# US 2016/0355489 A1 · New compounds having a selective pde4d inhibiting activity

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- Number: US 2016/0355489 A1
- Document ID: US20160355489A1
- Status: Published application
- Kind: A1
- Application number: 15/119,034
- Filed: 2015-02-10
- Published: 2016-12-08
- Earliest claimed: 2014-02-14
- Assignees: Universita' Degli Studi Di Genova; The Trustees of Columbia University; Maastricht University
- Applicants: Universita Degli Studi Di Genova; The Trustees of Columbia University; Maastricht University
- Inventors: Olga BRUNO; Chiara BRULLO; Alessia ROMUSSI; Ernesto FEDELE; Roberta RICCIARELLI; Ottavio ARANCIO; Jos PRICKAERTS
- Web page: https://patentgrep.com/patent/US20160355489A1

## CPC

- C07D 261/04: having one double bond between ring members or between a ring member and a non-ring member
- 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
- C07D 207/337: Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D 207/34: 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
- C07D 231/12: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D 261/08: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D 261/18: Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen
- C07D 401/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 403/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 413/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Compounds of formula (I), wherein Z=cyclopentyl. cyclopropylmethyl, —CH3; R′=—CH3, CHF2, X=formula (II) (III) (IV) (V) Y=—CO; —C═O(CH2), —CH(OH)—CH2, —CH2—C═O, —CH2—CH2—C═O; —CH2—CH(OH)—CH2, —CH2—CH(OCOR1)—CH2 NR2=—N(CH2—CH2OH)2, formula (VI) (VII) (VIII) (IX) (X) (XI) R1=optionally substituted C1-C8 alkyl, optionally substituted aryl; optionally substituted aralkyl, preferably C1-C3 alkyl, more preferably CH3; 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.

## Claims

### Claim 1

A compound of formula (I),
wherein:
Z=cyclopentyl, cyclopropylmethyl, or —CH3;
R′=—CH3, or CHF2;
X=
Y=—CO; —C═O(CH2), —CH(OH)—CH2, —CH2—C═O, —CH2—CH2—C═O; —CH2—CH(OH)—CH2, or —CH2—CH(OCOR1)—CH2;
NR2=—N(CH2—CH2OH)2
R1=optionally substituted C1-C8 alkyl, optionally substituted aryl or; optionally substituted aralkyl;
with the proviso that, when Z═CH3 and X=
then Y is not —CO, and with the further proviso that, when Z=cyclopentyl and X=
then Y—NR2 is different from CO or
and enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof.

### Claim 2 (depends on 1)

A compound according to claim 1, wherein Z=cyclopentyl R1=—C1-C3 alkyl.

### Claim 3 (depends on 2)

A compound according to claim 2, wherein
NR2=

### Claim 4 (depends on 3)

A compound according to claim 3, wherein
X=

### Claim 5 (depends on 1)

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.

### Claim at position 6

-11. (canceled)

### Claim 12 (depends on 1)

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

### Claim 13 (depends on 1)

A process for the preparation of a compound according to claim 1, in which Z=cyclopentyl, X=
Y=—CH2—C═O,
and R′, NR2 and R1 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)

### Claim 14 (depends on 1)

A process for the preparation of a compound according claim 1, in which
Z=cyclopentyl, X=
Y=—C═O, and R′,
NR2 and R1 are as defined in claim 1, comprising the reaction of a compound of formula (IV)
wherein R″ is C1-C4 alkyl,
with R2NH, wherein NR2 is as defined as in claim 1, to yield the following compound of formula (Ib)

### Claim 15 (depends on 1)

A process for the preparation of a compound according to claim 1, in which Z=cyclopentyl, X=
Y=—C═O, and
R′, NR2 and R1 are as defined in claim 1, comprising the reaction of a compound of formula (V)
wherein R″ is C1-C4 alkyl,
with R2NH, wherein NR2 is as defined in claim 1, to yield the following compound of formula (Ic)

### Claim 16 (depends on 1)

A process for the preparation of a compound according to claim 1, in which Z=cyclopentyl, X=
Y=—CH2—CH(OH)—CH2, and R′, NR2 and R1 are as defined in claim 1, comprising the reaction of a compound of formula (VI)
with R2NH, wherein NR2 is as defined in claim 1, to yield the following compound of formula (Id)

### Claim 17 (depends on 16)

The process according to claim 16, in which R′ is CHF2 and the relevant intermediate compound of formula (VIa) is prepared according to the following reaction scheme:
wherein the first step of converting 3,4-dihydroxybenzaldehyde into 4-(difluoromethoxy)-hydroxybenzaldehyde involves the reaction of 3,4-dihydroxybenzaldehyde with an ester of chlorodifluoroacetic acid, in the presence of Cs2CO3 under irradiation with microwaves at a potency lower or equal to 300 W.

### Claim 18 (depends on 1)

A process for the preparation of a compound according to claim 1, in which Z=cyclopentyl, X=
Y=—CH2—C═O or —CH2—CH2—C═O, and R′, NR2 and R1 are as defined in claim 1, comprising the reaction of a compound of formula (VII)
with a compound of formula J-(CH2)m—CONR2,
in which J=halogen, preferably Br or Cl, m=1 or 2 and NR2 is as defined in claim 1, to yield the following compound of formula (XXIII) or (XXIV):
wherein R′ and NR2 are as-defined in claim 1 and-Y=—CH2—C═O or —CH2—CH2—C═O.

### Claim 19 (depends on 1)

A process for the preparation of a compound according to claim 1, in which Z=cyclopentyl, X=
Y═CH2—CH(OH)—CH2, and R′, NR2 and R1 are as defined in claim 1, comprising the reaction of a compound of formula (VIII)
with R2NH, wherein NR2 is as defined in claim 1, to yield the following compound of formula (XXV):

### Claim 20 (depends on 1)

A process for the preparation of a compound according to claim 1, in which Z=cyclopentyl,
X=
Y=—CO and R′, NR2 and R1 are as defined in claim 1, comprising the reaction of a compound of formula (IX)
with R2NH, wherein NR2 is as defined in claim 1, to yield the following compound of formula (XXVI)