US2023107360A1PendingUtilityA1
Charged ion channel blockers and methods for use
Est. expiryMar 11, 2039(~12.7 yrs left)· nominal 20-yr term from priority
C07D 237/08C07D 231/12C07D 215/10C07D 213/71C07D 231/56C07D 231/14A61P 17/04C07D 233/90A61P 25/00C07D 213/82C07D 471/04C07D 213/26C07D 233/61C07D 213/04C07D 213/73C07D 213/56C07D 241/12C07D 217/22C07D 213/65C07D 213/74C07D 233/56C07D 217/10C07D 401/04C07D 213/75C07D 213/61C07D 213/85A61P 11/14C07D 233/64A61P 11/04A61K 31/4425
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Claims
Abstract
The invention provides compounds of Formula (I), or pharmaceutically acceptable salts 5 thereof: The compounds, compositions, methods and kits of the invention are useful for the treatment of pain, cough, itch, and neurogenic inflammation.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound represented by Formula (I)
wherein:
Y - is a pharmaceutically acceptable anion;
R F and R G together with the N + to which they are attached form an optionally substituted heteroaryl ring having zero, one or more heteroatoms in addition to the N + , or an optionally substituted bicyclic heteroaryl ring having zero, one or more heteroatoms in addition to the N + ;
R A , R B , and R c are each independently selected from H, D halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, nitrile, OR I , NR J R K , NR L C(O)R M , S(O)R N , SO 2 R O , SO 2 R O R P , SO 2 NR Q R R , SO 3 R S , CO 2 R T , C(O)R U , and C(O)NR V R W ; or R B and vicinal R C together with the carbon atoms to which they are attached form a substituted or unsubstituted 3-7-membered cycloalkyl or a substituted or unsubstituted aryl;
each of R I , R J , R K , R L , R M , R N , R O , R P , R Q , R R , R S , R T , R U , R V , and R W is independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl;
X 1 is selected from —CR X R Y —, —NR Z C(O)—, —NR Z C(O)CR X R Y —,— OC(O)—, —SC(O)—, —C(O)NR 1A —, —C(O)O—, —NR Z S(O) —, — S(O)NR Z —, —NR X C(O)NR Y —, —(O)CS—, —C(O)—, —S(O)—, and —S(O) 2 —;
each of R X , R Y , R z , and R 1A is independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl; and
each of R D and R E is independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, cycloalkyl, aryl, or heteroaryl; or R D and R E together with the carbon to which they are attached form a substituted or unsubstituted C 3 -C 7 cycloalkyl or a substituted or unsubstituted heterocyclic ring; or R D and R Z together with the carbon and the —N—C(O)—to which they are attached form an optionally substituted 5-8-membered lactam.
2 . The compound of claim 1 , wherein Y - is iodide, bromide, or chloride.
3 . The compound of claim 1 , wherein X 1 is —NHC(O)—.
4 . The compound of claim 1 , wherein each of R A and R B is independently selected from H, D, nitrile, halogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, and NR J R K ; and each of R J and R K is independently selected from H, substituted or unsubstituted C 1-4 alkyl, substituted or unsubstituted C 2-4 alkenyl, and substituted or unsubstituted C 2-4 alkynyl.
5 . The compound of claim 1 , wherein R A , R B , and R C are each independently selected from H, D, halogen, OR I , substituted or unsubstituted C 1 -C 4 alkyl, and NR J R K ; wherein each of R I , R J and R K is independently selected from H and substituted or unsubstituted C 1 -C 4 alkyl.
6 . The compound of claim 1 , wherein each of R A and R B is CH 3 , and R C is selected from the group consisting of H, CH 3 , halogen, nitrile, methoxy, and ethoxy.
7 . The compound of claim 1 , wherein R D is C 1-4 alkyl optionally substituted with a substituent selected from the group consisting of halogen, oxygen, C 3 - 8 cyclic alkyl, aryl, and heteroaryl.
8 . The compound of claim 1 , wherein R E is H, D, or C 1-4 alkyl optionally substituted with a substituent selected from the group consisting of halogen, oxygen, C 3 - 8 cyclic alkyl, aryl, and heteroaryl.
9 . The compound of claim 1 , wherein R D and R E are both hydrogen.
10 . The compound of claim 1 , wherein R D is hydrogen and R E is an C 1 -C 6 alkyl.
11 . The compound of claim 1 , wherein R D and R E are taken together with the carbon to which they are attached to form a C 3 -C 6 cycloalkyl including, but not limited to, cyclopropyl and cyclobutyl.
12 . The compound of claim 1 , wherein R F and R G together with the N + form an optionally substituted heteroaryl ring or an optionally substituted bicyclic heteroaryl ring comprising one or more heteroatoms selected from the following:
.
13 . The compound of claim 1 , wherein R F and R G together with the N + form an optionally substituted pyridinium ring.
14 . The compound of claim 1 , wherein the heteroaryl ring or bicyclic heteroaryl ring formed by R F and R G together is optionally substituted with a substituent selected from the group consisting of substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted and unsubstituted 3- to 15-membered heterocyclyl, alkoxy, or CO 2 R 2A , wherein R 2A is selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl.
