# US 2013/0156755 A1 · Cancer therapy using a combination of a hsp90 inhibitory compounds and a vegf inhibitor

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- Number: US 2013/0156755 A1
- Document ID: US20130156755A1
- Status: Published application
- Kind: A1
- Application number: 13/642,064
- Filed: 2011-04-19
- Published: 2013-06-20
- Earliest claimed: 2010-04-19
- Assignees: Synta Pharmaceuticals Corp.
- Inventors: Ronald K. Blackman; Kevin Paul Foley; David Proia
- Web page: https://patentgrep.com/patent/US20130156755A1

## CPC

- A61K 39/3955: {against proteinaceous materials, e.g. enzymes, hormones, lymphokines}
- A61K 31/4196: 1,2,4-Triazoles
- A61K 39/395: Antibodies (agglutinins A61K38/36 {; as drug carriers A61K47/50}); Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 35/00: Antineoplastic agents
- 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

A pharmaceutical combination comprising a VEGF inhibitor, and an Hsp90 inhibitor according to the following formulae (I) or (Ia) a tautomer, or a pharmaceutically acceptable salt thereof, wherein the variables in the structural formulae are defined herein. Also provided are methods for treating a proliferative disorder in a subject in need thereof, using pharmaceutical combinations described herein.

## Claims

### Claim 1

A pharmaceutical combination comprising an VEGF inhibitor and an Hsp90 inhibitor according to the following formulae:
or a tautomer, or a pharmaceutically acceptable salt thereof, wherein:
Z is OH, SH, or NH2;
X is CR4 or N;
R1 is —H, —OH, —SH, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanidino, a haloalkyl, a heteroalkyl, an alkoxy or cycloalkoxy, a haloalkoxy, —NR10R11, —OR7, —C(O)R7, —C(O)OR7, —C(S)R7, —C(O)SR7, —C(S)SR7, —C(S)OR7, —C(S)NR10R11, —C(NR8)OR7, —C(NR8)R7, —C(NR8)NR10R11, —C(NR8)SR7, —OC(O)R7, —OC(O)OR7, —OC(S)OR7, —OC(NR8)OR7, —SC(O)R7, —SC(O)OR7, —SC(NR8)OR7, —OC(S)R7, —SC(S)R7, —SC(S)OR7, —OC(O)NR10R11, —OC(S)NR10R11, —OC(NR8)NR10R11, —SC(O)NR10R11, —SC(NRONR10R11, —SC(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —C(O)NR10R11, —NR8C(O)R7, —NR7C(S)R7, —NR7C(S)OR7, —NR7C(NR8)R7, —NR7C(O)OR7, —NR7C(NR8)OR7, —NR7C(O)NR10R11, —NR7C(S)NR10R11, —NR7C(NR8)NR10R11, —SR7, —S(O)pR7, —OS(O)pR7, —OS(O)pOR7, —OS(O)pNR10R11, —S(O)pOR7, —NR8S(O)pR7, —NR7S(O)pNR10R11, —NR7S(O)pOR7, —S(O)pNIZ10R11, —SS(O)pR7, —SS(O)pOR7, —SS(O)pNR10R11, —OP(O)(OR7)2, or —SP(O)(OR7)2;
R2 is —H, —OH, —SH, —NR7H, —OR15, —SR15, —NHR15, —O(CH2)mOH, —O(CH2)mSH, —O(CH2)mNR7H, —S(CH2)mOH, —S(CH2)mSH, —S(CH2)mNR7H, —OC(O)NR10R11, —SC(O)NR10R11, —NR7C(O)NR10R11, —OC(O)R7, —SC(O)R7, —NR7C(O)R7, —OC(O)OR7, —SC(O)OR7, —NR7C(O)OR7, —OCH2C(O)R7, —SCH2C(O)R7, —NR7CH2C(O)R7, —OCH2C(O)OR7, —SCH2C(O)OR7, —NR7CH2C(O)OR7, —OCH2C(O)NR10R11, —SCH2C(O)NR10R11, —NR7CH2C(O)NR10R11, —OS(O)pR7, —SS(O)pR7, —NR7S(O)pR7, —OS(O)pNR10R11, —SS(O)pNR10R11, —NR7S(O)pNR10R11, —OS(O)pOR7, —SS(O)pOR7, —NR7S(O)pOR7, —OC(S)R7, —SC(S)R7, —NR7C(S)R7, —OC(S)OR7, —SC(S)OR7, —NR7C(S)OR7, —OC(S)NR10R11, —SC(S)NR10R11, —NR7C(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —NR7C(NR8)R7, —OC(NR8)OR7, —SC(NR8)OR7, —NR7C(NR8)OR7, —OC(NR8)NR10R11, —SC(NR8)NR10R11, or —NR7C(NR8)NR10R11;
R3 is —H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, a haloalkyl, a heteroalkyl, —C(O)R7, —(CH2)mC(O)OR7, —C(O)OR7, —OC(O)R7, —C(O)NR10R11, —S(O)pR7, —S(O)pOR7, or —S(O)pNR10R11;
R4 is —H, —OH, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, halo, cyano, nitro, guanidino, a haloalkyl, a heteroalkyl, —C(O)R7, —C(O)OR7, —OC(O)R7, —C(O)NR10R11, —NR8C(O)R7, —SR7, —S(O)pR7, —S(O)pR7, —S(O)pOR7, —NR8S(O)pR7, —S(O)pNR10R11, or R43 and R44 taken together with the carbon atoms to which they are attached form an optionally substituted cycloalkenyl, an optionally substituted aryl, an optionally substituted heterocyclyl, or an optionally substituted heteroaryl;
R7 and R8, for each occurrence, are, independently, —H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
R10 and R11, for each occurrence, are independently —H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R10 and R11, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
R15, for each occurrence, is independently, a lower alkyl;
p, for each occurrence, is, independently, 1 or 2; and
m, for each occurrence, is independently, 1, 2, 3, or 4.

