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US 2026/0146041 A1Published application
Pannexin-1 modulators and methods of treating disorders in which pannexin-1 is implicated
AssigneePannex Therapeutics Inc.
InventorsDavid Alexandre Bravo López, Gerhard Max Gross
Life of this patent
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Abstract
Disclosed herein are small molecule modulators of pannexin. Also disclosed herein are methods of treating disorders associated with exacerbated activation of ATP-induced signal pathways mediated by pannexin, such as pain and opioid addiction, by administering small molecule modulators of pannexin.
Claims23
A compound of formula I or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof:
- wherein,
- X and Y are individually C, CH or N, or preferably wherein Y is C, or CH and X is N;
- R1, R2 and R3 are independently hydrogen;
- lower alkyl, optionally substituted with hydroxy;
- lower cycloalkyl;
- lower alkenyl;
- lower alkoxy;
- lower alkynyl;
- phenyl;
- halogenated phenyl;
- halogen;
- a substituted or non-substituted aromatic or non-aromatic heterocycle, preferably diazine, pyrazole, diazole, triazole, or their alkyl derivatives;
- 2-hydroxyisopropyl;
- or have one of the following structures:
- wherein,
- X′ is C, CH, CH2, N, S, or O, or preferably can be CH2, N, or O;
- ×″ is independently C, CH, CH2, N, S, or O, preferably CH2, N, or O;
- X′″ is NH, N-lower alkyl or O;
- R1′-R5′ are independently absent, hydrogen, lower alkyl, lower cycloalkyl, halogen, OH, NH2, hydroxy-lower alkyl, or NH-lower alkyl, O-lower alkyl, O—PO—OR6′, O-Lower alkyl or alkyloxy-O—PO—O—R6′, or O—PO—O-lower alkyl-O—PO—R6′, preferably OH, NH2, NH-lower alkyl, wherein vicinal R1′ and R5′ may form a 5-7 membered ring moiety;
- R6′ is H or O-lower alkyl;
- R1″-R4″ are independently absent, hydrogen, lower alkyl, lower cycloalkyl, OH, NH2, hydroxy-lower alkyl, NH-lower alkyl, O-lower alkyl, O—PO—OR6′, O-lower alkyl or alkyloxy-O—PO—O—R6′, or O—PO—O-lower alkyl-O—PO—R6′, preferably OH, NH2, NH-lower alkyl, or halogen;
- Y′″ is halogen;
- and
- wherein the bonds between adjacent ring substituents X′ or adjacent ring substituents X″ may constitute single or double bonds;
- or
- a compound of formula I′ or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof:
- wherein,
- Xa or Xb is C, CH or N, or preferably Xa is C or CH, and Xb is N;
- Y is CH, CH2, C-lower alkyl, CH-lower alkyl, C-halogen, CH-halogen or C-dihalogen;
- Z is CH or N, preferably CH;
- wherein the bond between adjacent ring substituents Y may constitute a single or double bond;
- R1, R2, R3, and R4 are independently absent, hydrogen;
- lower alkyl;
- lower cycloalkyl;
- lower alkenyl;
- lower alkoxy;
- lower alkynyl;
- phenyl;
- halogenated phenyl;
- halogen;
- a substituted or non-substituted aromatic or non-aromatic heterocycle, preferably triazole, or diazine;
- 2-hydroxyisopropyl, or have one of the following structures:
- wherein,
- X′ is C, CH, CH2, N, S or O, preferably CH2, N, or O;
- X″ is C, CH, CH2, N, S or O, preferably CH2, N, or O;
- X′″ is NH, N-lower alkyl or O;
- R1′-R5′ are independently absent, or are H, lower alkyl, lower cycloalkyl, OH, NH2, NH-lower alkyl, halogen, O-lower alkyl, O—PO—OR6′, O-Lower alkyl or alkyloxy-O—PO—O—R6′, or O—PO—O-lower alkyl-O—PO—R6′, preferably OH, NH2, NH-lower alkyl, wherein vicinal R1′ and R5′ may form a 5-7 membered ring moiety;
- R6′ is H or O-lower alkyl;
- R1″-R4″ are independently absent, or are hydrogen, lower alkyl, lower cycloalkyl, or halogen;
- Y′″ is halogen, and
- wherein the bonds between adjacent ring substituents X′ or adjacent ring substituents X″ may constitute single or double bonds, forming thereby a non-aromatic or aromatic ring.
