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    公开号:AU2006228035A1
    申请号:U2006228035
    申请日:2006-10-11
    公开日:2006-11-02
    发明作者:Shoujun Chen；Zhenjian Du；Timothy Korbut；Keizo Koya；Guiqing Liang；Mitsunori Ono；Lijun Sun；Noriaki Tatsuta；Yaming Wu；Dan Zhou
    申请人:Synta Phamaceuticals Corp；
    IPC主号:A61K31-165
    专利说明:
    P100/0oI Rcgulation 3.2
    AUSTRALIA
    Patents Act 1990 COMPLETE SPECIFICATION STANDARD PATENT
    (ORIGINAL)
    Name of Applicant: Synta Pharmaceuticals Corp., of 45 Hartwell Avenue, Lexington, Massachusetts 02421, United States of America Actual Inventors: KOYA, Keizo KORBUT, Timothy ONO, Mitsunori TATSUTA, Noriaki WU, Yaming ZHOU, Dan DU, Zhenjian LIANG, Guiqing SUN, Lijun CHEN, Shoujun Address for Service: DAVIES COLLISON CAVE, Patent Trademark Attorneys, of 1 Nicholson Street, Melbourne, 3000, Victoria, Australia Ph: 03 9254 2777 Fax: 03 9254 2770 Attorney Code: DM "Bis (thio-hydrazide amide) compounds for treating multidrug resistant cancer" Invention Title: The following statement is a full description of this invention, including the best method of performing it known to us:- -1- 0 BIS(THIO-HYDRAZIDE AMIDE) COMPOUNDS FOR TREATING MULTI-DRUG RESISTANT CANCER This application is a divisional of Australian Patent Application No. 2004206865, the entire Cc contents of which are incorporated herein by reference.
    00
    O
    IND BACKGROUND OF THE INVENTION Many drugs are now available to be used in the treatment of cancer. However, in many cases the cancer either fails to respond to the anti-cancer therapy or its growth and spread is only slowed. Thus, there is still a need for new anti-cancer agents.
    Even when a tumor initially responds to an anti-cancer therapy by decreasing in size or even going into remission, the tumor often develops resistance to the drug.
    Drug resistant tumors are characterized by a resumption of their growth and/or reappearance after having seemingly gone into remission, despite the administration of increased dosages of the anti-cancer drug.
    For this reason, oncologists often administer combinations of anti-cancer drugs to a patient. Cancerous tumors are less likely to develop resistance when confronted with a multitude of different drugs, each having a different mode of action. Unfortunately, however, many tumors develop resistance, even when treated simultaneously with a number of different anti-cancer drugs. Cancers which reach this stage are referred to as "multi-drug resistant cancers", or simply "MDR cancers".
    There is little that can be done to halt or retard further progression of the disease, once a patient's cancer has become multi-drug resistant. Thus, there is an urgent need for new drugs which can be used to treat multi-drug resistant cancers.
    IN -2- SUMMARY OF THE INVENTION O It has now been found that certain bis[thio-hydrazide amide] compounds are Ssignificantly cytotoxic to cancer cells, including cancer cells that have become multidrug resistant. For example, Compound had an IC 50 of 0.005, 0.05 and 0.01 pM It 5 against the multi-drug resistant cell lines MES-SA/DX5, HL-60/TX1000 and O Bowes/OV2, respectively (see Example 15). The IC 50 for the anticancer drugs taxol 00 oO and vincristine was two to three orders of magnitude larger for the same cell lines IO (see Example 15). The structure of Compound is shown below: 0 0 H H S
    S
    Compound (1) In addition, the IC 50 for bis[thio-hydrazide amide] Compounds ranged from 0.05 to 0.005 [iM against MES-SA/DX5 (see Example 16). The structures of Compounds are provided in Figure 1. Moreover, the size of multi-drug resistant MES-SA/DX5 tumors in nude mice treated with bis[thio-hydrazide amide] Compound (16) was significantly reduced compared with tumors in mice treated only with vehicle (see Example 17). The structure of Compound (16) is shown below: 0 0 SN N H H S
    S
    Compound (16) It has also been found that the disclosed compounds enhance the anti-cancer activity of other anti-cancer agents, such as Epothilone D (Example 18). Based on these IN -3results, methods of treating a subject with a cancer, including cancers that have O become multi-drug resistant are disclosed herein.
    One embodiment of the present invention is a method of treating a subject with a multi-drug resistant cancer. The method comprises administering to the subject an effective amount of a compound represented by Structural Formula R3 z z R4 00 I S R 5
    R
    6
    S
    Y is a covalent bond or a substituted or unsubstituted straight chained hydrocarbyl group, or, Y, taken together with both >C=Z groups to which it is bonded, is a substituted or unsubstituted aromatic group. Preferably, Y is a covalent bond or -C(R 7 Rs)-.
    R,-R
    4 are independently an aliphatic group, a substituted aliphatic group, an aryl group or a substituted aryl group, or R 1 and R 3 taken together with the carbon and nitrogen atoms to which they are bonded, and/or R 2 and R4 taken together with the carbon and nitrogen atoms to which they are bonded, form a non-aromatic heterocyclic ring optionally fused to an aromatic ring. Preferably R, and R 2 are the same and R 3 and R 4 are the same.
    Rs-R 6 are independently an aliphatic group, a substituted aliphatic group, an aryl group or a substituted aryl group. Preferably, R, and R 6 are the same.
    R
    7 and R, are each independently an aliphatic or substituted aliphatic group, or R7 is -H and R 8 is a substituted or unsubstituted aryl group, or, R7 and Rs, taken together, are a C2-C6 substituted or unsubstituted alkylene group.
    Z is =O or =S.
    Another embodiment of the present invention is a method of treating a subject with cancer. The method comprising administering to the subject an effective amount -4of a compound represented by Structural Formula The compound represented by Structural Formula is administered as a monotherapy as the only anti-cancer drug administered to the subject). Optionally a second anti-cancer agent is coadministered to the subject, provided that the second anti-cancer agent is other than taxol or an analog oftaxol. When the subject is a mouse, then the compound is other than: S S Therefore, the method is commonly used with subjects other than mice. Preferably, the subject is a human subject.
    The disclosed method can often be used to treat cancers, including cancers that have become multi-drug resistant. Thus, the disclosed methods can often be used to treat cancers where other drug regimens have either failed or become ineffective.
    Because the compounds used in the method are relatively non-toxic, they cause minimal side effects and can used at relatively high doses.
    SBRIEF DESCRIPTION OF THE FIGURES O Figures 1A-1D are a list of structures of Compounds that are exemplified with the disclosed method.
    Figure 2 is a graph showing the average tumor size in nude mice (CD-1 It 5 nu/nu) over time after having been treated with vehicle or Compound (16) 0 The tumor volume is in mm 3 and the time is in days after having begun treatment.
    00 N The tumors are from the multi-drug resistant human uterine sarcoma SFigure 3 is a graph showing the average tumor volume in milliliters over time (in days) in nude mice (CD-1 nu/nu) treated with vehicle Epothilone D mg/kg) and Compound (50 mg/kg) and Epothilone(5 mg/kg) The tumors were generated from the human breast tumor cell line MDA-435.
    Figure 4 is a graph showing the average percent weight change in nude mice (CD-1 nu/nu) over time after having been treated with vehicle Epothilone D mg/kg) and Compound (50 mg/kg) and Epothilone(5 mg/kg) The mice were being treated for tumors generated tumors generated from the human breast tumor cell line MDA-435.
    DETAILED DESCRIPTION OF THE INVENTION In a first preferred embodiment, Y in Structural Formula taken together with both >C=Z groups to which it is bonded, is a substituted or unsubstituted arylene group and the compound is represented by Structural Formula (II): Rs R Ri N N Ar 6 R 2 S R s R6 S D -6-
    O
    O
    SR,-R 6 in Structural Formula (II) are as described in Structural Formula Ar O is a substituted or unsubstituted arylene group. Preferably, Ar is a nitrogen-containing Sheteroarylene group. Examples are shown below:
    IN
    O
    1 5 Ring A is substituted or unsubstituted.
    In a second preferred embodiment, Y in Structural Formula is a covalent bond, a substituted or unsubstituted straight chained hydrocarbyl group or a phenylene group. Preferably, Y is a covalent bond, -(CH 2
    CH
    2 trans-(CH=CH)-, cis-(CH=CH)-, or a 1,4-phenylene group. R 7 and R 8 are as described for Structural Formula Even more preferably, Y is a covalent bond or
    -C(R
    7 In a more preferred embodiment, Y in Structural Formula is a covalent bond or -C(R 7 and the compound used in the method of the present invention is represented by Structural Formula (EI): R3 0 R4 I
    I
    RI R2 S Ra
    R
    6
    S
    (III).
    R,-R
    6 are as described for Structural Formula Y' is a covalent bond or -C(R 7 and R7 and R 8 can be the same or different and are: i) each independently an aliphatic or substituted aliphatic group (preferably alkyl, more preferably methyl); ii)
    R
    7 is -H and R, is a substituted or unsubstituted aliphatic group (preferably alkyl, more preferably methyl) or a substituted or unsubstituted aryl group (preferably 0
    IND-
    C,1 thienyl, substituted thienyl, phenyl substituted phenyl, benzyl or substituted benzyl); or iii) R 7 and Rs, taken together, are a C2-C6 substituted or unsubstituted alkylene group (preferably propylene or butylene).
    In an even more preferred embodiment, the compound used in the method of t 5 the present invention is represented by Structural Formula (IV):
    R
    3 0 R4 00
    I
    R N R 2 H H S S
    (IV).
    In the compound represented by Structural Formula Y' is a covalent bond or -C(R 7 and R,-R 4 and R 7 are as described for Structural Formula In a first example of a compound represented by Structural Formula R, and R, are each a substituted or unsubstituted aryl group; R 3 and R4 are each a substituted or unsubstituted aliphatic group; R, is and R, is an aliphatic or substituted aliphatic group. Preferably in the compound represented by Structural Formula R I and R, are each a substituted or unsubstituted aryl group; R 3 and R 4 are each an alkyl group; and R 7 is -H and R, is -H or methyl. Even more preferably, in the compound represented by Structural Formula R, and R, are each a substituted or unsubstituted phenyl group; R 3 and R 4 are each methyl or ethyl; and R7 is -H and R, is -H or methyl. Suitable substituents for an aryl group represented by R, and R 2 and an aliphatic group represented by R 3
    R
    4 and R, are as described below for aryl and aliphatic groups.
    In a second example of a compound represented by Structural Formula (IV), R, and R, are both phenyl or substituted phenyl, R, and R 4 are both methyl, ethyl, phenyl, or thienyl, and R 7 and R, are as described in the first example of a compound represented by Structural Formula When R, and R 2 are both phenyl or substituted phenyl and R 3 and R 4 are both methyl, ethyl, phenyl, or thienyl, then preferably R 7 and taken together, are propylene or butylene.
    IN -8- SIn a third example of a compound represented by Structural Formula R, O and R 2 are both an aliphatic group or a substituted aliphatic group (preferably substituted or unsubstituted alkyl group, including a substituted or unsubstituted cycloalkyl group such as a substituted or unsubstituted cyclopropyl group); R 3 and R 4 t 5 are both an aryl group or a substituted aryl group, and R 7 and R, are as described the Sfirst example of a compound represented by Structural Formula (IV).
    oO In another example of a compound represented by Structural Formula R, D and R, are both substituted or unsubstituted aliphatic groups, R 3 and R 4 are both a lower alkyl group or a substituted lower alkyl group, and R 7 and R, are as described in the first example of a compound represented by Structural Formula (IV); preferably, R, and R 2 are both substituted or unsubstituted alkyl groups (more preferably substituted or unsubstituted cycloalkyl groups), R 3 and R 4 are both -H, methyl or ethyl, R 7 is -H and R 8 is -H or methyl.
    In yet another example of a compound represented by Structural Formula R, and R 2 are both C3-C8 cycloalkyl or substituted C3-C8 cycloalkyl and R 3 and R 4 are both methyl, ethyl, phenyl, or thienyl, and R 7 and R, are as described the first example of a compound represented by Structural Formula (IV) (preferably, R 7 and R, are: 1) both methyl; 2) taken together, are propylene or butylene; or 3) R 7 is -H and R, is lower alkyl, thienyl, phenyl or benzyl).
    In yet another example of a compound represented by Structural Formula R, and R2 are both a lower alkyl group or a substituted lower alkyl group, R 3 and R 4 are both methyl, ethyl or phenyl, and R7 and Rg are as described the first example of a compound represented by Structural Formula (IV).
    The following are specific examples of compounds represented by Structural Formula R, and R, are both phenyl; R 3 and R4 are both methyl; R7 is and R 8 is ethyl; R, and R 2 are both phenyl; R3 and R4 are both phenyl, and R 7 and R, are both methyl; R, and R2 are both 2-thienyl; R3 and R 4 are both phenyl, and R 7 and Rg are both methyl; R, and R2 are both 4-cyanophenyl; R3 and R4 are both methyl; R 7 is -H, and R, is methyl; R, and R 2 are both phenyl; R 3 and R 4 are both methyl; R7 is and R, is methyl; R, and R 2 are both phenyl; R3 and R4 are both methyl; R 7 is and Rg is benzyl; R, and R2 are both phenyl; R3 and R4 are both methyl; R 7 is and R 8 is I-N O -yethyl; R, and R, are both phenyl; R 3 and R 4 are both ethyl; R 7 is and R, is n-butyl; O R, and R, are both 2,5-dimethoxyphenyl; R3 and R4 are both methyl; R7 is and R, is methyl; R, and R 2 are both phenyl; R 3 and R 4 are both methyl; R7 is and R is iso-propyl; R and R 2 are both 3-nitrophenyl; R and R are both methyl; R is and iso-propyl; R, and R 2 are both 3-nitrophenyl; R 3 and R 4 are both methyl; R7 is and tI 5 R, is methyl; R, and R 2 are both 4-chlorophenyl; R 3 and R 4 are both methyl; R, is -H, 0 and R, is methyl; R, and R2 are both phenyl; R 3 and R4 are both methyl; R7 is and 00 C Rs is 3-thienyl; R, and R, are both phenyl; R 3 and R4 are both methyl, and R7 and R, D0 taken together, are propylene; R, and R 2 are both 2,3-dimethoxyphenyl; R3 and R 4 are Sboth methyl; R7 is and R, is methyl; R, and R 2 are both phenyl; R3 and R4 are both methyl; R7 is and R, is methyl; R, and R2 are both difluorophenyl; R3 and R4 are both methyl; R 7 is and R, is methyl; R, and R, are both 2,5-dichlorophenyl; R3 and R4 are both methyl; R7 is and R, is methyl; R, and R, are both 2,6-dimethoxyphenyl; R3 and R4 are both methyl; R, is and R, is methyl; R, and R2 are both 2,5-dimethylphenyl; R 3 and R4 are both methyl; R 7 is -H, and R, is methyl; R, and R2 are both 2,5-dimethoxyphenyl; R3 and R4 are both ethyl;
    R
    7 is and R, is methyl, and R, and R, are both 2,5-diethoxyphenyl; R3 and R4 are both methyl; R7 is and R, is methyl; R, and R, are both cyclopropyl; R3 and R4 are both methyl; R7 and R, are both R, and R 2 are both cyclopropyl; R 3 and R4 are both ethyl; R, and R, are both R, and R2 are both cyclopropyl; R 3 and R4 are both methyl; R7 is methyl; Rg is R, and R2 are both 1-methylcyclopropyl; R3 and R4 are both methyl; Y' is bond; R, and R, are both 1-methylcyclopropyl; R3 and R4 are both methyl; R7 and R, are both R, and R2 are both 1-methylcyclopropyl; R3 and R 4 are both methyl; R7 is methyl and R, is R, and R, are both 1-methylcyclopropyl;
    R
    3 and R4 are both methyl; R7 is ethyl and R 8 is R, and R 2 are both 1methylcyclopropyl; R3 and R 4 are both methyl; R 7 is n-propyl and R 8 is R, and R2 are both 1--methylcyclopropyl; R3 and R4 are both methyl; R7 and R 8 are both methyl; R, and R2 are both 1 -methylcyclopropyl; R3 and R4 are both ethyl; R7 and R, are both H; R, and R2 are both 1-methylcyclopropyl; R3 is methyl, and R4 is ethyl; R7 and R8 are both R, and R2 are both 2-methylcyclopropyl; R3 and R4 are both methyl; R7 and R, are both R, and R 2 are both 2-phenylcyclopropyl; R 3 and R4 are both methyl; R7 and R, are both R, and R 2 are both 1-phenylcyclopropyl; R3 and R4 are IN both methyl; R, and R, are both R, and R 2 are both cyclobutyl; R3 and R 4 are both O methyl; R, and R. are both R, and R2are both cyclopentyl; R and R4 are both 0 methyl; R, and R, are both R, and R2 are both cyclohexyl; R 3 and R 4 are both methyl; R, and R, are both R, and R2 are both cyclohexyl; R 3 and R 4 are both phenyl; R, and R, are both R, and R2 are both methyl; R3 and R 4 are both methyl; SR, and R, are both R, and R, are both methyl; R3 and R4 are both t-butyl; R, and N, R, are both R, and R2 are both methyl; R 3 and R 4 are both phenyl; R, and R, are 0 both R 1 and R, are both t-butyl; R3 and R4 are both methyl; R, and R, are both -H; NI R, and R, are ethyl; R 3 and R4 are both methyl; R 7 and R, are both R, and R 2 are both n-propyl; R3 and R 4 are both methyl; R7 and R, are both Y in these examples is preferably -C(R 7 In another preferred embodiment, the compound used in the method of the present invention is represented by Structural Formula
    R
    3 0 0 R4 H
    H
    R,-R4 in Structural Formula are as described in Structural Formula Y" is a covalent bond or -CH 2 In a first example of a compound represented by Structural Formula R 3 and R 4 are both a substituted or unsubstituted aliphatic group, preferably both a substituted or unsubstituted alkyl group and more preferably both a methyl or ethyl group When R3 and R4 in Structural Formula are both a substituted or unsubstituted aliphatic group, then: 1) R, and R, are preferably both a substituted or unsubstituted aliphatic group a substituted or unsubstituted alkyl group and preferably a C3-C8 substituted or unsubstituted cycloalkyl group such as a ,O -11-
    O
    c substituted or unsubstituted cyclopropyl group); or 2) R, and R 2 are preferably both a O substituted or unsubstituted aryl group a substituted or unsubstituted heteroaryl group or a substituted or unsubstituted phenyl group; or 3) R, is preferably a substituted or unsubstituted aliphatic group (preferably a substituted or unsubstituted cycloalkyl group such as a substituted or unsubstituted cyclopropyl group); and R, is preferably a substituted or unsubstituted aryl group a substituted or 00 CI unsubstituted heteroaryl group or a substituted or unsubstituted phenyl group.
