# US 8,772,543 B2 · Antiproliferative compounds, conjugates thereof, methods therefor, and uses thereof

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- Number: US 8,772,543 B2
- Document ID: US8772543B2
- Status: Granted
- Kind: B2
- Application number: 13/752,721
- Filed: 2013-01-29
- Published: 2013-08-08
- Granted: 2014-07-08
- Earliest claimed: 2009-08-03
- Assignees: Medarex, Inc.
- Applicants: Medarex, Inc.
- Inventors: Heng Cheng; Sanjeev Gangwar; Qiang Cong; Qian Zhang
- Web page: https://patentgrep.com/patent/US8772543B2

## CPC

- C07K 7/06: having 5 to 11 amino acids
- A61K 38/06: Tripeptides
- A61K 47/6811: {the drug being a protein or peptide, e.g. transferrin or bleomycin}
- A61K 47/6829: {Bacterial toxins, e.g. diphteria toxins or Pseudomonas exotoxin A}
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 35/04: specific for metastasis
- C07C 229/14: to carbon atoms of carbon skeletons containing rings
- C07C 229/16: to carbon atoms of hydrocarbon radicals substituted by amino or carboxyl groups, e.g. ethylenediamine-tetra-acetic acid, iminodiacetic acids
- C07K 5/021: {containing the structure -NH-(X)n-C(=0)-, n being 5 or 6; for n > 6, classification in C07K5/06 - C07K5/10, according to the moiety having normal peptide bonds}
- C07K 5/06139: {with the first amino acid being heterocyclic}
- C07K 5/10: Tetrapeptides
- C07K 16/18: against material from animals or humans
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- 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
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS

## Abstract

Antiproliferative compounds having a structure represented by formula (II), where n, R1, R2, R3, R4, and R5 are as defined herein, can be used to treat tumors, optionally when conjugated to a ligand such as an antibody:

## Claims

### Claim 1

A compound having a structure according to formula (VIII-b)
wherein R9 and R10 are independently H or an amine protecting group and R11 is H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, aryl, cycloaliphatic, alkylcycloaliphatic, arylalkyl, or alkylaryl.

### Claim 2 (depends on 1)

A compound according to claim 1, wherein R9 and R10 are independently selected from H, Boc (t-butoxycarbonyl), Troc (2,2,2-trichloroethoxy carbonyl), Bpoc (1-methyl-1-(4-biphenyl)ethoxycarbonyl), Cbz (benzyloxy carbonyl), Aloc (allyloxycarbonyl), methylamine, and Fmoc (9-flurenylmethoxycarbonyl).

### Claim 3 (depends on 2)

A compound according to claim 2, wherein R11 is H or C1-C5 alkyl.

### Claim 4 (depends on 3)

A compound according to claim 3, wherein R11 is Me.

### Claim 5 (depends on 1)

A compound according to claim 1, wherein R11 is H or C1-C5 alkyl.

### Claim 6 (depends on 5)

A compound according to claim 5, wherein R11 is Me.

### Claim 7 (depends on 1)

A compound according to claim 1, wherein R9 and R10 are different amine protecting groups.

### Claim 8 (depends on 7)

A compound according to claim 7, wherein R11 is H or C1-C5 alkyl.

### Claim 9 (depends on 8)

A compound according to claim 8, wherein R11 is Me.

### Claim 10 (depends on 1)

A compound according to claim 1, having a structure represented by the formula:

### Claim 11 (depends on 1)

A compound according to claim 1, having a structure represented by the formula

### Claim 12 (depends on 1)

A compound according to claim 1, having a structure represented by the formula

### Claim 13 (depends on 1)

A compound according to claim 1, having a structure represented by the formula

### Claim 14 (depends on 1)

A compound according to claim 1, having a structure represented by the formula

### Claim 15 (depends on 1)

A compound according to claim 1, having a structure represented by the formula