US2022041552A1PendingUtilityA1
Charged ion channel blockers and methods for use
Est. expiryAug 3, 2035(~9 yrs left)· nominal 20-yr term from priority
C07D 211/34A61K 31/452A61P 17/04C07D 207/08A61P 43/00A61P 17/00A61K 45/06A61P 17/06C07D 211/14C07D 295/037A61P 29/00C07C 237/04A61P 9/10A61K 31/40C07D 207/16A61K 31/4425A61P 25/00A61P 19/04A61P 25/02A61K 31/14
65
PatentIndex Score
0
Cited by
0
References
0
Claims
Abstract
The invention provides compounds, compositions, methods, and kits for the treatment of pain, itch, and neurogenic inflammation.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A quaternary amine compound having formula (I)
wherein
R 1F and R 1G together complete a heterocyclic ring having at least one nitrogen atom; and wherein
each of R 1A , R 1B , and R 1C is independently selected from H, halogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, OR 1I , NR 1J R 1K , NR 1L C(O)R 1M , S(O)R 1N , SO 2 R 1O R 1P SO 2 NR 1Q , R 1R , SO 3 R 1S CO 2 R 1T , C(O)R 1U , and C(O)NR 1V R 1W ; and each of R 1I , R 1J , R 1K , R 1L , R 1M , R 1N , R 1O , R 1P , R 1Q , R 1R , R 1S , R 1T , R 1U , R 1V , and R 1W is, independently, selected from H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, and C 2-4 heteroalkyl; wherein
X 1 is selected from —CR 1X R 1Y —, —NR 1Z C(O)—, —OC(O)—, —SC(O)—, —C(O)NR 1AA —, —CO 2 —, and —OC(S)—; and each of R 1X , R 1Y , R 1Z , and R 1AA is independently selected from H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, and C 2-4 heteroalkyl; wherein
each of R 1D and R 1E is independently selected from H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 2-4 heteroalkyl, optionally substituted with halogen, C 3-8 cyclic alkyl, aryl, or heteroaryl, and C 3-6 cycloalkyl or R 1D and R 1E together form a 3-6-membered heterocyclic or heteroalkyl ring; and wherein
R 1H is selected from C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 2-4 heteroalkyl, optionally substituted with halogen, C 3-8 cyclic alkyl, aryl, or heteroaryl, and C 3-6 cycloalkyl.
2 . The compound of claim 1 , wherein X 1 is —NHC(O)—.
3 . The compound of claim 1 or 2 , wherein each of R 1A and R 1B is independently selected from H, halogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, and NR 1J R 1K ; and each of R 1J and R 1K is independently selected from H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, and C 2-4 heteroalkyl; or wherein at least one R 1C is present.
4 . The compound of any one of claims 1 - 3 , wherein R 1D is C 1-4 alkyl optionally substituted with halogen, C 3-8 cyclic alkyl, aryl, or heteroaryl.
5 . The compound of any one of claims 1 - 4 , wherein R 1E is H or C 1-4 alkyl optionally substituted with halogen, C 3-8 cyclic alkyl, aryl, or heteroaryl.
6 . The compound of any one of claims 1 - 5 , wherein R 1H is C 1-4 alkyl optionally substituted with halogen, C 3-8 cyclic alkyl, aryl, or heteroaryl.
7 . The compound of any one of claims 1 - 6 , wherein said compound is a compound in Table 1.
8 . The compound of claim 7 , wherein said compound is
9 . The compound of claim 7 , wherein said compound is
10 . A quaternary amine compound having formula (II)
wherein
m is 0 or 1; wherein
each of R 2A , R 2B , and R 2C , is independently selected from H, halogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, CF 3 , OR 2H , NR 2I R 2J , NR 2K C(O)R 2L , S(O)R 2M , SO 2 R 2N R 2O , SO 2 NR 2P R 2Q , SO 3 R 2R , CO 2 R 2S , C(O)R 2T , and C(O)NR 2U R 2V ; and each of R 2H , R 2I , R 2J , R 2K , R 2L , R 2M , R 2N , R 2O , R 2P , R 2Q , R 2R , R 2S , R 2T , R 2U , and R 2V can, independently, be selected from H, C 1-4 alkyl, C 2-4 alkonyl, C 2-4 alkynyl, and C 2-4 heteroalkyl; wherein
n is 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9 and each R 2F is, independently, selected from halogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, CF 3 , OR 2H , NR 2I R 2J , NR 2K C(O)R 2L , S(O)R 2M , SO 2 R 2N R 2O , SO 2 NR 2P R 2Q , SO 3 R 2R , CO 2 R 2S , C(O)R 2T , and C(O)NR 2U R 2V ; and each of R 2H , R 2I , R 2J , R 2K , R 2L , R 2M , R 2N , R 2O , R 2P , R 2Q , R 2R , R 2S , R 2T , R 2U , and R 2V can, independently, be selected from H, C 1-4 alkyl, C 2-4 alkonyl, C 2-4 alkynyl, and C 2-4 heteroalkyl; and wherein
each of R 2D and R 2E is, independently, selected from C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 2-4 heteroalkyl, optionally substituted with halogen, cyclic alkyl, aryl, or heteroaryl, and C 3-6 cycloalkyl
11 . The compound of claim 10 , wherein each of R 2D and R 2E is C 1-4 alkyl optionally substituted with halogen, cyclic alkyl, aryl, or heteroaryl.
12 . The compound of claim 10 or 11 , wherein each of R 2A , R 2B , and R 2C is independently selected from H, halogen, C 1-4 alkyl, and CF 3 ; or wherein at least one R 2C is present; or wherein at least one R 2F is present.
13 . The compound of any one of claims 10 - 12 , wherein said compound is a compound in Table 2.
14 . The compound of claim 13 , wherein said compound is
15 . A quaternary amine compound having general formula (III)
wherein
n is 0, 1, 2, or 3; wherein
each of R 3A , R 3B , and R 3C is independently selected from H, halogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, OR 3I , NR 3J R 3K , NR 3L C(O)R 3M , S(O)R 3N , SO 2 R 3O R 3P , SO 2 NR 3Q R 3R , SO 3 R 3S , CO 2 R 3T , C(O)R 3U , and C(O)NR 3V R 3W ; and each of R 3I , R 3J , R 3K , R 3L , R 3M , R 3N , R 3O , R 3P , R 3Q , R 3R , R 3S , R 3T , R 3U , R 3V , and R 3W is independently selected from H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, and C 2-4 heteroalkyl; wherein
X 3 is selected from —NHC(O)—, and —C(O)NH; wherein
each of R 3D and R 3E can, independently, be selected from H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 2-4 heteroalkyl, optionally substituted with halogen, cyclic alkyl, aryl, or heteroaryl, and C 3-6 cycloalkyl, or R 1D and R 1E together can form a 3-6-membered heterocyclic or heteroalkyl ring; and wherein
each of R 3F , R 3G , and R 3H is independently selected from C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 2-4 heteroalkyl, optionally substituted with halogen, cyclic alkyl, aryl, or heteroaryl, and C 3-6 cycloalkyl
16 . The compound of claim 15 , wherein X 3 is —NHC(O)—
17 . The compound of claim 15 or 16 , wherein n is 0 or 1.
18 . The compound of any one of claims 15 - 17 , wherein each of R 3A , R 3B , and R 3C is independently selected from H, C 1-4 alkyl, and NR 3J R 3K ; and each of R 3J and R 3K is independently selected from H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, and C 2-4 heteroalkyl.
19 . The compound of any one of claims 15 - 18 , wherein each of R 3E , R 3F , and R 3G is independently selected from C 1-4 alkyl optionally substituted with halogen, cyclic alkyl, aryl, or heteroaryl, and C 3-6 cycloalkyl.
20 . The compound of any one of claims 15 - 19 , wherein said compound is any one of Compound Nos. 21-24 in Table 3.
21 . The compound of any one of claims 15 - 20 , wherein said compound is
22 . A composition comprising the quaternary amine compound of any one of claims 1 - 21 and a pharmaceutically acceptable excipient.
23 . The composition of claim 21 , wherein said composition is formulated for oral, intravenous, intramuscular, rectal, cutaneous, subcutaneous, topical, transdermal, sublingual, nasal, inhalation, vaginal, intrathecal, epidural, or ocular administration.
24 . A method for treating pain, itch, or a neurogenic inflammatory disorder in a patient, said method comprising administering to said patient a composition comprising the quaternary amine compound of any one of claims 1 - 21 , wherein said compound inhibits one or more voltage-gated ion channels present in nociceptors and/or pruriceptors when applied to the internal face of said channels but does not substantially inhibit said channels when applied to the external face of said channels, and wherein said compound is capable of entering nociceptors or pruriceptors through a channel-forming receptor when said receptor is activated and inhibiting said one or more voltage-gated ion channels present in said nociceptors.
25 . The method of claim 24 , wherein said channel-forming receptor is a transient receptor potential ion channel (TRP channel-forming receptor)
26 . The method of claim 24 or 25 , wherein said TRP channel-forming receptor is activated by an exogenous or endogenous agonist.
27 . The method of claim 25 or 26 , wherein said TRP channel-forming receptor is TRPA1 or TRPV1.
28 . The method of claim 27 , wherein said compound is capable of entering nociceptors or pruriceptors through said TRPA1 or TRPV1 receptor when said receptor is activated.
29 . The method of claim 24 , wherein said compound inhibits voltage-gated sodium channels.
30 . The method of claim 24 , wherein said pain is selected from the group consisting of neuropathic pain, inflammatory pain, nociceptive pain, pain due to infections, and procedural pain.
31 . The method of claim 24 , wherein said neurogenic inflammatory disorder is selected from the group consisting of allergic inflammation, asthma, chronic cough, conjunctivitis, rhinitis, psoriasis, inflammatory bowel disease, and interstitial cystitis, atopic dermatitis.
32 . The method of claim 24 , wherein said composition comprises a quaternary amine compound selected from the group consisting of:Join the waitlist — get patent alerts
Track US2022041552A1 — get alerts on status changes and closely related new filings.
We store only your email — no account needed. See our privacy policy.