Note: Descriptions are shown in the official language in which they were submitted.
CA 02393749 2002-06-07
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TITLE OF THE INVENTION
SUBSTITUTED 8-ARYLQUINOLINE PHOSPHODIESTERASE-4 INHIBITORS
BACKGROUND OF THE INVENTION
FIELD OF THE INVENTION
The present invention is directed to compounds that are substituted 8-
arylquinolines. In particular, this invention is directed to substituted 8-
arylquinolines
which are phosphodiesterase-4 inhibitors wherein the aryl group at the 8-
position
contains a substituent substituted-alkenyl group.
RELATED BACKGROUND
Hormones are compounds that variously affect cellular activity. In
many respects, hormones act as messengers to trigger specific cellular
responses and
activities. Many effects produced by hormones, however, are not caused by the
singular effect of just the hormone. Instead, the hormone first binds to a
receptor,
thereby triggering the release of a second compound that goes on to affect the
cellular
activity. In this scenario, the hormone is known as the first messenger while
the
second compound is called the second messenger. Cyclic adenosine monophosphate
(adenosine 3', 5'-cyclic monophosphate, "cAMP" or "cyclic AMP") is known as a
second messenger for hormones including epinephrine, glucagon, calcitonin,
corticotrophin, lipotropin, luteinizing hormone, norepinephrine, parathyroid
hormone,
thyroid-stimulating hormone, and vasopressin. Thus, cAMP mediates cellular
responses to hormones. Cyclic AMP also mediates cellular responses to various
neurotransmitters.
Phosphodiesterases ("PDE") are a family of enzymes that metabolize
3', 5' cyclic nucleotides to 5' nucleoside monophosphates, thereby terminating
cAMP
second messenger activity. A particular phosphodiesterase, phosphodiesterase-4
("PDE4", also known as "PDE-IV"), which is a high affinity, cAMP specific,
type IV
PDE, has generated interest as potential targets for the development of novel
anti-
asthmatic and anti-inflanimatory compounds. PDE4 is known to exist as at lease
four
-1-
SUBSTITUTE SHEET (RULE 26)
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isoenzymes, each of which is encoded by a distinct gene. Each of the four
known
PDE4 gene products is believed to play varying roles in allergic and/or
inflammatory
responses. Thus, it is believed that inhibition of PDE4, particularly the
specific PDE4
isoforms that produce detrimental responses, can beneficially affect allergy
and
inflammation symptoms. It would be desirable to provide novel compounds and
compositions that inhibit PDE4 activity.
A major concern with the use of PDE4 inhibitors is the side effect of
emesis which has been observed for several candidate compounds as described in
C.Burnouf et al., ("Burnouf '), Ann. Rep. In Med. Chem., 33:91-109(1998).
B.Hughes
et al., Br. J.Phannacol., 118:1183-1191(1996); M.J.Perry et al., Cell Biochem.
Biophys., 29:113-132(1998); S.B.Christensen et al., J.Med. Chem., 41:821-
835(1998);
and Burnouf describe the wide variation of the severity of the undesirable
side effects
exhibited by various compounds. As described in M.D.Houslay et al., Adv. In
Phannacol., 44:225-342(1998) and D.Spina et al., Adv. In Pharmacol., 44:33-
89(1998), there is great interest and research of therapeutic PDE4 inhibitors.
International Patent Publication W09422852 describes quinolines as
PDE4 inhibitors.
A.H.Cook, et al., J.Chenz. Soc., 413-417(1943) describes gamma-
pyridylquinolines. Other quinoline compounds are described in Kei Manabe et
al.,
J.Org. Cheri2., 58(24):6692-6700(1993); Kei Manabe et al., J.Am. Cheni. Soc.,
115 (12 :5324-5325(1993); and Kei Manabe et al., J.Am. Chein. Soc., 114 17
:6940-
6941(1992).
Compounds that include ringed systems are described by various
investigators as effective for a variety of therapies and utilities. For
example,
International Patent Publication No. WO 98/25883 describes ketobenzamides as
calpain inhibitors, European Patent Publication No. EP 811610 and U.S. Patent
Nos.
5,679,712, 5,693,672 and 5,747,54 1 describe substituted benzoylguanidine
sodium
channel blockers, U.S. Patent No. 5,736,297 describes ring systems useful as a
photosensitive composition.
U.S. Patent Nos. 5,491,147, 5,608,070, 5,622,977, 5,739,144,
5,776,958, 5,780,477, 5,786,354, 5,798,373, 5,849,770, 5,859,034, 5,866,593,
5,891,896, and International Patent Publication WO 95/35283 describe PDE4
-2-
SUBSTITUTE SHEET (RULE 26)
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inhibitors that are tri-substituted aryl or heteroaryl phenyl derivatives.
U.S. Patent No.
5,580,888 describes PDE4 inhibitors that are styryl derivatives. U.S. Patent
No.
5,550,137 describes PDE4 inhibitors that are phenylaminocarbonyl derivatives.
U.S.
Patent No. 5,340,827 describes PDE4 inhibitors that are phenylcarboxamide
compounds. U.S. Patent No. 5,780,478 describes PDE4 inhibitors that are tetra-
substituted phenyl derivatives. International Patent Publication WO 96/00215
describes substituted oxime derivatives useful as PDE4 inhibitors. U.S. Patent
No.
5,633,257 describes PDE4 inhibitors that are cyclo(alkyl and alkenyl)phenyl-
alkenyl
(aryl and heteroaryl) compounds.
However, there remains a need for novel compounds and compositions
that therapeutically inhibit PDE4 with minimal side effects.
SUMMARY OF THE INVENTION
The present invention is directed to novel substituted 8-arylquinolines
that are PDE4 inhibitors, wherein the aryl group at the 8-position is
substituted by a
substituted-allcenyl group. This invention also provides a pharmaceutical
composition
which includes an effective amount of the novel substituted 8-arylquinpline
and a
pharmaceutically acceptable carrier. This invention further provides a method
of
treatment in mammals of, for example, asthma, chronic bronchitis, chronic
obstructive pulmonary disease (COPD), eosinophilic granuloma, psoriasis and
other
benign or malignant proliferative skin diseases, endotoxic shock (and
associated
conditions such as laminitis and colic in horses), septic shock, ulcerative
colitis,
Crohn's disease, reperfusion injury of the myocardium and brain, inflammatory
arthritis, osteoporosis, chronic glomerulonephritis, atopic dermatitis,
urticaria, adult
respiratory distress syndrome, infant respiratory distress syndrome, chronic
obstructive pulmonary disease in animals, diabetes insipidus, allergic
rhinitis, allergic
conjunctivitis, vernal conjunctivitis, arterial restenosis, atherosclerosis,
neurogenic
inflammation, pain, cough, rheumatoid arthritis, ankylosing spondylitis,
transplant
rejection and graft versus host disease, hypersecretion of gastric acid,
bacterial,
fungal or viral induced sepsis or septic shock, inflammation and cytokine-
mediated
chronic tissue degeneration, osteoarthritis, cancer, cachexia, muscle wasting,
depression, memory impairment, monopolar depression, acute and chronic
-3-
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neurodegenerative disorders with inflammatory components, Parkinson disease,
Alzheimer's disease, spinal cord trauma, head injury, multiple sclerosis,
tumour
growth and cancerous invasion of normal tissues by the administration of an
effective
amount of the novel substituted 8-arylquinoline or a precursor compound which
forms
in vivo the novel substituted 8-arylquinoline.
BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 is a chemical schematic drawing of the general structure of the
compounds of the present invention.
Fig. 2 is a graph of Counts against Theta for an X-ray Powder
Diffraction of the Form A polymorph of the benzenesulfonic acid salt of 6-[1-
methyl-
1-(methyl sulfonyl)ethyl] -8- [3 - [ (E)-2- [3 -methyl-1, 2,4-oxadiazol-5-yl] -
2- [4-
(methylsulfonyl)phenyl]ethenyl]phenyl]quinoline.
Fig. 3 is a graph of Counts against Theta for an X-ray Powder
Diffraction of the Form B polymorph of the benzenesulfonic acid salt of 6-[1-
methyl-
1-(methylsulfonyl)ethyl]-8-[3-[(E)-2-[3-methyl-1,2,4-oxadiazol-5-yl]-2-[4-
(methylsulfonyl)phenyl]ethenyl]phenyl]quinoline.
Fig. 4 is a comparison of the X-ray Powder Diffractions of the Form A
polymorph (bottom trace) and the Form B (upper trace) of the benzenesulfonic
acid
salt of 6-[1-methyl-l-(methylsulfonyl)ethyl]-8-[3-[(E)-2-[3-methyl-1,2,4-
oxadiazol-5-
yl]-2-[4-(methylsulfonyl)phenyl]ethenyl]phenyl]quinoline.
Fig. 5 is a graph of the distinguishing feature peaks of the X-ray
Powder Diffraction of the Form A polymorph of the benzenesulfonic acid salt of
6-[1-
methyl-l-(methylsulfonyl)ethyl] -8- [3 - [ (E)-2- [3-methyl-1,2,4-oxadi azol-5
-yl] -2- [4-
(methylsulfonyl)phenyl]ethenyl]phenyl]quinoline.
-4-
SUBSTITUTE SHEET (RULE 26)
~
yC015Y CA 02393749 2002-06-07
Fig. 6 is a graph of the distinguishing feature peaks of the X-ray
Powder Diffraction of the Form B polymorph of the benzenesulfonic acid salt of
6-[1-
methyi-l-(methylsulfonyl)ethyl]-8-[3-[(E)-2-[3-methyl-1,2,4-oxadiazol-5-yl]-2-
[4-
(methylsulfonyl)phenyl]ethenyl]phen yl]quinoline.
DETAILED DESCRTPTION OF THE INVENTION
A compound of this invention is represented by Formula (T):
R1
S1 S2
N
Sg
A y R3
R2
or a pharmaceutically acceptable salt thereof, wherein
S1, S2, and S3 are independently H, -OH, halogen, -Cl-C6alkyl,
-N02, -CN, or -C1-C6alkoxy, wherein the alkyl and alkoxy groups are optionally
substituted with 1-5 substituents; wherein each substituent is independently a
halogen
or OH;
Rl is a H, OH, halogen, carbonyl, or -C1-C6alkyl, -cycloC3-C6alkyl,
-C2-C6alkenyl, -C1-C6alkoxy, aryl, heteroaryl, -CN, -heterocycloC3-C6alkyl, -
amino,
-CI-C6alkylamino, -(C1-C6alkyl)(Cl-C6alkyl)amino, -C1-C6alkyl(oxy)C1-C6aIky1,
-C(O)NH(aryl), -C(O)NH(heteroaryl), -SOnNH(aryl), -SOnNH(heteroaryl),
-SOnNH(C1-C6alkyl), -C(O)N(C0-C6alkyl)(C0-C6alkyl), -NH-SOn-(C1-C6alkyl),
-SOn-(C1-C6alkyl), -(Cl-C6alkyl)-O-C(CN)-dialkylamino, or
-(CI-C(alkyl)-SOn-(CI-C(alkyl) group, wherein any of the groups is optionally
substituted with 1-5 substituents; wherein each substituent is independently a
halogen,
-OH, -CN, -C1-C6alkyl, -cycloC3-C6alkyl, -C(O)(heterocycloC3-C6alkyl),
-C(O)-O-(CO-C6alkyl), -C(O)-aryloxy, -C1-C6alkoxy,
-5-
N9~ c
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-(CO-C6alkyl)(CO-C6alkyl)amino, cycloalkyloxy, acyl, acyloxy, -cycloC3-
C6alkyl,
heterocycloC3-C6alkyl, aryl, heteroaryl, carbonyl, carbamoyl, or -SOn-(C1-
C6alkyl);
A is CH, C-ester, or C-R4;
R2 and R3 independently is an aryl, heteroaryl, H, halogen, -CN,
-C1-C6alkyl, heterocycloC3-6alkyl, -C1-C6alkoxy, carbonyl, carbamoyl, -C(O)OH,
-(C1-C(alkyl)-SOn-(C1-C(alkyl), -C(O)N(CO-C(alkyl)(CO-C(alkyl), or
-C1-C6alkylacylamino group, wherein any of the groups is optionally
substituted with
1-5 substituents, wherein each substituent is independently an aryl,
heteroaryl,
halogen, -N02, -C(O)OH, carbonyl, -CN, -C1-C6alkyl, -SOn-(C1-C(alkyl),
-SOn-(aryl), aryloxy, -heteroaryloxy, C1-C6alkoxy, N-oxide,
-C(O)-heterocycloC3-C6alkyl, -NH-cycloC3-C6alkyl, amino, -OH, or
-(CO-C(alkyl)(CO-C(alkyl)amino, -C(O)-N(CO-C(a1kyl)(CO-C(a1ky1) substituent
group, wherein each substituent group independently is optionally substituted
with
-OH, C1-C6alkoxy, -C1-C6alkyl, -cycloC3-C6alky1, aryloxy, -C(O)OH,
-C(O)O(C1-C6alkyl), halogen, -N02, -CN, -SOn-(C1-C(alkyl), or
-C (O)-N(CO-C ( alkyl) (CO-C( allcyl);
one of R2 and R3 must be an aryl or heteroaryl, optionally substituted;
when R2 and R3 are both an aryl or heteroaryl, then R2 and R3 may be
optionally connected by a thio, oxy, or (C1-C4alkyl) bridge to form a fused
three ring
system;
R4 is an aryl, -C1-C6alkyl, heteroaryl, -CN, carbonyl, carbamoyl,
-(C 1-C( alkyl)-S On-(C 1-C( alkyl), -C (O)N(CO-C( alkyl) (CO-C( alkyl), or
-C1-C6alkylacylamino group, wherein any of the groups is optionally
substituted with
1-5 substituents, wherein each substituent is independently a carbonyl, -CN,
halogen,
-C(O)(CO-C(alkyl), -C(O)O(CO-C(alkyl), -C1-C6alkyl, -SOn-(C1-C6alkyl), -OH,
C1-C6alkoxy, or -(CO-C(alkyl)(CO-C(alkyl)amino, group;
n is independently 0, 1, or 2; and
R2 or R3 may optionally be joined to R4 by a bond to form a ring.
In one aspect, a compound of this invention is represented by Formula
(I) or a pharmaceutically acceptable salt thereof, wherein
-6-
SUBSTITUTE SHEET (RULE 26)
VjC015Y CA 02393749 2002-06-07
S1, S2, and S3 are independently H, -OH, halogen, -C1-C(alkyl,
-NO2, -CN, or -C1-C6alkoxy, wherein the alkyl and alkoxy groups are optionally
substituted with 1-5 substituents; wherein each substituent is independently a
halogen
or OH;
R1 is a H, OH, halogen, carbonyl, or -C1-C6alkyl, -cycloC3-C6a1kyI,
-C2-C6alkenyl, -C1-C6alkoxy, aryl, heteroaryl, -CN, -heterocycloC3-C6alkyl, -
amino,
-C1-C(alkylamino, -(Ci-C6alkyl)(C1-C6alkyl)amino, -Ci-C6alkyl(oxy)C1-C6alkyl,
-C(O)NH(aryl), -C(O)NH(heteroaryl), -SOnNH(aryl), -SOnNH(heteroaryl),
-SOnNH(C1-C6alkyl), -C(O)N(CO-C6alkyl)(CQ-C6alkyl), -NH-SOn-(C1-C6alkyl),
-SOn-(C1-C6alkyl), -(Cl-C6alkyl)-O-C(CN)-dialkylanlino, or
-(C1-C6alkyl)-SOn-(C1-Cgalkyl) group, wherein any of the groups is optionally
substituted with 1-5 substituents; wherein each substituent is independently a
halogen,
-OH, -CN, -C1-C6alkyl, -cycloC3-C6alkyl, -C(O)(heterocycloC3-C6alkyl),
-C(O)-O-(CO-C6alkyl), -C(O)-aryloxy, -Cl-C6alkoxy, -(Cp-C6alkyl)(CQ-
C(alkyl)amino, cycloalkyloxy, acyl, acyloxy, -cycloC3-C6alkyl, heterocycloC3-
C6alkyl, aryl, heteroaryl, carbonyl, carbamoyl, or -SOn-(C1-C(alkyl);
A is CH;
R2 and R3 independently is an aryl, heteroaryl, H, halogen, -CN,
-C1-C6alkyl, heterocyloC3-6alkyl, -C1-C6alkoxy, carbonyl, carbamoyl, -C(O)OH,
-(C1-Cbalkyl)-SOn-(C1-C6alkyl), -C(O)N(CQ-C6alkyl)(CQ-C6alkyl), or
-C1-C(alkylacylamino group, wherein any of the groups is optionally
substituted with
1-5 substituents, wherein each substituent is independently an aryl,
heteroaryl,
halogen, -N02, -C(O)OH, carbonyl, -CN, -C1-C(alkyl, -SOn-(C1-C6alkyi),
-SOn-(aryl), -aryloxy, -heteroaryloxy, C1-C(alkoxy, N-oxide,
-C(O)-heterocycloC3-C6alkyl, -NH-cycloC3-C6alkyl, anlino, -OH, or
-(CQ-C6alkyl)(CO-C6alkyl)amino, -C(O)-N(CQ-C(alkyl)(CQ-C(alkyl) substituent
group, wherein each substituent group independently is optionally substituted
with
-OH, C?-C6alkoxy, -C1-C6alkyl, -cycloC3-C6alkyl, -aryloxy, -C(O)OH,
-C(O)O(C1-C6alkyl), halogen, -N02, -CN, -SOn-(CI-C6alkyl), or
-C(O)-N(CQ-C6alkyl)(CQ-C6alkyl);
one of R2 and R3 must be an aryl or heteroaryl, optionally substituted;
-7-
*0
~010
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when R2 and R3 are both an aryl or heteroaryl, then R2 and R3 may be
optionally connected by a thio, oxy, or (C1-C4alkyl) bridge to form a fused
three ring
system; and
n is independently 0, 1, or 2.
In one embodiment of this aspect, a compound of this invention is
represented by Formula (I) or a pharmaceutically acceptable salt thereof,
wherein
S1, S2, and S3 are independently H, -OH, halogen, -C1-C6alkyl,
-NO2, -CN, or -C1-C6alkoxy, wherein the alkyl and alkoxy groups are optionally
substituted with 1-5 substituents; wherein each substituent is independently a
halogen
or OH;
R1 is a-C1-C(alkyl, optionally substituted with 1-5 substituents;
wherein each substituent is independently a halogen, -OH, -CN,
-C(O)(heterocycloC3-C6alkyl), -C(O)-O-(CO-C(alkyl), -C(O)-O-aryl, alkoxy,
cycloalkyloxy, acyl, acyloxy, -cycloC3-C6alkyl, heterocycloC3-C6alkyl, aryl,
heteroaryl, carbonyl, carbamoyl, or -SOn-(C1-C(alkyl),
-(CO-C( alky1)(CO-Cgalkyl)amino;
A is CH;
R2 and R3 independently is an aryl, heteroaryl, H, halogen, -CN,
-C1-C6alkyl, heterocyloC3-6alkyl,-C1-C6alkoxy, carbonyl, carbamoyl, -C(O)OH,
-(C1-C(alkyl)-SOn-(C1-C(alkyl), -C(O)N(CO-C(alkyl)(CO-C(alkyl), or
-C1-C6alkylacylamino group, wherein any of the groups is optionally
substituted with
1-5 substituents, wherein each substituent is independently an aryl,
heteroaryl,
halogen, -N02, -C(O)OH, carbonyl, -CN, -C1-C6alkyl, -SOn-(C1-C(alkyl),
-SOn-(aryl.), -O-aryl, -0-heteroaryl, C1-C6al.koxy, N-oxide,
-C(O)-heterocycloC3-C6alkyl, -NH-cycloC3-C6alkyl, amino, -OH, or
-(CO-C(alky1)(CO-C(a1ky1)amino, -C(O)-N(CO-C(alkyl)(CO-C(alkyl) substituent
group, wherein each substituent group independently is optionally substituted
with
-OH, C1-C6alkoxy, -C1-C(allcyl, -cycloC3-C6a1ky1, aryloxy, -C(O)OH,
-C(O)O(C1-C6alkyl), halogen, -NO2, -CN, -SOn-(C1-Cga1kyl), or
-C (O)-N(CO-C( alkyl) (CO-C( alkyl);
-S-
SUBSTITUTE SHEET (RULE 26)
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one of R2 and R3 must be an aryl or heteroaryl, optionally substituted;
when R2 and R3 are both an aryl or heteroaryl, then R2 and R3 may be
optionally connected by a thio, oxy, or (C1-C4alkyl) bridge to form a fused
three ring
system;
n is independently 0, 1, or 2.
In another embodiment of this aspect, a compound of this invention is
represented by Formula (1) or a pharmaceutically acceptable salt thereof,
wherein
S1, S2, and S3 are independently H, -OH, halogen, -C1-C6alkyl,
-NO2, -CN, or -C1-C(alkoxy, wherein said alkyl and alkoxy groups are
optionally
substituted with 1-5 substituents; wherein each substituent is independently a
halogen
or OH;
R1 is a-cycloC3-C(alkyl, optionally substituted with 1-5 substituents;
wherein each substituent is independently a halogen, -OH, -CN,
-C(O)(heterocycloC3-C6alkyl), -C(O)-O-(CO-C(alkyl), -C(O)-O-aryl, alkoxy,
cycloalkyloxy, acyl, acyloxy, -cycloC3-C6alkyl, heterocycloC3-C6alkyl, aryl,
heteroaryl, carbonyl, carbamoyl, or -SOn-(C1-C(alkyl);
AisCH;
R2 and R3 independently is an aryl, heteroaryl, H, halogen, -CN,
-C1-C(alkyl, heterocyloC3-6alkyl,-C1-C6alkoxy, carbonyl, carbamoyl, -C(O)OH,
-(C1-C6alkyl)-SOn-(C1-C6alkyl), -C(O)N(CO-C6alkyl)(CO-C6alkyl), or
-C1-C6alkylacylamino group, wherein any of the groups is optionally
substituted with
1-5 substituents, wherein each substituent is independently an aryl,
heteroaryl,
halogen, -NO2, -C(O)OH, carbonyl, -CN, -C1-C(alkyl, -SOn-(C1-C(allcyl),
-SOn-(aryl), -0-aryl, -0-heteroaryl, C1-C6alkoxy, N-oxide,
-C(O)-heterocycloC3-C6alkyl, -NH-cycloC3-C6alkyl, amino, -OH, or
-(CO-C(alkyl)(CO-C(alkyl)amino, -C(O)-N(CO-C(alkyl)(CO-C(alkyl) substituent
group, wherein each substituent group independently is optionally substituted
with
-OH, C1-C(alkoxy, -C1-C6alkyl, -cycloC3-C6alkyl, aryloxy, -C(O)OH,
-C(O)O(C1-C6alkyl), halogen, -N02, -CN, -SOn-(C1-C(alkyl), or
-C(O)-N(CO-C(alkyl)(CO-C(alkyl);
-9-
SUBSTITUTE SHEET (RULE 26)
N1C015Y CA 02393749 2002-06-07
one of R2 and R3 must be an aryl or heteroaryl, optionally substituted;
when R2 and R3 are both an aryl or heteroaryl, then R2 and R3 may be
optionally connected by a thio, oxy, or (C 1-C4alkyl) bridge to form a fused
three ring
system; and
n is independently 0, 1, or 2.
In yet another embodiment of this aspect, a compound of this invention
is represented by Formula (1) or a pharmaceutically acceptable salt thereof,
wherein
S1, S2, and S3 are independently H, -OH, halogen, -C1-Cbalkyl,
-N02, -CN, or -C1-C6alkoxy, wherein said alkyl and alkoxy groups are
optionally
substituted with 1-5 substituents; wherein each substituent is independently a
halogen
or OH;
R1 is a-C2-C(alkenyl, optionally substituted with 1-5 substituents;
wherein each substituent is independently a halogen, -OH, -CN,
-C(O)(heterocycloC3-C6alkyl), -C(O)-O-(CO-Cga)kyl), -C(O)-O-aryl, alkoxy,
cycloalkyloxy, acyl, acyloxy, -cycloC3-C6alkyl, heterocyclaC3-C6alkyl, aryl,
heteroaryl, carbonyl, carbamoyl, or -SOn-(C1-C(,alkyl);
A is CH;
R2 and R3 independently is an aryl, heteroaryl, H, halogen, -CN,
-C1-C6alkyl, heterocyloC3-6alkyl,-C1-C6alkoxy, carbonyl, carbamoyl, -C(O)OH,
-(C1-C(alkyl)-SOn-(C1-C6alkyl), -C(O)N(Cp-C6alkyl)(CO-C6alkyl), or
-Ci-C6alkylacylamino group, wherein any of the groups is optionally
substituted with
1-5 substituents, wherein each substituent is independently an aryl,
heteroaryl,
halogen, -N02, -C(O)OH, carbonyl, -CN, -C1-C6alkyl, -SOn-(C1-Cgalkyl),
-SOn-(aryl), -0-aryl, -0-heteroaryl, C1-C6alkoxy, N-oxide,
-C(O)-heterocycloC3-C6alkyl, -NH-cycloC3-C6alkyl, amino, -OH, or
-(Cp-C(alkyl)(CO-C[alkyl)amino, -C(O)-N(CO-C6alkyl)(CO-C6alkyl) substituent
group, wherein each substituent group independently is optionally substituted
with
-OH, C1-C(alkoxy, -C1-C(alkyl, -cycloC3-C6alkyl, aryloxy, -C(O)OH,
-C(O)O(C1-C6alkyl), halogen, -N02, -CN, -SOn-(C1-C6alkyl), or
-C(O)-N(CO-C{ alkyl)(CO-C{ alkyl);
-10-
N~E~
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one of R2 and R3 must be an aryl or heteroaryl, optionally substituted;
when R2 and R3 are both an aryl or heteroaryl, then R2 and R3 may be
optionally connected by a thio, oxy, or (C1-C4alkyl) bridge to form a fused
three ring
system;
n is independently 0, 1, or 2.
In another embodiment of this aspect, a compound of this invention is
represented by Formula (1) or a pharmaceutically acceptable salt thereof,
wherein
S1, S2, and S3 are independently H, -OH, halogen, -C1-C(alkyl,
-N02, -CN, or -C1-C6alkoxy, wherein said alkyl and alkoxy groups are
optionally
substituted with 1-5 substituents; wherein each substituent is independently a
halogen
or OH;
R1 is a heteroaryl, optionally substituted with 1-5 substituents; wherein
each substituent is independently a halogen, -OH, -CN, -C(O)(heterocycloC3-
C6alkyl), -C(O)-O-(CO-C(alkyl), -C(O)-O-aryl, alkoxy, cycloalkyloxy, acyl,
acyloxy,
-cycloC3-C6alkyl, heterocycloC3-C6allcyl, aryl, heteroaryl, carbonyl,
carbamoyl, or
-SOn-(C 1-C6alkyl);
A is CH;
R2 and R3 independently is an aryl, heteroaryl, H, halogen, -CN,
-C1-C6alkyl, heterocyloC3-6alkyl,-C1-C6alkoxy, carbonyl, carbamoyl, -C(O)OH,
-(C 1-C6alkyl)-SOn-(C 1-C6alkyl), -C(O)N(CO-C6alkyl)(CO-C6alkyl), or
-C1-C(alkylacylamino group, whereiin any of the groups is optionally
substituted with
1-5 substituents, wherein each substituent is independently an aryl,
heteroaryl,
halogen, -NO2, -C(O)OH, carbonyl, -CN, -C1-C(alkyl, -SOn-(C1-C(alkyl),
-SOn-(aryl), -aryloxy, -0-heteroaryl, C1-C6alkoxy, N-oxide,
-C(O)-heterocycloC3-C6alkyl, -NH-cycloC3-C6alkyl, amino, -OH, or
-(CO-C(alkyl)(CO-C(alkyl)amino, -C(O)-N(CO-C(alkyl)(CO-C(alkyl) substituent
group, wherein each substituent group independently is optionally substituted
with
-OH, C1-C6alkoxy, -C1-C6alkyl, -cycloC3-C6alkyl, -aryloxy, -C(O)OH,
-C(O)O(C1-C6alkyl), halogen, -N02, -CN, -SOn-(C1-C6alkyl), or
-C (O )-N (C O-C ( alkyl ) (C O-C ( alkyl) ;
-11-
SUBSTITUTE SHEET (RULE 26)
CA 02393749 2002-06-07
WO 01/46151 PCT/CA00/01559
one of R2 and R3 must be an aryl or heteroaryl, optionally substituted;
when R2 and R3 are both an aryl or heteroaryl, then R2 and R3 may be
optionally connected by a thio, oxy, or (C1-C4alkyl) bridge to form a fused
three ring
system;
n is independently 0, 1, or 2.
