AU737515B2 - Substituted imidazoles as modulators of multi-drug resistance - Google Patents

Description

.I

7 4 1

AUSTRALIA

PATENTS ACT 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT

ORIGINAL

Name of Applicant/s: Actual Inventor/s: Address of Service: Invention Title: Ontogen Corporation Adnan M. MJALLI and Sepehr SARSHAR SHELSTON WATERS MARGARET STREET SYDNEY NSW 2000 "SUBSTITUTED IMIDAZOLES AS MODULATORS OF MULTI-DRUG RESISTANCE" The following statement is a full description of this invention, including the best method of performing it known to us:- (File: 18869.00) -la- TITLE OF INVENTION SUBSTITUTED IMIDAZOLES AS MODULATORS OF MULTI-DRUG

RESISTANCE

FIELD OF INVENTION The present invention provides novel imidazole derivatives, novel pharmaceutical compositions containing same, methods of their use, and methods of their manufacture.

Such compounds are pharmacologically useful for restoring the sensitivity of multidrug resistant cells to cancer chemotherapeutic agents.

BACKGROUND OF THE INVENTION Any discussion of the prior art throughout the specification should in no way be considered as an admission that such prior art is widely known or forms part of common general knowledge in the field.

A major problem in the treatment of malignancies of the blood and solid tumors is the emergence of tumor cell resistance to chemotherapeutic agents and the subsequent patient relapse (Bradley et al., Cancer Res. 49:2790-2796, 1989; Raderer and Scheithaurer, Cancer 72:3553-3563, 1993). This resistance causes cancer victims to fail to respond to any antitumor agent, since the transformed tumor cells tend to exhibit clinical resistance to many drugs. The emergence of the resistant cells to multiple chemotherapeutic agents occurs either at the initial presentation (intrinsic resistance) or at the time of relapse (acquired resistance). Both of these phenomena are known as multi-drug resistance (MDR). MDR is associated with certain alterations in tumor cells resulting in reduced intracellular anticancer drug accumulation, including reduced membrane permeability and increased removal of drug from the cell via an energydependent efflux mechanism. Studies of this mechanism have led to the characterisation of genes capable of conferring resistance to chemotherapeutic agents. One of these genes, the P-glycoprotein or MDR1 gene, has been strongly implicated since overexpression of this gene can lead to resistance to anthracyclines, vinca alkaloids, and podophyllins, all important chemotherapeutic agents. MDR1 encodes a 170kDa membrane glycoprotein (gp-170 or Pgp) that acts as an ATP-dependent efflux pump, transporting a number of unrelated organic compounds out of the cell (Juranka et al., FASEB J. 3: 2583-2592, 1989). The level of expression of

I-'L

-2gp-170 has been shown to correlate with the degree of drug resistance (Raderer and Scheithaurer, Cancer 72: 3553-3563, 1993). gp-170 appears to act as a pump that actively extrudes a wide variety of structurally unrelated compounds, including a full range of antineoplastic drugs.

Another ATP-dependent membrane efflux pump, the product of the MRP gene, has also been implicated in the MDR phenomenon (Krishnamachary and Center, Cancer Res. 53: 3658-3661, 1993), as have other ATPdependent and enzymatic mechanisms.

Drugs of proven antitumor chemotherapeutic value to which MDR has been observed include vinblastine, vincristine, etoposide, teniposide, doxorubicin (adriamycin), daunorubicin, pliamycin (mithramycin), and actinomycin D (Jones et al., Cancer (Suppl) 72: 3484-3488, 1993). Many tumors are intrinsically multi-drug resistant adenocarcinomas of the colon and kidney) while other tumors acquire MDR during the course of 15 therapy neuroblastomas and childhood leukemias).

A variety of structurally diverse agents have been identified which can restore partially or sometimes completely the normal drug sensitivity to some MDR tumor cells. It is assumed that these chemosensitizers are effective as a result of their ability to interfere with gp-170, causing a reversal in the increase in drug efflux. Among these agents are calcium channel blockers verapamil and nifedipine), calmodulin inhibitors trifluoperazine), antibiotics erythromycin), cardiovascular agents quinidine), noncytotoxic analogs of anthracyclines and vinca alkaloids, the clinically useful immunosuppressants cyclosporin A (and 25 analogs thereof) and FK-506 (and analogs thereof), and derivatives of cyclopeptides (Lum et al., Cancer (Suppl) 72: 3502-3514, 1993).

However, at the present time, none of these agents has provided a significant contribution to the chemotherapeutic index for the treatment of cancer due to their significant pharmacological effects on other organ systems. An effective therapeutic agent for the reversal of MDR needs to have efficacy against the membrane pump as well as lack significant toxicity and other non-specific pharmacological effects.

The present invention describes a family of novel substituted imidazole derivatives that are effective in increasing the sensitivity of tumor cells resistant to anticancer chemotherapeutic agents, such as -3doxorubicin (DOX), taxol, and vinblastine (VLB), and enhancing the sensitivity of multi-drug resistant cells. These compounds have the effect of reducing the resistance of MDR tumor cells, and potentiating the sensitivity of cells to antitumor drugs, such as DOX, taxol, and VLB. These compounds are expected to have broad application in the chemotherapy of cancer.

It is an object of the present invention to overcome or ameliorate at least one of the disadvantages of the prior art, or to provide a useful alternative.

SUMMARY OF THE INVENTION According to a first aspect there is provided a compound of the formula 1 R3 R2 N N Formula 1 or a pharmaceutically acceptable salt thereof wherein; R, is selected from the group consisting of: substituted C 1 alkyl or substituted C 2-11,, alkenyl, wherein the substituent 15 is selected from the group consisting of hydroxy, C,- 6 alkyloxy, or mono-, di-, and tri-substituted aryl-C 0 alkyl, wherein aryl is selected from the group consisting of phenyl, furyl, thienyl, the substituents are selected Sfrom the group consisting of: phenyl, trans-2-phenylethenyl, 2-phenylethynyl, 2-phenylethyl, or in which the said phenyl group is mono- or disubstituted with a member selected from the group consisting of hydroxy, halo, C,4 alkyl and alkyloxy, (ii) substituted C,_ 6 alkyl, substituted C2-6 alkyloxy, substituted C 2 6 alkylthio, substituted C2-6alkylcarbonyl, wherein the substituent is selected from the group consisting of C, 6 alkoxy, C,-6alkylthio, (iii) CIo, 1

CO

2 R, C,.,,CONHRs, trans- CH=CHCO 2 Rs, or trans- CH=CHCONHR wherein R 5 is alkyl, or phenyl alkyl, (iv) C .6 alkoxycarbonylmethyleneoxy;

R

2 and R 3 are each independently selected from the group consisting of: furyl mono-, di, and tri-substituted phenyl and furyl wherein the substituents are independently selected from: halo, trifluoromethyl, alkyl, (ii) C 1 6 alkyloxy (iii) CI 6 alkyl-amino, di(Cl- 6 alkyl)-amino, with the proviso that at least one of the phenyl and furyl substituents be selected from (ii) or (iii); and R 4 is selected from the group consisting of: hydrogen; substituted alkyl or C 2 11 alkenyl wherein the substituent is .independently selected from the group consisting of hydrogen, hydroxy, halo, C., alkyloxy, C.

6 alkylthio, C-6alkylamino, phenyl-C-6 alkylamino, 15 C, 6 alkoxycarbonyl; or aryl Co,, alkyl wherein the aryl group is selected from the group consisting of phenyl, imidazolyl, furyl, and thienyl.

According to a second aspect there is provided a compound of the formula 1 R3 R2 N N

R

R1 Formula 1 wherein: R, is selected from the group consisting of substituted C, alkyl or substituted C2 1 1 alkenyl, wherein the substituents are selected from the group consisting of hydroxy, C,_ 6 alkyloxy; or mono-, di-, and tri-substituted aryl-Ci.

10 alkyl wherein aryl is selected from the group consisting of phenyl, furyl, thienyl, the substituents are selected from the group consisting of: 4a phenyl, trans-2-phenylethenyl, 2-phenylethynyl, 2-phenylethyl, or in which the said phenyl group is mono- or disubstituted with a member selected from the group consisting of hydroxy, halo, C-4 alkyl and C24 alkyloxy,

R

2 and R 3 are each independently a member selected from the group consisting of furyl and mono- and di-substituted phenyl and furyl wherein the substituents are independently selected from: halo, trifluoromethyl, C 1 -6 alkyl, (ii) C 1 6 alkyloxy, (iii) C.- 6 alkylamino, and di-(CI.

6 alkyl)-amino; with the proviso that at least one of the phenyl and furyl substituents be selected from (ii) or (iii), and o. R 4 is selected from the group consisting of: hydrogen; substituted C 1 .i alkyl or C 2 11 alkenyl wherein the substituents are 1 5 independently selected from the group consisting of hydrogen, hydroxy, halo, C.-6 alkyloxy, Cl.

6 alkylthio, C 1 -6 alkylamino, phenyl-C 1 -6 alkylamino, C 1 -6 alkoxycarbonyl; or aryl Co 0 1 1 alkyl wherein the aryl group is selected from the group consisting of phenyl, imidazolyl, furyl and thienyl.

20 According to a third aspect there is provided a compound of the formula 1

N

r Rl Formula 1 wherein: R, is selected from the group consisting of: substituted C 11 alkyl or substituted C 2 -11 alkenyl, wherein the substituents are selected from the group consisting ofhydroxy, C 1 -6 alkyloxy: or 4bmono-, di-, and tri-substituted aryl-Co- ll alkyl wherein aryl is selected from the group consisting ofphenyl, furyl, thienyl, the substituents are selected from the group consisting of: substituted C 1 -6 alkyl, substituted C 2 -6 alkyloxy, substituted C 2 .6 alkylthio, substituted C 2 6 alkoxycarbonyl, wherein the substituents are selected from the group consisting of C.

6 alkoxy, C 1 -6 alkylthio, R2 and R 3 are each independently selected from the group consisting of furyl, mono-, di, and tri-substituted phenyl and furyl wherein the substituents are independently selected from: halo, trifluoromethyl,

C

1 6 alkyl, (ii) C 1 6 alkyloxy, (iii) C.- 6 alkyl-amino, di(Ci.

6 alkyl)amino, with the proviso that at least one of the phenyl and furyl substituents be selected from (ii) or (iii), 15 and R4 is selected from the group consisting of: hydrogen; substituted C alkyl or C 2 11 alkenyl wherein the substituents are independently selected from the group consisting of hydrogen, hydroxy, halo, C.-6 alkyloxy, C 16 alkylthio, C 1 6 alkylamino, phenyl-C-.

6 alkylamino, C 1 6 20 alkoxycarbonyl; or aryl alkyl wherein the aryl group is selected from the group consisting of phenyl, imidazolyl, furyl and thienyl.

According to a fourth aspect there is provided a compound of the formula 1

R

3 R2 Formula 1 4c wherein:

R

1 is selected from the group consisting of: mono- substituted aryl-C 0 o, alkyl wherein aryl is selected from the group consisting ofphenyl, the substituents are selected from the group consisting of:

CI_

4 alkyl and C 2 4 alkyloxy, C 1 6

CO

2 R, trans-CH=CHCO 2 R, wherein R 5 is

C

1

I

6 alkyl, or phenyl C 1 6 alkyl,

R

2 and R 3 are each independently selected from the group consisting of mono substituted phenyl wherein the substituents are independently selected from:

C,.

6 alkyloxy and R 4 is selected from the group consisting of: hydrogen; substituted alkyl or C 2 4 11 alkenyl wherein the substituent is independently selected from the group consisting of hydrogen, hydroxy, halo, C 1 6 alkyloxy, C.

6 alkylthio, C_ 6 alkylamino, phenyl-C.-6 alkylamino, C_ 6 alkoxycarbonyl; or 15 aryl Co,, alkyl wherein the aryl group is selected from the group consisting of phenyl, imidazolyl, furyl and thienyl, and the pharmaceutically acceptable salts thereof.

According to a fifth aspect there is provided a compound according to formula 1 wherein R, is 4-hydroxyphenyl; R 2 and R 3 are methoxyphenyl; and R 4 is benzyl; or the pharmaceutically acceptable salts thereof.

N N R3R42

RI

Formula 1 According to a sixth aspect there is provided a compound according to formula 1 wherein R, is 4-carboxyphenyl; R2 and R3 are 4-(dimethylamino)-phenyl; and R4 is benzyl; or the pharmaceutically acceptable salts thereof.

R3. R2 Formula 1 4d a According to a seventh aspect there is provided a compound according to Formula 1 wherein R 1 is 4-methoxycarbonyl; R 2 and R 3 are 4-(dimethylamino)-phenyl; and R4 is hydrogen; or the pharmaceutically acceptable salts thereof.

R3 R2 N N

RI

Formula 1 According to an eighth aspect there is provided a compound according to Formula 1 wherein R, is 4-carboxyphenyl; R 2 and R 3 are (dimethylamino)-phenyl; and R4 is nhexyl; or the pharmaceutically acceptable salts thereof.

R3 R2 R4 N

RI

Formula 1 According to a ninth aspect there is provided a compound according to formula 1 10 wherein R, is 4-(methoxycarbonyl)-phenyl; R 2 and R 3 are (dimethylamino)-phenyl; and R4 is n-hexyl; or the pharmaceutically acceptable salts thereof.

R

3 R2 Formula 1 According to a tenth aspect there is provided a compound according to formula 1 wherein R, is 4-(carboxyethenyl)-phenyl; R2 and R 3 are (dimethylamino)-phenyl; and R4 is hydrogen; or the pharmaceutically acceptable salts thereof.

4e

R

3 R2 N N

RI

Formula 1 According to an eleventh aspect there is provided a compound according to formula 1 wherein R, is 4-(methoxycarbonyl)-phenyl; and R 2 and R 3 are (dimethylamino)-phenyl; and R4 is n-hexyl; or the pharmaceutically acceptable salts thereof.

a a a a a.

a Formula 1 According to a twelfth aspect there is provided a compound according to formula 1 wherein Ri is 4-hydroxyphenyl; R 2 and R 3 are -(dimethylamino)-phenyl; and R 4 is hydrogen; or the pharmaceutically acceptable salts thereof.

Formula 1 According to a thirteenth aspect there is provided a compound according to 'formula 1 wherein R, is 4-hydroxyphenyl; R 2 and R 3 are -(dimethylamino)-phenyl; and R4 is -phenylethyl; or the pharmaceutically acceptable salts thereof.

