Compositions and methods for treating inflammatory bowel disease - Patents.com

Abstract

The present invention relates to the unexpected discovery that oral administration of a charged sodium channel blocker, also called "Nocion," ameliorates inflammation in intestinal inflammatory diseases such as inflammatory bowel disease (IBD), ulcerative colitis, and / or Crohn's disease, without substantial systemic exposure, as evidenced by low plasma concentrations. The formulation is designed as an enteric coated tablet to release the composition at a selected location in the intestine.

Description

[Technical field]

[0001] Related Applications This application claims the benefit of U.S. Provisional Patent Application No. 63 / 337,833, filed May 3, 2022, the entire teachings of which are incorporated herein by reference.

[0002] The present invention relates to compositions and methods for treating inflammatory bowel disease. [Background technology]

[0003] Inflammatory bowel disease (IBD) includes two specific forms of chronic inflammation in the intestinal tract: ulcerative colitis (UC) and Crohn's disease (CD). Both disorders are clinically distinct, but share common features including prominent symptoms of abdominal pain, diarrhea, and intestinal dysfunction, accompanied by weakness, fatigue, and weight loss, all of which greatly impede quality of life. In addition to these symptoms, IBD is characterized by clinical signs such as endoscopically visible mucosal ulcers and swelling, tissue fragility, intestinal stenosis, fistulas, obstruction, and abdominal masses.

[0004] Treatment of UC and CD has focused on the role of inflammation in their pathogenesis. For example, tofacitinib and other similar drugs act as immune modulators by affecting pathways such as the intracellular JAK-STAT signaling pathway. However, these drugs have systemic distribution and, even when administered orally, can affect any cell that has their intended immune activity target and have a wide range of systemic effects, including the risk of serious infections, venous thrombosis, and thromboembolism, as well as a series of less severe side effects. Thus, there is a need to provide improved therapies with less risk. Summary of the Invention

[0005] The present invention relates to the unexpected discovery that oral administration of a charged sodium channel blocker, also known as "Nocion," ameliorates inflammation in intestinal inflammatory diseases such as IBD, ulcerative colitis, and / or Crohn's disease without substantial systemic exposure, as evidenced by low plasma concentrations. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0006] The compounds that can be used in the compositions, formulations and methods of the present invention include charged sodium channel blockers, also called Nocion.One or more Nocions can be formulated into pharmaceutically acceptable compositions or formulations, and preferably formulated for oral delivery, such as intestinal delivery.Preferred compositions include sustained release compositions. Preferred Nocions include those disclosed in PCT / US2020 / 22076 filed March 11, 2020 by Cole et al. (Attorney Docket No. 4270.3001WO); PCT / US2020 / 21985 filed March 11, 2020 by Cole et al. (Attorney Docket No. 4270.3002WO); PCT / US2020 / 59076 filed November 5, 2020 by Cole et al. (Attorney Docket No. 4270.3003WO); PCT / US2020 / 59097 filed November 5, 2020 by Cole et al. (Attorney Docket No. 4270.3004 ...8 filed March 1, 2020 by Cole et al. (Attorney Docket No. 4270.3005WO); PCT / US2020 / 59099 filed March 1, 2020 by Cole et al. (Attorney Docket No. 4270.3006WO); PCT / US2020 / 59098 filed March 1, 2020 by Cole et al. (Attorney Docket No. 4270.3007WO); These applications are described in PCT / US2020 / 22097 (Attorney Docket No. 4270.3005WO), filed on March 1, 2020 by Cole et al.; PCT / US2020 / 21978 (Attorney Docket No. 4270.3006WO), filed on March 11, 2020 by Cole et al.; PCT / US2020 / 22127 (Attorney Docket No. 4270.3007WO), filed on March 11, 2020 by Cole et al.; PCT / US2020 / 22142 (Attorney Docket No. 4270.3008WO), filed on March 11, 2020 by Cole et al.; and PCT / US2021 / 21697 (Attorney Docket No. 4270.3014WO), filed on March 10, 2021 by Cole et al.

[0007] The present invention relates to a compound of formula (I): [ka] (In the formula, Y - is a pharma- ceutically acceptable anion; R F and R G is N + together with form an optionally substituted heteroaryl ring having one or more heteroatoms or an optionally substituted bicyclic heteroaryl ring having one or more heteroatoms; R A , R B , and R C is H, D, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, nitrile, OR I , N.R. J R K , N.R. L C(O)R M , S(O)R N , SO2R O , SO2R O R P , SO2NR Q R R , SO3R S , CO2R T , C(O)R U , and C(O)NR V R W or R B and adjacent R C together with the carbon atom to which they are attached form a substituted or unsubstituted 3- to 7-membered cycloalkyl (C3-C7 cycloalkyl) or a substituted or unsubstituted aryl (e.g., phenyl); R I , R J , R K , R L , R M , R N , R O , R P , R Q , R R , RS , R T , R U , R V , and R W each is independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and substituted or unsubstituted heteroalkyl; X 1 -CR X R Y -, -NR Z C(O)-, -OC(O)-, -SC(O)-, -NR Z S(O)-, -S(O)NR Z -, -NR X C(O)NR Y -, -C(O)NR 1A -, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, and -(O)CS-; X 1 Ha-NR Z C(O)CR X R Y - can also be R X , R Y , R Z , and R 1A each is independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and substituted or unsubstituted heteroalkyl; R D and R E each is independently selected from H, D, substituted or unsubstituted alkyl (optionally substituted with halogen, cyclic alkyl, aryl, or heteroaryl), substituted or unsubstituted alkenyl (optionally substituted with halogen, cyclic alkyl, aryl, or heteroaryl), substituted or unsubstituted alkynyl (optionally substituted with halogen, cyclic alkyl, aryl, or heteroaryl), substituted or unsubstituted heteroalkyl (optionally substituted with halogen, cyclic alkyl, aryl, or heteroaryl), and cycloalkyl; or R D and R Etogether with the carbons to which they are attached form a substituted or unsubstituted 3- to 7-membered cycloalkyl (C3-C7 cycloalkyl) or a substituted or unsubstituted heterocyclic or heteroalkyl ring, or R D and R Z together with the carbon to which they are attached and -NC(O)- to form an optionally substituted 5- to 8-membered lactam) The present invention provides a compound represented by the formula:

[0008] In a preferred embodiment, X 1 is -NHC(O)- or -C(O)NH-. In further preferred embodiments, X 1 is -NHC(O)-.

[0009] In some embodiments, R A and R B Each of is H, D, halogen, substituted or unsubstituted C 1~4 (C1-C4) alkyl, and NR J R K are independently selected from; R J and R K Each of 1~4 alkyl; and / or R C is not H, for example halogen, C 1~4 Alkyl, and NR J R K It is.

[0010] In a preferred embodiment, R A and R B Each of is -CH3.

[0011] In certain other embodiments, R D is halogen, oxygen (oxo), C 3~8 (C3-C8) C optionally substituted with a substituent selected from the group consisting of cycloalkyl, aryl, and heteroaryl. 1~4 alkyl and / or R E is H, halogen, oxygen, C3~8 C optionally substituted with a substituent selected from the group consisting of cycloalkyl, aryl, and heteroaryl. 1~4 It is an alkyl.

[0012] In a preferred embodiment, R D and R E is independently selected from -H, -CH, -CHCH, and -(CH)CH. E is hydrogen, and R D is -H, -CH3, -CH2CH3, or -(CH2)2CH3.

[0013] In certain preferred embodiments, R D and R E are both hydrogen. In yet further preferred embodiments, R D is hydrogen, and R E is alkyl, for example, C1-C6 alkyl or C1-C4 alkyl, including, but not limited to, methyl, ethyl, propyl, and butyl. In certain additional preferred embodiments, R D and R E together with the carbon to which they are attached form a C3-C6 cycloalkyl, including but not limited to cyclopropyl or cyclobutyl.

[0014] The present invention relates to a compound of formula (II): [ka] (In the formula, Y - is a pharma- ceutically acceptable anion; R A , R B , and R C is H, D, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, OR I, C.N., N.R. J R K , N.R. L C(O)R M , S(O)R N , S(O)2R N , SO2R O R P , SO2NR Q R R , SO3R S , CO2R T ;C(O)R U , and C(O)NR V R W (preferably H, F, Cl, or CN, more preferably H); 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 each is independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl; R J and R K , or R V and R W , or R Q and R R can also be taken together with the nitrogen to which they are attached to form a substituted or unsubstituted 5-, 6-, 7-, or 8-membered ring; R A , R B , and / or R C can be taken together with the phenyl ring to which they are attached to form a fused bicyclic or tricyclic ring system, such as naphthyl, dihydroindenyl, tetrahydronaphthyl, quinolinyl, indolyl, etc.; X1 -CR X R Y -, -NR Z C(O)-, -OC(O)-, -SC(O)-, -C(O)NR 1A -, -C(O)O-, -C(O)-, -(O)CS-, -NR 1A S(O)-, -S(O)NR 1A -, -NR 1A C(O)NR 1A -, -S(O)-, and -S(O)2-; X 1 Ha-NR Z C(O)CR X R Y -Can also be; R X , R Y , R Z , and R 1A each is independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and substituted or unsubstituted heteroalkyl; R D and R E each is independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, and substituted or unsubstituted cycloalkyl, or R D and R E together with the carbons to which they are attached form a substituted or unsubstituted 3- to 6-membered cycloalkyl (C3-C6 cycloalkyl), a substituted or unsubstituted heterocycle, or a substituted or unsubstituted heteroalkyl ring; or R D and R Z together with the carbon to which they are attached and -NC(O)-, form an optionally substituted 5- to 8-membered lactam; R F and R G is N + together with R form an optionally substituted heterocycle having one or more nitrogen atoms, or F and R Geach of which is selected from substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, and substituted or unsubstituted C 3~6 cycloalkyl; R H is a substituted or unsubstituted aryl ring, or a substituted or unsubstituted heteroaryl ring. The present invention provides a compound represented by the formula:

[0015] In another embodiment, R H may be a substituted alkyl. The substituent is preferably an ester group, e.g., -OC(O)R 1B (In the formula, R 1B is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl). R 1B is preferably substituted or unsubstituted phenyl. H is preferably -CH2OC(O)-phenyl.

