# US 2016/0355499 A1 · Trpv1 antagonists including dihydroxy substituent and uses thereof

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- Number: US 2016/0355499 A1
- Document ID: US20160355499A1
- Status: Published application
- Kind: A1
- Application number: 15/179,612
- Filed: 2016-06-10
- Published: 2016-12-08
- Earliest claimed: 2007-04-27
- Assignees: Purdue Pharma L.P.
- Applicants: Purdue Pharma L.P.
- Inventors: Laykea TAFESSE
- Web page: https://patentgrep.com/patent/US20160355499A1

## CPC

- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 13/00: Drugs for disorders of the urinary system
- A61P 13/10: of the bladder
- A61P 23/00: Anaesthetics
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/04: Centrally acting analgesics, e.g. opioids
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 213/61: Halogen atoms or nitro radicals
- C07D 213/72: Nitrogen atoms (nitro radicals C07D213/61)
- C07D 213/74: Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 401/14: containing three or more hetero rings
- C07D 405/14: containing three or more hetero rings
- C07D 407/14: containing three or more hetero rings
- C07D 417/12: linked by a chain containing hetero atoms as chain links
- C07D 417/14: containing three or more hetero rings
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The invention relates to compounds of formula IA and pharmaceutically acceptable derivatives thereof, compositions comprising an effective amount of a compound of formula IA or a pharmaceutically acceptable derivative thereof, and methods for treating or preventing a condition such as pain, UI, an ulcer, IBD and IBS, comprising administering to an animal in need thereof an effective amount of a compound of formula IA or a pharmaceutically acceptable derivative thereof.