15 . The compound of claim 1 , wherein the compound is selected from those below:
Compound
Chemical Structure
Compound 1
Compound 2
Compound 3
Compound 4
Compound 5
Compound 6
Compound 7
Compound 8
Compound 9
Compound 10
Compound 11
Compound 12
Compound 13
Compound 14
Compound 15
Compound 16
Compound 17
Compound 18
Compound 19
Compound 20
Compound 21
Compound 22
Compound 23
Compound 24
Compound 25
Compound 26
Compound 27
Compound 28
Compound 29
Compound 30
Compound 31
Compound 32
Compound 33
Compound 34
Compound 35
Compound 36
Compound 37
Compound 38
Compound 39
Compound 40
Compound 41
Compound 42
Compound 43
Compound 44
Compound 45
Compound 46
Compound 47
Compound 48
Compound 49
Compound 50
Compound 51
Compound 52
Compound 53
Compound 54
Compound 55
Compound 56
Compound 57
Compound 58
Compound 59
Compound 60
Compound 61
Compound 62
Compound 63
Compound 64
Compound 65
Compound 66
Compound 67
Compound 68
Compound 69
Compound 70
Compound 71
Compound 72
Compound 73
Compound 74
Compound 75
Compound 76
Compound 77
Compound 78
Compound 79
Compound 80
Compound 81
Compound 82
Compound 83
Compound 84
Compound 85
Compound 86
Compound 87
Compound 88
Compound 89
Compound 90
Compound 91
Compound 92
Compound 93
Compound 94
Compound 95
Compound 96
Compound 97
Compound 98
Compound 99
Compound 100
Compound 101
Compound 102
Compound 103
Compound 104
Compound 105
Compound 106
Compound 107
Compound 108
Compound 109
Compound 110
Compound 111
Compound 112
Compound 113
Compound 114
Compound 115
Compound 116
Compound 117
Compound 118
Compound 119
Compound 120
Compound 121
Compound 122
Compound 123
Compound 124
Compound 125
Compound 126
Compound 127
Compound 128
Compound 129
.
16 . A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
17 . The composition of claim 16 , wherein said composition is formulated for oral, intravenous, intramuscular, rectal, cutaneous, subcutaneous, topical, transdermal, sublingual, nasal, inhalation, vaginal, intrathecal, epidural, or ocular administration.
18 . A method for treating pain, cough, itch, or a neurogenic inflammatory disorder in a patient, comprising administering to said patient an effective of a compound of claim 1 .
19 . The method of claim 18 , wherein said pain is selected from the group consisting of pain due to back and neck pain, lower back pain, cancer pain, gynecological and labor pain, fibromyalgia, arthritis, rheumatoid arthritis, osteoarthritis, rheumatological pains, orthopedic pains, acute and post herpetic neuralgia and other neuropathic pains (including peripheral neuropathy), sickle cell crises, vulvodynia, peri-anal pain, irritable bowel disease, irritable bowel syndrome, inflammatory bowel disease, oral mucositis, esophagitis, interstitial cystitis, urethritis and other urological pains, dental pain, headaches, trigeminal trophic syndrome, erythromelalgia, abdominal wall pain, chronic abdominal wall pain, allergic rhinitis, muscle pain, rectal pain, Levator ani syndrome, proctalgia fugax, hemorrhoid pain, stomach pain, skin ulcers, stomach ulcers, burn pain, ophthalmic irritation, conjunctivitis (e.g., allergic conjunctivitis), eye redness, dry eye, dry eye syndrome (chronic ocular pain), complex regional pain syndrome, post-surgical ocular pain, postoperative pain, acute postoperative pain, and procedural pain (i.e., pain associated with injections, draining an abscess, surgery, dental procedures, ophthalmic procedures, arthroscopies and use of other medical instrumentation, cosmetic surgical procedures, dermatological procedures, setting fractures, biopsies, and the like).
20 . The method of claim 18 , wherein said cough is selected from the group consisting of cough in patients with asthma, COPD, asthma-COPD overlap syndrome (ACOS), interstitial pulmonary fibrosis (IPF), idiopathic pulmonary fibrosis, post viral cough, post-infection cough, chronic idiopathic cough and lung cancer.
21 . The method of claim 18 , wherein said itch is selected from the group consisting of itch due to pruritus, brachioradial pruritus, chronic idiopathic pruritus, genital/anal pruritus, notalgia paresthetica, scalp pruritus, allergic dermatitis, contact dermatitis, atopic dermatitis, hand eczema, poison ivy, infections, parasites, insect bites, pregnancy, metabolic disorders, liver or renal failure, drug reactions, allergic reactions, eczema, genital and anal itch, hemorrhoid itch, and cancer.
22 . The method of claim 18 , wherein said neurogenic inflammatory disorder is selected from the group consisting of allergic inflammation, asthma, chronic cough, conjunctivitis, rhinitis, psoriasis, inflammatory bowel disease, interstitial cystitis, arthritis, colitis, contact dermatitis, diabetes, eczema, cystitis, gastritis, migraine headache, rosacea, sunburn, pancreatitis, chronic rhinosinusistis, traumatic brain injury, polymicrobial sepsis, tendinopathies, chronic urticaria, rheumatic disease, acute lung injury , exposure to irritants, inhalation of irritants, pollutants, chemical warfare agents, and atopic dermatitis.
23 . The method of claim 18 , wherein a compound represented by Formula (I) is used in combination with one or more exogenous large pore receptor agonists.Cited by (0)
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