US2018282293A1PendingUtilityA1
Neuraminidase Inhibitor Compounds, Compositions and Methods for the Use Thereof in Anti-Viral Treatments
Est. expiryJul 15, 2029(~3 yrs left)· nominal 20-yr term from priority
A61P 43/00C07H 15/18C07H 13/00C07D 309/14C07H 13/04C07H 13/12C07H 1/00A61K 31/655A61P 31/16A61K 31/351C07H 15/12
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Claims
Abstract
Compounds having a structure of Formula I and compositions comprising these compounds are provided. Uses of such compounds and compositions are provided for treatment or prophylaxis of viral infection. In particular, compounds and compositions may be for use in the treatment or prophylaxis of viral influenza.
Claims
exact text as granted — not AI-modified1 . A compound of formula I:
wherein
T is C(O)NH 2 , OH, COOH or COOR 1 ,
wherein R 1 is a C 1-20 linear, branched or cyclic, saturated or unsaturated, optionally substituted alkyl group,
wherein the optional substituent is selected from one or more of the group consisting of: oxo, OH, F, Cl, Br, I, NH 2 , CN, SH, SO 3 H and NO 2 , and
wherein zero to ten backbone carbons of the optionally substituted alkyl group are optionally and independently substituted with O, N or S;
Z is F, Cl, Br, COOMe, or OSO 2 R 2 ,
wherein R 2 is a C 1-20 linear, branched or cyclic, saturated or unsaturated, optionally substituted alkyl group,
wherein the optional substituent is selected from one or more of the group consisting of: oxo, OH, F, Cl, Br, I, NH 2 , CN, SH, SO 3 H and NO 2 , and
wherein zero to ten backbone carbons of the optionally substituted alkyl group are optionally and independently substituted with O, N or S;
A is selected from the group consisting of: H, F, Cl, Br, OH, CN, OR 3 , NO 2 , SO 2 R 3 , SR 3 and COR 3 ,
wherein R 3 is a C 1-20 linear, branched or cyclic, saturated or unsaturated, optionally substituted alkyl group,
wherein the optional substituent is selected from one or more of the group consisting of: oxo, OH, F, Cl, Br, I, NH 2 , CN, SH, SO 3 H and NO 2 , and
wherein zero to ten backbone carbons of the optionally substituted alkyl group are optionally and independently substituted with O, N or S;
D is selected from the group consisting of: H, F, Cl, Br, OH, CN, OR 4 , NO 2 , SO 2 R 4 , SR 4 and COR 4 , provided A and D are not both H, and
wherein R 4 is a C 1-20 linear, branched or cyclic, saturated or unsaturated, optionally substituted alkyl group,
wherein the optional substituent is selected from one or more of the group consisting of: oxo, OH, F, Cl, Br, I, NH 2 , CN, SH, SO 3 H and NO 2 , and
wherein zero to ten backbone carbons of the optionally substituted alkyl group are optionally and independently substituted with O, N or S;
collectively, A and D, optionally form an oxo group;
X is selected from the group consisting of: N 3 , NH 2 , NHR 5 , NHC(NH)NH 2 , NHC(NH)NHR 5 , NR 5 R 6 , NHC(NR 6 )NR 5 , and NHC(NH)N(R 5 )R 6 ,
wherein R 5 and R 6 are independently C 6 H 5 , CH 2 C 6 H 5 or a C 1-8 alkyl group;
E is selected from the group consisting of: NH 2 , NHC(O)CH 3 , OR 7 , NHR 7 and N(R 7 )(R 8 ),
wherein R 7 and R 8 are independently a C 1-20 linear, branched or cyclic, saturated or unsaturated, optionally substituted alkyl group,
wherein the optional substituent is selected from one or more of the group consisting of: oxo, OH, F, Cl, Br, I, NH 2 , CN, SH, SO 3 H and NO 2 , and
wherein zero to ten backbone carbons of the optionally substituted alkyl group are optionally and independently substituted with O, N or S;
Q is selected from the group consisting of: CH 2 OH, CH 2 R 9 , CH(R 9 )(R 10 ), C(R 9 )(R 10 )(R 11 ),
wherein
R 9 , R 10 and R 11 are independently CH 3 or CH 2 CH 3 , and
each of J and G is independently selected from the group: H, OH, OAc, OC(O)CH 3 , F, Cl, Br, NO 2 , CN, OR 12 , SO 2 R 12 , COR 12 and SR 12 ,
wherein R 12 is CH 3 , CH 2 CH 3 or CH 2 CH 2 CH 3 , and
M is H, OH, OAc, OC(O)CH 3 , NH 2 , F or Cl, and
L is H, OH, OAc, OC(O)R 13 or NH 2 ,
wherein R 13 is a C 1-20 linear, branched or cyclic, saturated or unsaturated, optionally substituted alkyl group,
wherein the optional substituent is selected from one or more of the group: oxo, OH, F, Cl, Br, I, NH 2 , CN, SH, SO 3 H and NO 2 , and
wherein zero to ten backbone carbons of the optionally substituted alkyl group are optionally and independently substituted with O, N or S.