    IO In a second example of a compound represented by Structural Formula
    SR
    3 and R 4 are both a substituted or unsubstituted heteroaryl group. When R 3 and R 4 in Structural Formula are both a substituted or unsubstituted heteroaryl group, then: 1) R I and R, are preferably both a substituted or unsubstituted phenyl group; 2) R, and R 2 are preferably both a substituted or unsubstituted heteroaryl group; 3) R, and R are preferably both a substituted or unsubstituted aliphatic group (preferably a substituted or unsubstituted alkyl group and more preferably a substituted or unsubstituted cycloalkyl group such as a substituted or unsubstituted cyclopropyl group); or 4) R, is preferably a substituted or unsubstituted aliphatic group (preferably a substituted or unsubstituted C3-C8 cycloalkyl group); and R, is preferably a substituted or unsubstituted aryl group a substituted or unsubstituted heteroaryl group or a substituted or unsubstituted phenyl group).
    In a third example of a compound represented by Structural Formula R 3 and R 4 are both a substituted or unsubstituted phenyl group. When R 3 and R4 in Structural Formula are both a substituted or unsubstituted phenyl group, then: 1)
    R
    1 and R2 are preferably both a substituted or unsubstituted phenyl group; 2) R, and R2 are preferably both a substituted or unsubstituted heteroaryl group; 3) R, and R, are both a substituted or unsubstituted aliphatic group (preferably a substituted or unsubstituted alkyl group and more preferably a C3-C8 substituted or unsubstituted cyclic aliphatic group such as a substituted or unsubstituted cyclopropyl group); or 4) R, is a substituted or unsubstituted aliphatic group (preferably a substituted or unsubstituted cycloalkyl group such as a cyclopropyl group); and R 2 is a substituted or unsubstituted aryl group a substituted or unsubstituted heteroaryl group or a substituted or unsubstituted phenyl group.
    I -12-
    O
    In a fourth example of a compound represented by Structural Formula R 1 O and R, are both a substituted or unsubstituted aryl group a substituted or unsubstituted heteroaryl group or a substituted or unsubstituted phenyl group). More preferably, R 3 and R 4 are both methyl.
    In a fifth example of a compound represented by Structural Formula R, 0 and R 2 are both a substituted or unsubstituted aliphatic group, preferably both a C substituted or unsubstituted alkyl group, including a C3-C8 cycloalkyl group Soptionally substituted with at least one alkyl group methyl, ethyl, n-propyl, nbutyl, n-pentyl, cyclopropyl, 1-methylcyclopropyl, 2-methylcyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl). When RI and R, in Structural Formula are both an aliphatic group or a substituted aliphatic group, then R 3 and R 4 are preferably both: 1) a substituted or unsubstituted aryl group a substituted or unsubstituted heteroaryl group or a substituted or unsubstituted phenyl group); or 2) a substituted or unsubstituted aliphatic group (preferably a substituted or unsubstituted alkyl group).
    In a sixth example of a compound represented by Structural Formula R, and R are both a substituted or unsubstituted cycloalkyl group, preferably both a substituted or unsubstituted cyclopropyl alkyl group and R 3 and R 4 are as described for Structural Formula In a seventh example of a compound represented by Structural Formula R, is a substituted or unsubstituted aliphatic group and R is a substituted or insubstituted aryl group and R 3 and R 4 are as described for Structural Formula The following are specific examples of compounds represented by Structural Formula R, and R 2 are both phenyl, and R 3 and R 4 are both o-CH 3 -phenyl; RI and
    R
    2 are both o-CH 3 C(O)O-phenyl, and R 3 and R 4 are phenyl; R, and R 2 are both phenyl, and R 3 and R 4 are both methyl; R, and R, are both phenyl, and R 3 and R 4 are both ethyl; R, and R 2 are both phenyl, and R 3 and R 4 are both n-propyl; R, and R 2 are both p-cyanophenyl, and R 3 and R 4 are both methyl; R, and R2 are both p-nitro phenyl, and R 3 and R 4 are both methyl; R, and R 2 are both 2,5-dimethoxyphenyl, and R3 and R4 are both methyl; R, and R, are both phenyl, and R3 and R 4 are both n-butyl; R, and R2 are both p-chlorophenyl, and R 3 and 4 are both methyl; R, and R2 are both
    I-ND
    3-nitrophenyl, and R 3 and (4 are both methyl; R, and R2 are both 3-cyanophenyl, and o 1(~3 and (4 are both methyl; R, and R 2 are both 3-fluorophenyl, and (3 and (4 are both methyl; and R, are both 2-furanyl, and (3 and (4 are both phenyl; and R, are both 2-methoxyphenyl, and R 3 and R 4 are both methyl; R, and R 2 are both 3methoxyphenyl, and R 3 and 1(4are both methyl; R, and R, are both 2,3 dimnethoxyphenyl, and R( and (4 are both methyl; R, and R 2 r OC) chlorophenyl, and (3 and 1(4are both ethyl; and R 2 are both and R 3 and R, are both methyl; R, and R,2 are both 2,5-dichiorophenyl, and (3 and R(4 are both methyl; and R 2 are both 2.5-dimethyiphenyl, and 1(3and R 4 are both methyl; R, and R, are both 2-methoxy-5-chlorophenyl, and (3 and R 4 are both methyl; R, and R,2 are both 3,6-dimethoxyphenyl, and R 3 and (4 are both methyl; R, and R2 are both phenyl, and R(3 and R 4 are both 2-ethyiphenyl; R, and R,2 are both 2and 1(3and 1(4are both methyl; or is phenyl; R2 is dimethoxyphenyl, and (3 and (4 are both mnethyl; and R, aeboth methyl, and R(3 and (4 are both p-CF 3 -phenyl; and (2 are both methyl, and 1(3and (4 are both o-
    CH
    3 -phenyl; and are both -CH 2 3 COOFI;and 1(3 and 1(4are both phenyl; R, and Rare both represented by the following structural formula: and R(3 and (4 are both phenyl; R, and R2 are both n -butyl, and (3 and (4 are both phenyl; and R,2 are both/7-pentyl, (3 and (4 are both phenyl; and (2 are both methyl, and (3 and (4 are both 2-pyridyl; R, and R2 are both cyclohexyl, and 1(3 and (4 are both phenyl; and R2 are both methyl, and R(3 and (4 are both 2-ethylphenyl; R, and R2 are both methyl, and 1(3and (4 are both 2,6-diciorophenyl; R,-R4 are all methyl; and R2 are both methyl, and (3 and (4 are both t-butyl; R, and R2 are both ethyl, and R,3 and (4 are both methyl; R, and R2 are both t-butyl, and R 3 and 1(4are both methyl; and R2 are both cyclopropyl, and (3 and (4 are both methyl; R, and IND -14-
    O
    SR
    2 are both cyclopropyl, and R 3 and R 4 are both ethyl; R, and R 2 are both 1- O methylcyclopropyl, and R 3 and R 4 are both methyl; R, and R 2 are both 2methylcyclopropyl, and R 3 and R 4 are both methyl; R, and R 2 are both 1phenylcyclopropyl, and R 3 and R 4 are both methyl; R, and R are both 2- If 5 phenylcyclopropyl, and R 3 and R 4 are both methyl; R, and R, are both cyclobutyl, and O R3 and R4 are both methyl; R, and R 2 are both cyclopentyl, and R3 and R 4 are both
    C
    methyl; R, is cyclopropyl, R, is phenyl, and R 3 and R4 are both methyl. In these I examples, Y" is preferably -CH 2 In another preferred embodiment, Y the compound used in the method of the present invention is represented by Structural Formula (VI):
    R
    3 o o R4 Rk N "yR2 S Rs RE S
    (VI)
    RI-R, in Structural Formula (VI) are as described for Structural Formula Y" is a covalent bond or In one example of a compound represented by Structural Formula R and R 6 are both an alkyl group (preferably methyl) or a phenyl group. When R, and
    R
    6 are both an alkyl group or a phenyl group, then R, and R, are preferably both phenyl or substituted phenyl and R 3 and R4 are preferably both an alkyl group.
    In a second example of a compound represented by Structural Formula R, and R 6 are both an alkyl group (preferably methyl) or a phenyl group. When and R 6 are both an alkyl group or a phenyl group, then R, and R 2 are preferably both alkyl or substituted alkyl and R 3 and R4 are preferably both phenyl or substituted phenyl. Alternatively, when R, and R, are both an alkyl group or a phenyl group, R, and R 2 are both an alkyl group or a substituted alkyl group and R3 and R 4 are both alkyl or substituted alkyl.
    IND
    O
    O
    c The following are more specific examples of compounds of the present o invention: R, and R 2 are both phenyl, R3 and R4 are both phenyl, R, and R 6 are both methyl, and R 7 and R 8 are both R, and R, are both phenyl, R3 and R4 are both phenyl, R, and R 6 are both n-hexyl, and R7 and R 8 are both R, and R 2 are both t 5 phenyl, R 3 and R4 are both methyl, R 5 and R 6 are both methyl, and R7 and R 8 are both RI and R 2 are both phenyl, R3 and R4 are both methyl, R, and R 6 are both methyl, 00 and R7 is -H and R, is methyl; R, and R 2 are both phenyl, R3 and R4 are both R, and R 6 are both phenyl, R7 is and R, is methyl; R, and R, are both 4- Ochlorophenyl, R 3 and R 4 are both methyl, R5 and R6 are both methyl, and R7 and R, are both R, and R 2 are both phenyl, R3 and R4 are both phenyl, R 5 and R 6 are both methyl, and R, and R, are both R, and R2 are both phenyl, R3 and R 4 are both phenyl, R, and R 6 are both n-hexyl, and R7 and R, are both R, and R, are both phenyl, R3 and R 4 are both methyl, R, and R 6 are both methyl, and R7 and R 8 are both R, and R 2 are both phenyl, R 3 and R4 are both methyl, R 5 and R are both methyl, and R7 is -H and R, is methyl; R, and R 2 are both phenyl, R3 and R4 are both R, and R 6 are both phenyl, R7 is and R, is methyl; R, and R2 are both 4chlorophenyl, R 3 and R4 are both methyl, R5 and R6 are both methyl, and R, and R 8 are both -H.
    In Structural Formulas R, and R 2 are the same or different; and/or R3 and R4 are the same or different; and/or R, and R 6 are the same or different.
    Preferably, R, and R2 are the same, R3 and R4 are the same and R5 and R6 are the same.
    A "straight chained hydrocarbyl group" is an alkylene group, with one or more (preferably one) internal methylene groups optionally replaced with a linkage group. x is a positive integer between 1 and about 10), preferably between 1 and about 6 and more preferably 1 or 2. A "linkage group" refers to a functional group which replaces a methylene in a straight chained hydrocarbyl.
    Examples of suitable linkage groups include a ketone alkene, alkyne, phenylene, ether thioether or amine wherein R" is defined below. A preferred linkage group is -C(R 7 wherein R7 and R, are defined above.
    Suitable substitutents for an alkylene group and a hydrocarbaryl group are those IND -16-
    O
    Swhich do not substantially interfere with the anti-cancer activity of the disclosed O compounds. R 7 and R 8 are preferred substituents for an alkylene or hydrocarbyl group represented by Y or Y'.
    An aliphatic group is a straight chained, branched or cyclic non-aromatic V 5 hydrocarbon which is completely saturated or which contains one or more units of Sunsaturation. Typically, a straight chained or branched aliphatic group has from 1 to about 20 carbon atoms, preferably from 1 to about 10, and a cyclic aliphatic group Shas from 3 to about 10 carbon atoms, preferably from 3 to about 8. An aliphatic N group is preferably a straight chained or branched alkyl group, e.g, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, pentyl or octyl, or a cycloalkyl group with 3 to about 8 carbon atoms. A C1-C20 straight chained or branched alkyl group or a C3-C8 cyclic alkyl group is also referred to as a "lower alkyl" group.
    Aromatic groups include carbocyclic aromatic groups such as phenyl, naphthyl, and anthracyl, and heteroaryl groups such as imidazolyl, thienyl, furanyl, pyridyl, pyrimidy, pyranyl, pyrazolyl, pyrroyl, pyrazinyl, thiazole, oxazolyl, and tetrazole.
    Aromatic groups also include fused polycyclic aromatic ring systems in which a carbocyclic aromatic ring or heteroaryl ring is fused to one or more other heteroaryl rings. Examples include benzothienyl, benzofuranyl, indolyl, quinolinyl, benzothiazole, benzooxazole, benzimidazole, quinolinyl, isoquinolinyl and isoindolyl.
    The term "arylene" refers to an aryl group which is connected to the remainder of the molecule by two other bonds. By way of example, the structure of a 1,4-phenylene group is shown below: Kw/v IND -17- Substituents for an arylene group are as described below for an aryl group.
    0 Non-aromatic heterocyclic rings are non-aromatic carbocyclic rings which include one or more heteroatoms such as nitrogen, oxygen or sulfur in the ring. The ring can be five, six, seven or eight-membered. Examples include tetrahydrofuranyl, tetrahyrothiophenyl, morpholino, thiomorpholino, pyrrolidinyl, piperazinyl, piperidinyl, and thiazolidinyl.
    00 C1 Suitable substituents on an aliphatic group (including an alkylene group), IND non-aromatic heterocyclic group, benzylic or aryl group (carbocyclic and heteroaryl) are those which do not substantially interfere with the anti-cancer activity of the disclosed compounds. A substituent substantially interferes with anti-cancer activity when the anti-cancer activity is reduced by more than about 50% in a compound with the substituent compared with a compound without the substituent. Examples of suitable substituents include -OH, halogen -Cl, -1 and -O-CORa,- CORE, -CN, -NO 2 -COOH, -SO 3 H, -NH 2 -NHIVa -N(RaRb), -COOWs, -CHO,
    CONH
    2
    -CONHR
    8 _CON(RaRb), -NHCORa, -NRCOR 8
    -NHCONH
    2 _NHCONRaH, _NHCON(RaRb), -NWCONH 2 -NRcCONRH, _NReCON(RaRb), -C(=MNH)-NH 2 -C(=NH)-NHV, Rb), -C(=NW)-NH 2 -C(=NRc)-NHRa, _C(=NRC)_N(RnRb), -NH-.C(=NH-)-NH 2 -NH-C(=MNL)-NH'a -N-(N)NRaR~ -NH-C(=NRc)-NH 2 _NHC(=NR.)_NHW, _NHC(=NRc)_N(RaRb), .}~d.C(NfWcyNH 2 _NdC(-qN )_NIWa -Nd-C(_cN(aR), -NHNJH 2 -NIMW2, 4-JIH(Rb, -SO 2
    NH
    2
    -SO
    2 NW~R, -502NI CH=CHR a, -CH=CRWRb, -CRc=CRaR b, -CRc=CH -CRc=CRaRb -CCR", -SH, -SOkR 2 (k isO0, 1 or 2) and -NH-C(=NII)-N1 2 R-WR are each independently an aliphatic, substituted aliphatic, benzyl, substituted benzyl, aryl or substituted aryl group, preferably an alkyl, benzylic or aryl group. In addition, -N(RaR taken together, can also form a substituted or unsubstituted non-aromatic heterocyclic group. A non-aromatic heterocyclic group, benzylic group or aryl group can also have an aliphatic or substituted aliphatic group as a substituent. A substituted aliphatic group can also have a non-aromatic heterocyclic ring, a substituted a non-aromatic heterocyclic ring, benzyl, substituted benzyl, aryl or substituted aryl group as a substituent. A substituted aliphatic, non- 0 -18- Saromatic heterocyclic group, substituted aryl, or substituted benzyl group can have O more than one substituent. Examples of preferred substituents for the groups represented by R'-Rd and -N(RaRb) taken together include amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkylaminocarbonyl, tn 5 dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxy, O nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, haloalkoxy, or oO C haloalkyl.
    INO Preferred substituents for a cycloalkyl group, including cycloalkyl groups Srepresented by R, and R 2 are alkyl groups, such as a methyl or ethyl group.
    Also included in the present invention are pharmaceutically acceptable salts of the compounds described herein. Compounds disclosed herein which possess a sufficiently acidic, a sufficiently basic, or both functional groups, and accordingly can react with any of a number of organic or inorganic bases, and inorganic and organic acids, to form a salt. Acids commonly employed to form acid addition salts from compounds with basic groups are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids such as p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, pbromophenyl-sulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like. Examples of such salts include the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, gamma-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, and the like.
    Base addition salts include those derived from inorganic bases, such as ammonium or alkali or alkaline earth metal hydroxides, carbonates, bicarbonates, and -19-
    O
    the like. Such bases useful in preparing the salts of this invention thus include 0 O sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium Scarbonate, and the like.
    A "subject" is a mammal, preferably a human, but can also be an animal in t 5 need of veterinary treatment, companion animals dogs, cats, and the like), O farm animals cows, sheep, pigs, horses, and the like) and laboratory animals 00 N rats, mice, guinea pigs, and the like).
    D An noted above, the present invention is directed to treating subjects with cancer. "Treating a subject with cancer" includes achieving, partially or substantially, one or more of the following: arresting the growth or spread of a cancer, reducing the extent of a cancer reducing size of a tumor or reducing the number of affected sites), inhibiting the growth rate of a cancer, and ameliorating or improving a clinical symptom or indicator associated with a cancer (such as tissue or serum components).
    Cancers that can be treated or prevented by the methods of the present invention include, but not limited to human sarcomas and carcinomas, e.g., fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, testicular tumor, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, retinoblastoma; leukemias, acute lymphocytic leukemia and acute myelocytic leukemia (myeloblastic, promyelocytic, myelomonocytic, monocytic and erythroleukemia); chronic leukemia (chronic myelocytic (granulocytic) leukemia and chronic IN 0 lymphocytic leukemia); and polycythemia vera, lymphoma (Hodgkin's disease and O non-Hodgkin's disease), multiple myeloma, Waldenstrobm's macroglobulinemia, and heavy chain disease.
    Other examples of leukemias include acute and/or chronic leukemias, e.g., lymphocytic leukemia as exemplified by the p388 (murine) cell line), large 00 granular lymphocytic leukemia, and lymphoblastic leukemia; T-cell leukemias, e.g., CN T-cell leukemia as exemplified by the CEM, Jurkat, and HSB-2 (acute), SYAC-1(murine) cell lines), T-lymphocytic leukemia, and T-lymphoblastic leukemia;
    O
    C" B cell leukemia as exemplified by the SB (acute) cell line) and B-lymphocytic leukemia; mixed cell leukemias, B and T cell leukemia and B and T lymphocytic leukemia; myeloid leukemias, granulocytic leukemia, myelocytic leukemia as exemplified by the HL-60 (promyelocyte) cell line), and myelogenous leukemia as exemplified by the K562(chronic)cell line); neutrophilic leukemia; eosinophilic leukemia; monocytic leukemia as exemplified by the THP-1 (acute) cell line); myelomonocytic leukemia; Naegeli-type myeloid leukemia; and nonlymphocytic leukemia. Other examples of leukemias are described in Chapter 60 of The Chemotherapy Sourcebook, Michael C. Perry Ed., Williams Williams (1992) and Section 36 of Holland Frie Cancer Medicine Ed., Bast et al. Eds., B.C. Decker Inc. (2000). The entire teachings of the preceding references are incorporated herein by reference.
    In one embodiment, the disclosed method is believed to be particularly effective in treating subject with non-solid tumors such as multiple myeloma. In another embodiment, the disclosed method is believed to be particularly effective against T-leukemia as exemplified by Jurkat and CEM cell lines); B-leukemia as exemplified by the SB cell line); promyelocytes as exemplified by the cell line); uterine sarcoma as exemplified by the MES-SA cell line); monocytic leukemia as exemplified by the THP-1(acute) cell line); and lymphoma as exemplified by the U937 cell line); most preferably, this embodiment of the method employs Compound The disclosed method is particularly effective at treating subjects whose cancer has become "multi-drug resistant". A cancer which initially responded to an ID-21anti-cancer drug becomes resistant to the anti-cancer drug when the anti-cancer drug O is no longer effective in treating the subject with the cancer. For example, many tumors will initially respond to treatment with an anti-cancer drug by decreasing in size or even going into remission, only to develop resistance to the drug. Drug tn 5 resistant tumors are characterized by a resumption of their growth and/or O reappearance after having seemingly gone into remission, despite the administration oO of increased dosages of the anti-cancer drug. Cancers that have developed resistance to two or more anti-cancer drugs are said to be "multi-drug resistant". For example, it is common for cancers to become resistant to three or more anti-cancer agents, often five or more anti-cancer agents and at times ten or more anti-cancer agents.
    An "effective amount" is the quantity of compound in which a beneficial clinical outcome is achieved when the compound is administered to a subject with a cancer. A "beneficial clinical outcome" includes a reduction in tumor mass, a reduction in metastasis, a reduction in the severity of the symptoms associated with the cancer and/or an increase in the longevity of the subject compared with the absence of the treatment. The precise amount of compound administered to a subject will depend on the type and severity of the disease or condition and on the characteristics of the subject, such as general health, age, sex, body weight and tolerance to drugs. It will also depend on the degree, severity and type of cancer.
    The skilled artisan will be able to determine appropriate dosages depending on these and other factors. Effective amounts of the disclosed compounds typically range between about 1 mg/mm 2 per day and about 10 grams/mm 2 per day, and preferably between 10 mg/mm 2 per day and about 5 grams/m 2 The disclosed compounds are administered by any suitable route, including, for example, orally in capsules, suspensions or tablets or by parenteral administration. Parenteral administration can include, for example, systemic administration, such as by intramuscular, intravenous, subcutaneous, or intraperitoneal injection. The compounds can also be administered orally dietary), topically, by inhalation intrabronchial, intranasal, oral inhalation or intranasal drops), or rectally, depending on the type of cancer to be treated. Oral or parenteral administration are preferred modes of administration.
    ND -22- 0 The disclosed compounds can be administered to the subject in conjunction O with an acceptable pharmaceutical carrier as part of a pharmaceutical composition for Streatment of cancer. Formulation of the compound to be administered will vary according to the route of administration selected solution, emulsion, capsule).
    S 5 Suitable pharmaceutical carriers may contain inert ingredients which do not interact 0 with the compound. Standard pharmaceutical formulation techniques can be CI employed, such as those described in Remington's Pharmaceutical Sciences, Mack SPublishing Company, Easton, PA. Suitable pharmaceutical carriers for parenteral CI administration include, for example, sterile water, physiological saline, bacteriostatic saline (saline containing about 0.9% mg/ml benzyl alcohol), phosphate-buffered saline, Hank's solution, Ringer's-lactate and the like. Methods for encapsulating compositions (such as in a coating of hard gelatin or cyclodextrasn) are known in the art (Baker, et al., "Controlled Release of Biological Active Agents", John Wiley and Sons, 1986).
    Optionally, the disclosed compounds can be co-administered with other anticancer agents such as Adriamycin, Dactinomycin, Bleomycin, Vinblastine, Cisplatin, acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine; ambomycin; ametantrone acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone; caracemide; carbetimer; carboplatin; carmustine; carubicin hydrochloride; carzelesin; cedefingol; chlorambucil; cirolemycin; cladribine; crisnatol mesylate; cyclophosphamide; cytarabine; dacarbazine; daunorubicin hydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate; diaziquone; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin; edatrexate; eflornithine hydrochloride; elsamitrucin; enloplatin; enpromate; epipropidine; epirubicin hydrochloride; erbulozole; esorubicin hydrochloride; estramustine; estramustine phosphate sodium; etanidazole; etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride; fazarabine; fenretinide; floxuridine; fludarabine phosphate; IND -23fluorouracil; flurocitabine; fosquidone; fostriecin sodium; gemcitabine; gemcitabine 0 hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide; ilmofosine; interleulcin 11 (including recombinant interleukin HI, or rIL2), interferon alfa-2a; interferon alfa-2b; interferon alfa-n 1; interferon alfa-n3; interferon beta-I a; interferon gamma-I b; iproplatin; irinotecan hydrochloride; lanreotide acetate; C) letrozole; leuprolide acetate; liarozole hydrochloride; lometrexol sodium; lomustine; 00 losoxantrone hydrochloride; masoprocol; maytansine; mechiorethamine IND hydrochloride; megestrol acetate; melengestrol acetate; meiphalan; menogaril; C) mercaptopurine; methotrexate; methotrexate sodium; metoprine; meturedepa; mitindomide; mitocarcin; mitocrornin; mitogillin; mitomalcin; mitomycin; mitosper; mitotane; initoxantrone hydrochloride; mycophenolic acid; nocodazole; nogalamycin; ormaplatin; oxisuran; pegaspargase; peliomycin; pentamustine; peplomycin sulfate; perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride; plicamycin.; plomestane; porfimer sodium; porfiromycin; prednimustine; procarbazine hydrochloride; puromycin; purornycin hydrochloride; pyrazofurin; riboprine; rogletimide; safingol; safingol hydrochloride; semustine; sirutrazene; sparfosate sodium; sparsomycin; spirogermanium hydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin; sulofenur; talisomycin; tecogalan sodium; tegafur; teloxantrone hydrochloride; temoporfin; teniposide; teroxirone; testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin; tirapazamine; toremifene citrate; trestolone acetate; triciribine phosphate; trimetrexate; trimetrexate glucuronate; triptorelin; tubulozole hydrochloride; uracil mustard; uredepa; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate; vinglycinate sulfate; vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate; vinzolidine sulfate; vorozole; zeniplatin; zinostatin; zorubicin hydrochloride.
    Other anti-cancer drugs include, but are not limited to: 20-epi-1,25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; arninolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; IND -24o antagonist G; antarelix; anti-dorsalizing rnorphogenetic protein-i; antiandrogen, 0 prostatic carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyro sine; baccatin 00 MI derivatives; balanol; batimastat; BCR/ABL antagonists; benzochlorins; N- benzoylstaurosporine; beta lactamn derivatives; beta-alethine; betaclamycin B; betulinic acid; bFGF inhibitor; bicalutamide; bisantrene; bisaziridinyispermine; c-I bisnafide; bistratene A; bizelesin; breflate; bropirimine; budotitan6; buthionine sulfoxirnine; calcipotriol; caiphostin C; camptothecin derivatives; canarypox IL-2; capecitabine; carboxamide-amino-triazole; carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor; carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chiorins; chioroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine; clomnifene analogues; clotrimazole; collismycin A; collismycin B; combretastatin A4; combretastatin analogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin. A; cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin; dexarnethasone; dexifosfamide; dexrazoxane; dexverapamil; diaziquone; didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine; 9- dioxamycin; diphenyl spiromustine; docosanol; dolasetron; doxifluridine; droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolomab; eflomnithine; elemene; emitefur; epirubicin; epristeride; estramustine analogue; estrogen agonists; estrogen antagonists; etanidazole; etoposide phosphate; exemestane; fadrozole; fazarabine; fenretinide; flgrastim; finasteride; flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicin hydrochloride; forfenimex; formestane; fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix; gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfani; heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene; idramantone; ilmofosine; ilomastat; imidazoacridones; imiquimod; immunostimulant peptides; insulin-like growth factor-i receptor inhibitor; interferon agonists; IND interferons; interleukins; iobenguane; iododoxorubicin; ipomeanol, iroplact; o irsogladine; isobengazole; isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide; leinainycin; lenograstim; lentinan sulfate; leptoistatin; letrozole; leukemia inhibiting factor; leukocyte alpha interferon; tf 5 leuprolide+estrogen~progesterone; leuprorelin; levamisole; liarozole; linear OC) polyamine analogue; lipophilic disaccharide peptide; lipophilic platinum compounds; lissoclinamide 7; lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone; IND lovastatin; loxoribine; lurtotecan; lutetium. texaphyrin; lysofylline; lytic peptides; maitansine; mannostatin A; niarimastat; masoprocol; maspin; matrilysin inhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone; meterelin; methioninase; metoclopramide; MIW inhibitor; mifepristone; miltefosine; mirimostim; mismatched double stranded RNA; mitoguazone; mitolactol; mitomycin. analogues; mitonafide; mitotoxin fibroblast growth factor-saporin; mitoxantrone; mofarotene; moigramostim; monoclonal antibody, human chorionic gonadotrophin; monophosphoryl lipid A+myobacteriuxn cell wall sk; mopidamol; multiple drug resistance gene inhibitor; multiple tumor suppressor 1 -based therapy; mustard anticancer agent; mycaperoxide B; mycobacterial cell wall extract; myriaporone; N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip; naloxone+pentazocine; napavin; naphterpin; nartograstirn; nedaplatin; nemorubicin; neridronic acid; neutral endopeptidase; nilutamide; nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn; 06-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone; ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin; oxaunomycin; palauamine; palmitoylrhizoxin; pamidronic acid; panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin; pentrozole; perfiubron; perfosfamide; perillyl alcohol; phenazinomycin;.
    phenylacetate; phosphatase inhibitors; picibanil; pilocarpine hydrochloride; pirarubicin; piritrexim; placetin A; placetin B; plasminogen activator inhibitor; platinum complex; platinum compounds; platinum-triamine complex; porfimer sodium; porfiromycin; prednisone; propyl bis-acridone; prostaglandin. J2; proteasome inhibitors; protein A-based immune modulator; protein kinase C inhibitor; protein -26kinase C inhibitors, microalgal; protein tyrosine phosphatase inhibitors; purine 0 nucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine; pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagonists; raltitrexed; ramosetron; ras famesyl protein transferase inhibitors; ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin; ribozymes; RII retinamide; rogletimide; rohitukine; romurtide; roquinimex; rubiginone Bl; ruboxyl; safingol; saintopin; SarCNU; sarcophytol A; sargramostin; Sdi 1 mimetics; semustine; senescence derived inhibitor 1; sense oligonucleotides; signal transduction inhibitors; signal transduction modulators; single chain antigen-binding protein; sizofiran; sobuzoxane; sodium borocaptate; sodium phenylacetate; solverol; somatomedin binding protein; sonermin; sparfosic acid; spicamycin D; spiromustine; splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem-cell division inhibitors; stipiamide; stromelysin inhibitors; sulfinosine; superactive vasoactive intestinal peptide antagonist; suradista; suramin; swainsonine; synthetic glycosaminoglycans; tallimustine; tamoxifen nethiodide; tauromustine; tazarotene; tecogalan sodium; tegafur; tellurapyrylium; telomerase inhibitors; temoporfin; temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocene bichloride; topsentin; toremifene; totipotent stem cell factor; translation inhibitors; tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenital sinus-derived growth inhibitory factor; urokinase receptor antagonists; vapreotide; variolin B; vector system, erythrocyte gene therapy; velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; and zinostatin stimalamer. Preferred additional anti-cancer drugs are 5-fluorouracil and leucovorin.
    Examples of therapeutic antibodies that can be used include but are not limited to HERCEPTIN® (Trastuzumab) (Genentech, CA) which is a humanized anti-HER2 monoclonal antibody for the treatment of patients with metastatic breast cancer; REOPROS (abciximab) (Centocor) which is an anti-glycoprotein ILb/ia INO -27receptor on the platelets for the prevention of clot formation; ZENAPAXOD 0 (daclizumab) (Roche Pharmaceuticals, Switzerland) which is an immunosuppressive, humanized anti-CD25 monoclonal antibody for the prevention of acute renal allograft rejection; PANOREXTM which is a murine anti-1I7-IA cell surface antigen IgG2a antibody (Glaxo Wellcome/Centocor); BEC2 which is a murine anti-idiotype 00 (GD3 epitope) IgO antibody (ImClone System); LMC-C225 which is a chimeric anti- EGFR IgG antibody (ImClone System); VITAXINmM which is a humanized antictVP3 integrin antibody (Applied Molecular Evolution/MedImmune); Campath c-i IHALDP-03 which is a humanized anti CD52 IgGI antibody (Leukosite); Smart M195 which is a humanized anti-CD33 IgG antibody (Protein Design Lab/Kanebo); RITUXAkN TM which is a chimeric anti-CD2O IgGi antibody (IDEC Pharm/Genentech, RochelZettyaku); LYMPHOCIDETM which is a humanized anti- CD22 IgG antibody (lInmunomedics); LYMPHOCIDETM Y-90 (Immunomedics); Lymphoscan (Tc-99m-labeled; radioimaging; lInmunomedics); Nuvion (against CD3; Protein Design Labs); CM3 is a humanized anti-ICAM3 antibody (ICOS Pharm); IDEC-l 14 is a primatied anti-CD8O antibody (IDEC Pharmlvlitsubishi); ZEVALINTm is a radiolabelled murine anti-CD2O antibody (IDEC/Schering AG); IDEC- 131 is a humanized anti-CD4OL antibody (IDECtEisai); IDEC-i151 is a primatized anti-CD4 antibody (IDEC); IiDEC- 152 is a primatized anti-CD23 antibody (IDEC/Seicagaku); SMART anti-CD3 is a humanized anti-CD3 IgG (Protein Design Lab); 5G1 is a humanized anti-complement factor 5 (C5) antibody (Alexion Pharm.); D2E7 is a humanized anti-TNF-a antibody (CAT/BASF); CDP870 is a humanized anti-TNF-x Fab fragment (Ceihtech); IDEC-151 is a primatized anti-CD4 IgGI antibody (IDEC PharmlSmitbKline Beecham); MDX-CD4 is a human anti- CD4 IgG antibody (MedarexlEisai/Genmab); CD2O-sreptdavidin (+biotin-yttrium NeoRx); CDP571 is a humanized anti-TNF-a IgG4 antibody (Celitech); LDP-02 is a humanized anti-cL4p7 antibody (LeukoSite/Genentech); OrthoClone OKT4A is a humanized anti-CD4 IgG antibody (Ortho Biotech); ANTOVATM is a humanized anti-CD4OL IgG antibody (Biogen); ANTEGREN'm is a humanized anti-VLA-4 IgG antibody (Elan); and CAT-i 152 is a human anti-TGF-P 2 antibody (Cambridge Ab Tech).
    -28-
    O
    Chemotherapeutic agents that can be used in the methods and compositions O of the invention include but are not limited to alkylating agents, antimetabolites, natural products, or hormones. Examples of alkylating agents useful for the treatment or prevention of T-cell malignancies in the methods and compositions of c 5 the invention include but are not limited to, nitrogen mustards
    O
    00 mechloroethamine, cyclophosphamide, chlorambucil, etc.), alkyl sulfonates CN busulfan), nitrosoureas carmustine, lomusitne, etc.), or triazenes (decarbazine, Setc.). Examples of antimetabolites useful for the treatment or prevention of T-cell c malignancies in the methods and compositions of the invention include but are not limited to folic acid analog methotrexate), or pyrimidine analogs Cytarabine), purine analogs mercaptopurine, thioguanine, pentostatin).
    Examples of natural products useful for the treatment or prevention of T-cell malignancies in the methods and compositions of the invention include but are not limited to vinca alkaloids vinblastin, vincristine), epipodophyllotoxins etoposide), antibiotics daunorubicin, doxorubicin, bleomycin), enzymes L-asparaginase), or biological response modifiers interferon alpha).
