# US 10,307,434 B2 · Nucleic acid prodrugs and methods of use thereof

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- Number: US 10,307,434 B2
- Document ID: US10307434B2
- Status: Granted
- Kind: B2
- Application number: 15/167,669
- Filed: 2016-05-27
- Published: 2016-12-01
- Granted: 2019-06-04
- Earliest claimed: 2009-07-06
- Assignees: Wave Life Sciences Ltd.
- Applicants: Wave Life Sciences Ltd.
- Inventors: Gregory L. Verdine; Meena; Naoki Iwamoto
- Web page: https://patentgrep.com/patent/US10307434B2

## CPC

- A61K 31/70: Carbohydrates; Sugars; Derivatives thereof (sorbitol A61K31/047)
- A61P 1/18: for pancreatic disorders, e.g. pancreatic enzymes
- A61P 3/02: Nutrients, e.g. vitamins, minerals
- A61P 35/00: Antineoplastic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07F 9/65515: {the oxygen atom being part of a five-membered ring}
- C07H 21/00: Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
- 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
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)
- 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

Described herein are nucleic acid prodrugs and nucleic acid prodrugs comprising chiral phosphorous moieties. Also described herein are methods of making and using nucleic acid prodrugs and nucleic acid prodrugs comprising chiral phosphorous moieties.

## Claims

### Claim 1

An oligonucleotide composition comprising a plurality of oligonucleotides of the following structure:
wherein:
each X-phosphonate independently has an Rp or Sp configuration;
R1 is —OH, or —ORa;
Ra is a blocking group;
each instance of R2 is independently hydrogen, —OH, -halogen, or —ORb, wherein Rb is a blocking group;
each instance of Ba is independently a blocked or unblocked adenine, cytosine, guanine, thymine, uracil or modified nucleobase, wherein each modified nucleobase is independently adenine, cytosine, guanine, thymine or uracil, modified by one or more modifications:
(1) a nucleobase is modified by one or more groups independently selected from acyl, halogen, amino, azide, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, heteroaryl, carboxyl, hydroxyl, biotin, avidin, streptavidin, substituted silyl, and combinations thereof;
(2) one or more atoms of a nucleobase are independently replaced with a different atom selected from carbon, nitrogen or sulfur;
(3) one or more double bonds in a nucleobase are independently hydrogenated; or
(4) one or more aryl or heteroaryl rings are independently inserted into a nucleobase; or is independently selected from uracil, thymine, adenine, cytosine, and guanine having their respective amino groups protected by acyl groups, 2-fluorouracil, 2-fluorocytosine, 5-bromouracil, 5-iodouracil, 2,6-diaminopurine, azacytosine, pseudoisocytosine, pseudouracil, 8-substituted purines, xanthine, hypoxanthine;
or a modified nucleobase is a group selected from one of the following groups:
(1)
(2) corrin or porphyrin, each optionally modified by one or more groups independently selected from acyl, halogen, amino, azide, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, heteroaryl, carboxyl, hydroxyl, biotin, avidin, streptavidin, substituted silyl, and combinations thereof;
(3) phenanthrene, pyrene, stillbene, isoxanthine, isozanthopterin, terphenyl, terthiophene, benzoterthiophene, coumarin, lumazine, tethered stillbene, benzo-uracil, or naphtho-uracil, each optionally modified by one or more groups independently selected from acyl, halogen, amino, azide, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, heteroaryl, carboxyl, hydroxyl, biotin, avidin, streptavidin, substituted silyl, and combinations thereof;
(4) 3-nitropyrrole, 5-bromouracil, 5-iodouracil, or 2,6-diaminopurine, or a nucleobase of 4-acetylcytidine; 5-(carboxyhydroxylmethyl)uridine; 2′-O-methylcytidine; 5-carboxymethylaminomethyl-2-thiouridine; 5-carboxymethylaminomethyluridine; dihydrouridine; 2′-O-methylpseudouridine; beta,D-galactosylqueosine; 2′-O-methylguanosine; N6-isopentenyladenosine; 1-methyladenosine; 1-methylpseudouridine; 1-methylguanosine; 1-methylinosine; 2,2-dimethylguanosine; 2-methyladenosine; 2-methylguanosine; N7-methylguanosine; 3-methyl-cytidine; 5-methylcytidine; N6-methyladenosine; 7-methylguanosine; 5-methylaminoethyluridine; 5-methoxyaminomethyl-2-thiouridine; beta,D-mannosylqueosine; 5-methoxycarbonylmethyluridine; 5-methoxyuridine; 2-methylthio-N6-isopentenyladenosine; N-((9-beta,D-ribofuranosyl-2-methylthiopurine-6-yl)carbamoyl)threonine; N-((9-beta,D-ribofuranosylpurine-6-yl)-N-methylcarbamoyl)threonine; uridine-5-oxyacetic acid methylester; uridine-5-oxyacetic acid (v); pseudouridine; queosine; 2-thiocytidine; 5-methyl-2-thiouridine; 2-thiouridine; 4-thiouridine; 5-methyluridine; 2′-O-methyl-5-methyluridine; or 2′-O-methyluridine; and
(5) heteroaryl or heterocyclyl optionally substituted with one or more groups independently selected from acyl, halogen, amino, azide, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, heteroaryl, carboxyl, hydroxyl, biotin, avidin, streptavidin, substituted silyl, and combinations thereof;
at least one X moiety is selected from —OCH2CH2S—S(O)2R10, OCH2CH2S—SCH2CH2OH, —OCH2CH2CO2H,
wherein:
R8 is a linear or branched alkyl, aryl, aralkyl, or aryloxylalkyl group having 1 to 15 carbon atoms,
R9 is an alkyl group having 1 to 4 carbon atoms;
R10 is an alkyl group having 1 to 4 carbon atoms;
R11 is alkyl, aryl, heteroaryl, heterocyclyl, or cycloalkyl;
R12 is hydrogen or alkyl;
R3 is hydrogen, a blocking group, a linking moiety connected to a solid support or a linking moiety connected to a nucleic acid;
n is an integer of 10 to about 200; and
the composition is stereodefined.

### Claim 2 (depends on 1)

The composition of claim 1, wherein the composition is stereodefined in that each X-phosphonate moiety is more than 98% diastereomerically pure within the composition as determined by 31P NMR spectroscopy or reverse-phase HPLC.

### Claim 3 (depends on 1)

The composition of claim 1, wherein at least one instance of X is selected from

### Claim 4 (depends on 1)

The composition of claim 1, wherein at least 25% of the X moieties are independently selected from

### Claim 5 (depends on 1)

The composition of claim 1, wherein each X moiety is independently selected from

### Claim 6 (depends on 1)

The composition of claim 1, wherein n is an integer of 15 to about 200.

### Claim 7 (depends on 1)

The composition of claim 1, wherein n is an integer of 20 to about 200.

### Claim 8 (depends on 1)

The composition of claim 1, wherein R1 is —OH.

### Claim 9 (depends on 1)

The composition of claim 1, wherein each instance of R2 is independently hydrogen, halogen, or —ORb.

### Claim 10 (depends on 8)

The composition of claim 8, wherein each instance of R2 is independently hydrogen, halogen, or —ORb.

### Claim 11 (depends on 8)

The composition of claim 8, wherein at least one R2 is hydrogen.

### Claim 12 (depends on 8)

The composition of claim 8, wherein at least one R2 is halogen.

### Claim 13 (depends on 8)

The composition of claim 8, wherein at least one R2 is —ORb.

### Claim 14 (depends on 12)

The composition of claim 12, wherein Rb is methyl.

### Claim 15 (depends on 1)

The composition of claim 1, wherein R3 is hydrogen.

### Claim 16 (depends on 10)

The composition of claim 10, wherein R3 is hydrogen.

### Claim 17 (depends on 1)

The composition of claim 1, wherein each instance of Ba is independently a blocked or unblocked adenine, cytosine, guanine, thymine, uracil or 5-methylcytosine.

### Claim 18 (depends on 8)

The composition of claim 8, wherein each instance of Ba is independently a blocked or unblocked adenine, cytosine, guanine, thymine, uracil or 5-methylcytosine.

### Claim 19 (depends on 10)

The composition of claim 10, wherein each instance of Ba is independently a blocked or unblocked adenine, cytosine, guanine, thymine, uracil or 5-methylcytosine.

### Claim 20 (depends on 16)

The composition of claim 16, wherein each instance of Ba is independently a blocked or unblocked adenine, cytosine, guanine, thymine, uracil or 5-methylcytosine.