BENZODIAZOLIUM COMPOUNDS AS ENaC INHIBITORS
First Claim
Patent Images
1. A compound of general formula (I) including all tautomeric forms, all enantiomers and isotopic variants and salts thereof:
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Abstract
Compounds of general formula (I) wherein R1, R2, R3, R4, R5 and X are as defined herein are inhibitors of the epithelial sodium channel (ENaC) and are useful for the treatment or prevention respiratory diseases and conditions, skin conditions and ocular conditions.
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Citations
31 Claims
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1. A compound of general formula (I) including all tautomeric forms, all enantiomers and isotopic variants and salts thereof:
- View Dependent Claims (2, 3, 5, 7, 8, 10, 12, 13, 15, 16, 18, 19, 20, 21, 25, 26, 27, 28, 29, 30)
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2. A compound according to claim 1 which is a compound of general formula (IA):
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3. A compound according to claim 1 wherein R1 is:
H, halo, —
R12, —
C(O)OR12 or —
OR12.
-
5. A compound according to claim 1 wherein R1 is -L1R10.
-
7. A compound according to claim 5 wherein L1 is selected from:
-
—
Z1—
, -Q1-, -Q1Z1—
, -Q1Q2—
, -Q1Q2Z1—
;—
OZ1—
;—
C(O)Q1-, —
C(O)Q1Z1—
;—
C(O)N(R7)Z1—
, C(O)N(R7)Q1-, —
C(O)N(R7)Z1Q1-, —
C(O)N(R7)Q1Z1—
, —
C(O)N(R7)Z1Q1Q2Z2—
, —
C(O)N(R7)Z1O(CH2CH2O)nZ2— and
—
C(O)N(R7)Z1Q1Z2N(R8)Z3—
.
-
-
8. A compound according to claim 5 wherein R10 is H, —
- N(R7)R8, —
N(R7)C(═
NR9)N(R8)2, —
N(R7)C(O)OR8, —
N(R7)—
C(O)—
(C1-3 alkylene)-N+(R8)3, —
N+(R8)3, OR7 or —
C(O)OR7.
- N(R7)R8, —
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10. A compound according to claim 5 wherein R10 is H;
- and wherein;
a) L1 is —
OZ1, wherein Z1 is C1-4 alkylene;
orb) L1 is selected from -Q1-, -Q1Q2- and —
C(O)N(R7)Q1-, where the Q1 group or, for -Q1Q2-, the Q2 group is a nitrogen-containing heterocyclyl group which is linked to the R10 group via a ring nitrogen atom;
orc) L1 is selected from; —
Z1—
, Q1, -Q1Z1—
, -Q1Q2, -Q1Q2Z1—
;—
OZ1—
, —
OQ1Z1—
, —
OQ1Q2Z1—
;—
C(O)Z1—
, —
C(O)Q1Z1—
, —
C(O)Q1Q2Z1—
;—
C(O)N(R7)Z1—
, —
C(O)N(R7)Q1Z1—
, —
C(O)N(R7)Q1Q2Z1—
;—
C(O)OZ1—
, —
C(O)OQ1Z1—
, —
C(O)OQ1Q2-, C(O)OQ1Q2Z1—
;—
C(═
NR9)N(R7)Z1—
, —
C(═
NR9)N(R7)Q1Z1— and
C(═
NR9)N(R7)Q1Q2Z1—
;
ord) L1 is selected from; -Q1Z1—
, —
Z1Q1Z2—
, -Q1Q2Z1—
;—
OQ1Z1—
, —
OZ1Q1Z2—
, —
OQ1Q2Z1—
;—
Z1O(CH2CH2O)nQ1Z2—
, -Q1Z1O(CH2CH2O)nZ2—
, —
Z1O(CH2CH2O)nZ2Q1Z3—
;—
C(O)Z1Q1Z2—
, —
C(O)Q1Z1—
, —
C(O)Q1Q2Z1—
, —
C(O)Q1N(R7)C(O)Z1Q2Z2—
, —
C(O)N(R7)Z1Q1Z2—
, —
C(O)N(R7)Q1Z1—
;—
C(O)N(R7)Q1Q2Z1—
, —
C(O)N(R7)Z1Q1Q2Z2—
, —
C(O)N(R7)Z1Q1OQ2OQ3Z2—
;Z1C(O)N(R7)Q1Z2—
, —
Z1C(O)Q1Z2—
, Z1C(O)N(R7)7Q1Q2Z2—
;—
C(O)OZ1Q1Z2—
, —
C(O)OQ1Z1—
, —
C(O)OQ1Q2Z1—
;Q1C(O)Q2Z1—
, Q1C(O)Q2Q3Z1—
;—
C(═
NR9)N(R7)Z1Q1Z2—
, —
C(═
NR9)N(R7)Q1Z1— and
—
C(═
NR9)N(R7)Q1Q2Z1—
;and the cyclic group Q1, Q2 or Q3 is a nitrogen containing heterocyclyl group linked to Z1 or Z2 or Z3 via a ring nitrogen atom;
ore) L1 contains a moiety Z1, Z2 or Z3 which is linked directly to R10 and is —
CH2[CH(OH)]4—
CH(OH)—
such that the group Z1R10, Z2R10 or Z3R10 is a moiety —
CH2[CH(OH)]4—
CH2OH.
