# US 8,772,313 B2 · Benzenesulfonyl or sulfonamide compounds suitable for treating disorders that respond to the modulation of the serotonin 5-HT6 receptor

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- Number: US 8,772,313 B2
- Document ID: US8772313B2
- Status: Granted
- Kind: B2
- Application number: 13/286,387
- Filed: 2011-11-01
- Published: 2012-05-24
- Granted: 2014-07-08
- Earliest claimed: 2010-11-01
- Assignees: Abbott Laboratories; AbbVie Deutschland GmbH & Co. KG
- Applicants: Andreas Haupt; Frauke Pohlki; Liliane Unger; Ana Lucia Relo; Karsten Wicke; Min Zhang
- Inventors: Andreas Haupt; Frauke Pohlki; Liliane Unger; Ana Lucia Relo; Karsten Wicke; Min Zhang
- Web page: https://patentgrep.com/patent/US8772313B2

## CPC

- C07D 209/52: condensed with a ring other than six-membered
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/18: Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 25/30: for treating abuse or dependence
- C07D 211/24: by sulfur atoms to which a second hetero atom is attached
- C07D 221/06: Ring systems of three rings
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention relates to benzenesulfonyl or sulfonamide compounds of formulae IA and IB wherein the variables have the meanings given in the claims and the description, pharmaceutical compositions containing them, and their use in therapy. The compounds possess valuable therapeutic properties and are particularly suitable for treating diseases that respond to modulation of the serotonin 5-HT6 receptor.

## Claims

### Claim 1

A compound of formula (IA)
or a stereoisomer, tautomer, or a physiologically tolerated acid addition salt thereof,
wherein
X1 is NR4;
R1 is selected from the group consisting of hydrogen, C1-C4-alkyl and fluorinated C1-C4-alkyl;
R2 is selected from the group consisting of hydrogen and C1-C4-alkyl;
R3 is selected from the group consisting of hydrogen, halogen, C1-C4-alkyl, fluorinated C1-C4-alkyl, C1-C4-alkoxy and fluorinated C1-C4-alkoxy;
R4 is selected from the group consisting of hydrogen, C1-C4-alkyl and fluorinated C1-C4-alkyl;
R5 is selected from the group consisting of C1-C6-hydroxyalkyl, C1-C6 alkoxy, C1-C6-hydroxyalkoxy, C1-C6-alkoxy-C1-C6-alkoxy, fluorinated C1-C6-alkoxy, fluorinated C1-C6-alkoxy-C1-C6-alkoxy, and a group -A-[O—B]p—O—R7;
where
A and B are independently of each other C1-C4-alkylene or fluorinated C1-C4-alkylene;
R7 is C1-C4-alkyl or fluorinated C1-C4-alkyl;
p is 0, 1, 2, 3, 4, 5 or 6;
R6 is selected from the group consisting of halogen, C1-C2-alkyl, fluorinated C1-C2-alkyl, C1-C2-alkoxy and fluorinated C1-C2-alkoxy;
G1 is CH2 or CH2CH2;
G2 is CH2 or CH2CH2;
o is 0, 1 or 2.

### Claim 2 (depends on 1)

The compound of claim 1, where A is C1-C2-alkylene.

### Claim 3 (depends on 2)

The compound of claim 2, where A is methylene (CH2) or 1,1-ethylene [CH(CH3)].

### Claim 4 (depends on 1)

The compound of claim 1, where B is C2-C3-alkylene.

### Claim 5 (depends on 1)

The compound of claim 1, where p is 0.

### Claim 6 (depends on 1)

The compound of claim 1, where R7 is C1-C2-alkyl or fluorinated C1-C2-alkyl.

### Claim 7 (depends on 1)

The compound of claim 1, where R5 is selected from the group consisting of fluorinated C1-C2-alkoxy, C1-C2-alkoxy-methyl, 1-(C1-C2-alkoxy)-ethyl, (fluorinated C1-C2-alkoxy)-methyl and 1-(fluorinated C1-C2-alkoxy)-ethyl.

