IP Library › Granted Patent US 11,319,290

Granted Patent B2

US 11,319,290 · App. 17/025,665 · Granted May 3, 2022

Substituted 3-dialkylaminomethyl-piperidin-4-yl-benzamides and methods of making and using same

Inventors: Brett A. Tounge (Blue Bell, PA); Shariff Bayoumy (North Wales, PA); Lawrence C. Kuo (Gwynedd Valley, PA); Scott L. Dax (Landenberg, PA)

Assignee: Mebias Discovery, Inc.

C07D221/00 A61K31/445 A61P23/00 C07D211/08 C07D401/06 C07D409/06

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Quick Facts

Patent No.: US 11,319,290
App. No.: 17/025,665
Granted: May 3, 2022
Kind: B2

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Abstract

The invention relates to certain substituted 3-dialkylaminomethyl-piperidin-4-yl-benzamides, and compositions comprising the same, which in certain embodiments are useful for treating and/or preventing pain in a subject in need thereof.

Claims (145)

1. A compound of formula (I):

wherein:

L is selected from the group consisting of —(CZ 1 Z 2 )—, —(CZ 1 Z 2 —CZ 1 Z 2 )—, and —(CZ 1 Z 2 —CZ 1 Z 2 —CZ 1 Z 2 )—;

R 1 is selected from the group consisting of

R 2 is hydrogen;

R 3 is hydrogen;

R 4 is selected from the group consisting of methyl and ethyl;

R 5 is selected from the group consisting of methyl and ethyl;

R 6 is selected from the group consisting of H and C 1 -C 6 alkyl;

each occurrence of Z 1 and Z 2 is independently selected from the group consisting of hydrogen and methyl;

X is S;

each occurrence of R is independently selected from the group consisting of hydrogen, fluoro, chloro, bromo, iodo, cyano, nitro, hydroxyl, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, C 2 -C 6 alkenyl, substituted C 2 -C 6 alkenyl, alkynyl, substituted C 2 -C 6 alkynyl, phenyl, substituted phenyl, —COOR 7 , and carboxamide;

and

each occurrence of p is independently selected from the group consisting of 0, 1, 2, and 3;

or a salt, solvate, enantiomer, diastereoisomer, or tautomer thereof, and any mixtures thereof.

2. The compound of claim 1 , wherein R 4 and R 5 are methyl.

3. The compound of claim 1 , wherein R 6 is selected from the group consisting of H and methyl.

4. The compound of claim 1 , wherein L is selected from the group consisting of methylene (—CH 2 —), 1,2-ethylene (—CH 2 —CH 2 —), and 1,3-propylene (—CH 2 —CH 2 —CH 2 —).

5. The compound of claim 1 , wherein R 1 is selected from the group consisting of phenyl, thienyl substituted phenyl, and substituted thienyl.

6. The compound of claim 1 , wherein R 2 and R 3 are H, wherein R 4 and R 5 are methyl, wherein R 6 is selected from the group consisting of H and methyl, wherein L is selected from the group consisting of methylene (—CH 2 —), 1,2-ethylene (—CH 2 —CH 2 —), and 1,3-propylene (—CH 2 —CH 2 —CH 2 —), and wherein R 1 is selected from the group consisting of phenyl, thienyl substituted phenyl, and substituted thienyl.

7. The compound of claim 1 , wherein the —R 6 and —CH 2 NR 4 R 5 groups have syn relative stereochemistry.

8. The compound of claim 7 , which is selected from the group consisting of:

and any mixtures thereof.

9. A compound selected from the group consisting of:

3-(-(2-Chloro-4-fluoro-benzyl)-3-dimethylaminomethyl-4-hydroxy-piperidin-4-yl)-benzamide (6);

(+)-Ent-A-syn-3-(1-(2-chloro-4-fluorobenzyl)-3-((dimethylamino)methyl)-4-hydroxy piperidin-4-yl)benzamide [(+)-Ent-A-syn-(6)];

(−)-Ent-B-syn-3-(1-(2-chloro-4-fluorobenzyl)-3-((dimethylamino)methyl)-4-hydroxy piperidin-4-yl)benzamide [(−)-Ent-B-syn-(6)];