In still another embodiment of this aspect, a compound of this
invention is represented by Formula (I) or a pharmaceutically acceptable salt
thereof,
wherein
S1, S2, and S3 are independently H, -OH, halogen, -C1-C(alkyl,
-N02, -CN, or -C1-C6alkoxy, wherein said alkyl and alkoxy groups are
optionally
substituted with 1-5 substituents; wherein each substituent is independently a
halogen
or OH;
R1 is a an -amino, -C1-C6alkylamino, or
-(C1-C(alkyl)(C1-C(alkyl)amino group, wherein any of the groups is optionally
substituted with 1-5 substituents; wherein each substituent is independently a
halogen,
-OH, -CN, -C(O)(heterocycloC3-C6alkyl), -C(O)-O-(CO-C(alkyl), -C(O)-O-aryl,
alkoxy, cycloalkyloxy, acyl, acyloxy, -cycloC3-C6alkyl, heterocycloC3-C6alkyl,
aryl,
heteroaryl, carbonyl, carbamoyl, or -SOn-(C1-C6alkyl);
A is CH;
R2 and R3 independently is an aryl, heteroaryl, H, halogen, -CN,
-C1-C6alkyl, heterocyloC3-6alkyl,-C1-C6alkoxy, carbonyl, carbamoyl, -C(O)OH,
-(C1-C(alkyl)-SOn-(C1-C(alkyl), -C(O)N(CO-C(alkyl)(CO-C(alkyl), or
-C1-C6alkylacylamino group, wherein any of the groups is optionally
substituted with
1-5 substituents, wherein each substituent is independently an aryl,
heteroaryl,
halogen, -NO2, -C(O)OH, carbonyl, -CN, -Cl-C6alkyl, -SOn-(C1-C(alkyl),
-SOn-(aryl), -aryloxy, -0-heteroaryl, C1-C6alkoxy, N-oxide,
-C(O)-heterocycloC3-C6alkyl, -NH-cycloC3-C6al1cyl, amino, -OH, or
-(CO-C(alkyl)(CO-C(alkyl)amino, -C(O)-N(CO-C(alkyl)(CO-C(alkyl) substituent
group, wherein each substituent group independently is optionally substituted
with
-OH, C1-C6alkoxy, -C1-C6alkyl, -cycloC3-C6alkyl, -aryloxy, -C(O)OH,
-12-
SUBSTITUTE SHEET (RULE 26)
V1C015N CA 02393749 2002-06-07
-C(O)O(C1-C6alkyl), halogen, -N02, -CN, -SOn-(C1-C6alkyl), or
-C(O)-N(C0-C6alkyl )(C0-C6alkyl);
one of R2 and R3 must be an aryl or heteroaryl, optionally substituted;
= when R2 and R3 are both an aryl or heteroaryl, then R2 and R3 may be
optionally connected by a thio, oxy, or (C1-C4alkyl) bridge to form a fused
three ring
system;
n is independently 0, 1, or 2.
In an embodiment of this aspect, a compound of this invention is
represented by Formula (I) or a pharmaceutically acceptable salt thereof,
wherein
S1, S2, and S3 are independently H, -OH, halogen, -C1-C6alkyl,
-N02, -CN, or -C1-C6alkoxy, wherein said alkyl and alkoxy groups are
optionally
substituted with 1-5 substituents; wherein each substituent is independently a
halogen
or OH;
R1 is a -C1-C6alkyl, -cycloC3-C6alkyl, -C2-C6alkenyl, -C1-C6alkoxy,
ary], heteroaryl, -CN, -heterocycloC3-C6alkyl, -amino, -C i -C6alkylamino,
-(C1-C6a1kyl)(C1-C6alkyl)amino, -C1-C6alkyl(oxy)Cl-C6alkyl, -C(O)NH(aryl),
-C(O)NH(heteroaryl), -SOnNH(aryI), -SOnNH(heteroaryI), -SOnNH(C1-C6alkyl),
-C(O)N(Cp-C(alkyl)(CO-C(alkyl), -NH-SOn-(C 1-C6alkyl), -SOn-(C 1-C6alkyl),
-carbamoyl, -(C1-C(a1ky1)-O-C(CN)-dialkylamino, or -(Ci-Cbalkyl)-SOn-(C1-
C6alkyl) group, wherein any of the groups is optionally substituted with 1-5
substituents; wherein each substituent is independently a halogen, -OH, -CN,
alkoxy,
cycloalkyloxy, acyl, acyloxy, -cycloC3-C6a1ky1, heterocycloC3-C6alkyl, aryl,
heteroaryl, carbonyl, carbamoyl, or -SOn-(C1-C6alkyl);
A is CH;
R2 is an aryl, optionally substituted with 1-5 substituents, wherein each
substituent is independently an aryl, heteroaryl, halogen, -N02, -C(O)OH,
carbonyl,
-CN, -C1-C6alkyl, -SOn-(C1-C6alkyl), -SOn-(ary]), -aryloxy, -0-heteroaryl, Ci-
C6alkoxy, N-oxide, -C(O)-heterocycloC3-C6alkyl, -NH-cycloC3-C6alkyl, amino,
-OH, or -(Cp-C6alkyl)(CO-C6alky])arnino, -C(O)-N(Cp-C6alkyl)(Cp-C6alkyl)
substituent group, wherein each substituent group independently is optionally
-13- oll ~
~
\=1C015Y CA 02393749 2002-06-07
substituted with -OH, C1-C6alkoxy, -C1-C6alkyl, -cycloC3-C6alkyl, -aryloxy,
-C(O)OH, -C(O)O(C1-C6alkyl), halogen, -N02, -CN, -SOn-(C1-C(alkyl), or
-C(O)-N(CO-C(alkyl ) (CO-C( alkyl );
R3 is a heteroaryl, optionally substituted with 1-5 substituents, wherein
each substituent is independently an aryl, heteroaryl, halogen, -N02, -C(O)OH,
carbonyl, -CN, -C1-C6alkyl, -SOn-(C1-C6alkyl), -SOn-(aryl), -aryloxy, -0-
heteroaryl,
C1-C6alkoxy, N-oxide, -C(O)-heterocycloC3-C6alkyl, -NH-cycloC3-C6alkyl, amino,
-OH, or -(CO-C(alkyl)(CO-C(alkyl)amino, -C(O)-N(CO-C6alkyl)(Cp-C6alkyl)
substituent group, wherein each substituent group independently is optionally
substituted with -OH, C1-C6alkoxy, -C1-C6alkyl, -cycloC3-C6alkyl, -aryloxy,
-C(O)OH, -C(O)O(C1-C6alkyl), halogen, -N02, -CN, -SOn-(CI-C6alkyl), or
-C(O)-N(CO-C6alkyl)(CO-C6alkyl); and
n is independently 0, 1, or 2.
In yet another embodiment of this aspect, a compound of this invention
is represented by Formula (I) or a pharmaceutically acceptable salt thereof,
wherein
S1, S2, and S3 are independently H, -OH, halogen, -C1-C6alkyl,
-N02, -CN, or -CI-C6alkoxy, wherein said alkyl and alkoxy groups are
optionally
substituted with 1-5 substituents; wherein each substituent is independently a
halogen
or OH;
R1 is a halogen, carbonyl, -C1-C6alkyl, -cycloC3-C6alkyl,
-C2-C6alkenyl, -C1-C6alkoxy, aryl, heteroaryl, -CN, -heterocycloC3-C6alkyl, -
amino,
-C 1-C(alkylamino, -(C1-C{alkyl)(C1-C(a1ky1)amino, -C1-C6alkyl(oxy)C1-C6alkyl,
-C(O)NH(aryl), -C(O)NH(heteroaryl), -SOnNH(aryl), -SOnNH(heteroaryl),
-SOnNH(Ci-C6alkyl), -C(O)N(CO-C6alkyl)(CO-C6alkyl), -NH-SOn-(C1-C6alkyl),
-SOn-(C1-C6alkyl), -carbamoyl, -(Ci-C(alkyl)-O-C(CN)-dialkylamino, or
-(C1-C(alkyl)-SOn-(C1-C6alkyl) group, wherein any of the groups is optionally
substituted with 1-5 substituents; wherein each substituent is independently a
halogen,
-OH, -CN, -C(O)(heterocycloC3-C6alkyl), -C(O)-O-(CO-C(alkyl), -C(O)-O-aryl,
alkoxy, cyc]oalkyloxy, acyl, acyloxy, -cycloC3-C6alkyl, heterocycloC3-C6alkyl,
aryl,
heteroaryl, carbonyl, carbamoyl, or -SOn-(C1-C6alkyl);
-14-
YlCOlSY CA 02393749 2002-06-07
A is CH;
R2 is an aryl, optionally substituted with 1-5 substituents, wherein each
substituent is independently an aryl, heteroaryl, halogen, -N02, -C(O)OH,
carbonyl,
-CN, -C1-C6alkyl, -SOn-(Cl-C(a1ky1), -SOn-(aryl), -aryloxy, -0-heteroaryl, C1-
C6alkoxy, N-oxide, -C(O)-heterocycloC3-C6alkyl, -NH-cycloC3-C6alkyl, amino,
-OH, or -(CO-C6alkyl)(CO-C6a1kyl)amino, -C(O)-N(CO-C6alkyl)(CO-C6all.yl)
substituent group, wherein each substituent group independently is optionally
substituted with -OH, C1-C6aIkoxy, -C1-C(,alkyl, -cycloC3-C6alkyl, -aryloxy,
-C(O)OH, -C(O)O(Cl-C6alkyl), halogen, -N02, -CN, -SOn-(C1-C6alky]), or
-C(O)-N(CO-C6alkyl)(CO-C6alkyl);
R3 is an aryl, optionally substituted with 1-5 substituents, wherein each
substituent is independently an aryl, heteroaryl, halogen, -N02, -C(O)OH,
carbonyl,
-CN, -C1-C6alkyl, -SOn-(C1-C6alkyl), -SOn-(aryl), -aryloxy, -0-heteroaryl, C1-
C6alkoxy, N-oxide, -C(O)-heterocycloC3-C6alkyl, -NH-cycloC3-C6alkyl, anzino,
-OH, or -(CO-C6alkyl)(CO-C6alkyl)amino, -C(O)-N(CO-C6alkyl)(CO-C6a1kyl)
substituent group, wherein each substituent group independently is optionally
substituted with -OH, CZ-Cbalkoxy, -C1-C6alkyl, -cycloC3-C6alkyl, -aryloxy,
-C(O)OH, -C(O)O(C1-C6alkyl), halogen, -N02, -CN, -SOn-(C1-Cbalkyl), or
-C(O)-N(CO-C6alkyl)(Cp-C6alkyl); and
n is independently 0, 1, or 2.
In still another embodiment of this aspect, a compound of this
invention is represented by Formula (I) or a pharmaceutically acceptable salt
thereof,
wherein
S1, S2, and S3 are independently H, -OH, halogen, -C1-C6alkyl,
-N02, -CN, or -C1-C6alkoxy, wherein said alkyl and alkoxy groups are
optionally
substituted with 1-5 substituents; wherein each substituent is independently a
halogen
or OH;
R1 is a halogen, carbonyl, -C1-C6alkyl, -cycloC3-C6alkyl,
-C2-C6alkenyl, -C1-C6alkoxy, aryl, heteroaryl, -CN, -heterocycloC3-C6alkyl, -
amino,
-C1-C6alkylamino, -(C1-C6alkyl)(C1-C6alkyl)amino, -C1-C6a1kyl(oxy)C1-C6a1kyl,
-C(O)NH(aryl), -C(O)NH(heteroaryl), -SOnNH(aryl), -SOnNH(heteroaryl),
-15- ~
CA 02393749 2002-06-07
WO 01/46151 PCT/CAOO/01559
-SOnNH(C1-C6alkyl), -C(O)N(CO-C(alkyl)(C0-C(alkyl), -NH-SOn-(C1-C6alkyl),
-SOn-(C1-C(alkyl), -carbamoyl, -(C1-C6alkyl)-O-C(CN)-dialkylamino, or
-(C1-C(alkyl)-SOn-(C1-C(alkyl) group, wherein any of the groups is optionally
substituted with 1-5 substituents; wherein each substituent is independently a
halogen,
-OH, -CN, -C(O)(heterocycloC3-C6alkyl), -C(O)-O-(CO-C(alkyl), -C(O)-O-aryl,
alkoxy, cycloalkyloxy, acyl, acyloxy, -cycloC3-C6alkyl, heterocycloC3-C6alkyl,
aryl,
heteroaryl, carbonyl, carbamoyl, or -SOn-(C1-C6a1ky1);
A is CH;
R2 is a carbonyl, optionally substituted with 1 substituent, wherein the
substituent is an, aryl, heteroaryl, -C(O)OH, carbonyl, -C1-C6alkyl, -0-aryl,
-O-heteroaryl, -O-(C1-C6alkyl), -heterocycloC3-C6alkyl, -NH-cycloC3-C6alkyl,
amino, -OH, or -(CO-C(a1ky1)(CO-C(allcyl)amino, substituent group, wherein
each
substituent group independently is optionally substituted with -OH, -O(C1-
C6alkyl),
-Ci-C6alkyl, -cycloC3-C6alkyl, -O(aryl), -C(O)OH, -C(O)O(C1-C6a1ky1), halogen,
-NO2, -CN, -SOn-(C1-C(alkyl), -cycloC3-C6alkyl or
-C(O)-N(CO-C( alkyl)(CO-C(alkyl);
R3 is an aryl, optionally substituted with 1-5 substituents, wherein each
substituent is independently an aryl, heteroaryl, halogen, -NO2, -C(O)OH,
carbonyl,
-CN, -C1-C6alkyl, -SOn-(C1-C6alkyl), -SOn-(aryl), -aryloxy, -0-heteroaryl, C1-
C6alkoxy, N-oxide, -C(O)-heterocycloC3-C6a1ky1, -NH-cycloC3-C6alkyl, amino,
-OH, or -(CO-C(alkyl)(CO-C(alkyl)amino, -C(O)-N(CO-C(alkyl)(CO-C(alkyl)
substituent group, wherein each substituent group independently is optionally
substituted with -OH, C1-C6alkoxy, -C1-C6alkyl, -cyc1oC3-C6a1ky1, -aryloxy,
-C(O)OH, -C(O)O(C1-C6a1kyl), halogen, -NO2, -CN, -SOn-(C1-C(alkyl), or
-C(O)-N(CO-C(alkyl)(CO-C(alkyl); and
n is independently 0, 1, or 2.
In yet another embodiment of this aspect, a compound of this invention
is represented by Formula (I) or a pharmaceutically acceptable salt thereof,
wherein
S1, S2, and S3 are independently H, -OH, halogen, -C1-C6alkyl,
-N02, -CN, or -C1-C(allcoxy, wherein said allcyl and alkoxy groups are
optionally
-16-
SUBSTITUTE SHEET (RULE 26)
:vjC 0 15; CA 02393749 2002-06-07
substituted with 1-5 substituents; wherein each substituent is independently a
halogen
or OH;
R1 is a halogen, carbonyl, -C1-C6alkyl, -cycloC3-C6alkyl,
-C2-C6alkenyl, -C1-C6alkoxy, aryl, heteroaryl, -CN, -heterocycloC3-C6alkyl, -
amino,
-C1-C(alkylamino, -(C1-C6alky1)(C1-C6alkyl)amino, -C1-C6alkyl(oxy)C1-C6alkyl,
-C(O)NH(aryl), -C(O)NH(heteroaryl), -SOnNH(aryl), -SOnNH(heteroaryl),
-SOnNH(C1-C6alkyl), -C(O)N(CO-C6alkyl)(CO-C6alkyl), -NH-SOn-(C1-C6alkyl),
-SOn-(C1-C6alkyl), -carbamoyl, -(C1-C6alkyl)-O-C(CN)-dialkylanzino, or
-(C1-C6alkyl)-SOn-(Ci-C(alkyl) group, wherein any of the groups is optionally
substituted with 1-5 substituents; wherein each substituent is independently a
halogen,
-OH, -CN, -C(O)(heterocycloC3-C6a1kyl), -C(O)-O-(CO-C6alkyl), -C(O)-O-aryl,
alkoxy, cycloalkyloxy, acyl, acyloxy, -cycloC3-C6alkyl, heterocycloC3-C6alkyl,
aryl,
heteroaryl, carbonyl, carbarnoyl, or -SOn-(C1-C{alkyl);
A is CH;
R2 is a carbamoyl, optionally substituted with 1-2 substituents,
wherein each substituent is independently a carbonyl, -CN, -C1-C6alkyl, -SOn-
(C1-
C6alkyl), -0-aryl, -0-heteroaryl, -C(O)-heterocycloC3-C6alkyl,
-NH-cycloC3-C6alkyl, amino, -OH, or -CI-C6alkyl(amino) substituent group,
wherein each substituent group independently is optionally substituted with -
OH,
-O(C1-C6alkyl), -O(aryl), -COOH, -COO(Cl-C(alkyl), halogen, -N02, -CN, or
-C(O)-N(CO-C6alkyl)(CO-C6alkyl);
R3 is an aryl, optionally substituted with 1-5 substituents, wherein each
substituent is independently an aryl, heteroaryl, halogen, -N02, -C(O)OH,
carbonyl,
-CN, -C1-C6alkyl, -SOn-(C1-C(alkyl), -SOn-(aryl), -aryloxy, -0-heteroaryl, C1-
C6alkoxy, N-oxide, -C(O)-heterocycloC3-C6alkyl, -NH-cycloC3-C6alkyl, amino,
-OH, or -(CO-C6alkyl)(CO-C6alkyl)amino, -C(O)-N(CO-C6alkyl)(CO-C6alkyl)
substituent group, wherein each substituent group independently is optionally
substituted with -OH, CI-C6alkoxy, -C1-C6alkyl, -cycloC3-C6alkyl, -aryloxy,
-C(O)OH, -C(O)O(C1-C6alkyl), halogen, -N02, -CN, -SOn-(C1-C(alkyl), or
-C(O)-N(CO-C6alkyl)(CO-C6alkyl); and
n is independently 0, 1, or 2.
-17-
C)5 CA 02393749 2002-06-07
In yet another embodiment of this aspect, a compound of this invention
is represented by Formula (I) or a pharmaceutically acceptable salt thereof,
wherein
S1, S2, and S3 are independently H, -OH, halogen, -C1-C6alkyl,
-N02, -CN, or -C1-C6alkoxy, wherein said alkyl and alkoxy groups are
optionally
substituted with 1-5 substituents; wherein each substituent is independently a
halogen
or OH;
RI is a halogen, carbonyl, -C1-C6alkyl, -cycloC3-C6alkyl,
-C2-C6alkenyl, -C1-C6alkoxy, aryl, heteroaryl, -CN, -heterocycloC3-C6alkyl, -
amino,
-C1-C6alkylamino, -(C1-C6alkyl)(C1-C6alkyl)amino, -C1-C6alkyl(oxy)C1-C6alkyl,
-C(O)NH(aryl), -C(O)NH(heteroaryl), -SOnNH(aryl), -SOnNH(heteroaryl),
-SOnNH(C1-C6alkyl), -C(O)N(CO-C6alkyl)(CO-C6alkyl), -NH-SOn-(C1-C6alkyl),
-SOn-(C1-C(alkyl), -carbamoyl, -(C1-C6alkyl)-O-C(CN)-dialkylamino, or
-(C1-C(alkyl)-SOn-(C1-C(alkyl) group, wherein any of the groups is optionally
substituted with 1-5 substituents; wherein each substituent is independently a
halogen,
-OH, -CN, -C(O)(heterocycloC3-C6alkyl), -C(O)-O-(CO-C(alkyl), -C(O)-O-aryl,
alkoxy, cycloalkyloxy, acyl, acyloxy, -cycloC3-C6alkyl, heterocycloC3-C6alkyl,
aryl,
heteroaryl, carbonyl, carbamoyl, or -SOn-(C1-C6alkyl);
A is CH;
R2 and R3 are each independently an aryl, optionally substituted,
connected to each other by a thio, oxy, or (C1-C4alkyl) bri dge to form a
fused three
ring system; and
n is independently 0, 1, or 2.
In yet another embodiment of this aspect, a compound of this invention
is represented by Formula (I) or a pharmaceutically acceptable salt thereof,
wherein
Sl, S2, and S3 are independently H, -OH, halogen, -CI-C6alkyl,
-N02, -CN, or -C1-C6alkoxy;
R1 is a halogen, carbonyl, -C1-C6alkyl, -cycloC3-C6alkyl,
-C2-C6alkenyl, -CI-C(alkoxy, aryl, heteroaryl, -CN, -heterocycloC3-C6alkyl, -
amino,
-C1-C6alkylaniino, -(C1-C6alkyl)(C1-C6alkyl)amino, -Ci-C6alkyl(oxy)C1-C6alkyl,
-C(O)NH(aryl), -C(O)NH(heteroaryl), -SOnNH(aryl), -SOnNH(heteroaryl),
-SOnNH(C1-C6alkyl), -C(O)N(CO-C(alkyl)(CO-C(alkyl), -NH-SOn-(C1-C6alkyl),
~'~
- 18 - ~~'",-
CA 02393749 2002-06-07
WO 01/46151 PCT/CAOO/01559
-SOn-(C1-C(alkyl), -carbamoyl, -(C1-C6alkyl)-O-C(CN)-dialkylamino, or
-(C1-C(alkyl)-SOn-(C1-C(alkyl) group, wherein any of the groups is optionally
substituted with 1-5 substituents; wherein each substituent is independently a
halogen,
-OH, -CN, -C(O)(heterocycloC3-C6alkyl), -C(O)-O-(CO-C(alkyl), -C(O)-O-aryl,
alkoxy, cycloalkyloxy, acyl, acyloxy, -cycloC3-C6alkyl, heterocycloC3-C6alkyl,
aryl,
heteroaryl, carbonyl, carbamoyl, or -SOn-(C1-C(alkyl);
A is CH;
R2 is a-(C1-C(alkyl)-SOn-(C1-C(alkyl), optionally substituted with
1-5 substituents, wherein each substituent is independently a halogen, -N02, -
COOH,
carbonyl, -CN, -C1-C6alkyl, -SOn-(Cl-C(alkyl), -0-aryl, -0-heteroaryl,
-C(O)-heterocycloC3-C6alkyl, -NH-cycloC3-C6alkyl, amino, -OH, or
-C1-C6alkyl(amino) substituent group, wherein each substituent group
independently
is optionally substituted with -OH, -O(C1-C(alkyl), -O(aryl), -COOH,
-COO(C1-C(alkyl), halogen, -N02, -CN, or -C(O)-N(CO-C(allcyl)(CO-C(alkyl);
R3 is an aryl, optionally substituted with 1-5 substituents, wherein each
substituent is independently an aryl, heteroaryl, halogen, -NO2, -C(O)OH,
carbonyl,
-CN, -C1-C6alkyl, -SOn-(C1-C(alkyl), -SOn-(aryl), -aryloxy, -0-heteroaryl, C1-
C6alkoxy, N-oxide, -C(O)-heterocycloC3-C6alkyl, -NH-cycloC3-C6alkyl, amino,
-OH, or -(CO-C(alkyl)(CO-C(alkyl)amino, -C(O)-N(CO-C(alkyl)(CO-C(alkyl)
substituent group, wherein each substituent group independently is optionally
substituted with -OH, C1-C(alkoxy, -C1-C(allcyl, -cycloC3-C6al1cyl, -aryloxy,
-C(O)OH, -C(O)O(C1-C6alkyl), halogen, -NO2, -CN, -SOn-(C1-C(alkyl), or
-C(O)-N(CO-C(alkyl)(CO-C(alkyl); and
n is independently 0, 1, or 2.
In yet another embodiment of this aspect, a compound of this invention
is represented by Formula (I) or a pharmaceutically acceptable salt thereof,
wherein
S1, S2, and S3 are independently H, -OH, halogen, -C1-C6alkyl,
-N02, -CN, or -C1-C6alkoxy, wherein said alkyl and alkoxy groups are
optionally
substituted with 1-5 substituents; wherein each substituent is independently a
halogen
or OH;
-19-
SUBSTITUTE SHEET (RULE 26)
CA 02393749 2002-06-07
V1C015Y
R1 is a halogen, carbonyl, -C1-C6alkyl, -cycloC3-C6alkyl,
-C2-C6alkenyl, -CI-C6alkoxy, aryl, heteroaryl, -CN, -heterocycloC3-C6alkyl, -
amino,
-C1-C6alkylarnino, -(C1-C6alkyl)(C1-C6alkyl)amino, -C1-C6alkyl(oxy)Cj-C6alkyl,
-C(O)NH(ary)), -C(O)NH(heteroaryl), -SOnNH(aryl), -SOnNH(heteroary[),
-SOnNH(C1-C6alkyl), -C(O)N(CO-C6alkyl)(CO-C6aIky1), -NH-SOn-(Ci-C6alkyl),
-SOn-(Cl-C6alkyl), -carbamoyl, -(C1-C6alkyl)-O-C(CN)-dialkylamino, or
-(C1-C(alkyl)-SOn-(CI-C6alkyl) group, wherein any of the groups is optionally
substituted with 1-5 substituents; wherein each substituent is independently a
halogen,
-OH, -CN, -C(O)(heterocycloC3-C6alkyl), -C(O)-O-(CO-C6alkyl), -C(O)-O-aryl,
alkoxy, cycloalkyloxy, acyl, acyloxy, -cycloC3-C6alkyl, heterocycloC3-C6alkyl,
aryl,
heteroaryl, carbonyl, carbamoyl, or -SOn-(C1-Cbalkyl);
A is CH;
R2 is a-C(O)N-(CO-C(alkyl)(CO-C(alkyl), optionally substituted with
1-5 substituents, wherein each substituent is independently a halogen, -N02, -
COOH,
carbonyl, -CN, -Ci-Cbalkyl, -SOn-(Cl-C{alkyl), aryloxy, -heteroaryloxy,
-C(O)-heterocycloC3-C6alkyl, -NH-cycloC3-C6alkyl, an-tino, -OH, or
-C1-C6alkyl(aniino) substituent group, wherein each substituent group
independently
is optionally substituted with -OH, -O(C1-C6alkyl), -O(aryl), -COOH,
-COO(C 1-C6alkyI), halogen, -N02, -CN, or -C(O)-N(CO-C6alkyl)(CO-C6alkyl);
R3 is an aryl, optionally substituted with 1-5 substituents, wherein each
substituent is independently an aryl, heteroaryl, halogen, -N02, -C(O)OH,
carbonyl,
-CN, -C1-C6alkyl, -SOn-(CI-C6alkyl), -SOn-(aryl), -aryloxy, -O-heteroaryl, C1-
C6alkoxy, N-oxide, -C(O)-heterocycloC3-C6alkyl, -NH-cycloC3-C6alkyl, amino,
-OH, or -(CO-C(alkyl)(Cp-C(alkyl)amino, -C(O)-N(CO-C6aIky1)(CO-C6a1ky1)
substituent group, wherein each substituent group independently is optionally
substituted with -OH, C1-C(alkoxy, -C1-Cbalkyl, -cycloC3-C6alkyl, -aryloxy,
-C(O)OH, -C(O)O(C1-C6alkyl), halogen, -N02, -CN, -SOn-(C1-C6a1ky]), or
-C(O)-N(CO-C6alkyl)(CO-C6alkyl); and
n is independently 0, 1, or 2.
