US2012046309A1PendingUtilityA1
Pyrimidine-2,4,6-triones for use in the treatment of amyotrophic lateral sclerosis
Est. expiryMay 5, 2029(~2.8 yrs left)· nominal 20-yr term from priority
Inventors:Donald R. KirschRadhia BenmohamedAnthony C. ArvanitesRichard I. MorimotoRichard B. SilvermanGuoyao Xia
A61P 25/00A61P 25/28C07D 413/06C07D 403/06C07D 239/62C07D 403/14C07D 409/06
32
PatentIndex Score
0
Cited by
0
References
0
Claims
Abstract
The present invention relates to the identification of inventive pyrimidine-2,4,6-triones (PYT compounds) and pharmaceutical compositions thereof for treating subjects with amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases. The invention also provides methods of preparing the inventive PYT compounds.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound of Formula I:
or a pharmaceutically acceptable salt thereof, wherein:
L 1 is a valence bond or a bivalent optionally substituted saturated, partially saturated, or unsaturated hydrocarbon chain, wherein 1-3 methylene units of L 1 are optionally and independently replaced by —NR—, —N(R)C(O)—, —C(O)N(R)—, —N(R)SO 2 —, —SO 2 N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —S(O)— or —SO 2 —; or wherein L 1 is —(C(R) 2 ) n — and wherein n is 1 to 6, inclusive;
R 1 is —R, —OR, —CN, —NO 2 , —SR, —S(O)R, —SO 2 R, —C(O)R, —CO 2 R, —C(O)N(R) 2 , —NRC(O)R, —NRC(O)N(R) 2 , —NRSO 2 R, —N(R) 2 , or wherein R 1 is phenyl, a 5-6 membered monocyclic saturated, partially saturated, or aromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered saturated, partially saturated, or aromatic bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein R 1 is optionally substituted with p occurrences of R a , wherein p is 0 to 5, inclusive;
each R a is independently selected from the group consisting of —R, —OR, —CN, —NO 2 , —SR, —S(O)R, —SO 2 R, —C(O)R, —CO 2 R, —C(O)N(R) 2 , —NRC(O)R, —NRC(O)N(R) 2 , —NRSO 2 R, —N(R) 2 , or wherein R a is an optionally substituted 5-6 membered monocyclic saturated, partially saturated, or aromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an optionally substituted 8-10 membered saturated, partially saturated, or aromatic bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
each R is independently hydrogen, halogen, optionally substituted C 1-6 aliphatic, optionally substituted phenyl, optionally substituted benzyl, or two R on the same nitrogen are taken together to form a 5-6 membered saturated, partially saturated, or aromatic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
L 2 is a valence bond or a bivalent optionally substituted saturated, partially saturated, or unsaturated hydrocarbon chain, wherein 1-3 methylene units of L 2 are optionally and independently replaced by —NR—, —N(R)C(O)—, —C(O)N(R)—, —N(R)SO 2 —, —SO 2 N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —S(O)— or —SO 2 —; or wherein L 2 is —(C(R) 2 ) m — and wherein m is 1 to 6, inclusive;
R 2 is —R, —OR, —CN, —NO 2 , —SR, —S(O)R, —SO 2 R, —C(O)R, —CO 2 R, —C(O)N(R) 2 , —NRC(O)R, —NRC(O)N(R) 2 , —NRSO 2 R, —N(R) 2 , or wherein R 2 is phenyl, a 5-6 membered monocyclic saturated, partially saturated, or aromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered saturated, partially saturated, or aromatic bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein R 2 is optionally substituted with q occurrences of R b , wherein q is 0 to 5, inclusive;
each R b is independently selected from the group consisting of —R, —OR, —CN, —NO 2 , —SR, —S(O)R, —SO 2 R, —C(O)R, —CO 2 R, —C(O)N(R) 2 , —NRC(O)R, —NRC(O)N(R) 2 , —NRSO 2 R, —N(R) 2 , or wherein R b is an optionally substituted 5-6 membered monocyclic saturated, partially saturated, or aromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an optionally substituted 8-10 membered saturated, partially saturated, or aromatic bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
R 3 and R 3′ are independently hydrogen, halogen, or optionally substituted C 1-6 aliphatic, or R 3 and R 3′ are taken together to form a C 1 alkenylene optionally substituted with one or two R c groups;
each R c is independently —R, —OR, —CN, —NO 2 , —SR, —S(O)R, —SO 2 R, —C(O)R, —CO 2 R, —C(O)N(R) 2 , —NRC(O)R, —NRC(O)N(R) 2 , —NRSO 2 R, —N(R) 2 , or wherein R c is phenyl, a 5-6 membered monocyclic saturated, partially saturated, or aromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered saturated, partially saturated, or aromatic bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein R c is optionally substituted with t occurrences of R d , wherein t is 0 to 5, inclusive; and
each R d is independently —R, —OR, —CN, —C(R) 3 , —NO 2 , —SR, —S(O)R, —SO 2 R, —C(O)R, —CO 2 R, —C(O)N(R) 2 , —NRC(O)R, —NRC(O)N(R) 2 , —NRSO 2 R, or —N(R) 2 .
