# US 9,751,870 B2 · Oxytocin receptor agonists for the treatment of CNS diseases

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- Number: US 9,751,870 B2
- Document ID: US9751870B2
- Status: Granted
- Kind: B2
- Application number: 14/802,469
- Filed: 2015-07-17
- Published: 2015-11-12
- Granted: 2017-09-05
- Earliest claimed: 2013-01-17
- Assignees: Hoffman-La Roche Inc.
- Applicants: Hoffmann-La Roche Inc.
- Inventors: Caterina Bissantz; Christophe Grundschober; Matthias Nettekoven; Jean-Marc Plancher; Walter Vifian
- Web page: https://patentgrep.com/patent/US9751870B2

## CPC

- C07D 417/04: directly linked by a ring-member-to-ring-member bond
- A61K 31/415: 1,2-Diazoles
- A61K 31/427: not condensed and containing further heterocyclic rings
- A61K 31/433: Thidiazoles
- A61K 31/4439: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465)
- A61K 31/506: not condensed and containing further heterocyclic rings
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/18: Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
- A61P 25/22: Anxiolytics
- A61P 25/24: Antidepressants
- 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
- A61P 25/32: Alcohol-abuse
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 231/42: Benzene-sulfonamido pyrazoles
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- C07D 403/04: directly linked by a ring-member-to-ring-member bond
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The invention relates to the use of a compound of formula I wherein A1 is phenyl or a five or six membered hereroaryl group, containing 1, 2 or 3 heteroatoms, selected from N or S; R1 is hydrogen, lower alkyl, halogen, lower alkyl substituted by halogen or cycloalkyl; A2 is phenyl; R2 is halogen, lower alkyl, lower alkyl substituted by halogen, lower alkoxy substituted by halogen, cyano, S-lower alkyl substituted by halogen, S(O)2-lower alkyl substituted by halogen; n is 1 or 2; or a pharmaceutically acceptable acid addition salt, or a racemic mixture or its corresponding enantiomer and/or optical isomers thereof, for the treatment of autism, stress, including post traumatic stress disorder, anxiety, including anxiety disorders and depression, schizophrenia, psychiatric disorders and memory loss, alcohol withdrawal, drug addiction and for the treatment of Prader-Willi Syndrome.

## Claims

### Claim 1

A method of treating a condition selected from the group consisting of autism, stress, post traumatic stress disorder, anxiety disorders, depression, schizophrenia, psychiatric disorders, memory loss, alcohol withdrawal, drug addiction and Prader-Willi Syndrome, comprising administering a compound of formula I
wherein
A1 is phenyl or a five or six membered heteroaryl group, containing 1, 2 or 3 heteroatoms, selected from N or S;
R1 is hydrogen, lower alkyl, halogen, lower alkyl substituted by halogen or cycloalkyl;
A2 is phenyl;
R2 is halogen, lower alkyl, lower alkyl substituted by halogen, lower alkoxy substituted by halogen, cyano, S-lower alkyl substituted by halogen, S(O)2-lower alkyl substituted by halogen;
n is 1 or 2;
or a pharmaceutically acceptable acid addition salt, a racemic mixture or its corresponding enantiomer and/or optical isomers thereof, to a patient in need thereof.

### Claim 2

A method of treating a condition selected from the group consisting of autism, stress, post traumatic stress disorder, anxiety disorders, depression, schizophrenia, psychiatric disorders, memory loss, alcohol withdrawal, drug addiction and Prader-Willi Syndrome, comprising administering a compound selected from the group consisting of
4-Chloro-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-benzenesulfonamide
N-(2-Pyridin-2-yl-2H-pyrazol-3-yl)-4-trifluoromethyl-benzenesulfonamide
4-Ethyl-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-benzenesulfonamide
4-Propyl-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-benzenesulfonamide
2-Chloro-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-4-trifluoromethyl-benzenesulfonamide
4-Difluoromethoxy-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-benzenesulfonamide
4-Chloro-N-[2-(4-fluoro-phenyl)-2H-pyrazol-3-yl]-benzenesulfonamide
4-Cyano-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-benzenesulfonamide
N-[2-(4-Methyl-thiazol-2-yl)-2H-pyrazol-3-yl]-4-trifluoromethyl-benzenesulfonamide
4-Chloro-N-[2-(4-methyl-thiazol-2-yl)-2H-pyrazol-3-yl]-benzenesulfonamide
4-Ethyl-N-[2-(4-methyl-thiazol-2-yl)-2H-pyrazol-3-yl]-benzenesulfonamide
N-(2-Pyrimidin-2-yl-2H-pyrazol-3-yl)-4-trifluoromethyl-benzenesulfonamide
2,4-Dichloro-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-benzenesulfonamide
4-Chloro-2-fluoro-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-benzenesulfonamide
4-(1-Fluoro-ethyl)-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-benzenesulfonamide
N-[2-(4-Methyl-pyridin-2-yl)-2H-pyrazol-3-yl]-4-trifluoromethyl-benzenesulfonamide
4-Chloro-N-[2-(4-methyl-pyridin-2-yl)-2H-pyrazol-3-yl]-benzenesulfonamide
4-Ethyl-N-[2-(4-methyl-pyridin-2-yl)-2H-pyrazol-3-yl]-benzenesulfonamide
4-Cyano-N-[2-(4-methyl-pyridin-2-yl)-2H-pyrazol-3-yl]-benzenesulfonamide
N-(2-Pyridin-2-yl-2H-pyrazol-3-yl)-4-trifluoromethylsulfanyl-benzenesulfonamide
4-Trifluoromethyl-N-[2-(2-trifluoromethyl-pyrimidin-4-yl)-2H-pyrazol-3-yl]-benzenesulfonamide
2-Fluoro-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-4-trifluoromethyl-benzenesulfonamide
N-(2-Pyridin-2-yl-2H-pyrazol-3-yl)-4-trifluoromethanesulfonyl-benzenesulfonamide
3-Fluoro-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-4-trifluoromethyl-benzenesulfonamide
N-[2-(3-Cyclopropyl-[1,2,4]thiadiazol-5-yl)-2H-pyrazol-3-yl]-4-ethyl-benzenesulfonamide and
4-Chloro-2-fluoro-N-[2-(4-methyl-thiazol-2-yl)-2H-pyrazol-3-yl]-benzenesulfonamide to a patient in need thereof.

### Claim 3

A pharmaceutical composition comprising a compound selected from the group consisting of
4-Chloro-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-benzenesulfonamide
N-(2-Pyridin-2-yl-2H-pyrazol-3-yl)-4-trifluoromethyl-benzenesulfonamide
4-Ethyl-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-benzenesulfonamide
4-Propyl-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-benzenesulfonamide
2-Chloro-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-4-trifluoromethyl-benzenesulfonamide
4-Difluoromethoxy-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-benzenesulfonamide
4-Chloro-N-[2-(4-fluoro-phenyl)-2H-pyrazol-3-yl]-benzenesulfonamide
4-Cyano-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-benzenesulfonamide
N-[2-(4-Methyl-thiazol-2-yl)-2H-pyrazol-3-yl]-4-trifluoromethyl-benzenesulfonamide
4-Chloro-N-[2-(4-methyl-thiazol-2-yl)-2H-pyrazol-3-yl]-benzenesulfonamide
4-Ethyl-N-[2-(4-methyl-thiazol-2-yl)-2H-pyrazol-3-yl]-benzenesulfonamide
N-(2-Pyrimidin-2-yl-2H-pyrazol-3-yl)-4-trifluoromethyl-benzenesulfonamide
2,4-Dichloro-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-benzenesulfonamide
4-Chloro-2-fluoro-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-benzenesulfonamide
4-(1-Fluoro-ethyl)-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-benzenesulfonamide
N-[2-(4-Methyl-pyridin-2-yl)-2H-pyrazol-3-yl]-4-trifluoromethyl-benzenesulfonamide
4-Chloro-N-[2-(4-methyl-pyridin-2-yl)-2H-pyrazol-3-yl]-benzenesulfonamide
4-Ethyl-N-[2-(4-methyl-pyridin-2-yl)-2H-pyrazol-3-yl]-benzenesulfonamide
4-Cyano-N-[2-(4-methyl-pyridin-2-yl)-2H-pyrazol-3-yl]-benzenesulfonamide
N-(2-Pyridin-2-yl-2H-pyrazol-3-yl)-4-trifluoromethylsulfanyl-benzenesulfonamide
4-Trifluoromethyl-N-[2-(2-trifluoromethyl-pyrimidin-4-yl)-2H-pyrazol-3-yl]-benzenesulfonamide
2-Fluoro-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-4-trifluoromethyl-benzenesulfonamide
N-(2-Pyridin-2-yl-2H-pyrazol-3-yl)-4-trifluoromethanesulfonyl-benzenesulfonamide
3-Fluoro-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-4-trifluoromethyl-benzenesulfonamide
N-[2-(3-Cyclopropyl-[1,2,4]thiadiazol-5-yl)-2H-pyrazol-3-yl]-4-ethyl-benzenesulfonamide and
4-Chloro-2-fluoro-N-[2-(4-methyl-thiazol-2-yl)-2H-pyrazol-3-yl]-benzenesulfonamide, or a pharmaceutically acceptable acid addition salt, a racemic mixture or its corresponding enantiomer and/or optical isomers thereof, and a therapeutically inert carrier.

