Note: Descriptions are shown in the official language in which they were submitted.
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NOVEL HETERO PYRROLE ANALOGS ACTING ON
CANNABINOID RECEPTORS
Field of the Invention
The present invention relates generally to biologically active hetero pyrrole
analogs such as imidazoles, thiazoles, oxazoles and pyrazoles capable of
interacting
with the CBI and/or the CB2 cannabinoid receptors, including neutral
antagonists,
inverse-agonists and partial agonists. Another aspect of the invention is
concerned
with such compounds having a range of useful applications including use of
certain
neutral antagonists, inverse-agonists and partial agonists to treat medical
conditions
with no or substantially reduced incidence of side-effects. Other aspects of
the
invention are concerned with new and improved hetero pyrrole analogs acting as
neutral antagonists, inverse-agonists and partial agonists selective for the
CB1
and/or the CB2 receptors and use of these new and improved hetero pyrrole
analogs
as peripherally acting or centrally acting compounds. Also, aspects of the
invention
are concerned with all isotopic variations of these compounds, combination
therapy
and pharmaceutical preparations and compositions employing the inventive
analogs
and methods of administering therapeutically effective amounts of the
inventive
analogs to provide a physiological effect.
Background of the Invention
Marijuana (Cannabis sativa) and derivatives have been used for medicinal and
recreational purposes. The major active constituent extracted from Cannabis
sativa
is the classical cannabinoid A9-Tetrahydrocannabinol (A9-THC). The effects of
such
cannabinoids are due to an interaction with specific high-affinity receptors.
Presently,
two cannabinoid receptors have been characterized: CB1, a central receptor
found in
the mammalian brain and a number of other sites in peripheral tissues; and
CB2, a
peripheral receptor found principally in cells related to the immune system.
The CB1
receptor is believed to mediate the psychoactive properties associated with
classical
cannabinoids. Characterization of these receptors has been made possible by
the
development of specific synthetic ligands such as the agonists WIN 55212-2 and
CP
55,940.
1
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In addition to acting at the cannabinoid receptors, cannabinoids such as A9-
THC also affect cellular membranes, thereby producing undesirable side effects
such
as drowsiness, impairment of monoamine oxidase function and impairment of non-
receptor mediated brain function. The addictive and psychotropic properties of
some
cannabinoids also limit their therapeutic value.
International Publication number WO 03/007887 A2 to Finke et al describes
imidazole derivatives alleged to have binding affinity for the central
cannabinoid
receptor. International Publication number WO 03/027076 A2 to Kruse et al also
describes some imidazole derivatives alleged to have binding affinity for
cannabinoid
receptors.
Brief Description of the Drawings
Figures 1A-1B are graphs showing cAMP accumulation with hCB1-HEK292
cells (Compound 2 and 15); and
Figures 2A-2C are graphs showing food intake, weigh change and body
weight following administration of Compound 15 to rats.
Summary of the Invention
Briefly stated, one embodiment of the invention is concerned with new and
improved cannabimimetic (cannabinoid like) imidazole analogs. The inventive
cannabimimetic imidazole ligands of this embodiment can be represented by
general
formula I and their enantiomers, diastereomers, geometric isomers, racemates,
tautomers, rotamers, atropisomers, metabolites, in vivo hydrolysable esters, N-
oxides, salts, solvates, hydrates, polymorphic forms( crystalline or
amorphous) or
pro-drugs:
R4 ______________________________ ( I R3
R1
Ny1 2)N 0
R2
2
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A comprises a direct bond, 0, or -(CH2)1N(R5)
B comprises a direct bond, 0, N(R5), - (CH2)1 - or -NH-S02 -
R5 is hydrogen, OH, alkyl or substituted alkyl and
1 is an integer from 0 to 3.
In a variation of formula 1, R1 and R2 each independently comprise -(CH2)n-Z.
n is an integer from 0 to about 7.
Z comprises H, halogen, CF3, CF2H, N3, NCS, CN, NO2, NX1X2, OX3, SX3,
OAc, OSO2X3, 0-acyl, S-acyl, S02-alkyl, SO-alkyl, SC(CH3)2C00X8,
OC(CH3)2C00X8 , C(CH3)2C00X8, Si(alkyl)3, 0-aroyl, 0(CH2)10X3, 0(CH2)JNX1X2,
alkyl-CN, NH-acyl, NH-aroyl, CHO, C(halogen)3, COOX3, SO3H, SO2NX1X2,
CONX1X2, NHC(0)0-alkyl, NHS02-alkyl, alkoxy, alkyl, alcohol, alkylmercapto,
alkylamino, di-alkylamino, alkylsulfinyl or alkylsulfonyl, CX4X8X8, -CH=CHX8 ,
-CCX8
X1 and X2 each independently comprise H or alkyl, or
X1 and X2 together comprise part of a heterocyclic ring having about 4 to
about
7 ring members and optionally one additional heteroatom selected from 0, N or
S, or
X1 and X2 together comprise part of an imide ring having about 5 to about 6
members,
X3 comprises H, alkyl, aryl, NO2, NO, (CH2)mCN, hydroxyloweralkyl, or alkyl-
NX1X2,
X4, X5, and X6 each independently comprise H, alkyl, carbocyclic ring,
hydroxyloweralkyl, alkyl-OH, halogen, CN, SNO, S(S02)alkyl, NX1X2, COOX3,
CONX3, OX7, or 0-alkyl-X7 wherein
X7 comprises H, alkyl, NO2, NO, P(0)(0X8)2, PH(0)(0X8), S(0)kN(alky1)2,
S(0)kX8, S(0)k0X8, COOX8, CONX8, SO3H, COX8, wherein
X5 comprises H, alkyl, carbocyclic ring, heterocyclic ring, aromatic ring,
heteroaromatic ring, or -CX9=CHX10 wherein
3
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X9 and X10 each independently comprise H or alkyl
Wherein m is an integer from 0 to 7
j is an integer from 0 to about 6, or
k is an integer from 0 to about 2
In a variation of formula I, R1 and R2 each independently comprise
-(CH2)n-Z.
n is an integer from 0 to about 7.
Z comprises a carbocyclic ring having about 4 to about 7 ring members, a
heterocyclic ring having about 4 to about 7 ring members, an aromatic ring
having
about 5 to about 7 ring members, a heteroaromatic ring having about 5 to about
7
ring members, a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a
heterotricyclic
ring, a polycyclic ring, a heteropolycyclic ring; or any above group
substituted on at
least one available ring atom by an alkyl group; or any above group
substituted on at
least one available ring nitrogen atom by a benzyl group, a substituted benzyl
group,
an alkoxybenzyl group, a substituted alkoxybenzyl group, a benzhydryl group or
a
substituted benzhydryl group; and wherein the connecting point between the -
(CH2)n-
group and the Z group can be any available ring carbon atom or any available
ring
nitrogen atom.
In a variation of formula I, R1 and R2 each independently comprise
-(CH2)n-Z.
n is an integer from 0 to about 7.
Z comprises a 5 member unsaturated ring having 0 to 4 independently
selected heteroatoms as ring members, a substituted 5 member unsaturated ring
having 0 to 4 independently selected heteroatoms as ring members, a 6 member
aromatic ring having 0 to 5 independently selected heteroatoms as ring members
or
a substituted 6 member aromatic ring having 0 to 5 independently selected
heteroatoms; and wherein the connecting point between the -(CH2)n- group and
the Z
group can be any available ring carbon atom or any available ring nitrogen
atom.
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In a variation of formula I, R1 and R2 each independently comprise
-(C H2)-Z.
n is an integer from 0 to about 7.
Z comprises 1-, 2- or 3-pyrrolidinyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or 4-
morpholinyl, 2-, 3- or 4-thiomorpholinyl, 1-, 2- or 3-azetidinyl, 1- or 2-
piperazinyl, 2- or
3-tetrahydrofuranyl; or any above group substituted on at least one available
ring
atom by an alkyl group; or any above group substituted on at least one
available ring
nitrogen atom by a benzyl group, a substituted benzyl group, an alkoxybenzyl
group,
a substituted alkoxybenzyl group, a benzhydryl group or a substituted
benzhydryl
group; and wherein the connecting point between the -(CH2)n- group and the Z
group
can be any available ring carbon atom or any available ring nitrogen atom.
In a variation of formula I, R1 and R2 each independently comprise -(CH2)n-Z.
n is an integer from 0 to about 7.
Z comprises
)i_xy ry y ' mx
N X
( NNYJX
\ ______ N , __
X X y N Y N
N \ X
Ny N N N y 0 \ 7-1 Y 01 X
Y N Or *ex
N
\N \N
N N N nrw
)6Nr1/ )(\- N' y
X
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wherein X and Y each independently comprise, H, halogen, CF3, CFA N3,
NOS, ON, NO2, NX1X2, OX3, SX3, OAc, 0S02X3, 0-acyl, S-acyl, S02-alkyl, SO-
alkyl, SC(CH3)2000X8, OC(CH3)2C00X8 , C(CH3)2000X8, Si(alkyl)3, alkyl-ON,
0-aroyl, 0(CH2)i0X3, 0(CH2)JNX1X2, NH-acyl, NH-aroyl, CHO, C(halogen)3, COOX3,
SO3H, SO2NX1X2, CONX1X2, NHC(0)0-alkyl, NHS02-alkyl, alkoxy, alkyl, alcohol,
alkylmercapto, alkylamino, di-alkylamino, alkylsulfinyl or alkylsulfonyl,
CX4X5X6, -
CH=CHX8 , -CCX8 ;
X1 and X2 each independently comprise H or alkyl, or
X1 and X2 together comprise part of a heterocyclic ring having about 4 to
about
7 ring members and optionally one additional heteroatom selected from 0, N or
S, or
X1 and X2 together comprise part of an imide ring having about 5 to about 6
members,
X3 comprises H, alkyl, aryl, NO2, (0H2)mCN, hydroxyloweralkyl, or alkyl-
NX1X2,
X4, X5, and X8 each independently comprise H, alkyl, carbocyclic ring,
hydroxyloweralkyl, alkyl-OH, halogen, ON, SNO, S(S02)alkyl, NX1X2, 000X3,
CONX3, OX7, or 0-alkyl-X7 wherein
X7 comprises H, alkyl, NO2, NO, P(0)(0X8)2, PH(0)(0X8), S(0)kN(alkyl)2,
S(0)kX8, S(0)k0X8, 000X8, CONX8, SO3H, COX8, wherein
X8 comprises H, alkyl, carbocyclic ring, heterocyclic ring, aromatic ring,
heteroaromatic ring, or -0X0=CHX10 wherein
X9 and X10 each independently comprise H or alkyl
Wherein m is an integer from 0 to 7
j is an integer from 0 to about 6, or
W comprises H or alkyl
k is an integer from 0 to about 2
In a variation of formula I, R1 and R2 each independently -(CH2)n-Z.
n is an integer from 0 to about 7.
Z comprises a carbocyclic ring having 6 ring atoms fused to a heterocyclic
ring
having from 5 to 7 ring atoms, a carbocyclic ring having 6 ring atoms fused to
a
6
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heteroaromatic ring having from 5 to 7 ring atoms, a heterocyclic ring having
6 ring
atoms fused to a heterocyclic ring having from 5 to 7 ring atoms, an
heterocyclic ring
having 6 ring atoms fused to a heteroaromatic ring having from 5 to 7 ring
atoms, an
aromatic ring having 6 ring atoms fused to a heterocyclic ring having from 5
to 7 ring
atoms, an aromatic ring having 6 ring atoms fused to a heteroaromatic ring
having
from 5 to 7 ring atoms, a heteroaromatic ring having 6 ring atoms fused to a
heterocyclic ring having from 5 to 7 ring atoms or a heteroaromatic ring
having 6 ring
atoms fused to a heteroaromatic ring having from 5 to 7 ring atoms.
In a variation of formula I, R1 and R2 each independently comprise -(CH2)n-Z;
n comprises an integer from 0 to about 7;
Z comprises an unsaturated ring having 5 ring atoms and 0 to 2 independently
selected heteroatoms as ring members fused to an unsaturated ring having 5
ring
atoms and 0 to 4 independently selected heteroatoms as ring members, an
unsaturated ring having 5 ring atoms and 0 to 2 independently selected
heteroatoms
as ring members fused to an unsaturated ring having 6 or 7 ring atoms and 0 to
3
independently selected heteroatoms as ring members or an unsaturated ring
having
6 ring atoms and 0 to 4 independently selected heteroatoms as ring members
fused
to an unsaturated ring having 6 or 7 ring atoms and 0 to 4 independently
selected
heteroatoms as ring members.
In a variation of formula I, R1 and R2 each independently comprise
-(CH2)m -Qi-(CH2)n-Z;
Q1 comprises NH, 0, S,-CH=CH-, -CO, SO2 or 0S02;
m is an integer from 1 to about 7;
n is an integer from 0 to about 7;
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Z comprises H, halogen, CF3, CF2H, N3, NCS, CN, NO2, NX1X2, OX3, SX3,
OAc, 0S02X3, 0-
acyl, S-acyl, S02-alkyl, SO-alkyl, SC(CH3)2C00X8,
OC(CH3)2C00X8 , C(CH3)2C00X8,
Si(alkyl)3, 0-aroyl, 0(CH2)i0X3,
0(CH2)iNX1X2, alkyl-CN, NH-acyl, NH-aroyl, CHO, C(halogen)3, COOX3, SO3H,
SO2NX1X2, CONX1X2, NHC(0)0-alkyl, NHS02-alkyl, alkoxy, alkyl, alcohol,
alkylmercapto, alkylamino, di-alkylamino, alkylsulfinyl or alkylsulfonyl,
CX4X5X8, -
CH=CHX8 , -CmCX8 ;
X1 and X2 each independently comprise H or alkyl:or
X1 and X2 together comprise part of a heterocyclic ring having about 4 to
about
7 ring members and optionally one additional heteroatom selected from 0, N or
S, or
X1 and X2 together comprise part of an imide ring having about 5 to about 6
members;
X3 comprises H, alkyl, NO2, NO, (CH2)mCN, hydroxyloweralkyl, or alkyl-NX1X2;
X4, X5, and X6 each independently comprise H, alkyl, 'carbocyclic ring,
hydroxyloweralkyl, alkyl-OH, halogen, CN, SNO, S(S02)alkyl, NX1X2, COOX3,
CONX3, OX7, or 0-alkyl-X7, wherein
X7 comprises H, alkyl, NO2, NO, P(0)(0X8)2, PH(0)(0X8), S(0)kN(alky1)2,
S(0)kX8, S(0)k0X8, COOX8, CONX8, SO3H, COX8, wherein
X8 comprises H, alkyl, carbocyclic ring, heterocyclic ring, aromatic ring,
heteroaromatic ring, or -CX0=CHX10, wherein
X9 and X10 each independently comprise H or alkyl;
m is an integer from 0 to 7;
j is an integer from 0 to about 6, and
k is an integer from 0 to about 2.
In a variation of formula I, R1 and R2 each independently comprise
-Q2-(CH2)n-Z,
Q2 is optionally present and if present comprises -CH2-NH, -CH2-0, -CH2-S,
-CH2-S02 or -CH2-0S02;
n is an integer from 0 to about 7;
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Z comprises H, halogen, CF3, CF2H, N3, NCS, CN, NO2, NX1X2, OX3, SX3,
OAc, 0S02X3, 0-acyl, S-acyl, S02-alkyl, SO-alkyl, SC(CH3)2C00X8,
OC(CH3)2000X8 , C(CH3)2C00X8, Si(alkyl)3, 0-aroyl, 0(CH2)j0X3, 0(CH2)iNX1X2,
alkyl-CN, NH-acyl, NH-aroyl, CHO, C(halogen)3, COOX3, SO3H, SO2NX1X2,
CONX1X2, NHC(0)0-alkyl, NHS02-alkyl, alkoxy, alkyl, alcohol,
alkylmercapto,
alkylamino, di-alkylamino, alkylsulfinyl or alkylsulfonyl, CX4X5X6, -CH=CHX8 ,
-C-7=-CX8
X1 and X2 each independently comprise H or alkyl, or
X1 and X2 together comprise part of a heterocyclic ring having about 4 to
about
7 ring members and optionally one additional heteroatom selected from 0, N or
S, or
X1 and X2 together comprise part of an imide ring having about 5 to about 6
members,
X3 comprises H, alkyl, NO2, NO, (CH2)mCN, hydroxyloweralkyl, or alkyl-NX1X2,
X4, X5, and X6 each independently comprise H, alkyl, carbocyclic ring,
hydroxyloweralkyl, alkyl-OH, halogen, CN, SNO, S(S02)alkyl, NX1X2, COOX3,
CONX3, OX7, or 0-alkyl-X7, wherein
X7 comprises H, alkyl, NO2, NO, P(0)(0X8)2, PH(0)(0X8), S(0)kN(alky1)2,
S(0)kX8, S(0)k0X8, COOX8, CONX8, SO3H, COX8, wherein
X8 comprises H, alkyl, carbocyclic ring, heterocyclic ring, aromatic ring,
heteroaromatic ring, or -CX0=CHX10, wherein
X9 and X10 each independently comprise H or alkyl;
m is an integer from 0 to 7;
j is an integer from 0 to about 6; and
k is an integer from 0 to about 2.
In a variation of formula I, R1 and R2 each independently comprise
-(CH2)m - 01 -(CH2)n-Z;
Qi comprises NH, 0, S, CH=CH, CC, CO, SO2 or 0S02;
m is an integer from 1 to about 7;
n is an integer from 0 to about 7; and
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Z comprises a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a
heterotricyclic ring, a polycyclic ring or a heteropolycyclic ring.
In a variation of formula I, R1 and R2 each independently comprise
-(CH2)m - Q1 -(CH2)n-Z;
Qi comprises NH, 0, S, CH=CH, CC, CO, SO2 or 0S02;
m is an integer from 1 to about 7;
n is an integer from 0 to about 7;
Z comprises a carbocyclic ring having about 4 to about 7 ring members, a
heterocyclic ring having about 4 to about 7 ring members, an aromatic ring
having
about 5 to about 7 ring members, a heteroaromatic ring having about 5 to about
7
ring members; a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a
heterotricyclic
ring, a polycyclic ring, a heteropolycyclic ring or any above group
substituted on at
least one available ring atom by an alkyl group or any above group substituted
on at
least one available ring nitrogen atom by a benzyl group, a substituted benzyl
group,
an alkoxybenzyl group, a substituted alkoxybenzyl group, a benzhydryl group or
a
substituted benzhydryl group; and wherein the connecting point between the -
(CH2)n-
group and the Z group can be any available ring carbon atom or any available
ring
nitrogen atom.