## Claims

### Claim 1

A compound of formula IA:
or a pharmaceutically acceptable salt, solvate, stereoisomer, geometric isomer or tautomer thereof, wherein
X is O, S, N—CN, N—OH, or N—OR10;
W is N or C;
the dashed line denotes the presence or absence of a bond, and when the dashed line denotes the presence of a bond or W is N then R4 is absent, otherwise R4 is —H, —OH, —OCF3, -halo, —(C1-C6)alkyl, —CH2OH, —CH2Cl, —CH2Br, —CH2I, —CH2F, —CH(halo)2, —CF3, —OR10, —SR10, —COOH, —COOR10, —C(O)R10, —C(O)H, —OC(O)R10, —OC(O)NHR10, —NHC(O)R13, —CON(R13)2, —S(O)2R10, or —NO2;
R10 is —(C1-C4)alkyl;
each R13 is independently —H, —(C1-C4)alkyl, —(C1-C4)alkenyl, —(C1-C4)alkynyl, or -phenyl;
Ar1 is
Ar2 is
c is the integer 0, 1, or 2;
Y1, Y2, and Y3 are independently C, N, or O;
wherein no more than one of Y1, Y2, or Y3 can be O, and for each Y1, Y2, and Y3 that is N, the N is bonded to one R21 group, and for each Y1, Y2, and Y3 that is C, the C is bonded to two R20 groups, provided that there are no more than a total of two (C1-C6)alkyl groups substituted on all of Y1, Y2, and Y3;
R12a and R12b are independently —H or —(C1-C6)alkyl;
E is ═O, ═S, ═CH(C1-C5)alkyl, ═CH(C1-C5)alkenyl, —NH(C1-C6)alkyl, or ═N—OR20;
R1 is —H, -halo, —(C1-C4)alkyl, —NO2, —CN, —OH, —OCH3, —NH2, —C(halo)3, —CH(halo)2, —CH2(halo), —OC(halo)3, —OCH(halo)2, or —OCH2(halo);
each R2 is independently:
(a) -halo, —OH, —O(C1-C4)alkyl, —CN, —NO2, —NH2, —(C1-C10)alkyl, —(C2-C10)alkenyl, —(C2-C10)alkynyl, or -phenyl, or
(b) a group of formula Q;
wherein Q is
Z1 is —H, —OR7, —SR7, —CH2—OR7, —CH2—SR7, —CH2—N(R20)2, or -halo;
Z2 is —H, —(C1-C6)alkyl, —(C2-C6)alkenyl, —(C2-C6)alkynyl, —CH2—OR7, -phenyl, or -halo;
each Z3 is independently —H, —(C1-C6)alkyl, —(C2-C6)alkenyl, —(C2-C6)alkynyl, or -phenyl;
Z4 is —H, —OH, —OR20, —(C1-C6)alkyl, or —N(R20)2;
J is —OR20, —SR20, —N(R20)2, or —CN;
provided that at least one R2 group is a group of formula Q, and provided that when Z1 is —OR7 or —SR7, then Z2 is not -halo;
each R3 is independently:
(a) —H, —(C1-C6)alkyl, or —CH2OR7; or
(b) two R3 groups together form a (C2-C6)bridge, which is unsubstituted or substituted with 1, 2 or 3 independently selected R8 groups, and which bridge optionally contains —HC═CH— within the (C2-C6)bridge; or
(c) two R3 groups together form a —CH2—N(Ra)—CH2— bridge, a
bridge, or a
bridge;
Ra is —H, —(C1-C6)alkyl, —(C3-C8)cycloalkyl, —CH2—C(O)—Rc, —(CH2)—C(O)—ORc, —(CH2)—C(O)—N(Rc)2, —(CH2)2—O—Rc, —(CH2)2—S(O)2—N(Rc)2, or —(CH2)2—N(Rc)S(O)2—Rc;
Rb is:
