# US 2014/0155391 A1 · 1-phenyl-2-pyridinyl alkyl alcohol derivatives as phosphodiesterase inhibitors

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- Number: US 2014/0155391 A1
- Document ID: US20140155391A1
- Status: Published application
- Kind: A1
- Application number: 14/097,445
- Filed: 2013-12-05
- Published: 2014-06-05
- Earliest claimed: 2012-12-05
- Assignees: Chiesi Farmaceutici S.p.A.
- Applicants: CHIESI FARMACEUTICI S.p.A.
- Inventors: Elisabetta ARMANI; Gabriele Amari; Oriana Esposito; Laura Carzaniga; Carmelida Capaldi
- Web page: https://patentgrep.com/patent/US20140155391A1

## CPC

- C07D 295/155: with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
- A61M 15/0065: {Inhalators with dosage or measuring devices (A61M15/0028 takes precedence; dosage devices incorporated in aerosol cans B65D83/52)}
- A61M 15/009: {using medicine packages with incorporated spraying means, e.g. aerosol cans (pocket atomiser of the injector type A61M11/08)}
- A61M 16/14: by mixing different fluids, one of them being in a liquid phase
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 11/02: Nasal agents, e.g. decongestants
- A61P 11/06: Antiasthmatics
- A61P 17/00: Drugs for dermatological disorders
- A61P 37/08: Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14)
- C07D 213/61: Halogen atoms or nitro radicals
- C07D 213/89: with hetero atoms directly attached to the ring nitrogen atom
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 407/12: linked by a chain containing hetero atoms as chain links
- C07D 417/12: linked by a chain containing hetero atoms as chain links
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61M: DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY (introducing media into or onto the bodies of animals A61D7/00; means for inserting tampons A61F13/26; devices for administering food or medicines orally A61J; containers for collecting, storing or administering blood or medical fluids A61J1/05); DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY (surgery A61B; chemical aspects of surgical articles A61L); DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR {(Electrotherapy, e.g. producing anaesthesia by the use of alternating or intermittent currents A61N1/36021)}
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Compounds of formula (I) described herein are inhibitors of the phosphodiesterase 4 (PDE4) enzyme and are useful for the prevention and/or treatment of an allergic disease state or a disease of the respiratory tract characterized by airway obstruction.

## Claims

### Claim 1

A compound represented by formula (I):
wherein:
R1 and R2 are the same or different and are independently:
H;
linear or branched (C1-C6) alkyl, optionally substituted by one or more substituents selected from (C3-C7) cycloalkyl and (C5-C7) cycloalkenyl;
(C1-C6) haloalkyl;
(C3-C7) cycloalkyl;
(C5-C7) cycloalkenyl;
linear or branched (C2-C6) alkenyl; or
linear or branched (C2-C6) alkynyl.
R3 is H, CN, NO2, CF3, or a halogen atom;
Z is a group (CH2)m wherein m=0 or 1;
A is a phenyl ring, which is optionally substituted by one or more substituents R4, which may be the same or different and are independently:
linear or branched (C1-C6) alkyl optionally substituted by one or more (C3-C7) cycloalkyl or (C3-C7)heterocycloalkyl;
(C1-C6) haloalkyl;
(C1-C6) alkylthio;
halogen;
NH2; or
OR7 wherein R7 is:
H;
(C1-C10) alkyl optionally substituted by a radical selected from the group consisting of (C3-C7) cycloalkyl, (C3-C7) heterocycloalkyl, aryl and heteroaryl;
(C1-C10) alkyl substituted by one group OH;
(C1-C6) haloalkyl;
(C3-C7) cycloalkyl;
(C1-C4)alkylaminocarbonyl;
(C1-C4)alkyloxycarbonyl;
(C3-C7) heterocycloalkyl optionally substituted by (C1-C4) alkyl; or
R5R6N—(C1-C10)alkylene wherein R5 and R6 are independently H or linear or branched (C1-C6) alkyl, or, together with the nitrogen atom to which they are linked, R5 and R6 form a saturated, partially saturated or unsaturated ring, wherein said ring is optionally substituted by (C1-C4) alkyl, halogen atoms, or R7R8N—(C1-C4)alkylene wherein R7 and R8 are the same or different and are independently H or linear or branched (C1-C6) alkyl, or, together with the nitrogen atom to which they are linked, R7 and R8 form a saturated or partially saturated ring;
W is:
—NR9SO2R10 wherein
R9 is:
(C1-C10) alkyl optionally substituted by (C3-C7) cycloalkyl, (C3-C7) heterocycloalkyl, (C3-C7) heterocycloalkylcarbonyl, wherein any such ring may be optionally substituted by one or more (C1-C4) alkyl or OH; or
R11R12N—(C1-C10)alkylene wherein R11 and R12 are independently H or (C1-C6) alkyl, each of which may optionally be substituted by a group OH; and
R10 is:
(C1-C4) alkyl optionally substituted by (C3-C7) cycloalkyl;
(C3-C7)cycloalkyl; or
phenyl, any of which may be optionally substituted with one or more halogen atoms or (C1-C4) alkyl group;
—CH2NR13SO2R14 wherein
R13:
H;
(C3-C7) cycloalkyl;
(C1-C10) alkyl optionally substituted by (C3-C7) cycloalkyl, (C3-C7) heterocycloalkyl, where any such ring may be optionally substituted by (C1-C4) alkyl; or
R11R12N—(C1-C10)alkylene wherein R11 and R12 are independently H or (C1-C6) alkyl, each of which may optionally be substituted by a group OH;
R14 is:
(C1-C4) alkyl;
(C3-C7) heterocycloalkyl-(C1-C4)alkylene; or
phenyl, any of which may be optionally substituted with one or more halogen atoms or (C1-C4) alkyl group;
—(C1-C4)alkylene-(C3-C7)heterocycloalkyl, which may be optionally substituted by one or more groups selected from the group consisting of oxo, OH, SH, (C1-C4) alkyl, and hydroxy(C1-C6)alkylene;
—(C3-C7) heterocycloalkyl ring, which may be optionally substituted by one or more groups selected from the group consisting of oxo, OH, SH, (C1-C4) alkyl, and hydroxy(C1-C6)alkylene;
—(C1-C4)alkylene-amino-(C3-C7)heterocycloalkyl, which may be optionally substituted by one or more groups selected from the group consisting of oxo, OH, SH, (C1-C4) alkyl, and hydroxy(C1-C6)alkylene
—SO2NR15R16 wherein
R15 is H or (C1-C10) alkyl; and
R16 is:
(C1-C10) alkyl which is optionally substituted by (C3-C7) cycloalkyl or (C3-C7) heterocycloalkyl, where any such ring may be optionally substituted by (C1-C4) alkyl; or
R11R12N—(C1-C10)alkylene wherein R11 and R12 are independently H or (C1-C6) alkyl, each of which may optionally be substituted by a group OH; or
R15 and R16, together with the nitrogen atom to which they are linked, form a (C3-C7) heterocycloalkyl ring optionally substituted by one or more (C1-C4) alkyl;
—NHSO2R17 wherein
R17 is:
(C1-C10) alkyl which is optionally substituted by (C3-C7)cycloalkyl, (C3-C7) heterocycloalkyl, aryl, or heteroaryl ring, where any such ring may be optionally substituted by (C1-C4) alkyl; or
R11R12N—(C1-C10)alkylene wherein R11 and R12 are independently H or (C1-C6) alkyl, each of which may optionally be substituted by a group OH;
—OSO2R18 wherein
R18 is:
(C1-C10) alkyl which is optionally substituted by halogen, OH, (C1-C4) alkoxyl, (C3-C7) cycloalkyl, (C3-C7) heterocycloalkyl, aryl, or heteroaryl, where any such ring may be optionally substituted by (C1-C4) alkyl; or
R11R12N—(C1-C10)alkylene wherein R11 and R12 are independently H or (C1-C6) alkyl, each of which may optionally be substituted by a group OH;
—OC(O)R19 wherein
R19 is:
(C3-C7) cycloalkyl, (C3-C7) heterocycloalkyl, where any such ring may be optionally substituted by (C1-C4) alkyl;
(C1-C10) alkyl which is optionally substituted by one or more of halogen, OH, NH2, (C3-C7) cycloalkyl, or (C3-C7) heterocycloalkyl, where any such ring may be optionally substituted by (C1-C4) alkyl; or
R11R12N—(C1-C10)alkylene wherein R11 and R12 are independently H or (C1-C6) alkyl, each of which may optionally be substituted by a group OH;
—C(O)R20 wherein
R20 is:
—NR21R22 wherein R21 and R22 are independently H, (C1-C6) alkyl, (C3-C7) cycloalkyl, or (C3-C7)heterocycloalkyl(C1-C4)alkylene, each of which may optionally be substituted by (C1-C4) alkyl, OH, or NH2, or, together with the nitrogen atom to which they are linked, R21 and R22 form a saturated or partially saturated heterocyclic ring which may be optionally substituted by (C1-C4) alkyl, OH, or NH2;
—OR23 wherein R23 is (C1-C10) alkyl which is substituted by one or more of halogen, OH, (C3-C7)cycloalkyl, or (C3-C7)heterocycloalkyl, where any such ring may be optionally substituted by (C1-C4) alkyl;
—NH—(C1-C4)alkylene-NR24R25 wherein
R24 and R25, the same or different, are independently H or (C1-C6) alkyl, or, together with the nitrogen atom to which they are linked, R24 and R25 form a saturated or partially saturated ring, which is optionally substituted by one ore more (C1-C4) alkyl groups;
—NHCOR26 wherein
R26 is:
R27R28N—(C1-C6)alkylene wherein R27 and R28 are the same or different and are independently H or (C1-C6) alkyl optionally substituted by OH or NH2, or, together with the nitrogen atom to which they are linked, R27 and R28 form a saturated or partially saturated ring, which is optionally substituted by one or more (C1-C4) alkyl, OH, or NH2 groups;
R27R28N-carbonyl-(C1-C6)alkylene wherein R27 and R28 are the same or different and are independently H or (C1-C6) alkyl optionally substituted by OH or NH2, or, together with the nitrogen atom to which they are linked, R27 and R28 form a saturated or partially saturated ring, which is optionally substituted by one or more (C1-C4) alkyl, OH, or NH2 groups; or
(C3-C7) heterocycloalkyl ring, which may be optionally substituted by one or more groups selected from the group consisting of oxo, OH, SH, and hydroxy(C1-C6)alkylene;
—NH—(C1-C4)alkylene-OR29 wherein R29 is H or (C1-C6) alkyl;
—CH2OC(O)R30 wherein R30 is selected from a (C1-C10) alkyl which is substituted by one or more halogen, OH, (C3-C7) heterocycloalkyl optionally substituted by OH or (C1-C4) alkyl
—CH2OC(O)R30 wherein
R30 is:
(C3-C7) cycloalkyl,
(C3-C7) heterocycloalkyl where any such ring may be optionally substituted by (C1-C4) alkyl;
(C1-C10) alkyl which is substituted by one or more halogen, OH, (C3-C7) cycloalkyl, (C3-C7) heterocycloalkyl where any such ring may be optionally substituted by OH or (C1-C4) alkyl; or
R11R12N—(C1-C10)alkylene wherein R11 and R12 are independently H or (C1-C6) alkyl, each of which may optionally be substituted by a group OH
or an N-oxide on the pyridine ring, or a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

A compound, N-oxide, or pharmaceutically acceptable salt according to claim 1, which is an N-oxides on the pyridine ring, represented by formula (Ia):

### Claim 3 (depends on 1)

A compound, N-oxide, or pharmaceutically acceptable salt according to claim 1, which has the absolute configuration of carbon (1) shown in formula (I)′:

### Claim 4 (depends on 1)

A compound, N-oxide, or pharmaceutically acceptable salt according to claim 1, wherein
R1 and R2 are different or the same and are:
H;
linear or branched (C1-C6) alkyl, optionally substituted by one or more substituents selected from (C3-C7) cycloalkyl;
(C1-C6) haloalkyl;
R3 is one or more substituents selected from the group consisting of CF3 and a halogen atom;
Z is a group (CH2)m wherein m=0 or 1;
A is a phenyl ring, which is optionally substituted by one or more substituents R4, which may be the same or different and are independently:
linear or branched (C1-C6) alkyl optionally substituted by one or more (C3-C7) cycloalkyl or (C3-C7)heterocycloalkyl;
(C1-C6) haloalkyl;
(C1-C6) alkylthio;
halogen;
NH2; or
OR7 wherein R7 is:
H;
(C1-C10) alkyl optionally substituted by a radical selected from the group consisting of (C3-C7) cycloalkyl, (C3-C7) heterocycloalkyl, aryl and heteroaryl;
(C1-C10) alkyl substituted by one group OH;
(C1-C6) haloalkyl;
(C3-C7) cycloalkyl; or
R5R6N—(C1-C10)alkylene wherein R5 and R6 are independently H or linear or branched (C1-C6) alkyl, or, together with the nitrogen atom to which they are linked, R5 and R6 form a saturated, partially saturated or unsaturated ring, wherein these rings are optionally substituted by (C1-C4) alkyl, halogen atoms or R7R8N—(C1-C4)alkylene wherein R7 and R8 are different or the same and are independently H or linear or branched (C1-C6) alkyl, or, together with the nitrogen atom to which they are linked, R7 and R8 form a saturated or partially saturated ring;
W is:
—NR9SO2R10 wherein:
R9 is:
(C1-C10) alkyl optionally substituted by (C3-C7) heterocycloalkyl, (C3-C7) heterocycloalkylcarbonyl, wherein any such ring may be optionally substituted by one or more of (C1-C4) alkyl or OH; or
R11R12N—(C1-C10)alkylene wherein R11 and R12 are independently H or (C1-C6) alkyl, each of which may optionally be substituted by a group OH; and
R10 is:
(C1-C4) alkyl optionally substituted by (C3-C7) cycloalkyl;
(C3-C7)cycloalkyl; or
phenyl, any of which may be optionally substituted with one or more halogen atoms or (C1-C4) alkyl group;
—CH2NR13SO2R14 wherein
R13 is:
H; or
(C1-C10) alkyl optionally substituted by (C3-C7) cycloalkyl, (C3-C7) heterocycloalkyl, where any such ring may be optionally substituted by (C1-C4) alkyl;
R14 is:
(C1-C4) alkyl;
(C3-C7) heterocycloalkyl-(C1-C4)alkylene;
phenyl, any of which may be optionally substituted with one or more of halogen atom or (C1-C4) alkyl group;
—(C1-C4)alkylene-(C3-C7)heterocycloalkyl, which may be optionally substituted by one or more groups selected from the group consisting of oxo, OH, (C1-C4) alkyl, and hydroxy(C1-C6)alkylene;
—(C3-C7) heterocycloalkyl ring, which may be optionally substituted by one or more groups selected from the group consisting of oxo, OH, (C1-C4) alkyl, and hydroxy(C1-C6)alkylene;
—(C1-C4)alkylene-amino-(C3-C7)heterocycloalkyl, which may be optionally substituted by one or more groups selected from the group consisting of oxo, OH, (C1-C4) alkyl, and hydroxy(C1-C6)alkylene
—SO2NR15R16 wherein
R15 is H; and
R16 is:
(C1-C10) alkyl which is optionally substituted by (C3-C7) heterocycloalkyl, which may be optionally substituted by (C1-C4) alkyl; or
R11R12N—(C1-C10)alkylene wherein R11 and R12 are independently H, methyl, ethyl, hydroxymethyl, or hydroxyethyl; or
R15 and R16, together with the nitrogen atom to which they are linked, form a (C3-C7) heterocycloalkyl ring optionally substituted by one or more (C1-C4) alkyl;
—NHSO2R17 wherein
R17 is:
(C1-C10) alkyl which is optionally substituted by (C3-C7)cycloalkyl, (C3-C7) heterocycloalkyl, aryl, or heteroaryl ring, where any such ring may be optionally substituted by (C1-C4) alkyl; or
R11R12N—(C1-C10)alkylene wherein R11 and R12 are independently H or (C1-C6) alkyl, each of which may optionally be substituted by a group OH;
—OSO2R18 wherein
R18 is:
(C1-C10) alkyl which is optionally substituted by halogen, OH, or (C1-C4) alkoxyl; or
R11R12N—(C1-C10)alkylene wherein R11 and R12 are independently H or (C1-C6) alkyl, each of which may optionally be substituted by a group OH;
—OC(O)R19 wherein
R19 is (C1-C10) alkyl which is optionally substituted by one or more of halogen, OH, NH2, (C3-C7) cycloalkyl, or (C3-C7) heterocycloalkyl, where any such ring may be optionally substituted by (C1-C4) alkyl;
—C(O)R20 wherein
R20 is:
—NR21R22 wherein R21 and R22 are independently H, (C1-C6) alkyl, (C3-C7) cycloalkyl, orv (C3-C7)heterocycloalkyl(C1-C4)alkylene, each of which may optionally be substituted by (C1-C4) alkyl, OH, NH2, or, together with the nitrogen atom to which they are linked, R21 and R22 form a saturated or partially saturated heterocyclic ring which may be optionally substituted by (C1-C4) alkyl, OH or NH2; or
—OR23 wherein R23 is (C1-C10) alkyl which is substituted by one or more of halogen, OH, (C3-C7)cycloalkyl, (C3-C7)heterocycloalkyl, where any such ring may be optionally substituted by (C1-C4) alkyl;
—NH—(C1-C4)alkylene-NR24R25 wherein
R24 and R25 are the same or different and are independently H or (C1-C6) alkyl, or, together with the nitrogen atom to which they are linked, R24 and R25 form a saturated or partially saturated ring, which is optionally substituted by one ore more (C1-C4) alkyl groups;
—NHCOR26 wherein
R26 is:
R27R28N—(C1-C6)alkylene wherein R27 and R28 are the same or different and are independently H or (C1-C6) alkyl optionally substituted by OH or NH2, or, together with the nitrogen atom to which they are linked, R27 and R28 form a saturated or partially saturated ring, which is optionally substituted by one or more (C1-C4) alkyl, OH or NH2 groups;
R27R28N-carbonyl-(C1-C6)alkylene wherein R27 and R28 are the same or different and are independently H or (C1-C6) alkyl optionally substituted by OH or NH2, or, together with the nitrogen atom to which they are linked, R27 and R28 form a saturated or partially saturated ring, which is optionally substituted by one or more (C1-C4) alkyl, OH, or NH2 groups; or
(C3-C7) heterocycloalkyl ring, which may be optionally substituted by one or more groups selected from the group consisting of oxo, OH, SH, and hydroxy(C1-C6)alkylene;
—NH—(C1-C4)alkylene-OR29 wherein R29 is H or (C1-C6) alkyl; or
—CH2OC(O)R30 wherein R30 is selected from a (C1-C10) alkyl which is substituted by one or more of halogen, OH, (C3-C7) heterocycloalkyl optionally substituted by OH or (C1-C4) alkyl.