2 . A compound of formula I:
wherein
T is C(O)NH 2 , COOH or COOR 1 ,
wherein R 1 is a C 1-20 linear, branched or cyclic, saturated or unsaturated, optionally substituted alkyl group,
wherein the optional substituent is selected from one or more of the group consisting of: oxo, OH, F, Cl, Br, I, NH 2 , CN, SH, SO 3 H and NO 2 , and
wherein zero to ten backbone carbons of the optionally substituted alkyl group are optionally and independently substituted with O, N or S;
Z is F or Cl;
A is F or C 1 ;
D is H;
X is selected from the group consisting of: NH 2 , NHCH 3 , NHCH 2 CH 3 , NHCH 2 CH 2 CH 3 , NHCH 2 CH 2 CH 2 CH 3 , and NHC(NH)NH 2 ;
E is NH 2 or NHC(O)CH 3 ;
Q is selected from the group consisting of:
wherein
each of J and G is independently selected from the group: H, OH, OAc, OC(O)CH 3 , F, Cl, Br, NO 2 , CN,
M is H, OH, OAc; and
L is H, OH, OAc.
3 . The compound of claim 1 , wherein T is COOH or COOR 1 ,
wherein R 1 is a C 1-20 linear, branched or cyclic, saturated or unsaturated, optionally substituted alkyl group,
wherein the optional substituent is selected from one or more of the group consisting of: oxo, OH, F, Cl, Br, I, NH 2 , CN, SH, SO 3 H and NO 2 .
4 . The compound of claim 1 , wherein T is C(O)OCH 3 , C(O)OCH 2 CH 3 , C(O)OCH 2 CH 2 CH 3 , C(O)OCH 2 CH 2 CH 2 CH 3 , C(O)OCH 2 CH 2 CH 2 CH 2 CH 3 , C(O)OCH 2 CH 2 CH 2 CH 2 CH 2 CH 3 , C(O)OCH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 , C(O)OCH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 , or COOH.
5 . The compound of claim 1 , wherein A is selected from the group consisting of: F, Cl, Br, OH, CN, and NO 2 .
6 . The compound of claim 1 , wherein A is selected from the group consisting of: F, C 1 , and OR 3 ,
wherein R 3 is a C 1-20 linear, branched or cyclic, saturated or unsaturated, optionally substituted alkyl group,
wherein the optional substituent is selected from one or more of the group consisting of: oxo, OH, F, Cl, Br, I, NH 2 , CN, SH, SO 3 H and NO 2 .
7 . The compound of claim 1 , wherein A is F or Cl.
8 . The compound of claim 1 , wherein A is F.
9 . The compound of claim 1 , wherein D is selected from the group consisting of: H, F, Cl, Br, OH, CN, and NO 2 , provided A and D are not both H.
10 . The compound of claim 1 , wherein D is selected from the group consisting of: H, F, and Cl, provided A and D are not both H.
11 . The compound of claim 1 , wherein D is F or Cl.
12 . The compound of claim 1 , wherein D is H, provided A and D are not both H.
13 . The compound of claim 1 , wherein X is selected from the group consisting of: NH 2 , NHR 5 , NHCH 3 , NHCH 2 CH 3 , NHC(NH)NH 2 , NHC(NH)NHR 5 , NHC(NR 6 )NR 5 , and NR 5 R 6 , wherein R 5 and R 6 are independently C 6 H 5 , CH 2 C 6 H 5 or a C 1-8 alkyl group.
14 . The compound of claim 1 , wherein X is selected from the group consisting of: NH 2 , NHCH 3 , NHCH 2 CH 3 , and NHC(NH)NH 2 .
15 . The compound of claim 1 , wherein X is NH 2 or NHC(NH)NH 2 .
16 . The compound of claim 1 , wherein E is selected from the group consisting of: NH 2 , NHC(O)CH 3 , OR 7 , NHR 7 ,
wherein R 7 is independently a C 1-10 linear, branched or cyclic, saturated or unsaturated, optionally substituted alkyl group,
wherein the optional substituent is selected from one or more of the group consisting of: oxo, OH, F, Cl, Br, I, NH 2 , CN, SH, SO 3 H and NO 2 , and
wherein zero to ten backbone carbons of the optionally substituted alkyl group are optionally and independently substituted with O, N or S.
17 . The compound of claim 1 , wherein E is NH 2 or NHC(O)CH 3 .
18 . The compound of claim 1 , wherein E is NHC(O)CH 3 .
19 . The compound of claim 1 , wherein Q is selected from the group consisting of: CH 2 R 9 , CH(R 9 )(R 10 ), C(R 9 )(R 10 )(R 11 ),
wherein
R 9 , R 10 and R 11 are independently CH 3 or CH 2 CH 3 , and
each of J and G is independently selected from the group: H, OH, OAc, OC(O)CH 3 , F, Cl, Br, NO 2 , CN, OR 12 , SO 2 R 12 , COR 12 and SR 12 ,
wherein R 12 is CH 3 , CH 2 CH 3 or CH 2 CH 2 CH 3 , and
M is H, OH, OAc, OC(O)CH 3 , NH 2 , F or Cl, and
L is H, OH, OAc, OC(O)R 13 or NH 2 ,
wherein R 13 is a C 1-20 linear, branched or cyclic, saturated or unsaturated, optionally substituted alkyl group, and
wherein the optional substituent is selected from one or more of the group:
oxo, OH, F, Cl, Br, I, NH 2 , CN, SH, SO 3 H and NO 2 .
20 . The compound of claim 1 , wherein Q is selected from the group consisting of:
each of J and G is independently selected from the group: H, OH, OAc, OC(O)CH 3 , F, Cl, Br, NO 2 , CN,
M is H, OH, OAc, OC(O)CH 3 , NH 2 , F or Cl, and
L is H, OH, OAc, OC(O)R 13 or NH 2 .
21 . The compound of claim 1 , wherein Q is selected from the group consisting of:
each of J and G is independently selected from the group: H, OH, OAc, M is H, OH, or OAc, and
L is H, OH, or OAc.
22 . The compound of claim 1 , wherein Q is:
each of J and G is independently selected from the group: H, OH, OAc,
M is H, OH, or OAc, and
L is H, OH, or OAc.
23 . The compound of claim 1 , wherein Q is:
each of J and G is independently selected from the group: OH, OAc,
M is OH, or OAc, and
L is OH, or OAc.
24 .- 29 . (canceled)
30 . A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable excipient.
31 . The pharmaceutical composition of claim 30 for modulating viral neuraminidase activity.
32 . The pharmaceutical composition of claim 31 , wherein the viral neuraminidase is a GH34 neuraminidase.
33 . The pharmaceutical composition of claim 31 , wherein modulating viral neuraminidase activity is for the treatment of influenza in a human subject.
34 . A method of modulating viral neuraminidase activity with one or more compounds according to claim 1 or a pharmaceutically acceptable salt thereof.
35 . The method of claim 34 , wherein the viral neuraminidase is a GH34 neuraminidase.
36 . The method of claim 34 , wherein modulating viral neuraminidase activity is for the treatment of influenza in an animal.
37 . The method of claim 36 , wherein the animal is a human.
38 . A commercial package comprising one or more compounds according to claim 1 or a pharmaceutically acceptable salt thereof.
39 . A method of preparing compound 2:
the method comprising:
reacting a compound SAN3:
with Selectfluor in the presence of MeNO 2 /H 2 O for at least 4 days to form compound 1:
reacting compound 1 with diethylaminosulfur trifluoride (DAST), CH 2 CL 2 at between −30° C.-0° C.
40 . The method according to claim 39 further comprising:
mixing compound 2 with NaOMe and MeOH;
then mixing with Pd/C, H 2 , and MeOH;
then mixing with LiOH, H 2 O, and MeOH to form compound 4:
41 . A method of preparing compound 12:
the method comprising:
mixing compound 2:
with NaOMe and MeOH;
then mixing with AcOH until neutral;
then mixing with PMe 3 , H 2 O, and MeOH; and
then reacting with compound VII:
in Et 3 N, MeOH, and DMF to produce compound VIII:
reacting compound VIII with LiOH, H 2 O, and THF;
then reacting with Pd/C, H 2 , H 2 O, and THF.
42 . A compound selected from one or more of the following:Join the waitlist — get patent alerts
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