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In yet another embodiment of this aspect, a compound of this invention
is represented by Formula (I) or a pharmaceutically acceptable salt thereof,
wherein
S1, S2, and S3 are independently H, -OH, halogen, -CI-Cbalkyl,
-N02, -CN, or -C1-C6alkoxy, wherein said alkyl and alkoxy groups are
optionally
substituted with 1-5 substituents; wherein each substituent is independently a
halogen
or OH;
R1 is a halogen, carbonyl, -C1-C6alkyl, -cycloC3-C6alkyl,
-C2-C6alkenyl, -C1-C6alkoxy, aryl, heteroaryl, -CN, -heterocycloC3-C6alkyl, -
amino,
-CI-C(alkylamino, -(C1-C6alkyl)(C1-C6alkyl)amino, -CI-C6alkyl(oxy)C1-C(alkyl,
-C(O)NH(aryl), -C(O)NH(heteroaryl), -SOnNH(ary1), -SOnNH(heteroaryl),
-SOnNH(C1-C6alkyl), -C(O)N(CO-C(alkyl)(Cp-Cbalkyl), -NH-SOn-(C1-C6alkyl),
-SOn-(C1-C6alkyl), -carbamoyl, -(C1-C6alkyl)-O-C(CN)-dialkylamino, or
-(C1-C(alkyl)-SOn-(CI-C6alkyl) group, wherein any of the groups is optionally
substituted with 1-5 substituents; wherein each substituent is independently a
halogen,
-OH, -CN, -C(O)(heterocycloC3-C6alkyl), -C(O)-O-(CO-C(alkyl), -C(O)-O-aryl,
alkoxy, cycloalkyloxy, acyl, acyloxy, -cycloC3-C6alkyl, heterocycloC3-C6alkyl,
aryl,
heteroaryl, carbonyl, carbamoyl, or -SOn-(Cl-Cbalkyl);
A is CH;
R2 is --CN;
R3 is an aryl, optionally substituted with 1-5 substituents, wherein each
substituent is independently an aryl, heteroaryl, halogen, -N02, -C(O)OH,
carbonyl,
-CN, -C1-C6alkyl, -SOn-(Cl-C(a1kyI), -SOn-(aryl), -aryloxy, -0-heteroaryl, C1-
C6alkoxy, N-oxide, -C(O)-heterocycloC3-C6alkyl, -NH-cycloC3-C6alkyl, amino,
-OH, or -(CO-C(alkyl)(CO-C(alkyl)amino, -C(O)-N(CO-C(alkyl)(CO-C(alkyl)
substituent group, wherein each substituent group independently is optionally
substituted with -OH, C1-C6alkoxy, -Cl-C6alkyl, -cycloC3-C6alkyl, -aryloxy,
-C(O)OH, -C(O)O(C1-C6alkyl), halogen, -N02, -CN, -SOn-(C1-C6alkyl), or
-C(O)-N(CO-C6alkyl)(CO-C6alkyl); and
n is independently 0, 1, or 2.
In yet another embodiment of this aspect, a compound of this invention
is represented by Formula (I) or a pharmaceutically acceptable salt thereof,
wherein
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S1, S2, and S3 are independently H, -OH, halogen, -C1-C6alkyl,
-N02, -CN, or -C1-C6alkoxy, wherein said alkyl and alkoxy groups are
optionally
substituted with 1-5 substituents; wherein each substituent is independently a
halogen
or OH;
R1 is -C1-C6alkyl, optionally substituted with 1-5 substituents;
wherein each substituent is independently a halogen, -OH, -CN, -C1-C(allcyl,
-cycloC3-C6alkyl, -C(O)(heterocycloC3-C6alkyl), -C(O)-O-(Cp-C(alkyl),
-C(O)-aryloxy, -C1-C6alkoxy, -(CO-C(alkyl)(CO-C(alkyl)amino, cycloalkyloxy,
acyl,
acyloxy, -cycloC3-C6al1cyl, heterocycloC3-C6alkyl, aryl, heteroaryl, carbonyl,
carbamoyl, or -SOn-(C1-C(alkyl);
A is CH,
R2 and R3 each independently is an aryl or heteroaryl, wherein each is
optionally substituted with 1-5 substituents, wherein each substituent is
independently
an aryl, heteroaryl, halogen, -N02, -C(O)OH, carbonyl, -CN, -C1-C6alkyl,
-SOn-(C1-C(alkyl), -SOn-(aryl), aryloxy, -heteroaryloxy, C1-C6alkoxy, N-oxide,
-C(O)-heterocycloC3-C6alkyl, -NH-cycloC3-C6alkyl, amino, -OH, or
-(CO-C(alkyl)(CO-C(alkyl)amino, -C(O)-N(CO-C(alkyl)(CO-C(alkyl) substituent
group, wherein each substituent group independently is optionally substituted
with
-OH, C1-C(alkoxy, -C1-C6alkyl, -cycloC3-C6alkyl, aryloxy, -C(O)OH,
-C(O)O(C1-C6alkyl), halogen, -N02, -CN, -SOn-(C1-C(alkyl), or
-C(O)-N(CO-C6alkyl)(CO-C6alkyl);
R2 and R3 may be optionally connected by a thio, oxy, or (C1-C4alkyl)
bridge to form a fused three ring system; and
n is independently 0, 1, or 2;
In yet another embodiment of this aspect, a compound of this invention
is represented by Formula (I) or a pharmaceutically acceptable salt thereof,
wherein
S1, S2, and S3 are each H;
R1 is -C1-C6allcyl, optionally substituted with 1-5 substituents;
wherein each substituent is independently a halogen, -OH, -CN, -C1-C6allcyl,
-cycloC3-C6alkyl, -C(O)(heterocycloC3-C6alkyl), -C(O)-O-(CO-C(alkyl),
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-C(O)-aryloxy, -C1-C6alkoxy, -(CO-C(alkyl)(CO-C(alkyl)amino, cycloalkyloxy,
acyl,
acyloxy, -cycloC3-C6alkyl, heterocycloC3-C6alkyl, aryl, heteroaryl, carbonyl,
carbamoyl, or -SOn-(C1-C(alkyl);
A is CH,
R2 and R3 each independently is an aryl or heteroaryl, wherein each is
optionally substituted with 1-5 substituents, wherein each substituent is
independently
an aryl, heteroaryl, halogen, -N02, -C(O)OH, carbonyl, -CN, -C1-C6alkyl,
-SOn-(C1-C(alkyl), -SOn-(aryl), aryloxy, -heteroaryloxy, C1-C6alkoxy, N-oxide,
-C(O)-heterocycloC3-C6alkyl, -NH-cycloC3-C6alkyl, amino, -OH, or
-(CO-C(alkyl)(CO-C(alkyl)amino, -C(O)-N(CO-C6alkyl)(CO-C6alkyl) substituent
group, wherein each substituent group independently is optionally substituted
with
-OH, C1-C6alkoxy, -C1-C6alkyl, -cycloC3-C6alkyl, aryloxy, -C(O)OH,
-C(O)O(C1-C6alkyl), halogen, -N02, -CN, -SOn-(C1-C(alkyl), or
-C (O)-N(CO-C( alkyl) (CO-C( alkyl);
R2 and R3 may be optionally connected by a thio, oxy, or (C1-C4alkyl)
bridge to form a fused three ring system; and
n is independently 0, 1, or 2;
As used herein, "alkyl" as well as other groups having the prefix "alk"
such as, for example, alkoxy, alkanoyl, alkenyl, alkynyl and the like, means
carbon
chains which may be linear or branched or combinations thereof. Examples of
alkyl
groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl,
pentyl,
hexyl, heptyl and the like. "Allcenyl", "alkynyl" and other like terms include
carbon
chains containing at least one unsaturated C-C bond.
The term "cycloalkyl" means carbocycles containing no heteroatoms,
and includes mono-, bi- and tricyclic saturated carbocycles, as well as fused
ring
systems. Such fused ring systems can include one ring that is partially or
fully
unsaturated such as a benzene ring to form fused ring systems such as
benzofused
carbocycles. Cycloalkyl includes such fused ring systems as spirofused ring
systems.
Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl,
decahydronaphthalene, adamantane, indanyl, indenyl, fluorenyl, 1,2,3,4-
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tetrahydronaphalene and the like. Similarly, "cycloalkenyl" means carbocycles
containing no heteroatoms and at least one non-aromatic C-C double bond, and
include mono-, bi- and tricyclic partially saturated carbocycles, as well as
benzofused
cycloalkenes. Examples of cycloalkenyl include cyclohexenyl, indenyl, and the
like.
The term "cycloalkyloxy" unless specifically stated otherwise includes
a cycloalkyl group connected to the oxy connecting atom.
The term "alkoxy" unless specifically stated otherwise includes an
alkyl group connected to the oxy connecting atom.
The term "aryl" unless specifically stated otherwise includes multiple
ring systems as well as single ring systems such as, for example, phenyl or
naphthyl.
The term "aryloxy" unless specifically stated otherwise includes
multiple ring systems as well as single ring systems such as, for example,
phenyl or
naphthyl, connected through the oxy connecting atom to the connecting site.
Ther term "CO-C6alkyl" includes alkyls containing 6, 5, 4, 3, 2, 1, or
no carbon atoms. An alkyl with no carbon atoms is a hydrogen atom substituent
or a
direct bond - depending on whether the alkyl is a terminus or a bridging
moiety.
The term "hetero" unless specifically stated otherwise includes one or
more 0, S, or N atoms. For example, heterocycloalkyl and heteroaryl include
ring
systems that contain one or more 0, S, or N atoms in the ring, including
mixtures of
such atoms. The hetero atoms replace ring carbon atoms. Thus, for example, a
heterocycloC5alkyl is a five membered ring containing from 5 to no carbon
atoms.
Examples of heteroaryl include, for example, pyridinyl, quinolinyl,
isoquinolinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinoxalinyl, furyl,
benzofuryl,
dibenzofuryl, thienyl, benzthienyl, pyrrolyl, indolyl, pyrazolyl, indazolyl,
oxazolyl,
isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, benzimidazolyl, oxadiazolyl,
thiadiazolyl, triazolyl, tetrazolyl.
The term "heteroaryloxy" unless specifically stated otherwise describes
a heteroaryl group connected through an oxy connecting atom to the connecting
site.
Examples of heteroaryl(C1_6)alkyl include, for example, furylmethyl,
furylethyl, thienylmethyl, thienylethyl, pyrazolylmethyl, oxazolylmethyl,
oxazolylethyl, isoxazolylmethyl, thiazolylmethyl, thiazolylethyl,
imidazolylmethyl,
imidazolylethyl, benzimidazolylmethyl, oxadiazolylmethyl, oxadiazolylethyl,
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thiadiazolylmethyl, thiadiazolylethyl, triazolylmethyl, triazolylethyl,
tetrazolylmethyl,
tetrazolylethyl, pyridinylmethyl, pyridinylethyl, pyridazinylmethyl,
pyrimidinylmethyl, pyrazinylmethyl, quinolinylmethyl, isoquinolinylmethyl and
quinoxalinylmethyl.
Examples of heterocycloC3_7alkyl include, for example, azetidinyl,
pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl,
imidazolinyl,
pyrolidin-2-one, piperidin-2-one, and thiomorpholinyl.
Examples of aryl(C1_6)alkyl include, for example, phenyl(C1_6)alkyl,
and naphthyl(Cl_6)alkyl.
Examples of heterocycloC3_7alkylcarbonyl(Cl_6)alkyl include, for
example, azetidinyl carbonyl(C1_6)alkyl, pyrrolidinyl carbonyl(C1_6)alkyl,
piperidinyl
carbonyl(C1_6)alkyl, piperazinyl carbonyl(C1_6)allcyl, morpholinyl
carbonyl(C1_6)alkyl,
and thiomorpholinyl carbonyl(Cl_6)alkyl.
The term "amine" unless specifically stated otherwise includes
primary, secondary and tertiary amines.
Unless otherwise stated, the term "carbamoyl" is used to include
-NHC(O)OC 1-C4alkyl, and -OC(O)NHC 1-C4alkyl.
The term "halogen" includes fluorine, chlorine, bromine and iodine
atoms.
The term "optionally substituted" is intended to include both
substituted and unsubstituted. Thus, for example, optionally substituted aryl
could
represent a pentafluorophenyl or a phenyl ring. Further, the substitution can
be made
at any of the groups. For example, substituted aryl(C1_6)alkyl includes
substitution on
the aryl group as well as substitution on the alkyl group.
Compounds described herein contain one or more double bonds and
may thus give rise to cis/trans isomers as well as other conformational
isomers. The
present invention includes all such possible isomers as well as mixtures of
such
isomers.
Compounds described herein can contain one or more asymmetric
centers and may thus give rise to diastereomers and optical isomers. The
present
invention includes all such possible diastereomers as well as their racemic
mixtures,
their substantially pure resolved enantiomers, all possible geometric isomers,
and
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pharmaceutically acceptable salts thereof. The above Formula I is shown
without a
definitive stereochemistry at certain positions. The present invention
includes all
stereoisomers of Formula I and pharmaceutically acceptable salts thereof.
Further,
mixtures of stereoisomers as well as isolated specific stereoisomers are also
included.
During the course of the synthetic procedures used to prepare such compounds,
or in
using racemization or epimerization procedures known to those skilled in the
art, the
products of such procedures can be a mixture of stereoisomers.
The term "pharmaceutically acceptable salts" refers to salts prepared
from pharmaceutically acceptable non-toxic bases or acids. When the compound
of
the present invention is acidic, its corresponding salt can be conveniently
prepared
from pharmaceutically acceptable non-toxic bases, including inorganic bases
and
organic bases. Salts derived from such inorganic bases include aluminum,
ammonium, calcium, copper (ic and ous), ferric, ferrous, lithium, magnesium,
manganese (ic and ous), potassium, sodium, zinc and the like salts.
Particularly
preferred are the ammonium, calcium, magnesium, potassium and sodium salts.
Salts
derived from pharmaceutically acceptable organic non-toxic bases include salts
of
primary, secondary, and tertiary amines, as well as cyclic amines and
substituted
amines such as naturally occurring and synthesized substituted amines. Other
pharmaceutically acceptable organic non-toxic bases from which salts can be
formed
include ion exchange resins such as, for example, arginine, betaine, caffeine,
choline,
N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanof, 2-
dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-
ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine,
isopropylamine,
lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins,
procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine,
tromethamine and the like.
When the compound of the present invention is basic, its
corresponding salt can be conveniently prepared from pharmaceutically
acceptable
non-toxic acids, including inorganic and organic acids. Such acids include,
for
example, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric,
ethanesulfonic,
fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic,
maleic,
malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic,
phosphoric,
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succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like.
Particularly preferred
are benzenesulfonic, citric, hydrobromic, hydrochloric, maleic, phosphoric,
sulfuric,
and tartaric acids.
The pharmaceutical compositions of the present invention comprise a
compound represented by Formula I (or pharmaceutically acceptable salts
thereof) as
an active ingredient, a pharmaceutically acceptable carrier and optionally
other
therapeutic ingredients or adjuvants. Such additional therapeutic ingredients
include,
for example, i) Leukotriene receptor antagonists, ii) Leukotriene biosynthesis
inhibitors, iii) corticosteroids, iv) Hl receptor antagonists, v) beta 2
adrenoceptor
agonists, vi) COX-2 selective inhibitors, vii) statins, viii) non-steroidal
anti-
inflammatory drugs ("NSAID"), and ix) M2/M3 antagonists. The compositions
include compositions suitable for oral, rectal, topical, and parenteral
(including
subcutaneous, intramuscular, and intravenous) administration, although the
most
suitable route in any given case will depend on the particular host, and
nature and
severity of the conditions for which the active ingredient is being
administered. The
pharmaceutical compositions may be conveniently presented in unit dosage form
and
prepared by any of the methods well known in the art of pharmacy.
Creams, ointments, jellies, solutions, or suspensions containing the
compound of Formula I can be employed for topical use. Mouth washes and
gargles
are included within the scope of topical use for the purposes of this
invention.
Dosage levels from about 0.001mg/kg to about 140mg/kg of body
weight per day are useful in the treatment of conditions such as asthma,
chronic
bronchitis, chronic obstructive pulmonary disease (COPD), eosinophilic
granuloma,
psoriasis and other benign or malignant proliferative slcin diseases,
endotoxic shock
(and associated conditions such as laminitis and colic in horses), septic
shock,
ulcerative colitis, Crohn's disease, reperfusion injury of the myocardium and
brain,
inflammatory arthritis, osteoporosis, chronic glomerulonephritis, atopic
dermatitis,
urticaria, adult respiratory distress syndrome, infant respiratory distress
syndrome,
chronic obstructive pulmonary disease in animals, diabetes insipidus, allergic
rhinitis,
allergic conjunctivitis, vernal conjunctivitis, arterial restenosis,
atherosclerosis,
neurogenic inflammation, pain, cough, rheumatoid arthritis, ankylosing
spondylitis,
transplant rejection and graft versus host disease, hypersecretion of gastric
acid,
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bacterial, fungal or viral induced sepsis or septic shock, inflammation and
cytokine-
mediated chronic tissue degeneration, osteoarthritis, cancer, cachexia, muscle
wasting,
depression, memory impairment, monopolar depression, acute and chronic
neurodegenerative disorders with inflammatory components, Parkinson disease,
Alzheimer's disease, spinal cord trauma, head injury, multiple sclerosis,
tumour
growth and cancerous invasion of normal tissues which are responsive to PDE4
inhibition, or alternatively about 0.05mg to about 7g per patient per day. For
example, inflammation may be effectively treated by the administration of from
about
0.01mg to 50mg of the compound per kilogram of body weight per day, or
alternatively about 0.5mg to about 2.5g per patient per day. Further, it is
understood
that the PDE4 inhibiting compounds of this invention can be administered at
prophylactically effective dosage levels to prevent the above-recited
conditions.
The amount of active ingredient that may be combined with the carrier
materials to produce a single dosage foim will vary depending upon the host
treated
and the particular mode of administration. For example, a formulation intended
for
the oral administration to humans may conveniently contain from about 0.5mg to
about 5g of active agent, compounded with an appropriate and convenient amount
of
carrier material which may vary from about 5 to about 95 percent of the total
composition. Unit dosage forms will generally contain between from about
0.01mg to
about 1000mg of the active ingredient, typically 0.01mg, 0.05mg, 0.25mg, lmg,
5mg,
25mg, 50mg, 100mg, 200mg, 300mg, 400mg, 500mg, 600mg, 800mg or 1000mg.
It is understood, however, that the specific dose level for any particular
patient will depend upon a variety of factors including the age, body weight,
general
health, sex, diet, time of administration, route of administration, rate of
excretion,
drug combination and the severity of the particular disease undergoing
therapy.
In practice, the compounds represented by Formula I, or
pharmaceutically acceptable salts thereof, of this invention can be combined
as the
active ingredient in intimate admixture with a pharmaceutical carrier
according to
conventional pharmaceutical compounding techniques. The carrier may take a
wide
variety of forms depending on the form of preparation desired for
administration, e.g.,
oral or parenteral (including intravenous). Thus, the pharmaceutical
compositions of
the present invention can be presented as discrete units suitable for oral
administration
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such as capsules, cachets or tablets each containing a predetermined amount of
the
active ingredient. Further, the compositions can be presented as a powder, as
granules, as a solution, as a suspension in an aqueous liquid, as a non-
aqueous liquid,
as an oil-in-water emulsion or as a water-in-oil liquid emulsion. In addition
to the
common dosage forms set out above, the compound represented by Formula I, or
pharmaceutically acceptable salts thereof, may also be administered by
controlled
release means and/or delivery devices. The compositions may be prepared by any
of
the methods of pharmacy. In general, such methods include a step of bringing
into
association the active ingredient with the carrier that constitutes one or
more
necessary ingredients. In general, the compositions are prepared by uniformly
and
intimately admixing the active ingredient with liquid carriers or finely
divided solid
carriers or both. The product can then be conveniently shaped into the desired
presentation.
Thus, the pharmaceutical compositions of this invention may include a
pharmaceutically acceptable carrier and a compound or a pharmaceutically
acceptable
salt of Formula I. The compounds of Formula I, or pharmaceutically acceptable
salts
thereof, can also be included in pharmaceutical compositions in combination
with one
or more other therapeutically active compounds.
The pharmaceutical carrier employed can be, for example, a solid,
liquid, or gas. Examples of solid carriers include lactose, terra alba,
sucrose, talc,
gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Examples
of liquid
carriers are sugar syrup, peanut oil, olive oil, and water. Examples of
gaseous carriers
include carbon dioxide and nitrogen.
In preparing the compositions for oral dosage form, any convenient
pharmaceutical media may be employed. For example, water, glycols, oils,
alcohols,
flavoring agents, preservatives, coloring agents and the like may be used to
form oral
liquid preparations such as suspensions, elixirs and solutions; while carriers
such as
starches, sugars, microcrystalline cellulose, diluents, granulating agents,
lubricants,
binders, disintegrating agents, and the like may be used to form oral solid
preparations
such as powders, capsules and tablets. Because of their ease of
administration, tablets
and capsules are the preferred oral dosage units whereby solid pharmaceutical
carriers
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are employed. Optionally, tablets may be coated by standard aqueous or
nonaqueous
techniques
A tablet containing the composition of this invention may be prepared
by compression or molding, optionally with one or more accessory ingredients
or
adjuvants. Compressed tablets may be prepared by compressing, in a suitable
machine, the active ingredient in a free-flowing form such as powder or
granules,
optionally mixed with a binder, lubricant, inert diluent, surface active or
dispersing
agent. Molded tablets may be made by molding in a suitable machine, a mixture
of
the powdered compound moistened with an inert liquid diluent. Each tablet
preferably contains from about 0.lmg to about 500mg of the active ingredient
and
each cachet or capsule preferably containing from about 0.1mg to about 500mg
of the
active ingredient.
Pharinaceutical compositions of the present invention suitable for
parenteral administration may be prepared as solutions or suspensions of the
active
compounds in water. A suitable surfactant can be included such as, for
example,
hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid
polyethylene glycols, and mixtures thereof in oils. Further, a preservative
can be
included to prevent the detrimental growth of microorganisms.
Pharmaceutical compositions of the present invention suitable for
injectable use include sterile aqueous solutions or dispersions. Furthermore,
the
compositions can be in the form of sterile powders for the extemporaneous
preparation of such sterile injectable solutions or dispersions. In all cases,
the final
injectable fortn must be sterile and must be effectively fluid for easy
syringability.
The pharmaceutical compositions must be stable under the conditions of
manufacture
and storage; thus, preferably should be preserved against the contaminating
action of
microorganisms such as bacteria and fungi. The carrier can be a solvent or
dispersion
medium containing, for example, water, ethanol, polyol (e.g. glycerol,
propylene
glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures
thereof.
Pharmaceutical compositions of the present invention can be in a form
suitable for topical use such as, for example, an aerosol, cream, ointment,
lotion,
dusting powder, or the like. Further, the compositions can be in a form
suitable for
use in transdermal devices. These formulations may be prepared, utilizing a
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compound represented by Formula I of this invention, or pharmaceutically
acceptable
salts thereof, via conventional processing methods. As an example, a cream or
ointment is prepared by mixing hydrophilic material and water, together with
about 5
wt% to about 10 wt% of the compound, to produce a cream or ointment having a
desired consistency.
Pharmaceutical compositions of this invention can be in a form
suitable for rectal administration wherein the carrier is a solid. It is
preferable that the
mixture forms unit dose suppositories. Suitable carriers include cocoa butter
and
other materials commonly used in the art. The suppositories may be
conveniently
formed by first admixing the composition with the softened or melted
carrier(s)
followed by chilling and shaping in moulds.
In addition to the aforementioned carrier ingredients, the
pharmaceutical formulations described above may include, as appropriate, one
or
more additional carrier ingredients such as diluents, buffers, flavoring
agents, binders,
surface-active agents, thickeners, lubricants, preservatives. (including anti-
oxidants)
and the like. Furthermore, other adjuvants can be included to render the
formulation
isotonic with the blood of the intended recipient. Compositions containing a
compound described by Formula I, or pharmaceutically acceptable salts thereof,
may
also be prepared in powder or liquid concentrate form.
The compounds and pharmaceutical compositions of this invention
have been found to exhibit biological activity as PDE4 inhibitors.
Accordingly,
another aspect of the invention is the treatment in mammals of, for example,
asthma,
chronic bronchitis, chronic obstructive pulmonary disease (COPD), eosinophilic
granuloma, psoriasis and other benign or malignant proliferative skin
diseases,
endotoxic shock (and associated conditions such as laminitis and colic in
horses),
septic shock, ulcerative colitis, Crohn's disease, reperfusion injury of the
myocardium
and brain, inflammatory arthritis, osteoporosis, chronic glomerulonephritis,
atopic
dermatitis, urticaria, adult respiratory distress syndrome, infant respiratory
distress
syndrome, chronic obstructive pulmonary disease in animals, diabetes
insipidus,
allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, arterial
restenosis,
atherosclerosis, neurogenic inflammation, pain, cough, rheumatoid arthritis,
ankylosing spondylitis, transplant rejection and graft versus host disease,
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hypersecretion of gastric acid, bacterial, fungal or viral induced sepsis or
septic shock,
inflammation and cytokine-mediated chronic tissue degeneration,
osteoarthritis,
cancer, cachexia, muscle wasting, depression, memory impairment, monopolar
depression, acute and chronic neurodegenerative disorders with inflammatory
components, Parkinson disease, Alzheimer's disease, spinal cord trauma, head
injury,
multiple sclerosis, tumour growth and cancerous invasion of normal tissues -
maladies that are amenable to amelioration through inhibition of the PDE4
isoenzyme
and the resulting elevated cCAMP levels - by the administration of an
effective
amount of the compounds of this invention. The term "mammals" includes humans,
as well as other animals such as, for example, dogs, cats, horses, pigs, and
cattle.
Accordingly, it is understood that the treatment of mammals other than humans
is the
treatment of clinical correlating afflictions to those above recited examples
that are
human afflictions.
Further, as described above, the compound of this invention can be
utilized in combination with other therapeutic compounds. In particular, the
combinations of the PDE4 inhibiting compound of this invention can be
advantageously used in combination with i) Leukotriene receptor antagonists,
ii)
Leukotriene biosynthesis inhibitors, iii) COX-2 selective inhibitors, iv)
statins, v)
NSAIDs, vi) M2/M3 antagonists, vii) corticosteroids, viii) Hl (histamine)
receptor
antagonists and ix) beta 2 adrenoceptor agonist.
In another aspect, it was found that the compound of this invention can
be formed as a metabolite in the mammalian system. For example, Example 19, (5-
{ (E)-2-(3-{ 6-[ 1-methyl-l-(methylsulfonyl)ethyl]-8-quinolinyl } phenyl)-1-[4-
(methylsulfonyl)phenyl]ethenyl } -1,2,4-oxadiazol-3-yl)methanol:
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H3C 0
CH3
KCH3
N 0
\ NN
H C~S
s O OH
which is a PDE4 inhibitor is formed in vivo as a metabolite when Example 14:
H3C 4
-CH3
KCH3'CH3
N N
>-CH3
~S O-N
H3C~ 0
is administered. Accordingly, the present invention includes prodrugs that
form
PDE4 inhibitors in vivo as a metabolite after administering such prodrugs to a
mammal. Further, this invention includes a method of treatment by a step of
administering a prodrug to form in vivo an effective amount of a PDE4
inhibitor
described by Formula I.
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SUBSTITUTE SHEET (RULE 26)
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In accordance with one aspect of the present invention there is provided the
use
of a compound of formula (I), as previously described, or a pharmaceutically
acceptable
salt thereof, in the manufacture of a medicament for the treatment or
prevention of
asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD),
psoriasis,
inflammatory arthritis, adult respiratory distress syndrome, infant
respiratory distress
syndrome, chronic obstructive pulmonary disease in animals, neurogenic
inflammation,
pain, rheumatoid arthritis, osteoarthritis, memory impairment, acute and
chronic
neurodegenerative disorders with inflammatory components, Alzheimer's disease.
33a
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The abbreviations used herein have the following tabulated meanings.
Abbreviations not tabulated below have their meanings as commonly used unless
specifically stated otherwise.
Ac = acetyl
Bn = benzyl
CAMP cyclic adenosine-3',5'-mono hos hate
DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene
DIBAL = diisobutylaluminum hydride
DMAP = 4-(dimethylamino) yridine
DMF = N,N-dimethylformamide
Et3N = triethylamine
GST glutathione transferase
HMDS hexamethyldisilazide
LDA = lithium diiso ro ylamide
m-CPBA = metachloroperbenzoic acid
MMPP = mono eroxy hthalic acid
MPPM monoperoxyphthalic acid, magnesium salt 6H20
Ms = methanesulfonyl = mesyl = SO2Me
Ms0 = methanesulfonate = mesylate
NSAID = non-steroidal anti-inflammatory drug
o-Tol = ortho-tolyl
OXONEO = 2KHSO5=KHSO4=K2SO4
PCC = pyridinium chlorochromate
PDC = pyridinium dichromate
PDE phosphodiesterase
Ph = phenyl
Phe = benzenediyl
PMB = para-methoxybenzyl
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Pye = pyridinediyl
r.t. = room temperature
Rac. = racemic
SAM = aminosulfonyl or sulfonamide or SO2NH2
SEM = 2-(trimethylsilyl)ethoxymethoxy
SPA = scintillation proximity assay
TBAF = tetra-n-butylammonium fluoride
Th = 2- or 3-thienyl
TFA = trifluoroacetic acid
TFAA = trifluoroacetic acid anhydride
THF = tetrahydrofuran
Thi = thiophenediyl
TLC = thin layer chromatography
TMS-CN = trimethylsilyl cyanide
TMSI trimethylsilyl iodide
Tz = 1H (or 2H)-tetrazol-5-yl
CAN ceric ammoniuin nitrate
C3H5 = allyl
ALKYL GROUP ABBREVIATIONS,
Me = Methyl
Et = ethyl
n-Pr = normal propyl
i-Pr = iso ro yl
n-Bu = normal butyl
i-Bu = isobutyl
s-Bu = secondary butyl
t-Bu = tertiary butyl
c-Pr = cyclo ro yl
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c-Bu = cyclobutyl
c-Pen = cyclopentyl
c-Hex = cyclohexyl
ASSAYS DEMONSTRATING BIOLOGICAL ACTIVITY
LPS AND FMLP-INDUCED TNF-a AND LTB4 ASSAYS IN HUMAN
WHOLE BLOOD
Whole blood provides a protein and cell-rich milieu appropriate for the
study of biochemical efficacy of anti-inflammatory compounds such as PDE4-
selective inhibitors. Normal non-stimulated human blood does not contain
detectable
levels of TNF-a and LTB4. Upon stimulation with LPS, activated monocytes
express
and secrete TNF-a up to 8 hours and plasma levels remain stable for 24 hours.
Published studies have shown that inhibition of TNF-a by increasing
intracellular
cAMP via PDE4 inhibition and/or enhanced adenylyl cyclase activity occurs at
the
transcriptional level. LTB4 synthesis is also sensitive to levels of
intracellular cA1VIP
and can be completely inhibited by PDE4-selective inhibitors. As there is
little LTB4
produced during a 24 hour LPS stimulation of whole blood, an additional LPS
stimulation followed by fMLP challenge of human whole blood is necessary for
LTB4
synthesis by activated neutrophils. Thus, by using the same blood sample, it
is
possible to evaluate the potency of a compound on two surrogate markers of
PDE4
activity in the whole blood by the following procedure.
Fresh blood was collected in heparinized tubes by venipuncture from
healthy human volunteers (male and female). These subjects had no apparent
inflammatory conditions and had not taken any NSAIDs for at least 4 days prior
to
blood collection. 500 L aliquots of blood were pre-incubated with either 2 L
of
vehicle (DMSO) or 2 L of test compound at varying concentrations for 15
minutes at
37 C. This was followed by the addition of either 10 L vehicle (PBS) as blanks
or
lO L LPS (l g/mL final concentration, #L-2630 (Sigma Chemical Co., St. Louis,
MO) from E. coli, serotype 0111:B4; diluted in 0.1% w/v BSA (in PBS)). After
24
hours of incubation at 37 C, another 10 L of PBS (blank) or 10 L of LPS (1
g/mL
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final concentration) was added to blood and incubated for 30 ininutes at 37 C.
The
blood was then challenged with either lO L of PBS (blank) or 10 L of fMLP (l M
final concentration, #F-3506 (Sigma); diluted in 1% w/v BSA (in PBS)) for 15
minutes at 37 C. The blood samples were centrifuged at 1500xg for 10 minutes
at
4 C to obtain plasma. A 50 L aliquot of plasma was mixed with 200 L methanol
for
protein precipitation and centrifuged as above. The supernatant was assayed
for
LTB4 using an enzyme immunoassay kit (#520111 from Cayman Chemical Co., Ann
Arbor, MI) according to the manufacturer's procedure. TNF-oc was assayed in
diluted
plasma (in PBS) using an ELISA kit (Cistron Biotechnology, Pine Brook, NJ)
according to manufacturer's procedure. The IC50 values of Examples 1-42
generally
ranged from 0.04 M to 8.71 M.
ANTI-ALLERGIC ACTIVITY IN VIVO
Compounds of the invention have been tested for effects on an IgE-
mediated allergic pulmonary inflammation induced by inhalation of antigen by
sensitized guinea pigs. Guinea pigs were initially sensitized to ovalbumin
under mild
cyclophosphamide-induced immunosuppression, by intraperitoneal injection of
antigen in combinations with aluminum hydroxide and pertussis vaccine. Booster
doses of antigen were given two and four weeks later. At six weeks, animals
were
challenged with aerosolized ovalbumin while under cover of an
intraperitoneally
administered anti-histamine agent (mepyramine). After a further 48h, bronchial
alveolar lavages (BAL) were performed and the numbers of eosinophils and other
leukocytes in the BAL fluids were counted. The lungs were also removed for
histological examination for inflammatory damage. Administration of compounds
of
the Examples (0.001-10mg/kg i.p. or p.o.), up to three times during the 48h
following
antigen challenge, lead to a significant reduction in the eosinophilia and the
accumulation of other inflammatory leukocytes. There was also less
inflammatory
damage in the lungs of animals treated with compounds of the Examples.
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SPA BASED PDE ACTIVITY ASSAY PROTOCOL
Compounds which inhibit the hydrolysis of cAMP to AMP by the
type-IV cAMP-specific phosphodiesterases were screened in a 96-well plate
format as
follows:
In a 96 well-plate at 30 C was added the test compound (dissolved in
2 L DMSO), 188mL of substrate buffer containing [2,8-3H] adenosine 3',5'-
cyclic
phosphate (cAMP, lOOnM to 50 M), 10mM MgC12, ImM EDTA, 50mM Tris, pH
7.5. The reaction was initiated by the addition of lOmL of human recombinant
PDE4
(the amount was controlled so that -10% product was formed in 10min.). The
reaction was stopped after 10min. by the addition of Img of PDE-SPA beads
(Amersham Pharmacia Biotech, Inc., Piscataway, NJ). The product AMP generated
was quantified on a Wallac Microbeta 96-well plate counter (EG&G Wallac Co.,
Gaithersburg, MD). The signal in the absence of enzyme was defined as the
background. 100% activity was defined as the signal detected in the presence
of
enzyme and DMSO with the background subtracted. Percentage of inhibition was
calculated accordingly. IC50 value was approximated with a non-linear
regression fit
using the standard 4-parameter/multiple binding sites equation from a ten
point
titration.
The IC50 values of Examples 1-42 were determined with lOOnM
cAMP using the purified GST fusion protein of the human recombinant
phosphodiesterase IVa (met-248) produced from a baculovirus/Sf-9 expression
system. The IC50 values of Examples 1-42 generally ranged from 0.14nM to
10.24nM, although one example had an IC50 value of 109nM.
The examples that follow are intended as an illustration of certain
preferred embodiments of the invention and no limitation of the invention is
implied.
Unless specifically stated otherwise, the experimental procedures were
performed under the following conditions. All operations were carried out at
room or
ambient temperature - that is, at a temperature in the range of 18-25 C.
Evaporation
of solvent was carried out using a rotary evaporator under reduced pressure
(600-
4000pascals: 4.5-30mm. Hg) with a bath temperature of up to 60 C. The course
of
reactions was followed by thin layer chromatography (TLC) and reaction times
are
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given for illustration only. Melting points are uncorrected and 'd' indicates
decomposition. The melting points given are those obtained for the materials
prepared as described. Polymorphism may result in isolation of materials with
different melting points in some preparations. The structure and purity of all
final
products were assured by at least one of the following techniques: TLC, mass
spectrometry, nuclear magnetic resonance (NMR) spectrometry or microanalytical
data. Yields are given for illustration only. When given, NMR data is in the
form of
delta (8) values for major diagnostic protons, given in parts per million
(ppm) relative
to tetramethylsilane (TMS) as internal standard, determined at 300 MHz, 400
MHz or
500 MHz using the indicated solvent. Conventional abbreviations used for
signal
shape are: s. singlet; d. doublet; t. triplet; m. multiplet; br. broad; etc.
In addition,
"Ar" signifies an aromatic signal. Chemical symbols have their usual meanings;
the
following abbreviations have also been used: v (volume), w (weight), b.p.
(boiling
point), m.p. (melting point), L (liter(s)), mL (milliliters), g (gram(s)), mg
(milligrams(s)), mol (moles), mmol (millimoles), eq (equivalent(s)).
Methods of Synthesis
Compounds of the present invention can be prepared according to the
following methods. The substituents are the same as in Formula I except where
defined otherwise.
SCHEME 1
Ketone Synthesis
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XAr1Y Ar- _ E-Ar~-
ArX V
IV
1. base or
organolithium
2. A 1. base or organolithium
2.Eor A
3. base or organolithium
4.AorE
OH
ArM A
III Ar QSMe
I I
OH
Ar ~
I ~ S02Me Ar ~ /
VI SMe ssl"~ VII
Ar
S02Me
VIII
Wherein X=halogen, H
Y=halogen, H
A=4-(methylthio)benzaldehyde
E=electrophile
Ar=aryl or heteroaryl
Referring to Scheme 1 above, and Scheme 1 Table below, the alcohol
intermediate II may be prepared by the reaction of an aryl or heteroaryl
metallic
species III such as an organomagnesium halide with 4-(methylthio)benzaldehyde
(A)
in an organic solvent such as THF. The alcohol intermediate II may also be
prepared
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by treatment an aryl or heteroaryl hydride or bromide IV with a base or an
organometallic such as n-butyllithium in an organic solvent such as THF,
followed by
4-(methylthio)benzaldehyde. Alternatively the alcohol intermediate II may also
be
prepared by the following chemical transformations: 1) Treatment of an aryl or
heteroaryl dihydride, halide-hydride or dihalide V with a base or an
organometallic
such as n-butyllithium in an organic solvent such as THF, followed by an
electrophile
such as acetone or 4-(methylthio)benzaldehyde; 2) Subsequent treatment with a
base
or an organometallic such as n-butyllithiuin in an organic solvent such as
THF,
followed by an electrophile such as acetone or 4-(methylthio)benzaldehyde,
where
the first or the second transformation must use 4-(methylthio)benzaldehyde as
the
electrophile. The sulfone-alcohol VI may be prepared by the oxidation of the
sulfide-
alcohol II with an oxidizing agent such as oxone in a solvent such as a
mixture of
THF/MeOH/H2O. The ketones VII and VIII may be prepared by the oxidation of the
alcohols II and VI, respectively, with an oxidizing agent such as Mn02 in a
solvent
such as CH2Cl2. The sulfone-ketone VIII may also be prepared by the oxidation
of
the sulfide-ketone VII with an oxidizing agent such as oxone in a solvent such
as a
mixture of THF/MeOH/H2O.
SCHEME 1 TABLE:
Ketones
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0
Ar QSOõMe
VII (n=O)
VIII (n=2)
Ar n Ketone Ar n Ketone
~ CH2 ~ CH2
F~ ~ 2 K1 H3C 'N 2 K7
H3C
CH2
NCH2 0 K2 H C~ 2 K8
N s
01,CH2 2 K3 2 K9
MeO2S
CH2 CH2
~U 2 K5 zz N 2 K10
H3C CH2 i CH2
H3~ S N 2 K6 H3c
~ N 2 K11
HO CH3
Ketone K1
(4-Fluorophenyl) [4-(methylsulfonyl)]phenyl ketone
Ketone K1 was prepared by the following procedure.
Step 1: (4-Fluorophenyl)[4-methylthio)phenyl]ketone
To a-78 C solution of 4-(methylthio)benzaldehyde (2.5g, 16.4mmol)
in THF (100ml) was added 4-fluorophenylmagnesium bromide (1.OM in THF,
19.7m1, 19.7mmol) dropwise. The resulting solution was stirred at -78 C for
3h., and
quenched with a saturated aqueous solution of NH4Cl. The mixture was then
diluted
with EtOAc and HCl 10%, extracted and washed (NaHCO3 (sat.), brine). The
organic
phase was dried over MgS04 and concentrated. The residue was then treated with
Mn02 (28.6g, 330mmol) in CH2C12 (150m1) and the reaction was stirred at r.t.
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overnight. The mixture was filtered through a plug of silica (EtOAc) to yield
2.6g of
the (4-Fluorophenyl) [4-methylthio)phenyl] ketone compound
Step 2: (4-Fluorophenyl) [4-(methylsulfonyl)phenyl] ketone
To a solution of the sulfide - in other words, the (4-Fluorophenyl)[4-
methylthio)phenyl]ketone - from the present step 1(2.0g, 8.1 mmol) in
THF/MeOHIH2O (80/40/40 ml) was added oxone (7.5g, 12.2mmol). The mixture
was stirred at r.t. for 4h, quenched with NaHCO3 (sat.), and diluted with
EtOAc. The
organic phase was washed with NaHCO3 (sat.), brine, dried over Na2SO4,
filtered and
concentrated. Crystallization (CH2C12/Hexanes) yielded (4-Fluorophenyl)[4-
(methylsulfonyl)phenyl]ketone, the K1 ketone compound, as a white solid.
Ketone K2
(1-Methyl-lH-imidazol-2-yl) [4-methylthio)phenyl]ketone
Ketone K2 was prepared by the following procedure.
Step 1: (1-Methyl-lH-imidazol-2-yl)[4-(methylthio)phenyl]methanol
To a solution of N-methylimidazole (10.0g, 122mmo1) in 500mL THF
at -78 C was added n-butyllithium (2.5M in hexanes, 48.7ml, 118mmo1) dropwise
and
the resulting solution was stirred at -78 C for 30min. 4-
(Methylthio)benzaldehyde
(14.73m1, 110mmo1) was then added at -78 C and the mixture was stirred until
completion by TLC, and quenched with NH4C1 (sat). The mixture was then diluted
with EtOAc, extracted and washed (NaHCO3 (sat.), brine). The organic phase was
dried over MgSO4, filtered and concentrated. Crystalisation (EtOAc/Hexanes)
yielded (1-Methyl-lH-imidazol-2-yl)[4-(methylthio)phenyl]methanol.
Step 2: (1-Methyl-lH-imidazol-2-yl)[4-(methylthio)phenyl]ketone
To a solution of the alcohol from the present step 1 (25.7g, 111mmo1)
in EtOAc (250m1) and CH2C12 (250m1) was added Mn02 (140g, 1.66mo1) and the
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reaction was stirred at r.t. overnight. The mixture was filtered through a
plug of silica
(EtOAc) to yield ketone K2.
Ketone K3
(4-Methylsulfonyl)(phenyl)ketone
Ketone K3 was prepared by the following procedure.
Step 1: (4-Methylthio)(phenyl)methanol
To a solution of 4-(methylthio)benzaldehyde (1.0g, 6.5mmol) in THF
(20mL) at 0 C was added phenylmagnesium chloride (2M, THF, 3.5mL, 7.Ommol).
After 0.5h at r.t., the mixture was neutralised with saturated NH4C1 solution,
diluted
with water and extracted with Et20. The organic extracts were washed (H20),
(brine), dried (MgSO4), filtered and concentrated. Purification by stirring
vigorously
in hexane/Et2O and filtration yielded (4-Methylthio)(phenyl)methanol as a
white
solid.
Step 2: (4-Methylthio)(phenyl)ketone
(4-Methylthio)(phenyl)ketone was obtained by treating the (4-
Methylthio)(phenyl)methanol from the present step 1 with Mn02 as in step 2 of
the
procedure for K4 below.
Step 3: (4-Methylsulfonyl)(phenyl)ketone
To a solution of (4-Methylthio)(phenyl)ketone from the present step 2
(0.98g, 4.3mmol) in CHC13 (lOmL) at 0 C was added mCPBA (m-chloroperbenzoic
acid) (1.7g, 10mmo1). After 0.5h at r.t., Ca(OH)2 (1.7g, 23mmol) was added to
the
mixture which was stirred for lh. Filtration on Celite and concentration
yielded
ketone K3 as a white solid.
Ketone K4
(1,3-Thiazol-2-yl) [4-(methylthio)phenyl]ketone
Ketone K4 was prepared by the following procedure.
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Step 1: (1,3-Thiazol-2-yl)[4-(methylthio)phenyl]methanol
To a-78 C solution of thiazole (5.0g, 58.7mmol) in THF (250m1) was
added n-butyllithium (2.5M in hexanes, 23.5ml, 58.7mmol) dropwise and the
resulting solution was stirred at -78 C for 10min. 4-(Methylthio)benzaldehyde
(7.lml, 53.4mmol) was then added at -78 C. The resulting mixture was stirred
until
completion, and quenched with a saturated aqueous solution of NH4C1. The
mixture
was then diluted with EtOAc and HCl 10%, extracted and washed (NaHCO3 (sat.),
brine). The organic phase was dried over MgSO4 and concentrated. The residue
was
then purified by flash chromatography (80% CH2C12/ 20% EtOAc) to yield (1,3-
Thiazol-2-yl)[4-(methylthio)phenyl]methanol.
Step 2: (1,3-Thiazol-2-yl)[4-(methylthio)phenyl]ketone
To a solution of the (1,3-Thiazol-2-yl)[4-(methylthio)phenyl]methanol
from the present step 1(10.0g, 42.1mmo1) in EtOAc (250m1) was added Mn02 (70g,
843mmo1) and the reaction was stirred at 25 C overnight. The mixture was
filtered
through a plug of silica (EtOAc) to form the K4lcetone compound.
Ketone K5
(1,3 -Thi azol-2-yl) [4-(methylsulfonyl)phenyl] ketone
Ketone K5 was prepared by the following procedure. To a solution of
K4 (1,3 -Thiazol-2-yl) [4-(methylthio)phenyl] ketone (8.2g, 34.7mmol) in
THF/MeOH/H20 (350/175/175 ml) was added oxone (42.6g, 69.4mmol). The
reaction was stirred at 25 C for 3h and quenched with a saturated aqueous
solution of
NaHCO3. The resulting mixture was then diluted with EtOAc, extracted and
washed
(NaHCO3 (sat.), brine). The organic phase was dried over MgSO4 and
concentrated.
The residue was then purified by crystallization (EtOAc/Hexanes) to yield of
(1,3-
Thiazol-2-yl) [4-(methylsulfonyl)phenyl]ketone.
Ketone K6
[5-(1-Hydroxy-l-Methylethyl)-1,3-thiazol-2-yl] [4-
(methylsulfonyl)phenyl]ketone
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Ketone K6 was prepared by the following procedure.
Step 1: [5-(1-Hydroxy-l-Methylethyl)-1,3-thiazol-2-yl] [4-
(methylthio)phenyl]ketone
To a-78 C solution of thiazole (1.0g, 12.Ommol) in THF (100m1) was
added n-butyllithium (2.3M in hexanes, 5.3m1, 12.3mmol) dropwise and the
resulting
solution was stirred at -78 C for 10min. 4-(Methylthio)benzaldehyde (7.1m1,
53.4mmo1) was then added at -78 C. The resulting mixture was stirred at r.t.
10min.
and cooled at -78 C. Then n-butyllithium (2.3M in hexanes, 5.3m1, 12.3mmol)
was
added dropwise and the resulting solution was stirred at 25 C for 10min and
quenched
with acetone (3.Oml). The mixture was then diluted with EtOAc and HCl 10%,
extracted and washed (NaHCO3 (sat.), brine). The organic phase was dried over
MgSO4 and concentrated. The residue was then treated with Mn02 (20.4g,
235mmol)
in CH2ClZ (250m1) and the reaction was stirred at r.t. overnight. The
resulting mixture
was then filtered through a plug of silica (EtOAc). Flash chromatography
(90%CH2ClZ/10%EtOAc) yielded [5-(1-Hydroxy-l-Methylethyl)-1,3-thiazol-2-yl][4-
(methylthio)phenyl]ketone.
Step 2: [5-(1-Hydroxy-l-Methylethyl)-1,3-thiazol-2-yl] [4-
(methylsulfonyl)phenyl]ketone
To a solution of the sulfide - that is, [5-(1-Hydroxy-l-Methylethyl)-
1,3-thiazol-2-yl][4-(methylthio)phenyl]lcetone - from present step 1(1.7g,
5.8mmol)
in THF/MeOH/H2O (100/50/50 ml) was added oxone (7.1g, 11.5mmol). The reaction
was stirred at 25 C for 3h and quenched with a saturated aqueous solution of
NaHCO3. The mixture was then diluted with EtOAc, extracted and washed (NaHCO3
(sat.), brine). The organic phase was dried over MgSO4 and concentrated. The
residue was then purified by crystallization (EtOAc/Hexanes) to yield ketone
K6.
Ketone K7
(6-Methyl-3-pyridinyl) [4-(methylsulfonyl)phenyl]ketone
Ketone K7 was prepared by the following procedure.
Step 1: (6-Methyl-3-pyridinyl)[4-(methylthio)phenyl]methanol
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To solution of 3-bromo-6-methylpyridine (760mg, leq) in THF
(20mL) at -78 C, was added slowly n-butyllithium in hexane (1.1 eq). The
solution
was then stirred 30min. 4-(thiomethyl)benzaldehyde (738mg, l.leq) was then
slowly
added. The solution was warmed to rt. NH4Cl (sat.) was added, then water and
EtOAc. The organic phase was separated, dried over MgSO4, and concentrated.
The
(6-Methyl-3-pyridinyl)[4-(methylthio)phenyl]methanol was obtained by
precipitation
with ether/hexane and was used without further purification for the next step.
Step 2: (6-Methyl-3-pyridinyl)[4-(methylsulfonyl)phenyl]methanol
Following the procedure of step 2 of ketone K1 above but substituting
the sulfide (6-Methyl-3-pyridinyl)[4-(methylthio)phenyl]methanol from the
present
step 1 for (4-fluorophenyl)[4-(methylthio)phenyl]lcetone as the starting
material, (6-
Methyl-3-pyridinyl)[4-(methylsulfonyl)phenyl]methanol was obtained.
Step 3: (6-Methyl-3-pyridinyl)[4-(methylsulfonyl)phenyl]ketone
Following the procedure of step 2 of ketone K2 above but substituting
the (6-Methyl-3-pyridinyl)[4-(methylsulfonyl)phenyl]methanol from the present
step
2 for (1-methyl-lH-imidazol-2-yl)[4-(methylthio)phenyl]methanol as the
starting
material, ketone K7 was obtained.
Ketone K8
(5-Methyl-2-pyridinyl) [4-(methylsulfonyl)phenyl]ketone
Ketone K8 was prepared by following the procedure described for
ketone K7 but substituting 2-bromo-5-methylpyridine for 3-bromo-6-
methylpyridine.
Ketone K9
Bis-[(4-methylsulfonyl)phenyl]ketone
Ketone K9 was prepared by following the procedure described for
ketone K7 but substituting 4-bromothioanisole for 3-bromo-6-methylpyridine and
using twice the amount of Oxone in the sulfide-oxidation step.
Ketone K10
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(2-Pyridinyl) [4-(methylsulfonyl)phenyl]ketone
Ketone K10 was prepared by following the procedure described for
ketone K7 but substituting 2-bromopyridine for 3-bromo-6-methylpyridine.
Ketone Kll
[5-(1-Hydroxy-l-methylethyl)-2-pyridinyl] [4-(methylsulfonyl)phenyl] ketone
Ketone K11 was prepared by the following procedure.
Step 1: [5-(1-Hydroxy-l-methylethyl)-2-pyridinyl] [4-
(methylthio)phenyl]methanol
To a suspension of 2,5-dibromopyridine (5.12g, leq) in ether at -78 C,
was added n-butyllithium in hexane (1.05eq) slowly. The resulting yellow-
orange
precipitate was strirred 30min. Then acetone (1.54m1, 1.05eq) was added. The
solution was kept at -78 C for another 30min. n-Butyllithium in hexane (1.leq)
was
slowly syringed to the resulting orange suspension. The suspension was then
stirred
lh at -78 C. Following this, 4-(methylthio)benzaldehyde (2.85 ml, 1.1 eq.) was
added. The resulting suspension was warmed to -35 C and quenched with a
solution
of NH4C1(sat.). Water and EtOAc were added and the organic layer dried over
MgSO4, evaporated and purified by flash chromatography (EtOAc) to give [5-(1-
Hydroxy-l-methylethyl)-2-pyridinyl] [4-(methylthio)phenyl] methanol.
Step 2: [5-(1-Hydroxy-l-methylethyl)-2-pyridinyl][4-
(methylsulfonyl)phenyl]methanol
Following the procedure described above for step 2 of ketone K1 but
substituting the sulfide - that is, [5-(1-Hydroxy-l-methylethyl)-2-pyridinyl]
[4-
(methylthio)phenyl]methanol - from the present step 1 for (4-fluorophenyl)[4-
(methylthio)phenyl]ketone as the starting material, [5-(1-Hydroxy-1-
methylethyl)-2-
pyridinyl] [4-(methylsulfonyl)phenyl]methanol was obtained.
Step 3: [5-(1-Hydroxy-l-methylethyl)-2-pyridinyl] [4-
(methylsulfonyl)phenyl]lcetone
Following the procedure described above for step 2 for lcetone K2 but
substituting the [5-(1-Hydroxy-l-methylethyl)-2-pyridinyl][4-
(methylsulfonyl)phenyl]methanol from the present step 2 for (1-methyl-lH-
imidazol-
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2-yl)[4-(methylthio)phenyl]methanol as the starting material, ketone K11 was
obtained.
The boronate compounds utilized to prepare the compounds of this
invention can be made according to Scheme 2 shown below:
SCHEME 2
Boronate Synthesis
Br
Br Ar
P+Ph3Br SOnMe Ar
xi VII or VIII MeOnS
IX (n=O)
X (n=2)
H3C CH3
H3C~CH
O, B-O
~ NZ Ar
MeO2S
XII
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Ketone (VII or VIII) Ar n Boronate (XII)
K2 H2CA~N~ 0 B1
CH3
K4 H2C~S7 0 B2
CH3
K8 HC IN 2 B3
2
H3C OH
K11 CH3 2 B4
H2C N
The aryl bromides IX and X may be prepared by treatment of
the benzyl phosphonium bromide XI with a base such as t-BuOK or LiH1VIDS in an
organic solvent such as THF, followed by the addition of the lcetone VII or
VIII to
the reaction mixture. The sulfide in IX may be converted to the sulfone X by
treatment with oxone in a solvent such as a mixture of THF/MeOH/H20. The
boronate ester XII can be prepared by heating the aryl bromide X with pinacol
diborane in the presence of a base such as KOAc and a catalyst such as
PdC12(dppf) in
a solvent such as DMF.
Boronate B1
Pinacol3-{ (E)-2-(1-methyl-lH-imidazol-2-yl)-2-[4-
(methylsulfonyl)phenyl] ethenyl } phenylboronate
Boronate B1 was prepared by the following procedure.
Step 1: (E/Z)-2-(3-Bromophenyl)-1-(1-methyl-lH-imidazol-2-yl)-1-[4-
(methylthi o)phenyl] ethene
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To a solution of (3-bromobenzyl)(triphenyl)phosphonium bromide
(10.2g, 19.9mmol) in THF (200mL) and CH3CN (50mL) at 25 C was added t-BuOK
(1.OM in THF, 19.9mL, 19.9mmol) dropwise and the resulting red solution was
stirred at r.t. for 20min. To this resulting ylide was then added at 25 C the
ketone K2
(4.4g, 18.9mmol). The resulting mixture was stirred at 60 C for 2 days and
quenched
with NH4C1(sat). The mixture was then diluted with EtOAc. The organic phase
was
washed with NaHCO3 (sat.), brine, dried over MgSO4, filtered and concentrated,
and
used directly in the next present step 2.
