# US 11,897,911 B2 · Nucleotide precursors, nucleotide analogs and oligomeric compounds containing the same

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- Number: US 11,897,911 B2
- Document ID: US11897911B2
- Status: Granted
- Kind: B2
- Application number: 16/978,603
- Filed: 2019-03-06
- Published: 2021-04-22
- Granted: 2024-02-13
- Earliest claimed: 2018-03-07
- Assignees: Sanofi
- Applicants: Sanofi
- Inventors: Armin Hofmeister; Kerstin Jahn-Hofmann
- Web page: https://patentgrep.com/patent/US11897911B2

## CPC

- A61P 35/00: Antineoplastic agents
- C07F 9/65583: {each of the hetero rings containing nitrogen as ring hetero atom}
- C07D 405/04: directly linked by a ring-member-to-ring-member bond
- C07D 413/04: directly linked by a ring-member-to-ring-member bond
- C07F 9/6533: Six-membered rings
- C07F 9/6552: {the oxygen atom being part of a six-membered ring}
- C07F 9/65586: {at least one of the hetero rings does not contain nitrogen as ring hetero atom}
- 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}
- C07H 15/26: Acyclic or carbocyclic radicals, substituted by hetero rings
- 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
- C07H 21/02: with ribosyl as saccharide radical
- Y02P 20/55: Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
- 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)
- 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)
- Y02P: CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS

## Abstract

The present disclosure relates to novel nucleotide precursors and nucleotide analogs that can be incorporated into oligonucleotides, including double-stranded oligonucleotides such as siRNAs. Oligonucleotides containing these analogs have superior biological activity, for example, increased in vitro stability and improved in vivo potency especially duration of action. The improved oligonucleotides are useful for silencing (e.g., reducing or eradicating) the expression of a target gene. In particular embodiments, this invention encompasses specific nucleotide analogs to be included in double-stranded RNAs (dsRNAs), and especially in siRNAs, that can hybridize to messenger RNAs (mRNAs) of interest, so as to reduce or block the expression of target genes of interest. The present compounds have general formula (I), wherein each of Ra, Rb, Rc and Rd is independently, H or a (C1-C6) alkyl group and B is a heterocyclic nucleobase.

## Claims

### Claim 1

A compound of formula (I):
wherein:
B is a heterocyclic nucleobase;
P1 and P2 are each, independently, H, a reactive phosphorus group or a protecting group;
Y is O, NH, NR1 or N—C(═O)—R1, wherein R1 is:
a (C1-C20) alkyl group,
a (C3-C8) cycloalkyl group, or
a group —[C(═O)]m-R2-(O—CH2-CH2)p-R3, wherein:
m is an integer of 0 or 1,
p is an integer ranging from 0 to 10,
R2 is a (C1-C20) alkylene group,
and
R3 is selected from the group consisting of a hydrogen atom, a (C1-C6) alkyl group, a (C1-C6) alkoxy group, a (C3-C8) cycloalkyl group, a (C3-C14) heterocycle, a (C6-C14) aryl group, and a (C5-C14) heteroaryl group,
or
R3 is a cell targeting moiety,
X1 and X2 are each, independently, a hydrogen atom, or a (C1-C6) alkyl group, and
each of Ra, Rb, Rc and Rd is, independently, H or a (C1-C6) alkyl group.

### Claim 2 (depends on 1)

The compound of formula (I) according to claim 1, wherein Y is NR1, and wherein R1 is a (C1-C20) alkyl group or a (C3-C8) cycloalkyl group, and P1, P2, Ra, Rb, Rc, Rd, X1, X2 and B are as defined for the general formula (I).

### Claim 3 (depends on 1)

The compound of formula (I) according to claim 1, wherein Y is N—C(═O)—R1, and wherein R1 is a (C1-C20) alkyl group,
and P1, P2, Ra, Rb, Rc, Rd, X1, X2 and B have the same meaning as defined for the general formula (I).

### Claim 4 (depends on 1)

The compound of formula (I) according to claim 1, wherein Y is NR1 with R1 being —[C(═O)]m-R2-(O—CH2-CH2)p-R3, wherein:
m is an integer of 0 or 1,
p is an integer ranging from 0 to 10,
R2 is a (C1-C20) alkylene group,
and
R3 is a cell targeting moiety,
X1 and X2 are each, independently, a hydrogen atom, or a (C1-C6) alkyl group, and
each of Ra, Rb, Rc and Rd is, independently, H or a (C1-C6) alkyl group.

### Claim 5 (depends on 4)

The compound of formula (I) according to claim 4, wherein R1 is the group —[C(═O)]m-R2-(O—CH2-CH2)p-R3, m is 0, p is 0, 1, 2, 3 or 4, R3 is a cell targeting moiety, B, P1, P2, Ra, Rb, Rc, Rd, X1, X2, and R2 are as in the general definition of the compound of formula (I).

### Claim 6 (depends on 4)

The compound of formula (I) according to claim 4, wherein:
R2 is an ethylene group, p is 0, or
R2 is a pentylene group, or
R2 is a (C12) alkylene group,
and X1 and X2 are both an hydrogen atom.

### Claim 7 (depends on 4)

The compound of formula (I) according to claim 4, wherein R2 is an ethylene group, p is 1, 2, 3, or 4, and X1 and X2 are both an hydrogen atom.

### Claim 8 (depends on 4)

The compound of formula (I) according to claim 4, wherein m is 1, p is 0, 1, or 2, R3 is a cell targeting moiety, and R2, B, P1, P2, Ra, Rb, Rc, Rd, X1, X2, are as in the general definition of the compound of formula (I).

### Claim 9 (depends on 8)

The compound of formula (I) according to claim 8, wherein R2
is a butylene,
a (C11) alkylene, or
a methylene; wherein
X1 and X2 both represent a hydrogen atom,
and B, P1, P2, Ra, Rb, Rc and Rd are as defined for the general formula (I).

### Claim 10 (depends on 4)

The compound of formula (I) according to claim 4, wherein R2 is a methylene group, p is 1 or 2, R3 is a cell targeting moiety, and B, P1, P2, Ra, Rb, Rc, Rd, X1, X2 are as defined for the general formula (I).

### Claim 11 (depends on 4)

The compound of formula (I) according to claim 4, wherein R3 is a compound of formula (III):
wherein A1, A2 and A3 are O—C(═O)—R4, wherein R4 is a (C1-C6) alkyl or a (C6-C10) aryl group;
A4 is O—C(═O)—R4 or NHC(═O)—R5, wherein R4 is defined as above and R5 is a (C1-C6) alkyl group.

### Claim 12 (depends on 11)

The compound of formula (I) according to claim 11, wherein R3 is 3,4,6-Tri-O-acetyl-D-N-Acetylgalactosylamine.

### Claim 13 (depends on 1)

The compound of formula (I) according to claim 1, wherein B is selected from the group consisting of a pyrimidine, a substituted pyrimidine, a purine and a substituted purine.

### Claim 14 (depends on 1)

The compound of formula (I) according to claim 1, wherein:
one of P1 or P2 is a O-4,4′-dimethoxytrityl group and the other of P1 and P2 is H, a reactive phosphorus group or a protecting group, or
one of P1 and P2 is a 2-cyanoethyl-N,N-diisopropylphosphoramidite group and the other of P1 and P2 is a protecting group, or
one of P1 and P2 is a 2-cyanoethyl-N,N-diisopropylphosphoramidite group and the other of P1 and P2 is 0-4,4′-dimethoxytrityl group,
and Y, B, X1, X2, Ra, Rb, Rc and Rd are as defined in claim 1.

### Claim 15 (depends on 1)

A method for preparing a compound of formula (I-A),
comprising the steps of:
a) oxidation of a compound of formula (X),
wherein B is a heterocyclic nucleobase and P1 and P2 each represents independently a protecting group as defined in the general formula (I) according to claim 1,
by reaction of the compound of formula (X) with an oxidizing reagent, whereby the following compound of formula (XI) is obtained:
and
b) subjecting the compound of formula (XI) to a step of reductive amination in the presence of the compound of formula (XII)
R1-NH2 (XII)
wherein R1 is as defined in the general formula (I) according to claim 1,
for obtaining the compound of formula (I-A):
wherein B is a heterocyclic nucleobase and P1 and P2 each represent independently a protecting group as defined in the general formula (I) according to claim 1.

### Claim 16 (depends on 1)

A method for preparing a compound of formula (I-E) comprising the steps of:
a) reducing the compound of formula (XI)
wherein P1, P2 and B are as defined in the general formula (I) according to claim 1, so as to obtain a compound of formula (XVII)
b) transferring the compound of formula (XVII) in the presence of a sulfonylating agent, so as to obtain the compound of formula (XVIII)
wherein Ts represents a tosyl group, and
c) subjecting the compound of formula (XVIII) to a basic condition, so as to obtain the compound of formula (I-E)

### Claim 17 (depends on 1)

A method for preparing a compound of formula (I-E) comprising the steps of:
a) transferring the compound of formula (XVII)
wherein P1, P2 and B are as defined in the general formula (I) according to claim 1, in the presence of an excess of a sulfonylating agent so as to obtain the compound of formula (XIX)
wherein Ts represents a tosyl group,
b) deprotecting the compound of formula (XIX) by removal of group P1 for obtaining the compound of formula (XX)
c) subjecting the compound of formula (XX) to a basic condition, so as to obtain the compound of formula (XXI)
and
d) replacing the tosyl group by the protecting group P1, so as to obtain the compound of formula (I-E)

### Claim 18

A compound of formula (I′):
wherein T1 and T2 are each independently a protecting group, —C(═O)(CH2)r-COOH, or —C(═O)(CH2)r-C(═O)NH—R7,
Wherein R7 represents a solid support material, r is an integer selected from 2, 3 and 4, and wherein:
B is a heterocyclic nucleobase;
Y is O, NH, NR1 or N—C(═O)—R1, wherein R1 is:
a (C1-C20) alkyl group,
a (C3-C8) cycloalkyl group, or
a group —[C(═O)]m-R2-(O—CH2-CH2)p-R3, wherein:
m is an integer of 0 or 1,
p is an integer ranging from 0 to 10,
R2 is a (C1-C20) alkylene group,
and
R3 is selected from the group consisting of a hydrogen atom, a (C1-C6) alkyl group, a (C1-C6) alkoxy group, a (C3-C8) cycloalkyl group, a (C3-C14) heterocycle, a (C6-C14) aryl group, and a (C5-C14) heteroaryl group,
or
R3 is a cell targeting moiety,
X1 and X2 are each, independently, a hydrogen atom, or a (C1-C6) alkyl group, and
each of Ra, Rb, Rc and Rd is, independently, H or a (C1-C6) alkyl group.

### Claim 19 (depends on 18)

The compound of formula (I′) according to claim 18, wherein one of T1 and T2 is C(═O)(CH2)r-C(═O)NH—R7,
wherein R7 is a CPG solid support or a polystyrene solid support,
and the other one of T1 and T2 is a protecting group, and r is 2.