US2018118735A1PendingUtilityA1
Inhibitors of leukotriene a4 hydrolase
Est. expiryMar 14, 2033(~6.7 yrs left)· nominal 20-yr term from priority
A61P 43/00A61P 9/10A61P 9/02A61P 9/00A61P 37/02A61P 37/06A61P 35/02A61P 3/10A61P 35/00A61P 37/08A61P 27/16A61P 27/00A61P 27/02A61P 25/02A61P 25/28A61P 29/00A61P 25/16A61P 25/14A61P 25/06A61P 11/06A61P 11/08A61P 1/00A61P 1/04A61P 25/00A61P 19/02A61P 11/00A61P 21/00A61P 17/04A61P 17/00A61P 17/10A61P 13/12A61P 11/02A61P 1/02A61P 17/06A61P 13/08C07D 413/14C07C 229/38C07D 401/14C07D 417/12C07D 405/14C07D 401/04C07D 401/12C07D 403/14C07D 213/74C07D 413/12C07C 217/58C07D 213/62C07D 211/60C07D 213/64C07D 417/14A61K 31/517A61K 31/506A61K 31/4545A61K 31/454A61K 31/451A61K 31/4439A61K 31/44A61K 31/395
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Claims
Abstract
The present invention is directed to compounds encompassed by the Formula (I), pharmaceutical compositions thereof, methods for inhibiting LTA-4 hydrolase, and methods for the treatment of a disease and disorder which is ameliorated by the inhibition of LTA4-h activity. Non-limiting examples of such diseases and conditions include inflammatory and autoimmune diseases and disorders.
Claims
exact text as granted — not AI-modified1 - 35 . (canceled)
36 . A method of treating a disease or disorder ameliorated by the inhibition of leukotriene A 4 hydrolase activity in a mammal, wherein the method comprises administering to a mammal in need thereof an effective amount of a compound of Formula (I):
wherein:
R is i) the group;
or
ii) the group;
or
iii) an optionally substituted heteroaryl;
n 1 , n 2 , and n 3 are each independently 0 to 2;
r is 0 to 4;
R 1a , R 1b , R 1c , R 1d and R 1e are each independently hydrogen, OR 10 , C(O)OR 10 , C(O)R 10 , optionally substituted C 1 -C 12 alkyl, optionally substituted C 2 -C 12 alkenyl, optionally substituted C 2 -C 12 alkynyl, optionally substituted C 3 -C 15 cycloalkyl, optionally substituted C 3 -C 15 cycloalkenyl, halo, cyano, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl;
R 1v , R 1w , R 1x , R 1y and R 1z are each independently hydrogen or fluoro;
R 3 is a direct bond, —O—, —R 12 —O—, —O—R 12 —, —O—R 12 —O—, an optionally substituted straight or branched C 1 to C12 alkylene chain, an optionally substituted straight or branched C 2 to C 12 alkenylene chain, or an optionally substituted straight or branched C 2 to C 12 alkynylene chain;
R 4 is a direct bond, —O—R 12a , an optionally substituted straight or branched C 1 to C 12 alkylene chain, an optionally substituted straight or branched C 2 to C 12 alkenylene chain, or an optionally substituted straight or branched C 2 to C 12 alkynylene chain;
each R 5a and R 6a are each independently hydrogen and optionally substituted alkyl;
or R 5a and R 6a together can be an oxo group;
R 7 is hydrogen, C(O)R 10 , C(O)OR 10 , C(O)—R 13 —N(R 10 )R 11 , N(R 10 )C(O)N(R 10 )R 11 , optionally substituted C 1 -C 12 alkyl, optionally substituted C 2 -C 12 alkenyl, optionally substituted C 2 -C 12 alkynyl, optionally substituted C 3 -C 15 cycloalkyl, optionally substituted C 3 -C 15 cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl;
each R 9 is independently —OR 10 , optionally substituted C 1 -C12 alkyl, optionally substituted C 2 -C 12 alkenyl, optionally substituted C 2 -C 12 alkynyl, halo, optionally substituted aryl, or optionally substituted heteroaryl;
each R 10 and R 11 is independently hydrogen, optionally substituted C 1 -C 12 alkyl, optionally substituted C 2 -C 12 alkenyl, optionally substituted C 2 -C 12 alkynyl, optionally substituted C 3 -C 15 cycloalkyl, optionally substituted C 3 -C 15 cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl;
or R 10 and R 11 , together with the nitrogen to which they are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl;
R 12 is an optionally substituted straight or branched C 1 to C 12 alkylene chain, an optionally substituted straight or branched C 2 to C 12 alkenylene chain, or an optionally substituted straight or branched C 2 to C 12 alkynylene chain;
R 12a is an optionally substituted straight or branched C 1 to C 12 alkylene chain, an optionally substituted straight or branched C 2 to C 12 alkenylene chain, or an optionally substituted straight or branched C 2 to C 12 alkynylene chain;
each R 13 is independently a direct bond, an optionally substituted straight or branched C 1 to C12 alkylene chain, an optionally substituted straight or branched C 2 to C 12 alkenylene chain, or an optionally substituted straight or branched C 3 to C 12 alkynylene chain; and
R 15 is an optionally substituted phenyl or an optionally substituted pyridyl;
as a single stereoisomer or as a mixture of stereoisomers; or a pharmaceutically acceptable salt thereof.
37 . The method of claim 36 , wherein the mammal is a human.
38 . The method of claim 37 , wherein the disease or disorder is an inflammatory or autoimmune disorder.
39 . The method of claim 37 , wherein the disease or disorder is a pulmonary or respiratory tract inflammation.
40 . The method of claim 37 , wherein the disease or disorder is selected from the group consisting of acute or chronic inflammation, anaphylactic reactions, allergic reactions, allergic contact dermatitis, allergic rhinitis, chemical and non-specific irritant contact dermatitis, urticaria, atopic dermatitis, psoriasis, cystic fibrosis, fistulas associated with Crohn's disease, pouchitis, septic or endotoxic shock, hemorrhagic shock, shock-like syndromes, capillary leak syndromes induced by immunotherapy of cancer, acute respiratory distress syndrome, traumatic shock, immune- and pathogen-induced pneumonias, immune complex-mediated pulmonary injury and chronic obstructive pulmonary disease, inflammatory bowel diseases, gastrointestinal ulcers, diseases associated with ischemia-reperfusion injury, immune-complex-mediated glomerulonephritis, autoimmune diseases acute and chronic organ transplant rejection, transplant arteriosclerosis and fibrosis, cardiovascular disorders, complications of diabetes, ocular disorders, neurodegenerative disorders, inflammatory and neuropathic pain including arthritic pain, periodontal disease including gingivitis, ear infections, migraine, benign prostatic hyperplasia, and cancers.
41 . (canceled)
42 . (canceled)
43 . The method of claim 39 , wherein the pulmonary and respiratory inflammation disorders is selected from the group consisting of asthma, chronic bronchitis, bronchiolitis, bronchiolitis obliterans, allergic inflammation of the respiratory tract, eosinophilic granuloma, pneumonias, pulmonary fibroses, pulmonary manifestations of connective tissue diseases, acute or chronic lung injury, chronic obstructive pulmonary diseases, adult respiratory distress syndrome, and other non-infectious inflammatory disorders of the lung characterized by eosinophil infiltration.
44 . The method of claim 40 , wherein the disease or disorder is cystic fibrosis.
45 - 50 . (canceled)
51 . The method of claim 36 , wherein the disease or disorder is an inflammatory skin condition.
52 . The method of claim 51 , wherein the inflammatory skin condition is selected from the group consisting of atopic dermatitis, acne, psoriasis and eczema.
53 . The method of claim 36 , wherein R 15 is an optionally substituted pyridyl.
54 . The method of claim 36 , wherein R 15 is an optionally substituted phenyl.
55 . The method of claim 53 , wherein R 15 has the following structure:
wherein each R 16 is independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 12 alkyl, optionally substituted C 2 -C 12 alkenyl, optionally substituted C 2 -C12 alkynyl, optionally substituted C 3 -C 15 cycloalkyl, optionally substituted C 3 -C 15 cycloalkenyl, halo, cyano, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, OR 10 , NO 2 , S(O) j R 10 , S(O) j NR 10 R 11 , C(O)R 10 , C(O)OR 10 , C(O)—R 13 —N(R 10 )R 11 , N(R 10 )C(O)N(R 10 )R 11 , N(R 10 )R 11 , and N(R 10 )C(O)R 10 ;
wherein w is an integer from 1 to 4; and
wherein j is 0, 1 or 2.