(a) —H, —(C1-C6)alkyl, —(C3-C8)cycloalkyl, -(3- to 7-membered)heterocycle, —N(Rc)2, —N(Rc)—(C3-C8)cycloalkyl, or —N(Rc)-(3- to 7-membered)heterocycle; or
(b) -phenyl, -(5- or 6-membered)heteroaryl, —N(Rc)-phenyl, or —N(Rc)-(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with 1, 2 or 3 independently selected R7 groups;
each Rc is independently —H or —(C1-C4)alkyl;
each R7 is independently —H, —(C1-C6)alkyl, —(C2-C6)alkenyl, —(C2-C6)alkynyl, —(C3-C8)cycloalkyl, —(C5-C8)cycloalkenyl, -phenyl, —(C1-C6)haloalkyl, —(C1-C6)hydroxyalkyl, —(C1-C6)alkoxy(C1-C6)alkyl, —(C1-C6)alkyl-N(R20)2, or —CON(R20)2;
each R8 and R9 is independently:
(a) —(C1-C6)alkyl, —(C2-C6)alkenyl, —(C2-C6)alkynyl, —(C3-C8)cycloalkyl, —(C5-C8)cycloalkenyl, or -phenyl, each of which is unsubstituted or substituted with 1 or 2 —OH groups; or
(b) —H, —CH2C(halo)3, —C(halo)3, —CH(halo)2, —CH2(halo), —OC(halo)3, —OCH(halo)2, —OCH2(halo), —SC(halo)3, —SCH(halo)2, —SCH2(halo), —CN, —O—CN, —OH, -halo, —N3, —NO2, —CH═NR7, —N(R7)2, —NR7OH, —OR7, —C(O)R7, —C(O)OR7, —OC(O)R7, —OC(O)OR7, —SR7, —S(O)R7, or —S(O)2R7;
each R11 is independently —CN, —OH, —(C1-C6)alkyl, —(C2-C6)alkenyl, -halo, —N3, —NO2, —N(R7)2, —CH═NR7, —NR7OH, —OR7, —C(O)R7, —C(O)OR7, —OC(O)R7, or —OC(O)OR7;
each R14 is independently —H, —(C1-C6)alkyl, —(C2-C6)alkenyl, —(C2-C6)alkynyl, —(C3-C8)cycloalkyl, —(C5-C8)cycloalkenyl, —(C1-C6)alkoxy-(C1-C6)alkyl, -phenyl, —C(halo)3, —CH(halo)2, —CH2(halo), -(3- to 7-membered)heterocycle, —(C1-C6)haloalkyl, —(C2-C6)haloalkenyl, —(C2-C6)haloalkynyl, —(C2-C6)hydroxyalkenyl, —(C2-C6)hydroxyalkynyl, —(C1-C6)alkoxy(C2-C6)alkyl, —(C1-C6)alkoxy(C2-C6)alkenyl, —(C1-C6)alkoxy(C2-C6)alkynyl, —(C1-C6)alkoxy(C3-C8)cycloalkyl, —CN, —OH, -halo, —OC(halo)3, —N3, —NO2, —CH═NR7, —N(R7)2, —NR7OH, —OR7, —SR7, —O(CH2)bOR7, —O(CH2)bSR7, —O(CH2)bN(R7)2, —N(R7)(CH2)bOR7, —N(R7)(CH2)bSR7, —N(R7)(CH2)bN(R7)2, —N(R7)COR7, —C(O)R7, —C(O)OR7, —OC(O)R7, —OC(O)OR7, —S(O)R7, —S(O)2R7, —S(O)2N(R7)2, —SO2C(halo)3, —SO2(3- to 7-membered)heterocycle, —CON(R7)2, —(C1-C5)alkyl-C═NOR7, —(C1-C5)alkyl-C(O)—N(R7)2, —(C1-C6)alkyl-NHSO2N(R7)2, or —(C1-C6)alkyl-C(═NH)—N(R7)2;
each R20 is independently —H, —(C1-C6)alkyl, or —(C3-C8)cycloalkyl;
each R21 is independently —H, —(C1-C6)alkyl,
each halo is independently —F, —Cl, —Br, or —I;
n is the integer 1, 2, or 3;
p is the integer 1 or 2;
each b is independently 1 or 2;
q is the integer 0, 1, 2, 3, or 4;
r is the integer 0, 1, 2, 3, 4, 5, or 6;
s is the integer 0, 1, 2, 3, 4, or 5;
t is the integer 0, 1, 2, or 3; and
m is the integer 0, 1, or 2.

