AU708115B2 - Novel potent inducers of terminal differentiation and methods of use thereof - Google Patents

Novel potent inducers of terminal differentiation and methods of use thereof Download PDF

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AU708115B2
AU708115B2 AU62063/96A AU6206396A AU708115B2 AU 708115 B2 AU708115 B2 AU 708115B2 AU 62063/96 A AU62063/96 A AU 62063/96A AU 6206396 A AU6206396 A AU 6206396A AU 708115 B2 AU708115 B2 AU 708115B2
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group
compound
hydroxyl
hydroxylamino
independently
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AU6206396A (en
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Ronald Breslow
Branko Jursic
Paul A. Marks
Richard A. Rifkind
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Sloan Kettering Institute for Cancer Research
Columbia University of New York
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Sloan Kettering Institute for Cancer Research
Columbia University of New York
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
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    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/44—Acylated amino or imino radicals
    • C07D277/46—Acylated amino or imino radicals by carboxylic acids, or sulfur or nitrogen analogues thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Description

1A NOVEL POTENT INDUCERS OF TERMINAL DIFFERENTIATION AND METHODS OF USE THREZOF Background of the Invention Throughout this application various publications are referenced by arabic numerals within parentheses. Full citations for these publications may be found at the end of the specification immediately preceding the claims.
The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this invention pertains.
15 Cancer is a disorder in which a population of cells has become, in varying degrees, unresponsive to the control mechanisms which normally govern proliferation and differentiation. For many years there have been two principal strategies for chemotherapeutic treatment of 20 cancer: a) blocking hormone-dependent tumor cell proliferation by interference with the production or peripheral action of sex hormones; and b) killing cancer cells directly by exposing them to cytotoxic substances, which injure both neoplastic and normal cell populations.
Relatively recently, cancer therapy is also being attempted by the induction of terminal differentiation of the neoplastic cells In cell culture models differentiation has been reported by exposure of cells to a variety of stimuli, including: cyclic AMP and retinoic acid aclarubicin and other anthracyclines There is abundant evidence that neoplastic transformation does not necessarily destroy the potential of cancer cells to differentiate There are many examples of tumor cells which do not respond to the normal -2regulators of proliferation and appear to be blocked in the expression of their differentiation program, and yet can be induced to differentiate and cease replicating.
A variety of agents, including some relatively simple polar compounds derivatives of vitamin D and retinoic acid (10-12), steroid hormones growth factors proteases (15,16), tumor promoters (17,18), and inhibitors of DNA or RNA synthesis (4,19- 24), can induce various transformed cell lines and primary human tumor explants to express more differentiated characteristics.
Early studies by the present inventors identified a series of polar compounds that were effective inducers of 15 differentiation in a number of transformed cell lines Of these, the most effective induce, was the hybrid polar/apolar compound N,N'-hexamethylene bsacetamide (HMBA) The use of this polar/apolar compound to induce murine erythroleukemia cells (MELC) to undergo erythroid differentiation with suppression of oncogenicity has proved a useful model to study inducermediated differentiation of transformed cells SHMBA-induced MELC terminal erythroid differentiation is a multistep process. Upon addition of HMBA to MELC (745A-DS19) in culture, there is a latent period of 10 to 12 hours before commitment to terminal differentiation is detected. Commitment is defined as the capacity of cells to express terminal differentiation despite removal of inducer Upon continued exposure to HMBA there is progressive recruitment of cells to differentiate. The present inventors have reported that MELC cell lines made resistant to relatively low levels of vincristine become markedly more sensitive to the inducing action of HMBA and can be induced to differentiate with little or no latent period (26).
HMBA is capable of inducing phenotypic changes consistent -3with differentiation in a broad variety of cells lines The characteristics of the drug induced effect have been most extensively studied in the murine erythroleukemia cell system (MELC) (5,25,27,28). MELC induction of differentiation is both time and concentration dependent. The minimum concentration required to demonstrate an effect in vitro in most strains is 2 to 3 mM; the minimum duration of continuous exposure generally required to induce differentiation in a substantial portion of the population without continuing drug exposure is about 36 hours.
The primary target of action of HMBA is not known. There is evidence that protein kinase C is involved in the 15 pathway of inducer-mediated differentiation The in vitro studies provided a basis for evaluating the potential of HMBA as a cytodifferentiation agent in the treatment of human cancers Several phase I clinical trials with HMBA have been completed (31-36).
20 Clinical trials have shown that this compound can induce a therapeutic response in patients with cancer (35,36).
However, these phase I clinical trials also have demonstrated that the potential efficacy of HMBA is limited, in part, by dose-related toxicity which prevents achieving optimal blood levels and by the need for intravenous administration of large quantities of the agent, over prolonged periods.
Recently, the present inventors have reported a number of compounds related to HMBA with polar groups separated by apolar linkages that, on a molar basis, are as active (37) or 100 times more active than HMBA As a class, however, it has been found that the symmetrical diners such as HMBA and related compounds are not the best cytodifferentiating agents.
It has unexpectedly been found that the best compounds -4comprise two polar end groups separated by a flexible chain of methylene groups, wherein one or both of the polar end groups is a large hydrophobic group.
Preferably, the polar end groups are different and only one is a large hydrophobic group. These compounds are unexpectedly a thousand times more active than HMBA and ten times more active than HMBA related compounds.
This new class of compounds of the present invention may be useful for selectively inducing terminal differentiation of neoplastic cells and therefore aid in treatment of tumors in patients.
.e ao a*
L
Summary of the Invention The present invention provides the compound having the structure: o I\ R1\ 02 herein each of R, and R 2 are independently the same as or different from each other; when R, and R 2 are the same, each is a substituted or unsubstituted arylamino, cycloalkylamino, pyridineamino, piperidino, 9-purine-6- 15 amine, or thiozoleamino group; when R, and R 2 are different, R, R 3
-N-R
4 wherein each of R 3 and R 4 are independently the same as or different from each other and are a hydrogen atom, a hydroxyl group, a substituted or unsubstituted, branched or unbranched alkyl, alkenyl, 20 cycloalkyl, aryl, alkyloxy, aryloxy, arylalkyloxy, or •pyridine group, or R, and R 4 bond together to form a piperidine group and PR is a hydroxylamino, hydroxyl, amino, alkylamino, dialkylamino or alkyloxy group; and n is an integer from about 4 to about 8.
*The present invention also provides the compound above "having the structure:
R-
N //0 CH -C 0 R2 wherein each of P and R4 are independently the same as or different from each other and are a hydrogen atom, a hydroxyl group, a substituted or unsubstituted, branched -6or unbranched alkyl, alkenyl, cycloalkyl, aryl, alkyloxy, aryloxy, arylalkyloxy, or pyridine group, or R 3 and R 4 bond together to form a piperidine group; R 2 is a hydroxylamino, hydroxyl, amino, alkylamino, dialkylamino or alkyloxy group; and n is an integer from about 4 to about 8.
The present invention also provides the compound above having the structure: 100 o( C 0
R
wherein R is a substituted or unsubstituted arylamino, ~.:cycloalkylamino, pyridineamino, piperidino, 9-purine-6azine, or thiozoleamino group; and n is an integer from about 4 to about 8.
The present invention also provides the compound having the structure: 0 0 00 C- (Cx C- N-C aiC /2m ax
Y
R
wherein each of X and Y are independently the same as or different from each other and are a hydroxyl, amino or hydroxylamino group, a substituted or unsubstituted alicyloxy, alkylamino, dialkylamino, arylamino, alkylarylamino, alkyloxyamino, aryloxyamino, alkyloxyalkylauino, or aryloxyalkylamino group; R is a hydrogen atom, a hydroxyl group, a substituted or unsubstituted alkyl, aryl, alkyloxy, or aryloxy group; and each of m and n are independently the same as or -7different from each other and are each an integer from about 0 to about 8.
The present invention further provides the compound having the structure: o o o o S/ I
Y
R
R
2 wherein each of X and Y are independently the same as or different from each other and are a hydroxyl, amino or hydroxylamino group, a substituted or unsubstituted alkyloxy, alkylamino, dialkylamino, arylamino, alkylarylamino, alkyloxyamino, aryloxyamino, alkyloxyalkylamino, or aryloxyalkylamino group; each of SR, and R2 are independently the same as or different from each other and are a hydrogen atom, a hydroxyl group, a substituted or unsubstituted alkyl, aryl, alkyloxy, or 20 aryloxy group; and each of m, n, and o are independently the same as or different from each other and are each an integer from about 0 to about 8.
The present invention still further provides the compound having the structure: 0 0 0 x i wherein each of X and Y are independently the same as or different from each other and are a hydroxyl, amino or hydroxylamino group, a substituted or unsubstituted alkyloxy, alkylamino, dialkylamino, arylamino, alkylarylamino, alkyloxyamino, aryloxyamino, -8alkyloxyalkylamino, or aryloxyalkylamino group; each of R, and R 2 are independently the same as or different from each other and are a hydrogen atom, a hydroxyl group, a substituted or unsubstituted alkyl, aryl, alkyloxy, or aryloxy group; and each of m and n are independently the same as or different from each other and are each an integer from about 0 to about 8.
The present invention also provides the compound having the structure: too.* wherein each of X and Y are independently the same as or different from each other and are a hydroxyl, amino or hydroxylamino group, a substituted or unsubstituted alkyloxy, alkylamino, dialkylamino, arylamino, 20 alkylarylamino, alkyloxyamino, aryloxyamino, alkyloxyalkylamino, or aryloxyalkylamino group; and each of m and n are independently the same as or different from each other and are each an integer from about 0 to about 8.
The present invention also provides the compound having the structure: ILI a I 0 0 wherein each of X and Y are independently the same as or different from each other and are a hydroxyl, amino or hydroxylamino group, a substituted or unsubstituted alkyloxy, alkylamino, dialkylamino, arylamino, alkylarylamino, alkyloxyamino, aryloxyamino, i I -9alkyloxyalkylamino, or aryloxyalkylamino group; each of R, and P 2 are independently the came as or dif ferent f rom each other and are a hydrogen atom, a hydroxyl group, a substituted or unsubstituted alkyl, aryl, alkyloxy, or aryloxy group; and each of a and n are independently the same as or dif ferent. f rom each other and are each an integer from about 0 to about 8.
The present invention further provides the compound having the structure: 0 CH 3 CH3 It 1C1 O
X-C-CH-(CH
2 )n-CH-C-Y a p wherein each of X and Y are independently the same as or ***different from each other and are a bydroxyl, amino or hydroxylamino group, a substituted or unsubtituted alkyloxy, alkylazino, dialkylamino, arylamino, alkylarylanino, alkyloxyanino, aryloryamino, alkyloxyalkylamino., or aryloxyalkylamino group; and n is an integer from about 0 to about S.
The present invention still further provides the compound having the structure: 0 0
R
Vherein each of X and Y are independently the same as or different from each other and are a hydroxyl, amino or hydroxylamino group, a substituted or unsubtituted alkyloxy, alkylamino, dialkylanino, arylamino, alkylarylanino, alkyloxyanino, aryloxyanino, alkyloxyalkylanino, or aryloxyalkylaino group; each of R, and R, are independently the same as or different from each other and are a hydrogen atom, a hydroxyl group, a substituted or unsubstituted alkyl, aryl, alkyloxy, aryloxy, carbonyihydroxyl1amino, or fluoro group; and each of m and n are independently the same as or different from each other and are each an integer from about 0 to about 8.
The present invention also provides the compound having the structure: 0 0 151 p pwherein each of R 1 and R2 are independently the same as or :pdifferent from each other and are a hydroxyl, alkyloxy, amino, hydroxylamino, alkylamino, dialkylamino, arylamino, alkylarylamino, alkyloxyamino, aryloxyamino, alkyloxyalkylamino, or aryloxyalkylano group.
The present invention also provides the compound having the structure: 250 0 C CK-CHO CH -C-C C 300 wherein each of 1 and R 2 are independently the same as or different from each other and are a hydroxyl, alkyloxy, amino, hydroxylamino, alkylamino, dialkylamino, arylamino, alkylarylamino, alkyloxyanino, aryloxyamino, alkyloxyalkylamino, or aryloxyalkylamino group.
