# US 10,870,662 B2 · Alpha-amino pateamine A derivatives and methods for treating chronic lymphocytic leukemia

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- Number: US 10,870,662 B2
- Document ID: US10870662B2
- Status: Granted
- Kind: B2
- Application number: 16/555,741
- Filed: 2019-08-29
- Published: 2019-12-19
- Granted: 2020-12-22
- Earliest claimed: 2015-03-31
- Assignees: The Texas A&M University System
- Applicants: The Texas A&M University System
- Inventors: Daniel Romo; Ken Hull; Mingzhao Zhu; Omar Robles
- Web page: https://patentgrep.com/patent/US10870662B2

## CPC

- C07D 513/08: Bridged systems
- A61K 47/6803: {Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates}
- A61K 47/6867: {the tumour determinant being from a cell of a blood cancer}
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- 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)

## Abstract

Pateamine A derivatives and pharmaceutical compositions that include the derivatives. The pateamine A derivatives are α-amino pateamine A derivatives that lack the C5-methyl group of pateamine A.

## Claims

### Claim 1

A compound having the formula:
or a stereoisomer, racemate, or a pharmaceutically acceptable salt thereof,
wherein
Z is selected from R and OR′,
wherein R is selected from C1-C6 alkyl, C1-C6 haloalkyl, C6-C10 aryl, and C3-C12 alkyl groups in which one or more carbons are replaced with O, NH, or N(CH3), and
wherein R1 is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C6-C10 aryl, and C3-C12 alkyl groups in which one or more carbons are replaced with O, NH, or N(CH3).

### Claim 2 (depends on 1)

A compound of claim 1 having the formula:
or a pharmaceutically acceptable salt thereof,
wherein
Z is selected from R and OR1,
wherein R is selected from C1-C6 alkyl, C1-C6 haloalkyl, C6-C10 aryl, and C3-C12 alkyl groups in which one or more carbons are replaced with O, NH, or N(CH3), and
wherein R1 is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C6-C10 aryl, and C3-C12 alkyl groups in which one or more carbons are replaced with O, NH, or N(CH3).

### Claim 3 (depends on 1)

The compound of claim 1 having the formula:
wherein A− is a pharmaceutically acceptable counter ion.

### Claim 4 (depends on 2)

The compound of claim 2 having the formula:
wherein A− is a pharmaceutically acceptable counter ion.

### Claim 5 (depends on 3)

The compound of claim 3, wherein A− is selected from the group consisting of chloride, bromide, iodide, sulfate, phosphate, formate, acetate, trifluoroacetate, maleate, fumarate, succinate, tartrate, oxalate, citrate, malate, benzoate, toluenesulfonate, methanesulfonate, and benzenesulfonate.

### Claim 6 (depends on 1)

The compound of claim 1, wherein Z is C1-C6 alkyl.

### Claim 7 (depends on 1)

The compound of claim 1, wherein Z is methyl.

### Claim 8 (depends on 1)

The compound of claim 1, wherein Z is C1-C6 haloalkyl.

### Claim 9 (depends on 1)

The compound of claim 1, wherein Z is trifluoromethyl.

### Claim 10 (depends on 1)

The compound of claim 1, wherein Z is C6-C10 aryl.

### Claim 11 (depends on 1)

The compound of claim 1, wherein Z is phenyl.

### Claim 12 (depends on 1)

The compound of claim 1, wherein Z is C3-C12 alkyl in which one or more carbons are replaced with O, NH, or N(CH3).

### Claim 13 (depends on 1)

The compound of claim 1, wherein Z is selected from CH2—O—CH3, CH2CH2—O—CH3, and —CH2CH2—O—CH2CH2—O—CH3.

### Claim 14 (depends on 1)

The compound of claim 1, wherein Z is selected from —CH2—NH—CH3, —CH2—N(CH3)2, —CH2CH2—NH—CH3, and —CH2CH2—N(CH3)2.

### Claim 15 (depends on 1)

A pharmaceutical composition, comprising a compound of claim 1, or a stereoisomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

### Claim 16 (depends on 1)

An antibody conjugate for the delivery of an α-amino pateamine derivative, comprising a compound of claim 1, or a stereoisomer or a pharmaceutically acceptable salt thereof, covalently coupled directly or through a linker unit to an antibody or functional fragment thereof, wherein the functional fragment is selected from the group consisting of Fab, Fab′, F(ab′)2, and Fv fragments; linear antibodies; single-chain antibody molecules; an scFv; an IgG ΔCH2, a minibody, a diabody, a triabody, a tetrabody, a dsFv; an sc-Fv-Fc; an (scFv)2; a fragment produced by a Fab expression library; an anti-idiotypic (anti-Id) antibody; and multispecific antibodies formed from antibody fragment(s).

### Claim 17 (depends on 16)

A pharmaceutical composition, comprising the antibody conjugate of claim 16 and a pharmaceutically acceptable carrier.

### Claim 18 (depends on 1)

A method for inhibiting growth of chronic lymphocytic leukemia (CLL) cells, comprising contacting CLL cells with a compound of claim 1, or a stereoisomer or a pharmaceutically acceptable salt thereof.

### Claim 19 (depends on 16)

A method for inhibiting growth of chronic lymphocytic leukemia (CLL) cells, comprising contacting CLL cells with an antibody conjugate of claim 16.

### Claim 20 (depends on 1)

A method for treating chronic lymphocytic leukemia (CLL), comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1, or a stereoisomer or a pharmaceutically acceptable salt thereof.

### Claim 21 (depends on 16)

A method for treating chronic lymphocytic leukemia (CLL), comprising administering to a subject in need thereof a therapeutically effective amount of a compound an antibody conjugate of claim 16.