# US 2014/0194377 A1 · Salts of Isophosphoramide Mustard and Analogs Thereof

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- Number: US 2014/0194377 A1
- Document ID: US20140194377A1
- Status: Published application
- Kind: A1
- Application number: 14/072,934
- Filed: 2013-11-06
- Published: 2014-07-10
- Earliest claimed: 2007-04-06
- Assignees: ZIOPHARM Oncology, Inc.
- Applicants: Ziopharm Oncology, Inc.
- Inventors: John C. AMEDIO, JR.; Barbara WALLNER; Philip B. KOMARNITSKY
- Web page: https://patentgrep.com/patent/US20140194377A1

## CPC

- C07F 9/22: Amides of acids of phosphorus
- A61K 31/337: having four-membered rings, e.g. taxol
- A61K 31/664: Amides of phosphorus acids
- A61K 31/704: attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin {(digitoxin A61K31/7048)}
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 213/74: Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
- C07F 9/2458: {of aliphatic amines}
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)
- 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

Disclosed herein are crystalline compounds of formula (I) wherein A+ represents a hydroxylated aliphatic ammonium species; and X and Y independently represent leaving groups.

## Claims

### Claim 1

A crystalline compound comprising IPM or an analog thereof, having a structure of formula (I)
wherein A+ is a hydroxylated aliphatic amine or an ammonium species; and
X and Y independently represent leaving groups.

### Claim 2 (depends on 1)

A crystalline compound of claim 1, wherein A+ is selected from selected from mono-,bis- or tris-(2-hydroxyethyl)amine, 2-hydroxy-tert-butylamine, N,N-dimethyl-N-(2-hydroxyethyl)amine, tris(hydroxymethyl)aminomethane (Tris), and the conjugate acid of Tris.

### Claim 3

(canceled)

### Claim 4 (depends on 1)

A crystalline compound of claim 1, wherein X and Y are independently halogen, or wherein X and Y are both Cl.

### Claim at position 5

5-6. (canceled)

### Claim 7 (depends on 1)

A crystalline compound of claim 1, wherein the IPM or analog thereof and the ammonium species are present in a ratio from 2:1 to 1:2 or 1:1.

### Claim 8

(canceled)

### Claim 9 (depends on 1)

A crystalline compound of claim 1, wherein the melting point of the crystalline compound is about 103 to about 106° C. or is 105 to 106° C.

### Claim 10

(canceled)

### Claim 11 (depends on 1)

A crystalline compound of claim 1, wherein the crystalline compound comprises a single polymorphic form of crystals.

### Claim at position 11

12-19. (canceled)

### Claim 20 (depends on 1)

A method for treating a hyperproliferative disorder, comprising administering a crystalline compound of claim 1.

### Claim 21 (depends on 20)

A method of claim 20, wherein the hyperproliferative disorder is selected from acute leukemias, chronic leukemias, polycythemia vera, lymphoma, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, Waldenstrom's macroglobulinemia, heavy chain disease, myelodysplastic syndrome, hairy cell leukemia, myelodysplasia, sarcomas and carcinomas, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, lymphoid malignancy, pancreatic cancer, breast cancer, lung cancers, ovarian cancer, prostate cancer, hepatocellular carcinoma, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, Wilms' tumor, cervical cancer, testicular tumor, bladder carcinoma, and CNS tumors.

### Claim 22

A lyophilisate comprising IPM or an analog thereof, having a structure of formula (I)
wherein A+ is a hydroxylated aliphatic ammonium counterion or an ammonium species; and
X and Y independently represent leaving groups.

### Claim 23 (depends on 22)

A lyophilisate of claim 22, wherein A+ represents a protonated amine selected from selected from mono-, bis- or tris-(2-hydroxyethyl)amine, 2-hydroxy-tert-butylamine, N,N-dimethyl-N-(2-hydroxyethyl)amine, tris(hydroxymethyl)aminomethane (Tris), and the conjugate acid of Tris.

### Claim 24

(canceled)

### Claim 25 (depends on 22)

A lyophilisate of claim 22, wherein X and Y are independently halogen, or wherein X and Y are both Cl.

### Claim at position 18

26-27. (canceled)

### Claim 28 (depends on 22)

A lyophilisate of claim 22, wherein the lyophilisate further comprises an excipient.

### Claim 29 (depends on 22)

A lyophilisate of claim 22,
wherein A+ represents an ammonium species selected from the protonated (conjugate acid) or quaternary forms of aliphatic amines and aromatic amines, including basic amino acids, heterocyclic amines, substituted and unsubstituted pyridines, guanidines and amidines.

### Claim at position 21

30-32. (canceled)

### Claim 33

A pharmaceutical composition adapted for oral administration, comprising a pharmaceutically acceptable diluent or excipient and a compound of the formula
wherein A+ represents a hydroxylated aliphatic ammonium counterion or an ammonium species; and
X and Y independently represent leaving groups.

### Claim at position 23

34-36. (canceled)

### Claim 37 (depends on 33)

A pharmaceutical composition of claim 33, wherein A+ represents a protonated amine selected from selected from mono-, bis- or tris-(2-hydroxyethyl)amine, 2-hydroxy-tert-butylamine, N,N-dimethyl-N-(2-hydroxyethyl)amine, tris(hydroxymethyl)aminomethane (Tris), and the conjugate acid of Tris.

### Claim at position 25

38-44. (canceled)

### Claim 45 (depends on 1)

A method of improving the efficacy of a chemotherapeutic agent, comprising administering the chemotherapeutic agent in combination with a compound of claim 1.

### Claim 46 (depends on 45)

A method of claim 45, wherein the chemotherapeutic agent is selected from docetaxel and doxorubicin.

### Claim at position 28

47-49. (canceled)

### Claim 50 (depends on 28)

A lyophilisate of claim 28, wherein the excipient is mannitol.

### Claim 51 (depends on 33)

A pharmaceutical composition adapted for oral administration of claim 33, wherein A+ represents an ammonium species selected from the protonated (conjugate acid) or quaternary forms of aliphatic amines and aromatic amines, including basic amino acids, heterocyclic amines, substituted and unsubstituted pyridines, guanidines and amidines