In a variation of formula I, R1 and R2 each independently comprise
-(CH2)m - Qi -(CH2)n-Z;
Qi comprises N, 0, S, CH=CH, CC, CO, SO2 or 0S02;
m is an integer from 1 to about 7;
n is an integer from 0 to about 7; and
Z comprises a 5 member unsaturated ring having 0 to 4 independently
selected heteroatoms as. ring members, a substituted 5 member unsaturated ring
having 0 to 4 independently selected heteroatoms as ring members, a 6 member
aromatic ring having 0 to 5 independently selected heteroatoms as ring members
or
a substituted 6 member aromatic ring having 0 to 5 independently selected
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heteroatoms; and wherein the connecting point between the -(CH2)n- group and
the Z
group can be any available ring carbon atom or any available ring nitrogen
atom.
In a variation of formula I R1 and R2 each independently comprise
-(CH2)m- Qi -(CH2)n-Z;
Qi comprises NH, 0, S, CH=CH, Cm-C, CO, SO2 or OS02;
m is an integer from 1 to about 7;
n is an integer from 0 to about 7; and
Z comprises 1-, 2- or 3-pyrrolidinyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or 4-
morpholinyl, 2-, 3- or 4-thiomorpholinyl, 1-, 2- or 3-azetidinyl, 1- or 2-
piperazinyl, 2- or
3-tetrahydrofuranyl; or any above group substituted on at least one available
ring
atom by an alkyl group; or any above group substituted on at least one
available ring
nitrogen atom by a benzyl group, a substituted benzyl group, an alkoxybenzyl
group,
a substituted alkoxybenzyl group, a benzhydryl group or a substituted
benzhydryl
group; and wherein the connecting point between the -(CH2),- group and the Z
group
can be any available ring carbon atom or any available ring nitrogen atom.
In a variation of formula I R1 and R2 each independently comprise
-(CH2)m- Qi -(CH2)n-Z;
Qi comprises N, 0, S, CH=CH, CC, CO, SO2 or OS02;
m is an integer from 1 to about 7;
n is an integer from 0 to about 7;
Z comprises
x
<.Ns ,
y =
X __________________________________ 11¨>-NX
W
x _____________________
N x y y Xy
N N\
Y I N Yor Y
N
\N,.
N
N-W N r
x\\-1, N Y -1CY
X
11
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wherein X and Y each independently comprise, H, halogen, CF3, CF2H, N3,
NCS, CN, NO2, NX1X2, OX3, SX3, OAc, 0S02X3, 0-acyl, S-acyl, S02-alkyl, SO-
alkyl, SC(CH3)2C00X8, OC(CH3)2000X8 , C(CH3)2C00X8, Si(alkyl)3, alkyl-CN,
0-aroyl, 0(CH2)10X3, 0(CH2)iNX1X2, NH-acyl, NH-aroyl, CHO, C(halogen)3, COOX3,
SO3H, SO2NX1X2, CONX1X2, NHC(0)0-alkyl, NHS02-alkyl, alkoxy, alkyl, alcohol,
alkylmercapto, alkylamino, di-alkylamino, alkylsulfinyl or alkylsulfonyl,
CX4X5X6, -
CH=CHX8 , -CmCX8 ;
X1 and X2 each independently comprise H or alkyl, or
X1 and X2 together comprise part of a heterocyclic ring having about 4 to
about
7 ring members and optionally one additional heteroatom selected from 0, N or
S, or
X1 and X2 together comprise part of an imide ring having about 5 to about 6
members,
X3 comprises H, alkyl, NO2, (CH2)mCN, hydroxyloweralkyl, or alkyl-NX1X2,
X4, X5, and X6 each independently comprise H, alkyl, carbocyclic ring,
hydroxyloweralkyl, alkyl-OH, halogen, CN, SNO, S(S02)alkyl, NX1X2, COOX3,
CONX3, OX7, or 0-alkyl-X7, wherein
X7 comprises H, alkyl, NO2, NO, P(0)(OX8)2, PH(0)(0X8), S(0)kN(alky1)2,
S(0)kX8, S(0)k0X8, COOX8, CONX8, SO3H, COX8, wherein
X8 comprises H, alkyl, carbocyclic ring, heterocyclic ring, aromatic ring,
heteroaromatic ring, or -CX9=CHX113, wherein
X9 and X10 each independently comprise H or alkyl;
m is an integer from 0 to 7;
j is an integer from 0 to about 6;
k is an integer from 0 to about 2; and
W comprises H or alkyl
In a variation of formula I R1 and R2 each independently comprise.
-(CH2)m - Qi -(CH2)n-Z;
Qi comprises NH, 0, S, CH=CH, CC, CO, SO2 or 0S02;
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m is an integer from 1 to about 7;
n is an integer from 0 to about 7; and
Z comprises an unsaturated ring having 5 ring atoms and 0 to 2 independently
selected heteroatoms as ring members fused to an unsaturated ring having 5
ring
atoms and 0 to 4 independently selected heteroatoms as ring members, an
unsaturated ring having 5 ring atoms and 0 to 2 independently selected
heteroatoms
as ring members fused to an unsaturated ring having 6 or 7 ring atoms and 0 to
4
independently selected heteroatoms as ring members or an unsaturated ring
having
6 ring atoms and 0 to 4 independently selected heteroatoms as ring members
fused
to an unsaturated ring having 6 or 7 ring atoms and 0 to 4 independently
selected
heteroatoms as ring members.
In a variation of formula I R1 and R2 each independently comprise
-(CH2)rn - Qi -(CH2)n-Z;
Q1 comprises NH, 0, S, CH=C1-1, CC, CO, SO2 or 0S02;
m is an integer from 1 to about 7;
n is an integer from 0 to about 7; and
Z comprises
QFJ
Nv
0 0
,\\H
or
13
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In a variation of formula I R1 and R2 each independently comprise
-T-(C H2)-Z;
n comprises an integer from 0 to about 7;
T comprises a carbocyclic ring having 3 to about 8 ring members, an
unsaturated ring having 3 to about 8 carbon atoms as ring members, an aromatic
ring
having 5 to about 8 carbon atoms as ring members, a heterocyclic ring having 3
to
about 8 ring members, a heteroaromatic ring having 5 to about 8 ring members,
a
bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic
ring, a polycyclic
ring or a heteropolycyclic ring;
Z comprises H, halogen, CF3, CF2H, N3, NCS, CN, NO2, NX1X2, OX3, SX3,
OAc, 0S02X3, 0-
acyl, S-acyl, S02-alkyl, SO-alkyl, SC(CH3)2C00X8,
OC(CH3)2C00X8 , C(CH3)2000X8, Si(alkyl)3, 0-aroyl, 0(CH2)j0X3, 0(CH2)\IX1X2,
alkyl-CN, NH-acyl, NH-aroyl, CHO, C(halogen)3, COOX3, SO3H, SO2NX1X2,
CONX1X2, NHC(0)0-alkyl, NHS02-alkyl, alkoxy, alkyl, alcohol,
alkylmercapto,
alkylamino, di-alkylamino, alkylsulfinyl or alkylsulfonyl, CX4X5X8, -CH=CHX8 ,
X1 and X2 each independently comprise H or alkyl, or
X1 and X2 together comprise part of a heterocyclic ring having about 4 to
about
7 ring members and optionally one additional heteroatom selected from 0, N or
S, or
X1 and X2 together comprise part of an imide ring having about 5 to about 6
members,
X3 comprises H, alkyl, NO2, NO, (CH2)mCN, hydroxyloweralkyl, or alkyl-NX1X2,
X4, X6, and X6 each independently comprise H, alkyl, carbocyclic ring,
hydroxyloweralkyl, alkyl-OH, halogen, CN, SNO, S(S02)alkyl, NX1X2, COOX3,
CONX3, OX7, or 0-alkyl-X7, wherein
X7 comprises H, alkyl, NO2, NO, P(0)(0X8)2, PH(0)(0X8), S(0)kN(alky1)2,
S(0)kX8, S(0)k0X8, COOX8, CONX8, SO3H, COX8, wherein
X8 comprises H, alkyl, carbocyclic ring, heterocyclic ring, aromatic ring,
heteroaromatic ring, or -CX0=CHX10, wherein
X9 and X10 each independently comprise H or alkyl;
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m is an integer from 0 to 7;
j is an integer from 0 to about 6; and
k is an integer from 0 to about 2
In a variation of formula I R1 and R2 each independently comprise
-T-(C H2)-Z;
n comprises an integer from 0 to about 7;
T comprises a carbocyclic ring having 3 to about 8 ring members, an
unsaturated ring having 3 to about 8 carbon atoms as ring members, an aromatic
ring
having 5 to about 8 carbon atoms as ring members, a heterocyclic ring having 3
to
about 8 ring members, a heteroaromatic ring having 5 to about 8 ring members,
a
bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic
ring, a polycyclic
ring or a heteropolycyclic ring; and
Z comprises a carbocyclic ring having about 4 to about 7 ring members, a
heterocyclic ring having about 4 to about 7 ring members, an aromatic ring
having
about 5 to about 7 ring members, a heteroaromatic ring having about 5 to about
7
ring members, a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a
heterotricyclic
ring, a polycyclic ring, a heteropolycyclic ring; or any above group
substituted on at
least one available ring atom by an alkyl group; or any above group
substituted on at
least one available ring nitrogen atom by a benzyl group, a substituted benzyl
group,
an alkoxybenzyl group, a substituted alkoxybenzyl group, a benzhydryl group or
a
substituted benzhydryl group; and wherein the connecting point between the -
(CH2)n-
group and the Z group can be any available ring carbon atom or any available
ring
nitrogen atom.
In a variation of formula I R1 and R2 each independently comprise
-T-(C H2)-Z;
n comprises an integer from 0 to about 7;
T comprises a carbocyclic ring having 3 to about 8 ring members, an
unsaturated ring having 3 to about 8 carbon atoms as ring members, an aromatic
ring
having 5 to about 8 carbon atoms as ring members, a heterocyclic ring having 3
to
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about 8 ring members, a heteroaromatic ring having 5 to about 8 ring members,
a
bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic
ring, a polycyclic
ring or a heteropolycyclic ring; and
Z comprises 1-, 2- or 3-pyrrolidinyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or 4-
morpholinyl, 2-, 3- or 4-thiomorpholinyl, 1-, 2- or 3-azetidinyl, 1- or 2-
piperazinyl, 2- or
3-tetrahydrofuranyl; or any above group substituted on at least one available
ring
atom by an alkyl group; or any above group substituted on at least one
available ring
nitrogen atom by a benzyl group, a substituted benzyl group, an alkoxybenzyl
group,
a substituted alkoxybenzyl group, a benzhydryl group or a substituted
benzhydryl
group; and wherein the connecting point between the -(CH2)n- group and the Z
group
can be any available ring carbon atom or any available ring nitrogen atom.
In a variation of formula I R1 and R2 each independently comprise
-T-(CH2)n-Z;
n comprises an integer from 0 to about 7;
T comprises a carbocyclic ring having 3 to about 8 ring members, an
unsaturated ring having 3 to about 8 carbon atoms as ring members, an aromatic
ring
having 5 to about 8 carbon atoms as ring members, a heterocyclic ring having 3
to
about 8 ring members, a heteroaromatic ring having 5 to about 8 ring members,
a
bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic
ring, a polycyclic
ring or a heteropolycyclic ring;
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Z comprises
at X
N\'SX \yµ14--N x
y , W Y
rµY-4_y S Y el Y N
01 Yor ee
Xy
y
\ N \ N
N N N
N'r
X\\-- 1 / )(\\ N Y y
X
wherein X and Y each independently comprise, H, halogen, CF3, CF2H, N3,
NCS, CN, NO2, NX1X2, OX3, SX3, OAc, 0S02X3, 0-acyl, S-acyl, S02-alkyl, SO-
alkyl,
SC(CH3)2C00X8, OC(CH3)2C00X8 , C(CH3)2C00X8, Si(alkyl)3, alkyl-CN, 0-aroyl,
0(CH2)i0X3, 0(CH2)JNX1X2, NH-acyl, NH-aroyl, CHO, C(halogen)3, COOX3, SO3H,
SO2NX1X2, CONX1X2, NHC(0)0-alkyl, NHS02-alkyl, alkoxy, alkyl, alcohol,
alkylmercapto, alkylamino, di-alkylamino, alkylsulfinyl or alkylsulfonyl,
CX4X5X6, -
CH=CHX8 , ;
X1 and X2 each independently comprise H or alkyl, or
X1 and X2 together comprise part of a heterocyclic ring having about 4 to
about
7 ring members and optionally one additional heteroatom selected from 0, N or
S, or
X1 and X2 together comprise part of an imide ring having about 5 to about 6
members,
X3 comprises H, alkyl, NO2, (CH2)mCN, hydroxyloweralkyl, or alkyl-NX1X2,
X4, X5, and X6 each independently comprise H, alkyl, carbocyclic ring,
hydroxyloweralkyl, alkyl-OH, halogen, CN, SNO, S(S02)alkyl, NX1X2, COOX3,
CONX3, OX7, or 0-alkyl-X7 wherein
X7 comprises H, alkyl, NO2, NO, P(0)(0X8)2, PH(0)(0X8), S(0)kN(alky1)2,
S(0)kX8, S(0)k0X8, 000X8, CONX8, SO3H, COX8, wherein
X8 comprises H, alkyl, carbocyclic ring, heterocyclic ring, aromatic ring,
heteroaromatic ring, or -CX9=CHX10 wherein
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X9 and X10 each independently comprise H or alkyl;
m is an integer from 0 to 7;
j is an integer from 0 to about 6;
k is an integer from 0 to about 2; and
W comprises H or alkyl.
In a variation of formula I R1 and R2 each independently comprise
-T-(CH2)n-Z;
n comprises an integer from 0 to about 7;
T comprises a carbocyclic ring having 3 to about 8 ring members, an
unsaturated ring having 3 to about 8 carbon atoms as ring members, an aromatic
ring
having 5 to about 8 carbon atoms as ring members, a heterocyclic ring having 3
to
about 8 ring members, a heteroaromatic ring having 5 to about 8 ring members,
a
bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic
ring, a polycyclic
ring or a heteropolycyclic ring;
Z comprises an unsaturated ring having 5 ring atoms and 0 to 2 independently
selected heteroatoms as ring members fused to an unsaturated ring having 5
ring
atoms and 0 to 4 independently selected heteroatoms as ring members, an
unsaturated ring having 5 ring atoms and 0 to 2 independently selected
heteroatoms
as ring members fused to an unsaturated ring having 6 or 7 ring atoms and 0 to
4
independently selected heteroatoms as ring members or an unsaturated ring
having
6 ring atoms and 0 to 3 independently selected heteroatoms as ring members
fused
to an unsaturated ring having 6 or 7 ring atoms and 0 to 4 independently
selected
heteroatoms as ring members.
In a variation of formula I R1 and R2 each independently comprise -T-(CH2)n-
Qi -(CH2)n-Z;
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each n independently comprises an integer from 0 to about 7;
T comprises a carbocyclic ring having 3 to about 8 ring members, an
unsaturated ring having 3 to about 8 carbon atoms as ring members, an aromatic
ring
having 5 to about 8 carbon atoms as ring members, a heterocyclic ring having 3
to
about 8 ring members, a heteroaromatic ring having 5 to about 8 ring members,
a
bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic
ring, a polycyclic
ring or a heteropolycyclic ring;
Qi comprises NH, 0, S, CH=CH, CC, CO, SO2 or 0S02;
Z comprises H, halogen, CF3, CF2H, N3, NCS, CN, NO2, NX1X2, OX3, SX3,
OAc, 0S02X3, 0-
acyl, S-acyl, S02-alkyl, SO-alkyl, SC(CH3)2C00X8,
OC(CH3)2C00X8 , C(CH3)2C00X8, Si(alkyl)3, 0-aroyl, 0(CH2)i0X3, 0(CH2)iNX1X2,
alkyl-CN, NH-acyl, NH-aroyl, CHO, C(halogen)3, COOX3, SO3H, SO2NX1X2,
CONX1X2, NHC(0)0-alkyl, NHS02-alkyl, alkoxy, alkyl, alcohol,
alkylmercapto,
alkylamino, di-alkylamino, alkylsulfinyl or alkylsulfonyl, CX4X5X6, -CH=CHX8 ,
-CCX8
X1 and X2 each independently comprise H or alkyl, or
X1 and X2 together comprise part of a heterocyclic ring having about 4 to
about
7 ring members and optionally one additional heteroatom selected from 0, N or
S, or
X1 and X2 together comprise part of an imide ring having about 5 to about 6
members,
X3 comprises H, alkyl, NO2, NO, (CH2)mCN, hydroxyloweralkyl, or alkyl-NX1X2,
X4, X5, and X8 each independently comprise H, alkyl, carbocyclic ring,
hydroxyloweralkyl, alkyl-OH, halogen, CN, SNO, S(S02)alkyl, NX1X2, COOX3,
CONX3, OX7, or 0-alkyl-X7, wherein
X7 comprises H, alkyl, NO2, NO, P(0)(0X8)2, PH(0)(0X8), S(0)kN(alky1)2,
S(0)kX8, S(0)k0X8, COOX8, CONX8, SO3H, COX8, wherein
X8 comprises H, alkyl, carbocyclic ring, heterocyclic ring, aromatic ring,
heteroaromatic ring, or -CX9=CHX10, wherein
X9 and X10 each independently comprise H or alkyl;
m is an integer from 0 to 7;
j is an integer from 0 to about 6; and
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k is an integer from 0 to about 2
In a variation of formula I R1 and R2 each independently comprise -T-(CH2)n-
Qi -(CH-Z;
each n independently comprises an integer from 0 to about 7;
T comprises a carbocyclic ring having 3 to about 8 ring members, an
unsaturated ring having 3 to about 8 carbon atoms as ring members, an aromatic
ring
having 5 to about 8 carbon atoms as ring members, a heterocyclic ring having 3
to
about 8 ring members, a heteroaromatic ring having 5 to about 8 ring members,
a
bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic
ring, a polycyclic
ring or a heteropolycyclic ring;
Qi comprises NH, 0, S, CH=CH, CC, CO, SO2 or 0S02;
Z comprises a carbocyclic ring having about 4 to about 7 ring members, a
heterocyclic ring having about 4 to about 7 ring members, an aromatic ring
having
about 5 to about 7 ring members, a heteroaromatic ring having about 5 to about
7
ring members, a bicyclic ring, a heterobicyclic ring, a polycyclic ring, a
heteropolycyclic ring; or any above group substituted on at least one
available ring
atom by an alkyl group; or any above group substituted on at least one
available ring
nitrogen atom by a benzyl group, a substituted benzyl group, an alkoxybenzyl
group,
a substituted alkoxybenzyl group, a benzhydryl group or a substituted
benzhydryl
group; and wherein the connecting point between the -(CH2)n- group and the Z
group
can be any available ring carbon atom or any available ring nitrogen atom.