- and wherein;
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12. A compound according to claim 8 wherein:
-
a) R10 is —
C(O)OR7; andL1 is selected from; -Q1- and -Q1Q2- where Q1 or, for -Q1Q2-, Q2 is a carbocyclyl or heterocyclyl group and is linked to R10 via a ring carbon atom;
orC(O)N(R7)Q1, where Q1 is a is a carbocyclyl or heterocyclyl group and is linked to R10 via a ring nitrogen atom;
orb) R10 is selected from —
N(R7)R8, —
N(R7)C(═
NR9)N(R8)2 and —
N(R7)C(O)OR8—
; andL1 is selected from; —
Z1—
,—
OZ1—
;—
C(O)N(R7)Z1—
, —
C(O)N(R7)Z1Q1Q2Z2—
, —
C(O)N(R7)Z1Q1Z2N(R8)Z3, —
C(O)N(R7)Z1O(CH2CH2O)nZ2;—
C(O)N(R7)Q1-, —
C(O)N(R7)Z1Q1- and —
C(O)Q1-, where Q1 is a carbocyclyl or heterocyclyl group and is linked to R10 via a ring carbon atom;and C(O)Q1Z1—
.
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13. A compound according to claim 12, wherein R10 is —
- N(R7)R8; and
one or both of R7 and R8 is a moiety —
CH2[CH(OH)]4—
CH2OH.
- N(R7)R8; and
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15. A compound according to claim 13 wherein R10 is
— - N{CH2[CH(OH)]4—
CH2OH}2.
- N{CH2[CH(OH)]4—
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16. A compound according to claim 12 wherein R10 is —
- —
N(R7)C(═
NR9)N(R8)2; andeach of R7 and R9 is selected from H and C1-4 alkyl; and one or both R8 groups are —
CH2[CH(OH)]4—
CH2OH.
- —
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18. A compound according to claim 1 wherein R2 and R3 are the same or different and are both unsubstituted C1-4 alkyl.
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19. A compound according to claim 1 wherein R4 and/or R5 is H.
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20. A compound according to claim 1 having a cation selected from:
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2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-1-ethyl-3-methyl-1H-1,3-benzodiazol-3-ium; 2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-1-ethyl-6-fluoro-3-methyl-1H-1,3-benzodiazol-3-ium; 2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-6-chloro-1-ethyl-3-methyl-1H-1,3-benzodiazol-3-ium; 2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-1-ethyl-6-methoxy-3-methyl-1H-1,3-benzodiazol-3-ium; 2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-1-ethyl-3-methyl-6-(trifluoromethyl)-1H-1,3-benzodiazol-3-ium; 2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-1-ethyl-3-methyl-6-(trifluoromethoxy)-1H-1,3-benzodiazol-3-ium; 2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-1,3-diethyl-6-methoxy-1H-1,3-benzodiazol-3-ium; 2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-3-benzyl-1-ethyl-6-methoxy-1H-1,3-benzodiazol-3-ium; 2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-1-ethyl-6-methoxy-3-(2-methoxy-2-oxoethyl)-1H-1,3-benzodiazol-3-ium; 2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-3-(carboxylatomethyl)-1-ethyl-6-methoxy-1H-1,3-benzodiazol-3-ium 2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-3-(carbamoylmethyl)-1-ethyl-6-methoxy-1H-1,3-benzodiazol-3-ium; 2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-1-ethyl-6-methoxy-3-[2-(methylsulfanyl)ethyl]-1H-1,3-benzodiazol-3-ium; 2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-1-ethyl-3-(2-hydroxyethyl)-6-methoxy-1H-1,3-benzodiazol-3-ium; 2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-1-ethyl-3-{2-[2-(2-hydroxyethoxy)ethoxy]ethyl}-6-methoxy-1H-1,3-benzodiazol-3-ium; 2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-1-benzyl-3-methyl-1H-1,3-benzodiazol-3-ium; 2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-3-benzyl-6-chloro-1-ethyl-1H-1,3-benzodiazol-3-ium; 2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-3-benzyl-1-ethyl-6-(trifluoromethyl)-1H-1,3-benzodiazol-3-ium; 2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-3-benzyl-1-[2-oxo-2-(piperidin-1-yl)ethyl]-1H-1,3-benzodiazol-3-ium; 2-[({3-amino-6-methyl-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-1-ethyl-6-methoxy-3-methyl-1H-1,3-benzodiazol-3-ium; 2-[({3-amino-7-methyl-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-6-chloro-1,3-diethyl-1H-1,3-benzodiazol-3-ium; 2-[({3-amino-7-chloro-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-6-chloro-1,3-diethyl-1H-1,3-benzodiazol-3-ium; 2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-6-(2-{[(tert-butoxy)carbonyl]amino}ethoxy)-1,3-diethyl-1H-1,3-benzodiazol-3-ium; 2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-6-(3-{[(tert-butoxy)carbonyl]amino}propoxy)-1,3-diethyl-1H-1,3-benzodiazol-3-ium; 2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-6-(3-{[(tert-butoxy)carbonyl]amino}propyl)-1,3-diethyl-1H-1,3-benzodiazol-3-ium; 2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-6-{1-[(tert-butoxy)carbonyl]piperidin-4-yl}-1,3-diethyl-1H-1,3-benzodiazol-3-ium; 2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-6-(1-{1-[(tert-butoxy)carbonyl]piperidin-4-yl}-1H-pyrazol-4-yl)-1,3-diethyl-1H-1,3-benzodiazol-3-ium; 2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-6-(2-aminoethoxy)-1,3-diethyl-1H-1,3-benzodiazol-3-ium; 2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-6-(3-aminopropoxy)-1,3-diethyl-1H-1,3-benzodiazol-3-ium; 2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-6-(3-aminopropyl)-1,3-diethyl-1H-1,3-benzodiazol-3-ium; 2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-1,3-diethyl-6-(piperidin-4-yl)-1H-1,3-benzodiazol-3-ium; 2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-1,3-diethyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1H-1,3-benzodiazol-3-ium; 2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-6-(2-carbamimidamidoethoxy)-1,3-diethyl-1H-1,3-benzodiazol-3-ium; 2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-6-(3-carbamimidamidopropyl)-1,3-diethyl-1H-1,3-benzodiazol-3-ium; 2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-6-carboxy-1,3-diethyl-1H-1,3-benzodiazol-3-ium; 2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-6-[(3-{[(tert-butoxy)carbonyl]amino}propyl)carbamoyl]-1,3-diethyl-1H-1,3-benzodiazol-3-ium formic acid; 2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-6-({1-[(tert-butoxy)carbonyl]piperidin-4-yl}carbamoyl)-1,3-diethyl-1H-1,3-benzodiazol-3-ium; 2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-6-(4-{[(tert-butoxy)carbonyl]amino}piperidine-1-carbonyl)-1,3-diethyl-1H-1,3-benzodiazol-3-ium; 2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-6-{[2-(4-{[(tert-butoxy)carbonyl]amino}piperidin-1-yl)ethyl]carbamoyl}-1,3-diethyl-1H-1,3-benzodiazol-3-ium; -[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-6-[(3-aminopropyl)carbamoyl]-1,3-diethyl-1H-1,3-benzodiazol-3-ium; 2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-1,3-diethyl-6-[(piperidin-4-yl)carbamoyl]-1H-1,3-benzodiazol-3-ium; 2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-6-(4-aminopiperidine-1-carbonyl)-1,3-diethyl-1H-1,3-benzodiazol-3-ium; 2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-6-{[2-(4-aminopiperidin-1-yl)ethyl]carbamoyl}-1,3-diethyl-1H-1,3-benzodiazol-3-ium; 2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-5-(2-{bis[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino}ethoxy)-1,3-diethyl-1H-1,3-benzodiazol-3-ium; 2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-5-(3-{bis[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino}propoxy)-1,3-diethyl-1H-1,3-benzodiazol-3-ium; 2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-5-(3-{bis[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino}propyl)-1,3-diethyl-1H-1,3-benzodiazol-3-ium; 2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-1,3-diethyl-6-{1-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]piperidin-4-yl}-1H-1,3-benzodiazol-3-ium; 2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-1,3-diethyl-6-(1-{1-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]piperidin-4-yl}-1H-pyrazol-4-yl)-1H-1,3-benzodiazol-3-ium; 2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-6-[(3-{bis[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino}propyl)carbamoyl]-1,3-diethyl-1H-1,3-benzodiazol-3-ium; 2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-1,3-diethyl-6-({1-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]piperidin-4-yl}carbamoyl)-1H-1,3-benzodiazol-3-ium; 2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)ethyl]-6-(4-{bis[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino}piperidine-1-carbonyl)-1,3-diethyl-1H-1,3-benzodiazol-3-ium; 2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-6-{[2-(4-{bis[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino}piperidin-1-yl)ethyl]carbarnoyl}-1,3-diethyl-1H-1,3-benzodiazol-3-ium; 2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-5-[4-({bis[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino}methyl)piperidine-1-carbonyl]-1,3-diethyl-1H-1,3-benzodiazol-3-ium; 2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-6-[(3R)-3-{bis[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino}pyrrolidine-1-carbonyl]-1,3-diethyl-1H-1,3-benzodiazol-3-ium; 2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-6-[(3S)-3-{bis[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino}pyrrolidine-1-carbonyl]-1,3-diethyl-1H-1,3-benzodiazol-3-ium; 2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-1,3-diethyl-6-{[(1r,4r)-4-{bis[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino}cyclohexyl]carbamoyl}-1H-1,3-benzodiazol-3-ium; 2-[({3-arnino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-1,3-diethyl-6-{[(1s,4s)-4-{bis[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino}cyclohexyl]carbamoyl}-1H-1,3-benzodiazol-3-ium; 2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-6-[(3-{bis[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino}propyl)(methyl)carbamoyl]-1,3-diethyl-1H-1,3-benzodiazol-3-ium; 2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-6-[(2-{bis[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino}ethyl)carbamoyl]-1,3-diethyl-1H-1,3-benzodiazol-3-ium; 2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-1,3-diethyl-5-{[(14S,15R,16R,17R)-14,15,16,17,18-pentahydroxy-12-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]-3,6,9-trioxa-12-azaoctadecan-1-yl]carbarnoyl}-1H-1,3-benzodiazol-3-ium; 2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-6-({2-[4′
-(2-{bis[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino}ethyl)-[1,1′
-biphenyl]-4-yl]ethyl}carbamoyl)-1,3-diethyl-1H-1,3-benzodiazol-3-ium;2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-6-{[(3S)-3-[(3-{bis[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino}propyl)amino]-3-carbamoylpropyl]carbamoyl}-1,3-diethyl-1H-1,3-benzodiazol-3-ium; 2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-6-{[4-(4-{3-[(3-{bis[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino}propyl)amino]-3-carbamoylpropyl}phenyl)butyl]carbamoyl}-1,3-diethyl-1H-1,3-benzodiazol-3-ium; 2-[({3-amino-7-chloro-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-6-carboxy-1,3-diethyl-1H-1,3-benzodiazol-3-ium; 2-[({3-amino-7-bromo-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-6-carboxy-1,3-diethyl-1H-1,3-benzodiazol-3-ium; 2-[({3-amino-7-chloro-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-6-(4-{bis[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino}piperidine-1-carbonyl)-1,3-diethyl-1H-1,3-benzodiazol-3-ium; 2-[({3-amino-7-bromo-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-6-(4-{bis[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino}piperidine-1-carbonyl)-1,3-diethyl-1H-1,3-benzodiazol-3-ium; and 2-[({3-amino-7-cyano-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-1,3-diethyl-6-methoxy-1H-1,3-benzodiazol-3-ium; and having an anion X−
as defined in claim 1.
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21. A process for the preparation of a compound of general formula (I) including all tautomeric forms, all enantiomers and isotopic variants and salts thereof:
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25. A method for the treatment or prophylaxis of respiratory diseases and conditions, skin conditions or ocular conditions, the method comprising administering to a patient in need of such treatment an effective amount of a compound according to claim 1.
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26. A method according to claim 25, wherein:
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the respiratory diseases and conditions are selected from cystic fibrosis, chronic obstructive pulmonary disease (COPD), chronic bronchitis, emphysema, bronchiectasis, including non-cystic fibrosis bronchiectasis, asthma and primary ciliary dyskinesia; the skin conditions are selected from psoriasis, atopic dermatitis and ichthyosis; and the ocular condition is dry eye disease.
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27. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable excipient.
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28. A pharmaceutical composition according to claim 27 formulated for nasal, bronchial (inhaled) or buccal administration as a dry powder for inhalation, an aerosol or a spray.
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29. A pharmaceutical composition according to claim 27, further including an additional active agent selected from:
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β
2 adrenoreceptor agonists such as metaproterenol, isoproterenol, isoprenaline, albuterol, salbutamol, formoterol, salmeterol, indacaterol, terbutaline, orciprenaline, bitolterol mesylate and pirbuterol;antihistamines, for example histamine H1 receptor antagonists such as loratadine, cetirizine, desloratadine, levocetirizine, fexofenadine, astemizole, azelastine and chlorpheniramine or H4 receptor antagonists; dornase alpha; corticosteroids such as prednisone, prednisolone, flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate mometasone furoate and fluticasone furoate; leukotriene antagonists such as montelukast and zafirlukast; CFTR repair therapies e.g. CFTR potentiators such as Ivacaftor and CFTR correctors such as Lumacaftor and Tezacaftor; TMEM16A modulators, particularly TMEM16A potentiators; and antibiotics.
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30. A product comprising a compound according to claim 1 and an additional agent useful in the treatment or prevention of respiratory conditions as a combined preparation for simultaneous, sequential or separate use in the treatment of a respiratory disease or condition, wherein the additional active agent is selected from:
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β
2 adrenoreceptor agonists such as metaproterenol, isoproterenol, isoprenaline, albuterol, salbutamol, formoterol, salmeterol, indacaterol, terbutaline, orciprenaline, bitolterol mesylate and pirbuterol;antihistamines, for example histamine H1 receptor antagonists such as loratadine, cetirizine, desloratadine, levocetirizine, fexofenadine, astemizole, azelastine and chlorpheniramine or H4 receptor antagonists; dornase alpha; corticosteroids such as prednisone, prednisolone, flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate mometasone furoate and fluticasone furoate; Leukotriene antagonists such as montelukast and zafirlukast; and antibiotics.
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2. A compound according to claim 1 which is a compound of general formula (IA):
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4. (canceled)
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6. (canceled)
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9. (canceled)
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11. (canceled)
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14. (canceled)
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17. (canceled)
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22-24. -24. (canceled)
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31. (canceled)
Specification
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Current AssigneeEnterprise Therapeutics Limited
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Original AssigneeEnterprise Therapeutics Limited
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InventorsMcCARTHY, Clive, HARGRAVE, Jonathan David, HAY, Duncan Alexander, SCHOFIELD, Thomas Beauregard, WENT, Naomi
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Granted Patent
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Time in Patent OfficeDays
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Field of Search
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US Class Current
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CPC Class CodesA61K 45/06 Mixtures of active ingredie...A61K 9/007 Pulmonary tract; AromatherapyA61P 11/12 MucolyticsC07D 487/04 Ortho-condensed systems