    Examples of alkylating agents useful for the treatment or prevention of cancer in the methods and compositions of the invention include but are not limited to, nitrogen mustards mechloroethamine, cyclophosphamide, chlorambucil, melphalan, etc.), ethylenimine and methylmelamines hexamethlymelamine, thiotepa), alkyl sulfonates busulfan), nitrosoureas carmustine, lomusitne, semustine, streptozocin, etc.), or triazenes (decarbazine, etc.). Examples of antimetabolites useful for the treatment or prevention of cancer in the methods and compositions of the invention include but are not limited to folic acid analog methotrexate), or pyrimidine analogs fluorouracil, floxouridine, Cytarabine), purine analogs mercaptopurine, thioguanine, pentostatin). Examples of natural products useful for the treatment or prevention of cancer in the methods and compositions of the invention include but are not limited to vinca alkaloids vinblastin, vincristine), epipodophyllotoxins etoposide, teniposide), antibiotics actinomycin D, daunorubicin, doxorubicin, bleomycin, plicamycin, mitomycin), enzymes L-asparaginase), or biological response modifiers INO -29interferon alpha). Examples of hormones and antagonists useful for the treatment or O prevention of cancer in the methods and compositions of the invention include but Sare not limited to adrenocorticosteroids prednisone), progestins hydroxyprogesterone caproate, megestrol acetate, medroxyprogesterone acetate), estrogens diethlystilbestrol, ethinyl estradiol), antiestrogen tamoxifen), Sandrogens testosterone propionate, fluoxymesterone), antiandrogen 00 Sflutamide), gonadotropin releasing hormone analog leuprolide). Other agents N that can be used in the methods and compositions of the invention for the treatment or prevention of cancer include platinum coordination complexes cisplatin, carboblatin), anthracenedione mitoxantrone), substituted urea hydroxyurea), methyl hydrazine derivative procarbazine), adrenocortical suppressant mitotane, aminoglutethimide).
    The compounds disclosed herein are believed to be particularly effective when co-administered with anti-cancer agents which act by arresting cells in the G2- M phases due to stabilized microtubules. Thus, the disclosed method preferably includes co-administered anti-cancer drugs which act by this mechanism. However, taxol and analogs of taxol are excluded from the present invention unless a multidrug resistant cancer is being treated. Examples of anti-cancer agents which act by arresting cells in the G2-M phases due to stabilized microtubules include without limitation the following marketed drugs and drugs in development: Erbulozole (also known as R-55104), Dolastatin 10 (also known as DLS-10 and NSC-376128), Mivobulin isethionate (also known as CI-980), Vincristine, NSC-639829, Discodermolide (also known as NVP-XX-A-296), ABT-751 (Abbott, also known as E-7010), Altorhyrtins (such as Altorhyrtin A and Altorhyrtin Spongistatins (such as Spongistatin 1, Spongistatin 2, Spongistatin 3, Spongistatin 4, Spongistatin Spongistatin 6, Spongistatin 7, Spongistatin 8, and Spongistatin Cemadotin hydrochloride (also known as LU-103793 and NSC-D-669356), Epothilones (such as Epothilone A, Epothilone B, Epothilone C (also known as desoxyepothilone A or dEpoA), Epothilone D (also referred to as KOS-862, dEpoB, and desoxyepothilone B Epothilone E, Epothilone F, Epothilone B N-oxide, Epothilone A N-oxide, 16-azaepothilone B, 2 1-aminoepothilone B (also known as BMS-310705), 21hydroxyepothilone D (also known as Desoxyepothilone F and dEpoF), 26- 0 fluoroepothilone), Auristatin PE (also known as NSC-654663), Soblidotin (also known as TZT-1027), LS-4559-P (Pharmacia, also known as LS-4577), LS-4578 (Pharmacia, also known as LS-477-P), LS-4477 (Pharmacia), LS-4559 (Pharniacia), RPR-1 12378 (Aventis), Vincristine sulfate, DZ-3358 (Daiiehi), FR-i 82877 00 (Fujisawa, also known as WS-9885B), GS- 164 (Takeda), GS- 198 (Takeda), KAR-2 N (Hungarian Academy of Sciences), BSF-22365 1 (BASF, also known as ILX-65 1 and LU-22365 SAH-49960 (Lilly/Novartis), SDZ-268970 (Lilly/Novartis), AM-97 (Armad/Kyowa Hakko), AM- 132 (Armad), AM-13 8 (Armad/Kyowa Hakko), IDN- 5005 (Indena), Cryptophycin 52 (also known as LY-355703), AC-7739 (Ajinomoto, also known as AVE-8063A and CS-39.HCI), AC-7700 (Ajinomoto, also known as AVE-8062, AVE-8062A, CS-39-L-Ser.HCI, and RPR-25 8062A), Vitilevuarnide, Tubulysin A, Canadensol, Centaureidin (also known as NSC- 106969), T- 13 8067 (Tularik, also known as T-67, TL-138067 and TI-138067), COBRA-i (Parker Hughes Institute, also known as DDE-261 and WI-26 HlO (Kansas State University), H16 (Kansas State University), Oncocidin Al (also known as BTO-956 and DIME), DDE-3 13 (Parker Hughes Institute), Fijianolide B, Laulimalide, SPA-2 (Parker Hughes Institute), SPA-i (Parker Hughes Institute, also known as SPIKET- 3-IAABU (Cytoskeleton/Mt. Sinai School of Medicine, also known as WvF-569), Narcosine (also known as NSC-5 366), Nascapine, D-24851 (Asta Medica), A- 105972 (Abbott), Hemiasterlin, 3-BAABU (Cytoskeleton/Mt. Sinai School of Medicine, also known as MF- 19 TMvPN (Arizona State University), Vanadocene acetylacetonate, T- 13 8026 (Tularik), Monsatrol, Inanocine (also known as NSC- 69866 3-IA-ABE (CytoskeletonlMt. Sinai School of Medicine), A-204197 (Abbott), T-607 (Tularik, also known as T-900607), RPR-1 15781 (Aventis), Eleutherobins (such as Desmethyleleutherobin, Desaetyleleutherobin, Isoeleutherobin A, and Z-Eleutherobin), Caribaeoside, Caribaeolin, Halichondrin B, D-641 31 (Asta Medica), D-68 144 (Asta Medica), Diazonamide A, A-293620 (Abbott), NPI-2350 (Nereus), Taccalonolide A, TUB-245 (Aventis), A-259754 (Abbott), Diozostatin, Phenylahistin (also known as NSCL-96F037), D-68838 (Asta Medica), D-68836 (Asta. Medica), Myoseverin B, D-4341 1 (Zentaris, also known as D-8 1862), A- IN -31- 289099 (Abbott), A-318315 (Abbott), HTI-286 (also known as SPA-110, 0 trifluoroacetate salt) (Wyeth), D-82317 (Zentaris), D-82318 (Zentaris), SC-12983 S(NCI), Resverastatin phosphate sodium, BPR-OY-007 (National Health Research Institutes), and SSR-250411 (Sanofi).
    Taxol, also referred to as "Paclitaxel", is a well-known anti-cancer drug 0 which acts by inhibiting microtubule formation. Many analogs oftaxol are known, 00 including taxotere, which is also referred to as ""Docetaxol". Other taxol analogs are Odisclosed in the co-pending U.S. Serial Nos. 10/193,075 and 10/193,639, both O entitled TAXOL ENHANCER COMPOUNDS and both filed July 10, 2002, the entire teachings of which are incorporated herein by reference. A "taxol analog" is defined herein to mean a compound which has the basic taxane skeleton and the ability to arrest cells in the G2-M phases due to stabilized microtubules. The basic taxane skeleton is shown below in Structural Formula (VII): O O
    HNH
    o
    (VI).
    Double bonds have been omitted from the cyclohexane rings in the taxane skeleton represented by Structural Formula (VII). It is to be understood that the basic taxane skeleton can include zero or one double bond in one or both cyclohexane rings. In addition, a wide variety of substituents can decorate the taxane skeleton without adversely affecting biological activity. A number of atoms have also omitted from O -32- Structural Formula (VII) to indicate sites in which structural variation commonly O occurs among taxol analogs. For example, substitution on the taxane skeleton with simply an oxygen atom indicates that hydroxyl, acyl, alkoxy or other oxygen-bearing substituent is commonly found at the site. It is to be understood that these and other S 5 substitutions on the taxane skeleton can also be made without losing the ability to OC enhance and stabilize microtubule formation.
    C The disclosed compounds can be prepared according to methods described in SExamples 1-14 and also according to methods described in the co-pending US serial CN No. 10/193,076, entitled SYNTHESIS OF TAXOL ENHANCERS, filed July 2002. The entire teachings of this application are incorporated herein by reference.
    Data showing the efficacy of the disclosed compounds are provided in Examples 15-18. Other anti-cancer data for the disclosed compounds are provided in the co-pending U.S. Serial Nos. 10/193,075 and 10/193,639, both entitled TAXOL ENHANCER COMPOUNDS and both filed July 10, 2002, the entire teachings of which are incorporated herein by reference.
    The present invention is illustrated by the following examples, which are not intended to be limiting in any way.
    EXEMPLIFICATION
    Example 1
    S
    S RINHNH 2
    I
    NaOH R R1- 0
    R
    R
    Thiobenzoic acid N-methylhydrazide were prepared in 88% yield by slight modification of the prior art (Acta Chem. Scand. 1961, 1087-1096); 'H NMR (CDC13) 8 3.3 3H), 6.0 2H), 7.3-7.4 5H); ESMS calcd (CHioN 2 166.1; found: 167.1 -33- Example 2 0-NHNH 2
    R
    (1300 2 0 r~J Boc R' CI N PBo R R 1) TFA
    R
    2) Lawessen's 2
    R
    -34- 0 Preparation of Thiocyclohexanoic acid N-phenylhydrazide O Phenyl hydrazine (5.4g, 50 mmol) was dissolved in dry dichloromethane SmL) in a 250 mL round bottom flask. Di-tert-butyl dicarbonate (10.9 g, 50 mmol) was then added with stirring at 0 The resultant solution was then stirred under c 5 reflux for 3 h. Removal of the volatile components under reduced pressure afforded a 00 colorless solid, which was washed with hexane and dried in vacuo. 10 g (yield 96%) C of the product was obtained as a colorless solid, which can be used in the next step 0 without further purification. 2.5 g (12 mmol) of this material was dissolved in dry pyridine (5 mL). Cyclohexanecarbonyl chloride (2.0 mL, 15 mmol) was then added slowly at 0 The red solution was stirred at 0 'C for half an hour and the resultant yellow suspension was stirred at rt for 3 h before pouring into ice-H 2 0 (100 mL).
    The precipitate product was collected by filtration and washed thoroughly with H 2 0.
    After one recrystallization from EtOH/H 2 0, 3.63 g of N-phenyl-Ncyclohexyl-N'-tert-butoxycarbonylhydrazide was obtained as a white powder; mp 141-143 'H NMR (CDC13) 6 0.9-2.3 11H), 1.4 9H), 6.9 (br, 1H), 7.4 (m, ppm.
    To a solution of N-phenyl-N-cyclohexyl-N'-tert-butoxycarbonylhydrazide (1.1 g, 3.46 mmol) in dichloromethane (6 mL) was added trifluoroacetic acid (6 mL) at 0 The resultant solution was stirred at 0 "C for half an hour. Volatile components were then removed under reduced pressure to afford a syrup, which was turned into a solid upon standing; this material was briefly mixed with cold 2 N NaOH (5 mL) for a few minutes at 0 Solid product was then collected by filtration and recrystallized from hexane to afford cyclohexanoic acid Nphenylhydrazide (0.6 g, 80% yield) as a white powder; 'H NMR (DMSO-d 6 6 0.8- 3.2 1H), 5.3 2H), 7.0-7.7 5H); ESMS calcd (C 1 3 H, N 2 218.3; found: 241.1 (M Na) A mixture of cyclohexanoic acid N-phenylhydrazide (0.25 g, 1.15 mmol) and Lawesson's Reagent (0.46 g, 1.15 mmol) in dry toluene (20 mL) was stirred under reflux for 1 h. After being cooled to room temperature, the mixture was filtered through a short column of silica gel (5 g) which was pre-washed with benzene.
    Removal of benzene afforded the crude product as a solid which was purified by IND column chromatography on silica gel using hexane/EtOAc 1 v/v) as eluant. 0. 1 0 of thiocyclohexanoic acid N-phenylh-ydrazide was obtained as an off white solid. 'H NMR (CDC1 3 )6 0.8-2.4 (mn, I11H), 5.65 (br, 1HT), 7.1-7.6 (mn, 5H); ESMS calcd (C 13 H,sN 2 234. 1; found: 235.1 00 5 Example 3 H RCOOH; DCC; DMAP (cat) R 0r Lawessori's R rS ~N H 3 C NH 2
    ONC
    2 H "2C -C 2H 3 C C l N H 2 H 3 C N N H 2 OC to RT Preparation of 2,5-Dimethoxyihiobenzoic acid N-methvlhvdrazine: DCC (4.5g, 21.8 mimol) was added in one portion to a solution of 2,5-dimethoxybenzoic acid (3.6g, 20 mol), methyihydrazine (1.2 ml, 23 mimol) and DMA-P (30 mg, cat. in CH 2
    CI
    2 ml) cooled in an ice bath. The reaction mixture was stirred overnight at room temperature. The slurry was cooled at -20'C for 1 h and filtered. The CH 2 C1 2 solution was evaporated and the residue was dried in vacuum. The resulting crude product was dissolved in toluene (50 ml). To this solution was added Lawesson's reagent (5.8 g, 14 inmol). The mixture was refluxed for 40 min, cooled to room temperature, and directly subjected to silica gel column chromatography (eluent: 25 to 35 ethyl acetate in hexanes) to give the 2,5-dimethoxythiobenzoic acid N-methylhydrazide (3.7 g, yield: 82%) as off-white solid. 'H NMR (300OM1Iz, CDCI 3 8 6.8 8-6.80(m, 3H), 5.46 2H1), 3.84(s, 311, 3.82 311), 3.28(s, 3H).
    Example 4 sR 3
    R
    2 DCC, DMI S HR3R2HS R N NH 2 HO OH R kN'NN )R
    R
    1 0 0 Method A R, 0 0 R, IN -36-
    O
    Preparation of N-Malonvl-bis[N'-methyl-N'-(thiobenzovl)hvdrazide]: To a stirred O solution of thiobenzoic acid N-methylhydrazide (0.166 g, 10 mmol), HOBt HlO (0.15 g, 11 mmol) and malonic acid (0.052 g, 5 mmol) in DMF (2 mL) was added DCC (0.22 g, 10.7 mmol) at 0 The resultant suspension was stirred at 0 'C for 1 h and at room temperature for 3 h. Precipitated material was filtered off and washed with SEtOAc (3 x 15 mL). Combined filtrate and washings was washed successively with C H 2 0 (2 x 20 mL), 5% citric acid (20 mL), H 2 0 (20 mL), Saturated NaHCO 3 (20 mL) 0and brine (20 mL). After being dried over Na 2
    SO
    4 the solvent was removed under C-i reduced pressure to afford the crude product as a yellow solid, which was washed with warm EtOAc. 0.16 g (yield 80%) of pure product was obtained as a yellow powder. R, 0.3 (Hexane/EtOAc 1:1 'H NMR (CDC13) 8 3.1 3.8 6H), 3.4 2H), 7.1 7.45 10 9.5 10.5 1H) ppm; ESMS calcd (CH 20
    N
    4 0 2
    S
    2 400.1; found: 399.1 (M-H) Preparation of N-(2-Methvlmalonvl-bis dimethoxv)thiobenzoyl]hvdrazide]: O S H H S O N' N. N 00 00 OO O "O DCC (4 g, 19 mmol) was added to a solution of acid N-methylhydrazide (3.7 g, 16.4 mmol) and 2-methylmalonic acid (2 g, 17 mmol) in DMF (20 ml) with stirring at 0°C. The reaction mixture was stirred for Ih at room temperature. The slurry was cooled at -20C for 1 h and filtered. The filtrate was diluted with EtOAc (300 ml), washed with water (50 ml x dried with Na 2
    SO
    4 The EtOAc solution was concentrated to minimum volume, and subjected to silica gel column chromatography (eluent: 1:4 to 2:1, ethyl acetate: hexanes) to give the IND -37title compound (3.5 g, 80 as yellow powder. 'H NMIR (CDCl 3 8 10. 12-9.14 (2H), o 7.12-6.81 (in, 4.01-3.78(mn, 6H), 3.75-3.22(m, 6H), 2 82 -2.62(m, 1.12- 0.11 ESMS cacld (C 24
    H
    30
    N
    4 0 6
    S
    2 ):534.16; found: 535.1 Preparation of 2-Methylmalonvl-bis(2-Amino-2,3-dibydro-isoindole. I-thione) 00 S S cI0 0 2-carboxybenzaldehyde (15 0 mg, I mmol) and carbazic acid (132 mg, I nirol) in 40 ml methanol was stirred at room temperature for 4 h. To this solution was added Pd/C (60 mng, containing 50 H 2 the reaction was under H 2 atmosphere for 3 h. The reaction mixture was filtered, and the solvent was evaporated. The resulting residue was subjected to silica gel column chromatography.
    (eluent: 20% to 50 EtOAc in hexanes) to obtain 50 mg of product. 'H NM4R (300M1I~z, CDCl 3 8.71-7.45 (in, 4H), 4.78 2H), 1.61 9H). The resulting product was dissolved in CF 3 COOH (5ml), stirred for 30 min. The CF 3 COOH was evaporated, and the residue was subjected to silica gel column chromatography (eluent: 50% to hexanes in EtOAc) to give 2-amino-2,3-dihydro-isoindol-1I-one (26mg) as a white solid. 'H NMvR (300Mhz, CDCI 3 7.85-7.39 (in, 4H), 4.54 (s, 2H). MS: 149 Subsequent Lawesson's thiolation and DCC coupling with 2methylnialoic acid under conditions described above afforded 2-methylmalonylbis(2-amino-2,3-dihydro-isoindole-1-thione) as a yellow powder. 'H NlvMi (CDCl 3 6 10.35 2H), 8.21-7.51(mn, 8H), 5.15(s, 4H), 1.62 ESMS cacid
    (C
    20 H1 8
    N
    4 0 2 410.09; found: 411.1 -38- SExample
    O
    R
    3
    R
    2 S CI Y S H R3 R 2 H S R NONH2 O O R N N'N R SRi R 1 0 0 Ri 00
    O
    Preparation of N-Malonvl-bis N'-methvl-N'-(thiobenzoyl)hvdrazidel: To a solution ofthiobenzoic acid N-methylhydrazine (10 g) stirred at 0 C were added subsequently triethylamine (8.5 mL) and malonyl dichloride (3.05 mL). The reaction mixture was stirred for 10 min, washed with water (3x50 mL), dried over sodium sulfate and concentrated. Purification by recrystallization from methylene dichloride (35 mL) gave the product as light yellow crystals (9.0 g, 75%) which was identical to the product obtained in Example 6.
