# US 9,000,135 B2 · Self-reactive arms and prodrugs comprising same

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- Number: US 9,000,135 B2
- Document ID: US9000135B2
- Status: Granted
- Kind: B2
- Application number: 13/699,173
- Filed: 2011-05-18
- Published: 2013-06-06
- Granted: 2015-04-07
- Earliest claimed: 2010-05-20
- Assignees: Centre Nationale De Recherche Scientifique; Universite De Poitiers
- Applicants: Sebastien Papot; Mickael Thomas
- Inventors: Sebastien Papot; Mickael Thomas
- Web page: https://patentgrep.com/patent/US9000135B2

## CPC

- A61K 47/549: {Sugars, nucleosides, nucleotides or nucleic acids}
- A61K 47/551: {one of the codrug's components being a vitamin, e.g. niacinamide, vitamin B3, cobalamin, vitamin B12, folate, vitamin A or retinoic acid}
- 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
- C07C 205/22: having one nitro groups bound to the ring
- C07D 475/04: with a nitrogen atom directly attached in position 2
- C07H 15/203: Monocyclic carbocyclic rings other than cyclohexane rings; Bicyclic carbocyclic ring systems
- C07H 15/252: Naphthacene radicals, e.g. daunomycins, adriamycins
- 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
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C07H: SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS (derivatives of aldonic or saccharic acids C07C, C07D; aldonic acids, saccharic acids C07C59/105, C07C59/285; cyanohydrins C07C255/16; glycals C07D; compounds of unknown constitution C07G; polysaccharides, derivatives thereof C08B; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification C12N15/00; sugar industry C13)

## Abstract

The present invention relates to a compound of general formula (I): in which: X is OH, NH2, NHOH or RNH, where R may be a linear or branched, saturated or unsaturated, C1-C10 alkyl radical, Y is H, or an electron-withdrawing group, in particular selected from NO2, CF3 or a halogen, R1 and R2 are H or a linear or branched, saturated or unsaturated, C1-C10 alkyl radical, F is a reactive functional group that can be activated by click chemistry.

## Claims

### Claim 1

A compound having a general formula (I):
wherein:
X is OH, NH2, NHOH or R′NH wherein R′ is a linear or branched, saturated or unsaturated, C1 to C10 alkyl radical,
Y is an electron-withdrawing group,
R1 and R2, independently of one another, are H or a linear or branched, saturated or unsaturated, C1 to C10 alkyl radical,
F is a reactive function group activable by click chemistry.

### Claim 2 (depends on 1)

The compound as claimed in claim 1, wherein X is OH.

### Claim 3 (depends on 1)

The compound as claimed in claim 1, wherein Y is NO2.

### Claim 4 (depends on 1)

The compound as claimed in claim 1, wherein R1 and R2 are H.

### Claim 5 (depends on 1)

The compound as claimed in claim 1, wherein F is —C≡CR′″, —N3, —SH, —C═CH2, cyclooctynes, maleimide, —SO2N3, or —COSR′″, wherein R′″ is H or a linear or branched, saturated or unsaturated, C1 to C10 alkyl radical.

### Claim 6 (depends on 1)

A compound having a general formula (II):
wherein:
R1 and R2 are as claimed in claim 1,
Y is an electron-withdrawing group,
X′ is O, NH, NOH, R′N wherein R′ is as claimed in claim 1,
E is a labile group linked to X′ by a carboxyl group or an ether bond,
A is O, S, NH, NR″ wherein R″ is a linear or branched, saturated or unsaturated, C1 to C10 alkyl group,
D is an active compound usable in therapy or diagnosis,
n=0 or 1, and Z is a linear or branched, saturated or unsaturated, C1-C10 alkylene group optionally interrupted by one or more heteroatoms selected from the group consisting of O or N, a glycosyl group, an O—(CHR3—CHR4—O—)m or N—(CHR3—CHR4—O—)m group in which m is a natural integer varying from 1 to 20, R3 and R4, independently of one another, are H or CH3, provided that R3 and R4 are not simultaneously CH3, a group coming from an amino acid or from a peptide, and a combination thereof,
L is a targeting ligand selected from the group consisting of a peptide, a protein, an antibody or an antibody fragment recognizing an antigen, a ligand of a cellular receptor, a biopolymer, a monosaccharide, an oligosaccharide, a hormone, a vitamin, a dendrimer, a polyamine, and a nanoparticle,
G is a group resulting from a click chemistry reaction between an F group, as claimed in claim 1, and an x-(Z)n-L group wherein Z and L are as claimed above and x is a reactive function group activable by click chemistry and capable of reacting with F, or a pharmaceutically acceptable salt thereof.

