Heterocyclic GTP Cyclohydrolase 1 Inhibitors For the Treatment of Pain
The present invention relates to the field of small molecule heterocyclic inhibitors of GTP cyclohydrolase (GCH-I), or a tautomer, prodrug, or pharmaceutically acceptable salt thereof. The invention also features pharmaceutical compositions of the compounds and the medical use of these compounds for the treatment or prevention of pain (e.g., inflammatory pain, nociceptive pain, functional pain, or neuropathic pain).
1 . A compound having a structure according to Formula (I):
or a tautomer, prodrug, or pharmaceutically acceptable salt thereof, wherein:
R 1 , R 2 , R 3 , and R 4 are each, independently, H, optionally substituted C 1-6 alkyl, or R 1 and R 2 , R 2 and R 3 , or R 2 and R 4 combine to form a double bond,
R 5 , R 6 , and R 7 are each, independently, H or optionally substituted C 1-6 alkyl, and
wherein one and only one of R 1 and R 2 , R 2 and R 3 , or R 2 and R 4 combine to form a double bond, and
when R 5 , R 6 , and R 7 are H, R 1 and R 2 combine to form a double bond and R 3 is H, or when R 5 , R 6 , and R 7 are H, R 2 and R 3 combine to form a double bond and R 1 is H, R 4 is not —CH 2 C 6 H 5 , —CH 2 (p-C 6 H 4 —CN), —CH 2 (p-C 6 H 4 —CH 3 ), —CH 2 CH═CH 2 , —CH 2 C(═O)-(p-C 6 H 4 -OMe), —CH 2 C(═O)NH-(o-C 6 H 4 -OEt), —CH 2 C(═O)NH-(2-methoxy-5-chloro-C 6 H 3 ), —CH 2 C(═O)NH-(2-methylcyclohexyl), or —CH 2 C(═O)NH-(p-C 6 H 4 —SO 2 (azepane)).
2 . The compound of claim 1 , wherein R 5 , R 6 , and R 7 are each H.
3 . The compound of claim 1 , wherein R 6 is optionally substituted C 1-6 alkyl.
4 . The compound of claim 1 or 2 , wherein R 1 and R 2 combine to form a double bond.
5 . The compound of claim 4 , wherein R 3 is H.
6 . The compound of claim 1 or 2 , wherein R 2 and R 3 combine to form a double bond.
7 . The compound of claim 6 , wherein R 1 is H.
8 . The compound of any of claims 1 - 7 , wherein R 4 is optionally substituted C 1-6 alkyl.
9 . The compound of claim 8 , wherein said C 1-6 alkyl group comprises a substituent selected from aryl, heteroaryl, cycloalkyl, heterocyclyl, alkenyl, hydroxyl, C 1-3 alkoxy, amino, or C 1-6 alkylamino, and wherein said aryl or heteroaryl is optionally substituted by C 1-4 alkyl, halogen, or nitrile.
10 . The compound of claim 1 , wherein said compound has a structure according to one of the following formulas:
11 . The compound of claim 10 , or a tautomer, prodrug, or pharmaceutically acceptable salt thereof, wherein said compound is selected from the group consisting of:
12 . The compound of claim 1 or 2 , wherein R 2 and R 4 combine to form a double bond.
13 . The compound of claim 1 or 2 , wherein said compound has a structure according to one of the following formulas:
14 . The compound of claim 13 , wherein said compound is selected from the group consisting of:
15 . A compound having a structure according to Formula (III):
or a tautomer, prodrug, or pharmaceutically acceptable salt thereof, wherein
X 1 is O or NR 1 ;
X 2 is O or NR 2 ;
R 1 and R 2 are each, independently, selected from H, or optionally substituted C 1-6 alkyl;
R 3 is H, halogen, or NR 8 R 9 , or R 3 combines with R 4 to form an oxo group; and
R 4 combines with R 1 or R 2 to form a C═N bond or R 4 combines with R 3 to form an oxo group;
R 5 , R 6 , R 7 , R 8 , and R 9 are each, independently, H or optionally substituted C 1-6 alkyl; and
when R 5 , R 6 , and R 7 are H, X 1 is NR 1 , R 1 and R 4 combine to form a C═N double bond, and X 2 is NH, R 3 is not H or NH 2 , and
when R 5 , R 6 , and R 7 are H, X 1 is NH, R 3 combines with R 4 to form an oxo group, and X 2 is NR 2 , R 2 is not H.
16 . The compound of claim 15 , wherein R 5 , R 6 , R 7 , R 8 , and R 9 are each H.
17 . The compound of claim 15 or 16 , wherein said C 1-6 alkyl group comprises a substituent selected from aryl, heteroaryl, cycloalkyl, heterocyclyl, hydroxyl, C 1-3 alkoxy, amino, or C 1-6 alkylamino, and wherein said aryl or heteroaryl is optionally substituted by C 1-4 alkyl, halogen, or nitrile.
18 . The compound of any of claims 15 - 17 , wherein said compound has the following structure:
19 . The compound of claim 18 , wherein said compound is selected from the group consisting of:
20 . The compound of any of claims 15 - 17 , wherein X 1 is NR 1 , X 2 is NR 2 , R 1 and R 2 are each, independently, H or optionally substituted C 1-6 alkyl, and R 3 combines with R 4 to form an oxo group.
21 . The compound of claim 20 , wherein said compound is
22 . The compound of any of claims 15 - 17 , wherein said compound has a structure according to
23 . The compound of claim 22 , wherein R 3 is H.
24 . The compound of claim 22 or 23 , wherein said compound has a structure according to
and wherein R 2 is optionally substituted C 1-6 alkyl.
25 . The compound of claim 24 , wherein said C 1-6 alkyl group comprises a substituent selected from aryl, heteroaryl, cycloalkyl, heterocyclyl, hydroxyl, C 1-3 alkoxy, amino, or C 1-6 alkylamino, and wherein said aryl or heteroaryl is optionally substituted by C 1-4 alkyl, halogen, or nitrile.
26 . The compound of claim 24 , wherein R 3 is Cl or Br.
27 . The compound of claim 22 , wherein said compound is selected from the group consisting of:
28 . The compound of any of claims 15 - 17 , wherein said compound has a structure according to the following formula:
29 . The compound of claim 28 , wherein R 5 , R 6 , R 7 , R 8 , and R 9 are each H, and R 2 is optionally substituted C 1-6 alkyl.
30 . The compound of claim 28 , wherein R 2 is H.
31 . The compound of any of claims 28 - 30 , wherein said C 1-6 alkyl group comprises a substituent selected from aryl, heteroaryl, cycloalkyl, heterocyclyl, hydroxyl, C 1-3 alkoxy, amino, or C 1-6 alkylamino, and wherein said aryl or heteroaryl is optionally substituted by C 1-4 alkyl, halogen, or nitrile.
32 . The compound of claim 29 , wherein said compound is
33 . A compound having a structure according to
or a tautomer, prodrug, or pharmaceutically acceptable salt thereof, or according to
or a tautomer, prodrug, or pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 5 , R 6 , and R 7 are each, independently, H or optionally substituted C 1-6 alkyl.
34 . The compound of claim 33 , wherein R 5 , R 6 , and R 7 are each H.
35 . The compound of claim 33 or 34 , wherein R 1 and R 3 are both H.
36 . The compound of any of claims 33 - 35 , wherein said C 1-6 alkyl group comprises a substituent selected from aryl, heteroaryl, cycloalkyl, heterocyclyl, hydroxyl, C 1-3 alkoxy, amino, or C 1-6 alkylamino, and wherein said aryl or heteroaryl is optionally substituted by C 1-4 alkyl, halogen, or nitrile.
37 . The compound of claim 36 , wherein R 2 is H.
38 . The compound of claim 37 , wherein said compound is selected from the group consisting of:
39 . A compound selected from the group consisting of:
or a tautomer, prodrug, or pharmaceutically acceptable salt thereof,
and
or a tautomer, prodrug, or pharmaceutically acceptable salt thereof, wherein each of R 1 , R 6 , and R 7 , is H or optionally substituted C 1-6 alkyl.
40 . The compound of claim 39 , wherein R 6 and R 7 are both H.
41 . The compound of claim 39 , wherein said C 1-6 alkyl group comprises a substituent selected from aryl, heteroaryl, cycloalkyl, heterocyclyl, hydroxyl, C 1-3 alkoxy, amino, or C 1-6 alkylamino, and wherein said aryl or heteroaryl is optionally substituted by C 1-4 alkyl, halogen, or nitrile.
42 . The compound of claim 41 , wherein R 1 is H.
43 . The compound of claim 39 , wherein said compound is
or a tautomer, prodrug, or pharmaceutically acceptable salt thereof.
44 . A compound according to Formula (VI),
or a tautomer, prodrug, or pharmaceutically acceptable salt thereof, wherein each of R 1 , R 2 , R 6 , and R 7 is, independently, H or optionally substituted C 1-6 alkyl.
45 . The compound of claim 44 , wherein R 6 and R 7 are both H.
46 . The compound of claim 44 , wherein said compound is
47 . The compound of any of claims 1 - 46 , wherein said compound is an inhibitor of GTP cyclohydrolase (GCH-1).
48 . A pharmaceutical composition comprising the compound of any of claims 1 - 47 , or any of the following compounds,
or a tautomer, prodrug, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
49 . A method of treating, reducing, or preventing a condition in a mammal, wherein said method comprises the administration of the compound of any of claims 1 - 47 , or any of the following compounds,
or a tautomer, prodrug, or pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 48 , to said mammal in a dosage sufficient to inhibit GCH-1.
50 . The method of claim 49 , wherein said condition is pain.
51 . The method of claim 50 , wherein said pain is neuropathic, inflammatory, nociceptive, or functional pain.
52 . The method of claim 50 or 51 , wherein said pain is chronic pain.
53 . The method of claim 50 or 51 , wherein said pain is acute pain.
54 . A method of inhibiting GCH-1 in a cell, wherein said method comprises contacting a cell with any of the compounds of claims 1 - 47 , or any of the following compounds,
or a tautomer, prodrug, or pharmaceutically acceptable salt thereof.