56 . The method of claim 55 , wherein R 15 has the structure:
57 . The method of claim 56 , wherein R 16 is selected from the group consisting of an optionally substituted heterocyclyl containing one or more ring nitrogen atoms, an optionally substituted heteroaryl containing one or more nitrogen atoms, NR 10 R 11 and OR 10 .
58 . The method of claim 56 , wherein R 16 is OR 10 , and wherein R 10 is selected from the group consisting of optionally substituted phenyl.
59 . The method of claim 56 , wherein R 16 is an N-heterocyclyl.
60 . The method of claim 59 , wherein R 16 is the group:
wherein each R 18 is independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 12 alkyl, optionally substituted C 2 -C 12 alkenyl, optionally substituted C 2 -C 12 alkynyl, optionally substituted C 3 -C 15 cycloalkyl, optionally substituted C 3 -C 15 cycloalkenyl, halo, cyano, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, OR 10 , NO 2 , C(O)R 10 , C(O)OR 10 , C(O)—R 13 —N(R 10 )R 11 , N(R 10 )C(O)N(R 10 )R 11 , NR 10 R 11 , and N(R 10 )C(O)R 10 ; and
and z is an integer from 0 to 5.
61 . The method of claim 60 , wherein R 16 has the structure:
62 . The method of claim 54 , wherein R 14 is phenyl optionally substituted with one or more R 17 , wherein R 17 is selected from the group consisting of hydrogen, optionally substituted C 1 -C12 alkyl, optionally substituted C 2 -C 12 alkenyl, optionally substituted C 2 -C 12 alkynyl, optionally substituted C 3 -C 15 cycloalkyl, optionally substituted C 3 -C 15 cycloalkenyl, halo, cyano, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, OR 10 , NO 2 , S(O) j R 10 , S(O) j NR 10 R 11 , C(O)R 10 , C(O)OR 10 , C(O)—R 13 —NR 10 R 11 , NR 10 C(O)NR 10 R 11 , NR 10 R 11 , and NR 10 C(O)R 10 .
63 . The method of claim 62 , wherein R 17 is selected from the group consisting of an optionally substituted heterocyclic containing one or more ring nitrogen atoms, an optionally substituted heteroaryl containing one or more nitrogen atoms, NR 10 R 11 and OR 10 .
64 . The method of claim 63 , wherein R 17 is OR 10 and wherein R 10 is an optionally substituted phenyl.
65 . The method of claim 63 , wherein R 17 is an optionally substituted N-heterocyclyl.
66 . The method of claim 36 , wherein each R 5a and R 6a are each independently hydrogen, alkyl, haloalkyl or hydroxyalkyl.
67 . The method of claim 36 , wherein R is the group:
68 . The method of claim 67 , wherein R 1a is hydrogen, C(O)OR 10 , C(O)R 10 , C(O)NR 10 R 11 , optionally substituted C 1 -C 12 alkyl, optionally substituted C 2 -C 12 alkenyl, optionally substituted C 2 -C 12 alkynyl, optionally substituted C 3 -C 15 cycloalkyl, optionally substituted C 3 -C 15 cycloalkenyl, halo, cyano, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl.
69 . The method of claim 68 , wherein R 1a is hydrogen, C(O)OR 10 , C(O)R 10 , C(O)NR 10 R 11 , optionally substituted alkyl, halo, optionally substituted phenyl, furanyl, thienyl, thiazolyl, or optionally substituted oxazolyl; and wherein R 1b , R 1c , R 1d and R 1e are each hydrogen.
70 . The method of claim 36 , wherein R is an optionally substituted heteroaryl.
71 . The method of claim 70 , wherein R is furanyl, oxazolyl, pyrazolyl, pyridinyl, triazolyl, thiazolyl, or benzothiazolyl, each of which is optionally substituted.
72 . The method of claim 36 , wherein R 3 is O.
73 . The method of claim 36 , wherein R 4 is a direct bond, an optionally substituted methylene or an optionally substituted ethylene.
74 . The method of claim 73 , wherein R 4 is methylene.
75 . The method of claim 73 , wherein R 4 is a direct bond.
76 . The method of claim 73 , wherein R 15 is optionally substituted phenyl.
77 . The method of claim 36 , wherein R 7 is hydrogen or optionally substituted C 1 -C 6 alkyl.
78 . The method of claim 36 selected from the compounds in the Tables below:
X =
Y =
X
Y
H
H
H
H
X
Y
H
CH 2 CH 2 —OMe
Me
H
Me
Me
H
H
H
H
H
H
H
H
H
H
H
H
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