# US 2014/0155350 A1 · Prodrugs of Neuraminidase Inhibitors

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- Number: US 2014/0155350 A1
- Document ID: US20140155350A1
- Status: Published application
- Kind: A1
- Application number: 14/091,004
- Filed: 2013-11-26
- Published: 2014-06-05
- Earliest claimed: 2008-04-15
- Assignees: SineVir Therapeutics LLC
- Inventors: John Hilfinger; Gordon Amidon
- Web page: https://patentgrep.com/patent/US20140155350A1

## CPC

- C07F 7/12: Organo silicon halides
- A61K 31/155: Amidines ([IMAGE cpc-sch-A61K-1029.gif]), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
- A61K 31/167: having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
- A61K 31/351: not condensed with another ring
- A61P 31/12: Antivirals
- A61P 31/16: for influenza or rhinoviruses
- C07C 279/16: having nitrogen atoms of guanidine groups bound to carbon atoms of rings other than six-membered aromatic rings
- C07D 231/14: with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D 307/89: with two oxygen atoms directly attached in positions 1 and 3
- C07D 309/28: with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- 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
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

A new class of neuramidase inhibitor prodrugs is provided characterized by a prodrug moiety of a carboxyl group modified to form a carbonyl ethoxy amino acid, a carbonyl ethoxy dipeptide or a carbonyl ethoxy tripeptide, a guanidine group modified to form a carbonyl ethoxy amino acid, a carbonyl ethoxy dipeptide, a carbonyl ethoxy tripeptide; a primary alcohol modified to form an esterified single amino acid, dipeptide or tripeptide of zanavimir of the unaltered therapeutic agent. Exemplary therapeutic agents so modified to form prodrugs include zanavimir, oseltamivir and peramivir. The prodrug has increased oral bioavailability relative to the unaltered neuraminidase inhibitor and is effective in the inhibition of viral infections involving neuraminidase in the viral reproductive cycle.

## Claims

### Claim at position 1

1-16. (canceled)

### Claim 17

A prodrug of a neuraminidase inhibitor, the prodrug having the formula (III):
where R14 is —CH(CH3)OC(O)(CH2)nCH(R′)NH2, CH(CH3)OC(O)(CH2)nCH(R′)NH2, —CH(CH3)OC(O)(CH2)nCH(R′)N(H)C(O)(CH2)nCH(R″)NH2, —CH(CH3)OC(O)(CH2)nCH(R′)N(H)C(O) (CH2)n CH(R″)N(H)C(O) (CH2)n CH(R″′)NH2, or —H;
n is zero or one;
R15 is in each occurrence independently —C(O)OCH(CH3)OC(O)(CH2)nCH(R′)NH2, —C(O)OCH(CH3)OC(O) (CH2)n CH(R′)N(H)C(O) (CH2)nCH(R″)NH2, —CH(CH3)O— C(O) (CH2)n CH(R′)N(H)C(O) (CH2)n CH(R″)N(H)C(O) (CH2)n CH(R″′)NH2, —H; each R16 is independently —H, an amino acid residue having the formula C(O) (CH2)n CH(R′)NH2, a dipeptide residue having the formula C(O) (CH2)n CH(R′)N(H)C(O) (CH2)n CH(R″)NH2, or a tripeptide residue —CH(CH3)O— C(O) (CH2)n CH(R′)N(H)C(O) (CH2)n CH(R″)N(H)C(O) (CH2)n CH(R′″)NH2, where R′, R″ and R″′ are each an independently selected amino acid side chain; R17 is H; and where at least one of R14, R15, and R16 includes an amino acid, dipeptide or tripeptide residue.

### Claim 18 (depends on 17)

The prodrug of claim 17, wherein both occurrences of R15 are H.

### Claim 19 (depends on 18)

The prodrug of claim 18, wherein both occurrences of R16 are H.

