# US 2019/0169206 A1 · Pharmaceutical compositions containing substituted polycyclic pyridone derivatives and prodrug thereof

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- Number: US 2019/0169206 A1
- Document ID: US20190169206A1
- Status: Published application
- Kind: A1
- Application number: 16/323,580
- Filed: 2017-08-09
- Published: 2019-06-06
- Earliest claimed: 2016-08-10
- Assignees: Shionogi & Co., Ltd.
- Applicants: Shionogi & Co., Ltd.
- Inventors: Makoto KAWAI; Kenji TOMITA; Toshiyuki AKIYAMA; Azusa OKANO; Masayoshi MIYAGAWA
- Web page: https://patentgrep.com/patent/US20190169206A1

## CPC

- A61K 9/0014: {Skin, i.e. galenical aspects of topical compositions (non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00)}
- C07D 498/14: Ortho-condensed systems
- A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)}
- A61K 9/0056: {Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals}
- A61K 9/0075: {for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles}
- A61K 9/0095: {Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches (A61K9/0007 takes precedence; eatable gels or foams A61K9/0056; oral mucosa adhesive forms A61K9/006)}
- A61K 9/06: Ointments; Bases therefor; {Other semi-solid forms, e.g. creams, sticks, gels (composition of ointments, creams or gels A61K47/00)}
- A61K 9/1623: {Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules}
- A61K 9/2018: {Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates}
- A61K 9/4858: {Organic compounds}
- A61K 9/7038: {Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer}
- A61K 31/5383: ortho- or peri-condensed with heterocyclic ring systems
- A61P 31/12: Antivirals
- A61P 31/16: for influenza or rhinoviruses
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07B 2200/13: Crystalline forms, e.g. polymorphs
- 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)
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)

## Abstract

The present invention provides a pharmaceutical composition containing the following compound having antiviral action: wherein each of the symbols is defined in the specification.

## Claims

### Claim at position 1

1-15. (canceled)

### Claim 16

I form, II-form, or III-form crystals of the compound of the following formula:

### Claim 17 (depends on 16)

The crystal according to claim 16, wherein the crystal has two or more peaks in diffraction angles (2θ) selected from 8.6±0.2°, 14.1±0.2°, 17.4±0.2°, 20.0±0.2°, 24.0±0.2°, 26.3±0.2°, 29.6±0.2° and 35.4±0.2° in an X-ray powder diffraction spectrum.

### Claim 18 (depends on 16)

The crystal according to claim 16, wherein the crystal has peaks in diffraction angles (2θ) of: 8.6±0.2°, 14.1±0.2°, 17.4±0.2°, 20.0±0.2°, 24.0±0.2°, 26.3±0.2°, 29.6±0.2° and 35.4±0.2° in an X-ray powder diffraction spectrum.

### Claim 19

(canceled)

### Claim 20 (depends on 16)

The pharmaceutical composition comprising the crystal according to claim 16.

### Claim 21 (depends on 20)

The pharmaceutical composition according to claim 20, which is an antiviral agent.

### Claim 22 (depends on 21)

The pharmaceutical composition according to claim 21, which is a cap-dependent endonuclease inhibitor.

### Claim at position 9

23-24. (canceled)

### Claim 25 (depends on 16)

A method for shortening time to alleviation of influenza symptoms to treat and/or prevent an influenza virus infectious disease, comprising:
administering an effective amount of the crystal according to claim 16.

### Claim 26 (depends on 16)

A method for reducing the influenza virus to treat and/or prevent an influenza virus infectious disease, comprising:
administering an effective amount of the crystal according to claim 16.

### Claim 27

A method for shortening time to alleviation of influenza symptoms to treat and/or prevent an influenza virus infectious disease, comprising:
administering an effective amount of a compound,
wherein the compound has one of the following formula:
or its pharmaceutically acceptable salt thereof,
wherein P is hydrogen or a group to form a prodrug.

