The (s)-enantiomer of mepazine

Patent metadata

Field	Value
Publication number	US-2016137635-A1
Application number	US-201414900527-A
Country	US
Kind code	A1
Filing date	Jun 25, 2014
Priority date	Jun 26, 2013
Publication date	May 19, 2016
Grant date	—

Abstract

The present invention relates to the (S)-enantiomer of mepazine, its applicability in therapy, a pharmacological composition comprising (S)-mepazine, and processes for the preparation of (S)-mepazine and one of its intermediates.

First claim

1 . A compound selected from the group consisting of 10-{[(3S)-1-methylpiperidin-3-yl]methyl}-10H-phenothiazine (the S-enantiomer of mepazine) and solvates, salts, isotopically labeled forms and combinations thereof.

2 . The compound of claim 1 which is the hydrochloride, acetate, or tartrate salt of (S)-mepazine.

3 . A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable excipient.

4 . A method of inhibiting a paracaspase, the method comprising contacting a paracaspase with a compound of claim 1 .

5 . (canceled)

6 . A method for treating or preventing a disease or disorder which is treatable by an inhibitor of a paracaspase, the method comprising administering to a subject a compound of claim 1 .

7 . The method of claim 6 , wherein the paracaspase is mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1).

8 . A process for the preparation of the compound of claim 1 , comprising the step of reacting phenothiazine with a piperidine derivative of the following formula (3)

wherein LG is a leaving group.

9 . The process of claim 8 , further comprising the step of converting a tertiary amine of the following formula (2)

into the piperidine derivative of formula (3).

10 . The process of claim 9 , further comprising the step of converting a carbamate of the following formula (1)

wherein R is an optionally substituted alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl group, into the tertiary amine of formula (2).

11 . The process of claim 10 , wherein the step of converting the carbamate of formula (1) into the tertiary amine of formula (2) is conducted in the presence of a reducing agent.

12 . The process of claim 9 , wherein the step of reacting phenothiazine with the piperidine derivative of formula (3) and/or the step of converting the tertiary amine of formula (2) into the piperidine derivative of formula (3) is conducted in the presence of a chemical base.

13 . The process of claim 8 , wherein LG is selected from the group consisting of Br, Cl, mesylate, triflate, and tosylate.

14 . A process for the preparation of a tertiary amine of the following formula (2)

comprising the step of reacting a carbamate of the following formula (1)

wherein R is an optionally substituted alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl group, with a reducing agent.

15 . The process of claim 14 , wherein the reducing agent is LiAlH 4 .

16 . The process of claim 11 , wherein the reducing agent is LiAlH 4 .

17 . The method of claim 6 , wherein the disease or disorder is (i) cancer, or (ii) a paracaspase-dependent immune disease.

18 . The method of claim 17 , wherein the cancer is a lymphoma.

19 . The method of claim 18 , wherein the lymphoma is mucosa-associated lymphoid tissue (MALT) lymphoma or diffuse large B-cell lymphoma (DLBCL), such as activated B-cell subtype of diffuse-large B cell lymphoma (ABC-DLBCL).

20 . The method of claim 17 , wherein the paracaspase-dependent immune disease is an allergic inflammation or an autoimmune disease, such as multiple sclerosis.

21 . A pharmaceutical composition comprising the compound of claim 2 and a pharmaceutically acceptable excipient.

Assignees

• Helmholtz Zentrum München Deutsches Forschungszentrum Für Gesundheit Und Umwelt Gmbh
• Univ Muenchen Ludwig Maximilians

Inventors

• Krappmann Daniel
• Nagel Daniel
• Schlauderer Florian
• Lammens Katja
• Hopfner Karl-Peter
• Chrusciel Robert A
• Kling Dale L

Classifications

• C07D417/06 Primary

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• C07D211/22

  by oxygen atoms · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/5415

  ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam · CPC title