2 . The compound according to claim 1 , wherein L 1 is a valence bond.
3 . The compound according to claim 1 , wherein L 1 is a bivalent optionally substituted saturated, partially saturated, or unsaturated hydrocarbon chain, wherein 1-3 methylene units of L 1 are optionally and independently replaced by —NR—, —N(R)C(O)—, —C(O)N(R)—, —N(R)SO 2 —, —SO 2 N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —S(O)— or —SO 2 —.
4 . The compound according to claim 1 , wherein L 1 is a bivalent, optionally substituted, saturated hydrocarbon chain, wherein 1 methylene unit of L 1 is replaced by —NR—, —N(R)C(O)—, —C(O)N(R)—, —N(R)SO 2 —, —SO 2 N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —S(O)— or —SO 2 —.
5 . The compound according to claim 4 , wherein L 1 is a bivalent optionally substituted saturated hydrocarbon chain, wherein 1 methylene unit of L 1 is replaced by —NR—, —O—, or —S—.
6 . The compound according to claim 5 , wherein L 1 is a bivalent optionally substituted saturated hydrocarbon chain, wherein 1 methylene unit of L 1 is replaced by —O—.
7 . The compound according to claim 1 , wherein L 1 is —(C(R) 2 ) n — and wherein n is 1 to 6.
8 . The compound according to claim 7 , wherein n is 2.
9 . The compound according to claim 7 , wherein n is 3.
10 . The compound according to claim 7 , wherein n is 4.
11 . The compound according to claim 7 , wherein at least one R is independently halogen.
12 . The compound according to claim 7 , wherein at least one R is independently fluorine.
13 . The compound according to claim 1 , wherein R 1 is —R, hydrogen, halogen, —OR, —CN, —NO 2 , —SR, —S(O)R, —SO 2 R, —C(O)R, —CO 2 R, —C(O)N(R) 2 , —NRC(O)R, —NRC(O)N(R) 2 , —NRSO 2 R, or —N(R) 2 .
14 . The compound according to claim 1 , wherein R 1 is unsubstituted phenyl.
15 . The compound according to claim 1 , wherein R 1 is phenyl optionally substituted with R a .
16 . The compound according to claim 15 , wherein p is 1.
17 . The compound according to claim 15 , wherein p is 2.
18 . The compound according to claim 15 , wherein p is 3.
19 . The compound according to claim 15 , wherein p is 4.
20 . The compound according to claim 15 , wherein p is 5.
21 . The compound according to claim 15 , wherein at least one R a is independently halogen.
22 . The compound according to claim 15 , wherein at least two R a are independently halogen.
23 . The compound according to claim 15 , wherein at least one R a is independently —OR.
24 . The compound according to claim 15 , wherein at least two R a are independently —OR.
25 . The compound according to claim 15 , wherein at least one R a is independently selected from the group consisting of methyl, ethyl, propyl, or butyl.