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In a variation of formula I R1 and R2 each independently comprise -T-(CH2)n-
Qi -(CH-Z;
each n independently comprises an integer from 0 to about 7;
T comprises a carbocyclic ring having 3 to about 8 ring members, an
unsaturated ring having 3 to about 8 carbon atoms as ring members, an aromatic
ring
having 5 to about 8 carbon atoms as ring members, a heterocyclic ring having 3
to
about 8 ring members, a heteroaromatic ring having 5 to about 8 ring members,
a
bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic
ring, a polycyclic
ring or a heteropolycyclic ring;
Qi comprises NH, 0, S, CH=CH, CC, CO, SO2 or 0S02;
Z comprises 1-, 2- or 3-pyrrolidinyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or 4-
morpholinyl, 2-, 3- or 4-thiomorpholinyl, 1-, 2- or 3-azetidinyl, 1- or 2-
piperazinyl, 2- or
3-tetrahydrofuranyl; or any above group substituted on at least one available
ring
atom by an alkyl group; or any above group substituted on at least one
available ring
nitrogen atom by a benzyl group, a substituted benzyl group, an alkoxybenzyl
group,
a substituted alkoxybenzyl group, a benzhydryl group or a substituted
benzhydryl
group; and wherein the connecting point between the -(CH2)n- group and the Z
group
can be any available ring carbon atom or any available ring nitrogen atom.
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In a variation of formula I R1 and R2 each independently comprise -T-(CH2)n-
Qi -(CH-Z;
each n independently comprises an integer from 0 to about 7;
T comprises a carbocyclic ring having 3 to about 8 ring members, an
unsaturated ring having 3 to about 8 carbon atoms as ring members, an aromatic
ring
having 5 to about 8 carbon atoms as ring members, a heterocyclic ring having 3
to
about 8 ring members, a heteroaromatic ring having 5 to about 8 ring members,
a
bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic
ring, a polycyclic
ring or a heteropolycyclic ring;
Q1 comprises NH, 0, S, CH=CH, CC, CO, SO2 or 0S02;
Z comprises
?,NO KNs , W X _ii\i- -NX
\
X X Y _____________ N N
X X X
X X
el N Yor 0.
N
\N. \ N
N N N N-W
\\- 1 / xY x
wherein X and Y each independently comprise, H, halogen, CF3, CF2H, N3,
NCS, CN, NO2, NX1X2, OX3, SX3, OAc, 0S02X3, 0-acyl, S-acyl, S02-alkyl, SO-
alkyl, SC(CH3)2C00X8, OC(CH3)2000X8 , C(CH3)2C00X8, Si(alkyl)3, alkyl-CN,
0-aroyl, 0(CH2)i0X3, 0(CH2)JNX1X2, NH-acyl, NH-aroyl, CHO, C(halogen)3, COOX3,
SO3H, SO2NX1X2, CONX1X2, NHC(0)0-alkyl, NHS02-alkyl, alkoxy, alkyl, alcohol,
alkylmercapto, alkylamino, di-alkylamino, alkylsulfinyl or alkylsulfonyl,
CX4X5X6, -
CH=CHX8 , -CCX8 ;
Xi and X2 each independently comprise H or alkyl, or
X1 and X2 together comprise part of a heterocyclic ring having about 4 to
about
7 ring members and optionally one additional heteroatom selected from 0, N or
S, or
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X1 and X2 together comprise part of an imide ring having about 5 to about 6
members,
X3 comprises H, alkyl, NO2, (CH2)mCN, hydroxyloweralkyl, or alkyl-NX1X2,
X4, X6, and X6 each independently comprise H, alkyl, carbocyclic ring,
hydroxyloweralkyl, alkyl-OH, halogen, CN, SNO, S(S02)alkyl, Nk1X2, COOX3,
CONX3, 0)(7, or 0-alkyl-X7, wherein
X7 comprises H, alkyl, NO2, NO, P(0)(0)(02, PI-1(0)(0M, S(0)kN(alkyl)2,
S(0)kX8, S(0)k0X8, COOX8, CONX8, SO3H, COX8, wherein
X8 comprises H, alkyl, carbocyclic ring, heterocyclic ring, aromatic ring,
heteroaromatic ring, or ¨CX9=CHX10, wherein
X9 and X10 each independently comprise H or alkyl;
m is an integer from 0 to 7;
j is an integer from 0 to about 6;
k is an integer from 0 to about 2; and
W comprises H or alkyl.
In a variation of formula I R1 and R2 each independently comprise ¨T¨(CH2)n¨
Qi ¨(CH2)n¨Z;
each n independently comprises an integer from 0 to about 7;
T comprises a carbocyclic ring having 3 to about 8 ring members, an
unsaturated ring having 3 to about 8 carbon atoms as ring members, an aromatic
ring
having 5 to about 8 carbon atoms as ring members, a heterocyclic ring having 3
to
about 8 ring members, a heteroaromatic ring having 5 to about 8 ring members,
a
bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic
ring, a polycyclic
ring or a heteropolycyclic ring;
Qi comprises NH, 0, S, CH=CH, CC, CO, SO2 or OS02; and
Z comprises an unsaturated ring having 5 ring atoms and 0 to 2 independently
selected heteroatoms as ring members fused to an unsaturated ring having 5
ring
atoms and 0 to 2 independently selected heteroatoms as ring members, an
unsaturated ring having 5 ring atoms and 0 to 2 independently selected
heteroatoms
as ring members fused to an unsaturated ring having 6 or 7 ring atoms and 0 to
4
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independently selected heteroatoms as ring members or an unsaturated ring
having
6 ring atoms and 0 to 3 independently selected heteroatoms as ring members
fused
to an unsaturated ring having 6 or 7 ring atoms and 0 to 4 independently
selected
heteroatoms as ring members.
In a variation of formula I, R1 and R2 each independently comprise
-T-(CI-12)n- Q1 -(CH-Z;
T comprises a carbocyclic ring having 3 to about 8 ring members, an
unsaturated ring having 3 to about 8 carbon atoms as ring members, an aromatic
ring
having 5 to about 8 carbon atoms as ring members, a heterocyclic ring having 3
to
about 8 ring members, a heteroaromatic ring having 5 to about 8 ring members,
a
bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic
ring, a polycyclic
ring or a heteropolycyclic ring;
each n independently comprises an integer from 0 to about 7;
Qi comprises NH, 0, S, CH=CH, CC, CO, SO2 or 0S02;
Z comprises:
-N/ )--E or -N N-E
wherein E comprises a C1 to about C4, linear or branched alkyl group, a
phenyl group, a substituted phenyl group, a benzyl group or a substituted
benzyl
group.
In a variation of formula I, R1 and R2 each independently comprise
-T-(C1-12)n- Q1 -(CH-Z;
T comprises a carbocyclic ring having 3 to about 8 ring members, an
unsaturated ring having 3 to about 8 carbon atoms as ring members, an
aromatic ring having 5 to about 8 carbon atoms as ring members, a
heterocyclic ring having 3 to about 8 ring members, a heteroaromatic ring
having 5 to about 8 ring members, a bicyclic ring, a heterobicyclic ring, a
tricyclic ring, a heterotricyclic ring, a polycyclic ring or a
heteropolycyclic ring;
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each n independently comprises an integer from 0 to about 7;
Q1 comprises NH, 0, S, CH=CH, CC, CO, SO2 or 0S02;
Z comprises
___________________________________ 0 0
¨
H
¨NO ¨NI _______________
\(CH2)k <(CH2)k <(CH2)k N \ or
wherein k is an integer from 1 to about 5. A1 and A2 each
independently comprise a Cl to about C4 alkyl group, a phenyl group
or a substituted phenyl group.
In a variation of formula I, R3 comprises
a carbocyclic ring having about 4 to about 7 members, a heterocyclic ring
having about 4 to about 7 members, an aromatic ring having about 5 to about 7
ring
members, a heteroaromatic ring having about 5 to about 7 members, a bicyclic
ring,
a heterobicyclic ring, a tricyclic ring, a heterotricyclic ring, a polycyclic
ring or a
heteropolycyclic ring.
J¨K
In a variation of formula I, R3 comprises
wherein G comprises CH, C(CH3), C(CN) or N;
L, K and J each independently comprise (CH2)n, (CH3)2, C=0, 0, -
CHOH, C(CH3)0M1, C(CH2)n(X)Y, NMi, SO2 SO or S;
n is an integer from 0 to about 7;
M1 is H, alkyl, C(0)M2, wherein
M2 is H, alkyl, NM3M4, 0M5 and M3, M4 and M5 are independently H,
OH or alkyl,and
X and Y each independently comprise, H, halogen, CF3, CF2H, N3,
NCS, CN, NO2, NX1X2, OX3, SX3, OAc, OSO2X3, 0-acyl, S-acyl, S02-alkyl,
SO-alkyl, SC(CH3)2C00X8, OC(CH3)2COOX8 C(CH3)2C00X8,
Si(alkyl)3,
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alkyl-CN, 0-
aroyl, 0(CH2)i0X3, 0(CH2)iNX1X2, NH-acyl, NH-aroyl, CHO,
C(halogen)3, COOX3, SOH, SO2NX1X2, CONX1X2, NHC(0)0-alkyl, NHS02-
alkyl, alkoxy, alkyl, alcohol,
alkylmercapto, alkylamino, di-alkylamino,
alkylsulfinyl or alkylsulfonyl, CX4X5X6, -CH=CHX8 , ;
X1 and X2 each independently comprise H or alkyl, or
X1 and X2 together comprise part of a heterocyclic ring having about 4 to
about
7 ring members and optionally one additional heteroatom selected from 0, N or
S, or
X1 and X2 together comprise part of an imide ring having about 5 to about 6
members,
X3 comprises H, alkyl, NO2, (CH2)mCN, hydroxyloweralkyl, or alkyl-NX1X2,
X4, X8, and X8 each independently comprise H, alkyl, carbocyclic ring,
hydroxyloweralkyl, alkyl-OH, halogen, CN, SNO, S(S02)alkyl, NX1X2, COOX3,
CONX3, OX7, or 0-alkyl-X7, wherein
X7 comprises H, alkyl, NO2, NO, P(0)(0X8)2, PH(0)(0X8), S(0)kN(alkyl)2,
S(0)kX8, S(0)k0X8, COOX8, CONX8, SO3H, COX8, wherein
X8 comprises H, alkyl, carbocyclic ring, heterocyclic ring, aromatic ring,
heteroaromatic ring, or -CX9=CHX10, wherein
X9 and X10 each independently comprise H or alkyl;
m is an integer from 0 to 7;
j is an integer from 0 to about 6; and
k is an integer from 0 to about 2.
In a variation of formula I, R3 comprises e
wherein G, L and J each independently comprise CH or N.
In a variation of formula I, R3 comprises
1:Ti( o
26 r
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X
N y
W
X; N X X =X \)ç/;( y ___ y Ny , y ''or
N
\fµl \N
N N N
XN\-- I / N Y __
X
wherein X and Y each independently comprise, H, halogen, CF3, CF2H, N3,
NCS, CN, NO2, NX1X2, OX3, SX3, OAc, 0S02X3, 0-acyl, S-acyl, S02-alkyl, SO-
alkyl, SC(CH3)2C00X8, OC(CH3)2C00X8 , C(CH3)2C00X8, Si(alkyl)3, alkyl-CN, 0-
aroyl, 0(CH2),OX3, 0(CH2)JNX1X2, NH-acyl, NH-aroyl, CHO, C(halogen)3, COOX3,
SO3H, SO2NX1X2, CONX1X2, NHC(0)0-alkyl, NHS02-alkyl, alkoxy, alkyl, alcohol,
alkylmercapto, alkylamino, di-alkylamino, alkylsulfinyl or alkylsulfonyl,
CX4X5X6, -
CH=CHX8 , -CCX8 ;
X1 and X2 each independently comprise H or alkyl, or
X1 and X2 together comprise part of a heterocyclic ring having about 4 to
about
7 ring members and optionally one additional heteroatom selected from 0, N or
S, or
X1 and X2 together comkrise part of an imide ring having about 5 to about 6
members,
X3 comprises H, alkyl, NO2, (CH2)mCN, hydroxyloweralkyl, or alkyl-NX1X2,
X4, X5, and X6 each independently comprise H, alkyl, carbocyclic ring,
hydroxyloweralkyl, alkyl-OH, halogen, CN, SNO, S(S02)alkyl, NX1X2, COOX3,
CONX3, OX7, or 0-alkyl-X7, wherein
X7 comprises H, alkyl, NO2, NO, P(0)(0X8)2, PH(0)(0X8), S(0)kN(alkyl)2,
S(0)kX8, S(0)k0X8, COOX8, CONX8, SO3H, COX8, wherein
X8 comprises H, alkyl, carbocyclic ring, heterocyclic ring, aromatic ring,
heteroaromatic ring, or -CX9=CHX10, wherein
X9 and X10 each independently comprise H or alkyl;
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m is an integer from 0 to 7;
j is an integer from 0 to about 6;
k is an integer from 0 to about 2; and
W comprises H or alkyl.
In a variation of formula I, R3 comprises a carbocyclic ring having 6 ring
atoms
fused to a heterocyclic ring having from 5 to 7 ring atoms, a carbocyclic ring
having 6
ring atoms fused to a heteroaromatic ring having from 5 to 7 ring atoms, a
heterocyclic ring having 6 ring atoms fused to a heterocyclic ring having from
5 to 7
ring atoms, a heterocyclic ring having 6 ring atoms fused to a heteroaromatic
ring
having from 5 to 7 ring atoms, an aromatic ring having 6 ring atoms fused to a
heterocyclic ring having from 5 to 7 ring atoms, an aromatic ring having 6
ring atoms
fused to a heteroaromatic ring having from 5 to 7 ring atoms, a heteroaromatic
ring
having 6 ring atoms fused to a heterocyclic ring having from 5 to 7 ring atoms
or a
heteroaromatic ring having 6 ring atoms fused to a heteroaromatic ring having
from 5
to 7 ring atoms.
In a variation of formula I, R4
comprises H, halogen, CF3, CF2H, N3, NCS, CN, NO2, phenyl, NX1X2, OX3,
SX3, OAc, 0S02X3, 0-acyl, S-acyl, S02-alkyl, SO-alkyl, SC(CH3)2C00X8,
OC(CH3)2C00X8 , C(CH3)2C00X8, Si(alkyl)3, alkyl-CN, 0-
aroyl, 0(CH2)j0X3,
0(CH2)iNX1X2, NH-acyl, NH-aroyl, CHO, C(halogen)3, COOX3, SO3H, SO2NX1X2,
CONX1X2, NHC(0)0-alkyl, NHS02-alkyl, alkoxy, alkyl, alcohol, alkylmercapto,
alkylamino, di-alkylamino, alkylsulfinyl or alkylsulfonyl, CX4X5X8, -CH=CHX8 ,
-CECX8
X1 and X2 each independently comprise H or alkyl, or
X1 and X2 together comprise part of a heterocyclic ring having about 4 to
about
7 ring members and optionally one additional heteroatom selected from 0, N or
S, or
X1 and X2 together comprise part of an imide ring having about 5 to about 6
members,
X3 comprises H, alkyl, NO2, (CH2)mCN, hydroxyloweralkyl, or alkyl-NX1X2,
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X4, X5, and X6 each independently comprise H, alkyl, carbocyclic ring,
hydroxyloweralkyl, alkyl-OH, halogen, CN, SNO, S(S02)alkyl, NX1X2, COOX3,
CONX3, OX7, or 0-alkyl-X7, wherein
X7 comprises H, alkyl, NO2, NO, P(0)(0X8)2, PH(0)(0X8), S(0)kN(alky1)2,
S(0)kX8, S(0)k0X8õ COOX8, CONX8, SO3H, COX8, wherein
X8 comprises H, alkyl, carbocyclic ring, heterocyclic ring, aromatic ring,
heteroaromatic ring, or ¨CX0=CHX10, wherein
X9 and X10 each independently comprise H or alkyl;
m is an integer from 0 to 7;
j is an integer from 0 to about 6; and
k is an integer from 0 to about 2.
In a variation of formula I, R4 comprises a carbocyclic ring having about 4 to
about 7 ring members, a heterocyclic ring having about 4 to about 7 ring
members,
an aromatic ring having about 5 to about 7 ring members, a heteroaromatic ring
having about 5 to about 7 ring members, a bicyclic ring, a heterobicyclic
ring, a
tricyclic ring, a heterotricyclic ring, a polycyclic ring or a
heteropolycyclic ring.