The present invention further provides the compound -11having the structure: ec- c \0 o wherein each of R, and R 2 are independently the same as or different from each other and are a hydroxyl, alkyloxy, amino, hydroxylamino, alkylamino, dialkylamino, arylamino, alkylarylamino, alkyloxyamino, aryloxyamino, alkyloxyalkylamino, or aryloxyalkylamino group.
In addition, the present invention provides a method of Sselectively inducing terminal differentiation of 15 neoplastic cells and thereby inhibiting proliferation of such cells which comprises contacting the cells under suitable conditions with an effective amount of any of the compounds above, effective to selectively induce terminal differentiation.
The present invention also provides a method of treating a patient having a tumor characterized by proliferation of neoplastic cells which comprises administering to the Spatient an effective amount of any of the compounds above, effective to selectively induce terminal differentiation of such neoplastic cells and thereby inhibit their proliferation.
Lastly, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically acceptable amount of any of the compounds above.
-12- Detailed Description of the Invention The present invention provides the compound having the structure: C- (CH 2
C\
0 -2 wherein each of R, and R, are independently the same as or different from each other; when R, and R, are the same, each is a substituted or unsubstituted arylamino, cycloalkyl-amino, pyridineamino, piperidino, 9-purine-6amine, or thiozoleamino group; when R, and R 2 are different, R, R 3
-N-R
4 wherein each of R, and R 4 are independently the same as or different from each other and are a hydrogen atom, a hydroxyl group, a substituted or unsubstituted, branched or unbranched alkyl, alkenyl, cycloalkyl, aryl, alkyloxy, aryloxy, arylalkyloxy, or pyridino group, or R, and R 4 bond together to form a piperidine group and R2 is a hydroxylamino, hydroxyl, *amino, alkylamino, dialkylamino or alkyloxy group; and n is an integer from about 4 to about 8.
25 The present invention also provides the compound above having the structure: 3. :so c R2 wherein each of R 3 and R 4 are independently the same as or different from each other and are a hydrogen atom, a hydroxyl group, a substituted or unsubstituted, branched or unbranched alkyl, alkenyl, cycloalkyl, aryl, alkyloxy, aryloxy, arylalkyloxy, or pyridine group, or R 3 and R 4 -13bond together to form a piperidine group; R 2 is a hydroxylamino, hydroxyl, amino, alkylamino, dialkylamino or alkyloxy group; and n is an integer from about 4 to about 8.
In the preferred embodiment of the compound above, R 2 is a hydroxylamino, hydroxyl, amino, methylamino, dimethylamino, or methyoxy group and ni is 6. Host preferably, R. is a hydrogen atom and R 3 is a substituted or unsubstituted phenyl group.
The phenyl group may be substituted with a methyl, cyano, nitro, trifluoromethyl, amino, aminocarbonyl, methylcyano, chioro, fluoro, bromo, iodo, 2,3-difluoro, 2,4-difluoro, 2,5-difluoro, 3,4-difluoro, 3, 2,6-difluoro, 1,2,3-trifluoro, 2,3,6-trifluoro, 2,4,6trifluoro, 3,4, 5-trifluoro, 2,3,5, 6-tetrafluoro, 2,3,4,5,6-pentafluoro, azido, hexyl,, t-butyl, phenyl, carboxyl, hydroxyl, methyoxy, benzyloxy, phenylaminooxy, phenylmethoxy, phenylamino-carbonyl, methyoxycarbony 1, methylaminocarbonyl, dimethylamino, dimethylazinocarbonyl, or hydroxylamino-carbonyl group.
In other preferred embodiments of the compound above, R.
to: 25 is a hydrogen atom and R 3 is a cyclohexyl group; R. is a hydrogen atom and R 3 is a methyoxy group; R 3 and R. each to.: bond together to form a piperidine group; R1. is a .hydrogen atom and R 3 is a hydroxyl group; R, is a too. hydrogen atom and N 3 is a benzyloxy group; R4 is a hydrogen atom and R 3 is a S-pyridine group; R, is a hydrogen atom and R 3 is a B-pyridine group; R 4 is a hydrogen atom and R 3 is a c-pyridine group; R 3 and R. are both methyl groups; or R. is a methyl group and R3is a phenyl group.
-14- The present invention also provides the compound having the structure: 0
R
wherein R is a substituted or unsubstituted arylamino, cycloalkylamino, pyridineamino, piperidino, 9-purine-6amine, or thiozoleamino group; and n is an integer f rom about 4 to about 8.
In the preferred embodiment of the compound above, R is a substituted or urisubstituted phenylaiuino, group. The phenylamino group may be substituted with a cyano, methylcyano, nitro, carboxyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, trifluoromethyl, hydroxylazinocarbonyl, N-hydroxylaminocarbonyl, methoxycarbonyl, chioro, fluoro, methyl, methoxy, 2,3difluoro, 2,3-difluoro, 2,4-difluoro, 2,5-difluoro, 2,6difluoro, 3, 5-difluoro, 2, 6-difluoro, 2,3, 6-trifluoro, ,2,3-trifluoro, 3,4,5-trifluoro, 2,3,4,5-tetrafluoro, or 2 ,3,4,5,6-pentafluoro group.
In another embodiment of the compound above, R is a cyclohexylamino group.
The present invention also provides the compound having the structure: 0 0 0 C C-H ji- C- (ccx 2
C\
I
Y
x
R
wherein each of X and Y are independently the same as or different from each other and are a hydroxyl, amino or hydroxylamino group, a substituted or unsubstituted alkyloxy, alkylamino, dialkylamino, arylamino, alkylarylamino, alkyloxyamino, aryloxyamino, alkyloxyalkylamino, or aryloxyalkylamino group; R is a hydrogen atom, a hydroxyl group, a substituted or unsubstituted alkyl, aryl, alkyloxy, or aryloxy group; and each of m and n are independently the same as or different from each other and are each an integer from about 0 to about 8.
In the preferred embodiment of the compound above, each of X, Y, and R is a hydroxyl group and each of m and n is The present invention also provides the compound having the structure: 0 0 wherein each of X and Y are independently the same as or different from each other and are a hydroxyl, amino or hydroxylamino group, a substituted or unsubstituted alkyloxy, alkylamino, dialkylamino, arylamino, 30 alkylarylamino, alkyloxyanino, aryloxyamino, alkyloxyalkylamino, or aryloxyalkylanino group; each of
R
1 and R 2 are independently the same as or different from each other and are a hydrogen atom, a hydroxyl group, a substituted or unsubstituted alkyl, aryl, alkyloxy, or aryloxy group; and each of m, n, and o are independently the same as or different from each other and are each an integer from about 0 to about 8.
|I
-16- In the preferred embodiment of the compound above, each of X and Y is a hydroxyl group and each of R, and R 2 is a methyl group. Most preferably, each of n and o is 6, and m is 2.
The present invention also provides the compound having the structure: o 2 C-e- (C--C RI wherein each of X and Y are independently the same as or different from each other and are a hydroxyl, amino or hydroxylamino group, a substituted or unsubstituted alkyloxy, alkylamino, dialkylamino, arylamino, alkylarylamino, alkyloxyamino, aryloxyamino, alkyloxyalkylamino, or aryloxyalkylamino group; each of and Rz are independently the same as or different from S* each other and are a hydrogen atom, a hydroxyl group, a substituted or unsubstituted alkyl, aryl, alkyloxy, or aryloxy group; and each of m and n are independently the o o 25 same as or different from each other and are each an integer from about 0 to about 8.
The present invention also provides the compound having the structure: wherein each of X and Y are independently the same as or -17dif ferent. f rom each other and are a hydroxyl, amino or hydroxylamino group, a substituted or unsubstituted alkyloxy, alkylamino, dialkylamino, arylamino, alicylarylamino, alkyloxyamino, aryloxyamino, a lkyloxyalkyl amino, or aryloxyalkcylamino group; and each of m and n are independently the same as or dif ferent f rom each other and are each an integer from about 0 to about 8.
In the preferred embodiment of the compound above, each of X and Y is a hydroxyl group and each of m and n is The present invention also provides the compound having the structure: xY 200 0 wherein each of X and Y are independently the same as or different from each other and are a hydroxyl, amino or hydroxylamino group, a substituted or unsubstituted .25 alkyloxy, alkylamino, dialicylamino, arylamino, alkylarylamino, alkyloxyamino, aryloxyamino, alkyloxyalkylamino, or aryloxyalkylazino group; each of 1 and R 2 are independently the same as or different from a each other and are a hydrogen atom, a hydroxyl group, a substituted or unsubstituted alkyl, aryl, alkcyloxy, or aryloxy group; and each of a and n are independently the same as or dif ferent from each other and are each an integer from about 0 to about 8.
-is- The present invention also provides the compound having the structure: 0 CH 3 H 0 X-C-CI{- (CH 2 n-CH-C-Y wherein each of X and Y are independently the sme as or different trom each other and are a hydroxyl, amino or hydroxylamino group, a substituted or unsubstituted alkyloxy, alkylemino, dialkylazino, arylamino, alkylarylamino, a ikyloxyanino, aryloxyanino, alkyloxyalkylauino, or aryloxyalkylamino group; and n is an integer from about 0 to about 8.
In the preferred embodiment of the compound above, each of Xand Yis adimethylamino groupand nis 4or The present invention also provides the compound having the structure: a- C-(
I
wherein each of X and Y are independently the same as or different from each other and are a hydroxyl, amino or hydroxylamino group, a substituted or uisubetituted alkyloxy, alkylazino, dialkylamino, arylamino, ::alkylarylanino, alkyloxyanino, aryloxyamino, alkyloxyalkylamino, or aryloxyalkylanino group; each of N1 and Nare independently the same as or different from each other and are a hydrogen atom, a hydroxyl group, a substituted or unsubstituted, alkyl, aryl, alkyloxy, JU4. A I V I.74&1 OO4 -19aryloxy, carbonylhydroxylanino, or f luoro group; and each of m and n are independently the same as or different from each other and are each an integer f rom about 0 to about 8.
In the preferred embodiment of the compound above,' each of X and Y is a hydroxylamino group, R, is a methyl group,
R
2 is a hydrogen atom, and each of m and n is 2. In another preferred embodiment, each of X and Y is a hydroxylamino group, R 1 is a carbonyihydroxylanino group,
R
2 is a hydrogen atom, and each of a and n is 5. In a further preferred embodiment, each of X and Y is a hydroxylamino group, each of R, and R 2 is a fluoro group, and each of m and n is 2.
The present invention also provides the compound having the structure: 200
RR
R* 2 '00,25 wherein each of R 1 and;R are independently the same as or different from each other and are a hydroxyl, alkyloxy, amino, hydroxylamino, alkylamino, dialkylamino, arylamino, alkylarylazino, alkyloxyamino, aryloxyamino, alkyloxyalkylamino, or aryloxyalkylamino group.
0 0 0 :::-Preferably,
R
1 is a phenylamino group and R 2 is a hydroxylamino group.
O. 0 The present invention also provides the compound having the structure: R 1\ 0 wherein each of Rand R 2 are independently the same as or different from each other and are a hydroxyl, alkyloxy, amino, hydroxylamino, alkylamino, dialkylamino, arylamino, alkylarylauino, alkyloxyanino, aryloxyamino, alkyloxyalkylamino, or aryloxyalkylamino group.
Preferably, is phenylamino group and R 2 is hydroxylamino group.
The present invention also provides the compound having the structure: R 0 difrn frmec.te n a hd ol kyo aio ydoyaio aklmn, dilyaio arl.io alyayaio lyoxaio rlxaio *lyoylyaio or .rlxakla ogop In th.rfre.mbdmneterPo 2i 01roya n grup The present invention also provides a method of -21selectively inducing terminal differentiation of neoplastic cells and thereby inhibiting proliferation of such cells which comprises contacting the cells under suitable conditions with an effective amount of any of the compounds above, effective to selectively induce terminal differentiation.
The contacting must be performed continuously for a prolonged period of time, i.e. for at least 48 hours, preferably for about 4-5 days or longer.
The method may be practiced in vivo or in vitro. If the method is practiced in yvitr, contacting may be effected by incubating the cells with the compound. The concentration of the compound in contact with the cells should be from about 1 AM to about 25 mM, preferably from 4 MM to about 5 mM. The concentration depends upon the individual compound and the state of the neoplastic cells.