(+)-Ent-A-anti-3-[1-(2-chloro-4-fluorobenzyl)-3-[(dimethylamino)methyl]-4-hydroxypiperidin-4-yl]benzamide [(+)-Ent-A-anti-(6)];

(−)-Ent-B-anti-3-[1-(2-chloro-4-fluorobenzyl)-3-[(dimethylamino)methyl]-4-hydroxypiperidin-4-yl]benzamide [(−)-Ent-B-anti-(6)];

3-(3-Dimethylaminomethyl-4-hydroxy-1-thiophen-3-ylmethyl-piperidin-4-yl)-benzamide (11);

(+)-Ent-A-syn-3-[3-[(dimethylamino)methyl]-4-hydroxy-1-[(thiophen-3-yl)methyl]piperidin-4-yl] benzamide [(+)-Ent-A-syn-(11)];

(−)-Ent-B-syn-3-[3-[(dimethylamino)methyl]-4-hydroxy-1-[(thiophen-3-yl)methyl]piperidin-4-yl] benzamide [(−)-Ent-B-syn-(11)];

(+)-Ent-A-anti-3-[(dimethylamino)methyl]-4-hydroxy-1-[(thiophen-3-yl)methyl]piperidin-4-yl] benzamide [(+)-Ent-A-anti-(11)];

(−)-Ent-B-anti-3-[3-[(dimethylamino)methyl]-4-hydroxy-1-[(thiophen-3-yl)methyl]piperidin-4-yl] benzamide [(−)-Ent-B-anti-(11)];

3-(3-Dimethylaminomethyl-4-hydroxy-1-phenethyl-piperidin-4-yl)-benzamide (9);

(+)-Ent-A-syn-3-[3-[(dimethylamino)methyl]-4-hydroxy-1-(2-phenylethyl)piperidin-4-yl]benzamide (45a);

(−)-Ent-B-syn-3-[3-[(dimethylamino)methyl]-4-hydroxy-1-(2-phenylethyl)piperidin-4-yl]benzamide (45b);

(+)-Ent-A-anti-3-[3-[(dimethylamino)methyl]-4-hydroxy-1-(2-phenylethyl)piperidin-4-yl]benzamide [(+)-Ent-A-anti-(9)];

(−)-Ent-B-anti-3-[3-[(dimethylamino)methyl]-4-hydroxy-1-(2-phenylethyl)piperidin-4-yl]benzamide [(−)-Ent-B-anti-(9)];

3-(1-(2-Chloro-4-fluorophenethyl)-3-((dimethylamino)methyl)-4-hydroxypiperidin-4-yl) benzamide (13);

3-((3S,4R)-1-(2-Chloro-4-fluorophenethyl)-3-((dimethylamino)methyl)-4-hydroxypiperidin-4-yl)benzamide (32a);

3-((3R,4S)-1-(2-Chloro-4-fluorophenethyl)-3-((dimethylamino)methyl)-4-hydroxypiperidin-4-yl)benzamide (32b);

(+)-Ent-A-anti-3-[1-[2-(2-chloro-4-fluorophenyl)ethyl]-3-[(dimethylamino)methyl]-4-hydroxypiperidin-4-yl]benzamide [(+)-Ent-A-anti-(13)];

(−)-Ent-B-anti-3-[1-[2-(2-chloro-4-fluorophenyl)ethyl]-3-[(dimethylamino)methyl]-4-hydroxypiperidin-4-yl]benzamide [(−)-Ent-B-anti-(13)];

3-(3-((Dimethylamino)methyl)-4-hydroxy-1-(4-methoxyphenethyl)piperidin-4-yl)benzamide (17);

(+)-Ent-A-syn-3-(3-((dimethylamino)methyl)-4-hydroxy-1-(4-methoxyphenethyl)piperidin-4-yl)benzamide [(+)-Ent-A-syn-(17)];

(−)-Ent-B-syn-3-(3-((dimethylamino)methyl)-4-hydroxy-1-(4-methoxyphenethyl)piperidin-4-yl)benzamide [(−)-Ent-B-syn-(17)];

(+)-Ent-A-anti-3-(3-((dimethylamino)methyl)-4-hydroxy-1-(4-methoxyphenethyl)piperidin-4-yl)benzamide [(+)-Ent-A-anti-(17)];

(−)-Ent-B-anti-3-(3-((dimethylamino)methyl)-4-hydroxy-1-(4-methoxyphenethyl)piperidin-4-yl)benzamide [(−)-Ent-B-anti-(17)];

3-(3-((Dimethylamino)methyl)-4-hydroxy-1-(4-hydroxyphenethyl)piperidin-4-yl)benzamide (18);

(+)-Ent-A-syn-3-[3-[(dimethylamino)methyl]-4-hydroxy-1-[2-(4-hydroxyphenyl)ethyl] piperidin-4-yl]benzamide (38a);

(−)-Ent-B-syn-3-[3-[(dimethylamino)methyl]-4-hydroxy-1-[2-(4-hydroxyphenyl)ethyl] piperidin-4-yl]benzamide (38b);

(+)-Ent-A-anti-3-[3-[(dimethylamino)methyl]-4-hydroxy-1-[2-(4-hydroxyphenyl)ethyl]piperidin-4-yl]benzamide [(+)-Ent-A-anti-(18)];

(−)-Ent-B-anti-3-[3-(dimethylamino)methyl]-4-hydroxy-1-[2-(4-hydroxyphenyl)ethyl] piperidin-4-yl]benzamide [(−)-Ent-B-anti-(18)];

3-(3-((Dimethylamino)methyl)-4-hydroxy-1-(2-(thiophen-3-yl)ethyl)piperidin-4-yl)benzamide (15);

3-(3S,4R)-3-((Dimethylamino)methyl)-4-hydroxy-1-(2-(thiophen-3-yl)ethyl)piperidin-4-yl)benzamide (41a);

3-((3R,4S)-3-((Dimethylamino)methyl)-4-hydroxy-1-(2-(thiophen-3-yl)ethyl)piperidin-4-yl)benzamide (41b);

(+)-Ent-A-anti-3-[3-[(dimethylamino)methyl]-4-hydroxy-1-[2-(thiophen-3-yl)ethyl]piperidin-4-yl]benzamide [(+)-Ent-A-anti-(15)];

(−)-Ent-B-anti-3-[3-[(dimethylamino)methyl]-4-hydroxy-1-[2-(thiophen-3-yl)ethyl]piperidin-4-yl]benzamide [(−)-Ent-B-anti-(15)];

3-[3-Dimethylaminomethyl-4-hydroxy-1-(3-phenyl-propyl)-piperidin-4-yl]-benzamide (20);

(+)-Ent-A-syn-3-[3-[(dimethylamino)methyl]-4-hydroxy-1-(3-phenylpropyl)piperidin-4-yl]benzamide (44a);

(−)-Ent-B-syn-3-[3-[(dimethylamino)methyl]-4-hydroxy-1-(3-phenylpropyl)piperidin-4-yl]benzamide (44b);

(+)-Ent-A-anti-3-[3-[(dimethylamino)methyl]-4-hydroxy-1-(3-phenylpropyl)piperidin-4-yl]benzamide [(+)-Ent-A-anti-(20)];

(−)-Ent-B-anti-3-[3-[(dimethylamino)methyl]-4-hydroxy-1-(3-phenylpropyl)piperidin-4-yl]benzamide [(−)-Ent-B-anti-(20)];

3-{1-[3-(2-Chloro-4-fluorophenyl)propyl]-3-[(dimethylamino)methyl]-4-hydroxypiperidin-4-yl}benzamide (23);

3-((3S,4R)-1-(3-(2-Chloro-4-fluorophenyl)propyl)-3-((dimethylamino)methyl)-4-hydroxypiperidin-4-yl)benzamide (23a);

3-((3R,4S)-1-(3-(2-Chloro-4-fluorophenyl)propyl)-3-((dimethylamino)methyl)-4-hydroxypiperidin-4-yl)benzamide (23b);

(+)-Ent-A-anti-3-[1-[3-(2-chloro-4-fluorophenyl)propyl]-3-[(dimethylamino)methyl]-4-hydroxypiperidin-4-yl]benzamide [(+)-Ent-A-anti-(23)];

(−)-Ent-B-anti-3-[1-(3-(2-chloro-4-fluorophenyl)propyl)-3-((dimethylamino)methyl)-4-hydroxypiperidin-4-yl)benzamide [(−)-Ent-B-anti-(23)];

or a salt, solvate, enantiomer, diastereoisomer, or tautomer thereof, and any mixtures thereof.

10. A pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and at least one compound of claim 1 .

11. A method of treating or ameliorating pain in a subject, the method comprising administering to the subject a therapeutically effective amount of at least one compound of formula (I):

wherein:

L is selected from the group consisting of —(CZ 1 Z 2 )—, —(CZ 1 Z 2 —CZ 1 Z 2 )—, and —(CZ 1 Z 2 —CZ 1 Z 2 —CZ 1 Z 2 )—;

R 1 is selected from the group consisting of

R 2 is hydrogen;

R 3 is hydrogen;

R 4 is selected from the group consisting of methyl and ethyl;

R 5 is selected from the group consisting of methyl and ethyl;

R 6 is selected from the group consisting of H and C 1 -C 6 alkyl;

each occurrence of Z 1 and Z 2 is independently selected from the group consisting of hydrogen and methyl;

X is S;

each occurrence of p is independently selected from the group consisting of 0, 1, 2, and 3;

or a salt, solvate, enantiomer, diastereoisomer, or tautomer thereof, and any mixtures thereof.

12. A method of treating or ameliorating pain in a subject, the method comprising administering to the subject a therapeutically effective amount of at least one compound is selected from the group of:

3-(-(2-Chloro-4-fluoro-benzyl)-3-dimethylaminomethyl-4-hydroxy-piperidin-4-yl)-benzamide (6);

(+)-Ent-A-syn-3-(1-(2-chloro-4-fluorobenzyl)-3-((dimethylamino)methyl)-4-hydroxy piperidin-4-yl)benzamide [(+)-Ent-A-syn-(6)];

(−)-Ent-B-syn-3-(1-(2-chloro-4-fluorobenzyl)-3-((dimethylamino)methyl)-4-hydroxy piperidin-4-yl)benzamide [(−)-Ent-B-syn-(6)];

(+)-Ent-A-anti-3-[1-(2-chloro-4-fluorobenzyl)-3-[(dimethylamino)methyl]-4-hydroxypiperidin-4-yl]benzamide [(+)-Ent-A-anti-(6)];

(−)-Ent-B-anti-3-[1-(2-chloro-4-fluorobenzyl)-3-[(dimethylamino)methyl]-4-hydroxypiperidin-4-yl]benzamide [(−)-Ent-B-anti-(6)];

3-(3-Dimethylaminomethyl-4-hydroxy-1-thiophen-3-ylmethyl-piperidin-4-yl)-benzamide (11);

(+)-Ent-A-syn-3-[3-[(dimethylamino)methyl]-4-hydroxy-1-[(thiophen-3-yl)methyl]piperidin-4-yl]benzamide [+)-Ent-A-syn-(11)];

(−)-Ent-B-syn-3-[3-[(dimethylamino)methyl]-4-hydroxy-1-[(thiophen-3-yl)methyl]piperidin-4-yl] benzamide [(−)-Ent-B-syn-(11)];

(+)-Ent-A-anti-3-[3-[(dimethylamino)methyl]-4-hydroxy-1-[(thiophen-3-yl)methyl]piperidin-4-yl] benzamide [(+)-Ent-A-anti-(11)];

(−)-Ent-B-anti-3-[3-[(dimethylamino)methyl]-4-hydroxy-1-[(thiophen-3-yl)methyl]piperidin-4-yl] benzamide [(−)-Ent-B-anti-(11)];

(+)-Ent-A-anti-3-[(dimethylamino)methyl]-1-[(5-fluoropyridin-3-yl)methyl]-4-hydroxypiperidin-4-yl]benzamide;

(−)-Ent-B-anti-3-[3-[(dimethylamino)methyl]-1-[(5-fluoropyridin-3-yl)methyl]-4-hydroxypiperidin-4-yl]benzamide;