### Claim 20 (depends on 19)

The prodrug of claim 19, wherein R14 is —CH(CH3)OC(O)(CH2)nCH(R′)NH2, CH(CH3)OC(O)(CH2)nCH(R′)NH2, —CH(CH3)OC(O)(CH2)nCH(R′)N(H)C(O)(CH2)nCH(R″)NH2, or —CH(CH3)OC(O)(CH2)nCH(R′)N(H)C(O) (CH2)n CH(R″)N(H)C(O) (CH2)n CH(R′″)NH2.

### Claim 21 (depends on 20)

The prodrug of claim 20, wherein R14 is CH(CH3)OC(O)(CH2)nCH(R′)NH2, wherein n is zero.

### Claim 22 (depends on 21)

The prodrug of claim 21, wherein R′ is —CH(CH3)2, —CH(CH2CH3)(CH3), —CH2—CH(CH3)2, or

### Claim 23 (depends on 22)

The prodrug of claim 22, wherein R′ is —CH(CH3)2 or —CH(CH2CH3)(CH3).

### Claim 24 (depends on 17)

The prodrug of claim 17, having the structure:

### Claim 25 (depends on 17)

The prodrug of claim 17, having the structure:

### Claim 26 (depends on 17)

A method of inhibiting a viral infection in a subject comprising: administering a neuraminidase inhibitor prodrug of claim 17, to the subject.

### Claim 27 (depends on 26)

The method of claim 26, wherein the viral infection is an influenza virus infection.

### Claim 28 (depends on 27)

The method of claim 27, wherein the subject is human.

### Claim 29

A prodrug of a neuraminidase inhibitor, the prodrug having the formula (VII):
where R19 is —CH(CH3)OC(O)(CH2)nCH(R′)NH2, —CH(CH3)OC(O)(CH2)nCH(R′)N(H)C(O)(CH2)nCH(R″)NH2, —CH(CH3)OC(O)(CH2)nCH(R′)N(H)C(O) (CH2)nCH(R″)N(H)C(O) (CH2)n CH(R′″)NH2, —H, —COC(CH3)2CH2R*, —COCH2CH2R*, or —COCH3; n is zero or one; R* is —H, —C1-C8 alkyl, or —C1-C6 alkyl having a heteroatom substituent of hydroxyl, carboxyl, or primary amine; R20 is in each occurrence independently —CH(CH3)OC(O)(CH2)nCH(R′)NH2, —CH(CH3)OC(O)(CH2)nCH(R′)N(H)C(O)(CH2)nCH(R″)NH2, —CH(CH3)OC(O)(CH2)nCH(R′)N(H)C(O) (CH2)n CH(R″)N(H)C(O) (CH2)n CH(R″′)NH2, or —H;
R′, R″ and R′″ are each an independently an amino acid side chain; and where at least one R19 or R20 includes an amino acid residue, dipeptide residue or tripeptide residue.

### Claim 30 (depends on 29)

The prodrug of claim 29, wherein both occurrences of R20 are H.

### Claim 31 (depends on 30)

The prodrug of claim 30, wherein R14 is —CH(CH3)OC(O)(CH2)nCH(R′)NH2, CH(CH3)OC(O)(CH2)nCH(R′)NH2, —CH(CH3)OC(O)(CH2)nCH(R′)N(H)C(O)(CH2)nCH(R″)NH2, or —CH(CH3)OC(O)(CH2)nCH(R′)N(H)C(O) (CH2)n CH(R″)N(H)C(O) (CH2)n CH(R″′)NH2.

### Claim 32 (depends on 31)

The prodrug of claim 31, wherein R14 is CH(CH3)OC(O)(CH2)nCH(R′)NH2, wherein n is zero.

### Claim 33 (depends on 32)

The prodrug of claim 32, wherein R′ is —CH(CH3)2, —CH(CH2CH3)(CH3), —CH2—CH(CH3)2, or

### Claim 34 (depends on 33)

The prodrug of claim 33, wherein R′ is —CH(CH3)2 or —CH(CH2CH3)(CH3).

### Claim 35 (depends on 29)

The prodrug of claim 29, having the structure:

### Claim 36 (depends on 29)

The prodrug of claim 29, having the structure: