US2016251374A1PendingUtilityA1
Filamin a binding anti-inflammatory and analgesic
Est. expiryNov 2, 2027(~1.3 yrs left)· nominal 20-yr term from priority
C07D 513/10C07D 498/10C07D 471/10
46
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Claims
Abstract
A compound or its pharmaceutically acceptable salt, optionally including both individual enantiomeric forms, a racemate, diastereomers and mixtures thereof, composition and method are disclosed that can provide analgesia and reduce inflammation. A contemplated compound has a structure that corresponds to Formula A, wherein the R group substituents, d, e, f, k, n, m, D, E, F, K, G, P, Q, W, and Z are defined within.
Claims
exact text as granted — not AI-modifiedWhat is claimed:
1 . A compound that corresponds in structure to Formula A or a pharmaceutically acceptable salt thereof, optionally including both individual enantiomeric forms, a racemate, diastereomers and mixtures thereof
wherein
Q is CHR 9 or C(O);
Z is CHR 10 or C(O), but only one of Q and Z is C(O);
each of m and n is zero or one and the sum of m+n is 1 or 2;
G, P and W are selected from the group consisting of NR 20 , NR 2 , NR 7 , S and O, where R 7 and R 2 are the same or different and are H, C(H) v (D) h where each of v and h is 0, 1, 2 or 3 and v+h=3, C(H) q (D) r -aliphatic C 1 -C 11 hydrocarbyl where each of q and r is 0, 1, or 2 and q+r=0, 1 or 2, aliphatic C 1 -C 12 hydrocarbyl sulfonyl or aliphatic C 1 -C 12 hydrocarboyl, and R 20 is X-circle A-R 1 as defined hereinafter, with the provisos that
i) only one of G, P and W is NR 20 ,
ii) one of G, P and W must be NR 20 ,
iii) P is NR 2 when other than NR 20 ,
iv) one of G and W is other than NR 2 or NR 7 in which R 2 or R 7 is H or an aliphatic C 1 hydrocarbyl when (a) the sum of m+n is 1 and (b) the other of G and W is NR 20 , NR 2 , or NR 7 bonded to a Z or Q, respectively, that is C(O), and
v) P is NR 2 in which R 2 is other than —S(O) 2 C 1 -C 3 -hydrocarbyl when (a) the sum of m+n is 1 and the Q or Z present is CH 2 , (b) the G or W that is not NR 20 is O, and (c) R 20 is —S(O) 2 phenyl-R 1 , where R 1 is H, C 1 -C 3 -hydrocarbyl or halogen;
X is SO 2 , C(O), CH 2 , CD 2 , OC(O), NHC(NH) or NHC(O);
each of d, e, f and k is either zero or one and the sum of (d+e+f+k)=2, e is zero when d is zero, and k is zero when f is zero;
D and F are the same or different and are CH or CD;
E and K are the same or different and are CH 2 , CHD or CD 2 ;
circle A is an aromatic or heteroaromatic ring system containing one ring or two fused rings;
R 1 represents up to three substituent groups that themselves are the same or different, R 1a , R 1b , and R 1c ,
wherein each of those three groups, R 1a-c , is separately selected from the group consisting of H, C 1 -C 6 hydrocarbyl, C 1 -C 6 hydrocarbyloxy, C 1 -C 6 hydrocarbyloxycarbonyl, trifluoromethyl, trifluoromethoxy, C 1 -C 7 hydrocarboyl, hydroxy-, trifluoromethyl- or halogen-substituted C 1 -C 7 hydrocarboyl, C 1 -C 6 hydrocarbylsulfonyl, C 1 -C 6 hydrocarbyloxysulfonyl, halogen, nitro, phenyl, cyano, carboxyl, C 1 -C 7 hydrocarbyl carboxylate, carboxamide or sulfonamide wherein the amido nitrogen in either group has the formula NR 3 R 4 wherein R 3 and R 4 are the same or different and are H, C 1 -C 4 hydrocarbyl, or R 3 and R 4 together with the depicted nitrogen form a 5-7-membered ring that optionally contains 1 or 2 additional hetero atoms that independently are nitrogen, oxygen or sulfur, MAr, where M is —CH 2 —, —O— or —N═N— and Ar is a single-ringed aryl or heteroaryl group, and NR 5 R 6 wherein R 5 and R 6 are the same or different and are H, C 1 -C 4 hydrocarbyl, C 1 -C 4 acyl, C 1 -C 4 hydrocarbylsulfonyl, or R 5 and R 6 together with the depicted nitrogen form a 5-7-membered ring that optionally contains 1 or 2 additional hetero atoms that independently are nitrogen, oxygen or sulfur;
R 8 , R 9 , and R 10 are each H, or two of R 8 , R 9 , and R 10 are H and one is a C 1 -C 8 hydrocarbyl group that is unsubstituted or is substituted with up to three atoms that are the same or different and are oxygen or nitrogen atoms;
R 11 , R 12 , R 13 and R 14 are all H, or R 11 and R 13 are H and R 12 and R 14 are H or D, or one of the pair R 11 and R 12 or the pair R 13 and R 14 together with the depicted ring form a saturated or unsaturated 6-membered ring, and the other pair are each H or they are H and D as recited herein.
2 . The compound or its pharmaceutically acceptable salt according to claim 1 , wherein said compound corresponds in structure to a formula selected from the group consisting of:
3 . The compound or its pharmaceutically acceptable salt according to claim 1 that corresponds in structure to Formula B, optionally including both individual enantiomeric forms, a racemate, diastereomers and mixtures thereof
wherein
G and W are selected from the group consisting of NR 20 , NR 7 , S and O, where R 2 and R 7 are the same or different and are H, C(H) v (D) h where each of v and h is 0, 1, 2 or 3 and v+h=3, C(H) q (D) r -aliphatic C 1 -C 11 hydrocarbyl where each of q and r is 0, 1, or 2 and q+r=0, 1 or 2, aliphatic C 1 -C 12 hydrocarbyl sulfonyl or aliphatic C 1 -C 12 hydrocarboyl, and R 20 is X-circle A-R 1 , with the provisos that:
i) only one of G or W is NR 20 ,
ii) that one of G and W must be NR 20 ,
iii) the G or W that is not NR 20 is other than NR 2 or NR 7 in which R 2 or R 7 is H or an aliphatic C 1 hydrocarbyl when (a) the sum of m+n is 1 and (b) the G or W that is NR 20 is bonded to a Z or Q, respectively, that is C(O), and
iv) R 2 of the depicted NR 2 is other than —S(O) 2 C 1 -C 3 -hydrocarbyl when (a) the sum of m+n is 1 and the Q or Z present is CH 2 , (b) the G or W that is not NR 20 is O, and (c) R 20 is —S(O) 2 phenyl-R 1 , where R 1 is H, C 1 -C 3 -hydrocarbyl or halogen.
4 . The compound or its pharmaceutically acceptable salt according to claim 3 , wherein said compound corresponds in structure to Formula I
wherein D and F are the same or different and are CH 2 , CHD or CD 2 , and W, X, Z, Q, n, m, circle A, R 1 , R 2 , R 8 and the R groups therein defined are as described previously, except that i) R 2 of the depicted NR 2 is other than —S(O) 2 C 1 -C 3 -hydrocarbyl when (a) the sum of m+n is 1 and the Q or Z present is CH 2 , (b) the G or W that is not NR 20 is O, and (c) R 20 is —S(O) 2 phenyl-R 1 , where R 1 is H, C 1 -C 3 -hydrocarbyl or halogen, and ii) W is other than NR 2 or NR 7 in which R 2 or R 7 is H or an aliphatic C 1 hydrocarbyl when (a) the sum of m+n is 1 and (b) Z is C(O).
