# US 2014/0193519 A1 · Indibulin therapy

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- Number: US 2014/0193519 A1
- Document ID: US20140193519A1
- Status: Published application
- Kind: A1
- Application number: 13/958,160
- Filed: 2013-08-02
- Published: 2014-07-10
- Earliest claimed: 2006-11-28
- Assignees: ZIOPHARM Oncology, Inc.
- Applicants: Ziopharm Oncology, Inc.
- Inventors: Barbara P. Wallner; Brian Eric Schwartz; Philip B. Komarnitsky; Gerald Bacher; Bernhard Kutscher; Gerhard Raab
- Web page: https://patentgrep.com/patent/US20140193519A1

## CPC

- A61K 31/4439: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465)
- A61K 31/138: Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine (atenolol A61K31/165; pindolol A61K31/404; timolol A61K31/5377)
- A61K 31/282: Platinum compounds
- A61K 31/337: having four-membered rings, e.g. taxol
- A61K 31/404: Indoles, e.g. pindolol
- A61K 31/437: the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
- A61K 31/47: Quinolines; Isoquinolines
- A61K 31/4709: Non-condensed quinolines and containing further heterocyclic rings
- A61K 31/475: having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine (vincamine A61K31/4375)
- A61K 31/496: Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
- A61K 31/513: having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
- A61K 31/517: ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
- A61K 31/53: having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine (melarsoprol A61K31/555 {; with four nitrogen atoms A61K31/495})
- A61K 31/565: not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
- A61K 31/566: having an oxo group in position 17, e.g. estrone
- A61K 31/569: substituted in position 17 alpha, e.g. ethisterone
- A61K 31/573: substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
- A61K 31/704: attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin {(digitoxin A61K31/7048)}
- A61K 31/7048: having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin {, digitoxin or digoxin}
- A61K 31/7068: having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
- A61K 33/243: Platinum; Compounds thereof
- A61K 38/08: Peptides having 5 to 11 amino acids {(A61K38/043 - A61K38/046 take precedence)}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 35/00: Antineoplastic agents
- A61P 35/04: specific for metastasis
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- 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

## Abstract

The invention provides combination therapy, wherein one or more other therapeutic agents are administered with indibulin or a pharmaceutically acceptable salt thereof and the combination is synergistic. Another aspect of the invention relates to the treatment of cancer with indibulin as a single agent. Another aspect of the invention relates to dosing regimen for administration of oral dosage forms of indibulin.

## Claims

### Claim 1

A method for treating cancer, comprising administering indibulin or a pharmaceutically acceptable salt thereof; and one or more other therapeutic agents, wherein the combination shows efficacy that is greater than the efficacy of either agent being administered alone.

### Claim 2 (depends on 1)

The method of claim 1, wherein the indibulin or a pharmaceutically acceptable salt thereof is administered orally or intravenously.

### Claim 3

(canceled)

### Claim 4 (depends on 1)

The method of claim 1, wherein the efficacy of indibulin and the one or more other therapeutic agents are synergistic or additive.

### Claim 5

(canceled)

### Claim 6 (depends on 1)

The method of claim 1, wherein the other therapeutic agent is selected from erlotinib, carboplatin, 5-fluorouracil, capecitabine, paclitaxel, tamoxifen, vinorelbine, cisplatin, gemcitabine, estramustine, doxorubicin, vinblastine, etoposide, and prednisolone.

### Claim 7 (depends on 1)

The method of claim 1, wherein the cancer is selected from lung, breast, ovarian, and prostate cancer.

### Claim 8 (depends on 1)

The method of claim 1, wherein the compound and the one or more other therapeutic agents are administered simultaneously.

### Claim 9

(canceled)

### Claim 10

(canceled)

### Claim 11

A kit comprising indibulin and another therapeutic agent selected from erlotinib, carboplatin, 5-fluorouracil, capecitabine, paclitaxel, tamoxifen, vinorelbine, cisplatin, gemcitabine, estramustine, doxorubicin, vinblastine, etoposide, and prednisolone.

