# US 11,299,506 B2 · Acylnucleoside phosphonates, prodrugs thereof and use thereof as medicament

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- Number: US 11,299,506 B2
- Document ID: US11299506B2
- Status: Granted
- Kind: B2
- Application number: 16/496,888
- Filed: 2018-03-21
- Published: 2020-04-02
- Granted: 2022-04-12
- Earliest claimed: 2017-03-23
- Assignees: Universite De Montpellier; Centre National De La Recherche Scientifique; Ecole Nationale Superieure De Chimie De Montpellier
- Applicants: Universite De Montpellier; Centre National De La Recherche Scientifique; Ecole Nationale Superieure De Chimie De Montpellier
- Inventors: Suzanne Peyrottes; Christian Perigaud; Sharon Wein-Grataud
- Web page: https://patentgrep.com/patent/US11299506B2

## CPC

- C07F 9/65616: {containing the ring system [IMAGE cpc-sch-C07F-1006.gif] having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs}
- A61K 31/52: Purines, e.g. adenine
- A61K 31/662: Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
- A61K 31/675: having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
- A61K 31/683: Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
- A61P 33/02: Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
- A61P 33/06: Antimalarials
- Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
- 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
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

Chemical compounds are provided belonging to the group of nucleotide analogues. More specifically, acylnucleoside phosphonate compounds are disclosed and also their method of preparation and their use as medicaments, in particular for the prevention and/or the treatment of diseases caused by infection by an organism that is auxotrophic for purines, such as Plasmodium falciparum. Also disclosed are pharmaceutical compositions containing such compounds.

## Claims

### Claim 1

A method for treatment of an infection caused by an organism auxotrophic for purines, said organism being selected from bacteria and protozoans,
wherein said infection is caused by an agent selected from: Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae, Plasmodium ovale, Plasmodium knowlesi, Giardia lamblia, Helicobacter pylori, Mycobacterium tuberculosis, Escherichia coli, Trypanosoma brucei, Babesia divergens, Babesia canis and Toxoplasma gondii, and
wherein said method comprises administering to a subject in need thereof a compound having the following general formula (I):
in which
A represents a heterocycle of formula (IIA) or a heterocycle of formula (IIB), as below:
in which:
W1 represents an oxygen atom or a sulfur atom;
W2 represents a halogen atom, a —OR5 group, a —SR5 group, a —NHR5 group or a —N(R5)2 group;
X1 represents a nitrogen atom or a —CH— group;
X2 represents a nitrogen atom, a —CR1 group or a —C═O group;
X3 represents a nitrogen atom or a —CH— group;
X4 represents a nitrogen atom, a —CR2 group or a —C═O group;
R1 represents:
a hydrogen atom, or
a halogen atom, or
a group selected from:
a —NHR5 group,
a —N(R5)2 group,
a —OR5 group,
a —SR5 group,
a C1-C6 alkyl group,
an aryl group,
a heteroaryl group;
R2 represents:
a hydrogen atom, or
a halogen atom, or
a group selected from:
a —NHR5 group,
a —N(R5)2 group,
a —OR5 group,
a C1-C6 alkyl group,
an aryl group,
a heteroaryl group;
a C2-C6 alkenyl group,
a C2-C6 alkynyl group,
an aryl (C1-C6) alkyl group,
a (C1-C6) alkylaryl group,
a heteroaryl(C1-C6)alkyl group;
R3 and R4, which are identical or different, each represent, independently of one another:
a —OR6 group, or
a —NHR7 group, or
a —N(R7)2 group;
R5 represents:
a hydrogen atom
a C1-C6 alkyl group,
a C2-C6 alkenyl group,
a C2-C6 alkynyl group,
an aryl group,
a C1-C6 acyl group,
an aryl(C1-C6)alkyl group,
said groups optionally containing one or more heteroatoms;
R6 represents:
a hydrogen atom, a sodium atom or a lithium atom, or
a group selected from:
an ammonium group,
a —N(RaRbRcRd)+ group with Ra, Rb, Rc and Rd, which are identical or different, each representing a hydrogen atom or a C1-C4 alkyl group,
an aryl group,
a S—(C1-C12)alkyl-2-dithioethyl group, said alkyl group optionally including at least one heteroatom,
a S—(C1-C12)aryl-2-dithioethyl group, said aryl group optionally including at least one heteroatom,
a S—(C1-C6)acyl-2-thioethyl group, said acyl group optionally including at least one heteroatom,
a (C1-C6)alkyloxy(C1C6)alkyl ester group,
an alkoxy(C1-C6)carbonyloxymethyl ester group,
a C12-C20 alkyl group optionally including at least one heteroatom,
R7 represents:
a C1-C6 alkyl chain,
an aryl group, or
an amino acid residue, an amino acid ester derivative or an amino acid amide derivative;
n is a whole number equal to 0, 1 or 2;
Y represents a substituent selected from: a halogen atom, a —OR5 group, a —SR5 group, a —NHR5 group and a —N(R5)2 group;
C* represents a chiral carbon atom,
or a stereoisomer or pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

The method according to claim 1, in which in formula (I) A represents a purine selected from: guanine, xanthine, hypoxanthine, adenine, 2-aminopurine and 2,6-diaminopurine.