Step 2: (E)-2-(3-Bromophenyl)-1-(1-methyl-lH-imidazol-2-yl)-1-[4-
(methylsulfonyl)phenyl]ethene
To a solution of the crude sulfide - that is, (E/Z)-2-(3-Bromophenyl)-
1-(1-methyl-lH-imidazol-2-yl)-1-[4-(methylthio)phenyl]ethene - from present
step 1
(18.9mmol) in THF/MeOH/H2O (200/100/100 ml) was added oxone (23.2g,
37.8mmol). The mixture was stirred at r.t. for 4h, quenched with NaHCO3
(sat.), and
diluted with EtOAc. The organic phase was washed with NaHCO3 (sat.), brine,
dried
over NaZSO4, filtered and concentrated. Flash chromatography (95%EtOAc/5%
Et3N)
yielded (E)-2-(3-Bromophenyl)-1-(1-methyl-lH-imidazol-2-yl)-1-[4-
(methylsulfonyl)phenyl]ethene (single isomer) as a foam.
Step 3: Pinacol 3-{ (E)-2-(1-methyl-lH-imidazol-2-yl)-2-[4-
(methylsulfonyl)phenyl] ethenyl }phenylboronate
A suspension of the bromide - that is, (E)-2-(3-Bromophenyl)-1-(1-
methyl-lH-imidazol-2-yl)-1-[4-(methylsulfonyl)phenyl]ethene - from present
step 2
(2.0g; 4.8mmol), pinacol diborane (1.5g ; 5.8mmol), KOAc (1.65g; 16.8mmol) and
PdC12(dppf) (0.2g; 0.24mmol) in 50mL of DMF was stirred at 90 C for 4h. The
resulting mixture was cooled to r.t., diluted with EtOAc, washed with H20
(3x), brine,
dried over Na2SO4, filtered and concentrated. Flash chromatography
(95%EtOAc/5%
Et3N) yielded boronate B1 as a foam.
Boronate B2
Pinacol 3-{ (E/Z)-2-(1,3-thiazol-2-yl)-2-[4-
(methylsulfonyl)phenyl]ethenyl }phenylboronate
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Boronate B2 was prepared by the following procedure.
Step 1: (E/Z)-2-(3-Bromophenyl)-1-(1,3-thiazol-2-yl)-1-[4-
(methylthi o)phenyl] ethene
To a solution of (3-bromobenzyl)(triphenyl)phosphonium bromide
(44.5g, 86.9mmol) in THF (500mL) and DMF (200mL) at 0 C was added LiHMDS
(1.OM in THF, 86.9mL, 86.9mmol) dropwise and the resulting red solution was
stirred at r.t. for 20min. To the resulting ylide was then added at 0 C the
ketone K4
(18.6g, 79.0mmol). The mixture was stirred until completion by TLC, and
quenched
with a NH4C1 (sat). The mixture was then diluted with EtOAc. The organic phase
was washed with NaHCO3 (sat.), brine, dried over MgSO4, filtered and
concentrated.
Flash chromatography (CH2C12) yielded (E/Z)-2-(3-Bromophenyl)-1-(1,3-thiazol-2-
yl)-1-[4-(methylthio)phenyl]ethene (1.5 to 1 mixture of isomers).
Step 2: (E/Z)-2-(3-Bromophenyl)-1-(1,3-thiazol-2-yl)-1-[4-
(methylsulfonyl)phenyl] ethene
To a solution of the sulfide - that is, (E/Z)-2-(3-Bromophenyl)-1-(1,3-
thiazol-2-yl)-1-[4-(methylthio)phenyl]ethene - from present step 1 (24.8g,
63.9mmol)
in THF/MeOH/H20 (600/300/300 ml) was added Oxone (78.5g, 128mmol). The
resulting reaction mixture was stirred at r.t. overnight. The resulting
mixture was
quenched with a NaHCO3 (sat), and diluted with EtOAc. The organic phase was
washed with NaHCO3 (sat.), brine, dried over Na2SO4, filtered and concentrated
to
yield (E/Z)-2-(3-Bromophenyl)-1-(1,3-thiazol-2-yl)-1-[4-
(methylsulfonyl)phenyl]ethene (3 to 2 mixture of isomers).
Step 3: Pinacol3-{ (E/Z)-2-(1,3-thiazol-2-yl)-2-[4-
(methylsulfonyl)phenyl]ethenyl }phenylboronate
A suspension of the bromide (E/Z)-2-(3-Bromophenyl)-1-(1,3-thiazol-
2-yl)-1-[4-(methylsulfonyl)phenyl]ethene from present step 2(15.0g, 35.7mmo1),
pinacol diborane (10.9g, 42.8mmol), KOAc (12.3g, 125mmo1) and PdC12(dppf)
(1.46g, 1.78mmol) in 350mL of DMF was stirred at 90 C for 4h. The resulting
mixture was cooled to r.t., diluted with EtOAc, washed with H20 (3x), brine,
dried
over Na2SO4, filtered and concentrated. Flash chromatography (Tol/Acetone,
9/1)
yielded boronate B2 (3 to 1 mixture of isomers) as a foam.
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Boronate B3
Pinacol3-{ (E)-2-(5-methyl-2-pyridinyl)-2-[4-
(methylsulfonyl)phenyl]ethenyl }phenylboronate
Boronate B3 was prepared by the following procedure.
Step 1: (E)-2-(3-Bromophenyl)-1-(5-methyl-2-pyridinyl)-1-[4-
(methyl sulfonyl)phenyl] ethylene
Following the procedure described for step 1 for boronate B1 but
substituting the ketone K8 for ketone K2 as the starting material, (E)-2-(3-
Bromophenyl)-1-(5-methyl-2-pyridinyl)-1-[4-(methylsulfonyl)phenyl]ethylene was
obtained after separation of the isomers by flash chromatography.
Step 2: Pinacol3-{ (E)-2-(5-methyl-2-pyridinyl)-2-[4-
(methylsulfonyl)phenyl]ethenyl }phenylboronate
Following the procedure described for step 3 for boronate B1 but
substituting the bromide (E)-2-(3-Bromophenyl)-1-(5-methyl-2-pyridinyl)-1-[4-
(methylsulfonyl)phenyl] ethylene from present step 1 for (E)-2-(3-Bromophenyl)-
1-(1-
methyl-lH-imidazol-2-yl)-1-[4-(methylsulfonyl)phenyl]ethene as the starting
material,
boronate B3 was obtained.
Boronate B4
Pinacol 3-{ (E)-2-(5-(1-hydroxy-l-methylethyl)-2-pyridinyl)-2-[4-
(methylsulfonyl)phenyl]ethenyl }phenylboronate
Boronate B4 was prepared by the following procedure.
Step 1: (E)-2-(3-Bromophenyl)-1-[5-(1-hydroxy-l-methylethyl)-2-
pyridinyl] -1- [4-(methyl sulf onyl)phenyl] ethene
Following the procedure described for step 1 for boronate B1 but
substituting the ketone K11 for lcetone K2 as the starting material, (E)-2-(3-
Bromophenyl)-1-[5-(1-hydroxy-l-methylethyl)-2-pyridinyl]-1-[4-
(methylsulfonyl)phenyl]ethene was obtained after separation of the isomers by
flash
chromatography.
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Step 2: Pinacol3-{ (E)-2-(5-(1-hydroxy-l-methylethyl)-2-pyridinyl)-2-
[4-(methylsulfonyl)phenyl]ethenyl }phenylboronate
Following the procedure described for step 3 for boronate B1 but
substituting the bromide (E)-2-(3-Bromophenyl)-1-[5-(1-hydroxy-l-methylethyl)-
2-
pyridinyl]-1-[4-(methylsulfonyl)phenyl]ethene from present step 1 for (E)-2-(3-
Bromophenyl)-1-(1-methyl-lH-imidazol-2-yl)-1-[4-(methylsulfonyl)phenyl]ethene
as
the starting material, boronate B4 was obtained.
The aryl bromide compounds utilized to prepare the compounds of this
invention can be made according to Schemes 3 and 4 shown below:
SCHEME 3
Oxadiazole Synthesis
p-MeOPhOH + CI,,CN om p-MeOPhO,,,CN
Xllla
I ~
MeO2S CO2H
N~OH XV
N R
RCN jl O11 -N
R'" NH2 MeO2S
XIII XIV XVI
R Oxadiazole (XVI)
Me OX1
p-MeOPhOCH2 OX2
Referring to Scheme 3 above, the nitrile intermediate XIIIa may be
prepared by the alkylation of 4-methoxyphenol with chloroacetonitrile in the
presence
of a base such as potassium carbonate in a solvent such as acetone. The amide-
oxime
XIV may be prepared by treatment of the nitrile XIII with hydroxyl amine in a
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SUBSTITUTE SHEET (RULE 26)
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solvent such as methanol in the presence of a base such as sodium acetate.
Formation
of the oxadizole XVI may be achieved by activation of the arylacetic acid XV
with
carbonyldiimidazole in a solvent such as D1VIF followed by the addition of the
amide-
oxime XIV and subsequent heating of the reaction mixture.
SCHEME 4
Aryl Bromide Synthesis
C CO2H
MeO2S Br Br
Br XV
~~ I I
CHO C02H INZ CONR1R2
XVII MeO2S MeO2S
XVIIia (AB1) XVIIIb
oxi
R1 R2 Aryl Bromide (XVIIIb)
Br
H i-Pr AB2 11 NYCH3 H H AB3
Me02S O-N
XVliic (AB5) H t-Bu AB4
Referring to Scheme 4 above, condensation of the aldehyde XVII by
heating with the arylacetic acid XV in the presence of a base such as
piperidine in a
solvent such as toluene produces the unsaturated acid XVIIIa. Formation of the
acid
chloride of XVIIla in situ by treatment with thionyl chloride and a base such
as
triethylamine in a solvent such as toluene, is followed by the addition of an
amine to
the reaction mixture to yield the amide XVIIIb. The oxadiazole-ethene XVIIIc
may
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be formed by heating OX1 with XVII in the presence of a base such as
piperidine in a
solvent such as toluene.
Scheme 4 appendix
Aryl Bromide Synthesis
Br Br Br
~I
I
I~ COZH I~ C02Me I~
Me02S ~ Me02S ~ MeO2S OH
XVIIIa (AB1) XVIIId XVIIIe
Br
MeO2S ~ NMe2
XVIIIf (AB6)
Referring to Scheme 4 appendix above, treatment of the acid XVIIIa
with diazomethane in a solvent such as THF produces the methyl ester XVIIId.
Reduction of the ester XVIIId using DIBAL-H in a solvent such as THF gives the
allylic alcohol XVIIIe. Conversion of the alcohol group in XVIIIe to a leaving
group
such as a mesylate using reagents such as methanesulfonyl chloride and
triethylamine
in a solvent such as THF, followed by displacement with a nucleophile such as
dimethylamine in a solvent such as DMF produces the compound XVIIIf.
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Aryl Bromide AB1
(E)-3-(3-Bromophenyl)-2-[4-(methylsulfonyl)phenyl]-2-propenoic acid
Aryl Bromide AB1 was prepared by the following procedure. To a
solution of 3-bromobenzaldehyde (12.9g, 70mmo1) in toluene (100mL) was added 4-
(methylsulfonyl)phenylacetic acid (15g, 70mmo1) and piperidine (2mL). After
overnight refluxing, the mixture was cooled down to r.t. To the slurry thus
formed,
toluene was added (10 mL) . Filtration gave (E)-3-(3-Bromophenyl)-2-[4-
(methylsulfonyl)phenyl]-2-propenoic acid as a white solid.
Aryl Bromide AB2
(E)-N-Isopropyl-3-(3-bromophenyl)-2-[4-(methylsulfonyl)phenyl] -2-propenamide
Aryl Bromide AB2 was prepared by the following procedure. To a
solution of AB1 (24.9g, 65mmo1) in toluene (250mL) was added thionyl chloride
(14.3mL, 196mmo1) and triethylamine (34mL, 245nunol). After stirring at r.t.
for
0.5h., isopropyl amine (28mL, 327mmo1) was added. After a further 2h at r.t.,
the
mixture was cooled to 0 C and was neutralised with saturated NH4Cl solution,
then
extracted with EtOAc. The organic extracts were washed (H20, brine), dried
(MgSO4), filtered and concentrated. Purification by flash chromatography
(Hex:EtOAc, 1:1 to pure EtOAc) yielded (E)-N-Isopropyl-3-(3-bromophenyl)-2-[4-
(methylsulfonyl)phenyl]-2-propenamide.
Aryl Bromide AB3
(E) -3-(3-Bromophenyl)-2-[4-(methylsulfonyl)phenyl]-2-propenamide
Aryl Bromide AB3 was prepared by following the procedure described
for aryl bromide AB2 but substituting ammonium hydroxide for isopropyl amine
as
the starting material.
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Aryl Bromide AB4
(E)-N-(t-Butyl)-3-(3-Bromophenyl)-2- [4-(methylsulfonyl)phenyl]-2-propenamide
Aryl Bromide AB4 was prepared by following the procedure described
for aryl bromide AB2 but substituting t-butyl amine for isopropyl amine as the
starting material.
Aryl Bromide AB5
(E)-1-(3-Bromophenyl)-2-(3-methyl-1,2,4-oxadiazol-5-yl)-2-[4-
(methylsulfonyl)phenyl] ethene
Aryl Bromide AB5 was prepared by the following procedure.
Step 1 (Scheme 3, Oxadiazole OX1): (3-Methyl-1,2,4-oxadiazol-5-yl)
[4-(methylsulfonyl)phenyl]methane
To a solution of 4-(methylsulfonyl)phenylacetic acid (15g, 70mmo1) in
DMF (300mL) at r.t., was added carbonyldiimidazole (12.5g, 77mmol). After 0.5h
at
r.t., acetamide oxime (5.7g, 77mrnol) was added. After stirring the resulting
mixture
overnight at r.t., the mixture was heated to 120 C for 6h. After cooling to
r.t., the
mixture was quenched with H20, and extracted with EtOAc. The organic extracts
were washed (H20, brine), dried (MgS04), filtered and concentrated.
Purification by
flash chromatography (Hex:EtOAc, 1:1) yielded (3-Methyl-1,2,4-oxadiazol-5-yl)
[4-
(methylsulfonyl)phenyl]methane.
Step 2 (Scheme 4): (E)-1-(3-Bromophenyl)-2-(3-methyl-1,2,4-
oxadiazol-5-yl)-2-[4-(methylsulfonyl)phenyl] ethene
To a solution of 3-bromobenzaldehyde (2.2g, 11.9mmo1) in toluene
(30mL) was added the product from step 1(OX1) (3.0g, 11.9mmo1) and piperidine
(0.4mL). After overnight refluxing, the mixture was cooled down to r.t. To the
resulting slurry, MeOH (30mL) was added. After further refluxing then cooling
to
0 C, filtration gave (E)-1-(3-Bromophenyl)-2-(3-methyl-1,2,4-oxadiazol-5-yl)-2-
[4-
(methylsulfonyl)phenyl]ethene as a white solid.
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The Bromoquinolines utilized to prepare the compounds of this
invention can be made according to Scheme 5 shown below:
SCHEME 5
Preparation of Bromoquinolines
CH3
Br i1 ~ R1 Ri
N ~ -~ N
Br Br Br
XIX XXa XXb
H3C CH3
R1
Br
XXc
Referring to Scheme 5 above and the Scheme 5 table below, treatment
of the bromomethyl compound XIX with a nucleophile such as sodium
methanesulfinate or potassium cyanide in a solvent such as DMF or a mixture of
DMF and water can be used to produce the compounds XXa. The compound XXb
may be prepared by treatment of XXa with a base such as potassium t-butoxide
(1.1
equivalents) in a solvent such as THF followed by the addition of the
resulting
mixture into a solution of methyl iodide in a solvent such as THF. The
compound
XXc may be prepared by treatment of XXb with a base such as potassium t-
butoxide
(1.1 equivalents) in a solvent such as THF followed by the addition of the
resulting
mixture into a solution of methyl iodide in a solvent such as THF. The
compound
XXc (where Rl = CN) may also be prepared by treatment of XXa with a base such
as
potassium t-butoxide (2.2 equivalents) and methyl iodide in a solvent such as
THF.
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The compound XXc (where Rl = SO2Me) may also be prepared by treatment of XXa
with a base such as potassium t-butoxide (1.3 equivalents) and methyl iodide
(1.6
equivalents) in a solvent such as THF, followed by an additional amount of
methyl
iodide (1.6 equivalents) and an additional amount of the same base (1.0
equivalents).
Scheme 5 Table
Bromoquinolines
R2 R3
i
qlrvl- R
Br
XX
Ri R2 R3 Bromoquinoline (XX)
SO2Me H H Q1
SO2Me Me H Q2
SO2Me Me Me Q3
CN H H Q4
CN Me Me Q5
Bromoquinoline Q1
6-(methylsulfonyl)methyl- 8-bromoquinoline
Bromoquinoline Q1 was prepared by the following procedure. DMF
(500mL) was added to 6-bromomethyl-8-bromoquinoline (60g, 200mmol) (described
in International Patent Publication WO 94/22852) and sodium methanesulfinate
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(27.6g, 270mmol). After stirring overnight at r.t., the mixture was quenched
with
H20 (2000mL), stirred for one hour, isolated by filtration and washed with
Et20 to
yield 6-(methylsulfonyl)methyl-8-bromoquinoline.
Bromoquinoline Q2
6-[ 1-(methylsulfonyl)ethyl]-8-bromoquinoline
Bromoquinoline Q2 was prepared by the following procedure. To a
solution of bromoquinoline Q1 (16.1g, 54mmol) in THF (500mL) at -78 C, was
added potassium t-butoxide (59mL, 1N in THF). After 0.5h at -78 C, the
resulting
mixture was stirred at 0 C for 45min and then transferred by canula dropwise
into a
solution of Mel (16.7mL, 268.3mmo1) in THF (160mL). After stirring overnight
at
r.t., the mixture was neutralised with saturated NH4C1 solution and extracted
with
EtOAc. The organic extracts were washed (H20), (brine), dried (MgSO4),
filtered and
concentrated. Stirring in ether, followed by isolation by filtration gave 6-[1-
(methylsulfonyl)ethyl]-8-bromoquinoline.
Bromoquinoline Q3
6-[ 1-methyl-l-(methylsulfonyl)ethyl]-8-bromoquinoline
Bromoquinoline Q3 was prepared by the following procedure. To a
solution of bromoquinoline Q2 (15.7g, 50mmol) in THF (500mL) at -78 C, was
added potassium t-butoxide (55mL, 1N in THF). After stirring 0.5h at -78 C,
the
resulting mixture was stirred at 0 C for 45min and then transfered dropwise
into a
solution of Mel (1'5.6mL, 250mmol) in THF (40mL) at 0 C. After stirring
overnight
at r.t., the mixture was neutralised with saturated NH4C1 solution, and
extracted with
EtOAc. The organic extracts were washed (H20, brine), dried (MgSO4), filtered
and
concentrated. Stirring in ether, followed by isolation by filtration gave 6-[1-
methyl-l-
(methylsulfonyl)ethyl]-8-bromoquinoline.
Bromoquinoline Q4
6-cyanomethyl-8-bromoquinoline
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Bromoquinoline Q4 was prepared by the following procedure. DMF
(lOmL) and H20 (5mL) were added to 6-bromomethyl-8-bromoquinoline (3g,
lOmmol) (described in International Patent Publication WO 94/22852) and
potassium
cyanide (1.6g, 25mmol). After heating at 100 C for 1 hour, the resulting
mixture was
quenched with H20 (100mL) and extracted with EtOAc. The organic extracts were
washed (H20, brine), dried (MgSOd), filtered and concentrated. Purification by
flash
chromatography (Hex:EtOAc, 3:1) yielded 6-cyanomethyl-8-bromoquinoline.
Bromoquinoline Q5
6-[ 1-methyl-l-cyanoethyl]-8-bromoquinoline
Bromoquinoline Q5 was prepared by the following procedure. To a
solution of bromoquinoline Q4 (3g, 12.1mmo1) in THF (100mL) at -78 C, was
added
Mel (1.7mL, 27mmol) followed by potassium t-butoxide (27mL, 27mmol). After 2h
at -78 C, the mixture was warmed to 0 C and was neutralised with saturated
NH4Cl
solution then extracted with EtOAc. The organic extracts were washed (H20,
brine),
dried (MgSO4), filtered and concentrated. Purification by flash chromatography
(Hex:EtOAc, 3:1) yielded 6-[1-methyl-l-cyanoethyl]-8-bromoquinoline.
The Benzyl Phosphorus Reagents utilized to prepare the compounds of
this invention can be made according to Scheme 6 shown below:
SCHEME 6
Preparation of Benzyl Phosphorus Reagents
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HTOH C CHs H3C CHs
CH 1 1
R R
H3C 3 B(OH)2
I R N
N + ~ ' ~ OH ~ Br X
xx xxi xxii XXIII (X = Br)
XXIV (X = OS02Me)
HgC C''H3
Ri
N
R2
XXV
R1 R2 Benz. Phos. Reag.(XXV)
H CH2P(Ph)3+Br P1
H CH2P(O)(OEt)2 P2
CN CH2P(O)(OEt)2 P3
The arylquinolines of the formula XXII may be prepared by coupling
bromoquinoline XX with the boronic acid XXI by heating in the presence of a
catalyst
such as Pd(PPh3)4 and a base such as sodium carbonate (aqueous) in a solvent
such as
a DME. The alcohol XXII may be converted to the bromide XXIII by treatment
with
HBr (aq) in a solvent such as acetic acid. The alcohol XXII may be converted
to the
methyl sulfonate ester XXIV by methanesulfonyl chloride in the presence of a
base
such as triethylamine in a solvent such as dichloromethane. The benzyl
phosphorous
reagents XXV may be prepared either by heating XXIII in the presence of PPh3
in a
solvent such as acetonitrile or by treating XXIII or XXIV with
diethylphosphite and a
base such as potassium t-butoxide in a solvent such as THF.
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Benzylphosphonium Bromide Pl
[3-(6-Isopropyl-8-quinolinyl)benzyl](triphenyl)phosphonium Bromide
Benzylphosphonium Bromide P1 was prepared by the following
procedure.
Step 1: 6-Isopropyl-8-[3-(hydroxymethyl)phenyl]quinoline
A mixture of 6-isopropyl-8-Bromoquinoline (11.1g, 44.4mmol)
(described in International Patent Publication WO 94/22852), 3-
(hydroxymethyl)phenylboronic acid (8.70g, 57.2mmol), Na2CO3 (2M, 71mL,
142mmo1) and Pd(PPh3)4 (2.51mg, 2.17mmol) in 280mL of DME was stirred at 80 C
for 5h. The resulting mixture was cooled to r.t., diluted with EtOAc, washed
with
brine, dried over Na2S04, filtered and concentrated. Flash chromatography
(Hex/EtOAc, 1/1) and stirring in CH2ClZ/hexane (1/9) yielded 6-Isopropyl-8-[3-
(hydroxymethyl)phenyl]quinoline as a white solid.
Step 2: 6-Isopropyl-8-[3-(bromomethyl)phenyl]quinoline
A suspension of the hydroxymethyl product compound from present
step 1 (7.40g, 26.7mmol) in AcOH (50mL) and HBr (50mL, 48% aq) was stirred for
12h at 100 C. The mixture was cooled to r.t., poured into NaOH (2N) in ice,
the pH
was adjusted to 8 and the mixture was diluted with ether. The organic phase
was
washed with brine, dried over MgSO4, filtered and concentrated to yield 6-
Isopropyl-
8-[3-(bromomethyl)phenyl]quinoline as a yellow solid.
Step 3: [3-(6-Isopropyl-8-quinolinyl)benzyl](triphenyl)phosphonium
Bromide
To a solution of the bromomethyl product compound from present step
2 (3.807g, 11.1mmo1) in 40mL of CH3CN was added triphenylphosphine (3.22g,
12.3mmo1). The mixture was stirred at 60 C for 12h, cooled to r.t., diluted
with ether,
filtered, and washed with ether to yield [3-(6-Isopropyl-8-
quinolinyl)benzyl](triphenyl)phosphonium Bromide.
Benzylphosphonate P2
Diethyl 3-(6-isopropyl-8-quinolinyl)benzylphosphonate
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Benzylphosphonate P2 was prepared by the following procedure. The
bromomethyl compound from from step 2 above of the synthesis of Pl (11.34g,
leq)
was dissolved in THF (170mL). Diethylphosphite (3.87mL, 1.05eq) was added and
the solution was cooled down to 0 C. Next, t-BuOK (3.87mL, 1N in THF) was
added
slowly. The reaction was stirred 2h and the quenched by addition of
NH4C1(sat),
water and EtOAc. The organic phase was separated and washed with brine, dried
over MgSO4 and concentrated. Purification by flash chromatography on silica
gel
(hexane:EtOAc, 1/9) gave Diethyl 3-(6-isopropyl-8-quinolinyl)benzylphosphonate
as
a clear oil.
Benzylphosphonate P3
Diethyl 3-[6-(1-cyano-l-methylethyl)-8-quinolinyl]benzylphosphonate
Benzylphosphonate P3 was prepared by the following procedure.
Step 1: 6-(1-Cyano-1-methylethyl)-8-[3-
(hydroxymethyl)phenyl] quinoline
Following step 1 described above of the procedure for
Benzylphosphonium Bromide Pl, but substituting the bromoquinoline Q5 for 6-
isopropyl-8-bromoquinoline as the starting material, 6-(1-Cyano-l-methylethyl)-
8-[3-
(hydroxymethyl)phenyl]quinoline was obtained.
Step 2: 3-[6-(1-Cyano-l-methylethyl)-8-quinolinyl]benzyl
methanesulfonate
To a solution of the alcohol6-(1-Cyano-l-methylethyl)-8-[3-
(hydroxymethyl)phenyl]quinoline from present step 1 (5.15g, 17mmo1) in CH202
(150mL) at -78 C was added Et3N (3.6mL, 26mmol) and methanesulfonyl chloride
("MsCl") (1.6mL, 2lmmol). After 0.5h at -78 C, the mixture was neutralised
with
saturated NH4C1 solution, diluted with water and extracted with ether. The
organic
extracts were washed (H20, brine), dried (MgSO4), filtered and concentrated to
yield
3-[6-(1-Cyano-l-methylethyl)-8-quinolinyl]benzyl methanesulfonate as a white
foam.
Step 3: Diethyl3-[6-(1-cyano-l-methylethyl)-8-
quinolinyl]benzylphosphonate
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To a solution of diethylphosphite (2.5mL, l8mmol) in THF (100mL) at
-78 C was added potassium t-butoxide (1M, THF, 16mL, 16mmo1) and the mesylate
compound 3-[6-(1-Cyano-l-methylethyl)-8-quinolinyl]benzyl methanesulfonate
from
present step 2(5.1g, 13.5mmol). After 0.5h at -78 C and 12h at r.t., the
resulting
mixture was neutralised with saturated NH4C1 solution, diluted with water and
extracted with ether. The organic extracts were washed (1120, brine), dried
(MgSO4),
filtered and concentrated. Purification by flash chromatography (Hex:EtOAc,
1:4 to
1:10) yielded Diethyl3-[6-(1-cyano-l-methylethyl)-8-
quinolinyl]benzylphosphonate
as an oil.
SCHEME 7
Benzyphosphorous Reagent - Ketone Coupling
H3C CHs
H3C H3 1 , R1
\ R VII N
N
R2 Rs
MeS
Benz. Phos. Reag.
(XXV) XXVI
VIII
H3C CH3
Ri
N ~
R4 R 3
Example (I)
Compounds corresponding to the formula I may be prepared using the
reaction pathways outlined in Scheme 7 above. The compound XXVI may be
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obtained by adding a solution of the ketone VII in a solvent such as THF to a
mixture
of the benzylphosphorous reagent XXV and a base such as potassium t-butoxide
in a
solvent such as THF. The compounds corresponding to the formula I may then be
prepared by treating XXVI with oxone in a mixture of solvents such as
THF/MeOH/water. Alternatively the compounds of formula I may be prepared by
reacting the lcetone VIII with XXV in the presence of a base such as potassium
t-
butoxide in a solvent such as THF.
Referring to Scheme 7 above and Table 1 below, the coupling of the
ketones with the benzyl phosphorous reagents resulted in the tabulated
Examples.
Tablel
Benz. Phos. Reag. Ketone Example
P2 K3 1
P2 K3 2
P1 K5 3
P1 K2 4
P2 K1 5
P2 K1 6
P2 K6 7
P3 K6 8
P3 K2 9
P2 Commercial 30
P2 K7 31
P2 K7 32
P2 K8 33
P2 K8 34
P2 K9 35
P3 K8 36
P3 K8 37
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Tablel
Benz. Phos. Reag. Ketone Example
P3 K9 38
P3 K10 39
SCHEME 8
Aryl Bromide - Bromoquinoline Coupling
H C 3C CH3 HsC R2
3 ~CH3
Br O~B-O I ~ CH3
Bromoquinoline N
(XX)
I ~ I ' I
R1 R1 Ri
Me02S Me02S Me02S
Aryl Bromide Boronate Example (I)
(XVIII) (used in situ)
Referring to Scheme 8, compounds corresponding to the formula I may
be prepared by in situ conversion of the aryl bromide XVIII to the
corresponding
boronate ester by heating with diboron pinacol ester, a catalyst such as [1,1'-
bis(diphenylphosphino)-ferrocene]dichloropalladium(II) and a base such as
potassium
acetate in a solvent such as DMF, followed by the addition of the
bromoquinoline
XX, an additional amount of the same catalyst, an additional amount of a base
such as
sodium carbonate (aqueous) and an additional period of heating.
Referring to Scheme 8 above, Table 2 and Table 2 appendix below, the
coupling of the Aryl Bromide with the Bromoquinoline resulted in the tabulated
Examples.
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Table 2
Aryl Bromide Bromoquinoline Example
AB5 Q3 14
AB5 Q3 15
AB2 Q5 16
AB2 Q5 17
AB2 Q3 20
AB1 Q5 21
AB5 Q5 22
AB3 Q5 23
AB4 Q5 24
AB 1 WO 94/22852 25
AB5 WO 94/22852 26
Table 2 appendix
Aryl Bromide Bromoquinoline Example
AB6 Q5 43
Compounds of this invention can be prepared by following Scheme 9
shown below.
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SCHEME 9
i
B(OH)2 R1 R
6"CHO N N XVI
XX X
CHO ~N
MeO2S ~ O OR2
XXVII 2
R = p-MeOPh
(Example 18)
/xv
R2=H
R1 R1 (Example 19)
N IN
I I NR2R3
C02H I
MeO2S MeO2S O
XXVIII Example (I)
NR2R3
N~D Example 27
NH-Q Example 28
CH3
NH-~CH3 Example 29
CH3
Scheme 9 outlines the preparation of compounds of formula I where
the aldehyde XXVII may be prepared by heating the bromoquinoline XX, 3-
formylbenzeneboronic acid, a catalyst such as Pd(PPh3)4 and a base such as
sodium
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carbonate (aqueous) in a solvent such as DME. The aldehyde XXVII may be
converted to Example 18 by heating with XVI in the presence of a base such as
piperidine in a solvent such as toluene. Example 19 may be obtained by
treatment of
Example 18 with cerric ammonium nitrate ("CAN") in a mixture of solvents such
as
acetonitrile/water. Alternatively the aldehyde XXVII may be converted to the
unsaturated acid XXVIII by heating with XV and a base such as piperidine in a
solvent such as toluene. The acid XXVIII may then be converted to the amide I
(Example 27, 28 and 29) by treatment with a coupling system such as EDCI,
HOBt,
and an amine in a solvent such as DMF.
Compounds of this invention can be prepared by coupling
Bromoquinoline compounds with Boronate compounds according to Scheme 10
below.
SCHEME 10
Bromoquinoline-Boronate Coupling
H3C
H3C \--,CH3 c~r CR ;Ool
Br 1Ar Ar
MeO2S MeO2Bromoquinoline
(XX) Boronate Example (I)
(XII)
Scheme 10 describes how compounds of formula I may be obtained by
coupling the bromoquinoline XX with the boronate ester XII in the presence of
a
catalyst such as Pd(OAc)2, PPh3, and a base such as sodium carbonate (aqueous)
in a
solvent such as n-propanol. Referring to Table 3, the coupling of the
Bromoquinoline
with Boronate resulted in the tabulated Examples.
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Table 3
Bromoquinoline Boronate Example
Q2 B2 10
Q3 B2 11
Q2 B1 12
Q3 B1 13
Q3 B3 40
Q3 B3 41
Q3 B4 42
EXAMPLES 1 and 2
6-isopropyl-8-(3-{ (Z/E)-2-[4-(methylsulfonyl)phenyl]-2-
phenylethenyl }phenyl)quinoline
CH3
~ \ \ CH3
N
I \ ( \
H3C,S
~/'Ii
Example 1
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CH3
~ \ \ CH3
N
\ / \
S,CH3
O O
Example 2
Examples 1 and 2 were prepared by the following procedure. To a
mixture of benzylphosphonate P2 (330mg, 0.83mmol) and ketone K3 (200mg,
0.77mmol) in THF (6mL) at r.t. was added potassium t-butoxide (1M, THF,
0.83mL,
0.83mmol). After lh at r.t., the mixture was diluted with water and extracted
with
Et20. The organic extracts were washed (H20), (brine), dried (MgSO4), filtered
and
concentrated. Purification by flash chromatography (Hex:EtOAc, 7:3) produced
Examples 1 and 2 as white foams with one product being less polar than the
other
product. Example 1 was the less polar Z-isomer and Example 2 was the more
polar
E-isomer.
Example 1: NMR 'H (400MHz, Acetone-d6) a 8.79 (q, 1H), 8.28 (q,
1H), 7.94 (d, 2H), 7.73 (d, 1H), 7.6-7.1 (m, 14H), 3.14 (m, 1H), 2.97 (s, 3H),
1.34 (d,
6H).
Example 2: NMR 1H (400MHz, Acetone-d6) a 8.78 (q, 1H), 8.25 (q,
1H), 7.89 (d, 2H), 7.71 (d, 1H), 7.6 (m, 3H), 7.45 (m, 3H), 7.39-7.2 (m, 8H),
3.11 (m,
4H), 1.34 (d, 6H).
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EXAMPLE 3
6-isopropyl-8-{ 3-[(E/Z)-2-[4-(methylsulfonyl)phenyl]-2-(1,3-thiazol-2-
yl)ethenyl]phenyl } quinoline
CH3
~ \ \ CH3
S _/ N
N
~N
\ I ~ \
S,CH3
O
0 Example 3 was prepared by the following procedure. To a suspension
of the benzylphosphonium bromide Pl (320mg, 0.531mmo1) in 2.5mL THF at -78 C
was added t-BuOK (1.OM in THF, 0.55mL, 0.55mmol) dropwise and the resulting
red
solution was stirred 30min at 0 C . To this ylide at -78 C was then added
ketone K5
(122mg, 0.455mmol) in 2mL of THF dropwise. The mixture was warmed to r.t.,
then
stired for lh, quenched with a NH4C1(sat.) and diluted with EtOAc. The organic
phase was washed with brine, dried over NaZSO4, filtered and concentrated.
Flash
chromatography (Silica cartridge, Hex/EtOAc 10 to 100% in 20min) yielded
Example
3 (1.5 to 1 mixture of isomers).
NMR 1H (500MHz in acetone-d6) a 8.79-8.78 (m, 1H), 8.26-8.23 (m,
1H), 8.01-7.92 (m, 3H), 7.84 (d, 0.4H, minor), 7.78 (d, 0.6H, major), 7.73-
7.47 (m,
lOH), 7.43 (dd, 1H), 7.34 (t, 0.6H, major), 7.27 (t, 0.4H, minor), 7.18 (d,
0.6H,
major), 7.09 (d, 0.4H, minor), 3.12 (m, 1H), 3.11 (s, 1.8H, major), 2.99 (s,
1.2H,
minor), 1.36-1.33 (m, 6H).
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MS (M+1) 511.
EXAMPLE 4
6-isopropyl-8-(3-{ (E)-2-(1-methyl-lH-imidazol-2-yl)-2-[4-
(methylsulfonyl)phenyl]ethenyl }phenyl)quinoline
CH3
~ \ \ CH3
N
O I ~ -.N
N
H3C"
H3C
Example 4 was prepared by the following procedure.
Step 1: 6-isopropyl-8-(3-{ (E)-2-(1-methyl-lH-imidazol-2-yl)-2-[4-
(methylthio)phenyl] ethenyl } phenyl)quinoline
Following the procedure for Example 3 but substituting the ketone K2
for K5 as the starting material, 6-isopropyl-8-(3-{(E)-2-(1-methyl-lH-imidazol-
2-yl)-
2-[4-(methylthio)phenyl]ethenyl }phenyl)quinoline was obtained.
Step 2: 6-isopropyl-8-(3-{ (E)-2-(1-methyl-lH-imidazol-2-yl)-2-[4-
(methylsulfonyl)phenyl] ethenyl } phenyl)quinoline
Following the procedure used for the preparation of the boronate B1
(step 2 of Scheme 2) but substituting the sulfide obtained in the present step
1 for
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(E/Z)-2-(3-B romophenyl)-1-(1-methyl-1 H-imidazol-2-yl)-1- [4-
(methylthio)phenyl]ethene as the starting material, Example 4 was obtained.
NMR 1H (500 MHz in acetone-d6) a 8.77 (dd, 1H), 8.24 (dd, 1H), 7.88
(d, 2H), 7.71(d, 1H), 7.59 (d, 1H), 7.53 (d, 2H), 7.48 (d, 2H), 7.41 (dd, 1H),
7.28 (t,
1H), 7.23 (s, 1H), 7.15 (d, 1H), 7.07 (d, 1H), 6.95 (d, 1H), 3.51 (s, 3H),
3.10 (m, 1H),
2.99 (s, 3H), 1.32 (d, 6H).
MS: (m+2): 509.4
EXAMPLES 5 and 6
6-isopropyl-8-(3-{ (Z/E)-2-(4-fluorophenyl)-2-[4-
(methylsulfonyl)phenyl]ethenyl }phenyl)quinoline
CH3
~ \ \ CH3
N
H3C /S F
OO
Example 5
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CH3
~ \ \ CH3
N
F S=p
-
CHg
Example 6
Examples 5 and 6 were prepared by the following procedure.
Following the procedure for Example 1 but substituting the ketone K1 for K3 as
the
starting material, and purification by flash chromatography
(50%EtOAc/50%Hexanes) yielded Examples 5 and 6.
1VMR 'H (500MHz in acetone-d6) Example 5: Major (Z) isomer: a
8.78 (dd, 1H), 8.25 (dd, 1H), 7.93 (d, 2H), 7.72 (d, 1H), 7.55-7.40 (m, 6H),
7.35 (m,
2H), 7.25 (t, 1H), 7.23 (s, 1H), 7.11 (t, 2H), 7.05 (d, 1H), 3.12 (m, 1H),
2.96 (s, 3H),
1.34 (d, 6H).
NMR 'H (500MHz in acetone-d6) Example 6: Minor (E) isomer: a
8.78 (dd, 1H), 8.35 (dd, 1H), 7.93 (d, 2H), 7.72 (d, 1H), 7.65-7.55 (m, 3H),
7.45 (dd,
1H), 7.35-7.15 (m, 9H), 3.12 (m, 4H), 1.34 (d, 6H).
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EXAMPLE 7
2-(2- { (E/Z)-2- [3 -(6-i sopropyl-8 -quinolinyl)phenyl] -1- [4-
(methylsulfonyl)phenyl] ethenyl } -1, 3-thi azol-5-yl)-2-propanol
H3C
CH3
I \ \ CH3
N OH
CH3
N S
\ I / \
S,CH3
O O
Example 7 was prepared by following the procedure for Example 1 but
substituting the ketone K6 for K3 as the starting material. Purification by
flash
chromatography (100%EtOAc) yielded Example 7 as a mixture of isomers.
NMR 'H (400MHz in acetone-d6) a 8.80 (m, 1H), 8.30 (m, 1H), 8.05
(d(major), 1.44H), 7.93 (d(minor), 0.55H), 7.85 (s(major), 0.72H), 7.77
(s,(minor),
0.28H), 7.75-7.45 (m, 7H) 7.35 (t(minor), 0.28H), 7.28 (t,(major), 0.72H),
7.21
(d(minor), 0.28H), 7.10 (d(major), 0.72H), 4.7 (m, 1H), 3.15 (m, 1H), 3.15
(s(minor),
0.84), 2.99 (s(major), 2.16H), 1.60 (m, 6H), 1.35 (m, 6H).
MS (m+l): 569.6
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EXAMPLE 8
2-[8-(3- { (E/Z)-2-[5-(1-hydroxy-l-methylethyl)-1,3-thiazol-2-yl]-2-[4-
(methylsulfonyl)phenyl]ethenyl }phenyl)-6-quinolinyl]-2-methylpropanenitrile
H3C ~ N
I \ \ H3 CH3 CH
3
N
N S OH
\ / \
,CH3
O
Example 8 was prepared by following the procedure for Example 1 but
substituting the ketone K6 for K3 and the benzyl phosponate P3 for P2 as the
starting
materials. Purification by flash chromatography (20%CH2Cl2/80%EtOAc) yielded
Example 8 as a mixture of isomers.
NMR 1H (400MHz in acetone-d6) a 8.92 (m, 1H), 8.45 (m, 1H), 8.10
(m, 1H), 8.05 (m, 1H), 7.93 (m, 1H), 7.85 (m, 2H), 7.77-7.55 (m, XH), 7.40
(t(minor), 0.43H), 7.28 (t,(major), 0.57H), 7.21 (d(minor), 0.43H),
7.10(d(major),
0.57H), 4.67 (s,(major), 0.57H), 4.63 (s(minor), 0.43H), 3.15 (s(minor),1.3H),
2.99
(s(major), 1.7H), 1.90 (m, 6H), 1.65 (s,(major), 3.4H), 1.45 (s(minor), 2.6H).
MS (m+1): 594.6
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EXAMPLE 9
2-methyl-2-[ 8-(3- { (E)-2-(1-methyl-lH-imidazol-2-yl)-2-[4-
(methylsulfonyl)phenyl]ethenyl }phenyl)-6-quinolinyl]propanenitrile
H3C CH3
N
N
N
0~ N -
O H3C
H3C
Example 9 was prepared by the following procedure.
Step 1: 2-methyl-2-[8-(3-{ (E)-2-(1-methyl-lH-imidazol-2-yl)-2-[4-
(methylthio)phenyl]ethenyl}phenyl)-6-quinolinyl]propanenitrile was prepared by
following the procedure for Example 1 but substituting the ketone K2 for K3
and the
benzyl phosphonate P3 for P2 as the starting materials.
Step 2: 2-methyl-2-[8-(3-{(E)-2-(1-methyl-lH-imidazol-2-yl)-2-[4-
(methylsulfonyl)phenyl]ethenyl}phenyl)-6-quinolinyl]propanenitrile, Example 9,
was
prepared by following the procedure used for the preparation of the boronate
B1 (step
2 of Scheme 2) but substituting the sulfide obtained in present step 1 for
(E/Z)-2-(3-
Bromophenyl)-1-(1-methyl-lH-imidazol-2-yl)-1-[4-(methylthio)phenyl]ethene as
the
starting material. Example 9 was obtained after purification by flash
chromatography
(97%EtOAc/3%Et3N).
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NMR 'H (400MHz in acetone-d6) c7 8.92 (dd, 1H), 8.45 (dd, 1H), 8.10
(d, 1H), 7.93 (d, 2H), 7.76 (d, 1H), 7.60-7.50 (m, 5H), 7.38 (t, 1H), 7.35 (s,
1H), 7.19
(m, 1H), 7.10 (m, 1H), 6.95 (m, 1H), 3.55 (s, 3H), 3.00 (s, 3H), 1.85 (s, 6H).
MS (m+1): 533.3
EXAMPLE 10
6-[ 1-(methylsulfonyl)ethyl]-8-{ 3-[(E)-2-[4-(methylsulfonyl)phenyl]-2-(1,3-
thiazol-2-
yl)ethenyl]phenyl }quinoline
O 0 ~CH3
S
~ \ \ CH3
N
N
U
0~ 0:s
H3C
Example 10 was prepared by the following procedure. A mixture of
bromoquinoline Q2 (105mg, 0.33mmol), boronate B2 (236mg, 0.51mmol), Na2CO3
(2M, 0.65mL, 1.3mmol), Pd(OAc)2 (6.3mg, 0.028mmo1) and PPh3 (28mg,
0.1 lmmol) in 4mL of n-propanol was stirred at 90 C for 2h. The mixture was
cooled
to r.t., diluted with EtOAc, washed with brine, dried over Na2SO4, filtered
and
concentrated. Flash chromatography (Tol/Acetone; 4/1) and stirring in
Hexane/EtOAc yielded Example 10 (single isomer) as a white solid.
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1V1VIlZ 'H (400MHz, Acetone-d6) a 8.89 (dd, IH), 8.39 (dd, 1H), 8.07
(d, 1H), 8.03 (d, 2H), 7.94 (s, 1H), 7.86 (d, 1H), 7.71-7.68 (m, 3H) 7.62-7.60
(m,
2H), 7.55 (dd, 1H), 7.45 (s, 1H) 7.34 (t, 1H), 7.18 (d, 1H), 4.67 (q, 1H),
3.04 (s, 3H),
2.86 (s, 3H) 1.88 (s,3H)
MS (M + 1) 576.
EXAMPLE 11
6-[ 1-methyl-l-(methylsulfonyl)ethyl]-8-{ 3-[(E)-2-[4-(methylsulfonyl)phenyl]-
2-(1,3-
thiazol-2-yl)ethenyl]phenyl } quinoline
O 0
CH3
CH3
I \ \ CH3
~ /
N
/ I
\
O~ ~ / S Z
N
I
\ ~
D;S
H3C
Example 11 was prepared by following the procedure described in
Example 10 but substituting bromoquinoline Q3 for Q2 and using boronate B2.
Flash
chromatography (Tol/Acetone; 9/1) and stirring in EtOAc/Hex yielded Example 11
(single isomer) as a white solid.
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NMR 1H (400MHz, Acetone-d6): a 8.90 (dd, 1H), 8.41 (dd, 1H), 8.23
(s, 1H), 8.02-7.99 (d, 3H), 7.95 (s, 1H), 7.86 (d, 1H), 7.70 (d, 2H), 7.60-
7.54 (m, 4H),
7.32 (t, 1H), 7.13 (d, 1H), 3.00 (s, 3H), 2.69 (s, 3H), 1.96 (s, 6H)
MS (M+1) 523.
EXAMPLE 12
8-(3-{ (Z)-2-(1-methyl-lH-imidazol-2-yl)-2-[4-
(methylsulfonyl)phenyl]ethenyl }phenyl)-6-[1-(methylsulfonyl)ethyl]quinoline
O ~ ,CH3
~ \ \ CH3
N
/-~
N NCHs
\ I / \
S~CH3
6
Example 12 was prepared following the procedure described in
Example 10 using the bromoquinoline Q2 but substituting the boronate Bl for
boronate B2. Flash chromatography (95%CH2ClZ/5%EtOH) yielded the Example 12
compound.
NMR 1H (400MHz in acetone-d6) a 8.92 (dd, 1H), 8.45 (dd, 1H), 8.10
(s, 1H), 7.93 (d, 2H), 7.76-7.65 (m, 4H), 7.59 (dd, 1H), 7.39 (t, 1H), 7.26
(s, 1H),
7.18 (s, 1H), 7.05 (m, 2H), 4.70 (q, 1H), 3.40 (s, 311), 3.13 (s, 3H), 2.93
(s, 3H), 1.87
(d, 3H).
MS (m+l): 572.4
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EXAMPLE 13
8-(3-{ (Z)-2-(1-methyl-lH-imidazol-2-yl)-2-[4-
(methylsulfonyl)phenyl]ethenyl }phenyl)-6-[1-methyl-l-
(methyl sulfonyl)ethyl] quinoline
O ~ CH3
CH3
~ \ \ CH3
N
~~
N ~ N,CH3
\ I / \
S-CH3
O O
Example 13 was prepared following the procedure described in
Example 10 but substituting the bromoquinoline Q3 for Q2 and substituting the
boronate B1 for boronate B2. Flash chromatography (95%EtOAc/5% Et3N) produced
Example 13 (single isomer) as a foam.
NMR 1H (400MHz in acetone-d6) a 8.92 (dd, 1H), 8.45 (dd, 1H), 8.37
(d, 1H), 8.05 (d, 1H), 7.93 (d, 2H), 7.76 (d, 1H), 7.69 (d, 2H), 7.65 (d, 1H),
7.59 (dd,
1H), 7.38 (t, 1H), 7.31 (s, 1H), 7.18 (s, 1H), 7.05 (m, 2H), 3.40 (s, 3H),
3.13 (s, 3H),
2.70 (s, 3H), 1.95 (s, 6H).
MS (m+l): 586.2
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EXAMPLES 14 and 15
6-[ 1-methyl-l-(methylsulfonyl)ethyl]-8-(3-{ (E/Z)-2-(3-methyl-1,2,4-oxadiazol-
5-yl)-
2-[4-(methylsulfonyl)phenyl]ethenyl }phenyl)quinoline
H3C 0
"
S.CH3
I \ \ O
N CH3
N\-CH3
O S O_N/
H3C'
Example 14
HC OSCH3
3 O
~ \ \ CH3
N H3 ~-- N
N O
-CH3
O'~
Example 15
- S5 -
SUBSTITUTE SHEET (RULE 26)
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Examples 14 and 15 were prepared by the following procedure. A
solution of the aryl bromide AB5 (249mg, 0.57mmol), diboron pinacol ester
(167mg,
0.66mmol), [1,1'-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) (12mg,
0.015mmo1) and potassium acetate (176mg, 1.8mmo1) in DMF (N,N-
Dimethylformamide) (10mL) was degassed and stirred at 80 C for 3h. To that
resulting mixture at 25 C was then added the bromoquinoline Q3 (150mg,
0.46mmol), [1,1'-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) (12mg,
0.015mmo1) and sodium carbonate (0.6mL, 2M). After degassing, the mixture was
heated at 80 C overnight. The mixture was then cooled to r.t. quenched with
H20,
and extracted with EtOAc. The organic extracts were washed (H20, brine), dried
(MgSO4), filtered and concentrated. Purification by flash chromatography
(hexane:EtOAc:Et3N, 22:68:10 then hexane:EtOAc, 3:1) yielded both isomers
(Example 14 and Example 15).
NMR 1H (500MHz, Acetone-d6) Major(E) isomer (Example 14): a
8.91 (dd, 1H), 8.42 (dd, 1H), 8.25 (d, 1H), 8.12 (s, 1H), 8.02 (d, 1H), 8.00
(d, 2H),
7.70 (m, 3H), 7.64 (s, 1H), 7.55 (dd, 1H), 7.38 (t, 1H), 7.23 (d, 1H), 3.03
(s, 3H),
2.69 (s, 3H), 2.33 (s, 3H), 1.96 (s, 6H).
MS (M+1): 588.2
Minor(Z) isomer (Example 15): a 8.92 (dd, 1H), 8.45 (dd, 1H), 8.29
(d, 1H), 8.07 (d, 1H), 7.99 (d, 2H), 7.88 (s, 1H), 7.75 (in, 3H), 7.62 (s,
1H), 7.58 (q,
1H), 7.48 (t, 1H), 7.24 (d, 1H) 3.16 (s, 3H), 2.70 (s, 3H), 2.38 (s, 311),
2.00 (s, 6H).
MS (M+1): 588.2
Alternatively, Example 14 can be made by the following procedure:
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glycerol
FeSO4
MeSOzOH I\ A~N Br
I
gr S03Na NBS N CH3~
NH2 Br Br
NO2
B(OH)2
I S02Me
/ MeI \ S02Me N / t-BuONa / Pd/C CHO
Br N
Br
I \ \ S
S02Me
\ N
N
LNL]
N piperidine Me02S
\ CHO 1. EDC/HOBt N
N--
NOH Me02S
2 lI
/ \NH2 Example 14
PhSO20H
OH
O
MeO2S
Benzenesulfonic acid salt
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Step 1. Skraup Reaction
glycerol
m-N02PhSO3Na
MsOH ct~ix Br NH2 Br
To methanesulfonic acid (8-10 equiv) at 20 C was added sodium m-
nitrobenzenesulfonate (0.6-0.8 equiv), followed by iron sulfate heptahydrate
(0.01-
0.05 equiv). To the resulting mixture was added 2-bromo-4-methylaniline (1
equiv).
Glycerol (2-3 equiv) was added and the resulting solution was heated
at 120-140 C and aged until the reaction was complete.
The mixture was cooled to 70-90 C and diluted with water. The
solution was then cooled to about 20 C, and neutralized with aqueous NaOH and
sodium bicarbonate. MTBE (methyl t-butyl ether) was added and the mixture was
filtered and the phases were separated (the product was in the MTBE layer).
Step 2. Bromination
\ AIBN I Br
NBS N
Br Br
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The MTBE solution from step 1 was solvent switched to
chlorobenzene. After filtered through Silica gel and partially concentrated, N-
bromosuccinimide (NBS, 0.6-0.8 equiv) and 2,2'-azobisisobutylnitrile (AIBN,
0.01-
0.1 equiv) were added. The degassed mixture was heated at 55-85 C. The
resulting
mixture was diluted with cyclohexane. Additional NBS (0.3-0.5 equiv) and AIBN
(0.01-0.05 equiv) were added. The degassed mixture was heated at about 55-85 C
until reaction completed. The mixture was cooled at 10-40 C and diluted with
cyclohexane and aged. The solid was isolated by filtration.
Step 3. Sulfone Formation
(1H3SO2Na (1sO2Me N
Br Br
To a solution of bromomethyl-bromoquinoline (product from previous
step, 1 equiv) in DMF was added powdered sodium methanesulfinate (1.0-1.5
equiv)
at 10-60 C. The mixture was heated at about 50-70 C for 30min. The mixture
was
diluted with water while maintaining temp at about 50-70 C with vigorous
stirring,
then cooled to about 10-20 C and aged.. The mixture was filtered and the solid
washed sequentially with 1:4 DMF/water and then water and dried.
Step 4. Methylation
H
SO2CH3
SO2CHg NaOtBu I\ \ S02CHg NaOtBu (N)
MeI, DMF N MeI, DMF Br Br Br
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A solution of the sulfone (product from the previous step, 1 equiv) in
DMF was cooled to about -10 to 0 C. Sodium t-butoxide (-1 equiv) was added. A
solution of methyl iodide/DMF solution (-1 equiv of Mel) was added slowly
while
maintaining temperature at about -10 to 0 C.
A second portion of solid sodium t-butoxide (- 1 equiv) was added,
followed by methyl iodide/DMF solution (-1 equiv) was added while maintaining
the
temperature at -5 to 10 C (Additional base and Mel may be added if the
reaction
was not completed). The reaction was quenched by adition of water and the
product
crystallized, which was isolated and dried.
Step 5. Suzuki Coupling
SO2CHg B(OH)2 Pd/C I\ \ SO2CHg
+ N
Br ~ CHO K2C03/DMF
80 C
CHO
To a solution of the sulfone from the previous step (1 equiv) was added
Pd/C (5 or 10 w%, 0.005-0.1 equiv), potassium carbonate (2-3 equiv), and 3-
formyl
phenylboronic acid (1-2 equiv). The degassed reaction mixture was heated at 60-
120 C until the reaction was complete. The mixture was filtered and the
filtrate was
diluted with water. The product crystallized and was isolated by filtration
and dried.
Step 6. Oxadiazole
~ OH 1. EDC/HOBt
I ~ N
HOI~ j
Me02S ~ 0 2. i Me02S ~ N
H2N
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To the mixture of hydroxy benzotriazole ("HOBt") hydrate (1-1.5
equiv), 4-methylsulfonylphenylacetic acid (1 equiv) in acetonitrile was added
EDC
hydrochloride (1-1.5 equiv). The sluiry was aged at about 20-30 C for 30min.
Other N-OH compounds, such as N-hydroxyphthalimide, 2-
hydroxypyridine N-oxide, N-hydroxysuccinimide, can also. be used to replace
HOBt.
Other carbodiimides, such as dicyclohexylcarbodiimide and
diisopropylcarbodiimide
can be used to replace EDC hydrochloride (ethyl
dimethylaminopropylcarbodiimide
hydrochloride).