    Example 6 R3 R2 S PhO OPh H R 3
    R
    2 R N NH2 O R0 0 'N NN .R Ri Method B R 1 0 O R 1 Preparation of N-Malonvl-bis N'-methyl-N'-(thiobenzovl)hvdrazide]: A stirred solution of thiobenzoic acid N-methylhydrazide (1.66 g, 10 mmol) and diphenyl malonate (1.30 g, 5.08 mmol) in dry THF (100 mL) was heated to reflux for 72 h.
    Volatile components were then removed under reduced pressure. The crude product was purified by column chromatography on silica gel using a mixture of hexane and EtOAc as eluant (gradient from 4:1 v/v to 1: 1 1.07 g (51% yield) of pure product N-malonyl-bis[N'-methyl-N'-(thiobenzoyl)hydrazide] was obtained as a yellow powder. Physical property was identical to that obtained in Example -39- Examiple 7
    S
    0 N'NH2 DCC, DMF0 O S H 1) TFA 2) DCC, DMF N'NH2 0 N N)KtN'1N' H H S O, A slurry of thiobenzoic acid N-methylhydra.zide (1.0 g, 6 mmnol), mono-tertbutyl malonate (1.0 niL, 6 minol), HOBt.H 2 0 (0.98 g, 7.2 mmol), and DCC (1.34 g, mmnol) in DMF (5 mL) was stirred at 0 TC for 3 h and then at room temperature for 3h. Precipitated material was filtered off and washed with EtOAc (3 x 20 mL).
    Combined filtrate and washings was washed successively with H 2 0 (2 x 20 niL), citric acid (20 niL), H 2 0 (20 rnL), Saturated NaHCO 3 (20 niL) and brine (20 niL).
    I After being dried over Na 2
    SO
    4 the solvent was removed under reduced pressure to O afford the crude product as a solid, which was washed with Et 2 O. 0.94 g (yield 51%) of pure product N'-Methyl-N'-thiobenzoyl-hydrazinocarbonyl)-acetic acid tert-butyl ester was obtained as a yellow powder. 'H NMR (CDC13) 6 1.6-1.7 (ds, 9H), 3.1-4.1 5 7.3-7.7 5H), 9.7-10.3 (ds, 1H)ppm; ESMS calcd (C, 5
    H
    2 0
    N
    2 0 3 308;
    O
    00 .found: 307 (MI-H) NC A solution of N'-methyl-N'-thiobenzoyl-hydrazinocarbonyl)-acetic acid tert- Sbutyl ester (0.19g, 0.6 mmol) and TFA (0.12 mL, 1.6 mmol) in dry DCM (10 mL)
    C
    was stirred at 10 OC 15 °C for 12 h (reaction was monitored by TLC). Volatile components were removed under reduced pressure (bath temperature below 5 After being dried in vacuo, DMF (3 mL) was added followed by the addition of DCC (0.13 g, 0.6 mmol), HOBtH 2 0 (93 mg, 0.7 mmol) and acid N-methylhydrazide (0.13 g, 0.57 mmol). The resultant solution was stirred at 0 *C for half an hour and then at room temperature for 3h. Precipitated material was filtered off and washed with EtOAc (3 x 10 mL). Combined filtrate and washings was washed successively with H 2 0 (2 x 10 mL), 5% citric acid (10 mL), H 2 0 mL), Saturated NaHCO 3 (20 mL) and brine (20 mL). After being dried over Na 2
    SO
    4 the solvent was removed under reduced pressure to afford the crude product as an oil, which was purified by SGC (4:1 hexane/EA to 2:1 EtOAc/Hexane). 0.14 g (yield 53%) of pure product was obtained as a yellow powder. 'H NMR (CDCl 3 8 3.1-3.9 18H), 6.7-7.4 9H)ppm; ESMS calcd (C, 2
    H
    24
    N
    4 0 4 S2): 460.1; found: 461.1
    (M+H)
    D -41-
    O
    O
    Example 8
    COO
    00 c- 1. anhydride R2 S SyR 2
    HCIO
    4 0 2. Na 2 S; HCI H
    H
    R1
    R
    1 Preparation of N-Malonyl-bis[N'-phenvl-N'-(thioacetyl)hydrazide] suspended in acetic anhydride (30 mL) and cooled in an ice bath. To it was added N N fA-NS A mixture of phenylhydrazine (30 mL) and ethyl malonate in xylene (150 mt) was heated to reflux overnight. The reaction was cooled to room temperature.
    The precipitates were collected via filtration and washed with ethanol to give Nmalonyl-bis(N'-phenylhydrazide) as a white solid (14 The hydrazide (3.4 g) was suspended in acetic anhydride (30 mL) and cooled in an ice bath. To it was added dropwise perchloric acid (57% in water, 3 mL). The reaction mixture turned to clear solution initially and then quickly solidified. After standing at room temperature for 1 h, ether (50 mL) was added. The resulting slurry was filtered and washed with ether (2 x 00 mL) to give the perchlorate salts as a white solid (5.7 The salts were taken into acetone and added as a slurry over 5 min to Na,S (0.6 M in water, 90 mL) stirred at room temperature. After 30 min, the reaction was acidified with HCI(c) to afford a yellow slurry. The solid was collected via filtration and washed with water (20 M1) INO -42and ether (2x25 mL) to give N-rnalony1-bis[N'-phenyl-N'-(thioacetyl)hydrazide] as an off-white solid (3.6 'H NMR (DMSO-d6): 8 11.5 (in, 2H); 7.5 (in, 10 3.2 (in, 2H); 2.6 3H); 2.5 3H). MS calcd (400.1); Found: 423.1 (M+Na).
    Example 9 00 IC H S 3R2H MeOHDEAD SR32
    S
    R N N N R N <N N R R, 0 0 R 1 R, 0 0 R, Preparation of N-Malonvl-bis[N-methvlN-hnlN -(obenzoyl)h drazidel To a stirred solution of N-inalonyl-bis[N' -phenyl-N'-(thiobenzoyl)hydrazidel (180 mng, 0.34 minol), MeOH (22 uL) and triphenyiphosphine (200 mg, 0.64 minol) in dry T.HF(l0 inL) was added a solution of DEAD 12 inL) in TI-F (3 mL) dropwise. The resultant orange solution was stirred at room temperature for 12 h.
    After removal of the volatile components, the crude product was purified by SGC (3:1 Hexane/EtOAc) to afford 98 mng (52% yield) of the title compound as syrup. 'H NIVR (CDCl 3 8 3.3-4.5 (in, 8H), 7.1-7.8 (in, 20 HMppin; ESMS calcd
    (C
    31
    H
    28
    N
    4 0 2
    S
    2 552; found: 551 Example 0 Lawessen's Reagent CL N-NA-KAWNN Y- PhHl.reflux,lIh
    IHSS
    I -43-
    O
    O
    -q- O A stirred mixture of N-malonyl-bis[N'-phenyl-N'-(thioacetyl)hydrazide) starting material (0.1 g, 0.25 mmol) and Lawesson's reagent (0.15 g, 0.37 mmol) in dry benzene (20 mL) was heated to reflux for 1 h. After being cooled to room In temperature, the mixture was filtered through a layer of silica gel, washed with THF O 5 (2 x 15 mL). The filtrate and washings were combined and concentrated under 00 N, reduced pressure. Flush column chromatography on silica gel (hexane to 4:1 O hexane/EtOAc to 2:1 hexane/EtOAc) afforded N-bisthiomalonyl-bis[N'-phenyl-N'- (thioacetyl)hydrazide as a clear syrup (16 mg, 'H NMR (CDC 3 6 3.80-3.95 8H), 7.02-7.30 9m, 10 ESMS calcd (CH4 2 0
    N
    4
    S
    4 432.06; found: 433.0
    (M+H)
    Example 11
    ,INH
    2 P2S, benzene tI NH 2 O Reflux
    S
    To a stirred solution of cyclohexanoic acid N-phenylhydrazide (0.1 g, 0.45 mmol) in dry benzene (5 mL) was added P 2 S, (0.2 g, 0.45 mol). The resultant suspension was heated to reflux for 3 h. After being cooled to room temperature, the mixture was diluted with benzene (5 mL) and was filtered through a short column of silica gel (2 washed with benzene and 2:1 hexane/EtOAc (15 mL each). The filtrate and washings were combined and concentrated to afford a solid. Crystallized from hexane to provide the intermediate thiocyclohexanoic acid N-phenylhydrazide as an off white solid; 'H NMR (CDC1) 6 0.8-2.4 11H), 5.65 (br, 1H), 7.1-7.6 5H); ESMS calcd (C 13
    H,,N
    2 234.1; found: 235.1 I -44-
    O
    NNN N H H 00 S S Cyclopropyl bromide (4.8g, 40 mmol) was added into 50 ml anhydrous THF solution containing magnesium powder (1.1g, 45 mmol), stirred for 30 min, and refluxed for another 30 min. After it was cooled, the clear reaction solution was added into carbon disulfide (4 ml, 67 mmol) at 0 OC, and stirred for 30 min at rt. The resulting mixture was then added into methylhydrazine (8 ml, 150mmol) at 0 and stirred for another 2 hours. To this solution was added water (40 ml) and extracted with EtOAc (60 ml x The organic solution was concentrated to minimum volume, and subjected to silica gel column chromatography (1:1 ethyl acetate: hexanes; ethyl acetate) to give thiocyclopropyl carboxylic acid N'-methyl hydrazide (2.8 g, 55 'H NMR (300MHz, CDC1 3 6 5.21 2H), 3.62 3H), 1.91 1H), 1.25 (m, 2H), 0.98 2H). ESMS cacld (C 5 sHN 2 130.1; found: 131.1 To the hydrazide EtOAc solution (2.8 g, 22 mmol, 40ml) containing TEA (2.2g, 22mmol) was added malonyl chloride EtOAc solution (1.6g, 1 Immol, 4ml) at 0 OC, and the reaction mixture was stirred at rt for 20 min. 20 ml water was added to quench the reaction, and the EtOAc layer was continuously washed twice with water (20 ml x 2).
    The EtOAc solution was concentrated to minimum volume, and subjected to silica gel column chromatography (eluant: 1:1-1:2 hexanes ethyl acetate) to give SBR- 11-5685 (2.1 g, yield: (2.1 g, yield: 'H NMR (300MHz, CDCI 3 10.01-8.95 2H), 3.78-3.41(m, 6H), 2.34-0.82 10H). ESMS cacld(C, 3
    H
    20
    N
    4 0 2
    S
    2 328.1; found: 327 I
    O
    SExample 13 O Preparation of 2-Methylmalonyl-bis(2-Amino-2,3-dihydro-isoindole- 1 -thione) S S I H H N-N N-N 00 O O 2-carboxybenzaldehyde (150 mg, nmmol) and carbazic acid (132 mg, 1
    C
    5 mmol) in 40 ml methanol was stirred at room temperature for 4 h. To this solution was added Pd/C (60 mg, containing 50 HO), the reaction was under H 2 atmosphere for 3 h. The reaction mixture was filtered, and the solvent was evaporated. The resulting residue was subjected to silica gel column chromatography.
    (eluent: 20% to 50 EtOAc in hexanes) to obtain 50 mg of product. 'H NMR (300MHz, CDC1 3 8 8.71-7.45 4H), 4.78 2H), 1.61(s, 9H). The resulting product was dissolved in CF 3 COOH (5ml), stirred for 30 min. The CF 3 COOH was evaporated, and the residue was subjected to silica gel column chromatography (eluent: 50% to hexanes in EtOAc) to give 2-amino-2,3-dihydro-isoindol-l-one (26mg) as a white solid. 'H NMR (300MHz, CDC1 3 8 7.85-7.39 4H), 4.54 (s, 2H). MS: 149 Subsequent Lawesson's thiolation and DCC coupling with 2methylmaloic acid under conditions described above afforded 2-methylmalonylbis(2-amino-2,3-dihydro-isoindole-l-thione) as a yellow powder. 'H NMR (CDCl1) 8 10.35 2H), 8.21-7.51(m, 8H), 5.15(s, 4H), 1.62 3H); ESMS cacld
    (C
    20
    H,
    8
    N
    4 0 2 410.09; found: 411.1 Example 14 The compounds shown below were prepared by the procedures described above. Analytical data is provided for these compounds.
    IND -46- S S C.)H
    H
    0 N N 0 0 00 'HI IR (CDCI 3 6 3.1 -3.8 (in, 3.4 2H), 7.1 7.45 (in, 10 9.5 -10.5 (N (in, 111) ppm; ESMS calcd (C I 9
    H,
    0
    N
    4 0 2
    S
    2 400. 1; found: 399.1 S H H 'H NMR (CDC1 3 8 1.0-1.3 5 (in, 611), 3.0-4.3 (mn, 611, 7.05-7.40 (in, 1011I), 9. 1-10.1 (mn, 211); ESMS cacid (C 2
    ,H
    2 4
    N
    4 0 2
    -S
    2 428.8; found: 427 Anal Calc For
    C
    2 4
    N
    4 0 2
    S
    2 (428.13) C, 58.85; H, 5.64; N, 13.07; S, 14.96. Found: C, 58.73; H1, 5.62; N, 12.97; S, 14.96.
    s H H S N A I 'H NMR (CDCl 3 8 0.7-1.0 (mn, 611), 1.4-1.9 (in, 411), 3.1-4.2 (in, 6H), 7.1-7.4 (in, 1011), 8.9-10.2 (mn, 211) ppm; ESMS (C 2 3
    H
    2 sN 4 0 2
    S
    2 456. 1; found: 455.1 s H H S N- N Y f>NN I 0 mp 141 143 TC; 'H NMvR (CDC1 3 5 0.6-1.05 (mn, 611), 1. 1- 1.9 (in, 811), 3.0-4.2 (in, 6H1), 7.0-7.35 (mn, 1011), 8.9-11 (ins, 214). ESMS (C 25
    H
    32
    N
    4 0 2
    S
    2 484.2; found: 483.1 Anal Caic For C 25
    H
    3 2
    N
    4 0 2
    S
    2 (484.2) C, 61.95; H, 6.65; N, 11.56; S, 13.23.
    Found: C, 61.98; H,6.52; N, 11.26; S, 13.16.
    INO -47- 0 ~0 0 'H NMR (DMSO-d 6 5 0.4-0.9 (dd, 3H, J 2.7 IH), 3.1 3.6 (mn, 6H), 7.1 (mn, IlOH), 10.9 (br, 2H)ppm; ESMS (C 10
    H
    2 2
    N
    4 0 2
    S
    2 414; found: 413 00 c-iH H S 0~ 0 'H NMIR (CDC1 3 5 0.5 3H, J 1.1-1.6 (mn, 2H1), 2.7 1H. J 3.1 3.3 (in, 6H), 7.0-7.3 (mn, 1011), 10.25 211)ppin; MS (C 2
    H
    24
    N
    4 0 2
    S
    2 428. 1; found: 427.1 s H H 'H NMR (CDC1 3 5 0.5 611, J 0.9-1.2 (in, 1H), 3.0-41 (in, 7.1-7.4(m, 1011), 10. 3 211)ppm; ESMS (C 22
    H
    26
    N
    4 0 2
    S
    2 442. 1; found: 44 1.1 S H H N N N, 'H NMR (CDC1 3 5 0.4-1.3 (mn, 5H1), 1.5-1.8 (mn, 211), 3.0-3.7 (mn, 611), 7.1-7.5 (mn, 1011), 11I 211) ppin; MS (C23H 2
    ,N
    4
    O
    2
    S
    2 456. 1; found: 455.1 IND -48- 0 H Y H SJ
    N'N
    'H NMIR (CDC1 3 5 2.1 2H, J 2.9 1H, J 3.1-3.5 (in, 6H), 6.8-7.4 (n IND 15 I11 2H)ppm; MS (C 26
    H
    26
    N
    4 0 2
    S
    2 490. 1; found: 489.1 Crl L" 0 q 1 'H NMR (CDC1 3 8 0.4 3H, J 1.0-1.4 (in, 6H), 2.75 I1H), 3.0-4.3 (mn, 4H), 7.1-7.4 (mn, I OH), 10. 6 ESMS Caic For (C 22
    H
    26
    N
    4 0 2
    S
    2 442. 1; found: 44 1.1 Anal Caic For C 22
    H
    2 6
    N
    4 0,S, (442.15) C, 59.70; H, 5.92; N, 12.66; S, 14.49.
    Found: C, 59.64; H, 5.92; N, 12.59; S, 14.47.
    s H H- S N A -~yN, 0 b 'HNMR (DMSO-d 6 5 0.9-1.8m, 22$, 3.1-3.5 (mn, 7.2-7.6 (mn, 10OH, 11.1 11.7 (ins, ppm; ESMS calcd (C 29
    H
    36
    N
    4 0 2
    S
    2 found: 537.3(M-H)+.