### Claim 28 (depends on 27)

The method of claim 27, wherein the group to form a prodrug is the following formulae:
—C(═O)—PR0, a)
—C(═O)—PR1, b)
—C(═O)-L-PR1, c)
—C(═O)-L-O—PR1, d)
—C(═O)-L-O-L-O—PR1, e)
—C(═O)-L-O—C(═O)—PR1, f)
—C(═O)—O—PR2, g)
—C(═O)—N(—K)(PR2), h)
—C(═O)—O-L-O—PR2, i)
—C(PR3)2—O—PR4, j)
—C(PR3)2—O-L-O—PR4, k)
—C(PR3)2—O—C(═O)—PR4, l)
—C(PR3)2—O—C(═O)—O—PR4, m)
—C(PR3)2—O—C(═O)—N(—K)—PR4, n)
—C(PR3)2—O—C(═O)—O-L-O—PR4, o)
—C(PR3)2—O—C(═O)—O-L-N(PR4)2, p)
—C(PR3)2—O—C(═O)—N(—K)-L-O—PR4, q)
—C(PR3)2—O—C(═O)—N(—K)-L-N(PR4)2, r)
—C(PR3)2—O—C(═O)—O-L-O-L-O—PR4, s)
—C(PR3)2—O—C(═O)—O-L-N(—K)—C(═O)—PR4, t)
—C(PR3)2—O—P(═O)(—PR5)2, u)
—C(PR3)2—PR6, v)
—C(═N+(PR7)2)(—N(PR7)2), w)
—C(PR3)2—C(PR3)2—C(═O)—O—PR2, x)
—C(PR3)2—N(—K)—C(═O)—O—PR2, y)
—P(═O)(—PR8)(—PR9), z)
—S(═O)2—PR10, aa)
—PR11, and ab)
—C(PR3)2—C(PR3)2—O—PR2, ac)
wherein L is straight or branched alkylene, or straight or branched alkenylene;
K is hydrogen, or alkyl optionally substituted by substituent group A;
PR0 is alkyl optionally substituted by substituent group A, or alkenyl optionally substituted by substituent group A;
PR1 is carbocyclyl group optionally substituted by substituent group A, heterocyclyl group optionally substituted by substituent group A, alkylamino optionally substituted by substituent group A, or alkylsulfanyl optionally substituted by substituent group A;
PR2 is alkyl optionally substituted by substituent group A, carbocyclyl group optionally substituted by substituent group A, heterocyclyl group optionally substituted by substituent group A, carbocyclylalkyl optionally substituted by substituent group A, heterocyclylalkyl optionally substituted by substituent group A or trialkylsilyl;
PR3 is each independently hydrogen or alkyl;
PR4 is each independently alkyl optionally substituted by substituent group A, carbocyclyl group optionally substituted by substituent group A, heterocyclyl group optionally substituted by substituent group A, alkylamino optionally substituted by substituent group A, carbocyclylalkyl optionally substituted by substituent group A, heterocyclylalkyl optionally substituted by substituent group A, or trialkylsilyl;
PR5 is each independently hydroxy or OBn;
PR6 is carbocyclyl group optionally substituted by substituent group A, or heterocyclyl group optionally substituted by substituent group A;
PR7 is each independently alkyl optionally substituted by substituent group A;
PR8 is alkyloxy optionally substituted by substituent group A;
PR9 is alkyloxy optionally substituted by substituent group A, alkylamino optionally substituted by substituent group A, carbocyclyloxy optionally substituted by substituent group A, heterocyclyloxy optionally substituted by substituent group A, carbocyclylamino optionally substituted by substituent group A or heterocyclylamino optionally substituted by substituent group A;
PR8 and PR9 may be taken together with an adjacent phosphorus atom to form heterocycle optionally substituted by substituent group A;
PR10 is alkyl optionally substituted by substituent group A, carbocyclyl group optionally substituted by substituent group A, heterocyclyl group optionally substituted by substituent group A, carbocyclylalkyl optionally substituted by substituent group A or heterocyclylalkyl optionally substituted by substituent group A; and
PR11 is alkyl optionally substituted by substituent group A, alkenyl optionally substituted by substituent group A, carbocyclyl group optionally substituted by substituent group A, or heterocyclyl group optionally substituted by substituent group A;
Substituent group A; oxo, alkyl, hydroxyalkyl, amino, alkylamino, carbocyclyl group, heterocyclyl group, carbocyclylalkyl, alkylcarbonyl, halogen, hydroxy, carboxy, alkylcarbonylamino, alkylcarbonylaminoalkyl, alkylcarbonyloxy, alkyloxycarbonyl, alkyloxycarbonylalkyl, alkyloxycarbonyloxy, alkylaminocarbonyloxy, alkylaminoalkyl, alkyloxy, cyano, nitro, azido, alkylsulfonyl, trialkylsilyl and phospho.

