IP Library › Granted Patent US 11,040,048

Granted Patent B2

US 11,040,048 · App. 16/061,495 · Granted Jun 22, 2021

Medicament for treating influenza characterized by combining a Cap-dependent endonuclease inhibitor and an anti-influenza drug

Inventors: Takao Shishido (Osaka, JP); Takeshi Noshi (Osaka, JP); Atsuko Yamamoto (Osaka, JP); Mitsutaka Kitano (Osaka, JP)

Assignee: SHIONOGI & CO., LTD.

A61K31/685 A61K31/196 A61K31/351 A61K31/426 A61K31/506 A61K31/53 A61K31/5383 A61K31/664 A61K39/3955 A61K45/06 A61P31/16

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Quick Facts

Patent No.: US 11,040,048
App. No.: 16/061,495
Granted: Jun 22, 2021
Kind: B2

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Abstract

A medicament characterized in that (A) a compound represented by the formula (I): its pharmaceutically acceptable salt, or a solvate thereof, wherein P is hydrogen or a group to form a prodrug; A 1 is CR 1A R 1B , S or O; A 2 is CR 2A R 2B , S or O; A 3 is CR 3A R 3B , S or O; A 4 is each independently CR 4A R 4B , S or O; the number of hetero atoms among atoms constituting the ring which consists of A 1 , A 2 , A 3 , A 4 , nitrogen atom adjacent to A 1 and carbon atom adjacent to A 4 is 1 or 2; R 1A and R 1B are each independently hydrogen, halogen, alkyl or the like; R 2A and R 2B are each independently hydrogen, halogen, alkyl, or the like; R 3A and R 3B are each independently hydrogen, halogen, alkyl, or the like; R 4A are each independently hydrogen, halogen, alkyl, or the like; R 4B are each independently hydrogen, halogen, alkyl, or the like; R 3A and R 3B may be taken together with an adjacent carbon atom to form non-aromatic carbocycle or non-aromatic heterocycle; n is any integer of 1 to 2; and R 1 is or the like, is combined with (B) compound(s) having an anti-influenza activity, its pharmaceutically acceptable salt or a solvate thereof and/or an antibody having anti-influenza activity, is useful for treating or preventing influenza.

Claims (203)

1. A pharmaceutical composition comprising:

(A) a compound represented by the following formula:

or a pharmaceutically acceptable salt thereof,

wherein:

P is hydrogen or a group selected from the group consisting of:

a) —C(═O)—P R0 ,

b) —C(═O)—P R1 ,

c) —C(═O)-L-P R1 ,

d) —C(═O)-L-O—P R1 ,

e) —C(═O)-L-O-L-O—P R1 ,

f) —C(═O)-L-O—C(═O)—P R1 ,

g) —C(═O)—O—P R2 ,

h) —C(═O)—N(—K)(P R2 ),

i) —C(═O)—O-L-O—P R2 ,

i′) —C(═O)—O-L-N(—K)(P R2 ),

j) —C(P R3 ) 2 —O—P R4 ,

k) —C(P R3 ) 2 —O-L-O—P R4 ,

l) —C(P R3 ) 2 —O—C(═O)—P R4 ,

m) —C(P R3 ) 2 —O—C(═O)—O—P R4 ,

n) —C(P R3 ) 2 —O—C(═O)—N(—K)—P R4 ,

o) —C(P R3 ) 2 —O—C(═O)—O-L-O—P R4 ,

p) —C(P R3 ) 2 —O—C(═O)—O-L-N(P R4 ) 2 ,

q) —C(P R3 ) 2 —O—C(═O)—N(—K)-L-O—P R4 ,

r) —C(P R3 ) 2 —O—C(═O)—N(—K)-L-N(P R4 ) 2 ,

s) —C(P R3 ) 2 —O—C(═O)—O-L-O-L-O—P R4 ,

t) —C(P R3 ) 2 —O—C(═O)—O-L-N(—K)—C(═O)—P R4 ,

u) —C(P R3 ) 2 —O—P(═O)(—P R5 ) 2 ,

v) —(C(P R3 ) 2 ) p —P R6 ,

w) —C(═N + (P R7 ) 2 )(—N(P R7 ) 2 ),

x) —(C(P R3 ) 2 ) q —C(═O)—O—P R2 ,

x′) —(C(P R3 ) 2 ) q —C(═O)—N(—K)—P R4 ,

x″) —(C(P R3 ) 2 ) q —C(═O)—P R1 ,

y) —C(P R3 ) 2 —N(—K)—C(═O)—O—P R2 ,

z) —P(═O)(—P R8 )(—P R9 ),

aa) —S(═O) 2 P R10 ,

ab) —P R11 ,

ac) —(C(P R3 ) 2 ) r —O—P R12 , and

ad) —(C(P R3 ) 2 ) t —N(—K)—P R13 ,

wherein L is straight or branched alkylene optionally substituted by substituent group B, or straight or branched alkenylene optionally substituted by substituent group B;