5 . The compound or its pharmaceutically acceptable salt according to claim 4 , wherein X is C(O), CH 2 , CD 2 , or SO 2 .
6 . The compound or its pharmaceutically acceptable salt according to claim 4 , wherein W is NR 7 , S or O.
7 . The compound or its pharmaceutically acceptable salt according to claim 4 , wherein circle A is selected from the group consisting of phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl (1,3,5-triazinyl, 1,2,4-triazinyl and 1,2,3-triazinyl), furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, naphthyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, isobenzothiophenyl, benzoxazolyl, benzisoxazole, quinolyl, isoquinolyl, quinazolyl, cinnolinyl, quinoxalinyl, naphthyridinyl, and benzopyrimidinyl.
8 . The compound or its pharmaceutically acceptable salt according to claim 4 , wherein one of Q and Z is CH 2 and the other is absent.
9 . The compound or its pharmaceutically acceptable salt according to claim 4 , wherein said compound corresponds in structure to a formula selected from the group consisting of:
10 . The compound or its pharmaceutically acceptable salt according to claim 3 , wherein said compound corresponds in structure to Formula II
wherein D and F are the same or different and are CH 2 , CHD or CD 2 , and X, W, circle A, R 1 , R 2 and the R groups therein defined are as described previously, except that R 2 of the depicted NR 2 is other than —S(O) 2 C 1 -C 3 -hydrocarbyl when W is O, and X-circle A-R 1 is —S(O) 2 phenyl-R 1 , where R 1 is H, C 1 -C 3 -hydrocarbyl or halogen.
11 . The compound or its pharmaceutically acceptable salt according to claim 10 , wherein X is C(O), CH 2 , CD 2 , or SO 2 .
12 . The compound or its pharmaceutically acceptable salt according to claim 10 , wherein W is NR 7 , S or O.
13 . The compound or its pharmaceutically acceptable salt according to claim 10 , wherein circle A is selected from the group consisting of phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl (1,3,5-triazinyl, 1,2,4-triazinyl and 1,2,3-triazinyl), furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, naphthyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, isobenzothiophenyl, benzoxazolyl, benzisoxazole, quinolyl, isoquinolyl, quinazolyl, cinnolinyl, quinoxalinyl, naphthyridinyl, and benzopyrimidinyl.
14 . The compound or its pharmaceutically acceptable salt according to claim 10 , wherein one of D and F is CH 2 .
15 . The compound or its pharmaceutically acceptable salt according to claim 10 , wherein said compound corresponds in structure to a formula selected from the group consisting of:
16 . The compound or its pharmaceutically acceptable salt according to claim 3 , wherein said compound corresponds in structure to Formula III
wherein D and F are the same or different and are CH 2 , CHD or CD 2 ; each of m and n is one; and W, X, Z, Q, circle A, R 1 , R 2 and the R groups therein defined are as described previously, except that i) one of Z and Q is C(O), and ii) W is other than NR 2 or NR 7 in which R 2 and R 7 is H or an aliphatic C 1 hydrocarbyl when Z is C(O).
17 . The compound or its pharmaceutically acceptable salt according to claim 16 , wherein X is C(O), CH 2 , CD 2 , or SO 2 .
18 . The compound or its pharmaceutically acceptable salt according to claim 16 , wherein W is NR 7 , S or O.
19 . The compound or its pharmaceutically acceptable salt according to claim 16 , wherein circle A is selected from the group consisting of phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl (1,3,5-triazinyl, 1,2,4-triazinyl and 1,2,3-triazinyl), furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, naphthyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, isobenzothiophenyl, benzoxazolyl, benzisoxazole, quinolyl, isoquinolyl, quinazolyl, cinnolinyl, quinoxalinyl, naphthyridinyl, and benzopyrimidinyl.
20 . The compound or its pharmaceutically acceptable salt according to claim 16 , wherein one of Q and Z is C(O) and the other is CH 2 .
