US 7,071,335 B2Granted

2-pyridinyl-1-piperazine therapeutic agents useful for treating pain

AssigneeEuro-Celtique S.A.

InventorsDonald J. Kyle, Sun Qun

Life of this patent

Estimating the term…

Abstract

A Compound of formula (wherein X is O or S and R1–R5 are disclosed herein) or a pharmaceutically acceptable salt thereof (each being a “Piperazine Compound”), pharmaceutical compositions comprising a Piperazine 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 Piperazine Compound are disclosed.

Claims83

Dependent claims

A compound of formula:

or a pharmaceutically acceptable salt thereof, wherein:
X is O or S;
R1 is methyl or halo;
R2 is:
(a) —(C2–C6)alkyl, —(C2–C3)alkenyl, —CH3, —CH2F, or —CHF2, which is substituted with one or more of —NO2, —CH═NR6, or —NR6OH;
or
(b) —(CH2)mC(O)R6, —(CH2)mOR6, or —(CH2)mSR6, which is unsubstituted or substituted with one or more of —CN, —OH, -halo, —NO2, —CH═NR6, or —NR6OH;
R3 is:
(a) —(C1–C6)alkyl, —(C2–C6)alkenyl, —(C2–C6)alkynyl, —(CH2)nOR6, which is unsubstituted or substituted with one or more of —CN, —OH, -halo, —NO2, —CH═NR6, or —NR6OH;
or
(b) —H, -halo, —NO2, —CN, or —NH2;
R4 is —H;
R5 is:
(a) —(C2–C6)alkenyl, or —(C2–C6)alkynyl;
or
(b) —(C3–C8)cycloalkyl, —(C5–C8)cycloalkenyl, —(C6)aryl, —(C10)aryl, —(C14)aryl, —(C3–C7)heterocycle, —(C1–C6)alkyl(C6)aryl, —(C1–C6)alkyl(C10)aryl, —(C1–C6)alkyl(C14)aryl, —(C1–C6)alkyl(C3–C7)heterocycle, —(C2–C6)alkenyl(C6)aryl, —(C2–C6)alkenyl(C10)aryl, —(C2–C6)alkenyl(C14)aryl, —(C2–C6)alkenyl(C3–C7)heterocycle, —(C2–C6)alkynyl(C3–C8)cycloalkyl, —(C2–C6)alkynyl(C5–C8)cycloalkenyl, —(C2–C6)alkynyl(C6)aryl, —(C2–C6)alkynyl(C10)aryl, —(C2–C6)alkynyl(C14)aryl, or —(C2–C6)alkynyl(C3–C7)heterocycle, which is unsubstituted or substituted with one or more R7 groups;
each R6 is independently —H, —(C1–C6)alkyl, —(C2–C6)alkenyl, —(C2–C6)alkynyl, —(C3–C8)cycloalkyl, —(C5–C8)cycloalkenyl, —(C6)aryl, —(C3–C5)heterocycle, —C(halo)3, or —CH(halo)2;
each R7 is independently —(C1–C6)alkyl, —(C2–C6)alkenyl, —(C2–C6)alkynyl, —(CH2)n(C3–C8)cycloalkyl, —(CH2)n(C5–C8)cycloalkenyl, —(CH2)n(C6)aryl, —(CH2)nSR6, —(CH2)nCH(halo)2, —(CH2)nC(halo)3, -halo, or —(CH2)nOR6;
m is 1 or 2;
and
n is an integer ranging from 0 to 2.

18 more elements

A compound of formula:

or a pharmaceutically acceptable salt thereof, wherein:
X is O or S;
R1 is methyl or halo;
R2 is:
(a) —(C2–C6)alkyl, —(C2–C3)alkenyl, —CH3, —CH2F, or —CHF2, which is substituted with one or more of —NO2, —CH═NR6, or —NR6OH;
or
(b) —(CH2)mC(O)R6, (CH2)mOR6, or —(CH2)mSR6, which is unsubstituted or substituted with one or more of —CN, —OH, -halo, —NO2, —CH═NR6, or —NR6OH;
R3 is:
(a) —(C1–C6)alkyl, —(C2–C6)alkenyl, —(C2–C6)alkynyl, —(CH2)nOR6, which is unsubstituted or substituted with one or more of —CN, —OH, -halo, —NO2, —CH═NR6, or —NR6OH;
or
(b) —H, -halo, —NO2, —CN, or —NH2;
R4 is —H;
R5 is:
(a) —(C2–C6)alkenyl, or —(C2–C6)alkynyl;
or
(b) —(C3–C8)cycloalkyl, —(C5–C8)cycloalkenyl, —(C6)aryl, —(C10)aryl, —(C14)aryl, —(C3–C7)heterocycle, —(C1–C6)alkyl(C6)aryl, —(C1–C6)alkyl(C10)aryl, —(C1–C6)alkyl(C14)aryl, —(C1–C6)alkyl(C3–C7)heterocycle, —(C2–C6)alkenyl(C6)aryl, —(C2–C6)alkenyl(C10)aryl, —(C2–C6)alkenyl(C14)aryl, —(C2–C6)alkenyl(C3–C7)heterocycle, —(C2–C6)alkynyl(C3–C8)cycloalkyl, —(C2–C6)alkynyl(C5–C8)cycloalkenyl, —(C2–C6)alkynyl(C6)aryl, —(C2–C6)alkynyl(C10)aryl, —(C2–C6)alkynyl(C14)aryl, or —(C2–C6)alkynyl(C3–C7)heterocycle, which is unsubstituted or substituted with one or more R7 groups;
each R6 is independently —H, —(C1–C6)alkyl, —(C2–C6)alkenyl, —(C2–C6)alkynyl, —(C3–C8)cycloalkyl, —(C5–C8)cycloalkenyl, —(C6)aryl, —(C3–C8)heterocycle, —C(halo)3, or —CH(halo)2;
each R7 is independently —(C1–C6)alkyl, —(C2–C6)alkenyl, —(C2–C6)alkynyl, —(CH2)n(C3–C8)cycloalkyl, —(CH2)n(C5–C8)cycloalkenyl, —(CH2)n(C6)aryl, —(CH2)nSR6, —(CH2)nCH(halo)2, —(CH2)nC(halo)3, -halo, or —(CH2)nOR6;
m is 1 or 2;
and
n is an integer ranging from 0 to 2;
wherein X is S.

19 more elements

A compound of formula:

or a pharmaceutically acceptable salt thereof, wherein:
X is O;
R1 is methyl or halo;
R2 is:
(a) —(C2–C6)alkyl, —(C2–C3)alkenyl, —CH3, —CH2F, or —CHF2, which is substituted with one or more of —NO2, —CH═NR6, or —NR6OH;
or
(b) —(CH2)mC(O)R6, (CH2)mOR6, or —(CH2)mSR6, which is unsubstituted or substituted with one or more of —CN, —OH, -halo, —NO2, —CH═NR6, or —NR6OH;
R3 is:
(a) —(C1–C6)alkyl, —(C2–C6)alkenyl, —(C2–C6)alkynyl, —(CH2)nOR6, which is unsubstituted or substituted with one or more of —CN, —OH, -halo, —NO2, —CH═NR6, or —NR6OH;
or
(b) —H, -halo, —NO2, —CN, or —NH2;
R4 is —H;
R5 is:
(a) —(C2–C6)alkenyl, or —(C2–C6)alkynyl;
or
(b) —(C3–C8)cycloalkyl, —(C5–C8)cycloalkenyl, —(C6)aryl, —(C10)aryl, —(C14)aryl, —(C3–C7)heterocycle, —(C1–C6)alkyl(C6)aryl, —(C1–C6)alkyl(C10)aryl, —(C1–C6)alkyl(C14)aryl, —(C1–C6)alkyl(C3–C7)heterocycle, —(C2–C6)alkenyl(C6)aryl, —(C2–C6)alkenyl(C10)aryl, —(C2–C6)alkenyl(C14)aryl, —(C2–C6)alkenyl(C3–C7)heterocycle, —(C2–C6)alkynyl(C3–C8)cycloalkyl, —(C2–C6)alkynyl(C5–C8)cycloalkenyl, —(C2–C6)alkynyl(C6)aryl, —(C2–C6)alkynyl(C10)aryl, —(C2–C6)alkynyl(C14)aryl, or —(C2–C6)alkynyl(C3–C7)heterocycle, which is unsubstituted or substituted with one or more R7 groups;
each R6 is independently —H, —(C1–C6)alkyl, —(C2–C6)alkenyl, —(C2–C6)alkynyl, —(C3–C8)cycloalkyl, —(C5–C8)cycloalkenyl, —(C6)aryl, —(C3–C5)heterocycle, —C(halo)3, or —CH(halo)2;
each R7 is independently —(C1–C6)alkyl, —(C2–C6)alkenyl, —(C2–C6)alkynyl, —(CH2)n(C3–C8)cycloalkyl, —(CH2)n(C5–C8)cycloalkenyl, —(CH2)n(C6)aryl, —(CH2)nSR6, —(CH2)nCH(halo)2, —(CH2)nC(halo)3, -halo, or —(CH2)nOR6;
m is 1 or 2;
and
n is an integer ranging from 0 to 2;
wherein R1 is methyl.