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A compound of formula II or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof:
- wherein,
- X is N;
- Y is C;
- and Z is N, C or CH;
- wherein bonds between adjacent ring substituents X, Y and/or Z constitute single or double bonds;
- R1-R4 are independently absent when Z is N, or,
- one or more of R1-R4 or R1′-R4′ are lower to medium chain oxo- or keto fatty acids, optionally substituted with oxo or lower alkyl;
- H;
- halogen;
- lower alkyl;
- lower cycloalkyl;
- or COOH;
- or
- one or more of R1-R4 or R1′-R4′ comprise the substituent of Formula X:
- wherein,
- X′ is CH, CO, N or O, preferably wherein X′ comprises up to two N or O;
- R1″-R5″ are independently absent, or are H;
- lower alkyl;
- lower cycloalkyl;
- halogen;
- NH2;
- NH-lower alkyl;
- hydroxy;
- oxo;
- COOH, SO2NH2;
- SO2NH-loweralkyl;
- a substituted or non-substituted aromatic or non-aromatic heterocycle, preferably tetrazole;
- or comprises the substituent of Formula XI:
- wherein,
- X′″ is CH, CH2, CO, N or O, or preferably wherein Xiv comprises up to two N or O;
- R1′″-R5′″ are independently absent, H, halogen, NH2, lower alkyl, lower cycloalkyl, NH-lower alkyl, hydroxy, COOH, SO2NH2, SO2NH-loweralkyl;
- a substituted or non-substituted aromatic or non-aromatic heterocycle, preferably tetrazole;
- or preferably wherein only one of R1′″-R5′″ comprises a non-substituted aromatic or non-aromatic heterocycle;
- wherein the bonds between adjacent ring substituents Xiv may constitute single or double bonds, forming thereby a non-aromatic or aromatic ring;
- or
- one or more of R1-R4 comprise the substituent of formula XII:
- wherein,
- Y′ is absent or can each be, independently, CH2, CH2(CH3);
- CO, SO, SO2, CHOH or NH;
- and Z′ is COOH;
- SO2NH2;
- a substituted or non-substituted aromatic or non-aromatic heterocycle, preferably tetrazole;
- forming a C3-C8 linear or branched chain;
- or
- one or more of R1-R4 comprise the substituent of formula XIII:
- wherein,
- Y″ is COOH, SO2NH2, or tetrazole;
- and X′″ is N or O;
- or
- a compound of formula III, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof;
- wherein,
- each Z is independently selected from CH or C;
- each X is independently selected from CH, C, CH2, O, N, S, SO, or SO2;
- each Y is independently selected from N, C, CH, CH2, CO, SO, S, or N-alkyl;
- wherein the bonds between adjacent ring substituents X, Z and/or Y constitute single or double bonds;
- each R1 is either absent or is H, halogen, O, NH2, N-lower cycloalkyl, a phenyl group, alkyl group, optionally substituted with one or both of oxo and carboxy, OH, SO2N(CH3)2, C(O)N(CH3)2, a five membered heterocycle, preferably tetrazole, —CO—(CH2)n—COOH, wherein n is 0-4, wherein R1 optionally may form together with neighboring substituents, an aromatic or aliphatic 5, 6, or 7-membered ring system, which may contain an heteroatom, optionally substituted with one or more COOH, carboxamide, alkoxy, oxo, halogen, or triazole groups, or R, optionally comprises the substituent of Formula XIV:
- wherein,
- X′ is absent or is O, N, or N-lower cycloalkyl;
- A is CH or may be a direct bond when X′ is absent;
- Y′ is O, N, N-lower cycloalkyl, CH2, CH-lower alkyl, or CH—OH, or preferably X′ is absent or is O and the Y′-ring contains 1 or 2 N or O atoms;
- wherein the bonds between adjacent substituents Y′ and other atoms in the ring constitute single or double bonds, thereby forming a non-aromatic or aromatic ring;
- and
- R2 is absent, or is halogen;
- H;
- lower alkyl, optionally substituted with carboxy or oxo;
- hydroxy;
- alkoxy, COOH;
- SO2NH2;
- SO2NH—O—CH3, SO2NH—C(O)—CH3, SO2N(CH3)2, SO2-lower alkyl;
- C(O)N(CH3)2, a substituted or non-substituted aromatic or non-aromatic heterocycle, preferably triazole or tetrazole;
- or comprises the substituent of formula XV;
- wherein,
- B′ is attachment side, wherein B′ may comprise a linker or a direct bond, wherein the linker is —N—;
- and R3 is independently H, COOH, SO2NH2, SO2NH-lower alkyl, halogen, or a substituted or non-substituted aromatic or non-aromatic heterocycle, preferably triazole or tetrazole;
- or
- a compound of formula IV or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof:
- wherein,
- each X is independently selected from CH or C;
- X′ is C;
- Each Y is independently selected from N, CH, C, SO2 or CO;
- R1 and R2 are each independently H, COOH O—CH3, lower cycloalkyl, or join together to form a five- or six-membered heterocyclic ring, which is optionally substituted;
- R3-R7 is each independently H, COOH O—CH3, lower cycloalkyl, or comprises the substituent of formula XVI:
- wherein,
- Z is —N—CO—N or lower alkyl-CO—N;
- X″ is lower alkyl or partly halogenated lower alkyl;
- and
- R1′-R5′ are independently H;
- CHF2;
- COOH SO2NH2;
- NH—CH2—COOH;
- lower alkyl, lower alkyl-COOH, lower alkyl-CO—,lower alkyl-COOH, —O—CO—CH3, OCH3, N—CO—N—O-lower alkyl, N—CO—N—O—CF2, —SO2—N (lower alkyl)2, lower alkyl-O-lower alkyl-COOH, SO2—N-lower alkyl-phenylcarboxylic acid;
- or a substituted or non-substituted aromatic or non-aromatic heterocycle, preferably tetrazole, which may optionally be connected to the bicyclic ring of formula IV with a lower alkyl linker;
- or
- a compound of formula V or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof:
- wherein,
- X is CH2, C, or CH;
- X′ is either C or CH;
- Y is C or CH;
- Y′ is C;
- Z is independently N, O, or N-lower alkyl;
- Z′ is O;
- R2 is H, halogen, lower alkyl, ketobutyric acid, cyclohexanonecarboxylic acid or hydroxymethyl(cyclohexenone);
- wherein the bonds between adjacent ring substituents X, X′ and/or Z constitute single or double bonds, and wherein the bonds between adjacent Y and/or Y′ constitute single or double bonds;
- Z″ can be CH or N, or lower alkyl, lower cycloalkyl, alkyl ether or cycloalkyl;
- and R1 can be H, lower alkyl, halogen, O-lower alkyl, COOH, N—CO—N—O-lower alkyl or cycloalkyl, partly halogenated lower alkyl or cycloalkyl, —CO—CH3, -lower alkyl-O-phenyl carboxylic acid with a lower alkyl substituent, or
- wherein,
- Z′″ is lower alkyl or cycloalkyl, R3 is each independently H, COOH NH—CO—NH—OCH3 or partly halogenated NH—CO—NH—CH3, O-lower alkyl, CO—CH3 or lower alkyl, and R4 is lower alkyl;
- or
- a compound of formula VI or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof:
- wherein,
- independently X is N or CH;
- R1 is NH2, NH-lower alkyl, OH, or O-lower cycloalkyl;
