PYRIMIDINE-2,4,6-TRIONES FOR USE IN THE TREATMENT OF AMYOTROPHIC LATERAL SCLEROSIS
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.
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.