# US 9,434,721 B2 · Therapeutic agents useful for treating pain

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- Number: US 9,434,721 B2
- Document ID: US9434721B2
- Status: Granted
- Kind: B2
- Application number: 14/099,738
- Filed: 2013-12-06
- Published: 2014-05-22
- Granted: 2016-09-06
- Earliest claimed: 2002-12-24
- Assignees: Purdue Pharma L.P.
- Applicants: Purdue Pharma L.P.
- Inventors: Qun Sun; Laykea Tafesse; Sam Victory
- Web page: https://patentgrep.com/patent/US9434721B2

## CPC

- C07D 417/12: linked by a chain containing hetero atoms as chain links
- A61K 31/495: having six-membered rings with two {or more} nitrogen atoms as the only ring heteroatoms, e.g. piperazine {or tetrazines}(A61K31/48 takes precedence {; with three nitrogen atoms A61K31/53})
- 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 1/08: for nausea, cinetosis or vertigo; Antiemetics
- A61P 7/12: Antidiuretics, e.g. drugs for diabetes insipidus (ADH A61P5/10)
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 13/00: Drugs for disorders of the urinary system
- A61P 13/02: of urine or of the urinary tract, e.g. urine acidifiers
- A61P 17/04: Antipruritics
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- A61P 21/02: Muscle relaxants, e.g. for tetanus or cramps
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/02: for peripheral neuropathies
- A61P 25/04: Centrally acting analgesics, e.g. opioids
- A61P 25/06: Antimigraine agents
- A61P 25/08: Antiepileptics; Anticonvulsants
- A61P 25/14: for treating abnormal movements, e.g. chorea, dyskinesia
- A61P 25/16: Anti-Parkinson drugs
- A61P 25/18: Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
- A61P 25/22: Anxiolytics
- A61P 25/24: Antidepressants
- 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
- A61P 25/30: for treating abuse or dependence
- A61P 27/02: Ophthalmic agents
- 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 401/12: linked by a chain containing hetero atoms as chain links
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D 413/12: linked by a chain containing hetero atoms as chain links
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

A compound of formula: wherein Ar1, A, R3, x, and m are as disclosed herein and Ar2 is a benzothiazolyl, benzooxazolyl, or benzoimidazolyl group or a pharmaceutically acceptable salt thereof (a “Benzoazolylpiperazine Compound”), compositions comprising a Benzoazolylpiperazine Compound, and methods for treating or preventing pain, UI, an ulcer, IBD, IBS, an addictive disorder, Parkinson's disease, parkinsonism, anxiety, epilepsy, stroke, a seizure, a pruritic condition, psychosis, a cognitive disorder, a memory deficit, restricted brain function, Huntington's chorea, amyotrophic lateral sclerosis, dementia, retinopathy, a muscle spasm, a migraine, vomiting, dyskinesia, or depression in an animal comprising administering to an animal in need thereof an effective amount of a Benzoazolylpiperazine Compound are disclosed.

## Claims

### Claim 1

A method for treating pain in an animal, comprising administering to an animal in need thereof an effective amount of a compound of formula:
or a pharmaceutically acceptable salt thereof, wherein:
Ar1 is:
A is:
R1 is —Cl, Br, —I, —(C1-C6)alkyl, —NO2, —CN, —OH, —OCH3, —NH2, —C(halo)3, —CH(halo)2, or —CH2(halo);
each R2 is independently:
(a) -halo, —CN, —OH, —O(C1-C6)alkyl, —NO2, or —NH2; or
(b) —(C1-C10)alkyl, —(C2-C10)alkenyl, —(C2-C10)alkynyl, —(C3-C10)cycloalkyl, —(C8-C14)bicycloalkyl, —(C8-C14)tricycloalkyl, —(C5-C10)cycloalkenyl, —(C8-C14)bicycloalkenyl, —(C8-C14)tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups; or
(c) -phenyl, -naphthyl, —(C14)aryl, or -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R6 groups;
each R3 is independently:
(a) -halo, —CN, —OH, —O(C1-C6)alkyl, —NO2, or —NH2; or
(b) —(C1-C10)alkyl, —(C2-C10)alkenyl, —(C2-C10)alkynyl, —(C3-C10)cycloalkyl, —(C8-C14)bicycloalkyl, —(C8-C14)tricycloalkyl, —(C5-C10)cycloalkenyl, —(C8-C14)bicycloalkenyl, —(C8-C14)tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups; or
(c) -phenyl, -naphthyl, —(C14)aryl, or -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R6 groups;
R4 is —H or —(C1-C6)alkyl;
each R5 is independently —CN, —OH, -halo, —N3, —NO2, —N(R7)2, —CH═NR7, —NR7OH, —OR7, —C(O)R7, —C(O)OR7, —OC(O)R7, —OC(O)OR7, —SR7, —S(O)R7, or —S(O)2R7;
each R6 is independently —(C1-C6)alkyl, —(C2-C6)alkenyl, —(C2-C6)alkynyl, —(C3-C8)cycloalkyl, —(C5-C8)cycloalkenyl, -phenyl, —(C3-C5)heterocycle, —C(halo)3, —CH(halo)2, —CH2(halo), —CN, —OH, -halo, —N3, —NO2, —N(R7)2, —CH═NR7, —NR7OH, —OR7, —C(O)R7, —C(O)OR7, —OC(O)R7, —OC(O)OR7, —SR7, —S(O)R7, or —S(O)2R7;
each R7 is independently —H, —(C1-C6)alkyl, —(C2-C6)alkenyl, —(C2-C6)alkynyl, —(C3-C8)cycloalkyl, —(C5-C8)cycloalkenyl, -phenyl, —(C3-C5)heterocycle, —C(halo)3, —CH2(halo), or —CH(halo)2;
R8 and R9 are each independently —H, —(C1-C6)alkyl, —(C2-C6)alkenyl, —(C2-C6)alkynyl, —(C3-C8)cycloalkyl, —(C5-C8)cycloalkenyl, -phenyl, —C(halo)3, —CH(halo)2, —CH2(halo), —CN, —OH, -halo, —N3, —N(R7)2, —CH═NR7, —NR7OH, —OR7, —C(O)RD, —C(O)OR7, —OC(O)R7, —OC(O)OR7, —SR7, —S(O)R7, or —S(O)2R7;
each -halo is —F, —Cl, —Br, or —I;
n is an integer ranging from 0 to 3;
m is 0 or 1; and
x is 1.

### Claim 2 (depends on 1)

The method of claim 1, wherein A is —C(O)N(R4)—.

### Claim 3 (depends on 1)

The method of claim 1, wherein A is —C(S)N(R4)—.

### Claim 4 (depends on 2)

The method of claim 2, wherein n is 0 or 1.

### Claim 5 (depends on 4)

The method of claim 4, wherein n is 1 and R2 is —(C1-C10)alkyl, —(C2-C10)alkenyl, —(C2-C10)alkynyl, —(C3-C10)cycloalkyl, —(C8-C14)bicycloalkyl, —(C8-C14)tricycloalkyl, —(C5-C10)cycloalkenyl, —(C8-C14)bicycloalkenyl, —(C8-C14)tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups.

### Claim 6 (depends on 5)

The method of claim 5, wherein R2 is —(C1-C10)alkyl substituted with two R5 groups.

### Claim 7 (depends on 1)

The method of claim 1, wherein R3 is attached to a carbon atom adjacent to a nitrogen atom attached to the -(A)x- group.

### Claim 8 (depends on 7)

The method of claim 7, wherein R3 is —CH3.

### Claim 9 (depends on 1)

The method of claim 1, wherein:
R1 is —CH3, —CF3, —Cl, —Br, or —I;
m is 0;
n is 0;
A is —C(O)N(R4)—;
R4 is —H;
R8 is —H; and
R9 is —CH3, —CF3, —OCH2CH3, tert-butyl, —Cl, —Br, or —F.

### Claim 10 (depends on 9)

The method of claim 9, wherein R1 is —CH3 or —Cl and R9 is —Cl, —Br, or —F.

### Claim 11 (depends on 1)

The method of claim 1, wherein:
R1 is —CH3, —CF3, —Cl, —Br, or —I;
m is 1;
R3 is —(C1-C10)alkyl;
n is 0;
A is —C(O)N(R4)—;
R4 is —H;
R8 is —H; and
R9 is —CH3, —CF3, —OCH2CH3, tert-butyl, —Cl, —Br, or —F.

### Claim 12 (depends on 11)

The method of claim 11, wherein R3 is —CH3.

### Claim 13 (depends on 12)

The method of claim 12, wherein R1 is —CH3 or —Cl and R9 is —Cl, —Br, or —F.

### Claim 14 (depends on 1)

The method of claim 1, wherein:
R1 is —CH3, —CF3, —Cl, —Br, or —I;
m is 0;
n is 0;
A is —C(O)N(R4)—;
R4 is —H;
R8 is —CH3, —CF3, —OCH2CH3, tert-butyl, —Cl, —Br, or —F; and
R9 is —H.

### Claim 15 (depends on 14)

The method of claim 14, wherein R1 is —CH3 or —Cl and R8 is —Cl, —Br, or —F.

### Claim 16 (depends on 1)

The method of claim 1, wherein:
R1 is —CH3, —CF3, —Cl, —Br, or —I;
m is 1;
R3 is —(C1-C10)alkyl;
n is 0;
A is —C(O)N(R4)—;
R4 is —H;
R8 is —CH3, —CF3, —OCH2CH3, tert-butyl, —Cl, —Br, or —F; and
R9 is —H.

### Claim 17 (depends on 16)

The method of claim 16, wherein R3 is —CH3.

### Claim 18 (depends on 17)

The method of claim 17, wherein R1 is —CH3 or —Cl and R8 is —Cl, —Br, or —F.

### Claim 19

A method for treating pain in an animal, comprising administering to an animal in need thereof an effective amount of a compound of formula:
or a pharmaceutically acceptable salt thereof, wherein:
Ar1 is:
A is:
R1 is —H, -halo, —(C1-C6)alkyl, —NO2, —CN, —OH, —OCH3, —NH2, —C(halo)3, —CH(halo)2, or —CH2(halo);
each R2, when present, is independently:
(a) -halo, —CN, —OH, —O(C1-C6)alkyl, —NO2, or —NH2; or
(b) —(C1-C10)alkyl, —(C2-C10)alkenyl, —(C2-C10)alkynyl, —(C3-C10)cycloalkyl, —(C8-C14)bicycloalkyl, —(C8-C14)tricycloalkyl, —(C5-C10)cycloalkenyl, —(C8-C14)bicycloalkenyl, C14)tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups; or
(c) -phenyl, -naphthyl, —(C14)aryl, or -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R6 groups;
each R3 is independently:
(a) -halo, —CN, —OH, —O(C1-C6)alkyl, —NO2, or —NH2; or
(b) —(C1-C10)alkyl, —(C2-C10)alkenyl, —(C2-C10)alkynyl, —(C3-C10)cycloalkyl, —(C8-C14)bicycloalkyl, —(C8-C14)tricycloalkyl, —(C5-C10)cycloalkenyl, —(C8-C14)bicycloalkenyl, —(C8-C14)tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups; or
(c) -phenyl, -naphthyl, —(C14)aryl, or -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R6 groups;
R4 is —H or —(C1-C6)alkyl;
each R5 is independently —CN, —OH, -halo, —N3, —NO2, —N(R7)2, —CH═NR7, —NR7OH, —OR7, —C(O)R7, —C(O)OR7, —OC(O)R7, —OC(O)OR7, —SR7, —S(O)R7, or —S(O)2R7;
each R6 is independently —(C1-C6)alkyl, —(C2-C6)alkenyl, —(C2-C6)alkynyl, —(C3-C8)cycloalkyl, —(C5-C8)cycloalkenyl, -phenyl, —(C3-C5)heterocycle, —C(halo)3, —CH(halo)2, —CH2(halo), —CN, —OH, -halo, —N3, —NO2, —N(R7)2, —CH═NR7, —NR7OH, —OR7, —C(O)R7, —C(O)OR7, —OC(O)R7, —OC(O)OR7, —SR7, —S(O)R7, or —S(O)2R7;
each R7 is independently —H, —(C1-C6)alkyl, —(C2-C6)alkenyl, —(C2-C6)alkynyl, —(C3-C8)cycloalkyl, —(C5-C8)cycloalkenyl, -phenyl, —(C3-C5)heterocycle, —C(halo)3, —CH2(halo), or —CH(halo)2;
R8 and R9 are each independently —H, —(C1-C6)alkyl, —(C2-C6)alkenyl, —(C2-C6)alkynyl, —(C3-C8)cycloalkyl, —(C5-C8)cycloalkenyl, -phenyl, —C(halo)3, —CH(halo)2, —CH2(halo), —CN, —OH, -halo, —N3, —N(R7)2, —CH═NR7, —NR7OH, —OR7, —C(O)R7, —C(O)OR7, —OC(O)R7, —OC(O)OR7, —SR7, —S(O)R7, or —S(O)2R7;
R10 is —H or —(C1-C4)alkyl;
each -halo is —F, —Cl, —Br, or —I;
p, when present, is an integer ranging from 0 to 2;
m is 0 or 1; and
x is 1;
provided that for a compound of formula (IIb) Ar1 is not

### Claim 20 (depends on 19)

The method of claim 19, wherein p is 0 or 1.

### Claim 21 (depends on 20)

The method of claim 20, wherein p is 1 and R2 is —(C1-C10)alkyl, —(C2-C10)alkenyl, —(C2-C10)alkynyl, —(C3-C10)cycloalkyl, —(C8-C14)bicycloalkyl, —(C8-C14)tricycloalkyl, —(C5-C10)cycloalkenyl, —(C8-C14)bicycloalkenyl, —(C8-C14)tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups.

### Claim 22 (depends on 21)

The method of claim 21, wherein R2 is —(C1-C10)alkyl substituted with two R5 groups.

### Claim 23 (depends on 19)

The method of claim 19, wherein R3 is attached to a carbon atom adjacent to a nitrogen atom attached to the -(A)x- group.

### Claim 24 (depends on 23)

The method of claim 23, wherein R3 is —CH3.

### Claim 25 (depends on 24)

The method of claim 24, wherein R10 is —H or —CH3.

### Claim 26 (depends on 19)

The method of claim 19, wherein:
R1 is —CH3, —CF3, —Cl, —Br, or —I;
m is 0;
p is 0;
R4 is —H;
R8 is —H; and
R9 is —CH3, —CF3, —OCH2CH3, tert-butyl, —Cl, —Br, or —F.

### Claim 27 (depends on 26)

The method of claim 26, wherein R1 is —CH3 or —Cl and R9 is —Cl, —Br, or —F.

### Claim 28 (depends on 19)

The method of claim 19, wherein:
R1 is —CH3, —CF3, —Cl, —Br, or —I;
m is 1;
R3 is —(C1-C10)alkyl;
p is 0;
R4 is —H;
R8 is —H; and
R9 is —CH3, —CF3, —OCH2CH3, tert-butyl, —Cl, —Br, or —F.

### Claim 29 (depends on 28)

The method of claim 28, wherein R3 is attached to a carbon atom adjacent to a nitrogen atom attached to the -(A)x- group.

### Claim 30 (depends on 29)

The method of claim 29, wherein R3 is —CH3.

### Claim 31 (depends on 30)

The method of claim 30, wherein R1 is —CH3 or —Cl and R9 is —Cl, —Br, or —F.

### Claim 32 (depends on 30)

The method of claim 30, wherein the compound is selected from:
and pharmaceutically acceptable salts thereof.

### Claim 33 (depends on 19)

The method of claim 19, wherein the compound is selected from:
and pharmaceutically acceptable salts thereof.

### Claim 34

A method for treating pain in an animal, comprising administering to an animal in need thereof an effective amount of a compound which is:
or a pharmaceutically acceptable salt thereof.