### Claim 12

A method for treating cancer, comprising administering an indolyl-3-glyoxylic acid derivative of Formula (I) or a pharmaceutically acceptable salt thereof and one or more other therapeutic agents, wherein the combination shows efficacy that is greater than the efficacy of either agent being administered alone
wherein
R is selected from hydrogen; (C1-C6)-alkyl, where the alkyl group is optionally mono- or polysubstituted with a phenyl ring which is optionally mono- or polysubstituted with halogen, (C1-C6)-alkyl, (C3-C7)-cycloalkyl, carboxyl, carboxyl esterified with (C1-C6)-alkanol, trifluoromethyl, hydroxyl, methoxy, ethoxy, benzyloxy or a benzyl group which is mono- or polysubstituted on the phenyl moiety with (C1-C6)-alkyl groups, halogen or trifluoromethyl; benzyloxycarbonyl; tertiary-butoxycarbonyl; and acetyl;
R1 is selected from a phenyl ring, which is optionally mono- or polysubstituted with (C1-C6)-alkyl, (C1-C6)-alkoxy, cyano, halogen, trifluoromethyl, hydroxyl, benzyloxy, nitro, amino, (C1-C6)-alkylamino, (C1-C6)-alkoxycarbonylamino, carboxyl, or by carboxyl esterified with C1-C6-alkanol; a pyridine structure of the Formula (II)
or an N-oxide thereof, where the pyridine structure is alternatively bonded to the ring carbon atoms 2, 3 or 4 and is optionally substituted with the substituents R5 and R6, wherein R5 and R6 are identical or different and are selected from (C1-C6)-alkyl, (C3-C7)-cycloalkyl, (C1-C6)—alkoxy, nitro, amino, hydroxyl, halogen, trifluoromethyl, ethoxycarbonylamino, and carboxyalkyloxy in which the alkyl group comprises 1-4 C atoms; 2- or 4-pyrimidinyl, wherein the 2-pyrimidinyl ring is optionally mono- or polysubstituted with a methyl group; 2-, 3-, 4- or 8-quinolyl structure which is optionally substituted with (C1-C6)-alkyl, halogen, nitro, amino or (C1-C6)-alkylamino; 2-, 3-, or 4-quinolylmethyl group, where the ring carbons of the pyridylmethyl, the quinolyl, and the quinolylmethyl are optionally substituted with (C1-C6)-alkyl, (C1-C6)-alkoxy, nitro, amino or (C1-C6)-alkoxycarbonylamino; and allylaminocarbonyl-2-methylprop-1-yl;
R1 in the case in which R is hydrogen, methyl, benzyl, benzyloxycarbonyl, tert-butoxycarbonyl, or acetyl, is further selected from —CH2COOH; —CH(CH3)—COOH; —(CH3)2—CH—(CH2)2—CH—COO—; H3C—H2C—CH(CH3)—CH(COOH)—; HO—H2C—CH(COOH)—; phenyl-CH2—CH(COOH)—; (4-imidazolyl)-CH2—CH—(COOH)—; HN═(NH2)—NH—(CH2)3—CH(COOH)—; H2N—(CH2)4—CH(COOH)—; H2N—CO—CH2—CH—(COOH)—; and HOOC—(CH2)2—CH(COOH)—;
R1, in the case in which R is hydrogen, benzyloxycarbonyl, tert-butoxycarbonyl, acetyl or benzyl, may be the acid radical of a natural or unnatural amino acid (e.g. α-glycyl, α-sarcosyl, α-seryl, α-phenylalanyl, α-histidyl, α-prolyl, α-arginyl, α-lysyl, α-asparagyl or α-glutamyl), where the amino groups of the respective amino acids may be protected or unprotected, wherein suitable protecting groups include, but are not limited to, benzyloxycarbonyl, tert-butoxycarbonyl, or acetyl, and in the case where R1 is asparagyl or glutamyl, the second, unbonded carboxyl group is present as a free carboxyl group or in the form of an ester of a C1-C6-alkanol (e.g. as a methyl, ethyl or as a tert-butyl ester);
R and R1 can further form, together with the nitrogen atom to which they are bonded, a piperazine ring of the Formula (III) or a homopiperazine ring, provided R1 is an aminoalkylene group, in which
R7 is selected from alkyl; phenyl which is optionally mono- or polysubstituted with (C1-C6)-alkyl, (C1-C6)-alkoxy, halogen, nitro, amino or by (C1-C6)-alkylamino; benzhydryl and bis-p-fluorobenzhydryl;
R2 is selected from hydrogen; (C1-C6)-alkyl, wherein the alkyl group is optionally mono- or polysubstituted with halogen, phenyl (wherein the phenyl is optionally mono- or polysubstituted with halogen, (C1-C6)-alkyl, (C3-C7)-cycloalkyl, carboxyl, carboxyl esterified with C1-C6-alkanol, trifluoromethyl, hydroxyl, methoxy, ethoxy or benzyloxy), 2-quinolyl (optionally mono- or polysubstituted with halogen, (C1-C4-alkyl or (C1-C4)-alkoxy), or 2-, 3- or 4-pyridyl (optionally mono- or polysubstituted with halogen, (C1-C4)-alkyl or (C1-C4)-alkoxy); aroyl (where the aryl moiety is optionally mono- or polysubstituted with halogen, (C1-C6)-alkyl, (C3-C7)-cycloalkyl, carboxyl, carboxyl esterified with C1-C6-alkanol, trifluoromethyl, hydroxyl, methoxy, ethoxy or benzyloxy);
R3 and R4 are identical or different and are selected from hydrogen, (C1-C6)-alkyl, (C3-C7)-cycloalkyl, (C1-C6)-alkanoyl, (C1-C6)-alkoxy, halogen, benzyloxy, nitro, amino, (C1-C4)-mono or dialkyl-substituted amino, (C1-C6)-alkoxycarbonylamino and (C1-C6)-alkoxycarbonylamino-(C1-C6)-alkyl;
Z is O or S.

