Piperazine derivatives for influenza virus inhibitions
The present invention provides piperazine derivatives exhibiting high affinity to the stem region (viral membrane proximal part) of influenza hemagglutinin as determined through competition binding and high virus neutralization activity while having low cytotoxity. Furthermore, the present invention relates to pharmaceutical compositions comprising said piperazine derivatives, methods of preparing said piperazine derivatives, as well as said piperazine derivatives for use in medical prevention or treatment, especially for preventing or treating influenza.
1. A compound having formula (I) or a stereoisomer, a pharmaceutically acceptable salt, a solvate, or a polymorph thereof, wherein:
B is —CH 2 — or —CH 2 CH 2 —;
W is N;
either:
a) X is CR 4 or N, wherein R 4 is hydrogen, methyl, ethyl or propyl; and R 1 is hydrogen; —CH 2 OH; —CH 2 OCH 3 ; —C(O)CH 3 ; —C(O)OCH 3 ; —C(O)OCH 2 CH 3 ; —C(O)NH 2 ; —C(O)NH(CH 2 ) 2 OCH 3 ; —C(O)NH(CH 3 ); —C(O)NH(CH 2 )CH 3 , wherein n is 2 or 3; or —C(O)NH(CH 2 ) o NH 2 , wherein o is 2 or 3; or a carbocyclic or heterocyclic radical selected from the group consisting of cyclohexyl, pyridyl, pyrrolyl, oxazolyl, oxadiazolyl, pyrazolyl, triazolyl, tetrazolyl, thiadiazolyl, and imidazolidyl, optionally substituted with one or more substituents independently selected from oxo, methyl, ethyl, cyclopropyl, methoxy, methylacetamide, methanamine, azetidine, hydroxyazetidinyl, hydroxycyclobutyl and morpholinomethanone; or
b) X is CR 4 , and R 1 and CR 4 are taken together to form a carbocyclic or heterocyclic radical;
Y 1 is —(CH 2 ) p —, wherein p is 0, 1, 2 or 3;
Y 2 is —(CH 2 ) q —, wherein q is 0, 1, 2 or 3;
Z 1 and Z 2 are independently selected from the group consisting of CH or N, with the proviso that at least one of Z 1 and Z 2 is CH;
R 2 is hydrogen, methyl, —C(O)NH 2 , or —CH 2 C(O)NH 2 and R 3 is hydrogen; or R 2 and R 3 are taken together to form 1,2-ethanediyl or 1,3-propanediyl;
Ar is a 5-membered or 6-membered aromatic or heteroaromatic ring, optionally substituted with at least one halogen; and
A is benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzofuranyl, isoquinolinyl, quinazolyl, benzimidazolyl, pyridooxazolyl, or methoxyphenyl acetamide, optionally substituted with one or more substituents independently selected from the group consisting of halogen, —OH, —O—CH 3 , —CH 3 , —CF 3 , —OCF 3 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —NHC(O)CH 3 , —NHSO 2 CH 3 , cyclopropoxy or methylenesulfonyl nitrile.
2. The compound according to claim 1 , wherein B is —CH 2 — and R 3 is hydrogen.
3. The compound according to claim 1 , wherein X is CH.
4. The compound according to claim 1 , wherein W is N, B is —CH 2 —, and X is CH.
5. The compound according to claim 1 , wherein p and q are 0.
6. The compound according to claim 1 , wherein A is benzoxazol-2-yl.
7. The compound according to claim 6 , wherein said benzoxazol-2-yl comprises a substituent in the 5-position, said substituent in the 5-position being selected from the group consisting of —OCH 3 , —CF 3 , —OCF 3 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —NHC(O)CH 3 , and cyclopropoxy.
8. The compound according to claim 7 , wherein said substituent in the 5-position is selected from the group consisting of —OCF 3 , —NC(O)CH 3 , and cyclopropoxy.
9. The compound according to claim 1 , wherein Ar is an optionally fluorinated phenylene, an optionally fluorinated furandiyl, or an optionally fluorinated pyridinediyl.
10. The compound according to claim 9 , wherein Ar is 1,3-phenylene; 2-fluoro-1,5-phenylene; 3-fluoro-1,5-phenylene; furan-2,5-diyl; pyridine-2,4-diyl; or pyridine-2,6-diyl.
11. A compound having formula (I) or a stereoisomer, a pharmaceutically acceptable salt, a solvate, or a polymorph thereof, wherein:
B is —CH 2 — or —CH 2 CH 2 —;
W is CH or N;
either:
c) X is CR 4 or N, wherein R 4 is hydrogen, methyl, ethyl or propyl; and R 1 is hydrogen; —CH 2 OH; —CH 2 OCH 3 ; —C(O)CH 3 ; —C(O)OCH 3 ; —C(O)OCH 2 CH 3 ; —C(O)NH 2 ; —C(O)NH(CH 2 ) 2 OCH 3 ; —C(O)NH(CH 3 ) m , wherein m is 1 or 2; —C(O)NH(CH 2 ) n CH 3 , wherein n is 2 or 3; or —C(O)NH(CH 2 ) o NH 2 , wherein o is 2 or 3; or a carbocyclic or heterocyclic radical selected from the group consisting of cyclohexyl, pyridyl, pyrrolyl, oxazolyl, oxadiazolyl, pyrazolyl, triazolyl, tetrazolyl, thiadiazolyl, and imidazolidyl, optionally substituted with one or more substituents independently selected from oxo, methyl, ethyl, cyclopropyl, methoxy, methylacetamide, methanamine, azetidine, hydroxyazetidinyl, hydroxycyclobutyl and morpholinomethanone; or
d) X is CR 4 , and R 1 , C, and R 4 are taken together to form a carbocyclic or heterocyclic radical;
Y 1 is —(CH 2 ) p —, wherein p is 0, 1, 2 or 3;
Y 2 is —(CH 2 ) q —, wherein q is 0, 1, 2 or 3;
Z 1 and Z 2 are independently selected from the group consisting of CH or N, with the proviso that at least one of Z 1 and Z 2 is CH;
R 2 is hydrogen, methyl, —C(O)NH 2 , or —CH 2 C(O)NH 2 and R 3 is hydrogen; or R 2 and R 3 are taken together to form 1,2-ethanediyl or 1,3-propanediyl;
Ar is an optionally fluorinated phenylene, an optionally fluorinated furandiyl, or an optionally fluorinated pyridinediyl; and
A is benzoxazol-2-yl, optionally substituted with one or more substituents independently selected from the group consisting of halogen, —OH, —O—CH 3 , —CH 3 , —CF 3 , —OCF 3 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —NHC(O)CH 3 , —NHSO 2 CH 3 , cyclopropoxy, and methylenesulfonyl nitrile.
12. The compound according to claim 11 , wherein W is N.
13. A method of preparing a compound according to claim 1 , comprising:
reacting an intermediate of the formula Ia, wherein L is a leaving group, with an intermediate of the formula Ib, in the presence of a base and a solvent.
14. The method of claim 13 , wherein A is benzoxazol-2-yl, substituted with one or more substituents independently selected from the group consisting of halogen, —OH, —OCH 3 , —CH 3 , —CF 3 , —OCF 3 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —NHC(O)CH 3 , —NHSO 2 CH 3 , cyclopropoxy and methylenesulfonyl nitrile.
15. The method of claim 13 , wherein Ar is an optionally fluorinated phenylene, an optionally fluorinated furandiyl, or an optionally fluorinated pyridinediyl.
16. A pharmaceutical composition, comprising:
an effective amount of a compound according to claim 1 as an active ingredient; and
a pharmaceutically acceptable carrier.
17. A pharmaceutical composition comprising:
an effective amount of a compound according to claim 11 as an active ingredient, and
a pharmaceutically acceptable carrier.
18. A method of preparing a pharmaceutical composition, comprising intimately mixing a pharmaceutically acceptable carrier with a therapeutically effective amount of a compound according to claim 1 .
19. A method of treating influenza in a subject in need thereof, comprising administering to the subject an effective amount of a compound having formula (I) or a stereoisomer, a pharmaceutically acceptable salt, a solvate, or a polymorph thereof, wherein:
B is —CH 2 — or —CH 2 CH 2 —;
W is CH or N;
either:
a) X is CR 4 or N, wherein R 4 is hydrogen, methyl, ethyl or propyl; and R 1 is hydrogen; —CH 2 OH; —CH 2 OCH 3 ; —C(O)CH 3 ; —C(O)OCH 3 ; —C(O)OCH 2 CH 3 ; —C(O) NH 2 ; —C(O) NH(CH 2 ) 2 OCH 3 ; —C(O) NH(CH 3 ); —C(O) NH(CH 2 )CH 3 , wherein n is 2 or 3; or —C(O)NH(CH 2 ) o NH 2 , wherein o is 2 or 3; or a carbocyclic or heterocyclic radical selected from the group consisting of cyclohexyl, pyridyl, pyrrolyl, oxazolyl, oxadiazolyl, pyrazolyl, triazolyl, tetrazolyl, thiadiazolyl, and imidazolidyl, optionally substituted with one or more substituents independently selected from oxo, methyl, ethyl, cyclopropyl, methoxy, methylacetamide, methanamine, azetidine, hydroxyazetidinyl, hydroxycyclobutyl and morpholinomethanone; or
b) X is CR 4 , and R 1 , C, and R 4 are taken together to form a carbocyclic or heterocyclic radical;
Y 1 is —(CH 2 ) p —, wherein p is 0, 1, 2 or 3;
Y 2 is —(CH 2 ) q —, wherein q is 0, 1, 2 or 3;
Z 1 and Z 2 are independently selected from the group consisting of CH or N, with the proviso that at least one of Z 1 and Z 2 is CH;
R 2 is hydrogen, methyl, —C(O)NH 2 , or —CH 2 C(O)NH 2 and R 3 is hydrogen; or R 2 and R 3 are taken together to form 1,2-ethanediyl or 1,3-propanediyl;
Ar is a 5-membered or 6-membered aromatic or heteroaromatic ring, optionally substituted with at least one halogen; and
A is benzyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzofuranyl, isoquinolinyl, quinazolyl, benzimidazolyl, pyridooxazolyl, or methoxyphenyl acetamide, optionally substituted with one or more substituents independently selected from the group consisting of halogen, —OH, —O—CH 3 , —CH 3 , —CF 3 , —OCF 3 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —NHC(O)CH 3 , —NHSO 2 CH 3 , cyclopropoxy or methylenesulfonyl nitrile.
20. A method of treating influenza in a subject in need thereof, comprising administering an effective amount of a composition according to claim 16 to the subject.