Compounds having a selective PDE4D inhibiting activity

Patent metadata

Field	Value
Publication number	US-10017480-B2
Application number	US-201515119034-A
Country	US
Kind code	B2
Filing date	Feb 10, 2015
Priority date	Feb 14, 2014
Publication date	Jul 10, 2018
Grant date	Jul 10, 2018

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

The invention claimed is:

1. A compound of formula (I):

wherein:
Z=cyclopentyl;
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 ,

 and
R 1 =C 1 -C 3 alkyl,

and enantiomers, diastereoisomers, and pharmaceutically acceptable salts thereof.

2. A compound according to claim 1 , wherein X =

3. A compound according to claim 1 , having the formula:
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 dihydrochloride;
1-{3-[3-(Cyclopentyloxy)-4-methoxyphenyl]-1H-pyrazol-1-yl}-3-(2,6-dimethylmorpholin-4-yl) propan-2-ol dihydrochloride;
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; or
{4-[3-(Cyclopentyloxy)-4-methoxy-phenyl]-1H-pyrrol-3-yl}-(4-hydroxy-piperidin-1-yl) -methanone.

4. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.

5. A process for the preparation of a compound of formula (I):

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

Y=—CH 2 —C═O; and
NR 2 =—N(CH 2 —CH 2 OH) 2 ,

comprising reacting a compound of formula (II):

with a compound of formula (III):

to yield the compound of formula (Ia):

6. A process for the preparation of a compound according to claim 1 , wherein:
X=

Y=—C═O; and
NR 2 =—N(CH 2 —CH 2 OH) 2 ,

comprising reacting a compound of formula (V):

wherein R″ is C 1 -C 4 alkyl, with R 2 NH, to yield the compound of formula (Ic):

7. A process for the preparation of a compound according to claim 1 , wherein:
X=

Y=—CH 2 —CH(OH)—CH 2 ; and
NR 2 =—N(CH 2 —CH 2 OH) 2 ,

comprising reacting a compound of formula (VI):

with R 2 NH to yield:

8. The process according to claim 7 , wherein R′ is —CHF 2 and the corresponding intermediate compound of formula (VIa) is prepared according to the reaction scheme:

wherein the first step of converting 3,4-dihydroxybenzaldehyde into 3,4-(difluoromethoxy)-hydroxybenzaldehyde involves the reaction of 3,4-dihydroxybenzaldehyde with an ester of chlorodifluoroacetic acid in the presence of Cs 2 CO 3 under irradiation with microwaves at a potency lower or equal to 300 W.

9. A process for the preparation of a compound according to claim 1 , wherein:
X=

and
Y=—CH 2 —C═O or —CH 2 —CH 2 —C═O,

comprising reacting a compound of formula (VII):

with a compound of formula J-(CH 2 ) m —CONR 2 , wherein J=halogen and m=1 or 2, to yield the compound of formula (XXIII):

wherein Y=—CH 2 —C═O or to yield the compound of formula (XXIV):

wherein Y=—CH 2 —CH 2 —C═O.

10. A process for the preparation of a compound according to claim 1 , wherein:
X=

Y=CH 2 —CH(OH)—CH 2 ; and
NR 2 =—N(CH 2 —CH 2 OH) 2 ,

comprising reacting a compound of formula (VIII):

Assignees

• Univ Degli Studi Genova
• Univ Columbia
• Maastricht Univ
• Univ Degli Studi Genova

Inventors

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

Classifications

• C07D261/18

  Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen · CPC title

• C07D401/06

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

• C07D261/08

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

• C07D231/12

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

• C07D261/04 Primary

  having one double bond between ring members or between a ring member and a non-ring member · CPC title