### Claim 8 (depends on 7)

The compound of claim 7, where R5 is selected from the group consisting of fluoromethoxy, difluoromethoxy, trifluoromethoxy, methoxymethyl, ethoxymethyl, 2,2,2-trifluoroethoxymethyl and 1-methoxyethyl.

### Claim 9 (depends on 8)

The compound of claim 8, where R5 is selected from the group consisting of difluoromethoxy, methoxymethyl, ethoxymethyl, 2,2,2-trifluoroethoxymethyl and 1-methoxyethyl.

### Claim 10 (depends on 1)

The compound of claim 1, where R5 is bound in the 2- or 3-position, relative to the 1-position of the sulfonyl(amino) group SO2—X1.

### Claim 11 (depends on 1)

The compound of claim 1, where R1 is hydrogen or C1-C4 alkyl.

### Claim 12 (depends on 1)

The compound of claim 1, where R2 is hydrogen.

### Claim 13 (depends on 1)

The compound of claim 1, where R3 is selected from the group consisting of methoxy, ethoxy, methyl and ethyl.

### Claim 14 (depends on 1)

The compound of claim 1, where R4 is hydrogen or methyl.

### Claim 15 (depends on 1)

The compound of claim 1, where R6 is selected from the group consisting of F, Cl, methyl, difluoro-methyl, trifluoromethyl, methoxy, difluoromethoxy and trifluoromethoxy.

### Claim 16 (depends on 1)

The compound of claim 1, where o is 0 or 1.

### Claim 17 (depends on 1)

The compound of claim 1, where G1 is CH2 and G2 is CH2; or G1 is CH2 and G2 is CH2CH2; or G1 is CH2CH2 and G2 is CH2.