4f- R1 Formula 1 According to a fourteenth aspect there is provided a compound according to formula 1 wherein R 1 is 4-carboxyphenyl; R 2 and R 3 are -(dimethylamino)-phenyl; and

R

4 is -phenylethyl; or the pharmaceutically acceptable salts thereof.

R

3 R4^ Formula 1 According to a fifteenth aspect there is provided a compound according to formula 1 wherein R, is 4-(trans-2-carboxyethenyl)-phenyl; R 2 and R 3 are -(dimethylamino)phenyl; and R 4 is -phenylethyl; or the pharmaceutically acceptable salts thereof.

R3 R2 R4 NN Rl Formula 1 According to a sixteenth aspect there is provided a compound according to formula 1 wherein R, is 4-phenyl; R 2 and R 3 are 4-methoxyphenyl; and R 4 is (methoxycarbonyl)-n-pentyl; or the pharmaceutically acceptable salts thereof.

4g R R2 R1 Formula 1 According to a seventeenth aspect there is provided a compound according to formula 1 wherein R, is trans-4-stilbenyl; R 2 and R 3 are 4-methoxyphenyl; and R 4 is 3- (imidazol-1-yl)-n-propyl; or the pharmaceutically acceptable salts thereof.

S

S

S.

S

S

*5

S

S

S

R4 Formula 1 According to an eighteenth aspect there is provided a compound according to formula 1 wherein R, is 4-phenyl; R 2 and R 3 are 4-(dimethylamino)-phenyl; and R 4 is (methoxycarbonyl)-n-pentyl; or the pharmaceutically acceptable salts thereof.

Formula 1 According to a nineteenth aspect there is provided a compound according to formula 1 wherein R 1 is 4-phenyl; R 2 and R 3 are 4-methoxyphenyl; and R 4 is 3(imidazol- I-yl)-n-propyl; or the pharmaceutically acceptable salts thereof.

4h

R

3

R

R4 NyN

RI

Formula 1 According to a twentieth aspect there is provided a compound according to formula 1 wherein R, is 4-phenyl; R 2 and R 3 are 4-methoxyphenyl; and R 4 is n-hexyl; or the pharmaceutically acceptable salts thereof.

According to a twenty-first aspect there is provided a method of treatment for increasing the sensitivity of tumor cells to anti-cancer chemotherapeutic agents, said tumor cells being susceptible to anticancer chemotherapeutic agents, and said tumor cells having become resistant to chemotherapy comprising administration to a mammalian :species in need of such treatment a therapeutically effective amount of a compound of the first aspect and a pharmaceutically acceptable carrier.

According to a twenty-second aspect there is provided a method of treatment of tumor cells, said tumor cells being susceptible to anti-cancer chemotherapeutic agents, and said tumor cells having become resistant to chemotherapy comprising: administration to a mammalian species in need of such treatment, of a therapeutically effective amount of said anti-cancer chemotherapeutic agent, and an effective amount of a compound of the first aspect.

According to a twenty-third aspect there is provided a pharmaceutical composition for increasing the sensitivity of tumor cells to anti-cancer chemotherapeutic agents, said tumors cells having become resistant to chemotherapy comprising a therapeutically effective amount of a compound of the first aspect and a pharmaceutically acceptable carrier.

According to a twenty-fourth aspect there is provided a pharmaceutical composition for increasing the sensitivity of tumor cells to anti-cancer chemotherapeutic agents, said tumors cells having become resistant to chemotherapy comprising: a therapeutically effective amount of an anti-cancer chemotherapeutic agent selected from /a the group consisting of taxol, vinblastine, vincristine, daunorubicin, and doxorubicin, an 4i effective amount of a compound of the first aspect, and a pharmaceutically acceptable carrier.

According to a twenty-fifth aspect there is provided use of a compound according to any one of the first to twentieth aspects for the manufacture of a medicament for increasing sensitivity of tumor cells to anti-cancer chemotherapeutic agents, said tumor cells being susceptible to anti-cancer chemical agents and said tumor cells having become resistant to chemotherapy.

According to a twenty-sixth aspect there is provided use of a compound according to any one of the first to twentieth aspects and an anti-cancer chemotherapeutic agent for the manufacture of a medicament for treatment of tumor cells, said tumor cells being Ssusceptible to said anti-cancer chemotherapeutic agents, and said tumor cells having become resistant to chemotherapy.

According to a twenty-seventh aspect there is provided a compound of the formula 1 SR3 R2 2 N N

R

15 Formula 1 wherein: RI is selected from the group consisting of: substituted C.r-l alkyl or substituted C 2-11 alkenyl, wherein the substituents are selected from the group consisting of hydroxy, C 6 alkyloxy: or mono-, di-, and tri-substituted aryl-Co:n 1 alkyl wherein aryl is selected from the group consisting of phenyl, furyl, thienyl, the substituents are selected from the group consisting of:

C

I 1

CO

2 Rs, C. 1 1 CONHRs, trans-CH=CHCO 2

R

5 or trans-CH=CHCONHR wherein R 5 is C 1 11 alkyl, or phenyl C 1 alkyl, C.-6 alkoxycarbonylmethyleneoxy, -4j-

R

2 and R 3 are each independently selected from the group consisting of furyl mono-, di, and tri-substituted phenyl and furyl wherein the substituents are independently selected from: halo, trifluoromethyl, C1.

6 alkyl, (ii) C1- 6 alkyloxy, (iii) Cl-6alkyl-amino, di(C 1 l6 alkyl)amino, with the proviso that at least one of the phenyl and furyl substituents be selected from (ii) or (iii), and R 4 is selected from the group consisting of: hydrogen; substituted Ci.l alkyl or C 2 1 alkenyl wherein the substituents are independently selected from the group consisting of hydrogen, hydroxy, halo, C 1 6 x b oalkyloxy, C-.

6 alkylthio, C 1 -6alkylamino, phenyl-C 1 -6-alkylamino, 5 Ci-6alkoxycarbonyl; or aryl Co. 11 alkyl wherein the aryl group is selected from phenyl, imidazolyl, furyl, or thienyl; or the pharmaceutically acceptable salts thereof.

According to a twenty-eighth aspect there is provided a compound of the formula 1 R3 R2 _NgN

RI

Formula 1 wherein: RI is selected from the group consisting of: substituted C 1 alkyl or substituted C 2-11 alkenyl, wherein the substituents are selected from the group consisting of hydroxy, C.-6 alkyloxy: or mono-, di-, and tri-substituted aryl-Co.- alkyl wherein aryl is selected from the group consisting of phenyl, furyl, thienyl, the substituents are selected from the group consisting of: -4kphenyl, trans-2-phenylethenyl, 2-phenylethynyl, 2-phenylethyl, or in which the said phenyl group is mono- or disubstituted with a member selected from the group consisting ofhydroxy, halo, Ci-4 alkyl and C 24 alkyloxy,

R

2 and R 3 are each independently selected from the group consisting of furyl, mono-, di, and tri-substituted phenyl and furyl wherein the substituents are independently selected from: halo, trifluoromethyl, C1- 6 alkyl, (ii) C 1 6 alkyloxy, (iii) C 1 6 alkyl-amino, di(Cl_6 alkyl)amino, with the proviso that at least one of the phenyl and furyl substituents be selected from (ii) or (iii), and R 4 is selected from the group consisting of: S(a) hydrogen; aryl Co.

1 alkyl wherein the aryl group is selected from phenyl, 15 imidazolyl, furyl, or thienyl; or the pharmaceutically acceptable salts thereof.

According to a twenty-ninth aspect there is provided a compound of formula 1 SR3 R 2 Ri Formula 1 wherein: R, is selected from the group consisting of: substituted C I- alkyl or substituted C 2-11 alkenyl, wherein the substituents are selected from the group consisting of hydroxy, C1-6 alkyloxy; or mono-, di-, and tri-substituted aryl-Co- I alkyl wherein aryl is selected from the group consisting of phenyl, furyl, thienyl, the substituents are selected 25 from the group consisting of: o.

Formula 1 wherein: RI is selected from the group consisting of: substituted Ci 1 alkyl or substituted C 2-11 alkenyl, wherein the substituents are selected from the group consisting of hydroxy, C 1 6 aikyloxy; or mono-, di-, and tri-substituted aryl-C 011 alkyl wherein aryl is selected from the group consisting of phenyl, furyl, thienyl, the substituents are selected *f 25 from the group consisting of: -41phenyl, trans-2-phenylethenyl, 2-phenylethynyl, 2-phenylethyl, or in which the said phenyl group is mono- or disubstituted with a member selected from the group consisting of hydroxy, halo, CI-4 alkyl and C2.4alkyloxy,

R

2 and R 3 are each independently selected from the group consisting of furyl, mono-, di, and tri-substituted phenyl and furyl wherein the substituents are independently selected from: halo, trifluoromethyl, CI-6 alkyl, (ii) C 1 6 alkyloxy, (iii) C 1 6 alkyl-amino, di(Ci.6 alkyl)amino, with the proviso that at least one of the phenyl and furyl substituents be selected from (ii) or (iii), and R 4 is selected from the group consisting of: hydrogen; substituted C 1 .ll alkyl or C2- 1 1 alkenyl wherein the substituents are 1 independently selected from the group consisting of hydrogen, hydroxy, halo, C 1 -6 15 alkyloxy, C.-6 alkylthio, C.-6 alkylamino, phenyl-C 1 .6 alkylamino, C 1 -6 alkoxycarbonyl; or the pharmaceutically acceptable salts thereof.

According to a thirtieth aspect there is provided a compound of the formula 1 S. R3 R 4 N N R1 Formula 1 wherein: RI is selected from the group consisting of: mono-, di-, and tri-substituted aryl- Co.

11 alkyl wherein aryl is selected from the group consisting of phenyl, furyl, thienyl, the substituents are selected from the group consisting of: phenyl, trans-2-phenylethenyl, 2-phenylethynyl, 2-phenylethyl, or in which the said phenyl group is mono- or disubstituted with a member selected from the zo group consisting of hydroxy, halo, C-4 alkyl and C 2 4 alkyloxy, 4m

R

2 and R 3 are each independently selected from the group consisting of furyl, mono-, di, and tri-substituted phenyl and furyl wherein the substituents are independently selected from: halo, trifluoromethyl, C 1 -6 alkyl, (ii) C 1- 6 alkyloxy, (iii) C 16 alkyl-amino, di(C 16 alkyl)amino, with the proviso that at least one of the phenyl and furyl substituents be selected from (ii) or (iii), and R4 is selected from the group consisting of: hydrogen; substituted C alkyl or C 2 11 alkenyl wherein the substituents are independently selected from the group consisting of hydrogen, hydroxy, halo, C.-6 alkyloxy, CI.

6 alkylthio, Ci.

6 alkylamino, phenyl-CI.

6 alkylamino, C 1 -6 alkoxycarbonyl; or 0 00 15 aryl Co. 1 1 alkyl wherein the aryl group is selected from phenyl, imidazolyl, furyl, or thienyl; or the pharmaceutically acceptable salts thereof.

According to a thirty-first aspect there is provided a compound of the formula 1

R

3 R2 000**** R* N N 0000 R1 Formula 1 wherein: R, is selected from the group consisting of: mono-, di-, and tri-substituted aryl- Co.l- alkyl wherein aryl is selected from the group consisting of phenyl, furyl, thienyl, the substituents are selected from the group consisting of: substituted C 1 -6 alkyl, substituted C 2 6 alkyloxy, substituted C 2 -6 alkylthio, substituted C 2 .6 alkoxycarbonyl, wherein the substituents are selected from the f/ s ^group consisting of C 1 6 alkoxy, C 1 -6 alkylthio, 4n

R

2 and R3 are each independently selected from the group consisting of furyl, mono-, di, and tri-substituted phenyl and furyl wherein the substituents are independently selected from: halo, trifluoromethyl, C 1 -6 alkyl, (ii) C1- 6 alkyloxy, (iii) C.- 6 alkyl-amino, di(C 1 -6 alkyl)amino, with the proviso that at least one of the phenyl and furyl substituents be selected from (ii) or (iii), and R 4 is selected from the group consisting of: hydrogen; substituted C 1 1 alkyl or C 2 11 alkenyl wherein the substituents are independently selected from the group consisting of hydrogen, hydroxy, halo, C 1 -6 o alkyloxy, C.- 6 alkylthio, CI-6 alkylamino, phenyl-C 1 6 alkylamino, C -6 alkoxycarbonyl; or 0 aryl Co- 0 alkyl wherein the aryl group is selected from phenyl, imidazolyl, furyl, or thienyl; :or the pharmaceutically acceptable salts thereof.

According to a thirty-second aspect there is provided a compound of the formula 1 oooo R3 R2

RR

Formula 1 wherein: RI is selected from the group consisting of: mono-, di-, and tri-substituted aryl- Co 0 1 alkyl wherein aryl is selected from the group consisting of phenyl, furyl, thienyl, the substituents are selected from the group consisting of; Ci I C0 2

R

5

C

1

-ICONHR

5 trans-CH=CHCO 2

R

5 or trans-CH=CHCONHR wherein Rs is C 1 lalkyl, or phenyl Ci., alkyl, Cl-6 alkoxycarbonylmethyleneoxy, -4o-

R

2 and R 3 are each independently selected from the group consisting of furyl, mono-, di, and tri-substituted phenyl and furyl wherein the substituents are independently selected from: halo, trifluoromethyl, C 1 6 alkyl (ii) C 1 6 alkyloxy, (iii) C 1 6 alkyl-amino, di(CI_ 6 alkyl)amino, with the proviso that at least one of the phenyl and furyl substituents be selected from (ii) or (iii), and R 4 is selected from the group consisting of: hydrogen; substituted C 1 .ll alkyl or C2- 1 1 alkenyl wherein the substituents are independently selected from the group consisting of hydrogen, hydroxy, halo, C 1 -6 alkyloxy, C 1 -6alkylthio, Cl_6alkylamino, phenyl-CI-6alkylamino, Ci-6 alkoxycarbonyl; or aryl Co- 11 alkyl wherein the aryl group is selected from phenyl, imidazolyl, furyl, or thienyl; or the pharmaceutically acceptable salts thereof.

According to a thirty-third aspect there is provided a compound of formula 1 R3 R2 .o N N R1 Formula 1 wherein: R, is selected from the group consisting of: mono-, di-, and tri-substituted aryl- Co 0 1 alkyl wherein aryl is selected from the group consisting of phenyl, furyl, thienyl, the substituents are selected from the group consisting of: phenyl, trans-2-phenylethenyl, 2-phenylethynyl, 2-phenylethyl, or in which the said phenyl group is mono- or disubstituted with a member selected from the group consisting of hydroxy, halo, C 1 4 alkyl and C24 alkyloxy, 4 p

R

2 and R 3 are each independently selected from the group consisting of furyl, mono-, di, and tri-substituted phenyl and furyl wherein the substituents are independently selected from: halo, trifluoromethyl, Ci.

6 alkyl, (ii) CI.

6 alkyloxy, (iii) CI- 6 alkyl-amino, di(CI.

6 alkyl)amino, with the proviso that at least one of the phenyl and furyl substituents be selected from (ii) or (iii), and R 4 is selected from the group consisting of: hydrogen; aryl Co-. alkyl wherein the aryl group is selected from phenyl, ~imidazolyl, furyl, or thienyl; or the pharmaceutically acceptable salts thereof.

According to a thirty-fourth aspect there is provided a compound of formula 1 R3 R2 R

R,

15 Formula 1 wherein: R, is selected from the group consisting of: mono-, di-, and tri-substituted aryl- Co 0 alkyl wherein aryl is selected from the group consisting of phenyl, furyl, thienyl, the substituents are selected from the group consisting of: phenyl, trans-2-phenylethenyl, 2-phenylethynyl, 2-phenylethyl, or in which the said phenyl group is mono- or disubstituted with a member selected from the group consisting of hydroxy, halo, C 14 alkyl and C24 alkyloxy,

R

2 and R 3 are each independently selected from the group consisting of furyl, mono-, di, and tri-substituted phenyl and furyl wherein the substituents are 25 independently selected from: S halo, trifluoromethyl, Ci 6 alkyl, 4q (ii) C 1 -6 alkyloxy, (iii) C 1 6 alkyl-amino, di(C 1 6 alkyl)amino; with the proviso that at least one of the phenyl and furyl substituents be selected from (ii) or (iii), and R 4 is selected from the group consisting of: hydrogen; substituted Cl-i alkyl or C 2 11 alkenyl wherein the substituents are independently selected from the group consisting of hydrogen, hydroxy, halo, C -6 alkyloxy, Ci-6alkylthio, C-6alkylamino, phenyl-CI-6 alkylamino, CI-6 alkoxycarbonyl; or the pharmaceutically acceptable salts thereof.

According to a thirty-fifth aspect there is provided a compound of the formula 1

N

N: R p Formula 1 S* wherein: R, is selected from the group consisting of: substituted alkyl or substituted

C

2 1 1 alkenyl, wherein the substituents are selected from the group consisting of hydroxy,

C-.

6 alkyloxy: or

R

2 and R 3 are each independently selected from the group consisting of furyl, mono-, di, and tri-substituted phenyl and furyl wherein the substituents are independently selected from: halo, trifluoromethyl, C 1 -6 alkyl, (ii) C 1 6 alkyloxy, (iii) C 16 alkyl-amino, di(Ci.6 alkyl)amino, with the proviso that at least one of the phenyl and furyl substituents be selected from (ii) or (iii), and R 4 is selected from the group consisting of: 4rhydrogen; aryl Co-1 1 alkyl wherein the aryl group is selected from phenyl, imidazolyl, furyl, or thienyl; or the pharmaceutically acceptable salts thereof.

According to a thirty-sixth aspect there is provided a compound of the formula 1

R

3

R

2 R4N

R

Formula 1 wherein: o R, is selected from the group consisting of: substituted C 11 alkyl or substituted

C

2 11 alkenyl, wherein the substituents are selected from the group consisting of hydroxy,

C

1 .6 alkyloxy; or

R

2 and R 3 are each independently selected from the group consisting of furyl, mono-, di, and tri-substituted phenyl and furyl wherein the substituents are independently selected from: S(i) halo, trifluoromethyl, Ci-6 alkyl, 15 (ii) alkyloxy, C(iii) C- 6 alkyl-amino, di(CI.

6 alkyl)amino, with the proviso that at least one of the phenyl and furyl substituents be selected from (ii) or (iii), and R 4 is selected from the group consisting of: hydrogen; substituted C1- 1 alkyl or C 2 l alkenyl wherein the substituents are independently selected from the group consisting of hydrogen, hydroxy, halo, C 1 -6 alkyloxy, C 1 -6 alkylthio, Ci- 6 alkylamino, phenyl-C 1 .6 alkylamino, C 1 -6 alkoxycarbonyl; or the pharmaceutically acceptable salts thereof.

-4s- According to a thirty-seventh aspect there is provided a compound of the formula 1 R3 R 2 N N R4 N T

RI

Formula 1 wherein: RI is selected from the group consisting of: substituted Cl-6 alkyl or substituted C 2 6 alkenyl, wherein the substituents are selected from the group consisting C 6 alkyloxy; or mono-, di-, and tri-substituted aryl-Co-i 0 alkyl wherein aryl is selected from the group consisting ofphenyl, the substituents are selected from the group consisting of:

C

1 -4 alkyl and C24 alkyloxy, C 1 i- CO 2

R

5

C

1 11 CONHRs, trans-CH=CHCO 2 Rs, or trans-CH=CHCONHR 5 wherein R 5 is Cl-_ 1 alkyl, or phenyl C1- 11 alkyl,

R

2 and R 3 are each independently selected from the group consisting of, mono-, di, and tri-substituted phenyl wherein the substituents are independently selected from:

C

1 -6 alkyloxy, 15 (ii) C1- 6 alkyl-amino, di(Cl 1 6 alkyl)amino, and R 4 is selected from the group consisting of: hydrogen; substituted C,, 6 alkyl or C 2 6 alkenyl wherein the substituents are independently selected from the group consisting of hydrogen, C 1 6 alkyloxy,

C

1 6 alkylamino, or aryl Co-i I alkyl wherein the aryl group is selected from phenyl; or the pharmaceutically acceptable salts thereof.

4t According to a thirty-eighth aspect there is provided a compound of the formula 1

R

3 R2 SN N

Y

R1 Formula 1 wherein: R, is selected from the group consisting of: substituted C 2 6 alkenyl, C1.6 alkyl wherein the substituents are selected from the group consisting C 1 6 alkyloxy; or mono- substituted aryl-Co-_ 1 alkyl wherein aryl is selected from the group consisting ofphenyl, the substituents are selected from the group consisting of;

C

1 -4 alkyl and C2-4 alkyloxy, C.6CO 2

R

5 trans-CH=CHCO 2

R

5 wherein R 5 is C 6 alkyl, or phenyl C 1 -6 alkyl,

R

2 and R 3 are each independently selected from the group consisting of, mono-, di, o: and tri-substituted phenyl wherein the substituents are independently selected from:

C

1 6 alkyloxy, (ii) C1- 6 alkyl-amino, di(C 1 6 alkyl)amino, and 15 R4 is selected from the group consisting of: 0 hydrogen; C1.

6 alkyloxy, C 1 6 alkylamino, or aryl CO-6 alkyl wherein the aryl group is selected from phenyl, imidazol; or the pharmaceutically acceptable salts thereof.

According to a thirty-ninth aspect there is provided a compound of the formula 1 Formula 1 4uwherein: RI is selected from the group consisting of: substituted C 2 6 alkenyl, C2-6 alkyl wherein the substituents are selected from the group consisting Ci-6 alkyloxy; or mono- substituted aryl-C 0 6 alkyl wherein aryl is selected from the group consisting ofphenyl, the substituents are selected from the group consisting of: Cl-4 alkyl and C 2 4 alkyloxy, CI-6CO 2

R

5 trans-CH=CHCO 2

R

5 wherein R 5 is Ci-alkyl, or phenyl C.-6 alkyl,

R

2 and R 3 are each independently selected from the group consisting of, mono-, di, and tri-substituted phenyl wherein the substituents are independently selected from: f.o: C 1-6 alkyl-amino and di(C 1 -6 alkyl)amino, and

R

4 is hydrogen; or the pharmaceutically acceptable salts thereof.

According to a fortieth aspect there is provided a compound of the formula 1 R3 R 2 N N I

R\

15 Formula 1 wherein: R is selected from the group consisting of: substituted C2- 6 alkenyl, C 2 6 alkyl wherein the substituents are selected from the group consisting Cl- 6 alkyloxy; or mono- substituted aryl-Co.

1 alkyl wherein aryl is selected from the group consisting ofphenyl, the substituents are selected from the group consisting of:

C

1 4 alkyl and C2-4 alkyloxy, C- 1 6

CO

2 R, trans-CH=CHCO 2 R, wherein R 5 is Cl.

6 alkyl, or phenyl Ci.

6 alkyl,

R

2 and R 3 are each independently selected from the group consisting of, mono S 25 substituted phenyl wherein the substituents are independently selected from: 4v CI-6 alkyl-amino, di(C 1 6 alkyl)amino, CI- 6 alkyloxy and R 4 is selected from the group consisting of: hydrogen, C 1 6 alkyloxy, C-.

6 alkylamino, or aryl Co- 6 alkyl wherein the aryl group is selected from phenyl, imidazol; or the pharmaceutically acceptable salts thereof.

It is an advantage of this invention in one embodiment to provide compounds that have sufficient activity to sensitize multi-drug resistant tumor cells to antineoplastic agents.

It is advantage of this invention to provide in one embodiment a method of sensitizing multi-drug resistant tumor cells using the novel compounds of the present invention.

A further advantage is to provide in one embodiment a method of treatment of MDR or drug-sensitive tumor cells by administering a sufficient amount of a compound of the present invention, prior to, together with, or subsequent to the administration of an antitumor chemotherapeutic agent.

A further advantage is to provide in one embodiment pharmaceutical compositions for increasing the sensitivity of tumor cells to antitumor chemotherapeutic agents and thus for the treatment of tumors that are susceptible to anti-cancer chemotherapeutic agents but have become resistant to such chemotherapy.

Unless the context clearly requires otherwise, throughout the description and the 0 20 claims, the words 'comprise', 'comprising', and the like are to be construed in an inclusive sense as opposed to an exclusive or exhaustive sense; that is to say, in the sense of "including, but not limited to".

DETAILED DESCRIPTION OF THE INVENTION The present invention encompasses compounds of general structural Formula 1 R3 R2 R4--N N SFormula 1 SO 4FF or a pharmaceutically acceptable salt, ester, or prodrug thereof wherein: R1 is: substituted ClI- 11 alkyl or substituted C2-1 1 alkenyl, wherein the substituent is selected from the group consisting of hydrogen, hydroxy, halo, Cl-6 alkyloxy, Cl-6 alkylthio, Cl-6 alkylamino, phenyl-CI-6 alkyloxy, phenyl-Cl1-6 alkylthio, and phenyl-Cl1-6 alkylamino; or aryl-Co- 11 -alkyl, wherein the aryl group is selected from the group consisting of phenyl, naphthyl, pyridyl, furyl, pyrryl, thienyl, isothiazolyl, imidazolyl, benzimidazoiyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, benzofuryl, benzothienyl, pyrazolyl, indolyl, isoindolyl, purinyl, carbazolyl, isoxazolyl, thiazolyl, oxazolyl, benzthiazolyl, and.

benzoxazolyl; and mono-, di-, and tri-substituted-aryl CO- 1-alkyl wherein aryl is as defined above and wherein the substituents are independently selected from 1 5 trifluoromethyl, hydroxy, halo, phenyl, trans- 2-phenyie thenyl, 2-phenylethynyl, 2-phenylethyl, :wherein the phenyl group is optionally mono- or di-substituted with hydroxy, halo, Ci1-4 alkyl, or Cl1-4 alkyloxy, 060. carboxy, amino, optionally substituted Cl1-6 alkyl, C 1 6 alkyloxy, Ci1-6 alkylthio, C 1-6 alkylamino, C 1-6 alkyicarbonyl, C 1-6 alkylcarbonylamino, Ci1.-6 alkylaminocarbonyl, C 1-6 alkoxycarbonyl, wherein the substituent is selected from the group consisting of amino, 0:00 carboxy, CI-6 alkoxy, Cl-6 alkylthio, CI-6 alkylamino, and 0 di-(Cl-6) alkylamino, ClI-II iCO2R5, Cl1- I ICONHR5, trans-CH=CHCO2R5, or trans- CH=CHCONHR5 wherein R5 is hydrogen, Cl-i11 alkyl, or phenylC .I 1 alkyl, carboxymethyleneoxy, and Ci -6 alkoxycarbonylmethyleneoxy; p' -6- R2 and R3 are each independently: aryl wherein the aryl group is as defined under the definition of R1 above; and mono-, di-, and tri-substituted aryl wherein the substituents are independently selected from hydroxy, halo, trifluoromethyl, C1-6 alkyl, C1-6 alkyloxy, C1-6 alkylthio, amino, Cl-6 alkylamino, di-(C1-6 alkyl)amino, phenyl-C1-6 alkylamino, and di-(phenyl-Cl-6 alkyl) amino; and R4 is: hydrogen; substituted C1-11 alkyl or C2-1 1 alkenyl wherein the substituent is selected from the group consisting of hydrogen, hydroxy, halo, C1-6 alkyloxy, C1-6 alkylthio, C1-6 alkylamino, phenyl-C1-6 alkyloxy, phenyl- C1-6 alkylthio, and phenyl-C1-6 alkylamino, carboxy, and C1-6 alkoxycarbonyl; or aryl CO-11 alkyl wherein the aryl group is as defined under the definition of R1 above; and mono-, di-, and tri-substituted-aryl CO-11-alkyl wherein aryl is as defined above and wherein the substituents are independently selected from C1-6 alkyl, trifluoromethyl, hydroxy, halo, C1-6 alkyloxy, amino, C1-6 alkylamino, aminoC1-6 alkyl, carboxy, and carboxyC1-6 alkyl.

A preferred embodiment concerns compounds wherein: R1 is aryl, wherein the aryl group is selected from the group consisting of phenyl, naphthyl, pyridyl, furyl, pyrryl, thienyl, imidazolyl, benzimidazolyl, pyrimidyl, quinolyl, isoquinolyl, benzofuryl, benzothienyl, indolyl, thiazolyl, oxazolyl, benzthiazolyl, and benzoxazolyl; and monoand di-substituted-aryl wherein aryl is as defined above and wherein the substituents are independently selected from

I.

-7hydroxy, halo, phenyl, trans-2-phenylethenyl, wherein the phenyl group is optionally mono- or di-substituted with hydroxy, halo, C1-4 alkyl, or C1-4 alkyloxy, carboxy, amino, optionally substituted C1-6 alkyl, C1-6 alkyloxy, C1-6 alkylthio, C1-6 alkylamino, C1-6 alkoxycarbonyl, wherein the substituent is selected from the group consisting of amino, carboxy, C1-3 alkoxy, C1-3 alkylthio, C1-3 alkylamino, and di-(C1-3) alkylamino, trans-CH=CHCO2R5, or trans-CH=CHCONHR5 wherein R5 is hydrogen or Cl-6 alkyl, 15 carboxymethyleneoxy, and C1-6 alkoxycarbonylmethyleneoxy; R2 and R3 are each independently phenyl and mono- and di-substituted phenyl wherein the substituents are independently selected from hydroxy, halo, trifluoromethyl, C1-6 alkyl, C1-6 alkyloxy, Cl-6 alkylthio, amino, C1-6 alkylamino, and di-(Cl-6 alkyl)-amino; and R4 is hydrogen; substituted C1-6 alkyl, wherein the substituent is selected from the group consisting of hydrogen, hydroxy, halo, C1-6 alkyloxy, C1-6 alkylthio, C1-6 alkylamino, carboxy, and C1-6 alkoxycarbonyl; or mono- or di-substituted aryl CO-3 alkyl, wherein the aryl group is selected from the group consisting of phenyl, pyridyl, furyl, thienyl, imidazolyl, thiazolyl, and oxazolyl, and wherein the substituents are independently selected from hydrogen, C1-6 alkyl, trifluoromethyl, hydroxy, halo, C1-6 alkyloxy, amino, C1-6 alkylamino, aminoC1-6 alkyl, carboxy, and carboxyCl-6 alkyl.

A still more preferred group comprises compounds wherein: i.

-8- R1 is mono- or di-substituted phenyl, wherein the substituents are selected from the group consisting of hydroxy, trans-2-phenylethenyl, wherein the phenyl group is optionally mono- or di-substituted with hydroxy, halo, C1-4 alkyl, or C1-4 alkyloxy, carboxy, optionally substituted C1-4 alkyl, Cl-4 alkyloxy, C1-4 alkylthio, C1-4 alkylamino, C1-4 alkoxycarbonyl, wherein the substituent is selected from the group consisting of amino, carboxy, C1-3 alkoxy, C1-3 alkylthio, C1-3 alkylamino, and di-(C1-3) alkylamino, trans-CH=CHCO2R5, or trans-CH=CHCONHR5 wherein R5 is hydrogen or C1-4 alkyl, carboxymethyleneoxy, and C1-4 alkoxycarbonylmethyleneoxy; R2 and R3 are each independently phenyl or mono-substituted phenyl wherein the substituent is selected from the group consisting of C1-3 alkyl, C1-3 alkyloxy, amino, Cl-3 alkylamino, and di-(Cl-3 alkyl)amino; and R4 is hydrogen; substituted Cl-6 alkyl, wherein the substitutent is selected from the group consisting of hydrogen, carboxy, and C1-3 alkoxycarbonyl; or mono-substituted aryl CO-3 alkyl, wherein the aryl group is selected from the group consisting of phenyl, pyridyl, and imidazolyl and wherein the substituent is selected from the group consisting of hydrogen, C1-4 alkyl, trifluoromethyl, hydroxy, halo, Cl-4 alkyloxy, amino, C1-4 alkylamino, carboxy, and carboxyC1-4 alkyl.

Novel compounds of the present invention include but are not limited to the following compounds: 2-(4-hydroxyphenyl)-1,4,5-triphenyl-imidazole trifluoroacetic acid salt; -9- 1 -benzyl-2-(4-hydroxyphenyl)-4,5-di-(4-methoxyphenyl)-imidazole trifluoroacetic acid salt; 2-(4-carboxyphenyl)-4,5-di-[4-(diniethylamino)-phenyl]- 1 (H)-imidazole; 4,5-di-1i4-(dimethylamino)-phenyll -2-[4-(methoxycarbonyl)-phenyl]- I1(H)imidazole; 2-(4-carboxyphenyl)-4,5 -di-[4-(dimethylamino)-phenyl] -1 -(n-hexyl)imidazole; -di-14-(dimethylamino)-phenyl] -1 -(n-hexy [4-(methoxycarbonyl)phenyl] -imidazole; 2-[4-(trans-2-carboxyethenyl)-phenyl] -4,5-di-[14-(dimethylamino)-phenyl]- 1 (H)-imidazole; -di- [4-(dimethylamino)-phenyl] (4 [trans-(2-methoxycarbonyl)ethenyl] -phenyl I 1(H)-imidazole; [4-(dimethylamino)-phenyl] -2-(4-hydroxyphenyl)-l1(H)-imidazole; 4.:15 4,5 -di (dimethylam ino)-phenyl] (4 -hyd rox yphenyl)-1I -(2-phenylethyl)imidazole; 2 -c arboxyphenyl) -4,5 -di [4 imeth ylIam in o)-phenyl 1 -phenylethyl)imidazole; 2- [4-(trans-2-carboxyethenyl)-phenyl] -4 ,5-di -[4-(dimethylamino)-phenyl] 1 -(2-phenylethyl)-imidazole; -di- (4-methoxyphenyl1)-2- 4- [trans- (2-me thoxycarbonyl)-ethenyl] phenyl 1-1-[5-(methoxycarbonyl)-n-pentyl)-imidazole; 2-(trans-4-stilbenyl)- 1 -[3-(imidazol- I -yl)-n-propyl]-4,5-di-(4methoxyphenyl)-imidazole; 4,5 -di- [4-(dimethylamino)-phenyl] -2-1(4 -[trans-(2-methoxycarbonyl)ethenyl] -phenyl) -1 -[5-(methoxycarbonyl)-n-pentyl-] -imidazole; *4,5-di-(4-methoxyphenyl)-2- I4-[3-(dimethylamino)-propyloxy]-phenyl 1-1 (n-hexyl)-imidazole; *4,5-di-(4-methoxyphenyl)-2- {4-[3-(dimethylamino)-propyloxy]-phenyl) 1-I- [3-(imidazol- 1 -yl)-n-propyl]-imidazole.

As used herein "alkyl" is intended to include both branched- and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, methyl ethyl propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, iso-propyl iso-butyl (i- Bu), tert-butyl sec-butyl iso-pentyl, and the like, as well as saturated alicyclic hydrocarbon groups having the specified number of carbon atoms, cyclopentyl, cyclohexyl, and the like. "Alkyloxy" (or "alkoxy") represents an alkyl group having the indicated number of carbon atoms attached through the oxygen bridge, methoxy, ethoxy, propyloxy, and the like. "Alkenyl" is intended to include hydrocarbon groups of either a straight or branched configuration with one or more carbon-carbon double bonds which may occur in any stable point along the chain, such as ethenyl, propenyl or allyl, butenyl, pentenyl, and the like. The carbon-carbon double bonds may have either the cis- or trans-configuration.

The term "halo" means fluoro, chloro, bromo, or iodo.

The term "prodrug" refers to a compound that is made more active 15 in vivo.

Pharmaceutically acceptable salts of the compounds of formula 1, where a basic or acidic group is present in the structure, are also included within the scope of this invention. When an acidic substituent is present, such as -COOH and P(O)(OH)2, there can be formed the ammonium, calcium, magnesium, sodium, potassium salt, and the like, for use as the dosage form. Salts derived from pharmaceutically acceptable organic nontoxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic .amines, and basic ion-exchange resins, such as arginine, betaine, caffeine, choline, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, S.glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like. When a basic group is present, such as amino or a basic heteroaryl radical, such as pyridyl, an acidic salt, such as hydrochloride, hydrobromide, acetate, maleate, pamoate, methanesulfonate, p-toluenesulfonate, and the like, can be used as the dosage form.

-11- Also, in the case of the -COOH or -P(O)(OH)2 being present, pharmaceutically acceptable esters can be employed, methyl, tertbutyl, pivaloyloxymethyl, and the like, and those esters known in the art for modifying solubility or hydrolysis characteristics for use as sustained release or prodrug formulations.

In addition, some of the compounds of the instant invention may form solvates with water or common organic solvents. Such solvates are encompassed within the scope of the invention.

The term "therapeutically effective amount" shall mean that amount of drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal, or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.

The compounds of the present invention are conveniently prepared using either solid-phase or solution phase synthetic methods. These two 15 methods are described generally below and depicted in the following reaction Schemes. Where appropriate, the synthetic methods utilize readily available starting materials, reagents, and conventional synthetic procedures. In these reactions, it is also possible to make use of variants which are themselves known to those of ordinary skill in this art, but are not mentioned in greater detail.

The solid-phase methods, which are depicted in Schemes 1 and 4, employ either an aldehyde linker or a FMOC-amino acid linker on solid supports.

The solid-phase method using an aldehyde linker (Scheme 1) involves synthesis of the substituted imidazoles of the present invention by reaction of an arylaldehyde linked to a solid support of general formula 3 with a 1,2-diarylethanedione of general formula 1 in the presence of an amine (R4NH2) of general formula 2 and ammonium acetate and subsequent cleavage of the desired substituted imidazole from the solid support with trifluoroacetic acid to afford compounds of general formula 4. The solid supports of general formula 3 comprise either a carboxyaldehyde resin or an alkoxyaldehyde resin.

-12- SCHEME 1 R2 R 3 o o 1

R

4

-NH

2 NHlaOAc CF3C R4--N

NH*

2 CHO 1. AcOH. 100°C, 4 h L 2.20% TFA/CH 2 ,C1

I

N

K N E K R E T

R

0 1

SOH

oo4 |WANG 4 3 0, The synthesis of the carboxyaldehyde resin of general formula 3 is shown in Scheme 2 and employs methodologies described by Lu et al., J.

S. Org. Chem. 46: 3433,1981. A typical procedure involves reacting 6 mmol (1 equiv) of Wang resin Wang, J. Amer. Chem. Soc. 95: 1328, 1973) S 10 in 130 mL of dry solvent (the resin should be swollen in the appropriate solvent for a minimum of 2 hours prior to coupling; the choice of solvent is dictated by the solubility of the carboxyaldehyde linker). The solvent can be dichloromethane, tetrahydrofuran, or N,N-dimethylformamide (DMF). To this mixture is added 18 mmol of the appropriate 15 carboxyaldehyde (3 equiv), 18 mmol (3 equiv.) of dicyclohexylcarbodiimide (DCC) or diisopropylcarbodiimide (DIC) and 6 mmol (1 equiv.) of 4-dimethylaminopyridine. The mixture is magnetically stirred for 48 hours at ambient temperatures. The supematant is then filtered off and the resin thoroughly washed with DMF (500 mL), methanol (500 mL), dichloromethane (500 mL), and methanol (500 mL).

The polymer is dried in vacuo (0.1 mmHg) for 24 hours. Coupling yields are determined by cleaving 100 mg of the resin with a solution of -13trifluoroacetic acid in dichloromethane for 20 minutes at ambient temperatures. In case of low coupling yields the procedure can be repeated.

SCHEME 2

OH

G- /I WANG -OH WANG Resin 0 HC0 *CHO

CHO

WANG -OH0 o WANG DCC. DMAP, 23 0 C. 48 h CHO 3 The carboxyaldehyde may also be coupled to Tentagel PHB resin (E.

10 Bayer, Angew. Chem. Int. Ed. Engl. 30: 113-129, 1991) as the solid support in place of Wang resin. A typical procedure involves reacting 0.24 mmol (1 equiv) of Tentagel PHB resin in 13 mL of dry solvent (the resin should be swollen in the appropriate solvent for a minimum of 2 hours prior to coupling; the choice of solvent is dictated by the solubility of the carboxyaldehyde linker). The solvent can be dichloromethane, tetrahydrofuran, or N,N-dimethylformamide. To this mixture is added 1.2 e mmol (5 equiv) of the appropriate carboxyaldehyde, 1.2 mmol (5 equiv) of diisopropylcarbodiimide, and 0.24 mmol of 4-dimethylaminopyridine.

The mixture is stirred magnetically for 24 hours at ambient temperatures.

The supernatant is then filtered off and the resin thoroughly washed with DMF (100 mL), methanol (100 mL), dichloromethane (100 mL), and methanol (100 mL). The polymer is dried in vacuo (0.1 mmHg) for 24 hours. Coupling yields are determined by cleaving 100 mg of the resin with a solution of 20% trifluoroacetic acid in dichloromethane for minutes at ambient temperatures.

-14- Examples of carboxyaldehyde linkers used in the generation of resins and coupling yields are as follows:

CO

2 H

CO

2

H

CO

2 H CO 2 H

K

0

CHOCHO

CHO

CHO

Coupling Yields: Wang Resin 87% 70% 80% Tentagel PHB 0:: The synthesis of the alkoxyaldehyde resin of general formula 3 is shown in Scheme 3 and employs methodologies described by Richter and 15 Gadek, Tetrahedron Lett. 35: 4705 (1994). A typical procedure involves reacting 1 mmol (1 equiv.) of Wang resin in 4-ethylmorpholine (5 mL) with 3 mmol (3 equiv.) of the appropriate alkoxyaldehyde in the presence of 3 mmol (3 equiv.) of triphenylphosphine. The flask is cooled to 0°C and 3 mmol (3 equiv.) of di-isopropyl azodicarboxylate (DIAD) is added dropwise to the mixture. The reaction is placed in a sonicator bath for 1 hour at 23 0 C. Following sonication, the mixture is magnetically stirred for 16 hours at ambient temperatures. The supematant is then filtered off and the resin thoroughly washed with acetic acid (50 mL), methanol (50 mL), dichloromethane (50 mL), and methanol (50 mL). The polymer is then dried in vacuo (0.1mmHg) for 24 hours. Coupling yields are determined by cleaving 100 mg of the resin with a solution of 20% trifluoroacetic acid in dichloromethane for 20 minutes at ambient temperatures. In case of low coupling yields the procedure can be repeated.

SCHEME 3 WANG OH

CHO

DIAD. Ph 3 P. 4-ethylmorpholine, 23*C, 16 h

WANG-

CHO

4 Examples of alkoxyaldehyde linkers used in the generation of resins and coupling yields are as follows: *0 0

OH

CHO

40% Coupling Yields with Wang Resin The solid-phase method using a FMOC-amino acid linker (Scheme 4) involves synthesis of the substituted imidazoles by reaction of the 1,2ethanediones of general formula 1 with the aldehydes of general formula 2 and the amine-linked resin of general formula 3 in the presence of ammonium acetate followed by treatment with 20% trifluoroacetic acid in dichloromethane to afford the substituted imidazole compounds of general formula 4.

-16- SCHEME4 R2 R 3

SR

3

CF

3

CO,

R

4 -CHO NH 4 OAc H 2 NH 2 AcOH, 100-C. 15 h R N R L 2. 20% TFA/CCl1 I L N I K N E K R E T

R

is shown in Scheme 5 and employs methodologies described by G.B. Fields and R.L. Noble, Int. J. Peptide Res. 35: 161 (1990) and references cited therein. A typical procedure involves reacting 3 mmol (1 equiv) of Wang resin in dry dichloromethane (92 mL) (the resin should be swollen in dichloromethane for a minimum of 2 hours prior to coupling) with 9 mmol (3 equiv) of the Fmoc-amino acid in the presence of 9 mmol (3 equiv) of DCC or DIC and 3 mmol (1 equiv) of 4-dimethylaminopyridine.

The mixture is stirred magnetically for 48 hours at ambient temperatures.

SThe supernatant is then filtered off and the resin thoroughly washed with DMF (500 mL), methanol (500 mL), water (500 mL), methanol (500 mL), dichloromethane (500 mL), and methanol (500 mL). The polymer is dried in vacuo (0.1 mmHg) for 24 hours. Coupling yields are determined by cleaving 100 mg of the resin with a solution of 20% trifluoroacetic acid in dichloromethane for 20 minutes at ambient temperatures. In case of low coupling yields the procedure can be repeated.

-17- SCHEME 0 NHFmoc DIC. DMAP. 23 0 C. 48 h WANG OH 0

WANG-

NHFmoc 3 An example of an Fmoc-amino acid linker and coupling yield is as follows: 0 iL A^ /NHFmoc HOy v v Coupling Yield Wang resin Fmoc: The solution-phase methods for preparing the imidazoles of the present invention are shown in Schemes 6 and 7. The synthesis of the (1H)-imidazole derivatives is shown in Scheme 6 and involves reaction of the 1,2-ethanediones of general formula 1 with aldehydes of general formula 2 in the presence of ammonium acetate in acetic acid at 100 0 C to afford (1H)-imidazoles of general formula 3.

-18- SCHEME 6 R2 R 3 o o1 1

CHO

I

R,

NH OAc, AcOH, 100C, 4h The synthesis of the N-substituted imidazole derivatives in solution phase is shown in Scheme 7 and involves reaction of the 1,2-ethanediones of general formula 1 with aldehydes of general formula 2 and primary amines of general formula 4 in the presence of ammonium acetate in acetic acid at 100 0 C to afford N-substituted imidazoles of general formula 3.

SCHEME 7 R2

R

3 0 O R2 R 3 S 1 a AcOH, reflux, 2 h

R

4

-NH

2 NH40AC R-N N

CHO

RI

Rl 2 The compounds described herein are capable of sensitizing multidrug resistant tumor cells to antitumor chemotherapeutic agents, such as doxorubicin and vinblastine. They also have the ability to potentiate the sensitivity of tumor cells susceptible to these chemotherapeutic agents.

This invention also relates to a method of sensitizing multidrug- -19resistant tumor cells to antitumor chemotherapeutic agents. It also relates to a method of increasing the sensitivity of drug-susceptible tumor cells to antitumor chemotherapeutic agents. In addition, this invention relates to a method of preventing the emergence of MDR tumor cells during a course of treatment with antitumor chemotherapeutic agents. Finally, this invention relates to a method of reducing the effective dosage of an antitumor chemotherapeutic agent during a course of treatment. It has been found that compounds of Formula 1 have the ability to increase the sensitivity of MDR mammalian cells in culture.

Cytotoxic drugs are commonly used as antitumor chemotherapeutic agents. These agents are also called antiproliferative agents. The desired effect of cytotoxic drugs is selective cell death with destruction of the malignant neoplastic cells and relative sparing of normal cells.

Cytotoxic drugs have also proved valuable in the treatment of other 15 neoplastic disorders including connective or autoimmune diseases, metabolic disorders, dermatological diseases, and DNA virus infections.

Proper use of cytotoxic drugs requires a thorough familiarity with the natural history and pathophysiology of the disease before selecting the cytotoxic agent, determining a dose, and undertaking therapy. Each patient must be carefully evaluated, with attention directed toward factors which may potentiate toxicity, such as overt or occult infections, bleeding dyscrasias, poor nutritional status, and severe metabolic disturbances. In addition, the functional condition of certain major organs, such as liver, kidneys, and bone marrow, is extremely important. Therefore, the 25 selection of the appropriate cytotoxic agent and devising an effective therapeutic regimen is influenced by the presentation of the patient.

Cytotoxic drugs as antitumor chemotherapeutic agents can be subdivided into several broad categories, including, alkylating agents, such as mechlorethamine, cyclophosphamide, melphalan, uracil mustard, chlorambucil, busulfan, carmustine, lomustine, semustine, streptozoticin, and decrabazine; antimetabolites, such as methotrexate, fluorouracil, fluorodeoxyuridine, cytarabine, azarabine, idoxuridine, mercaptopurine, azathioprine, thioguanine, and adenine arabinoside; natural product derivatives, such as vinblastine, vincristine, dactinomycin, daunorubicin, doxorubicin, mithramycin, bleomycin, etoposide, teniposide, and

F

:0 mitomycin-C; and miscellaneous agents, such as hydroxyurea, procarbezine, mititane, and cis-platinum.

Important antitumor chemotherapeutic agents (with the usual effective dosage) to which clinical multidrug-resistance has been observed include vinblastine (0.1 mg per kilogram per week), vincristine (0.01 mg per kilogram per week), etoposide (35 to 50 mg per square meter per day), dactinomycin (0.15 mg per kilogram per day), doxorubicin (500 to 600 mg per square meter), daunorubicin (65 to 75 mg per square meter per week), and mithramycin (0.025 mg per kilogram per day). MDR has been shown to occur in vitro as well as in the clinic.

Multidrug-resistant cell lines are easily obtainable for in vitro determination of drug sensitization by compounds of the present invention.

In vitro potentiation of antineoplastic cytotoxicity by the imidazole derivatives of the present invention was measured in both CEM/VLB 1000 15 and SK/VLB 1000 cell lines. The multidrug resistant cell lines were obtained from Dr. Victor Ling, Ontario Cancer Institute, Toronto, Canada.

The CEM/VLB 1000 cell line was maintained as a suspension in minimum essential medium supplemented with 10% of fetal bovine serum in a humidied atmosphere of 95% air and 5% C02 while the SK/VLB 1000 cell line was maintained as adherent cells using the identical medium conditions as the CEM cells. The CEM/VLB 1000 cells were seeded at a density of x 104 cells/well in a 96 well microtiter plate while the SK/VLB 1000 cell line was seeded at a density of 2,500 cells/well after trypsinization.

Vinblastine (5 p.g/mL, for the CEM cells) or Taxol (3 p.g/mL, for the SK cells) and compound (0.01 to 50 pM) were added directly to the wells.

After an incubation of 48 hours in presence of drug, alamar blue Page et al.,Int. J. Oncol. 3: 473-476, 1993) was added (20 gL to the 200 gL cell suspension) for a period of 24 hours after which the fluorescence (excitation 530 nM, emission 590 nM) was read for each well using a "CytoFluor" microtiter fluorometer plate reader. This assay measures the minimal concentration of compound necessary to enhance the cytotoxicity

(EC

5 0) of vinblastine in the MDR cell line. The compounds of the present invention had EC 5 0 values in the range of 0.3 to 10 pM.

Enhancement of 3 H-vinblastine accumulation was also measured in the cell line. Coming Easy-Wash 96 well plates were pretreated with PBS -21and 1% BSA for 60 minutes and then dried. CEM/VLB1000 cells were seeded at 2 x 105, 40 pLL volume. Plates were incubated at 37 0 C for 30-60 minutes prior to use. The reference reversing agent, verapamil, or the compound of the present invention was added to the well followed by addition of media containing 3 H-vinblastine (final concentration 550 nM). Plates were allowed to incubate for 3 hours at 37 0 C. Cells were harvested onto pretreated Wallace filtermats B (pretreated overnight with 0.1% polyethyleneimine) using a TomTek harvester-96. After filtering, the filtermats were allowed to dry completely. Meltix B scintillant was then added to the filtermats. The filters were then placed in a 90 0 C oven for approximately 3-5 minutes and then removed. Scintillant was allowed to solidify on the filtermats. Filtermats were then placed in sample bags and read on a Wallace BetaPlate scintillation counter. The effect of compounds of the present invention in the cytotoxicity potentiation assays 15 and vinblastine (VLB) accumulation assay is given in the Table below: Cytotoxicity Potentiation [-H1VLB Accumulation (1M) 2 Example CEM/VLB1000 SK/VLB1000 CEM/VLB1000 Cells Cells Cells 1 NT 3 NT 2 NT NT 2 25 3 10 NT NT 4 0.3 1.0 5 3.0 10 12 6 5.0 NT NT 7 10 NT NT 8 0.3 0.3 9 10 10 2.0 20 11 10 NT NT 12 10 NT NT 13 0.6 20 NT -22- 14 0.4 1 NT 0.6 5 NT 16 2.0 10 NT 17 20 20 NT 1 Values presented are the midpoint (EC 5 0) of the minimum and maximum cytotoxicity induced by 5 p.g/mL vinblastine and the specific compound of the present invention.

2 Values presented are the midpoint (EC50) of the minimum and maximum increase in accumulation of 3 H-vinblastine caused by the specific compound of the present invention.

3 NT Not tested.

The modulation of multidrug-resistance demonstrated by the 15 imidazole derivatives described herein provides a method of treatment of multidrug-resistant tumors. The multidrug-resistance modulatory properties of the compounds described herein also provides a method for the prevention of the emergence of multi-drug resistant tumors during the course of cancer treatment. These same compounds additionally provide a method for reducing the required dosage of an antitumor chemotherapeutic agent.

All of the methods of this invention involve the administration of a compound of Formula 1 prior to, together with, or subsequent to the administration of an antitumor chemotherapeutic agent; and the administration of a combination of a compound of Formula 1 and an antitumor chemotherapeutic agent.

Thus, the compounds of Formula 1 are useful in the treatment of multidrug-resistant tumor cells or tumor cells in general, either separately or in combination with an antitumor chemotherapeutic agent. These compounds may be administered orally, topically or parenterally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants, and vehicles. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrastemal injection or infusion techniques.

-23- The present invention also has the objective of providing suitable topical, oral, and parenteral pharmaceutical formulations for use in the novel methods of treatment of the present invention. The compounds of the present invention may be administered orally as tablets, aqueous or oily suspensions, lozenges, troches, powders, granules, emulsions, capsules, syrups or elixirs. The composition for oral use may contain one or more agents selected from the group of sweetening agents, flavouring agents, colouring agents and preserving agents in order to produce pharmaceutically elegant and palatable preparations. The tablets contain the acting ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be, for example, inert diluents such as calcium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, such as corn starch or alginic acid; binding 15 agents, such as starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. These tablets may be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. Coating may also be performed using techniques described in the U.S. Patent Nos. 4,256,108; 4,160,452; and 4,265,874 to form osmotic therapeutic tablets for control release.

Formulations for oral use may be in the form of hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin. They may also be in the form of soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.

Aqueous suspensions normally contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspension. Such expicients may be suspending agent such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents which may be naturally occurring phosphatide such as lecithin; a condensation product of an alkylene -24oxide with a fatty acid, for example, polyoxyethylene stearate; a condensation product of ethylene oxide with a long chain aliphatic alcohol, for example, heptadecaethylenoxycetanol; a condensation product of ethylene oxide with a partial ester derived from a fatty acid and hexitol such as polyoxyethylene sorbitol monooleate, or a condensation product of ethylene oxide with a partial ester derived from fatty acids and hexitol anhydrides, for example polyoxyethylene sorbitan monooleate.

The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to known methods using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.

The sterile injectable preparation may also a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles 15 and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic monoor diglycerides. In adition, fatty acids such as oleic acid find use in the preparation of injectables.

A compound of Formula 1 may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperature but liquid at the rectal temperature 25 and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.

The compounds of the present invention may also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed froam a variety of phospholipids, such ascholesterol, stearylamine, or phosphatidylcholines.

For topical use, creams, ointments, jellies, solutions or suspensions, etc., containing the compounds of Formula 1 are employed.

Dosage levels of the compounds of the present invention are of the order of about 0.5 mg to about 100 mg per kilogram body weight, with a preferred dosage range between about 20 mg to about 50 mg per kilogram body weight per day(from about 25 mg to about 5 gms per patient per day). The amount of active ingredient that may be combined with the carrier materials to produce a single dosage will vary depending upon the host treated and the particular mode of administration. For example, a formulation intended for oral administration to humans may contain 5 mg to 1 g of an active compound with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition. Dosage unit forms will generally contain between from about 5 mg to about 500 mg of active ingredient.

It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of 15 excretion, drug combination and the severity of the particular disease undergoing therapy.

The following Examples are intended to illustrate the preparation of compounds of Formula 1, and as such are not intended to limit the invention as set forth in the claims appended thereto. Furthermore, the compounds described in the following examples are not to be construed as forming the only genus that is considerd as the invention, and any combination of the compounds or their moieties may itself form a genus.

The structure and purity of all final products were assured by at least one of the following methods: thin-layer chromatography (TLC), mass spectroscopy, nuclear magnetic resonance (NMR) spectroscopy, or combustion analysis. NMR data is in the form of delta values for major diagnostic protons, given in parts per million (ppm) relative to tetramethylsilane (TMS) as internal standard, determined at 400 MHz in deuteriochloroform (CDCI3); conventional abbreviations used for signal shape are: s, singlet; d, doublet; t, triplet; m, multiplet; br., broad; etc.

The following abbreviations have also been used: v (volume), w (weight), L (liter), mL (milliliter), g (gram), mg (milligram), mol (moles), mmol (millimoles), equiv (equivalents).

The Examples were prepared using either Method A or Method B.

-26- Method A involves synthesis on a solid support either with aldehyde linkers as shown in Scheme 1 above or FMOC-amino acid linkers as shown in Scheme 4 above.

In a typical Method A procedure using an aldehyde linker, to 0.1 mmol (1 equiv.) of the carboxyaldehyde resin or alkoxyaldehyde resin was added 1 mmol (1 equiv.) of 1,2-diarylethanedione, 1 mmol (10 equiv.) of the amine (R4NH2), 0.14 mmol (1.4 equiv.) of ammonium acetate, and 1.6 mL of acetic acid. The mixture was magnetically stirred for 12 to hours at 100 0 C. The resin was filtered and washed with dichloromethane (40 mL), N,N-dimethylformamide (20 mL), methanol (20 mL), dichloromethane (40 mL), and methanol (40 mL). The product was cleaved from the resin with a solution of 20% trifluoroacetic acid in dichloromethane for 20 minutes at ambient temperatures. The substituted imidazoles were purified using reverse-phase HPLC Rainin Dynamax C18 columns and mixtures of water and acetonitrile containing 0.1% trifluoroacetic acid as the mobile phase.

In a typical Method A procedure using a FMOC-amino acid linker, 0.1 mmol (1 equiv.) of the FMOC-amino acid resin was deprotected using piperidine in DMF (10 mL) at ambient temperatures for 20 minutes.

The resin was washed with DMF (10 mL), dichloromethane (2 x 20 mL), methanol (2 x 20 mL), and acetic acid (2 x 20 mL). To the deprotected resin was added 1 mmol (10 equiv.) of the 1,2-diarylethanedione, 1 mmol (10 equiv.) of ammonium acetate and 1.6 mL of acetic acid. The mixture was magnetically stirred for 12 to 15 hours at 100 0 C. The resin was filtered and washed with dichloromethane (40 mL), DMF (20 mL), methanol (20 mL), dichloromethane (40 mL), and methanol (40 mL). The product was cleaved from the resin with a solution of 20% trifluoroacetic acid in dichloromethane for 20 minutes at ambient temperatures. The substituted imidazoles were purified using reverse-phase HPLC Rainin Dynamax C18 columns and mixtures of water and acetonitrile containing 0.1% trifluoroacetic acid as the mobile phase.

Method B involves synthesis of the substituted (IH)-imidazoles in solution phase as shown in Scheme 6 above. In a typical Method B procedure, 1 mmol (1 equiv.) of the 1,2-ethanedione, 1 mmol (1 equiv.) of the aldehyde, and 20 mmol (20 equiv.) of ammonium acetate in glacial -27acetic acid (9 mL) were heated to reflux for 4 hours. The extent of the reaction was monitored by thin layer chromatography and nuclear magnetic resonance (NMR) spectroscopy. Once all starting material had disappeared, the solution was cooled to 23 0 C and added dropwise to a vigorously stirred mixture of diethyl ether (200 mL) and saturated aqueous sodium hydrogencarbonate (200 mL). Ethyl acetate (200 mL) was added, and the organic layer was separated. The organic layer was washed with saturated aqueous sodium hydrogencarbonate (200 mL) and saturated brine solution (200 mL). The aqueous layers were combined and washed with ethyl acetate (200 mL). The combined organic layers were dried over sodium sulfate, filtered, and solvent removed in vacuo. The derived imidazoles were purified using reverse-phase HPLC Rainin Dynamax C18 columns and mixtures of water and acetonitrile containing 0.1% trifluoroacetic acid as the mobile phase.

Method C involves synthesis of the N-substituted imidazoles in solution phase as shown in Scheme 7 above. In a typical Method C procedure, 2 mmol (1 equiv.) of the 1,2-ethanedione, 2 mmol (1 equiv.) of the aldehyde, 10 mmol (5 equiv) of the primary amine, and 3 mmol equiv.) of ammonium acetate in glacial acetic acid (5 mL) were heated to 20 reflux for 2 hours. The extent of the reaction was monitored by thin layer chromatography and nuclear magnetic resonance (NMR) spectroscopy.

Once all starting material had disappeared, the solution was cooled to 23°C and added dropwise to a vigorously stirred mixture of diethyl ether (200 S: mL) and saturated aqueous sodium hydrogencarbonate (200 mL) or 3.0 N sodium hydroxide (200 mL). Ethyl acetate (200 mL) was added, and the organic layer was separated. The organic layer was washed with saturated aqueous sodium hydrogencarbonate (200 mL) or 3.0 N sodium hydroxide (200 mL) and saturated brine solution (200 mL). The aqueous layers were combined and washed with ethyl acetate (200 mL). The combined organic 30 layers were dried over sodium sulfate, filtered, and solvent removed in vacuo. The derived N-substituted imidazoles were purified by recrystallization, flash chromatography on Merck F60 silica gel, or reverse-phase HPLC on Rainin Dynamax C18 columns and mixtures of water and acetonitrile containing 0.1% trifluoroacetic acid as the mobile phase.

-28- EXAMPLE I

CF

3 CO2j Prepared by method A.

2H), m, I1IH).

I H-NMR: 8 d, 2H), (7.06, d, 4H), (7.15, d, EXAMPLE 2

CF

3 C0 2 Prepared by method A. I H-NMR: 5 s, 3H), s, 3H), (5.14, s, 2H), mn, 9H), (7.09, d, 2H), (7.21, d, 2H), d, 2H), d, 2H).

EXAMPLE 3 -29- C0 2

H

Prepared by method A. IH-NMR:8 54H), (7.95, dd, 4H).

s, 12H), d, 4H), (7.25, d, EXAMPLE 4 NMe 2 O0 2 Me Prepared by method A, followed by reaction with trimethylsilyldiazomethane in 4:1 methanol-benzene. I H-NMR: 85(2.9, s, 12H), s, 3H), d, 4H), d, 4H), d, 2H), (8.05, d, 2H).

Me 2

N,

*5 *5

*SSS

5555

S

Prepared by method A. IH-NMR: 5 t, 3H), m, 6H), (1.3, m, 2H), s, 6H), s, 6H), (3.78, dd, 2H), (6.58, d, 2H), (6.72, dd, 4H), (7.19, d, 2H), (7.21, d, 2H), d, 2H).

EXAMPLE 6

CH

3 (CH9<

CO

2 Me Prepared by method A, followed by reaction with trimethylsilyldiazomethane in 4:1 methanol -benzene. IH-NMR: 58(0.6, t, 3H), (0.9-1.0, m, 6H), m, 2H), s, 6H), s, 6H), dd, 2H), s, 3H), (6.58, d, 2H), (6.78, d, 2H), (7.24, d, 2H), (7.42, d, 2H), (7.78, d, 2H), (8.05, d, 2H).

-31 EXAMPLE 7 ,NMe 2

'H=CHCO

2

H

Prepared by method A. 1 H-NMR: 8 s, 12H), d, LR), (6.62, d, 4H), broad d, 4H), (7.43, d, 2H), d, IR), dl, 2H).

EXAMPLE 8 ,NMe 2 Me 2

N

Prepared by method B, followed by reaction with trimethylsilyldiazomethane in 4:1 methanol-benzene. IH-NMR: 8 s, 12H), (3.78, s, 3H), (6.35, d, I1H), d, 4H), (7.38, broad d, 4H), (7.4, d, 2H), d, 1H), d, 2H).

-32- EXAMPLE 9

OH

Prepared by method A. IH-NMR: 8 s, 12H), (6.75, d, 2H), d, 4H), d, 4H), (7.65, d, 2H).

EXAMPLE NMe 2 0S*O 0*

OH

Prepared by method A. IH-NMR: 6 t, 2H), s, 6H), s, 6H), 2H), (6.58, d, 2H), (6.72, dd, 2H), m, 4H), m, (7.19, d, 2H), (7.25, d, 2H).

EXAMPLE 11 -33- NMe 2 Me 2

N

O-jf'- 0.0.

SOO*

00 0 a 00..

C

Prepared by method A. IH-NMR: 8 t, 2H), s, 6H), s, 6H), d, 2H), (6.58, d, 2H), (6.72, dd, 2H), d, 2H), m, 3H), (7.19, d, 2H), (7.35, dd, 4H), (8.05, d, 2H).

EXAMPLE 12 0

CH=CHCO

2

H

Prepared by method A. IH-NMR: 5 t, 2H), s, 6H), s, 6H), d, 2H), d, 1H), d, 2H), d, 2H), m, 14H).

EXAMPLE 13 -34- 0 MeOA N

!:N

IC

CH=CHCO

2 Me Prepared by method A, followed by reaction with trimethylsilyldiazomethane in 4:1 methanol-benzene. IH-NMR: 8 m, 2H), m, 4H), (2.05, t, 2H), (3.55, s, 3H), s, 3H), s, 3H), (3.85, s, 3H), (3.85, t, 2H), (6.45, d, 1H), d, 2H), (6.95, d, 2H), (7.25, d, 2H), d, 2H), d, 2H), d, 2H), d, IRH).

EXAMPLE 14 Se

S...O

N N Prepared by method C. I H-NMR: 8 m, 2H), t, 2H), s, 3H), (3.84, s, 3H), t, 2H), (6.42, s, I1H), (6.72, d, 2H), (6.89, s, I1H), (6.98, d, 2H), (7.14, m, 2H), (7.24, m, 3H), (7.35, t, 2H), (7.44, d, 2H), (7.52, d, 2H), (7.58, s, 3H).

EXAMPLE 0

CH=CHCO

2 Me Prepared by method A, followed by reaction with trimethylsilyldiazomethane in 4:1 methanol-benzene. 1 H-NMR: 8 m, 2H) (13 ,4)'28 ,6 30 ,3 38 ,3 (3.85, t, 2H), (6.45, d, IR), (6.58, d, 2H), (6.75, d, 2H), d, 2H), (7.4, d, 2H), d, 2H), d, 2H), d, I1H).

EXAMPLE 16 see* fee* feet -36- Prepred y mthodC. H-NM: 8(0.7, t, 3H), m, 4H), m, 2H), m, 2H), m, 2H), s, 6H), (2.45, t, 2H), s, 3H), (3.75, t, 2H), (3.84, s, 3H), (4.05, t, 2H), (6.72, d, 2H), (6.98, d, 4H), (7.22, d, 2H), d, 2H), (7.52, d, 2H).

EXAMPLE 17 9. .37- 0

N

Prepared by method C. I H-NMR: 8 m, 2H), (1.92, m, 2H), s, 6H), t, 2H), t, 2H), (3.66, s, 3H), (3.78, t, 2H), (3.82, s, 3H), (4.05, t, 2H), (6.42, s, 1H), (6.72, d, 2H), (6.85, s, IR), (6.91, m, 4H), (7.04, s, 1H), d, 2H), (7.41, d, 2H),

Claims (35)

1. A compound of the formula 1 R3 R2 N N R1 Formula 1 or a pharmaceutically acceptable salt thereof wherein; R, is selected from the group consisting of: substituted alkyl or substituted C 2-11 alkenyl, wherein the substituent is selected from the group consisting of hydroxy, C, 6 alkyloxy, or mono-, di-, and tri-substituted aryl-Co., alkyl, wherein aryl is selected from the group consisting ofphenyl, furyl, thienyl, the substituents are selected from the group consisting of: phenyl, trans-2-phenylethenyl, 2-phenylethynyl, 2-phenylethyl, or in which the said phenyl group is mono- or disubstituted with a member selected from the group consisting of hydroxy, halo, C_ 1 4 alkyl and alkyloxy, 15 (ii) substituted C,16 alkyl, substituted C 26 alkyloxy, substituted C 26 alkylthio, Ssubstituted C 2 6 alkylcarbonyl, wherein the substituent is selected from the group consisting of C 1 6 alkoxy, C,-alkylthio, (iii) C0 2 Rs, CICnCONHRs, trans- CH=CHCO 2 Rs, or trans- CH=CHCONHR, wherein R, is alkyl, or phenyl alkyl, (iv) C 1 6 alkoxycarbonylmethyleneoxy; R 2 and R 3 are each independently selected from the group consisting of: furyl mono-, di, and tri-substituted phenyl and furyl wherein the substituents are independently selected from: halo, trifluoromethyl, C 1 -6 alkyl, (ii) C,_ 6 alkyloxy (iii) C,- 6 alkyl-amino, di(C, 6 alkyl)-amino, -39- with the proviso that at least one of the phenyl and furyl substituents be selected from (ii) or (iii); and R 4 is selected from the group consisting of: hydrogen; substituted Cl 1 alkyl or C2- 1 1 alkenyl wherein the substituent is independently selected from the group consisting of hydrogen, hydroxy, halo, Cl-6 alkyloxy, Cl. 6 alkylthio, C-. 6 alkylamino, phenyl-C-. 6 alkylamino, Cl-6alkoxycarbonyl; or aryl Co-i alkyl wherein the aryl group is selected from the group consisting of phenyl, imidazolyl, furyl, and thienyl.

2. A compound of the formula 1 R 3 R2 N N Rd__7 0 0* 00*0 0 0 0 0 0 0 0 Formula 1 f \c P UPAT'~ wherein: R, is selected from the group consisting of substituted C 1 ll alkyl or substituted C 2 11 alkenyl, wherein the substituents are selected from the group consisting ofhydroxy, CI- 6 alkyloxy; or mono-, di-, and tri-substituted aryl-Ci- 1 0 alkyl wherein aryl is selected from the group consisting of phenyl, furyl, thienyl, the substituents are selected from the group consisting of: phenyl, trans-2-phenylethenyl, 2-phenylethynyl, 2-phenylethyl, or in which the said phenyl group is mono- or disubstituted with a member selected from the group consisting of hydroxy, halo, C-4 alkyl and C24 alkyloxy, R 2 and R 3 are each independently a member selected from the group consisting of furyl and mono- and di-substituted phenyl and furyl wherein the substituents are independently selected from: halo, trifluoromethyl, CI-6 alkyl, (ii) CI. 6 alkyloxy, (iii) C 1 6 alkylamino, and di-(C 1 6 alkyl)-amino; with the proviso that at least one of the phenyl and furyl substituents be selected from (ii) or (iii), and R 4 is selected from the group consisting of: hydrogen; substituted alkyl or C 2 11 alkenyl wherein the substituents are independently selected from the group consisting of hydrogen, hydroxy, halo, C 1 -6 alkyloxy, C 1 6 alkylthio, C 1 6 alkylamino, phenyl-Cl. 6 alkylamino, C.-6 alkoxycarbonyl; or aryl Co.- 1 alkyl wherein the aryl group is selected from the group consisting of phenyl, imidazolyl, furyl and thienyl.