26 . The compound according to claim 1 , wherein R 1 is of the formula:
27 . The compound according to claim 1 , wherein R 1 is selected from:
28 . The compound according to claim 1 , wherein R 1 is selected from:
29 . The compound according to claim 1 , wherein R 1 is selected from:
30 . The compound according to claim 1 , wherein R 1 is selected from:
31 . The compound according to claim 1 , wherein R 1 is of the formula:
32 . The compound according to claim 1 , wherein R 1 is an optionally substituted 5-membered monocyclic saturated, partially saturated, or aromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
33 . The compound according to claim 1 , wherein R 1 is an unsubstituted 5-membered aromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
34 . The compound according to claim 1 , wherein R 1 is a substituted 5-membered aromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
35 . The compound according to claim 1 , wherein R 1 is optionally substituted thiophene.
36 . The compound according to claim 1 , wherein R 1 is optionally substituted furan.
37 . The compound according to claim 1 , wherein R 1 is an unsubstituted 6-membered monocyclic saturated, partially saturated, or aromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
38 . The compound according to claim 1 , wherein R 1 is a substituted 6-membered monocyclic saturated, partially saturated, or aromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
39 . The compound according to claim 1 , wherein R 1 is an optionally substituted 8 membered saturated, partially saturated, or aromatic bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
40 . The compound according to claim 1 , wherein R 1 is an optionally substituted 9 membered saturated, partially saturated, or aromatic bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
41 . The compound according to claim 1 , wherein R 1 is an optionally substituted 10 membered saturated, partially saturated, or aromatic bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
42 . The compound according to claim 1 , wherein R 1 is R.
43 . The compound according to claim 42 , wherein R is selected from the group consisting of hydrogen, methyl, ethyl, propyl, or butyl.
44 . The compound according to claim 1 , wherein L 2 is a valence bond.
45 . The compound according to claim 1 , wherein L 2 is a bivalent optionally substituted saturated, partially saturated, or unsaturated hydrocarbon chain, wherein 1-3 methylene units of L 2 are optionally and independently replaced by —NR—, —N(R)C(O)—, —C(O)N(R)—, —N(R)SO 2 —, —SO 2 N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —S(O)— or —SO 2 —.
46 . The compound according to claim 1 , wherein L 2 is a bivalent optionally substituted saturated hydrocarbon chain, wherein 1 methylene unit of L 2 is replaced by —NR—, —N(R)C(O)—, —C(O)N(R)—, —N(R)SO 2 —, —SO 2 N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —S(O)— or —SO 2 —.
47 . The compound according to claim 1 , wherein L 2 is a bivalent optionally substituted saturated hydrocarbon chain, wherein 1 methylene unit of L 2 is replaced by —NR—, —O—, or —S—.
48 . The compound according to claim 1 , wherein L 2 is a bivalent optionally substituted saturated hydrocarbon chain, wherein 1 methylene unit of L 2 is replaced by —O—.
49 . The compound according to claim 1 , wherein L 2 is —(C(R) 2 ) m — and wherein m is 1 to 6.
50 . The compound according to claim 49 , wherein m is 2.
51 . The compound according to claim 49 , wherein m is 3.
52 . The compound according to claim 49 , wherein m is 4.
53 . The compound according to claim 49 , wherein at least one R is independently halogen.
54 . The compound according to claim 49 , wherein at least one R is independently fluorine.
55 . The compound according to claim 1 , wherein R 2 is —R, —OR, —CN, —NO 2 , —SR, —S(O)R, —SO 2 R, —C(O)R, —CO 2 R, —C(O)N(R) 2 , —NRC(O)R, —NRC(O)N(R) 2 , —NRSO 2 R, or —N(R) 2 .
56 . The compound according to claim 1 , wherein R 2 is unsubstituted phenyl.
57 . The compound according to claim 1 , wherein R 2 is phenyl optionally substituted with R b .
58 . The compound according to claim 57 , wherein q is 1.
59 . The compound according to claim 57 , wherein q is 2.
60 . The compound according to claim 57 , wherein q is 3.
61 . The compound according to claim 57 , wherein q is 4.
62 . The compound according to claim 57 , wherein q is 5.
63 . The compound according to claim 57 , wherein at least one R b is independently halogen.
64 . The compound according to claim 57 , wherein at least two R b are independently halogen.
65 . The compound according to claim 57 , wherein at least one R b is independently —OR.