In an advantageous variation of formula I, R4 comprises
0 0
, H N 0
or
In a variation of formula I, R4 comprises ¨(CH2)d¨Z;
d is an integer from 1 to about 6;
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comprises H, halogen, CF3, CF2H, N3, NCS, CN, NO2, phenyl, NX1X2, OX3,
SX3, OAc, 0S02X3, 0-acyl, S-acyl, S02-alkyl, SO-alkyl, SC(CH3)2C00X8,
OC(CH3)2C00X8 , C(CH3)2C00X8, Si(alkyl)3, alkyl-CN, 0-
aroyl, 0(CH2)JOX3,
0(CH2)1r1X1X2, NH-acyl, NH-aroyl, CHO, C(halogen)3, COOX3, SO3H, SO2NX1X2,
CONX1X2, NHC(0)0-alkyl, NHS02-alkyl, alkoxy, alkyl, alcohol, alkylmercapto,
alkylamino, di-alkylamino, alkylsulfinyl or alkylsulfonyl, CX4X8X8, -CH=CHX8 ,
-CCX8
X1 and X2 each independently comprise H or alkyl, or
X1 and X2 together comprise part of a heterocyclic ring having about 4 to
about
7 ring members and optionally one additional heteroatom selected from 0, N or
S, or
X1 and X2 together comprise part of an imide ring having about 5 to about 6
members,
X3 comprises H, alkyl, NO2, (CH2)mCN, hydroxyloweralkyl, or alkyl-NX1X2,
X4, X6, and X6 each independently comprise H, alkyl, carbocyclic ring,
hydroxyloweralkyl, alkyl-OH, halogen, CN, SNO, S(S02)alkyl, NX1X2, COOX3,
CONX3, OX7, or 0-alkyl-X7, wherein
X7 comprises H, alkyl, NO2, NO, P(0)(0X8)2, PH(0)(0X8), S(0)kN(alkyl)2,
S(0)kX8, S(0)k0X8, COOX8, CONX8, SO3H, COX8, wherein
X8 comprises H, alkyl, carbocyclic ring, heterocyclic ring, aromatic ring,
heteroaromatic ring, or -CX0=CHX10, wherein
X9 and X10 each independently comprise H or alkyl;
m is an integer from 0 to 7;
j is an integer from 0 to about 6; and
k is an integer from 0 to about 2.
In a variation of formula I, R4 comprises -CH2OH or -CH2Oalkyl.
In a variation of formula I, R4 comprises -(CH2)d-Z;
d is an integer from 1 to about 6; and
Z comprises a carbocyclic ring having about 4 to about 7 ring members, a
heterocyclic ring having about 4 to about 7 ring members, an aromatic ring
having
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about 5 to about 7 ring members, a heteroaromatic ring having about 5 to about
7
ring members, a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a
heterotricyclic
ring, a polycyclic ring, a heteropolycyclic ring; or any above group
substituted on at
least one available ring atom by an alkyl group; or any above group
substituted on at
least one available ring nitrogen atom by a benzyl group, a substituted benzyl
group,
an alkoxybenzyl group, a substituted alkoxybenzyl group, a benzhydryl group or
a
substituted benzhydryl group; and wherein the connecting point between the -
(CH2)d-
group and the Z group can be any available ring carbon atom or any available
ring
nitrogen atom.
In a variation of formula I, R4 comprises -(CH2)d-Z;
d is an integer from 1 to about 6; and
Z comprises 1-, 2- or 3-pyrrolidinyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or 4-
morpholinyl, 2-, 3- or 4-thiomorpholinyl, 1-, 2- or 3-azetidinyl, 1- or 2-
piperazinyl, 2- or
3-tetrahydrofuranyl; or any above group substituted on at least one ring atom
by an
alkyl group; or any above group substituted on at least one available ring
nitrogen
atom by a benzyl group, a substituted benzyl group, an alkoxybenzyl group, a
substituted alkoxybenzyl group, a benzhydryl group or a substituted benzhydryl
group; and wherein the connecting point between the -(CH2)d- group and the Z
group
can be any available ring carbon atom or any available ring nitrogen atom.
In a variation of formula I, R4 comprises -(CH2 )m - Q1 -(CH2)n-Z;
Qi comprises NH, 0, S, CH=CH, C1=-C, CO, SO2 or 0S02;
m is an integer from 1 to about 7;
n is an integer from 0 to about 7;
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Z comprises H, halogen, CF3, CF2H, N3, NCS, CN, NO2, phenyl, NX1X2, OX3,
SX3, OAc, 0S02X3, 0-acyl, S-acyl, S02-alkyl, SO-alkyl, SC(CH3)2C00X8,
OC(CH3)2C00X8 , C(CH3)2C00X8, Si(alkyl)3, alkyl-CN, 0-
aroyl, 0(CH2)10X3,
0(CH2)1NX1X2, NH-acyl, NH-aroyl, CHO, C(halogen)3, COOX3, SO3H, SO2NX1X2,
CONX1X2, NHC(0)0-alkyl, NHS02-alkyl, alkoxy, alkyl, alcohol, alkylmercapto,
alkylamino, di-alkylamino, alkylsulfinyl or alkylsulfonyl, CX4X5X6, -CH=CHX8 ,
-CCX8
X1 and X2 each independently comprise H or alkyl, or
X1 and X2 together comprise part of a heterocyclic ring having about 4 to
about
7 ring members and optionally one additional heteroatom selected from 0, N or
S, or
X1 and X2 together comprise part of an imide ring having about 5 to about 6
members,
X3 comprises H, alkyl, NO2, (CH2)mCN, hydroxyloweralkyl, or alkyl-NX1X2,
X4, X5, and X6 each independently comprise H, alkyl, carbocyclic ring,
hydroxyloweralkyl, alkyl-OH, halogen, CN, SNO, S(S02)alkyl, NX1X2, COOX3,
CONX3, OX7, or 0-alkyl-X7, wherein
X7 comprises H, alkyl, NO2, NO, P(0)(0X8)2, PH(0)(0X8), S(0)kN(alky1)2,
S(0)kX8, S(0)k0X8, COOX8, CONX8, SO3H, COX8, wherein
X8 comprises H, alkyl, carbocyclic ring, heterocyclic ring, aromatic ring,
heteroaromatic ring, or -CX9=CHX10, wherein
X9 and X10 each independently comprise H or alkyl;
m is an integer from 0 to 7;
j is an integer from 0 to about 6; and
k is an integer from 0 to about 2.
In a variation of formula I, R4 comprises -(CH2)m - Q1 -(CH2)n-Z;
Qi comprises NH, 0, S, CH=CH, CC, CO, SO2 or OS02;
m is an integer from 1 to about 7;
n is an integer from 0 to about 7; and
Z comprises a carbocyclic ring having about 4 to about 7 ring members, a
heterocyclic ring having about 4 to about 7 ring members, an aromatic ring
having
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about 5 to about 7 ring members, a heteroaromatic ring having about 5 to about
7
ring members; a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a
heterotricyclic
ring, a polycyclic ring, a heteropolycyclic ring; or any above group
substituted on at
least one available ring atom by an alkyl group; or any above group
substituted on at
least one available ring nitrogen atom by a benzyl group, a substituted benzyl
group,
an alkoxybenzyl group, a substituted alkoxybenzyl group, a benzhydryl group or
a
substituted benzhydryl group; and wherein the connecting point between the -
(CH2)n-
group and the Z group can be any available ring carbon atom or any available
ring
nitrogen atom.
In a variation of formula I R4 comprises ¨(CH2)m ¨ Q1 ¨(CH2)n¨Z.
Qi comprises NH, 0, S, CH=CH, CC, CO, SO2 or 0S02.
m is an integer from 1 to about 7.
n is an integer from 0 to about 7.
Z comprises 1-, 2- or 3-pyrrolidinyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or 4-
morpholinyl, 2-, 3- or 4-thiomorpholinyl, 1-, 2- or 3-azetidinyl, 1- or 2-
piperazinyl, 2- or
3-tetrahydrofuranyl; or any above group substituted on at least one available
ring
atom by an alkyl; or any above group substituted on at least one available
ring
nitrogen atom by a benzyl group, a substituted benzyl group, an alkoxybenzyl
group,
a substituted alkoxybenzyl group, a benzhydryl group or a substituted
benzhydryl
group; and wherein the connecting point between the -(CH2)n- group and the Z
group
can be any available ring carbon atom or any available ring nitrogen atom.
In a variation of formula I R4 comprises ¨(CH2)m ¨ Q1 ¨(CH2)n¨Z.
Qi comprises NH, 0, S, CH=CH, CC, CO, SO2 or 0S02. =
m is an integer from 1 to about 7.
n is an integer from 0 to about 7.
Z comprises
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kX p Ks \-N jax
Wy, N- Y, N
N; ,X __ y X Ny ___ y 0\_;111 Y el Y el N N Yor
ee Y
N NN N
X\\-- I / )(\=\ N Y \ky
X
wherein X and Y each independently comprise, H, halogen, CF3, CF2H, N3,
NCS, CN, NO2, NX1X2, OX3, SX3, OAc, 0S02X3, 0-acyl, S-acyl, S02-alkyl, SO-
alkyl,
SC(CH3)2C00X8, OC(CH3)2C00X8 , C(CH3)2C00X8, Si(alkyl)3, alkyl-CN, 0-aroyl,
0(CH2)i0X3, 0(CH2)iNX1X2, NH-acyl, NH-aroyl, CHO, C(halogen)3, COOX3, SO3H,
SO2NX1X2, CONX1X2, NHC(0)0-alkyl, NHS02-alkyl alkoxy, alkyl, alcohol,
alkylmercapto, alkylamino, di-alkylamino, alkylsulfinyl or alkylsulfonyl,
CX4X5X6, -
CH=CHX8 , -CCX8 ;
X1 and X2 each independently comprise H or alkyl, or
X1 and X2 together comprise part of a heterocyclic ring having about 4 to
about
7 ring members and optionally one additional heteroatom selected from 0, N or
S, or
X1 and X2 together comprise part of an imide ring having about 5 to about 6
members,
X3 comprises H, alkyl, NO2, (CH2)mCN, hydroxyloweralkyl, or alkyl-NX1X2,
X4, X6, and X6 each independently comprise H, alkyl, carbocyclic ring,
hydroxyloweralkyl, alkyl-OH, halogen, CN, SNO, S(S02)alkyl, NX1X2, COOX3,
CONX3, OX7, or 0-alkyl-X7, wherein
X7 comprises H, alkyl, NO2, NO, P(0)(0X8)2, PH(0)(0X8), S(0)kN(alkyl)2,
S(0)kX8, S(0)k0X8, COOX8, CONX8, SO3H, COX8, wherein
X8 comprises H, alkyl, carbocyclic ring, heterocyclic ring, aromatic ring,
heteroaromatic ring, or -CX9=CHX10, wherein
X9 and X10 each independently comprise H or alkyl;
m is an integer from 0 to 7;
j is an integer from 0 to about 6;
k is an integer from 0 to about 2;
W comprises H or alkyl.
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In any variation of formula I, when A is a direct bond; and B is N(R5); and
either of R1 and R2 is phenyl [optionally substituted with one more halogen
atoms,
(C1-C6) alkyl, (C1-C6) alkoxy, trifluoromethyl, cyano, nitro, (C1-C6) alkyl
sulfonyl, (C1-
C6) alkyl sulfonyl amino, (C1-C6) alkyl carbonyl-amino, (C1-C6) alkyl amino-
carbonyl-
amino or phenyl], (C2-C6) alkyl, cyclohexyl [optionally substituted with (C1-
C6) alkyl,
(C1-C6) alkoxy, trifluoromethyl, cyano or one or more fluorine atoms], 1-
napthyl or 2-
napthyl [optionally substituted with one or more halogen atoms, (C1-C6) alkyl,
(C1-C6)
alkoxy, trifluoromethyl or cyano], benzyl [optionally substituted on the
phenyl ring with
one or more halogen atoms, (Ci-C6) alkyl, (C1-C6) alkoxy, trifluoromethyl or
cyano], a
5- to 10-membered saturated or unsaturated heterocyclic radical [optionally
substituted with one or more fluorine atoms, (C1-C6) alkyl, (C1-C6) alkoxy,
trifluoromethyl or cyano] and a 5- to 10- membered aromatic monocyclic or
bicyclic
heterocyclic radical [optionally substituted with one more halogen atoms, (C1-
C6)
alkyl, (C1-C6) alkoxy, trifloromethyl, cyano, nitro or phenyl] and R3 is any
above
described variation; then R4 can not be H, (C1-C6) alkyl, benzyl, chloro, or
bromo.
In any variation of formula I, when A is a direct bond; and B is N(R5); and
either R1 or R2 is phenyl, thienyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl,
pyrimidinyl,
pyrazinyl, pyridazinyl, triazinyl or any above group substituted with 1, 2, 3
or 4
substituents which can be the same or different, selected from C1_3 alkyl,
C1_3 alkoxy,
hydroxy, halogen, trifluoromethyl, trifluoromethylthio, trifluoromethoxy,
nitro, amino,
mono- or dialkyl (C1_2)-amino, mono- or dialkyl (C1_2)-amido, (C1_3)-
alkoxycarbonyl,
carboxyl, cyano, carbomyl, acetyl and naphthyl; and R3 is any above described
variation; then R4 can not be H, halogen, CN, carbomyl, formyl, acetyl,
trifluoroacetyl,
fluoroacetyl, propionyl, sulfamoyl, methanesulfonyl, methylsulfanyl, branched
or
unbranched C1-4 alkyl group, which C1_4 alkyl group may be substituted with 1
to 3
fluoro atoms or with a single bromo, chloro, iodo, cyano or hydroxy group.
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Another embodiment of the invention comprises cannabimimetic thiazole and
oxazole ligands represented by formula II and their enantiomers,
diastereomers,
geometric isomers, racemates, tautomers, rotamers, atropisomers, metabolites,
in
vivo hydrolysable esters, N-oxides, salts, solvates, hydrates, polymorphic
forms(
crystalline or amorphous) or pro-drugs:
R1 R2
WNvy N
A
yR3
0
wherein A, B, R1, R2 and R3 are as defined above for compounds of formula
W comprises S or 0.
In any variation of formula II, when A is a direct bond; B is NR5 as defined
above; R1 and R3 are any above described variation; and W is S; then R2 cannot
be
a phenyl group with one or more substituents selected from branched or
unbranched
C1_3-alkyl, branched or unbranched C1_3-alkoxy, hydroxy, halogen, CF3,
trifluoromethylthio, trifluoromethoxy, nitro, amino, mono-or dialkyl(C1_2)-
amino, mono-
or dialkyl(C1_2)-amido, branched or unbranched (C1_3)-alkoxycarbonyl,
trifluoromethylsulfonyl, sulfamoyl, branched or unbranched (C1_3)-sulfonyl,
carboxyl,
cyano, carbamoyl, branched or unbranched dialkyl(C1_3)-aminosulfonyl, branched
or
unbranched monoalkyl(C1_3)-aminosulfonyl and acetyl.
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Another embodiment of the invention comprises cannabimimetic triazole
ligands represented by formula III and their enantiomers, diastereomers,
geometric
isomers, racemates, tautomers, rotamers, atropisomers, metabolites, in vivo
hydrolysable esters, N-oxides, salts, solvates, hydrates, polymorphic forms(
crystalline or amorphous) or pro-drugs:
R1 \ R2
N N
A R3
0
III
wherein A, B, R1, R2 and R3 are as defined above for compounds of formula
In any variation of formula III, when A is a direct bond; B is NR5; R3 is any
above described variation; then either or both of R1 and R2 cannot be a
phenyl,
naphthyl, thienyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, or triazinyl
group, or any
above group substituted with 1-4 substituents, which can be same or different,
selected from branched or unbranched (C1_3)alkyl or alkoxy, hydroxy, halogen,
trifluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro, amino, mono- or
dialkyl (C1-
2)-amino, mono- or dialkyl (C1_2)-amido, (Ci_3)-alkoxycarbonyl,
trifluoromethylsulfonyl,
sulfomyl, (Ci_3)-alkylsulfonyl, carboxyl, cyano, carbomyl, (C1_3)-
dialkylaminosulfonyl,
(C1_3)-monoalkylamino-sulfonyl and acetyl.
Another embodiment of the invention comprises cannabimimetic pyrazole
ligands represented by formula IV and their enantiomers, diastereomers,
geometric
isomers, racemates, tautomers, rotamers, atropisomers, metabolites, in vivo
hydrolysable esters, N-oxides, salts, solvates, hydrates, polymorphic forms(
crystalline or amorphous) or pro-drugs:
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R4\ zA13
R3
N 0
Ri ,
R2
Iv
wherein A, 13, R2 and R3 are as defined above for compounds of formula I.
In a variation of formula IV, R1 comprises -T-(CH2)n-Q-(CH2)n-Z.
each n independently comprises an integer from 0 to about 7.
T comprises a carbocyclic ring having 3 to about 8 ring members, an
unsaturated ring having 3 to about 8 carbon atoms as ring members, an aromatic
ring
having 5 to about 8 carbon atoms as ring members, a heterocyclic ring having 3
to
about 8 ring members, a heteroaromatic ring having 5 to about 8 ring members,
a
bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic
ring, a polycyclic
ring or a heteropolycyclic ring.
Q comprises CH=CH,
Z comprises H, halogen, CF3, CF2H, N3, NCS, CN, NO2, NX1X2, OX3, SX3,
OAc, 0S02X3, 0-
acyl, S-acyl, S02-alkyl, SO-alkyl, SC(CH3)2C00X8,
OC(CH3)2C00X8 , C(CH3)2C00X8, Si(alkyl)3, 0-aroyl, 0(CH2)10X3, 0(CH2)1NX1X2,
alkyl-CN, NH-acyl, NH-aroyl, CHO, C(halogen)3, COOX3, SO3H, SO2NX1X2,
CONX1X2, NHC(0)0-alkyl,
NHS02-alkyl alkoxy, alkyl, alcohol, alkylmercapto,
alkylamino, di-alkylamino, alkylsuffinyl or alkylsulfonyl, CX4X5X8, -CH=CHX8 ,
-Cm-CX8
X1 and X2 each independently comprise H or alkyl, or
X1 and X2 together comprise part of a heterocyclic ring having about 4 to
about
7 ring members and optionally one additional heteroatom selected from 0, N or
S, or
X1 and X2 together comprise part of an imide ring having about 5 to about 6
members,
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X3 comprises H, alkyl, NO2, NO, (CH2)mCN, hydroxyloweralkyl, or alkyl-NX1X2,
X4, X5, and X6 each independently comprise H, alkyl, carbocyclic ring,
hydroxyloweralkyl, alkyl-OH, halogen, ON, SNO, S(S02)alkyl, NX1X2, COOX3,
CONX3, OX7, or 0-alkyl-X7, wherein
X7 comprises H, alkyl, NO2, NO, P(0)(0)(8)2, PH(0)(OX8), S(0)kN(alky1)2,
S(0)kX8, S(0)k0X8, COOX8, CONX8, SO3H, COX8, wherein
X8 comprises H, alkyl, carbocyclic ring, heterocyclic ring, aromatic ring,
heteroaromatic ring, or -CX9=CHX10, wherein
X9 and X10 each independently comprise H or alkyl;
m is an integer from 0 to 7;
j is an integer from 0 to about 6; and
k is an integer from 0 to about 2.
In a variation of formula IV R1 comprises -T-(CH2)n-Q-(CH2)n-Z.
each n independently comprises an integer from 0 to about 7.
T comprises a carbocyclic ring having 3 to about 8 ring members, an
unsaturated ring having 3 to about 8 carbon atoms as ring members, an aromatic
ring
having 5 to about 8 carbon atoms as ring members, a heterocyclic ring having 3
to
about 8 ring members, a heteroaromatic ring having 5 to about 8 ring members,
a
bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic
ring, a polycyclic
ring or a heteropolycyclic ring.
Q comprises CH=CH,
Z comprises a carbocyclic ring having about 4 to about 7 ring members, a
heterocyclic ring having about 4 to about 7 ring members, an aromatic ring
having
about 5 to about 7 ring members, a heteroaromatic ring having about 5 to about
7
ring members, a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a
heterotricyclic
ring, a polycyclic ring, a heteropolycyclic ring; or any above group
substituted on at
least one available ring atom by an alkyl group; or any above group
substituted on at
least one available ring nitrogen atom by a benzyl group, a substituted benzyl
group,
an alkoxybenzyl group, a substituted alkoxybenzyl group, a benzhydryl group or
a
substituted benzhydryl group; and wherein the connecting point between the -
(CH2)n-
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group and the Z group can be any available ring carbon atom or any available
ring
nitrogen atom.
In a variation of formula IV, R1 comprises -T-(CH2)n-Q-(CH2)n-Z.
each n independently comprises an integer from 0 to about 7.
T comprises a carbocyclic ring having 3 to about 8 ring members, an
unsaturated ring having 3 to about 8 carbon atoms as ring members, an aromatic
ring
having 5 to about 8 carbon atoms as ring members, a heterocyclic ring having 3
to
about 8 ring members, a heteroaromatic ring having 5 to about 8 ring members,
a
bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic
ring, a polycyclic
ring or a heteropolycyclic ring.
Q comprises CH=CH,
Z comprises 1-, 2- or 3-pyrrolidinyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or 4-
morpholinyl, 2-, 3- or 4-thiomorpholinyl, 1-, 2- or 3-azetidinyl, 1- or 2-
piperazinyl, 2- or
3-tetrahydrofuranyl; or any above group substituted on at least one available
ring
atom by an alkyl group; or any above group substituted on at least one
available ring
nitrogen atom by a benzyl group, a substituted benzyl group, an alkoxybenzyl
group,
a substituted alkoxybenzyl group, a benzhydryl group or a substituted
benzhydryl
group; and wherein the connecting point between the -(CH2)n- group and the Z
group
can be any available ring carbon atom or any available ring nitrogen atom.
In a variation of formula IV, R1 comprises -T-(CH2)n-Q-(CH2)n-Z.
each n independently comprises an integer from 0 to about 7.
T comprises a carbocyclic ring having 3 to about 8 ring members, an
unsaturated ring having 3 to about 8 carbon atoms as ring members, an aromatic
ring
having 5 to about 8 carbon atoms as ring members, a heterocyclic ring having 3
to
about 8 ring members, a heteroaromatic ring having 5 to about 8 ring members,
a
bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic
ring, a polycyclic
ring or a heteropolycyclic ring.
Q comprises CH=CH,
Z comprises
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)-(`( _____________________________ ja X
N N L\Lx
N x x Y, W y N-j N'N
N _1(
N Yor Y
\1=1 \N
N N NNW
X\\i- I / x)LN \-11`),
X
wherein X and Y each independently comprise, H, halogen, CF3, CF2H, N3,
NCS, CN, NO2, NX1X2, OX3, SX3, OAc, 0S02X3, 0-acyl, S-acyl, S02-alkyl, SO-
alkyl,
SC(CH3)2000X8, OC(CH3)2C00X8 , C(CH3)2C00X8, Si(alkyl)3, alkyl-CN, 0-aroyl,
0(CH2)i0X3, 0(CH2)iNX1X2, NH-acyl, NH-aroyl, CHO, C(halogen)3, COOX3, SO3H,
SO2NX1X2, CONX1X2, NHC(0)0-alkyl, NHS02-alkyl alkoxy, alkyl, alcohol,
alkylmercapto, alkylamino, di-alkylamino, alkylsulfinyl or alkylsulfonyl,
CX4X8X8, -
CH=CHX8 , -CCX8 ;
X1 and X2 each independently comprise H or alkyl, or
X1 and X2 together comprise part of a heterocyclic ring having about 4 to
about
7 ring members and optionally one additional heteroatom selected from 0, N or
S, or
X1 and X2 together comprise part of an imide ring having about 5 to about 6
members,
X3 comprises H, alkyl, NO2, (CH2)mCN, hydroxyloweralkyl, or alkyl-NX1X2,
X4, X5, and X6 each independently comprise H, alkyl, carbocyclic ring,
hydroxyloweralkyl, alkyl-OH, halogen, CN, SNO, S(S02)alkyl, NX1X2, COOX3,
CONX3, OX7, or 0-alkyl-X7, wherein
X7 comprises H, alkyl, NO2, NO, P(0)(0X8)2, PH(0)(0X8), S(0)kN(alky1)2,
S(0)kX8, S(0)k0X8, COOX8, CONX8, SO3H, COX8, wherein
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X8 comprises H, alkyl, carbocyclic ring, heterocyclic ring, aromatic ring,
heteroaromatic ring, or -CX9=CHX10, wherein
X9 and X10 each independently comprise H or alkyl;
m is an integer from 0 to 7;
j is an integer from 0 to about 6;
k is an integer from 0 to about 2; and
W comprises H or alkyl.
In a variation of formula IV, R1 comprises -T-(CH2)n-Q-(CH2)n-Z.
each n independently comprises an integer from 0 to about 7.
T comprises a carbocyclic ring having 3 to about 8 ring members, an
unsaturated ring having 3 to about 8 carbon atoms as ring members, an aromatic
ring
having 5 to about 8 carbon atoms as ring members, a heterocyclic ring having 3
to
about 8 ring members, a heteroaromatic ring having 5 to about 8 ring members,
a
bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic
ring, a polycyclic
ring or a heteropolycyclic ring.
Q comprises CH=CH,
Z comprises an unsaturated ring having 5 ring atoms and 0 to 2 independently
selected heteroatoms as ring members fused to an unsaturated ring having 5
ring
atoms and 0 to 4 independently selected heteroatoms as ring members, an
unsaturated ring having 5 ring atoms and 0 to 2 independently ,selected
heteroatoms
as ring members fused to an unsaturated ring having 6 or 7 ring atoms and 0 to
4
independently selected heteroatoms as ring members or an unsaturated ring
having
6 ring atoms and 0 to 3 independently selected heteroatoms as ring members
fused
to an unsaturated ring having 6 or 7 ring atoms and 0 to 4 independently
selected
heteroatoms as ring members
In a variation of formula IV, R1 comprises -T-(CH2)n- Q-(CH2)n-Z.
T comprises a carbocyclic ring having 3 to about 8 ring members, an
unsaturated ring having 3 to about 8 carbon atoms as ring members, an aromatic
ring
having 5 to about 8 carbon atoms as ring members, a heterocyclic ring having 3
to
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about 8 ring members, a heteroaromatic ring having 5 to about 8 ring members,
a
bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic
ring, a polycyclic
ring or a heteropolycyclic ring.
each n independently comprises an integer from 0 to about 7.
Q comprises CH=CH,
Z comprises )¨E or
E comprises a Cl to about 04, linear or branched alkyl group, a phenyl
group, a substituted phenyl group, a benzyl group or a substituted benzyl
group.
In a variation of formula IV, R1 comprises -TACH2)n- Q-(CH2),-Z.
T comprises a carbocyclic ring having 3 to about 8 ring members, an
unsaturated ring having 3 to about 8 carbon atoms as ring members, an aromatic
ring
having 5 to about 8 carbon atoms as ring members, a heterocyclic ring having 3
to
about 8 ring members, a heteroaromatic ring having 5 to about 8 ring members,
a
bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic
ring, a polycyclic
ring or a heteropolycyclic ring.
each n independently comprises an integer from 0 to about 7.
Q comprises CH=CH, CC.
Z comprises
______________________________________ 0 H ,A1 0
-NO ¨N1 ____________________ CH2)k <(ICH2 )k ¨Nx or
N(CH2)k <(I 2
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k is an integer from 1 to about 5. A1 and A2 each independently
comprise a Cl to about C4 alkyl group, a phenyl group or a substituted phenyl
group.
The inventive compounds in any formula, embodiment or variation include any
and all possible isomers and steroisomers. In general, the compositions of the
invention may be alternately formulated to comprise, consist of, or consist
essentially
of, any appropriate components herein disclosed. The compositions of the
invention
may additionally, or alternatively, be formulated so as to be devoid, or
substantially
free, of any components, materials, ingredients, adjuvants or species used in
the
prior art compositions or that are otherwise not necessary to the achievement
of the
function and/or objectives of the present invention.
Unless otherwise specifically defined, "acyl" refers to the general formula
-C(0)alkyl.
Unless otherwise specifically defined, "acyloxy" refers to the general formula
-0-acyl.
Unless otherwise specifically defined, "alcohol" refers to the general formula
alkyl-OH and includes primary, secondary and tertiary variations.
Unless otherwise specifically defined, "alkyl" or "lower alkyl" refers to a
linear,
branched or cyclic alkyl group having from 1 to about 10 carbon atoms, and
advantageously 1 to about 7 carbon atoms including, for example, methyl,
ethyl,
propyl, butyl, hexyl, octyl, isopropyl, isobutyl, tert-butyl, cyclopropyl,
cyclohexyl,
cyclooctyl, vinyl and allyl. The alkyl group can be saturated or unsaturated.
The alkyl
group can be unsubstituted, singly substituted or, if possible, multiply
substituted,
with substituent groups in any possible position. Unless otherwise
specifically
limited, a cyclic alkyl group includes monocyclic, bicyclic, tricyclic,
tetracyclic and
polycyclic rings, for example norbornyl, adamantyl and related terpenes.
Unless otherwise specifically defined, "alkoxy" refers to the general formula
-0-alkyl.
Unless otherwise specifically defined, "alkylmercapto" refers to the general
formula -S-alkyl.
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Unless otherwise specifically defined, "alkylamino" refers to the general
formula -(NH)-alkyl.
Unless otherwise specifically defined, "di-alkylamino" refers to the general
formula -N-(alkyl)2. Unless otherwise specifically limited di-alkylamino
includes
cyclic amine compounds such as piperidine and morpholine.
Unless otherwise specifically defined, an aromatic ring is an unsaturated ring
structure having about 5 to about 7 ring members and including only carbon as
ring
atoms. The aromatic ring structure can be unsubstituted, singly substituted
or, if
possible, multiply substituted, with substituent groups in any possible
position.
Unless otherwise specifically defined, "aryl" refers to an aromatic ring
system
that includes only carbon as ring atoms, for example phenyl, biphenyl or
naphthyl.
The aryl group can be unsubstituted, singly substituted or, if possible,
multiply
substituted, with substituent groups in any possible position.
Unless otherwise specifically defined, "aroyl" refers to the general formula
-C(=0)-aryl.
Unless otherwise specifically defined, a bicyclic ring structure comprises 2
fused or bridged rings that include only carbon as ring atoms. The bicyclic
ring
structure can be saturated or unsaturated. The bicyclic ring structure can be
unsubstituted, singly substituted or, if possible, multiply substituted, with
substituent
groups in any possible position. The individual rings may or may not be of the
same
type. Examples of bicyclic ring structures include naphthalene and
bicyclooctane.
Unless otherwise specifically defined, a carbocyclic ring is a non-aromatic
ring
structure, saturated or unsaturated, having about 3 to about 8 ring members
that
includes only carbon as ring atoms, for example, cyclohexadiene or
cyclohexane.
The carbocyclic ring can be unsubstituted, singly substituted or, if possible,
multiply
substituted, with substituent groups in any possible position.
Unless otherwise specifically defined, "halogen" refers to an atom selected
from fluorine, chlorine, bromine and iodine.
Unless otherwise specifically defined, a heteroaromatic ring is an unsaturated
ring structure having about 5 to about 8 ring members independently selected
from
carbon atoms and one or more heteroatoms, including oxygen, nitrogen and/or
sulfur,
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for example, pyridine, furan, quinoline, and their derivatives. The
heteroaromatic ring
can be unsubstituted, singly substituted or, if possible, multiply
substituted, with
substituent groups in any possible position.
Unless otherwise specifically defined, a heterobicyclic ring structure
comprises
2 fused or bridged rings having ring members independently selected from
carbon
and one or more heteroatoms, including oxygen, nitrogen and/or sulfur. The
heterobicyclic ring structure can be saturated or unsaturated. The
heterobicyclic ring
can be unsubstituted, singly substituted or, if possible, multiply
substituted, with
substituent groups in any possible position. The individual rings may or may
not be
of the same type. Examples of heterobicyclic ring structures include
isobenzofuran
and indole.
Unless otherwise specifically defined, a heterocyclic ring is a saturated or
unsaturated ring structure having about 3 to about 8 ring members
independently
selected from carbon atoms and one or more heteroatoms, including oxygen,
nitrogen and/or sulfur; for example, piperidine, morpholine, piperazine,
pyrrolidine,
thiomorpholine, 1,1-dioxothiomorpholine and their derivatives. The
heterocyclic ring
can be unsubstituted, singly substituted or, if possible, multiply
substituted, with
substituent groups in any possible position.
Unless otherwise specifically defined, a heterotricyclic ring structure
comprises
3 fused, bridged, or both fused and bridged rings having ring members
independently
selected from carbon and one or more heteroatoms, including oxygen, nitrogen
and/or sulfur. The heterotricyclic ring structure may be saturated or
unsaturated.
The heterotricyclic ring structure can be unsubstituted, singly substituted
or, if
possible, multiply substituted, with substituent groups in any possible
position. The
individual rings may or may not be of the same type. Examples of
heterotricyclic ring
structures include carbazole, phenanthroline, phenazine, 2,4,10-
trioxaadamantane
and tetradecahydro-phenanthroline.
Unless otherwise specifically defined, a heteropolycyclic ring structure
comprises more than 3 rings that may be fused, bridged or both fused and
bridged
and that have ring members independently selected from carbon and one or more
heteroatoms, including oxygen, nitrogen and/or sulfur. The heteropolycyclic
ring
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structure can be saturated or unsaturated. The heteropolycyclic ring structure
can be
unsubstituted, singly substituted or, if possible, multiply substituted, with
substituent
groups in any possible position. The individual rings may or may not be of the
same
type. Examples of heteropolycyclic ring structures include azaadamantine,
tropane,
homotropane and 5-norbornene-2,3-dicarboximide.
Unless otherwise specifically defined, the term "phenacyl" refers to the
general
formula ¨phenyl¨acyl.
Unless otherwise specifically defined, a polycyclic ring structure comprises
more than 3 rings that may be fused, bridged or both fused and bridged, and
that
includes carbon as ring atoms. The polycyclic ring structure can be saturated
or
unsaturated. The polycyclic ring structure can be unsubstituted, singly
substituted or,
if possible, multiply substituted, with substituent groups in any possible
position. The
individual rings may or may not be of the same type. Examples of polycyclic
ring
structures include adamantine, bicyclooctane, norbornane and bicyclononanes.
Unless otherwise specifically defined, a spirocycle refers to a ring system
wherein a single atom is the only common member of two rings. A spirocycle can
comprise a saturated carbocyclic ring comprising about 3 to about 8 ring
members, a
heterocyclic ring comprising about 3 to about 8 ring atoms wherein up to about
3 ring
atoms may be N, S, or 0 or a combination thereof.
Unless otherwise specifically defined, a tricyclic ring structure comprises 3
rings that may be fused, bridged or both fused and bridged, and that includes
carbon
as ring atoms. The tricyclic ring structure can be saturated or unsaturated.
The
tricyclic ring structure can be unsubstituted, singly substituted or, if
possible, multiply
substituted, with substituent groups in any possible position. and may be
substituted
or unsubstituted. The individual rings may or may not be of the same type.
Examples of tricyclic ring structures include fluorene and anthracene.
Unless otherwise specifically limited the term substituted means substituted
by
a below-described substituent group in any possible position. Substituent
groups for
the above moieties useful in the invention are those groups that do not
significantly
diminish the biological activity of the inventive compound. Substituent groups
that do
not significantly diminish the biological activity of the inventive compound
include, for
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example, H, halogen, N3, NCS, CN, NO2, NX1X2, OX3, C(X3)3, OAc, 0-acyl, 0-
aroyl,
NH-acyl, NH-aroyl, NHCOalkyl, CHO, C(halogen)3, COOX3, SO3H, P03H2,
SO2NX1X2, CONX1X2, alkyl, alcohol, alkoxy, alkylmercapto, alkylamino, di-
alkylamino, sulfonamide, thioalkoxy or methylene dioxy when the substituted
structure has two adjacent carbon atoms, wherein X1 and X2 each independently
comprise H or alkyl, or X1 and X2 together comprise part of a heterocyclic
ring having
about 4 to about 7 ring members and optionally one additional heteroatom
selected
from 0, N or S, or X1 and X2 together comprise part of an imide ring having
about 5
to about 6 members and X3 comprises H, alkyl, hydroxyloweralkyl, or alkyl-
NX1X2.
Unless otherwise specifically limited a substituent group may be in any
possible
position.
Some of the inventive compounds show a high affinity for at least one of the
cannabinoid receptors. Thus, another aspect of the invention is use of at
least one of
the inventive compounds to interact with a cannabinoid receptor.
Some of the novel heteropyrrole derivatives show selectivity for the CB1
cannabinoid receptor. These inventive CB1 selective analogs are able to
interact
with the CB1 cannabinoid receptors present in the CNS as well as the periphery
without affecting the CB2 receptors to the same degree. Therefore, still
another
aspect of the invention is use of at least one of the inventive compounds to
preferentially interact with a CBI cannabinoid receptors present either in the
CNS or
the periphery.
