# US 10,946,013 B2 · Methods for treating central nervous system disorders using vdac inhibitors

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- Number: US 10,946,013 B2
- Document ID: US10946013B2
- Status: Granted
- Kind: B2
- Application number: 16/560,668
- Filed: 2019-09-04
- Published: 2020-01-02
- Granted: 2021-03-16
- Earliest claimed: 2015-09-14
- Assignees: The National Institute for Biotechnology In the Negev Ltd.
- Applicants: The National Institute for Biotechnology in the Negev Ltd.
- Inventors: Varda Shoshan-Barmatz; Arie Lev Gruzman
- Web page: https://patentgrep.com/patent/US10946013B2

## CPC

- A61K 31/496: Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
- A61K 31/435: having six-membered rings with one nitrogen as the only ring hetero atom
- A61K 31/4468: having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
- A61K 31/454: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
- A61K 31/495: having six-membered rings with two {or more} nitrogen atoms as the only ring heteroatoms, e.g. piperazine {or tetrazines}(A61K31/48 takes precedence {; with three nitrogen atoms A61K31/53})
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)

## Abstract

The present invention relates to use of small organic compounds interacting with the Voltage-Dependent Anion Channel (VDAC) for the treatment of diseases associated with central nervous system (CNS) disorders, including psychotic disorders, mood disorders, neurodegenerative diseases. In particular the present invention relates to the use of substituted piperazine- and piperidine-derivatives and pharmaceutical compositions comprising same for the treatment of psychotic disorders including schizophrenia, mood disorders, and neurodegenerative diseases.

## Claims

### Claim 1

A method for treating a CNS-associated disorder selected from the group consisting of psychotic disorder, mood disorder and neurodegenerative disease, the method comprising the step of administering to a subject in need thereof at least one compound of the general formula (I):
wherein:
A is carbon (C) or nitrogen (N);
R3 is absent, a hydrogen, an unsubstituted or substituted amide, or a heteroalkyl comprising 3-12 atoms (apart from hydrogen atoms), wherein at least one atom is a nitrogen, sulfur or oxygen atom, wherein when A is nitrogen (N), R3 is absent;
L1 is absent or is an amino linking group —NR4—, wherein R4 is hydrogen, a C1-5-alkyl, a C1-5-alkylene or a substituted alkyl —CH2R, wherein R is a functional group selected from the group consisting of hydrogen, halo, haloalkyl, cyano, nitro, hydroxyl, alkyl, alkenyl, aryl, alkoxyl, aryloxyl, aralkoxyl, alkylcarbamido, arylcarbamido, amino, alkylamino, arylamino, dialkylamino, diarylamino, arylalkylamino, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, carboxyl, alkoxycarbonyl, aryloxycarbonyl, sulfo, alkylsulfonylamido, alkylsulfonyl, arylsulfonyl, alkylsulfinyl, arylsulfinyl and heteroaryl;
R1 is a phenyl, which is optionally substituted with one or more of Z;
Z is independently at each occurrence a functional group selected from the group consisting of, hydrogen, halo, haloalkyl, haloalkoxy, perhaloalkoxy or C1-2-perfluoroalkoxy, cyano, nitro, hydroxyl, alkyl, alkenyl, aryl, alkoxyl, aryloxyl, aralkoxyl, alkylcarbamido, arylcarbamido, amino, alkylamino, arylamino, dialkylamino, diarylamino, arylalkylamino, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, carboxyl, alkoxycarbonyl, aryloxycarbonyl, sulfo, alkylsulfonylamido, alkylsulfonyl, arylsulfonyl, alkylsulfinyl, arylsulfinyl and heteroaryl;
L2 is a linking group such that:
when A is nitrogen (N), L2 is selected from the group consisting of butanamidylene, N-methylbutanamidylene, N,N-dimethylbutanamidylene, 4-hydroxybutanamidylene, 4-oxobutanamidylene, 4-hydroxy-N-methylbutanamidylene and 4-oxo-N-methylbutanamidylene, wherein the carbon (C) in third position of the butanamide moiety is bonded to the nitrogen (N) of the piperazine ring and the nitrogen (N) of the butanamide moiety is bonded to R2; or L2 is selected from the group consisting of 2-pyrrolidone, pyrrolidine-2,5-dione, 5-thioxo-2-pyrrolidone or 5-methoxy-2-pyrrolidone, wherein a carbon (C) of the pyrrolidine moiety is bonded to the nitrogen (N) of the piperazine ring and the nitrogen (N) of the pyrrolidine moiety is bonded to R2; and
when A is carbon (C), L2 is selected from the group consisting of C1-4alkylene or a group consisting of 4-10 atoms, apart from hydrogen atoms, optionally forming a ring, wherein at least one of the atoms is nitrogen, said nitrogen forming part of an amide group;
R2 is a phenyl or a naphthyl, optionally substituted with halogen;
or an enantiomer, diastereomer, mixture or salt thereof.

### Claim 2 (depends on 1)

The method of claim 1, wherein L2 is a linking group selected from the group consisting of 4-hydroxybutanamidylene having the formula HO—CH2—C*H—CH2—C(O)NH— wherein the asterisk denotes an attachment point, and pyrrolidine-2,5-dionylene.

### Claim 3 (depends on 1)

The method of claim 1, wherein A is carbon (C), R3 is an unsubstituted or substituted amide or a heteroalkyl group, and L2 is methylene.

