US 6,387,949 B1Granted

Substituted urea compounds useful in pain management

AssigneeAstraZeneca Canada Inc.

InventorsDaniel Delorme, Vlad Gregor, Niklas Plobeck, Edward Roberts, Eric Sun

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Abstract

Compounds of general formula I are disclosed and claimed in the present application, as well as their pharmaceutically acceptable salts, pharmaceutical compositions comprising the novel compounds and their use in therapy, in particular in the management of pain.

Claims15

Dependent claims

A compound according to formula I:

wherein:
m and n are each independently an integer from 1-3, and one or more of the hydrogens in the alkylene chain may optionally be substituted by any one of a C1-C6 alkyl;
a C1-C6 alkoxy;
or a hydroxy;
or
one or more of the methylene groups may optionally be substituted by a heteroatom selected from O, N or S;
R1 is selected from hydrogen;
a branched or straight C1-C6 alkyl;
a C2-C6 alkenyl;
a C3-C8 cycloalkyl;
a C4-C8(alkyl-cycloalkyl) wherein the alkyl is a C1-C2 alkyl and the cycloalkyl is a C3-C6 cycloalkyl;
R2 is selected from any of:
(i) hydrogen;
(ii) a straight or branched C1-C6 alkyl;
a C2-C6 alkenyl;
or a C2-C6 alkynyl;
(iii) a ((CH2)q-aryl);
(iv) a ((CH2)r-heteroaryl) wherein the heteroaryl has from 5 to 10 atoms, each heteroatom being selected from any of S, N and O;
and wherein the heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y, wherein each Y is as defined below;
and wherein q and r are each independently an integer from 0 to 3;
(v) a C3-C10 cycloalkyl, optionally comprising one or more unsaturations and optionally substituted by one or more heteroaryls, wherein each heteroaryl has from 5 to 10 atoms and each heteroatom is selected from any of S, N and O;
and wherein an aryl or heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y, wherein each Y is as defined below;
(vi) a heteroaryl having from 5 to 10 atoms, each heteroatom being selected from any of S, N and O;
wherein the heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y, wherein each Y is as defined below;
or R1 and R2 may optionally form a heterocyclic ring, which may optionally be saturated or unsaturated;
R3 is selected from any one of:
(i) hydrogen;
(ii) a straight or branched C1-C6 alkyl;
C2-C6 alkenyl;
or C2-C6 alkynyl;
(iii) a C6-C10 arylalkyl, wherein the aryl may optionally be substituted by one or more heteroaryls having from 5 to 10 atoms, each heteroatom being selected from any of S, N and O;
and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y, wherein each Y is as defined below;
(iv) a heteroaryl-(C5-C10 alkyl), wherein the heteroaryl has from 5 to 10 atoms, each heteroatom being selected from any of S, N, O, and wherein the heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y, wherein each Y is as defined below;
(v) a C3-C10 cycloalkyl, optionally comprising one or more unsaturations and optionally substituted by one or more heteroaryls having from 5 to 10 atoms, each heteroatom being selected from any of S, N and O, and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y, wherein each Y is as defined below;
(vi) a (C3-C6 cycloalkyl-(CH2)q) wherein q is an integer from 1 to 3;
R4 is selected from:
(i) hydrogen;
(ii) a straight or branched C1-C6 alkyl;
C2C6 alkenyl;
or C2-C6 alkynyl;
(iii) a C6-C10 arylalkyl, wherein the aryl may optionally be substituted by one or more heteroaryls having from 5 to 10 atoms, each heteroatom being selected from any of S, N and O;
and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y, wherein each Y is as defined below;
(iv) a heteroaryl-(C5-C10 alkyl), wherein the heteroaryl has from 5 to 10 atoms, each heteroatom being selected from any of S, N and O, and wherein the heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y, wherein each Y is as defined below;
(v) a C3-C10 cycloalkyl, optionally comprising one or more unsaturations and optionally substituted by one or more heteroaryls wherein each heteroaryl has from 5 to 10 atoms and each heteroatom is selected from any of S, N and O;
and wherein an aryl or heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y, wherein each Y is as defined below;
(vi) a heteroaryl having from 5 to 10 atoms, each heteroatom being selected from any of S, N and O;
wherein the heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y, wherein each Y is as defined below;
R5 is selected from any one of:
(i) hydrogen;
(ii) a straight or branched C1-C6 alkyl;
C2-C6 alkenyl;
or C2-C6 alkynyl;
(iii) a C6-C10 arylalkyl, wherein the aryl may optionally be substituted by one or more heteroaryls having from 5 to 10 atoms, each heteroatom being selected from any of S, N and O;
and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y, wherein each Y is as defined below;
(iv) a heteroaryl-(C5-C10 alkyl), wherein the heteroaryl has from 5 to 10 atoms, each heteroatom being selected from any S, N and O, and wherein the heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y, wherein each Y is as defined below;
(v) a C3-C10 cycloalkyl, optionally comprising one or more unsaturations and optionally substituted by one or more heteroaryls having from 5 to 10 atoms, each heteroatom being selected from any of S, N and O, and wherein an aryl or heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y, wherein each Y is as defined below;
(vi) a heteroaryl having from 5 to 10 atoms, each heteroatom being selected from any of S, N and O, wherein the heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y, wherein each Y is as defined below;
wherein R7, R8, R9, R10 and R11 are each independently selected from:
(a) hydrogen;
(b) a straight or branched C1-C6 alkyl;
C2-C6 alkenyl;
or C2-C6 alkynyl;
(c) a C6-C10 arylalkyl, wherein the aryl may optionally be substituted by one or more heteroaryls having from 5 to 10 atoms, each heteroatom being selected from any of S, N and O, and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y, wherein each Y is as defined below;
(d) a heteroaryl-C5-C10 alkyl), wherein the heteroaryl has from 5 to 10 atoms, each heteroatom being selected from any of S, N and O, and wherein the heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y, wherein each Y is as defined below;
(e) a C3-C10 cycloalkyl, optionally comprising one or more unsaturations and optionally substituted by one or more heteroaryls, each heteroaryl having from 5 to 10 atoms, and each heteroatom being selected from any of S, N and O;
and wherein an aryl or heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y, wherein each Y is as defined below;
or R4 and R5 may optionally form a heterocyclic ring, which may optionally be saturated or unsaturated;
Y is each and independently selected from any of CH3;
—(CH2)p1 CF3;
halogen;
C1-C3 alkoxy;
hydroxy;
—NO2;
—OCF3;
—CONRaRb;
—COORa;
—CORa;
—(CH2)p2NRaRb;
—(CH2)p3CH3;
(CH2)p4SORaRb;
—(CH2)p6SO2Ra;
(CH2)p6SO2NRa;
C4-C8(alkyl-cycloalkyl), wherein the alkyl is a C1-C2 alkyl and the cycloalkyl is a C3-C6 cycloalkyl;
1 or 2 heteroaryls having from 5 to 10 atoms, each heteroatom being selective from any of S, N and O;
and oxides selected from N-oxides or sulfoxides;
and wherein:
Ra and Rb are each independently selected from hydrogen;
a branched or straight C1-C6 alkyl;
a C1-C6 alkenyl;
a C3-C8 cycloalkyl;
and wherein p1, p2, p4, p5 are p6 are each and independently 0, 1 or 2;
and p3 is 1 or 2;
as well as pharmaceutically acceptable salts of the compound of formula I and isomers, hydrates, isoforms and prodrugs thereof.

90 more elements

Dependencies are inferred from the claim text.

Facts

Application: 09/555,580Filed 1 Jun 2000
Priority: SE 980220822 Jun 1998
Granted: 14 May 2002
Term ends: Not estimatedThe source records don’t support an estimate.

Classification13 codes

C07D 213/89
Having three double bonds between ring members or between ring members and non-ring members: with hetero atoms directly attached to the ring…
C07C 211/27
Of an unsaturated carbon skeleton containing at least one six-membered aromatic ring: having amino groups linked to the six-membered aromatic ring…
C07C 273/1854
Of substituted ureas: by reactions not involving the formation of the N-C-N- moiety
C07C 275/28
Derivatives of urea, i.e. compounds containing any of the groups [IMAGE cpc-sch-C07C-0967.gif], the nitrogen atoms not being part of nitro or…:…

Family

No related US applications are recorded in the indexed filing history.

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Abstract

A compound according to formula I:

wherein:
m and n are each independently an integer from 1-3, and one or more of the hydrogens in the alkylene chain may optionally be substituted by any one of a C1-C6 alkyl;
a C1-C6 alkoxy;
or a hydroxy;
or
one or more of the methylene groups may optionally be substituted by a heteroatom selected from O, N or S;
R1 is selected from hydrogen;
a branched or straight C1-C6 alkyl;
a C2-C6 alkenyl;
a C3-C8 cycloalkyl;
a C4-C8(alkyl-cycloalkyl) wherein the alkyl is a C1-C2 alkyl and the cycloalkyl is a C3-C6 cycloalkyl;
R2 is selected from any of:
(i) hydrogen;
(ii) a straight or branched C1-C6 alkyl;
a C2-C6 alkenyl;
or a C2-C6 alkynyl;
(iii) a ((CH2)q-aryl);
(iv) a ((CH2)r-heteroaryl) wherein the heteroaryl has from 5 to 10 atoms, each heteroatom being selected from any of S, N and O;
and wherein the heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y, wherein each Y is as defined below;
and wherein q and r are each independently an integer from 0 to 3;
(v) a C3-C10 cycloalkyl, optionally comprising one or more unsaturations and optionally substituted by one or more heteroaryls, wherein each heteroaryl has from 5 to 10 atoms and each heteroatom is selected from any of S, N and O;
and wherein an aryl or heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y, wherein each Y is as defined below;
(vi) a heteroaryl having from 5 to 10 atoms, each heteroatom being selected from any of S, N and O;
wherein the heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y, wherein each Y is as defined below;
or R1 and R2 may optionally form a heterocyclic ring, which may optionally be saturated or unsaturated;
R3 is selected from any one of:
(i) hydrogen;
(ii) a straight or branched C1-C6 alkyl;
C2-C6 alkenyl;
or C2-C6 alkynyl;
(iii) a C6-C10 arylalkyl, wherein the aryl may optionally be substituted by one or more heteroaryls having from 5 to 10 atoms, each heteroatom being selected from any of S, N and O;
and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y, wherein each Y is as defined below;
(iv) a heteroaryl-(C5-C10 alkyl), wherein the heteroaryl has from 5 to 10 atoms, each heteroatom being selected from any of S, N, O, and wherein the heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y, wherein each Y is as defined below;
(v) a C3-C10 cycloalkyl, optionally comprising one or more unsaturations and optionally substituted by one or more heteroaryls having from 5 to 10 atoms, each heteroatom being selected from any of S, N and O, and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y, wherein each Y is as defined below;
(vi) a (C3-C6 cycloalkyl-(CH2)q) wherein q is an integer from 1 to 3;
R4 is selected from:
(i) hydrogen;
(ii) a straight or branched C1-C6 alkyl;
C2C6 alkenyl;
or C2-C6 alkynyl;
(iii) a C6-C10 arylalkyl, wherein the aryl may optionally be substituted by one or more heteroaryls having from 5 to 10 atoms, each heteroatom being selected from any of S, N and O;
and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y, wherein each Y is as defined below;
(iv) a heteroaryl-(C5-C10 alkyl), wherein the heteroaryl has from 5 to 10 atoms, each heteroatom being selected from any of S, N and O, and wherein the heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y, wherein each Y is as defined below;
(v) a C3-C10 cycloalkyl, optionally comprising one or more unsaturations and optionally substituted by one or more heteroaryls wherein each heteroaryl has from 5 to 10 atoms and each heteroatom is selected from any of S, N and O;
and wherein an aryl or heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y, wherein each Y is as defined below;
(vi) a heteroaryl having from 5 to 10 atoms, each heteroatom being selected from any of S, N and O;
wherein the heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y, wherein each Y is as defined below;
R5 is selected from any one of:
(i) hydrogen;
(ii) a straight or branched C1-C6 alkyl;
C2-C6 alkenyl;
or C2-C6 alkynyl;
(iii) a C6-C10 arylalkyl, wherein the aryl may optionally be substituted by one or more heteroaryls having from 5 to 10 atoms, each heteroatom being selected from any of S, N and O;
and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y, wherein each Y is as defined below;
(iv) a heteroaryl-(C5-C10 alkyl), wherein the heteroaryl has from 5 to 10 atoms, each heteroatom being selected from any S, N and O, and wherein the heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y, wherein each Y is as defined below;
(v) a C3-C10 cycloalkyl, optionally comprising one or more unsaturations and optionally substituted by one or more heteroaryls having from 5 to 10 atoms, each heteroatom being selected from any of S, N and O, and wherein an aryl or heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y, wherein each Y is as defined below;
(vi) a heteroaryl having from 5 to 10 atoms, each heteroatom being selected from any of S, N and O, wherein the heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y, wherein each Y is as defined below;
wherein R7, R8, R9, R10 and R11 are each independently selected from:
(a) hydrogen;
(b) a straight or branched C1-C6 alkyl;
C2-C6 alkenyl;
or C2-C6 alkynyl;
(c) a C6-C10 arylalkyl, wherein the aryl may optionally be substituted by one or more heteroaryls having from 5 to 10 atoms, each heteroatom being selected from any of S, N and O, and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y, wherein each Y is as defined below;
(d) a heteroaryl-C5-C10 alkyl), wherein the heteroaryl has from 5 to 10 atoms, each heteroatom being selected from any of S, N and O, and wherein the heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y, wherein each Y is as defined below;
(e) a C3-C10 cycloalkyl, optionally comprising one or more unsaturations and optionally substituted by one or more heteroaryls, each heteroaryl having from 5 to 10 atoms, and each heteroatom being selected from any of S, N and O;
and wherein an aryl or heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y, wherein each Y is as defined below;
or R4 and R5 may optionally form a heterocyclic ring, which may optionally be saturated or unsaturated;
Y is each and independently selected from any of CH3;
—(CH2)p1 CF3;
halogen;
C1-C3 alkoxy;
hydroxy;
—NO2;
—OCF3;
—CONRaRb;
—COORa;
—CORa;
—(CH2)p2NRaRb;
—(CH2)p3CH3;
(CH2)p4SORaRb;
—(CH2)p6SO2Ra;
(CH2)p6SO2NRa;
C4-C8(alkyl-cycloalkyl), wherein the alkyl is a C1-C2 alkyl and the cycloalkyl is a C3-C6 cycloalkyl;
1 or 2 heteroaryls having from 5 to 10 atoms, each heteroatom being selective from any of S, N and O;
and oxides selected from N-oxides or sulfoxides;
and wherein:
Ra and Rb are each independently selected from hydrogen;
a branched or straight C1-C6 alkyl;
a C1-C6 alkenyl;
a C3-C8 cycloalkyl;
and wherein p1, p2, p4, p5 are p6 are each and independently 0, 1 or 2;
and p3 is 1 or 2;
as well as pharmaceutically acceptable salts of the compound of formula I and isomers, hydrates, isoforms and prodrugs thereof.

90 more elements

Facts

Application

09/555,580Filed 1 Jun 2000

Priority

SE 980220822 Jun 1998

Granted

14 May 2002

Term ends

Not estimatedThe source records don’t support an estimate.

Classification13 codes

C07D 213/89
Having three double bonds between ring members or between ring members and non-ring members: with hetero atoms directly attached to the ring…
C07C 211/27
Of an unsaturated carbon skeleton containing at least one six-membered aromatic ring: having amino groups linked to the six-membered aromatic ring…
C07C 273/1854
Of substituted ureas: by reactions not involving the formation of the N-C-N- moiety
C07C 275/28
Derivatives of urea, i.e. compounds containing any of the groups [IMAGE cpc-sch-C07C-0967.gif], the nitrogen atoms not being part of nitro or…:…