The inventive heteropyrrole analogs described herein, and physiologically
acceptable salts thereof, have pharmacological properties when administered in
therapeutically effective amounts for providing a physiological response.
Thus,
another aspect of the invention is the administration of a therapeutically
effective
amount of at least one of the inventive compounds, or a physiologically
acceptable
salt thereof, to an individual or animal to provide a physiological response.
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A better understanding of the invention will be obtained from the following
detailed description of the article and the desired features, properties,
characteristics,
and the relation of the elements as well as the process steps, one with
respect to
each of the others, as set forth and exemplified in the description and
illustrative
embodiments.
Detailed Description
As used herein a "therapeutically effective amount" of a compound, is the
quantity of a compound which, when administered to an individual or animal,
results
in a sufficiently high level of that compound in the individual or animal to
cause a
physiological response, for example a discernible increase or decrease in
stimulation
of cannabinoid receptors. The inventive compounds described herein, and
physiologically acceptable salts thereof, have pharmacological properties when
administered in therapeutically effective amounts individually or in
combination for
providing a physiological response useful to treat marijuana abuse, obesity,
lifestyle
choices such as a desire to lose weight, other metabolic disorders including
improvement in lipid profiles and insulin related deficiencies, hepatic
disease,
cardiometabolic diseases, congestive obstructive pulmonary disorders,
inflammatory
bowel disease, smoking cessation, bone defects, arthritis, inflammation,
benign
prostatic hypertrophy, asthma, migraine, chronic-intestinal pseudo
obstruction,
constipation, schizophrenia, epilepsy, stress, memory disorders, migraine,
vomiting,
thymic disorders, dyskinesia, kinetic disorder, anxiety disorders, psychotic
disorders,
cognitive disorders, appetite disorders, mood disorders, delirious disorders,
neuropathies, Parkinson's disease, Alzheimers disease, depression,
psychosomatic-
induced disease, diabetes, sexual dysfunctions, as well as for alcohol,
opioid,
nicotine and cocaine addiction, etc. Additionally, these analogs can be useful
in
cancer chemotherapy. Typically, a "therapeutically effective amount" of an
inventive
compound is believed to range from about 0.01 mg/day to about 1,000 mg/day.
As used herein, an "individual" refers to a human. An "animal" refers to, for
example nonhuman-primates such as monkeys and baboons, veterinary animals,
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such as rodents, dogs, cats, horses and the like, and farm animals, such as
cows,
pigs and the like
In a certain embodiments, the compound disclosed in the invention can be
used in combination with other acceptable pharmaceutical substances.
In embodiments in which compounds of the disclosure is used in combination
with Rimonabant (Accomplia, Sanofi-Aventis) or other CBI antagonists, it will
be
possible to reduce or even eliminate one or more of these side-effects,
particularly
nausea. That is, it is possible to reduce the amount of Rimonabant or other
CB1
antagonists administered to the individual who has had, is receiving or is
about to
receive a therapeutically effective amount of the compound of the disclosure.
In one
embodiment, the amount of Rimonabant administered to the individual is reduced
by
1.5 to 5-fold compared to the accepted therapeutic amount. The individual is
then
dosed with a therapeutically effective amount of at least one of the compounds
of the
disclosure. Of course, it is also possible to increase the length of time
between
doses of Rimonabant with the same or similar effect.
Accordingly, one embodiment provides for a method for reducing unwanted
side-effects (one or more of nausea, dizziness, diarrhea, and anxiety)
typically
associated with administration of SR141716A (AccompliaTm/Rimonabant) or other
CBI antagonists to certain individuals. A particular method involves
administering a
therapeutically effective amount of at least one of the compounds of the
disclosure so
as to reduce the side-effects in that individual. As discussed, the method can
involve
reducing the amount of SR141716A (AccompliaTm/Rimonabant) or other CB1
antagonists administered to the individual.
As will be apparent, the compounds of the invention can be used alone or in
combination with other CBI receptor antagonists or anti-obesity agents known
to the
field. Examples of such agents include SR141716A or
AccompliaTm/rimonabant(Sanofi-Aventis), Xenical (Roche), Meridia (Abbott,
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Sibutramine), surinabant (Sanofi-Aventis), AVE1625(Sanofi-Aventis), CP-946,598
or
otenabant (Pfizer), rosonabant(Esteve), taranabant (Merck), SLV-319 (Solvay
Pharmaceuticals/BMS), V24343 (Vernalis), Qnexa(Vivus), Contrave(Orexigen),
Empatic(Orexigen), lorcaserin(Arena), Phentermine.
Compounds of the invention can also be used in combination with a a potassium
channel opener,
opiod antagonist, anticonvulsant agent, contraceptive agent,
antipsychotic agent, anticonstipation agent, nicotine receptor agonist or
partial
agonist, CB2 agonist, melanin-concentrating hormone receptor antagonist, anti-
psychotic agents, peroxisome proliferator-activated receptors agonists,
ghrelin
antagonists, GLP-1 agonist, fatty acid amide hydrolase inhibitor, an
intestinal-acting
microsomal triglyceride transfer protein inhibitor, a dipeptidyl-peptidase IV
inhibitor, a
statin, a sterol absorption inhibitor (f3-lactam), Beta-3 adrenergic agonist,
a
biguanide, Sodium glucose transport (SGLT2) antagonist,
cyclooxygenase-2
inhibitor, renin inhibitor, monoamine oxidase inhibitor, CETP inhibitor, ACAT
inhibitor,
DGAT-1 inhibitor, Mitochondrial Transfer Protein inhibitor, noradrenalin-
serotonin-
dopamine reuptake inhibitor or a lipase inhibitor.
In one embodiment, less than five compounds of the disclosure, preferably
one or two of same is used in combination with less than five of the known CB1
antagonists, preferably one or two of same.
In one embodiment, the compound disclosed in the invention could in itself act
as a drug with a combination effect. For example compounds disclosed in the
invention could dually act as a CBI antagonist as well as 118-hydroxy steroid
dehydrogenase-1 inhibitor. In certain embodiments, the compound could act
dually
as a CBI antagonist as well as a nitric oxide donor.
By "physiologically acceptable salts" is meant, salts typically useful for
pharmaceutical applications including acid addition salts and basic salts.
Examples of
acid addition salts are hydrochloride salts, hydrobromide salts, methane
sulfonate
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salts etc. Examples of basic salts are salts where the cation is selected from
alkali
metals, such as sodium and potassium, alkaline earth metals, such as calcium,
and
ammonium ions. Other examples of physiologically acceptable salts can be found
in
"Remington's Pharmaceutical Sciences" 17. Ed. Alfonso R. Gennaro (Ed.), Mark
Publishing Company, Easton, Pa., U.S.A., 1985 and more recent editions, and in
Encyclopedia of Pharmaceutical Technology.
Polymorphic forms show improved physiochemical properties and stability for
formulation purposes. In one embodiment, the compounds disclosed in the
invention
could exist in various solid forms. The solid forms can be crystalline and
amorphous
forms, but not limited to, solvates, hydrates, hydrolyzable esters and N-
oxides of the
compounds defined in the specification. These solid forms can be obtained by
treating either the free base or their salts at a certain adjusted pH and
certain
temperature with an solvent or a combination of solvents. The solvents can be
and
not limited to a hydrocarbon solvent such as toluene, xylene, hexanes,
heptane, or
petroleum ether, alcohol such as methanol, ethanol, n-butanol, n-propanol and
2-
propanol, di-isopropyl ether, ethyl-acetate, dichloromethane, acetic acid,
acetone,
tetrahydrofuran, dichloromethane, and water.
In one embodiment, in order to improve the dehepaticability of the compound
disclosed in the present invention for the required physiological effect, a
"pro-drug" of
the same can be made available. For example, the pro-drug such as an in-vivo
hydrolyzable ester can be a obtained by conjugation of the parent drug with a
low-
molecular weight alcohol or a high molecular weight polyethylene glycol(PEG).
In
certain embodiments, the compound disclosed in the invention could contain a
nitrate
ester group.
In one embodiment, the compounds in the present invention could exist as
enantiomers, diastereomers, geometric isomers, racemates, tautomers, rotamers,
atropisomers or metabolites.
In one embodiment, some compounds disclosed in the invention can be
"neutral antagonists". These agents are said to have no effect on intrinsic
receptor
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activity at least in certain test systems. However, these agents may be able
to block
receptor binding and activation, usually by a competitive agonist.
In some embodiments, it would be desirable to have antagonists that exhibit
essentially no CBI receptor activity and which block or significantly reduce
receptor
activation by a suitable agonist. It would be further desirable to have
neutral
antagonists of the CBI receptor that can be used to prevent, treat, or reduce
the
severity of symptoms of certain medical conditions. It would be especially
desirable
to have neutral antagonists that exhibit no or minimal side-effects in vivo.
In another embodiment, the compound disclosed in the present invention may
act preferentially at the CB1 receptors located in the periphery. In certain
embodiments, the compounds do not penetrate the blood-brain-barrier, have
restricted penetration or have slow penetration. In certain embodiments,
peripherally
acting compounds may have advantages over centrally acting compounds, for
example, reduced psychotropic adverse effects.
A compound acting on the CB1 receptors located in the periphery could be
behave either as a neutral antagonist, an inverse agonists or a partial
antagonist.
A compound acting on the CB1 receptors located centrally, could behave
as a neutral antagonist, an inverse agonists or a partial antagonist.
In another embodiment, the compounds disclosed in the invention could act
either as inverse agonists with no or reduced side effects. In other
embodiments, the
compounds could act as partial agonists with no or reduced side effects.
The compounds of the present invention can be administered by a variety of
known methods, including orally, rectally, or by parenteral routes (e.g.,
intramuscular,
intravenous, subcutaneous, nasal or topical). The form in which the compounds
are
administered will be determined by the route of administration. Such forms
include,
but are not limited to, capsular and tablet formulations (for oral and rectal
administration), liquid formulations (for oral, intravenous, intramuscular,
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subcutaneous, ocular, intranasal, inhalation-based and transdermal
administration)
and slow releasing microcarriers (for rectal, intramuscular or intravenous
administration). The formulations can also contain a physiologically
acceptable
vehicle and optional adjuvants, flavorings, colorants and preservatives.
Suitable
physiologically acceptable vehicles include, for example, saline, sterile
water,
Ringer's solution and isotonic sodium chloride solutions. The specific dosage
level of
active ingredient will depend upon a number of factors, including, for
example,
biological activity of the particular preparation, age, body weight, sex and
general
health of the individual being treated.
In another embodiment, the compounds of the present disclosure can also
comprise isotopes at one or more of their atoms. For example, the compounds
can
be radiolabeled with isotopes, such as 2H (deuterium written as D) 3H (tritium
written
as T), 11C (carbon-11), 13C (carbon-13), 14C (carbon-14), 150 (oxygen-15), 170
(oxygen-17), 18Q (oxygen-18), 13N (nitrogen-13), 15N (nitrogen-15), 18F
(fluorine-18),
7813r (bromine-75), 76Br (bromine-76), 77Br (bromine-77), 8 _
2Br (bromine-82), 1231
(iodine-123), 124 (iodine-124), 1281 (iodine-125) or 1311 (iodine-131), 38CI
(chlorine-36)
or 35S (sulphur-35), The present disclosure encompasses all isotopic
variations of
the described compounds, whether natural or unnatural, radioactive or not.
An isotope is one of two or more species of the same element. Each isotope
of an element will have the same number of protons in its nucleus, the same
atomic
number and the same position in the Periodic Table. However each isotope of
that
element will have a different number of neutrons in its nucleus and therefore
a
different mass than other isotopes of that species. The term nuclide is
sometimes
used synonymously with the term isotope. As used herein a natural isotope has
an
atomic mass corresponding most closely with the atomic mass shown for that
element in the Periodic Table. As used herein an unnatural isotope has an
atomic
mass that is further removed from the atomic mass shown for that element in
the
Periodic Table than the natural isotope. For example, protium (hydrogen-1 or
1H) is
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the natural isotope of hydrogen and deuterium (hydrogen-2 or 2H) and tritium
(hydrogen-3 or 3H) are all unnatural isotopes of hydrogen.
In a particular embodiment, some of the halogen containing analogs, for
example those analogs comprising iodide and fluoride, are potential
radioactive
probes for imaging in vivo the distribution of cannabinoid receptors. For
radio-imaging
applications 11C, 18F, 1251, 1231, 1241, 1311 , 75Br, - 75
-Br, or
77Br will generally be most
useful.
Some of the radioactive isotope containing analogs have potential as
radiopharmaceutical analogs (disclosed analogs that have been labeled with
radioactive isotopes). These radiopharmaceuticals can be administered to
individuals or animals and the emitted radiation can be measured. The majority
of
these diagnostic tests involve the formation of an image using a camera
suitable to
detect the emitted radiation. Positron emission tomography (PET) is one
nuclear
medicine tomographic imaging technique, which produces a three-dimensional
image
or map of functional processes in a patient's body. To conduct the PET scan, a
short-lived radiopharmaceutical analog that decays by emitting a positron is
administered into the subject (usually by injection into the blood stream).
There is a
waiting period while the radiopharmaceutical analog becomes concentrated in
tissues
of interest such as a cannabinoid receptor. After the waiting period the
patient is
placed in an imaging scanner. The scanner collects multiple images and a
computer
is used to apply an algorithm to the multiple images and provide a three
dimensional
image. Single photon emission computed tomography (SPECT) is another nuclear
medicine tomographic imaging technique. To conduct the SPECT scan, a short-
lived
radiopharmaceutical analog that decays to produce a gamma ray is administered
into
the subject. There is a waiting period while the radiopharmaceutical analog
becomes
concentrated in tissues of interest such as a cannabinoid receptor. After the
waiting
period the patient is placed in an imaging scanner and SPECT imaging is
performed
by using a gamma camera to acquire multiple two dimensional images from
multiple
angles. A computer is then used to apply an algorithm to the multiple images
to
provide a three dimensional image.
CA 02753061 2011-08-19
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Table 1
N
r/9 r9
0 0 0
0
HO ,N-- HO N--/
N. 0
1 N\N ti / N\N. ti i \ H
, HO
11 N N
0/ arrir CI 01 Ain CI ---- 116
CI 0 N
i\
,N \
I
IV 010 I
lei CI
CI NC CI MS0 CI
1 2 3 4 CI
0 0
0 0 ........., 0
N
, H i N N- (,...11.0 N_
-;
,
,N ,
N N / N N / N
0 il CI le gib CI
0 0 CI
IMPli el is CI
-----=
I I
AcS CI I a 7 CI 8 CI
6
O o
0
N0
N.0
/ \ H / \ H / o
so NN ,N
N 110 abiN CI
---;,-
411 CI
---;,-- SO ilk CI
IIIV ----;,-
IMP
SCN CI
MsS 9 CI 02N0
10 CI 11
0 00 =
0 .
N _--)=c .\......0=N--) o N N
----../ / \ H / \ H
N,N
,N
so N / N
0 are% le CI 40 CI
so c, ,...õ
w ....õ
,-;,...
I
CI 1413 CI
NC CI
12 13 14
9 9 9
ri=o
rS=0
0 (TO 0
0
0 0
N---/i
N--..../
N
N
/ \ H i \ i \
ti ' ,N
,N ,N ,N 01101
101 N ci
0 N ci
NH ..õ,õ..
S CI I 01 N CI
el el
1101 I.
CI
NC CI CI CI
18
16 17
56
CA 02753061 2011-08-19
WO 2010/104488 PCT/US2009/001054
=
,
(---9
o 0
O 0
0 0 0
02N0 N---/
N
N 7 / H
N
N
=
7 \ \ H / \ H
, \ \
N ,N
N ,N ,N
110 N CI
Br
10110 CI
I 110 N ci
le I 0 its% ci
CI NC CI
CI CI
19 20 21 22
9(-0\
rs,=0
0 0
0 0
N---../ N--/
N NC
N
/ \ H N / \ H N
,N / \ H
,N / \ H
,N ,N
I I I 01 I a N h C I so N ci
N
/ ,---- * Abi CI
----"
11111111 -----
/ 116 aihN CI
I
WI ISI
I-
NC 25 ci 26
IIIV
;I CI NC
24 CI a
o 23
NC o /
o
0 NC 0
.0 0
N .r9
N-....../1 (.
N CN
N
NC/ \ H
N / \ H / \ H
N
/ \ H ,N,N
II0
,N
N.
0 iiihN CI 0 * CI gill CI I
--- ,N c,
-"
.õ---
,
w w w w
NC CI NC 29 ci ci
a 2
27 8
9 ,
9 o
rs\ NC =0 0
N.N-../) N CN
0 / \ H
NC .N--.Y ,N
N / \ H N
7 \ H ,N
01 itrib CI
,N
1111.
600 N ci
0 AnN CI ../...-
I
IIIV illi NC CI
NC CI
CI 33
32
31
57
CA 02753061 2011-08-19
WO 2010/104488 PCT/US2009/001054
(-9,
0 0 ../
, rs,..
0 .
.
,N r- N
/ _____________________________________________________ ?\---H
N-N
/Y
NN \ ,N
S --,..
N
*
\ S CI CI
\ S, ci
CI CI
3
CI 6
NC NC 35
34 NC ,
(----,=0
0 0 _________________________________________________ 0
),õ___ NJ ,N---._/
0 N N' / \(\\---H
N
CI / __ \c H --, ,N
/ __________________ ?--H ,N N
,N N \ S CI
\ S CI
N // 0
CI
C
CI
CI
NC 39
NC 38
37
9
0
.0 NC 0
,N--../
NC 0
,N--..../
NC /
_________________________________________ N N
N ?\'- / __ \c >.\--H
/ _________________ \\)\--H ,N H ,N
,N
N
N
S CI // \ S = ci // . \ S Cl
\
// Ig
42
Cl Cl CI
NC NC
NC 40 41
0 NCp. 0 9
1=0 0 NC)b,
N
N.--)
N / __ ?-iti
---, ,N
N
,N / HN
NN N \---
,N S 0 ci
S Cl --..
=
I
WI I \ S s Cl //
CI
CI
N
Cl C
43 45
44
58
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The invention will be further described in more detail by the following
synthetic
examples. These examples are offered to illustrate the invention, and are not
to be
construed in any way as limiting the scope of the invention.