The method may also comprise initially treating the cells with an antitumor agent so as to render them resistant to :an antitumor agent and subsequently contacting the resulting resistant cells under suitable conditions with 25 an effective amount of any of the compounds above, effective to selectively induce terminal differentiation of such cells.
The antitumor agent may be one of numerous chemotherapy agents such as an alkylating agent, an antimetabolite, a hormonal agent, an antibiotic, colchicine, a vinca alkaloid, L-asparaginase, procarbazine, hydroxyurea, mitotane, nitrosoureas or an imidazole carboxamide.
Suitable agents are those agents which promote 9 o' .35 depolarization of tubulin. Preferably the antitumor agent is colchicine or a vinca alkaloid; especially preferred are vinblastine and vincristine. In
J,
-22embodiments where the antitumor agent is vincristine, the cells preferably are treated so that they are resistant to vincristine at a concentration of about 5 mg/ml. The treating of the cells to render them resistant to an antitumor agent may be effected by contacting the cells with the agent for a period of at least 3-5 days. The contacting of the resulting cells with any of the compounds above is performed as described previously.
The present invention also provides a method of treating a patient having a tumor characterized by proliferation of neoplastic cells which comprises administering to the patient an effective amount of any of the compounds above, effective to selectively induce terminal differentiation of such neoplastic cells and thereby inhibit their proliferation.
The method of the present invention is intended for the treatment of human patients with tumors. However, it is also likely that the method would be effective in the treatment of tumors in other mammals. The term tumor is intended to include any cancer caused by the proliferation of neoplastic cells, such as lung cancer, acute lymphoid myeloma, bladder melanoma, renal 25 carcinoma, breast carcinoma, or colorectal carcinoma.
The administration of the compound to the patient may be effected orally or parenterally. To date, administration intravenously has proven to be effective. The administration of the compound must be performed continuously for a prolonged period of time, such as for at least 3 days and preferably more than 5 days. In the S most preferred embodiments, the administration is effected continuously for at least 10 days and is repeated at intervals wherein at each interval the 35 administration is continuously effected for at least days. For example, the administration may be effected at intervals as short as 5-10 days, up to about 25-35 days *1 -23and continuously for at least 10 days during each such interval. The optimal interval period will vary depending on the type of patient and tumor. For example, in the incidence of acute leukemia, the so called myelodysplastic syndrome, continuous infusion would seem to be indicated so long as the patient tolerated the drug without toxicity and there was a positive response.
The amount of the compound administered to the patient is less than an amount which would cause toxicity in the patient. In the certain embodiments, the amount of the compound which is administered to the patient is less than the amount which causes a concentration of the compound in the patient's plasma to equal or exceed the toxic level of the compound. Preferably, the concentration of the compound in the patient's plasma is maintained at about 1.0 mM. It has been found with HMBA that administration of the compound in an amount from about 5 gm/m 2 /day to about 30 gm/m 2 /day, particularly 20 about 20 gm/m 2 /day, is effective without producing toxicity in the patient. The optimal amount of the compound which should be administered to the patient in the practice of the present invention will depend on the particular compound used and the type of cancer being 25 treated.
This invention, in addition to the above listed compounds, is intended to encompass the use of homologs and analogs of such compounds. In this context, homologs are molecules having substantial structural similarities to the above-described compounds and analogs are !molecules having substantial biological similarities regardless of structural similarities.
The method may also comprise initially administering to the patient an amount of an antitumor agent to render the cells resistant to an antitumor agent and subsequently -24administering to the patient an effective amount of any of the compounds above, effective to selectively induce terminal differentiation of such neoplastic cells and thereby inhibit their proliferation.
The antitumor agent may be one of numerous chemotherapy agents such as an alkylating agent, an antimetabolite, a hormonal agent, an antibiotic, colchicine, a vinca alkaloid, L-asparaginase, procarbazine, hydroxyurea, mitotane, nitrosoureas or an imidazole carboxamide.
Suitable agents are those agents which promote depolarization of tubulin. Preferably the antitumor agent is colchicine or a vinca alkaloid; especially preferred are vinblastine and vincristine. In embodiments where the antitumor agent is vincristine, an amount is administered to render the cells are resistant to vincristine at a concentration of about 5 mg/ml. The administration of the agent is performed essentially as described above for the administration of any of the 20 compounds. Preferably, the administration of the agent is for a period of at least 3-5 days. The administration of any of the compounds above is performed as described previously.
25 The present invention also provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier, such as sterile pyrogen-free water, and a 9. therapeutically acceptable amount of any of the compounds above. Preferably, the effective amount is an amount effective to selectively induce terminal differentiation of suitable neoplastic cells and less than an amount which causes toxicity in a patient.
Lastly, the present invention provides the-pharmaceutical composition above in combination with an antitumor agent.
The antitumor agent may be any of the agents previously described.
The invention is illustrated in the Experimental Details section which follows. This section is set forth to aid in an understanding of the invention but is not intended to, and should not be construed to, limit in any way the invention as set forth in the claims which follow thereafter.
S S
.S
S
S
I
-26- Experimental Details Cells and Materials MELC 745A-DS19 cells and the variants of MELC derived from this cell line, namely, the vincristine-resistant MELC V3.17 and VCR.C(2)15 cell lines and the dimethylsulfoxide-resistant cell line, DR10 were maintained in alpha minimal essential medium containing 10% fetal calf serum Cell cultures for all experiments were initiated with cells in logarithmic growth phase (day 2 cultured cells) at a density of 105 cells/ml. Inducer compounds were added in the final concentrations indicated below, dissolved in culture medium without fetal calf serum unless otherwise indicated. Cell density and benzidine reactively were determined as described (16).
Commitment to terminal differentiation, characterized by 20 limited cell division (colony size <32 cells) and accumulation of hemoglobin (benzidine reactive colonies) was assayed by a colony cloning assay using 2% methylcellulose as described (25) (see Table 1 for results).
HL-60 human leukemia cells, derived from peripheral blood leukocytes of a patient with acute promyelocytic leukemia Induced differentiation of HL-60 cells assayed by determining the proportion of cells that developed the capacity to reduce nitroblue tetrazolium (NBT) (41) (see Table 2 for results).
Chemistry The compounds having the structure: 0
NHOH
-27- Preparation of PhCH2ONHOC(CH) 6
COOCH
3 A solution of suberic acid monomethyl ester (1.9 g; 0.01 mol), oxaloyl chloride (1.75 mL; 2.54 g; 0.02 mol) and 0.1 mL DMF in benzene (200 mL) was stirred overnight at room temperature. The solvent was evaporated and oily residue was dissolved in chloroform (-20 mL) and mixed together with chloroform solution (100 mL) of 0benzylhydroxylamine (2.46 g; 0.02 mol) and pyridine (1.6 mL; 1.68 g; 0.02 mol). The reaction mixture was stirred at room temperature overnight. The chloroform solution was washed with water (50 mL), 10% hydrochloric acid, and again with water (2 x 50 mL). The organic layer was dried over anhydrous magnesium sulfate and evaporated.
The solid residue was slurried in hexanes (-100 mL) and filtered. The yield of PhCH 2
ONHOC(C
2 6
COOCH
3 was 2.61 g
S./
I y -OHN 3 25 The above suberic acid monobenzyloxyamide monomethyl ester (1 g; 3.4 aol) was dissolved in dry methanol aL) and 5% Pd-C (50 ag) was added. The black suspension was shaken under hydrogen pressure (-50 psi) overnight at room temperature. The catalyst was separated by filtration, and filtrate was evaporated. The solid residue was slurried in hexanes (-20 aL) and filtered.
The yield of the monomethyl ester monohydroxamic acid of suberic acid was 900 mg H NMR (DMSO-d 6 200 MHz), 6(ppm) 10.31 NHOH, 1H);
I
-28- 8.89 broad, NHOH, 1H1); 3.57 CH 3 3H) 2.27 (t, J=7. 4Hz, CH 2
COOCH
3 2H) 1. 91 J=7. 4Hz, CH 2 CONHOH, 2H); 1.49 (in, 4H), 1.24(m, 4H).
0 //0 C C C 6 HOHN OH Suberic acid monobenzyloxyanide monomethyl ester (1g; 3.4 mmol) and potassium hydroxide (210 mg; 3.75 mmcl) were dissolved in 10 uL of methanol-water mixture. The reaction mixture was ref luxed two hours and solvent was evaporated. The solid residue was dissolved in 5 mL water and acidified with conc. hydrochloric acid to White precipitate was filtered, dried and crystallized from ethyl acetate-hexanes. The yield of suberic acid monobenzyloxyamide was 820 mg The product was dissolved in methanol (50 uL) and 5% Pd-C (50 mg) was added. The reaction mixture was shaken under hydrogen pressure (50 psi) overnight. The catalyst was separated 00.. by filtration and filtrate was evaporated. The solid residue was slurried in hexanes and filtered. The yield of suberic acid monohydroxamic acid was 520 mg 1H NNR (DMSO-d 6 200 M0(z), S(ppm) 11.96 broad, COOH, 1H); 10.31 NHOH, 111); 8.63 broad, 111101, 1H); 2.17 (s, J-7.4Hz, CH 2 COOH, 2H); 1.91 CH 2 CONHOH, 211); 1.46 (m, 4H) 1. 22 (ma, 4H) Compounds having the structure:
II
1 N H -29- General Procedure A pyridine (500 mL) solution of O-benzylhydroxylamine (2.46 g; 0.02 mol), the corresponding amine (0.02 mol) and suberoyl chloride was stirred at room temperature overnight. The solvent was evaporated and the semisolid residue was dissolved in 1000 mL chloroform-methanol the resulting solution was washed with water (2 x 100 mL), 10% hydrochloric acid (3 x 100 mL), and again with water (2 x 100 mL). Organic layer was dried over anhydrous magnesium sulfate and evaporated. The solid residue was dissolved in methanol (100 mL) and 5% Pd-C was added. The black suspension was shaken under hydrogen pressure ('50 psi) overnight. The catalyst was separated by filtration, and the filtrate was evaporated.
The target products were isolated by column chromatography on silica gel with ethyl acetatetetrahydrofuran.
0 0
(CH
HOHN
NHOCH
3 Yield 1.1 g 'H NMR (DMSO-D 6 200 MHz), 6(ppm) 10.93 NHOCH 3 1H); 10.32 NHOH, 1H); 8.66 NHOH, 1H); 3.55 CH3, 3H); 1.91 J-7.6Hz, CH2CO-,4H); 1.45 4H); 1.20 4H).
(CH 6 HOHNq Yield 1.2 g 'H NMR (DMSO-d, 200 MHz), S(ppm) 10.31 NHOH, 1H); 8.60 broad, NHOH, 1H); 7.57 (d, J=7.6Hz,
NH-C
6 1H), 3.40 CH-NH, 1H); 1.99 (t, J=7Hz, CH 2 CONHCH,,, 2H); 1.91 J=7.6Hz, CH 2 CONHOH, 2H); 1.63 4H); 1.44 6H); 1.20 8H).
1 C- (CH
)-C
HOmqN N
(CH
3 2 Yield 870 mg 'H NMR (DMSO-D 6 200 Mlz), 6(ppm) 10.31 NHOH, 1H); 8.67 broad, NHOH, 1H); 2.85 (d, J-30Hz, N(CH 3 2 6H); 2.24 J=7.4Hz,
CH
2
CON(CH
3 2H); 1.91 J=7.4Hz, CH 2 COONHOH, 2H); 1.50 4H); 1.20 (a, 4H).
20 0 "2 C CH2
C
6
NHOH
Yield 1.4 g 'H NMR (DMSO-d 6 200 MHz), 6(ppm) 10.31 NHOH, 1H); 8.67 NHOH, 1M); 3.40 (2t, CH 2 N, 4H); 2.20 J-7.4 Hz, CHCON(CH 2 5 21); 1.91 J=7.4Hz,
CH
2 CONHOH, 2H); 1.10-1.60 broad, 14 H).
CoaDound having structure: *2 C W&WE2I
NNOCH
2C6 8.