19 more elements

A compound of formula:

or a pharmaceutically acceptable salt thereof, wherein:
X is O or S;
R1 is methyl or halo;
R2 is:
(a) —(C2–C6)alkyl, —(C2–C3)alkenyl, —(CH2)nC(O)R6, —(CH2)nOR6, —(CH2)nSR6, which is unsubstituted or substituted with one or more of —CN, —OH, -halo, —NO2, —CH═NR6, or —NR6OH;
(b) —CH3, —CH2F, or —CHF2, which is unsubstituted or substituted with one or more of —CN, —OH, —Cl, —Br, —I, —NO2, —CH═NR6, or —NR6OH;
or
(c) —H, -halo, —NO2, —CN, or —NH2;
R3 is:
(a) —(C1–C6)alkyl, —(C2–C6)alkenyl, or —(C2–C6)alkynyl, which is substituted with one or more of —CH═NR6 or —NR6OH;
or
(b) —(CH2)mOR6, which is unsubstituted or substituted with one or more of —CN, —OH, -halo, —NO2, —CH═NR6, or —NR6OH;
R4 is —H;
R5 is:
(a) —(C2–C6)alkenyl, or —(C2–C6)alkynyl;
or
(b) —(C3–C8)cycloalkyl, —(C5–C8)cycloalkenyl, —(C6)aryl, —(C10)aryl, —(C14)aryl, —(C3–C7)heterocycle, —(C1–C6)alkyl(C6)aryl, —(C1–C6)alkyl(C10)aryl, —(C1–C6)alkyl(C14)aryl, —(C1–C6)alkyl(C3–C7)heterocycle, —(C2–C6)alkenyl(C6)aryl, —(C2–C6)alkenyl(C10)aryl, —(C2–C6)alkenyl(C14)aryl, —(C2–C6)alkenyl(C3–C7)heterocycle, —(C2–C6)alkynyl(C3–C8)cycloalkyl, —(C2–C6)alkynyl(C5–C8)cycloalkenyl, —(C2–C6)alkynyl(C6)aryl, —(C2–C6)alkynyl(C10)aryl, —(C2–C6)alkynyl(C14)aryl, or —(C2–C6)alkynyl(C3–C7)heterocycle, which is unsubstituted or substituted with one or more R7 groups;
each R6 is independently —H, —(C1–C6)alkyl, —(C2–C6)alkenyl, —(C2–C6)alkynyl, —(C3–C8)cycloalkyl, —(C5–C8)cycloalkenyl, —(C6)aryl, —(C3–C5)heterocycle, —C(halo)3, or —CH(halo)2;
each R7 is independently —(C1–C6)alkyl, —(C2–C6)alkenyl, —(C2–C6)alkynyl, —(CH2)n(C3–C8)cycloalkyl, —(CH2)n(C5–C8)cycloalkenyl, —(CH2)n(C6)aryl, —(CH2)nSR6, —(CH2)nCH(halo)2, —(CH2)nC(halo)3, -halo, or —(CH2)nOR6;
m is 1 or 2;
and
n is an integer ranging from 0 to 2.

19 more elements

A pharmaceutical composition comprising an effective amount of a compound of formula:

or a pharmaceutically acceptable salt thereof, wherein:
R1 is methyl or halo;
R2 is:
(a) —(C2–C6)alkyl, —(C2–C3)alkenyl, —(CH2)nC(O)R6, —(CH2)nOR6, —(CH2)nSR6, which is unsubstituted or substituted with one or more of —CN, —OH, -halo, —NO2, —CH═NR6, or —NR6OH;
(b) —CH3, —CH2F, or —CHF2, which is unsubstituted or substituted with one or more of —CN, —OH, —Cl, —Br, —I, —NO2, —CH═NR6, or —NR6OH;
or
(c) —H, -halo, —NO2, —CN, or —NH2;
R3 is:
(a) —(C1–C6)alkyl, —(C2–C6)alkenyl, —(C2–C6)alkynyl, —(CH2)nOR6, which is unsubstituted or substituted with one or more of —CN, —OH, -halo, —NO2, —CH═NR6, or —NR6OH;
or
(b) —H, -halo, —NO2, —CN, or —NH2;
R4 is —H;
R5 is:
(a) —(C2–C6)alkenyl, or —(C2–C6)alkynyl;
or
(b) —(C3–C8)cycloalkyl, —(C5–C8)cycloalkenyl, —(C6)aryl, —(C10)aryl, —(C14)aryl, —(C3–C7)heterocycle, —(C1–C6)alkyl(C6)aryl, —(C1–C6)alkyl(C10)aryl, —(C1–C6)alkyl(C14)aryl, —(C1–C6)alkyl(C3–C7)heterocycle, —(C2–C6)alkenyl(C6)aryl, —(C2–C6)alkenyl(C10)aryl, —(C2–C6)alkenyl(C14)aryl, —(C2–C6)alkenyl(C3–C7)heterocycle, —(C2–C6)alkynyl(C3–C8)cycloalkyl, —(C2–C6)alkynyl(C5–C8)cycloalkenyl, —(C2–C6)alkynyl(C6)aryl, —(C2–C6)alkynyl(C10)aryl, —(C2–C6)alkynyl(C14)aryl, or —(C2–C6)alkynyl(C3–C7)heterocycle, which is unsubstituted or substituted with one or more R7 groups;
each R6 is independently —H, —(C1–C6)alkyl, —(C2–C6)alkenyl, —(C2–C6)alkynyl, —(C3–C8)cycloalkyl, —(C5–C8)cycloalkenyl, —(C6)aryl, —(C3–C5)heterocycle, —C(halo)3, or —CH(halo)2;
each R7 is independently —(C1–C6)alkyl, —(C2–C6)alkenyl, —(C2–C6)alkynyl, —(CH2)n(C3–C8)cycloalkyl, —(CH2)n(C5–C8)cycloalkenyl, —(CH2)n(C6)aryl, —(CH2)nSR6, —(CH2)nCH(halo)2, —(CH2)nC(halo)3, -halo, or —(CH2)nOR6;
and
n is an integer ranging from 0 to 2;
and
a pharmaceutically acceptable carrier or excipient and further comprising an opioid analgesic, a non-opioid analgesic, an anti-emetic agent, or any mixture thereof.

19 more elements

A pharmaceutical composition comprising an effective amount of a compound of formula:

or a pharmaceutically acceptable salt thereof, wherein:
R1 is methyl or halo;
R2 is:
(a) —(C2–C6)alkyl, —(C2–C3)alkenyl, —(CH2)nC(O)R6, —(CH2)nOR6, —(CH2)nSR6, which is unsubstituted or substituted with one or more of —CN, —OH, -halo, —NO2, —CH═NR6, or —NR6OH;
(b) —CH3, —CH2F, or —CHF2, which is unsubstituted or substituted with one or more of —CN, —OH, —Cl, —Br, —I, —NO2, —CH═NR6, or —NR6OH;
or
(c) —H, -halo, —NO2, —CN, or —NH2;
R3 is:
(a) —(C1–C6)alkyl, —(C2–C6)alkenyl, —(C2–C6)alkynyl, —(CH2)nOR6, which is unsubstituted or substituted with one or more of —CN, —OH, -halo, —NO2, —CH═NR6, or —NR6OH;
or
(b) —H, -halo, —NO2, —CN, or —NH2;
R4 is —H;
R5 is:
(a) —(C1–C6)alkyl, —(C2–C6)alkenyl, or —(C2–C6)alkynyl;
or
(b) —(C3–C8)cycloalkyl, —(C5–C8)cycloalkenyl, —(C6)aryl, —(C10)aryl, —(C14)aryl, —(C3–C7)heterocycle, —(C1–C6)alkyl(C6)aryl, —(C1–C6)alkyl(C10)aryl, —(C1–C6)alkyl(C14)aryl, —(C1–C6)alkyl(C3–C7)heterocycle, —(C2–C6)alkenyl(C6)aryl, —(C2–C6)alkenyl(C10)aryl, —(C2–C6)alkenyl(C14)aryl, —(C2–C6)alkenyl(C3–C7)heterocycle, —(C2–C6)alkynyl(C3–C8)cycloalkyl, —(C2–C6)alkynyl(C5–C8)cycloalkenyl, —(C2–C6)alkynyl(C6)aryl, —(C2–C6)alkynyl(C10)aryl, —(C2–C6)alkynyl(C14)aryl, or —(C2–C6)alkynyl(C3–C7)heterocycle, which is unsubstituted or substituted with one or more R7 groups;
each R6 is independently —H, —(C1–C6)alkyl, —(C2–C6)alkenyl, —(C2–C6)alkynyl, —(C3–C8)cycloalkyl, —(C5–C8)cycloalkenyl, —(C6)aryl, —(C3–C5)heterocycle, —C(halo)3, or —CH(halo)2;
each R7 is independently —(C1–C6)alkyl, —(C2–C6)alkenyl, —(C2–C6)alkynyl, —(CH2)n(C3–C8)cycloalkyl, —(CH2)n(C5–C8)cycloalkenyl, —(CH2)n(C6)aryl, —(CH2)nSR6, —(CH2)nCH(halo)2, —(CH2)nC(halo)3, -halo, or —(CH2)nOR6;
and
n is an integer ranging from 0 to 2;
and
a pharmaceutically acceptable carrier or excipient and further comprising an opioid analgesic,
a non-opioid analgesic, an anti-emetic agent, or any mixture thereof.

20 more elements

Dependencies are inferred from the claim text.

Facts

Application: 10/355,186Filed 31 Jan 2003 · us provisional application
Priority: 1 Feb 2002
Published: US 2004/0044003 A14 Mar 2004
Granted: 4 Jul 2006
Term ends: Not estimatedThe source records don’t support an estimate.

Classification24 codes

C07D 405/12
Containing two hetero rings: linked by a chain containing hetero atoms as chain links
A61P 1/04
Drugs for disorders of the alimentary tract or the digestive system: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of…
A61P 1/08
Drugs for disorders of the alimentary tract or the digestive system: for nausea, cinetosis or vertigo; Antiemetics
A61P 9/10
Drugs for disorders of the cardiovascular system: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary…

Family

Application60/352,855Us provisional application · filed 1 Feb 2002
Application60/411,043Us provisional application · filed 17 Sep 2002
US 2004/0044003 A1Pre-grant publication · published 4 Mar 2004
US 7,071,335 B2This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

Facts

Application

10/355,186Filed 31 Jan 2003 · us provisional application

Priority

1 Feb 2002

Published

US 2004/0044003 A14 Mar 2004

Granted

4 Jul 2006

Term ends

Not estimatedThe source records don’t support an estimate.

Classification24 codes

C07D 405/12
Containing two hetero rings: linked by a chain containing hetero atoms as chain links
A61P 1/04
Drugs for disorders of the alimentary tract or the digestive system: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of…
A61P 1/08
Drugs for disorders of the alimentary tract or the digestive system: for nausea, cinetosis or vertigo; Antiemetics
A61P 9/10
Drugs for disorders of the cardiovascular system: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary…