New compounds having a selective pde4d inhibiting activity

Patent metadata

Field	Value
Publication number	US-2016355489-A1
Application number	US-201515119034-A
Country	US
Kind code	A1
Filing date	Feb 10, 2015
Priority date	Feb 14, 2014
Publication date	Dec 8, 2016
Grant date	—

Abstract

Compounds of formula (I), wherein Z=cyclopentyl. cyclopropylmethyl, —CH 3 ; R′=—CH 3 , CHF 2 , X=formula (II) (III) (IV) (V) Y=—CO; —C═O(CH 2 ), —CH(OH)—CH 2 , —CH 2 —C═O, —CH 2 —CH 2 —C═O; —CH 2 —CH(OH)—CH 2 , —CH 2 —CH(OCOR 1 )—CH 2 NR 2 =—N(CH 2 —CH 2 OH) 2 , formula (VI) (VII) (VIII) (IX) (X) (XI) R 1 =optionally substituted C 1 -C 8 alkyl, optionally substituted aryl; optionally substituted aralkyl, preferably C 1 -C 3 alkyl, more preferably CH 3 ; and enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof; these compounds have a PDE4D inhibiting activity and can be used as a medicament for treating dementia, in particular Alzheimer disease, and for improving memory.

First claim

1 . A compound of formula (I),

wherein:
Z=cyclopentyl, cyclopropylmethyl, or —CH 3 ;
R′=—CH 3 , or CHF 2 ;
X=

Y=—CO; —C═O(CH 2 ), —CH(OH)—CH 2 , —CH 2 —C═O, —CH 2 —CH 2 —C═O; —CH 2 —CH(OH)—CH 2 , or —CH 2 —CH(OCOR 1 )—CH 2 ;
NR 2 =—N(CH 2 —CH 2 OH) 2

R 1 =optionally substituted C 1 -C 8 alkyl, optionally substituted aryl or; optionally substituted aralkyl;
with the proviso that, when Z═CH 3 and X=

then Y is not —CO, and with the further proviso that, when Z=cyclopentyl and X=

then Y—NR 2 is different from CO or

and enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof.

2 . A compound according to claim 1 , wherein Z=cyclopentyl R 1 =—C 1 -C 3 alkyl.