### Claim 4 (depends on 1)

The method of claim 1, wherein the compound is of general Formula (Ia):
wherein:
L2′ is L2; and
Y is halogen;
or an enantiomer, diastereomer, mixture or salt thereof.

### Claim 5 (depends on 4)

The method of claim 4, wherein carbon (C) at position 3 of L2′ is bonded to the nitrogen (N) of the piperazine ring or of the piperidine ring, and the nitrogen (N) of said L2′ is bonded to the phenyl group.

### Claim 6 (depends on 1)

The method of claim 1, wherein the compound is of the general formula (Ib):
wherein:
L1 is absent;
L2″ is a pyrrolidinylene linking group, optionally substituted with one or two of alkyl, hydroxy, oxo or thioxo group;
Y is halogen;
or an enantiomer, diastereomer, mixture or salt thereof.

### Claim 7 (depends on 6)

The method of claim 6, wherein L2″ is selected from the group consisting of 2-pyrrolidonylene, pyrrolidine-2,5-dionylene, 5-thioxo-2-pyrrolidinonylene and 5-methoxy-2-pyrrolidinonylene.

### Claim 8 (depends on 6)

The method of claim 6, wherein a carbon (C) atom of the pyrrolidinyl moiety L2″ is bonded to the nitrogen (N) of the piperazine ring or the piperidine ring and the nitrogen (N) of the pyrrolidinyl moiety is bonded to the phenyl group.

### Claim 9 (depends on 1)

The method of claim 1, wherein the compound is of the general formula (Ic):
wherein:
L1 is —NH—;
Y1 and Y2 are each independently absent or a halogen;
or an enantiomer, diastereomer, mixture or salt thereof.

### Claim 10 (depends on 9)

The method of claim 9, wherein R3 is —C(O)NHCH2C(O)OH group.

### Claim 11 (depends on 1)

The method of claim 1, wherein Z is C1-2-alkoxy or C1-2-perfluoroalkoxy.

### Claim 12 (depends on 1)

The method of claim 1, wherein the compound is of the general formula (Id):
wherein
Z is C1-2-perfluoroalkoxy, and Y is halogen.

### Claim 13 (depends on 12)

The method of claim 12, wherein the compound is selected from the group consisting of a compound represented by the structure of Formula 1:
and a compound represented by the structure of Formula 2:
or an enantiomer, diastereomer, mixture or salt thereof.

### Claim 14 (depends on 10)

The method of claim 10, wherein the compound is represented by the structure of Formula 3:
or an enantiomer, diastereomer, mixture or salt thereof.

### Claim 15

A method for treating a CNS-associated disorder selected from the group consisting of psychotic disorder, mood disorder and neurodegenerative disease, the method comprising administering to a subject in need thereof at least one compound of Formula (IIa):
wherein:
A is carbon (C);
R3 is hydrogen, an unsubstituted or substituted amide, or heteroalkyl chain comprising 3-12 atoms, apart from hydrogen atoms, wherein at least one is a heteroatom, selected from the group consisting of nitrogen, sulfur and oxygen;
L1 is an amino linking group —NR4—, wherein R4 is hydrogen, a C1-5-alkyl, a C1-5-alkylene or a substituted alkyl —CH2R, wherein R is a functional group selected from the group consisting of hydrogen, halo, haloalkyl, cyano, nitro, hydroxyl, alkyl, alkenyl, aryl, alkoxyl, aryloxyl, aralkoxyl, alkylcarbamido, arylcarbamido, amino, alkylamino, arylamino, dialkylamino, diarylamino, arylalkylamino, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, carboxyl, alkoxycarbonyl, aryloxycarbonyl, sulfo, alkylsulfonylamido, alkylsulfonyl, arylsulfonyl, alkylsulfinyl, arylsulfinyl or heteroaryl;
when R3 is heteroalkyl group comprising 3-12 atoms, apart from hydrogen atoms, then L1 forms a ring with R3;
R1 is an aromatic moiety, which is optionally substituted with one or more of C1-2-alkoxy, and/or C1-2-perfluoroalkoxy;
L2 is a linking group consisting of 4-10 atoms, apart from hydrogen atoms, optionally forming a ring, whereof at least one of the atoms is nitrogen, said nitrogen forming part of an amide group or L2 is C1-5alkyl or C1-5alkylene; said linking group L2 bonds piperidine or piperazine moiety at nitrogen (N) atom; and
R2 is an aryl, optionally substituted with halogen, optionally when R2 is a phenyl it is substituted with halogen, further optionally when R2 is naphthyl, L2 is an alkylenyl group;
or an enantiomer, diastereomer, mixture or salt thereof.

### Claim 16 (depends on 15)

The method according to claim 15, wherein the compound of Formula (IIa) has the Formula 10:

### Claim 17 (depends on 15)

The method according to claim 15, wherein the compound of Formula (IIa) has the Formula 11:

### Claim 18 (depends on 1)

The method of claim 1, wherein the compound is administered within a pharmaceutical composition further comprising pharmaceutically acceptable excipients, diluents or carriers.

### Claim 19 (depends on 1)

The method of claim 1, wherein:
the psychotic disorder is schizophrenia;
the mood disorder is selected from the group consisting of bipolar disorder, major depressive disorder, persistent depressive disorder and anxiety disorder; or
the neurodegenerative disease is selected from the group consisting of Alzheimer's disease, Parkinson disease and Amyotrophic Lateral Sclerosis (ALS).

### Claim 20 (depends on 1)

The method of claim 1, wherein the compound is selected from the group consisting of: