M.p.
• Compound 100 was synthesized using 9-fluorospiro[naphmo[l,2- ⁇ ][l,4]oxatiiiine-2,4'- piperidine]-5,6-dione, 3 ⁇ (trifiuoromethyl)phenyl chloridocarbonate, EtOAc as the solvent and conditions outlined in procedure S. M.p.
• Compound 101 was synthesized using 9-chlorospiiO[naphmo[l,2- ⁇ ][l,4]oxathiine-2,4 ! - piperidine]-5,6-dione, 3-(trifluorometliyl)phenyl chloridocarbonate, triethylamine instead of aqueous sodium bicarbonate, dichloromethane as a solvent and conditions outlined in procedure S. M.p.
• Compound 102 was synthesized using spiiO[azepane-4,2'-napl ⁇ tho[l,2-b][l,4]oxathiine]-5',6'- dione, 3-(trifluoromethyl)phenyl chloridocarbonate, trietliylamine instead of aqueous sodium bicarbonate, dichloromethane as a solvent and conditions outlined in procedure S. M.p.
• Compound 103 was synthesized using spiro[napMio[l,2-b][l,4]oxathiine-2,3'- ⁇ i ⁇ eridine]- 5,6-dione, 3-(trifluoromethyl) ⁇ henyl chloridocarbonate, triethylamine instead of aqueous sodium bicarbonate, dichloromethane as a solvent and conditions outlined in procedure S. M.p.
• Compound 104 was synthesized using 8-methoxyspiro[naphmo[l,2-b][l,4]oxathiine-2,4'- piperidine]-5,6-dione, 3-(trifluoromethyl) phenyl chloroformate, triethylainine instead of aqueous sodium bicarbonate, dichloromethane as a solvent and conditions outlined in procedure S. M.p.
• Compound 105 was synthesized using 9-phenylspiro[napMio[l,2-Z?][l,4]oxamiine-2,4'- pi ⁇ eridine]-5,6-dione, 3-(trifluorometliyl) phenyl chloroformate, triethylamine instead of aqueous sodium bicarbonate, dichloromethane as a solvent and conditions outlined in procedure S. M.p.
• Compound 106 was synthesized using 9-methoxyspko[naphmo[l,2-b][l,4]oxafliiine-2,4'- piperidine]-5,6-dione, 3-(frifluoromethyl) phenyl chloroformate, triethylamine instead of aqueous sodium bicarbonate, dichloromethane as a solvent and conditions outlined in procedure S. M.p.
• Compound 107 was synthesized using r-piperidui-4-yls ⁇ iro[iraphtho[l,2-b][l,4]oxathiine- 2,4'-piperidine]-5,6-dione bis hydrochloride, triethylarnine instead of aqueous sodium bicarbonate, dichloromethane as a solvent and conditions outlined in procedure S. M.p.
• Compound 108 was synthesized using 4-aminospiro[cyclohexane-l,2'-naphtho[l,2- ⁇ ][l,4]oxafhiine]-5',6'-dione hydrochloride, 3-(trifiuoromethyl) phenyl chloroformate, triethyl amine to neutralize the hydrochloride and conditions outlined in procedure S. M.p.
• EtOAc 40 inL
• Compound 117 was synthesized using spiro[napli1iio[l,2-&][l,4]oxathiine-2,4 t - ⁇ i ⁇ eridine]- 5,6-dione, 2-(bromomemyl)te1xahydrofuran and conditions outlined in procedure V.
• Compound 118 was synthesized using spiro[naphtho[l,2- ⁇ ][l,4]oxatliiine-2,4'-piperidine]- 5,6-dione, l-(bromometIiyl)-2-fluoiObenzene and conditions outlined in procedure V.
• Compound 119 was synthesized using spiiO[napMio[l,2- ⁇ ][l,4]oxathiiiie-2,4'-piperidine]- 5,6-dione, 2-(bromomethyl)tetrahydra-2i7-pyran and conditions outlined in procedure V.
• Compound 120 was synthesized using sp ⁇ O[naphtho[l,2- ⁇ ][l,4]oxatliiine-2,4'-piperidine]- 5,6-dione, l-(bromomethyl)-4-methylbenzene and conditions outlined in procedure V.
• Compound 121 was synthesized using spiro[naphtho[l,2-Z)][l,4]oxatliiine-2,4 l -piperidine]- 5,6-dione, l-(bromomethyl)-3-methoxybenzene and conditions outlined in procedure V.
• Compound 123 was synthesized using spiro[naphtho[l,2- ⁇ ][l,4]oxamime-2,4'-piperidine]- 5,6-dione, 4-(bromomethyl)benzonitrile and conditions outlined in procedure V.
• Compound 124 was synthesized using spiro[na ⁇ hmo[l,2- ⁇ ][l,4]oxathiine-2,4'-piperidine]-
• Compound 125 was synthesized using spiro[naphtho[l,2-&][l,4]oxathiine ⁇ 2,4'-piperidine]- 5,6-dione, l-(biOmomethyl)-4-fluorobenzene and conditions outlined in procedure V.
• Compound 127 was synthesized using spiro[naphtho[l,2- ⁇ ][l,4]oxathiine-2,4'-piperidine]- 5,6-dione, 2-bromopentane and conditions outlined in procedure V.
• Compound 128 was synthesized using spiro[napMio[l,2- ⁇ ][l,4]oxathime-2,4'-piperidine]- 5,6-dione, 1-bromodecane and conditions outlined in procedure V.
• Compound 129 was synthesized using spiro[naphtho[l,2- ⁇ ][l,4]oxathiine-2,4'-piperidine]- 5,6-dione, 2-(bromomeuiyl)-l-chloro-3-fluorobenzene and conditions outlined in procedure V.
• Compound 130 was synthesized using spiro[naphmo[l,2- ⁇ ][l,4]oxathiine-2,4'- ⁇ iperidme]- 5,6-dione, (bromomethyl)benzene and conditions outlined in procedure V.
• Compound 132 was synthesized using spiro[naphtho[l,2- ⁇ ][l,4]oxathiine-2,4'-pi ⁇ eridine]- 5,6-dione, 3-(bromomethyl)pentane and conditions outlined in procedure V.
• Compound 133 was synthesized using spiro[napMio[l,2- ⁇ ][l,4]oxathiiiie-2,4'-piperidine]- 5,6-dione, l-(bromomethyl)-3-methylbenzene and conditions outlined in procedure V.
• LCMS: 406 [M+H]; R t l.02 mm.
• Compound 135 was synthesized using spiro[naphmo[l,2-Z>][l,4]oxathiine-2,4'-piperidine]- 5,6-dione, 3-bromocyclohexene and conditions outlined in procedure V.
• LCMS: 382 [M+H]; R t 0.94 min.
• Compound 136 was synthesized using spiro[naphtho[l,2- ⁇ ][l,4]oxatliiine-2,4'- ⁇ i ⁇ eridine]- 5,6-dione, (bromomethyl)cyclohexane and conditions outlined in procedure V.
• LCMS: 398 [M+H]; R t l.03 min.
• Compound 137 was synthesized using spiro[naphtho[l,2- ⁇ ][l,4]oxamiine-2,4'-piperidine]- 5,6-dione, (l-biOmoethyl)benzene and conditions outlined in procedure V.
• LCMS: 406 [M+H]; R t 0.96 min.
• Compound 138 was synthesized using spiro[naphmo[l,2-&][l,4]oxatliiine-2,4'-piperidme]- 5,6-dione, bromocyclopentane and conditions outlined in procedure V.
• LCMS: 370 [M+H]; R t 0.90 min.
• Compound 140 was synthesized using spiro[naphmo[l,2- ⁇ ][l,4]oxamiine-2,4'-piperidine]- 5,6-dione, (2-biOmoethoxy)benzene and conditions outlined in procedure V.
• LCMS: 422 [M+H]; R 1 LOl miii.
• Compound 141 was synthesized using spiro[iia ⁇ hmo[l,2-&][l,4]oxatliiine-2,4'-piperidine]- 5,6-dione, 4-bromo-l,l,l-trifluorobutane and conditions outlined in procedure V.
• LCMS: 412 [M+H]; R t 0.96 min.
• Compound 145 was synthesized using spiro[naphmo[l,2-Z?][l,4]oxautiine-2,4'-piperidine]- 5,6-dione, l-(2-bromoetlioxy)-4-chloiObenzene and conditions outlined in procedure V.
• LCMS: 456 [M+H]; R t 1.07 min.
• Compound 147 was synthesized using 9-methoxyspiro[napMio[l,2-b][l,4]oxatliiine-2,4'- piperidine]-5,6-dione,l-(bromomemyl)-4-fluorobenzene and conditions outlined in procedure V. M.p.
• Compound 148 was synthesized using 9-phenyls ⁇ iro[iraphtho[l,2-b][l,4]oxamiine-2,4'- piperidine]-5,6-dione and l-(bromomethyl)-4-fluorobenzene and conditions outlined in procedure V. Mp.
• Compound 149 was synthesized using spiro[naphtho[l,2-b][l,4]oxafliime-2,4'-piperidine]- 5,6-dione and (4-bromobutyl)benzene and conditions outlined in procedure V. M.p.
• Compound 150 was synthesized using spiiO[naphtho[l,2-b][l,4]oxathiine-2,4'-piperidine]- 5,6-dione and l-chloro-4-(3-iodopropoxy)benzene and conditions outlined in procedure V. M.p.
• Compound 151 was synthesized using spiro[naphtho[l,2-b][l,4]oxatliime-2,4'-piperidine]- 5,6-dione and l-fluoro-4-(3-iodo ⁇ ropoxy)benzene and conditions outlined in procedure V. M.p.
• Compound 152 was synthesized using spiro[napMio[l,2-&][l,4]oxathiine-2,4'- ⁇ iperidine]- 5,6-dione, 2-bromopropane and conditions outlined in procedure V.
• the crude product was purified by flash column chromatorgraphy (SiO 2 , 8% CH 3 OH in diehloromethane).
• the product obtained after the chromatography was futher purified by crystallization from hexanes and dichloromethane to give the desired product as a purple solid (0.405 g, 51%). Mp.
• Compound 144 was synthesized using sptfo[naphuio[l,2- ⁇ ][l,4]oxathiine-2,4'-piperidine]- 5,6-dione, bromo-3-phenoxypropaiie and conditions outlined in procedure W. M.p.
• Compound 154 was synthesized using 8-methoxyspiro[naphtho[l,2- ⁇ ][l,4]oxathiine-2,4'- piperidine]-5,6-dione, l-(bromomethyl)-4-fluorobenzene ad conditions outlined in procedure W. Mp.
• Compound 155 was synthesized using spko[naphma[l,2-Z)][l,4]oxathiine-2,4'-piperidine]- 5,6-dione, (2-bromoetliyl)-benzene and conditions outlined in procedure W. M.p.
• Compound 156 was synthesized using 9-bromospiro[naphtlio[l,2-b][l,4]oxatliiine-2,4'- piperidine]-5,6-dione, l-(bromomethyl)-4-fluorobenzeiie and conditions outlined in general procedure W. M.p.
• Compound 145 was synthesized using spiro[napMra[l,2- ⁇ ][l,4]oxathiine-2,4'-piperidine]- 5,6-dione, l-(2-bromoethoxy)-4-chlorobenzene and conditions outlined in general procedure W. M.p.
• Compound 158 was synthesized using spiro[naphtho[l,2 -Z>][l,4]oxathime-2,4'-piperidine]- 5,6-dione, 2-(phenoxymethyl)oxirane and conditions outlined in procedure X.
• Compound 159 was synthesized using spiro[naphtho[l,2- ⁇ ][l,4]oxatliiine-2,4'-piperidine]- 5,6-dione, 2-metliyl-2-vinyloxirane and conditions outlined in procedure X.
• Compound 160 was synthesized using spiro[naphmo[l,2- ⁇ ][l,4]oxatiiiine-2,4'-piperidine]- 5,6-dione, 2-(2,2,2-trifluoroethyl)oxirane and conditions outlined in procedure X.
• Compound 161 was synmesized using spko[naphmo[l,2-£][l,4]oxamiine-2,4'-piperidine]- 5,6-dione, 6-oxabicyclo[3.1.0]hexane and conditions outlined in procedure X.
• Compound 162 was synthesized using spko[naphmo[l,2- ⁇ ][l,4]oxathiine-2,4'-piperidine]- 5,6-dione, 2-butyloxirane and conditions outlined in procedure X.
• Compound 163 was synthesized using spiro[naphtlio[l,2- ⁇ ][l,4]oxathiine-2,4'-pi ⁇ eridine]- 5,6-dione, 2-benzyloxirane and conditions outlined in procedure X.
• Compound 164 was synthesized using spko[naphtiio[l,2-Z>][l,4]oxamiine-2,4'-piperidine]- 5,6-dione, 2-[(4-fluorophenoxy)methyl]oxirane and conditions outlined in procedure X.
• Compound 166 was synthesized using spiro[iraphtho[l,2-Z>][l,4]oxathiine-2,4'-piperidine]- 5,6-dione, 4-(oxiran-2-ylmethyl)morpholine and conditions outlined in procedure X.
• Compound 168 was synthesized using spiro[napMio[l,2- ⁇ ][l,4]oxathiine-2,4'-piperidine]- 5,6-dione, 2-ethyloxirane and conditions outlined in procedure X.
• Compound 170 was synthesized using spiro[napMio[l,2- ⁇ ][l,4]oxathiine-2,4'-piperidine]- 5,6-dione, 2-[(4-ethylphenoxy)methyl]oxirane and conditions outlined in procedure X.
• LCMS: 480 [M+H]; R t l.09 min.
• Compound 172 was synthesized using spiro[naphtho[l,2-&][l,4]oxamiine-2,4'-piperidine]- 5,6-dione, 2-[(2-chlorophenoxy)metliyl]oxirane and conditions outlined in procedure X.
• LCMS: 486 [M+H]; R t 1.04 min.

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• 2006
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