### Claim 7 (depends on 6)

The compound as claimed in claim 6, wherein Y is NO2 in the ortho position of X′, and R1 and R2 are H.

### Claim 8 (depends on 6)

The compound as claimed claim 6, wherein D is a compound having therapeutic activity.

### Claim 9 (depends on 6)

The compound as claimed in claim 6, wherein D comprises an active compound or a plurality of active compounds.

### Claim 10 (depends on 6)

The compound as claimed in claim 6, wherein the labile group E is a substrate of glucuronidases.

### Claim 11 (depends on 6)

The compound as claimed in claim 6, wherein L is a ligand of a cellular receptor.

### Claim 12 (depends on 6)

The compound as claimed in claim 6, wherein n=1 and Z is a C1-C5 alkylene group.

### Claim 13 (depends on 6)

The compound as claimed in claim 6, wherein n=1 and Z is a glycosyl group selected from the group consisting of a glucosyl group, a galactosyl group, a malmosyl group, and a lactosyl group.

### Claim 14 (depends on 6)

The compound as claimed in claim 6, wherein n=1 and Z is a O—(CHR3—CHR4—O—)m or N—(CHR3—CHR4—O—)m group wherein in is a natural integer varying from 2 to 18.

### Claim 15 (depends on 6)

The compound as claimed in claim 6, wherein n=1 and Z is a group coming from an amino acid or from a peptide.

### Claim 16 (depends on 6)

The compound as claimed in claim 6, wherein n=1 and Z is a combination of a glycosyl group and a O—(CHR3—CHR4—O—)m or N—(CHR3—CHR4—O—)m group.

### Claim 17 (depends on 6)

The compound as claimed in claim 6, wherein n=0.

### Claim 18 (depends on 6)

A method for preparing a compound as claimed in claim 6, comprising providing a compound having the general formula (I):
wherein:
X is OH, NH2, NHOH or R′NH wherein R′ is a linear or branched, saturated or unsaturated, C1 to C10 alkyl radical,
Y is an electron-withdrawing group,
R1 and R2 are H or a linear or branched, saturated or unsaturated, C1 to C10 alkyl radical,
F is a reactive function group activable by click chemistry,
to react with D-v, E-w, and L-(Z)n-x groups, wherein D, E and L and Z are as claimed in claim 6, and v, w and x are each a reactive function group such that, with regard to the compound having the general formula (I), v reacts with OH linked to the benzyl carbon, or said previously activated OH, w reacts with X, and x reacts with F.

### Claim 19 (depends on 18)

The method as claimed in claim 18, wherein v is selected from the group consisting of NH2, NHR″, OH, and SH.

### Claim 20 (depends on 18)

The method as claimed in claim 18, wherein w is a halide radical.

### Claim 21 (depends on 18)

The method as claimed in claim 18 wherein x and F are selected from the group consisting of following pairs of reactive function groups activable by click chemistry, (—N3, —C≡CR′″), (—SH, —C═CH2), (—N3, cyclooctynes), (—SH, maleimide), and (—SO2N3, —COSR′″), wherein R′″ is H or a linear or branched, saturated or unsaturated, C1 to C10 alkyl radical.

### Claim 22 (depends on 18)

A compound or a pharmaceutically acceptable salt thereof, obtainable by the method as claimed in claim 18.

### Claim 23 (depends on 6)

A pharmaceutical or diagnostic composition comprising at least an effective quantity of at least one compound having the general formula (II) as claimed in claim 6, or a pharmaceutically acceptable salt thereof.

### Claim 24 (depends on 23)

The pharmaceutical composition as claimed in claim 23, wherein the compound has the general formula (II), or a pharmaceutically acceptable salt thereof, wherein the active compound D is an active anti-cancer compound, and the composition is intended for a prevention and/or treatment of a cancer.

### Claim 25 (depends on 6)

A kit for preparing a compound having the general formula (II) as claimed in claim 6, or a pharmaceutically acceptable salt thereof, comprising at least one compound having the general formula (I):
wherein:
X is OH, NH2, NHOH or R′NH wherein R′ is a linear or branched, saturated or unsaturated, C1 to C10 alkyl radical,
Y is an electron-withdrawing group,
R1 and R2 are H or a linear or branched, saturated or unsaturated, C1 to C10 alkyl radical,
F is a reactive function group activable by click chemistry,
and at least one selected from the group consisting of D-v, E-w, and L-(Z)n-x, wherein L, Z, n, D and E are as claimed in claim 6, and v, w and x are each a reactive function group such that with regard to the compound having the general formula (I) and the D-v, E-w, and L-(Z)n-x being conditioned separately.

### Claim 26 (depends on 1)

The compound as claimed in claim 1, wherein Y is NO2, CF3, or a halogen group.