# US 8,785,617 B2 · Oligomeric compounds for the modulation of HIF-1A expression

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- Number: US 8,785,617 B2
- Document ID: US8785617B2
- Status: Granted
- Kind: B2
- Application number: 13/725,540
- Filed: 2012-12-21
- Published: 2013-05-09
- Granted: 2014-07-22
- Earliest claimed: 2002-04-05
- Assignees: Santaris Pharma A/S
- Applicants: Enzon Pharmaceuticals, Inc.; Santaris Pharma A/S
- Inventors: Charlotte Albaek Thrue; Anja Molhart Hog; Paul E. G. Kristjansen
- Web page: https://patentgrep.com/patent/US8785617B2

## CPC

- A61K 31/7088: Compounds having three or more nucleosides or nucleotides
- A61K 31/70: Carbohydrates; Sugars; Derivatives thereof (sorbitol A61K31/047)
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/12: Antivirals
- A61P 35/00: Antineoplastic agents
- A61P 35/04: specific for metastasis
- A61P 37/02: Immunomodulators
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07H 21/04: with deoxyribosyl as saccharide radical
- C12N 15/113: Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; {Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing (when used in plants C12N15/8218)}
- A61K 38/00: Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00)
- C12N 2310/315: Phosphorothioates
- C12N 2310/3231: having an additional ring, e.g. LNA, ENA
- C12N 2310/331: Universal or degenerate base
- C12N 2310/334: Modified C
- C12N 2310/3341: 5-Methylcytosine
- C12N 2310/335: Modified T or U
- C12N 2310/341: Gapmers, i.e. of the type ===---===
- 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
- 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)
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)

## Abstract

Oligonucleotides directed against the hypoxia-inducible factor-1α (HIF-1α) gene are provided for modulating the expression of HIF-1α. The compositions comprise oligonucleotides, particularly antisense oligonucleotides, targeted to nucleic acids encoding the HIF-1α. Methods of using these compounds for modulation of HIF-1α expression and for the treatment of diseases associated with the hypoxia-inducible factor-1α are provided. Examples of diseases are cancer and pre-eclampsia. The oligonucleotides may be composed of deoxyribonucleosides, a nucleic acid analog, or Locked Nucleic Acid (LNA) or a combination thereof.

## Claims

### Claim 1

A compound of 16 to 50 nucleotides or nucleotide analogues, comprising SEQ ID NO: 3, wherein adjacent nucleotides or nucleotide analogues are covalently linked by an internucleotide linkage, wherein the compound comprises at least one nucleotide analogue, and wherein the compound modulates HIF-1α expression.

### Claim 2 (depends on 1)

The compound according to claim 1 which inhibits the expression of HIF-1α in a cell or tissue.

### Claim 3 (depends on 1)

The compound according to claim 1, which is an antisense oligonucleotide.

### Claim 4 (depends on 3)

The compound according to claim 3, wherein the nucleotide analogue is a Locked Nucleic Acid (LNA) unit.

### Claim 5 (depends on 4)

The compound according to claim 4, wherein the LNA unit has the structure:
wherein Z and Z* are independently selected from the group consisting of an internucleotide linkage, a terminal group and a protecting group,
B constitutes a natural or non-natural nucleobase,
X and Y are independently selected from —O—, —S—, —N(H)—, —N(R)—, —CH2—, —CH— (if part of a double bond), —CH2—O—, —CH2—S—, —CH2—N(H)—, —CH2—N(R)—, —CH2—CH2—, and
—CH2—CH— (if part of a double bond) in which RH is selected from hydrogen and C1-4-alkyl.

### Claim 6 (depends on 4)

The compound according to claim 4, wherein the LNA unit has a structure of any of the following formulas:
wherein X is independently selected from —O—, —S—, —NH—, and N(RH) in which RH is selected from hydrogen and C1-4-alkyl,
Z and Z* are independently selected from the group consisting of an internucleotide linkage, a terminal group and a protecting group; and
B constitutes a natural or non-natural nucleobase.