    IND -49- 'H M (DMSO-d 6 8 3.20 (br, 2H), 7.1-7.6 (mn, 20 11.5 2H) ppm; ESMS o calcd 24
    N
    4 0 2
    S
    2 524. 1; found: 523.1 s H H Oe 00 ola 000 IND'H NMR (CDC1 3 5 3.0-4.3 (mn, 14H), 6.6-7.5 (mn, 8H), 10.4 2H) ppm; ESMS calcd (C 2
    ,H
    24
    N
    4 0,S 2 460.2; found: 461.2 4 s H H S 'H NMR (CDCI 3 8 2.65-3.60 (in, 8H), 7.2-7.4 (mn, 8H), 11. 1 (br, 2H); ESMS calcd
    (C,
    9
    H,
    8 C1 2
    N
    4 0 1
    S
    2 468.0; found: 467.9 (M-H) 4 s HJH H N' N, 0 0 'H NMR (CDC1 3 5 0.4 3H, J 2.7 1H, J 3.0-3.8 (mn, 6H), 7.2-8.2 (in, 8H), 10.5-10.7 (mns, 2H) ppm; ESMS calcd (C 20
    H,
    0 C1 2
    N
    4 0 2
    S
    2 482.0; found: 481.0 0 2
    NNO
    N02 IND 'H NMIR (CDC1 3 )8 m, 6W), 7.3-7.7 (in, 4H), 8.0-8.3 (in, 4H), 10.9 2H); 0 ESMS calcd (C 10
    H,
    8
    N
    6 0 6
    S
    2 490.0; found: 489.0 S H H N'm Nl'-N N" Cl ~0 0 O 'H NMvR (CDCI 3 8 3.1-3.9 (in, 14H), 6.7-7.8 (in, 8W), 9.0-10 (in, 2W) ppm; ESMS calcd (C 2
    ,H
    24
    N
    4 0 4
    S
    2 460. 1; found: 459.1 H H N N (SBR-1 1-5032): 'H NIIR(CDCI 3 )563.0-3.9 14W),6.7-7.3 9.0-10(in, 2H) ppm; ESMS calcd (C 2
    ,H
    24
    N
    4 0 4
    S
    2 460.1; found: 459.1 H
    H
    N 0 'H NMvR (acetone-d 6 6 3.5 2H), 6.45 2H, J 6.9 2H-, J 7.2-7.6 (mn, 12W), 10.6 2H) ppm; ESMS calcd (C25H 20
    N
    4 0 4
    S
    2 504. 1; found: 503.1 IND -51- 'H NMv~R (DMSO-d6) 8 2.60 6H), 3.05 6H), 3.40 2H), 7.15-7.50 (in, o 8H)ppm; ESMS calcd (C 27
    H
    24 Cl,N 6 0 4
    S
    2 630. 1; found: 629.1 000 001 0 00 'H NMR (CDC1 3 8 10.06-8.82 (2M-1, 7. 16-6.8 1 4 .01-3.8 1(m, 3.78- 3.1 1(m,6H), 2.81-2.58(in,2H): ESMS cacid (C23H 2 eN 4
    O
    6
    S
    2 520.15; found: 521 0 S HH S 'H NMR (CDCI 3 8 10.38-9.01 7.12-6.82 (mn, 6H), 3 .9 2 -3.78(m, 12W), 3.75- 3.06(m, 6H), 2.61-2.51 (in, 2W); ESMS cacid (C 23
    H
    28
    N
    4 0 6
    S
    2 520.15; found: 521 'NO N'N N .N01- 'H NlvlR (CDC1 3 8 9.45-8.63 (2H1), 7.18-6.81 (mn, 6H), 4 .01-3.80(m, 6H), 3.78- 3.24(m, 6H1), 2 .62-2.50(m, 1W, 1.74-0.11 (mn, 311); ESMS cacid
    (C
    24
    H
    30
    N
    4 0 6
    S
    2 ):534.16; found: 535
    IN
    52- 'H NMR (CDC1 3 810.19-8.61 (2H1), 7.26-6.52(m, 3.81-3.08(m, 811), 3.01- 2.88(m, 121H). ESMS cacid (C23H 30
    N
    6
    O
    2
    S
    2 486.19; found: 487 cI CI 1H NMR (CDC1 3 5 9.92-8.80 7.41-6.72 (in, 611), 4.01-3.81(m,6H), 3.80-3.15 2.76-2.42(m, 2H); ESMS cacid (C 11 11 22
    C
    2
    N
    4 0 4
    S
    2 ):528.05; found: 529(M+11).
    1H NMR (CDC 3 8 10.21-9.02(2H1), 7.60-6.81 (in, 611), 4.14-3.88(rn, 6H1), 3.87-3.18 2.84-2.65(m, 11),1.10-0.16 (in, 311); ESMS cacid (C22H, 4 Ci 2
    N
    4
    O
    4
    S
    2 542.06; found: 543(M+H).
    -53- 'H NIR (CDG1 3 5 10.02-9.20 7.63-7.01 (in, 6H), 4.21-3.22(m, 6H), 1.88-1.36 (rn, 2H); ESMS cacid (Cl 19
    H
    16
    F
    4
    N
    4 0 2 472.07; found: 473 'H NMIR (CDC1 3 8 7.93-7.61 7.40-6.92 (in, 6H), 3.98-3.41 (mn, 2.19-0.93 (mn, 4H); ESMS cacid (C,,H 18
    F
    4
    N
    4 0,S 2 486.08; found: 487 'H NMR (CDCI 3 S 10. 12-9.21(2M), 7.67-7.23 (in, 6M), 3.94-3.22 (in, 6H), 2.01-1.21 ESMS cacid (C 19
    H
    1 6 C1 4
    N
    4 0 2
    S
    2 535.95; found: 537(M+H4).
    -54- 'HNMR (CDC1 3 S7.78-7.23 4.56-3.10 (in,6H), 21.34-1.12 4H); ESMS cacld (C 20
    H,
    8 Cl 4
    N
    4 0 2
    S
    2 549.96; found: 551 'H NMR (CDC1 3 5 9.92-9.0 1 7.38-7.15 6.66-6.5 1 3.98-3.75 12H), 3.72-3.21 2.01-0.42 (in, 4W; ESMS cacid (C 24
    H
    3
    ON
    4 0 6
    S
    2 ):534.16; found: 535 'H NMR (CDCI 3 8 10.5 1-9.82 7.42-6.80 6H1), 3.92-3.04(m, 6H), 2.60- 1.21 (mn, 14H); ESMS cacid (C23H 2
    ,N
    4
    O
    2
    S
    2 456.17; found: 457(M+W).
    1H NMR (CDCI 3 8 10.51-8.82 7.11-6.89. (mn, 611), 3.81-3.02 (in, 611), 2.40- 1.02 (mn, 16H1); ESMS cacid (C' 4
    H
    30
    N
    4 0 2
    S
    2 470.18; found: 471(M+W).
    O SH H SO0 Nr- N 1:1 ,O "0 'H NMR (CDCL 3 5 9.86-8.42 (2H1), 7.01-6,6 (in, 611), 4.18-3.51 (mn, 16H), 3.22-2.26 (211), 1.40-1.04 (mn, ESMS cacid (C2,H 32
    N
    4
    O
    6
    S
    2 ):548.18; found: 547 (M-11).
    OS H HSO11 N 00 N .N1 'H NUIR (CDCL 3 5 9.99-8.41 7.01-6.68 (mn, 6H1), 4.18-3.56 (in, 1611), 1.40- 0.02 (in,101); ESMS cacid (C, 6
    H
    34
    N
    4 0 6
    S
    2 562.19; found: 561(M-H).
    r0 11H NMR (CDC1 3 8 10.12-8.82 (211), 7.03-6.62 (mn, 6H1), 4.21-3.87 (mn, 811), 3.84- 3.01(mn, 6H), 2.71-2.42 (mn, 211), 1.56-1.21 (in, 1211); ESMS cacid (C 27
    H
    36
    N
    4 0 6 S 2 576.21; found: 577(N4+1-1).
    sL%0 IND -56-
    'HNMR(CDC
    3 59.81-8.79 (2H4), 7.01-6.64 (in, 6H), 4.21-3.81 8H), 3.80-3.22 0 6H), 1.54-1.20 (in, 131H1), 1.01-0.16 (in, 3H); ESMS cacid (C 2
    ,H
    38
    N
    4 0 6
    S
    2 590.22; found: 591(M+H).
    0 2 N
    NO
    2 00 s 0 0 IDH
    H
    'H NMR (DMSO-d 6 858.25 J=8.1 Hz, 4H4), 7.50 J=8.1 Hz, 4H), 3.7-3.3 (mn, 8H); ESMS cacid for C 19 H,gN 6 0 6
    S
    2 490.1; Found: 489.0 ~Ns 0 0s, H H 'H sNM (CDCL 3 8 3.6-3.4 (in, 8H), 2.7-2.5 (mn, 6H); ESMS cacid for C 9 H1 6
    N
    4 0 2
    S
    2 276.1; Found: 274.9 (M-1-D.
    N IN 0 0 N.Nl-NN, H H 'H NMvIR (CDC1 3 8 10.25 (mn, 2H), 7.7-7.4 (mn, 81H), 3.7 (mn, 2H), 3.35 (in, 6H4); ESMS cacid for C 2 ,H,sN 6 0 2
    S
    2 450. 1; Found: 449.0
    IN
    W N flA
    N
    H H IND -57- 'H NMR (CDC1 3 8 8.2 2H), 7.7-7.5 (in, 4H), 3.7-3.4 (mn, 8H), 2.9-2. 8 (in, 6H); o) ESMS cacid for C, 9
    H
    22
    N
    6 0 2
    S
    2 430.1; Found: 431.1 CN CN 00 N. .N)I AN c-iH
    H
    'H NMR (CDC1 3 8 10.0-9.2 (mn, 2H), 7.9-7.45 (in, 8H), 4.0-3.4 (i,8H; ESMS cacid for C 2
    ,H,
    8
    N
    6 0 2
    S
    2 450.1; Found: 451.0 (M4+H).
    F F H H 'H NMR (CDCI 3 5 10.1-9.4 7.5-7.2 (in, 8H), 3.9-3.3 (mn, 8H); ESMS cacid for
    C,
    9 Hl 8
    F
    2
    N
    4 0 2
    S
    2 436.1; Found: 437.1 (M4+H).
    -58- 'H NMR (CDC1 3 5 3.3 2H), 3.6 6H), 5.25 4H), 7.05-7.3 (in, 16H), 7.6 (s, 211), 7.9 2H1, J 10.56 21-)ppm; ESMS calcd (C 37
    H,
    4
    N
    6 0, 2 D: 658.2; found: 659.2 00 'H NMR (DMSO) 8 11.98 (2H1), 7.44-7.12 (in, 1011), 3.69-3.14(s, 6H). ESMS cacid
    (C,
    8
    H,
    8
    N
    4 0 2
    S
    2 386.09: found: 387.1 'H NMR (CHCI 3 )5 9.48-8.55 7.56-7.20(m, 1OH), 3.80-3.31(m, 6H), 2.88- 2.22(m, 4H). ESMS cacld (C 20
    H
    22
    N
    4 0 2
    S
    2 414.12; found: 415.1 s -NH hO I N-H -59- 'H NMR (300 MHz, CDC1 3 8 10.21-9.91 2H), 8.06-7.32 (mn, 14H), 3.91-3.56 (in, 6H). ESMS cacid (C 24
    H
    22
    N
    4 0 2
    S
    2 462.12; found: 463
    S
    0 'H NMR (300 Ivll-z, DMSO-d 6 8 11.60-11.40 (in, 2H), 7.48-6.46(m, 1 2H), 3.64- 3.3.30(mn, 6H). ESMS cacid (C 20
    H
    2 0
    N
    4 0 2
    S
    2 412. 10; found: 413
    S
    N
    *N
    I 1 0 NNy 'H NMR (300 Mvl-z, CDCI 3 6 7.5 8-7.20(m, 12H), 3.68-3.20(m, 6H). ESMS cacid
    (C
    2 0
    H
    2
    ON
    4 0 2
    S
    2 412. 10; found: 413 s
    -O
    'H NMR (300 MIHz, CDC1 3 )8 9.65-8.70 8.01-7.21(m, 14H), 3.84-3.40(m, 61-).
    ESMS cacid (C 24
    H
    22 NA0S 2 462.12: found: 463 Sy,- 0 0 -,fS 'H NUvR (CDC1 3 5 2.63 2H); 2.18 6H); 1.25 1 8H). MS calcd for C1 5
    H-
    2 gN 4 0 2
    S
    2 360.2; Found: 383.1 (M+Na).
    'H NMiR (CDCL 3 5 7.3 (mn, 1IOH); 3.2 (mn, 2H); 2.45 J=7.4 Hz, 4K); 2.21 J=7.4 Hz, 4H); 1.90 (in, 8H). MS calcd for C 25
    H
    28 N,0 6
    S
    2 544.15; Found: 567.2 (M+iNa).
    aT0 00s YOiI~ 'H NMIR (CDC1 3 6 7.4-1 18H); 3.3 (br s, 2H); 2.5 (br s, 6H). MS calcd for
    C
    3
    ,H
    28
    N
    4 0 3 S: 5 36.2: Found: 5 37.2 (M4+K).
    IA ~Z"H 3
    H
    3 cII 2 'H NMR (CDC1 3 567.2 (in, 18H); 3.5 (br s, 2K); 2.4 (br s, 6K). MS calcd for
    C
    3 lH2 8
    N
    4 0 2
    S
    2 5 52.2: Found: 5 53.2 -61-
    N
    H
    CH
    3
    CH
    3 'H NMR (CDC1 3 5 7.8-7.4 (br s, 8H), 3.75-3.5 (in, 2H), 3.95-3.8(m, 4H), 2.58 (s, 6H), 1.4 (in, 6H). ESMS cacid for C 23
    H
    2 8
    N
    4 0 2
    S
    2 456.2; Found: 479.2 (M+Na).
    'H NMR (CDCL 3 8 7.5 (br s, 18H), 3.4 (br s, 2H), 2.45 6H). ESMS cacid for
    C
    33
    H
    28
    N
    4 0 6
    S
    2 640. 1; Found 64 1.1
    H
    3 C ss
    H
    3 14N N N 'H NMR (CDC1 3 588.3-8.05 (mn, 4H), 7.75 J=8.0 Hz, 2H), 7.1 (br s, 2H), 3.74 (s, 2H), 2.38 6H). ESMS cacid for C, 7
    H,
    8
    N
    6 0 2 402. 1. Found: 403.1
    H
    3 C Q 0 s CH 3 SCI 0 0 CI c i H H 00 'H NMR (CDCI 3 857.7-7.2 6H), 3.2 2H), 2.58 3H), 2.15 3H). ESMS C cacid for C, H, 6 C1 4
    NO
    3 S: 519.9; Found: 520.9 NN S SN U l
    H
    'H NMR (CDCI 3
    -D
    2 8 7.45-7.15 20 1.6 (br s, 6H). ESMS cacid for
    C
    3
    H
    2 8
    N
    4 0 2
    S
    2 552.2; Found: 553.2 I;LT 0 0
    H
    'H NMR (DMSO-d 6 5 11.3 2H), 7.75 J=6.0 Hz, 2H), 7.5-7.4 12 6.9 2H); ESMS cacid for C 27
    H
    24
    N
    4 0 2
    S
    4 564.1; Found: 565.2 I I 0 0 I I N" N N I N Y*H H Y -63- 'H NMR (30M-z, CDC1 3 6 10.18-8.60 (in,2H), 7.26-6.46 (in, 8H), 3.80-3.02(m, 6M, 3 .00-2.80(m, 12W). 1.
    7 8 -1.56(m, 2W). ESMS cacld(C 23
    H
    30
    N
    4 0 2
    S
    2 ):486.19; found: 487 00 'H NMR (300M4Hz, DMSQ): 5 10.90-10.81 (in, 2W), 7.50-7.2 1 (in, 10HW, 3.78- 3.36(m, 6H), 2 .64-0.50(mn, lOW). ESMS cacld(C 20
    H
    2 sN 4 0 2
    -S
    2 456.17; found: 457
    CN
    'H NMvR (300MHz, CDC1 3 8 10.00-9.71 (mn, 2Hf), 7.72-7.21 8W1, 3.80-3.26(m, 6H). ESMS cacld(C 20 Hj 6
    N
    6 0 2
    S
    2 ):436.08; found: 437
    IND
    0
    IND
    'H NMR (30MHz, CDCI 3 8 10.60-9.41 (mn, 2H1), 7.15-6.23(in, 6H1), 3.89-3.28(m,.
    6H), 3 .76(S, 121H). ESMS cacld(C 22
    H
    28
    N
    4 0 6
    S
    2 :506.13; found: 507 (M4+H).
    C
    H
    )y N N N
    H
    s 'H NMR (3001vMHz, DMSO): 8 7.40-7.12 (mn, 10H1), 3.70-2.80(m, 6H), 1.84-0.72(m, 16H1). ESMS cacld(C 26 H34N 4
    O
    2
    S
    2 ):498.21; found: 499 'H NMR (300MIHz, CDC1 3 8 10.42-9.53 (in, 2H), 7.55-6.87(m, 8H), 3.99-3.28(rn, 6H), ESMS cacld(CjgH, 0
    N
    4
    F,
    2 0 2
    S
    2 22.07; found: 423 (M+JI).
    I N
    NS
    INNN
    H 0 s N0 2 'H NMR (300M4Hz, DMSO): 8 12.08 (br. 2H), 8.27-7.24 (mn, 8H), 3 7 0-3.15(m, 6H-).
    ESMS cacld(C, 8
    H,
    6
    N
    6 06S 2 ):476.06; found: 477 -66- 'H NMR (300MHz, CDC1 3 8 10.12-9.83 (in, 2H1), 7.15-6.63(m, 6H), 3.99-2.91(mn, 6H), ESMS cacld(C 2 2
    H
    26
    N
    4 0 6
    S
    2 ):506.13; found: 507 0 0 S
    S
    'I-NMR(300MHz,DMSO): 8 11.12-10.54 (in, 211), 8.27-7.18 (mn, 10H), 4.26- 3.72(mn, 2H), 3.37-3.18(m, 2H). ESMS cacld(C,,H, 6
    N
    4 0 2
    S
    2 ):372.07; found: 371 (M-
    H).
    N
    H
    'H NNf (300Mlz, DMSO): 8 11.52 (br, 2H), 7.95-7.33(mi, I1OH), 3.42-3.22(m, 6H), 2.48(m, 2H). ESMS cacld(C23H 20
    NO
    2
    S
    4 12.05; found: 513 0 0
    N
    H
    N
    H
    1H NMvR (300MFz, CDC1 3 8 7.81-7.28(m, 8H), 3.82(s, 6H). ESMS cacld(C 2 2 H,sN 4 0 2
    S
    4 :498.03; found: 499 'H1 NMR (300MIz, CDC1 3 5 10.02-9.11 (in, 2H1), 8.16-7.28(mn, 81H), 3.99-3.08(m, 6H1), 2.90-1.20(m, 2H1). ESMS cacld(CQlH 2 4
    N
    4
    OS
    2 ):516.1 1; found: 517 IND -68-
    C.)
    00 M0 N N 0 'H NMR (300M~z, DMSO): 8 7.99 (in, 8H), 8.16-7.28(m, 8H), 3.80-3.14(mi, 6M), N1 1.80-1.21(m, 2H). ESMS cacld(C 2 2
    H
    20
    N
    4 0 6
    S
    2 ):488.08; found: 487 0 01-, 1 1 Si
    S
    'H NUR (300M1-z, CDC1 3 8 10.82-10.5 5 (mn, 2H), 7.91-7.29(m, I OH), 3.64- 3.1 1(in, 6H), 1.90-1.40(m, 2H). ESMS cacld(CjqH2 0
    N
    4 0,S 2 ):400.19; found: 399 (M-
    H).
    'H NM (CDC1 3 6 7.3 8 (in, 10OH, 2.40 6H), 1.5-1.6 ESMS cacid for
    C
    21
    H
    24
    N
    4 0 2
    S
    2 564. 1; Found: 565.2 -69- 'H NMvR (DMSO-d 6 8 O.9-1.8m, 22H), 3.1-3.5 (in. 21H), 7.2-7.6 (in, I01OH), 11.1 11.7 (ins, 2H) ppm; ESMS calcd (C 29
    H
    36
    N
    4 0 2
    S
    2 ):536.3; found: 537.3(M-H)'.
    'H NMR (CDCI 3 8 3.6-3.4 (mn, 8H), 2.7-2.5 (mn, 6H); ESMS cacid for C 9
    H
    16
    N
    4 0 2
    S
    2 276. 1; Found: 274.9 >rN.NIJ N.Ny<r 'H NN'R (CDC1 3 8 2.63 2H); 2.18 6H); 1.25 18H)..MS calcd for
    C
    15
    H
    28
    N
    4 0 2
    S
    2 360.2; Found: 383.1 'H NM (CDC1 3 5 7.3 (mn, I1OH); 3.2 (mn, 2H); 2.45 J=7.4 Hz, 4H); 2.21 J=7.4 Hz, 4H); 1.90 (mn, 8W). MS calcd for C 25
    H
    2
    ,N
    4 0 6
    S
    2 544.15; Found: 5 67.2 s~T CH 13
    C)
    NNl
    N
    H HI
    CH
    3
    CH
    3 00 'H NMR (CDC1 3 6 7.8-7.4 (br s, SH), 3.75-3.5 2H), 3.95-3.8(m, 4H), 2.58 (s, CI 6H), 1.4 6H). ESMS cacid for C 23
    H
    2
    ,N
    4
    OS
    2 456.2; Found: 479.2 (M+Na).
    H3CIS O 0 SJ..CH 3 NN N H H 'H NvR (CDC1 3 6 8.3-8.05 4H), 7.75 J=8.0 Hz, 2H), 7.1 (br s, 2H), 3.74 2H), 2.38 6H). ESMS cacid for C, 7
    H,
    8
    N
    6 0 2
    S
    2 402.1. Found: 403.1
    N/
    H
    H
    ZI-I A
    N
    1H NvR (CDCI 3 67.38 10 2.40 6H), 1.5-1.6 ESMS cacid for
    C,,H
    24
    N
    4 0 2 564.1; Found: 565.2 0 0 N N H H s s 'H NMR (300MHz, DMSO): 6 11.95 2H), 7.48-7.07(m, 10$, 3.52(s, 6H). ESMS cacld(C, 8
    H,
    8
    N
    4 0 2
    S
    2 ):386.09; found: 387 IND -71- 0 0 H H S S 'H NMR (300M~z, CDCI 3 8 9.66-8.83 (in, 2H), 3.73-3.23(m, 6H), 2.10-1.20 00 ESMS cacld(C 1 5
    H
    28
    N
    4 0 2
    S
    2 ):360.17; found: 359 0 0 Y"H
    H
    S S 'H NMR (300MIHz, CDC1 3 8 3.66-3.42(m. 6H), 2.84-2.58(m, 4H), 1.40-1.19(m, 611).
    ESMS cacld(CjjH 20
    N
    4 0 2
    S
    2 04.I10; found: 3 03 0 0 H H S S 'H NMR (300MIHz, CDCL 3 8 4.15-3.40(m, 6H), 2.00- 1.01 14$. ESMS cacld(C 1 4
    H
    22
    N
    4 0 2
    S
    2 ):342.12; found: 341 1 0 0 H H
    SS
    'H NMR (300M14z, CDC1 3 8 3.90-3.18(m, 6H), 2.1 1-0.91 I1OH). ESMS cacld(C 2
    H,
    8
    N
    4 0 2
    S
    2 14.09; found: 313 -72- 'H NMIR (300M4Hz, CDCJ 3 8 10.08-9.01(m, 2H), 3.68-3.20(m, 6H), 2.59-1.12(m, 16H1).
    ESMS cacld(COUH 2
    N
    4 0 2 SO)356.13; found: 355 'H NMR (300Mi~z, CDC1 3 5 10.22-9.41(m, 2H1), 7.48-7.20(m, 5H), 3,82-3.02(m, 6H), 2.38-0.82(m, 7H). ESMS cacld(C 6
    H,
    0
    N
    4 0 2
    S
    2 364.10; found: 363 0 0 YH
    H
    S S 'H NMvR (300M1-lz, CDC1 3 5 10.03-9.02(m, 2H1), 3.71-3.42(mn, 6H), 2.80-0.8 1(m, 16H1).
    ESMS cacld(C, 3
    H
    24
    N
    4 0 2
    S'
    2 332.13; found: 331 0 0 'H NNvII (300M4Hz, CDC1 3 8 3.78-3.08(m, 6H1), 1.90-0.81(m, i8H). ESMS cacld(C 5
    H
    24
    N
    4 0 9
    -S
    2 3 56.13; found: 3 55 -73- 'H NMR (300MHz, CDCI 3 6 10.00-8.79(m, 2H1), 3.65-3.07(m, 611), 2.79-1 .08(m, 24H1).
    ESMS cacld(CjqH 32
    N
    4 0 2
    S
    2 412.20; found: 411 (M-H) 4 0 00 H
    H
    S S 'H NMR (30M1hl, CDC1 3 8 9.79(br, 2H1), 3.79-3.41 6H1), 1.60-0.75(m, 18H). ESMS cacld(C, 5
    H
    24
    N
    4 0 2
    S
    2 356.13; found: 355
    H
    'H NMR (300MHz, CDC1 3 8 10.03-9.14(mn, 2H), 4.21-3.39(m, 4H1), 2.20-0.76(m, 181-1). ESMS cacld(C, 5
    H
    24
    N
    4 0 2 356.13; found: 355 (M-Hy+.
    N N y H
    H
    S
    S
    'H NMR (300MHz, CDC1 3 5 7.57(br, 2H1), 3.72(s, 2.95(m, 6H1), 1.96-0.8 1(m, ESMS cacld(C 2 jH 36
    N
    4 0 2
    S
    2 ):440. 13; found: 439 -74- 'H NNM (300MlHz, CDC1 3 5 10.09-8.95(mn, 2M, 3.78-3.05(m, 6m-I, 2.04-1.22(m, ESMS cacld(C, 7
    H
    2 gN 4 0 2
    S
    2 ):384.17; found: 383 0 N N
    H
    S
    S
    'H NMiR(300MIHz, CDCI 3 5 10.09-8.5 1(m, 2H), 7.41-7.0 1(mn, I1OH), 3.62-.3.02(m, 1.78-1.03(m, I1OH). ESMS cacld(C 2 5
    H
    28
    N
    4 0 2
    S
    2 480.17; found: 479 0 0 N N H H
    SS
    'H NMR (300MlHz, CDC1 3 8 10.09-8.81 (in, 2H), 7.5 1-7.11 I1OH), 3.80-3.06(m, 6H), 2.92-1.53(m, lOB). ESMS cacld(C2,H 2 8
    N
    4 0 2
    S
    2 480.17; found: 479 IO
    O
    O
    SExample O Compound Demonstrates Multi-Drug Resistant Specific Anti-Cancer Activity In Vitro o H H
    O
    8 s
    S
    N 5 Compound (1) The in vitro activity of the compounds was assessed in a selected set of human cancer cell lines. Three pairs of tumor cell lines (non-resistant/resistant) were used to identify novel potent antitumor compounds which are capable of overcoming multi-drug resistance.
    HL-60, a model of myeloid leukemia, was obtained from ATCC (ATCC CCL-240); and HL60/TX1000 was isolated in vitro by subculturing HL-60 in progressively higher concentration of Taxol. HL-60/TX1000 cells over-express mdr-1 mRNA and p-glycoprotein (PCP), as determined by western blot and immunofluorescence labeling with antiPGP antibodies. The cells are cross-resistant to Taxol, Vincristine, Adriamycin, Etoposide and Doxorubicin.
    MES-SA, a model of uterine sarcoma, is sensitive to a number of chemotherapeutic agents, including Doxorubicin, Dactinomycin, Mitomycin C, Taxol and Bleomycin, but resistant to Vinblastine and Cisplatin. MES-SA was established in the presence of increasing concentrations of Doxorubicin. The cells express high levels of mdr-1 mRNA and p-glycoprotein and exhibit cross resistance to more than fifteen chemotherapeutic agents including Taxol, Etoposide, Mitomycin C, Colchicine, Vinblastine, Dactinomycin, 5-Fluorouracil, Methotrexate O -76-
    O
    and others. Both MES-SA and MES-SA/Dx5 were purchased from ATCC (ATCC
    O
    CRL-1976 and ATCC CRL-1977, respectively).
    Bowes is a melanoma cell line; and Bowes/OV2 is a Vincristine resistant f) Bowes melanoma cell line.
    O
    oO 5 The cell lines were maintained in RPMI1640 (GIBCO) supplemented with N 10% FCS, 100 units/ml penicillin, 100 ug/ml streptomycin, and 2 mM L-glutamine.
    SThe cells were split every third day and diluted to a concentration of 2 x 10' cells/ml one day before experiment. All experiments were performed on exponentially growing cell culture. Cell densities were 2.5 x 104 cells/ml in all experiment except special.
    A stock solution of Compound Taxol (positive control) and Vincristine (positive control) were prepared by dissolving the compound at a concentration of 1 mM in 100% DMSO. Final concentrations were obtained by diluting the stock solution directly into the tissue culture medium. Cells were incubated with varying concentrations of compounds for 72 hours and the IC 50 was determined by MTS (i.e.
    3-(4.5-dimethylthiazol-2-yl)-2.5-diphenyl tetrazolium bromide) assay. The IC 50 is the concentration of compound required to inhibit 50% tumor cell growth. The results are shown in Table 1.
    Table 1 Inhibition of Growth of Multi-Drug Resistant Tumor Cell Lines by Anti- Cancer Agents and Compound (1)
    ID
    0 0 IC 50 (uM) MES-SA MES-SA/DX5 HL-60 HL-60/TX1000 Bowes Bowes/OVZ raxol 0.005 5 0.002 5 0.005 Vincristine 0.004 5 0.002 5 0.002 Compound 0.05 0.005 0.4 0.05 0.2 0.01 As can be seen from the data in Table 1, Taxol and Vincristine demonstrated significantly high anti-cancer activity (IC 50 0.002-0.005 uM) agaist normal cancer cell lines (MES-SA, HL-60, Bowes). However, these anti-cancer drugs were significantly less effective (IC 50 5 uM) against the MDR cell lines HL-60/TX1000, Bowes/OV2). On the other hand, Compound surprisingly showed higher anti-cancer activity against all three MDR cell lines. The specificity were 10 0.05/0.005), 8 and 20 against HL60/TX1000, and Bowes/OV2, respectively.
    Example 16 Compounds Demonstrate High Anti-Cancer Activity Against Multi-Drug Resistant MES-SA/DX5 In Vitro The protocol described in Example 15 was used to test Compounds for investigating inhibitory activity of cancer cell growth of MES-SA/DX5, which is -78a MDR uterine sarcoma cell line. The results are shown in Table 2, below.
    Table 2 Inhibition of Growth of the Multi-Drug Resistant Tumor Cell Line MESby Compounds ICso (uM) Compound Taxol 2 0.005 3 0.05 4 0.005 0.05 6 0.005 7 0.01 8 0.005 9 0.005 0.005 11 0.005 12 0.005 13 0.05 14 0.01 0.005 16 0.05 17 0.005 18 0.01 As can be seen from the data in Table 2, Compounds demonstrated significant anti-cancer activity (ICs 0 0.05-0.005 uM) against the multi-drug resistant (MDR) cell line MES-SA/DX5, while Taxol showed very week anti-cancer activity (ICo 5 5 uM) against the same MDR cell line.
    S-79- N Example 17 Compound (16) Demonstrates Anti-Cancer Activity Against Multi- O Drug Resistant Human Uterine Sarcoma MES/SA-DX5 Tumors in Nude Mice S0 0 0S
    C
    N 5 Compound (16)
    PROCEDURE
    A supplemented media was prepared from 50% DMEM/Dulbecco Modified Eagle Medium (High Glucose), 50% RPMI 1640, 10% FBS/Fetal Bovine Serum (Hybridoma Tested; Sterile Filtered), 1% L-Glutamine, 1% Penicillin-Streptomycin, 1% MEM Sodium Pyruvate and 1% MEM Non-Essential Amino Acids. FBS was obtained from Sigma Chemical Co. and other ingredients were obtained from Invitrogen Life Technologies, USA). The supplemental media was warmed to 37 °C and 50 ml of media was added to a 175 cm 2 tissue culture flask.
    The cells used in the assay were multi-drug resistant MES-SA/DX-5 Human Uterine Sarcoma cells from the American Type Culture Collection. 1 vial of MEScells from the liquid nitrogen frozen cell stock was removed. The frozen vial of cells was immediately placed into a 37 OC water bath and gently swirled until thawed. The freeze-vial was wiped with 70% ethanol and cells were immediately pipetted into the 175 cm 2 tissue culture flask containing supplemented media. The cells were incubated overnight and the media was removed and replaced with fresh supplemented media the next day. The flask was incubated until the cells became about 90% confluent. This took anywhere from 5-7 days.
    I 0 0 SThe flask was washed with 10 ml of sterile room temperature phosphate
    O
    buffered saline (PBS). The cells were trypsinized by adding 5 ml of warmed Trypsin-EDTA (Invitrogen) to the flask of cells. The cells were then incubated for S2-3 minutes at 37 °C until cells begun to detach from the surface of the flask. An c 00 5 equal volume of supplemented media (5 ml) was added to the flask. All the cells O were collected into 50 ml tube, and centrifuged at 1000 RPM for 5 minutes at 200 C.
    O
    SThe supernatant was aspirated and the cell pellet was resuspended in 10 ml of supplemented media and the cells were counted. 1-3 million cells/flask were seeded into 5-7 tissue culture flasks (175 cm 2 Each flask contained 50 ml of supplemented media. The flasks were incubated until about 90% confluent. The passaging of the cells was repeated until enough cells had been grown for tumor implantation.
    The above procedure for trypsinizing and centrifuging the cells were followed.
    The supernatant was aspirated and the cell pellet was resuspended in 10 ml of sterile PBS and the cells were counted. The cells were centrifuged and then resuspended with appropriate volume of sterile PBS for injection of correct number of cells needed for tumor implantation. 100 million cells were suspended with 2.0 ml of sterile PBS to a final concentration of 50 million cells/ml in order to inject 5 million cells in 0.1 ml/mouse.
    Five million MES-SA/DX5 cells were injected subcutaneously into the flan (lateral side) of female CB.17/SCID mice (Age 6-7 wks). These mice were obtained from Taconic, Germantown, NY. (Nomenclature: C.B-Igh-lbIcrTac-Prkdcc") CB. 17/SCID (FOX CHASE SCID) and are homozygous for the autosomal recessive scid (severe combined immunodeficient) gene and lack both T and B cells due to a defect in V(D)J recombination. Therefore, they easily accept foreign tissue transplants. These tumors were allowed to grow until they reached a size of about O -81- 0 200-300 mm 3 before they were excised and prepared as a single cell suspension.
    O These cells were then seeded into tissue culture flasks. The cells went through two passages in vitro before the tumor cells were collected.
    SMice (CD-1 nu/nu) were obtained from Charles River Laboratories: nomenclature: Crl:CD-l-nuBR, Age: 6-8 weeks. The mice were allowed to N acclimate for 1 week prior to their being used in an experimental procedure.
    SImplantation of the MES-SA/DX5 tumor cell suspension took place in the lateral flank of the female CD-1 nu/nu mouse. Five million tumor cells in 0.1 mL of PBS were injected using a 27G (1/2 inch) needle. MES-SA/DX5 tumors developed after 2-3 weeks after implantation.
    Compound stock solutions were prepared by dissolving the compound in cellculture-grade DMSO (dimethyl sulfoxide) at the desired concentration. This stock solution in DMSO was sonicated in an ultrasonic water bath until all the powder dissolved.
    The Formulation Solvent was prepared as follows: 20% of Cremophore (Polyoxyl 40 Hydrogenated Castor Oil obtained from BASF corp.) in water was prepared by first heating 100 Cremophore RH40 in a water bath at 50-60 °C until it liquefied and became clear. 10 ml of the 100 Cremophore RH40 aliquoted into a conical centrifuge tube containing 40 ml of sterile water (1:5 dilution of Cremophore RH40). The 20% Cremophore RH40 solution was reheated until it became clear again, and mixed by inverting the tube several times. This 20 Cremophore RH40 solution was stored at room temperature, and was kept for up to 3 months.
    Preparation of Dosing Solution for Compound Administration: The compound stock solution was diluted 1:10 with 20% Cremophore RH40: 1) 2.0 ml of 10 mg/ml S-82- 0 Sdosing solution of Compound (16) was prepared by diluting 100 mg/ml Compound Stock solution with 1.8 ml of 20 Cremophore RH40 water solution. The final formulation for the dosing solution was 10% DMSO, 18% Cremophore RH40 and n 72% water.
    0o 5 The Dosing Solution (Dosing Volume: 0.01 ml/gram 10 ml/ kg) was Ni injected intravenously into the mice bearing MES-SA/DX-5 human sarcoma tumor.
    PROTOCOL
    Group Compounds (Dose) 1 Vehicle Only 2 Compound (16) (15 mg/kg) Dosing Schedule 3 times a week (Monday, Wednesday, Friday) for 3 weeks mice were used for each group
    RESULTS
    Figure 2 shows the effects of Compound (16) on inhibiting tumor growth of As can be seen from Figure 2, Compound (16) significantly inhibits the tumor growth without any obvious toxicity such as body weight suppression and behavior changes.
    Example 18 Combination Treatment of Compound and Epothilone D Demonstrated Anti-tumor Activity Against Human Breast Carcinoma MDA-435 in Nude Mice
    PROCEDURE
    I -83-
    O
    SA supplemented media was prepared from 50% DMEM/Dulbecco Modified SEagle Medium (High Glucose), 50% RPMI 1640, 10% FBS/Fetal Bovine Serum (Hybridoma Tested; Sterile Filtered), 1% L-Glutamine, 1% Penicillin-Streptomycin, tt 1% MEM Sodium Pyruvate and 1% MEM Non-Essential Amino Acids. FBS was 00 5 obtained from Sigma Chemical Co. and other ingredients were obtained from I Invitrogen Life Technologies, USA). The supplemental media was warmed to 37 °C Sand 50 ml of media was added to a 175 cm 2 tissue culture flask.
    The cells used in the assay were MDA-435 Human Breast Carcinoma from the American Type Culture Collection. 1 vial of MDA-435 cells from the liquid nitrogen frozen cell stock was removed. The frozen vial of cells was immediately placed into a 37 °C water bath and gently swirled until thawed. The freeze-vial was wiped with 70% ethanol and cells were immediately pipetted into the 175 cm 2 tissue culture flask containing supplemented media. The cells were incubated overnight and the media was removed and replaced with fresh supplemented media the next day. The flask was incubated until flask became about 90% confluent. This took anywhere from 5-7 days.
    The flask was washed with 10 ml of sterile room temperature phosphate buffered saline (PBS). The cells were trypsinized by adding 5 ml of warmed Trypsin-EDTA (Invitrogen) to the flask of cells. The cells were then incubated for 2-3 minutes at 37 "C until cells begun to detach from the surface of the flask. An equal volume of supplemented media (5 ml) was added to the flask. All the cells were collected into 50 ml tube, and centrifuged at 1000 RPM for 5 minutes at 200 C.
    The supernatant was aspirated and the cell pellet was resuspended in 10 ml of supplemented media and the cells were counted. 1-3 million cells/flask were seeded into 5-7 tissue culture flasks (175 cm 2 Each flask contained 50 ml of supplemented D -84-
    O
    O
    media. The flasks were incubated until about 90% confluent. The passaging of the 0 cells was repeated until enough cells have been grown for tumor implantation.
    The above procedure for trypsinizing and centrifuging the cells were followed.
    in The supematant was aspirated and the cell pellet was resuspended in 10 ml of sterile cO 5 PBS and the cells were counted. The cells were centrifuged and then resuspended i with appropriate volume of sterile PBS for injection of correct number of cells O needed for tumor implantation. In the case of MDA-435, 100 million cells were suspended with 2.0 ml of sterile PBS to a final concentration of 50 million cells/ml in order to inject 5 million cells in 0.1 ml/mouse.
    Mice (CD-1 nu/nu) were obtained from Charles River Laboratories: nomenclature: Crl:CD-1-nuBR, Age: 6-8 weeks. The mice were allowed to acclimate for 1 week prior to their being used in an experimental procedure.
    Implantation of the MDA-435 tumor cell suspension took place into the corpus adiposum of the female CD-1 nu/nu mouse. This fat body is located in the ventral abdominal viscera of the mouse. Tumor cells were implanted subsutaneously into the fat body located in the right quadrant of the abdomen at the juncture of the os coxae (pelvic bone) and the os femoris (femur). 5 million MDA-435 cells in 0.1 ml of sterile PBS were injected using 27 G (1/2 inch) needle. MDA-435 tumors developed 2-3 weeks after implantation.
    Compound stock solutions were prepared by dissolving the compound in cellculture-grade DMSO (dimethyl sulfoxide) at the desired concentration. This stock solution in DMSO was sonicated in an ultrasonic water bath until all the powder dissolved.
    The Formulation Solvent was prepared as follows: 20% of Cremophore (Polyoxyl 40 Hydrogenated Castor Oil obtained from BASF corp.) in water was I 0 Sprepared by first heating 100 Cremophore RH40 in a water bath at 50-60 oC until O it liquefied and became clear. 10 ml of the 100 Cremophore RH40 aliquoted into a conical centrifuge tube containing 40 ml of sterile water (1:5 dilution of InCremophore RH40). The 20% Cremophore RH40 solution was reheated until it O 5 became clear again, and mixed by inverting the tube several times. This 20 N Cremophore RH40 solution was stored at room temperature, and was kept for up to S3 months.
    Preparation of Dosing Solution for Compound Administration: The compound stock solution was diluted 1:10 with 20% Cremophore RH40: 1) 2.0 ml of 10 mg/ml dosing solution of Compound was prepared by diluting 100 mg/ml Compound Stock solution with 1.8 ml of 20 Cremophore RH40 water solution; and 2) a dosoing solution comprising 2.0 ml of 1 mg/ml ofEpothilone D and 5 mg/ml of Compound was obtained by mixing 0.1 ml of Compound DMSO stock solution (50 mg/ml) and 0.1 ml ofEpothilone D DMSO stock solution (10 mg/ml) and diluting with 1.8 ml of 20 Cremophore RH40 water solution. The final formulation for the dosing solution was 10% DMSO, 18% Cremophore RH40 and 72% water.
    The Dosing Solution (Dosing Volume: 0.01 ml/gram 10 ml/ kg) was injected intravenously into the mice bearing MDA-435 human breast tumor.
    PROTOCOL
    Group Compounds (Dose) 1 Vehicle Only 2 Epothilone D (5 mg/kg) 3 Epothilone D (5 mg/kg) Compound (50 mg/kg) Dosing Schedule 3 times a week (Monday, Wednesday, Friday) for 3 weeks. mice were used for each group N -86- 0
    RESULTS
    O Figure 3 shows the effects of Compound on enhancing anti-tumor activity ofEpothilone D. As can be seen from Figure 3, Compound significantly Senhanced anti-tumor activity of Epothilone D on human breast tumor MDA-435 in nude mice. Figure 4 shows the effects of treatment ofEpothilone D and the oO CN combination of Compound and Epothilone D on the body weight of nude mice Sbearing MDA-435 human breast tumor. As can be seen from Figure 4, Compound enhanced anti-tumor activity of Epothilone D without increasing toxicity.
    Example 19: Compound(l) Has Anti-leukemia Activity in vitro The in vitro activity of the compounds was determined in a selected set of human leukemia cell lines. CEM (T-cell leukemia), Jurkat (T-cell leukemia), K562 (chronic myelocyte), THP-1 (monocyte), SB (B-cell leukemia), U937 (lymphoma) were purchased from ATCC. H2 leukemia cell line was a gift from Harvard Medical School.
    'The cell lines were maintained in RPMI1640(GIBCO) supplemented with FCS, 100 units/ml penicillin, 100 ug/ml streptomycin, and 2 mM L-glutamine.
    The cells were split every third day and diluted to a concentration of 2 x 105 cells/mL one day before experiment. All experiments were performed on exponentially growing cell culture. Cell densities were 2.5 x 104 cells/mL in all experiments.
    Compound was prepared by dissolving the compound at a concentration of 10 mM in 100% DMSO. Final concentrations 10, 1, 0.1, 0.01 and 0.001 pM were obtained by diluting the stock solution directly into the tissue culture medium. Cells were incubated with varying concentrations of compounds for 72 hours and the IC50 was determined by MTS 3-(4.5.-dimethylthiazol-2-yl)-2.5-diphenyl tetrazolium bromide) assay. IC50 is the concentration of compound required to inhibit 50% tumor cell growth. Table 3 shows the in vitro IC50 (pM) cytotoxicity results of Compound versus vincristin and taxol.
    S-87-
    -I-
    C) 0 0 Table 3: In vitro Cytotoxicity (IC50, p.M) of Compound versus Vincristin and in Taxol mc 00 00 5
    ID
    CI 10 Cell Compound Line Species Cell type Vincristin Taxol 39SK Human normal fibroblast >10 1 1 Jurkat Human T cell leukemia 0.005 0.001 0.001 CEM Human cell leukemia 0.01 0.005 0.01 K-562 Human hronic myelocvte 0.05 0.005 0.005 THP-1 Human monocyte 0.01 0.005 0.005 U937 Human lymphoma 0.05 0.005 0.005 SB Human B cell leukemia 0.005 0.001 0.001 H2 Human Leukemia 0.005 0.005 0.005 Example 20: Compound 1 inhibits human T-cell leukemia growth (CEM cell line) Human T-cell leukemia cell line, CEM, was obtained fiom American Type Culture Collection. Eight-week old female SCID mice were purchased from Charles Rive Laboratories (Wilmington, MA). FITC conjugated anti-human HLA- A,B,C was obtained from BD ParMingen (Cat 32294X). ACK lysing buffer was obtained from BioWhittaker.
    CEM cells (Ixl 10 cells in 100 l.1 saline) were implanted intravenously into female SCID mice through the tail vein. Vehicle and Compound were administrated intraperitoneally twice a day and total for 3 weeks. After three weeks treatment, bloods were taken from mouse retro-orbital sinus at 33. Red blood cells were partially lyzed with ACK lysing buffer. The cells were stained with FITC conjugated anti-human HLA-A,B,C antibody for one hour at 4 0 C. FACS analysis was performed to quantitate the amount of CEM cells in the blood. White blood cells were gated for FACS analysis. The results showed that about 3 7 7 4 and 1.
    07 of CEM cells were detected in the white blood cells from vehicle treated, Compound treated, and untreated group respectively (Table 4).
    0 S-88- 0 S Table 4 Summary of CEM cell quantitation at day 33 0 5 00
    IN
    reatment circulating leukemia cells relative to vehicle Vehicle 37.7 100 Compound 4.6 12.2 ntreated mice 1.07 2.8 While this invention has been particularly shown and described with references to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims.
    Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.
    The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates.
    权利要求:
    Claims (17)
    [1] 1. A method of treating a subject with melanoma, said method comprising I administering to the subject an effective amount of a compound represented by the following structural formula: 00 R 3 Z Z R4 R JN R 2 i R 1 I I S R5 R 6 S or a pharmaceutically acceptable salt thereof, wherein: Y is a covalent bond or a substituted or unsubstituted straight chained hydrocarbyl group, or, Y, taken together with both >C=Z groups to which it is bonded, is a substituted or unsubstituted aromatic group; RI-R 4 are independently an aliphatic group, a substituted aliphatic group, an aryl group or a substituted aryl group, or RI and R 3 taken together with the carbon and nitrogen atoms to which they are bonded, and/or R 2 and R4 taken together with the carbon and nitrogen atoms to which they are bonded, form a non-aromatic heterocyclic ring optionally fused to an aromatic ring; Rs-R6 are independently an aliphatic group, a substituted aliphatic group, an aryl group or a substituted aryl group; and Z is =O or =S; wherein the subject is optionally co-administered a second anti-cancer agent other than taxol or an analog of taxol.
    [2] 2. The method of Claim 1 wherein R, and R 2 are the same and R 3 and R4 are the same. IO c-I 0
    [3] 3. The method of Claim 2 wherein Y, taken together with both >C=Z groups to which it is bonded, is a substituted or unsubstituted arylene group. n
    [4] 4. The method of Claim 3 wherein the compound is represented by the 0 following structural formula: 00 C
    [5] 5 RX SR3 N R RN N NR 2 Y I I S Rs R 6 S wherein Ring A is substituted or unsubstituted and X is -CH- or The method of Claim 2 wherein Y is a covalent bond, a substituted or unsubstituted straight chained hydrocarbyl group or a phenylene group.
    [6] 6. The method of Claim 5 wherein Y is a covalent bond, -(CH 2 CH 2 trans-(CH=CH)-, cis-(CH=CH)-, or a 1,4-phenylene group.
    [7] 7. The method of Claim 2 wherein the compound is represented by the following structural formula: R3 O R 4 Ny NR2 I I S S R5 R 6 S wherein Y' is a covalent bond or and R 7 and R, are each independently an aliphatic or substituted aliphatic group, or R 7 is -H and R 8 is a substituted or unsubstituted aryl group, or, R 7 and R 8 taken together, are a C2-C6 substituted or unsubstituted alkylene group. ID -91- -I- O
    [8] 8. The method of Claim 7 wherein the compound is represented by the following structural formula: 00 HO H SS S Y' is a covalent bond or -C(R 7 R, and R 2 are each a substituted or unsubstituted aryl group; R 3 and R 4 are each a substituted or unsubstituted aliphatic group; R 7 is and R 8 is an aliphatic or substituted aliphatic group.
    [9] 9. The method of Claim 8 wherein R, and R, are the same and R 3 and R 4 are the same.
    [10] The method of Claim 9 wherein R 3 and R 4 are each an alkyl group and R, is -H or methyl.
    [11] 11. The method of Claim 10 wherein R, and R 2 are each a substituted or unsubstituted phenyl group and R 3 and R4 are each methyl or ethyl.
    [12] 12. The method of Claim 11 wherein the phenyl group represented by R, and the phenyl group represented by R 2 are optionally substituted with one or more groups selected from -OH, -Br, -Cl, -O-COR", -COR", -CN, NO,, -COOH, -SO 3 H, -NH -NHRa, -COOR", -CHO, -CONH 2 CONHR", -CON(RRb), -NHCOR', -NRCORa, -NHCONH, -NHCONR"H, -92- _NHCON(R.Rb), -NRCONH 2 -NRCONRnH, -NR-CON(R.Rb), -C(=NH)-N 2 -C(=NH)-NHR 0 -C(=NH)-N(RBRb), -C(=NRC)-NH 2 NR)NHR, -NI-C(NH)-NH,2 -NH-C(=NH)-NHRa, _NHC(=NH)N(RaRb), _NHC(=NRc)_NH 2 _NHC(=NRc)_NHRa, _NHC(=NR)_N(RaRb), 00 a(NH-NR, NRIC(=NH)N(W"Rb), -NRd-C(=NR)-NH2, _NRdC(=NRc)_NBpa, _NdWC(=NRc)_N(aRb), -NHNH, -NHNHR8, -NIWJRb, -SO 2 NH 2 -SO 2 NHR 8 _SO 2 NRRb, -CH=CHR 0 -CH=CRaRb, -CR=CRRb,-CRc=CHRa, -CR=CRaRb, -CCR 8 -SH, -SR 0 -S(O) 2 R 8 a non-aromatic heterocyclic group, a substituted non-aromatic heterocyclic group, a benzyl group, a substituted benzyl group, an aryl group or substituted aryl group, wherein Ra-Rd are each independently an alkyl group, substituted alkyl group, benzyl, substituted benzyl, aromatic or substituted aromatic group, or, -N(RaRb), taken together, form a substituted or unsubstituted non-aromatic heterocyclic group.
    [13] 13. The method of Claim 1 wherein the compound is represented by the following structural formula: Y'H H S S wherein Y" is a covalent bond or -CH 2 and R, and R 2 are both a substituted or unsubstituted aliphatic group.
    [14] 14. The method of Claim 13 wherein R, and R, are both C3-C8 cycloalkyl group optionally substituted with at least one alkyl group. O -93- 0
    [15] 15. The method of Claim 14 wherein R 3 and R 4 are both a substituted or O unsubstituted alkyl group.
    [16] 16. The method of Claim 15 wherein R, and R 2 are both cyclopropyl or Cc1 -methylcyclopropyl. oO 00 CN 5
    [17] 17. The method of Claim 1, wherein the compound is: o;or N H H S S CH 3 0 0 CH 3 N N N 10 H H S S
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    同族专利:
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    WO2008024301A3|2006-08-21|2008-07-10|Synta Pharmaceuticals Corp|Bis for use in preventing or delaying the recurrence of melanoma|
    US7652168B2|2001-07-10|2010-01-26|Synta Pharmaceuticals Corp.|Synthesis of taxol enhancers|
    US7671092B2|2001-07-10|2010-03-02|Synta Pharmaceuticals Corp.|Paclitaxel enhancer compounds|
    US7750042B2|2001-07-10|2010-07-06|Synta Pharmaceuticals Corp.|Paclitaxel enhancer compound|
    US7763658B2|2003-01-15|2010-07-27|Synta Pharmaceuticals Corp.|Treatment for cancers|
    US7795313B2|2004-06-23|2010-09-14|Synta Pharmaceuticals Corp.|Bis salts for treatment of cancers|
    US7939564B2|2006-08-31|2011-05-10|Synta Pharmaceuticals Corp.|Combination with bis for treating cancer|
    US8017654B2|2005-04-15|2011-09-13|Synta Pharmaceuticals Corp.|Combination cancer therapy with bis amide compounds|
    US9156783B2|2006-08-21|2015-10-13|Synta Pharmaceuticals Corp.|Compounds for treating proliferative disorders|TWI297335B|2001-07-10|2008-06-01|Synta Pharmaceuticals Corp|Taxol enhancer compounds|
    TWI332943B|2001-07-10|2010-11-11|Synta Pharmaceuticals Corp|Taxol enhancer compounds|
    法律状态:
    2010-06-17| FGA| Letters patent sealed or granted (standard patent)|
    2016-08-11| MK14| Patent ceased section 143(a) (annual fees not paid) or expired|
    优先权:
    申请号 | 申请日 | 专利标题
    US60/440,406||2003-01-15||
    AU2004206865A|AU2004206865B2|2003-01-15|2004-01-15|Biscompounds for treating multi-drug resistant cancer|
    AU2006228035A|AU2006228035B2|2003-01-15|2006-10-11|Biscompounds for treating multi-drug resistant cancer|AU2006228035A| AU2006228035B2|2003-01-15|2006-10-11|Biscompounds for treating multi-drug resistant cancer|
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