### Claim 2 (depends on 1)

The combination of claim 1, wherein the Hsp90 inhibitor is selected from the group consisting of:
3-(2,4-dihydroxyphenyl)-4-(1-ethyl-indol-4-yl)-5-mercapto-[1,2,4]triazole,
3-(2,4-dihydroxyphenyl)-4-(1-isopropyl-indol-4-yl)-5-mercapto-[1,2,4]triazole,
3-(2,4-dihydroxyphenyl)-4-(indol-4-yl)-5-mercapto-[1,2,4]triazole,
3-(2,4-dihydroxyphenyl)-4-(1-methoxyethyl-indol-4-yl)-5-mercapto-[1,2,4]triazole,
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-isopropyl-indol-4-yl)-5-mercapto-[1,2,4]triazole,
3-(2,4-dihydroxyphenyl)-4-(1-dimethylcarbamoyl-indol-4-yl)-5-mercapto-[1,2,4]triazole,
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-propyl-indol-4-yl)-5-mercapto-[1,2,4]triazole,
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1,2,3-trimethyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(2,3-dimethyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-acetyl-2,3-dimethyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-propyl-2,3-dimethyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-n-butyl-indol-4-yl)-5-mercapto-[1,2,4]triazole,
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-n-pentyl-indol-4-yl)-5-mercapto-[1,2,4]triazole,
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-n-hexyl-indol-4-yl)-5-mercapto-[1,2,4]triazole,
3-(2,4-dihydroxy-5-cyclopropyl-phenyl)-4-(1-(1-methylcyclopropyl)-indol-4-yl)-5-mercapto-[1,2,4]triazole,
3-(2,4-dihydroxy-5-cyclopropyl-phenyl)-4-(1,2,3-trimethyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-methyl-3-ethyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1,3-dimethyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-methyl-3-isopropyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1,2-dimethyl-indol-5-yl)-5-mercapto-1,2,4]triazole,
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(N-methyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,
3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1,3-dimethyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,
3-(2,4-dihydroxy-5-cyclopropyl-phenyl)-4-(1,3-dimethyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,
3-(2,4-dihydroxy-5-cyclopropyl-phenyl)-4-(1-methyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,
3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1H-indol-5-yl)-5-mercapto-[1,2,4]triazole,
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1,2-dimethyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,
3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1-ethyl-indol-5-yl)-5-mercapto-[1,2,4]triazole, and
3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1-propyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,
5-hydroxy-4-(5-hydroxy-4-(1-methyl-1H-indol-5-yl)-4H-1,2,4-triazol-3-yl)-2-isopropylphenyl dihydrogen phosphate,
sodium 5-hydroxy-4-(5-hydroxy-4-(1-methyl-1H-indol-5-yl)-4H-1,2,4-triazol-3-yl)-2-isopropylphenyl phosphate,
2-(3,4-dimethoxyphenethyl)-5-hydroxy-4-(5-hydroxy-4-(1-methyl-1H-indol-5-yl)-4H-1,2,4-triazol-3-yl)phenyl dihydrogen phosphate,
5-hydroxy-2-isopropyl-4-(5-mercapto-4-(4-methoxybenzyl)-4H-1,2,4-triazol-3-yl)phenyl dihydrogen phosphate,
5-hydroxy-4-(5-hydroxy-4-(4-methoxybenzyl)-4H-1,2,4-triazol-3-yl)-2-isopropylphenyl dihydrogen phosphate,
4-(4-(1,3-dimethyl-1H-indol-5-yl)-5-hydroxy-4H-1,2,4-triazol-3-yl)-2-ethyl-5-hydroxyphenyl dihydrogen phosphate,
or a tautomer, or a pharmaceutically acceptable salt thereof.

