Therapeutically active bicyclic-sulphonamides and pharmaceutical compositions

Patent metadata

Field	Value
Publication number	US-10865194-B2
Application number	US-201715803362-A
Country	US
Kind code	B2
Filing date	Nov 3, 2017
Priority date	Nov 3, 2017
Publication date	Dec 15, 2020
Grant date	Dec 15, 2020

Abstract

wherein R1 represents an unsubstituted or a substituted heteroaryl ring; R2, R3, R4, and R5 are independently selected from hydrogen, alkyl, hydroxyalkyl, and alkyl-O-alkyl, provided that either R2 and R3, or R4 and R5 are linked or taken together to form a bridge between the carbon atoms to which R2 and R3, or R4 and R5 respectively are directly linked, whereby the N-containing ring in Formula 1 is an azabicyclo moiety. The compounds and compositions including the compounds may be used in therapy as brain-cell-death protectants, for example, in the treatment of chronic neurodegenerative diseases. The compounds are active as inhibitors of N-acylethanolamine-hydrolysing acid amidase (NAAA) and may be used for the therapeutic treatment and prevention of pain and inflammatory disorders and other disorders which benefit from the modulation of fatty acid ethanolamides, particularly palmitoylethanolamide (PEA).

First claim

The invention claimed is:

1. A compound having the structure of Formula I,

wherein:
R1 represents an unsubstituted or a substituted pyrazolyl or isoxazolyl ring;
R2, R3, R4 and R5 are independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl and alkyl-O-alkyl;
provided that either R2 and R3 or R4 and R5 are linked or taken together to form a bridge between the carbon atoms to which R2 and R3 or R4 and R5 respectively are directly linked wherein the heterocyclic N-containing ring shown in Formula I has a meaning selected from the group consisting of:

wherein Z is selected from CR vi R vii , O, or can be absent;
R ii , R iii , R iv and R v are independently selected from the group consisting of hydrogen and alkyl;
R vi and R vii are independently selected from the group consisting of hydrogen and alkyl;
R6 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, cyano and halogen;
X is selected from the group consisting of O, S and NR x ;
R X is independently selected from the group consisting of hydrogen and alkyl;
R7 is selected from the group consisting of phenyl, pyrimidinyl, pyrazinyl, pyridazinyl, 1,3-benzoxazolyl, quinolinyl, and quinoxalinyl;
or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or racemic mixture thereof.

2. A compound according to claim 1 , wherein R1 is a pyrazolyl, which is unsubstituted or mono- or bi-substituted with C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, aryl, heteroaryl, COR xi , COOR xi , heterocycloalkyl, CONHR xi , CONR xi R xii , OH, O—C 1 -C 6 alkyl, O—C 3 -C 6 cycloalkyl, O-heterocycloalkyl, O-heteroaryl, O-aryl, O-halo C 1 -C 6 alkyl, C 1 -C 6 alkyl—O—C 1 -C 6 alkyl, C 1 -C 6 alkyl—O—C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl-O-heterocycloalkyl, C 1 -C 6 alkyl-O-aryl, CN, NO 2 , NR xiii (R xii )COR xiii N(R xii )COOR xiv , N(R xii )CONR xiii R xiv , N(R xii )SOR xiii , SOR xiii , halogen and hydroxy-C 1 -C 6 alkyl;
R xi is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, aryl, heteroaryl;
R xii is selected from the group consisting of hydrogen, C 1 -C 6 alkyl;
R xiii is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, aryl, heteroaryl and hydroxy-C 1 -C 6 alkyl;
R xiv is selected from the group consisting of hydrogen, C 1 -C 6 alkyl.

3. A compound according to claim 1 wherein R1 is selected from the group consisting of pyrazolyl, and isoxazolyl, unsubstituted or mono- or bi-sub stituted with C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, aryl, OH, O—C 1 -C 6 alkyl, O-halo C 1 -C 6 alkyl, CN, NO 2 and halogen.

4. A compound according to claim 1 , wherein X is oxygen.

5. A compound according to claim 1 wherein R6 is hydrogen or C 1 -C 4 alkyl.

6. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutical acceptable carrier, excipient or diluent.

7. A compound according to claim 1 , selected from the group consisting of:
(1R,3s,5S)-8-[(3,5-Dimethyl-1H-pyrazol-4-yl)sulfonyl]-3-phenoxy-8-azabicyclo[3.2.1]octane,
(1R,3r,5 S)-8-[(3,5-Dimethyl-1H-pyrazol-4-yl)sulfonyl]-3-phenoxy-8-azabicyclo[3.2.1]octane,
(1R,3s,5 S)-8-[(3,5-Dimethyl-1H-pyrazol-4-yl)sulfonyl]-3-pyridazin-3-yloxy-8-azabicyclo[3.2.1]octane,
(1R,3r,5 S)-9-[(3,5-Dimethyl-1H-pyrazol-4-yl)sulfonyl]-3-(pyrazin-2-yloxy)-9-azabicyclo[3.3.1]nonane,
(1R,3 s,5 S)-9-[(3,5-Dimethyl-1H-pyrazol-4-yl)sulfonyl]-3-(pyrazin-2-yloxy)-9-azabicyclo[3.3.1]nonane,
(1R,3s,5 S)-9-[(3,5-Dimethyl-1H-pyrazol-4-yl)sulfonyl]-7-pyrazin-2-yloxy-3-oxa-9-azabicyclo[3.3.1]nonane,
(1R,3r,5 S)-9-[(3, 5-Dimethyl-1H-pyrazol-4-yl)sulfonyl]-7-pyrazin-2-yloxy-3-oxa-9-azabicyclo[3.3.1]nonane,
(1R,5S,9r)-7-(3,5-Dimethyl-1H-pyrazol-4-yl)sulfonyl)-9-(pyrazin-2-yloxy)-3-oxa-7-azabicyclo[3.3.1]nonane,
(1R,5S,9s)-7-(3,5-Dimethyl-1H-pyrazol-4-yl)sulfonyl)-9-(pyrazin-2-yloxy)-3-oxa-7-azabicyclo[3.3.1]nonane,
(1R,5S,8r)-3-(3,5-Dimethyl-1H-pyrazol-4-yl)sulfonyl)-8-(pyrazin-2-yloxy)-3-azabicyclo[3.2.1]octane,
(1R,5S,9r)-3-(3,5-Dimethyl-1H-pyrazol-4-yl)sulfonyl)-9-(pyrazin-2-yloxy)-3-azabicyclo[3.3.1]nonane, and
(1R,5S,9s)-3-(3,5-Dimethyl-1H-pyrazol-4-yl)sulfonyl)-9-(pyrazin-2-yloxy)-3-azabicyclo[3.3.1]nonane.

Assignees

• Fondazione St Italiano Tecnologia

Inventors

• Bertozzi Fabio
• Bandiera Tiziano
• Pontis Silvia
• Reggiani Angelo
• Giacomina Francesca
• Di Fruscia Paolo

Classifications

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61K31/4523

  containing further heterocyclic ring systems · CPC title

• A61P25/28

  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 · CPC title

• C07D401/14

  containing three or more hetero rings · CPC title

• C07D401/12 Primary

  linked by a chain containing hetero atoms as chain links · CPC title