3. A compound of the formula 1 R3 R2 wherein: group consisting Of CR4 alkoxy, C-6 alkythio, *o R1 L 15 Formula 1 wherein: R 1 is selected from the group consisting of: substituted C 1 .n 1 alkyl or substituted C 2 1 1 alkenyl, wherein the substituents are selected from the group consisting of hydroxy, C 1 6 alkyloxy: or mono-, di-, and tri-substituted aryl-Co_. alkyl wherein aryl is selected from the group consisting ofphenyl, furyl, thienyl, the substituents are selected from the group consisting of: substituted C 1 6 alkyl, substituted C2- 6 alkyloxy, substituted C 2 6 alkylthio, substituted C 2 6 alkoxycarbonyl, wherein the substituents are selected from the group consisting of C 1 6 alkoxy, 6 alkylthio, .\AN -41- R 2 and R 3 are each independently selected from the group consisting of furyl, mono-, di, and tri-substituted phenyl and furyl wherein the substituents are independently selected from: halo, trifluoromethyl, C 6 alkyl, (ii) C 1 6 alkyloxy, (iii) C 1 6 alkyl-amino, di(C 1 6 alkyl)amino, with the proviso that at least one of the phenyl and furyl substituents be selected from (ii) or (iii), and R 4 is selected from the group consisting of: 0 hydrogen; substituted C.I, alkyl or C2- 11 alkenyl wherein the substituents are independently selected from the group consisting of hydrogen, hydroxy, halo, C-. 6 alkyloxy, C1- 6 alkylthio, C 16 alkylamino, phenyl-C. 6 alkylamino, C 1 6 alkoxycarbonyl; or 5 aryl Co-.i alkyl wherein the aryl group is selected from the group consisting of phenyl, imidazolyl, furyl and thienyl. 4 oooo 4

4. o oo .4 p 4 4 4 p 4 4o44e0 oooo 4 4 4. 4 4. 4* 4 4 4. 4 4 4 *m ol Qo o 4. A compound of the formula 1 Formula 1 wherein: RI is selected from the group consisting of: mono- substituted aryl-Co. 1 1 alkyl wherein aryl is selected from the group consisting of phenyl, the substituents are selected from the group consisting of: C1-4 alkyl and C 2 -4 alkyloxy, Ci. 6 CO 2 R 5 trans-CH=CHCO 2 R 5 wherein R 5 is CI. 6 alkyl, or phenyl C 1 6 alkyl, 0 R 2 and R 3 are each independently selected from the group consisting of mono Ssubstituted phenyl wherein the substituents are independently selected from: COU LTT.. -42- C, 1 alkyloxy and R 4 is selected from the group consisting of: hydrogen; substituted alkyl or C2-, alkenyl wherein the substituent is independently selected from the group consisting of hydrogen, hydroxy, halo, C 1 6 alkyloxy, C 1 -6 alkylthio, C- 6 alkylamino, phenyl-C,,. alkylamino, C,_ 6 alkoxycarbonyl; or aryl Co,, alkyl wherein the aryl group is selected from the group consisting ofphenyl, imidazolyl, furyl and thienyl, and the pharmaceutically acceptable salts thereof. A compound according to formula 1 wherein R, is 4-hydroxyphenyl; R 2 and R 3 are methoxyphenyl; and R 4 is benzyl; or the pharmaceutically acceptable salts thereof. R3 R2 N N :.o 1 4* R Formula 1 15 6. A compound according to formula 1 wherein R, is 4-carboxyphenyl; R 2 and R3 are 4-(dimethylamino)-phenyl; and R4 is benzyl; or the pharmaceutically acceptable salts thereof. SR3 R2 NNR R1 Formula 1

7. A compound according to Formula 1 wherein R, is 4-methoxycarbonyl; R 2 and R3 are 4-(dimethylamino)-phenyl; and R4 is hydrogen; or the pharmaceutically acceptable salts thereof. 0 Pf 43 Formula 1

8. A compound according to Formula I wherein R, is 4-carboxyphenyl; R 2 and R 3 are (dimethylamino)-phenyl; and R 4 is n-hexyl; or the pharmaceutically acceptable salts thereof. S OSS@ S OSSS 0 S 0000 S S OS 00 S S S 5555 55 S S S S 555 5 S SOSS SO S S 55 0 55 55 5 OSSS S 0 SSOS 5 5 5. 5 S 0 S R4- Formula 1

9. A compound according to formula 1 wherein R, is 4-(methoxycarbonyl)-phenyl; R 2 and R 3 are (dimethylamino)-phenyl; and R 4 is n-hexyl; or the pharmaceutically 10 acceptable salts thereof. R4 Formula 1 A compound according to formula 1 wherein R, is 4-(carboxyethenyl)-phenyl; R 2 and Rj are (dimethylamino)-phenyl; and R 4 is hydrogen; or the pharmaceutically acceptable salts thereof. -44- R 3 R4/ Formula 1

11. A compound according to formula 1 wherein R, is 4-(methoxycarbonyl)-phenyl; and R 2 and R 3 are (dimethylamino)-phenyl; and R 4 is n-hexyl; or the pharmaceutically acceptable salts thereof. e. R4- Formula 1

12. A compound according to formula 1 wherein R 1 is 4-hydroxyphenyl; R 2 and R 3 are -(dimethylamino)-phenyl; and R 4 is hydrogen; or the pharmaceutically acceptable salts thereof. Formula 1

13. A compound according to formula 1 wherein R 1 is 4-hydroxyphenyl; R 2 and R 3 are -(dimethylamino)-phenyl; and R 4 is -phenylethyl; or the pharmaceutically acceptable salts thereof. *I 0 0 0 00 .000. :.0.0 lo: 0 0 0::0: 0. Formula 1

14. A compound according to formula 1 wherein R, is 4-carboxyphenyl; R 2 and R 3 are -(dimethylamino)-phenyl; and R 4 is -phenylethyl; or the pharmaceutically acceptable salts thereof. R3 R2 N N RI Formula 1

15. A compound according to formula 1 wherein R, is 4-(trans-2-carboxyethenyl)- phenyl; R 2 and R 3 are -(dimethylamino)-phenyl; and R 4 is -phenylethyl; or the pharmaceutically acceptable salts thereof. R 3 R2 N N RI Formula 1

16. A compound according to formula 1 wherein R, is 4-phenyl; R 2 and R 3 are 4-methoxyphenyl; and R 4 is 5-(methoxycarbonyl)-n-pentyl; or the pharmaceutically acceptable salts thereof. -46- Rl Formula 1

17. A compound according to formula 1 wherein Ri is trans-4-stilbenyl; R 2 and R 3 are 4-methoxyphenyl; and R 4 is 3-(imidazol-1-yl)-n-propyl; or the pharmaceutically 5 acceptable salts thereof. N RFormula 1 S 10 pharmaceutically acceptable salts thereof *o R R2 R 4 Formula 1

19. A compound according to formula 1 wherein R, is 4-phenyl; R 2 and R 3 are 4-methoxyphenyl; and R 4 is 3(imidazoi-1-yl)-n-propyl; or the pharmaceutically, P 15 acceptable salts thereof. -47- R 1 Formula 1 A compound according to formula 1 wherein R 1 is 4-phenyl; R 2 and R 3 are 4- methoxyphenyl; and R 4 is n-hexyl; or the pharmaceutically acceptable salts thereof.

21. A method of treatment for increasing the sensitivity of tumor cells to anti-cancer chemotherapeutic agents, said tumor cells being susceptible to anticancer chemotherapeutic agents, and said tumor cells having become resistant to chemotherapy comprising administration to a mammalian species in need of such treatment a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier. 9

22. A method of treatment of tumor cells, said tumor cells being susceptible to anti- *cancer chemotherapeutic agents, and said tumor cells having become resistant to chemo- o 15 therapy comprising: administration to a mammalian species in need of such treatment, of a therapeutically effective amount of said anti-cancer chemotherapeutic agent, and an effective amount of a compound of claim 1.

23.. A method of treatment of tumor cells according to claim 22, comprising: administration to a mammalian species in need of such treatment a therapeutically effective amount of an anti-cancer chemotherapeutic agent selected from the group consisting of taxol, vinblastine, vincristine, daunorubicin, and doxorubicin.

24. A pharmaceutical composition for increasing the sensitivity of tumor cells to anti- cancer chemotherapeutic agents, said tumor cells having become resistant to chemo- S. therapy comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier. -48- a a a. A pharmaceutical composition for increasing the sensitivity of tumor cells to anti- cancer chemotherapeutic agents, said tumors cells having become resistant to chemo- therapy comprising: a therapeutically effective amount of an anti-cancer chemotherapeutic agent selected from the group consisting of taxol, vinblastine, vincristine, daunorubicin, and doxorubicin, an effective amount of a compound of claim 1, and a pharmaceutically acceptable carrier.

26. Use of a compound according to any one of claims 1 to 20 for the manufacture of a medicament for increasing sensitivity of tumor cells to anti-cancer chemotherapeutic agents, said tumor cells being susceptible to anti-cancer chemical agents and said tumor cells having become resistant to chemotherapy.

27. Use of a compound according to any one of claims 1 to 20 and an anti-cancer 15 chemotherapeutic agent for the manufacture of a medicament for treatment of tumor cells,, said tumor cells being susceptible to said anti-cancer chemotherapeutic agents, and said tumor cells having become resistant to chemotherapy.

28. Use of a compound according to claim 27, wherein the anti-cancer chemotherapeutic agent is selected from the group consisting of taxol, vinblastine, vincristine, daunorubicin, and doxorubicin.

29. A compound of the formula 1 R4 Formula 1 wherein: s R, is selected from the group consisting of: I -49- substituted C i- alkyl or substituted C 2-11 alkenyl, wherein the substituents are selected from the group consisting of hydroxy, C1- 6 alkyloxy: or mono-, di-, and tri-substituted aryl-Co- 11 alkyl wherein aryl is selected from the group consisting ofphenyl, furyl, thienyl, the substituents are selected from the group consisting of: CI- 11 C0 2 R 5 CI. 11 CONHRs, trans-CH=CHCO 2 R 5 or trans-CH=CHCONHR wherein R 5 is C 1 11 alkyl, or phenyl C 1 l alkyl, C 1 -6 alkoxycarbonylmethyleneoxy, R 2 and R 3 are each independently selected from the group consisting of furyl mono-, di, and tri-substituted phenyl and furyl wherein the substituents are 10 independently selected from: halo, trifluoromethyl, C1- 6 alkyl, (ii) C 6 alkyloxy, (iii) C 1 6 alkyl-amino, di(CI-6 alkyl)amino, with the proviso that at least one of the phenyl and furyl substituents be selected from (ii) or (iii), S* and R 4 is selected from the group consisting of: hydrogen; substituted Cl. ialkyl or C 2 11 alkenyl wherein the substituents are independently selected from the group consisting of hydrogen, hydroxy, halo, C 1 6 20 alkyloxy, Cl. 6 alkylthio, C 6 alkylamino, phenyl-C 1 6 -alkylamino, Cl. 6 alkoxycarbonyl; or aryl Co- 11 alkyl wherein the aryl group is selected from phenyl, imidazolyl, furyl, or thienyl; or the pharmaceutically acceptable salts thereof. A compound of the formula 1 R 3 R2 N N Formula 1 wherein: RI is selected from the group consisting of: substituted Ci-i I alkyl or substituted C 2-11 alkenyl, wherein the substituents are selected from the group consisting of hydroxy, CI- 6 alkyloxy: or mono-, di-, and tri-substituted aryl-Co.- 1 alkyl wherein aryl is selected from the group consisting of phenyl, furyl, thienyl, the substituents are selected from the group consisting of: phenyl, trans-2-phenylethenyl, 2-phenylethynyl, 2-phenylethyl, or in which the said phenyl group is mono- or disubstituted with a member selected from the 10 group consisting of hydroxy, halo, C-4 alkyl and C 2 4 alkyloxy, R 2 and R 3 are each independently selected from the group consisting of furyl, mono-, di, and tri-substituted phenyl and furyl wherein the substituents are independently selected from: halo, trifluoromethyl, C 1 -6 alkyl, (ii) C 1-6 alkyloxy, (iii) CI- 6 alkyl-amino, di(Ci 1 6 alkyl)amino, with the proviso that at least one of the phenyl and furyl substituents be selected from (ii) or (iii), and R 4 is selected from the group consisting of: 0*0 20 hydrogen; aryl Co- 11 alkyl wherein the aryl group is selected from phenyl, imidazolyl, furyl, or thienyl; or the pharmaceutically acceptable salts thereof.

31. A compound of formula 1 R3 R2 'w 2 R4 Formula 1 -51 wherein: RI is selected from the group consisting of: substituted C 1 11 alkyl or substituted C 2-11 alkenyl, wherein the substituents are selected from the group consisting ofhydroxy, C 1 -6 alkyloxy; or mono-, di-, and tri-substituted aryl-Co. 11 alkyl wherein aryl is selected from the group consisting ofphenyl, furyl, thienyl, the substituents are selected from the group consisting of: phenyl, trans-2-phenylethenyl, 2-phenylethynyl, 2-phenylethyl, or in which the said phenyl group is mono- or disubstituted with a member selected from the 10 group consisting of hydroxy, halo, C 1 4 alkyl and C2 4 alkyloxy, R 2 and R 3 are each independently selected from the group consisting of furyl, mono-, di, and tri-substituted phenyl and furyl wherein the substituents are :R independently selected from: S. halo, trifluoromethyl, C 1 6 alkyl, (ii) C 1 6 alkyloxy, (iii) C. 6 alkyl-amino, di(Cl- 6 alkyl)amino, with the proviso that at least one of the phenyl and furyl substituents be selected from (ii) or.(iii), and R 4 is selected from the group consisting of: S hydrogen; 20 substituted C. 11 alkyl or C2- 11 alkenyl wherein the substituents are independently selected from the group consisting of hydrogen, hydroxy, halo, C 1 6 alkyloxy, C 1 6 alkylthio, C 16 alkylamino, phenyl-C1-6 alkylamino, C 1 -6 alkoxycarbonyl; or the pharmaceutically acceptable salts thereof.

32. A compound of the formula 1 N N R4_ /N Formula 1 -52- wherein: RI is selected from the group consisting of: mono-, di-, and tri-substituted aryl- Co- 0 alkyl wherein aryl is selected from the group consisting of phenyl, furyl, thienyl, the substituents are selected from the group consisting of: phenyl, trans-2-phenylethenyl, 2-phenylethynyl, 2-phenylethyl, or in which the said phenyl group is mono- or disubstituted with a member selected from the group consisting of hydroxy, halo, C-4 alkyl and C2-4 alkyloxy, R 2 and R 3 are each independently selected from the group consisting of furyl, mono-, di, and tri-substituted phenyl and furyl wherein the substituents are 10 independently selected from: halo, trifluoromethyl, Ci- 6 alkyl, (ii) C .6 alkyloxy, (iii) C. 6 alkyl-amino, di(C1. 6 alkyl)amino, with the proviso that at least one of the phenyl and furyl substituents be selected from (ii) or (iii), and R 4 is selected from the group consisting of: hydrogen; substituted C-11 alkyl or C2- 1 alkenyl wherein the substituents are ~independently selected from the group consisting of hydrogen, hydroxy, halo, Ci-6 20 alkyloxy, Cl6alkylthio, C 1 6alkylamino, phenyl-C 1 6 alkylamino, C 1 -6 alkoxycarbonyl; or aryl Co- 1 alkyl wherein the aryl group is selected from phenyl, imidazolyl, furyl, or thienyl; or the pharmaceutically acceptable salts thereof.

33. A compound of the formula 1 R3 R2 S r R4 Formula 1 -53- wherein: R, is selected from the group consisting of: mono-, di-, and tri-substituted aryl- Co-, 0 alkyl wherein aryl is selected from the group consisting of phenyl, furyl, thienyl, the substituents are selected from the group consisting of: substituted C 1 6 alkyl, substituted C 2 6 alkyloxy, substituted C 2 6 alkylthio, substituted C 2 6 alkoxycarbonyl, wherein the substituents are selected from the group consisting of C-_6 alkoxy, Ci. 6 alkylthio, R 2 and R 3 are each independently selected from the group consisting of furyl, mono-, di, and tri-substituted phenyl and furyl wherein the substituents are 10 independently selected from: halo, trifluoromethyl, C.-6 alkyl, (ii) C 16 alkyloxy, (iii) C1- 6 alkyl-amino, di(C 1 6 alkyl)amino, C with the proviso that at least one of the phenyl and furyl substituents be selected from (ii) or (iii), Sand R 4 is selected from the group consisting of: hydrogen; substituted C.I 1 alkyl or C 2 11 alkenyl wherein the substituents are independently selected from the group consisting of hydrogen, hydroxy, halo, C-. 6 :20 alkyloxy, C 1 -6 alkylthio, CI. 6 alkylamino, phenyl-CI. 6 alkylamino, CI. 6 C alkoxycarbonyl; or aryl Co- 1 l alkyl wherein the aryl group is selected from phenyl, imidazolyl, furyl, or thienyl; or the pharmaceutically acceptable salts thereof.

34. A compound of the formula 1 R3 2 N N if T? Formula 1 -54- wherein: RI is selected from the group consisting of: mono-, di-, and tri-substituted aryl- Co- 1 alkyl wherein aryl is selected from the group consisting ofphenyl, furyl, thienyl, the substituents are selected from the group consisting of; C. 1 C0 2 R 5 C. CONHR 5 trans-CH=CHCO 2 R 5 or trans-CH=CHCONHR wherein R 5 is C 1 11 alkyl, or phenyl C 1 11 alkyl, C 1 -6 alkoxycarbonylmethyleneoxy, R 2 and R 3 are each independently selected from the group consisting of furyl, mono-, di, and tri-substituted phenyl and furyl wherein the substituents are independently selected from: 10 halo, trifluoromethyl, C.-6 alkyl (ii) Ci- 6 alkyloxy, (iii) C.- 6 alkyl-amino, di(Cl.6 alkyl)amino, with the proviso that at least one of the phenyl and furyl-substituents be selected from (ii) or (iii), and R 4 is selected from the group consisting of: hydrogen; substituted alkyl or C 2 11 alkenyl wherein the substituents are independently selected from the group consisting of hydrogen, hydroxy, halo, C 1 -6 alkyloxy, Cl. 6 alkylthio, C,_6alkylamino, phenyl-Cl-6alkylamino, C 1 -6 alkoxycarbonyl; or 20 aryl Co. 11 alkyl wherein the aryl group is selected from phenyl, imidazolyl, furyl, or thienyl; or the pharmaceutically acceptable salts thereof. A compound of formula 1 R 3 R2 Formula 1 wherein: R, is selected from the group consisting of: mono-, di-, and tri-substituted aryl- Co 0 alkyl wherein aryl is selected from the group consisting of phenyl, furyl, thienyl, the substituents are selected from the group consisting of: phenyl, trans-2-phenylethenyl, 2-phenylethynyl, 2-phenylethyl, or in which the said phenyl group is mono- or disubstituted with a member selected from the group consisting of hydroxy, halo, C14 alkyl and C 2 -4 alkyloxy, R 2 and R 3 are each independently selected from the group consisting of furyl, mono-, di, and tri-substituted phenyl and furyl wherein the substituents are 10 independently selected from: halo, trifluoromethyl, C-. 6 alkyl, *oo (ii) Ci. 6 alkyloxy, o (iii) C1- 6 alkyl-amino, di(C1 6 alkyl)amino, with the proviso that at least one of the phenyl and furyl substituents be selected from (ii) or (iii), *00000 and R 4 is selected from the group consisting of: hydrogen; aryl Co- 11 alkyl wherein the aryl group is selected from phenyl, imidazolyl, furyl, or thienyl; 20 or the pharmaceutically acceptable salts thereof.

36. A compound of formula 1 R3 R2 N N RI Formula 1 wherein: S 25 R, is selected from the group consisting of: mono-, di-, and tri-substituted aryl- Si Co- 1 alkyl wherein aryl is selected from the group consisting of phenyl, furyl, thienyl, ,the substituents are selected from the group consisting-of: -56- phenyl, trans-2-phenylethenyl, 2-phenylethynyl, 2-phenylethyl, or in which the said phenyl group is mono- or disubstituted with a member selected from the group consisting of hydroxy, halo, C-4 alkyl and C2-4 alkyloxy, R 2 and R 3 are each independently selected from the group consisting of furyl, mono-, di, and tri-substituted phenyl and furyl wherein the substituents are independently selected from: halo, trifluoromethyl, Ci. 6 alkyl, (ii) C1- 6 alkyloxy, (iii) C 1 6 alkyl-amino, di(C 1 6 alkyl)amino; 10 with the proviso that at least one of the phenyl and furyl substituents be selected from (ii) or (iii), and R 4 is selected from the group consisting of: hydrogen; substituted CIl alkyl or C 2 1 1 alkenyl wherein the substituents are independently selected from the group consisting of hydrogen, hydroxy, halo, C 1 I 6 alkyloxy, Ci-6alkylthio, C 1 6 alkylamino, phenyl-CI. 6 alkylamino, C 1 -6 alkoxycarbonyl; or the pharmaceutically acceptable salts thereof. 0 20 37. A compound of the formula 1 R3 R2 N N R1 Formula 1 wherein: RI is selected from the group consisting of: substituted C 1 1 alkyl or substituted C 2 1 1 alkenyl, wherein the substituents are selected from the group consisting of hydroxy, C 1 -6 alkyloxy: or OFF\< -57- R 2 and R 3 are each independently selected from the group consisting of furyl, mono-, di, and tri-substituted phenyl and furyl wherein the substituents are independently selected from: halo, trifluoromethyl, Cl-6 alkyl, (ii) C 1 6 alkyloxy, (iii) C 1 6 alkyl-amino, di(C 1 i 6 alkyl)amino, with the proviso that at least one of the phenyl and furyl substituents be selected from (ii) or (iii), and R 4 is selected from the group consisting of: 10 hydrogen; aryl Co-. alkyl wherein the aryl group is selected from phenyl, imidazolyl, furyl, or thienyl; or the pharmaceutically acceptable salts thereof. 15 38. A compound of the formula 1 000* OSO@ 0 0 0 0 0 0 *0*0 *0 0 0 00 0 0 0*00 Formula 1 wherein: RI is selected from the group consisting of: substituted Ci-1 1 alkyl or substituted C 2 11 alkenyl, wherein the substituents are selected from the group consisting of hydroxy, CI- 6 alkyloxy; or R 2 and R 3 are each independently selected from the group consisting of furyl, mono-, di, and tri-substituted phenyl and furyl wherein the substituents are independently selected from: halo, trifluoromethyl, CI- 6 alkyl, (ii) alkyloxy, "lk y\ (iii) C1.6 alkyl-amino, di(C 1 6 alkyl)amino, -58- with the proviso that at least one of the phenyl and furyl substituents be selected from (ii) or (iii), and R 4 is selected from the group consisting of: hydrogen; substituted Ci.i-, alkyl or C 2 -1 1 alkenyl wherein the substituents are independently selected from the group consisting of hydrogen, hydroxy, halo, CI-6 alkyloxy, C 1 6 alkylthio, C 1 -6 alkylamino, phenyl-Cl. 6 alkylamino, C.-6 alkoxycarbonyl; or the pharmaceutically acceptable salts thereof. Good .604 00 *0 0 .00. I* 0*0** 000 *0. *0 0 0.00 *a, 0*0* PR0 0 00*0 *0 0* .0 0 0*00 @0 C (iSF /Sc-

39. A compound of the formula 1 Formula 1 wherein: RI is selected from the group consisting of: substituted C.-6 alkyl or substituted C2-6 alkenyl, wherein the substituents are selected from the group consisting C 16 alkyloxy; or mono-, di-, and tri-substituted aryl-Co 11 alkyl wherein aryl is selected from the group consisting of phenyl, the substituents are selected from the group consisting of: C-. 4 alkyl and C 2 -4 alkyloxy, C 1 CO 2 R 5 CI. 1 CONHR 5 trans-CH=CHCO 2 R 5 or trans-CH=CHCONHR 5 wherein R 5 is C 1 1 1 alkyl, or phenyl C.l-i alkyl, R 2 and R 3 are each independently selected from the group consisting of, mono-, di, and tri-substituted phenyl wherein the substituents are independently selected from: C1- 6 alkyloxy, (ii) Cl. 6 alkyl-amino, di(C 1 6 alkyl)amino, and R 4 is selected from the group consisting of: hydrogen; -59- substituted C -6alkyl or C 2 -6alkenyl wherein the substituents are independently selected from the group consisting of hydrogen, C 1 6 alkyloxy, Cl. 6 alkylamino, or aryl Co- 1 l alkyl wherein the aryl group is selected from phenyl; or the pharmaceutically acceptable salts thereof. A compound of the formula 1 R3 R 2 N N 4 RI Formula 1 :wherein: R, is selected from the group consisting of: substituted C 2 6 alkenyl, C 16 alkyl wherein the substituents are selected from the group consisting C 1 -6 alkyloxy; or mono- substituted aryl-Co 0 1 1 alkyl wherein aryl is selected from the group 0 consisting of phenyl, the substituents are selected from the group consisting of; Ci-4 alkyl and C 2 4 alkyloxy, C- 6 CO 2 R 5 trans-CH=CHCO 2 R 5 wherein R 5 is 15 CI. 6 alkyl, or phenyl C 1 6 alkyl, R 2 and R 3 are each independently selected from the group consisting of, mono-, di, and tri-substituted phenyl wherein the substituents are independently selected from: C 1 6 alkyloxy, (ii) C 6 alkyl-amino, di(C1- 6 alkyl)amino, and R 4 is selected from the group consisting of: hydrogen; C 1 6 alkyloxy, C 1 6 alkylamino, or aryl CO- 6 alkyl wherein the aryl group is selected from phenyl, imidazol; or the pharmaceutically acceptable salts thereof. OPF\

41. A compound of the formula 1 R 4 Formula 1 0000 *ee a** C S *0 S *00o S0 S S 0 AS 0 S *Sr S C 5* o oooo oO ooo o go o wherein: R, is selected from the group consisting of: 5 substituted C 2 -6 alkenyl, C 2 6 alkyl wherein the substituents are selected from the group consisting C.-6 alkyloxy; or mono- substituted aryl-Co. 6 alkyl wherein aryl is selected from the group consisting ofphenyl, the substituents are selected from the group consisting of: Cl. 4 alkyl and C24 alkyloxy, CI. 6 CO 2 R 5 trans-CH=CHCO 2 R 5 wherein R 5 is 10 C 1 alkyl, or phenyl Ci. 6 alkyl, R 2 and R 3 are each independently selected from the group consisting of, mono-, di, and tri-substituted phenyl wherein the substituents are independently selected from: Cl. 6 alkyl-amino and di(C 1 6 alkyl)amino, and R 4 is hydrogen; 15 or the pharmaceutically acceptable salts thereof.

42. A compound of the formula 1 R4_ Formula 1 US 0 OFF\ wherein: R, is selected from the group consisting of: substituted C 2 6 alkenyl, C 2 6 alkyl wherein the substituents are selected from the group consisting CI-6 alkyloxy; or -61- mono- substituted aryl-Co.- 1 alkyl wherein aryl is selected from the group consisting ofphenyl, the substituents are selected from the group consisting of: Cl.4 alkyl and C24 alkyloxy, C 1 6 CO 2 R 5 trans-CH=CHCO 2 R 5 wherein R 5 is C 1 I 6 alkyl, or phenyl C 1 6 alkyl, R 2 and R 3 are each independently selected from the group consisting of, mono substituted phenyl wherein the substituents are independently selected from: C 1 6 alkyl-amino, di(C,. 6 alkyl)amino, C 1 -6 alkyloxy and R 4 is selected from the group consisting of: hydrogen, C.-6 alkyloxy, Ci. 6 alkylamino, or aryl Co-6 alkyl wherein the aryl group is selected from phenyl, imidazol; 10 or the pharmaceutically acceptable salts thereof. *0* o: 43. A compound of formula 1, substantially as herein described with reference to any one of the examples.

44. A method of treatment for increasing the sensitivity of tumor cells to anti-cancer chemotherapeutic agents, substantially as herein described with reference to any one of the examples. °B

45. A method of treatment of tumor cells, substantially as herein described with 20 reference to any one of the examples.

46. A pharmaceutical composition for increasing the sensitivity of tumor cells to anti- cancer chemotherapeutic agents, substantially as herein described with reference to any one of the examples.

47. Use of a compound of formula 1, substantially as herein described with reference to any one of the examples but excluding comparative examples. DATED this 2nd day of February, 2001. S 30 ONTOGEN CORPORATION Attorney: IVAN A. RAJKOVIC SFellow Institute of Patent and Trade Mark Attorneys of Australia of BALDWIN SHELSTON WATERS