K is hydrogen, or alkyl optionally substituted by substituent group A;

P R0 is alkyl optionally substituted by substituent group A, or alkenyl optionally substituted by substituent group A;

P R1 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;

P R2 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;

P R3 is each independently hydrogen, alkyl or hydroxy;

two P R3 on adjacent carbon atom may be taken together to form alkenylene or alkylene;

P R4 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;

P R5 is each independently hydroxy or OBn;

P R6 is carbocyclyl group optionally substituted by substituent group A, or heterocyclyl group optionally substituted by substituent group A;

P R7 is each independently alkyl optionally substituted by substituent group A;

P R8 is alkyloxy optionally substituted by substituent group A;

P R9 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; or

P R8 and P R9 may be taken together with an adjacent phosphorus atom to form heterocycle optionally substituted by substituent group A;

P R10 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;

P R11 is alkyl optionally substituted by substituent group A, alkenyl optionally substituted by substituent group A, alkynyl optionally substituted by substituent group A, carbocyclyl group optionally substituted by substituent group A, or heterocyclyl group optionally substituted by substituent group A;

P R12 is each independently hydrogen or alkyl optionally substituted by substituent group A;

P R13 is alkylsulfonyl optionally substituted by substituent group A;

p is any integer of 2 to 3;

q is any integer of 1 to 2;

r is any integer of 2 to 4; and

t is any integer of 2 to 4;

wherein substituent group A is selected from the group consisting of oxo, alkyl, alkenyl, haloalkyl, hydroxyalkyl, amino, alkylamino, carbocyclyl group, heterocyclyl group, carbocyclylalkyl, spiro ring, alkylcarbonyl, halogen, hydroxy, carboxy, alkylcarbonylamino, alkylcarbonylaminoalkyl, alkylcarbonyloxy, alkyloxycarbonyl, alkyloxycarbonylalkyl, alkyloxycarbonyloxy, alkylaminocarbonyloxy, alkylaminoalkyl, alkyloxy, cyano, nitro, azido, alkylsulfonyl, trialkylsilyl and phospho; and

substituent group B is selected from the group consisting of spiro ring and halogen, and

(B) at least one compound selected from the group consisting of Oseltamivir, Zanamivir, Peramivir, Laninamivir, and VX-787, or a pharmaceutically acceptable salt thereof.

2. The pharmaceutical composition according to claim 1 , wherein P is hydrogen or a group of the following formula:

m) —C(P R3 ) 2 —O—C(═O)—O—P R4 ,

wherein

P R3 is each independently hydrogen, or alkyl;

P R4 is alkyl optionally substituted by substituent group A, carbocyclyl group optionally substituted by substituent group A, or heterocyclyl group optionally substituted by substituent group A;

wherein substituent group A is selected from the group consisting of oxo, alkyl, alkylamino, carbocyclyl group, heterocyclyl group, alkylcarbonyl, halogen, hydroxy, alkylcarbonylamino, alkylcarbonyloxy, alkyloxycarbonyl, alkyloxycarbonylalkyl, alkylaminocarbonyloxy, alkyloxy, nitro, azido, alkylsulfonyl and trialkylsilyl.

3. The pharmaceutical composition according to claim 1 , wherein P is hydrogen or a group selected from the group consisting of:

a) —C(═O)—P R0 ,

b) —C(═O)—P R1 ,

g) —C(═O)—O—P R2 ,

h) —C(═O)—N(—K)(P R2 ),

i) —C(═O)—O-L-O—P R2 ,

i′) —C(═O)—O-L-N(—K)(P R2 ),

1) —C(P R3 ) 2 —O—C(═O)—P R4 ,

m) —C(P R3 ) 2 —O—C(═O)—O—P R4 ,

o) —C(P R3 ) 2 —O—C(═O)—O-L-O—P R4 ,

t) —C(P R2 —O—C(═O)—O-L-N(—K)—C(═O)—P R4 ,

v) —(C(P R3 ) 2 ) p —P R6 ,

x) —C(P R3 ) 2 ) q —C(═O)—O—P R2 ,

x′) —(C(P R3 ) 2 ) q —C(═O)—N(—K)—P R4 ,

x″) —(C(P R3 ) 2 ) q —C(═O)—P R1 ,

y) —C(P R3 ) 2 —N(—K)—C(═O)—O—P R2 ,

z) —P(═O)(—P R8 )(—P R9 ),

aa) —S(═O) 2 P R10 ,

ab) —P R11 ,

ac) —(C(P R3 ) 2 ) r —O—P R12 , and

ad) —(C(P R3 ) 2 ) t —N(—K)—P R13 ,

wherein L is straight or branched alkylene optionally substituted by substituent group B;