### Claim 13 (depends on 12)

The method of claim 12, wherein R2 is selected from (C1-C6)-alkyl, wherein the alkyl group is optionally mono- or polysubstituted with halogen, phenyl (wherein the phenyl is optionally mono- or polysubstituted with halogen, (C1-C6)-alkyl, (C3-C7)-cycloalkyl, carboxyl, carboxyl esterified with C1-C6-alkanol, trifluoromethyl, hydroxyl, methoxy, ethoxy or benzyloxy), 2-quinolyl (optionally mono- or polysubstituted with halogen, (C1-C4)-alkyl or (C1-C4)-alkoxy), or 2-, 3- or 4-pyridyl (optionally mono- or polysubstituted with halogen, (C1-C4)-alkyl or (C1-C4)-alkoxy); aroyl (where the aryl moiety is optionally mono- or polysubstituted with halogen, (C1-C6)-alkyl, (C3-C7)-cycloalkyl, carboxyl, carboxyl esterified with C1-C6-alkanol, trifluoromethyl, hydroxyl, methoxy, ethoxy or benzyloxy).

### Claim 14 (depends on 12)

The method of claim 12, wherein the other therapeutic agent is selected from erlotinib, carboplatin, 5-fluorouracil, capecitabine, paclitaxel, tamoxifen, vinorelbine, cisplatin, gemcitabine, estramustine, doxorubicin, vinblastine, etoposide, and prednisolone.

### Claim 15

(canceled)

### Claim 16 (depends on 12)

The method of claim 12, wherein the indolyl-3-glyoxylic acid derivative is indibulin.

### Claim 17 (depends on 24)

The method of claim 24, further comprising administering the indolyl-3-glyoxylic acid derivative in combination with another agent or therapy method.

### Claim 18 (depends on 17)

The method of claim 17, wherein other agent or therapy is selected from a chemotherapeutic, radiotherapy, hormonal therapeutic agents, targeted therapy, immunotherapy, gene therapy, or surgery.

### Claim 19 (depends on 18)

The method of claim 18, wherein the other agent is a chemotherapeutic.

### Claim 20 (depends on 17)

The method of claim 17, wherein the individual components of the combination are administered simultaneously, sequentially, or separately.

### Claim 21 (depends on 17)

The method of claim 17, wherein the indolyl-3-glyoxylic acid derivative is indibulin.

### Claim 22 (depends on 17)

method of claim 17, wherein the cancer is selected from adenoid cystic carcinoma, renal cell carcinoma, breast cancer, ovarian cancer, prostate cancer, vulvar cancer, glioblastoma, and lung cancer.

### Claim 23 (depends on 22)

The method of claim 22, wherein the cancer is selected from renal cell carcinoma, breast cancer, vulvar cancer, glioblastoma, and lung cancer.

### Claim 24

A method for the treatment of cancer, comprising administering an indolyl-3-glyoxylic acid derivative with a daily dose of 100 to 2000 mg.

### Claim 25

(canceled)

### Claim 26 (depends on 24)

The method of claim 24, wherein the indolyl-3-glyoxylic acid derivative is administered once daily, twice daily, or as a continuous treatment.

### Claim 27

(canceled)

### Claim 28

(canceled)