### Claim 18 (depends on 1)

The compound of claim 1, where
X1 is NH;
R1 is hydrogen;
R2 is hydrogen;
R3 is methoxy;
R5 is 2-difluoromethoxy, relative to the 1-position of the sulfonylamino group SO2—NH;
R6 is 5-methyl, relative to the 1-position of the sulfonylamino group SO2—NH and to the 2-position of 2-difluoromethoxy as radical R5;
G1 is CH2;
G2 is CH2; and
o is 1;
or
X1 is NH;
R1 is methyl;
R2 is hydrogen;
R3 is methoxy;
R5 is 2-difluoromethoxy, relative to the 1-position of the sulfonylamino group SO2—NH;
R6 is 5-methyl, relative to the 1-position of the sulfonylamino group SO2—NH and to the 2-position of 2-difluoromethoxy as radical R5;
G1 is CH2;
G2 is CH2; and
o is 1;
or
X1 is NH;
R1 is hydrogen;
R2 is hydrogen;
R3 is methoxy;
R5 is 2-methoxymethyl, relative to the 1-position of the sulfonylamino group SO2—NH;
G1 is CH2;
G2 is CH2; and
o is 0;
or
X1 is NH;
R1 is hydrogen;
R2 is hydrogen;
R3 is methoxy;
R5 is 2-difluoromethoxy, relative to the 1-position of the sulfonylamino group SO2—NH;
R6 is 5-methyl, relative to the 1-position of the sulfonylamino group SO2—NH and to the 2-position of 2-difluoromethoxy as radical R5;
G1 is CH2;
G2 is CH2CH2; and
o is 1;
or
X1 is NH;
R1 is hydrogen;
R2 is hydrogen;
R3 is methoxy;
R5 is 2-difluoromethoxy, relative to the 1-position of the sulfonylamino group SO2—NH;
R6 is 5-methyl, relative to the 1-position of the sulfonylamino group SO2—NH and to the 2-position of 2-difluoromethoxy as radical R5;
G1 is CH2CH2;
G2 is CH2; and
o is 1;
or
X1 is NH;
R1 is hydrogen;
R2 is hydrogen;
R3 is methoxy;
R5 is 2-difluoromethoxy, relative to the 1-position of the sulfonylamino group SO2—NH;
R6 is 4-methyl, relative to the 1-position of the sulfonylamino group SO2—NH and to the 2-position of 2-difluoromethoxy as radical R5;
G1 is CH2;
G2 is CH2; and
o is 1;
or
X1 is NH;
R1 is methyl;
R2 is hydrogen;
R3 is methoxy;
R5 is 2-difluoromethoxy, relative to the 1-position of the sulfonylamino group SO2—NH;
R6 is 4-methyl, relative to the 1-position of the sulfonylamino group SO2—NH and to the 2-position of 2-difluoromethoxy as radical R5;
G1 is CH2;
G2 is CH2; and
o is 1;
or
X1 is NH;
R1 is hydrogen;
R2 is hydrogen;
R3 is methoxy;
R5 is 2-difluoromethoxy, relative to the 1-position of the sulfonylamino group SO2—NH;
R6 is 4-methyl, relative to the 1-position of the sulfonylamino group SO2—NH and to the 2-position of 2-difluoromethoxy as radical R5;
G1 is CH2;
G2 is CH2CH2; and
o is 1;
or
X1 is NH;
R1 is hydrogen;
R2 is hydrogen;
R3 is methoxy;
R5 is 2-difluoromethoxy, relative to the 1-position of the sulfonylamino group SO2—NH;
R6 is 4-methyl, relative to the 1-position of the sulfonylamino group SO2—NH and to the 2-position of 2-difluoromethoxy as radical R5;
G1 is CH2CH2;
G1 is CH2; and
o is 1;
or
X1 is NH;
R1 is hydrogen;
R2 is hydrogen;
R3 is ethoxy;
R5 is 2-difluoromethoxy, relative to the 1-position of the sulfonylamino group SO2—NH;
R6 is 5-methyl, relative to the 1-position of the sulfonylamino group SO2—NH and to the 2-position of 2-difluoromethoxy as radical R5;
G1 is CH2;
G2 is CH2; and
o is 1;
or
X1 is NH;
R is methyl;
R2 is hydrogen;
R3 is ethoxy;
R5 is 2-difluoromethoxy, relative to the 1-position of the sulfonylamino group SO2—NH;
R6 is 5-methyl, relative to the 1-position of the sulfonylamino group SO2—NH and to the 2-position of 2-difluoromethoxy as radical R5;
G1 is CH2;
G2 is CH2; and
o is 1;
or
X1 is NH;
R1 is hydrogen;
R2 is hydrogen;
R3 is ethoxy;
R5 is 2-methoxymethyl, relative to the 1-position of the sulfonylamino group SO2—NH;
G1 is CH2;
G2 is CH2; and
o is 0;
or
X1 is NH;
R1 is hydrogen;
R2 is hydrogen;
R3 is ethoxy;
R5 is 2-difluoromethoxy, relative to the 1-position of the sulfonylamino group SO2—NH;
R6 is 5-methyl, relative to the 1-position of the sulfonylamino group SO2—NH and to the 2-position of 2-difluoromethoxy as radical R5;
G1 is CH2;
G2 is CH2CH2; and
o is 1;
or
X1 is NH;
R1 is hydrogen;
R2 is hydrogen;
R3 is ethoxy;
R5 is 2-difluoromethoxy, relative to the 1-position of the sulfonylamino group SO2—NH;
R6 is 5-methyl, relative to the 1-position of the sulfonylamino group SO2—NH and to the 2-position of 2-difluoromethoxy as radical R5;
G1 is CH2CH2;
G1 is CH2; and
o is 1;
or
X1 is NH;
R1 is hydrogen;
R2 is hydrogen;
R3 is ethoxy;
R5 is 2-difluoromethoxy, relative to the 1-position of the sulfonylamino group SO2—NH;
R6 is 4-methyl, relative to the 1-position of the sulfonylamino group SO2—NH and to the 2-position of 2-difluoromethoxy as radical R5;
G1 is CH2;
G2 is CH2; and
o is 1;
or
X1 is NH;
R1 is methyl;
R2 is hydrogen;
R3 is ethoxy;
R5 is 2-difluoromethoxy, relative to the 1-position of the sulfonylamino group SO2—NH;
R6 is 4-methyl, relative to the 1-position of the sulfonylamino group SO2—NH and to the 2-position of 2-difluoromethoxy as radical R5;
G1 is CH2;
G2 is CH2; and
o is 1;
or
X1 is NH;
R1 is hydrogen;
R2 is hydrogen;
R3 is ethoxy;
R5 is 2-difluoromethoxy, relative to the 1-position of the sulfonylamino group SO2—NH;
R6 is 4-methyl, relative to the 1-position of the sulfonylamino group SO2—NH and to the 2-position of 2-difluoromethoxy as radical R5;
G1 is CH2;
G2 is CH2CH2; and
o is 1;
or
X1 is NH;
R1 is hydrogen;
R2 is hydrogen;
R3 is ethoxy;
R5 is 2-difluoromethoxy, relative to the 1-position of the sulfonylamino group SO2—NH;
R6 is 4-methyl, relative to the 1-position of the sulfonylamino group SO2—NH and to the 2-position of 2-difluoromethoxy as radical R5; G1 is CH2CH2;
G1 is CH2; and
o is 1;
or
X1 is NH;
R1 is hydrogen;
R2 is hydrogen;
R3 is methoxy;
R5 is 2-methoxymethyl, relative to the 1-position of the sulfonylamino group SO2—NH;
G1 is CH2CH2;
G2 is CH2; and
o is 0;
or
X1 is NH;
R1 is methyl;
R2 is hydrogen;
R3 is methoxy;
R5 is 2-difluoromethoxy, relative to the 1-position of the sulfonylamino group SO2—NH;
R6 is 5-methyl, relative to the 1-position of the sulfonylamino group SO2—NH and to the 2-position of 2-difluoromethoxy as radical R5;
G1 is CH2CH2;
G2 is CH2; and
o is 1.

### Claim 19 (depends on 1)

The compound of claim 1, wherein at least one hydrogen atom has been replaced by a deuterium atom.

### Claim 20 (depends on 1)

A pharmaceutical composition comprising at least one compound of claim 1, a stereoisomer, tautomer and/or physiologically tolerated acid addition salt thereof, and at least one physiologically acceptable carrier and/or auxiliary substance.

### Claim 21 (depends on 1)

The compound of claim 1, or astereoisomer, tautomer, or physiologically tolerated acid addition salt thereof, selected from the group consisting of:
N-(2-Difluoromethoxy-5-methyl-phenyl)-4-methoxy-3-pyrrolidin-3-yl-benzenesulfonamide;
N-(2-Difluoromethoxy-5-methyl-phenyl)-4-methoxy-3-(1-methyl-pyrrolidin-3-yl)-benzenesulfonamide;
4-Methoxy-N-(2-methoxymethyl-phenyl)-3-pyrrolidin-3-yl-benzenesulfonamide;
N-(2-Difluoromethoxy-5-methyl-phenyl)-4-methoxy-3-pipendin-4-yl-benzenesulfonamide;
N-(2-Difluoromethoxy-4-methyl-phenyl)-4-methoxy-3-pipendin-4-yl-benzenesulfonamide;
4-Methoxy-N-(2-methoxymethyl-phenyl)-3-piperidin-4-yl-benzenesulfonamide; and
N-(2-Difluoromethoxy-5-methyl-phenyl)-4-methoxy-3-(1-methyl-pipendin-4-yl)-benzenesulfonamide.