- R2 and R3 can be H, lower alkyl, SO2NH2 or comprise the substituent of formula XVIII:
- wherein,
- X′ is a direct bond, NH, N—CH3 or CH2;
- Y′ is H or lower alkyl;
- and Z′ is H, lower alkyl, COOH, SO2NH2, SO2NH—CH3, or a substituted or non-substituted aromatic or non-aromatic heterocycle, preferably tetrazole, wherein X′ is N—CH3 when both Y′ and Z′ are H;
- or
- a compound of formula VII or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof:
- wherein,
- X is N or C, X′ is CH or N;
- X″ is N, or CH;
- Y is CH or C;
- Z is CH2— or C═O;
- wherein the bond between adjacent ring substituents Y constitute a single or double bond;
- R1 comprises a substituent of formula XIX:
- wherein,
- R1′-R3′ can be independently halogen, carboxylic acid, SO2NH2, SO2—NH-lower alkyl, COOH, or NO2, or a substituted or non-substituted aromatic or non-aromatic heterocycle, preferably tetrazole;
- or
- R1 can comprise a substituent of formula XX:
- wherein,
- Y′ is N, CH, or C;
- R″ is independently H, halogen, dihalogen or lower alkyl;
- R2 is H, lower cycloalkyl or a substituted or non-substituted aromatic or non-aromatic heterocycle, preferably 1,3-diazolidine;
- R3 is halogen, carboxylic acid, SO2NH2, or SO2—NH-lower alkyl, or a substituted or non-substituted aromatic or non-aromatic heterocycle, preferably tetrazole;
- R4 is H, halogen, or low alkyl ketoacid, preferably ketopropionic acid;
- R5 is absent if X is N or CH;
- if X is C, R5 is a substituted or non-substituted aromatic or non-aromatic heterocycle, preferably pyrrolidine, a piperidine, pyrazine, or a bicyclic structure of formula XXI:
- wherein
- Y″ is N, N-lower alkyl, or COOH;
- or
- a compound of formula VIII or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof:
- wherein
- X is SO7, NR4 or O;
- Z is C or N;
- Y is N, CR3 or CH;
- R1-R4 are each independently H, oxo, halogen, —(CH2)n—COOH, wherein n=0 to 6, —NH—C(O)—NH—CH3, —NH—C(O)—NH—CHF2, alkyl or alkoxy, optionally substituted with COOH or oxo, or wherein one or more of R1-R4 comprise a substituent of Formula XXII:
- wherein,
- A is attachment side, wherein the substituent of Formula XXII is attached directly or through a linker L to the compound of formula VIII, wherein L is alkyl, —CH2—C(O)—NH—, or —NH—C(O)—NH—;
- X′ is H, O, N, or N-lower cycloalkyl;
- Y′ is O, N, N-lower cycloalkyl, CH2, CR5, CHR5, wherein R5 is alkyl, hydroxy, alkoxy, halogen, wherein the alkyl is optionally substituted by one or more of COOH oxo, alkoxy, halogen, or hydroxylamine, wherein adjacent Y′ are bonded with a single or double bond, and wherein two R5 attached to two adjacent Y′ are optionally joined to form an aromatic or non-aromatic five- or six-membered ring;
- preferably X′ is O and the Y′-ring contains 1 or 2 N or O atoms.
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A pharmaceutical composition comprising a compound of formula I, I′, II, III, IV, V, VI, VII, or VIII or a salt or solvate thereof, and one or more pharmaceutically acceptable excipients.
A method of treating a disease or disorder related to PANX1 abnormal signaling comprising administering a compound of formula I, I′, II, III, IV, V, VI, VII, or VIII, or a salt or solvate thereof, to a subject in need thereof.
Dependencies are inferred from the claim text.