-31- The chloroform (500 mL) solution of O-benzylhydroxylamine (1.23 g; 0.01 mol), O-(trimethylsilyl)hydroxylamiie (1.1 g; 0.01 mol), pyridine (1.6 mL; 1.7 g; 0.02 mol) and suberoyl chloride (1.8 mL; 2.11 g; 0.01 mol) was stirred at room temperature overnight. The reaction suspension was diluted with methanol (100 mL), washed with hydrochloric acid (3 x 100 mL). The organic layer was dried over anhydrous magnesium sulfate and evaporated.
The solid residue was subjected to chromatography on silica gel 'in ethyl acetate-tetrahydrofuran The yield was 500 mg 'H NIMff (DHSO-d 6 200 Mz), 5 (ppm) 11. 09 NHOCH 2
C
6
E
5 1H) 10. 31 NHOH, 1H) 8. 67 (s, broad, NHOH, 1H) 7.36 C 6
H
5 5H) 1 4.76 CH 2
C
6
H
5 2H) 1.92 J-7.4Hz, CH 2 CO-, 4H) 1.45 (in, 4H); 1.20 (in, 4H).
Coinound havina the structure:
HORN
Into a cooled solution of potassium hydroxide (2.24 g; 0.04 mol) and O-benzylhydroxylauine hydrochloride in UL of tetrahydrofuran-water mixture, 6bromohexanoyl chloride (3.1 mL; 4.27 g; 0.02 mol) was added. The reaction mixture was stirred at room temperature for one hour. The solvent was evaporated and solid residue was partitioned between chloroform (200 inL) and water (100 mL). Chloroform layer was washed with hydrochloric acid (3 x 50 uL) and water (2 x 50 uL). The organic layer was dried over anhydrous magnesium sulfate and evaporated. The product was purified by crystallization from ethyl acetate-hexanes. The yield of N-benzyloxy-6-bromohexanoyl amide was 4.7 g A -32dimethylsulfoxide (250 mL) solution of N-benzyloxy-6bromohexanoyl amide (4.5 g; 15 mmol) and sodium cyanide (7.35 g; 0.15 mol) was heated at 1306C overnight. The solvent was evaporated and solid residue was partitioned between chloroform (300 mL) and water (300 mL). The chloroform layer was washed with water (5 x 100 mL), dried over anhydrous magnesium sulfate, and evaporated.
The oily residue was purified by column chromatography on silica gel in ethyl acetate-tetrahydrofuran as an eluent. The yield of N-benzyloxy-6-cyanohexanoylamide was 1.62 g The product was dissolved in methanol mL) and 5% Pd-C (100 mg) was added. The black suspension was shaken under hydrogen pressure (-50 psi) overnight. The catalyst was isolated by filtration and filtrate was evaporated. The solid residue was slurried in hexanes ('20 mL) and filtered. The yield of Nhydroxy-6-cyanohexanoylamide was 900 ag (overall yield IH NMR (DMSO-d 6 200 MHz), 6(ppm) 10.32 NHOH, 1H); 8.65 NHOH, 1H); 2.45 (t,J-7Hz, CH 2 CN, 2H) 1.93 J-7Hz, CH 2 CONHOH, 2H); 1.49 4H); 1.33 2H).
**Compounds having the structure: o R- C-(CH 2
C
n
OH
General Procedure (09C) solution of potassium hydroxide (1.12 g; 0.02 mol) and corresponding amine (0.01 mol) in 30 mL of tetrahydrofuran-water mixture. The reaction mixture was stirred at room temperature about one hour.
Solvent was evaporated and the solid residue was -33partitioned between chloroform (300 mL) and water (300 ML) In some cases a small amount of methanol is necessary to dissolve all solid. The organic layer was washed with 10t potassium hydroxide (3 x 30 mL) The basic water extract was acidified with 10% hydrochloric acid. The precipitate was collected by filtration, dried and purified by crystallization from ethyl acetate or by column chromatography on silica gel in ethyl acetatetetrahydrofuran The yields are from 20-37%.
-NH- C- (CH 2
)OH
'H NMR (DHSO-d 6 200 MHz), 6(ppm) 11.97 COOH, 1H); 9.84 NH, 1H1); 7.57 J=7.4Hz, ortho aromatic *protons, 211); 7.26 J-8.411z, meta aromatic protons, 2H1); 6.99 J-7.4Hz, para aromatic proton, 1H1), 2.27 J-7Hz, CH 2 CONHPh, 2H1); 2.18 J-7.2Hz, 211); 1.52 (mn, 411); 1.28 (in, 411).
25.:N25 00 NH- C
(CR
2 C 1- 6 l 'H NE (DMSO-d 6 200 MHz), 6(ppm) 11.95 COOH, 111); 10.20 NH, 11H); 8.10 aromatic proton, 111); 7.75 (an, aromatic proton, 1H); 7.45 (mn, aromnatic proton, 2H); 2.28 (t,J-7o4Hz, CH 2 CONHAr, 2H1); 2.21 (t,J=7.21z, CH 2
COOH,
211); 1.46 (mn, 411); 1.20 411).
1 NC- N- C- (CH C 6
OH
-34- 'H NMR (DMSO-d 6 200 MHz), 6(ppm) 11.95 COOH, 1H); 10.29 NH, 1H); 7.75 aromatic protons, 4H); 2.33 J=7.2Hz, CH 2 CONHAr, 2H); 2.18 J=7.4Hz, CH 2
COOH,
2H); 1.53 4H); 1.27 4H).
II 0 0 2 N /NH- C- (CH 2
C
6
OH
'H NMR (DMSO-d 6 200MHz), 11.98 broad, COOH, 1H); 10.48 NH, 1H); 8.21 J=9.2Hz, aromatic protons, 2H); 7.82 J-9.2Hz, aromatic proton, 2H); 2.36 (t, J=7.4Hz, CH 2 CONHAr, 2H); 2.18 J=7.2Hz, CH 2 COOH, 2H); 1.55 4H); 1.29 4H).
1jI N N-C- (M 2)-C 6
OH
o 'H NMR (DMSO-d 6 200 MHz) 8 (ppm) 12.00 broad COOH, 1H); 10.24 NH, 1H); 8.38 J-5.8Hz, aromatic protons, 2H); 7.55 J-5.8Hz, aromatic protons, 2H); 2.33 J=7.2Hz, CH 2 CONHAr, 2H); 2.18 J=7.2Hz,
CH
2 COOH); 1.52 4H); 1.27 4H).
0 unN-e-- -q sC2 6- OR 'HNMR (DNSO-d 6 200MHz), 8(ppm) 11.95 COON, 1H); 7.58 J-8Hz); 3.50 CH, 1H); 2.17 J=7.2Hz, CH 2
COOH,
2H) 2. 00 J-7Hz, CH 2 CONH-, 2H) 1. 60 41) 1. 4 6 (m, 6H); 1.20 SH).
In the same way the following compounds were prepared and characterized: (CH -C
OH
wherein n 4, 5, 6, 7, and 8; R is hydrogen; 3-, and 4-cyano; and 4-nitro; and 4methylcyano; and 4-trifluoromethyl; and 4 -fluoro; (CH C n
OK
0 OS @0 9e 9 9 9* 9 9 0@9S
S
0.SS 9. 0 9* 9 @0
S.
9 4
S.
S 0 .9 4 *5
S
@9 *999 0 S. 00 9 9 0 *040.e 9 wherein n 4, 5, 6, 7, and 8;
'H
N
I
-(C'1 2
-C
n
OH
wherein n 4, 5, 6, 7, and 8;
NHO
00 wherein n 4, 5, 6, 7, and 8; -36-
N
C- (CH )c 2n wherein n 4, 5, 6, 7, and 8; ic C- (CM )-C 12/ 06.
0 b o o: wherein n 4, 5, 6, 7, and 8; 6 wherein R is and 4-carboxy; 2 3 and 4 aninocarbonyl; and 4-methylaminocarbonyl; 2-, and 4-dinothylaminocarbonyl; and 4-chioro; and 4-bromo; and 4-iodo; 3, and 4methyl; and 4 methoxy; and 4-hydroxy; and 4-amino; and and 4-diimethylamino.
Compounds having the general structure: 0# c- (cm (C2nC HO
OH
-37wherein n 4, 5, 6, and 7.
General Procedure A A pyridine (500 mL) suspension of O-benzylhydroxylamine hydrochloride (3.2 g; 0.02 mol) and the corresponding diacid dichloride (0.04 mol) was stirred at room temperature for three days. Water (10 mL) was added and stirring was continued overnight. The solvent was evaporated and solid residue was purified by column chromatography on silica gel in tetrahydrofuran-methanol.
The diacid product was dissolved in methanol (100 mL) and Pd-C (100 mg) was added. The reaction suspension was shaken overnight under hydrogen pressure (-50 psi). The 15 catalyst was separated by filtration, solid residue was washed with hot methanol (5 x 50 ml). The combined methanolic filtrates were evaporated. The solid residue was slurried in acetone and filtered. The yield was General procedure B A pyridine (500 ml) solution of 0-benzylhydroxylamine (2.46 g; 0.02 mol) and the corresponding dicarboxylic acid monobenzyl ester monoacid chloride (0.04 mol) was stirred at room temperature overnight. The solvent was evaporated. The semisolid residue was dissolved in chloroform (300 mL) and extracted with 5% hydrochloric acid (2 x 50 mL), 10% potassium hydroxide (3 x 100 mL), and water (2 x 100 mL). The organic layer was dried over anhydrous magnesium sulfate and evaporated. The solid residue was purified by column chromatography on silica gel in ethyl acetate. The tribenzyl product was dissolved in methanol (100 mL) and 5% Pd-C (100 ag) was added. The reaction suspension was shaken under hydrogen pressure ("50 psi) at room temperature overnight. The solid was separated by filtration and washed with hot -38methanol (5 x 50 ML). The combined methanol filtrates were evaporated to solid residue. The solid residue was slurried in cooled acetone and filtered. The yield of target product was 30-60%.
0 C- (C2 N- C- (H 2
)-C
HO/ 25
O
'H NMR (DHSO-d 6 2 00MHz) 6 (ppm) 11 .5 3 COOH, 1H) 2. 41 J=7.2Hz, CH 2 CON(OH)COCH, 4H); 2.1.8 J=7.OHz,
CH
2 COOH, 4H); 1.52 8h); 1.22 MS (FAB, V, glycerin) 346(M4 1) Com2ounds having the structure: 0 0 C- (cii c-1- C11 3 2-L; -(C2 i-C no gn I a A pyridine (500 mL) solution of the monomethyl ester monoacid chloride of dicarboxylic acid (0.02 mol) and N, N I-dinothyl-l, w-diamincalkane 01 mol) was stirred at room temperature overnight. Solvent warn evaporated and oily residue was dissolved in chloroform (300 uL).
Chloroform solution was washed with water (3 x 50 aL), potassium hydroxide (3 x 50 uL), 10% hydrochloric acid (3 x 50 aL), and again with water (3 x 50 mL). The organic layer was dried and evaporated. The oily residue was dissolved in potassium hydroxide (1.2 g; 0.021 mol) in 80% methanol (100 mL). The reaction mixture was ref luxed two hours. The solvent was evaporated and solid residue was dissolved in water (50 ML) and extracted with chloroform (3 x 50 mL). Water solution was acidified to -39pH~ 5 and concentrated (to volume of about 10 mL). The water solution or suspension was cooled down and precipitate was separated by filtration. The solid product was purified by crystallization from ethyl acetate. The yield was 40-60%.
0 0 0 \II
C
HO CH3 CH 3
OH
1H NMR (CDCl 3 200 MHZ), 6(ppm) 8.15 broad, COOH, 2H); 3.52 3.45 (2s, CH 2 N, 4H) 3.01 2.93 (2s, CH 3
N,
6H) 2.30 (4t, CH 2 CO, 8H) 1.60 8H) 1.32 8H) 'H NMR (DMSO-d 6 200 MHz), 6(ppm) 3.44 3.336 3.36 (3s, CH 2 N, 4H) 2.94+2.90+2.79 (3s, CIJN, 6H); 2.27 2.23 2.12 (3t, CH 2 CO, 8H); 1.46 8H); 1.23 8H).