[0016] The present invention relates to a compound of formula (III): [ka] (In the formula, Y - is a pharma- ceutically acceptable anion; R A , R B , and R C is H, D, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, OR I , N.R. J R K , N.R. L C(O)R M , C.N., S(O)R. N , S(O)2R N , SO2R O R P , SO2NR Q R R, SO3R S , CO2R T , C(O)R U , and C(O)NR V R W are each independently selected from 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 each is independently selected from H, D, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and substituted or unsubstituted heteroalkyl; X 1 -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-, -C(O)-, -(O)CS-, -NR 1A S(O)-, -S(O)NR 1A -, -NR 1A C(O)NR 1A -, -S(O)-, and -S(O)-; R X , R Y , R Z , and R 1A each is independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and substituted or unsubstituted heteroalkyl, or R X , R Y , R Z , or R 1A is R D Or R Eand together with the atom to which they are attached form an optionally substituted cycloalkyl (e.g., C3-C6 cycloalkyl) or an optionally substituted heterocycle (e.g., a 3-15 membered heterocycle); R D and R E each is independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, and substituted or unsubstituted cycloalkyl, or R D and R E together with the carbons to which they are attached form a substituted or unsubstituted cycloalkyl (e.g., C3-C6 cycloalkyl) or a substituted or unsubstituted heterocycle (e.g., a 3-15 membered heterocycle); R F , R G , and R H each of which is H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted -C6-C 10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted -CH2-C5-C 10 Aryl and substituted or unsubstituted -CH2-C5~C 10 or alternatively, R F , R G , and R H Two or three of them are bound to P + together with, including but not limited to, optionally substituted heteroaryl rings, P + or forming an optionally substituted heterocyclyl (e.g., a 3- to 15-membered heterocycle) having zero, one, or more heteroatoms in addition to or R D , R E , R F , R G , and R H Two or three of the+ together with, but not limited to, heteroaryl rings, P + and optionally substituted heterocycles having 0, 1 or more heteroatoms in addition to the above; for example, R E , R F , and R G Two of them are P + Together with P + In addition to the above, a heterocyclic ring containing 0, 1 or more heteroatoms is formed. The present invention provides a compound represented by the formula:

[0017] The present invention further relates to phosphonium derivatives of sodium channel blocker compounds (e.g., caine compounds) that contain amine groups, where the amine of the sodium channel blocker compound is replaced with phosphonium. Examples of sodium channel blocker compounds include, but are not limited to, lidocaine, bupivacaine, mepivacaine, etidocaine, prilocaine, tocainide, ropivacaine, proparacaine, alokaine, encainide, procainamide, metoclopramide, flecainide, tetracaine, benzocaine, oxybuprocaine, butambine, propoxycaine, dyclonine, pramocaine, chloroprocaine, proparacaine, piperocaine, hexylcaine, naepine, cyclomethylcaine, and dibucaine, articaine, mexiletine, bupropion, ambroxol, procaine, tolperinone, and their substituted derivatives.

[0018] The present invention relates to a compound of formula (IV): [ka] (In the formula, Y - is a pharma- ceutically acceptable anion; R A and R B H, 2H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, OR I , N.R. J R K , N.R. L C(O)R M , S(O)R N , S(O)2R N , SO2R O R P , SO2NR Q R R , SO3R S , CO2R T , C(O)R U , and C(O)NR V R W are each independently selected from 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 Each of the above is H, 2 independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and substituted or unsubstituted heteroalkyl; X 1 -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-, -C(O)-, -(O)CS-, -NR 1A S(O)-, -S(O)NR 1A -, -NR 1A C(O)NR 1A -, -S(O)-, and -S(O)-; RX , R Y , R Z , and R 1A Each of the above is H, 2 H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and substituted or unsubstituted heteroalkyl, or R X , R Y , R Z , or R 1A is R D Or R E and together with the atom to which they are attached form an optionally substituted cycloalkyl (e.g., C3-C6 cycloalkyl) or an optionally substituted heterocycle (e.g., a 3-15 membered heterocycle); R D and R E Each of the above is H, 2 H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, and substituted or unsubstituted cycloalkyl, or R D and R E together with the carbons to which they are attached form a substituted or unsubstituted cycloalkyl (e.g., C3-C6 cycloalkyl) or a substituted or unsubstituted heterocycle (e.g., a 3-15 membered heterocycle); R F , R G , and R H Each of the above is H, 2 H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted -C6-C 10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted -CH2-C5-C 10 Aryl and substituted or unsubstituted -CH2-C5~C 10 or alternatively, R F , R G , and RH Two or three of them are bound to P + together with, including but not limited to, optionally substituted heteroaryl rings, P + or forming an optionally substituted heterocyclyl (e.g., a 3- to 15-membered heterocycle) having zero, one, or more heteroatoms in addition to or R D , R E , R F , R G , and R H Two or three of them are bound to P + together with, but not limited to, heteroaryl rings, P + and optionally substituted heterocycles having 0, 1 or more heteroatoms in addition to the above; for example, R E , R F , and R G Two of them are P + Together with P + In addition to the above, a heterocyclic ring containing 0, 1 or more heteroatoms is formed. The present invention provides a compound represented by the formula:

[0019] The present invention relates to a compound of formula (V): [ka] (In the formula, Y - is a pharma- ceutically acceptable anion; R F and R G are the N to which they are bonded. + together with form an optionally substituted heteroaryl ring having one or more heteroatoms or an optionally substituted bicyclic heteroaryl ring having one or more heteroatoms; R A and R B is H, D, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, nitrile, ORI , N.R. J R K , N.R. L C(O)R M , S(O)R N , SO2R O , SO2R O R P , SO2NR Q R R , SO3R S , CO2R T , C(O)R U , and C(O)NR V R W are each independently selected from 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 each is independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and substituted or unsubstituted heteroalkyl; X 1 -CR X R Y -, -NR Z C(O)-, -NR Z C(O)CR X R Y -, -OC(O)-, -SC(O)-, -NR Z S(O)-, -S(O)NR Z -, -NR X C(O)NR Y -, -C(O)NR 1A selected from -, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, and -(O)CS-; R X , R Y , R Z , and R 1Aeach is independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and substituted or unsubstituted heteroalkyl, or any other R X , R Y , R Z , R 1A , R D , or R E may together with any intervening atoms form a substituted or unsubstituted ring; R D and R E each is independently selected from H, D, substituted or unsubstituted alkyl (optionally substituted with halogen, cyclic alkyl, aryl, or heteroaryl), substituted or unsubstituted alkenyl (optionally substituted with halogen, cyclic alkyl, aryl, or heteroaryl), substituted or unsubstituted alkynyl (optionally substituted with halogen, cyclic alkyl, aryl, or heteroaryl), substituted or unsubstituted heteroalkyl (optionally substituted with halogen, cyclic alkyl, aryl, or heteroaryl), and cycloalkyl; or R D and R E together with the carbons to which they are attached form a substituted or unsubstituted 3- to 7-membered cycloalkyl (C3-C7 cycloalkyl) or a substituted or unsubstituted heterocyclic or heteroalkyl ring, or R D and R Z together with the carbon to which they are attached and -NC(O)- to form an optionally substituted 5- to 8-membered lactam) The present invention provides a compound represented by the formula:

[0020] In a preferred embodiment, X 1 is -NHC(O)- or -C(O)NH-. In further preferred embodiments, X 1 is -NHC(O)-.

[0021] In some embodiments, R A and R B H, D, halogen, ORI , substituted or unsubstituted C1-C4 alkyl, and COR T are independently selected from; R I and R T is independently selected from substituted and unsubstituted C1-C4 alkyl.

[0022] In a preferred embodiment, R A is CH3 and R B CO2R T and R T is H and substituted or unsubstituted C 1~4 In an additional preferred embodiment, R A is CH3 and R B is selected from CO2CH3 and CO2CH2CH3. In a further preferred embodiment, R A is methyl, R B is C(O)OCH3. In yet another preferred embodiment, R A is methyl, R B is C(O)OCH2CH3. In yet another preferred embodiment, R A is methyl, R B is methyl.

[0023] In certain other embodiments, R D is halogen, oxygen (oxo), C 3~8 (C3-C8) C optionally substituted with a substituent selected from the group consisting of cycloalkyl, aryl, and heteroaryl. 1~4 alkyl, and / or R E is H, halogen, oxygen, C 3~8 C optionally substituted with a substituent selected from the group consisting of cycloalkyl, aryl, and heteroaryl. 1~4 It is an alkyl.

[0024] In a preferred embodiment, R D and R E is independently selected from -H, -CH, -CHCH, and -(CH)CH. Eis hydrogen, and R D is -H, -CH3, -CH2CH3, or -(CH2)2CH3.

[0025] In certain preferred embodiments, R D is selected from hydrogen and ethyl; R E is hydrogen. In yet an additional preferred embodiment, R D is selected from hydrogen and ethyl; R E is alkyl, for example, C1-C6 alkyl or C1-C4 alkyl, including, but not limited to, methyl, ethyl, propyl, and butyl. D is hydrogen, and R E is hydrogen. In yet an additional preferred embodiment, R D is ethyl, and R E is hydrogen. In certain additional preferred embodiments, R D and R E together with the carbon to which they are attached form a C3-C6 cycloalkyl, including but not limited to cyclopropyl or cyclobutyl.

[0026] In some embodiments, Y - includes, but is not limited to, a halide ion, a substituted or unsubstituted alkylsulfonate, a substituted or unsubstituted arylsulfonate, an aliphatic carboxylate, a substituted aliphatic carboxylate, an aryl carboxylate, a substituted aryl carboxylate, a heterocyclyl carboxylate, or a substituted heterocyclyl carboxylate.

[0027] In a further embodiment, Y - is a halide ion. In one embodiment, Y - is a halide ion selected from bromide, chloride, and iodide.

[0028] The present invention relates to a compound of formula (VI): [ka] (In the formula, Y - is a pharma- ceutically acceptable anion; R A and R B is H, D, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, OR I , N.R. J R K , N.R. L C(O)R M , S(O)R N , S(O)2R N , SO2R O R P , SO2NR Q R R , SO3R S , CO2R T , C(O)R U , and C(O)NR V R W are each independently selected from 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 each is independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and substituted or unsubstituted heteroalkyl; X 1 -CR X R Y -, -NR Z C(O)-, -OC(O)-, -SC(O)-, -C(O)NR 1A -, -C(O)O-, -C(O)-, -(O)CS-, -NR 1A S(O)-, -S(O)NR 1A -, -NR 1A C(O)NR 1A-, -S(O)-, and -S(O)2-; X 1 Ha-NR Z C(O)CR X R Y -Can also be; R X , R Y , R Z , and R 1A each is independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and substituted or unsubstituted heteroalkyl, or any other R X , R Y , R Z , R 1A , R D , or R E may together with any intervening atoms form a substituted or unsubstituted ring; R D and R E each is independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, and substituted or unsubstituted cycloalkyl, or R D and R E together with the carbons to which they are attached form a substituted or unsubstituted 3- to 6-membered cycloalkyl (C3-C6 cycloalkyl), a substituted or unsubstituted heterocycle, or a substituted or unsubstituted heteroalkyl ring, or R D and R Z together with the carbon to which they are attached and -NC(O)-, form an optionally substituted 5- to 8-membered lactam; R F and R G are the N to which they are bonded. + together with R form an optionally substituted heterocycle having one or more nitrogen atoms, or F and R G each of which is selected from substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, and substituted or unsubstituted C3~6 cycloalkyl; R H is a substituted or unsubstituted aryl ring, or a substituted or unsubstituted heteroaryl ring. The present invention provides a compound represented by the formula:

[0029] In another embodiment, R H may be a substituted alkyl. The substituent is preferably an ester group, e.g., -OC(O)R 1B (In the formula, R 1B is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl). R 1B is preferably substituted or unsubstituted phenyl. H is preferably -CH2OC(O)-phenyl.