To the slurry was added acetamide oxime (1-1.5 equiv). The resulting
mixture was then heated at reflux until the reaction was complete. The
resulting
solution was concentrated and diluted with ethyl acetate. To the resulting
mixture
was washed with aqueous sodium bicarbonate. The solution was solvent switched
to
2-propanol and product crystallized upon cooling, which was isolated and
dried.
Step 7. Condensation to form Example 14
(<O2Me
N
S02Me
N piperidine
N + Me02S 1 -~ \
/ ~ ' \ I O
CHO N
Me02S
To a slurry of the aldehyde from step 5 above (1 equiv) in 2-propanol
was added the oxadiazole from step 6 above (1-1.5 equiv), followed by
piperidine
(0.2-1.5 equiv).
In place of 2-propanol, other solvents such as, for example, D1VIF,
acetonitrile, 1-propanol, toluene, esters, and other alcohols. Piperidine
serves as a
basic initiator. In place of piperidine, other amine bases, especially
secondary amines,
can be used.
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The resulting mixture was heated at reflux over molecular sieves until
reaction completed. After cooling, the product was isolated by filtration and
dried.
EXAMPLES 16 and 17
(E/Z)-3-{ 3-[6-(1-cyano-l-methylethyl)-8-quinolinyl]phenyl }-N-isopropyl-2-[4-
(methylsulfonyl)phenyl]-2-propenamide
H3C CH3
I \ \ ~
N
N
H
O~ 0 I
NY CHs
,S CH3
H3C
Example 16
H3C N
( \ \ CH3
N
H CH3
C N--C
Th:c I H3
H3
O/0
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Example 17
Examples 16 and 17 were prepared following the procedure described
previously for Examples 14 and 15 but substituting the aryl bromide AB2 for
AB5
and the bromoquinoline Q5 for Q3 as the starting materials. Examples 16 and 17
were obtained as a 4:1 mixture.
NMR 1H (500 MHz, Acetone-d6) Major(E) isomer (Example 16): a
8.89 (dd, 1H), 8.43 (dd, 1H), 8.09 (d, 1H), 7.90 (d, 214), 7.81 (d, 1H), 7.68
(s, 1H),
7.57 (m, 4 H), 7.45 (s, 111), 7.29 (t, 1H), 7.04 (d, 1 H), 6.71 (bd, 1H), 4.13
(m, 1H)
2.92 (s, 3H), 1.87 (s, 6H), 1.12 (d, 6H).
MS (M+1): 538.3
Minor(Z) isomer (Example 17): c9 8.93 (dd, 1H), 8.48 (dd, 1H), 8.14
(d, 1H), 7.94 (m, 4H), 7.85 (d, 2H), 7.70 (dd, 2H), 7.59 (q, 114), 7.50 (m, 2
H), 7.28
(s, 1H), 4.15 (m, 1H) 3.13 (s, 3H), 1.91 (s, 6H), 1.04 (d, 6H).
MS (M+1)': 538.3
EXAMPLE 18
8-(3-{ (E)-2-{ 3-[(4-methoxyphenoxy)methyl]-1,2,4-oxadiazol-5-yl }-2-[4-
(methylsulfonyl)phenyl]ethenyl }phenyl)-6-[1-methyl-l-
(methylsulfonyl)ethyl]quinoline
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H3C 0SCH3
I \ \ O
N CH3
O\N
S
O N/ H3C" "
0 O
O-CH3
Example 18 was prepared by the following procedure.
Step 1 (Scheme 3): (4-methoxyphenoxy)acetonitrile
A mixture of 4-methoxyphenol (lOg, 80mmo1), chloroacetonitrile
(7.OmL, 11 lmmol) and K2C03 (26g, 188mmo1) in acetone (150 mL) was stirred at
r.t. for 18h. The mixture was filtered, concentrated and purified by flash
chromatography (Hex:EtOAc, 4:1) to yield (4-methoxyphenoxy)acetonitrile as a
clear
oil.
Step 2 (Scheme 3): (4-methoxyphenoxy)acetamide oxime
A mixture of the (4-methoxyphenoxy)acetonitrile product (5.Og, 31mmo1) from
step
1, hydroxylamine hydrochloride (4.3g, 62mmol) and sodium acetate (5.1g,
62mmol)
in MeOH (100mL) was stirred at r.t. for 2h. The resulting mixture was filtered
on
Celite , concentrated, stirred in CHC13 for 18h and filtered. The resulting
solution
was concentrated to yield (4-methoxyphenoxy)acetamide oxime as a gum.
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Step 3 (Scheme 3, Oxadiazole OX2): 3-[(4-methoxyphenoxy)methyl]-
5- [4-(methylsulfonyl)benzyl]-1,2,4-oxadiazole
3-[(4-methoxyphenoxy)methyl]-5- [4-(methylsulfonyl)benzyl] -1,2,4-
oxadiazole was prepared following the procedure as described in Scheme 3 for
AB5
step 1(OXl) but substituting the (4-methoxyphenoxy)acetamide oxime from step 2
above for acetamide oxime and heating the reaction at 90 C for 6h.
Purification by
flash chromatography (Hex:EtOAc, 3:2 to 1:4) yielded the desired material as a
pale
brown solid.
Step 4: 3-{ 6-[1-methyl-l-(methylsulfonyl)ethyl]-8-
quinolinyl }benzaldehyde
To bromoquinoline Q3 (10.1g, 30.9mmol) 3-formylbenzeneboronic
acid (5.8g, 38.7mmol), tetrakis(triphenylphosphine)-palladium (0) (2.1g
1.86mmol)
and sodium carbonate (39mL, 2M ) was added DME (330mL). After degassing, the
mixture was heated at 80 C overnight. After cooling to r.t. the resulting
mixture was
quenched with H20, and extracted with EtOAc. The organic extracts were washed
(H20, brine), dried (MgSO4), filtered and concentrated. Stirring in ether,
followed by
isolation by filtration gave 3-{6-[1-methyl-l-(methylsulfonyl)ethyl]-8-
quinolinyl } benzaldehyde.
Step 5: 8-(3-{ (E)-2-{ 3-[(4-methoxyphenoxy)methyl]-1,2,4-oxadiazol-
5-yl }-2-[4-(methylsulfonyl)phenyl]ethenyl }phenyl)-6-[1-methyl-l-
(methylsulfonyl)ethyl] quinoline
A mixture of the product from present step 4 (150mg, 0.42mmol), the
oxadiazole OX2 from present step 3 above (175mg, 0.47mmol) and piperidine
(0.1mL, l.Ommol) in toluene (0.6mL) was heated at 120 C for 3h. The mixture
was
purified by flash chromatography (Hex:EtOAc, 3:2 to 1:4) to yield Example 18
as a
foam.
1VMR 1H (400MHz, Acetone-d6) 8 8.90 (q, 1H), 8.42 (q, 1H), 8.24 (d,
1H), 8.20 (s, 1H), 8.02 (m, 3H), 7.75-7.66 (m, 4H), 7.55 (q, 1H), 7.39 (t,
1H), 7.25 (d,
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1H), 7.00 (d, 2H), 6.87 (d, 2H), 5.17 (s, 2H), 3.73 (s, 3H), 3.03 (s, 3H),
2.80 (s, 3H),
1.96 (s, 6H).
EXAMPLE 19
(5-{ (E)-2-(3-{ 6-[ 1-methyl-l-(methylsulfonyl)ethyl]-8-quinolinyl }phenyl)-1-
[4-
(methylsulfonyl)phenyl]ethenyl }-1,2,4-oxadiazol-3-yl)methanol
H3C 0SCH3
I \ \ O
N CH3
. / ~
O\
N
HO~ I ~ N /
C~S s O OH
Example 19 was prepared by the following procedure. To a solution
of the Example 18 compound (250mg, 0.35mmo1) in acetonitrile:water (4:1, 8 mL)
was added CAN (330mg, 0.62mmol) in two portions at r.t. After 3h at r.t., the
mixture was diluted with saturated NaHCO3 solution, diluted with water and
extracted with EtOAc. The organic extracts were washed (H20), (brine), dried
(MgSO4), filtered and concentrated. Purification by flash chromatography
(Hex:EtOAc, 3:7) yielded (5-{(E)-2-(3-{6-[1-methyl-l-(methylsulfonyl)ethyl]-8-
quinolinyl }phenyl)-1-[4-(methylsulfonyl)phenyl]ethenyl }-1,2,4-oxadiazol-3-
yl)methanol as a pale yellow foam.
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NMR 1H (400MHz, Acetone-d6) a 8.90 (q, 1H), 8.42 (q, 1H), 8.25 (d,
1H), 8.15 (s, 1H), 8.02 (m, 3H), 7.73-7.65 (m, 4H), 7.55 (q, 1H), 7.38 (t,
111), 7.23 (d,
1H), 4.67 (m, 3H), 3.04 (s, 3H), 2.82 (s, 3H), 1.96 (s, 6H).
EXAMPLE 20
(E)-N-isopropyl-3-(3-{ 6-[ 1-methyl-l-(methylsulfonyl)ethyl]-8-quinolinyl }
phenyl)-2-
[4-(methylsulfonyl)phenyl]-2-propenamide
H3C 0
~S,CH3
I \ \ O
N CH3
H3CCH3
Nr
p
H3C/ C
Example 20 was prepared by following the procedure described above
for Examples 14 and 15 but substituting the aryl bromide AB2 for AB5, and
using the
bromoquinoline Q3, as the starting materials.
NMR 1H (300MHz, Acetone-d6) a 8.89 (dd, 1H), 8.41 (dd, 1H), 8.22
(d, 1H), 7.99 (d, 1H), 7.88 (d, 2H), 7.67 (s, 1H), 7.53 (m, 4H), 7.43 (s, 1H),
7.28 (t,
1H), 7.05 (d, 1H), 6.71 (bd, 1H), 4.14 (m, 1H) 2.9 (s, 3H), 1.95 (s, 6H), 1.13
(d, 6H).
MS(M+1): 591.3
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EXAMPLE 21
(E)-3-{ 3-[6-(1-cyano-l-methylethyl)-8-quinolinyl]phenyl }-2-[4-
(methylsulfonyl)phenyl]-2-propenoic acid
H3C CH3
N
I \ \ \
i /
N
/ I
\
I OH
~ \
OS / O
H3C" \O
Example 21 was prepared by following the procedure described above
for Examples 14 and 15 but substituting the aryl bromide AB1 for AB5 and the
bromoquinoline Q5 for Q3 as the starting materials.
NMR 1H (500MHz, Methanol) a 8.8 (dd, 1H), 8.38 (dd, 1H), 8.04 (d,
2H), 7.88 (d, 2H), 7.66 (d, 1H), 7.55 (m, 4H), 7.36 (t, 1H), 7.29 (s, 1H),
7.18 (d, 1H),
2.93 (s, 3H), 1.88 (s, 6H).
MS (M-C02): 451.4 (negative ion).
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EXAMPLE 22
2-methyl-2-[8-(3-{ (E)-2-(3-methyl-1,2,4-oxadiazol-5-yl)-2-[4-
(methylsulfonyl)phenyl]ethenyl }phenyl)-6-quinolinyl]propanenitrile
H3C CH3
I \ \ ~
N
N
O\
O\ N /N
S
H3C ' CH3
Example 22 was prepared by following the procedure described for
Examples 14 and 15 using the aryl bromide AB5 and substituting the
bromoquinoline
Q5 for Q3 as the starting materials.
NMR 1H (500 MHz, Acetone-d6) a 8.90 (dd, 1H), 8.43 (dd, 1H), 8.1
(d, 2H), 8.01 (d, 2H), 7.83 (d, 1H), 7.71 (t, 3H), 7.66 (s, 1H), 7.56 (q,
111), 7.55 (dd,
1H), 7.38 (t, 1H), 7.22 (d, 1H), 3.03 (s, 3H), 2.33 (s, 3H), 1.87 (s, 6H)
MS (M+1): 535.2
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EXAMPLE 23
(E)-3-{ 3-[6-(1-cyano-l-methylethyl)-8-quinolinyl]phenyl }-2-[4-
(methylsulfonyl)phenyl]-2-propenamide
H3C CH3
N
~ \ \ \
N
NH2
OS o
H3C~ ~0
Example 23 was prepared by following the procedure described above
for Examples 14 and 15 but substituting the aryl bromide AB3 for AB5 and the
bromoquinoline Q5 for Q3 as the starting materials, the title compound was
obtained.
1V1VIR 1H (500MHz, Acetone-d6) a 8.89 (dd, 1H), 8.43 (dd, 1H), 8.08
(d, 1H), 7.93 (d, 2H), 7.8 (d, 2H), 7.6 (m, 4H), 7.48 (s, 1H), 7.31 (t, 1H),
7.08 (d,
1H), 6.6 (bs, 1H), 6.7 (bs, 1H), 2.93 (s, 3H), 1.87 (s, 6H)
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EXAMPLE 24
(E)-N-(tert-butyl)-3-{ 3-[6-(1-cyano-l-methylethyl)-8-quinolinyl]phenyl }-2-[4-
(methylsulfonyl)phenyl] -2-propenami de
H3C
CH3
( \ \ ~
N
~ /
N
/ I
\
~ N CH3
\ CH3
O~ I / O CH3
H3C-S'-0
Example 24 was prepared by following the procedure described for
Examples 14 and 15 but substituting, the aryl bromide AB4 for AB5 and the
bromoquinoline Q5 for Q3 as the starting materials.
NMR 'H (500MHz, Acetone-d6) c7 8.89 (dd, 1H), 8.43 (dd, 1H), 8.08
(d, 1H), 7.92 (d, 2H), 7.79 (d, 1H), 7.58 (m, 5H), 7.45 (s, 1H), 7.29 (t, 1H),
7.04 (d,
1H), 6.4 (bs, 1H), 2.93 (s, 3H), 1.87 (s, 6H), 1.36 (s, 9H).
MS(M+1)553.
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EXAMPLE 25
(E)-3-[3-(6-isopropyl-8-quinolinyl)phenyl]-2-[4-(methylsulfonyl)phenyl]-2-
propenoic
acid
CH3
~ \ \ CH3
N
I OH
,~ o
H3C-S-~10
Example 25 was prepared by following the procedure described for
Examples 14 and 15 but substituting the aryl bromide AB1 for AB5, and 5-
isopropyl-
8-bromoquinoline (described in International Patent Publication W09422852) for
Q3, as the starting materials.
NMR 1H (500MHz, Acetone-d6) 7 8.69 (dd, 1H), 8.26 (dd, 1H), 7.85
(s, 1H), 7.83 (d, 2H), 7.68 (s, 1H), 7.51 (d, 2H), 7.49 (m, 2H), 7.36 (dd,
1H), 7.31 (t,
1H), 7.20 (s, 1H), 7.13 (d, 1H), 3.1 (m, 1H), 2.93 (s, 3H), 1.36 (d, 6H).
MS(M+1)472.
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EXAMPLE 26
6-isopropyl-8-(3-{ (E)-2-(3-methyl-1,2,4-oxadiazol-5-yl)-2-[4-
(methylsulfonyl)phenyl]ethenyl }phenyl)quinoline
CH3
~ \ \ CH3
N /
/ I
\
~
O
\ I .
O~ N
~ / N ~
H3C-S'~*O ~
CH3
Example 26 was prepared by following the procedure described for
Examples 14 and 15 using the aryl bromide AB5, and substituting 5-isopropyl-8-
bromoquinoline (described in International Patent Publication W09422852) for
Q3
as the starting materials.
1VMR 1H (500MHz, Acetone-d6) 8 8.80 (dd, 1H), 8.29 (dd, 1H), 8.12
(s, 1H), 8.03 (d, 2H), 7.76 (s, 1H), 7.73 (m, 3H), 7.59 (s, 1H), 7.53 (d, 1H),
7.47 (q,
1H), 7.36 (t, 1H), 7.22 (d, 1H), 3.1 (m, 1H), 2.93 (s, 3H), 2.33 (s, 3H) 1.36
(d, 6H).
MS (M+l) 510.
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EXAMPLE 27
(E)-3-(3-{ 6-[ 1-methyl-l-(methylsulfonyl)ethyl]-8-quinolinyl } phenyl)-2-[4-
(methylsulf onyl)phenyl] -1-(1-pyrroli dinyl)-2-propen-1-one
H3C CH3
gCH3
~1\\
N O0
0 \ N
O
H3C-S"0 >
Example 27 was prepared by the following procedure.
Step 1: (E)-3-(3-{ 6-[1-methyl-l-(methylsulfonyl)ethyl]-8-
quinolinyl }phenyl)-2-[4-(methylsulfonyl)phenyl]-2-propenoic acid
A mixture of 3-{6-[1-methyl-l-(methylsulfonyl)ethyl]-8-
quinolinyl}benzaldehyde from step 4 of Example 18 (2.33g, 6.60mmo1), 4-
(methylsulfonyl)phenyl acetic acid (1.71g, 7.98mmol) and piperidine (0.20m1,
1.98mmol) in lOmL of toluene was refluxed for 2 days. The mixture was cooled
to
r.t., diluted with CH2ClZ, subjected to flash chromatography
(CH2Cl2/EtOAc/AcOH,
50/50/1) and finally stirred with (Et20/CH2CI2) and isolated to give (E)-3-(3-
{6-[1-
methyl-l-(methylsulfonyl)ethyl]-8-quinolinyl } phenyl)-2-[4-
(methylsulfonyl)phenyl]-
2-propenoic acid (single isomer) as a white solid.
NMR 1H (400MHz, Acetone-d6): a 8.89 (dd, 1H), 8.39 (dd, 1H), 8.07
(d, 1H), 8.03 (d, 2H), 7.94 (s, 1H), 7.86 (d, 1H), 7.71-7.68 (m, 3H) 7.62-7.60
(m, 2H),
7.55 (dd, 1H), 7.45 (s, 1H) 7.34 (t, 1H), 7.18 (d, 1H), 4.67 (q, 1H), 3.04 (s,
3H), 2.86
(s, 3H) 1.88 (s,3H).
MS (M + 1) 576.
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Step 2: (E)-3-(3-{ 6-[l-methyl-l-(methylsulfonyl)ethyl]-8-
quinolinyl }phenyl)-2-[4-(methylsulfonyl)phenyl]-1-(1-pyrrolidinyl)-2-propen-l-
one
A mixture of (E)-3-(3-{6-[1-methyl-l-(methylsulfonyl)ethyl]-8-
quinolinyl }phenyl)-2-[4-(methylsulfonyl)phenyl]-2-propenoic acid (104mg,
0.19mmo1) from the present step 1 above, pyrrolidine (24 L, 0.29mmol), EDCI (1-
(3-
Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride) (55mg, 0.29mmol) and
HOBt (1-Hydroxybenzotriazole hydrate) (34mg, 0.25mmol) in lml of DMF was
stirred at r.t. for 12h. The mixture was diluted with EtOAc, washed with NH4C1
(sat),
H20 (3x), brine, dried over Na2SO4, filtered and concentrated. Stirring in
EtOAc/Hex
yielded Example 27 as a white solid.
NMR 1H (400MHz, Acetone-d6): a 8.88 (dd, 1H), 8.40 (dd, 111), 8.22
(d, 1H), 8.98 (d, 1H), 7.88 (d, 2H), 7.67 (d, 2H), 7.60 (d, 1H) 7.55-7.52 (m,
2H) 7.34
(t, 1H), 7.18 (d, 1H), 7.03 (bs, NH) 3.58 (bs, 2H), 3.44 (bs, 2H), 3.02 (s,
3H), 2.69 (s,
3H) 1.95 (s, 6H), 1.88 (bs, 4H).
MS (M + 1) 603.
EXAMPLE 28
(E)-N-cyclopropyl-3-(3-{ 6-[1-methyl-l-(methylsulfonyl)ethyl]-8-quinolinyl
}phenyl)-
2-[4-(methylsulfonyl)phenyl]-2-propenamide
H3C CH3
SCH3
~ [\\
N OO
H
N
O~ 0
H3C,S~"~O
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Example 28 was prepared by following the procedure for step 2 of
Example 27 but substituting cyclopropyl amine for pyrrolidine, thus yielding a
white
solid.
NMR 1H (400 MHz, acetone-d6): a 8.89 (dd, 114), 8.41 (dd, 1 H), 8.23
(d, 1H), 7.98 (d, 1H), 7.87 (d, 2H), 7.68 (s, 1H), 7.59-7.53 (m, 4H), 7.43 (s,
1H), 7.29
(t, 1H), 7.04 (d, 1H), 6.94 (bs, 1H), 2.89 (s, 3H), 2.84-2.80 (m, 1H), 2.69
(s, 3H),
1.96 (s, 6H), 0.67-0.63 (m, 2H), 0.49-0.45 (m, 2H).
MS(M+1)589.
EXAMPLE 29
(E)-N-(tert-butyl)-3-(3-{ 6-[1-methyl-l-(methylsulfonyl)ethyl]-8-quinolinyl
}phenyl)-
2- [4-(methylsulfonyl)phenyl] -2-propenamide
H3C CH3
SCH3
~]~-,
N O0
N CH3
~CH3
~~ O CH3
H3C-S,:~10
Example 29 was prepared as a white solid by following the procedure
for step 2 of Example 27 but substituting t-butyl amine amine for pyrrolidine.
NMR 'H (400MHz, acetone-d6): a 8.89 (dd, 1H), 8.41 (dd, 1H), 8.23
(d, 1H), 7.98 (d, 1H), 7.90 (d, 2H), 7.59-7.53 (m, 5H), 7.43 (s, 1H), 7.30 (t,
1H), 7.05
(d, 1H), 6.43 (bs, 1H), 2.94 (s, 314), 2.69 (s, 3H), 1.96 (s, 6H), 1.36 (s,
911)
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MS (M+l) 606.
EXAMPLE 30
8- { 3-[2,2-bis(4-chlorophenyl)vinyl]phenyl }-6-isopropylquinoline
CH3
itc, CH3
C
I Example 30 was prepared by the following procedure. To a mixture
of the benzylphosphonate P2 (100mg, 0.25mmol), 4,4'-dichlorobenzophenone
(63mg,
0.25mmo1),) in THF (2mL) at r.t. was added potassium t-butoxide (1M, THF,
0.35mL, 0.35mmo1). After lh at r.t., the mixture was diluted with water/NH4.C1
and
extracted with EtOAc. The organic extracts were washed (H20), (brine), dried
(MgSO4), filtered and concentrated. Purification by flash chromatography
(Hex:EtOAc, 8:2) yielded Example 30 as a white foam.
NMR 'H (300MHz, acetone-d6) a 8.79 (dd, 1H), 8.28 (dd, 1H), 7.74
(d, 1H), 7.60 (d, 1H), 7.48-7.25 (m, 12H), 7.20-7.16 (m, 2H) 3.13 (hept, 1H),
1.36
(d, 6H).
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EXAMPLES 31 AND 32
6-isopropyl-8-(3-{ (E/Z)-2-(6-methyl-3-pyridinyl)-2-[4-
(methylsulfonyl)phenyl]ethenyl }phenyl)quinoline
CH3
CH3H3C "
Js
1 0
CH3
Example 31
CH3
I \ \ CH3
N
I \ I N
3
O;S CH3
CH3
Example 32
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Examples 31 and 32 were prepared by following the procedure
described for Example 30 but substituting the ketone K7 for 4,4'-
dichlorobenzophenone and using the benzylphosphonate P2 as the starting
materials.
1VMR 1H (300MHz, Acetone-d6) (E) isomer (Example 31): a 8.79 (dd,
1H), 8.43 (d, 1H), 8.27 (dd, 1H), 7.95 (d, 2H), 7.73 (d, 1H), 7.57-7.43 (m,
7H),
7.32-7.19 (m, 3H), 7.10 (d, 1H), 3.15 (hept, 1H), 2.98 (s, 3H), 1.34 (d, 6H).
(Z) isomer (Example 32): c9 8.79 (dd, 1H), 8.35 (d, 1H), 8.28 (dd, 1H),
7.92 (d, 2H), 7.74 (d, 1H), 7.61-7.30 (m, 10H), 7.19 (d, 1H), 3.13 (s, 3H),
3.11
(hept, 1H), 1.35 (d, 6H).
EXAMPLES 33 AND 34
6-isopropyl-8-(3-{ (E/Z)-2-(5-methyl-2-pyridinyl)-2-[4-
(methylsulfonyl)phenyl]ethenyl }phenyl)quinoline
CH3
I \ \ CH3
N ~
/
\
N I
~ \ ~ \
C / / S: 0
Hs 0
CH3
Example 33
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CH3
CFi3o;S 3
j
CHg
Example 34
Examples 33 and 34 were prepared by following the procedure
described for Example 30 but substituting the ketone K8 for 4,4'-
dichlorobenzophenone and using the benzylphosphonate P2 as the starting
materials.
NNIR 1H (300MHz, Acetone-d6) (E) isomer (Example 33): a 8.80 (dd,
1H), 8.48 (s, 1H), 8.28 (dd, 1H), 7.99-7.96 (m, 3H), 7.97 (m, 1H), 7.74 (d,
1H), 7.61-
7.44 (m, 6H), 7.27 (t, 1H), 7.07 (d, 1H), 6.97 (d, 1H), 3.15 (hept, 1H), 2.96
(s, 3H),
1.36 (d, 6H).
NMR 'H (300MHz, Acetone-d6) (Z) isomer (Example 34): a 8.79 (dd,
1H), 8.52 (s, 1H), 8.29 (dd, 1H), 7.89 (d, 2H), 7.75 (d, 1H), 7.65-7.54 (m,
4H), 7.47
(dd, 1H), 7.42-7.23, (m, 5H), 7.11 (d, 1H), 3.12 (s, 3H), 3.12 (hept, 1H),
1.36 (d, 6H).
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EXAMPLE 35
8-(3-{ 2,2-bis [4-(methylsulfonyl)phenyl] vinyl } phenyl)-6-isopropylquinoline
CH3
( \ \ CH3
N ~
/ I
\
~
\ \
0;S S~
O1- I / I / ~CH3
CH3 0 0
Example 35 was prepared by following the procedure described for
Example 30 but substituting the ketone K9 for 4,4'-dichlorobenzophenone and
using
the benzylphosphonate P2 as the starting materials.
NMR 1H (500MHz, Acetone-d6): a 8.80 (dd, 1H), 8.29 (dd, 1H), 7.98
(d, 2H), 7.93 (d, 2H), 7.75 (d, 1H), 7.61 (d, 2H), 7.59-7.56 (m, 3H), 7.50 (d,
1H),
7.48-7.44 (m, 3H) 7.30 (t, 1H), 7.12 (d, 1H), 3.14 (hept, 1H), 3.13 (s, 3H),
2.97(s,
3H), 1.35 (d, 6H).
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EXAMPLES 36 AND 37
2-methyl-2-[8-(3-{ (E/Z)-2-(5-methyl-2-pyridinyl)-2-[4-
(methylsulfonyl)phenyl]ethenyl }phenyl)-6-quinolinyl]propanenitrile
H3C CH3
I
Ni / ~ N
H \ \ ~
/ I
\
N
I ~ I \
/ / S:O
3C
C O
Example 36
C CH3
N
HIN
O O%S 3
CH3
Example 37
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Examples 36 and 37 were prepared by following the procedure
described for Example 30 but substituting the ketone K8 for 4,4'-
dichlorobenzophenone and substituting the benzylphosphonate P3 for P2 as the
starting materials.
NMR 1H (500MHz, Acetone-d6) (E) isomer (Example 36): a 8.90 (dd,
1H), 8.47 (s, 1H), 8.43 (dd, 1H), 8.08 (d, 1H), 8.00 (s, 1H), 7.97 (d, 2H),
7.83 (d,
1H) 7.57-7.53 (m, 5H), 7.50 (s, 1H), 7.28 (t, 1H), 7.06 (d, 1H), 6.96 (d, 1H),
2.96 (s,
3H), 2.33 (s, 3H), 1.88 (s, 6H).
NMR 1H (300NIHz, Acetone-d6) (Z) isomer (Example 37): a 8.89 (dd,
1H), 8.51 (s, 1H), 8.45 (dd, 1H), 8.09 (d, 1H), 7.89 (d, 2H), 7.72 (d, 1H),
7.62-
7.56 (m, 5H), 7.43-7.42 (m, 2H) 7.30 (t, 111), 7.25 (d, 1H), 7.10 (d, 1H),
3.11 (s,
3H), 2.34 (s, 3H), 1.87 (s, 6H).
EXAMPLE 38
2-[8-(3-{ 2,2-bis[4-(methylsulfonyl)phenyl]vinyl }phenyl)-6-quinolinyl]-2-
methylpropanenitrile
H3C CHs
I \ \ ~
N
N
\
O_~ I / ~ / ~CH3
O/CH3 O 0
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Example 38 was prepared by following the procedure described for
Example 30 but substituting the ketone K9 for 4,4'-dichlorobenzophenone and
substituting the benzylphosphonate P3 for P2 as the starting materials.
NMR 1H (500MHz, Acetone-d6): a 8.90 (dd, 1H), 8.44 (dd, 1H), 8.09
(d, 1H), 7.97 (d, 2H), 7.92 (d, 211), 7.81 (d, 1H), 7.61 (d, 2H) 7.58-7.55 (m,
3H),
7.53 (s, 1H), 7.44 (s, 1H), 7.32 (t, 1H), 7.13 (d, 1H), 6.96 (d, 1H), 3.13 (s,
3H), 2.97
(s, 3H), 1.86 (s, 6H).
EXAMPLE 39
2-methyl-2-(8-{ 3-[(E)-2-[4-(methylsulfonyl)phenyl]-2-(2-
pyridinyl)ethenyl]phenyl }-
6-quinolinyl)propanenitrile
H3C CH3
N
2-N
O
/ O
OCH3
Example 39 was prepared by following the procedure described for
Example 30 but substituting the ketone K10 for 4,4'-dichlorobenzophenone and
substituting the benzylphosphonate P3 for P2 as the starting materials.
NMR 1H (300MHz, Acetone-d6): 7 8.90 (dd, 1H), 8.45 (dd, 1H),
8.11-8.09 (m, 2H), 7.84-7.80 (m, 3H), 7.72-7.69 (m, 1H), 7.63-7.52 (m, 5H),
7.43-
7.38 (m, 2H), 7.33 (t, 1H) 7.28 (s, 1H), 7.14 (d, 1H), 2.97 (s, 3H), 1.86 (s,
6H)
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EXAMPLES 40 AND 41
6-[ 1-methyl-l-(methylsulfonyl)ethyl]-8-(3- { (E/Z)-2-(5-methyl-2-pyridinyl)-2-
[4-
(methylsulfonyl)phenyl]ethenyl }phenyl)quinoline
H3C CH3
~ \ \ "o
N / C/ CHs
/ I
\
N I
~ \ ~ \ ~O
H3C / / ~S"'CH
0 3
Example 40
H3C CH3
~ \ \ S5~,o
N 0~ CH3
N
H3C'S' CH3
O
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Example 41
Examples 41 and 42 were prepared by following the procedure
described in Example 10 but substituting bromoquinoline Q3 for Q2 and
substituting
boronate B3 for boronate B2.
NMR 1H (400MHz, Acetone-d6) (E) isomer (Example 40): a 8.91
(dd, 1H), 8.45 (s, 1H), 8.41 (dd, 1H), 8.23 (d, 1H), 8.01-8.00 (m, 2H), 7.95
(d,
2H), 7.57-7.54 (m, 4H), 7.51 (d, 1H) 7.49 (s, 1H), 7.28 (t, 1H), 7.07 (d, 1H),
6.96
(d, 1H), 2.94 (s, 3H), 2.69 (s, 3H), 2.33 (s, 3H), 1.97 (s, 6H).
1VMR 1H (400MHz, Acetone-d6) (Z) isomer (Example 41): c9 8.88 (dd,
1H), 8.49 (s, 1H), 8.42 (dd, 1H), 8.24 (dd, 1H), 7.94 (d, 114), 7.88 (d, 2H),
7.61-
7.55 (m, 514), 7.47 (s, 1H), 7.40 (s, 1H), 7.29 (t, 1H), 7.24 (d, 114), 7.06
(d, 1H),
3.12 (s, 3H), 2.68 (s, 3H), 2.33 (s, 3H), 1.96 (s, 6H).
EXAMPLE 42
2-(6-{ (E)-2-(3-{ 6-[1-methyl-l-(methylsulfonyl)ethyl]-8-quinolinyl }phenyl)-1-
[4-(methylsulfonyl)phenyl]ethenyl }-3-pyridinyl)-2-propanol
H3C CH3
gCH3
I I O
N O
N
H3C CH3
S~
HO CH3 ~
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Example 42 was prepared by following the procedure described in
Example 10 but substituting bromoquinoline Q3 for Q2 and substituting boronate
B4
for boronate B2.
1VMR 1H (500 MHz, Acetone-d6): a 8.91 (dd, 1H), 8.80 (d, 1H), 8.42
(dd, 1H), 8.23 (d, 1H), 8.03-8.01 (m, 2H), 7.96 (d, 1H), 7.82 (dd, 1H), 7.58-
7.54 (m,
4H), 7.51 (s, 1H), 7.29 (t, 1H), 7.08 (d, 1H), 7.01 (d, 1H), 4.31 (s, 1H),
2.96 (s, 3H),
2.70 (s, 31=1), 1.96 (s, 6H), 1.56 (s, 6H).
EXAMPLE 43
N
N I
S
0
p/I
Example 43 was prepared following the procedure described
previously for Examples 14 and 15 but substituting the aryl bromide AB6 for
AB5
and the bromoquinoline Q5 for Q3 as the starting materials.
Additional Examples are the following:
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0
O~
N~ S
\ / \
S
O/ p
O
gl ~
I IO
N
O
\ / \
S
O//~O
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O
SI /
I O
N 0
O~ S
S
0~0~
0
S
o~
N /
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SUBSTITUTE SHEET (RULE 26)
CA 02393749 2002-06-07
WO 01/46151 PCT/CA00/01559
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SUBSTITUTE SHEET (RULE 26)
CA 02393749 2002-06-07
WO 01/46151 PCT/CA00/01559
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CA 02393749 2002-06-07
WO 01/46151 PCT/CA00/01559
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CA 02393749 2002-06-07
WO 01/46151 PCT/CA00/01559
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CA 02393749 2002-06-07
WO 01/46151 PCT/CA00/01559
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- 124 -
SUBSTITUTE SHEET (RULE 26)
CA 02393749 2002-06-07
WO 01/46151 PCT/CA00/01559
N
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-125-
SUBSTITUTE SHEET (RULE 26)
CA 02393749 2002-06-07
WO 01/46151 PCT/CA00/01559
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-126-
SUBSTITUTE SHEET (RULE 26)
CA 02393749 2002-06-07
WO 01/46151 PCT/CA00/01559
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CA 02393749 2002-06-07
WO 01/46151 PCT/CA00/01559
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CA 02393749 2002-06-07
WO 01/46151 PCT/CA00/01559
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CA 02393749 2002-06-07
WO 01/46151 PCT/CA00/01559
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-130-
SUBSTITUTE SHEET (RULE 26)
CA 02393749 2002-06-07
WO 01/46151 PCT/CA00/01559
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CA 02393749 2002-06-07
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-132-
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CA 02393749 2002-06-07
WO 01/46151 PCT/CA00/01559
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-133-
SUBSTITUTE SHEET (RULE 26)
CA 02393749 2002-06-07
WO 01/46151 PCT/CA00/01559
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- 134 -
SUBSTITUTE SHEET (RULE 26)
CA 02393749 2002-06-07
WO 01/46151 PCT/CA00/01559
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-135-
SUBSTITUTE SHEET (RULE 26)
CA 02393749 2002-06-07
WO 01/46151 PCT/CA00/01559
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-136-
SUBSTITUTE SHEET (RULE 26)
CA 02393749 2002-06-07
WO 01/46151 PCT/CA00/01559
N
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-137-
SUBSTITUTE SHEET (RULE 26)
CA 02393749 2002-06-07
WO 01/46151 PCT/CA00/01559
N
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-138-
SUBSTITUTE SHEET (RULE 26)
CA 02393749 2002-06-07
WO 01/46151 PCT/CA00/01559
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SUBSTITUTE SHEET (RULE 26)
CA 02393749 2002-06-07
WO 01/46151 PCT/CA00/01559
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SUBSTITUTE SHEET (RULE 26)
CA 02393749 2002-06-07
WO 01/46151 PCT/CA00/01559
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-141-
SUBSTITUTE SHEET (RULE 26)
CA 02393749 2002-06-07
WO 01/46151 PCT/CA00/01559
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-142-
SUBSTITUTE SHEET (RULE 26)
CA 02393749 2002-06-07
WO 01/46151 PCT/CA00/01559
N
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-143-
SUBSTITUTE SHEET (RULE 26)
CA 02393749 2002-06-07
WO 01/46151 PCT/CA00/01559
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-144-
SUBSTITUTE SHEET (RULE 26)
CA 02393749 2002-06-07
WO 01/46151 PCT/CA00/01559
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-145-
SUBSTITUTE SHEET (RULE 26)
CA 02393749 2002-06-07
WO 01/46151 PCT/CA00/01559
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-146-
SUBSTITUTE SHEET (RULE 26)
CA 02393749 2002-06-07
WO 01/46151 PCT/CA00/01559
/ \ N
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-147-
SUBSTITUTE SHEET (RULE 26)
CA 02393749 2002-06-07
WO 01/46151 PCT/CA00/01559 I
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-148-
SUBSTITUTE SHEET (RULE 26)
CA 02393749 2002-06-07
WO 01/46151 PCT/CA00/01559
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-149-
SUBSTITUTE SHEET (RULE 26)
CA 02393749 2002-06-07
WO 01/46151 PCT/CA00/01559
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-150-
SUBSTITUTE SHEET (RULE 26)
CA 02393749 2002-06-07
WO 01/46151 PCT/CA00/01559
N+/O-
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-151-
SUBSTITUTE SHEET (RULE 26)
CA 02393749 2002-06-07
WO 01/46151 PCT/CA00/01559
N
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-152-
SUBSTITUTE SHEET (RULE 26)
CA 02393749 2002-06-07
WO 01/46151 PCT/CA00/01559
N / N-N
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-153-
SUBSTITUTE SHEET (RULE 26)
CA 02393749 2002-06-07
WO 01/46151 PCT/CA00/01559
/ O O
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-154-
SUBSTITUTE SHEET (RULE 26)
CA 02393749 2002-06-07
WO 01/46151 PCT/CA00/01559
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-155-
SUBSTITUTE SHEET (RULE 26)
CA 02393749 2002-06-07
WO 01/46151 PCT/CA00/01559
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-156-
SUBSTITUTE SHEET (RULE 26)
CA 02393749 2002-06-07
WO 01/46151 PCT/CA00/01559
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-157-
SUBSTITUTE SHEET (RULE 26)
CA 02393749 2002-06-07
WO 01/46151 PCT/CAOO/01559
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SUBSTITUTE SHEET (RULE 26)
CA 02393749 2002-06-07
WO 01/46151 PCT/CAOO/01559
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-159-
SUBSTITUTE SHEET (RULE 26)
CA 02393749 2002-06-07
WO 01/46151 PCT/CA00/01559
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- 160 -
SUBSTITUTE SHEET (RULE 26)
CA 02393749 2002-06-07
WO 01/46151 PCT/CA00/01559
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- 161 -
SUBSTITUTE SHEET (RULE 26)
CA 02393749 2002-06-07
WO 01/46151 PCT/CA00/01559
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-162-
SUBSTITUTE SHEET (RULE 26)
CA 02393749 2002-06-07
WO 01/46151 PCT/CA00/01559
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-163-
SUBSTITUTE SHEET (RULE 26)
CA 02393749 2002-06-07
WO 01/46151 PCT/CA00/01559
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- 164 -
SUBSTITUTE SHEET (RULE 26)
CA 02393749 2002-06-07
WO 01/46151 PCT/CA00/01559
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-165-
SUBSTITUTE SHEET (RULE 26)
CA 02393749 2002-06-07
WO 01/46151 PCT/CA00/01559
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-166-
SUBSTITUTE SHEET (RULE 26)
CA 02393749 2002-06-07
WO 01/46151 PCT/CA00/01559
N
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-167-
SUBSTITUTE SHEET (RULE 26)
CA 02393749 2002-06-07
WO 01/46151 PCT/CA00/01559
N N-N
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-168-
SUBSTITUTE SHEET (RULE 26)
CA 02393749 2002-06-07
WO 01/46151 PCT/CA00/01559
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-169-
SUBSTITUTE SHEET (RULE 26)
CA 02393749 2002-06-07
WO 01/46151 PCT/CA00/01559
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-170-
SUBSTITUTE SHEET (RULE 26)
CA 02393749 2002-06-07
WO 01/46151 PCT/CA00/01559
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- 171 -
SUBSTITUTE SHEET (RULE 26)
CA 02393749 2002-06-07
WO 01/46151 PCT/CA00/01559
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-172-
SUBSTITUTE SHEET (RULE 26)
CA 02393749 2002-06-07
WO 01/46151 PCT/CA00/01559
F I I
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-173-
SUBSTITUTE SHEET (RULE 26)
CA 02393749 2002-06-07
WO 01/46151 PCT/CA00/01559
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- 174 -
SUBSTITUTE SHEET (RULE 26)
CA 02393749 2002-06-07
WO 01/46151 PCT/CA00/01559
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-175-
SUBSTITUTE SHEET (RULE 26)
CA 02393749 2002-06-07
WO 01/46151 PCT/CA00/01559
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-176-
SUBSTITUTE SHEET (RULE 26)
CA 02393749 2002-06-07
WO 01/46151 PCT/CA00/01559
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-177-
SUBSTITUTE SHEET (RULE 26)
CA 02393749 2002-06-07
WO 01/46151 PCT/CA00/01559
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- 178 -
SUBSTITUTE SHEET (RULE 26)
CA 02393749 2002-06-07
WO 01/46151 PCT/CA00/01559
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-179-
SUBSTITUTE SHEET (RULE 26)
CA 02393749 2002-06-07
WO 01/46151 PCT/CA00/01559
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-180-
SUBSTITUTE SHEET (RULE 26)
CA 02393749 2002-06-07
WO 01/46151 PCT/CA00/01559
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- 181 -
SUBSTITUTE SHEET (RULE 26)
CA 02393749 2002-06-07
WO 01/46151 PCT/CA00/01559
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-182-
SUBSTITUTE SHEET (RULE 26)
CA 02393749 2002-06-07
WO 01/46151 PCT/CAOO/01559
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-183-
SUBSTITUTE SHEET (RULE 26)
CA 02393749 2002-06-07
WO 01/46151 PCT/CA00/01559
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- 184 -
SUBSTITUTE SHEET (RULE 26)
CA 02393749 2002-06-07
WO 01/46151 PCT/CA00/01559
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-185-
SUBSTITUTE SHEET (RULE 26)
CA 02393749 2002-06-07
WO 01/46151 PCT/CA00/01559
0
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-186-
SUBSTITUTE SHEET (RULE 26)
CA 02393749 2002-06-07
WO 01/46151 PCT/CA00/01559
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-187-
SUBSTITUTE SHEET (RULE 26)
CA 02393749 2002-06-07
WO 01/46151 PCT/CA00/01559
0
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-188-
SUBSTITUTE SHEET (RULE 26)
CA 02393749 2002-06-07
WO 01/46151 PCT/CA00/01559
F F
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-189-
SUBSTITUTE SHEET (RULE 26)
CA 02393749 2002-06-07
WO 01/46151 PCT/CAOO/01559
N N
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-190-
SUBSTITUTE SHEET (RULE 26)
CA 02393749 2002-06-07
WO 01/46151 PCT/CA00/01559
N
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- 191 -
SUBSTITUTE SHEET (RULE 26)
CA 02393749 2002-06-07
WO 01/46151 PCT/CA00/01559
N
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-192-
SUBSTITUTE SHEET (RULE 26)
CA 02393749 2002-06-07
WO 01/46151 PCT/CA00/01559
O
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-193-
SUBSTITUTE SHEET (RULE 26)
CA 02393749 2002-06-07
WO 01/46151 PCT/CA00/01559
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-194-
SUBSTITUTE SHEET (RULE 26)
CA 02393749 2002-06-07
WO 01/46151 PCT/CA00/01559
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-195-
SUBSTITUTE SHEET (RULE 26)
CA 02393749 2002-06-07
WO 01/46151 PCT/CA00/01559
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-196-
SUBSTITUTE SHEET (RULE 26)
CA 02393749 2002-06-07
WO 01/46151 PCT/CA00/01559
F F
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- 197 -
SUBSTITUTE SHEET (RULE 26)
CA 02393749 2002-06-07
WO 01/46151 PCT/CA00/01559
N -N
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-198-
SUBSTITUTE SHEET (RULE 26)
CA 02393749 2002-06-07
WO 01/46151 PCT/CA00/01559
\ \ O
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-199-
SUBSTITUTE SHEET (RULE 26)
CA 02393749 2002-06-07
WO 01/46151 PCT/CA00/01559
N
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- 200 -
SUBSTITUTE SHEET (RULE 26)
CA 02393749 2002-06-07
WO 01/46151 PCT/CA00/01559
NS
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-201-
SUBSTITUTE SHEET (RULE 26)
CA 02393749 2002-06-07
WO 01/46151 PCT/CA00/01559
N
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-202-
SUBSTITUTE SHEET (RULE 26)
CA 02393749 2002-06-07
WO 01/46151 PCT/CA00/01559
0
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N
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- 203 -
SUBSTITUTE SHEET (RULE 26)
CA 02393749 2002-06-07
WO 01/46151 PCT/CA00/01559
0
N
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N-N
N N
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- 204 -
SUBSTITUTE SHEET (RULE 26)
CA 02393749 2002-06-07
WO 01/46151 PCT/CA00/01559
O 0
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- 205 -
SUBSTITUTE SHEET (RULE 26)
CA 02393749 2002-06-07
WO 01/46151 PCT/CA00/01559
0
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-206-
SUBSTITUTE SHEET (RULE 26)
CA 02393749 2002-06-07
WO 01/46151 PCT/CA00/01559
N
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- 207 -
SUBSTITUTE SHEET (RULE 26)
CA 02393749 2002-06-07
WO 01/46151 PCT/CA00/01559
0
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-208-
SUBSTITUTE SHEET (RULE 26)
CA 02393749 2002-06-07
WO 01/46151 PCT/CA00/01559
F
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- 209 -
SUBSTITUTE SHEET (RULE 26)
CA 02393749 2002-06-07
WO 01/46151 PCT/CA00/01559
0
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-210-
SUBSTITUTE SHEET (RULE 26)
CA 02393749 2002-06-07
WO 01/46151 PCT/CA00/01559
O
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- 211 -
SUBSTITUTE SHEET (RULE 26)
CA 02393749 2002-06-07
WO 01/46151 PCT/CA00/01559
0 O,
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-212-
SUBSTITUTE SHEET (RULE 26)
CA 02393749 2002-06-07
WO 01/46151 PCT/CAOO/01559
N
O
N
N
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ON
S
O
Salts of the Examples
As discussed above, pharmaceutically acceptable salts are often
desirable. Examples of such salts are described below:
General Method for Salt Preparation
Salts of the compounds of this invention that are basic may be prepared in
several ways:
a) The compound is dissolved in acceptable solvent such as ethyl acetate. An
acceptable acid such as hydrochloric acid in an acceptable solvent such as 1,4-
- 213 -
SUBSTITUTE SHEET (RULE 26)
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dioxane is then added. The precipitated salt slurry is aged and the salt is
then
isolated by filtration.
b) The compound and an acceptable acid such as benzenesulfonic acid are
dissolved in an acceptable solvent such as isopropyl acetate or in a mixture
of
solvents such as isopropyl acetate and methanol. The salt may then be isolated
by concentration or a solvent switch, leading to precipitation, followed by
filtration. The more stable crystal form of the salt may be obtained by
equilibration of the precipitated salt slurry by heating and aging prior to
filtration. Seed crystals from previous batches may also be added prior to
equilibration of the salt slurry, to initiate the process of crystallization
and
equilibration.
SULFURIC ACID SALT OF THE EXAMPLE 14 COMPOUND
The sulfuric acid salt of the example 14 compound was prepared by
dissolving the compound (1.00 equiv) in refluxing ethyl acetate. After cooling
to
room temperature, sulfuric acid (1.04 equiv) was added slowly, while stirring.
The
resulting suspension was stirred a further 40 minutes and the solid was
isolated by
filtration and washed with ethyl acetate to give the sulfuric acid salt of the
example 14
compound.
1H NMR (500 MHz, acetone-d6): d 9.45 (d, 1H), 9.23 (d, 1H), 8.65 (d,
1H), 8.25 (d, 1H), 8.16 (dd, 1H), 8.10 (s, 1H), 7.99 (d, 2H), 7.80 (d, 2H),
7.60 (d, 1H),
7.49 (s, 1H), 7.45 (t, 1H), 7.30 (d, 1H), 3.09 (s, 3H), 2.77 (s, 3H), 2.33 (s,
3H), 2.01
(s, 6H).
METHANESULFONIC ACID SALT OF THE EXAMPLE 14 COMPOUND
The methanesulfonic acid salt of the example 14 compound was
prepared by dissolving the compound (1.0 equiv) in refluxing ethyl acetate.
After
cooling to room temperature, methanesulfonic acid (1.1 equiv) was added
slowly,
while stirring. The resulting suspension was stirred, allowed to concentrate
by
evaporation and the solid was isolated by filtration and washed with ether to
give the
methanesulfonic acid salt of the example 14 compound.
- 214 -
SUBSTITUTE SHEET (RULE 26)
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1H NMR (500 MHz, acetone-d6): d 9.45 (d, 1H), 9.32 (d, 1H), 8.70 (s,
1H), 8.27 (s, 1H), 8.22 (t, 1H), 8.11 (s, 1H), 7.99 (d, 2H), 7.78 (d, 2H),
7.61 (d, 1H),
7.49 (m, 214), 7.35 (d, 1H), 3.09 (s, 3H), 2.78 (s, 3H), 2.33 (s, 3H), 2.01
(s, 6H).
p-TOLUENESULFONIC ACID SALT OF THE EXAMPLE 14 COMPOLTND
The p-toluenesulfonic acid salt of the example 14 compound was
prepared by dissolving the compound (1.0 equiv) in refluxing ethyl acetate.
After
cooling to room temperature, p-toluenesulfonic acid (1.1 equiv) in ethyl
acetate was
added slowly. The solution was concentrated and the suspension was aged with
stirring and periodic sonication at room temperature for 3 days. The solid was
then
isolated by filtration and washed with ethyl acetate to give the p-
toluenesulfonic acid
salt of the example 14 compound).
mp 184-185 C.
1H NMR (500 MHz, acetone-d6): d 9.58 (d, 1H), 9.22 (d, 1H), 8.63 (s,
1H), 8.23 (d, 1H), 8.16 (m, 1H), 8.03 (s, 1H), 7.94 (d, 2H), 7.73 (d, 2H),
7.55 (m, 3H),
7.45 (s, 1H), 7.40 (t, 1H), 7.27 (d, 1H), 7.12 (d, 2H), 3.07 (s, 3H), 2.75 (s,
3H), 2.33
(s, 3H), 2.29 (s, 3H), 2.01 (s, 6H).
2-NAPHTHALENESULFONIC ACID SALT OF THE EXAMPLE 14 COMPOUND
The 2-naphthalenesulfonic acid salt of the example 14 compound was
prepared by dissolving the coinpound (1.0 equiv) in refluxing ethyl acetate.
After
cooling to room temperature, 2-naphthalenesulfonic acid (1.1 equiv) in ethyl
acetate
was added slowly, followed by ethanol. Toluene was then added to the solution,
followed by concentration. More toluene was then added and the suspension was
aged with stirring and periodic sonication at room temperature for 24h. The
solid was
then isolated by filtration and washed with toluene to give the 2-
naphthalenesulfonic
acid salt of the example 14 compound.
mp 202-204 C.
1H NMR (500 MHz, acetone-d6): d 9.64 (d, 1H), 9.30 (d, 1H), 8.67 (d,
1H), 8.25 (d, 1H), 8.23 (m, 1H), 8.16 (s, 1H), 7.99 (s, 1H), 7.91 (d, 2H),
7.87 (m, 2H),
7.82 (d, 1H), 7.72 (dd, 1H), 7.68 (d, 2H), 7.54 (d, 1H), 7.52 (m, 2H), 7.43
(brs, 1H),
7.37 (t, 1H), 7.22 (d, 1H), 3.03 (s, 3H), 2.76 (s, 3H), 2.33 (s, 3H), 2.02 (s,
6H).
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SUBSTITUTE SHEET (RULE 26)
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WO 01/46151 PCT/CA00/01559
HYDROCHLORIDE SALT OF THE EXAMPLE 43 COMPOUND
The hydrochloride salt of the example 43 compound was prepared by
dissolving the compound (1.0 equiv) in ethyl acetate with heating and
sonication.
After cooling the solution to room temperature, HCl in 1,4-dioxane (4M, 1.0
equiv)
was added while stirring. The suspension was stirred for a further 5 minutes
and the
solid was isolated by filtration to give the mono-hydrochloride salt of the
example 43
compound.
BENZENESULFONIC ACID SALT OF THE EXAMPLE 14 COMPOUND
The benzenesulfonic acid salt of the Example 14 compound is
available in two crystalline forms ("Form A" and "Form B"). The forms are
produced
by the following procedures:
Salt Formation
(Ii>SO2Me (SO2Me
N / _ Ethyl Acetate N
/
+ HO3S~ ~ + 03S ~ ~
methanol / I
/ I
\ \
\ I O1 N \ I Ol
N
I / N~ I / N~
MeOZS Me02S
Form A
To a slurry of the Example 14 compound (1 equiv) in ethyl acetate was
added benzenesulfonic acid (1-1.2 equiv). Other esters may be used in place of
ethyl
acetate. Methanol was added and the resulting mixture was heated until the
solid
dissolved. Other alcohols such as ethanol or propanol may be used in place of
the
methanol.
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SUBSTITUTE SHEET (RULE 26)
CA 02393749 2006-04-03
The resulting solution was filtered and concentrated. The product
crystallized during concentration. The resulting mixture was diluted with
ethyl
acetate and aged. The yellow solid was collected by filtration.
HPLC indicated a 1:1 molar ratio of 6-[I-methyl-l-
(methylsulfonyl)ethyl]-8-[3-[(E)-2-[3-methyl-I,2,4-oxadiazol-5-yl]-2-[4-
(methylsulfonyl)phenyl]ethenyl]phenyl]quinoline and benzenesulfonic acid.
m.p. by DSC: 193 C.
The X-ray Powder Diffraction ("XRPD") Spectrogram for the Form A
is shown in Fig. 2. The identifying peaks are tabulated below and shown in
Fig. 5.
Peaks Identifying
Form A
Polymorph
( 2Theta)
10_0
19.5
21.4
22.4
30.5
Form B
To a slurry of the Example 14 compound (1 equiv) in a mixture of
isopropyl acetate (i-PzOAc) and methanol (1:1) was added benzenesulfonic acid
(1-
1.2 equiv). Other esters may be used in place of i-PrOAc and other alcohols
such as
ethanol or propanol may be used in place of methanol. The mixture was aged at
20 -
50 C until the solids dissolved. The resulting solution was filtered and
distilled
while the volume was maintained by addition of a 9:1 (v/v) mixture of i-
PrOAc/methanol. The product crystallized during the distiIlation.
The resulting mixture was aged at 20 - 70 C for 2-10 h to ensure
complete formation of Form B. The resulting off-white solid was isolated by
filtration and dried.
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HPLC indicated a 1:1 molar ratio of 6-[1-methyl-1-
(methylsulfonyl)ethyl]-8-[3-[(E)-2-[3-methyl-1,2,4-oxadiazol-5-yl]-2-[4-
(methylsulfonyl)phenyl]ethenyl]phenyl]quinoline and benzenesulfonic acid.
m.p. by DSC: 210 C
The XRPD Spectrogram for the Form B is shown in Fig. 3. The
identifying peaks are tabulated below and shown in Fig. 6. The spectra are
compared
in Fig. 4 with the identifying peaks pointed out by arrows.
Peaks
Identifying
Form B
Polymorph
( 2Theta)
14.4
17.7
20.0
20.2
23.7
28.9
Other variations or modifications, which will be obvious to those
slalled in the art, are within the scope and teachings of this invention. This
invention
is not to be limited except as set forth in the following claims.
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