66 . The compound according to claim 57 , wherein at least two R b are independently —OR.
67 . The compound according to claim 57 , wherein at least one R b is independently selected from the group consisting of methyl, ethyl, propyl, or butyl.
68 . The compound according to claim 1 , wherein R 2 is of the formula:
69 . The compound according to claim 1 , wherein R 2 is selected from:
70 . The compound according to claim 1 , wherein R 2 is selected from:
71 . The compound according to claim 1 , wherein R 2 is selected from:
72 . The compound according to claim 1 , wherein R 2 is selected from:
73 . The compound according to claim 1 , wherein R 2 is of the formula:
74 . The compound according to claim 1 , wherein R 2 is an optionally substituted 5-membered monocyclic saturated, partially saturated, or aromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
75 . The compound according to claim 1 , wherein R 2 is an unsubstituted 5-membered aromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
76 . The compound according to claim 1 , wherein R 2 is a substituted 5-membered aromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
77 . The compound according to claim 1 , wherein R 2 is optionally substituted thiophene.
78 . The compound according to claim 1 , wherein R 2 is optionally substituted furan.
79 . The compound according to claim 1 , wherein R 2 is an unsubstituted 6-membered monocyclic saturated, partially saturated, or aromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
80 . The compound according to claim 1 , wherein R 2 is a substituted 6-membered monocyclic saturated, partially saturated, or aromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
81 . The compound according to claim 1 , wherein R 2 is an optionally substituted 8 membered saturated, partially saturated, or aromatic bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
82 . The compound according to claim 1 , wherein R 2 is an optionally substituted 9 membered saturated, partially saturated, or aromatic bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
83 . The compound according to claim 1 , wherein R 2 is an optionally substituted 10 membered saturated, partially saturated, or aromatic bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
84 . The compound according to claim 1 , wherein R 2 is R.
85 . The compound according to claim 84 , wherein R is selected from the group consisting of hydrogen, methyl, ethyl, propyl, or butyl.
86 . The compound according to claim 1 , wherein at least one of R 3 or R 3′ is hydrogen.
87 . The compound according to claim 1 , wherein both R 3 and R 3′ are hydrogen.
88 . The compound according to claim 1 , wherein at least one of R 3 or R 3′ is fluorine.
89 . The compound according to claim 1 , of one of the formulae:
90 . The compound according to claim 1 , of one of the formulae:
91 . The compound according to claim 1 , of the formula:
92 . The compound according to claim 1 , of one of the formulae:
93 . The compound according to claim 1 , of one of the formulae:
94 . The compound according to claim 1 , of any one of the formulae:
95 . The compound according to claim 1 , of any one of the formulae:
96 . The compound according to claim 1 , of the following formula:
97 . The compound according to claim 1 , of the following formula:
98 . The compound according to claim 97 , wherein at least one R a is independently a halogen.
99 . The compound according to claim 97 , wherein at least one R b is independently a halogen.
100 . The compound according to claim 1 , wherein R 3 and R 3′ are taken together to form a C 1 alkenylene optionally substituted with one or two R c groups.
101 . The compound according to claim 1 , wherein R 3 and R 3′ are taken together to form a C 1 alkenylene optionally substituted with one R c group.
102 . The compound according to claim 1 , of the formula:
103 . The compound according to claim 1 , of the formula:
104 . The compound according to claim 1 , of the formula:
105 . The compound according to claim 1 , of any one of the following formulae:
106 . The compound according to claim 1 , of any one of the formulae:
107 . The compound according to claim 1 , of the formula:
108 . The compound according to claim 1 , of either of the following formulae:
109 . The compound according to claim 1 , of either of the following formulae:
110 . The compound according to claim 1 , of either of the following formulae:
111 . The compound according to claim 1 , of either of the following formulae:
112 . The compound according to claim 1 , of any one of the following formulae:
113 . The compound according to claim 1 , of any one of the following formulae:
114 . The compound according to claim 1 , of any one of the following formulae:
115 . The compound according to claim 1 , of any one of the following formulae:
116 . The compound according to claim 1 , of any one of the following formulae:
117 . A pharmaceutical composition comprising:
a compound of any one of claims 1 - 116 , and a pharmaceutically acceptable excipient.