Compound synthesis and formulation
Example 1
1-(4-(4-cyanobut-1-ynyl)pheny1)-2-(2,4-dichloropheny1)-N-morpholino-5-
(pyrrolidin-1-
ylmethyl)-1H-imidazole-4-carboxamide (compound 12)
Step A
N-(4-bromopheny1)-2,4-dichlorobenzimidamide
To a magnetically stirred solution of EtMgBr (3.3 mL, 3M in diethyl ether, 10
mmol) in
THF (30 mL) 4-bromoaniline (1.72 g, 10 mmol) was slowly added portion wise.
After
the solution was stirred for 30 min., 2,4-dichlorobenzonitrile (1.72g, 10
mmol) was
added. The resulting solution was stirred at room temperature (RT) overnight.
The
reaction mixture was quenched with water and extracted with ethyl acetate. The
combined extracts were dried over anhydrous MgSO4, filtered and evaporated
under
reduced pressure to give the benzimidamide as an off-white solid (2.45g,
71.2%).
Step B
Ethyl 1-(4-bromopheny1)-2-(2,4-dichloropheny1)-5-methyl-1H-imidazole-4-
carboxylate
To a magnetically stirred solution of above imidamide from step A (2.45g, 7
mmol) in
30 mL anhydrous toluene were added ethyl 3-bromo-2-oxobutanoate (1.48g, 7
mmol)
and Na2CO3 (0.74g, 7 mmol). The contents were stirred at 100 C for 12 hours.
The
reaction was brought to RT. The reaction mixture was quenched with water and
extracted with ethyl acetate. The combined extracts were dried over anhydrous
MgSO4, filtered and evaporated under reduced pressure. Purification by column
chromatography gave the ester as pale white solid (1.5 g, 46.4%).
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Step C
2-(2,4-dichloropheny1)-1-(4-iodopheny1)-N-morpholino-5-(pyrrol1din-1-ylmethyl)-
1H-
imidazole-4-carboxamide (compound 8)
To a magnetically stirred solution of ester from step B (1.5 g, 3.3 mmol) in
carbon
tetrachloride (20 mL) N-bromosuccinimide (0.58g, 3.3 mmol) was added along
with a
catalytic amount of and 2,2'-azobisisobutyronitrile (AIBN, 15 mg). The
resulting
mixture was refluxed for 3 h. After cooling to RT, the precipitate was
filtered. The
filtrate was washed with 2x50 ml water and the organic layer was dried over
anhydrous sodium sulfate, filtered, and evaporated. Flash column
chromatography
on silica gel with petroleum ether/ethyl acetate (1:9) gave bromo derivative
(1 mg,
56% yield) as a pale yellow solid. The bromo derivative ( 1g, 1.88 mmol) was
taken in
acetonitrile (50 ml) and to that Hunnig's base (0.26g, 2 mmol) and pyrrolidine
(0.14g,
2 mmol) were added. The reaction mixture was heated at 60-65 C for 1 h hour.
After cooling the reaction mixture was concentrated to give an oily residue
which was
subsequently dissolved in dichloromethane (50 ml). This was washed with 2x25
ml
water and the organic layer was dried over anhydrous sodium sulfate, filtered,
and
evaporated. Flash column chromatography on silica gel with petroleum
ether/ethyl
acetate (1:1) gave ester (700 mg, 71.2%) as a white solid. To the suspension
of AlC13
(0.53 g, 4 mmol) in dichloroethane (20 mL) was added 4-aminomorpholine (0.41
g, 4
mmol) at 0 C and stirred for 25 min at that temperature. To this was added a
solution of ester from step C (700 mg, 1.3 mmol) in dichloroethane (5 mL). The
reaction was brought to RT and stirred at that temperature for 8h. The
reaction was
quenched with dilute HCI and the organic layer was extracted with
dichloromethane.
The combined extracts were dried over anhydrous MgSO4, filtered and evaporated
under reduced pressure. Purification by column chromatography gave the amide
as
an off-white solid (500 mg, 60%).
1H NMR (500 MHz, CDCI3-d) 8.39 (s, 1H), 7.65 (d, J = 8.30 Hz, 2H), 7.34 (s,
1H),
7.27 - 7.32 (m, 1H), 7.22 - 7.26 (m, 1H), 7.05 (d, J = 8.30 Hz, 2H), 3.87 (t,
J = 4.39
Hz, 4H), 3.83 (s, 2H), 2.94 (br. s., 4H), 2.50 (br. s., 4H), 1.69 (br. s., 4H)
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Step D
The amide from step C (500 mg, 0.79 mmol) was taken and subjected to the
Sonogashira reaction as was performed in example 3F to give compound 12 ( 200
mg, 47.5%).
1H NMR (500 MHz, CDC13-d) 8.19- 8.52 (m, 1H), 7.47 (d, J = 7.81 Hz, 3H), 7.35
(d, J
= 1.95 Hz, 3H), 7.29 - 7.30 (m, 1H), 7.25 - 7.28 (m, 1H), 4.04 - 4.92 (m, 2H),
3.90 (t, J
= 4.39 Hz, 4H), 2.98 (br. s., 4H), 2.73 - 2.88 (m, 2H), 2.63 - 2.74(m, 2H),
2.02 (br. s.,
4H), 1.74 (none, 4H)
Example 2
4-(4-(1-(2,4-dichloropheny1)-4-methy1-3-(piperidin-1-ylcarbamoy1)-1H-pyrazol-5-
yl)phenyl)but-3-ynyl nitrate (compound 10)
To a stirred solution of compound 5 [1-(2,4-dichloropheny1)-5-(4-(4-iodobut-1-
ynyl)pheny1)-4-methyl-N-(piperidin-1-y1)-1H-pyrazole-3-carboxamideR60 mg, 0.9
mmol) taken in acetonitrile (20 ml) and to that silver nitrate (33.5 mg, 0.19
mmol)
was added. The reaction mixture was heated for 2 hours. After cooling to RT,
the
precipitate was filtered. The filtrate was concentrated to give an oily
residue which
was subsequently dissolved in dichloromethane (20 ml). This was washed with
2x5
ml water and the organic layer was dried over anhydrous sodium sulfate,
filtered, and
evaporated. Flash column chromatography on silica gel with petroleum
ether/ethyl
acetate (1:1) gave compound 2 (40 mg, 74.6% yield) as a white solid.
1H NMR (500 MHz, CDC13-d) 7.65 (s, 1H), 7.43 (s, 1H), 7.36 (d, J = 8.30 Hz,
2H),
7.29 - 7.33 (m, 2H), 7.07 (d, J = 8.30 Hz, 2H), 4.64 (t, J = 6.84 Hz, 2H),
2.74 - 3.02
(m, 6H), 2.39 (s, 3H), 1.69- 1.90 (m, 4H), 1.45 (br. s., 2H)
Example 3
5-(4-(4-cyanobut-1-ynyl) pheny1)-1-(2,4-dichloropheny1)-4-methyl-N-(1,1-dioxo-
thiomorpholino)-1H-pyrazole-3-carboxamide (compound 15)
Step A
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4'-iodopropiophenone
lodobenzene (100g, 0.49 mol) was taken in a dry 1L3 neck flask equipped with a
N2
inlet and to it 200 ml of CS2 was added. The contents were cooled to 0-5 C and
then
AlC13(80 g, 0.6 moles) and subsequently propionyl chloride (60 g, 0.64 mol)
were
added while keeping the temperature (internal) at 5-10 C. The contents were
stirred
for 24 hrs.The reaction mixture was poured into a 5 liter plastic beaker
containing 1L
of 10% HCI + 1Kg of crushed ice. The resultant slurry was extracted with 1L of
ethyl
acetate. The organic layer was separated and washed with 2x500 ml of water and
500 ml of brine. The organic layer was dried over sodium sulphate and
concentrated
at 40 C to give 4'-iodopropiophenone (48 g, 38%).
1H NMR (500 MHz, CDCI3-d) 7.82 (d, 2H), 7.67 (d, J = 8.30 Hz, 2H), 2.96 (q, J
= 7.00
Hz, 2H), 1.22 (t, J = 7.32 Hz, 3H)
Step B
Lithium-4-ethoxy-1-(4-iodopheny1)-2-methy1-3,4-dioxobut-1-en-1-olate
4'-iodopropiophenone obtained from step A was taken in a 2L 3 neck flask
equipped
with a nitrogen inlet. To that 500 ml of diethyl ether was added and the
contents were
cooled at -78 C using a dry-ice acetone bath. The reaction mixture was stirred
for 15
minutes. Subsequently, a 1 M solution of lithium bis(trimethylsilyl)amide in
hexanes
(222 ml, 0.22 mol) was added drop wise over 1 hour. The contents were stirred
at -
78 C an additional 1 hour after diethyl oxalate which (32.3 g, 0.22 mol) taken
in
diethyl ether was added over 30 minutes. The contents were stirred for 2 hours
at -
78 C after which the cooling bath was removed. The contents were brought to
room
temperature over 10 hours. The solids were filtered under a stream of nitrogen
and
then washed with 200 ml of ether. The solid obtained was air dried for 1 hour
and
was taken as such to the next reaction directly (52 g, 76.9%).
Step C
ethyl 1-(2,4-dichlorophenyI)-5-(4-iodopheny1)-4-methyl-1H-pyrazole-3-
carboxylate
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The lithium salt obtained from step B was taken in a 1 liter 1 neck flask and
to that
2,4-dichlorophenylhydrzine hydrochloride (30.3 g, 0.14 mol) and 1.5 liters of
anhydrous ethanol were added in on portion. The resulting mixture was stirred
at
room temperature for 24 hours. The solids were filtered, washed with ethanol
and
then dried under vacuum to give a light yellow of ethyl 2-(2-(2,4-
dichlorophenyl)hydrazono)-4-(4-iodopheny1)-3-methy1-4-oxobutanoate (27 g). The
solids were taken in a 1 L 1 neck flask and to that 1 liter of glacial acetic
acid was
added. The mixture was refluxed for 4 hours. Acetic acid was distilled out
completely
and to the residue 500 ml of ethyl acetate was added. The organic layer was
separated, washed with 1 liter of water, dried over sodium sulphate and
concentrated
to give the crude ester. The ester was purified by column chromatography using
a
10% ethyl acetate-hexane mixture to give the pure ester (15 g, 57.6%).
1H NMR (500 MHz, CDCI3-d) 7.69 (d, J = 8.30 Hz, 2H), 7.41 (s, 1H), 7.29 - 7.39
(m,
2H), 6.89 (d, J = 8.30 Hz, 2H), 4.48 (q, J = 7.32 Hz, 2H), 2.35 (s, 3H), 1.37 -
1.53 (m,
3H)
Step D
1-(2,4-dichlorophenyI)-5-(4-iodopheny1)-4-methyl-1H-pyrazole-3-carboxylic acid
The ester (10 g, 19.9 mmoles) obtained from step C was taken in 500 ml 1 neck
flask
and to it 300 ml of 7:2:1 mixture of THF-methanol-water along with solid
lithium
hydroxide (2.5 g, 104.6 mol) was added. The mixture was refluxed for 12 hours.
The
solvents were removed totally and to the residue 200 ml of DCM was added. To
that
100 ml of water was added and the mixture was acidified to pH¨ 2 using
concentrated HCI. The organic layer was separated, washed with 100 ml of
brine,
dried over sodium sulphate and concentrated to give the acid. This was taken
directly
to the next step (9.4 g, 100%).
1H NMR (500 MHz, CDCI3-d) 7.70 (d, J 7 8.30 Hz, 2H), 7.44 (s, 1H), 7.30 - 7.38
(m,
2H), 6.90 (d, J = 8.30 Hz, 2H), 2.37 (s, 3H)
Step E
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1-(2,4-dichloropheny1)-4-methy1-5-(4-iodopheny1)-N-(1,1-dioxothiomorpholino)-
1H-
pyrazole-3-carboxamide (compound 16)
The acid (7.5 g, 15.8 mmol) obtained from step D was taken in a 500 ml 1 neck
flask
equipped with a nitrogen inlet and to it 200 ml of DCM, 4-aminothiomorpholine-
1,1-
dioxide (2.61 g, 17.4 mmol), TBTU (5.59g, 17.4 mmol) and DIPEA (2.25 g, 17.4
mmol) were added and the contents were stirred for 1 hour. To the reaction
mixture,
100 ml of water was added and the contents were acidified to pH-2 using
concentrated HC1. The organic layer was separated, washed with brine, dried
over
sodium sulphate and concentrated to give the amide (3 g, 31.2%).
1H NMR (500 MHz, CDCI3-d) 8.07 (s, 1H), 7.67 (d, J = 8.30 Hz, 2H), 7.45 (d, J
=
1.95 Hz, 1H), 7.29 - 7.34 (m, 1H), 7.25 (s, 1H), 6.85 (d, J = 8.30 Hz, 2H),
3.44 - 3.66
(m, 4H), 3.26 (d, J = 4.88 Hz, 4H), 2.35 (s, 3H)
Step F
To a stirred solution of amide obtained from step E (2 g, 3.3 mmol) in
pyrrolidine (40
ml), under an argon atmosphere, tetrakis(triphenylphosphine)palladium(0) (0.4
g, 0.3
mmol) was added. The reaction mixture was stirred for 5 min at room
temperature,
and subsequently 4-cyano-1-butyne (0.78 g, 9.9 mmol) in pyrrolidine (1.5 ml)
was
added over 5 minutes. The resulting mixture was heated at 80-85 C for 10 h.
The
reaction was hydrolyzed with a saturated aqueous solution of ammonium chloride
and extracted with ethyl acetate. The organic extract was dried over MgSO4 and
the
solvent was removed in vacuo. Purification by flash column chromatography on
silica
gel (eluant ethylacetate) gave compound 15 as a white solid (0.8 g, 43.7%)
1H NMR (500 MHz, CDCI3-d) 8.08 (s, 1H), 7.43 (s, 1H), 7.37 (d, J = 7.81 Hz,
2H),
7.28 - 7.34 (m, 1H), 7.24 (s, 1H), 7.06 (d, J = 7.81 Hz, 2H), 3.56 (d, J =
4.88 Hz, 4H),
3.26 (br. s., 4H), 2.72 - 2.87 (m, 2H), 2.57 - 2.71 (m, 2H), 2.37 (s, 3H)
Example 4
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5-(5-(4-cyanobut-1-ynyl)thiophen-2-y1)-1-(2,4-dichloropheny1)-4-methyl-N-
(piperidin-1-
y1)-1H-pyrazole-3-carboxamide (compound 34)
Step A
N-Methoxy-N-methylpropionamide:
Pyridine (17 mL, 0.4 mol) at 0 C was added dropwise to a solution of 0,N-
dimethyl-
hydroxylamine hydrochloride (10 g, 0.1 mol) and propionyl chloride (10 g, 0.1
mol) in
anhydrous dichloromethane (250 mL). The solution was stirred at room
temperature
for 24 h, washed with 2x 50 ml of 5% hydrochloric acid, 100 ml of saturated
NaHCO3
and 100 ml brine, dried over MgSO4 and concentrated under reduced pressure to
give colorless oil (10 g, 89 %).
Step B
1-(5-iodothiophen-2-yl)propan-1-one
38.4 ml of a 2M solution of lithium diisopropylamide (8.2 g, 76.8 mmol) in THF-
heptane-ethylbenzene was added to THE (50 ml) taken in a 500 three neck RB
flask
equipped with a nitrogen inlet. The mixture was cooled to -40 C and then 2-
iodothiophene (16.1 g, 76.8 mmol) taken in 50 ml of THE was added with
vigorous
stirring. After 10 minutes the mixture was warmed to -10 C and stirred for 30
min.
The reaction mixture was re-cooled to -40 C and N-methoxy-N-methylpropionamide
(9 g, 76.8 mmol) taken in 50 ml of THE was added in one portion. The reaction
mixture was allowed to warm slowly to 0 C and then the reaction was quenched
with
saturated 50 ml of NH4CI solution. The contents were extracted with 3 x 100 ml
of
DCM, dried over MgSO4 and concentrated to give an oily residue. This was
purified
by flash chromatography to give the title compound (10 g, 49%).