K is hydrogen, or alkyl optionally substituted by substituent group A;

P R0 is alkyl optionally substituted by substituent group A;

P R1 is carbocyclyl group optionally substituted by substituent group A or heterocyclyl group optionally substituted by substituent group A;

P R3 is each independently hydrogen, alkyl or hydroxy;

two P R3 on adjacent carbon atom may be taken together to form alkenylene or alkylene;

P R4 is alkyl optionally substituted by substituent group A, carbocyclyl group optionally substituted by substituent group A or heterocyclyl group optionally substituted by substituent group A;

P R6 is carbocyclyl group optionally substituted by substituent group A or heterocyclyl group optionally substituted by substituent group A;

P R8 is alkyloxy optionally substituted by substituent group A;

P R8 and P R9 may be taken together with an adjacent phosphorus atom to form heterocycle optionally substituted by substituent group A;

P R10 is alkyl optionally substituted by substituent group A, carbocyclyl group optionally substituted by substituent group A or carbocyclylalkyl optionally substituted by substituent group A;

P R12 is each independently hydrogen or alkyl optionally substituted by substituent group A;

P R13 is alkylsulfonyl optionally substituted by substituent group A;

p is any integer of 2 to 3;

q is any integer of 1 to 2;

r is any integer of 2 to 4; and

t is any integer of 2 to 4;

wherein substituent group A is selected from the group consisting of oxo, alkyl, alkenyl, haloalkyl, alkylamino, carbocyclyl group, heterocyclyl group, spiro ring, alkylcarbonyl, halogen, hydroxy, carboxy, alkylcarbonylamino, alkylcarbonylaminoalkyl, alkylcarbonyloxy, alkyloxycarbonyl, alkyloxycarbonylalkyl, alkyloxycarbonyloxy, alkylaminocarbonyloxy, alkylaminoalkyl, alkyloxy, cyano, nitro, azido, alkylsulfonyl, trialkylsilyl and phospho; and

substituent group B is spiro ring.

4. The pharmaceutical composition according to claim 1 , wherein (A) is a compound represented by the formula:

or a pharmaceutically acceptable salt thereof.

5. The pharmaceutical composition according to claim 4 , wherein (A) is a compound represented by the formula:

or a pharmaceutically acceptable salt thereof.

6. The pharmaceutical composition according to claim 4 , wherein (A) is a compound represented by the formula:

or a pharmaceutically acceptable salt thereof.

7. A method of treating influenza comprising administering a combination of

(A) a compound represented by the following formula:

wherein

P is hydrogen or a group selected from the group consisting of:

a) —C(═O)—P R0 ,

b) —C(═O)—P R1 ,

c) —C(═O)-L-P R1 ,

d) —C(═O)-L-O—P R1 ,

e) —C(═O)-L-O-L-O—P R1 ,

f) —C(═O)-L-O—C(═O)—P R1 ,

g) —C(═O)—O—P R2 ,

h) —C(═O)—N(—K)(P R2 ),

i) —C(═O)—O-L-O—P R2 ,

i′) —C(═O)—O-L-N(—K)(P R2 ),

j) —C(P R3 ) 2 —O—P R4 ,

k) —C(P R3 ) 2 —O-L-O—P R4 ,

1) —C(P R3 ) 2 —O—C(═O)—P R4 ,

m) —C(P R3 ) 2 —O—C(═O)—O—P R4 ,

n) —C(P R3 ) 2 —O—C(═O)—N(—K)—P R4 ,

o) —C(P R3 ) 2 —O—C(═O)—O-L-O—P R4 ,

p) —C(P R3 ) 2 —O—C(═O)—O-L-N(P R4 ) 2 ,

q) —C(P R3 ) 2 —O—C(═O)—N(—K)-L-O—P R4 ,

r) —C(P R3 ) 2 —O—C(═O)—N(—K)-L-N(P R4 ) 2 ,

s) —C(P R3 ) 2 —O—C(═O)—O-L-O-L-O—P R4 ,

t) —C(P R3 ) 2 —O—C(═O)—O-L-N(—K)—C(═O)—P R4 ,

u) —C(P R3 ) 2 —O—P(═O)(—P R5 ) 2 ,

v) —(C(P R3 ) 2 ) p —P R6 ,

w) —C(═N + (P R7 ) 2 )(—N(P R7 ) 2 ),

x) —(C(P R3 ) 2 ) q —C(═O)—O—P R2 ,

x′) —(C(P R3 ) 2 ) q —C(═O)—N(—K)—P R4 ,

x″) —(C(P R3 ) 2 ) q —C(═O)—P R1 ,

y) —C(P R3 ) 2 —N(—K)—C(═O)—O—P R2 ,

z) —P(═O)(—P R8 )(—P R9 ),

aa) —S(═O) 2 P R10 ,

ab) —P R11 ,

ac) —(C(P R3 ) 2 ) r —O—P R12 , and

ad) —(C(P R3 ) 2 ) t —N(—K)—P R13 ,

wherein L is straight or branched alkylene optionally substituted by substituent group B, or straight or branched alkenylene optionally substituted by substituent group B;

K is hydrogen, or alkyl optionally substituted by substituent group A;

P R0 is alkyl optionally substituted by substituent group A, or alkenyl optionally substituted by substituent group A;

P R3 is each independently hydrogen, alkyl or hydroxy;

two P R3 on adjacent carbon atom may be taken together to form alkenylene or alkylene;

P R5 is each independently hydroxy or OBn;

P R6 is carbocyclyl group optionally substituted by substituent group A, or heterocyclyl group optionally substituted by substituent group A;

P R7 is each independently alkyl optionally substituted by substituent group A;

P R8 is alkyloxy optionally substituted by substituent group A;

P R8 and P R9 may be taken together with an adjacent phosphorus atom to form heterocycle optionally substituted by substituent group A;

P R12 is each independently hydrogen or alkyl optionally substituted by substituent group A;

P R13 is alkylsulfonyl optionally substituted by substituent group A;

p is any integer of 2 to 3;

q is any integer of 1 to 2;

r is any integer of 2 to 4; and

t is any integer of 2 to 4;

or a pharmaceutically acceptable salt thereof, and

(B) at least one compound selected from the group consisting of Oseltamivir, Zanamivir, Peramivir, Laninamivir, and VX-787, or a pharmaceutically acceptable salt thereof,

in a therapeutically effective amount thereof to an individual in need of treatment for influenza.

8. The method according to claim 7 , wherein

P is hydrogen or a group of the formula —C(P R3 ) 2 —O—C(═O)—O—P R4 ;

P R3 is each independently hydrogen or alkyl;

P R4 is alkyl optionally substituted by substituent group A, carbocyclyl group optionally substituted by substituent group A, or heterocyclyl group optionally substituted by substituent group A; and

substituent group A is selected from the group consisting of oxo, alkyl, alkylamino, carbocyclyl group, heterocyclyl group, alkylcarbonyl, halogen, hydroxy, alkylcarbonylamino, alkylcarbonyloxy, alkyloxycarbonyl, alkyloxycarbonylalkyl, alkylaminocarbonyloxy, alkyloxy, nitro, azido, alkylsulfonyl and trialkylsilyl.

9. The method according to claim 7 , wherein

(A) is a compound represented by the formula:

or a pharmaceutically acceptable salt thereof.

10. The method according to claim 7 , wherein the combination of (A) and (B) is administered simultaneously or sequentially to the individual.

11. The method according to claim 9 , wherein the combination of (A) and (B) is administered simultaneously or sequentially to the individual.

12. The method according to claim 9 , wherein

(A) is a compound represented by the formula:

or a pharmaceutically acceptable salt thereof.

13. The method according to claim 9 , wherein

(A) is a compound represented by the formula:

or a pharmaceutically acceptable salt thereof.

14. The method according to claim 11 , wherein

(A) is a compound represented by the formula:

or a pharmaceutically acceptable salt thereof.

15. The method according to claim 11 , wherein

(A) is a compound represented by the formula:

or a pharmaceutically acceptable salt thereof.

Assignments (1)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 12, 2018

From: SHISHIDO, TAKAO; NOSHI, TAKESHI; YAMAMOTO, ATSUKO; KITANO, MITSUTAKA

To: SHIONOGI & CO., LTD.

Reel/Frame 046057/0016 →

Priority Claims (1)

JP JP2015-244492 · Dec 15, 2015 · national

Continuity (1)

Related Publication 20200261481A1 · Aug 20, 2020

Cited By (1)

US 12,233,066