118 . The composition of claim 117 , wherein the neurodegenerative disease is ALS.
119 . A pharmaceutical composition for treating a disease associated with abnormal protein aggregation comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable excipient.
120 . A method comprising steps of:
administering to a subject suffering from or susceptible to amyotrophic lateral sclerosis an effective amount of a compound of any of claims 1 - 116 , such that the severity or incidence of one or more symptoms of ALS is reduced, or its onset is delayed.
121 . A method comprising steps of:
administering to a subject suffering from or susceptible to abnormal protein aggregation an amount of a compound of any of claims 1 - 116 , sufficient to reduce or delay such abnormal protein aggregation.
122 . The method of claim 121 , wherein the protein aggregates are G93A SOD1 protein aggregates.
123 . The method of claim 122 , wherein the protein aggregates are G85R SOD1 protein aggregates.
124 . The method of claim 120 or claim 121 , wherein the subject is a test subject.
125 . The method of claim 120 or claim 121 , wherein the subject is a human.
126 . The method of claim 120 or claim 121 , wherein the subject is an adult human.
127 . The method of claim 120 or claim 121 , wherein the compound is administered in doses of less than about 20 mg/day.
128 . The method of claim 120 or claim 121 , wherein the compound is administered in doses ranging from about 1 mg/kg/day to about 50 mg/kg/day.
129 . The method of claim 120 or claim 121 , wherein the compound is administered in doses ranging from about 1 mg/kg/day to about 40 mg/kg/day.
130 . The method of claim 120 or claim 121 , wherein the compound is administered in doses ranging from about 1 mg/kg/day to about 30 mg/kg/day.
131 . The method of claim 120 or claim 121 , wherein the compound is administered in doses ranging from about 1 mg/kg/day to about 20 mg/kg/day.
132 . The method of claim 120 or claim 121 , wherein the compound is administered in doses ranging from about 1 mg/kg/day to about 10 mg/kg/day.
133 . The method of claim 120 or claim 121 , wherein the compound is administered systemically.
134 . The method of claim 133 , wherein the compound is administered intravenously.
135 . The method of claim 133 , wherein the compound is administered intraperitonealy.
136 . The method of claim 133 , wherein the compound is administered orally.
137 . The method of claim 120 or claim 121 , further comprising the step of monitoring the subject.
138 . The method of claim 137 , wherein the subject is monitored by monitoring motor function.
139 . The method of claim 120 or claim 121 , wherein the subject is monitored by monitoring body weight.
140 . The method of claim 120 or claim 121 , wherein the subject is monitored by monitoring survival time.
141 . The method of claim 120 or claim 121 , wherein the subject is monitored one, two, three, four, or five times a day.
142 . The method of claim 120 or claim 121 , wherein the subject is monitored one, two, three, four or five times a week.
143 . The method of claim 142 , wherein the subject is monitored twice a week.
144 . The method of claim 142 , wherein said monitoring occurs for the duration of the subject's life.
145 . The method of claim 144 , wherein the subject is monitored three times a day.
146 . A method comprising the steps of:
administering to a cell in vitro a therapeutically effective amount of the compound of any of claims 1 - 116 to inhibit or reverse abnormal protein aggregation.
147 . A method comprising steps of:
administering to a cell in vitro an effective amount of the compound of any of claims 1 - 116 to protect against aggregated SOD1.
148 . A method comprising steps of:
administering to a cell in vitro an effective amount of the compound of any of claims 1 - 116 to modulate proteasome function.
149 . The method of any one of claims 147 - 149 , wherein the cells are mammalian cells.
150 . The method of claim 146 , wherein the protein aggregates are G93A SOD1 protein aggregates.
151 . The method of claim 146 , wherein the protein aggregates are G85R SOD1 protein aggregates.
152 . The method of claim 147 , wherein the SOD1 is G93A SOD1.
153 . The method of claim 147 , wherein the SOD1 is G85R SOD1.
154 . The compound of any one of claims 1 - 116 , which compound is in an isolated state.
155 . The compound of claim 154 , which compound is in a pure state.Cited by (0)
No later patents cite this yet.
References (0)
No backward citations on record.