US 12,336,977 B2Granted

Nitenin analogue compounds and their use in the treatment of chronic and acute pain

AssigneeSea4US - Biotecnologia E Recursos Marinhos, Lda.

InventorsPedro Afonso Dos Santos Baltazar De Lima, Beatriz Szwarc Dos Santos, Ana Rosa Maço Abreu, André Emanuel Pinheiro Bastos, Rui Gomes, Marisa Isabel Lopes De Sousa, Joana Maria Monteiro Serrão, Sílvia Patrícia Pena Lino, Patrícia Isabel Da Silveira Máximo, Luísa Maria Pinto Ferreira, Paula Cristina De Sério Branco, Henrique Sovela Mourão, Vanessa Alexandra Rosado Sabino, Ming Him Tong, Laurent Alain Claudetrembleau, Ana Maria Ferreira Da Costa Lourenço, Miguel Angelo Segão Mondragão

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Abstract

The present disclosure relates to nitenin analogue compounds (of formulas I, II, III and IV) and their use as pharmaceutical agent in the treatment, prevention or reduction of both acute and chronic pain. The mode of action disclosed herein allows nitenin and nitenin analogue compounds to act as analgesic through reduction of K30 currents rather than their potentiation. Related to their high efficacy in the treatment of pain, these compounds are highly selective for slow voltage-activated potassium (K30 ) currents expressed in the small diameter dorsal root neurons (sDRGns), mainly on those mediated by the voltage-dependent potassium channel (KV), KV1.3. Such findings, together with those showing that nitenin and nitenin analogue compounds act as activity dependent blockers also lead to very reduced side-effects. The results disclosed herein show that nitenin and nitenin analogue compounds described herein are a viable alternative to the already existing pharmaceutical compounds used in the treatment of pain.

Claims15

Dependent claims

A compound of formula I, II, or III, or a pharmaceutically acceptable salt thereof,

wherein
represents a carbon-carbon single bond or a carbon-carbon double bond;
X is selected from O, NH, CH2;
Y is selected from CH, CH2;
Z is selected from C, N;
G is selected from O;
T is selected from, SH;
One of R1 and R2 is H, and then R1 is selected from alkenyl, cycloalkyl or —CH2—R3 or R2 is selected from alkyl, alkenyl, cycloalkyl, aryl or —CH2—R3;
wherein for R1, R3 is selected from, cycloalkyl, heteroaryl, —R4-R5 and for R2, R3 is selected from aryl, cycloalkyl, heteroaryl, —R4-R5;
wherein R4 is selected from alkyl, alkenyl;
wherein R5 is selected from aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted gama-lactone;
Q is selected from C, CH;
D is selected from C, CH;
One of A and E is H and the other is selected from OH, SH, C4 or C7-C12 alkyl, alkenyl, R6-R7, wherein R6 is selected from C2-C12 alkyl, alkenyl, and R7 is selected from substituted or unsubstituted aryl, except phenyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted gama-lactone;
J is selected from H, OH, SH, NH2, and halogen;
wherein the compound is not nitenin, dihydronitenin nor their respective, enantiomers, and stereoisomers;
wherein aryl refers to a monovalent aromatic hydrocarbon radical comprising 6-20 carbon atoms (C6-C20) that is derived by removing a hydrogen atom from an aromatic ring;
alkyl refers to a saturated monovalent hydrocarbon radical comprising one to four carbon atoms (C1-C4) and may be linear, or cyclic;
heteroaryl refers to a monovalent aromatic radical comprising 5 to 20 atoms, one or more 5-,6-, or 7-membered rings, and one or more heteroatoms independently chosen from nitrogen, oxygen, phosphorous, and sulfur;
cycloalkyl is a cyclic alkyl;
and alkenyl refers to a monovalent hydrocarbon radical comprising four to eight carbon atoms (C2-C8) with at least one site of unsaturation.

18 more elements

A pharmaceutical composition comprising one or more compounds of formula I, II or III, or a pharmaceutically acceptable salt thereo, and a pharmacologically acceptable diluent or carrier

wherein
represents a carbon-carbon single bond or a carbon-carbon double bond;
X is selected from O, NH, CH2;
Y is selected from CH, CH2;
Z is selected from C, N;
G is selected from O;
T is selected from, SH;
One of R1 and R2 is H, and then R1 is selected from alkenyl, cycloalkyl or —CH2—R3 or R2 is selected from alkyl, alkenyl, cycloalkyl, aryl or —CH2—R3;
wherein for R1, R3 is selected from, cycloalkyl, heteroaryl, —R4-R5 and for R2, R3 is selected from aryl, cycloalkyl, heteroaryl, —R4-R5;
wherein R4 is selected from alkyl, alkenyl;
wherein R5 is selected from aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted gama-lactone;
Q is selected from C, CH;
D is selected from C, CH;
One of A and E is H and the other is selected from OH, SH, C4 or C7—C12 alkyl, alkenyl, R6-R7, wherein R6 is selected from C2-C12 alkyl, alkenyl, and R7 is selected from substituted or unsubstituted aryl, except phenyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted gamma-lactone;
J is selected from H, OH, SH, NH2, and halogen;
wherein aryl refers to a monovalent aromatic hydrocarbon radical comprising 6-20 carbon atoms (C6-C20) that is derived by removing a hydrogen atom from an aromatic ring;
alkyl refers to a saturated monovalent hydrocarbon radical comprising one to four carbon atoms (C1-C4) and may be linear, or cyclic;
heteroaryl refers to a monovalent aromatic radical comprising 5 to 20 atoms, one or more 5-, 6-, or 7-membered rings, and one or more heteroatoms independently chosen from nitrogen, oxygen, phosphorous, and sulfur;
cycloalkyl is a cyclic alkyl;
and alkenyl refers to a monovalent hydrocarbon radical comprising four to eight carbon atoms (C4-C8) with at least one site of unsaturation.

17 more elements

Dependencies are inferred from the claim text.

Facts

Application: 17/631,135Filed 22 Jul 2020
Priority: PT 11568531 Jul 2019
Published: US 2022/0288017 A115 Sep 2022
Granted: 24 Jun 2025
Term ends: Not estimatedThe source records don’t support an estimate.

Classification13 codes

A61K 31/365
Having oxygen as the only ring hetero atom, e.g. fungichromin: lactones
C07D 407/06
Containing two hetero rings: linked by a carbon chain containing only aliphatic carbon atoms
A61K 31/353
Condensed with carbocyclic rings, e.g. methantheline: 3,4-Dihydrobenzopyrans, e.g. chroman, catechin
A61P 3/10
For glucose homeostasis: for hyperglycaemia, e.g. antidiabetics