### Claim 2 (depends on 1)

The compound of claim 1 or a pharmaceutically acceptable salt, solvate, stereoisomer, geometric isomer or tautomer thereof, wherein X is O.

### Claim 3

A compound of formula II:
or a pharmaceutically acceptable salt, solvate, stereoisomer, geometric isomer or tautomer thereof, wherein
X is O, S, N—CN, N—OH, or N—OR10;
W is N or C;
the dashed line denotes the presence or absence of a bond, and when the dashed line denotes the presence of a bond or W is N then R4 is absent, otherwise R4 is —H, —OH, —OCF3, -halo, —(C1-C6)alkyl, —CH2OH, —CH2Cl, —CH2Br, —CH2I, —CH2F, —CH(halo)2, —CF3, —OR10, —SR10, —COOH, —COOR10, —C(O)R10, —C(O)H, —OC(O)R10, —OC(O)NHR10, —NHC(O)R13, —CON(R13)2, —S(O)2R10, or —NO2;
R10 is —(C1-C4)alkyl;
each R13 is independently —H, —(C1-C4)alkyl, —(C1-C4)alkenyl, —(C1-C4)alkynyl, or -phenyl;
Ar1 is
Ar2 is
c is the integer 0, 1, or 2;
Y1, Y2, and Y3 are independently C or N;
wherein for each Y1, Y2, and Y3 that is N, the N is bonded to one R20 group, and for each Y1, Y2, and Y3 that is C, the C is bonded to two R20 groups, provided that there are no more than a total of two (C1-C6)alkyl groups substituted on all of Y1, Y2, and Y3;
R12a and R12b are independently —H or —(C1-C6)alkyl;
E is ═O, ═S, ═CH(C1-C5)alkyl, ═CH(C1-C5)alkenyl, —NH(C1-C6)alkyl, or ═N—OR20;
R1 is —H, -halo, —(C1-C4)alkyl, —NO2, —CN, —OH, —OCH3, —NH2, —C(halo)3, —CH(halo)2, —CH2(halo), —OC(halo)3, —OCH(halo)2, or —OCH2(halo);
each R2 is independently:
(a) -halo, —OH, —O(C1-C4)alkyl, —CN, —NO2, —NH2, —(C1-C10)alkyl, —(C2-C10)alkenyl, —(C2-C10)alkynyl, or -phenyl, or
(b) a group of formula Q;
wherein Q is
Z1 is —OH, —SH, —N(R20)2, —CH2—OH, —CH2—SH, or —CH2—N(R20)2;
Z2 is —H, —CH3, or —CH2OR7 and
each Z3 is independently —H or —CH3;
J is —OH, —SH, or —N(R20)2;
provided that at least one R2 group is a group of formula Q;
each R3 is independently:
(a) —H or —(C1-C6)alkyl; or
(b) two R3 groups together form a (C2-C6)bridge, which is unsubstituted or substituted with 1, 2 or 3 independently selected R8 groups, and which bridge optionally contains —HC═CH— within the (C2-C6)bridge; or
(c) two R3 groups together form a —CH2—N(Ra)—CH2— bridge, a
bridge, or a
bridge;
Ra is —H, —(C1-C6)alkyl, —(C3-C8)cycloalkyl, —CH2—C(O)—Rc, —(CH2)—C(O)—ORc, —(CH2)—C(O)—N(Rc)2, —(CH2)2—O—Rc, —(CH2)2—S(O)2—N(Rc)2, or —(CH2)2—N(R)S(O)2—Rc;
Rb is:
(a) —H, —(C1-C6)alkyl, —(C3-C8)cycloalkyl, -(3- to 7-membered)heterocycle, —N(Rc)2, —N(Rc)—(C3-C8)cycloalkyl, or —N(Rc)-(3- to 7-membered)heterocycle; or
(b) -phenyl, -(5- or 6-membered)heteroaryl, —N(Rc)-phenyl, or —N(Rc)-(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with 1, 2 or 3 independently selected R7 groups;
each Rc is independently —H or —(C1-C4)alkyl;
each R7 is independently —H, —(C1-C6)alkyl, —(C2-C6)alkenyl, —(C2-C6)alkynyl, —(C3-C8)cycloalkyl, —(C5-C8)cycloalkenyl, -phenyl, —(C1-C6)haloalkyl, —(C1-C6)hydroxyalkyl, —(C1-C6)alkoxy(C1-C6)alkyl, —(C1-C6)alkyl-N(R20)2, or —CON(R20)2;
each R8 and R9 is independently:
(a) —(C1-C6)alkyl, —(C2-C6)alkenyl, —(C2-C6)alkynyl, —(C3-C8)cycloalkyl, —(C5-C8)cycloalkenyl, or -phenyl, each of which is unsubstituted or substituted with 1 or 2 —OH groups; or
(b) —H, —CH2C(halo)3, —C(halo)3, —CH(halo)2, —CH2(halo), —OC(halo)3, —OCH(halo)2, —OCH2(halo), —SC(halo)3, —SCH(halo)2, —SCH2(halo), —CN, —O—CN, —OH, -halo, —N3, —NO2, —CH═NR7, —N(R7)2, —NR7OH, —OR7, —C(O)R7, —C(O)OR7, —OC(O)R7, —OC(O)OR7, —SR7, —S(O)R7, or —S(O)2R7;
each R11 is independently —CN, —OH, —(C1-C6)alkyl, —(C2-C6)alkenyl, -halo, —N3, —NO2, —N(R7)2, —CH═NR7, —NR7OH, —OR7, —C(O)R7, —C(O)OR7, —OC(O)R7, or —OC(O)OR7;
each R14 is independently —H, —(C1-C6)alkyl, —(C2-C6)alkenyl, —(C2-C6)alkynyl, —(C3-C8)cycloalkyl, —(C5-C8)cycloalkenyl, —(C1-C6)alkoxy-(C1-C6)alkyl, -phenyl, —C(halo)3, —CH(halo)2, —CH2(halo), -(3- to 7-membered)heterocycle, —(C1-C6)haloalkyl, —(C2-C6)haloalkenyl, —(C2-C6)haloalkynyl, —(C2-C6)hydroxyalkenyl, —(C2-C6)hydroxyalkynyl, —(C1-C6)alkoxy(C2-C6)alkyl, —(C1-C6)alkoxy(C2-C6)alkenyl, —(C1-C6)alkoxy(C2-C6)alkynyl, —(C1-C6)alkoxy(C3-C8)cycloalkyl, —CN, —OH, -halo, —OC(halo)3, —N3, —NO2, —CH═NR7, —N(R7)2, —NR7H, —OR7, —SR7, —O(CH2)bOR7, —O(CH2)bSR7, —O(CH2)bN(R7)2, —N(R7)(CH2)bOR7, —N(R7)(CH2)bSR7, —N(R7)(CH2)bN(R7)2, —N(R7)COR7, —C(O)R7, —C(O)OR7, —OC(O)R7, —OC(O)OR7, —S(O)R7, —S(O)2R7, —S(O)2N(R7)2, —SO2C(halo)3, —SO2(3- to 7-membered)heterocycle, —CON(R7)2, —(C1-C5)alkyl-C═NOR7, —(C1-C5)alkyl-C(O)—N(R7)2, —(C1-C6)alkyl-NHSO2N(R7)2, or —(C1-C6)alkyl-C(═NH)—N(R7)2;
each R20 is independently —H, —(C1-C6)alkyl, or —(C3-C8)cycloalkyl;
each halo is independently —F, —Cl, —Br, or —I;
n is the integer 1, 2, or 3;
p is the integer 1 or 2;
each b is independently 1 or 2;
q is the integer 0, 1, 2, 3, or 4;
r is the integer 0, 1, 2, 3, 4, 5, or 6;
s is the integer 0, 1, 2, 3, 4, or 5;
t is the integer 0, 1, 2, or 3; and
m is the integer 0, 1, or 2.