### Claim 5 (depends on 1)

A pharmaceutical composition, comprising a compound, N-oxide, or pharmaceutically acceptable salt according to claim 1, and one or more pharmaceutically acceptable carriers and/or excipients.

### Claim 6 (depends on 1)

A method for the prevention and/or treatment of an allergic disease state or a disease of the respiratory tract characterized by airway obstruction, comprising administering an effective amount of a compound, N-oxide, or pharmaceutically acceptable salt according to claim 1 to a subject in need thereof.

### Claim 7 (depends on 6)

A method according to claim 6, which is for the prevention and/or treatment of a disease of the respiratory tract characterized by airway obstruction.

### Claim 8 (depends on 7)

A method according to claim 7, wherein said disease of the respiratory tract characterized by airway obstruction is asthma or COPD.

### Claim 9 (depends on 6)

A method according to claim 6, which is for the prevention and/or treatment of an allergic disease state.

### Claim 10 (depends on 9)

A method according to claim 9, wherein said allergic disease state is atopic dermatitis, urticarial, or allergic rhinitis.

### Claim 11 (depends on 5)

A device, comprising a pharmaceutical composition according to claim 5.

### Claim 12 (depends on 5)

A kit, comprising a pharmaceutical composition according to claim 5 and a device which is a single- or multi-dose dry powder inhaler, a metered dose inhaler, or a soft mist nebulizer.