### Claim 4

A compound selected from the group consisting of
4-Chloro-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-benzenesulfonamide
N-(2-Pyridin-2-yl-2H-pyrazol-3-yl)-4-trifluoromethyl-benzenesulfonamide
4-Ethyl-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-benzenesulfonamide
4-Propyl-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-benzenesulfonamide
2-Chloro-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-4-trifluoromethyl-benzenesulfonamide
4-Difluoromethoxy-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-benzenesulfonamide
4-Chloro-N-[2-(4-fluoro-phenyl)-2H-pyrazol-3-yl]-benzenesulfonamide
4-Cyano-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-benzenesulfonamide
N-[2-(4-Methyl-thiazol-2-yl)-2H-pyrazol-3-yl]-4-trifluoromethyl-benzenesulfonamide
4-Chloro-N-[2-(4-methyl-thiazol-2-yl)-2H-pyrazol-3-yl]-benzenesulfonamide
4-Ethyl-N-[2-(4-methyl-thiazol-2-yl)-2H-pyrazol-3-yl]-benzenesulfonamide
N-(2-Pyrimidin-2-yl-2H-pyrazol-3-yl)-4-trifluoromethyl-benzenesulfonamide
2,4-Dichloro-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-benzenesulfonamide
4-Chloro-2-fluoro-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-benzenesulfonamide
4-(1-Fluoro-ethyl)-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-benzenesulfonamide
N-[2-(4-Methyl-pyridin-2-yl)-2H-pyrazol-3-yl]-4-trifluoromethyl-benzenesulfonamide
4-Chloro-N-[2-(4-methyl-pyridin-2-yl)-2H-pyrazol-3-yl]-benzenesulfonamide
4-Ethyl-N-[2-(4-methyl-pyridin-2-yl)-2H-pyrazol-3-yl]-benzenesulfonamide
4-Cyano-N-[2-(4-methyl-pyridin-2-yl)-2H-pyrazol-3-yl]-benzenesulfonamide
N-(2-Pyridin-2-yl-2H-pyrazol-3-yl)-4-trifluoromethylsulfanyl-benzenesulfonamide
4-Trifluoromethyl-N-[2-(2-trifluoromethyl-pyrimidin-4-yl)-2H-pyrazol-3-yl]-benzenesulfonamide
2-Fluoro-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-4-trifluoromethyl-benzenesulfonamide
N-(2-Pyridin-2-yl-2H-pyrazol-3-yl)-4-trifluoromethanesulfonyl-benzenesulfonamide
3-Fluoro-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-4-trifluoromethyl-benzenesulfonamide
N-[2-(3-Cyclopropyl-[1,2,4]thiadiazol-5-yl)-2H-pyrazol-3-yl]-4-ethyl-benzenesulfonamide and
4-Chloro-2-fluoro-N-[2-(4-methyl-thiazol-2-yl)-2H-pyrazol-3-yl]-benzenesulfonamide or a pharmaceutically acceptable acid addition salt, a racemic mixture or its corresponding enantiomer and/or optical isomers thereof.

### Claim 5

A compound of formula IA,
wherein
A1 is thiazolyl, pyrimidinyl or 1,2,4-thiadiazolyl;
R1 is hydrogen, lower alkyl, halogen, lower alkyl substituted by halogen or cycloalkyl;
A2 is phenyl;
R2 is halogen, lower alkyl, lower alkyl substituted by halogen, lower alkoxy substituted by halogen, cyano, S-lower alkyl substituted by halogen, S(O)2-lower alkyl substituted by halogen;
n is 1 or 2;
or a pharmaceutically acceptable acid addition salt, a racemic mixture or its corresponding enantiomer and/or optical isomers thereof.

### Claim 6

A compound selected from the group consisting of
N-[2-(4-Methyl-thiazol-2-yl)-2H-pyrazol-3-yl]-4-trifluoromethyl-benzenesulfonamide
4-Chloro-N-[2-(4-methyl-thiazol-2-yl)-2H-pyrazol-3-yl]-benzenesulfonamide
4-Ethyl-N-[2-(4-methyl-thiazol-2-yl)-2H-pyrazol-3-yl]-benzenesulfonamide
N-(2-Pyrimidin-2-yl-2H-pyrazol-3-yl)-4-trifluoromethyl-benzenesulfonamide
4-Trifluoromethyl-N-[2-(2-trifluoromethyl-pyrimidin-4-yl)-2H-pyrazol-3-yl]-benzenesulfonamide
N-[2-(3-Cyclopropyl-[1,2,4]thiadiazol-5-yl)-2H-pyrazol-3-yl]-4-ethyl-benzenesulfonamide and
4-Chloro-2-fluoro-N-[2-(4-methyl-thiazol-2-yl)-2H-pyrazol-3-yl]-benzenesulfonamide.

### Claim 7

A process for preparation of a compound of formula IA, or a pharmaceutically acceptable acid addition salt, a racemic mixture or its corresponding enantiomer and/or optical isomers thereof, which process comprises
a) reacting a compound of formula
with a compound of formula
to afford the compound of formula IA
wherein formula IA is as follows
wherein
A1 is thiazolyl, pyrimidinyl or 1,2,4-thiadiazolyl;
R1 is hydrogen, lower alkyl, halogen, lower alkyl substituted by halogen or cycloalkyl;
A2 is phenyl;
R2 is halogen, lower alkyl, lower alkyl substituted by halogen, lower alkoxy substituted by halogen, cyano, S-lower alkyl substituted by halogen, S(O)2-lower alkyl substituted by halogen;
n is 1 or 2.