# US 10,501,490 B2 · Taccalonolide microtubule stabilizers

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- Number: US 10,501,490 B2
- Document ID: US10501490B2
- Status: Granted
- Kind: B2
- Application number: 15/653,397
- Filed: 2017-07-18
- Published: 2017-11-02
- Granted: 2019-12-10
- Earliest claimed: 2011-06-06
- Assignees: Board of Regents, The University of Texas System
- Applicants: The Board of Regents of the University of Texas System
- Inventors: Susan L. Mooberry; Jiangnan Peng; April L. Risinger; Jing Li
- Web page: https://patentgrep.com/patent/US10501490B2

## CPC

- C07J 71/001: {Oxiranes}
- A61K 31/585: containing lactone rings, e.g. oxandrolone, bufalin
- A61K 36/894: Dioscoreaceae (Yam family)
- A61P 35/00: Antineoplastic agents
- C07D 493/08: Bridged systems
- C07J 71/0005: {Oxygen-containing hetero ring}
- C07J: STEROIDS (seco-steroids C07C)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The invention provides epoxytaccalonolide microtubule stabilizers and their use as anti-proliferative microtubule stabilizing agents.

## Claims

### Claim 1

A compound of the formula:
wherein:
------ is present and is a single bond;
R1 is hydrogen, amino, cyano, azido, halo, hydroxy, oxo, alkyl(C≤12), alkenyl(C≤12), alkoxy(C≤12), acyl(C≤12), acyloxy(C≤12), alkylamino(C≤12), dialkylamino(C≤12), amido(C≤12), alkylthio(C≤12), aryl(C≤12), aralkyl(C≤12), heterocycloalkyl(C≤12), or substituted versions thereof in which one or more hydrogen atoms has been independently replaced by —OH, —F, —Cl, —Br, —I, —NH2, —NO2, —CO2H, —CO2CH3, —CN, —SH, —OCH3, —OCH2CH3, —C(O)CH3, —N(CH3)2, —C(O)NH2, —OC(O)CH3, or —S(O)2NH2;
R2 is hydrogen, amino, cyano, azido, halo, hydroxy, oxo, alkyl(C≤12), alkenyl(C≤12), alkoxy(C≤12), acyl(C≤12), acyloxy(C≤12), alkylamino(C≤12), dialkylamino(C≤12), amido(C≤12), alkylthio(C≤12), aryl(C≤12), aralkyl(C≤12), heterocycloalkyl(C≤12, or substituted versions thereof in which one or more hydrogen atoms has been independently replaced by —OH, —F, —Cl, —Br, —I, —NH2, —NO2, —CO2H, —CO2CH3, —CN, —SH, —OCH3, —OCH2CH3, —C(O)CH3, —N(CH3)2, —C(O)NH2, —OC(O)CH3, or —S(O)2NH2,
or R2 is taken together with R3 to form an epoxide at C-2/C-3;
R3 is hydrogen, amino, cyano, azido, halo, hydroxy, oxo, alkyl(C≤12), alkenyl(C≤12), alkoxy(C≤12), acyl(C≤12), acyloxy(C≤12), alkylamino(C≤12), dialkylamino(C≤12), amido(C≤12), alkylthio(C≤12), aryl(C≤12), aralkyl(C≤12), heterocycloalkyl(C≤12, or substituted versions thereof in which one or more hydrogen atoms has been independently replaced by —OH, —F, —Cl, —Br, —I, —NH2, —NO2, —CO2H, —CO2CH3, —CN, —SH, —OCH3, —OCH2CH3, —C(O)CH3, —N(CH3)2, —C(O)NH2, —OC(O)CH3, or —S(O)2NH2,
or R3 is taken together with R2 as defined above;
R5 is absent, hydrogen, amino, cyano, azido, halo, hydroxy, alkyl(C≤12), alkenyl(C≤12), alkoxy(C≤12), acyl(C≤12), acyloxy(C≤12), alkylamino(C≤12), dialkylamino(C≤12), amido(C≤12), alkylthio(C≤12), aryl(C≤12), aralkyl(C≤12), heterocycloalkyl(C≤12, or substituted versions thereof in which one or more hydrogen atoms has been independently replaced by —OH, —F, —Cl, —Br, —I, —NH2, —NO2, —CO2H, —CO2CH3, —CN, —SH, —OCH3, —OCH2CH3, —C(O)CH3, —N(CH3)2, —C(O)NH2, —OC(O)CH3, or —S(O)2NH2;
R6 is hydrogen, amino, cyano, azido, halo, hydroxy, alkyl(C≤12), alkenyl(C≤12), alkoxy(C≤12), acyl(C≤12), acyloxy(C≤12), alkylamino(C≤12), dialkylamino(C≤12), amido(C≤12), alkylthio(C≤12), aryl(C≤12), aralkyl(C≤12), heterocycloalkyl(C≤12, or substituted versions thereof in which one or more hydrogen atoms has been independently replaced by —OH, —F, —Cl, —Br, —I, —NH2, —NO2, —CO2H, —CO2CH3, —CN, —SH, —OCH3, —OCH2CH3, —C(O)CH3, —N(CH3)2, —C(O)NH2, —OC(O)CH3, or —S(O)2NH2,
or R6 is taken together with R7 to form an epoxide at C-6/C-7;
R6′ when present is hydrogen, amino, cyano, azido, halo, hydroxy, alkyl(C≤12), alkenyl(C≤12), alkoxy(C≤12), acyl(C≤12), acyloxy(C≤12), alkylamino(C≤12), dialkylamino(C≤12), amido(C≤12), alkylthio(C≤12), aryl(C≤12), aralkyl(C≤12), heterocycloalkyl(C≤12), or substituted versions thereof in which one or more hydrogen atoms has been independently replaced by —OH, —F, —Cl, —Br, —I, —NH2, —NO2, —CO2H, —CO2CH3, —CN, —SH, —OCH3, —OCH2CH3, —C(O)CH3, —N(CH3)2, —C(O)NH2, —OC(O)CH3, or —S(O)2NH2;
R7 is hydrogen, amino, cyano, azido, halo, hydroxy, alkyl(C≤12), alkenyl(C≤12), alkoxy(C≤12), acyl(C≤12), acyloxy(C≤12), alkylamino(C≤12), dialkylamino(C≤12), amido(C≤12), alkylthio(C≤12), aryl(C≤12), aralkyl(C≤12), heterocycloalkyl(C≤12), or substituted versions thereof in which one or more hydrogen atoms has been independently replaced by —OH, —F, —Cl, —Br, —I, —NH2, —NO2, —CO2H, —CO2CH3, —CN, —SH, —OCH3, —OCH2CH3, —C(O)CH3, —N(CH3)2, —C(O)NH2, —OC(O)CH3, or —S(O)2NH2, or oxo if R7′ is not present,
or R7 is taken together with R6 as defined above;
R7′ when present is hydrogen, amino, cyano, azido, halo, hydroxy, alkyl(C≤12), alkenyl(C≤12), alkoxy(C≤12), acyl(C≤12), acyloxy(C≤12), alkylamino(C≤12), dialkylamino(C≤12), amido(C≤12), alkylthio(C≤12), aryl(C≤12), aralkyl(C≤12), heterocycloalkyl(C≤12), or substituted versions thereof in which one or more hydrogen atoms has been independently replaced by —OH, —F, —Cl, —Br, —I, —NH2, —NO2, —CO2H, —CO2CH3, —CN, —SH, —OCH3, —OCH2CH3, —C(O)CH3, —N(CH3)2, —C(O)NH2, —OC(O)CH3, or —S(O)2NH2;
R11 is hydrogen, amino, cyano, azido, halo, hydroxy, alkyl(C≤12), alkenyl(C≤12), alkoxy(C≤12), acyl(C≤12), acyloxy(C≤12), alkylamino(C≤12), dialkylamino(C≤12), amido(C≤12), alkylthio(C≤12), aryl(C≤12), aralkyl(C≤12), heterocycloalkyl(C≤12), or substituted versions thereof in which one or more hydrogen atoms has been independently replaced by —OH, —F, —Cl, —Br, —I, —NH2, —NO2, —CO2H, —CO2CH3, —CN, —SH, —OCH3, —OCH2CH3, —C(O)CH3, —N(CH3)2, —C(O)NH2, —OC(O)CH3, or —S(O)2NH2;
R12 is hydrogen, amino, cyano, azido, halo, hydroxy, alkyl(C≤12), alkenyl(C≤12), alkoxy(C≤12), acyl(C≤12), acyloxy(C≤12), alkylamino(C≤12), dialkylamino(C≤12), amido(C≤12), alkylthio(C≤12), aryl(C≤12), aralkyl(C≤12), heterocycloalkyl(C≤12), or substituted versions thereof in which one or more hydrogen atoms has been independently replaced by —OH, —F, —Cl, —Br, —I, —NH2, —NO2, —CO2H, —CO2CH3, —CN, —SH, —OCH3, —OCH2CH3, —C(O)CH3, —N(CH3)2, —C(O)NH2, —OC(O)CH3, or —S(O)2NH2;
R15 is hydrogen, amino, cyano, azido, halo, hydroxy, oxo, alkyl(C≤12), alkenyl(C≤12), alkoxy(C≤12), acyl(C≤12), acyloxy(C≤12), alkylamino(C≤12), dialkylamino(C≤12), amido(C≤12), alkylthio(C≤12), aryl(C≤12), aralkyl(C≤12), heterocycloalkyl(C≤12), or substituted versions thereof in which one or more hydrogen atoms has been independently replaced by —OH, —F, —Cl, —Br, —I, —NH2, —NO2, —CO2H, —CO2CH3, —CN, —SH, —OCH3, —OCH2CH3, —C(O)CH3, —N(CH3)2, —C(O)NH2, —OC(O)CH3, or —S(O)2NH2;
R20 is hydrogen, amino, cyano, azido, halo, hydroxy, hydroperoxy, alkyl(C≤12), alkenyl(C≤12), alkoxy(C≤12), acyl(C≤12), acyloxy(C≤12), alkylamino(C≤12), dialkylamino(C≤12), amido(C≤12), alkylthio((C≤12), aryl(C≤12), aralkyl(C≤12), heterocycloalkyl(C<12), or substituted versions thereof in which one or more hydrogen atoms has been independently replaced by —OH, —F, —Cl, —Br, —I, —NH2, —NO2, —CO2H, —CO2CH3, —CN, —SH, —OCH3, —OCH2CH3, —C(O)CH3, —N(CH3)2, —C(O)NH2, —OC(O)CH3, or —S(O)2NH2;
R21 is hydrogen, amino, cyano, azido, halo, hydroxy, alkyl(C≤12), alkenyl(C≤12), alkoxy(C≤12), acyl(C≤12), acyloxy(C≤12), alkylamino(C≤12), dialkylamino(C≤12), amido(C<12), alkylthio(C≤12), aryl(C≤12), aralkyl(C≤12), heterocycloalkyl(C≤12), or substituted versions thereof in which one or more hydrogen atoms has been independently replaced by —OH, —F, —Cl, —Br, —I, —NH2, —NO2, —CO2H, —CO2CH3, —CN, —SH, —OCH3, —OCH2CH3, —C(O)CH3, —N(CH3)2, —C(O)NH2, —OC(O)CH3, or —S(O)2NH2;
R25 is hydrogen, amino, cyano, azido, halo, hydroxy, alkyl(C≤12), alkenyl(C≤12), alkoxy(C≤12), acyl(C≤12), acyloxy(C≤12), alkylamino(C≤12), dialkylamino(C≤12), amido(C≤12), alkylthio(C≤12), aryl(C≤12), aralkyl(C≤12), heterocycloalkyl(C≤12), or substituted versions thereof in which one or more hydrogen atoms has been independently replaced by —OH, —F, —Cl, —Br, A, —NH2, —NO2, —CO2H, —CO2CH3, —CN, —SH, —OCH3, —OCH2CH3, —C(O)CH3, —N(CH3)2, —C(O)NH2, —OC(O)CH3, or —S(O)2NH2;
R26 is hydrogen, amino, cyano, azido, halo, hydroxy, alkyl(C≤12), alkenyl(C≤12), alkoxy(C≤12), acyl(C≤12), acyloxy(C≤12), alkylamino(C≤12), dialkylamino(C≤12), amido(C≤12), alkylthio(C≤12), aryl(C≤12), aralkyl(C≤12), heterocycloalkyl(C<12), or substituted versions thereof in which one or more hydrogen atoms has been independently replaced by —OH, —F, —Cl, —Br, —I, —NH2, —NO2, —CO2H, —CO2CH3, —CN, —SH, —OCH3, —OCH2CH3, —C(O)CH3, —N(CH3)2, —C(O)NH2, —OC(O)CH3, or —S(O)2NH2, or oxo if R26′ is not present;
R26′ when present is hydrogen, amino, cyano, azido, halo, hydroxy, alkyl(C≤12), alkenyl(C≤12), alkoxy(C≤12), acyl(C≤12), acyloxy(C≤12), alkylamino(C≤12), dialkylamino(C≤12), amido(C≤12), alkylthio(C≤12), aryl(C≤12), aralkyl(C≤12), heterocycloalkyl(C≤12), or substituted versions thereof in which one or more hydrogen atoms has been independently replaced by —OH, —F, —Cl, —Br, —I, —NH2, —NO2, —CO2H, —CO2CH3, —CN, —SH, —OCH3, —OCH2CH3, —C(O)CH3, —N(CH3)2, —C(O)NH2, —OC(O)CH3, or —S(O)2NH2;
R27 is hydrogen, amino, cyano, azido, halo, hydroxy, alkyl(C≤12), alkenyl(C≤12), alkoxy(C≤12), acyl(C≤12), acyloxy(C≤12), alkylamino(C≤12), dialkylamino(C≤12), amido(C≤12), alkylthio(C≤12), aryl(C≤12), aralkyl(C≤12), heterocycloalkyl(C≤12), or substituted versions thereof in which one or more hydrogen atoms has been independently replaced by —OH, —F, —Cl, —Br, —I, —NH2, —NO2, —CO2H, —CO2CH3, —CN, —SH, —OCH3, —OCH2CH3, —C(O)CH3, —N(CH3)2, —C(O)NH2, —OC(O)CH3, or —S(O)2NH2; and
X is O, NR′, or CR′2, wherein each R′ is independently hydrogen or alkyl(C≤6);
or a pharmaceutically acceptable salt thereof,
provided, however, that Formula I does not include the compound wherein R1 is acetoxy, R2 taken together with R3 forms an epoxide at C-2/C-3, R5 is hydrogen, R6 is oxo and R6′ is not present, R7 is hydroxy and R7′ is hydrogen, each of R11, R12, and R15 are acetoxy, one of R20 or R21 is methyl and the other is hydrogen, R25 is OH, R26 is oxo and R26′ is not present, R27 is methyl, and X is O.

### Claim 2 (depends on 1)

The compound of claim 1, wherein R1 is acyloxy(C≤12).

### Claim 3 (depends on 1)

The compound of claim 1, wherein R2 and R3, taken together, form an epoxide at C-2/C-3.

### Claim 4 (depends on 1)

The compound of claim 1, wherein X is O.

### Claim 5 (depends on 1)

The compound of claim 1, wherein R1 is hydroxy, alkoxy(C≤12), or acyloxy(C≤12);
R2 is halo or hydroxy, or R2 is taken together with R3 to form an epoxide at C-2/C-3;
R3 is halo or hydroxy, or R3 is taken together with R2 as defined above;
R5 is hydrogen, amino, hydroxy, alkoxy(C≤12), alkylamino(C≤12), or dialkylamino(C≤12);
R6 is hydrogen, hydroxy, alkoxy(C≤12), or acyloxy(C≤12);
R6′ when present is hydrogen, hydroxy, alkoxy(C≤12), or acyloxy(C≤12);
R7 is hydrogen, hydroxy, alkoxy(C≤12), or acyloxy(C≤12), or oxo if R7′ is not present;
R7′ when present is hydrogen, hydroxy, alkoxy(C≤12), or acyloxy(C≤12);
R11 is hydrogen, hydroxy, alkyl(C≤12), alkoxy(C≤12), or acyloxy(C≤12);
R12 is hydrogen, hydroxy, alkyl(C≤12), alkoxy(C≤12), or acyloxy(C≤12);
R15 is hydrogen, hydroxy, alkyl(C≤12), alkoxy(C≤12), or acyloxy(C≤12);
R20 is hydrogen, hydroxy, hydroperoxy, alkoxy(C≤12), or acyloxy(C≤12);
R21 is hydrogen or alkyl(C≤12);
R25 is hydrogen, hydroxy, alkoxy(C≤12), or acyloxy(C≤12);
R26 is hydrogen, hydroxy or alkoxy(C≤12), or oxo if R26′ is not present;
R26′ when present, is hydrogen, hydroxy, or alkoxy(C≤12); and
R27 is hydrogen or alkyl(C≤12).

### Claim 6 (depends on 1)

A composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.

### Claim 7 (depends on 1)

A method of ameliorating a hyperproliferative disorder in a patient, wherein the hyperproliferative disorder is selected from breast cancer, ovarian cancer, lung cancer, cervical cancer, and prostate cancer, the method comprising administering to the patient an effective amount of the compound of claim 1.

### Claim 8 (depends on 1)

A method of producing the compound of claim 1, the method comprising:
(a) dissolving a taccalonolide-containing crude extract of the roots and/or rhizomes of a Tacca species in an organic solvent, thereby forming a solution; and
(b) subjecting the solution to epoxidation,
thereby producing the compound.

### Claim 9

A compound selected from taccalonolide AJ, epoxytaccalonolide AQ, epoxytaccalonolide AS, epoxytaccalonolide AR, taccalonolide AF, epoxytaccalonolide D, epoxytaccalonolide E, epoxytaccalonolide F, epoxytaccalonolide L, epoxytaccalonolide N, epoxytaccalonolide G, epoxytaccalonolide R, epoxytaccalonolide S, epoxytaccalonolide T, epoxytaccalonolide U, epoxytaccalonolide Z, epoxytaccalonolide AA, epoxytaccalonolide AB, epoxytaccalonolide AG, epoxytaccalonolide AH, epoxytaccalonolide AI, epoxytaccalonolide AL, epoxytaccalonolide AM, epoxytaccalonolide AN, epoxytaccalonolide AP, epoxytaccalonolide I, epoxytaccalonolide J, epoxytaccalonolide K, epoxytaccalonolide M, epoxytaccalonolide O, epoxytaccalonolide P, epoxytaccalonolide V, epoxytaccalonolide H, epoxytaccalonolide H2, epoxytaccalonolide AD, epoxytaccalonolide AE, epoxytaccalonolide W, epoxytaccalonolide AC, epoxy-TA-NaBH4-12, epoxy-TA-NaBH4-10, and epoxy-TB-Ac-16, or pharmaceutically acceptable salts thereof.

### Claim 10 (depends on 9)

The compound of claim 9, wherein the compound is selected from taccalonolide AJ, taccalonolide AF, epoxytaccalonolide D, epoxytaccalonolide E, epoxytaccalonolide F, epoxytaccalonolide L, epoxytaccalonolide N, epoxytaccalonolide G, epoxytaccalonolide R, epoxytaccalonolide S, epoxytaccalonolide T, epoxytaccalonolide U, epoxytaccalonolide Z, epoxytaccalonolide AA, epoxytaccalonolide AB, epoxytaccalonolide AG, epoxytaccalonolide AH, epoxytaccalonolide AI, epoxytaccalonolide I, epoxytaccalonolide J, epoxytaccalonolide K, epoxytaccalonolide M, epoxytaccalonolide V, epoxytaccalonolide H, epoxytaccalonolide H2, epoxytaccalonolide AD, epoxytaccalonolide AE, epoxytaccalonolide W, epoxytaccalonolide AC, epoxy-TA-NaBH4-12, epoxy-TA-NaBH4-10, and epoxy-TB-Ac-16.

### Claim 11 (depends on 9)

The compound of claim 9, wherein the compound is taccalonolide AF.

### Claim 12 (depends on 9)

The compound of claim 9, wherein the compound is taccalonolide AJ.

### Claim 13 (depends on 9)

A composition comprising the compound of claim 9 and a pharmaceutically acceptable carrier.

### Claim 14 (depends on 9)

A method of ameliorating a hyperproliferative disorder in a patient, wherein the hyperproliferative disorder is selected from breast cancer, ovarian cancer, lung cancer, cervical cancer, and prostate cancer, the method comprising administering to the patient an effective amount of the compound of claim 9.

### Claim 15 (depends on 9)

A method of producing the compound of claim 9, the method comprising:
(a) dissolving a taccalonolide-containing crude extract of the roots and/or rhizomes of a Tacca species in an organic solvent, thereby forming a solution; and
(b) subjecting the solution to epoxidation,
thereby producing the compound.