### Claim 3 (depends on 2)

The method according to claim 2, wherein in formula (I):
A represents guanine;
n is equal to 1;
Y represents a hydroxyl group;
the chiral carbon C* has configuration R, and
R3 and R4 each represent an —OR6 group in which R6 is a sodium atom.

### Claim 4 (depends on 1)

The method according to claim 1 wherein said infection is an infection caused by Plasmodium falciparum.

### Claim 5

A compound having the following general formula (I):
in which
A represents a heterocycle having formula (IIA) as below:
in which:
W1 represents an oxygen atom or a sulfur atom;
X1 represents a nitrogen atom or a —CH— group;
X2 represents a nitrogen atom, a —CR1 group or a —C═O group;
X3 represents a nitrogen atom or a —CH— group;
X4 represents a nitrogen atom, a —CR2 group or a —C═O group;
R1 represents:
a hydrogen atom, or
a halogen atom, or
a group selected from:
a —NHR5 group,
a —N(R5)2 group,
a —OR5 group,
a —SR5 group,
a C1-C6 alkyl group,
an aryl group,
a heteroaryl group;
R2 represents:
a hydrogen atom, or
a halogen atom, or
a group selected from:
a —NHR5 group,
a —N(R5)2 group,
a —OR5 group,
a C1-C6 alkyl group,
an aryl group,
a heteroaryl group;
a C2-C6 alkenyl group,
a C2-C6 alkynyl group,
an aryl (C1-C6)alkyl group,
a (C1-C6)alkylaryl group,
a heteroaryl(C1-C6)alkyl group;
R3 and R4, which are identical or different, each represent, independently of one another:
a —OR6 group, or
a —NHR7 group, or
a —N(R7)2 group;
R5 represents:
a hydrogen atom
a C1-C6 alkyl group,
a C2-C6 alkenyl group,
a C2-C6 alkynyl group,
an aryl group,
a C1-C6 acyl group,
an aryl(C1-C6)alkyl group,
said groups optionally containing one or more heteroatoms;
R6 represents:
a hydrogen atom, a sodium atom or a lithium atom, or
a group selected from:
an ammonium group
a —N(RaRbRcRd)+ group with Ra, Rb, Rc and Rd, which are identical or different, each representing a hydrogen atom or a C1-C4 alkyl group,
an aryl group,
a S—(C1-C12)alkyl-2-dithioethyl group, said alkyl group optionally including at least one heteroatom,
a S—(C1-C12)aryl-2-dithioethyl group, said aryl group optionally including at least one heteroatom,
a S—(C1-C6)acyl-2-thioethyl group, said acyl group optionally including at least one heteroatom,
a (C1-C6)alkyloxy(C1C6)alkyl ester group,
an alkoxy(C1-C6)carbonyloxymethyl ester group,
a C12-C20 alkyl group optionally including at least one heteroatom,
R7 represents:
a C1-C6 alkyl chain,
an aryl group, or
an amino acid residue, an amino acid ester derivative or an amino acid amide derivative;
n is a whole number equal to 0, 1 or 2;
Y represents a substituent selected from: a chlorine atom, bromine atom, iodine atom, a —OR5 group, a —SR5 group, a —NHR5 group and a —N(R5)2 group;
C* represents a chiral carbon atom.

### Claim 6 (depends on 5)

The compound according to claim 5, wherein:
W1 represents an oxygen atom;
X1 represents a nitrogen atom;
X2 represents a —CR1 group, R1 representing a hydrogen atom;
X3 represents a nitrogen atom;
X4 represents a —CR2 group with R2 representing a —NH2 group;
n is equal to 1;
Y represents a hydroxyl group;
the chiral carbon C* has configuration R, and
R3 and R4 each represent a —OR6 group in which R6 is a sodium atom.

### Claim 7 (depends on 5)

A pharmaceutical composition including at least one compound according to claim 5, and at least one pharmaceutically acceptable excipient.

### Claim 8 (depends on 7)

The method for treatment of an infection caused by an organism that is auxotrophic for purines, said organism being selected from the bacteria and the protozoa, wherein said infection is caused by an agent selected from: Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae, Plasmodium ovale, Plasmodium knowlesi, Giardia lamblia, Helicobacter pylori, Mycobacterium tuberculosis, Escherichia coli, Trypanosoma brucei, Babesia divergens, Babesia canis and Toxoplasma gondii, and
wherein said method comprises administering to a subject in need thereof a pharmaceutical composition according to claim 7.

### Claim 9 (depends on 6)

A pharmaceutical composition including at least one compound according to claim 6, and at least one pharmaceutically acceptable excipient.

### Claim 10 (depends on 7)

A method for treating malaria caused by Plasmodium falciparum infection, the method comprising administering to a subject in need of treatment the composition of claim 7.

### Claim 11

A pharmaceutical composition including at least one pharmaceutically acceptable excipient, and at least one compound having the following general formula (I):
in which
A represents a heterocycle having formula (IIB) as below:
in which:
W2 represents a halogen atom, a —OR5 group, a —SR5 group, a —NHR5 group or a —N(R5)2 group;
X1 represents a nitrogen atom or a —CH— group;
X2 represents a nitrogen atom, a —CR1 group or a —C═O group;
X3 represents a nitrogen atom or a —CH— group;
X4 represents a nitrogen atom, a —CR2 group or a —C═O group;
R1 represents:
a hydrogen atom, or
a halogen atom, or
a group selected from:
a —NHR5 group,
a —N(R5)2 group,
a —OR5 group,
a —SR5 group,
a C1-C6 alkyl group,
an aryl group,
a heteroaryl group;
R2 represents:
a hydrogen atom, or
a halogen atom, or
a group selected from:
a —NHR5 group,
a —N(R5)2 group,
a —OR5 group,
a C1-C6 alkyl group,
an aryl group,
a heteroaryl group;
a C2-C6 alkenyl group,
a C2-C6 alkynyl group,
an aryl (C1-C6)alkyl group,
a (C1-C6)alkylaryl group,
a heteroaryl(C1-C6)alkyl group;
R3 and R4, which are identical or different, each represent, independently of one another:
a —OR6 group, or
a —NHR7 group, or
a —N(R7)2 group;
R5 represents:
a hydrogen atom
a C1-C6 alkyl group,
a C2-C6 alkenyl group,
a C2-C6 alkynyl group,
an aryl group,
a C1-C6 acyl group,
an aryl(C1-C6)alkyl group,
said groups optionally containing one or more heteroatoms;
R6 represents:
a hydrogen atom, a sodium atom or a lithium atom, or
a group selected from:
an ammonium group
a —N(RaRbRcRd)+ group with Ra, Rb, Rc and Rd, which are identical or different, each representing a hydrogen atom or a C1-C4 alkyl group,
an aryl group,
a S—(C1-C12)alkyl-2-dithioethyl group, said alkyl group optionally including at least one heteroatom,
a S—(C1-C12)aryl-2-dithioethyl group, said aryl group optionally including at least one heteroatom,
a S—(C1-C6)acyl-2-thioethyl group, said acyl group optionally including at least one heteroatom,
a (C1-C6)alkyloxy(C1C6)alkyl ester group,
an alkoxy(C1-C6)carbonyloxymethyl ester group,
a C12-C20 alkyl group optionally including at least one heteroatom,
R7 represents:
a C1-C6 alkyl chain,
an aryl group, or
an amino acid residue, an amino acid ester derivative or an amino acid amide derivative;
n is a whole number equal to 0, 1 or 2;
Y represents a substituent selected from: a chlorine atom, bromine atom, iodine atom, a —OR5 group, a —SR5 group, a —NHR5 group and a —N(R5)2 group;
C* represents a chiral carbon atom,
with the exception of the compounds in which:
W2 represents the —NH2 group;
X1 represents a nitrogen atom;
X2 represents a —CR1 group, R1 representing a hydrogen atom;
X3 represents a nitrogen atom;
X4 represents a —CR2 group, R2 representing a hydrogen atom;
n is equal to 1;
Y represents a hydrogen atom, hydroxyl group or an —NH2 group;
the chiral carbon C* has configuration R or S, and
R3 and R4 each represent a —OR6 group in which R6 is a sodium atom.

### Claim 12 (depends on 11)

A method for treatment of an infection caused by an organism that is auxotrophic for purines, said organism being selected from the bacteria and the protozoa, wherein said infection is caused by an agent selected from: Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae, Plasmodium ovale, Plasmodium knowlesi, Giardia lamblia, Helicobacter pylori, Mycobacterium tuberculosis, Escherichia coli, Trypanosoma brucei, Babesia divergens, Babesia canis and Toxoplasma gondii, and
wherein said method comprises administering to a subject in need thereof a pharmaceutical composition according to claim 11.

### Claim 13 (depends on 11)

A method for treating malaria caused by Plasmodium falciparum infection, the method comprising administering to a subject in need of treatment the composition of claim 11.