### Claim 4 (depends on 3)

The compound of claim 3 or a pharmaceutically acceptable salt, solvate, stereoisomer, geometric isomer or tautomer thereof, wherein X is O.

### Claim 5

A compound of formula III:
or a pharmaceutically acceptable salt thereof, wherein
X is O, S, N—CN, N—OH, or N—OR10;
W is N or C;
the dashed line denotes the presence or absence of a bond, and when the dashed line denotes the presence of a bond or W is N then R4 is absent, otherwise R4 is —H, —OH, —OCF3, -halo, —(C1-C6)alkyl, —CH2OH, —CH2Cl, —CH2Br, —CH2I, —CH2F, —CH(halo)2, —CF3, —OR10, —SR10, —COOH, —COOR10, —C(O)R10, —C(O)H, —OC(O)R10, —OC(O)NHR10, —NHC(O)R13, —CON(R13)2, —S(O)2R10, or —NO2;
each R3 is independently:
(a) —H or —(C1-C6)alkyl; or
(b) two R3 groups together form a (C2-C6)bridge, which is unsubstituted or substituted with 1, 2 or 3 independently selected R8 groups, and which bridge optionally contains —HC═CH— within the (C2-C6)bridge; or
(c) two R3 groups together form a —CH2—N(Ra)—CH2— bridge, a
bridge, or a
bridge;
Ra is —H, —(C1-C6)alkyl, —(C3-C8)cycloalkyl, —CH2—C(O)—Rc, —(CH2)—C(O)—ORc, —(CH2)—C(O)—N(Rc)2, —(CH2)2—O—Rc, —(CH2)2—S(O)2—N(Rc)2, or —(CH2)2—N(R)S(O)2—R;
Rb is:
(a) —H, —(C1-C6)alkyl, —(C3-C8)cycloalkyl, -(3- to 7-membered)heterocycle, —N(Rc)2, —N(Rc)—(C3-C8)cycloalkyl, or —N(Rc)-(3- to 7-membered)heterocycle; or
(b) -phenyl, -(5- or 6-membered)heteroaryl, —N(Rc)-phenyl, or —N(R)-(5- to 10-membered) heteroaryl, each of which is unsubstituted or substituted with 1, 2 or 3 independently selected R7 groups;
each Rc is independently —H or —(C1-C4)alkyl;
m is the integer 0, 1, or 2;
wherein Ar1 is:
R1 is —Cl, —F, —CF3, or —CH3;
wherein Ar2 is:
R14 is —H, —Cl, —F, —Br, —CF3, —OCF3, —(C1-C6)alkyl, —SO2CF3, —SO2(C1-C6)alkyl, —OCH3, —OCH2CH3, or —OCH(CH3)2;
R14′ is —H, —Cl, —F, —Br, —CF3, —OCF3, —(C1-C6)alkyl, —SO2CF3, —SO2(C1-C6)alkyl, —OCH3, —OCH2CH3, or —OCH(CH3)2; and
R8 and R9 are independently —H, —Cl, —Br, —F, —CH3, —OCH3, —OCH2CH3, —CF3, —OCF3, iso-propyl, or tert-butyl.

### Claim 6 (depends on 5)

The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein X is O.

### Claim 7 (depends on 5)

The compounds of claim 5 or a pharmaceutically acceptable salt thereof, wherein R4 is -halo.

### Claim 8 (depends on 5)

The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein R1 is —Cl, —F, or —CF3.

### Claim 9 (depends on 5)

The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein W is C and the dashed line is absent.

### Claim 10 (depends on 1)

The compound of claim 1, wherein the pharmaceutically acceptable salt, solvate, stereoisomer, geometric isomer or tautomer is a pharmaceutically acceptable salt.

### Claim 11 (depends on 3)

The compound of claim 3, wherein the pharmaceutically acceptable salt, solvate, stereoisomer, geometric isomer or tautomer is a pharmaceutically acceptable salt.

### Claim 12 (depends on 1)

A composition comprising the compound of claim 1 or a pharmaceutically acceptable salt, solvate, stereoisomer, geometric isomer or tautomer thereof and a pharmaceutically acceptable carrier or excipient.

### Claim 13 (depends on 3)

A composition comprising the compound of claim 3 or a pharmaceutically acceptable salt, solvate, stereoisomer, geometric isomer or tautomer thereof and a pharmaceutically acceptable carrier or excipient.

### Claim 14 (depends on 5)

A composition comprising the compound of claim 5 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.

### Claim 15 (depends on 1)

A method for treating or preventing pain, UI, an ulcer, IBD, or IBS in an animal, comprising administering to an animal in need thereof, an effective amount of the compound of claim 1 or a pharmaceutically acceptable salt, solvate, stereoisomer, geometric isomer or tautomer thereof.

### Claim 16 (depends on 3)

A method for treating or preventing pain, UI, an ulcer, IBD, or IBS in an animal, comprising administering to an animal in need thereof, an effective amount of the compound of claim 3 or a pharmaceutically acceptable salt, solvate, stereoisomer, geometric isomer or tautomer thereof.

### Claim 17 (depends on 5)

A method for treating or preventing pain, UI, an ulcer, IBD, or IBS in an animal, comprising administering to an animal in need thereof, an effective amount of the compound of claim 5 or a pharmaceutically acceptable salt thereof.

### Claim 18 (depends on 1)

A method of inhibiting TRPV1 function in a cell comprising contacting a cell capable of expressing TRPV1 with an effective amount of the compound of claim 1 or a pharmaceutically acceptable salt, solvate, stereoisomer, geometric isomer or tautomer thereof.

### Claim 19 (depends on 3)

A method of inhibiting TRPV1 function in a cell comprising contacting a cell capable of expressing TRPV1 with an effective amount of the compound of claim 3 or a pharmaceutically acceptable salt, solvate, stereoisomer, geometric isomer or tautomer thereof.

### Claim 20 (depends on 5)

A method of inhibiting TRPV1 function in a cell comprising contacting a cell capable of expressing TRPV1 with an effective amount of the compound of claim 5 or a pharmaceutically acceptable salt thereof.