Compounds having the structure: O. 0 0 0 I C- (CH 2 NH- C- C-NH-(CH 2 n
C
HO NOH 0* :A Pyridine (500 mL) Solution of 6-aminocaproic acid (2.6 g; 0.02 mol) and terephthaloyl chloride (2 g; 0.01 *25 mol) was stirred at room temperature overnight (-12 hours) and at 90 0 C for 23 hours. The solvent was evaporated, and the solid residue was crystallized from water (10 mL) four times. Yield was 800 mg 1H NMR (DSMO-d 6 200 MHz), 6 (ppm) 12.8 broad, COOH, 2H); 8.54+7.72 (2t, NH, 2H); 3.24 2.98 (2m, NHCH 2 4H); 2.20 2.03 (2m, CH 2 CO, 4H); 1.50 8H) 1.32 4H).
Compound having the structure: 72'O
.NH
C
0 -NHOH Into a mixture of aniline (2.75 g; 0.03 mol), Hydroxylamine hydrochloride (2.08 g; 0.03 mol), and potassium hydroxide (5.50 g; 0.09 mol), and potassium hydroxide (5.50 g; 0.09 mol) in 50% tetrahydrofuran (100 mL) was slowly added at room temperature a tetrahydrofurane (20) mL) solution of terephthaloyl chloride (6 g; 0.03 mol). The reaction suspension was stirred at room temperature for thirty minutes. The solvent was evaporated. The solid residue was slurried in hot methanol (1000 mL) and dried over anhydrous magnesium sulfate. The methanol solution was separated by filtration and filtrate was evaporated. The solid residue was slurried in 20 mL cooled methanol and filtered. The white crystals were washed with ether x 50 mL) and dried. The yield was 4.6 g 'H NMR (DSMO-d 6 200 MHz), 6(ppm) 11.35 broad, NHOH, 1H); 10.35 NHPh, 1H); 9.19 NHOH, 1H); 8.03 J=8 Hz, terephthalic protons, 2H); 7.89 J=8 Hz, terephthalic protons, 2H) 7,82 J=7.4Hz, ortho anilide protons, 2H); 7.34 J=7.4Hz, ortho anilide protons, 2H); 7.34 J=7.4Hz, meta anilide protons, 2H); 7.10 J=7.4Hz, para anilide proton, 1H).
*25 Compound having the structure: o o 0 0 NH-C-CH= CH- -CH=CH-C
"NHOH
NHOH
A solution of 1,4-phenylenediacrylic acid (2.18 g); 0.01 mol) in thionyl chloride (50 mL; 81.55 g; 0.68 mol) was refluxed overnight. Excess thionyl chloride was evaporated. The solid was dissolved in THF (20 mL), and added to a cooled solution of potassium hydroxide (1.12g; 0.02 mol) and aniline in tetrahydrofuran. The reaction mixture was stirred at room temperature for thirty minutes. The solvent was evaporated. The solid residue was slurried in water s and filtered. White crystals were dissolved in a small -41amount of metn'anol and purified on a silica gel column in tetrahydrofuran. The yield was 315 mg 1 H NMR (DMSO-d., 2 00 MHz) 8 (ppm) 10. 80 NHOH, 1H) 10. 2 3 (s, NHPh, 1H); 9.09 NHOH, 1H); 7.69 J=7.6Hz, ortho anilide protons, 2H); 7.64 phenylene protons, 4H), 7.55 J=15.8Hz, PhNHOCCH=CH-, 1H); 7.40 3=15.8Hz, HONHOCCH=CH-, 1H); 7.33 J=7.8Hz, meta anilide protons, 2H); 7.06 J=7.2Hz, para anilide protons, 1H); 6.89 J=15.8Hz, PhNHOCCH=CH-, 1H) 6.51 (d, J=15.8iz, HOHNOCCH=CH-, 1H).
Com~ounds-havingt the structure: 020 A .hoo .r 15uino rityaie(. L .0g 0.0 h orsodn mn 00 o)addai dichlorid- a treda omteprtr p hreiinat wa fomd 4he 5rciitt was sepanded8.
200 A~ souinIM 14~,10 -42- 'H NMR (DMSO-d 6 200 MHz), 6(ppm) 10.23 NH, 2H); 7.82 J=9Hz, aromatic protons, 4H), 7.60 J=9Hz, aromatic protons, 4H), 2.31 J=7.4Hz, CH 2 CO, 4H); 2.61 4H); 1.32 4H).
100 2I&M, (C 2 )C /0 0 N OM 'H NMR (DMSO-d 6 200 MHz), 6(ppm) 10.48 NH, 2H); 8.18 J=9.2Hz, aromatic protons, 4H); 7.81 J=9.2Hz, aromatic protons, 4H0; 2.37 J=7.2Hz, CH 2 CO-, 4H); 1.60 4H); 1.33 4H).
0 o /c/c 2o* 0 agW 1 NMR (DMSO-d 6 200 MHz), 89.91 NH, 2H), 7.58 (d, J=8.6Hz, aromatic protons,. 4H); 7.26 J-8.6 Hz, aromatic protons, 4H); 3.94 CH 2 CN, 4H); 2.29 (t, J=7.4Hz, CH 2 CO-, 4H); 1.60 4H); 1.31 4H).
113 4W-ML1I o- a) C s omaas
*=INC%
a 'H NMR (DMSO-d6, 200 MHz), S(ppm) 10.08 CONHAr, 2H); 7.79 J-8.6Hz, aromatic protons, 4H); 7.63 J-8Hz, aromatic protons, 4H), 7.22 H 3 CHNCO-, 2H); 3.32 (s,
CH
3 6H); 2.31 J-7Hz, CH 2 6H); 1.59 4H); 1.31 4H).
a UOM MR"- (clY C oM 1/amm -43- 'H NNR (DHSO-d 6 1 200 ]MHz), S(ppm) 10.90 broad, NHOH, 2H); 10.05 NHAr, 2H); 8.90 broad, NHOH, 2H); 7.68 J=9Hz, aromatic protons, 4H); 7.62 J=9Hz, aromatic protons, 4H) 2. 31 3=7.2Hz, CH 2 CO-, 4H) 1. 59 (in, 4H); 1.30 (mn, 4H).
C- (CH 1/ 26 0 X0 'H NMR (DMSO-d 6 200 MHz), 6(ppm) 10.06 broad, NH, 2H); 8.71 J-2.6Hz, aromatic protons, 2H); 7.31 (d d, aromatic protons, 2H); 2.32 J=7.4Hz, CHCO-, 4H); 1.59 (in, 4H); 1.33 (mn, 4H).
0e 9 99.9 *999 9* 9* *9 9 9.
9 9 *9**99 9 9 C l q 5 r C- (CH )-c 'H ?IMR (DMSO-d 6 200 MHz), S(ppm) 12.00 broad, NH, 2H) 7.43 J-3.6Hz, aromatic protons, 2H) 7.16 (d, J=3.6Hz, aromatic protons, 2H) 2.41 J=7.2Hz, CH 2
CONH-
4H) 1.58 (mn, 4H1); 1.28 4H).
In the similar manner, the following compounds were prepared and characterized: (CK2)
CS-
a wherein n 4, 5, 6, 7, and 8; all compounds are symmetrical wherein R is and 4cyano; and 4-methylcyano; and 4-nitro, -44and 4-carboxy; and 4-aminocarbonyl; 2-, 3- and 4-methylaminocarbonyl; and 4dimethylaminocarbonyl; and and 4-trif luoromethyl; //0 c
(CK
2
)-C
wherein R is 4-hydroxylaminocarbonyl; 4-methoxycarbonyl; and 4-chioro; and 4-fluoro; and 4-methyl; and 4-methoxy; 2,3-difluoro; 2,4difluoro; 2,5-difluoro; 2,6-difluoro; 1,2,3,trifluoro, 3,4,5-trifluoro; 2,3,5, 6-tetrafluoro; 2,3, 4, 5,6-pentaf luoro.
15 N //0 2~ )-c a *fl.
a a a.
a a.
a.
a .a 00 0 C- (CH2 )-c 0 l
-M
0 C- (cH 2 0
NE
15 2 Comipounds-havinct-the structure: 0 99* 0 *00020 whri n General- (OKeur AC dicddclrd (.1ml a dddt tre slto f oasu ydoie ;00 o) hyroyamn hdocloid R0 ;0 1ml n h (100 wheei n eutn recto 4,xur 5as 6,ire 7,ant8 eneprate trode soiA eiu.Te oi eiu a Aludied iceharod (00 ol) asd ded oe anstirred (100siu suat. The emtn etaton soixture was sirdat -46by filtration and evaporated to a solid residue. The product was purified by column chromatography on silica gel in ethyl acetate-tetrahydrofuran (in most cases 3:1).
The yields were 15-30%.
General procedure B A solution of corresponding monomethyl ester of dicarboxylic acid (0.01 mol), oxaloyl chloride (0.03 mol), and a few drops DMF in benzene (500 mL) was stirred at room temperature overnight. The solvent was evaporated and the oily residue was dissolved in dry benzene (3 x 50 mL) and evaporated again. The tetrahydrofuran (50 mL) solution of monoester monoacid 15 chloride of the corresponding dicarboxylic acid was slowly added to a cooled solution of the corresponding amine (0.01 mol) and pyridine (1.6 mL; 1.6 g; 0.02 mol) in tetrahydrofuran (200 mL). The reaction mixture was stirred at room temperature for an hour. The solvent was evaporated, the reside was dissolved in chloroform (300 mL), and the chloroform solution was washed with hydrochloric acid (3 x 50 mL), 10% potassium hydroxide (3 x 50 mL), and water (3 x 50 mL). The organic layer was dried over anhydrous magnesium sulfate and evaporated, 25 yielding the pure monoester monoamide of dicarboxylic acid. The product was dissolved in 80% methanol with potassium hydroxide (0.56 g; 0.01 mol). The reaction mixture was refluxed two hours and evaporated to solid residue. The residue was dissolved in water (-20 mL) and acidified to "pH 5 with 10% hydrochloric acid. The monoacid monoamide of the dicarboxylic acid was isolated by filtration of precipitate or extraction water solution with chloroform. The isolated monoacid monoamide of the dicarboxylic acid was mixed together with an equivalent amount of 0-benzylhydroxylamine and 1,3-dicyclohexylcarbodiimide in pyridine ('100 mL per 0.01 mol of 0benzylhydroxylamine) and was stirred at room temperature -47overnight. The solvent was evaporated and the solid residue was partitioned between chloroform (500 mL) and hydrochloric acid (300 mL). The organic layer was washed with water (3 x 100 mL) and dried over anhydrous magnesium sulfate. The solvent was evaporated to solid residue. The solid residue was dissolved in large amounts of tetrahydrofuran and filtered through a short column of silica gel. The crude product was dissolved in methanol (100 mL) and 5% Pd-C was added. The reaction suspension was shaken under hydrogen pressure (-50 psi) overnight. The catalyst was separated by filtration and filtrate was evaporated to solid residue. The solid residue was slurried in hexanes and filtered. Mostly pure product was isolated in this way. If necessary 15 further purification was achieved by column chromatography on silica gel with ethyl acetatetetrahydrofuran. The yields were from 35% to General procedure C A pyridine (500 mL solution of O-benxylhydroxylamine (1.23; 0.01 mol), the corresponding amine (0.01 mol), and the dichloride of the dicarboxylic acid (0.01 mol) was stirred at room temperature overnight. The solvent was 25 evaporated and the white solid residue contains, judged by 'H NMR, two symmetrical amides and a target unsymmetrical one. The solid residue was slurried in methanol and dried over anhydrous magnesium sulfate. The filtrate was evaporated and the solid residue was dissolved in methanol ('100 mL). Into the methanol solution 5% Pd-C (100 mg) was added and the black suspension was shaken under hydrogen pressure ("50 psi) overnight. The catalyst was separated by filtration and the filtrate was evaporated. The product was isolated by column chromatography on silica with ethyl acetatetetrahydrofuran. The yields were from 20% to -48- General Procedure D A chloroform solution of triethylamnine (3 ML; 2.18 g; 0.0215 mol), the corresponding amine (0.01 mol), 0-trimethylsilyl)hydroxylamine (1.05 g, 0.01 mol), and the corresponding diacid chloride of the dicarboxylic acid (0.01 mol) was stirred at room temperature overnight. The solvent was evaporated, the residue was dissolved in methanol (-10 mL), and into the methanol solution lot ammonium chloride (-10 uL) was added. The resulting suspension was stirred at 500C for two hours.
The solvent was evaporated. The solid residue was slurried in methanol (300 m.L) and dried over anhydrous magnesium sulfate. The methanol solution was separated by filtration and evaporated to a solid residue. The product was isolated by silica gel column chromatography with ethyl acetate-tetrahydrofuran. The yields were 33%.
0/ H- C- (C1 )-C 6
MHOH
Elemental analysis: Calc. 63.62 7.63 10.60 *.Found 63.58 7.59 10.48 1 H NMlE (DMSO-d 6 200 MHz), 6(ppm) 10.31 NHOH, 1H); 9.83 11MPh, 1H); 8.64 MHOH, 1H); 7.57 J-8.2Hz, ortho aromatic protons, 2H); 7.26 J-8.4Hz, meta aromatic protons, 2H), 6.99 J-7.4Hz, para aromatic protons, 1H); 2.27 J-7.4Hz, CH 2 CONHPh, 2H) 1.93 (t,
CH
2 CONHOH, 2H) 1. 52 (in, 4H) 1. 26 (mn, 4H) MS (Fab, Glycerin) 172, 204, 232, 249, 265, (100%, M1 1).
-49- 0T,~ H HC (CH 2 -C
NHOIH
'H NNR (DMSO-d 6 200 M4Hz), S (ppm) 10. 31 NHOH, 1H); 10.08 NHPh, 1H); 8.64 NHOH, 1H); 7.78 (d, J=7.6Hz, aromatic protons, 1H); 7.66 J=7.4Hz, aromatic protons, 1H); 7.48 J=7.8Hz, aromatic protons, 1H); 7.29 J-7.4Hz, aromatic protons, 1H); 2.34 3=7Hz, CH 2 CONHAr, 2H); 1.93 3=7.4Hz,
CH
2 CONHOH, 2H); 1.58 (mn, 4H); 1.27 (mn, 4H).
KC
0T 0 IC (CH 2)-CI b
KHOH
'H NMa (DMSO-d 6 200 M4Hz) 6 (ppm) 10. 31 NHOH, 1H); 10.21 NHPh, 1H); 8.65 NHOH, 1H); 8.09 (s, :.aromatic proton, 1H) 7.77 (mn, aromatic proton, 1H) 7.49 (mn, aromatic proton, IN) 2.31 3=7.2Hz, CHCONHAr, 2H); 1.93 3=7.2Hz, CH 2 CONHOH, 2H); 1.51 (mn, 4H).
.0 N 0 0 (CH )-C OV aH NM DS 6 2.00 MHz) 6 (ppn) 10.35 N~,1) 10.31 NHOH, 1H); 8.63 NHOH aromatic proton 2H); 7.88 J=8Hz, aromatic protons, 2H) 7.57 3=8Hz, aromatic proton, 1H); 2.33 3=7.6Hz, CH 2 CONHAr, 2H) 1.93 J-7.4Hz, CH 2 CONHOH, 2H), 1.52 (mn, 4H); 1.27 (mn, 4H).
0 0 11 1 2)2 C
NMRO
'H NMR (DMSO-d 6 200 MHz), 6(ppm) 10.33 NHOH, 1H); 10.15 NHAr, 1H); 10.09 NHPh, 1H); 8.66 NHOH, 1H); 7.91 J=8.6Hz, aromatic protons, 2H); 7.76 (d, J=7.8Hz, ortho, aniline protons, 2H); 7.71 J=8.6Hz, aromatic protons, 2H); 7.33 J=7.6Hz, meta anilide protons, 7.07 J=7.4Hz, para anilide protons); 2.33 J=7.5Hz, CH 2 NHAr, 2H); 1.93 J=7.2Hz, CH 2
CNHH,
2H); 1.51 (in, 4H); 1.28 (mn, 4H).
0 ,0 NH- C- (Co
C
6
NHOH
'H NMR (DMSO-d 200 MHz) 6 (ppm) 10. 32 NHOH, 111); 10.21 NHAr, 1H) 8.65 NHOH, 1H) 7.31 (d of d, J-lOHz(2.2Hz), aromatic protons, 2H); 6.84 (t of t, J-9. 4Hz 4Hz) aromatic protons, 1H) 2. 29 CH 2 CONHAr, 2H1); 1.93 J-7.2Hz, CH 2 CONHOH, 2H); 1.51 (in, 4H); 1.26 *30 (in, 4H).
In the same manner the following compounds were prepared ***and characterized: wherein n 4, 5, 6, 7, and 8; and R is and 4- 14 -51cyano; and 4-methylcyano; and 4-nitro; and 4-carboxy; and 4-aminocarbonyl; 2-, and 4-methylaninocarbonyl; and 4dimethylaminocarbonyl; and and 4trifluoromethyl;
R
NHII/0 C- (CH 2 )-c 0 NHOH wherein R is 4-hydroxylaminocarbonyl; 4-methoxycarbonyl; 4-tetrazoyl; and 4-chioro; 2 3 and 4 fluoro; and 4-methyl; and 4-methoxy; 2,3-difluoro; 2,4-difluoro; 2,5-difluoro; 2,6difluoro; 1,2, 3-trifluoro; 3,4, 5-trifluoro; 2,4,5trifluoro; 2,4,6-trifluoro; 2,3,6-trifluoro; 2,3,5,6tetrafluoro; 2,3,4,5,6-pentafluoro; 2 3- and 4 phenyl; and 4-benzyloxy; 4-hexyl; and 4-tbutyl; C (Ca2 C-cH 2 6 0 NHOH 4, I -52- Compounds havina the structure:
R
(CH
C
n N (CH 3 0 2 wherein n 4, 5, 6, 7, and 8; and R is hydrogen or methyl.
A diacid dichloride (0.01 mol) was added into a stirred solution of potassium hydroxide (1.68 g; 0.03 mol), aniline or N-methylaniline (0.01 mol), and dimethylamine hydrochloride (0.805 g; 0.01 mol) in 50% tetrahydrofuran (100 mL). The reaction mixture was stirred thirty minutes at room temperature. The solvent was partitioned between chloroform (400 mL) and water (300 mL) The organic layer was washed with 10% hydrochloric acid (3 x 20 100 mL), 10% potassium hydroxide (3 x 100 mL), and water (2 x 100 mL). The organic layer was dried over anhydrous magnesium sulfate and evaporated. The solid residue was slurried in hexanes and filtered. The yield were 25-34%.
H
N *O N (CH 3 para aromatic proton, 2.85 J-=2Hz, 2.28 J=7.2Hz, CH 2 CO, 2H) 2.24 J=7.4Hz, CH 2
CO,
2H); 1.51 4H); 1.29 4H).
-53- N N C- (CH 2) C 0 n (3)2 'H NHR (DMSO-d 6 200 MHz) 6(ppm) 7.30 (MI C 6
H
5 l 5H) 3.13
H
3 CNPh, 3H); 2.83 J=26Hz, N (CH 3 2 6H) 2. 17 (t, J=7.6Hz, CH 2 CON (CH 3 2 f 2H) 1.98 (t I J=7.4Hz,
CH
2
CON(CH
3 )Ph, 2H); 1.41 (mn, 4H); 1.11 (int, 4H).
-54- TABLE 1 Mol. Optimal Weigrht Coric. (uM) Benz idine Reactive Cells M% CPD Structure
H/
C-(CH
2 0 NHOH n =4 (known compound) n= n= 6 n- 7 n 8 236 250 264 278 292 *t *0
U.
S U
S
S. 5 55
*S
S 5
(CH
2
OH
(CH
2 6I//
OH
274 274 294 a. a S
S
S
oAN.
12.5 TABLE 1 (continued) Benz idine Mol. Optimal Reactive CPD Structure Weight Conc.(uM) Cells M%
H
N 0 9 ~~(CH 2 6 -C25500
HO
C- (CH 2 6 -C 355 250 26 0 OH
(H
3 C) 2 N 11 C- (CH 2 6 -C 216 60 53 0 %HOH HO 0 C- (CH 2 6 -C 189 250 tfHOH 5H 3 CO\0 13 C- (C26C 203 60 17 0 NHOH 0 *14 NC (CH2) S-C\ NHH156 125
H
3 COHN /0 /C-(CH2) 6 -C 218 20 43 *0 KHOH -56- TABLE 1 (continued) Benz idine Mol. optimal Reactive CPD Structure Weight Conc.L.kMl Cells (%I
H
N 0 16 C- (C.6C 270 8 O KHOH 17 (CH 2 6K 256 62 0 NHOH (CHO) 3 CONH 0 18 C- (C26-/ 260 31 38
NHOH
CH NH 0 1 9 KiI 2 -(C26-l 278 5 24 1C\
KHOH
0 C(CHO 6
C\
0 KHOH R 4-methyl 273 20 52 *21 R -4-cyaio 289 7 *22 R 3-cyao 289 5 23 R 2-cyano 289 16 24 R 3-nitro, 309 5 -57- TABLE 1 (continued)
CPD
26 27 28 29 31 32 33 *SS* 34 35 C. *S 36 37 38 39 Structure R 4-nitro R 3-trifluoromethyl R 4-trifluoromethyl R 2-amino R 4-cyanomethyl R 3-chioro R 4-azido, (N 3 R 2-rluoro R 3-f luoro R 4-f luoro R 4-benzyloxy R 4-methyoxycarbonyl R 4-methylaninocarbonyl R 2-bromo R 2-chioro R 4-bromo Mol.
Weight 309 332 332 279 303 298.5 304 282 282 282 370 322 321 343 298.5 343 Benzidine optimal Reactive Conc~.MI Cells M% 0.8 30 5 47 20 54 1 2 33 2 47 4 1 4 43 4 4 28 30 16 8 4 34 1.6 47 -58- TABLE 1 (continued)
CPD
41 42 43 44 46 47 48 49 51 52 53
C
C
C C
C.
C.
C.
C
C. C
C.
C
CC..
C
CC..
C.
C
C
Structure R 2,3-difluoro R 2,4,5-trifluoro R 2,3,6-trifluoro R 2,4,6-trifluoro R 2,4-difluoro R 2,3,4,5,6-pentafluoro R 3,4-difluoro R 3,4,5-trifluoro R 2,5-difluoro R 3,5-difluoro R 2-uiethoxy R 3-methoxy R 4-methoxy 0 NHOH Hol.
Weight 300 318 318 318 300 354 300 318 300 300 294 294 294 290 optimal Conic. (uM) 8 8 31 16 6 31 4 8 4 2 8 6 6 20 Benz idine Reactive Cells M% 24 36 53 47 53 61 73 36 38 37 -59- TABLE 1 (continued) Benz idine Mol. Optimal Reactive CPD Structure Weight Conc.(uM Cells E%I
H
256 30 53
NHOH
H
R N 0 0 Na 56 R 4-trifluoromethyl 460 50 57 R 4(N)-hydroxylamino- 442 8 carbonyl, *58 R 4-cyanomethyl 402 50 *59 R 2,4-difluoro 396 500 54 R 2,6-difluoro 396 100 21 61 R 3,5-difluoro 396 125 31 *62 R 2,3,6-triluoro 432 250 28 *63 R 2,4,6-trifluoro 432 125 64 R 2,3,4,5,6-pentafluoro 504 125 13 R 4-nitro 414 25 14 TABE 1(continued) Benzidine Mol. optimal Reactive CPD Structure Weight ConcJjfE.. Cells M% 0 CH 3 CjH 0 66 C-CH- (CH 2 5 -CH-C\ 270 1250
(H
3
C)
2 N N (CH 3 2 0 I9I 67 C-CH- (Cl! 2 4 -CH-C 256 2500
(H
3 C)ZNN C32 0 CH 3 0 68 C n22-C-(H)2C204 125 56 H0H1d NHOH :CONHOH 0? 1 333 60 HOID( N HOH 0 F A 0 C- (CH 2 2 -CH- (CH 2 2 -C 22616 1 P HOHN FKN H 4 40,0e -61- TABLE 1 (continued) Mol. optimal Weight Conc. (uM) Benz idine Reactive Cells M% CPD Structure C (CH 2 0/ n= 4 n= 5 n= 6 n= 7 n 8 310 324 338 352 366 100 250 100 100 S. @4 9. 4 4 4* 5 6 4 4* 9 S 4 04 5* 4 4449 04 9 444* 0* 44
SS
6 4 54 4 *5*4 4* 44 4 4 444*44 4 -62- TABL 2 Induction of Differentiation of HI Mol.
CPD
2 3 6 7 22 21 26 25 250 264 274 274 289 289 332 309 Optimal Conc. (uN) 7 1 20 20 1.7 2 6 3 1 2.5 1 2
NBT
Positive M% 22 21 21 28 6 27 18 32 7 0@ *S
S
S
0S S S 0005 *0 S S S
S.
5* S S OOeS 0O
S
5*SS @5 55 S
*S
5 0 0@ 55S*
S
5555 @6 5 0 0 SeeS..
S
322 304 303 318 P:\OPER\MRO\62063-96.280 7/10/98 -62A- 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.
*9 o
C
o•
C
a•.
o a a a C C a a C C
C
a a *.t -63- References: 1. Sporn, Roberts, and Driscoll, J.S.
(1985) in Cancer: Principles and Practice of Oncolgoqy, eds. Hellman, Rosenberg, and DeVita, Jr., Ed. 2, Lippincott, Philadelphia), P. 49.
2. Breitman, Selonick, and Collins, S.J.
(1980) Proc. Natl. Acad. Sci. USA 77: 2936-2940.
3. Olsson, I.L. and Breitman, T.R. (1982) Cancer Res.
42: 3924-3927.
4. Schwartz, E.L. and Sartorelli, A.C. (1982) Cancer Res. 42: 2651-2655.
Harks, Sheffery, and Rifkind, R.A. (1987) Res.. 47: 659.
6. Sachs, L. (1978) Natur (Lond.) 274: 535.
7. Friend, Scher, Holland, and Sato, T.
(1971) Proc. Natl. Acad. Sci. (USA) 68: 378-382.
S. Tanaka, Levy, Terada, Breslow, R., Rifkind, and Marks, P.A. (1975) Proc. Natl.
Aca. ScL (USA) 72: 1003-1006.
9. Reuben, Wife, Breslow, Rifkind, and Marks, P.A. (1976) Proc. Natl. Acad. Sci.
(USA) 73: 862-866.
Abe, Miyaura, Sakagami, Takeda, H., Konno, Yamazaki, Yoshika, and Suda, T.
(1981) Proc. Natl. Aced. Sci. (USA) 78: 4990-4994.
I
-64- 11. Schwartz, Snoddy, Kreutter, D., Rasmussen, and Sartorelli, A.C. (1983) Proc. Am.
Assoc. Cancer-Res. 24: 18.
12. Tanenaga, Hozumi, and Sakagami, Y. (1980) Cancer Res. 40: 914-919.
13. Lotem, J. and Sachs, L. (1975) Int. J. Cancer 73 1-740.
14. Metcalf, D. (1985) Science, 229: 16-22.
Scher, Scher, and Waxman, S. (1983) Z~p Hematol. 11: 490-498.
16. Scher, Scher, and Waxman, S. (1982) Biochem. Biovhys. Res. Comm. 109: 348-354.
17. Huberman, E. and Callahan, M.F. (1979) Prc al Acd Si (USA) 76: 1293-1297.
0 018. Lottem, J. and Sachs, L. (1979) Proc. Nati. Acad.
~L(USA) 76: 5158-5162.
19. Terada, Epner, Nudel, Salmon, J., Fiba-ch, Rifkindo and Marks, P.A. (1978) Proc. Natl. Acad. Sci. (USA) 75: 2795-2799.
Morin, N.J. and Sartorelli, A.C. (1984) Cancer Res 44: 2807-2812.
*21. Schwartz, Brown, Nierenberg, Marsh, and Sartorelli, A.C. (1983) Cancer Res. 43: 2725-2730.
22. Sugano, Furusawa, Kawaguchi, and Ikawa, Y. (1973) Bibi. Hematol. 39: 943-954.
23. Ebert, Wars, and Buell, D.N. (1976) Cancer Res. 36: 1809-1813.
24. Hayashi, Okabe, and Hozumi, M. (1979) Gann 235-238.
Fibach, Reuben, Rifkind, and Marks, P.A. (1977) Cancer Res. 37: 440-444.
26. Melloni, Pontremoli, Damiani, Viotti, Weich, Rifkind, and Harks, P.A. (1988) Proc. Natl. Acad. Sci. (USA) 85: 3835-3839.
27. Reuben, Khanna, Gazitt, Breslow, R., Rifkind, and Harks, P.A. (1978) J. Biol. Chemn.
253: 4214-4218.
:28. Marks, P.A. and Rifkind, R.A. (1988) International Journal of Cell Cloning 6: 230-240.
Melloni, Pontremoli, Michetti, Sacco, Cakiroglu, Jackson, Rifkind, R.A., and Harks, P.A. (1987) Proc. Natl. Acad. Sciences (USA) 84: 5282-5286.
Harks, P.A. and Rifkind, R.A. (1984) Cace 54: 2766-2769.
31. Egorin, Sigman, L.M. VanEcho, Forrest, Whitacre, and Aisner, J. (1987) Cancer 47: 617-623.
32. Rowinaky, Ettinger, Grochow, L.B., Brundrett, Cates, and Donehower, R.C.
(1986) J. Clin. Oncol. 4: 1835-1844.
-66- 33. Rowinsky, E.L. Ettinger, McGUire, Noe, Grochow, and Donehower, R.C. (1987) Cancer Res. 47: 5788-5795.
34. Callery, Egorin, Geelhaar, and Nayer, M.S.B. (1986) Cancer Res. 46: 4900-4903.
Young, C.W. Fanucchi, Walsh, Blatzer, Yaldaie, Stevens, Gordon C. Tong, Rifkind, and Marks, P.A. (1988) Cancer ResL. 48: 7304-7309.
36. Andreeff, Young, Clarkson, Fetten, J., Rifkind, and Harks, P.A. (1988) Blood 72: 186a.
37. Marks, Breslow, Rifkind, Ngo, L., and Singh, R. (1989) Proc. Natl. Acad. Sci. (USA) 86: 6358-6362.
38. Breslow, Jursic, Yan, Friedman, E., Lang, Ngo, Rifkind, and Marks, P.A.
(1991) Proc. Natl. Acad. Sci. (USA) 88: 5542-5546.
39. Ohta, Tanaka, Terada, Miller, O.J., Bank, Marks, and Rifkind, R.A. (1976) Proc. Natl. Acad. Sci. (USA) 73: 1232-1236.
Collins, Gallo, and Gallagher, R.E.
(1978) MNatuare (London) 270; 405-409.
Synder, Egorin, Geelhaar, L.A., Hamburger, and Callery, P.S. (1988) Cace Res, 48; 3613-3616.
PLR r' i 1 -67- THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS: 1. A compound having the structure: 0 0 0 0 II II 2 )n-c
R
wherein each X and Y are independently the same as or different from each other and are a hydroxyl, amino or hydroxylamino group, a substituted or unsubstituted alkyloxy, alkylamino, dialkylamino, arylamino, alkylarylamino, alkyloxyamino, aryloxyamino, alkyloxyalkylamino, or aryloxyalkylamino group; R is a hydrogen atom, a hydroxyl group, a substituted or unsubstituted alkyl, aryl, alkyloxy, or aryloxy group; and each of m and n are independently the same as or different from each other and are each an integer from 0 to 8.
go 2. A compound of claim 1, wherein each of X, Y, and R is a hydroxyl group and each of m and n is e 3. A compound having the structure: 0 0 0 *i C-(CG)m-C-N-(GC)n-N-C-(Co-C\ R, R: X Y wherein each of X and Y are independently the same as or different from each other and are a hydroxyl, amino or hydroxylamino group, a substituted or unsubstituted alkyloxy, alkylamino, dialkylamino, arylamino, alkylarylamino, alkyloxyamino, aryloxyamino, alkyloxyalkylamino, or

Claims (38)

  1. 4. A compound of claim 3, wherein each of X and Y is a hydroxyl group and of Ri and R 2 is a methyl group. A compound of claim 4, wherein each of n and o is 6, and m is 2.
  2. 6. A compound having the structure: 0 0 0 0 G(Qm- N-C I- I" Y R2 wherein each of X and Y are independently the same as or different from each other and are a hydroxyl, amino or hydroxylamino group, a substituted or unsubstituted alkyloxy, alkylamino, dialkylamino, arylamino, alkylarylamino, alkyloxyamino, aryloxyamino, alkyloxyalkylamino, or aryloxyalkylamino group; each of RiandR 2 are independently the same as or different from each other and are a hydrogen atom, a hydroxyl group, a substituted alkyl, aryl, alkyloxy, or aryloxy group; and each of m and n are independently the same as or different from each other and are each an integer from 7 0 to 8. ;:i'Lll .!IP' 42] 1 5 -69-
  3. 7. A compound of claim 6, wherein each of X and Y is a hydroxyl group and each of m and n is
  4. 8. A compound having the structure: X II Y x 1 1-- 0 0 wherein each of X and Y are independently the same as or different from each other and are a hydroxyl, amino or hydroxylamino group, a substituted or unsubstituted alkyloxy, alkylamino, dialkylamino, arylamino, alkylarylamino, alkyloxyamino, aryloxyamino, alkyloxyalkylamino, or aryloxyalkylamino group; each of Ri and R 2 are independently the same as or different from each other and are a hydrogen atom, a hydroxyl group, a substituted or unsubstituted alkyl, aryl, alkyloxy, or aryloxy group; and each of m and n are independently the same or different from each other and are each an integer from 0 to 8.
  5. 9. A compound having the structure: e60 p O Sfrom each other and are a hydroxyl, alkyloxy, amino, hydroxylamino, alkylamino, dialkylamino, arylamino, alkylarylamino, alkyloxyamino, aryloxyamino, alkyloxyalkylamino, or aryloxyalkylamino group; R, and R 2 are 7A not both hydroxyl, hydroxylamino or arylamino. P, UPhR MR0~ 1 42L-A2 CLI W 70 A compound of claim 9, wherein R, is a phenylamino group and R 2 is a hydroxylamino group.
  6. 11. A compound having the structure: wherein each of R, and R 2 are independently the same as or different from each other and are a hydroxyl, alkyloxy, amino, hydroxylamino, alkylamino, dialkylamino, arylamino, alkylarylamino, alkyloxyamino, aryloxyamino, alkyloxyalkylamino, or aryloxyalkylamino group; provided that R, and R 2 are not both hydroxyl or hydroxylamino.
  7. 12. A compound of claim 11, wherein R, is phenylamino group and R 2 is a hydroxylamino group.
  8. 13. A compound having the structure: R 0 0 R p. p p pp p p p p. p. p. p p p p p. p p p p p p p p p p. p p p. Ac,. [77 /5 K/cT wherein R is a phenylamino group substituted with a cyano, methylcyano, nitro, carboxyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, trifluoromethyl, hydroxylaminocarbonyl, N-hydroxylaminocarbonyl, methoxycarbonyl, chioro, fluoro, methyl, methoxy, 2,3- difluoro, 2,4-difluoro, 2,5-difluoro, 2,6-difluoro, difiluoro, 2,3,6-trifluoro, 2,4,6-trifluoro, 1,2,3-trifluoro, 3,4,5-trifluoro, 2,3,4, 5-tetrafluoro, or 2,3,4,5,6- P OPER MRO 1542h) 2L 0 S( 59 71 pentafluoro; and n is an integer from 4 to 8.
  9. 14. A compound having the structure: 0 0 yj -NH-C-C-26CO A compound having the structure: N=-C 0 0 1 1 11 O NH- C- (C-4 2 6 C- OH
  10. 16. A compound having the structure: 9. 9. 9 9 *99* 9. Se .9 9*9e 9 S. 9* 99 9 9 9 U 9 *5*9 *99e 9* 9s *99* 9* 9 99 9. 9 9 9. 9 999 9 9. *9 S 9 9 999 9 9. .9 9
  11. 17. A compound having the structure: 0 0 ONH- C- (C2j- C- NH-OH*
  12. 18. The compound according to any one of claims 14-17 substantially as hereinbefore described with reference to the accompanying Examples and/or drawings. A compound having the structure: P OPER MRO 184:1 k CLM 5 W -72- 0 0 0 0 0 C(C )fm-C-1 C -C-NH-C- C Y wherein each of X and Y are independently the same as or different from each other and are a hydroxyl, amino or hydroxylamino group, a substituted or unsubstituted alkyloxy, alkylamino, dialkylamino, arylamino, alkylarylamino, alkyloxyamino, aryloxyamino, alkyloxyalkylamino, or aryloxyalkylamino group; and each of m and n are independently the same as of different from each other and are each an integer from 0 to 8. A compound of claim 19, wherein each of X and Y is a hydroxyl group and each of m and n is
  13. 21. A compound having the structure: 0 0 C (C1)n- C- x Y wherein each of X and Y independently the same as or different from each other and are a hydroxyl, amino or hydroxylamino group, a substituted or unsubstituted alkyloxy, alkylamino, dialkylamino, arylamino, alkylarylamino, alkyloxyamino, aryloxyamino, alkyloxyalkylamino, or aryloxyalkylamino group; and n is an integer from 1 to 8 provided that X and Y are not both dialkylamino. OPLR MR- j i -73
  14. 22. A compound having the structure: 0 RI 0 I 4 )n-C\ x I Y R 2 wherein each of X and Y are independently the same as or different from each other and are a hydroxyl, amino or hydroxylamino group, a substituted or unsubstituted alkyloxy, alkylamino, dialkylamino, arylamino, alkylarylamino, alkyloxyamino, aryloxyamino, alkyloxyalkylamino, or aryloxyalkylamino group, provided that when X is a hydroxy or alkyloxy, Y cannot be a hydroxy or alkyloxy; RI and R 2 are independently the same as or different from each other and are a hydrogen atom, a substituted or unsubstituted alkyl, aryl, alkyloxy, aryloxy, carbonylhydroxylamino, or fluoro group; provided that Ri and R 2 are not both hydrogen atoms; and m and n are independently the same as or different from each other and are each an integer from 1 to 8.
  15. 23. A compound of claim 22, wherein each of X and Y is a hydroxylamino group; RI is a methyl group; R 2 is a hydrogen .atom; and each of m and n is 2.
  16. 24. A compound of claim 22, wherein each of X and Y is a hydroxylamino group; R, is a carbonylhydroxylamino group; R, is s hydrogen atom; and each of m and n is A compound of claim 22, wherein each of X and Y is a hydroxylamino group; each of Ri and R 2 is a fluoro group; and each of m and n is 2. A compound having the structure: P CP. NIRO Pi4-4lAj LNI -74- R C wherein each of R, and R 2 are independently the same as or different from each other and are a hydroxyl, alkyloxy, amino, hydroxylamino, alkylamino, dialkylamino, arylamino, alkylarylamino, alkyloxyamino, aryloxyamino, alkyloxyalkylamino, or aryloxyalkylamino group; provided that R, and R, are not both hydroxylamino.
  17. 27. A compound of claim 26, wherein RI is a hydroxylamino group.
  18. 28. A compound of claim 26, wherein R 2 is a hydroxylamino group.
  19. 29. A method of selectively inducing terminal differentiation of neoplastic cells and thereby inhibiting proliferation of such cells which comprises contacting the cells under suitable conditions with an effective amount of the compound of any one of claims 1, 3, 6, 8, 11, 13, 19, 21, 22 or 26 effective to 9 selectively induce terminal differentiation. a
  20. 30. A method of treating a patient having a tumor characterized by proliferation of neoplastic cells which comprises administering to the patient and effective amount of the compound of any one of claims 1, 3, 6, 8, 11, 13, 19, 21, 22 or 26 effective to selectively induce terminal differentiation of such neoplastic cells and thereby inhibit their proliferation.
  21. 31. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of the compound of any one- of claims 1, 3, 6, 8, 11, 13, 19, 21, 22 or 26. P OPER NIMRO IS4'iA CI I 5 99
  22. 32. A pharmaceutical composition of claim 31, wherein the effective amount is an amount effective to selectively induce terminal differentiation of suitable neoplastic cells and less than an amount which causes toxicity in a patient.
  23. 33. A pharmaceutical composition of claim 32 in combination with an antitumor agent.
  24. 34. A method of selectively inducing terminal differentiation of neoplastic cells and thereby inhibiting proliferation of such cells which comprises contacting the cells under suitable conditions with an effective amount of the compound having the structure: different from each other; when R and R2 are the same, each R3 and R4 are independently the same as or different from each :other and are a hydrogen atom, a hydroxyl group, a substituted 99 .and wherein a hydroxylamino, hydroxyl, amino, alkylthe saminoe as or alkyloxy different froup;m each other; when integer from 4 to 8same, or each Spharmaceutically acceptable salt thereof; and wherein the i Re and R 4 are independently the same as or different from each other and are a hydrogen atom, a hydroxyl group, a substituted or unsubstituted, branched or unbranched alkyl, alkenyl, and R is a hydroxylamino, hydroxyl, amino, alkylamino, or grup whe alkyloxy group; and n is an integer from 4 to 8, or a 1,z 7 pharmaceutically acceptable salt thereof; and wherein the P OPER MRO IS4-2!) CL.M '2UJ -76- amount of the compound is effective to selectively induce terminal differentiation. A method of claim 34 wherein the Ri represents NHOH, R 2 represents OH, and n represents 6.
  25. 36. A method of claim 34 wherein the compound has the structure: C-(C2)n- C o R, wherein each of R 3 and R 4 are independently the same as or different from each other and are a hydrogen atom, a hydroxyl group, a substituted or unsubstituted, branched or unbranched alkyl, alkenyl, cycloalkyl, aryl, alkyloxy, aryloxy, arylalkyloxy, or pyridine group, or R 3 and R 4 bond together to form a piperidine group; R 2 is a hydroxylamino, hydroxyl, amino, alkylamino, or alkyloxy group; and n is an integer from 4 to 8, or a pharmaceutically acceptable salt thereof; and S. S wherein the amount of compound is effective to selectively induce terminal differentiation.
  26. 37. A method of treating a patient having a tumor characterized by proliferation of neoplastic cells which comprises administering to the patient an effective amount of the compound having the structure: 0 S. R\ 0 R H 2 wherein each of R, and R 2 are independently the same as or iPER MRO l'.42!X) L'L 5 Y S, -77- different from each other; when R, and R 2 are the same, each is a substituted or unsubstituted cycloalkylamino, pyridineamino, piperidino, 9-purine-6-amine, or thiazoleamino group; when Ri and R 2 are different, Ri=R 3 -N-R 4 wherein each of R 3 and R 4 are independently the same as or different from each other and are a hydrogen atom, a hydroxyl group, a substituted or unsubstituted, branched or unbranched alkyl, alkenyl, cycloalkyl, aryl, alkyloxy, aryloxy, arylalkyloxy, or pyridine group, or R 3 and R 4 bond together to form a piperidine group and R 2 is a hydroxylamino, hydroxyl, amino, alkylamino, or alkyloxy group; and n is an integer from 4 to 8, or a pharmaceutically acceptable salt thereof; and wherein the amount of compound is effective to selectively induce terminal differentiation of such neoplastic cells and thereby inhibit their proliferation.
  27. 38. A method of claim 37 wherein the R, represents NHOH, R 2 represents OH, and n represents 6.
  28. 39. A method of claim 37 wherein the compound has the structure: R3 /R4 0 R2 S S 5 S *5 5 S. S. S 5* S S S S 5* S S *5 5 55 S 5 S 555 5 *5 S* S. S N' (7- §4 wherein each of R 3 and R 4 are independently the same as or different from each other and are a hydrogen atom, a hydroxyl group, a substituted or unsubstituted, branched or unbranched alkyl, alkenyl, cycloalkyl, aryl, alkyloxy, aryloxy, arylalkyloxy, or pyridine group, or R 3 and R 4 bond together to form a piperidine group; R 2 is a hydroxylamino, hydroxyl, amino, alkylamino, or alkyloxy group; and n is an integer from P CPLR MNRO 8-0-5 L\l 5 -78- 4 to 8, or a pharmaceutically acceptable salt thereof; and wherein the amount of compound is effective to selectively induce terminal differentiation of such neoplastic cells and thereby inhibit their proliferation. A method of claim 37 wherein the R 2 of the structure is a hydroxylamino, hydroxyl, amino, methylamino, or methyoxy group and n is 6.
  29. 41. A method of claim 37 wherein R 4 of the structure is a hydrogen atom and R 3 is a substituted or unsubstituted phenyl group.
  30. 42. A method of claim 41 wherein the phenyl group is substituted with a methyl, cyano, nitro, trifluoromethyl, amino, aminocarbonyl, methylcyano, chloro, fluoro, bromo, iodo, 2,3- difluoro, 2,4-difluoro, 2,5-difluoro, 3,4-difluoro, difluoro, 2,6-difluoro, 1,2,3-trifluoro, 2,3,6-trifluoro, 2,4,6-trifluoro, 3,4,5-trifluoro, 2,3,5,6-tetrafluoro, 2,3,4,5,6-pentafluoro, azido, hexyl, t-butyl, phenyl, carboxyl, hydroxyl, methoxy, phenyloxy, benzyloxy, phenylaminooxy, phenylaminocarbonyl, methyoxycarbonyl, methylaminocarbonyl, dimethylamino, dimethylaminocarbonyl, or hydroxylaminocarbonyl group. S S
  31. 43. A method of claim 39, wherein R 4 of the structure is a go hydrogen atom and R 3 is a cyclohexyl group.
  32. 44. A method of claim 39, wherein R 4 of the structure is a hydrogen atom and R 3 is a methyoxy group. A method of claim 39, wherein R 3 and R 4 bond together to form a piperidine group.
  33. 46. A method of claim 39, wherein R 4 of the structure is a hydrogen atom and R 3 is a hydroxyl group. 79
  34. 47. A method of claim 39, wherein R, of the structure is a hydrogen atom and R 3 is a benzyloxy group.
  35. 48. A method of claim 39, wherein R 4 of the structure is a hydrogen atom and R 3 is a 5-pyridine group.
  36. 49. A method of claim 39, wherein R 4 of the structure is a hydrogen atom and R 3 is a P-pyridine group. A method of claim 39, wherein R 4 of the structure is a hydrogen atom and R 3 is a a-pyridine group.
  37. 51. A method of claim 39, wherein R 3 and R 4 are both methyl groups.
  38. 52. A method of claim 39, wherein R 4 of the structure is a methyl group and R 3 is a phenyl group. o City of New York COLLISON CAVE 0 a S DATED this TWENTY FOURTH day of MAY, 1999 Sloan-Kettering Institute for Cancer Research AND The Trustees of Columbia University in the City of New York DAVIES COLLISON CAVE :e Patent Attorneys for the Applicant X, U P-\OPER\JMSWM-0392D1V 13/8/96 ABSTRACT OF THE DISCLOSURE The present invention provides compounds which may be used to selectively induce terminal differentiation of neoplastic cells and thereby inhibit proliferation of such cells. The invention also provides a method and pharmaceutical composition for treating a patient having a tumor characterized by a proliferation of neoplastic cells. 6-
AU62063/96A 1991-10-04 1996-08-13 Novel potent inducers of terminal differentiation and methods of use thereof Expired AU708115B2 (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU1271476A (en) * 1975-04-08 1977-10-13 Bayer Ag Carboxylic acid amides
AU6972691A (en) * 1989-11-14 1991-06-26 Sloan-Kettering Institute For Cancer Research Novel potent inducers of terminal differentiation and method of use thereof
AU1996192A (en) * 1991-05-13 1992-12-30 Oral-D Substituted orally effective ion chelators related to deferoxamine

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU1271476A (en) * 1975-04-08 1977-10-13 Bayer Ag Carboxylic acid amides
AU6972691A (en) * 1989-11-14 1991-06-26 Sloan-Kettering Institute For Cancer Research Novel potent inducers of terminal differentiation and method of use thereof
AU1996192A (en) * 1991-05-13 1992-12-30 Oral-D Substituted orally effective ion chelators related to deferoxamine

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