### Claim 29 (depends on 27)

The method of claim 27, wherein the group to form a prodrug is the following formulae:
—C(═O)—PR0, a)
—C(═O)—O—PR2, g)
—C(═O)—O-L-O—PR2, i)
—C(PR3)2—O—C(═O)—PR4, l)
—C(PR3)2—O—C(═O)—O—PR4,and m)
—C(PR3)2—O—C(═O)—O-L-O—PR4, o)
wherein L is straight or branched lower alkylene;
PR0 is alkyl
PR2 is alkyl;
PR3 is each independently hydrogen; and
PR4 is alkyl, or heterocyclyl group optionally substituted by substituent group A;
Substituent group A; alkyl.

### Claim 30 (depends on 27)

The method of claim 27, wherein the group to form a prodrug is the following formula:
—C(PR3)2—O—C(═O)—O—PR4 m)
wherein PR3 is each independently hydrogen; and
PR4 is alkyl, or heterocyclyl group optionally substituted by substituent group A;
Substituent group A; alkyl.

### Claim 31 (depends on 27)

The method of claim 27, wherein the compound is one of the following formulae:
or its pharmaceutically acceptable salt thereof.

### Claim 32 (depends on 27)

The method of claim 27, wherein the compound is one of the following formulae:
or its pharmaceutically acceptable salt thereof.

### Claim 33

A method for reducing the influenza virus to treat and/or prevent an influenza virus infectious disease, comprising:
administering an effective amount of a compound,
wherein the compound has one of the following formula:
or its pharmaceutically acceptable salt thereof,
wherein P is hydrogen or a group to form a prodrug.