[0030] The present invention relates to a compound of formula (VII): [ka] (In the formula, Y - is a pharma- ceutically acceptable anion; R A CO2R T and; R T is substituted or unsubstituted alkyl (preferably methyl or ethyl); R B is H, D, halogen, or substituted or unsubstituted alkyl; preferably methyl or ethyl; R C is H, D, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, OR I , C.N., N.R. J R K , N.R.L C(O)R M , S(O)R N , S(O)2R N , SO2R O R P , SO2NR Q R R , SO3R S , CO2R T ;C(O)R U , and C(O)NR V R W (preferably H, F, Cl, or CN, more preferably H); 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 each is independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl; R J and R K , or R V and R W , or R Q and R R can also be taken together with the nitrogen to which they are attached to form a substituted or unsubstituted 5-, 6-, 7-, or 8-membered ring; X 1 -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-, -C(O)-, -(O)CS-, -NR 1AS(O)-, -S(O)NR 1A -, -NR 1A C(O)NR 1A -, -S(O)-, and -S(O)-; R X , R Y , R Z , and R 1A each is independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, and substituted or unsubstituted alkynyl. In a preferred embodiment, X 1 Ha-NR Z In an additional preferred embodiment, R Z is hydrogen. In yet further preferred embodiments, X 1 Ha-NR Z C(O)- and R Z is hydrogen. In certain preferred embodiments, X 1 is -NHC(O)-; R Z is H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and substituted or unsubstituted heteroalkyl (preferably H); R D and R E each is independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, and substituted or unsubstituted cycloalkyl; or R D and R E together with the carbons to which they are attached form a substituted or unsubstituted cycloalkyl (e.g., C3-C6 cycloalkyl) or a substituted or unsubstituted heterocycle (e.g., a 3- to 15-membered heterocycle); or or R D and R Z together with the carbon to which they are attached and -NC(O)- to form a substituted or unsubstituted lactam; R F , R G , and R Heach of is absent, H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted -C6-C 10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted -CH2-C5-C 10 Aryl and substituted or unsubstituted -CH2-C5~C 10 or alternatively, R F , R G , and R H Two or three of the N to which they are attached + together with, including but not limited to, optionally substituted heteroaryl rings, N + or forming an optionally substituted heterocyclyl (e.g., a 3- to 15-membered heterocycle) having zero, one, or more heteroatoms in addition to or R D , R E , R F , R G , and R H Two or three of the + together with, but not limited to, heteroaryl rings, + and optionally substituted heterocycles having 0, 1 or more heteroatoms in addition to the above; for example, R E , R F , and R G Two of them are N + Together with N + In addition to the above, it forms a heterocyclic ring having zero, one or more heteroatoms.

[0031] The present invention further relates to derivatives of sodium channel blocker compounds (e.g., caine compounds) that contain dimethylanilide, in which the ortho-methyl of the sodium channel blocker compound is replaced with an ester. Examples of sodium channel blocker compounds include, but are not limited to, lidocaine, bupivacaine, mepivacaine, etidocaine, prilocaine, tocainide, ropivacaine, proparacaine, alokaine, encainide, procainamide, metoclopramide, flecainide, tetracaine, benzocaine, oxybuprocaine, butambine, propoxycaine, dyclonine, pramocaine, chloroprocaine, proparacaine, piperocaine, hexylcaine, naepine, cyclomethylcaine, and dibucaine, articaine, mexiletine, bupropion, ambroxol, procaine, tolperinone, and their substituted derivatives.

[0032] The present invention relates to a compound of formula (VIII): [ka] (In the formula, Y - is a pharma- ceutically acceptable anion; n is 1, 2, 3, or 4; R A , R B , and R C is H, D, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, OR I , C.N., N.R. J R K , N.R. L C(O)R M , S(O)R N , S(O)2R N , SO2R O R P , SO2NR Q R R , SO3R S, CO2R T ;C(O)R U , and C(O)NR V R W (preferably R A and R B is methyl, R C is H, F, Cl, or CN, more preferably H); 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 each is independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl; R J and R K , or R V and R W , or R Q and R R can also be taken together with the nitrogen to which they are attached to form a substituted or unsubstituted 5-, 6-, 7-, or 8-membered ring; R A , R B , and / or R C can be taken together with the phenyl ring to which they are attached to form a fused bicyclic or tricyclic ring system, such as naphthyl, dihydroindenyl, tetrahydronaphthyl, quinolinyl, indolyl, etc.; X 1 -CR X R Y -, -NR Z C(O)-, -OC(O)-, -SC(O)-, -C(O)NR 1A -, -C(O)O-, -C(O)-, -(O)CS-, -NR1A S(O)-, -S(O)NR 1A -, -NR 1A C(O)NR 1A -, -S(O)-, and -S(O)2-; X 1 Ha-NR Z C(O)CR X R Y -Can also be; R X , R Y , R Z , and R 1A each is independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and substituted or unsubstituted heteroalkyl; R D and R E each is independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, and substituted or unsubstituted cycloalkyl, or R D and R E together with the carbons to which they are attached form a substituted or unsubstituted 3- to 6-membered cycloalkyl (C3-C6 cycloalkyl), a substituted or unsubstituted heterocycle, or a substituted or unsubstituted heteroalkyl ring; or R D and R Z together with the carbon to which they are attached and -NC(O)-, form an optionally substituted 5- to 8-membered lactam; R H is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl; in certain embodiments, R H can be a substituted or unsubstituted aralkyl or heteroarylalkyl; in additional embodiments, R H may be a substituted or unsubstituted alkyl carboxylate, a substituted or unsubstituted alkyl carboxamide; R 1Bis substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, preferably substituted or unsubstituted phenyl. The present invention provides a compound represented by the formula:

[0033] The present invention relates to a compound of formula (IX): [ka] (In the formula, Y - is a pharma- ceutically acceptable anion; R 1 is selected from the group consisting of methyl, ethyl, propyl (including n-propyl and isopropyl), butyl (including n-butyl, iso-butyl, tert-butyl, and sec-butyl), cyclohexyl, phenyl, and CH2C(O)NHR3; R 2 is hydrogen or methyl; R 3 is hydrogen, methyl, or ethyl) The present invention provides a compound represented by the formula:

[0034] In some embodiments, Y - is a halide ion, a sulfonate (including, for example, substituted or unsubstituted alkylsulfonates and substituted or unsubstituted arylsulfonates), or a carboxylate (including, for example, substituted or unsubstituted alkyl or aliphatic carboxylates, substituted or unsubstituted aryl carboxylates, or substituted or unsubstituted heterocyclyl carboxylates).

[0035] In a further embodiment, Y - is a halide ion. In one embodiment, Y - is a halide ion selected from bromide, chloride, and iodide.

[0036] The present invention relates to a compound of formula (X): [ka] (In the formula, Y - is a pharma- ceutically acceptable anion; R 1 and R 2 One of the groups is hydrogen, and the other is R 1 and R 2 The other is methyl, ethyl, unsubstituted phenyl, and C(O)OR 3 selected from the group consisting of; R 3 is selected from the group consisting of hydrogen, methyl, and ethyl. The present invention provides a compound represented by the formula:

[0037] In some embodiments, Y - is a halide ion, a sulfonate (including, for example, substituted or unsubstituted alkyl sulfonates and substituted or unsubstituted aryl sulfonates), a carboxylate (including, for example, substituted or unsubstituted alkyl or aliphatic carboxylates, substituted or unsubstituted aryl carboxylates, or substituted or unsubstituted heterocyclyl carboxylates).

[0038] In a further embodiment, Y - is a halide ion. In one embodiment, Y - is a halide ion selected from bromide, chloride, and iodide.

[0039] The present invention relates to a compound of formula (XI): [ka] (In the formula, Y - is a pharma- ceutically acceptable anion; q is 0, 1, 2, or 3; R D is hydrogen, methyl, or ethyl) The present invention provides a compound represented by the formula:

[0040] The present invention relates to a compound of formula (XII): [ka] (In the formula, Y - is a pharma- ceutically acceptable anion; R1, R2, R3, R4, R5, and R6 are independently selected from hydrogen, C1-C4 alkyl, C1-C4 heteroalkyl, aryl, or heteroaryl; n is 0, 1, 2, 3, 4, and 5; (q is 0, 1, 2, 3, 4, or 5) The present invention provides a compound represented by the formula:

[0041] The present invention relates to a compound of formula (XIII): [ka] (In the formula, Y - is a pharma- ceutically acceptable anion; R A , R B , and R C is H, D, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, OR I , CN, CF3, NR J R K , N.R. L C(O)R M , S(O)R N , S(O)2R N , SO2R O R P , SO2NR Q R R , SO3R S , CO2R T ;C(O)R U , and C(O)NR V R W are each independently selected from R I , R J , RK , 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 each is independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, or R J and R K , or R V and R W , or R Q and R R can also be combined with the nitrogen to which they are attached to form a substituted or unsubstituted 5-, 6-, 7-, or 8-membered ring; R A , R B , and / or R C can be taken together with the phenyl ring to which they are attached to form a fused bicyclic or tricyclic ring system, such as naphthyl, dihydroindenyl, tetrahydronaphthyl, quinolinyl, indolyl, etc.; R1, R2, R3, R4, R5, and R6 are independently selected from hydrogen, C1-C4 alkyl, C1-C4 heteroalkyl, cycloalkyl, aryl, or heteroaryl, preferably hydrogen, methyl, or ethyl; n is 0, 1, 2, 3, 4, and 5; or R1, R2, R3, R4, R5, and / or R6, together with the carbon or carbons to which they are attached, form a substituted or unsubstituted cycloalkyl (e.g., C3-C6 cycloalkyl) or a substituted or unsubstituted heterocycle (e.g., a 3-15 membered heterocycle); R F and R G is N +together with, but not limited to, heteroaryl rings, + and optionally substituted heterocycles having 0, 1 or more heteroatoms in addition to the above; for example, R E , R F , and R G Two of them are N + Together with N + and forming a heterocyclic ring having 0, 1 or more heteroatoms; R H is a substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, such as -CH-cycloalkyl, -C2H4-cycloalkyl, substituted or unsubstituted -CH2-C5-C 10 Aryl, substituted or unsubstituted -C2H4-C5~C 10 Aryl, substituted or unsubstituted -CH2-C5~C 10 Heteroaryl, substituted or unsubstituted -C2H4-C5~C 10 Heteroaryl, -CH2OC(O)R T , -CH2CO2R T , -CH2C(O)NR V R W , -C2H4OCOR T , -C2H4OR I or R F , R G , and R H is N + together with to form a substituted or unsubstituted heteroaryl ring (e.g., pyridinyl or phenyl-pyridinyl) or a bridged heterocycle). The present invention provides a compound represented by the formula:

[0042] Charged sodium channel blockers are also described in WO 2017 / 024037 to Bean et al., WO 2011 / 006073 to Woolf et al., WO 2008 / 063603 to Bean et al., and U.S. Pat. No. 8,865,741 to Thompson et al., which are incorporated by reference in their entireties.

[0043] Traditionally, a limitation in administering molecules that block sodium channels as therapeutic agents is that most of such externally applied molecules are hydrophobic and can easily cross membranes. Because of this, they enter all cells and therefore do not have the selectivity to affect only nociceptors. This weakens the therapeutic potential since the drug is not limited to acting only on nociceptors. Furthermore, this behavior poses the risk of systemically mediated side effects since the molecules reach and affect cells throughout the body. Under certain circumstances, these large pore cationic channels (LPCCs) can be activated in the absence of exogenous agonists / ligands by exposure to endogenous inflammatory activators such as those produced by tissue injury, infection, autoimmunity, atopy, ischemia, hypoxia, cellular stress, immune cell activation, immune mediator production, and oxidative stress. These endogenous inflammation-related substances, including but not limited to prostaglandins, nitric oxide (NO), superoxide (HO), cysteine-reactive inflammatory mediators such as 4-hydroxynonenal, endogenous alkenyl aldehydes, endocannabinoids, and immune mediators (e.g., interleukin 1 (IL-1), nerve growth factor (NGF), and bradykinin), can activate LPCCs expressed on nociceptors, opening them and thereby allowing charged sodium channel blocking compounds that cannot cross the cell membrane to enter the nociceptor via the LPCCs and inhibit the activity of voltage-gated sodium channels, thereby preventing the initiation of an action potential.

[0044] The present inventors have identified compounds that can pass through LPCCs that are selectively expressed on visceral nociceptors. Since inflammation opens LPCCs, the ion channel blockers of the present invention can enter these channels on nociceptors and block voltage-gated sodium channels. However, because the ion channel blockers of the present invention are positively charged, they are not membrane permeable and therefore cannot enter cells in the absence of open LPCCs. Thus, these compounds cannot pass through normal cells.

[0045] Furthermore, the compounds do not enter the systemic circulation upon oral administration. Thus, the ion channel blockers of the present invention can selectively target activated visceral nociceptors in the intestinal lumen without affecting or passing through other types of cells. The ability to block the activity of intestinal visceral nociceptors allows these compounds to effectively treat pain mediated by visceral nociceptors, and further to effectively treat manifestations of neurogenic inflammation mediated by intestinal visceral nociceptors, thereby effectively treating one or more symptoms, signs, or sequelae of IBD. Thus, the present invention provides a method of treating intestinal inflammation, such as IBD, UC, or CD, by administering to a patient an effective amount of a composition comprising Nocion, such as a compound having formula (I)-(XIII), where the compound inhibits one or more voltage-gated ion channels present in the visceral nociceptors when these channels are activated by existing inflammation such as that resulting in IBD. Preferably, administration of the composition is oral, which allows the active ingredient to have direct access to the affected area when exposed to the intestinal lumen.

[0046] In embodiments, the LPCC is a transient receptor potential type ion channel (TRP channel). In embodiments, the channel is TRPA1, TRPV1-4, TRPM8, ASIC, or P2X. In certain embodiments, the compound can enter the visceral nociceptor via the TRPA1, TRPV1-4, TRPM8, ASIC, or P2X receptor / channel when the receptor / channel is activated, for example, by a local inflammatory process. In embodiments, the methods, compositions, and formulations of the invention treat both nociceptive pain mediated by visceral nociceptors and neurogenic inflammation mediated by visceral nociceptors.

[0047] Each embodiment described herein may be taken in combination with one, any, or all other embodiments as if presented in all permutations herein. The compositions of the present invention may include racemic mixtures, pure enantiomers, or one enantiomer in excess of the other. For example, the compositions may include at least 5, 10, 20, 30, 40, 50, 60, 70, 80, or 90% enantiomeric excess. In one embodiment, the enantiomeric excess is at least 95%. The compounds of the present invention include all enantiomers that may be defined as (R)- or (S)- in terms of absolute stereochemistry, as well as their racemic and optically pure forms, and are not limited to those described herein in any of their pharma- ceutically acceptable forms, including enantiomers, salts, solvates, polymorphs, solvatomorphs, hydrates, anhydrates, and other crystalline forms, and combinations thereof. Similarly, all tautomeric forms are intended to be included. Preferably, the pharmaceutical composition comprises the compound of the present invention as the R enantiomer in substantially pure form; or the pharmaceutical composition comprises the compound of the present invention as the S enantiomer in substantially pure form; or the pharmaceutical composition comprises the compound of the present invention as an enantiomeric mixture containing an excess of the R enantiomer or an excess of the S enantiomer. It is particularly preferred that the pharmaceutical composition contains the compound of the present invention as a substantially pure optical isomer. For the avoidance of doubt, the compound of the present invention may be used in the form of a solvate, if desired.

[0048] Section 1: Definitions As used herein, the words "a" and "an" are intended to include one or more, unless otherwise specified.

[0049] As used herein, the term "affected area" refers to an anatomical site affected by intestinal inflammation, such as IBD, UC, or CD, which may include, but is not limited to, mucosal edema, atrophy, ulcers, erosions, fissures, pockmarks, aphthous lesions, and similar abnormalities and areas of tissue damage.

[0050] As used herein, the term "active ingredient" refers to a composition disclosed herein having biological activity for treating intestinal inflammation, such as IBD, UC, or CD. The present invention features the inclusion of such active ingredients in a formulation for oral administration. As used herein, terms such as "treatment," "treat," "therapy," "therapeutic," and the like refer to an intervention intended to correct, heal, mitigate, ameliorate, relieve, or otherwise beneficially affect a disorder or condition affecting the health of a patient. A disorder is a condition that alters the homeostatic health of a patient, including, but not limited to, an acute or chronic disease, or a pathological condition that predisposes a mammal to an acute or chronic disease. Both UC and CD are classified as IBD and are suitable disorders for treatment with the compositions and formulations of the present invention.

[0051] "Inflammation" refers to a local response to injury, tissue damage, or other stimuli, such as those caused by the immune system (immune-mediated inflammation) and / or those caused by the nervous system (neurogenic inflammation), typically resulting in symptoms including redness, heat, swelling, pain, tissue damage, and / or loss of function. "Neurogenic inflammation" refers to inflammation mediated or contributed to by neurons (e.g., nociceptors) or other components of the central or peripheral nervous system. As used herein, the term "inflammation" can refer to acute or chronic inflammation.

[0052] "Patient" means an animal. In one embodiment, the patient is a human. Other animals that can be treated using the methods, compositions, and kits of the present invention include, but are not limited to, non-human primates (e.g., monkeys, gorillas, chimpanzees), farm animals (e.g., horses, pigs, goats, rabbits, sheep, cows, llamas), and companion animals (e.g., guinea pigs, rats, mice, lizards, snakes, dogs, cats, fish, hamsters, and birds).

[0053] Compounds useful in the present invention include those described herein in any of their pharma- ceutically acceptable forms, including, but not limited to, isomers such as diastereomers and enantiomers, salts, esters, amides, thioesters, solvates, and polymorphs thereof, as well as racemic mixtures and pure isomers of the compounds described herein. The term "pharma-ceutically acceptable" refers to a substance that, within the bounds of sound medical judgment, is suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and is commensurate with a reasonable benefit / risk ratio. Compounds useful in the present invention include their pharma-ceutically acceptable anions and their charged moieties. The term "pharma-ceutically acceptable anions" as used herein refers to the conjugate base of a pharma-ceutically acceptable acid. Such acids are described in Stahl, PH and Wermuth, CG (editors), Handbook of Pharmaceutical Salts: Properties, Selection and Use, Wiley VCH (2008).Pharmaceutically acceptable acids include, but are not limited to, acetic acid, dichloroacetic acid, adipic acid, alginic acid, L-ascorbic acid, L-aspartic acid, benzenesulfonic acid, 4-acetamidobenzoic acid, benzoic acid, p-bromophenylsulfonic acid, (+)-camphoric acid, (+)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, sulfuric acid, boric acid, citric acid, formic acid, fumaric acid, galactaric acid, gentisic acid, D-glucoheptonic acid, D-gluconic acid, D-glucuronic acid, glutamic acid, glutaric acid, 2-oxo- Glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, isobutyric acid, DL-lactic acid, lactobionic acid, lauric acid, maleic acid, (-)-L-malic acid, malonic acid, DL-mandelic acid, methanesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, propionic acid, (-)-L-pyroglutamic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, and undecylenic acid. Pharmaceutically acceptable anions include the conjugate bases of any of the acids shown above. "Charged moiety" refers to a moiety that gains a proton at physiological pH, thereby becoming positively charged (e.g., ammonium, guanidinium, or amidinium), or a moiety that contains a net formal positive charge without protonation (e.g., quaternary ammonium). Charged moieties are preferably permanently charged. Pharmaceutically acceptable salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base function with a suitable organic acid.Representative acid addition salts include, but are not limited to, acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, isopropyl alcohol, ethyl ... These include cethionate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, mesylate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, valerate, and the like.

[0054] The compounds of the present invention, including the salts of the compounds, can exist in unsolvated forms as well as solvated forms, including hydrated and unhydrated forms. In general, solvated forms are equivalent to unsolvated forms and are included within the scope of the present invention. Non-limiting examples of hydrates include monohydrates, dihydrates, hemihydrates, and the like. In certain embodiments, the compounds are hemihydrates. Non-limiting examples of solvates include ethanol solvates, acetone solvates, and the like. "Solvates" refers to solvent addition forms that contain stoichiometric or non-stoichiometric amounts of solvent. The compounds of the present invention can exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.

[0055] By "therapeutically effective amount" or "effective amount" is meant an amount sufficient to bring about a desired result, for example, reduction or elimination of symptoms, signs, or sequelae associated with or resulting from IBD, or to reduce the incidence or severity of other diseases associated with IBD, such as colon cancer. As used herein, the term "symptom" refers to the subjectively experienced manifestation of a disease or disorder, while "sign" refers to the manifestation of a disease or disorder as perceived by an external observer, and "sequelae" refers to the long-term consequences of a disease or disorder.

[0056] Section 2: Preparations A. Preparations in general Formulations containing the compounds of the present invention used to treat intestinal inflammation, such as IBD, US, or CD, can be prepared for oral administration. Dosage forms prepared for oral administration can include liquids or solids. Advantageously, oral dosage forms are prepared as sustained release formulations to delay the release of one or more active ingredients (one or more Nocions) for a period of time sufficient to allow the dosage form to pass through the intestine by peristalsis until it reaches the localized area requiring treatment. As used herein, the term "sustained release" refers to any formulation for oral compositions that releases the active ingredient from the oral dosage form at a slower rate than immediate release or is controlled to release at a specific location in the intestine. The term "sustained release" can be applied to compositions with controlled release or delayed release components, or both, as described in more detail below.