21 . The compound or its pharmaceutically acceptable salt according to claim 16 , wherein said compound corresponds in structure to a formula selected from the group consisting of:
22 . The compound or its pharmaceutically acceptable salt according to claim 1 that corresponds in structure to Formula C, optionally including both individual enantiomeric forms, a racemate, diastereomers and mixtures thereof
wherein
G and W are selected from the group consisting of NR 2 , NR 7 , S and O, where R 2 and R 7 are the same or different and are H, C(H) v (D) h where each of v and h is 0, 1, 2 or 3 and v+h=3, C(H) q (D) r -aliphatic C 1 -C 11 hydrocarbyl where each of q and r is 0, 1, or 2 and q+r=0, 1 or 2, aliphatic C 1 -C 12 hydrocarbyl sulfonyl or aliphatic C 1 -C 12 hydrocarboyl, with the provisos that:
i) one of G and W must be NR 2 or NR 7 , and
ii) one of G and W is other than NR 2 or NR 7 in which R 2 or R 7 is H or an aliphatic C 1 hydrocarbyl when (a) the sum of m+n is 1 and (b) the other of G and W is NR 2 or NR 7 bonded to a Z or Q, respectively, that is C(O).
23 . The compound or its pharmaceutically acceptable salt according to claim 22 , wherein said compound corresponds in structure to a formula selected from the group consisting of:
24 . The compound or its pharmaceutically acceptable salt according to claim 22 , wherein e and g are both zero.
25 . The compound or its pharmaceutically acceptable salt according to claim 24 , wherein said compound corresponds in structure to Formula IV
wherein D and F are the same or different and are CH 2 , CHD or CD 2 ; and W, X, Z, Q, circle A, R 1 , R 2 , R 8 and the R groups therein defined are as described previously, except that i) W is other than NR 2 or NR 7 in which R 2 or R 7 is H or an aliphatic C 1 hydrocarbyl when the sum of m+n is 1 and Z is C(O), and ii) R 2 of the depicted NR 2 group is other than H or an aliphatic C 1 hydrocarbyl when the sum of m+n is 1, W is NR 2 or NR 7 and Q is C(O).
26 . The compound or its pharmaceutically acceptable salt according to claim 25 , wherein X is C(O), CH 2 , CD 2 , or SO 2 .
27 . The compound or its pharmaceutically acceptable salt according to claim 25 , wherein W is NR 7 , S or O.
28 . The compound or its pharmaceutically acceptable salt according to claim 25 , wherein circle A is selected from the group consisting of phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl (1,3,5-triazinyl, 1,2,4-triazinyl and 1,2,3-triazinyl), furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, naphthyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, isobenzothiophenyl, benzoxazolyl, benzisoxazole, quinolyl, isoquinolyl, quinazolyl, cinnolinyl, quinoxalinyl, naphthyridinyl, and benzopyrimidinyl.
29 . The compound or its pharmaceutically acceptable salt according to claim 25 , wherein one of Q and Z is C(O) and the other is CH 2 .
30 . The compound or its pharmaceutically acceptable salt according to claim 25 , wherein said compound corresponds in structure to a formula:
31 . The compound or its pharmaceutically acceptable salt according to claim 22 , wherein said compound corresponds in structure to Formula V
wherein D and F are the same or different and are CH 2 , CHD or CD 2 ; and X, W, circle A, R 1 , R 2 and the R groups therein defined are as described previously.
32 . The compound or its pharmaceutically acceptable salt according to claim 31 , wherein X is C(O), CH 2 , CD 2 , or SO 2 .
33 . The compound or its pharmaceutically acceptable salt according to claim 31 , wherein W is NR 7 , S or O.
34 . The compound or its pharmaceutically acceptable salt according to claim 31 , wherein circle A is selected from the group consisting of phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl (1,3,5-triazinyl, 1,2,4-triazinyl and 1,2,3-triazinyl), furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, naphthyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, isobenzothiophenyl, benzoxazolyl, benzisoxazole, quinolyl, isoquinolyl, quinazolyl, cinnolinyl, quinoxalinyl, naphthyridinyl, and benzopyrimidinyl.
35 . The compound or its pharmaceutically acceptable salt according to claim 31 , wherein one of D and F is CH 2 .
36 . The compound or its pharmaceutically acceptable salt according to claim 31 , wherein said compound corresponds in structure to a formula:
37 . The compound or its pharmaceutically acceptable salt according to claim 22 , wherein said compound corresponds in structure to Formula VI
wherein D and F are the same or different and are CH 2 , CHD or CD 2 ; and each of m and n is one; W, X, Z, Q, circle A, R 1 , R 2 and the R groups therein defined are as described previously, and each of m and n is 1, except that i) one of Z and Q is C(O), ii) W is other than NR 2 or NR 7 in which R 2 or R 7 is H or an aliphatic C 1 hydrocarbyl when Z is C(O), and iii) R 2 of the depicted NR 2 group is other than H or an aliphatic C 1 hydrocarbyl when W is NR 2 or NR 7 , and Q is C(O).
38 . The compound or its pharmaceutically acceptable salt according to claim 37 , wherein X is C(O), CH 2 , CD 2 , or SO 2 .
39 . The compound or its pharmaceutically acceptable salt according to claim 37 , wherein W is NR 7 , S or O.
40 . The compound or its pharmaceutically acceptable salt according to claim 37 , wherein circle A is selected from the group consisting of phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl (1,3,5-triazinyl, 1,2,4-triazinyl and 1,2,3-triazinyl), furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, naphthyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, isobenzothiophenyl, benzoxazolyl, benzisoxazole, quinolyl, isoquinolyl, quinazolyl, cinnolinyl, quinoxalinyl, naphthyridinyl, and benzopyrimidinyl.
41 . The compound or its pharmaceutically acceptable salt according to claim 36 , wherein one of Q and Z is C(O) and the other is CH 2 .
42 . The compound or its pharmaceutically acceptable salt according to claim 37 , wherein said compound corresponds in structure to a formula:
43 . A pharmaceutical composition comprising an analgesic effective amount of a compound of claim 1 dissolved or dispersed in a physiologically tolerable carrier.
44 . A pharmaceutical composition comprising an analgesic effective amount of a compound of claim 2 dissolved or dispersed in a physiologically tolerable carrier.
45 . A pharmaceutical composition comprising an analgesic effective amount of a compound of claim 22 dissolved or dispersed in a physiologically tolerable carrier
46 . A method of reducing one or both of inflammation and pain in a host mammal in need thereof that comprises administering to that host mammal a pharmaceutical composition containing an analgesic effective amount of a compound of Formula A or a pharmaceutically acceptable salt thereof, optionally including both individual enantiomeric forms, diastereomers and mixtures thereof dissolved or dispersed in a physiologically tolerable carrier
wherein
Q is CHR 9 or C(O);
Z is CHR 10 or C(O), but only one of Q and Z is C(O);
each of m and n is zero or one and the sum of m+n is 1 or 2;
G, P and W are selected from the group consisting of NR 20 , NR 2 , NR 7 , S and O, where R 7 and R 2 are the same or different and are H, C(H) v (D) h where each of v and h is 0, 1, 2 or 3 and v+h=3, C(H) q (D) r -aliphatic C 1 -C 11 hydrocarbyl where each of q and r is 0, 1, or 2 and q+r=0, 1 or 2, aliphatic C 1 -C 12 hydrocarbyl sulfonyl or aliphatic C 1 -C 12 hydrocarboyl, and R 20 is X-circle A-R 1 as defined hereinafter, with the provisos that
i) only one of G, P and W is NR 20 ,
ii) one of G, P and W must be NR 20 ,
iii) P is NR 2 when other than NR 20 ,
iv) one of G and W is other than NR 2 or NR 7 in which R 2 and R 7 is H or an aliphatic C 1 hydrocarbyl when (a) the sum of m+n is 1 and (b) the other of G and W is NR 20 , NR 2 , or NR 7 bonded to a Z or Q, respectively, that is C(O); and
v) P is NR 2 in which R 2 is other than —S(O) 2 C 1 -C 3 -hydrocarbyl when (a) the sum of m+n is 1 and the Q or Z that is present is CH 2 , (b) the G or W that is not NR 20 is O, and (c) R 20 is —S(O) 2 phenyl-R 1 , where R 1 is H, C 1 —O 3 -hydrocarbyl or halogen;
X is SO 2 , C(O), CH 2 , CD 2 , OC(O), NHC(NH) or NHC(O);
each of d, e, f and k is either zero or one and the sum of (d+e+f+k)=2, e is zero when d is zero, and k is zero when f is zero;
D and F are the same or different and are CH or CD;
E and K are the same or different and are CH 2 , CHD or CD 2 ;
circle A is an aromatic or heteroaromatic ring system containing one ring or two fused rings;
R 1 represents up to three substituent groups that themselves are the same or different, R 1a , R 1b , and R 1c ,
wherein each of those three groups, R 1a-c , is separately selected from the group consisting of H, C 1 -C 6 hydrocarbyl, C 1 -C 6 hydrocarbyloxy, C 1 -C 6 hydrocarbyloxycarbonyl, trifluoromethyl, trifluoromethoxy, C 1 -C 7 hydrocarboyl, hydroxy-, trifluoromethyl- or halogen-substituted C 1 -C 7 hydrocarboyl, C 1 -C 6 hydrocarbylsulfonyl, C 1 -C 6 hydrocarbyloxysulfonyl, halogen, nitro, phenyl, cyano, carboxyl, C 1 -C 7 hydrocarbyl carboxylate, carboxamide or sulfonamide wherein the amido nitrogen in either group has the formula NR 3 R 4 wherein R 3 and R 4 are the same or different and are H, C 1 -C 4 hydrocarbyl, or R 3 and R 4 together with the depicted nitrogen form a 5-7-membered ring that optionally contains 1 or 2 additional hetero atoms that independently are nitrogen, oxygen or sulfur, MAr, where M is —CH 2 —, —O— or —N═N— and Ar is a single-ringed aryl or heteroaryl group, and NR 5 R 6 wherein R 5 and R 6 are the same or different and are H, C 1 -C 4 hydrocarbyl, C 1 -C 4 acyl, C 1 -C 4 hydrocarbylsulfonyl, or R 5 and R 6 together with the depicted nitrogen form a 5-7-membered ring that optionally contains 1 or 2 additional hetero atoms that independently are nitrogen, oxygen or sulfur;
R 8 , R 9 , and R 10 are each H, or two of R 8 , R 9 , and R 10 are H and one is a C 1 -C 8 hydrocarbyl group that is unsubstituted or is substituted with up to three atoms that are the same or different and are oxygen or nitrogen atoms;
R 11 , R 12 , R 13 and R 14 are all H, or R 11 and R 13 are H and R 12 and R 14 are H or D, or one of the pair R 11 and R 12 or the pair R 13 and R 14 together with the depicted ring form a saturated or unsaturated 6-membered ring, and the other pair are each H or they are H and D as recited herein.
47 . The method according to claim 46 , wherein said host mammal is selected from the group consisting of a primate, a laboratory rodent, a companion animal, and a food animal.
48 . The method according to claim 46 , wherein said composition is administered a plurality of times over a period of days.
49 . The method according to claim 46 , wherein said composition is administered a plurality of times in one day.
50 . The method according to claim 46 , wherein said composition is administered perorally.
51 . The method according to claim 46 , wherein said composition is administered parenterally.Join the waitlist — get patent alerts
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