### Claim 34 (depends on 33)

The method of claim 33, wherein the group to form a prodrug is the following formulae:
—C(═O)—PR0, a)
—C(═O)—PR1, b)
—C(═O)-L-PR1, c)
—C(═O)-L-O—PR1, d)
—C(═O)-L-O-L-O—PR1, e)
—C(═O)-L-O—C(═O)—PR1, f)
—C(═O)—O—PR2, g)
—C(═O)—N(—K)(PR2), h)
—C(═O)—O-L-O—PR2, i)
—C(PR3)2—O—PR4, j)
—C(PR3)2—O-L-O—PR4, k)
—C(PR3)2—O—C(═O)—PR4, l)
—C(PR3)2—O—C(═O)—O—PR4, m)
—C(PR3)2—O—C(═O)—N(—K)—PR4, n)
—C(PR3)2—O—C(═O)—O-L-O—PR4, o)
—C(PR3)2—O—C(═O)—O-L-N(PR4)2, p)
—C(PR3)2—O—C(═O)—N(—K)-L-O—PR4, q)
—C(PR3)2—O—C(═O)—N(—K)-L-N(PR4)2, r)
—C(PR3)2—O—C(═O)—O-L-O-L-O—PR4, s)
—C(PR3)2—O—C(═O)—O-L-N(—K)—C(═O)—PR4, t)
—C(PR3)2—O—P(═O)(—PR5)2, u)
—C(PR3)2—PR6, v)
—C(═N+(PR7)2)(—N(PR7)2), w)
—C(PR3)2—C(PR3)2—C(═O)—O—PR2, x)
—C(PR3)2—N(—K)—C(═O)—O—PR2, y)
—P(═O)(—PR8)(—PR9), z)
—S(═O)2—PR10, aa)
—PR11, and ab)
—C(PR3)2—C(PR3)2—O—PR2, ac)
wherein L is straight or branched alkylene, or straight or branched alkenylene;
K is hydrogen, or alkyl optionally substituted by substituent group A;
PR0 is alkyl optionally substituted by substituent group A, or alkenyl optionally substituted by substituent group A;
PR1 is carbocyclyl group optionally substituted by substituent group A, heterocyclyl group optionally substituted by substituent group A, alkylamino optionally substituted by substituent group A, or alkylsulfanyl optionally substituted by substituent group A;
PR2 is alkyl optionally substituted by substituent group A, carbocyclyl group optionally substituted by substituent group A, heterocyclyl group optionally substituted by substituent group A, carbocyclylalkyl optionally substituted by substituent group A, heterocyclylalkyl optionally substituted by substituent group A or trialkylsilyl;
PR3 is each independently hydrogen or alkyl;
PR4 is each independently alkyl optionally substituted by substituent group A, carbocyclyl group optionally substituted by substituent group A, heterocyclyl group optionally substituted by substituent group A, alkylamino optionally substituted by substituent group A, carbocyclylalkyl optionally substituted by substituent group A, heterocyclylalkyl optionally substituted by substituent group A, or trialkylsilyl;
PR5 is each independently hydroxy or OBn;
PR6 is carbocyclyl group optionally substituted by substituent group A, or heterocyclyl group optionally substituted by substituent group A;
PR7 is each independently alkyl optionally substituted by substituent group A;
PR8 is alkyloxy optionally substituted by substituent group A;
PR9 is alkyloxy optionally substituted by substituent group A, alkylamino optionally substituted by substituent group A, carbocyclyloxy optionally substituted by substituent group A, heterocyclyloxy optionally substituted by substituent group A, carbocyclylamino optionally substituted by substituent group A or heterocyclylamino optionally substituted by substituent group A;
PR8 and PR9 may be taken together with an adjacent phosphorus atom to form heterocycle optionally substituted by substituent group A;
PR10 is alkyl optionally substituted by substituent group A, carbocyclyl group optionally substituted by substituent group A, heterocyclyl group optionally substituted by substituent group A, carbocyclylalkyl optionally substituted by substituent group A or heterocyclylalkyl optionally substituted by substituent group A; and
PR11 is alkyl optionally substituted by substituent group A, alkenyl optionally substituted by substituent group A, carbocyclyl group optionally substituted by substituent group A, or heterocyclyl group optionally substituted by substituent group A;
Substituent group A; oxo, alkyl, hydroxyalkyl, amino, alkylamino, carbocyclyl group, heterocyclyl group, carbocyclylalkyl, alkylcarbonyl, halogen, hydroxy, carboxy, alkylcarbonylamino, alkylcarbonylaminoalkyl, alkylcarbonyloxy, alkyloxycarbonyl, alkyloxycarbonylalkyl, alkyloxycarbonyloxy, alkylaminocarbonyloxy, alkylaminoalkyl, alkyloxy, cyano, nitro, azido, alkylsulfonyl, trialkylsilyl and phospho.

### Claim 35 (depends on 33)

The method of claim 33, wherein the group to form a prodrug is the following formulae:
—C(═O)—PR0, a)
—C(═O)—O—PR2, g)
—C(═O)—O-L-O—PR2, i)
—C(PR3)2—O—C(═O)—PR4, l)
—C(PR3)2—O—C(═O)—O—PR4,and m)
—C(PR3)2—O—C(═O)—O-L-O—PR4, o)
wherein L is straight or branched lower alkylene;
PR0 is alkyl
PR2 is alkyl;
PR3 is each independently hydrogen; and
PR4 is alkyl, or heterocyclyl group optionally substituted by substituent group A;
Substituent group A; alkyl.

### Claim 36 (depends on 33)

The method of claim 33, wherein the group to form a prodrug is the following formula:
—C(PR3)2—O—C(═O)—O—PR4 m)
wherein PR3 is each independently hydrogen; and
PR4 is alkyl, or heterocyclyl group optionally substituted by substituent group A;
Substituent group A; alkyl.

### Claim 37 (depends on 33)

The method of claim 33, wherein the compound is one of the following formulae:
or its pharmaceutically acceptable salt thereof.

### Claim 38 (depends on 33)

The method of claim 33, wherein the compound is one of the following formulae:
or its pharmaceutically acceptable salt thereof.