### Claim 7 (depends on 5)

The compound according to claim 5, wherein the internucleotide linkage is selected from the group consisting of —O—P(O)2—O—, —O—P(O,S)—O—, —O—P(S)2—O—, —S—P(O)2—O—, —S—P(O,S)—O—, —S—P(S)2—O—, —O—P(O)2—S—, —O—P(O,S)—S—, —S—P(O)2—S—, —O—PO(RH)—O—, O—PO(OCH3)—O—, —O—PO(NRH)—O—, —O—PO(OCH2CH2S—R)—O—, —O—PO(BH3)—O—, —O—PO(NHRH)—O—, —O—P(O)2—HRH—, —NRH—P(O)2—O—, and —NR″—CO—O—, where RH is selected form hydrogen and C1-4-alkyl.

### Claim 8 (depends on 7)

The compound of claim 7, wherein at least one internucleotide linkage is a phosphorothioate linkage.

### Claim 9 (depends on 5)

The compound according to claim 5, wherein at least one nucleobase is a modified nucleobase independently selected from the group consisting of 5-methylcytosine, isocytosine, pseudoisocytosine, 5-bromouracil, 5-propynyluracil, 6-aminopurine, 2-aminopurine, inosine, diaminopurine, and 2-chloro-6-aminopurine.

### Claim 10 (depends on 4)

The compound according to claim 4, wherein each of the LNA units is independently selected from β-D-oxy-LNA, β-D-thio-LNA, β-D-amino-LNA, α-L-oxy-LNA, α-L-thio-LNA and α-L-amino-LNA.

### Claim 11 (depends on 3)

The compound of claim 3, wherein the antisense oligonucleotide is a chimeric oligonucleotide.

### Claim 12 (depends on 11)

The compound of claim 11, wherein the chimeric oligonucleotide is a gapmer, a headmer, or a tailmer.

### Claim 13 (depends on 4)

The compound according to claim 4, which comprises at least four LNA units.

### Claim 14 (depends on 1)

A composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier or diluent.

### Claim 15 (depends on 1)

A pharmaceutical composition comprising the compound of claim 1 in the form of a pharmaceutically acceptable salt.

### Claim 16 (depends on 1)

A pharmaceutical composition comprising the compound of claim 1, which is in the form of a conjugate.

### Claim 17 (depends on 1)

A pharmaceutical composition comprising the compound of claim 1, which is in the form of a pro-drug.

### Claim 18

A compound represented by the formula: TsGsGsTsgsasgsgscstsgstsCsCsGsA (SEQ ID NO. 3) wherein uppercase letters denote oxy-LNA nucleotides, lowercase letters denote deoxynucleotides and the subscript “s” denotes a phosphorothioate linkage.

### Claim 19

A compound selected from:
(SEQ ID NO. 3)
TsGsGsTsgsasgsgscstsgstsMeCsMeCsGsA,
(SEQ ID NO. 96)
tsgsgstsgsasgsgscstsgstscscsgsa,
(SEQ ID NO. 97)
TGGTsgsasgsgscstsgstsMeCMeCGA,
(SEQ ID NO. 99)
TGGTGAGGscstsgstscscsgsa
(SEQ ID NO. 100)
tsgsgstsgsasgsgsMeCTGTMeCMeCGA
(SEQ ID NO. 105)
TsGsGstsgsasgsgscstsgstsMeCsMeCsGsA,
(SEQ ID NO. 106)
TsGsGstsgsasgsgscstsgstsMeCsMeCsGsa,
(SEQ ID NO. 107)
TsGsGsTsgsasgsgscstsgstsMeCsMeCsGsa,
(SEQ ID NO. 108)
TsGsGsTsGsAsgsgscstsgstscscsgsa,
(SEQ ID NO. 109)
TGGtsgsasgsgscstsgstsMeCMeCGA,
(SEQ ID NO. 110)
TGGtsgsasgsgscstsgstsMeCMeCGa,
(SEQ ID NO. 111)
TGGTgsasgsgscstsgstsMeCMeCGa,
and
(SEQ ID NO. 112)
TGGTGAgsgscstsgstscscsgsa,
wherein uppercase letters denote oxy-LNA nucleotides, lowercase letters denote deoxynucleotides, the subscript “s” denotes a phosphorothioate linkage, and wherein MeC denotes an oxy LNA monomer containing a 5-methyl cytosine base.