3 . A compound according to claim 2 , wherein
NR 2 =

4 . A compound according to claim 3 , wherein
X=

5 . A compound according to claim 1 , having the following formula:
4-({3-[3-(Cyclopentyloxy)-4-methoxyphenyl]-4,5-dihydroisoxazol-5 yl}carbonyl)morpholine; 4-({3-[3-(Cyclopentyloxy)-4-methoxyphenyl]-4,5-dihydroisoxazol-5-yl}carbonyl)-2,6-dimethylmorpholine; 1-({3-[3-(Cyclopentyloxy)-4-methoxyphenyl]-4,5-dihydroisoxazol-5-yl}carbonyl)piperidin-4-ol; 3-[3-(Cyclopentyloxy)-4-methoxyphenyl]-5-(pyrrolidin-1-ylcarbonyl)-4,5-dihydroisoxazole; 3-[3-(Cyclopentyloxy)-4-methoxyphenyl]-N,N-bis(2-hydroxyethyl)-4,5-dihydroisoxazole-5-carboxamide; 4-({3-[3-(Cyclopentyloxy)-4-methoxyphenyl]-4,5-dihydroisoxazol-5-yl}acetyl)morpholine; 4-({3-[3-(Cyclopentiloxy)-4-methoxyphenyl]-4,5-dihydroisoxazol-5-yl}acetil) 2,6-dimethylmorpholine; 1-({3-[3-(Cyclopentyloxy)-4-methoxyphenyl]-4,5-dihydroisoxazol-5-yl}acetyl)piperidin-4-ol; 3-[3-(Cyclopentyloxy)-4-methoxyphenyl]-5-(2-oxo-2-pyrrolidin-1-yl ethyl)-4, 5-dihydroisoxazole; 1-({3-[3-(Cyclopentyloxy)-4-methoxyphenyl]-4,5-dihydroisoxazol-5-yl}acetyl)piperidine; 1-({3-[3-(Cyclopentyloxy)-4-methoxyphenyl]-4,5-dihydroisoxazol-5-yl}acetyl)piperazine; 2-{3-[3-(Cyclopentyloxy)-4-methoxyphenyl]-4,5-dihydroisoxazol-5-yl}-N,N-bis(2-hydroxyethyl)acetamide; 4-({3-[3-(Cyclopentyloxy)-4-methoxyphenyl]-4,5-dihydroisoxazol-5-yl}acetyl)morpholine; 4-({3-[3-(Cyclopentiloxy)-4-methoxyphenyl]-4,5-dihydroisoxazol-5-yl}acetil) 2,6-dimethylmorpholine; 1-{3-[3-(Cyclopentyloxy)-4-methoxyphenyl]isoxazol-5-yl}-2-morpholin-4-ylethanone hydrochloride; 1-{3-[3-(Cyclopentyloxy)-4-methoxyphenyl]isoxazol-5-yl}-2-(2,6-dimethylmorpholin-4-yl)ethanone hydrochloride; 1-{3-[3-(Cyclopentyloxy)-4-methoxyphenyl]isoxazol-5-yl}-2-morpholin-4-ylethanol; 1-{3-[3-(Cyclopentyloxy)-4-methoxyphenyl]isoxazol-5-yl}-2-(2,6-dimethylmorpholin-4-yl)ethanol; 4-({3-[3-(Cyclopentyloxy)-4-methoxyphenyl]isoxazol-5-yl}carbonyl)morpholine; 4-({3-[3-(Cyclopentyloxy)-4-methoxyphenyl]isoxazol-5-yl}carbonyl)-2,6-dimethylmorpholine; 1-{3-[3-(Cyclopentyloxy)-4-methoxyphenyl]-1H-pyrazol-1-yl}-3-morpholin-4-ylpropan-2-ol dihydrocloride; 1-{3-[3-(Cyclopentyloxy)-4-methoxyphenyl]-1H-pyrazol-1-yl}-3-(2,6-dimethylmorpholin-4-yl)propan-2-ol dihydrocloride; 1-(3-{3-[3-(cyclopentyloxy)-4-methoxyphenyl]-1H-pyrazol-1-yl}-2-hydroxypropyl)piperidin-4-ol; 2-{3-[3-(cyclopentyloxy)-4-methoxyphenyl]-1H-pyrazol-1-yl}-1-(morpholin-4-ylmethyl)ethyl acetate; 4-({3-[3-(Cyclopentyloxy)-4-methoxyphenyl]-1H-pyrazol-1-yl}acetyl)morpholine; 4-({3-[3-(Cyclopentyloxy)-4-methoxyphenyl]-1H-pyrazol-1-yl}acetyl)2,6-dimethylmorpholine; 4-(3-{3-[3-(cyclopentyloxy)-4-methoxyphenyl]-1H-pyrazol-1-yl}propanoyl)morpholine; 4-(3-{3-[3-(cyclopentyloxy)-4-methoxyphenyl]-1H-pyrazol-1-yl}propanoyl)2,6-dimethylmorpholine; 4-(3-{3-[3-(cyclopentyloxy)-4-(difluoromethoxy)phenyl]-1H-pyrazol-1-yl}propanoyl)morpholine; 2-{3-[3-(cyclopentyloxy)-4-methoxy-phenyl]-pyrrol-1-yl}-1-morpholin-4-yl-ethanone; 2-{3-[3-(Cyclopentyloxy)-4-methoxy-phenyl]-pyrrol-1-yl}-1-(2,6-dimethyl-morpholin-4-yl)-ethanone; 2-{3-[3-(Cyclopentyloxy)-4-methoxy-phenyl]-pyrrol-1-yl}-1-(4-hydroxy-piperidin-1-yl)-ethanone; 3-{3-[3-(cyclopentyloxy)-4-methoxy-phenyl]-pyrrol-1-yl}-1-morpholin-4-yl-propan-1-one; 3-{3-[3-(Cyclopentyloxy)-4-methoxy-phenyl]-pyrrol-1-yl}-1-(4-hydroxy-piperidin-1-yl)-propan-1-one; 1-{3-[3-(Cyclopentyloxy)-4-methoxy-phenyl]-pyrrol-1-yl}-3-morpholin-4-yl-propan-2-ol; 1-{3-[3-(Cyclopentyloxy)-4-methoxy-phenyl]-pyrrol-1-yl}-3-(2,6-dimethyl-morpholin-4-yl)-propan-2-ol; 1-(3-{3-[3-(cyclopentyloxy)-4-methoxy-phenyl]-pyrrol-1-yl}-2-hydroxy-propyl)-piperidin-4-ol; {4-[3-(Cyclopentyloxy)-4-methoxy-phenyl]-1H-pyrrol-3-yl}-morpholin-4-yl-methanone; {4-[3-(Cyclopentyloxy)-4-methoxy-phenyl]-1H-pyrrol-3-yl}-(2,6-dimethyl-morpholin-4-yl)-methanone; and {4-[3-(Cyclopentyloxy)-4-methoxy-phenyl]-1H-pyrrol-3-yl}-(4-hydroxy-piperidin-1-yl)-methanone.

6 .- 11 . (canceled)

12 . A pharmaceutical composition comprising at least one compound according to claim 1 and a pharmaceutically acceptable carrier.

13 . A process for the preparation of a compound according to claim 1 , in which Z=cyclopentyl, X=

Y=—CH 2 —C═O,
and R′, NR 2 and R 1 are as defined in claim 1 , comprising the reaction of a compound of formula (II)

with a compound of formula (III)

to yield the following compound of formula (Ia)

14 . A process for the preparation of a compound according claim 1 , in which
Z=cyclopentyl, X=

Y=—C═O, and R′,
NR 2 and R 1 are as defined in claim 1 , comprising the reaction of a compound of formula (IV)

wherein R″ is C 1 -C 4 alkyl,
with R 2 NH, wherein NR 2 is as defined as in claim 1 , to yield the following compound of formula (Ib)

15 . A process for the preparation of a compound according to claim 1 , in which Z=cyclopentyl, X=

Y=—C═O, and
R′, NR 2 and R 1 are as defined in claim 1 , comprising the reaction of a compound of formula (V)

wherein R″ is C 1 -C 4 alkyl,
with R 2 NH, wherein NR 2 is as defined in claim 1 , to yield the following compou

Assignees

• Univ Degli Studi Genova
• Univ Columbia
• Maastricht Univ

Inventors

• Bruno Olga
• Brullo Chiara
• Romussi Alessia
• Fedele Ernesto
• Ricciarelli Roberta
• Arancio Ottavio
• Prickaerts Jos

Classifications

• C07D401/06

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

• C07D207/34

  with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms · CPC title

• C07D261/08

  with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms · CPC title

• C07D413/06

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

• C07D231/12

  with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms · CPC title