[0057] Liquid formulations for oral use may incorporate aqueous solutions, suitably flavored syrups, aqueous or oily suspensions, and flavored emulsions using edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles. In accordance with the present invention, Nocion may be dissolved or suspended in a liquid vehicle. A liquid oral sustained release system may be prepared that allows intraluminal delivery of the active ingredient to one or more affected areas to have a direct effect on the affected area. Techniques for preparing liquid oral sustained release systems are well known to those skilled in the art. As applied to the present invention, liquid sustained release techniques may include, but are not limited to, the use of controlled release spherical particles containing Nocion suspended in a liquid vehicle, including liposomes; the use of ion exchange resins or sparingly soluble salts to produce colloids or suspensions with sustained release properties; and the use of gelling systems such as alginate-based gels or chitosan-based gels with sustained release properties.

[0058] Solid dosage forms for oral use include tablets containing one or more Nocions in a mixture with non-toxic pharma- ceutically acceptable excipients. These excipients may be, for example, inert diluents or fillers (e.g., sucrose, sorbitol, sugar, mannitol, microcrystalline cellulose, starches such as potato starch, calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate, or sodium phosphate), granulating and disintegrating agents (e.g., cellulose derivatives such as microcrystalline cellulose, starches such as potato starch, croscarmellose sodium, alginates, or alginic acid), binders (e.g., sucrose, glucose, sorbitol, gum arabic, alginic acid, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, magnesium aluminum silicate, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, ethylcellulose, polyvinylpyrrolidone, or polyethylene glycol), and lubricants, glidants, and antiadherents (e.g., magnesium stearate, zinc stearate, stearic acid, silica, hydrogenated vegetable oils, or talc). Other pharma-ceutically acceptable excipients may be colorants, flavorings, plasticizers, humectants, buffers, flavorings (e.g., hydroxypropylmethylcellulose, hydroxypropylcellulose), etc. One or more compounds of the present invention may be mixed together or dispensed in tablets, capsules, or other vehicles, and may be optionally combined with other biologically active agents that contribute to the treatment of IBD. Formulations for oral use may be provided as chewable tablets, or as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent (e.g., potato starch, lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate, or kaolin), or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin, or olive oil. Powders, granules, and pellets may be prepared with the above-mentioned ingredients under tablets and capsules in a conventional manner, for example, using a mixer, fluid bed equipment, or spray drying equipment.

[0059] b. Exemplary Sustained Release Formulations A solid oral sustained release system can be manufactured that allows intraluminal delivery of active ingredient to one or more affected areas to have a direct therapeutic effect on the affected area. The sustained release of active ingredient from a solid dosage form can be achieved by any means known in the art, including but not limited to the use of matrix dosage forms, multiparticulate dosage forms, reservoirs, and pulsatile dosage forms. Such dosage forms can also be prepared for delayed release of active ingredient. Features characteristic of both delayed release and controlled release systems can be incorporated into the same dosage form.

[0060] In embodiments, matrix dosage forms can be prepared for controlled release by incorporating one or more active ingredients into a suitable matrix.When the matrix is ​​digested or degraded, the active ingredient is released over time, resulting in controlled release.Generally, matrix materials can include erodible or non-erodible polymeric matrices, and erodible matrices include water-swellable, water-soluble, or water-erodible polymers that contain and support active ingredients.Then, the aqueous swelling matrix gradually degrades as it passes through the intestine, releasing the active ingredient that it supports into the surrounding environment. Polymers suitable for use in forming such matrices are well known in the art, including linear, branched, or crosslinked homopolymers or copolymers, e.g., naturally occurring polysaccharides such as chitosan, dextran, pullulan; starches such as dextrin and maltodextrin; gums such as xanthan gum, guar gum, carrageenan, gum arabic; hydrophilic colloids such as pectin; alginates; gelatin; collagen; polyvinylpyrrolidone (PVP), polyvinyl alcohol, polyacrylamide, polyacrylates, glycerol fatty acid esters, and the like; polymers containing ethacrylic acid or methacrylic acid (EUDRAGIT®), or other acrylic acid derivatives; and celluloses such as ethyl cellulose, methylethyl cellulose, carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, and the like. Exemplary matrix materials can include substances such as hydrated methylcellulose, carnauba wax, and stearyl alcohol, carbopol 934, silicone, glyceryl tristearate, methyl acrylate-methyl methacrylate, polyvinyl chloride, polyethylene, and / or halogenated fluorocarbons.

[0061] The erodible matrix system may contain other additives and excipients familiar to those skilled in the art of pharmacy, including, but not limited to, solubility enhancers or retardants, stability enhancers, osmagens, binders, buffers, etc. In non-erodible matrix systems, the active ingredient is distributed within the inert matrix and released by diffusion through the matrix to the surrounding environment. Materials used to form the inert matrix include plastics such as ethylene and vinyl acetate copolymers, methyl acrylate-methyl methacrylate copolymers, polyvinyl chloride, and polyethylene; hydrophilic polymers such as cellulose acetate, ethyl cellulose, and cross-linked PVP; various relatively insoluble polymeric materials, including waxes, triglycerides, and fatty compounds. Further examples can be found in standard references such as Remington: The Science and Practice of Pharmacy, 23rd Edition (2020), as is familiar to those skilled in the art.

[0062] It is also possible to prepare a matrix that supports a plurality of particles containing an active ingredient, where the particles comprise a mixture of the active ingredient and a second matrix material, the second matrix material further modifying the release of the active ingredient. This arrangement produces a multiparticulate dosage form. The second matrix material itself may be substantially water-soluble or water-insoluble, and in either case may contain an agent to modify the release of the active ingredient from the second matrix.

[0063] In an embodiment, a reservoir system can be prepared for the controlled release of an active ingredient, such as Nocion. In a reservoir system, a reservoir containing the active ingredient is surrounded by a rate-limiting membrane. The active ingredient is distributed to the surrounding environment by passing through the membrane, using mass transport mechanisms well known in the art, such as diffusion across the membrane or dissolution into the liquid-filled pores of the membrane itself. The reservoir system can be formed with a single large reservoir within the dosage form, for example, within a tablet, or can contain multiple particles, for example, as a capsule containing multiple reservoir particles, each encapsulated by its own membrane. As will be understood by those skilled in the art, the membrane can be amorphous or crystalline, and can have any type of form or composition that allows for providing controlled permeability to the active ingredient, such as porous hydrophilic membranes, interfacially polymerized membranes, hydrogel membranes, ionic membranes, etc. The release rate of the active ingredient can be engineered with various aspects of the reservoir system, such as the composition of the active ingredient deposit within the reservoir and the binder used therefor, the nature and thickness of the membrane, the surface-to-volume ratio of the reservoir element (whether unilocular or multiparticulate).

[0064] Pulsatile dosage forms suitable for controlled release include tablet or bead cores with active ingredient surrounded by a semipermeable membrane that can be destroyed or disintegrated by contact with the environment, resulting in substantially complete and immediate release of the active ingredient when the membrane ruptures. Such systems are classified into three categories: time-controlled release, where the degradation of the outer layer occurs as a function of time, for example as the surface erodes or the internal environment of the system accumulates water and swells; stimulus-induced release, where degradation occurs in response to an environmental stimulus, such as pH or exposure to hydrolytic enzymes; and externally induced, where degradation occurs after exposure to an external stimulus, such as ultrasound or electromagnetic radiation. Techniques for producing such systems, which can allow for control of the timing of the release of Nocion in the small or large intestine, so that it is optimally positioned to reach the area or areas requiring treatment, are well known in the art.

[0065] c. Coating Any of the above methods for sustained release can be mitigated or adjusted by the application of one or more external coating layers. The coating can be applied in one or more layers to the outer surface of the dosage form and / or can be applied in one or more layers to small components within the dosage form, such as active ingredient-containing particles that form part of a multiparticulate system.

[0066] Coatings are advantageous for preparing delayed and controlled release dosage forms by applying a coating to the entire dosage form or to its components that has the desired properties for sustained release. As an example, a tablet can be formed that contains an active ingredient compressed into a core matrix that is coated with a first coating that controls the release of the active ingredient over time during passage through the intestine, and a second layer that covers the entire dosage form and completely prevents the release of the active ingredient for a certain period of time or until a certain biological environment is reached. For example, a twice-coated tablet formulated to contain one or more Nocions can pass through the stomach relatively intact, keeping the underlying inner coating and tablet intact, if ingested and has an outer coating selected to withstand the acid conditions therein. The dosage form then enters the duodenum, where a higher pH can disrupt (erode, dissolve, etc.) the acid-resistant outer coating to expose the inner coating. The inner coating can be formulated to provide a controlled release of the active ingredient from the underlying tablet. Once the outer coating is disrupted, the controlled release properties of the inner coating can determine the release profile of the active ingredient. Alternatively, if only an outer coating is provided, it may protect the dosage form sufficiently to delay release of the active ingredient completely, after which the controlled release of the active ingredient is regulated by the properties of the matrix or vehicle in which it is carried.

[0067] Materials suitable for outer delayed release coatings, including drugs commonly referred to as enteric coatings for delayed release pharmaceuticals, are well known in the art. Enteric coatings known in the art are typically resistant to gastric acid and do not dissolve at a pH of less than 4. Thus, they can protect the underlying tablet from dissolution when passing through the stomach. Examples of enteric coatings suitable for use as outer delayed release layers include cellulose derivatives such as cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate succinate, carboxymethylethylcellulose, methylcellulose phthalate, hydroxypropyl methylcellulose phthalate, and ethylhydroxycellulose phthalate; vinyl polymers such as polyvinyl acetate phthalate, vinyl acetate-maleic anhydride copolymer; polyacrylates; and polymethacrylates such as methyl acrylate-methacrylic acid copolymer, methacrylate-methacrylic acid-octyl acrylate copolymer; and styrene-maleic acid monoester copolymers, any of which can be used alone or in combination. Certain of these materials, including cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, and acrylic copolymers, such as those commercially available as part of the Eudragit® family (Rohm Pharma), including Eudragit® L100, Eudragit® S100, and Eudragit® L30 D55, are pH sensitive.

[0068] The controlled release coating can be designed to provide an appropriate delivery schedule for the active ingredient so that it can reach one or more diseased sites in the intestine. It is understood that diseased sites in the intestine are the treatment target of the active ingredient. In CD, diseased sites are found in the colon. Thus, the active ingredient needs to reach the colon without being absorbed more proximally if it is to access and treat the lesion via an intraluminal approach. In the case of CD, the lesion can include the entire intestinal tract, both the small intestine and the large intestine. Thus, it is desirable for the controlled release coating to adequately protect the active ingredient so that it can access the various sites affected by the disease, potentially including the entire length of the small intestine and colon.

[0069] In embodiments, the release is specifically directed to the vicinity of one or more affected areas. In other embodiments, the active ingredient is released proximally and can proceed in the intestine to treat lesions encountered during transit, provided that there is no significant absorption of the active ingredient. Controlled release coatings for these purposes include agents well known in pharmaceutical formulations and safe for oral administration, including, but not limited to, agents or combinations of agents such as shellac, beeswax, glycowax, castor wax, carnauba wax, stearyl alcohol, glyceryl monostearate, glyceryl distearate, glycerol palmitosterate, ethyl cellulose, acrylic resins, dl-polylactic acid, cellulose acetate butyrate, polyvinyl chloride, polyvinyl acetate, vinylpyrrolidone, polyethylene, polymethacrylate, methyl methacrylate, 2-hydroxymethacrylate, methacrylate hydrogel, 1,3 butylene glycol, ethylene glycol methacrylate, and / or polyethylene glycol.

[0070] Section 3: Treatment methods Disclosed herein is a method for treating intestinal inflammation, such as IBD, UC, and CD, comprising orally administering a therapeutically effective amount of one or more Nocion or compounds of the present invention to a patient in need thereof. Advantageously, oral administration involves providing a sustained release formulation that can provide delayed release of the active ingredient, controlled release of the active ingredient, or both. The sustained release formulation can be designed to maximize release at selected locations in the intestine based on the clinical needs of the patient. For example, a sustained release formulation for an IBD patient with UC can target maximum release in the colon, with the formulation providing delayed release until it has traversed most of the small intestine or until it has reached the colon itself. A sustained release formulation for an IBD patient with CD can target release along the length of the small intestine, with delayed release ensuring passage through the stomach and controlled release allowing the active ingredient to access multiple affected areas along the length of the small intestine.

[0071] In general, the oral dosage of any of the compounds of the present invention administered to humans depends on the nature of the compound and can be readily determined by one of skill in the art. Typically, such dosages can be about 0.001 mg to 2000 mg per day, preferably about 1 mg to 1000 mg per day, more preferably about 5 mg to 500 mg per day. Doses of up to 200 mg per day or more may be required. Administration of one or more compounds can be daily, every other day, or at other intervals. Doses can be provided once, twice, three times, or four times per day, or more frequently. Recognizing that IBD is a lifelong disease that may require long-term or lifelong treatment to prevent symptoms, pathological changes in intestinal tissue, or sequelae such as colon cancer, the duration of treatment can range from one day to a full year or more.

[0072] It is understood that IBD itself is considered incurable and is accompanied by a variety of symptoms and frequent exacerbations. However, clinical symptoms may not correspond linearly to the anatomical state of the disease or its progression. Therefore, objective measurements are useful to evaluate and monitor disease activity. Physicians currently rely on a combination of symptoms, radiological examinations, histological examination of tissue specimens, endoscopic examinations, and laboratory indicators to make treatment decisions. These techniques, which are currently implemented and will be improved in the future, can be collectively referred to as "monitoring" IBD. Biomarkers that enable monitoring have been identified in blood, stool, urine, breath, and tissue, and many others are under investigation. The use of monitoring techniques may allow for monitoring disease activity, evaluation of the effectiveness of treatment, and prediction of the future course of the disease. Monitoring techniques in current practice include, but are not limited to, detection and measurement of serological antibodies such as autoantibodies and antimicrobial antibodies, detection and measurement of circulating non-coding RNA, serum metabolic profiling, serum protein profiling, detection and measurement of identified disease markers such as oncostatin M, serum galectins, C-reactive protein, fecal calprotectin, pro-inflammatory cytokines, and vitamin D levels.

[0073] Dosage and schedule can be arranged according to clinical indications such as relapse or persistence of symptoms. Dosing can also be arranged in light of objective measures of disease persistence, disease progression, or disease regression. In embodiments, treatment protocols including pre-established dosing schedules can be adapted to the clinical needs of the patient by reference to one or more objective measures, such as biomarkers reflecting the state of the disease or the state of inflammation believed to be due to the disease. In embodiments, after obtaining baseline objective measurements corresponding to the state of the disease, a predetermined induction dose is administered for a first period of time, after which a second set of objective measurements is obtained. Based on the second set of objective measurements, a second dose or dosing schedule is determined and administered. In embodiments, the second dose or dosing schedule is less than the induction dose or less frequent than the induction dosing schedule, and in embodiments, this second treatment regimen is intended for chronic administration. In embodiments, a third set of objective measurements is taken during the second treatment regimen, after which the dosage and / or dosing schedule can be modified. In other embodiments, no induction dose is administered, but objective measurements are taken before starting treatment and at regular intervals during treatment, and dosing is adjusted accordingly.

[0074] Treatment of IBD using the method of the present invention can include adjusting the amount of active ingredient in a single dose, the frequency or schedule of administration, the type of dosage form for delivering the active ingredient, or other parameters that affect the amount of active ingredient that reaches a particular affected area in the intestinal tract within a given time frame (collectively, "modifying" the treatment regimen). Using the information obtained from monitoring as described above, the treatment regimen can be modified to optimize the course of treatment. In some embodiments, the change in one or more monitoring parameters can be used to increase or decrease the amount of active ingredient administered in a single dose, or to change the frequency of administration within a single 24-hour period, or to change the duration of treatment (e.g., to allow intermittent courses of treatment for different periods). Other modifications of the treatment regimen based on the monitoring parameters can be envisioned by those skilled in the art. EXAMPLES

[0075] Example 1: Anti-inflammatory activity of Nocion in the dextran sodium (DSS) model of ulcerative colitis As an exemplary Nocion, a charged sodium channel blocker represented by the following formula (XIV) (referred to as "NTX 1170") was administered to a DSS mouse model of ulcerative colitis, comparing its anti-inflammatory effects with those of tofacitinib and infliximab. [ka]

[0076] The anti-inflammatory efficacy of Nocion, exemplified by the compound of formula XIV (NTX 1170) (100 mg / kg QD PO), was compared to infliximab (5 mg / kg QD IP) and tofacitinib (5 mg / kg BID PO) in mice fed 2.5% DSS in drinking water for 6 days. Body weight, stool consistency, and the presence of blood in the stool were measured over 6 days and constitute the Disease Activity Index (DAI). On day 7, the study was terminated and colons and plasma were collected for cytokine measurements, histology evaluation, and pharmacokinetic (PK) analysis.

[0077] The compound of formula XIV produced a 60% (P<0.05) improvement in DAI compared with a 38% (P<0.001) reduction by tofacitinib and a 14% (NS) reduction by infliximab. Several plasma cytokines (IP-10, MIG, TNF-α, G-CSF, and Mip-1β) were upregulated by DSS treatment and significantly reduced by NTX-1170. Tofacitinib significantly reduced MIG, TNF-α, G-CSF, and Mip-1β levels, whereas infliximab reduced only TNF-α, G-CSF, and Mip-1β levels. Colonic KC, IL-15, and RANTES levels were significantly increased by DSS treatment and significantly reduced by NTX-1170, whereas neither tofacitinib nor infliximab significantly reduced these cytokines. Histopathological analysis of the colon revealed that NTX-1170 significantly reduced the extent of inflammatory infiltration, the layer of infiltration extension, and the amount of crypt damage. Tofacitinib only reduced the extent of infiltration, and infliximab had no significant effect. Analysis of terminal plasma and colon samples showed very low levels of the compound of formula XIV in plasma and high levels in colon, with a colon / plasma ratio of >3500.

[0078] These data indicate that charged sodium channel blocking compounds, exemplified by the compound shown in Formula II, inhibit neurogenic inflammation and provide significant efficacy in the DSS model of UC, thus providing a treatment option for UC with the potential for greater efficacy than current treatments such as infliximab and tofacitinib.

[0079] Although the present invention has been particularly shown and described with reference to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention as encompassed by the appended claims. While specific embodiments of the present invention have been disclosed herein, the above specification is illustrative and not restrictive. Many variations of the present invention will become apparent to those skilled in the art upon review of this specification. Modifications of the described modes for carrying out the invention that are obvious to those skilled in the art of medicine, immunology, pharmacology, endocrinology, or related fields are intended to be within the scope of the present invention.

[0080] Unless otherwise indicated, all numbers expressing reaction conditions, quantities of ingredients, and so forth used in the specification and claims are to be understood as being modified in all instances by the term "about." Accordingly, unless otherwise indicated, the numerical parameters set forth herein are approximations that may vary depending upon the desired properties sought to be obtained by the present invention.

Claims

1. A pharmaceutical formulation for treating intestinal inflammation, comprising a therapeutically effective amount of a charged sodium channel blocker, wherein the pharmaceutical formulation is administered orally.

2. The pharmaceutical preparation according to claim 1, wherein the intestinal inflammation is selected from the group consisting of inflammatory bowel disease, ulcerative colitis, and Crohn's disease.

3. The pharmaceutical formulation according to claim 1, wherein the formulation is designed to release the composition at a selected location in the intestine.

4. The pharmaceutical preparation according to claim 1, wherein the preparation is an enteric-coated tablet.

5. The aforementioned compound is of formula (I): 【Chemistry 1】 (In the formula, Y － is a pharmaceutically acceptable anion; R Ｆ and R Ｇ is, N ＋ Together with them, they form an optionally substituted heteroaryl ring having one or more heteroatoms or an optionally substituted bicyclic heteroaryl ring having one or more heteroatoms; 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 are each independently selected therefrom; or R Ｂ and adjacent R Ｃ together with the carbon atom to which they are attached form a substituted or unsubstituted 3- to 7-membered cycloalkyl (C ３ -C ７ cycloalkyl) or a substituted or unsubstituted aryl; 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 Each of these is independently selected from H, D, substituted or unsubstituted alkyls, substituted or unsubstituted alkenyls, substituted or unsubstituted alkynyls, and substituted or unsubstituted heteroalkyls; X １ is, -CR Ｘ R Ｙ -, -NR Ｚ C(O)-, -OC(O)-, -SC(O)-, -NR Ｚ S(O)-, -S(O)NR Ｚ -, -NR Ｘ C(O)NR Ｙ -, -C(O)NR １Ａ -, -C(O)O-, -C(O)-, -S(O)-, -S(O) ２ -, and -(O)CS- selected; X １ Ha-NR Ｚ C(O)CR Ｘ R Ｙ - It is also possible that R Ｘ , R Ｙ , R Ｚ , and R １Ａ Each of these is independently selected from H, D, substituted or unsubstituted alkyls, substituted or unsubstituted alkenyls, substituted or unsubstituted alkynyls, and substituted or unsubstituted heteroalkyls; R Ｄ and R Ｅ Each of these is independently selected from H, D, substituted or unsubstituted alkyls (optionally substituted with halogens, cyclic alkyls, aryls, or heteroaryls), substituted or unsubstituted alkenyls (optionally substituted with halogens, cyclic alkyls, aryls, or heteroaryls), substituted or unsubstituted alkynyls (optionally substituted with halogens, cyclic alkyls, aryls, or heteroaryls), substituted or unsubstituted heteroalkyls (optionally substituted with halogens, cyclic alkyls, aryls, or heteroaryls), and cycloalkyls, or R Ｄ and R Ｅ These, together with the carbon to which they are bonded, form substituted or unsubstituted 3- to 7-membered cycloalkyl (C) atoms. ３ ~C ７ Forms a cycloalkyl (or substituted or unsubstituted heterocyclic or heteroalkyl ring), or R Ｄ and R Ｚ These, together with the carbon atoms to which they are bonded and the -N-C(O)-, optionally form substituted 5- to 8-membered lactams. A pharmaceutical preparation according to claim 1, having the following characteristics.

6. The aforementioned compound is of formula (II): 【Chemistry 2】 (In the formula, Y － is a pharmaceutically acceptable anion; 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, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, OR Ｉ 、CN、NR Ｊ R Ｋ 、NR Ｌ C(O)R Ｍ 、S(O)R Ｎ 、S(O) ２ R Ｎ 、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 RW are each independently selected therefrom; 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 Each of is independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocycloalkyl; R Ｊ and R Ｋ , or R Ｖ and R Ｗ , or R Ｑ and R Ｒ They can also form substituted or unsubstituted 5, 6, 7, or 8-membered rings together with the nitrogen atoms to which they are bonded; R Ａ , R Ｂ , and / or R Ｃ These, together with the phenyl ring to which they are bonded, can form condensed bicyclic or tricyclic ring systems including naphthyl, dihydroindenyl, tetrahydronaphthyl, quinolinyl, and indolyl; X １ is, -CR Ｘ R Ｙ -, -NR Ｚ C(O)-, -OC(O)-, -SC(O)-, -C(O)NR １Ａ -, -C(O)O-, -C(O)-, -(O)CS-, -NR １Ａ S(O)-, -S(O)NR １Ａ -, -NR １Ａ C(O)NR １Ａ -, -S(O)-, and -S(O) ２ - Selected from; X １ Ha-NR Ｚ C(O)CR Ｘ R Ｙ - It is also possible; R Ｘ , R Ｙ , R Ｚ , and R １Ａ Each of these is independently selected from H, D, substituted or unsubstituted alkyls, substituted or unsubstituted alkenyls, substituted or unsubstituted alkynyls, and substituted or unsubstituted heteroalkyls; R Ｄ and R Ｅ Each of these is independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, and substituted or unsubstituted cycloalkyl, or R Ｄ and R Ｅ These, together with the carbon to which they are bonded, form substituted or unsubstituted 3-6 membered cycloalkyl (C) atoms. ３ ~C ６ Forming a cycloalkyl, substituted or unsubstituted heterocyclic ring, or a substituted or unsubstituted heteroalkyl ring, or R Ｄ and R Ｚ These, together with the carbons to which they are bonded and the -N-C(O)-, form optionally substituted 5- to 8-membered lactams; R Ｆ and R Ｇ is, N ＋ Together with these, they form a heterocycle having one or more nitrogen atoms, and which may be substituted, or R Ｆ and R Ｇ Each of these is a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted heteroalkyl, and a substituted or unsubstituted C ３～６ Selected independently from cycloalkyl; R Ｈ (This refers to a substituted or unsubstituted aryl ring, or a substituted or unsubstituted heteroaryl ring.) A pharmaceutical preparation according to claim 1, having the following characteristics.

7. The aforementioned compound is of formula (III): 【Transformation 3】 (In the formula, Y － is a pharmaceutically acceptable anion; R Ａ , R Ｂ , and R Ｃ H, D, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, OR Ｉ , NR Ｊ R Ｋ , NR Ｌ C(O)R Ｍ , CN, S(O)R Ｎ , S(O) ２ R Ｎ 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 Each is independently selected from; 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 Each of these is independently selected from H, D, halogens, substituted or unsubstituted alkyls, substituted or unsubstituted alkenyls, substituted or unsubstituted alkynyls, and substituted or unsubstituted heteroalkyls; X １ is, -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-, -C(O)-, -(O)CS-, -NR １Ａ S(O)-, -S(O)NR １Ａ -, -NR １Ａ C(O)NR １Ａ -, -S(O)-, and -S(O) ２ - Selected from; R Ｘ , R Ｙ , R Ｚ , and R １Ａ Each of these is independently selected from H, D, substituted or unsubstituted alkyls, substituted or unsubstituted alkenyls, substituted or unsubstituted alkynyls, and substituted or unsubstituted heteroalkyls, or R Ｘ , R Ｙ , R Ｚ , or R １Ａ R Ｄ Or R Ｅ And together with the atoms to which they are bonded, they may form substituted cycloalkyl or substituted heterocycles; R Ｄ and R Ｅ Each of these is independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, and substituted or unsubstituted cycloalkyl, or R Ｄ and R Ｅ These, together with the carbon atoms to which they are bonded, form substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycles; R Ｆ , R Ｇ , and R Ｈ Each of these is H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted -C ６ ~C １０ Aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, substituted or unsubstituted -CH ２ -C ５ ~C １０ Aryl, and substituted or unsubstituted CH ２ -C ５ ~C １０ Either selected independently from heteroaryls, or instead, R Ｆ , R Ｇ , and R Ｈ Two or three of them are P, which is connected to them. ＋ Together with, and not limited to, P, which may include substituted heteroaryl rings. ＋ In addition, it may form a substituted heterocycline having zero, one, or more heteroatoms, or R Ｄ , R Ｅ , R Ｆ , R Ｇ , and R Ｈ Two or three of them are P ＋ Together with, and not limited to, P, which contains a heteroaryl ring ＋ In addition, it may form a substituted heterocycle having zero, one, or more heteroatoms;) A pharmaceutical preparation according to claim 1, having the following characteristics.

8. The aforementioned compound is of formula (IV): 【Chemistry 4】 (In the formula, Y － is a pharmaceutically acceptable anion; R Ａ and R Ｂ H, ２ H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, OR Ｉ , NR Ｊ R Ｋ , NR Ｌ C(O)R Ｍ S(O)R Ｎ , S(O) ２ R Ｎ 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 Each is independently selected from; 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 Each of these is H, ２ Independently selected from H, substituted or unsubstituted alkyls, substituted or unsubstituted alkenyls, substituted or unsubstituted alkynyls, and substituted or unsubstituted heteroalkyls; X １ is, -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-, -C(O)-, -(O)CS-, -NR １Ａ S(O)-, -S(O)NR １Ａ -, -NR １Ａ C(O)NR １Ａ -, -S(O)-, and -S(O) ２ - Selected from; R Ｘ , R Ｙ , R Ｚ , and R １Ａ Each of these is H, ２ H, independently selected from substituted or unsubstituted alkyls, substituted or unsubstituted alkenyls, substituted or unsubstituted alkynyls, and substituted or unsubstituted heteroalkyls, or R Ｘ , R Ｙ , R Ｚ , or R １Ａ R Ｄ Or R Ｅ And together with the atoms to which they are bonded, they may form substituted cycloalkyl or substituted heterocycles; R Ｄ and R Ｅ Each of these is H, ２ H, independently selected from substituted or unsubstituted alkyls, substituted or unsubstituted alkenyls, substituted or unsubstituted alkynyls, substituted or unsubstituted heteroalkyls, and substituted or unsubstituted cycloalkyls, or R Ｄ and R Ｅ These, together with the carbon atoms to which they are bonded, form substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycles; R Ｆ , R Ｇ , and R Ｈ Each of these is H, ２ H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted -C ６ ~C １０ Aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, substituted or unsubstituted -CH ２ -C ５ ~C １０ Aryl, and substituted or unsubstituted CH ２ -C ５ ~C １０ Either selected independently from heteroaryls, or instead, R Ｆ , R Ｇ , and R Ｈ Two or three of them are P, which is connected to them. ＋ Together with, and not limited to, P, which may include substituted heteroaryl rings. ＋ In addition, it forms a substituted heterocycline if it has zero, one, or more heteroatoms, or R Ｄ , R Ｅ , R Ｆ , R Ｇ , and R Ｈ Two or three of them are P, which is connected to them. ＋ Together with, and not limited to, P, which contains a heteroaryl ring ＋ In addition, it may have zero, one, or more heteroatoms to form a substituted heterocycle;) A pharmaceutical preparation according to claim 1, having the following characteristics.

9. The aforementioned compound is of formula (V): 【Transformation 5】 (In the formula, Y － is a pharmaceutically acceptable anion; R Ｆ and R Ｇ The N that they are joined together ＋ Together with them, they form an optionally substituted heteroaryl ring having one or more heteroatoms or an optionally substituted bicyclic heteroaryl ring having one or more heteroatoms; R Ａ and R Ｂ H, D, halogens, substituted or unsubstituted alkyls, substituted or unsubstituted alkenyls, substituted or unsubstituted alkynyls, nitriles, 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 Each is independently selected from; 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 Each of these is independently selected from H, D, substituted or unsubstituted alkyls, substituted or unsubstituted alkenyls, substituted or unsubstituted alkynyls, and substituted or unsubstituted heteroalkyls; X １ is, -CR Ｘ R Ｙ -, -NR Ｚ C(O)-, -NR Ｚ C(O)CR Ｘ R Ｙ -, -OC(O)-, -SC(O)-, -NR Ｚ S(O)-, -S(O)NR Ｚ -, -NR Ｘ C(O)NR Ｙ -, -C(O)NR １Ａ -, -C(O)O-, -C(O)-, -S(O)-, -S(O) ２ - and -(O)CS- are selected; R Ｘ , R Ｙ , R Ｚ , and R １Ａ Each of these is independently selected from H, D, substituted or unsubstituted alkyls, substituted or unsubstituted alkenyls, substituted or unsubstituted alkynyls, and substituted or unsubstituted heteroalkyls, or any other R Ｘ , R Ｙ , R Ｚ , R １Ａ , R Ｄ , or R Ｅ Together with any intervening atom, it can form a substituted or unsubstituted ring; R Ｄ and R Ｅ Each of these is independently selected from H, D, substituted or unsubstituted alkyls (optionally substituted with halogens, cyclic alkyls, aryls, or heteroaryls), substituted or unsubstituted alkenyls (optionally substituted with halogens, cyclic alkyls, aryls, or heteroaryls), substituted or unsubstituted alkynyls (optionally substituted with halogens, cyclic alkyls, aryls, or heteroaryls), substituted or unsubstituted heteroalkyls (optionally substituted with halogens, cyclic alkyls, aryls, or heteroaryls), and cycloalkyls, or R Ｄ and R Ｅ These, together with the carbon to which they are bonded, form substituted or unsubstituted 3- to 7-membered cycloalkyl (C) atoms. ３ ~C ７ Forms a cycloalkyl (or substituted or unsubstituted heterocyclic or heteroalkyl ring), or R Ｄ and R Ｚ These, together with the carbon atoms to which they are bonded and the -N-C(O)-, optionally form substituted 5- to 8-membered lactams. A pharmaceutical preparation according to claim 1, having the following characteristics.

10. The compound can be used to treat or prevent pain, itching, and neurogenic inflammation, and the compound is of formula (VI): 【Transformation 6】 (In the formula, Y － is a pharmaceutically acceptable anion; R Ａ and R Ｂ H, D, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, OR Ｉ , NR Ｊ R Ｋ , NR Ｌ C(O)R Ｍ S(O)R Ｎ , S(O) ２ R Ｎ 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 Each is independently selected from; 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 Each of these is independently selected from H, D, substituted or unsubstituted alkyls, substituted or unsubstituted alkenyls, substituted or unsubstituted alkynyls, and substituted or unsubstituted heteroalkyls; X １ is, -CR Ｘ R Ｙ -, -NR Ｚ C(O)-, -OC(O)-, -SC(O)-, -C(O)NR １Ａ -, -C(O)O-, -C(O)-, -(O)CS-, -NR １Ａ S(O)-, -S(O)NR １Ａ -, -NR １Ａ C(O)NR １Ａ -, -S(O)-, and -S(O) ２ - Selected from; X １ Ha-NR Ｚ C(O)CR Ｘ R Ｙ - It is also possible; R Ｘ , R Ｙ , R Ｚ , and R １Ａ Each of these is independently selected from H, D, substituted or unsubstituted alkyls, substituted or unsubstituted alkenyls, substituted or unsubstituted alkynyls, and substituted or unsubstituted heteroalkyls, or any other R Ｘ , R Ｙ , R Ｚ , R １Ａ , R Ｄ , or R Ｅ Together with any intervening atom, it can form a substituted or unsubstituted ring; R Ｄ and R Ｅ Each of these is independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, and substituted or unsubstituted cycloalkyl, or R Ｄ and R Ｅ These, together with the carbon to which they are bonded, form substituted or unsubstituted 3-6 membered cycloalkyl (C) atoms. ３ ~C ６ Forming a cycloalkyl, substituted or unsubstituted heterocyclic ring, or a substituted or unsubstituted heteroalkyl ring, or R Ｄ and R Ｚ These, together with the carbons to which they are bonded and the -N-C(O)-, form optionally substituted 5- to 8-membered lactams; R Ｆ and R Ｇ The N that they are joined together ＋ Together with these, they form a heterocycle having one or more nitrogen atoms, and which may be substituted, or R Ｆ and R Ｇ Each of these is a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted heteroalkyl, and a substituted or unsubstituted C ３～６ Selected independently from cycloalkyl; R Ｈ (This refers to a substituted or unsubstituted aryl ring, or a substituted or unsubstituted heteroaryl ring.) A pharmaceutical preparation according to claim 1, having the following characteristics.

11. The aforementioned compound is of formula (VII): 【Transformation 7】 (In the formula, Y － is a pharmaceutically acceptable anion; R Ａ CO ２ R Ｔ And; R Ｔ is a substituted or unsubstituted alkyl group; R Ｂ is H, D, halogen, or substituted or unsubstituted alkyl; R Ｃ H, D, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, OR Ｉ , CN, NR Ｊ R Ｋ , NR Ｌ C(O)R Ｍ S(O)R Ｎ , S(O) ２ R Ｎ 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 Selected from R or W; 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 Each of is independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocycloalkyl; R Ｊ and R Ｋ , or R Ｖ and R Ｗ , or R Ｑ and R Ｒ They can also form substituted or unsubstituted 5, 6, 7, or 8-membered rings together with the nitrogen atoms to which they are bonded; X １ is, -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-, -C(O)-, -(O)CS-, -NR １Ａ S(O)-, -S(O)NR １Ａ -, -NR １Ａ C(O)NR １Ａ -, -S(O)-, and -S(O) ２ - may be selected from; R Ｘ , R Ｙ , R Ｚ , and R １Ａ Each of these is independently selected from H, D, substituted or unsubstituted alkyls, substituted or unsubstituted alkenyls, and substituted or unsubstituted alkynyls. A pharmaceutical preparation according to claim 1, having the following characteristics.

12. The aforementioned compound is of formula (VIII): 【Transformation 8】 (In the formula, Y － is a pharmaceutically acceptable anion; n is 1, 2, 3, or 4; R Ａ , R Ｂ , and R Ｃ H, D, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, OR Ｉ , CN, NR Ｊ R Ｋ , NR Ｌ C(O)R Ｍ S(O)R Ｎ , S(O) ２ R Ｎ 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 Each is independently selected from; 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 Each of is independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocycloalkyl; R Ｊ and R Ｋ , or R Ｖ and R Ｗ , or R Ｑ and R Ｒ They can also form substituted or unsubstituted 5, 6, 7, or 8-membered rings together with the nitrogen atoms to which they are bonded; R Ａ , R Ｂ , and / or R Ｃ These, together with the phenyl ring to which they are bonded, can form condensed bicyclic or tricyclic ring systems including naphthyl, dihydroindenyl, tetrahydronaphthyl, quinolinyl, and indolyl; X １ is, -CR Ｘ R Ｙ -, -NR Ｚ C(O)-, -OC(O)-, -SC(O)-, -C(O)NR １Ａ -, -C(O)O-, -C(O)-, -(O)CS-, -NR １Ａ S(O)-, -S(O)NR １Ａ -, -NR １Ａ C(O)NR １Ａ -, -S(O)-, and -S(O) ２ - Selected from; X １ Ha-NR Ｚ C(O)CR Ｘ R Ｙ - It is also possible; R Ｘ , R Ｙ , R Ｚ , and R １Ａ Each of these is independently selected from H, D, substituted or unsubstituted alkyls, substituted or unsubstituted alkenyls, substituted or unsubstituted alkynyls, and substituted or unsubstituted heteroalkyls; R Ｄ and R Ｅ Each of these is independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, and substituted or unsubstituted cycloalkyl, or R Ｄ and R Ｅ These, together with the carbon to which they are bonded, form substituted or unsubstituted 3-6 membered cycloalkyl (C) atoms. ３ ~C ６ Forming a cycloalkyl, substituted or unsubstituted heterocyclic ring, or a substituted or unsubstituted heteroalkyl ring, or R Ｄ and R Ｚ These, together with the carbons to which they are bonded and the -N-C(O)-, form optionally substituted 5- to 8-membered lactams; R Ｈ is a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted cycloalkyl, or a substituted or unsubstituted heterocycloalkyl; in certain embodiments, R Ｈ R can be substituted or unsubstituted aralkyl or heteroarylalkyl; in additional embodiments, R Ｈ This can be a substituted or unsubstituted alkylcarboxylate, or a substituted or unsubstituted alkylcarboxamide; R １Ｂ (These are substituted or unsubstituted aryls or substituted or unsubstituted heteroaryls.) A pharmaceutical preparation according to claim 1, having the following characteristics.

13. The aforementioned compound is of formula (IX): 【Chemistry 9】 (In the formula, Y － is a pharmaceutically acceptable anion; R １ These include methyl, ethyl, propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, tert-butyl, and sec-butyl), cyclohexyl, phenyl, and CH ２ C(O)NHR ３ Selected from the group consisting of; R ２ is hydrogen or methyl; R ３ (These are hydrogen, methyl, or ethyl.) A pharmaceutical preparation according to claim 1, having the following characteristics.

14. The aforementioned compound is given by formula (X): 【Chemistry 10】 (In the formula, Y － is a pharmaceutically acceptable anion; R １ and R ２ One of them is hydrogen, R １ and R ２ The other is methyl, ethyl, unsubstituted phenyl, and C(O)OR ３ Selected from the group consisting of; R ３ (Selected from the group consisting of hydrogen, methyl, and ethyl.) A pharmaceutical preparation according to claim 1, having the following characteristics.

15. The aforementioned compound is of formula (XI): 【Chemistry 11】 (In the formula, Y － is a pharmaceutically acceptable anion; q is 0, 1, 2, or 3; R Ｄ (These are hydrogen, methyl, or ethyl.) A pharmaceutical preparation according to claim 1, having the following characteristics.

16. The aforementioned compound is of formula (XII): 【Chemistry 12】 (In the formula, Y － is a pharmaceutically acceptable anion; R １ , R ２ , R ３ , R ４ , R ５ , and R ６ is independently selected from hydrogen, C1-C4 alkyl, C1-C4 heteroalkyl, aryl, or heteroaryl; n is 0, 1, 2, 3, 4, and 5; (q is 0, 1, 2, 3, 4, or 5) A pharmaceutical preparation according to claim 1, having the following characteristics.

17. The aforementioned compound is of formula (XIII): 【Chemistry 13】 (In the formula, Y － is a pharmaceutically acceptable anion; R Ａ , R Ｂ , and R Ｃ H, D, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, OR Ｉ ,CN,CF ３ , NR Ｊ R Ｋ , NR Ｌ C(O)R Ｍ S(O)R Ｎ , S(O) ２ R Ｎ 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 Each is independently selected from; 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 Each of these is independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, or R Ｊ and R Ｋ , or R Ｖ and R Ｗ , or R Ｑ and R Ｒ These can also form substituted or unsubstituted 5, 6, 7, or 8-membered rings together with the nitrogen atoms to which they are bonded; R Ａ , R Ｂ , and / or R Ｃ These, together with the phenyl ring to which they are bonded, can form condensed bicyclic or tricyclic ring systems including naphthyl, dihydroindenyl, tetrahydronaphthyl, quinolinyl, and indolyl; R １ , R ２ , R ３ , R ４ , R ５ , and R ６ is hydrogen, C １ ~C ４ Alkyl, C １ ~C ４ Independently selected from heteroalkyl, cycloalkyl, aryl, or heteroaryl; n is 0, 1, 2, 3, 4, and 5; or R １ , R ２ , R ３ , R ４ , R ５ , and / or R ６ These, together with one or more carbon atoms to which they are bonded, form substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycles; R Ｆ and R Ｇ is, N ＋ Together with, and not limited to, N, which includes heteroaryl rings ＋ In addition, it may form a substituted heterocycle having zero, one, or more heteroatoms; R H is selected from substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl, and includes CH ２ -Cycloalkyl, -C ２ H ４ -Cycloalkyl, substituted or unsubstituted-CH ２ -C ５ ~C １０ Aryl, substituted, or unsubstituted - C ２ H ４ -C ５ ~C １０ Aryl, substituted, or unsubstituted CH ２ -C ５ ~C １０ Heteroaryl, substituted or unsubstituted - C ２ H ４ -C ５ ~C １０ Heteroaryl, -CH ２ OC(O)R Ｔ ien-CH ２ CO ２ R Ｔ ien-CH ２ C(O)NR Ｖ R Ｗ , -C ２ H ４ OCOR Ｔ , -C ２ H ４ OR Ｉ It includes, or R Ｆ , R Ｇ , and R Ｈ is, N ＋ (Together, they form substituted or unsubstituted heteroaryl rings or bridging heterocycles.) A pharmaceutical preparation according to claim 1, having the following characteristics.

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