### Claim 3 (depends on 1)

The combination of claim 1, wherein the Hsp90 inhibitor is selected from the group consisting of:
3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(1-isopropyl-7-methoxy-indol-4-yl)-5-mercapto-[1,2,4]triazole;
3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(N-methyl-indol-5-yl)-5-mercapto-[1,2,4]triazole;
3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1-methyl-indol-5-yl)-5-hydroxy-[1,2,4]triazole;
or a tautomer or pharmaceutically acceptable salt thereof.

### Claim 4 (depends on 1)

The combination of claim 1, wherein the Hsp90 inhibitor is 3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1-methyl-indol-5-yl)-5-hydroxy-[1,2,4]triazole or a tautomer or a pharmaceutically acceptable salt thereof.

### Claim 5 (depends on 1)

The combination of claim 1, wherein the Hsp90 inhibitor is 5-hydroxy-4-(5-hydroxy-4-(1-methyl-1H-indol-5-yl)-4H-1,2,4-triazol-3-yl)-2-isopropylphenyl dihydrogen phosphate, or a tautomer, or a pharmaceutically acceptable salt thereof.

### Claim 6 (depends on 4)

The combination of claim 4, wherein the VEGF inhibitor is bevacizumab, sunitinib, or sorafenib.

### Claim 7 (depends on 6)

The combination according to claim 6, wherein the VEGF inhibitor is bevacizumab.

### Claim 8 (depends on 1)

The combination according to claim 1, wherein the Hsp90 inhibitor is 3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1-methyl-indol-5-yl)-5-hydroxy-[1,2,4]triazole, or a tautomer or a pharmaceutically acceptable salt thereof, and the VEGF inhibitor is bevacizumab.

### Claim 9 (depends on 1)

The combination according to claim 1, wherein the Hsp90 inhibitor is 5-hydroxy-4-(5-hydroxy-4-(1-methyl-1H-indol-5-yl)-4H-1,2,4-triazol-3-yl)-2-isopropylphenyl dihydrogen phosphate, or a tautomer, or a pharmaceutically acceptable salt thereof, and the VEGF inhibitor is bevacizumab.

### Claim 10 (depends on 1)

A method of treating or preventing a proliferative disorder in a subject, comprising administering to a subject an effective amount of the combination of claim 1.

### Claim 11 (depends on 10)

The method of claim 10, wherein the proliferative disorder is cancer.

### Claim 12 (depends on 11)

The method of claim 11, wherein the cancer is associated with VEGF.

### Claim 13 (depends on 11)

The method of claim 11, wherein the cancer is metastatic colorectal cancer, metastatic or non-metastatic breast cancer, non-small cell lung cancer, renal cell carcinoma, pancreatic cancer, ovarian cancer, hormone refractory prostate cancer, glioblastoma multiforme, non-metastatic unresectable liver cancer, gliosarcoma, malignant glioma, peritoneal cancer, fallopian tube cancer, rectal cancer, kidney cancer, Hodgkin's lymphoma, colorectal cancer, neuroendocrine carcinoma, bladder cancer, uveal melanoma, hormone sensitive breast cancer, hepatocellular cancer, gastric cancer, squamous cell carcinoma, cervical cancer, uterine cancer, chronic lymphocytic leukemia, lymphoma, myeloma, Karposi's sarcoma, urothelial carcinoma, mesothelioma, malignant fibrous histiocytoma or leiomyosarcoma.

### Claim 14 (depends on 13)

The method of claim 13, wherein the cancer is metastatic colorectal cancer, metastatic or non-metastatic breast cancer, metastatic non-small cell lung cancer, renal cell carcinoma, metastatic or unresectable locally advanced pancreatic cancer, ovarian cancer, hormone refractory prostate cancer, glioblastoma multiforme, or non-metastatic unresectable liver cancer.

### Claim 15 (depends on 14)

The method of claim 14, wherein the cancer is metastatic non-small cell lung cancer.

### Claim 16 (depends on 14)

The method of claim 14, wherein the cancer is metastatic breast cancer.

### Claim 17 (depends on 14)

The method of claim 14, wherein the cancer is metastatic colorectal cancer.

### Claim 18 (depends on 14)

The method of claim 14, wherein the cancer is metastatic glioblastoma multiforme.

### Claim 19 (depends on 10)

The method of any one of claim 10, wherein the subject is human.

### Claim 20 (depends on 1)

A method of inhibiting the growth of a cancer or tumor cell in a subject, the method comprising the steps of: (a) contacting the cell with an effective amount of a compound of formulae (I) or (Ia) as defined in claim 1, and (b) exposing the cell to an effective amount of a VEGF inhibitor, wherein the VEGF inhibitor is selected from the group consisting of bevacizumab, sunitinib, or sorafenib.

### Claim 21 (depends on 20)

The method of claim 20, wherein the compound is 3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1-methyl-indol-5-yl)-5-hydroxy-[1,2,4]triazole, or a tautomer or a pharmaceutically acceptable salt thereof and the VEGF inhibitor is bevacizumab.

### Claim 22 (depends on 20)

The method of claim 20, wherein the compound is 5-hydroxy-4-(5-hydroxy-4-(1-methyl-1H-indol-5-yl)-4H-1,2,4-triazol-3-yl)-2-isopropylphenyl dihydrogen phosphate, or a tautomer, or a pharmaceutically acceptable salt thereof, and the VEGF inhibitor is bevacizumab.

### Claim 23 (depends on 1)

A method of treating a subject with cancer. comprising the steps of: administering to the subject an effective amount of a compound of formulae (I) or (Ia) as defined in claim 1, and (b) admistering to the subject an effect amount of a VEGF inhibitor, wherein the VEGF inhibitor is selected from the group consisting of bevacizumab, sunitinib, or sorafenib.

### Claim 24 (depends on 23)

The method of claim 23, wherein the compound is 3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1-methyl-indol-5-yl)-5-hydroxy-[1,2,4]triazole, or a tautomer or a pharmaceutically acceptable salt thereof and the VEGF inhibitor is bevacizumab.

### Claim 25 (depends on 23)

The method of claim 23, wherein the compound is 5-hydroxy-4-(5-hydroxy-4-(1-methyl-1H-indol-5-yl)-4H-1,2,4-triazol-3-yl)-2-isopropylphenyl dihydrogen phosphate, or a tautomer, or a pharmaceutically acceptable salt thereof, and the VEGF inhibitor is bevacizumab.