1H NMR (500 MHz, CDC13-d) 7.32 (d, 1H), 7.27- 7.30 (m, 1H), 2.86 (q, J = 7.32
Hz,
2H), 1.21 (t, J = 7.32 Hz, 3H)
Step C
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ethy11-(2,4-dichloropheny1)-5-(5-iodothiophen-2-y1)-4-methyl-1H-pyrazole-3-
carboxylate
The title compound was obtained as in example 3
1H NMR (500 MHz, CDC13-d) 7.46 (d, J = 1.95 Hz, 1H), 7.35 - 7.39 (m, 1H), 7.34
(d,
1H), 7.14 (d, J = 3.91 Hz, 1H), 6.55 (d, J = 3.91 Hz, 1H), 4.45 (q, J = 6.84
Hz, 2H),
2.42 (s, 3H), 1.42 (t, J = 7.08 Hz, 3H)
Step D
1-(2,4-dichloropheny1)-5-(5-iodothiophen-2-y1)-4-methyl-N-(piperidin-1-y1)-1H-
pyrazole-3-carboxamide
The title compound was obtained as in example 3
Step E
The title compound was obtained as in example 3
1H NMR (500 MHz, CDCI3-d) 7.60 (br. s., 1H), 7.50 (d, J = 1.95 Hz, 1H), 7.35 -
7.39
(m, 1H), 7.31 - 7.35 (m, 1H), 7.05 (d, J = 3.91 Hz, 1H), 6.72 (d, J = 3.42 Hz,
1H), 2.85
(br. s., 4H), 2.80 (t, J = 7.08 Hz, 2H), 2.56 - 2.70 (m, 2H), 2.47 (s, 3H),
1.75 (quin, J =
5.62 Hz, 4H), 1.43 (br. s., 2H)
Example 5
1-(2,4-dichloropheny1)-5-(5-iodothiophen-2-y1)-4-methyl-N-(1,1-
dioxothiomorpholino)-
1H-pyrazole-3-carboxamide (compound 44)
1H NMR (500 MHz, CDCI3-d) 8.10 (s, 1H), 7.54 (d, J = 1.95 Hz, 1H), 7.36- 7.42
(m,
1H), 7.33 (d, 1H), 7.17 (d, J = 3.91 Hz, 1H), 6.57 (d, J = 3.91 Hz, 1H), 3.57
(br. s.,
4H), 3.28 (br. s., 4H), 2.47 (s, 3H)
Example 6
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N-(1-cyanocyclopropy1)-1-(2 ,4-d ichloropheny1)-5-(5-iodothiophen-2-y1)-4-
methy1-1H-
pyrazole-3-carboxamide (compound 43)
1H NMR (500 MHz, CDC13-d) 7.53 (s, 1H), 7.41 (none, 1H), 7.30- 7.34 (m, 1H),
7.17
(d, J = 3.91 Hz, 1H), 6.57 (d, J = 3.91 Hz, 1H), 2.46 - 2.57 (m, 3H), 1.63
(br. s., 2H),
1.35 - 1.42 (m, 2H)
Example 7
5-(4-(4-cyanobut-1-ynyl)pheny1)-1-(2,4-dichloropheny1)-4-(hydroxymethyl)-N-
morpholino-1H-pyrazole-3-carboxamide (compound 2)
1H NMR (500 MHz, CDC13-d) 7.84 (s, 1H), 7.45 (d, J = 2.44 Hz, 1H), 7.37 (d, J
=
8.30 Hz, 2H), 7.29 - 7.33 (m, 1H), 7.25 (s, 1H), 7.07 (d, J = 8.30 Hz, 2H),
5.01 (t, J =
7.08 Hz, 1H), 4.63 (d, J = 7.32 Hz, 2H), 3.89 (t, J = 4.64 Hz, 4H), 2.96 (d, J
= 4.39
Hz, 4H), 2.72 - 2.84 (m, 2H), 2.56 - 2.69 (m, 2H)
Example 8
4-(4-(1-(2,4-dichloropheny1)-4-methy1-3-(piperidin-1-ylcarbamoy1)-1H-pyrazol-5-
yl)phenyl)but-3-ynyl methanesulfonate (compound 9)
1H NMR (500 MHz, CDC13-d) 7.67 (br. s., 1H), 7.43 (s, 1H), 7.35 (d, J = 7.81
Hz,
2H), 7.29 - 7.33 (m, 2H), 7.07 (d, J = 8.30 Hz, 2H), 4.39 (t, J = 6.59 Hz,
2H), 3.08 (s,
3H), 2.77 - 2.96 (m, 6H), 2.39 (s, 3H), 1.77 (br. s., 4H), 1.45 (br. s., 2H)
Example 9
S-4-(4-(1-(2,4-dichloropheny1)-4-methy1-3-(piperidi n-1-ylcarbamoy1)-1H-
pyrazol-5-
yl)phenyl)but-3-ynyl ethanethioate (compound 5)
1H NMR (500 MHz, CDC13-d) 7.62 (s, 1H), 7.41 (s, 1H), 7.33 (d, J = 8.30 Hz,
2H),
7.27 - 7.30 (m, 2H), 7.04 (d, J = 8.30 Hz, 2H), 3.10 (t, J = 7.08 Hz, 2H),
2.87 (br. s.,
4H), 2.69 (t, J = 7.08 Hz, 2H), 2.36 (d, J = 8.79 Hz, 6H), 1.75 (quin, J =
5.62 Hz, 4H),
1.43 (br. s., 2H)
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Example 10
1-(2,4-dichloropheny1)-5-(4-(4-iodobut-1-ynyl)pheny1)-4-methyl-N-(piperidin-1-
y1)-1H-
pyrazole-3-carboxamide (compound 6)
1H NMR (500 MHz, CDCI3-d) 7.63 (s, 1H), 7.41 (s, 1H), 7.36 (d, J = 8.30 Hz,
2H),
7.27 - 7.31 (m, 2H), 7.05 (d, J = 8.30 Hz, 2H), 3.30 (t, J = 7.32 Hz, 2H),
3.00 (t, J =
7.32 Hz, 2H), 2.86 (br. s., 4H), 2.37 (s, 3H), 1.67- 1.84 (m, 4H), 1.43 (br.
s., 2H)
Example 11
5-(4-(but-3-en-1-ynyl)pheny1)-1-(2,4-dichloropheny1)-4-methyl-N-(piperidin-1-
y1)-1H-
pyrazole-3-carboxamide (compound 13)
1H NMR (500 MHz, CDCI3-d) 7.63 (s, 1H), 7.41 (s, 1H), 7.37 (d, J = 7.81 Hz,
2H),
7.27 (br. s., 2H), 7.06 (d, J = 7.81 Hz, 2H), 6.00 (dd, J = 11.23, 17.58 Hz,
1H), 5.49 -
5.81 (m, 2H), 2.87 (br. s., 4H), 2.38 (s, 3H), 1.64- 1.89 (m, 4H), 1.43 (br.
s., 2H)
Example 12
5-(4-(4-azidobut-1-ynyl)phenyI)-1-(2,4-dichloropheny1)-4-methyl-N-(piperidi n-
1-yI)-1H-
pyrazole-3-carboxam ide (compound 14)
1H NMR (500 MHz, CDCI3-d) D 7.62 (s, 1H), 7.41 (s, 1H), 7.35 (d, J = 7.81 Hz,
2H),
7.27 - 7.29 (m, 2H), 7.04 (d, J = 8.30 Hz, 2H), 3.46 (t, J = 6.59 Hz, 2H),
2.87 (br. s.,
4H), 2.71 (t, J = 6.59 Hz, 2H), 2.37 (s, 3H), 1.64 - 1.86 (m, 4H), 1.43 (br.
s., 2H)
Example 13
1-(2,4-dichlorophenyI)-5-(4-(4-isothiocyanatobut-1-ynyl)pheny1)-4-methyl-N-
(piperidin-
1-yI)-1H-pyrazole-3-carboxamide (compound 11)
1H NMR (500 MHz, CDCI3-d) 7.63 (br. s., 1H), 7.42 (s, 1H), 7.38 (d, J = 8.30
Hz,
2H), 7.27 - 7.30 (m, 2H), 7.06 (d, J = 8.30 Hz, 2H), 3.70 (t, J = 6.59 Hz,
2H), 2.87 (br.
s., 4H), 2.82 (t, J= 6.59 Hz, 2H), 2.38 (s, 3H), 1.70 - 1.83 (m, 4H), 1.43
(br. s., 2H)
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Example 14
5-(4-(4-cyanobut-1-ynyl)pheny1)-1-(2,4-dichloropheny1)-4-ethyl-N-(piperidin-1-
y1)-1H-
pyrazole-3-carboxamide (compound 22)
1H NMR (500 MHz, CDCI3-d) 7.65 (s, 1H), 7.41 (s, 1H), 7.35 (d, J = 8.30 Hz,
2H),
7.28 - 7.30 (m, 1H), 7.27 (s, 1H), 7.07 (d, J = 7.81 Hz, 2H), 2.87 (br. s.,
4H), 2.70 -
2.82 (m, 4H), 2.54 - 2.69 (m, 2H), 1.76 (quin, J = 5.62 Hz, 4H), 1.43 (br. s.,
2H), 1.21
=
(t, J= 7.32 Hz, 3H)
Example 15
5-(4-(4-cyanobut-1-ynyl)phenyI)-1-(2,4-dichloropheny1)-4-ethyl-N-morpholino-1H-
pyrazole-3-carboxamide (compound 25)
1H NMR (500 MHz, CDCI3-d) 7.71 (s, 1H), 7.42 (s, 1H), 7.36 (d, J = 8.30 Hz,
2H),
7.30 (none, 1H), 7.26 (s, 1H), 7.08 (d, J = 8.30 Hz, 2H), 3.78 - 3.93 (m, 4H),
2.95 (br.
s., 4H), 2.73 - 2.85 (m, 4H), 2.59 - 2.69 (m, 2H), 1.21 (t, J = 7.32 Hz, 3H)
Example 16
3-((4-(1-(2,4-dichloropheny1)-4-methy1-3-(piperidin-1-ylcarbamoy1)-1H-pyrazol-
5-
y1)phenypethynyl)pyridine 1-oxide (compound 23)
1H NMR (500 MHz, CDCI3-d) 0 8.31 (s, 1H), 8.17 (d, J = 6.84 Hz, 1H), 7.64 (s,
1H),
7.48 (d, J = 8.30 Hz, 2H), 7.43 (s, 1H), 7.36 (d, J = 8.30 Hz, 1H), 7.31 (s,
2H), 7.28
(s, 1H), 7.14 (d, J = 8.30 Hz, 2H), 2.87 (br. s., 4H), 2.40 (s, 3H), 1.76
(quin, J = 5.62
Hz, 4H), 1.44 (br. s., 2H)
Example 17
1-(2,4-dichloropheny1)-4-ethyl-N-morpholino-5-pheny1-1H-pyrazole-3-carboxamide
(compound 20)
1H NMR (500 MHz, CDCI3-d) 7.72 (s, 1H), 7.41 (s, 1H), 7.28 -7.37 (m, 3H), 7.27
(s,
2H), 7.08 - 7.19 (m, 2H), 3.63 - 4.07 (m, 4H), 2.86 - 3.15 (m, 4H), 2.78 (q, J
= 7.32
Hz, 2H), 1.22 (t, J = 7.32 Hz, 3H)
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Example 18
5-(4-(4-cyanobut-1-ynyl)phenyI)-1-(2,4-dichloropheny1)-4-ethyl-N-(1,1-dioxo-
thiomorpholino)-1H-pyrazole-3-carboxamide (compound 24)
1H NMR (500 MHz, CDCI3-d) 8.10 (s, 1H), 7.43 (d, J = 1.95 Hz, 1H), 7.37 (d, J
=
8.30 Hz, 2H), 7.28 - 7.32 (m, 1H), 7.24 (s, 1H), 7.07 (d, J = 8.30 Hz, 2H),
3.47 - 3.63
(m, 4H), 3.27 (d, J = 4.88 Hz, 4H), 2.71 - 2.84 (m, 4H), 2.59 - 2.69 (m, 2H),
1.61 (s,
3H), 1.21 (t, J = 7.32 Hz, 3H)
Example 19
4-cyano-5-(4-(4-cyanobut-1-ynyl)pheny1)-1-(2,4-dichloropheny1)-N-(piperidin-1-
y1)-1H-
pyrazole-3-carboxamide (compound 28)
1H NMR (500 MHz, CDCI3-d) 7.54 (br. s., 1H), 7.49 (d, J = 1.95 Hz, 1H), 7.32 -
7.44
(m, 4H), 7.25 (d, 2H), 2.91 (br. s., 4H), 2.73 - 2.85 (m, 2H), 2.59 - 2.72 (m,
2H), 1.67 -
1.87 (m, 4H), 1.44 (br. s., 2H)
Example 20
4-cyano-5-(4-(4-cyanobut-1-ynyl)pheny1)-1-(2,4-dichloropheny1)-N-morpholino-1H-
pyrazole-3-carboxamide (compound 29)
1H NMR (500 MHz, CDCI3-d) 7.61 (s, 1H), 7.50 (s, 1H), 7.35- 7.47 (m, 4H), 7.27
(d,
2H), 3.74 - 3.93 (m, 4H), 2.91 - 3.07 (m, 4H), 2.73 - 2.87 (m, 2H), 2.58 -
2.71 (m, 2H)
Example 21
5-(4-(4-cyanobut-1-ynyl)phenyI)-1-(2,4-dichloropheny1)-4-cyano-N-(1,1-dioxo-
thiomorpholino)-1H-pyrazole-3-carboxamide (compound 32)
1H NMR (500 MHz, CDCI3-d) 7.98 (s, 1H), 7.51 (d, J = 1.95 Hz, 1H), 7.38 - 7.45
(m,
3H), 7.33 - 7.38 (m, 1H), 7.25 (d, 2H), 3.50 - 3.68 (m, 4H), 3.17 - 3.34 (m,
4H), 2.72 -
2.90 (m, 2H), 2.55 - 2.70 (m, 2H)
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Forskolin-Stimulated cAMP Assay
Intracellular cAMP levels were measured with a competitive protein-binding
assay using intact HEK293 cells expressing hCB1 or hCB2 and a cAMP
immunoassay kit from Sigma (St. Louis, MO). In short, forskolin stimulated
cells
were incubated with various concentrations of compound, cAMP anti-body and
cAMP
conjugate for 2 hours at ambient temperature. The reaction was stopped by
emptying the wells followed by the addition of p-NPP substrate and incubation
for 1
hour. This reaction was stopped and absorbance intensity, detected at 405 nm,
was
inversely proportional to the concentration of cAMP produced by the cells. The
results were expressed as percent inhibition of forskolin-stimulated cAMP
accumulation and EC50 curves were generated with the use of GraphPad Prism
software.
For example compound 2 and compound 15 did not change the forskolin-
stimulated cAMP accumulation in CB1 transfected HEK cells (Figures 1A and 1B)
and are therefore considered to be a CBI neutral antagonists.
The results are from one assay done in triplicate.
Reference herein to a "standard forskolin-stimulated cAMP assay" or like
phrase refers to the foregoing assay method.
[3H]CP55,940 Competitive Binding Assay
Some of the inventive analogs were tested for CBI receptor binding affinity
and for CB2 receptor affinity (to determine selectivity). As used herein,
"binding
affinity" is represented by the K1 value which is the inhibition constant
correlated with
the concentration of an analog required to occupy the 50% of the total number
(Bmax) of the receptors. The lower the Ki value the higher the binding
affinity. As
used herein an analog is said to have "binding selectivity" if it has higher
binding
affinity for one receptor compared to the other receptor; e.g. a cannabinoid
analog
71
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which has a Ki of 0.1 nM for CB1 and 10 nM for CB2, is 100 times more
selective for
the CBI receptor.
For the CBI receptor binding studies, membranes were prepared from rat
forebrain membranes according to the procedure of P. R. Dodd et at, A Rapid
Method for Preparing Synaptosomes: Comparison with Alternative Procedures,
Brain
Res., 107 - 118 (1981). The binding of the novel analogues to the CB1
cannabinoid
receptor was assessed as described in W. A. Devane et al, Determination and
Characterization of a Cannabinoid Receptor in a Rat Brain, Mol. Pharmacol.,
34, 605
- 613 (1988) and A. Charalambous et at, 5'-azido g THC: A Novel_ Photoaffinity
Label for the Cannabinoid Receptor_, J. Med. Chem., 35, 3076 - 3079 (1992)
with the
following changes.
Membranes, previously frozen at -80 C, were thawed on ice. To the stirred
suspension was added three volumes of TME (25 mM Tris-HCI buffer, 5 mM MgC12
and 1 mM EDTA) at a pH 7.4. The suspension was incubated at 4 C for 30 min. At
the end of the incubation, the membranes were pelleted and washed three times
with
TME.
The treated membranes were subsequently used in the binding assay
described below. Approximately 30 j.tg of membranes were incubated in
silanized
96-well microtiter plate with TME containing 0.1% essentially fatty acid-free
bovine
serum albumin (BSA), 0.8 nM [3H] CP-55,940, and various concentrations of test
materials in a final volume of 200 L. The assays were incubated for 1 hour at
30 C
and then immediately filtered using Packard Filtermate 196 harvester and
Whatman
GF/C filterplates and washed with wash buffer (TME) containing 0.5% BSA.
Radioactivity was detected using MicroScint 20 scintillation cocktail added
directly to
the dried filterplates, and the filterplates were counted using a Packard
Instruments
Top-Count. Nonspecific binding was assessed using 100 nM CP-55,940. Data
collected from three independent experiments performed with duplicate
determinations was normalized between 100% and 0% specific binding for CH] CP-
55,940, determined using buffer and 100 nM CP-55,940. The normalized data was
analyzed using a 4-parameter nonlinear logistic equation to yield IC50 values.
Data
from at least two independent experiments performed in duplicate was used to
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calculate IC50 values which were converted to K1 values using the assumptions
of
Cheng et at, Relationship Between the Inhibition Constant (KO and the
concentration
of Inhibitor which causes 50% Inhibition (IC) of an Enzymatic Reaction,
Biochem.
Pharmacol., 22, 3099-3102, (1973)
For the CB2 receptor binding studies, membranes were prepared from frozen
mouse spleen essentially according to the procedure of P. R. Dodd et at, A
Rapid
Method for Preparing Synaptosomes: Comparison with Alternative Procedures,
Brain
Res., 226, 107 - 118 (1981) Silanized
centrifuge tubes were used throughout to minimize receptor loss due to
adsorption.
The CB2 binding assay was conducted in the same manner as for the CB1 binding
assay. The binding affinities (K1) were also expressed in nanomoles (nM).
The CB1 cannabinoid receptor binding affinities (Ki) for some of the compounds
disclosed in the invention range between 0.5 nM and less than 100 nM . The CB2
cannabinoid receptor binding affinities (Ki) for the synthesized analogs range
between 60 nM and 5000 nM. For example, CB1 cannabinoid receptor binding
affinity (Ki) for compound 2 is 7 nM and the CB2 cannabinoid receptor binding
affinity
(Ki) is 1672 nM. The CB1 selectivity for some of the compounds range from 5 to
greater than 5000.
Distribution and the Blood Brain Barrier:
Mice (CD-1, weighing 25-30 g) are dosed intravenously or by oral gavage with
0.1-2 mg/kg of the compound dissolved in appropriate vehicle. Fifteen minutes
post-
injection or 30 and 60 minutes post-gavage, the animals are sacrificed
humanely by
decapitation followed by blood collection (-500 pL) and tissue dissection;
samples
are flash frozen with liquid nitrogen to prevent post-mortem degradation of
the
compounds or endogenous ligands. Tissues (plasma or brain) are extracted and
analyzed using a Thermo-Finnigan Quantum Ultra triple quadrupole mass
spectrometer with an Agilent 1100 HPLC front-end. Chromatographic separation
is
achieved using a Phenomenex Gemini column (2 x 50 mm, 54 Hardware consists
73
CA 02753061 2015-10-22
of a Finnigan TSQ Quantum Ultra triple quad mass spectrometer with both an
APC1
and ESI source and an Agilent 1100 front end. The mass spectrometer with
mobile
phase consisting of 0.1% formic acid in water (A) and 0.1% formic acid in
methanol
(B). SR141716 gets into the brain better at 1.8%/g (% of the total dose per
gram
brain) at 15 minutes post IV as compared to compound 2 which is 0.6%.
74
