Note: Descriptions are shown in the official language in which they were submitted.
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SUBSTITUTED TRIAZOLO-PYRIDAZINE DERIVATIVES AS
LIGANDS FOR GABA RECEPTORS
The present invention relates to a class of substituted triazolo-
pyridazine derivatives and to their use in therapy. More particularly, this
invention is concerned with substituted 1,2,4-triazolo[4,3-b]pyridazine
derivatives which are ligands for GABAA receptors and are therefore
useful in the therapy of deleterious mental states.
Receptors for the major inhibitory neurotransmitter, gamma-
aminobutyric acid (GABA), are divided into two main classes: (1) GABAA
receptors, which are members of the ligand-gated ion channel superfamily;
and (2) GABAB receptors, which may be members of the G-protein linked
receptor superfamily. Since the first cDNAs encoding individual GABAA
receptor subunits were cloned the number of known members of the
mammalian family has grown to thirteen (six (x subunits, three (3 subunits,
three y subunits and one 8 subunit). It may be that further subunits
remain to be discovered; however, none has been reported since 1993.
Although knowledge of the diversity of the GABAA receptor gene
family represents a huge step forward in our understanding of this ligand-
gated ion channel, insight into the extent of subtype diversity is still at an
early stage. It has been indicated that an a subunit, a[3 subunit and a y
subunit constitute the minimum requirement for forming a fully
functional GABAA receptor expressed by transiently transfecting cDNAs
into cells. As indicated above, a b subunit also exists, but is present only
to a minor extent in GABAA receptor populations.
Studies of receptor size and visualisation by electron microscopy
conclude that, like other members of the ligand-gated ion channel family,
the native GABAA receptor exists in pentameric form. The selection of at
least one a, one P and one y subunit from a repertoire of thirteen allows for
the possible existence of more than 10,000 pentameric subunit
combinations. Moreover, this calculation overlooks the additional
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permutations that would be possible if the arrangement of subunits
around the ion channel had no constraints (i.e. there could be 120 possible
variants for a receptor composed of five different subunits).
Receptor subtype assemblies which do exist include, amongst many
others, al(32y2, a2(32/3y2, a3(3y2/3, a2Ry1, a5(33y2/3, a6(3y2, a605 and a408.
Subtype assemblies containing an al subunit are present in most areas of
the brain and are thought to account for over 40% of GABAA receptors in
the rat. Subtype assemblies containing a2 and a3 subunits respectively
are thought to account for about 25% and 17% of GABAA receptors in the
rat. Subtype assemblies containing an a5 subunit are expressed
predominantly in the hippocampus and cortex and are thought to
represent about 4% of GABAA receptors in the rat.
A characteristic property of all known GABAA receptors is the
presence of a number of modulatory sites, one of which is the
benzodiazepine (BZ) binding site. The BZ binding site is the most explored
of the GABAA receptor modulatory sites, and is the site through which
anxiolytic drugs such as diazepam and temazepam exert their effect.
Before the cloning of the GABAA receptor gene family, the benzodiazepine
binding site was historically subdivided into two subtypes, BZ1 and BZ2,
on the basis of radioligand binding studies. The BZ1 subtype has been
shown to be pharmacologically equivalent to a GABAA receptor comprising
the al subunit in combination with a(3 subunit and y2. This is the most
abundant GABAA receptor subtype, and is believed to represent almost
half of all GABAA receptors in the brain.
Two other major populations are the a2(3y2 and a3py2/3 subtypes.
Together these constitute approximately a further 35% of the total GABAA
receptor repertoire. Pharmacologically this combination appears to be
equivalent to the BZ2 subtype as defined previously by radioligand
binding, although the BZ2 subtype may also include certain a5-containing
subtype assemblies. The physiological role of these subtypes has hitherto
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been unclear because no sufficiently selective agonists or antagonists were
known.
It is now believed that agents acting as BZ agonists at al(3y2, a2[3y2
or a3[3y2 subunits will possess desirable anxiolytic properties. Compounds
which are modulators of the benzodiazepine binding site of the GABAA
receptor by acting as BZ agonists are referred to hereinafter as "GABAA
receptor agonists". The al-selective GABAA receptor agonists alpidem and
zolpidem are clinically prescribed as hypnotic agents, suggesting that at
least some of the sedation associated with known anxiolytic drugs which
act at the BZ1 binding site is mediated through GABAA receptors
containing the al subunit. Accordingly, it is considered that GABAA
receptor agonists which bind more effectively to the a2 and/or a3 subunit
than to al will be effective in the treatment of anxiety with a reduced
propensity to cause sedation. Also, agents which are antagonists or
inverse agonists at al might be employed to reverse sedation or hypnosis
caused by a1 agonists.
The compounds of the present invention, being selective ligands for
GABAA receptors, are therefore of use in the treatment and/or prevention
of a variety of disorders of the central nervous system. Such disorders
include anxiety disorders, such as panic disorder with or without
agoraphobia, agoraphobia without history of panic disorder, animal and
other phobias including social phobias, obsessive-compulsive disorder,
stress disorders including post-traumatic and acute stress disorder, and
generalized or substance-induced anxiety disorder; neuroses; convulsions;
migraine; and depressive or bipolar disorders, for example single-episode
or recurrent major depressive disorder, dysthymic disorder, bipolar I and
bipolar II manic disorders, and cyclothymic disorder.
In DE-A-2741763, and in US Patents 4,260,755, 4,260,756 and
4,654,343, are described various classes of 1,2,4-triazolo[4,3-b]pyridazine
derivatives which are alleged to be useful as anxiolytic agents. The
compounds described in DE-A-2741763 and in US Patents 4,260,755 and.
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4,654,343 possess a phenyl substituent at the 6-position of the triazolo-
pyridazine ring system. The compounds described in US Patent 4,260,756,
meanwhile, possess a heteroaryl moiety at the 6- or 8-position. In none of
these publications, however, is there any disclosure or suggestion of 1,2,4-
triazolo[4,3-b]pyridazine derivatives wherein the substituent at the
6-position is attached through a directly linked oxygen atom.
EP-A-0085840 and EP-A-0134946 describe related series of 1,2,4-
triazolo[3,4-a]phthalazine derivatives which are stated to possess
antianxiety activity. However, there is no disclosure nor any suggestion in
either of these publications of replacing the benzo moiety of the triazolo-
phthalazine ring system with any other functionality.
The present invention provides a class of triazolo-pyridazine
derivatives which possess desirable binding properties at various GABAA
receptor subtypes. The compounds in accordance with the present
invention have good affinity as ligands for the a2 and/or a3 subunit of the
human GABAA receptor. The compounds of this invention may display
more effective binding to the a2 and/or a3 subunit than to the al subunit.
Desirably, the compounds of the invention will exhibit functional
selectivity in terms of a selective efficacy for the a2 and/or a3 subunit
relative to the al subunit.
The compounds of the present invention are GABAA receptor
subtype ligands having a binding affinity (K) for the a2 and/or a3 subunit,
as measured in the assay described hereinbelow, of 100 nM or less,
typically of 50 nM or less, and ideally of 10 nM or less. The compounds in
accordance with this invention may possess at least a 2-fold, suitably at
least a 5-fold, and advantageously at least a 10-fold, selectivity affinity
for
the a2 and/or a3 subunit relative to the al subunit. However, compounds
which are unselective in terms of their binding affinity for the a2 and/or
a3 subunit relative to the al subunit are also encompassed within the
scope of the present invention; such compounds will desirably exhibit
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functional selectivity in terms of a selective efficacy for the a2 and/or a3
subunit relative to the al subunit.
The present invention provides a compound of formula I, or a salt or
prodrug thereof:
N-N
Y R'
N
Z N
O, R 2
(I)
wherein
Y represents hydrogen or CI_r, alkyl; and
Z represents C1_6 alkyl, C3.7 cycloalkyl, C4.7 cycloalkenyl, aryl, C3_7
heterocycloalkyl, heteroaryl or di(Cl.s)alkylamino, any of which groups
may be optionally substituted; or
Y and Z are taken together with the two intervening carbon atoms
to form a ring selected from C5_9 cycloalkenyl, Cs_Io bicycloalkenyl,
tetrahydropyridinyl, pyridinyl and phenyl, any of which rings may be
optionally benzo-fused and/or substituted;
Rl represents C3_7 cycloalkyl, phenyl, furyl, thienyl or pyridinyl, any
of which groups may be optionally substituted; and
R2 represents cyano(Ci.6)alkyl, hydroxy(CI _c)alkyl, C3_7
cycloalkyl(C1_6)alkyl, propargyl, C3-7 heterocycloalkylcarbonyl(C1_6)alkyl,
aryl(C1-6)alkyl or heteroaryl(Ci.6)alkyl, any of which groups may be
optionally substituted;
provided that, when Y and Z are taken together with the two
intervening carbon atoms to form an optionally substituted phenyl ring,
then R2 is other than hydroxy(C1_6)alkyl.
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-6-
In addition, the present invention provides a compound of formula I
as defined above, or a salt or prodrug thereof, wherein
Y represents hydrogen or C1_6 alkyl; and
Z represents Ci_6 alkyl, C3-7 cycloalkyl, aryl, C3-7 heterocycloalkyl or
heteroaryl, any of which groups may be optionally substituted; or
Y and Z are taken together with the two intervening carbon atoms
to form a ring selected from C5-9 cycloalkenyl, C6_io bicycloalkenyl,
tetrahydropyridinyl, pyridinyl and phenyl, any of which rings may be
optionally benzo-fused and/or substituted; and
R' and R2 are as defined above;
provided that, when Y and Z are taken together with the two
intervening carbon atoms to form an optionally substituted phenyl ring,
then R2 is other than hydroxy(Ci_s)alkyl.
The present invention also provides a compound of formula I as
defined above, or a salt or prodrug thereof, wherein
Y represents hydrogen or CI-6 alkyl; and
Z represents Ci.6 alkyl, C3_7 cycloalkyl, aiyl, Cs_, heterocycloalkyl or
heteroaryl, any of which groups may be optionally substituted; or
Y and Z are taken together with the two intervening carbon atoms
to form a ring selected from C5.9 cycloalkenyl, C6_io bicycloalkenyl,
tetrahydropyridinyl, pyridinyl and phenyl, any of which rings may be
optionally benzo-fused and/or substituted;
R1 is as defined above; and
R2 represents hydroxy(C1-s)alkyl, C3_7 cycloalkyl(Ci.s)alkyl, C3.7
heterocycloalkylcarbonyl(Ci-6)alkyl, aryl(C1_6)alkyl or
heteroaryl(C1_r')alkyl,
any of which groups may be optionally substituted;
provided that, when Y and Z are taken together with the two
intervening carbon atoms to form an optionally substituted phenyl ring,
then R2 is other than hydroxy(CI_o)alkyl.
The present invention further provides a compound of formula I as
defined above, or a salt or prodrug thereof, wherein
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Y represents hydrogen or C1.6 alkyl; and
Z represents Ci_s alkyl, C3.7 cycloalkyl, aryl, C3_7 heterocycloalkyl or
heteroaryl, any of which groups may be optionally substituted; or
Y and Z are taken together with the two intervening carbon atoms
to form a ring selected from C5.9 cycloalkenyl, Cs_1o bicycloalkenyl,
tetrahydropyridinyl and pyridinyl, any of which rings may be optionally
benzo-fused and/or substituted;
R1 is as defined above; and
R2 represents hydroxy(Cl.s)alkyl, C3_7 cycloalkyl(C1.6)alkyl, C3.7
heterocycloalkylcarbonyl(Cl.(;)alkyl, aryl(Ci.s)alkyl or
heteroaryl(Ci.6)alkyl,
any of which groups may be optionally substituted.
Where Y and Z are taken together with the two intervening carbon
atoms to form a ring, the resulting compounds of formula I above
incorporate the relevant cycloalkenyl, bicycloalkenyl, tetrahydropyridinyl,
pyridinyl or phenyl ring fused to the central triazolo-pyridazine ring
system as depicted in formula I.
Where Y and Z are taken together with the two intervening carbon
atoms to form a C5_9 cycloalkenyl ring, this ring may be a cyclopentenyl,
cyclohexenyl, cycloheptenyl, cyclooctenyl or cyclononenyl ring, suitably
cyclohexenyl or cycloheptenyl.
Where Y and Z are taken together with the two intervening carbon
atoms to form a Cs_io bicycloalkenyl ring, this ring may be a
bicyclo[2.1.1]hex-2-enyl, bicyclo[2.2.1]hept-2-enyl, bicyclo[2.2.2]oct-2-enyl,
bicyclo[3.2.2]non-6-enyl or bicyclo[3.3.2]dec-9-enyl ring, suitably
bicyclo[2.2.1]hept-2-enyl, bicyclo[2.2.2]oct-2-enyl or bicyclo[3.2.2]non-6-
enyl, and especially bicyclo[2.2.2]oct-2-enyl.
Where Y and Z are taken together with the two intervening carbon
atoms to form a ring, this ring may be optionally benzo-fused. By way of
illustration, Y and Z taken together with the two intervening carbon
atoms may represent a benzo-fused cyclohexenyl ring, whereby the
resulting ring is dihydronaphthyl.
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-8-
The groups Y, Z, Rl and R2 may be unsubstituted, or substituted by
one or more, suitably by one or two, substituents. In general, the groups
Y, Z, R' and R2 will be unsubstituted or monosubstituted. Examples of
optional substituents on the groups Y, Z, R' and R2 include Ci-6 alkyl,
aryl(C1-s)alkyl, pyridyl(Ci-e)alkyl, halogen, halo(C1.s)alkyl, cyano,
cyano(C1-s)alkyl, hydroxy, hydroxymethyl, Ci-s alkoxy, C3_7
cycloalkyl(Ci-s)alkoxy, C3-7 cycloalkoxy, amino(Ci.s)alkyl,
di(Ci-s)alkylamino(Ci.s)alkyl, di(Ci.6)alkylaminocarbonyl(C1-s)alkyl,
1V (Ci-6)alkylpiperidinyl, pyrrolidinyl(C1-s)alkyl, piperazinyl(C1-(;)alkyl,
morpholinyl(C1-s)alkyl, di(Ci-6)alkylmorpholinyl(Ci.6)alkyl and
imidazolyl(C1-s)alkyl. Illustrative substituents include Ci.6 alkvl,
aryl(Cis)alkyl, pyridyl(C1-6)alkyl, halogen, halo(Ci-s)alkyl, cyano,
cyano(C1-6)alkyl, hydroxy, hydroxymethyl, C1.6 alkoxy, Ca-7
cycloalkyl(Ci-6)alkoxy, di(Ci.s)alkylamino(Ci_6)alkyl,
di(C1-6)alkylaminocarbonyl(Ci.c,)alkyl, morpholinyl(Ci-(;)alkyl and
imidazolyl(Ci-6)alkyl. Representative substituents include C1-6 alkyl,
aryl(Ci-s)alkyl, halogen, cyano, hydroxy, hydroxymethyl, C1-6 alkoxy and
C3-7 cycloalkyl(Ci_6)alkoxy.
As used herein, the expression "Ci-6 alkyl" includes methvl and
ethyl groups, and straight-chained or branched propyl, butyl, pentyl and
hexyl groups. Particular alkyl groups are methyl, ethyl, n-propyl,
isopropyl, tert-butyl and 1,1-dimethylpropyl. Derived expressions such as
"C1-6 alkoxy" are to be construed accordingly.
Typical C3.7 cycloalkyl groups include cyclopropyl, cyclobutyl,
cyclopentyl and cyclohexyl.
The expression "C3-7 cycloalkyl(Ci-s)alkyl" as used herein includes
cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl and
cyclohexylmethyl.
Typical C4-7 cycloalkenyl groups include cyclobutenyl, cyclopentenyl
and cyclohexenyl.
Typical aryl groups include phenyl and naphthyl, preferably phenyl.
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The expression "aryl(C1.6)alkyP" as used herein includes benzyl,
phenylethyl, phenylpropyl and naphthylmethyl.
Suitable heterocycloalkyl groups include azetidinyl, pyrrolidinyl,
piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl groups.
Suitable heteroaryl groups include 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 and tetrazolyl groups.
The expression "heteroaryl(Ci.(;)alkyl" as used herein includes
furylmethyl, furylethyl, thienylmethyl, thienylethyl, pyrazolylmethyl,
oxazolylmethyl, oxazolylethyl, isoxazolylmethyl, thiazolylmethyl,
thiazolylethyl, imidazolylmethyl, imidazolylethyl, benzimidazolylmethyl,
oxadiazolylmethyl, oxadiazolylethyl, thiadiazolylmethyl, thiadiazolylethyl,
triazolylmethyl, triazolylethyl, tetrazolylmethyl, tetrazolylethyl,
pyridinylmethyl, pyridinylethyl, pyridazinylmethyl, pyrimidinylmethyl,
pyrazinylmethyl, quinolinylmethyl, isoquinolinylmethyl and
quinoxalinylmethyl.
The term "halogen" as used herein includes fluorine, chlorine,
bromine and iodine, especially fluorine or chlorine.
For use in medicine, the salts of the compounds of formula I will be
pharmaceutically acceptable salts. Other salts may, however, be useful in
the preparation of the compounds according to the invention or of their
pharmaceutically acceptable salts. Suitable pharmaceutically acceptable
salts of the compounds of this invention include acid addition salts which
may, for example, be formed by mixing a solution of the compound
according to the invention with a solution of a pharmaceutically acceptable
acid such as hydrochloric acid, sulphuric acid, methanesulphonic acid,
fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, oxalic
acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.
Furthermore, where the compounds of the invention carry an acidic
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moiety, suitable pharmaceutically acceptable salts thereof may include
alkali metal salts, e.g. sodium or potassium salts; alkaline earth metal
salts, e.g. calcium or magnesium salts; and salts formed with suitable
organic ligands, e.g. quaternary ammonium salts.
The present invention includes within its scope prodrugs of the
compounds of formula I above. In general, such prodrugs will be
functional derivatives of the compounds of formula I which are readily
convertible in vivo into the required compound of formula I. Conventional
procedures for the selection and preparation of suitable prodrug
derivatives are described, for example, in Design of Prodrugs, ed. H.
Bundgaard, Elsevier, 1985.
Where the compounds according to the invention have at least one
asymmetric centre, they may accordingly exist as enantiomers. Where the
compounds according to the invention possess two or more asymmetric
centres, they may additionally exist as diastereoisomers. It is to be
understood that all such isomers and mixtures thereof in any proportion
are encompassed within the scope of the present invention.
Suitably, Y represents hydrogen or methyl, especially hydrogen.
Examples of suitable values for the substituent Z include methyl,
ethyl, isopropyl, tert-butyl, 1,1-dimethylpropyl, methyl-cyclopropyl,
cyclobutyl, methyl-cyclobutyl, cyclopentyl, methyl-cyclopentyl, cyclohexyl,
cyclobutenyl, phenyl, pyrrolidinyl, methyl-pyrrolidinyl, piperidinyl,
morpholinyl, thiomorpholinyl, pyridinyl, furyl, thienyl, chloro-thienyl and
diethylamino. Illustrative values of Z include methyl, ethyl, isopropyl,
tert-butyl, methyl-cyclopropyl, cyclobutyl, methyl-cyclobutyl, cyclopentyl,
methyl-cyclopentyl, cyclohexyl, phenyl, pyrrolidinyl, methyl-pyrrolidinyl,
piperidinyl, morpholinyl, thiomorpholinyl, pyridinyl, furyl, thienyl and
chloro-thienyl. Typical values include methyl, ethyl, phenyl, piperidinyl,
pyridinyl and thienyl.
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In a particular embodiment, the substituent Z represents C$_7
cycloalkyl, either unsubstituted or substituted by C1_6 alkyl, especially
methyl. Favourably, Z represents cyclobutyl.
When Y and Z are taken together with the two intervening carbon
atoms to form a ring, representative compounds according to the invention
include those of structure IA to IL, especially IA to IK:
N-N N-N N-N
1 \- Ri ~Rl R' ~R'
R'' N I N N
N OR2 ORz D.RL
(IA) (IB) (IC)
N-N N-N N-N
R'' ! l~ R'
II ~ R' 1 ~>-- , N
R; N R:, N R I
N N N
0.Rz R
(ID) (IE) (IF)
N-N N-N
R4 Rr Rl
N N I N
iN N iN
R'
O, R2 O, Rz
(IG) (IH)
N-N R 3 N-N 3 N-N
1 ~R, R
N~ N I N ~,r/
N N-i N N
3
R O, R2 R2 O.
(IJ) (IK) (IL)
wherein Rl and R2 are as defined above;
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R3 represents hydrogen, Ci-6 alkyl, aryl(Ci-s)alkyl, halogen, cyano,
hydroxy, hydroxymethyl or C1-6 alkoxy; and
R4 represents hydrogen or C1_6 alkyl.
Suitably, R3 represents hydrogen or C1-6 alkyl, especially hydrogen
or methyl.
Suitably, R4 represents hydrogen or methyl.
Favoured triazolo-pyridazine derivatives according to the present
invention include the compounds represented by formula IE as depicted
above.
Examples of typical optional substituents on the group R' include
methyl, fluoro and methoxy.
Representative values of R1 include cyclopropyl, phenyl,
methylphenyl, fluorophenyl, difluorophenyl, methoxyphenyl, furyl,
thienyl, methyl-thienyl and pyridinyl. Particular values include
cyclopropyl, phenyl, methylphenyl, fluorophenyl, methoxyphenyl and
pyridinyl. More particularly, R1 may represent unsubstituted or
monosubstituted phenyl. Most particularly, Rl represents phenyl.
Suitable values for the substituent R2 in the compounds according
to the invention include cyanomethyl, hydroxybutyl, cyclohexylmethyl,
propargyl, pyrrolidinylcarbonylmethyl, benzyl, pyrazolylmethyl,
isoxazolylmethyl, thiazolylmethyl, thiazolylethyl, imidazolylmethyl,
benzimidazolylmethyl, oxadiazolylmethyl, triazolylmethyl,
tetrazolylmethyl, pyridinylmethyl, pyridazinylmethyl, pyrimidinylmethyl,
pyrazinylmethyl, quinolinylmethyl, isoquinolinylmethyl and
quinoxalinylmethyl, any of which groups may be optionally substituted by
one or more substituents. Typical values of R2 include hydroxybutyl,
cyclohexylmethyl, pyrrolidinylcarbonylmethyl, benzyl, pyrazolylmethyl,
thiazolylmethyl, imidazolylmethyl, triazolylmethyl, pyridinylmethyl,
pyridazinylmethyl, pyrimidinylmethyl, pyrazinylmethyl,
quinolinylmethyl, isoquinolinylmethyl and quinoxalinylmethyl, any of
which groups may be optionally substituted by one or more substituents.
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Examples of suitable optional substituents on the group R2 include
C1.6 alkyl, aryl(Ci.6)alkyl, pyridyl(Cls)alkyl, halogen, halo(Ci.6)alkyl,
cyano, cyano(Ci-s)alkyl, hydroxymethyl, C1_6 alkoxy, C3.7
cycloalkyl(Cl.s)alkoxy, amino(C1_6)alkyl, di(Ci.s)alkylamino(C1_6)alkyl,
di(C1-s)alkylaminocarbonyl(Ci.6)alkyl, N-(Cl.c)alkylpiperidinyl,
pyrrolidinyl(Ci-s)alkyl, piperazinyl(Ci.s)alkyl, morpholinyl(Ci-6)alkyl and
di(Ci_6)alkylmorpholinyl(C1.6)alkyl. Illustrative substituents include Ci-r,
alkyl, aryl(Ci_r,)alkyl, pyridyl(Ci_6)alkyl, halogen, halo(Ci.s)alkyl, cyano,
cyano(Ci_6)alkyl, hydroxymethyl, C1-s alkoxy, C3_7 cycloalkyl(Ci.6)alkoxy
di(Cls)alkylamino(Ci_c)alkyl, di(Ci-s)alkvlaminocarbonyl(Ci_(;)alkyl and
morpholinyl(Ci-c)alkyl. Typical substituents include Ci_6 alkyl,
aryl(C1.6)alkyl, halogen, cyano, hydroxymethyl, C1.6 alkoxy and C3_7
cycloalkyl(C 1_6)alkoxy.
Specific illustrations of particular substituents on the group R2
include methyl, ethyl, n-propyl, benzyl, pyridinylmethyl, chloro,
chloromethyl, cyano, cyanomethyl, hydroxymethyl, ethoxy,
cyclopropylmethoxy, dimethylaminomethyl, aminoethyl,
dimethylaminoethyl, dimethylaminocarbonvlmethyl, N-methylpiperidinyl,
pyrrolidinylethyl, piperazinylethyl, morpholinylmethyl and
dimethylmorpholinylmethyl.
More specific illustrations of particular substituents on the group R2
include methyl, ethyl, n-propyl, benzyl, pyridinylmethyl, chloro,
chloromethyl, cyano, cyanomethyl, hydroxymethyl, ethoxy,
cyclopropylmethoxy, dimethylaminomethyl, dimethylaminoethyl,
dimethylaminocarbonylmethyl and morpholinylmethyl.
Representative values of R2 include cyanomethyl, hydroxybutyl,
h,ydroxymethyl-cyclohexylmethyl, propargyl, dimethylaminomethyl-
propargyl, dimethylmorpholinylmethyl-propargyl,
pyrrolidinylcarbonylmethyl, cyanobenzyl, hydroxymethyl-benzyl,
pyrazolylmethyl, dimethyl-pyrazolylmethyl, methyl-isoxazolylmethyl,
thiazolylmethyl, methyl-thiazolylmethyl, ethyl-thiazolylmethyl, methyl-
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thiazolylethyl, imidazolylmethyl, methyl-imidazolylmethyl, ethyl-
imidazolylmethyl, benzyl-imidazolylmethyl, benzimidazolylmethyl,
methyl-oxadiazolylmethyl, triazolylmethyl, methyl-triazolylmethyl,
propyl-triazolylmethyl, benzyl-triazolylmethyl, pyridinylmethyl-
triazolylmethyl, cyanomethyl-triazolylmethyl, dimethylaminomethyl-
triazolylmethyl, aminoethyl-triazolylmethyl, dimethylaminoethyl-
triazolylmethyl, dimethylaminocarbonylmethyl-triazolylmethyl, 1V
methylpiperidinyl-triazolylmethyl, pyrrolidinylethyl-triazolylmethyl,
piperazinylethyl-triazolylmethyl, morpholinylethyl-triazolylmethyl,
methyl-tetrazolylmethyl, pyridinylmethyl, methyl-pyridinylmethyl,
dimethyl-pyridinylmethyl, ethoxy-pyridinylmethyl, cyclopropylmethoxy-
pyridinylmethyl, pyridazinylmethyl, chloro-pyridazinylmethyl,
pyrimidinylmethyl, pyrazinylmethyl, quinolinylmethyl,
isoquinolinylmethyl and quinoxalinylmethyl.
Illustrative values of R2 include cyanomethyl, hydroxybutyl,
hydroxymethyl-cyclohexylmethyl, propargyl, dimethylaminomethyl-
propargyl, pyrrolidinylcarbonylmethyl, cyanobenzyl, hydroxymethyl-
benzyl, pyrazolylmethyl, dimethyl-pyrazolylmethyl, methyl-
isoxazolylmethyl, thiazolylmethyl, methyl-thiazolylmethyl, ethyl-
thiazolylmethyl, methyl-thiazolylethyl, imidazolylmethyl, methyl-
imidazolylmethyl, ethyl-imidazolylmethyl, benzyl-imidazolylmethyl,
benzimidazolylmethyl, methyl-oxadiazolylmethyl, triazolylmethyl, methyl-
triazolylmethyl, propyl-triazolylmethyl, benzyl-triazolylmethyl,
pyridinylmethyl-triazolylmethyl, cyanomethyl-triazolylmethyl,
dimethylaminomethyl-triazolylmethyl, dimethylaminoethyl-
triazolylmethyl, dimethylaminocarbonylmethyl-triazolylmethyl,
morpholinylethyl-triazolylmethyl, methyl-tetrazolylmethyl,
pyridinylmethyl, methyl-pyridinylmethyl, dimethyl-pyridinylmethyl,
ethoxy-pyridinylmethyl, cyclopropylmethoxy-pyridinylmethyl,
pyridazinylmethyl, chloro-pyridazinylmethyl, pyrimidinylmethyl,
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pyrazinylmethyl, quinolinylmethyl, isoquinolinylmethyl and
quinoxalinylmethyl.
Particular values of R2 include hydroxybutyl, hydroxymethyl-
cyclohexylmethyl, pyrrolidinylcarbonylmethyl, cyanobenzyl,
hydroxymethyl-benzyl, pyrazolylmethyl, dimethyl-pyrazolylmethyl,
thiazolylmethyl, methyl-thiazolylmethyl, ethyl-thiazolylmethyl,
imidazolylmethyl, methyl-imidazolylmethyl, ethyl-imidazolvlmethyl,
benzyl-imidazolylmethyl, methyl-triazolylmethyl, pyridinylmethyl,
methyl-pyridinylmethyl, dimethyl-pyridinylmethyl, ethoxy-
pyridinylmethyl, cyclopropylmethoxy-pyridinylmethyl, pyridazinylmethyl,
chloro-pyridazinylmethyl, pyrimidinylmethyl, pyrazinylmethyl,
quinolinylmethyl, isoquinolinylmethyl and quinoxalinylmethyl.
A favoured value of R2 is methyl-triazolylmethyl.
A particular sub-class of compounds according to the invention is
represented by the compounds of formula IIA, and salts and prodrugs
thereof:
N-N
N R,
I
N
0 _ (CH2)n _ R 12
(IIA)
wherein Rl is as defined above;
n is 1, 2, 3 or 4, typically 1; and
R12 represents hydroxy; or C3_7 cycloalkyl, C3_7
heterocycloalkylcarbonyl, aryl or heteroaryl, any of which groups may be
optionally substituted.
Examples of optional substituents on the group R12 suitably include
C1_G alkyl, aryl(Ci_G)alkyl, halogen, cyano, hydroxymethyl, C1_6 alkoxy and
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C3_7 cycloalkyl(Ci.s)alkoxy. Typical substituents include methyl, ethyl,
benzyl, chloro, cyano, hydroxymethyl, ethoxy and cyclopropylmethoxy.
Particular values of R12 include hydroxy, hydroxymethyl-cyclohexyl,
pyrrolidinylcarbonyl, cyanophenyl, hydroxymethyl-phenyl, pyrazolyl,
dimethylpyrazolyl, thiazolyl, methylthiazolyl, ethylthiazolyl, imidazolyl,
methylimidazolyl, ethylimidazolyl, benzylimidazolyl, methyltriazolyl,
pyridinyl, methylpyridinyl, dimethyl-pyridinyl, ethoxypyridinyl,
cyclopropylmethoxy-pyridinyl, pyridazinyl, chloropyridazinyl, pyrimidinyl,
pyrazinyl, quinolinyl, isoquinolinyl and quinoxalinyl.
Another sub-class of compounds according to the invention is
represented by the compounds of formula IIB, and salts and prodrugs
thereof:
N-N
Y' R'
N
1 i
Z N
O - (CH,,)R, - R22
(IIB)
wherein
Yl represents hydrogen or methyl;
Z' represents C1.6 alkyl, C3_7 cycloalkyl, C4.7 cycloalkenyl, aryl, C3_7
heterocycloalkyl, heteroaryl or di(Cl.s)alkylamino, any of which groups
may be optionally substituted;
Rl is as defined with reference to formula I above;
m is 1 or 2, preferably 1; and
R22 represents aryl or heteroaryl, either of which groups may be
optionally substituted.
The present invention also provides a compound of formula IIB as
defined above, or a salt or prodrug thereof, wherein
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Z' represents C1-6 alkyl, C3.7 cycloalkyl, aryl, C3.7 heterocycloalkyl or
heteroaryl, any of which groups may be optionally substituted; and
Yl, R1, m and R22 are as defined above.
Suitably, Y' represents hydrogen.
Examples of typical substituents on the group Z' include Ci-s alkyl
and halogen, especially methyl or chloro.
Representative values for the group Z' include methyl, ethyl,
isopropyl, tert-butyl, 1,1-dimethylpropyl, methyl-cyclopropyl, cyclobutyl,
methyl-cyclobutyl, cyclopentyl, methyl-cyclopentyl, cyclohexyl,
cyclobutenyl, phenyl, pyrrolidinyl, methyl-pyrrolidinyl, piperidinyl,
morpholinyl, thiomorpholinyl, pyridinyl, furyl, thienyl, chloro-thienyl and
diethylamino.
Particular values for the group Zi include methyl, ethyl, isopropyl,
tert-butyl, methyl-cyclopropyl, cyclobutyl, methyl-cyclobutyl, cyclopentyl,
methyl-cyclopentyl, cyclohexyl, phenyl, pyrrolidinyl, methyl-pyrrolidinyl,
piperidinyl, morpholinyl, thiomorpholinyl, pyridinyl, furyl, thienyl and
chloro-thienyl.
A favoured value of Z1 is cyclobutyl.
Examples of typical substituents on the group R22 include Ci.6 alkyl,
aryl(Cl.s)alkyl, pyridyl(Ci.s)alkyl, halogen, cyano, cyano(C1_6)alkyl,
hydroxymethyl, C1.6 alkoxy, C3_7 cycloalkyl(Ci.(,,)alkoxy,
di(Ci-s)alkylamino(Cl.s)alkyl, amino(Cl.s)alkyl,
di(Cl.s)alkylaminocarbonyl(Ci_s)alkyl, N-(C1-6)alkylpiperidinyl,
pyrrolidinyl(CI_s)alkyl, piperazinyl(C1-s)alkyl and morpholinyl(Cl.s)alkyl.
Representative substituents include C1.6 alkyl, aryl(CI-s)alkyl,
pyridyl(Ci_s)alkyl, halogen, cyano, cyano(C1_s)alkyl, hydroxymethyl, Ci.s
alkoxy, C3.7 cycloalkyl(Ci_s)alkoxy, di(Cj.,)alkylamino(Ci.s)alkyl,
di(Ci_6)alkylaminocarbonyl(Ci_6)alkyl and morpholinyl(C1_6)alkyl.
Illustrative values of specific substituents on the group R22 include
methyl, ethyl, n-propyl, benzyl, pyridinylmethyl, chloro, cyano,
cyanomethyl, hydroxymethyl, ethoxy, cyclopropylmethoxy,
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dimethylaminomethyl, aminoethyl, dimethylaminoethyl,
dimethylaminocarbonylmethyl, N-methylpiperidinyl, pyrrolidinylethvl,
piperazinylethyl and morpholinylmethyl.
Representative values of specific substituents on the group R22
include methyl, ethyl, n-propyl, benzyl, pyridinylmethyl, chloro, cyano,
cyanomethyl, hydroxymethyl, ethoxy, cyclopropylmethoxy,
dimethylaminomethyl, dimethylaminoethyl,
dimethylaminocarbonylmethyl and morpholinylmethyl.
Particular values of R22 include cyanophenyl, hydroxymethyl-
phenyl, pyrazolyl, dimethyl-pyrazolyl, methyl-isoxazolyl, thiazolyl, methyl-
thiazolyl, ethyl-thiazolyl, imidazolyl, methyl-imidazolyl, ethyl-imidazolvl,
benzyl-imidazolyl, benzimidazolyl, methyl-oxadiazolyl, triazolyl, methvl-
triazolyl, propyl-triazolyl, benzyl-triazolyl, pyridinylmethyl-triazolyl,
cyanomethyl-triazolyl, dimethylaminomethyl-triazolyl, aminoethyl-
triazolyl, dimethylaminoethyl-triazolyl, dimethylaminocarbonylmethyl-
triazolyl, N-methylpiperidinyl-triazolyl, pyrrolidinylethyl-triazolyl,
piperazinylethyl-triazolyl, morpholinylethyl-triazolyl, methyl-tetrazolvl,
pyridinyl, methyl-pyridinyl, dimethyl-pyridinyl, ethoxy-pyridinyl,
cyclopropylmethoxy-pyridinyl, pyridazinyl, chloro-pyridazinyl,
pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl and quinoxalinyl.
Specific values of R22 include cyanophenyl, hydroxymethyl-phenyl,
pyrazolyl, dimethyl-pyrazolyl, methyl-isoxazolyl, thiazolyl, methyl-
thiazolyl, ethyl-thiazolyl, imidazolyl, methyl-imidazolyl, ethyl-imidazolyl,
benzyl-imidazolyl, benzimidazolyl, methyl-oxadiazolyl, triazolyl, methyl-
triazolyl, propyl-triazolyl, benzyl-triazolyl, pyridinylmethyl-triazolyl,
cyanomethyl-triazolyl, dimethylaminomethyl-triazolyl,
dimethylaminoethyl-triazolyl, dimethylaminocarbonylmethyl-triazolyl,
morpholinylethyl-triazolyl, methyl-tetrazolyl, pyridinyl, methyl-pyridinyl,
dimethyl-pyridinyl, ethoxy-pyridinyl, cyclopropylmethoxy-pyridinyl,
pyridazinyl, chloro-pyridazinyl, pyrimidinyl, pyrazinyl, quinolinyl,
isoquinolinyl and quinoxalinyl.
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A favoured value of R22 is methyl-triazolyl.
A particular subset of the compounds of formula IIB above is
represented by the compounds of formula IIC, and pharmaceutically
acceptable salts thereof
N-N
/ R
N
R5 ~ 1
r N
0,
I
NN
N R3
(IZC
wherein
Rl is as defined with reference to formula I above;
Q represents the residue of a cyclopropyl, cyclobutyl, cyclopentyl or
cyclohexyl ring;
R5 represents hydrogen or methyl; and
R6 represents hydrogen or methyl.
In relation to formula IIC above, R1 suitably represents phenyl.
In a favoured embodiment, Q suitably represents the residue of a
cyclobutyl ring.
Suitably, R5 represents hydrogen.
Suitably, R6 represents methyl.
Specific compounds within the scope of the present invention
include:
3-phenyl-6-(2-pyridyl)methyloxy-7,8,9, 10-tetrahydro-(7, 10-ethano)-1,2,4-
triazolo[3, 4-a]phthalazine;
3, 7-diphe nyl-6- (2 -pyridyl)methyloxy- 1, 2, 4-triazolo [4, 3-b]pyridazine;
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3-phenyl-6-(2-pyridyl)methyloxy-7,8, 9,10-tetrahydro-1, 2, 4-triazolo [3,4-
a]phthalazine;
7, 8-dimethyl-3-phenyl-6-(2-pyridyl)methyloxy-1,2,4-triazolo[4, 3-
b]pyridazine;
7-methyl-3-phenyl-6-(2-pyridyl)methyloxy-1,2,4-triazolo[4, 3-b]pyridazine;
7 -ethyl- 3-p he nyl- 6- (2-pyridyl)methyloxy- 1,2,4-triazolo [4, 3-b]
pyridazine;
7, 8-benzo- 3-p henyl-6-(2-pyridyl)methyloxy-7, 8, 9,10-tetrahydro-1, 2, 4-
triazolo [3, 4-a]phthalazine;
8-methyl-3, 7-diphenyl-6-(2-pyridyl)methyloxy-1,2,4-triazolo[4,3-
b]pyridazine;
3-phenyl-6-(2-pyridyl)methyloxy-7,8,9, 10-tetrahydro-(7, 10-methano)- 1,2,4-
triazolo[3, 4-a] p hthalazine;
3-phenyl-5-(pyridin-2-ylmethoxy)- 1, 2, 3a, 4, 7-pentaazacyclopenta-
[a]naphthalene;
3-phenyl-5- (pyridin-2-ylmethoxy)- 1,2,3a, 4,8-pentaazacyclopenta-
[a]naphthalene;
8-methyl-3-phenyl-6-(2-pyridyl)methyloxy-7, 8,9,10-tetrahydro-1, 2,4-
triazolo [3, 4- a] phthalazine;
3-phenyl-6-(2-pyridyl)methyloxy-(7, 8-pentano)-1, 2, 4-triazolo [4,3-
b]pyridazine;
8, 8-dimethyl-3-phenyl-6-(2-pyridyl)methyloxy-7, 8, 9,10-tetrahydro-1, 2, 4-
triazolo [3, 4-ajphthalazine;
3-phenyl-7-(piperidin-1-yl)-6-(pyridin-2-ylmethoxy)-1, 2,4-triazolo[4,3-
b]pyridazine;
8-phenyl-7-(pyridin-4-yl)-6-(pyridin-2-ylmethoxy)-1,2,4-triazolo[4,3-
b]pyridazine;
3-phenyl-5-(pyridin-2-ylmethoxy)-6,7,8,9-tetrahydro- 1,2,3a,4,8-pentaaza-
cyclopenta [a] naphthalene;
3-phenyl-5- (pyridin-2-ylmethoxy)-6, 7, 8, 9-tetrahydro-1, 2, 3a, 4, 7-p entaa
za-
cyclopenta [a] naphthalene;
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7-methyl-3-phenyl-5-(pyridin-2-ylmethoxy)-6, 7, 8, 9-tetrahydro-1, 2, 3a, 4, 7-
pentaazacyclopenta[a]naphthalene;
3-phenyl-6-(pyridin-2-ylmethoxy)-7-(thiophen-2-yl)-1,2,4-triazolo [4,3-
b]pyridazine;
3-phenyl-6- (pyridin- 2-ylmethoxy) - 7 - (thiop hen- 3 -yl) - 1,2,4-
triazolo[4,3-
b]pyridazine;
3-phenyl-6- (2-pyridyl)methyloxy-7,8,9, 10-tetrahydro-(7, 10-propano)- 1, 2,4-
triazolo[3, 4-a]phthalazine;
3- (4-methyl)phenyl-6-(2-pyridyl)methyloxy-7,8,9, 1 0-tetrahydro-(7, 10-
ethano)-1,2,4-triazolo[3,4-a]phthalazine;
3- (3-methoxy)phenyl-6-(2-pyridyl)methyloxy-7, 8, 9,10-tetrahydro-(7,10-
ethano)-1,2,4-triazolo[3,4-a]phthalazine;
3-(2-fluoro)phenyl-6-(2-pyridyl)methyloxy-7,8,9, 10-tetrahydro-(7, 10-
ethano)- 1, 2, 4-triazolo [3, 4-a] p hthalazine ;
3-(3-pyridyl)-6-(2-pyridyl)methyloxy-7,8,9, 10-tetrahydro-(7, 10-ethano)-
1,2, 4-triazolo [3, 4-a] phthalazine;
3-cyciopropyl-6-(2-pyridyl)methyloxy-7,8,9,10-tetrahydro-(7,10-ethano)-
1, 2, 4-triazolo [3, 4-a]phthalazine;
6- [(6-methyl)-2-pyridyl]methyloxy-3-phenyl-7, 8,9,10-tetrahydro-(7,10-
ethano)-1,2,4-triazolo[3,4-a]phthalazine;
6- [(3-methyl)-2-pyridyl]methyloxy-3-phenyl-7, 8,9,10-tetrahydro-(7,10-
ethano)-1, 2, 4-triazolo [3, 4-a]phthalazine ;
6-[(4-methyl)-2-pyridyl]methyloxy-3-phenyl-7,8,9, 10-tetrahydro-(7, 10-
ethano)-1,2, 4-triazolo [3, 4-a]phthalazine;
6-[(5-methyl)-2-pyridyl]methyloxy-3-phenyl-7,8,9, 10-tetrahydro-(7, 10-
ethano)-1,2, 4-triazolo [3, 4-a]phthalazine;
3-phenyl-6-(3-pyridyl)methyloxy-7, 8,9,10-tetrahydro-(7,10-ethano)-1, 2, 4-
triazolo [3, 4-a]phthalazine;
3-phenyl-6-(4-pyridyl)methyloxy-7,8,9, 10-tetrahydro-(7, 10-ethano)-1,2,4-
triazolo[3,4-a]phthalazine;
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3-p henyl-6- [2-(1-methyl)imidazolyl]methyloxy-7, 8, 9,10-tetrahydro-(7,10-
ethano)-1, 2, 4-triazolo [3,4-a]phthalazine;
6-(3-cyanophenyl)methyloxy-3-phenyl-7, 8, 9,10-tetrahydro-(7,10-ethano)-
1, 2, 4-triazolo [3, 4-a]phthalazine;
6- [1-(3,5-dimethyl)pyrazolyl]methyloxy-3-phenyl-7,8,9, 10-tetrahydro-(7, 10-
ethano)- 1,2, 4-triazolo [3, 4-a] phthalazine;
6- [4-(2-methyl)thiazolyl]methyloxy-3-phenyl-7,8,9, 10-tetrahydro-(7, 10-
ethano)- 1,2,4-triazolo [3,4-a]phthalazine;
3-phenyl-6-(2-quinoxalinyl)methyloxy-7,8,9, 10-tetrahydro-(7, 10-ethano)-
1, 2, 4-triazolo [3, 4-a] p hthalazine;
3-phenyl-6-(3-pyridazinyl)methyloxy-7,8,9, 10-tetrahydro-(7, 10-ethano)-
1,2, 4-triazolo [3, 4-a]phthalazine;
6-(1-benzylimidazol-2-yl)methyloxy-3-phenyl-7,8,9,10-tetrahydro-(7,10-
e thano)-1, 2, 4-triazolo [3, 4-a] p hthalazine;
3-phenyl-6-(isoquinolin-1-yl)methyloxy-7,8,9, 10-tetrahydro-(7, 10-ethano)-
1,2, 4-triazolo [3, 4-a] p hthalazine;
6-(1-ethylimidazol-2-yl)methyloxy-3-phenyl-7,8,9,10-tetrahydro-(7,10-
ethano)-1, 2, 4-triazolo [3, 4-a]phthalazine;
3-phenyl-6-(1-pyrazolyl)methyloxy-7,8,9,10-tetrahydro-(7,10-ethano)-1,2,4-
triazolo[3,4-a]phthalazine;
3-phenyl-6- (N-pyrrolidinylcarbonyl)methyloxy-7, 8, 9,10-tetrahvdro-(7,10-
ethano)-1, 2, 4-triazolo [3, 4-a]phthalazine;
6-[4-(3-methyl)pyridyl]methyloxy-3-phenyl-7,8,9,10-tetrahydro-(7,10-
ethano)-1,2,4-triazolo[3,4-a]phthalazine;
3-phenyl-6-(2-quinolinyl)methyloxy-7,8,9, 10-tetrahydro-(7, 10-ethano)-
1, 2, 4-triazolo [3,4-a]phthalazine;
6-(2-imidazolyl)methyloxy-3-phenyl-7,8,9, 10-tetrahydro-(7, 10-ethano)-
1, 2, 4-triazolo [3, 4-a] p hthalazine;
3-phenyl-6-(2-thiazolyl)methyloxy-7,8,9, 10-tetrahydro-(7, 10-ethano)- 1,2,4-
triazolo[3,4-a]phthalazine;
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6-[2-(5-methyl)thiazolyl]methyloxy-3-phenyl-7,8,9,10-tetrahydro-(7,10-
ethano)-1, 2, 4-triazolo [3, 4-a]phthalazine;
6-[2-(4-methyl)thiazolyl]methyloxy-3-phenyl-7,8,9,10-tetrahydro-(7,10-
ethano)-1, 2, 4-triazolo [3,4-a]phthalazine;
6- [2-(3,5-dimethyl)pyridyl]methyloxy-3-phenyl-7,8,9, 10-tetrahydro-(7, 10-
ethano)- 1,2, 4-triazolo [3, 4-a]p hthalazine;
3-phenyl-6-(2-pyrazinyl)methyloxy-7,8,9, 10-tetrahydro-(7, 10-ethano)- 1,2,4-
triazolo[3,4-a]phthalazine;
6- [2-(4, 6-dimethyl)pyridyl] methyloxy-3-phenyl-7, 8, 9,10-tetrahydro- (7,10-
ethano)- 1, 2, 4-triazolo [3, 4-a]phthalazine;
3-phenyl-6-(4-thiazolyl)methyloxy-7,8,9, 10-tetrahydro-(7, 10-ethano)- 1,2,4-
triazolo[3,4-a]phthalazine;
6-[2-(5,6-dimethyl)pyridyl]methyloxy-3-phenyl-7,8,9,10-tetrahydro-(7,10-
ethano)-1,2,4-triazolo[3,4-a]phthalazine;
6-(4-methylimidazol-2-yl)methyloxy-3-phenyl-7,8,9, 10-tetrahydro-(7, 10-
ethano)- 1,2, 4-triazolo [3, 4-a]phthalazine;
3-phenyl-6-(4-pyrimidinyl)methyloxy-7,8,9, 10-tetrahydro-(7, 10-ethano)-
1,2, 4-triazolo [3, 4-a] p hthalazine;
6-[4-(2-ethyl)thiazolyl]methyloxy-3-phenyl-7,8,9, 10-tetrahydro-(7, 10-
ethano)-1,2,4-triazolo[3,4-a]phthalazine;
6-(6-chloropyridazin-3-yl)methyloxy-3-phenyl-7,8,9, 10-tetrahydro-(7, 10-
ethano)- 1, 2, 4-tria zolo [ 3, 4- a] p hthal azine;
6-(2-imidazolyl)methyloxy-3-(4-methylphenyl)-7,8,9,10-tetrahydro-(7,10-
ethano)-1,2,4-triazolo[3,4-a]phthalazine;
6-(4-hydroxymethylphenyl)methyloxy-3-phenyl-7,8,9, 10-tetrahydro-(7, 10-
ethano)- 1,2,4-triazolo[3,4-a]phthalazine;
6-(4-hydroxybutyl)oxy-3-phenyl-7,8,9, 10-tetrahydro-(7, 10-ethano)- 1,2,4-
triazolo[3, 4-a] p hthalazine;
6- (4-hydroxymethylcyclohexyl)methyloxy-3-phenyl-7, 8, 9,10-tetrahydro-
(7, 10-ethano)- 1,2,4-triazolo[3,4-a]phthalazine;
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6-(3-hydroxymethylphenyl)methyloxy-3-phenyl-7,8,9, 10-tetrahydro- (7, 10-
ethano)- 1,2,4-triazolo [3, 4-a]phthalazine;
6-(1-methyl-1, 2, 4-triazol-3-yl)methyloxy-3-phenyl-7, 8, 9,10-tetrahydro-
(7,10-ethano)-1, 2, 4-triazolo [3, 4-a]phthalazine;
6-(2-methyl-1,2,4-triazol-3-yl)methyloxy-3-phenyl-7,8,9, 10-tetrahydro-
(7, 10-ethano)- 1,2,4-triazolo[3,4-a]phthalazine;
3-phenyl-6-(3-cyclopropylmethyloxy-2-pyridyl)methyloxy-7,8,9, 10-
tetrahydro-(7, 10-ethano)- 1,2,4-triazolo[3,4-a]phthalazine;
3-phenyl-6-(3-ethoxy-2-pyridyl)methyloxy-7,8,9, 10-tetrahydro-(7, 10-
ethano)-1, 2, 4-triazolo [3, 4-a]phthalazine;
6- (6-methylpyridin-2-yl)methyloxy-3-p henyl-1, 2, 4-triazolo [3, 4-
a]phthalazine;
6-(1-methyl-1H-1,2,4-triazol-3-ylmethoxy)-3, 7-diphenyl-1,2,4-triazolo[4,3-
b]pyridazine;
6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-3,7-diphenyl-1,2,4-triazolo[4,3-
b]pyridazine;
3, 7-diphenyl-6-(2H-1, 2,4-triazol-3-ylmethoxy)-1,2,4-triazolo [4, 3-
b]pyridazine;
6-(2-methyl-2H-tetrazol-5-ylmethoxy)-3, 7-diphenyl-1, 2, 4-triazolo [4,3-b] -
pyridazine;
3, 7-diphenyl-6-(2-propyl-2H-1, 2, 4-triazol-3-ylmethoxy)-1, 2, 4-triazolo [4,
3-
b]pyridazine;
3, 7-diphenyl-6-(1-propyl-1H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo [4, 3-
b]pyridazine;
6-(1-methyl-1H-imidazol-4-ylmethoxy)-3,7-diphenyl-1,2,4-triazolo[4,3-
b]pyridazine; '
6- (3-methyl-3H-imidazol-4-ylmethoxy)-3, 7-diphenyl-1, 2, 4-triazolo [4, 3-
b]pyridazine;
6 - (4- methyl-4H- 1, 2, 4-triazol-3-ylmethoxy)- 3, 7-diphenyl-1, 2, 4-
triazolo [4, 3-
b]pyridazine;
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6-(5-methyl-2H- 1, 2, 4-triazol-3-ylmethoxy)-3, 7-diphenyl-1, 2, 4-triazolo
[4, 3-
b]pyridazine;
6- (3-methyl-3H-1, 2, 3-triazol-4-ylmethoxy)- 3, 7-dip henyl-1, 2, 4-triazolo
[4, 3-
b]pyridazine;
3-(4-methoxyphenyl)-6-(1-methyl-lH-1,2,4-triazol-3-ylmethoxy)-7-phenyl-
1, 2, 4-triazolo [4, 3-b] pyridazine;
6-(3-methylpyridin-2-ylmethoxy)-3-phenyl-7-(piperidin-1-yl)-1, 2, 4-
triazolo[4, 3-b]pyridazine;
7-(morpholin-4-yl)-3-phenyl-6-(pyridin-2-ylmethoxy)- 1,2,4-triazolo[4,3-
b]pyridazine;
3-phenyl-7-(pyridin-3-yl)-6-(pyridin-2-ylmethoxy)- 1,2,4-triazolo[4, 3-
b]pyridazine;
8-methyl-6-(2-methyl-2H-1, 2, 4-triazol-3-ylmethoxy)-3, 7-diphenyl-1, 2, 4-
triazolo [4, 3-b]pyridazine;
6-(1-methyl-1H-1,2,4-triazol-3-ylmethoxy)-7-(morpholin-4-yl)-3-phenyl-
1, 2, 4-triazolo [4, 3-b] pyridazine;
6-(2-methyl-2H- 1, 2,4-triazol- 3-ylmethoxy)-7-(morp holin-4-yl)-3-phenyl-
1,2,4-triazolo [4, 3-b]pyridazine;
7-cyclohexyl-6-(2-methyl-2H- 1,2,4-triazol-3-ylmethoxy)-3-phenyl- 1,2,4-
triazolo[4,3-b]pyridazine;
7-cyclohexyl-6-(1-methyl-1H-1,2,4-triazol-3-ylmethoxy)-3-phenyl-1,2, 4-
triazolo [4, 3-b]pyridazine;
7 -cyclopentyl-6-(2-methyl-2H- 1,2,4-triazol-3-ylmethoxy)- 3-phenyl- 1, 2, 4-
triazolo [4, 3-b]pyridazine;
8-methyl-6-(1-methyl-1H-1,2,4-triazol-3-ylmethoxy)-3,7-diphenyl-1,2,4-
triazolo [4, 3-b]pyridazine;
7-cyclobutyl-6-(1-methyl-lH-1,2,4-triazol-3-ylmethoxy)-3-phenyl-1, 2, 4-
triazolo [4, 3-b]pyridazine;
7-tert-butyl-6-(2-methyl-2H- 1,2,4-triazol-3-ylmethoxy)-3-phenyl- 1, 2, 4-
triazoio[4,3-b]pyridazine;
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7-cyclobutyl-6-(2-methyl-2H-1, 2, 4-triazol-3-ylmethoxy)-3-phenyl-1, 2,4-
triazolo [4, 3-b]pyridazine;
7-ethyl-6-(2-methyl- 2H-1, 2, 4-triazol-3-ylmethoxy)-3-phenyl-1, 2, 4-
triazolo [4, 3-b]pyridazine;
7-tert-butyl-6-(1-methyl-lH-1,2,4-triazol-3-ylmethoxy)-3-phenyl-1,2,4-
triazolo[4, 3-b]pyridazine;
7-ethyl-6-(1-methyl-1H-1,2,4-triazol-3-ylmethoxy)-3-phenyl-1,2,4-
triazolo [4, 3-b]pyridazine;
7-methyl-6-(2-methyl-2H- 1,2, 4-triazol- 3-ylmethoxy)- 3-p henyl-1, 2, 4-
triazolo[4,3-b]pyridazine;
7-(1-methylcyclobutyl)-6-(2-methyl-2H-1, 2,4-triazol-3-ylmethoxy)-3-
phenyl-1, 2, 4-triazolo [4, 3-b]pyridazine;
7-methyl-6-(1-methyl-lH-1,2,4-triazol-3-ylmethoxy)-3-phenyl-1,2,4-
triazolo [4, 3-b]pyridazine;
7-cyclobutyl-3-phenyl-6-(2H- 1,2,4-triazol-3-ylmethoxy)- 1,2,4-triazolo [4,3-
b]pyridazine;
7-cyclopentyl-6-(pyridin-2-ylmethoxy)-3-(thiophen-2-yl)-1,2,4-triazolo [4, 3-
b]pyridazine;
7-cyclopentyl-3-(2,4-difluorophenyl)-6-(1-methyl-1H-1, 2,4-triazol-3-
ylmethoxy)- 1,2,4-triazolo[4,3-b]pyridazine;
7 -cyclopentyl-6- (1-methyl-1H-1, 2, 4-triazol-3-ylmethoxy)- 3-(thiop hen-2-
yl) -
1, 2, 4-triazolo [4, 3-b]pyridazine;
7-cyclopentyl-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(thiophen-2-yl)-
1, 2, 4-triazolo [4, 3-b] pyridazine;
7-cyclopentyl-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(pyridin-4-yl)-
1, 2, 4-triazolo [4, 3-b]pyridazine;
7-cyclopentyl-3-(2-fluorophenyl)-6-(1-methyl-lH-1, 2,4-triazol-3-
ylmethoxy)-1,2,4-triazolo [4, 3-b]pyridazine;
7 -cyclopentyl-3-(2-fluorophe nyl)-6-(2-methyl-2H-1, 2, 4-triazol-3-
ylmethoxy)-1,2,4-triazolo[4,3-b]pyridazine;
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7-cyclopentyl-3-(2-fluorophenyl)-6-(pyridin-2-ylmethoxy)- 1, 2, 4-triazolo [4,
3-
b]pyridazine;
7-cyclopentyl-3-(2, 4-difluorophenyl)-6-(2-methyl-2H-1, 2, 4-triazol-3-
ylmethoxy)-1, 2, 4-triazolo [4, 3-b]pyridazine;
7-cyclopentyl-3-phenyl-6-(pyridin-2-ylmethoxy)- 1,2, 4-triazolo [4, 3-
b]pyridazine;
7-cyclopentyl-8-methyl-6-(2-methyl-2H- 1,2, 4-triazol-3-ylmethoxy)-3-
phenyl-1, 2, 4-triazolo [4, 3-b]pyridazine;
7-cyclopentyl-3-phenyl-6-(2H- 1,2,4-triazol-3-ylmethoxy)- 1,2,4-triazolo[4,3-
b]pyridazine;
3-(4-methylphenyl)-7-phenyl-6-(pyridin-2-ylmethoxy)- 1,2, 4-triazolo [4, 3-
b]pyridazine;
3-(4-methylphenyl)-6-(3-methylpyridin-2-ylmethoxy)-7-phenyl- 1,2,4-
triazolo[4,3-b]pyridazine;
6-(1-ethyl-lH-imidazol-2-ylmethoxy)-3-(4-methylphenyl)-7-phenyl-1,2,4-
triazolo [4, 3-b]pyridazine;
3-p henyl-6-(pyridin-2-ylmethoxy)-7-(thiomorp holin-4-yl)-1, 2, 4-triazolo [4,
3-
b]pyridazine;
6-[2-(4-methylthiazol-5-yl)ethoxy]-3, 7-diphenyl-1,2,4-triazolo [4,3-
b]pyridazine;
(f)-7-(2-methylpyrrolidin-1-yl)-3-p 1-yl)-3-phenyl-6-(pyridin-2-ylme2, 4-
triazolo [4, 3-b]pyridazine;
6-(1-methyl-1H-1,2,4-triazol-3-ylmethoxy)-3-phenyl-7-(pyridin-4-yl)-1,2,4-
triazolo [4, 3-b]pyridazine;
7-cyclopentyl-6-(1-methyl-lH-1,2,4-triazol-3-ylmethoxy)-3-phenyl-1,2,4-
triazolo[4, 3-b]pyridazine;
7-isopropyl-6-(1-methyl-1H-1,2,4-triazol-3-ylmethoxy)-3-phenyl-1,2,4-
triazolo [4, 3-b]pyridazine;
3-cyclopropyl-6-(1-methyl-IH-1,2,4-triazol-3-ylmethoxy)-7-phenyl-1,2,4-
triazolo[4,3-b]pyridazine;
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3-(2-fluorophenyl)-6-(2-methyl-2H- 1,2,4-triazol-3-ylmethoxy)-7-phenyl-
1, 2,4-triazolo [4, 3-b]pyridazine;
3-(2-fluorophenyl)-6-(1-methyl-lH-1, 2, 4-triazol-3-ylmethoxy)-7-phenyl-
1, 2, 4-triazolo [4, 3-b]pyridazine;
6-(1-methyl-lH-1,2,4-triazol-3-ylmethoxy)-7-phenyl-3-(thiophen-2-yl)-
1, 2, 4-triazolo [4, 3-b]pyridazine;
6-(1-methyl-lH-1, 2,4-triazol-3-ylmethoxy)- 7-phenyl- 3- (pyridin-3-vl)-1, 2,
4-
triazolo[4, 3-b]pyridazine;
6-(2-methyl-2H- 1,2, 4-triazol-3-ylmethoxy)-7-phenyl-3-(thiophen-2-yl)-
1 , 2, 4-triazolo [4, 3-b]pyridazine;
6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-7-phenyl-3-(pyridin-3-yl)-1,2,4-
triazolo [4, 3-b] pyridazine;
3-(furan-3-yl)-6-(1-methyl-lH-1,2,4-triazol-3-ylmethoxy)-7-phenyl-1,2,4-
triazolo [4, 3-b]pyridazine;
6-(1-methyl-1H-1,2,4-triazol-3-ylmethoxy)-7-phenyl-3-(thiophen-2-yl)-
1, 2, 4-triazolo [4, 3-b]pyridazine;
6-(5-methyl- 1,2, 4-oxadiazol-3-ylmethoxy)-3, 7-diphenyl-1, 2, 4-triazolo [4,
3-
b]pyridazine;
7-phenyl-3-(thiophen-2-yl)-6- (2H-1, 2, 4-triazol-3-ylmethoxy)-1, 2, 4-
triazolo[4,3-b]pyridazine;
3-(furan-2-yl)-6-(1-methyl-1H-1,2,4-triazol-3-ylmethoxy)-7-phenyl-1,2,4-
triazolo[4, 3-b]pyridazine;
6-(1-methyl-lH-1,2, 4-triazol-3-ylmethoxy)-3-phenyl-7-(thiophen-3-yl)-
1, 2, 4-triazolo [4, 3-b]pyridazine;
6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-7-(thiophen-3-yl)-1,2,4-
triazolo[4, 3-b]pyridazine;
3-phenyl- 7-(thiophen-3-yl)-6-(2H- 1,2,4-triazol-3-ylmethoxy)- 1,2,4-
triazolo[4, 3-b] pyridazine;
6-(2-methyl-2H- 1,2,4-triazol-3-ylmethoxy)-3-phenyl-7-(thiophen-2-yl)-
1,2, 4-triazolo[4, 3-b]pyridazine;
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6-(1-methyl-lH-1, 2, 4-triazol-3-ylmethoxy)-3-phenyl-7-(thiophen-2-yl)-
1, 2, 4-triazolo [4, 3-b]pyridazine;
7-(furan-2-yl)-6-(2-methyl-2H- 1,2,4-triazol-3-ylmethoxy)-3-phenyl- 1,2,4-
triazolo [4, 3-b]pyridazine;
7-(furan-2-yl)-6-(1-methyl-lH-1,2,4-triazol-3-ylmethoxy)-3-phenyl-1,2,4-
triazolo [4, 3-b]pyridazine;
6-(3-methyl- 1, 2, 4-oxadiazol-5-ylmethoxy)-3, 7-diphen,yl-1, 2, 4-triazolo
[4, 3-
b]pyridazine;
3-(4-fluorophenyl)-6-(1-methyl-1H-1, 2, 4-triazol-3-ylmethoxy)-7-phenyl-
1, 2, 4-triazolo [4, 3-b] pyridazine;
3, 7-diphenyl-6-(2H-1, 2, 3-triazol-4-ylmethoxy)-1, 2, 4-triazolo [4, 3-
b]pyridazine;
3, 7-diphe nyl-6-(pyrazin-2-ylmethoxy)-1, 2, 4-tria zolo [4, 3-b] pyridazine;
3-(4-methylphenyl)-6-(1-methyl-1H-1, 2, 4-triazol- 3-ylmethoxy)-7-phenyl-
1 , 2, 4-triazolo [4, 3-b] pyridazine;
6- (4-methylthiazol- 2-ylmethoxy)- 3, 7-dip he nyl- 1,2, 4-triazolo [4, 3-
b]pyridazine;
6-(5-methylthiazol-2-ylmethoxy)-3, 7-diphenyl-1, 2, 4-triazolo [4, 3-
b]pyridazine;
3,7-diphenyl-6-(pyrimidin-4-ylmethoxy)-1,2,4-triazolo[4,3-b]pyridazine;
3,7-diphenyl-6-(pyridazin-3-ylmethoxy)-1,2,4-triazolo[4, 3-b]pyridazine;
6-(1-methyl-1H-1,2, 4-triazol-3-ylmethoxy)-7-(morpholin-4-yl)-3-(thiophen-
2-yl)-1, 2, 4-triazolo [4, 3-b]pyridazine;
3, 7-diphenyl-6-(thiazol-4-ylmethoxy)-1, 2, 4-triazolo [4, 3-b]pyridazine;
6-(5-methylisoxazol-3-ylmethoxy)-3,7-diphenyl-1,2,4-triazolo[4,3-
b]pyridazine;
3-(3-fluorophenyl)-6-(1-methyl-1H-1,2,4-triazol-3-ylmethoxy)-7-(morpholin-
4-yl)-1, 2, 4-triazolo [4, 3-b]pyridazine;
3, 7-diphenyl-6-(pyrimidin-2-ylmethoxy)-1, 2, 4-triazolo [4, 3-b] pyridazine;
6-(2-methyl-2H-1,2,3-triazol-4-ylmethoxy)-3,7-diphenyl-1,2,4-triazolo[4,3-
b]pyridazine;
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7-(1-methylcyclobutyl)-6-(1-methyl-lH-1, 2, 4-triazol-3-ylmethoxy)-3-
phenyl-1, 2, 4-triazolo [4, 3-b]pyridazine;
7-isopropyl-6-(2-methyl-2H-1, 2,4-triazol-3-ylmethoxy)-3-phenyl-1, 2, 4-
triazolo [4, 3 -b] pyridazine;
7-tert-butyl-3-(2-fluorophenyl)-6-(1-methyl-lH-1,2,4-triazol-3-ylmethoxy)-
1, 2, 4-triazolo [4, 3-b]pyridazine;
7-cyclopentyl-3-(4-methoxyphenyl)-6-(2-methyl-2H- 1,2, 4-triazol-3-
ylmeth,oxy)-1, 2, 4-triazolo [4, 3-b]pyridazine;
7- (1-methylcyclop entyl)-6-(1-methyl-lH-1, 2, 4-triazol- 3-ylmethoxy)-3-
phenyl-1,2,4-triazolo[4,3-b]pyridazine;
7-(1-methylcyclopentyl)-6-(2-methyl-2H-1, 2, 4-triazol-3-ylmethoxy)-3-
phenyl-1, 2, 4-triazolo [4, 3-b]pyridazine;
7-cyclopentyl-3-(furan-2-yl)-6-(2-methyl-2H- 1,2,4-triazol- 3-ylmethoxy)-
1, 2, 4-triazolo [4, 3-b] pyridazine;
7-cyclopentyl-3-(furan-2-yl)-6-(1-methyl-1H-1,2,4-triazol-3-ylmethoxy)-
1, 2, 4-triazolo [4, 3-b]pyridazine;
3-(3, 7-diphe nyl-1, 2, 4-triazolo [4, 3-b] pyridazin-6-yloxymethyl) -1, 2, 4-
triazol-
1-ylacetonitrile;
7-(1-methylcyclopropyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-3-
phenyl-1,2,4-triazolo[4,3-b]pyridazine;
7-(1-methylcyclopropyl)-6-(1-methyl-lH-1, 2,4-triazol-3-ylmethoxy)-3-
phenyl-1, 2, 4-triazolo [4, 3-b]pyridazine;
3-(3-fluorophenyl)-6-(1-methyl-1H-1, 2, 4-triazol-3-ylmethoxy) - 7-phenyl-
1, 2, 4-triazolo [4, 3-b] pyridazine;
7-(1-methylcyclopentyl)-6-(3-methylpyridin-2-ylmethoxy)-3-phenyl-1,2,4-
triazolo [4, 3-b] pyridazine;
6-(1-methyl-lH-1, 2, 3-triazol-4-ylmethoxy)-3, 7-dip henyl-1, 2, 4-triazolo
[4, 3-
b]pyridazine;
3-(5-methylthiophen-2-yl)-6-(1-methyl-1H-1, 2, 4-triazol-3-ylmethoxy)- 7-
p henyl-1, 2, 4-triazolo [4, 3-b]pyridazine;
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2- [3-(3, 7-diphenyl-1, 2, 4-triazolo [4, 3-b]pyridazin-6-yloxymethyl)-1,2, 4-
triazol-l-yl] -N,N-dimethylacetamide;
3, 7-diphenyl-6-[1-(pyridin-2-ylmethyl)-IH-1,2,4-triazol-3-ylmethoxy]-1, 2,4-
triazolo [4, 3-b]pyridazine;
6-(1-benzyl-1H-1,2,4-triazol-3-ylmethoxy)-3,7-diphenyl-1,2,4-triazolo[4,3-
b]pyridazine;
2- [5-(3, 7-diphenyl-1, 2, 4-triazolo [4, 3-b]pyridazin-6-yloxymethyl)-1,2, 4-
triazol-l-yl] acetamide;
N- [2- [3-(3,7-diphenyl- 1, 2,4-triazolo[4,3-b]pyridazin-6-yloxymethyl)- 1,2,4-
triazol-l-yl]ethyl]-N,N-dimethylamine;
3, 7-diphenyl-6-(pyrimidin-5-ylmethoxy)-1, 2, 4-triazolo [4, 3-b]pyridazine;
6- [1-(2- (morpholin-4-yl)-ethyl)- IH-1,2, 4-triazol-3-ylmethoxy] -3, 7-
diphenyl-
1, 2,4-triazolo [4, 3-b]pyridazine;
6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-3-phenyl-7-(pyrrolidin-l-yl)-
1 , 2,4-triazolo [4, 3-b]pyridazine;
7- (5-chlorothiophen-2-yl)-6-(2-methyl-2H-1, 2, 4-triazol-3-ylmethoxy)-3-
phenyl-1, 2, 4-triazolo [4, 3-b]pyridazine;
7-(5-chlorothiophen-2-yl)-6-(1-methyl-1H-1, 1H-1,2,4-triazol-3-ylmethoxy)-3-
phen2, 4-triazolo [4, 3-b]pyridazine;
6-(IH-benzimidazol-2-ylmethoxy)-3-(2,4-difluorophenyl)-7-(1-
methylcyclopentyl)-1, 2, 4-triazolo [4, 3-b] pyridazine;
3-(furan-3-yl)-6-(2-pyridyl)methyloxy-7,8,9, 10-tetrahydro- 1,2,4-
triazolo[3, 4-a]phthalazine;
7-cyclobutyl-3-phenyl-6-(prop-2-ynyloxy)- 1,2,4-triazolo [4, 3-b]pyridazine;
(7-cyclobutyl-3-phenyl-1,2,4-triazolo[4,3-b]pyridazin-6-yloxy)acetonitrile;
N- [4-(7-cyclobutyl-3-phenyl-1, 2, 4-triazolo [4, 3-b]pyridazin-6-yloxy)but-2-
ynyl] -N, N-dime thylamine;
2- [3-(3, 7-diphenyl-1,2,4-triazolo[4, 3-b]pyridazin-6-yloxymethyl)-1,2,4-
triazol-l-yl] ethylamine;
3,7-diphenyl-6-[1-(2-(pyrrolidin-1-yl)ethyl)-1H-1,2,4-triazol-3-ylmethoxy]-
1, 2, 4-triazolo [4, 3-b] pyridazine;
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6- [1-(1-methylpiperidin-4-yl)-1H-1, 2, 4-triazol-3-ylmethoxy] -3, 7-diphenyl-
1, 2, 4-triazolo [4, 3-b]pyridazine;
3, 7-diphenyl-6- [1-(2-(piperazin-l-yl)ethyl)-1H-1, 2, 4-triazol-3-ylmethoxy] -
1,2,4-triazolo[4, 3-b]pyridazine;
7-(1-methylcyclopentyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2,4-
difluorophenyl)-1, 2, 4-triazolo [4, 3-b]pyridazine;
7-(cyclobut- 1-enyl)-6-(2-methyl-2H- 1,2, 4-triazol-3-ylmethoxy)- 3-p henyl-
1, 2, 4-triazolo [4, 3-b] pyridazine;
7-(furan-3-yl)-6-(1-methyl-lH-1,2,4-triazol-3-ylmethoxy)-3-phenyl-1,2,4-
triazolo[4,3-b]pyridazine;
N,N-diethyl-N- [6-(1-methyl-1H-1,2,4-triazol-3-ylmethoxy)-3-phenyl-1,2,4-
triazolo [4, 3-b]pyridazin-7-yl] amine;
7-(1-methylcyclopentyl)-6-(1-methyl-1H-1,2,4-triazol-3-ylmethoxy)-3-(2,4-
difluorophenyl)-1, 2, 4-triazolo [4, 3-b]pyridazine;
7-(1,1-dimethylpropyl)-6-(1-methyl-1H-1,2,4-triazol-3-ylmethoxy)-3-
phenyl-1, 2, 4-triazolo [4, 3-b]pyridazine;
6-(2-methyl-2H- 1, 2,4-triazol-3-ylmethoxy)-3-(4-fluorophenyl)-7-(thiophen-
3-yl)-1, 2, 4-triazolo [4, 3-b] pyridazine;
6-(1-methyl-1H-1,2, 1,2,4-triazol-3-ylmethoxy)-3-(4-fluorophenyl) - 7-(thiophe
3-yl)- 1, 2, 4-triazolo [4, 3-b]pyridazine;
6-(2-methyl-2H- 1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-7-(thiophen-
3-yl)- 1,2, 4-triazolo [4, 3-b]pyridazine;
3-(2-fluorophenyl)-7-(1-methylcyclobutyl)-6-(2-methyl-2H-1, 2, 4-triazol-3-
ylmethoxy)-1, 2, 4-triazolo [4, 3-b]pyridazine;
3-(2-fluorophenyl)-7-(1-methylcyclobutyl)-6-(1-methyl-1H-1,2,4-triazol-3-
ylmethoxy)-1, 2, 4-triazolo [4, 3-b]pyridazine;
6- (1-methyl-1H-1, 2, 4-triazol-3-ylmethoxy)- 3-(2-fluorop he nyl)- 7- (thiop
he n-
3-yl)-1, 2, 4-triazolo [4, 3-b]pyridazine;
8-methyl-7-(1-methylcyclobutyl)-6-(1-methyl-1H-1, 2, 4-triazol-3-
ylmethoxy)-3-phenyl-1,2,4-triazolo[4,3-b]pyridazine;
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8-methyl-7-(1-methylcyclobutyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-3-
phenyl-1,2,4-triazolo[4,3-b]pyridazine;
6-(1-methyl-lH-1,2,4-triazol-3-ylmethoxy)-3-phenyl-7-(pyrrolidin-l-yl)-1,2,4-
triazolo[4,3-b]pyridazine;
7-cyclobutyl-8-methyl-6-(2-methyl-2H- 1,2,4-triazol-3-ylmethoxy)-3-phenyl-
1,2,4-
triazolo[4, 3 -b] pyridazine;
7-cyclobutyl-8-methyl-6-(1-methyl-1 H- 1,2,4-triazol-3-ylmethoxy)-3-phenyl-
1,2,4-
triazolo[4,3-b]pyridazine;
7-(1-methylcyclopentyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-3 -(2-
fluorophenyl)- 1,2,4-triazolo[4,3-b]pyridazine;
7-(1-methylcyclopentyl)-6-(1-methyl-1 H- 1,2,4-triazol-3-ylmethoxy)-3-(2-
fluorophenyl)- 1,2,4-triazolo[4,3-b]pyridazine;
7-cyclobutyl-6- [4-(2,6-dimethylmorpholin-4-yl)but-2-ynyloxy]-3-phenyl-1,2,4-
triazolo[4,3-b]pyridazine;
and salts and prodrugs thereof.
Also provided by the present invention is use of a compound of the
invention, or a pharmaceutically acceptable salt thereof or a prodrug thereof,
for
the manufacture of a medicament for the treatment and/or prevention of anxiety
or
the treatment and/or prevention of convulsions.
There is also provided by the invention use of a compound of the invention,
or a pharmaceutically acceptable salt thereof or a prodrug thereof, for the
manufacture of a medicament for the treatment and/or prevention of anxiety
with
substantially no sedation.
Also provided by the present invention is a compound of the invention, or a
pharmaceutically acceptable salt thereof or a prodrug thereof, for use in the
treatment and/or prevention of anxiety or for use in the treatment and/or
prevention of convulsions.
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- 33a -
Also provided by the present invention is a pharmaceutical composition for
the treatment and/or prevention of anxiety, comprising a compound of the
invention, or a pharmaceutically acceptable salt thereof or a prodrug thereof,
in
association with a pharmaceutically acceptable carrier.
Also provided by the present invention is a pharmaceutical composition for
the treatment and/or prevention of convulsions comprising a compound of the
invention, or a pharmaceutically acceptable salt thereof or a prodrug thereof,
in
association with a pharmaceutically acceptable carrier.
Also provided by the present invention is a method for the treatment and/or
prevention of anxiety which comprises administering to a patient in need of
such
treatment an effective amount of a compound of formula I as defined above or a
pharmaceutically acceptable salt thereof or a prodrug thereof.
Further provided by the present invention is a method for the treatment
and/or prevention of convulsions (e.g. in a patient suffering from epilepsy or
a
related disorder) which comprises administering to a patient in need of such
treatment an effective amount of a compound of formula I as defined above or a
pharmaceutically acceptable salt thereof or a prodrug thereof.
In another aspect, the present invention provides a non-sedating anxiolytic
compound which is a modulator of the benzodiazepine binding site of the human
GABAA receptor, having a binding affinity (K;) for the 0 subunit of the human
GABAA receptor of 10 nM or less, which elicits at least a 40% potentiation of
the
GABA EC20 response in stably transfected
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recombinant cell lines expressing the a3 subunit of the human GABAA
receptor, and which elicits at most a 30% potentiation of the GABA EC20
response in stably transfected cell lines expressing the al subunit of the
human GABAA receptor.
In this aspect of the invention, the binding affinity (Ki) of
compounds for the a3 subunit of the human GABAA receptor is
conveniently as measured in the assay described hereinbelow. The a3
subunit binding affinity (K;) of compounds fulfilling this aspect of the
invention is 10 nM or less, preferably 2 nM or less, and more preferably 1
nM or less.
In this aspect of the invention, the potentiation of the GABA EC20
response in stably transfected cell lines expressing the a3 and al subunits
of the human GABAA receptor can conveniently be measured by
procedures analogous to the protocol described in Wafford et al., Mol.
Pharmacol., 1996, 50, 670-678. The procedure will suitably be carried out
utilising cultures of stably transfected eukaryotic cells, typically of stably
transfected mouse Ltk- fibroblast cells.
The compounds fulfilling this aspect of the invention will elicit at
least a 40%, preferably at least a 50%, and more preferably at least a 60%,
potentiation of the GABA EC2o response in stably transfected recombinant
cell lines expressing the a3 subunit of the human GABAA receptor.
Moreover, the compounds fulfilling this aspect of the invention will elicit
at most a 30%, preferably at most a 20%, and more preferably at most a
10%, potentiation of the GABA ECao response in stably transfected
recombinant cell lines expressing the al subunit of the human GABAk
receptor.
The compounds fulfilling this aspect of the invention exhibit
anxiolytic activity, as demonstrated by a positive response in the elevated
plus maze and conditioned suppression of drinking tests (cf. Dawson et al.,
Psychopharn2acology, 1995, 121, 109-117). Moreover, the compounds
fulfilling this aspect of the invention are substantially non-sedating, as
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confirmed by an appropriate result obtained from the response sensitivity
(chain-pulling) test (cf. Bayley et al., J. Psychopharmacol., 1996, 10, 206-
213).
The compounds fulfilling this aspect of the invention also exhibit
anticonvulsant activity. This is demonstrated by their ability to block
pentylenetetrazole-induced seizures in rats and mice, following a protocol
analogous to that described by Bristow et al. in J. Pharmacol. Exp. Ther.,
1996, 279, 492-501.
In order to elicit their behavioural effects, the compounds fulfilling
this aspect of the invention will be brain-penetrant; in other words, these
compounds will be capable of crossing the so-called "blood-brain barrier".
Preferably, the compounds fulfilling this aspect of the invention will be
capable of exerting their beneficial therapeutic action following
administration by the oral route.
A representative compound fulfilling this aspect of the invention is
7-cyclobutyl-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-3-phenyl-1,2,4-
triazolo [4, 3-b]pyridazine.
In a further aspect, the present application provides a method of
screening for non-sedating anxiolytic compounds, which comprises:
(1) contacting a panel of test compounds with (a) a stably
transfected recombinant cell line expressing the a3 subunit of the human
GABAA receptor; and (b) a stably transfected recombinant cell line
expressing the al subunit of the human GABAA receptor;
(2) measuring the potentiation of the GABA ECzo response elicited
by each test compound in each of the stably transfected cell lines (a) and
(b); and
(3) selecting out those test compounds which elicit at least a 40%
potentiation of the GABA EC2o response in the cell line expressing the a3
subunit, and at most a 30% potentiation of the GABA ECzo response in the
cell line expressing the al subunit.
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The invention also provides pharmaceutical compositions
comprising one or more compounds of this invention in association with a
pharmaceutically acceptable carrier. Preferably these compositions are in
unit dosage forms such as tablets, pills, capsules, powders, granules,
sterile parenteral solutions or suspensions, metered aerosol or liquid
sprays, drops, ampoules, auto-injector devices or suppositories; for oral,
parenteral, intranasal, sublingual or rectal administration, or for
administration by inhalation or insufflation. For preparing solid
compositions such as tablets, the principal active ingredient is mixed with
a pharmaceutical carrier, e.g. conventional tableting ingredients such as
corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium
stearate, dicalcium phosphate or gums, and other pharmaceutical
diluents, e.g. water, to form a solid preformulation composition containing
a homogeneous mixture of a compound of the present invention, or a
pharmaceutically acceptable salt thereof. When referring to these
preformulation compositions as homogeneous, it is meant that the active
ingredient is dispersed evenly throughout the composition so that the
composition may be readily subdivided into equally effective unit dosage
forms such as tablets, pills and capsules. This solid preformulation
composition is then subdivided into unit dosage forms of the type described
above containing from 0.1 to about 500 mg of the active ingredient of the
present invention. Typical unit dosage forms contain from 1 to 100 mg, for
example 1, 2, 5, 10, 25, 50 or 100 mg, of the active ingredient. The tablets
or pills of the novel composition can be coated or otherwise compounded to
provide a dosage form affording the advantage of prolonged action. For
example, the tablet or pill can comprise an inner dosage and an outer
dosage component, the latter being in the form of an envelope over the
former. The two components can be separated by an enteric layer which
serves to resist disintegration in the stomach and permits the inner
component to pass intact into the duodenum or to be delayed in release. A
variety of materials can be used for such enteric layers or coatings, such
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materials including a number of polymeric acids and mixtures of polymeric
acids with such materials as shellac, cetyl alcohol and cellulose acetate.
The liquid forms in which the novel compositions of the present
invention may be incorporated for administration orally or by injection
include aqueous solutions, suitably flavoured syrups, aqueous or oil
suspensions, and flavoured emulsions with edible oils such as cottonseed
oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar
pharmaceutical vehicles. Suitable dispersing or suspending agents for
aqueous suspensions include synthetic and natural gums such as
tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose,
methylcellulose, polyvinyl-pyrrolidone or gelatin.
In the treatment of anxiety, a suitable dosage level is about 0.01 to
250 mg/kg per day, preferably about 0.05 to 100 mg/kg per day, and
especially about 0.05 to 5 mg/kg per day. The compounds may be
administered on a regimen of 1 to 4 times per day.
The compounds of formula I as defined above may be prepared by a
process which comprises reacting a compound of formula III with a
compound of formula IV:
N-N
Y R'
~ N Rz - OH
iN
Z
L'
(III) (IV)
wherein Y, Z, Rl and R2 are as defined above; and L1 represents a suitable
leaving group.
The leaving group L1 is typically a halogen atom, especially chloro.
The reaction between compounds III and IV is conveniently effected
by stirring the reactants in a suitable solvent, typically N,1V dimethyl-
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formamide, in the presence of a strong base such as sodium hydride or
lithium bis(trimethylsilyl)amide.
The intermediates of formula III above may be prepared by reacting
a compound of formula V with a substantially equimolar amount of a
hydrazine derivative of formula VI:
L2
y O
N ~
~ I
-- N R' NHNH2
Z
L1
m (VI)
wherein Y, Z, Rl and Ll are as defined above, and L2 represents a suitable
leaving group; followed, if necessary, by separation of the resulting
mixture of isomers by conventional means.
The leaving group L2 is typically a halogen atom, especially chloro.
In the intermediates of formula V, the leaving groups Li and L2 may be
the same or different, but are suitably the same, preferably both chloro.
The reaction between compounds V and VI is conveniently effected
by heating the reactants in the presence of a base such as triethylamine,
typically at reflux in an inert solvent such as xylene or 1,4-dioxane.
Where Y and Z are different, the reaction between compounds V and
VI will, as indicated above, usually give rise to a mixture of isomeric
products depending upon whether the hydrazine derivative VI displaces
the leaving group L1 or L2. Thus, in addition to the required product of
formula III, the isomeric compound wherein the Y and Z moieties are
reversed will usually be obtained to some extent. For this reason it will
generally be necessary to separate the resulting mixture of isomers by
conventional methods such as chromatography.
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In another procedure, the compounds of formula I as defined above
may be prepared by a process which comprises reacting a compound of
formula VII with a compound of formula VIII:
N-N
Y ~ -R'
, N
iN R'2-La
Z
OH
(ViI) (VIII)
wherein Y, Z, R1 and R2 are as defined above; and L3 represents a suitable
leaving group.
The leaving group L3 is suitably a halogen atom, typically chloro or
bromo.
The reaction between compounds VII and VIII is conveniently
effected by stirring the reactants in a suitable solvent, typically N,N-
dimethylformamide, in the presence of a strong base such as sodium
hydride.
The intermediates of formula VII above may conveniently be
prepared by reacting a compound of formula III as defined above with an
alkali metal hydroxide, e.g. sodium hydroxide. The reaction is
conveniently effected in an inert solvent such as aqueous 1,4-dioxane,
ideally at the reflux temperature of the solvent.
In a further procedure, the compounds of formula I as defined above
may be prepared by a process which comprises reacting a compound of
formula Z-COzH with a compound of formula IX:
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-
N-N
Y / x R
I ~
N
y N
O1-1 R2
(IX)
wherein Y, Z, R1 and R2 are as defined above; in the presence of silver
nitrate and ammonium persulphate.
The reaction is conveniently carried out under acidic conditions in a
suitable solvent, for example using sulphuric acid in water or aqueous
acetonitrile, typically at an elevated temperature.
The intermediates of formula IX correspond to the compounds of
formula I as defined above wherein Z is hydrogen, and they may therefore
be prepared by methods analogous to those described above for preparing
the corresponding compounds of formula I.
In a still further procedure, the compounds of formula I as defined
above may be prepared by a process which comprises reacting a compound
of formula X with a compound of formula XI:
N-N
Y L4
I N
N R' - Sn(Alk)3
Z
O1-1 R2
(X) (XI)
wherein Y, Z, R1 and R2 are as defined above, Alk represents a C1_c alkyl
group, typically n-butyl, and L4 represents a suitable leaving group; in the
presence of a transition metal catalyst.
The leaving group L4 is suitably a halogen atom, e.g. bromo.
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A suitable transition metal catalyst of use in the reaction between
compounds X and XI comprises dichlorobis(triphenylphosphine)-
palladium(II).
The reaction between compounds X and XI is conveniently effected
in an inert solvent such as N,N-dimethylformamide, typically at an
elevated temperature.
The intermediates of formula X may be prepared by reacting a
compound of formula IV as defined above with a compound of formula XII:
N-N
\
Y ~ C
I N
I
iN
Z
Li
(XII)
wherein Y, Z, L1 and L4 are as defined above; under conditions analogous
to those described above for the reaction between compounds III and IV.
Where they are not commercially available, the starting materials
of formula IV, V, VI, VIII, XI and XII may be prepared by methods
analogous to those described in the accompanying Examples, or by
standard methods well known from the art.
It will be understood that any compound of formula I initially
obtained from any of the above processes may, where appropriate,
subsequently be elaborated into a further compound of formula I by
techniques known from the art. For example, a compound of formula IJ or
IK as defined above wherein R3 is hydrogen can be subjected to catalytic
hydrogenation under standard conditions to afford the corresponding
compound of formula IG or IH respectively wherein R4 is hydrogen.
Moreover, a compound of formula IG or IH as defined above wherein R4 is
hydrogen may be converted into the corresponding compound wherein R4
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is C1_6 alkyl by a conventional reductive alkylation procedure, for example
by treatment with the appropriate aldehyde or ketone in the presence of a
reducing agent such as sodium cyanoborohydride. Similarly, a compound
of formula I initially obtained wherein R2 is unsubstituted may be
converted into a corresponding compound wherein R2 is substituted,
typically by standard alkylation procedures, for example by treatment
with a haloalkyl derivative in the presence of sodium hydride and
N,N-dimethylformamide, or with a hydroxyalkyl derivative in the
presence of triphenylphosphine and diethyl azodicarboxylate.
Furthermore, a compound of formula I initially obtained wherein R2
represents cyano(C1_6)alkyl may be converted into the corresponding
3-substituted 1,2,4-triazol-5-yl(C1.6)alkyl analogue by treatment with the
appropriate acyl hydrazine derivative in the presence of a base such as
sodium methoxide. Similarly, a compound of formula I initially obtained
wherein R2 represents an optionally substituted propargyl moiety may be
converted into the corresponding 1,2,3-triazolylmethyl analogue by
treatment with azide anion. A compound of formula I initially obtained
wherein the R2 substituent is substituted by a halogen atom, e.g. chloro,
may be converted into the corresponding compound wherein the R2
substituent is substituted by a di(C1.6)alkylamino moiety by treatment
with the appropriate di(C1_6)alkylamine, typically with heating in a solvent
such as 1,4-dioxane in a sealed tube.
Where the above-described processes for the preparation of the
compounds according to the invention give rise to mixtures of
stereoisomers, these isomers may be separated by conventional techniques
such as preparative chromatography. The novel compounds may be
prepared in racemic form, or individual enantiomers may be prepared
either by enantiospecific synthesis or by resolution. The novel compounds
may, for example, be resolved into their component enantiomers by
standard techniques such as preparative HPLC, or the formation of
diastereomeric pairs by salt formation with an optically active acid, such
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as (-)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-l-tartaric acid,
followed by fractional crystallization and regeneration of the free base.
The novel compounds may also be resolved by formation of diastereomeric
esters or amides, followed by chromatographic separation and removal of
the chiral auxiliary.
During any of the above synthetic sequences it may be necessary
and/or desirable to protect sensitive or reactive groups on any of the
molecules concerned. This may be achieved by means of conventional
protecting groups, such as those described in Protective Groups in Organic
Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene &
P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons,
1991. The protecting groups may be removed at a convenient subsequent
stage using methods known from the art.
The following Examples illustrate the preparation of compounds
according to the invention.
The compounds in accordance with this invention potently inhibit
the binding of [3H]-flumazenil to the benzodiazepine binding site of human
GABAA receptors containing the a2 or a3 subunit stably expressed in Ltk-
cells.
Reagents
= Phosphate buffered saline (PBS).
= Assay buffer: 10 mM KH2PO4, 100 mM KCI, pH 7.4 at room temperature.
=[3H]-Flumazenil (18 nM for al(33y2 cells; 18 nM for a2R3y2 cells; 10 nM
for a3[i3y2 cells) in assay buffer.
= Flunitrazepam 100 M in assay buffer.
= Cells resuspended in assay buffer (1 tray to 10 ml).
Harvesting Cells
Supernatant is removed from cells. PBS (approximately 20 ml) is
added. The cells are scraped and placed in a 50 ml centrifuge tube. The
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procedure is repeated with a further 10 ml of PBS to ensure that most of
the cells are removed. The cells are pelleted by centrifuging for 20 min at
3000 rpm in a benchtop centrifuge, and then frozen if desired. The pellets
are resuspended in 10 ml of buffer per tray (25 cm x 25 cm) of cells.
Assay
Can be carried out in deep 96-well plates or in tubes. Each tube
contains:
= 300 l of assay buffer.
= 50 l of [3H]-flumazenil (final concentration for a1[i3y2: 1.8 nM; for
a2(33y2: 1.8 nM; for a3p3y2: 1.0 nM).
= 50 l of buffer or solvent carrier (e.g. 10% DMSO) if compounds are
dissolved in 10% DMSO (total); test compound or flunitrazepam (to
determine non-specific binding), 10 M final concentration.
= 100 l of cells.
Assays are incubated for 1 hour at 40 C, then filtered using either a
Tomtec or Brandel cell harvester onto GF/B filters followed by 3 x 3 ml
washes with ice cold assay buffer. Filters are dried and counted by liquid
scintillation counting. Expected values for total binding are 3000-4000
dpm for total counts and less than 200 dpm for non-specific binding if
using liquid scintillation counting, or 1500-2000 dpm for total counts and
less than 200 dpm for non-specific binding if counting with meltilex solid
scintillant. Binding parameters are determined by non-linear least
squares regression analysis, from which the inhibition constant K; can be
calculated for each test compound.
The compounds of the accompanying Examples were tested in the
above assay, and all were found to possess a K; value for displacement of
[3H]Ro 15-1788 from the a2 and/or a3 subunit of the human GABAA
receptor of 100 nM or less.
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EXAMPLE 1
3-Phen l-6- 2- rid 1 meth lox -7 8 9 10-tetrah dro- 7 10-ethano -1 2 4-
triazolo j3, 4-aJphthalazine
a) 4 5-Diazatricyclo[6.2.2.2, 7]dodec-2(7)-ene-3 6-dione
Bicyclo[2.2.2]oct-2-ene-2,3-dicarboxylic acid anhydride (prepared as
described in J. Org. Chem., 1993, 6740-6744) (60.8 g, 0.342 mol) was
dissolved in 50% aqueous acetic acid (1600 ml) with sodium acetate
trihydrate (55.5 g, 1.2 mol eq) and hydrazine hydrate (19.82 ml, 1.2 mol
eq). The reaction mixture was heated under reflux for 16 h then allowed
to cool. The solid produced was collected by filtration and washed with
water and diethyl ether before drying in a vacuum oven at 80 C to give the
required product (59.3 g, m.p. = 214 C). 1H NMR (250 MHz, DMSO) S 1.16
(4H, d, J= 7.1 Hz), 1.69 (4H, d, J= 7.1 Hz), 3.18 (2H, s), 11.31 (2H, br, s,
NH); MS (ES+) m/e 193 [MH]
b) 3,6-dichloro-4,5-diazatricvclo[6.2.2.2 7]dodeca-2(7) 3 5-triene
The product from Example 1 Step a) (59.2 g) was dissolved in
phosphorus oxychloride (300 ml) and heated under reflux for 14 h. The
solvent was removed under vacuum and azeotroped 2x toluene. The
residue was dissolved in dichloromethane (200 ml) and stirred rapidly and
the solution was neutralised by the addition of solid and aqueous sodium
hydrogen carbonate (cautiously). When effervescence had ceased, the
organic layer was separated and the aqueous layer was extracted with
dichloromethane (2x200 ml). The combined organic layers were dried
(MgSO4), filtered and evaporated to give to give the required product (59.5
g, m.p. > 370 C). 'H NMR (250 MHz, CDC13) S 1.39 (4H, d, J = 8.1 Hz),
1.92 (4H, d, J= 8.1 Hz), 3.47 (2H, s); MS (ES+) m/e 229 [MH]+.
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c) 6-Chloro-3-nhenyl-7,8,9,10-tetrahydro-(7,10-ethano)-1 2 4-
triazolo [3, 4-ajphthalazine
The product from Example 1 Step b) (2.5 g, 0.011 mol) was
suspended in xylene (50 ml) with benzoylhydrazine (1.65 g, 1.1 mol eq)
and triethylamine (1.68 ml, 1.1 mol eq) and the reaction mixture was
heated under reflux for 6 days. The solvent was removed under high
vacuum and the residue was purified by chromatography on silica gel
using 0-50% ethyl acetate in dichloromethane as eluent followed by
recrystallisation from ethyl acetate/hexane to give the required product
(1.3 g, m.p. = 186-188 C). 1H NMR (250 MHz, CDC13) 5 1.43-1.59 (4H, m),
1.91-2.05 (4H, m), 3.57 (1H, s), 4.07 (1H, s), 7.58 (3H, m), 8.58 (2H, dd, J=
7.8 and 1.5 Hz); MS (ES+) m/e 311 [MH]+. Anal. Found C, 65.56; H, 4.83;
N, 17.74. C17H15C1N4 requires C, 65.70; H, 4.87; N, 18.03%.
d) 3-Phenvl-6-(2-pyridyl)methvloxy-7,8,9,10-tetrahydro-(7 10-ethano)-
1, 2, 4-triazolo [3, 4-a]phthalazine
To a solution of 2-pyridylcarbinol (0.263 ml, 0.0024 mol) in DMF (20
ml) was added sodium hydride (0.113 g of a 60% dispersion in oil, 1.75 mol
eq) and the reaction mixture was stirred at room temperature for 15
minutes. After this time, the product from Example 1 Step c) (0.5 g,
0.0016 mol) was added and the reaction mixture was stirred at room
temperature for 1 hour. Water was added until the solution became
cloudy and after stirring for a further 15 minutes a solid was collected by
filtration. This solid was recrystallised from ethyl acetate to give the
required product (0.112 g, m.p. = 196-198 C). 1H NMR (360 MHz, CDC13)
S 1.45 (4H, m), 1.95 (4H, m), 3.58 (1H, s), 4.00 (1H, s), 7.26 (1H, m), 5.48
(2H, s), 7.44-7.53 (4H, m), 7.77 (1H, m), 8.40 (2H, dd, J= 7.8 and 1.5 Hz),
8.68 (1H, m); MS (ES+) m/e 384 [MH]+. Anal. Found C, 71.76; H, 5.54; N,
18.03. C24H2iN50 requires C, 72.04; H, 5.52; N, 18.26%.
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EXAMPLE 2
3, 7-Diphenyl-6-(2-pyridyi)meth_yloxy-1, 2, 4-triazolo [4, 3-blpyridazine
This compound was prepared using the procedures described in
Example 1 Steps a), b), c) and d) with phenylmaleic anhydride being used
instead of bicyclo[2.2.2]oct-2-ene-2,3-dicarboxylic acid anhydride in Step
a). The 7-phenyl isomer produced in Step c) was lower running on tlc than
the 8-phenyl isomer and so separation of the regioisomers was effected at
this stage by silica gel chromatography using 0-5% ethyl acetate in
dichloromethane as eluent. Data for the title compound: m.p. = 203 C. 'H
NMR (360 MHz, CDC13) S 5.65 (2H, s), 7.24 (1H, m), 7.34 (1H, d, J= 7.8
Hz), 7.53 (6H, m), 7.69 (3H, m), 8.07 (1H, s), 8.41 (2H, d, J= 6.6 Hz), 8.65
(1H, m); MS (ES+) m/e 380 [MH]+. Anal. Found C, 72.59; H, 4.47; N, 18.04.
C23H17N50 requires C, 72.81; H, 4.52; N, 18.46%.
EXAMPLE 3
3-Phenyl-6-(2-pyridyl)methyloxy-7,8,9,10-tetrahydro-1.2,4-triazolo[3 4-
alphthalazine
This compound was prepared using the procedures described in
Example 1 Steps a), b), c) and d) with tetrahydrophthalic anhydride being
used instead of bicyclo[2.2.2]oct-2-ene-2,3-dicarboxylic acid anhydride in
Step a). Data for the title compound: m.p. = 194 C. 'H NMR (360 MHz,
CDC13) 5 1.94 (4H, m), 2.74 (2H, m), 3.14 (2H, m), 5.56 (2H, s), 7.27 (1H,
m), 7.47 (4H, m), 7.73 (1H, m), 8.36 (2H, d, J= 6.6 Hz), 8.66 (1H, m); MS
(ES+) m/e 358 [MH]+. Anal. Found C, 70.50; H, 5.25; N, 19.27. C21Hi9N50
requires C, 70.57; H, 5.76; N, 19.59%.
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EXAMPLE 4
7,8-Dimethyl-3-phenyl-6-(2-p,Yridyl)methyloxy-1,2,4-triazolof4 3-
blpyridazine
This compound was prepared using the procedures described in
Example 1 Steps c) and d) with 3,6-dichloro-4,5-dimethylpyridazine being
used instead of 3,6-dichloro-4,5-diazatricyclo[6.2.2.2, 7]dodeca-2(7),3,5-
triene in step c). Data for the title compound: m.p. = 185 C. 'H NMR (360
MHz, CDC13) S 2.35 (3H, s), 2.69 (3H, s), 5.58 (2H, s), 7.27 (1H, m), 7.47
(4H, m), 7.75 (1H, ddd, J= 7.8, 7.8 & 1.8 Hz), 8.37 (2H, d, J= 7.6 Hz), 8.65
(1H, m); MS (ES+) m/e 332 [MH]+. Anal. Found C, 68.38; H, 4.82; N, 20.64.
C19H17N50 requires C, 68.87; H, 5.17; N, 21.13%.
EXAMPLE 5
7-Methvl-3-phenyl-6-(2-pyridyl)methyloxy-1, 2, 4-triazolo [4, 3-b]pyridazine
This compound was prepared using the procedures described in
Example 1 Steps c) and d) with 3,6-dichloro-4-methylpyridazine being
used instead of 3,6-dichloro-4,5-diazatricyclo[6.2.2.2, 7]dodeca-2(7),3,5-
triene in Step c). The 7-methyl isomer produced in Step c) was lower
running on tlc than the 8-methyl isomer and so separation of the
regioisomers was effected at this stage by silica gel chromatography using
0-10% ethyl acetate in dichloromethane as eluent. Data for the title
compound: m.p. = 199 C. 'H NMR (360 MHz, CDC13) 8 2.42 (3H, s), 5.59
(2H, s), 7.28 (1H, m), 7.49 (4H, m), 7.76 (1H, ddd, J= 7.8, 7.8 & 1.8 Hz),
7.83 (1H, s), 8.37 (2H, d, J= 7.6 Hz), 8.65 (1H, m); MS (ES+) m/e 318
[MH]+. Anal. Found C, 68.09; H, 4.31; N, 22.01. CisHiaN50 requires C,
68.12; H, 4.76; N, 22.06%.
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EXAMPLE 6
7-Ethyl-3-phenyl-6-(2-pyridyl)methyloxy-1,2,4-triazolo j4 3-blpyridazine
bis-hydrochloride
This compound was prepared using the procedures described in
Example 1 Steps a), b), c) and d) with ethyl maleic anhydride (Synth.
Coinmun., 1990, 2491) being used instead of bicyclo[2.2.2]oct-2-ene-2,3-
dicarboxylic acid anhydride in Step a). The 7-ethyl isomer produced in
Step c) was lower running on tlc than the 8-ethyl isomer and so separation
of the regioisomers was effected at this stage by silica gel chromatography
using 0-10% ethyl acetate in dichloromethane as eluent. Data for the title
compound: m.p. = 193 C. 1H NMR (360 MHz, DMSO) S 1.31 (3H, t, J=
7.4Hz), 2.81 (2H, q, J= 7.4Hz), 5.85 (2H, s), 7.58 (3H, m), 7.80 (1H, m),
7.99 (1H, d, J= 7.9 Hz), 8.23 (3H, m), 8.34 (1H, m), 8.84 (1H, d, J= 4.7
Hz); MS (ES+) m/e 332 [MH]+. Anal. Found C, 56.20; H, 4.53; N, 17.28.
C19Hi7N50.2HC1 requires C, 56.45; H, 4.74; N, 17.32%.
EXAMPLE 7
7,8-Benzo-3-phenyl-6-(2-pyridvl)methyloxv-7 8 9 10-tetrahvdro-1 2 4-
triazoloL3,4-a]phthalazine
This compound was prepared using the procedures described in
Example 1 Steps a), b), c) and d) with 3,4-dihydro-1,2-
napthalenedicarboxylic anhydride being used instead of bicyclo[2.2.2]oct-2-
ene-2,3-dicarboxylic acid anhydride in Step a). The 7,8-benzo isomer
produced in Step c) was lower running on tlc than the 9,10-benzo isomer
and so separation of the regioisomers was effected at this stage by silica
gel chromatography using 0-30% ethyl acetate in dichloromethane as
eluent. Data for the title compound: m.p. = 240 C. 1H NMR (360 MHz,
CDC13) 5 3.02 (2H, t, J= 7.9 Hz), 3.38 (2H, t, J= 7.9 Hz), 5.74 (2H, s), 7.31
(4H, m), 7.51 (4H, m), 7.74 (1H, m), 8.37 (3H, m), 8.71 (1H, m); MS (ES+)
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m/e 406 [MH]+. Anal. Found C, 73.81; H, 4.48; N, 16.96. C25Hi9N50
requires C, 74.06; H, 4.72; N, 17.27%.
EXAMPLE 8
8-Methyl-3,7-diphenyl-6-(2-pyridyl)methyloxy-1 2 4-triazolo[4 3-
b]pyridazine
This compound was prepared using the procedures described in
Example 1 Steps a), b), c) and d) with 3-methyl-4-phenyl maleic anhydride
being used instead of bicyclo[2.2.2]oct-2-ene-2,3-dicarboxylic acid
anhydride in Step a). The 7-phenyl-8-methyl isomer produced in Step c)
was lower running on tic than the 7-methyl-8-phenyl isomer and so
separation of the regioisomers was effected at this stage by silica gel
chromatography using 0-15% ethyl acetate in dichioromethane as eluent.
Data for the title compound: m.p. = 182 C. 1H NMR (360 MHz, DMSO) S
2.45 (3H, s), 5.50 (2H, s), 7.30 (2H, m), 7.54 (8H, m), 7.77 (1H, m), 8.25
(2H, d, J= 7.8 Hz), 8.58 (1H, m); MS (ES+) m/e 394 [MH]+. Anal. Fouind C,
72.05; H, 4.94; N, 16.55. C24H19N50Ø5 EtOAc. requires C, 72.27; H, 5.09;
N, 16.86%.
EXAMPLE 9
( )-3-Phenvl-6-(2-pyridyl)methyloxy-7,8 9 10-tetrahydro-(7 10-methano)-
1,2,4-triazolo[3,4-a]phthalazine
This compound was prepared using the procedures described in
Example 1 Steps a), b), c) and d) with 2-norbornene-2,3-dicarboxylic
anhydride being used instead of bicyclo[2.2.2]oct-2-ene-2,3-dicarboxylic
acid anhydride in Step a). Data for the title compound: m.p. = 182 C. 'H
NMR (360 MHz, CDC13) 8 1.31 (2H, m), 1.69 (1H, d, J= 9.2 Hz), 1.95 (1H,
d, J= 9.2 Hz), 2.12 (2H, m), 3.76 (1H, s), 4.14 (1H, s), 5.59 (2H, s), 7.28
(1H, m), 7.48 (4H, m), 7.76 (1H, m), 8.36 (2H, d, J= 7.8 Hz), 8.68 (1H, m);
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MS (ES+) m/e 370 [MH]+. Anal. Found C, 71.53; H, 5.18; N, 18.96.
C22H19NsO requires C, 72.08; H, 5.13; N, 18.89%.
EXAMPLES 10 and 11
3-Phenyl-5-(nyridin-2-ylmethoxv)-1, 2, 3a,4, 7-pentaazacyclopenta-
[a]naphthalene 0.25 Hydrate and 3-Phenyl-5-(pyridin-2-ylmethoxy)-
1,2,3a,4,8-pentaazacyclopenta[a]naphthalene 0.5 Hydrate
a) 5-Chloro-3-phenyl-1,2,3a,4,7-pentaazacyclopenta[ajnaphthalene and
5-Chloro-3-nhenyl-1, 2, 3a,4, 8-pentaazacyclopenta [a] naphthalene
This 1:1 mixture of chloroimidates was prepared using the
procedures described in Example 1, Steps a), b) and c) with 3,4-
pyridinedicarboxylic anhydride being used instead of bicyclo[2.2.2]oct-2-
ene-2,3-dicarboxylic acid anhydride. Data for the mixture: 1H NMR (250
MHz, CDC13) S 7.54-7.62 (3H, m), 8.04 (0.5H, dd, J= 7.3, 1.5 Hz), 8.38-8.46
(2H, m), 8.71 (0.5H, dd, J= 7.3, 1.5 Hz), 9.15 (0.5H, d, J= 8.0 Hz), 9.17
(0.5H, d, J= 8.0 Hz), 9.60 (0.5H, s), 10.11 (0.5H, s); MS (ES+) m/e 284
[MH]+, 282 [MH]+.
b) 3-Phenyl-5-(pyridin-2-ylmethoxy)-1,2,3a.4,7-pentaazacyclopenta-
ja]naphthalene 0.25 Hydrate and 3-Phenyl-5-(pyridin-2-ylmethoxy)-
1,2,3a,4,8-pentaazacyclopentafa]naphthalene 0.5 H dy rate
Sodium hydride (76 mg of a 60% dispersion in oil, 1.9 mmol) was
added to a solution of 2-pyridyl carbinol (180 ml, 1.9 mmol) in dry DMF
(10 ml) at room temperature under nitrogen. After 45 minutes the
mixture of chloroimidates from Step a) (380 mg, 1.35 mmol) was added.
After a further 1 hour at room temperature the reaction mixture was
diluted with water (200 ml) and extracted with dichloromethane (400 ml
and 2x200 ml). The combined extracts were washed with brine (100 ml),
dried (MgSO4), filtered and evaporated. The residue was recrystallised
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from methanol to give the mixture of phthalazines (136 mg) as a 1:1
mixture - inseparable by conventional chromatography. The two isomers
were separated by preparative HPLC using a Pirkle type 3,5-
dinitrobenzoyl phenyl glycine column to give:
first eluting:- 3-Phenyl-5-(pyridin-2-ylmethoxy)-1,2,3a,4,7-
pentaazacyclopenta [a] naphthalene 0.25 Hydrate: m.p. >190 C; 1H NMR
(360 MHz, CDC13) 5 5.79 (2H, s), 7.34-7.37 (1H, m), 7.52-7.58 (3H, m), 7.61
(1H, d, J= 7.9 Hz), 7.83 (1H, t, J= 7.7 Hz), 8.34 (2H, d, J= 8.9 Hz), 8.47
(1H, d, J= 7.8 Hz), 8.90 (1H, d, J= 4.0 Hz), 9.11 (1H, d, J= 5.3 Hz), 9.61
(1H, s); (Regiochemistry was established using nOe data). MS (ES+) m/e
355 [MH]+. Anal. Found C, 67.00; H, 3.87; N, 23.37. C2oH14NsO. 0.25 H20
requires C, 66.93; H, 4.07; N, 23.42%.
and second eluting:- 3-Phenyl-5-(pyridin-2-ylmethoxy)-1,2,3a,4,8-
pentaazacyclopenta[a]naphthalene 0.5 Hydrate: m.p. >170 C; 'H NMR
(360 MHz, CDC13) S 5.75 (2H, s), 7.33-7.37 (1H, m), 7.50-7.60 (4H, m), 7.82
(1H, t, J = 7.8 Hz), 8.07 (1H, d, J= 5.3 Hz), 8.29-8.33 (2H, m), 8.68-8.70
(1H, m), 9.05 (1H, d, J= 5.3 Hz), 10.03 (1H, s); (Regiochemistry was
established using nOe data). MS (ES+) m/e 355 [MH]+. Anal. Found C,
66.25; H, 3.89; N, 22.73. C2oH14N6O. 0.5 H20 requires C, 66.11; H, 4.16;
N, 23.13%.
EXAMPLE 12
(f)-8-Methvl-3-phenyl-6-(2-pyridyl)methyloxy-7,8,9,10-tetrahydro-1 2 4-
triazolo j3, 4-a]phthalazine
a) Ethv14-methyl-2-(trifluoromethanesulfonyloxv)cyclohex-1-
enecarboxvlate
To a solution of ethyl 4-methyl-2-cyclohexanone-l-carboxylate (50g,
0.27 mol) in dichloromethane (500ml) at -10 C was added N,N-
diisopropylethylamine (52m1, 0.3mol) followed by dropwise addition of
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trifluoromethanesulphonyl chloride (57m1, 0.3mol) keeping the
temperature between -5 and -10 C. The reaction mixture was allowed to
warm to room temperature and stirred for 3 hours. TLC showed 80%
reaction, it was cooled to -5 C and more N,N-diisopropylethylamine (14m1,
0.1mo1) was added followed by trifluoromethanesulphonyl chloride
(15.5m1, 0.1mo1) and the reaction mixture was stirred for 15 hours at room
temperature. The mixture was washed with cold water (2x200m1), cold
saturated sodium bicarbonate (2x200m1) and brine (1x200ml). The
organic layer was dried (MgSO4), filtered and evaporated to give the
required product (85g) as a colourless oil. 'H NMR (250 MHz, CDCla) S
1.04 (3H, d, J=6.5 Hz), 1.43 (3H, m), 1.73-2.09 (4H, m), 2.39-2.63 (3H, m),
4.25 (2H, m).
b) 1-Ethyl2-methyl4-methvlcyclohex-l-ene-1,2-dicarbox 1~
To a solution of the product from Example 12 Step a (85g, 0.27mol)
in DMF (500m1) at -20 C was added palladium(II) acetate (1.85g,
0.0083mol), bis(diphenylphosphino)ferrocene (9g, 0.0162mol), methanol
(250m1) and triethylamine (75.5m1, 0.54mo1). Carbon monoxide gas was
passed through the solution for 15 minutes and then the reaction was
heated to 60 C and kept under an atmosphere of carbon monoxide for 15
hours. The solution was left to cool, and solvent was removed under high
vacuum. The residue was dissolved in ethyl acetate, then washed with
water (4x200m1) and brine (1x200m1). The organic layer was dried
(MgSO4), filtered and evaporated to give the crude product which was
purified by chromatography on silica gel using 0-10% ethyl acetate in
hexane to give the required product (27g) as a pale yellow oil. 1H NMR
(250 MHz, CDC13) 8 1.12 (3H, d, J= 6.5 Hz), 1.33 (3H, m), 1.70-1.96 (4H,
m), 2.35-2.61 (3H, m), 3.73 (3H, s) 4.25 (2H, m).
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-.54 -
c) 4-Methylcyclohex-l-ene-1, 2-dicarboxvlic acid
To a solution of the product from Example 12 Step b (33g, 0.15mo1)
in ethanol (200m1) was added a solution of potassium hydroxide (32.7g,
0.6mol) in water (20m1) and heated at reflux for 15 hours. The solution
was left to cool, solvent was removed under high vacuum, water (200m1)
was added, then concentrated hydrochloric acid added until pH 2. The
aqueous layer was extracted with dichloromethane (5x200 ml), the
combined organic layers were washed with brine (lx200ml), dried
(MgSO4), filtered and evaporated to give the required product as a pale
yellow oil (16.7g). 1H NMR (250 MHz, DMSO) 8 1.15 (3H, d, J= 6.5 Hz),
1.21 (1H, m), 1.86 (3H, m), 2.37 (3H, m), 3.34 (2H, bs).
d) 4-Methyl-(3, 4, 5, 6-tetrahydro)p hthalic anhydride
The product from Example 12 Step c (16.5g, 0.89mo1) was refluxed
in acetic anhydride (200m1) for 15 hours. The acetic anhydride was
removed under high vacuum, the residue was dissolved in toluene and
then evaporated to give the required product as an oil (15.2g). 'H NMR
(250 MHz, DMSO) 8 1.03 (3H, d, J= 6.5 Hz), 1.24 (1H, m), 1.96 (3H, m),
2.23 (3H, m).
e) 6-Methyl-5,6,7,8-tetrahydrophthalazine-1,4-dione
This compound was prepared using the procedures described in
Example 1 Step a) using 4-methyl-(3,4,5,6-tetrahydro)phthalic anhydride
instead of bicyclo[2.2.2]oct-2-ene-2,3-dicarboxylic acid anhydride. Data for
the title compound: 'H NMR (250 MHz, DMSO) S 1.13 (3H, d, J= 6.8 Hz),
1.19 (1H, m), 1.76 (3H, m), 2.29 (1H, m), 2.50 (2H, m), 11.2 (2H, bs); MS
(ES+) m/e 181 [MH]+.
f) 1,4-Dichloro-6-methyl-5,6,7,8-tetrahydrophthalazine
This compound was prepared using the procedures described in
Example 1 Step b) using 6-methyl-5,6,7,8-tetrahydrophthalazine-1,4-dione
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instead of 4,5-diazatricyclo[6.2.2.2, 7]dodec-2(7)-ene-3,6-dione. Data for the
title compound: 1H NMR (250 MHz, CDC13) 5 1.29 (3H, d, J = 7.0 Hz), 1.90
(4H, m), 2.54 (1H, m), 2.93 (1H, m), 3.18 (1H, m); MS (ES+) m/e 217 + 219
Im I-11
g) ( )-6-Chloro-8-methyl-3-phenyl-7,8,9,10-tetrahydro-1 2 4-
triazolo[3,4-alphthalazine and ( )-6-chloro-9-methyl-3-phenyl-7,8,9 10-
tetrahydro-1, 2,4-triazolo[3,4-a]phthalazine
This compound was prepared using the procedures described in
Example 1 Step c) using 1,4-dichloro-6-methyl-5,6,7,8-
tetrahydrophthalazine instead of 3,6-dichloro-4,5-diazatricyclo[6.2.2.2, 7]-
dodeca-2(7),3,5-triene. The reaction gave a mixture of the title compounds
in an approximate ratio of 1:1. The compounds were not separated at this
stage. Data for the mixture of title compounds: 1H NMR (250 MHz, CDC13)
S 1.12 (3H, m), 1.44 (1H, m), 2.21 (2H, m), 2.77 (3H, m), 3.40 (1H, m), 7.74
(3H, m), 8.43 (2H, m); MS (ES+) m/e 299 + 301 [MH]+.
h) ( )-8-Methyl-3-phenyl-6-(2-pyridyl)methyloxy-7,8,9 10-tetrahydro-
1,2,4-triazolof 3,4-alphthalazine
This compound was prepared using the procedures described in
Example 1 Step d) using the mixture from Example 12 Step g) instead of
3-phenyl-6-(2-pyridyl)methyloxy-7,8,9, 10-tetrahydro-(7, 10-ethano)-1,2,4-
triazolo[3,4-a]phthalazine. The two products were separated using silica
gel chromatography, 0-8% methanol in dichloromethane. The higher Rf
product was recrystallised from ethyl acetate/dichloromethane to give the
title compound. 'H NMR (250 MHz, DMSO) 8 1.23 (3H, d, J= 6.3 Hz),
2.05 (2H, m), 2.35 (1H, m), 3.00 (2H, m), 3.24 (1H, m), 5.71 (2H, s), 7.58
(5H, m), 8.08 (1H, m), 8.36 (2H, m), 8.80 (1H, m); m.p. 185-187 C; MS
(ES+) m/e 372 [MH]+.
The lower Rf product was also isolated and shown to be ( )-9-
methyl-3-phenyl-6-(2-pyridyl)methyloxy-7,8,9,10-tetrahydro-1, 2,4-
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triazolo[3,4-a]phthalazine. Data for this compound is for the
trifluoroacetate salt; 'H NMR (250 MHz, DMSO) 8 1.13 (3H, d, J = 6.5 Hz),
1.24 (1H, m), 1.96 (2H, m), 2.80 (3H, m), 3.16 (1H, m), 5.60 (2H, s), 7.70
(5H, m), 8.08 (1H, d, J= 7.8 Hz), 8.20 (2H, m), 8.65 (1H, m); m.p.152-
154 C; MS (ES+) m/e 372 [MH]+. The structure was proven by COSY and
NOE experiments.
EXAMPLE 13
3-Phenyl-6-(2-pyridyl)methyloxy-(7,8-pentano)-1,2,4-triazolo[4 3-
b]pyridazine
This compound was prepared using the procedures described in
Example 1 Steps a), b), c) and d) with 1-cycloheptene-1,2-dicarboxylic
anhydride (Proc. Indian Acad. Sci., Sect. A, 1978, 87A (10), 371) being
used instead of bicyclo[2.2.2]oct-2-ene-2,3-dicarboxylic acid anhydride in
Step a). Data for the title compound: m.p. = 208 C. 'H NMR (360 MHz,
CDC13) S 1.71 (2H, m), 1.81 (2H, m), 1.99 (2H, m), 3.01 (2H, m), 3.38 (2H,
m), 5.58 (2H, s), 7.28 (1H, m), 7.48 (4H, m), 7.76 (1H, m), 8.37 (2H, d, J=
7.8 Hz), 8.67 (1H, m); MS (ES+) m/e 372 [MH]+. Anal. Found C, 70.52; H,
5.25; N, 18.44. C22H21N50Ø1 H20 requires C, 70.80; H, 5.72; N, 18.76%.
EXAMPLE 14
8,8-Dimethvl-3-phenyl-6-(2-pyridyl)methyloxy-7,8,9,10-tetrahydro-1 2 4-
triazoloj3,4-alphthalazine
a) Dimethyl 4,4-(dimethvl)cyclohexene-1,2-dicarboxylate
This compound was prepared in 62% yield by a similar procedure to
that described in Example 12, Step a), but using 2-carbomethoxy-4,4-
dimethylcyclohexanone (Liu, H.-J.; Browne, E. N. C.; Chew, S. Y., Can. J.
Chein., 1988, 66, 2345-2347). 1H NMR (360 MHz, CDCIa) 8 0.96 (6H, s),
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1.42 (2H, t, J= 6.4 Hz), 2.12 (2H, t, J= 2.6 Hz), 2.38 (2H, m), 3.76 (3H, s),
3.76 (3H, s); MS (ES+) m/e 249 [M+Na]+, 227 [M+H]+, 195 (M-OMe]+.
b) 4,4-(Dimethvl)cyclohexene-1.2-dicarboxylic acid
A mixture of the product from Example 14, Step a) (3.78 g, 16.7
mmol) and potassium hydroxide (3.50 g, 66.9 mmol) in ethanol (23 ml) and
water (28 ml) was heated at 80 C for 23 h. After cooling, the mixture was
concentrated to about 15 ml, introduced onto a Dowex 50WX8-200 ion
exchange column, and eluted with 0-20% MeOH/H20 to give 2.73 g (82%)
of the required product as a pale brown solid. 1H NMR (250 MHz, d6-
DMSO) S 1.09 (9H, s), 1.61 (2H, t, J= 6.2 Hz), 2.26 (2H, t, J= 2.8 Hz), 2.48
(2H, m).
c) 4,4-(Dimethyl)cyclohexene-1,2-dicarboxylic anhydride
This compound was prepared in 93% yield by a similar procedure to
that described in Example 12, Step d), but using the product from
Example 14, Step c). 1H NMR (250 MHz, d6-DMSO) 5 0.96 (6H, s), 1.48
(2H, t, J= 6.2 Hz), 2.13 (2H, t, J= 2.8 Hz), 2.35 (2H, m).
d) 6,6-Dimethyl-5,6,7,8-tetrahydrophthalazine-1 4-dione
This compound was prepared in 92% yield by a similar procedure to
that described in Example 1, Step a), but using the product from Example
14, Step c). 'H NMR (250 MHz, ds-DMSO) S 0.92 (6H, s), 1.43 (2H, t, J=
6.4 Hz), 2.16 (2H, s), 2.38 (2H, t, J= 6.4 Hz); MS (ES) m/e 195 [M+H]+
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-58-
e) 1, 4-Dichloro-5, 6, 7, 8-tetrahydro-6, 6-dimethylphthalazine
This compound was prepared in 99% yield by a similar procedure to
that described in Example 1, Step b), but using the product from Example
14, Step d). 1H NMR (360 MHz, CDC13) 1.04 (6H, s), 1.65 (2H, t, J= 6.6
Hz), 2.53 (2H, s), 2.78 (2H, t, J= 6.6 and 1.3 Hz); MS (ES) m/e 235/233/231
[M+H]+.
f) 6-Chloro-7,8,9,10-tetrahydro-8,8-dimethyl-3-nhenvl-1,2,4-
triazolo[3,4-alphthalazine
A mixture of the product from Example 14, Step e) (2.53 g, 10.9
mmol), triethylamine (1.83 ml, 13.1 mmol) and benzoic hydrazide (1.79 g,
13.1 mmol) in xylene (50 ml) was heated at reflux for 3 days with a Dean-
Stark trap fitted. The solvent was removed in vacuo and dichloromethane
(50 ml) was added to the residue. The mixture was stirred, filtered from a
white solid, and the filtrate was evaporated in vacuo. The residue was
purified by flash chromatography (silica gel, 10-20% EtOAc/CH2C12) to
give 2.18 g (64%) of a partly separated mixture of the 9,9-dimethyl isomer
and the required product. 'H NMR (250 MHz, CDC13) S 1.10 (6H, s), 1.72
(2H, t, J= 6.5 Hz), 2.56 (2H, m), 3.26 (2H, m), 7.51-7.60 (3H, m), 8.42-8.47
(2H, m); MS (ES) m/e 315/313 [M+H]+.
g) 8 8-Dimethyl-3-phenyl-6-(2 pyridyl)methyloxy-7,8,9.10-tetrahvdro-
1 2, 4-triazolo [3, 4-a]phthalazine
To a stirred mixture of sodium hydride (60% dispersion in oil, 40.4
mg, 1.01 mmol) in anhydrous DMF (5 ml), under nitrogen, was added 2-
pyridylcarbinol (95 ml, 0.985 mmol) and the mixture was stirred at room
temperature for 1 h. This was then added by cannula to a stirred mixture
of the product from Example 14, Step f) (0.205 g, 0.655 mmol) in
anhydrous DMF (5 ml) and the mixture was stirred for another 28 h,
adding more sodium hydride (8.4 and 7.6 mg) after 18 and 25 h. The
mixture was partitioned between EtOAc (50 ml) and water (50 ml) and the
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aqueous layer was extracted further with EtOAc (2 x 50 ml). The
combined organic extracts were dried (Na2SO4) and evaporated in vacuo.
The residue was purified by flash chromatography (silica gel, 2%
MeOH/CH2C12 then alumina, 80% EtOAc/CH2C12) to give 71.4 mg (28%) of
the required product; mp 133-136 C (CH2C12-EtOAc-hexane); 1H NMR
(360 MHz, d6-DMSO) 1.10 (6H, s), 1.71 (2H, t, J= 6.5 Hz), 2.53 (2H, m),
3.20 (2H, m), 5.59 (2H, s), 7.31 (1H, m), 7.47-7.54 (4H, m), 7.80 (1H, dd, J
= 7.8 and 1.7 Hz), 8.37 (2H, dd, J= 8.0 and 1.3 Hz), 8.67 (1H, m); MS (ES)
m/e 386 [M+H]+. Anal. found C, 71.41; H, 6.12; N, 17.99. C23H23N50
requires C, 71.67; H, 6.01; N, 18.17%.
EXAMPLE 15
3-Phenyl-7-(piperidin-l-yl)-6-(pyridin-2-vlmethoxy)-1 2 4-triazolo[4 3-
bJpyridazine. 0.45 Hydrate
a) 4-Bromo-1,2-dihydropyridazine-3,6-dione
A mixture of bromomaleic anhydride (50 g, 283 mmol) and sodium
acetate (76.5 g, 562 mmol) in 40% acetic acid/water (750 ml) was treated
with hydrazine monohydrate (16.5 ml, 339 mmol) at room temperature
under nitrogen. The brown solution was stirred and heated at 100 C for
18 hours. Upon cooling the mixture was poured into water (1 1) and
extracted with ethyl acetate (6 x 500 ml). The combined extracts were
dried (MgSOa), filtered and evaporated to afford the title compound (20 g,
37%) as an orange solid. 1H NMR (250 MHz, d6-DMSO) S 7.68 (1H, br s).
MS (ES+) m/e 193 [MH]+, 191 [MH]+. This material was used without
further purification.
b) 4-Bromo-3,6-dichloronyridazine
A solution of 4-bromo-1,2-dihydropyridazine-3,6-dione (10 g, 52
mmol) in phosphorus oxychloride (100 ml) was stirred and heated at 100 C
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under nitrogen for 16 hours. Upon cooling the excess phosphorus
oxychloride was removed in uacuo. The residue was azeotroped with
toluene (x2), then taken up in dichloromethane/water. The mixture was
carefully basified with sodium hydrogen carbonate (solid). It was
necessary to further dilute the mixture to get two clear layers. The two
layers were separated and the aqueous was extracted with
dichloromethane (x3). The combined extracts were dried (Na2SO4), filtered
and evaporated. The residue was purified by chromatography on silica
gel, eluting with dichloromethane to afford the title compound (5.0 g, 42%)
as a colourless solid. 'H NMR (250 MHz, CDCIs) S 7.68 (1H, br s). MS
(ES+) m/e 230 [MH]+, 228 [MH]+.
c) 3,6-Dichloro-4-(pineridin-1-yl)pyridazine
Piperidine (475 ml, 4.8 mmol) was added to a stirred
solution/suspension of 4-bromo-3,6-dichloropyridazine (1.0 g, 4.4 mmol)
and potassium carbonate (1.2 g, 8.7 mmol) in dry DMF (40 ml) at room
temperature under nitrogen. The mixture was stirred at room
temperature for 16 hours, then at 60 C for 3 hours. The reaction was
poured into water (250 ml). The aqueous was extracted with ethyl acetate
(x3). The combined extracts were dried (MgSO4), filtered and evaporated.
The residue was purified by chromatography on silica gel, eluting with
0.5% methanol/dichloromethane to afford the title compound (1.0 g, 98%)
as a colourless oil. 'H NMR (250 MHz, CDC13) S 1.63-1.81 (6H, m), 3.24-
3.29 (4H, m), 6.84 (1H, s). MS (ES+) m/e 234 [MH]+, 232 [MH]+.
d) 6-Chloro-3-phenyl-7-(piperidin-l-yl)-1,2,4-triazolo[4,3-b]pyridazine
A mixture of 3,6-dichloro-4-(piperidin-1-yl)pyridazine (0.55 g, 2.4
mmol), benzoyl hydrazine (370 mg, 2.7 mmol), triethylamine (375 ml, 2.7
mmol) and p-toluenesulphonic acid monohydrate (510 mg, 2.7 mmol) in
xylene (mixture of isomers, 10 ml) was stirred and heated at reflux under
nitrogen for 24 hours. Upon cooling the xylene was removed in vacuo and
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the residue was partitioned between dichloromethane and water. The
aqueous was further extracted with dichloromethane (x3). The combined
extracts were dried (Na2SO4), filtered and evaporated. The residue was
purified by chromatography on silica gel, eluting with 30% ethyl
acetate/dichloromethane to afford the undesired regioisomer (less polar)
(177 mg, 23%) and the title compound (383 mg, 50%) (more polar). Data
for the title compound: 1H NMR (250 MHz, CDC13) 5 1.62-1.86 (6H, m),
3.09-3.13 (4H, m), 7.42 (1H, s), 7.50-7.60 (3H, m), 8.40-8.44 (2H, m).
e) 3-Phenyl-7-(pineridin-l-yl)-6-(pyridin-2-vlmethoxy)-1 2 4-
triazolo f 4. 3-b]pyridazine. 0.45 Hydrate
Sodium hydride (60% dispersion in oil, 39 mg, 0.96 mmol) was
added to a solution of 2-pyridyl carbinol (104 mg, 0.96 mmol) in dry DMF
(10 ml) at room temperature under nitrogen. After 1 hour at room
temperature a solution of 6-chloro-3-phenyl-7-(piperidin-1-yl)-1,2,4-
triazolo[4,3-b]pyridazine (200 mg, 0.64 mmol) in dry DMF (10 ml) was
added via syringe. The mixture was stirred at room temperature for 16
hours. The DMF was then removed in vacuo and the residue was
partitioned between dichloromethane and water. The aqueous was further
extracted with dichloromethane (2x100 ml). The combined extracts were
dried (Na2SO4), filtered and evaporated. The residue (248 mg) was
purified by crystallisation from ethyl acetate/hexane (x2) to afford the title
compound (130 mg, 53%). 1H NMR (250 MHz, CDC13) 5 1.64-1.86 (6H, m),
3.20-3.26 (4H, m), 5.63 (2H, br s), 7.22-7.32 (2H, m), 7.42-7.56 (4H, m),
7.76 (1H, td, J=7.7, 1.6 Hz), 8.31-8.35 (2H, m), 8.66 (1H, br s).
(Regiochemistry was established using nOe data). MS (ES+) m/e 387
Anal. Found C, 66.97; H, 5.85; N, 21.30. C22H22NGO. 0.45 H20
requires C, 67.08; H, 5.63; N, 20.96%.
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EXAMPLE 16
3-Phenyl-7-(pyridin-4-yl)-6-(pyridin-2-ylmethoxv)-1, 2.4-triazolo [4, 3-
blpyridazine. 0.5 Hydrate
a) 3,6-Dichloro-4-(pyridin-4-yl)pyridazine
A mixture of 4-bromo-1,2-dihydropyridazine-3,6-dione (see Example
15, Step a) (530 mg, 2.8 mmol) and 4-pyridyl boronic acid, di-lithium salt
(500 mg, 3.7 mmol) and sodium carbonate (800 mg, 7.6 mmol) in 1,2-
dimethoxyethane (20 ml) was deoxygenated by three 'evacuate/fill with
nitrogen' cycles. Tetrakis(triphenylphosphine)palladium(0) (350 mg, 0.3
mmol) was then added and the reaction mixture was deoxygenated again
with another three 'evacuate/fill with nitrogen' cycles. The mixture was
then stirred and heated at reflux under nitrogen and protected from light
for 16 hours. Upon cooling the volatiles were removed in vacuo. The
residue was used without further purification.
The solid from above was taken up in phosphorus oxychloride (10
ml). The dark suspension was heated at reflux for 20 hours. Upon cooling
the volatiles were removed iia vacuo. The residue was azeotroped with
toluene (x2), then partitioned between dichloromethane and water. The
mixture was cautiously basified with solid sodium carbonate. The two
layers were separated (a precipitate forms which may be removed by
filtration through celite). The aqueous was further extracted with
dichloromethane (x3). The combined extracts were dried (MgSO4), filtered
and evaporated. The residue was purified by chromatography on silica
gel, eluting with 3% methanol/dichloromethane to afford the title
compound (240 mg, 38% over the two steps) as a pale yellow solid. 'H
NMR (250 MHz, dc,-DMSO) S 7.77-7.79 (2H, m), 8.37 (1H, s), 8.90-8.93 (2H,
m). MS (ES+) m/e 226 [MH]+, 228 [MH]+.
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b) 6-Chloro-3-phenyl-7-(pyridin-4-yl)-1,2,4-triazoloj4,3-b]pyridazine
A mixture of 3,6-dichloro-4-(pyridin-4-yl)pyridazine (390 mg, 1.7
mmol), benzoyl hydrazine (260 mg, 1.9 mmol), triethylamine (270 ml, 1.9
mmol) and p-toluenesulphonic acid (32 mg, 0.2 mmol) in xylene (mixture of
isomers) (5 ml) was stirred and heated at reflux under nitrogen for 20
hours. The mixture was partitioned between dichloromethane and
saturated aqueous potassium carbonate. The aqueous was further
extracted with dichloromethane (x3). The combined extracts were dried
(sodium sulphate), filtered and evaporated. The residue was purified by
chromatography on silica gel eluting with 3% methanol/dichloromethane
to afford the title compound (218 mg, 42%) as a pale yellow solid. 1H NMR
(360 MHz, d6-DMSO) 8 7.60-7.69 (5H, m), 8.36-8.38 (2H, m), 8.72 (1H, s),
8.78-8.80 (2H, m). MS (ES+) m/e 308 [MH]+, 310 [MHJ+.
c) 3-Phenyl-7-(pyridin-4-yl)-6-(pyridin-2-ylmethoxy)-1,2,4-triazolo[4 3-
b]pyridazine. 0.5 Hydrate
2-Pyridylcarbinol (105 ml, 1.1 mmol) was added to a stirred
suspension of sodium hydride (60% dispersion in oil, 40 mg, 1.0 mmol) in
dry DMF (10 ml) at room temperature under nitrogen. After 1 hour a
solution of the 6-chloro-3-phenyl-7-(pyridin-4-yl)-1,2,4-triazolo[4,3-
b]pyridazine (200 mg, 0.65 mmol) in dry DMF (10 + 5 ml) was added. The
solution was stirred at room temperature for 16 hours, then poured into
water (100 ml). The aqueous was extracted with ethyl acetate (5x100 ml).
The combined extracts were dried (Na2SO4), filtered and evaporated. The
residue was triturated with ethyl acetate (20 ml) at room temperature.
The remaining solid (170 mg) was recrystallised from hot ethyl acetate to
afford the title compound (120 mg, 49%) as a colourless solid, m.p. =
215 C dec. 1H NMR (360 MHz, d6-DMSO) S 5.76 (2H, s), 7.47-7.50 (1H,
m), 7.67-7.72 (4H, m), 7.97-8.02 (3H, m), 8.38-8.42 (2H, m), 8.72-8.78 (2H,
m), 8.87-8.89 (2H, m). MS (ES+) 381 [MH]+. Anal. Found C, 68.21; H, 4.10;
N, 21.34. C22H16N60 Ø5 H20 requires C, 67.86; H, 4.40; N, 21.58%.
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EXAMPLES 17 and 18
3-Phenyl-5-(pyridin-2-vlmethoxy)-6,7,8 9-tetrahydro-1 2 3a 4 8-
pentaazacyclopenta[a]naphthalene 0.35 Hydrate and 3-Phenvl-5-(pyridin-
2-ylmethoxv)-6 7 8 9-tetrahydro-1 2 3a 4 7-pentaaza-
cyclopenta[a]naphthalene 0.75 Hydrate
a) 3-Phenyl-5-(pyridin-2-ylmethoxy)-6,7 8 9-tetrahydro-1 2 3a 4 8-
pentaazacyclopentafalnaphthalene and 3-Phenyl-5-(pyridin-2-vlmethoxv)-
6,7,8,9-tetrahvdro-1,2,3a,4, 7-pentaazacyclopenta Llnaphthalene
A mixture of 3-phenyl-5-(pyridin-2-ylmethoxy)-1,2,3a,4,7-pentaaza-
cyclopenta[a]naphthalene and 3-phenyl-5-(pyridin-2-ylmethoxy)-
1, 2,3a,4,8-pentaazacyclopenta[a] naphthalene (see Examples 10 and 11),
2N HCl (1.0 ml, 2 mmol) in methanol (140 ml) was hydrogenated over
platinum oxide (140 mg) at 30 psi for 45 minutes at room temperature.
The catalyst was removed by filtration through celite, washing with
methanol. The filtrate was evaporated and the residue was purified by
chromatography on silica gel eluting with dichloromethane/methanol/
ammonia - 80:8:1 to afford the title amines (465 mg, 65%) as a yellow
solid. The mixture was inseparable by flash chromatography. The two
isomers were separated using the protocol described in Steps b), c) and d)
below.
b) 3-Phenvl-5-(pyridin-2-vlmethoxy)-6,9-dihydro-7H-1 2 3a 4 8-
pentaazacyclopentafalnaphthalene-8-carboxvlic acid tert-butyl ester and 3-
Phenyl-5-(pvridin-2-ylmethoxv)-8 9-dihydro-6H-1 2 3a 4 7-pentaaza-
cyclopentafalnaphthalene-7-carboxvlic acid tert-butyl ester
Di-tert-butyl dicarbonate (700 mg, 3.2 mmol) was added to a stirred
solution of a mixture of 3-phenyl-5-(pyridin-2-ylmethoxy)-6,7,8,9-
tetrahydro-1,2,3a,4,8-pentaazacyclopenta[a]naphthalene and 3-phenyl-5-
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(pyridin-2-ylmethoxy)-6, 7, 8,9-tetrahydro-1, 2, 3a, 4, 7-pentaaza-
cyclopenta[a]naphthalene (555 mg, 1.55 mmol) and triethylamine (550 ml,
3.9 mmol) and 4-dimethylaminopyridine (20 mg, 0.16 mmol) in dry
dichloromethane at 0 C under nitrogen. The reaction was allowed to come
to room temperature over 1 hour, then stirred at this temperature for 16
hours. The mixture was partitioned between dichloromethane and
saturated aqueous sodium hydrogen carbonate. The aqueous was further
extracted with dichloromethane (x2). The combined extracts were dried
(Na2SO4), filtered and evaporated. The residue was purified by
chromatography on silica gel, eluting with 5% methanol/dichloromethane
to afford the title compounds as a mixture (610 mg, 86%) as a colourless
solid.
The two components could be separated by medium pressure liquid
chromatography on silica, eluting with ethyl acetate to give:
less polar: 3-Phenyl-5-(pyridin-2-ylmethoxy)-6,9-dihydro-7H-
1,2,3a,4,8-pentaazacyclopenta[a]naphthalene-8-carboxylic acid tert-butyl
ester (274 mg). A sample was recrystallised from ethyl acetate/hexane:
m.p. = 170-173 C. 'H NMR (250 MHz, CDC13) S 1.52 (9H, s), 2.84-2.90
(2H, m), 3.81 (2H, t, J= 5.8 Hz), 5.00 (2H, br s), 5.60 (2H, s), 7.32 (1H, dd,
J= 7.5, 4.9 Hz), 7.49-7.55 (4H, m), 7.79 (1H, td, J= 7.7, 1.8 Hz), 8.34-8.38
(2H, m), 8.64-8.69 (1H, m). MS (ES+) m/e 459 [MH]+. Anal. Found C, 61.83;
H, 5.60; N, 17.52. C25H26Nr,03 . 1.4 H20 requires C, 62.07; H, 6.00; N,
17.37%.
more polar: 3-Phenyl-5-(pyridin-2-ylmethoxy)-8, 9-dihydro-6H-
1,2,3a,4,7-pentaazacyclopenta[a]naphthalene-7-carboxylic acid tert-butyl
ester (227 mg). A sample was recrystallised from ethyl acetate/hexane:
m.p. = 166-168 C. 1H NMR (250 MHz, CDC13) S 1.53 (9H, s), 3.20-3.26
(2H, m), 3.82 (2H, t, J= 5.8 Hz), 4.62 (2H, br s), 5.61 (2H, s), 7.31 (1H, dd,
J= 7.0, 5.5 Hz), 7.48-7.56 (4H, m), 7.79 (1H, td, J= 7.7, 1.7 Hz), 8.35-8.38
(2H, m), 8.64-8.68 (1H, m). MS (ES+) m/e 459 [MH]+. Anal. Found C, 65.76;
H, 5.81; N, 18.25. C25H26N603 requires C, 65.49; H, 5.71; N, 18.32%.
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c) 3-Phenyl-5-(pyridin-2-ylmethoxv)-6,7,8,9-tetrahydro-1,2,3a 4 8-
uentaazacyclopenta [a]naphthalene 0.35 Hydrate
Trifluoroacetic acid (3 ml) was added to a solution of 3-phenyl-5-
(pyridin-2-ylmethoxy)-6, 9-dihydro-7H-1, 2, 3a, 4, 8-pentaazacyclo-
penta[a]naphthalene-8-carboxylic acid tert-butyl ester (255 mg, 0.56 mmol)
in dry dichioromethane (3 ml) at 0 C under nitrogen. After 1 hour the
volatiles were removed in vacuo and the residue was partitioned between
dichloromethane and saturated aqueous potassium carbonate. The
aqueous was further extracted with dichloromethane (x2). The combined
extracts were dried (Na2SO4), filtered and evaporated. The residue was
purified by chromatography on silica gel, eluting with
dichloromethane/methanol/ammonia (60:8:1 -> 50:8:1) to afford the title
amine (176 mg, 88%) as a colourless solid, m.p. = 175-178 C. 1H NMR
(360 MHz, d6-DMSO) S 2.62-2.66 (2H, m), 3.08 (2H, t, J= 5.7 Hz), 4.13
(2H, s), 5.56 (2H, s), 7.37 (1H, dd, J = 6.9, 5.3 Hz), 7.50-7.59 (4H, m), 7.87
(1H, td, J= 7.7, 1.7), 8.22-8.25 (2H, m), 8.62-8.64 (1H, m). MS (ES+) m/e
359 [MH]+. Anal. Found C, 66.14; H, 4.98; N, 22.71. C2oHisNsOØ35 H20
requires C, 65.86; H, 5.17; N, 23.04%.
d) 3-Phenyl-5-(pyridin-2-ylmethoxy)-6,7,8,9-tetrahvdro-1,2.3a,4,7-
pentaazacvclopenta [a] naphthalene 0.75 Hydrate
Trifluoroacetic acid (3 ml) was added to a solution of 3-phenyl-5-
(pyridin-2-ylmethoxy)-8,9-dihydro-6H-1,2, 3a,4,7-pentaazacyclopenta[a]-
naphthalene-7-carboxylic acid tert-butyl ester (217 mg, 0.47 mmol) in dry
dichloromethane (3 ml) at 0 C under nitrogen. After 1 hour the volatiles
were removed in vacuo and the residue was partitioned between
dichloromethane and saturated aqueous potassium carbonate. The
aqueous was further extracted with dichloromethane (x2). The combined
extracts were dried (Na2SO4), filtered and evaporated. The residue was
purified by chromatography on silica gel, eluting with dichloromethane/
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methanol/ammonia (60:8:1) to afford the title amine (162 mg, 96%) as a
colourless solid, m.p. = 157-159 C. 1H NMR (360 MHz, d6-DMSO) S 2.92-
2.96 (2H, m), 3.07 (2H, t, J= 5.8 Hz), 3.84 (2H, s), 5.56 (2H, s), 7.36 (1H,
dd, J= 6.7, 4.9 Hz), 7.52-7.60 (4H, m), 7.87 (1H, td, J= 7.8, 1.7), 8.23 (2H,
dd, J= 6.3, 1.9 Hz), 8.62-8.64 (1H, m). MS (ES+) m/e 359 [MH]+. Anal.
Found C, 64.93; H, 5.31; N, 22.30. C2oH18N60 Ø75 H20 requires C, 64.59;
H, 5.29; N, 22.60%.
EXAMPLE 19
7-Methyl-3-phenyl-5-(pyridin-2-ylmethoxy)-6,7,8,9-tetrahydro-1,2,3a,4 7-
pentaazacyclopenta[a] naphthalene
Sodium cyanoborohydride (55 mg, 0.88 mmol) was added to a
stirred solution of 3-phenyl-5-(pyridin-2-ylmethoxy)-6,7,8,9-tetrahydro-
1,2,3a,4,7-pentaazacyclopenta[a]naphthalene (126 mg, 0.35 mmol) and
acetic acid (100 ml, 1.75 mmol) in dry methanol (10 ml) at room
temperature under nitrogen. The mixture was cooled to 0 C and aqueous
formaldehyde (35 ml, 0.48 mmol) was added. The reaction was stirred at
0 C for 30 minutes, then at room temperature for 5 hours. The reaction
was quenched with saturated aqueous potassium carbonate (5 ml). The
volatiles were removed in vacuo, then the residue was partitioned between
dichloromethane and water. The aqueous was further extracted with
dichloromethane (x3). The combined extracts were dried (Na2SO4), filtered
and evaporated. The residue was purified by chromatography on silica
gel, eluting with dichloromethane/methanol/ammonia (95:5:0.5 -). 92:7:1)
to afford the title amine (130 mg, 100%) as a colourless solid. This
material was recrystallised from ethyl acetate: m.p. 186-188 C. 1H NMR
(360 MHz, CDC13) S 2.57 (3H, s), 2.84 (2H, t, J= 5.7 Hz), 3.27-3.31 (2H, m),
3.61 (2H, br s), 5.59 (2H, s), 7.28 (1H, dd, J = 6.7, 4.9 Hz), 7.45-7.52 (4H,
m), 7.75 (1H, td, J= 7.8, 1.8 Hz), 8.35 (2H, dd, J 8.3, 1.8 Hz), 8.64-8.68
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(1H, m). MS (ES+) m/e 373 [MH]+. Anal. Found C, 67.95; H, 5.57; N, 22.43.
C21H2oNs0 requires C, 67.73; H, 5.41; N, 22.57%.
EXAMPLE 20
3-Phenyl-6-(pyridin-2-ylmethoxv)-7-(thiophen-2-yl)-1,2,4-triazolo[4 3-
blpyridazine 0.45 Hydrate
This compound was prepared using the procedures described in
Example 16 Steps a), b) and c) except 2-thiophene boronic acid was used
instead of 4-pyridyl boronic acid, dilithium salt in Step a) and 1.1
equivalents of p-toluenesulphonic acid was used in Step b) instead of 0.1
equivalents.
Data for the title compound: 1H NMR (250 MHz, CDC13) 8 5.74 (2H,
s), 7.18 (1H, dd, J= 5.2, 3.8 Hz), 7.28-7.34 (1H, m), 7.50-7.58 (5H, m), 7.74-
7.77 (2H, m), 8.28 (1H, s), 8.38-8.42 (2H, m), 8.68-8.72 (1H, m). MS (ES+)
m/e 386 [MH]+. Anal. Found C, 64.46; H, 4.16; N, 17.63. C21Hi5N50S. 0.45
H20. 0.05 (C4H,oO) requires C, 64.10; H, 3.82; N, 17.35%.
EXAMPLE 21
3-Phenyl-6-(pyridin-2-ylmethoxv)-7-(thiophen-3-yl)-1, 2,4-triazolo(4, 3-
b]pvridazine 0.2 Hydrate
This compound was prepared using the procedures described in
Example 16 Steps a), b) and c) except 3-thiophene boronic acid was used
instead of 4-pyridyl boronic acid, dilithium salt in Step a) and 1.1
equivalents of p-toluenesulphonic acid was used in Step b) instead of 0.1
equivalents.
Data for the title compound: 'H NMR (250 MHz, CDC13) 6 5.70 (2H,
s), 7.26-7.32 (1H, m), 7.44-7.58 (6H, m), 7.70-7.80 (1H, m), 7.96 (1H, br s),
8.20 (1H, s), 8.40-8.43 (2H, m), 8.58 (1H, br d, J= 5.6 Hz). MS (ES+) m/e
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386 [MH]+. Anal. Found C, 64.83; H, 4.11; N, 17.78. C21H15N5OS. 0.2 H20.
0.07 (C4HloO) requires C, 65.04; H, 3.69; N, 17.38%.
EXAIVIPLE 22
(t)-3-Phenyl-6-(2-pvridyl)methvloxy-7,8,9 10-tetrahvdro-(7 10-propano)-
1, 2, 4-triazolo [3, 4-alphthalazine
This compound was prepared using the procedures described in
Example 1 Steps a), b), c) and d) with bicyclo[3.2.2]non-6-ene-6,7-
dicarboxylic acid anhydride (J. Chem. Soc., 2524, 1970) being used instead
of bicyclo[2.2.2]oct-2-ene-2,3-dicarboxylic acid anhydride in Step a). Data
for the title compound: m.p. = 187 C. 1H NMR (360 MHz, CDC13) S 1.42-
2.19 (lOH, m), 3.56 (1H, s), 3.98 (1H, s), 5.60 (2H, s), 7.28 (1H, m), 7.48
(4H, m), 7.74 (1H, m), 8.38 (2H, d, J= 7.8 Hz), 8.66 (1H, m); MS (ES+) m/e
398 [MH]+. Anal. Found C, 72.93; H, 5.85; N, 17.64. C24H23N50 requires C,
72.52; H, 5.83; N, 17.62%.
EXAMPLE 23
3-(4-Methvl)phenyl-6-(2-pyridvl)methvloxv-7 8 9 10-tetrahydro-(7 10-
ethano)-1, 2, 4-triazolol3, 4-al phthalazine
This compound was prepared using the procedures described in
Example 1 Steps a), b), c) and d) with 4-toluic hydrazide being used
instead of benzoyl hydrazine in Step c). Data for the title compound: m.p.
= 167 C. 'H NMR (360 MHz, DMSO) 6 1.40 (4H, m), 1.90 (4H, m), 2.40
(3H, s), 3.48 (1H, s), 3.74 (1H, s), 5.57 (2H, s), 7.36 (3H, m), 7.57 (1H, d,
J=
7.8 Hz), 7.87 (1H, ddd, J= 7.8, 7.8 & 1.7 Hz), 8.14 (2H, d, J= 8.2 Hz), 8.68
(1H, m); MS (ESI) m/e 398 [MH]+. Anal. Found C, 72.37; H, 5.73; N, 17.62.
C24H23N50 requires C, 72.52; H, 5.83; N, 17.62%.
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EXAMPLE 24
3-(3-Methoxy)phenyl-6-(2-pyridyl)methyloxy-7, 8, 9,10-tetrahydro-(7 10-
ethano)-1, 2, 4-triazolo f 3, 4-a]phthalazine
This compound was prepared using the procedures described in
Example 1 Steps a), b), c) and d) with 3-methoxybenzhydrazide being used
instead of benzoyl hydrazine in Step c). Data for the title compound: m.p.
= 185 C. 1H NMR (360 MHz, DMSO) 8 1.40 (4H, m), 1.91 (4H, m), 3.49
(1H, s), 3.76 (1H, s), 3.85 (3H, s), 5.59 (2H, s), 7.08 (1H, m), 7.37 (1H, m),
7.47 (1H, t, J= 8.0 Hz), 7.59 (1H, d, J= 7.9 Hz), 7.88 (2H, m), 7.96 (1H,
m), 8.64 (1H, m); MS (ES+) m/e 414 [MH]+. Anal. Found C, 69.36; H, 5.65;
N, 16.58. C24H23N502 requires C, 69.72; H, 5.61; N, 16.94%.
EXAMPLE 25
3-(2-Fluoro)phenyl-6-(2-pyridyl)methyloxy-7,8,9,10-tetrahydro-(7,10-
ethano)-1, 2, 4-triazolo [3 , 4-al phthalazine
This compound was prepared using the procedures described in
Example 1 Steps a), b), c) and d) with 2-fluorobenzhydrazide being used
instead of benzoyl hydrazine in Step c). Data for the title compound: m.p.
= 159 C. iH NMR (360 MHz, CDC13) b 1.51 (4H, m), 1.92 (4H, m), 3.56
(1H, s), 3.98 (1H, s), 5.46 (2H, s), 7.26 (3H, m), 7.44 (1H, d, J= 7.8 Hz),
7.54 (1H, m), 7.71 (1H, m), 7.80 (1H, m), 8.63 (1H, m); MS (ES+) m/e 402
[MH]+. Anal. Found C, 68.81; H, 4.81; N, 17.17. C23H2oFN50 requires C,
68.81; H, 5.02; N, 17.45%.
EXAMPLE 26
3- (3-Pyridyl)-6-(2-pyridyl)methyloxy-7, 8, 9,10-tetrahydro-(7,10-ethano)-
1,2,4-triazolo[3,4-alphthalazine
This compound was prepared using the procedures described in
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Example 1 Steps a), b), c) and d) with nicotinic acid hydrazide being used
instead of benzoyl hydrazine in Step c). Data for the title compound: m.p.
= 198 C. 'H NMR (360 MHz, CDC13) S 1.49 (4H, m), 1.96 (4H, m), 3.59
(1H, s), 3.99 (1H, s), 5.61 (2H, s), 7.28 (1H, m), 7.49 (2H, m), 7.78 (1H, m),
8.72 (3H, m), 9.69 (1H, s); MS (ES+) m/e 385 [MH]+. Anal. Found C, 67.56;
H, 5.66; N, 19.51. C22H2oNs0 requires C, 67.27; H, 5.65; N, 19.61%.
EXAMPLE 27
3-Cyclopropyl-6-(2-pyridyl)methyloxy-7, 8 9 10-tetrahydro-(7 10-ethano)-
1, 2, 4-triazolo [3, 4-a]phthalazine
This compound was prepared using the procedures described in
Example 1 Steps a), b), c) and d) with cyclopropanecarboxylic acid
hydrazide being used instead of benzoyl hydrazine in Step c). Data for the
title compound: m.p. = 160 C. 1H NMR (360 MHz, CDC13) 5 1.09 (2H, m),
1.31 (2H, m), 1.44 (4H, m), 1.89 (4H, m), 2.38 (1H, m), 3.52 (1H, s), 3.90
(1H, s), 5.57 (2H, s), 7.28 (1H, m), 7.52 (1H, d, J= 7.9 Hz), 7.76 (1H, m),
8.64 (1H, m); MS (ES+) m/e 348 [MH]+. Anal. Found C, 69.12; H, 5.85; N,
20.19. C2oH21N50 requires C, 69.14; H, 6.09; N, 20.16%.
EXAMPLE 28
6-((6-Methyl)-2-pyridyl)methyloxy-3-phenyl-7 8 9 10-tetrahydro-(7 10-
ethano)-1,2,4-triazolof3,4-a]phthalazine hydrochloride
This compound was prepared using the procedures described in
Example 1 Steps a), b), c) and d) with 6-methyl-2-hydroxymethyl pyridine
being used instead of 2-pyridylcarbinol in Step d). An additional step at
the end of the synthesis was to dissolve the compound in a solution of
hydrogen chloride in methanol before evaporation and recrystallisation.
Data for the title compound: m.p. = 255 C. 1H NMR (360 MHz, DMSO) a
1.42 (4H, m), 1.91 (4H, m), 2.71 (3H, s), 3.51 (1H, s), 3.78 (1H, s), 5.80
(2H,
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s), 7.59 (4H, m), 7.80 (1H, d, J= 7.8 Hz), 8.22 (1H, m), 8.30 (2H, d, J= 7.9
Hz); MS (ES+) m/e 398 [MH]+. Anal. Found C, 61.67; H, 5.36; N, 14.74.
C24H23N50.HC1 requires C, 61.28; H, 5.36; N, 14.89%.
EXAMPLE 29
6-((3-Methyl)-2-pyridyl)methyloxy-3-phenyl-7,8,9,10-tetrahydro-(7 10-
ethano) -1, 2, 4-tria zolo [3, 4-a]phthalazine
This compound was prepared using the procedures described in
Example 1 Steps a), b), c) and d) with 3-methyl-2-hydroxymethyl pyridine
being used instead of 2-pyridylcarbinol in Step d). Data for the title
compound: m.p. = 245 C. 1H NMR (360 MHz, CDC13) S 1.48 (4H, m), 1.88
(4H, m), 2.43 (3H, s), 3.47 (1H, s), 3.98 (1H, s), 5.63 (2H, s), 7.26 (1H, m),
7.49 (3H, m), 7.60 (1H, d, J= 7.5 Hz), 8.43 (2H, d, J= 7.8 Hz), 8.48 (1H, d,
J= 7.1Hz); MS (ES+) m/e 398 [MH]+. Anal. Found C, 72.09; H, 5.76; N,
17.79. C24H23N50Ø1H20 requires C, 72.20; H, 5.86; N, 17.54%.
EXAMPLE 30
6-((4-Methyl)-2-pyridyl)methyloxy-3-phenyl-7,8,9,10-tetrahydro-(7,10-
ethano)-1, 2, 4-triazolo [3, 4-alphthalazine
This compound was prepared using the procedures described in
Example 1 Steps a), b), c) and d) with 4-methyl-2-hydroxymethyl pyridine
being used instead of 2-pyridylcarbinol in Step d). Data for the title
compound: m.p. = 190 C. 1H NMR (360 MHz, CDC13) 5 1.49 (4H, m), 1.93
(4H, m), 2.39 (3H, s), 3.58 (1H, s), 3.99 (1H, s), 5.59 (2H, s), 7.13 (1H, d,
J=
7.3 Hz), 7.35 (1H, s), 7.50 (3H, m), 8.41 (2H, d, J = 7.8 Hz), 8.51 (1H, d, J
7.3Hz); MS (ES+) m/e 398 [MH]+. Anal. Found C, 72.91; H, 5.78; N, 17.32.
C24H23N50 requires C, 72.52; H, 5.83; N, 17.62%.
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EXAMPLE 31
6-((5-Meth l~)-2-pyridvl)methyloxy-3-phenvl-7.8.9,10-tetrahydro-(7,10-
ethano)-1,2,4-triazolof3,4-a]phthalazine
This compound was prepared using the procedures described in
Example 1 Steps a), b), c) and d) with 5-methyl-2-hydroxymethyl pyridine
being used instead of 2-pyridylcarbinol in Step d). Data for the title
compound: m.p. = 205 C. 1H NMR (360 MHz, CDC13) 8 1.48 (4H, m), 1.92
(4H, m), 2.38 (3H, s), 3.56 (1H, s), 3.99 (1H, s), 5.58 (5H, s), 8.45 (3H, m);
MS (ES+) m/e 398 [MH]+. Anal. Found C, 72.66; H, 5.72; N, 17.32.
C24H23N50 requires C, 72.52; H, 5.83; N, 17.62%.
EXAMPLE 32
3-Phenyl-6-(3-pvridyl)methyloxy-7,8,9,10-tetrahydro-(7,10-ethano)-1,2,4-
triazolo [3,4-a]phthalazine
This compound was prepared using the procedures described in
Example 1 Steps a), b), c) and d) with 3-pyridylcarbinol being used instead
of 2-pyridylcarbinol in Step d). Data for the title compound: m.p. = 202 C.
1H NMR (360 MHz, DMSO) 6 1.39 (4H, m), 1.90 (4H, m), 3.40 (1H, s), 3.74
(1H, s), 5.58 (2H, s), 7.46 (1H, m), 7.56 (3H, m), 7.97 (1H, d, J= 7.8 Hz),
8.36 (2H, d, J= 7.9 Hz), 8.58 (1H, m), 8.77 (1H, m); MS (ES+) m/e 384
[MH]+. Anal. Found C, 72.70; H, 5.49; N, 18.19. C24H21N50 requires C,
72.04; H, 5.52; N, 18.26%0.
EXAMPLE 33
3-Phenvl-6-(4-pYridvl)methvloxv-7,8,9,10-tetrahydro-(7,10-ethano)-1 2 4-
triazolo j3,4-alphthalazine
This compound was prepared using the procedures described in
Example 1 Steps a), b), c) and d) with 4-pyridylcarbinol being used instead
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of 2-pyridylcarbinol in Step d). Data for the title compound: m.p. = 205 C.
'H NMR (360 MHz, CDCla) S 1.49 (4H, m), 1.95 (4H, m), 3.55 (1H, s), 3.99
(1H, s), 5.49 (2H, s), 7.41 (2H, d, J= 6.0 Hz), 7.49 (3H, m), 8.32 (2H, d, J=
7.8 Hz), 8.69 (2H, d, J = 6.0 Hz); MS (ES+) m/e 384 [MH]+. Anal. Found C,
71.29; H, 5.16; N, 17.82. C24H21N50Ø1H20 requires C, 71.70; H, 5.54; N,
18.18%.
EXAMPLE 34
3-Phenyl-6-(2-(1-methyl)imidazolyl)methyloxy-7,8,9,10-tetrahydro-(7 10-
ethano)-1, 2, 4-triazolo [3, 4-a] p hthalazine
This compound was prepared using the procedures described in
Example I Steps a), b), c) and d) with 1-methyl-2-hydroxymethyl-
imidazole being used instead of 2-pyridylcarbinol in Step d). Data for the
title compound: m.p. = 274 C. 1H NMR (360 MHz, CDsOD) 8 1.52 (4H, m),
2.03 (4H, m), 3.50 (1H, s), 3.82 (3H, s), 3.88 (1H, s), 5.64 (2H, s), 7.05
(1H,
s), 7.23 (1H, s), 7.66 (3H, m), 8.41 (2H, d, J= 7.8 Hz); MS (ES+) m/e 387
[MH]+. Anal. Found C, 68.20; H, 5.69; N, 21.77. C22H22N60 requires C,
68.38; H, 5.74; N, 21.75%.
EXAMPLE 35
6-(3-Cyanophenyl)methyloxy-3-phenyl-7,8, 9,10-tetrahydro-(7,10-ethano)-
1,2,4-triazolo[3,4-a phthalazine
a) 6-Hydroxy-3-phenyl-7,8,9,10-tetrahydro-(7,10-ethano)-1,2,4-
triazolo [3, 4- ajp hthalazine
The product from Example 1 Step c) (3.0 g, 9.6 mmol) was dissolved
in 10% aqueous 1,4-dioxan (100 ml) with sodium hydroxide solution (24 ml
of 2 N, 5 molar equivs) and the reaction mixture was heated under reflux
for 3 days. The organic solvent was removed by rotary evaporation and
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the residue was partitioned between water (250 ml) and diethyl ether (250
ml). The aqueous layer was separated and washed twice more with
diethyl ether (100 ml), then treated with 5 N hydrochloric acid until a pH
of 2 was attained. The solid which precipitated out of solution was
collected by filtration to give the required product (2.7 g, m.p. - 300 C,
dec.). 'H NMR (250 MHz, CDC13) S 1.35 (4H, m), 2.00 (4H, m), 3.49 (1H,
s), 3.84 (1H, s), 7.71 (3H, m), 8.54 (2H, d, J= 7.8 Hz); MS (ES+) m/e 293
[MH]+. Anal. Found C, 69.33; H, 5.32; N, 19.17. C17Hi5N40 requires C,
69.86; H, 5.19; N, 19.23%.
b) 6-(3-Cyanophenyl)methyloxy-3-phenyl-7 8 9 10-tetrahydro-(7 10-
ethano)-1, 2, 4-triazolo (3, 4-a] p hth alazine
The product from Example 35 Step a) (0.3 g, 1.02 mmol) was
dissolved in dimethylformamide (40 ml) with 60% sodium hydride (0.049g,
1.2 mol eq) and heated at 80 C for 20 minutes. Then a-bromo-meta-
toluonitrile (0.22 g, 1.1 mol eq) was added and heating continued for 14 h.
Water was added until the solution became cloudy and the solid that was
precipitated was collected by filtration then purified by chromatography
on silica gel using 0-30% ethyl acetate in dichloromethane as eluent. The
product was recrystallised from ethyl acetate/hexane to give the required
compound (0.22 g). Data for the title compound: m.p. = 216 C. 'H NMR
(360 MHz, CDC13) 8 1.48 (4H, m), 1.93 (4H, m), 3.54 (1H, s), 3.98 (1H, s),
5.80 (2H, s), 7.42 (1H, d, J= 3.2 Hz), 7.50 (3H, m), 7.86 (1H, d, J= 3.2
Hz), 8.45 (2H, d, J= 7.8 Hz); MS (ES+) m/e 408 [MH]+. Anal. Found C,
64.54; H, 4.98; N, 17.79. C21Hi9N50S requires C, 64.76; H, 4.92; N,
17.98%.
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EXAMPLE 36
6-(1-(3,5-Dimethyl)pyrazolyl)methyloxy-3-phenyl-7,8 9 10-tetrahydro-
(7,10-ethano)-1, 2, 4-triazolo [3,4-a]phthalazine
This compound was prepared using the procedures described in
Example 1 Steps a), b), c) and d) with 1-hydroxymethyl-3,5-dimethyl-
pyrazole being used instead of 2-pyridylcarbinol in Step d). Data for the
title compound: m.p. = 210 C. 1H NMR (360 MHz, CDC13) S 1.43 (4H, m),
1.89 (4H, m), 2.27 (3H, s), 2.32 (3H, s), 3.41 (1H, s), 3.96 (1H, s), 5.96
(1H,
s), 6.27 (2H, s), 7.54 (3H, m), 8.51 (2H, d, J= 7.8Hz); MS (ES+) m/e 401
[MH]+. Anal. Found C, 69.32; H, 6.07; N, 21.01. C23H24N60 requires C,
68.98; H, 6.04; N, 20.99%.
EXAMPLE 37
6-(4-(2-Methyl)thiazolyl)methyloxy-3-phenvl-7, 8, 9,10-tetrahydro-(7 10-
ethano)- 1,2, 4-triazolo [3, 4-a]phthalazine
This compound was prepared using the procedure described in
Example 35 Step b) with 4-chloromethyl-2-methylthiazole being used
instead of a-bromo-7neta-toluonitrile. Data for the title compound: m.p. _
180 C. 1H NMR (360 MHz, CDC13) 8 1.47 (4H, m), 1.91 (4H, m), 2.76 (3H,
s), 3.53 (1H, s), 4.00 (1H, s), 5.55 (2H, s), 7.26 (1H, s), 7.52 (3H, m), 8.48
(2H, d, J = 7.8 Hz); MS (ES+) m/e 404 [MH]+. Anal. Found C, 65.82; H,
5.17; N, 17.25. C24H21N50S requires C, 65.49; H, 5.25; N, 17.36%.
EXAMPLE 38
3-Phenyl-6-(2-quinoxalinyl)methyloxy-7,8,9,10-tetrahydro-(7 10-ethano)-
1.2, 4-triazolo j3, 4- a]i)hthalazine
This compound was prepared using the procedure described in
Example 35 Step b) with 2-chloromethylquinoxaline being used instead of
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a-bromo-meta-toluonitrile. Data for the title compound: m.p. = 250 C. 1H
NMR (360 MHz, DMSO) 8 1.43 (4H, m), 1.92 (4H, m), 3.54 (1H, s), 3.75
(1H, s), 5.88 (2H, s), 7.44 (3H, m), 7.89 (2H, m), 8.13 (4H, m), 9.18 (1H, s);
MS (ES+) m/e 435 [MH]+. Anal. Found C, 71.15; H, 5.10; N, 18.66.
C26H22N60Ø375 H20 requires C, 70.77; H, 5.20; N, 19.05%.
EXAMPLE 39
3-Phenyl-6-(3-pyridazinyl)methyloxy-7,8,9,10-tetrahydro-(7,10-ethano)-
1,2,4-triazolo[3,4-alphthalazine
This compound was prepared using the procedure described in
Example 35 Step b) with 3-chloromethylpyridazine (prepared by the
procedure of Jeronim et al., Chem. Ber., 1987, 120, 649-651) being used
instead of a-bromo-meta-toluonitrile. 3-Chloromethylpyridazine is a
particularly unstable reagent and appears to rapidly polymerise on
heating, so the reaction was carried out immediately after formation of the
alkylating agent. Data for the title compound: m.p. = 215 C. iH NMR
(360 MHz, CDC13) 8 1.49 (4H, m), 1.91 (4H, m), 3.54 (1H, s), 4.01 (1H, s),
5.85 (2H, s), 7.54 (4H, m), 7.71 (1H, dd, J= 8.5 and 1.7 Hz), 8.36 (2H, d, J
= 7.8 Hz), 9.22 (1H, dd, J= 4.9 and 1.7 Hz); MS (ES+) m/e 385 [MH]+.
Anal. Found C, 68.60; H, 5.31; N, 21.65. C22H2oNr0 requires C, 68.73; H,
5.24; N, 21.86%.
EXAMPLE 40
6- (1-Benzyl-2-imidazolyl)methyloxy-3-nhenyl-7, 8, 9,10-tetrahydro-(7,10-
e 10-
ethano2, 4-triazolo (3, 4-a1p hthalazine
This compound was prepared using the procedures described in
Example 1 Steps a), b), c) and d) with 1-benzyl-2-(hydroxymethyl)-
imidazole (prepared according to the procedure of Birker, Godefroi, Helder
and Reedijk, J. Am. Chein. Soc., 1982, 104, 7556) being used instead of 2-
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pyridylcarbinol in Step d). Data for the title compound: m.p. = 205 C. 1H
NMR (360 MHz, CDC13) S 1.20 (2H, m), 1.43 (2H, m), 1.80 (4H, m), 3.11
(1H, t, J= 2.8 Hz), 3.92 (1H, t, J= 2.7 Hz), 5.24 (2H, s), 5.55 (2H, s), 7.03
(3H, m), 7.18 (1H, d, J= 1.2 Hz), 7.28 (3H, m), 7.50 (3H, m), 8.43 (2H, m);
MS (ES+) m/e 463 [MH]+. Anal. Found C, 71.49; H, 5.62; N, 17.82.
C28H26N60Ø5H20 requires C, 71.32; H, 5.77; N, 17.82%.
EXAMPLE 41
3-Phenyl-6-(isoguinolin-1-yl)methyloxy-7, 8, 9.10-tetrahydro-(7 10-ethano)-
1, 2, 4-triazolo f 3, 4-a]phthalazine
This compound was prepared using the procedure described in
Example 35 Step b) with 1-chloromethylisoquinoline being used instead of
a-bromo-meta-toluonitrile. Data for the title compound: m.p. = 230 C. 1H
NMR (360 MHz, CDC13) S 1.45 (4H, m), 1.88 (4H, m), 3.45 (1H, s), 3.97
(1H, s), 6.09 (2H, s), 7.43 (3H, m), 7.71 (3H, m), 7.93 (1H, d, J= 8.2 Hz),
8.24 (1H, d, J= 8.4 Hz), 8.42 (2H, m), 8.58 (1H, d, J= 6.2 Hz); MS (ES+)
m/e 434 [MH]+. Anal. Found C, 75.04; H, 5.25; N, 16.40. C27H23N50
requires C, 74.81; H, 5.35; N, 16.16%.
EXAMPLE 42
6-(1-Ethyl-2-imidazolyl)methyloxy-3-phenyl-7, 8,9 10-tetrahydro-(7 10-
ethano)-1,2,4-triazolo[3,4-alphthalazine
This compound was prepared using the procedures described in
Example 1 Steps a), b), c) and d) with 1-ethyl-2-(hydroxymethyl)imidazole
(prepared according to the procedure of Tasaka, Teranishi, Matsushita,
Tamura, Hayashi, Okanogi and Itoh, Chem. Pharin. Bull., 1994, 42, 85)
being used instead of 2-pyridylcarbinol in Step d). Data for the title
compound: m.p. = 254 C. 1H NMR (500 MHz, DMSO) S 1.34 (3H, t, J= 7.2
Hz), 1.36 (4H, m), 1.87 (4H, m), 3.28 (1H, s), 3.74 (1H, s), 5.58 (2H, q, J
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7.2 Hz), 5.55 (2H, s), 6.96 (1H, s), 7.33 (1H, s), 7.58 (3H, m), 8.50 (2H, m);
MS (ES+) m/e 401 [MH]+. Anal. Found C, 68.98; H, 6.07; N, 20.74.
C23H24N60 requires C, 68.98; H, 6.04; N, 20.99%.
EXAMPLE 43
3-Phenyl-6-(1-pyrazolyl)methyloxy-7,8,9,10-tetrahydro-(7 10-ethano)-1 2 4-
triazolo L, 4-a]phthalazine
This compound was prepared using the procedures described in
Example 1 Steps a), b), c) and d) with 1-(hydroxymethyl)pyrazole
(prepared according to the procedure of Julia, Martinez-Martorell and
Elguero, Heterocycles, 1986, 24, 2233) being used instead of 2-
pyridylcarbinol in Step d). In the final step, it was necessary to add the
product from Step c) at the same time as the sodium hydride, in order to
yield the correct product. Data for the title compound: m.p. = 196 C. 'H
NMR (360 MHz, DMSO) S 1.47 (4H, m), 1.99 (4H, m), 3.38 (1H, s), 3.87
(IH, s), 6.51 (1H, m), 6.62 (2H, s), 7.73 (4H, m), 8.18 (1H, m), 8.60 (2H, m);
MS (ES+) m/e 373 [MH]+. Anal. Found C, 67.73; H, 5.42; N, 22.48.
C21H2oN6O requires C, 67.73; H, 5.41; N, 22.57%.
EXAMPLE 44
3-Phenyl-6-(N-pyrrolidinylcarbonvDmethyloxy-7,8,9,10-tetrahydro-(7 10-
e thano)-1, 2, 4-triazolo L3, 4-a] p hthalazine
a) N-Chloromethylcarbonylpyrrolidine
To a solution of pyrrolidine (5g, 0.07 mol) in dichloromethane (100
ml) at 0 C was added triethylamine (11.8ml, 0.084 mol) followed by
dropwise addition of chloroacetyl chloride (6.2 ml, 0.077 mol) in
dichoromethane (20 ml), stirred for 2 hrs, left to warm to room
temperature. The reaction was washed with water (2xlOOml), brine
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(lxlOO ml), the organic layers were dried (MgSO4), filtered and evaporated
to give the required product (9.8 g) which was used without purification.
b) 3-Phenyl-6-(N-nyrrolidinylcarbonyl)methvloxy-7,8,9,10-tetrahydro-
(7,10-ethano)-1, 2, 4-triazoloj3, 4-a]phthalazine
This compound was prepared using the procedure described in
Example 35 Step b) with N-chloromethylcarbonylpyrrohdine being used
instead of a-bromo-ineta-toluonitrile. Data for the title compound: m.p. _
219-221 C. 'H NMR (360 MHz, DMSO) 6 1.38 (4H, m), 1.77 (2H, m), 1.95
(6H, s), 3.30 (2H, m), 3.39 (1H, s), 3.44 (2H, m), 3.75 (1H, s), 5.11 (2H, s),
7.53 (3H, m), 8.29 (2H, m); MS (ES+) m/e 404 [MH]*. Anal. Found C,
68.12; H, 6.23; N, 17.03. C23H25N502 requires C, 68.47; H, 6.24; N, 17.36%.
EXAMPLE 45
6-(4-(3-Methyl)pyridyl)methyloxy-3-phenyl-7,8,9,10-tetrahydro-(7,10-
ethano)-1, 2, 4-triazolo [3, 4-alphthalazine
This compound was prepared using the procedures described in
Example 1 Steps a), b), c) and d) with 4-hydroxymethyl-3-methylpyridine
being used instead of 2-pyridylcarbinol in Step d). Data for the title
compound: m.p. = 226 C. 1H NMR (360 MHz, CDC13) 6 1.48 (4H, m), 1.93
(4H, m), 2.40 (3H, s), 3.54 (1H, s), 4.00 (1H, s), 5.49 (2H, s), 7.39 (1H, d,
J=
5.0 Hz), 7.45 (3H, m), 8.31 (2H, m), 8.47 (2H, d, J= 7.8Hz); MS (ES+) m/e
399 [MH]*. Anal. Found C, 71.50; H, 6.11; N, 16.50. Ca4HasN5O requires
C, 71.16; H, 6.00; N, 16.87%.
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EXAMPLE 46
3-Phenyl-6-(2-a uinolinyl)methvloxv-7, 8, 9,10-tetrahydro-(7 10-ethano)-
1, 2, 4-triazolo [3,4-a]phthalazine
This compound was prepared using the procedure described in
Example 35 Step b) with 2-chloromethylquinoline being used instead of a-
bromo-meta-toluonitrile. Data for the title compound: m.p. = 203 C. 1H
NMR (360 MHz, CDC13) S 1.51 (4H, m), 1.95 (4H, m), 3.61 (1H, s), 4.00
(1H, s), 5.80 (2H, s), 7.44 (3H, m), 7.53 (2H, m), 7.82 (2H, m), 8.30 (4H, m);
MS (ES+) m/e 434 [MH]+. Anal. Found C, 74.92; H, 5.38; N, 15.96.
C27H23N50 requires C, 74.81; H, 5.35; N, 16.16%.
EXAMPLE 47
6-(2-Imidazolyl)methyloxy-3-phenyl-7,8,9,10-tetrahvdro-(7 10-ethano)-
1,2,4-triazolo[3,4-a]phthalazine hydrochloride
a) 2-(Hydroxymethyl)-1-[[2-(trimethvlsilyl)ethoxylmethyllimidazole
To 1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-imidazole-2-
carboxaldehyde (prepared according to the procedure of Whitten,
Matthews and McCarthy, J. Org. Chein., 1986, 51, 1891) (7.45 g) in
methanol (30 ml) was added sodium borohydride (0.42 g) at 0. C with
stirring. The solution was stirred at 0 C for 40 min. Saturated sodium
chloride solution (15 ml) was added, and the mixture stirred at room
temperature for 15 min. The methanol was removed in vacuo, and the
resultant aqueous solution was washed with ethyl acetate (3 x 50 ml). The
organic layers were combined, dried (sodium sulfate) and concentrated in
vacuo to yield an oil, which crystallised at 0 C. The solid was washed and
recrystallised from hexane to yield 1-[[2-(trimethylsilyl)ethoxy]methyl]-2-
(hydroxymethyl)imidazole as colourless crystals (1.99 g). 'H NMR (250
MHz, CDC13) 8 0.00 (9H, s), 0.93 (2H, t, J= 8.2 Hz), 3.54 (2H, t, J= 8.2
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Hz), 4.73 (2H, s), 4.77 (2H, br s), 5.39 (2H, s), 6.94 (1H, d, J = 1.4 Hz),
7.00
(1H, d, J= 1.4 Hz) ; MS (ES+) m/e 229 [MH]+.
b) 6-(2-Imidazolyl)methyloxy-3-phenyl-7.8,9,10-tetrahydro-(7 10-
ethano)-1,2,4-triazolo[3,4-a]phthalazine hydrochloride
This compound was prepared using the procedures described in
Example 1 Steps a), b), c) and d) with 1-[[2-(trimethylsilyl)ethoxy]methyl]-
2-(hydroxymethyl)imidazole being used instead of 2-pyridylcarbinol in
Step d). An additional step was to take the product of Step d) and stir it at
50 C in 5 N hydrochloric acid for 90 min before evaporation and
recrystallisation from ethyl acetate/methanol. Data for the title
compound: m.p. = 219 C (dec.). 'H NMR (360 MHz, DMSO) S 1.42 (4H, m),
1.91 (4H, m), 3.51 (1H, s), 3.78 (1H, s), 5.84 (2H, s), 7.59 (3H, m), 7.76
(2H,
s), 8.23 (2H, m) ; MS (ES+) m/e 373 [MH]+. Anal. Found C, 55.07; H, 5.11;
N, 18.22. C21H2oN60. 2HCl. 0.7H20 requires C, 55.08; H, 5.15; N, 18.35%.
EXAMPLE 48
3-Phenyl-6-(2-thiazolyl)methyloxy-7,8,9,10-tetrahydro-(7,10-ethano)-1,2.4-
triazolo [3, 4-a] p hthalazine
This compound was prepared using the procedures described in
Example 1 Steps a), b), c) and d) with 2-hydroxymethylthiazole being used
instead of 2-pyridylcarbinol in Step d). Data for the title compound: m.p. =
183 C. 'H NMR (360 MHz, CDC13) S 1.48 (4H, m), 1.92 (4H, m), 3.51 (1H,
s), 3.99 (1H, s), 5.49 (2H, s), 7.52 (4H, m), 7.69 (2H, m), 7.81 (1H, m), 8.35
(2H, d, J= 7.8 Hz); MS (ES+) m/e 390 [MH]+. Anal. Found C, 73.93; H,
5.17; N, 17.37. C28H21N50 requires C, 73.68; H, 5.19; N, 17.19%.
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EX-AMPLE 49
6-(2-(5-Methyl)thiazolyl)methvloxy-3-phenyl-7 8 9 10-tetrahydro-(7 10-
ethano)-1, 2, 4-triazolo [3, 4-a]phthalazine
This compound was prepared using the procedures described in
Example 1 Steps a), b), c) and d) with 2-hydroxymethyl-5-methylthiazole
being used instead of 2-pyridylcarbinol in Step d). Data for the title
compound: m.p. = 228 C. 1H NMR (360 MHz, CDC13) S 1.47 (4H, m), 1.93
(4H, m), 2.50 (3H, s), 3.53 (1H, s), 3.99 (1H, s), 5.74 (2H, s), 6.95 (1H, s),
7.51 (3H, m), 8.45 (2H, d, J= 7.8 Hz); MS (ES+) m/e 404 [MH]+. Anal.
Found C, 65.92; H, 5.30; N, 17.21. C22H21N50S requires C, 65.49; H, 5.25;
N, 17.36%.
EXAMPLE 50
6- (2-(4-Methyl)thiazolyl)methvloxy-3-phenvl-7 8 9 10-tetrahvdro-(7 10-
ethano)- 1,2, 4-triazolo j3 , 4-a]p hthalazine
This compound was prepared using the procedures described in
Example 1 Steps a), b), c) and d) with 2-hydroxymethyl-4-methylthiazole
being used instead of 2-pyridylcarbinol in Step d). Data for the title
compound: m.p. = 165 C. 1H NMR (360 MHz, CDC13) 8 1.47 (4H, m), 1.92
(4H, m), 2.49 (3H, s), 3.52 (1H, s), 3.98 (1H, s), 5.70 (2H, s), 7.49 (4H, m),
8.46 (2H, d, J = 7.9 Hz); MS (ES+) m/e 404 [MH]+. Anal. Found C, 65.92;
H, 5.33; N, 17.09. C22H21N50S requires C, 65.49; H, 5.25; N, 17.36%.
EXAMPLE 51
6-(2-(3,5-Dimethyl)pyridyl)methyloxy-3-phenyl-7 8 9 10-tetrahydro-(7 10-
ethano)-1, 214-triazolo [3, 4-alp hthalazine
This compound was prepared using the procedures described in
Example 1 Steps a), b), c) and d) with 2-hydroxymethyl-3,5-dimethyl-
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pyridine (prepared by the procedure of Boekelheide and Linn, J. Am.
Chem. Soc., 1954, 76, 1286) being used instead of 2-pyridylcarbinol in Step
d). Data for the title compound: m.p. = 199 C. 'H NMR (360 MHz, CDC13)
1.46 (4H, m), 1.86 (4H, m), 2.34 (3H, s), 2.38 (3H, s), 3.44 (1H, s), 3.96
5 (1H, s), 5.57 (2H, s), 7.39 (1H, s), 7.49 (3H, m), 8.31 (1H, s), 8.47 (2H,
d, J=
7.8 Hz); MS (ES+) m/e 412 [MH]+. Anal. Found C, 72.51; H, 6.12; N, 16.86.
C25H25N50Ø1H20 requires C, 72.65; H, 6.15; N, 16.94%.
EXAMPLE 52
3-Phenyl-6-(2-pyrazinyl)methyloxy-7,8,9,10-tetrahydro-(7 10-ethano)-
1, 2, 4-triazolo L3, 4-a]p hthalazine
This compound was prepared using the procedure described in
Example 35 Step b) with 2-chloromethylpyrazine (prepared by the
procedure of Jeronim et al., Chem. Ber., 1987, 120, 649-651) being used
instead of a-bromo-meta-toluonitrile. Data for the title compound: m.p. _
215 C. 1H NMR (360 MHz, CDC13) 5 1.50 (4H, m), 1.94 (4H, m), 3.57 (1H,
s), 4.00 (1H, s), 5.65 (2H, s), 7.51 (3H, m), 8.38 (2H, d, J= 7.8 Hz), 8.63
(2H, m), 8.84 (1H, s); MS (ES+) m/e 385 [MH]+. Anal. Found C, 68.53; H,
5.24; N, 21.86. C22H2oN60 requires C, 68.73; H, 5.24; N, 21.86%.
EXAMPLE 53
6-(2-(4,6-Dimethyl)pyridyl)methyloxy-3-phenyl-7,8,9,10-tetrahydro-(? 10-
ethano)-1, 2.4-triazolo [3, 4-a]phthalazine
This compound was prepared using the procedure described in
Example 1 Steps a), b), c) and d) with 2-hydroxymethyl-4,6-
dimethylpyridine (prepared in an analogous manner to the procedure of
Boekelheide and Linn, J. Ain. Chem. Soc., 1954, 76, 1286) being used
instead of 2-pyridylcarbinol in Step d). Data for the title compound: m.p. _
200 C. 'H NMR (360 MHz, CDC13) 5 1.48 (4H, m), 1.93 (4H, m), 2.34 (3H,.
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s), 2.59 (3H, s), 3.57 (1H, s), 3.98 (1H, s), 5.55 (2H, s), 6.98 (1H, s), 7.14
(1H, s), 7.51 (3H, m), 8.43 (2H, m); MS (ES+) m/e 412 [MH]+.
EXAMPLE 54
3-Phenyl-6-(4-thiazolyl)methvloxy-7, 8, 9.10-tetrahvdro-(7,10-ethano) -1, 2, 4-
triazolo [3, 4-a]phthalazine
This compound was prepared using the procedures described in
Example 1 Steps a), b), c) and d) with 4-hydroxymethylthiazole (prepared
in an analogous manner to the procedure of Boekelheide and Linn, J. Am.
Chem. Soc., 1954, 76, 1286) being used instead of 2-pyridylcarbinol in Step
d). Data for the title compound: m.p. = 219 C. 1H NMR (360 MHz, CDC13)
b 1.46 (4H, m), 1.89 (4H, m), 3.51 (1H, s), 3.97 (1H, s), 5.66 (2H, s), 7.52
(4H, m), 8.46 (2H, d, J= 7.8 Hz), 8.88 (1H, s); MS (ES+) m/e 390 [MH]+.
Anal. Found C, 64.71; H, 4.90; N, 17.88. C21H19N50S requires C, 64.76; H,
4.91; N, 17.98%.
EXAMPLE 55
6-(2-(5.6-Dimethyl)gyridyl)methyloxy-3-phenyl-7,8.9,10-tetrahvdro-(7.10-
e th ano)-1, 2. 4-triazolo [3, 4- aj p hthalazine
This compound was prepared using the procedures described in
Example 1 Steps a), b), c) and d) with 2-hydroxymethyl-5,6-dimethyl-
pyridine (prepared as described in WO 93/21158) being used instead of 2-
pyridylcarbinol in Step d). Data for the title compound: m.p. = 250 C. 1H
NMR (360 MHz, CDBOD) S 1.58 (4H, m), 2.10 (4H, m), 2.56 (3H, s), 2.84
(3H, s), 3.71 (1H, s), 3.83 (1H, s), 5.95 (2H, s), 7.75 (3H, m), 8.05 (1H, d,
J=
8.06 Hz), 8.39 (3H, m); MS (ES+) m/e 412 [MH]+. Anal. Found C, 62.62; H,
5.44; N, 14.39. C25H25Ns0.1.9HC1 requires C, 62.46; H, 5.64; N, 14.53%.
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EXAMPLE 56
6-(4-Methvl-2-imidazolyl)methyloxy- 3-t)henyl-7 , 8, 9,10-tetrahydro-(7 10-
ethano)-1, 2, 4-triazolo [3, 4-alphthalazine hvdrochloride
a) 2-(Hydroxymethyl)-4-methyl-l-[[2-(trimethylsilyl)ethoxy]methyll-
imidazole and 2-(Hydroxymethyl)-5-methyl- i-[[2-(trimethylsilyl)ethoxy]-
methyl]imidazole
This mixture of compounds was prepared in an analogous manner
to 1-[[2-(trimethylsilyl)ethoxy]methyl]-2-(hydroxymethyl)imidazole (see
Example 47, Step a). No attempt was made to separate the 4- and 5-
methyl substituted isomers, as both compounds would yield the desired
product upon removal of the silicon protecting group. Data for 1-[[2-
(trimethylsilyl)ethoxy]methyl]-4(5)-methyl-2-(hydroxymethyl)imidazole:
1H NMR (250 MHz, CDC13) 5 0.00 (9H, s), 0.91 (2H, m), 2.18 and 2.25 (3H,
2 x s), 3.53 (2H, m), 3.53 (2H, m), 4.66 and 4.68 (2H, 2 x s), 5.30 and 5.33
(2H, 2 x s), 6.65 and 6.69 (1H, 2 x s); MS (ES+) m/e 243 [MH]+.
b) 6-(4-Methyl-2-imidazolyl)methyloxy-3-phenyl-7,8,9,10-tetrahydro-
(7,10-ethano)-1,2,4-triazolo[3,4-a]phthalazine hydrochloride
This compound was prepared using the procedure described in
Example 1 Steps a), b), c) and d) with the products from Example 56 a)
being used instead of 2-pyridylcarbinol in Step d). An additional step was
to take the product of Step d) and stir it at 50 C in 5 N hydrochloric acid
for 90 min before evaporation and recrystallisation from ethanol/ethyl
acetate. Data for the title compound: m.p. = 220 C (dec.). 'H NMR (360
MHz, DMSO) S 1.43 (4H, m), 1.91 (4H, m), 2.29 (3H, s), 3.50 (1H, s), 3.77
(IH, s), 5.80 (2H, s), 7.43 (1H, s), 7.59 (3H, m), 8.28 (2H, m); MS (ES+) m/e
387 [MH]+. Anal. Found C, 54.0; H, 6.0; N, 16.5. C22H22Nc0.2HC1. 1.8H20.
0.2C4H802 requires C, 53.76; H, 5.78; N, 16.48%.
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EXA.MPLE 57
3-Phenyl-6-(4_pyrimidinyl)methyloxy-7,8,9,10-tetrahydro-(7,10-ethano)-
1, 2,4-triazoloj3,4-ajQhthalazine
This compound was prepared using the procedure described in
Example 35 Step b) with 4-chloromethylpyrimidine (prepared by the
procedure of Jeronim et al., Chem. Ber., 1987, 120, 649-651) being used
instead of a-bromo-meta-toluonitrile. Data for the title compound: m.p.
194 C. 'H NMR (360 MHz, CDC13) S 1.51 (4H, m), 1.96 (4H, m), 3.59 (1H,
s), 4.01 (1H, s), 5.58 (2H, s), 7.49 (4H, m), 8.33 (2H, d, J= 7.8 Hz), 8.81
(1H, m), 9.26 (1H, s); MS (ES+) m/e 385 [MH]+. Anal. Found C, 68.64; H,
5.29; N, 21.58. C22H2oN60 requires C, 68.73; H, 5.24; N, 21.86%.
EXA.MPLE 58
6-(4-(2-Ethyl)thiazolyl)methylox y-3-phenyl-7,8,9,10-tetrahydro-(7,10-
ethano)-1,2,4-triazolo(3,4-a]phthalazine hydrochloride
This compound was prepared using the procedure described in
Example 35 Step b) with 4-chloromethyl-2-ethylthiazole being used
instead of a-bromo-meta-toluonitrile. Data for the title compound: m.p. _
168 C. 'H NMR (360 MHz, CDC13) S 1.46 (7H, m), 1.99 (4H, m), 3.13 (2H,
t, J= 7.6 Hz), 3.66 (1H, s), 4.53 (IH, s), 5.67 (2H, s), 7.42 (1H, s), 7.62
(3H,
m), 8.45 (2H, m); MS (ES+) m/e 418 [MH]+. Anal. Found C, 59.66; H, 5.32;
N, 14.90. C23H23N50S. HCI. 0.5H20 requires C, 59.67; H, 5.44, 15.12%.
EXAMPLE 59
6-(6-Chloro-3-pyridazinyl)methyloxy-3-phenyl-7,8,9,10-tetrahydro-(7 10-
ethano)-1,2,4-triazolo[3,4-alphthalazine
This compound was prepared using the procedure described in
Example 35 Step b) with 3-chloromethyl-6-chloro-pyridazine (prepared by.
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the procedure of Jeronim et al., Chem. Ber., 1987, 120, 649-651) being used
instead of a-bromo-meta-toluonitrile. Data for the title compound: m.p. _
206 C. 1H NMR (360 MHz, CDC13) S 1.51 (4H, m), 1.94 (4H, m), 3.51 (1H,
s), 4.00 (1H, s), 5.81 (2H, s), 7.51 (4H, m), 7.67 (1H, d, J= 8.8 Hz), 8.34
(2H, d, J= 7.7 Hz); MS (ES+) m/e 419 [MH]+. Anal. Found C, 62.95; H,
4.43; N, 19.60. C22H1sC1N60. O.1H2O requires C, 62.81; H, 4.60; N, 19.98%.
EXAMPLE 60
6-(2-Imidazolvl)methyloxy-3-(4-methylphenyl)-7,8,9,10-tetrahydro-(7 10-
ethano)-1,2,4-triazolo[3,4-a]phthalazine hydrochloride
This compound was prepared using the procedure described in
Example 1 Steps a), b), c) and d), with 4-toluic hydrazide being used
instead of benzoyl hydrazine in Step c), and 1-[[2-(trimethylsilyl)-
ethoxy]methyl]-2-(hydroxymethyl)imidazole (prepared as described in
Example 47, Step a) being used instead of 2-pyridylcarbinol in Step d). An
additional step was to take the product of Step d) and stir it at 50 C in 5 N
hydrochloric acid for 90 min before evaporation and recrystallisation from
ethanol/ethyl acetate. Data for the title compound: m.p. = 214 C (dec.). iH
NMR (360 MHz, DMSO) S 1.42 (4H, m), 1.91 (4H, m), 2.43 (3H, s), 3.51
(1H, s), 3.78 (1H, s), 5.86 (2H, s), 7.43 (2H, d, J= 8.1 Hz), 7.76 (2H, s),
8.12
(2H, d, J= 8.2 Hz) ; MS (ES+) m/e 387 [MH]+. Anal. Found C, 54.64; H,
5.72; N, 16.94. C22H22N60. 2HC1. 1.5 H20 requires C, 54.33; H, 5.60; N,
17.28%.
EXAMPLE 61
6-(4-HYdroxvmethylphenyl)methyloxv-3-phenyl-7, 8, 9,10-tetrahydro-(7 10-
e thano) -1, 2, 4-triazolo [3, 4-a] phthalazine
The title compound was prepared as part of a rapid analogue library
using the following methodology. To 4-hydroxymethylbenzyl alcohol (200
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mg) in a test tube with a ground glass joint sealed with a septum under
nitrogen was added a solution of 6-chloro-3-phenyl-7,8,9,10-tetrahydro-
(7,10-ethano)-1,2,4-triazolo[3,4-a]phthalazine (50 mg) in
dimethylformamide (1.5 ml), followed by lithium bis(trimethylsilyl)amide
as a 1 mol solution in hexanes (0.5 ml). The reaction was stirred at room
temperature for 18 hrs. TLC showed complete reaction and so the mixture
was poured into water (10 ml) and the precipitate formed was isolated by
filtration and dried in a vacuum oven at 80 C to yield the title compound
(48 mg). It was characterized by mass spectrometry and HPLC; MS (ES+)
m/e 413 [MH]+, HPLC >98% (run on an HP 1090, using a Hichrom
S5ODS2, 23cm column, flow rate of 1 ml/min and 50% acetonitrile/pH 3.5
phosphate buffer as the mobile phase).
EXAMPLE 62
6-(4-Hvdroxybutyl)oxy-3-phenyl-7, 8,9,10-tetrahydro- (7,10-ethano)-1, 2, 4-
tria zolo [3. 4- a] p hthal azine
This compound was prepared using the procedure described in
Example 61 with 1,4-dihydroxybutane being used instead of 4-
hydroxymethylbenzyl alcohol. Data for the title compound: MS (ES+) m/e
365 [MH]+, HPLC >99% (run on an HP1090, using a Hichrom S5ODS2,
23cm column, flow rate of 1 ml/min and 50% acetonitrile/pH 3.5 phosphate
buffer as the mobile phase).
EXAMPLE 63
6-cis/trans-(4-Hydroxymethylcyclohexyl)methyloxy-3-phenyl-7,8 9,10-
tetrahvdro-(7,10-ethano)-1,2,4-triazolo(3,4-a]phthalazine
This compound was prepared using the procedure described in
Example 61 with cis/trans-1,4-dihydroxymethylcyclohexane being used
instead of 4-hydroxyniethylbenzyl alcohol. Data for the title compound:
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MS (ES+) m/e 419 [MH]+, HPLC 82% and 17% (run on an HP1090, using a
Hichrom S5ODS2, 23cm column, flow rate of 1 ml/min and 50%
acetonitrile/pH 3.5 phosphate buffer as the mobile phase).
EXAMPLE 64
6-(3-Hydroxymethylphenyl)methyloxy-3-phenyl-7,8 9 10-tetrahydro-(7 10-
ethano)-1,2,4-triazolof 3,4-alphthalazine
This compound was prepared using the procedure described in
Example 61 with 3-hydroxymethylbenzyl alcohol being used instead of 4-
hydroxymethylbenzyl alcohol. Data for the title compound: MS (ES+) m/e
413 [MH]+, HPLC >99% (run on an HP1090, using a Hichrom S5ODS2,
23cm column, flow rate of 1 ml/min and 50% acetonitrile/pH 3.5 phosphate
buffer as the mobile phase).
EXAMPLE 65
6-(1-Methyl-1, 2,4-triazol-3-yl)methyloxy-3-phenvl-7,8,9,10-tetrahvdro-
(7,10-ethano)-1,2,4-triazolo f 3,4-a]phthalazine
This compound was prepared using the procedures described in
Example 1 Steps a), b), c) and d) with (1-methyl-lH-1,2,4-triazol-3-yl)-
methanol (prepared using the conditions described in EP-A-421210) being
used instead of 2-pyridylcarbinol in Step d). Data for the title compound:
m.p. = 237 C. 1H NMR (360 MHz, CDC13) S 1.47 (4H, m), 1.88 (4H, m),
3.51 (1H, s), 3.96 (4H, s), 5.54 (2H, s), 7.50 (3H, m), 8.07 (1H, s), 8.52
(2H,
d, J= 7.8 Hz); MS (ES+) m/e 388 [MH]+. Anal. Found C, 64.90; H, 5.38; N,
25.18. C21H21N70 requires C, 65.10; H, 5.46; N, 23.51%.
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EXAMPLE 66
6-(2-Methyl-1,2,4-triazol-3-yl)methyloxv-3-phenvl-7,8,9,10-tetrah dro-
(7 ,10-ethano)-1, 2, 4-tria zolo [3 , 4-a] p hthala zine
This compound was prepared using the procedures described in
Example 1 Steps a), b), c) and d) with (2-methyl-2H-1,2,4-triazol-3-
yl)methanol (prepared using the conditions described in EP-A-421210)
being used instead of 2-pyridylcarbinol in Step d). Data for the title
compound: m.p. = 270 C. 'H NMR (360 MHz, CDC13) S 1.46 (4H, m), 1.93
(4H, m), 3.45 (1H, s), 3.96 (3H, s), 3.99 (1H, s), 5.62 (2H, s), 7.52 (3H, m),
7.94 (1H, s), 8.39 (2H, d, J= 7.8 Hz); MS (ES+) m/e 388 [MH]+. Anal.
Found C, 65.40; H, 5.47; N, 25.29. C21H2iN70 requires C, 65.10; H, 5.46;
N, 23.51%.
EXAMPLE 67
3-Phenyl-6-(3-cyclopropylmethyloxy-2-pyridyl)methyloxy- 7, 8, 9,10-
tetrahydro-(7,10-ethano)-1,2,4-triazolo f 3,4-a]phthalazine
a) 3-Cyclopropylmethyloxy-2-hydroxymethyl pyridine
Potassium hydroxide (5.2 g, 0.093 mol) was ground to a powder
under nitrogen, added to DMSO (30 ml) and stirred for 20 min under
nitrogen at room temperature. The mixture was cooled to 0 C and
3-hydroxy-2-hydroxymethyl pyridine hydrochloride (5.0 g, 0.031 mol) was
added. The slurry was stirred at 0 C for 1 h before the addition of
cyclopropylmethyl bromide (3.01 ml, 4.2 g, 0.031 mol). The mixture was
allowed to warm to room temperature and stirred under nitrogen
overnight. Water (100 ml) was added, and the resultant solution was
acidified to pH 1 with hydrochloric acid (5 N). The solution was washed
with dichloromethane (3 x 100 ml), basified to pH 14 with sodium
hydroxide solution (4 N), and washed again with dichloromethane (3 x 100
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ml). The organic layers from the second extraction were combined,
washed with water (1 x 100 ml) and saturated sodium chloride solution (1
x 100 ml), dried over magnesium sulfate and concentrated in vacuo to give
3-cyclopropylmethyloxy-2-hydroxymethyl pyridine as a dark brown solid
(2.40 g). 1H NMR (250 MHz, CDC13) S 0.35 (2H, m), 0.65 (2H, m), 1.26
(1H, m), 3.85 (2H, d, J= 6.8 Hz), 4.33 (1H, br s), 4.77 (2H, s), 7.13 (2H, m),
8.13 (2H, m); MS (ES+) m/e 180 [MH]+.
b) 3-Phenyl-6-(3-cyclopropylmethyloxy-2-pyridyl)methvloxy-7,8 9 10-
tetrahydro-(7,10-ethano)-1,2,4-triazolof 3,4-ajphthalazine
This compound was prepared using the procedure described in
Example 1 Steps a), b), c) and d) with 3-cyclopropylmethyloxy-2-
hydroxymethyl pyridine being used instead of 2-pyridylcarbinol in Step d).
Data for the title compound: m.p. = 213 C. 1H NMR (360 MHz, CDC13) 8
0.28 (2H, m), 0.53 (2H, m), 1.17 (1H, m), 1.47 (4H, m), 1.88 (4H, m) 3.50
(1H, s), 3.88 (2H, d, J= 6.7 Hz), 3.96 (1H, s), 5.67 (2H, s), 7.26 (2H, m),
7.47 (3H, m), 8.22 (1H, m), 8.46 (2H, d, J= 6.6 Hz); MS (ES+) m/e 454
[MH]+. Anal. Found C, 71.43; H, 5.98; N, 15.39. C27H27N502 requires C,
71.50; H, 6.00; N, 15.44%.
EXAMPLE 68
3-Phenyl-6-(3-ethoxy-2-pyridyl)methyloxy-7,8,9,10-tetrahydro-(7,10-
ethano)-1, 2, 4-triazolo [3, 4-alp hthalazine
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a) 3-Ethoxy-2-hydroxymethvl p r~ idine
This compound was prepared using the procedure described in
Example 67 Step a), with iodoethane being used instead of
cyclopropylmethyl bromide. 1H NMR (250 MHz, CDCla) 8 1.44 (3H, t,
J 7.0 Hz), 4.06 (2H, q, J=7.0 Hz), 4.75 (2H, s), 7.16 (2H, m), 8.14 (1H, m);
MS (ES+) m/e 154 [MH]+.
b) 3-Phenyl-6-(3-ethoxy-2-pyridyl)methyloxy-7,8,9,10-tetrahydro-(7 10-
ethano)-1, 2, 4-triazolo[3, 4-a]phthalazine
This compound was prepared using the procedure described in
Example 1 Steps a), b), c) and d) with 3-ethoxy-2-hydroxymethyl pyridine
being used instead of 2-pyridylcarbinol in step d). Data for the title
compound: m.p. = 230 C. 'H NMR (360 MHz, CDC13) 8 1.38 (3H, t, J=7
Hz), 1.44 (4H, m), 1.88 (4H, m), 3.50 (1H, t, J=2.6 Hz), 3.96 (1H, t, J=2.6
Hz), 4.10 (2H, q, J=6.9 Hz), 5.64 (2H, s), 7.26 (2H, m), 7.49 (3H, m), 8.23
(1H, m), 8.45 (2H, m); MS (ES+) m/e 428 [MH]+. Anal. Found C, 70.50; H,
5.93; N, 16.41. C25H25N502 requires C, 70.24; H, 5.89; N, 16.38%.
EXAMPLE 69
6-(6-Methylnyridin-2-yl)methyloxv-3-phenyl-1, 2, 4-triazolo[3, 4-
a]phthalazine
a) 2-Acetoxymethyl-6-methylpyridine
Acetic anhydride (23m1) was heated to 110 C and 2,6-lutidine-N-
oxide (20g) was added dropwise over 1 hour. The solution was heated at
110 C for five hours. After cooling, the crude mixture was distilled to yield
2-acetoxymethyl-6-methylpyridine (18.4g, b.p. 110-120 C @ 15mmHg).
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b) 2-Hydroxymethyl-6-methylpyridine
2-Acetoxymethyl-6-methylpyridine (5g) was added to saturated
hydrochloric acid in methanol (250ml, prepared by adding 25m1 of acetyl
chloride to 225m1 of methanol). The reaction mixture was stirred at room
temperature for 18 hours. The solvent was removed under vacuum and
the residue was dissolved in dichloromethane (100ml) and washed with 2N
sodium hydroxide solution (3 x 50m1). The combined organic layers were
washed with brine (1 x 200m1), then dried (MgSO4), filtered and
evaporated to give the required product as an oil (2.6g). 'H NMR (250
MHz, CDC13) 8 2.54 (3H, s), 3.80 (1H, bs), 4.72 (2H, s), 7.04 (2H, d,
J=7.7Hz), 7.57 (1H, t, J=7.7Hz).
c) 1-Chloro-4-hydrazinophthalazine hydrochloride
To a stirred solution of hydrazine hydrate (40m1) in ethanol (120m1)
at 80 C was added 1,4-dichlorophthalazine (20g). This reaction mixture
was stirred at 80 C for 0.5 hours, then left to cool and the product was
collected by filtration and dried under vacuum to give 1-chloro-4-
hydrazinophthalazine hydrochloride (14.6g). 1H NMR (250 MHz, DMSO) 8
4.64 (2H, vbs), 7.2 (1H, vbs), 7.92 (4H, bm).
d) 6-Chloro-3-phenyl-1,2,4-triazolo[3,4-a]phthalazine
To a solution of 1-chloro-4-hydrazinophthalazine hydrochloride
(IOg) in dioxan (220m1) was added triethylamine (7.24ml) and benzoyl
chloride (6.04m1). This mixture was heated at reflux for 8 hours under
nitrogen. After cooling the reaction mixture was concentrated under
vacuum and the solid obtained was collected by filtration, washed with
water and diethyl ether and dried under vacuum, to yield the title
compound (12.0g). 'H NMR (250 MHz, DMSO) 8 7.60 (3H, m), 8.00 (1H, t,
J=8.4Hz), 8.19 (1H, t, J=8.4Hz), 8.31 (3H, m), 8.61 (1H, d, J=6.3Hz).
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e) 6-(6-Methylpyridin-2-yl)methyloxy-3-phenyl-1,2,4-triazolo[3 4-
a]phthalazine
To a solution of 2-hydroxymethyl-6-methylpyridine (Example 67
part b, 0.5g), in anhydrous dimethylformamide (20m1) under nitrogen was
added sodium hydride (107mg of 60% in oil) and the reaction mixture was
stirred at room temperature for 0.5 hours. To this mixture was added 6-
chloro-3-phenyl-1,2,4-triazolo[3,4-a]phthalazine (Example 67 part d,
330mg) and the solution was heated to 80 C for 0.25 hours. After cooling
the solvent was removed under vacuum, and the residue was dissolved in
dichloromethane (30m1) and washed with water and brine. After drying
(MgSO4), the solution was filtered and evaporated to give the required
product which was recrystallised from a mixture of ethyl acetate and
hexane to give the title compound (210mg, m.p. 186-187 C). 1H NMR (360
MHz, DMSO) 6 2.52 (3H, s), 5.65 (2H, s), 7.25 (1H, d, J=7.7Hz), 7.49 (1H,
d, J=7.7Hz), 7.58 (3H, m), 7.76 (1H, t, J=7.7Hz), 7.94 (1H, t, J=7.6Hz),
8.08 (1H, t, J=7.7Hz), 8.30 (3H, m), 8.58 (1H, d, J=7.6Hz); MS (ES+) m/e
368 [MH]+. Anal. Found C, 71.32; H, 4.44; N, 18.53. C22H17N50. H20
requires C, 71.22; H, 4.73; N, 18.88%.
EXAMPLE 70
6-(1-Methyl-1H-1,2,4-triazol-3-ylmethoxy)-3,7-diphenyl-1,2,4-triazolof4 3-
b1pyridazine
This compound was prepared in 82% yield using a similar procedure
to that described in Example 2, Step d, but using (1-methyl-lH-1,2,4-
triazol-3-yl)methanol (prepared as described in Example 65) instead of 2-
pyridylcarbinol. In this case the reaction mixture was partitioned between
water and ethyl acetate with saturated aqueous NaC1 added to aid in the
separation of the layers. The aqueous layer was further extracted with
ethyl acetate, and the combined organic extracts were dried (Na2SO4) and
evaporated iiL vacuo. The residue was purified by flash chromatography
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(silica gel, 2% MeOH/CH2C12), and recrystallised from EtOAc-CH2C12.
Data for the title compound: mp 229-233 C; 1H NMR (360 MHz, CDC13) S
3.92 (3H, s), 5.61 (2H, s), 7.45-7.59 (6H, m), 7.68 (2H, dd, J= 7.9, J' = 1.6
Hz), 8.03 (1H, s), 8.05 (1H, s), 8.55 (2H, m); MS (ES+) m/e 384 [MH]+. Anal.
Found C, 66.05; H, 4.34; N, 25.68. C21H17N70 requires C, 65.79; H, 4.47;
N, 25.57%.
EXAMPLE 71
6-(2-Methyl-2H-1,2,4-triazol-3-vlmethoxv)-3,7-diphenyl-1 2 4-triazolo[4 3-
b]pyridazine
This compound was prepared in 40% yield using a similar procedure
to that described in Example 2, Step d, but using (2-methyl-2H 1,2,4-
triazol-3-yl)methanol (prepared as described in Example 66) instead of 2-
pyridylcarbinol. Data for the title compound: mp 198-202 C; 1H NMR (360
MHz, CDC13) 5 3.74 (3H, s), 5.67 (2H, s), 7.47-7.61 (8H, m), 7.90 (1H, s),
8.08 (1H, s), 8.42 (2H, m); MS (ES+) m/e 384 [MH]+. Anal. Found C, 63.70;
H, 4.45; N, 24.59. C21H17N70. 0.7H20 requires C, 63.69; H, 4.68; N,
24.75%.
EXAMPLE 72
3,7-Diphenyl-6-(2H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo[4 3-
bJpvridazine
a) j2-(2-(Trimethylsilanyl)ethoxymethyl)-2H-1,2,4-triazol-3-
yllmethanol
1-(2-(Trimethylsilanyl)ethoxymethyl)-1H-1,2,4-triazole (6.57g)
(prepared as described by Fugina et al., Heterocycles, 1992, 303-314) was
dissolved in THF (110 ml) and cooled to -70 C whereupon butyllithium
(23.12 ml of a 1.6 M solution in hexane) was added dropwise over 15
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minutes keeping the temperature at -70 C. After 1 hour DMF (2.4 ml, 1
mol eq) was added and the reaction mixture was allowed to warm to 0 C
over 30 minutes. Saturated ammonium chloride solution (300 ml) was
added and the mixture was extracted with ethyl acetate (2 x 300 ml). The
organic layer was dried (Na2SO4), filtered and concentrated in vacuo to
give a clear oil (6.5g). This oil was dissolved in methanol (120 ml) and
sodium borohydride (1.08 ml, 1 mol eq) was added in portions over 20
minutes. After 1 h the solvent was removed under vacuum and the
residue was partitioned between water (50 ml) and dichloromethane (2 x
100 ml). The combined organic layers were washed with brine (1 x 30 ml)
and dried (Na2SO4), filtered and concentrated in vacuo to give a clear oil
which was purified by chromatography on silica gel using 0-4% methanol
in dichloromethane as eluent to give the required compound (5 g) as a
clear oil. 1H NMR (250 MHz, CDC13) b 0.00 (9H, s), 0.93 (2H, t, J= 8.2 Hz),
3.63 (2H, t, J= 8.2 Hz), 4.87 (2H, s), 4.11 (1H, br s), 5.28 (2H, s), 7.85
(1H,
s).
b) 3,7-Diphenyl-6-[2-(2-(trimethylsilanyl)ethoxymethyl)-2H-1,2,4-
triazol-3-ylmethoxy1-1, 2, 4-triazolo [4, 3-bjpyridazine
This compound was prepared using the procedures described in
Example 2 a), b), c) and d) with the product from Example 72 a) being used
instead of 2-pyridylcarbinol. 1H NMR (250 MHz, CDC13) S 0.00 (9H, s),
0.83 (2H, t, J= 8.2 Hz), 3.55 (2H, t, J= 8.2 Hz), 5.46 (2H, s), 5.78 (2H, s),
7.55-7.68 (8H, m), 8.00 (1H, s), 8.15 (1H, s), 8.45 (2H, d, J=7.8 Hz).
c) 3,7-Dii)henyl-6-(2H-1,2,4-triazol-3-ylmethoxv)-1,2,4-triazolo[4,3-
blpvridazine
The product from Example 72 Step b) (0.68 g) was suspended in
ethanol (10 ml) with 2 N hydrochloric acid (21 ml) and heated at 65 C for
5.5 h. Saturated sodium carbonate solution was added dropwise until a
solid precipitated and this was collected by filtration and washed several.
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times with water in the sinter funnel. The solid was recrystallised from
methanol to give the required product (0.245 g, m.p. = 248 C). 1H NMR
(360 MHz, ds-DMSO) S 5.61 (2H, s), 7.48-7.63 (6H, m), 7.44-7.77 (2H, m),
8.40 (4H, m), 14.13 (1H, br s); MS (ES+) m/e 370 [MH]+. Anal. Found C,
65.02; H, 4.04; N, 26.35. C2oH15N70 requires C, 65.03; H, 4.09; N, 26.54%.
EXAMPLE 73
6-(2-Methyl-2H-tetrazol-5-ylmethoxy)-3,7-diphenyl-1,2,4-triazolo[4 3-bL
pyridazine
a) 3,7-Diphenyl-1,2,4-triazolof4,3-b]pyridazin-6-one
To a solution of 6-chloro-3,7-diphenyl-1,2,4-triazolo[4,3-b]pyridazine
(from Example 2, Step c) (1.02 g, 3.34 mmol) in 1,4-dioxane (60 ml) and
water (12 ml) was added 4 M aqueous NaOH (4.17 ml, 16.7 mmol), and the
solution was heated at reflux for 7.5 h whilst stirring magnetically. The
mixture was then concentrated in vacuo and the aqueous residue was
partitioned between water (200 ml) and diethyl ether (100 ml). The
aqueous layer was then acidified with 5 M aqueous HC1 until the pH was
ca. 3. The resulting precipitated solid was collected by filtration, washed
with water, then hexane, and dried at 60 C under vacuum to give 0.8885 g
(92%) of the title compound as a white solid. 'H NMR (360 MHz, d6-
DMSO) 8 7.47-7.63 (6H, m), 7.71 (2H, dd, J = 8.0, J = 1.8 Hz), 8.31 (1H, s),
8.46 (2H, m), 12.80 (1H, br s); MS (ES+) m/e 289 [MH]+.
b) 6-(2-Methyl-2H-tetrazol-5-vlmethox -3,7-dii)henyl-1 2 4-
triazolo [4, 3-b]pyridazine
To the product from Example 73, Step a (0.15 g, 0.52 mmol) in
anhydrous DMF (5 ml) was added sodium hydride (60% dispersion in oil,
31.2 mg, 0.780 mmol) and the mixture was stirred under nitrogen at room
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temperature for 45 min then at 80 C for another 20 min. After allowing to
cool, a solution of 5-chloromethyl-2-methyl-2H-tetrazole (Moderhack, D.,
Chem. Ber., 1975, 108, 887-896) (0.103 g, 0.780 mmol) in anhydrous DMF
(4 ml) was added and the mixture was stirred at room temperature under
nitrogen for 1.5 h, then at 80 C for 17 h. The mixture was then
partitioned between water (30 ml) and ethyl acetate (40 ml). The aqueous
layer was further extracted with ethyl acetate (9 x 40 ml) and the
combined organic extracts were dried (MgSO4), and evaporated in vacuo.
The residue was recrystallised from EtOAc-CH2C12-MeOH to afford 0.1002
g (50%) of the title compound as a white solid: mp 228-233 C; 'H NMR
(360 MHz, CDC13) 8 4.36 (3H, s), 5.79 (2H, s), 7.47-7.60 (8H, m), 8.07 (1H,
s), 8.48 (2H, m); MS (ES+) m/e 385 [MH]+. Anal. Found C, 62.01; H, 4.13;
N, 28.92. C2oH1sN80. 0.17H20 requires C, 62.00; H, 4.25; N, 28.92%.
EXAMPLE 74
3, 7-Diphenyl-6-(2-propyl-2H-1.2,4-triazol-3-ylmethoxv)-1,2,4-triazolo(4,3-
blpyridazine
a) 3- and 5-(tert-Butyldimethylsilanyloxvmethyl)-1-t)ropvl-lH-1,2 4-
triazole
To a stirred mixture of sodium hydride (60% dispersion in oil, 1.5 g,
37.5 mmol) and 1-iodopropane (4.4 ml, 45 mmol) in anhydrous DMF (100
ml), cooled under nitrogen to 0 C, was added dropwise over 10 min a
solution of 3-(tert-butyldimethylsilanyloxymethyl)-1H-1,2,4-triazole
(prepared as described in EP-A-421210) (8.0 g, 37.5 mmol) in anhydrous
DMF (25 ml). The mixture was stirred under nitrogen at 0 C for 25 min,
more sodium hydride (60% dispersion in oil, 0.45 g, 11.3 mmol) was added,
and the mixture was stirred for another 30 min. Water (300 ml) was then
added and the mixture was extracted with ethyl acetate (3 x 100 ml). The
combined organic extracts were washed with brine (100 ml), dried
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(Na2SO4) and evaporated in vacuo. The residue was purified by flash
chromatography (silica gel, 40-50% EtOAc/hexane; and alumina, 15%
EtOAc/hexane) to yield 4.10 g (43%) of 5-(tert-
butyldimethylsilanyloxymethyl)-1-propyl-lH-1,2,4-triazole and 2.97 g
(31%) of 3-(tert-butyldimethylsilanyloxymethyl)-1-propyl-1HH1,2,4-triazole
as colourless oils.
3-(tert-Butvldimethylsilanvloxymethyl)-1-nropyl-lH-1, 2, 4-triazole: 'H
NMR (250 MHz, CDC13) S 0.12 (6H, s), 0.92 (9H, s), 0.93 (3H, t, J= 7.3
Hz), 1.91 (2H, sextet, J= 7.3 Hz), 4.09 (2H, t, J= 7.1Hz), 4.77 (2H, s), 8.03
(1H, s).
5-(tert-Butyldimethylsilanyloxymethyl)-1-propyl-lH-1, 2, 4-triazole: 'H
NMR (250 MHz, CDC13) S 0.10 (6H, s), 0.90 (9H, s), 0.95 (3H, t, J= 7.4
Hz), 1.92 (2H, sextet, J= 7.4 Hz), 4.19 (2H, m), 4.84 (2H, s), 7.81 (1H, s).
b) (2-ProQyl-2H-1,2,4-triazol-3-yl)methanol
To a solution of 5-(tert-butyldimethylsilanyloxymethyl)-1-propyl-lH-
1,2,4-triazole (from Step a) (4.10 g, 16.1 mmol) in ethanol (18 ml) and
methanol (36 ml) was added 4 M aqueous NaOH (6 ml, 24 mmol) and the
mixture was stirred at room temperature for 19 h, then at 45 C for
another 5 h. The solvents were removed in vacuo and the residue was
purified by flash chromatography (silica gel, EtOAc, then 10%
MeOH/CH2Cl2) to leave 1.976 g (87%) of the title compound as a pale
yellow oil: 'H NMR (250 MHz, CDC13) 8 0.95 (3H, t, J = 7.4 Hz), 1.91 (2H,
sextet, J= 7.4 Hz), 4.16 (2H, t, J= 7.3 Hz), 4.76 (2H, s), 7.81 (1H, s).
c) 3,7-Diphenyl-6-(2-propyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2 4-
triazolo[4, 3-blpyridazine
This compound was prepared in 44% yield using a similar procedure
to that described in Example 2, Step d, but using (2-propyl-2H-1,2,4-
triazol-3-yl)methanol (from Step b) instead of 2-pyridylcarbinol. Data for
the title compound: mp 211-213 C; 1H NMR (250 MHz, CDC13) 8 0.68 (3H, .
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t, J= 7.4 Hz), 1.65 (2H, sextet, J= 7.4 Hz), 3.96 (2H, t, J= 7.4 Hz), 5.66
(2H, s), 7.45-7.63 (8H, m), 7.93 (1H, s), 8.09 (1H, s), 8.46 (2H, m); MS (ES+)
m/e 412 [MH]+. Anal. Found C, 66.75; H, 4.82; N, 23.60. C23H21N70
requires C, 67.14; H, 5.14; N, 23.83%.
EXAMPLE 75
3,7-DiAhenyl-6-(1-propyl-lH-1,2,4-triazol-3-ylmethoxy)-1 2 4-triazolo[4 3-
blpyridazine
a) (1-Propyl-lH-1,2,4-triazol-3-yl)methanol
To a solution of 3-(tert-butyldimethylsilanyloxymethyl)-1-propyl-lH-
1,2,4-triazole (from Example 74, Step a) (2.97 g, 11.6 mmol) in ethanol (13
ml) and methanol (26 ml) was added 4 M aqueous NaOH (4.3 ml, 17.4
mmol) and the mixture was stirred at 45 C for 2 days. The solvents were
removed in vacuo and the residue was purified by flash chromatography
(silica gel, EtOAc, then 10% MeOH/CH2C12) to leave 1.509 g (92%) of the
title compound as a white solid: 1H NMR (250 MHz, CDC13) S 0.94 (3H, t, J
= 7.4 Hz), 1.92 (2H, sextet, J= 7.4 Hz), 4.10 (2H, t, J= 7.1 Hz), 4.76 (2H,
s), 8.01 (1H, s).
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b) 3.7-Diphenyl-6-(1-propyl-lH-1,2,4-triazol-3-ylmethoxy)-1,2,4-
triazolo [4, 3-b]pyridazine
This compound was prepared in 70% yield using a similar procedure
to that described in Example 2, Step d, but using (1-propyl-lH-1,2,4-
triazol-3-yl)methanol (from Step a) instead of 2-pyridylcarbinol. Data for
the title compound: mp 212-214 C; 1H NMR (360 MHz, CDC13) 8 0.90 (3H,
t, J= 7.4 Hz), 1.90 (2H, sextet, J = 7.3 Hz), 4.10 (2H, t, J = 7.0 Hz), 5.62
(2H, s), 7.45-7.58 (6H, m), 7.68 (2H, m), 8.03 (1H, s), 8.06 (1H, s), 8.56
(2H,
m); MS (ES+) m/e 412 [MH]+. Anal. Found C, 67.51; H, 5.01; N, 23.86.
C23H21N70 requires C, 67.14; H, 5.14; N, 23.83%.
EXAMPLE 76
6-(1-Methyl-lH-imidazol-4-vlmethoxy)-3,7-diphenyl-1,2,4-triazoloL,3-
b]pyridazine
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a) 4- and 5-(tert-Butyldimethvlsilanyloxymethvl)-1-methvl-lH-
imidazole
To a solution of 5-(tert-butyldimethylsilanyloxymethyl)-1H-
imidazole (Amino, Y.; Eto, H.; Eguchi, C., Chem. Pharm. Bull., 1989, 37,
1481-1487) (3.158 g, 14.9 mmol) in anhydrous THF (25 ml), cooled to -78 C
under nitrogen, was added a 1.6 M solution of butyllithium in hexanes
(10.2 ml, 16.4 mmol). The mixture was stirred under nitrogen at -78 C for
30 min, then iodomethane (0.97 ml, 15.6 mmol) was added. The mixture
was allowed to warm to room temperature and stirred for 5 h. Water (150
ml) was then added and the mixture was extracted with diethyl ether (150
ml). The organic extract was washed with brine, dried (MgSO4) and
evaporated in vacuo. The residue was purified by flash chromatography
(alumina, 40% EtOAc/hexane) to yield 0.4732 g (14%) of 4-(tert-
butyldimethylsilanyloxymethyl)-1-methyl-lH-imidazole and 1.463 g (43%)
of 5-(tert-butyldimethylsilanyloxymethyl)-1-methyl-lH-imidazole.
4-(tert-Butyldimethylsilanyloxymethyl)-1-methyl-lH-imidazole: 'H NMR
(250 MHz, CDC13) S 0.11 (6H, s), 0.93 (9H, s), 3.65 (3H, s), 4.68 (2H, s),
6.80 (1H, s), 7.35 (1H, s).
5-(tert-Butyldimethylsilanyloxymethyl)-1-methyl-lH-imidazole: 'H NMR
(250 MHz, CDC13) 8 0.05 (6H, s), 0.88 (9H, s), 3.67 (3H, m), 4.65 (2H, s),
6.90 (ZH, s), 7.41 (1H, s).
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b) (1-Methyl-lH-imidazol-4-yl)methanol
To a solution of 4-(tert-butyldimethylsilanyloxymethyl)-1-methyl-
1H-imidazole (from Step a) (0.4732 g, 2.09 mmol) in ethanol (2.4 ml) and
methanol (4.7 ml) was added 4 M aqueous NaOH (0.778 ml, 3.14 mmol)
and the mixture was stirred at 45 C for 2 days. The mixture was then
evaporated in vacuo and the residue was purified by flash chromatography
(silica gel, CH2C12-MeOH-NH3 (aq); 80:20:2) to leave 0.224 g (96%) of the
title compound: 'H NMR (250 MHz, CDC13) 8 3.66 (3H, s), 4.58 (2H, s),
6.84 (1H, s), 7.39 (1H, s).
c) 6-(1-Methyl-lH-imidazol-4-ylmethoxy)-3 7-diphenyl-1 2 4-
triazolo [4. 3-bl pyridazine
This compound was prepared in 44% yield using a similar procedure
to that described in Example 2, Step d, but using (1-methyl-lH-imidazol-4-
yl)methanol (from Step b) instead of 2-pyridylcarbinol. Data for the title
compound: mp 199-202 C; 'H NMR (360 MHz, CDC13) S 3.63 (3H, s), 5.50
(2H, s), 6.88 (1H, s), 7.41-7.64 (9H, m), 8.02 (1H, s), 8.56 (2H, m); MS (ES+)
m/e 383 [MH]+. Anal. Found C, 69.02; H, 4.42; N, 21.55. C22H18N60.
0.025H20 requires C, 69.01; H, 4.75; N, 21.95%.
EXAMPLE 77
6-(3-Methyl-3H-imidazol-4-ylmethoxy)-3,7-diphenyl-1 2 4-triazolof4 3-
b]pyridazine
a) (3-Methyl-3H-imidazol-4-yl)methanol
To a solution of 5-(tert-butyldimethylsilanyloxymethyl)-1-methyl-
1H-imidazole (from Example 76, Step a) (0.100 g, 0.442 mmol) in ethanol
(0.5 ml) and methanol (1 ml) was added 4 M aqueous NaOH (0.165 ml,
0.66 mmol) and the mixture was stirred at room temperature for 2 h, then
at 50 C for 16 h. The mixture was then evaporated in vacuo and the
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residue was purified by flash chromatography (silica gel, CH2C12-MeOH-
NH3(aq); 80:20:2) to leave 31.3 mg (63%) of the title compound: 'H NMR
(250 MHz, CDC13) 6 3.71 (3H, s), 4.62 (2H, s), 6.87 (1H, s), 7.38 (1H, s).
b) 6-(3-Methyl-3H-imidazol-4-ylmethoxy)-3,7-diphenyl-1 2 4-
triazolo[4, 3-blpyridazine
This compound was prepared in 30% yield using a similar procedure
to that described in Example 2, Step d, but using (3-methyl-3H-imidazol-4-
yl)methanol (from Step a) instead of 2-pyridylcarbinol. Data for the title
compound: mp 195-196 C; 1H NMR (250 MHz, CDC13) 6 3.53 (3H, s), 5.52
(2H, s), 7.20 (1H, s), 7.44-7.65 (9H, m), 8.04 (1H, s), 8.49 (2H, m); MS (ES+)
m/e 383 [MH]+. Anal. Found C, 68.31; H, 4.38; N, 21.55.
C22H18N60Ø12H20 requires C, 68.70; H, 4.78; N, 21.85%.
EXAMPLE 78
6-(4-Methyl-4H-1,2,4-triazol-3-vlmethoxy)-3,7-diphenyl-1 2 4-triazolo[4 3-
b]pyridazine
This compound was prepared in 46% yield using a similar procedure
to that described in Example 2, Step d, but using (4-methyl-4H-1,2,4-
triazoi-3-yl)methanol (WO 95/34542) instead of 2-pyridylcarbinol. Data for
the title compound: mp 230-235 C; 1H NMR (360 MHz, CDC13) 5 3.50 (3H,
s), 5.74 (2H, s), 7.45-7.62 (8H, m), 8.07 (1H, s), 8.12 (1H, s), 8.49 (2H, m);
MS (ES+) m/e 384 [MH]+. Anal. Found C, 65.48; H, 4.34; N, 25.31.
C21H17N7O requires C, 65.79; H, 4.47; N, 25.57%.
EXAMPLE 79
6-(5-Methvl-2H-1,2,4-triazol-3-ylmethoxy)-3 7-diphenyl-1 2 4-triazoloj4 3-
b]pvridazine
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a) 3 7-Di hen l-1 2 4-triazolo 4 3-b ridazin-6- lox acetonitrile
To a stirred solution of 3,7-diphenyl-1,2,4-triazolo[4,3-b]pyridazin-6-
one (from Example 73, Step a) (0.4021 g, 1.39 mmol) in anhydrous DMF
(20 ml) under nitrogen was added sodium hydride (60% dispersion in oil,
84.0 mg, 2.10 mmol) and the mixture was stirred at room temperature for
30 min, then at 80 C for 20 min. After allowing to cool, bromoacetonitrile
(0.146 ml, 2.10 mmol) was added dropwise and the mixture was stirred at
room temperature for 14 h. The mixture was then partitioned between
ethyl acetate (100 ml) and water (100 ml), adding saturated aqueous NaCI
to aid in the separation of the layers. The aqueous layer was extracted
further with ethyl acetate (2 x 100 ml) and the combined organic extracts
were dried (Na2SO4), and evaporated in vacuo. The residue was purified
by flash chromatography (silica gel, 2% MeOH/CH2C12) to afford 0.4566 g
(100%) of the title compound as a buff solid: 'H NMR (360 MHz, CDC13) b
5.11 (2H, s), 7.52-7.63 (8H, m), 8.12 (1H, s), 8.45 (2H, m); MS (ES+) m/e
328 [MH]
b) 6-(5-Methyl-2H-1,2,4-triazol-3-ylmethoxy)-3 7-diphenyl-1 2 4-
triazolo j4, 3-bl pyridazine
To an ice-cooled solution of the product from Step a (0.280 g, 0.855
mmol) in anhydrous methanol (35 ml) under nitrogen was added sodium
methoxide (2.6 mg, 0.048 mmol), and the mixture was stirred at room
temperature under nitrogen for 19 h, then at 50 C for 3 days, adding
anhydrous dichloromethane (3 ml) to dissolve solids. After allowing to
cool, the mixture was neutralised by adding acetic acid (2.5 ml, 0.044
mmol). Acetic hydrazide (63 mg, 0.850 mmol) was then added and the
mixture was stirred at room temperature for 20 h, then at 50 C for 23 h.
After allowing to cool, the resulting brown solid was collected by filtration,
and washed with dichloromethane to leave 230 mg of the intermediate
acylimidrazone. This was then heated at 145 C under high vacuum for 2
days, and the residue was purified by preparative TLC (silica gel, 5%
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MeOH/CH2C12) and recrystallised to leave 61 mg (19%) of the title
compound as a white solid: mp 233-235 C; 'H NMR (360 MHz, CDC13) S
2.50 (3H, s), 5.61 (2H, s), 7.41-7.52 (6H, m), 7.58-7.59 (2H, m), 7.96 (1H,
s),
8.44 (2H, m); MS (ES+) m/e 384 [MH]+.
EXAMPLE 80
6-(3-Methyl-3H-1,2,3-triazol-4-vlmethoxv)-3 7-diphenyl-1 2 4-triazolo[4 3-
b]pyridazine
a) 3-Methvl-3H-1,2,3-triazole-4-carboxaldehvde
To a stirred solution of 1-methyl-lH-1,2,3-triazole (0.500 g, 6.02
mmol) in anhydrous THF (20 ml), cooled to -70 C under nitrogen, was
added dropwise a 1.6 M solution of butyl lithium in hexanes (4.23 ml, 6.77
mmol). The mixture was stirred at this temperature for 1 h, then
anhydrous DMF (0.465 ml, 6.02 mmol) was added, and the mixture was
allowed to warm to 0 C over 30 min. Saturated aqueous NH4C1 (25 ml)
was then added and the mixture was extracted with ethyl acetate. The
organic layer was dried (Na2SO4) and evaporated in vacuo. The residue
was purified by flash chromatography (silica gel, 40% EtOAc/hexane) to
give 0.128 g (19%) of the title compound as a yellow oil: 1H NMR (360
MHz, d6-DMSO) S 4.27 (3H, s), 8.45 (1H, s), 10. 01 (1H, s); MS (ES+) m/e
144 [M+MeOH+H]+, 111[M]+.
b) (3-Methyl-3H-1, 2, 3-triazol-4-yl)-methanol
To a stirred solution of the product from Step a(0.128 g, 1.15 mmol)
in anhydrous methanol (1.1 ml), cooled to 0 C under nitrogen, was added
sodium borohydride (14.8 mg, 0.390 mmol) and the mixture was stirred at
this temperature for 1 h. Saturated aqueous NaCl (5 ml) was then added
and the mixture was stirred for 10 min. The aqueous layer was extracted
with ethyl acetate, and the combined organic extracts were dried (Na2SO4).
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-
and evaporated in vacuo. The residue was purified by flash
chromatography (silica gel, 5% MeOH/CH2C12) to afford 86.3 mg (66%) of
the title compound: iH NMR (250 MHz, CDC13) S 4.10 (3H, s), 4.77 (2H, s),
7.53 (1H, s).
c) 6-(3-Methvl-3H-1,2,3-triazol-4-vlmethoxv)-3 7-diphenvl-1 2 4-
triazolo[4, 3-b]pyridazine
This compound was prepared in 29% yield using a similar procedure
to that described in Example 2, Step d, but using (3-methyl-3H-1,2,3-
triazol-4-yl)methanol (from Step b) instead of 2-pyridylcarbinol. Data for
the title compound: mp 190-193 C; 1H NMR (360 MHz, CDC13) S 3.94 (3H,
s), 5.60 (2H, s), 7.49 (5H, s), 7.54-7.63 (3H, m), 7.75 (1H, s), 8.08 (1H, s),
8.41 (2H, dd, J=8.3, 1.6 Hz); MS (ES+) m/e 384 [MH]+. Anal. Found C,
62.88; H, 4.63; N, 24.10. C21H17N70.H20 requires C, 62.83; H, 4.77; N,
24.42%.
EXAMPLE 81
3-(4-Methoxvnhenyi)-6-(1-methyl-1H-1.2 4-triazol-3-ylmethoxv)-7-phenvl-
1, 2, 4-triazolo [4. 3-blpyridazine
This compound was prepared using the procedures described in
Example 2 a), b), c), d) with 4-methoxybenzyl hydrazide being used instead
of benzoyl hydrazine in Step c) and (1-methyl-lH-1,2,4-triazol-3-
yl)methanol being used instead of 2-pyridylcarbinol in Step d).
Data for the title compound: m.p. = 205-206 C. 'H NMR (360 MHz, d6-
DMSO) 8 3.87 (6H, s), 5.54 (2H, s), 7.16-7.18 (2H, d, J=7.2 Hz), 7.49 (3H,
m), 7.74 (2H, m), 8.36 (1H, s), 8.41-8.43 (2H, d. J=7.2 Hz), 8.49 (1H. s); MS
(ES+) m/e 414 [MH+].
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EXAMPLE 82
6-(3-MethylAVridin-2-ylmethoxy)-3_phenyl-7-(piperidin-l-yl)-1 2 4
triazolo [4, 3-b] p yridazine
The compound was prepared using the procedures described in
Example 15 Steps a), b), c), d) and e) with 3-methyl-2-pyridinemethanol
being used instead of 2-pyridylcarbinol. Data for the title compound: mp =
160 C. 1H NMR (250 MHz, CDC13) 8 1.52-1.81 (6H, m), 2.45 (1H, s), 3.08-
3.28 (4H, m), 5.63 (1H, s), 7.20-7.30 (1H, m), 7.38-7.52 (4H, m), 7.60 (1H,
d, J= 7.6 Hz), 8.25-8.36 (2H, m); MS (ES+) m/e 401 [MH]+. Anal. Found C,
69.01; H, 6.00; N, 21.00. C23H24N60 requires C, 68.98; H, 6.04; N, 20.99%.
EXAMPLE 83
7-(Morpholin-4-yl)-3-phenyl-6-(pyridin-2-ylmethoxy)-1 2 4-triazolof4 3-
b]pyridazine
This compound was prepared using the procedures described in
Example 15 Steps a), b), c), d) and e) with morpholine used instead of
piperidine in Step c). Data for the title compound: mp = 214 C. IH NMR
(360 MHz, CDC13) 8 3.30-3.38 (4H, m), 3.88-3.94 (4H, m), 5.64 (2H, s), 7.30
(2H, t, J= 5.76 Hz), 7.45-7.58 (3H, m), 7.78 (1H, dt, J= 7.8, 1.7 Hz), 8.26-
8.35 (2H, m), 8.67 (1H, d, J= 7.2 Hz); MS (ES+) m/e 389 [MH]+. Anal.
Found C, 64.37, H, 5.22; N, 21.62. C21HzoN602. 0.15H20 requires C, 64.49;
H, 5.22; N, 21.49%.
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EXAMPLE 84
3-Phenyl-7-(pyridin-3-yl)-6-(pyridin-2-ylmethoxy)-1 2 4-triazolof4 3-
b]pyridazine
This compound was prepared using the procedures described in
Example 16 Steps a), b) and c) using 3-pyridyl boronic acid, instead of 4-
pyridyl boronic acid in Step a). Data for the title compound: mp = 206 C.
'H NMR (360 MHz, CDC13) 8 5.66 (2H, s), 7.28 (1H, t, J= 6.5 Hz), 7.35
(1H, d, J= 7.8 Hz), 7.40-7.62 (4H, m), 7.72 (1H, td, 7.7, 1.7 Hz), 8.04 (1H,
dt, J= 7.7, 1.7 Hz), 8.11 (1H, s), 8.43 (2H, dd, J= 9.6, 1.3 Hz), 8.64 (1H, d,
J= 6.5 Hz), 8.74 (1H, d, J= 6.5 Hz), 8.95 (1H, s); MS (ES+) m/e 381 [MH]+.
Anal. Found C, 69.33; H, 4.27; N, 21.57. C22H16N60. 0.15(C2H5)20 requires
C, 69.33; H, 4.51; N, 21.47%.
EXAMPLE 85
8-Methyl-6-(2-methyl-2H-1,2 4-triazol-3-ylmethoxy)-3 7-diphenyl-1 2 4-
triazolo [4, 3-b]pyridazine
This compound was prepared using the procedures described in
Example 8 Steps a), b), c) and d) with (2-methyl-2H-1,2,4-triazol-3-
yl)methanol (prepared using the conditions described in (EP-A-421210)
being used instead of 2-pyridyl carbinol in Step d). Data for the title
compound: mp = 195 C. 1H NMR (360 MHz, CDC13) 6 2.57 (3H, s), 3.56
(3H, s), 5.57 (2H, s), 7.28 (2H, dd, J= 7.7, 2.2 Hz), 7.47-7.60 (6H, m), 7.84
(1H, s), 8.44 (2H, dd, J= 6.8, 2.0 Hz), 7.47-7.60 (6H, m), 7.84 (1H, s), 8.44
(2H, dd, J= 6.8, 2.0 Hz); MS (ES+) m/e 398 [MH]+. Anal. Found C, 66.52;
H, 4.87; N, 23.74. C22HisN;O requires C, 66.49; H, 4.82; N, 24.67%.
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EXAMPLE 86
6-(1-Methyl-lH-1, 2, 4-triazol-3-ylmethoxy)-7-(morpholin-4-yl)-3-phenvl-
1, 2, 4-triazolo[4, 3-blpvridazine
This compound was prepared using the procedures described in
Example 15 Steps a), b), c), d) and e) with morpholine used instead of
piperidine in Step c) and with (1-methyl-lH-1,2,4-triazol-3-yl)methanol
(prepared using the conditions in EP-A-421210) being used instead of 2-
pyridyl carbinol in Step e). Data for the title compound: mp = 205-206 C.
1H NMR (360 MHz, CDC13) S 3.28 (4H, t, J = 5.5 Hz), 3.88 (4H, t, J = 4.7
Hz), 3.94 (3H, s), 5.59 (2H, s), 7.21 (1H, s), 7.45-7.55 (3H, m), 8.05 (1H,
s),
8.46 (2H, dd, J = 2.0, 6.9 Hz); MS (ES+) m/e 393 [MH]+. Anal. Found C,
58.55; H, 4.95; N, 28.42. C19H2oN802 requires C, 58.15; H, 5.14; N, 28.55%.
EXAMPLE 87
6-(2-Methyl-2H-1,2,4-triazol-3-ylmethoxy)-7-(morpholin-4- ly )-3-phen y1-
1, 2, 4-triazolo f 4, 3-b]pyridazine
This compound was prepared using the procedures described in
Example 86 Steps a), b), c), d) and e) with (2-methyl-2H-1,2,4-triazol-3-yl)-
methanol (prepared using the conditions described in EP-A-421210) being
used instead of (1-methyl-lH-1,2,4-triazol-3-yl)methanol in Step e). Data
for the title compound: mp = 210-211 C. zH NMR (360 MHz, CDC13) 8 3.21
(4H, t, J= 4.7 Hz), 3.84 (4H, t, J= 4.7 Hz), 3.97 (3H, s), 5.63 (2H, s), 7.24
(1H, s), 7.47-7.56 (3H, m), 7.93 (1H, s), 8.27 (2H, dd, J= 1.7, 8.3 Hz); MS
(ES+) m/e 393 [MH]+. Anal. Found C, 58.34; H, 4.88; N, 28.33. C19H2oN802
requires C, 58.15; H, 5.14; N, 28.55%.
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EXAMPLE 88
7-Cyciohexyl-6-(2-methYl-2H-1,2,4-triazol-3-ylmethoxy)-3-phenyl-1 2 4-
triazolo (4, 3-b]pyridazine
a) 6-Chloro-3-nhenyl-1,2,4-triazolo[4,3-bjpyridazine
3,6-Dichloropyridazine (20 g, 134 mmol) was suspended in xylene
(200 ml) with benzoylhydrazine (20.1 g, 1.1 mol eq) and triethylamine
hydrochloride (20.3 g, 1.1 mol eq) and the reaction mixture was heated
under reflux for 2 hours. The solvent was removed under high vacuum
and the residue was purified by chromatography on silica gel using 1%
methanol in dichloromethane as eluent to give the required product (17.1
g, mp = 199 C). 1H NMR (250 MHz, CDC13) S 7.16 (1H, d, J= 9.7 Hz), 7.53-
7.61 (3H, m), 8.16 (1H, d, J= 9.7 Hz), 8.44-8.50 (2H, m); MS (ES+) m/e 231
[MH]+.
b) 6-(2-Methyl-2H-1,2,4-triazol-3 ylmethoxy)-3 phenyl-1,2,4-
triazolo f 4, 3-blpyridazine
To a solution of (2-methyl-2H-1,2,4-triazol-3-yl)methanol (0.9 g, 8.0
mmol) (prepared using the conditions described in EP-A-421210) in DMF
(30 ml) was added sodium hydride (0.32 g of a 60% dispersion in oil, 1.6
mol eq.) and the reaction mixture was stirred at room temperature for 30
minutes. After this time the product from Example 88 Step a) (1.15 g, 5.0
mmol) was added as a solution in DMF (20 ml) and the reaction mixture
was stirred at room temperature for 2 hours. The reaction mixture was
diluted with water (200 ml) and the aqueous extracted with
dichloromethane (4 x 150 ml). The combined extracts were dried
(Na2SO4), filtered and evaporated. The residue was purified by
chromatography on silica gel using 4% MeOH in dichloromethane as
eluent to give the required product, (1.5 g, mp = 254 C). 1H NMR (360
MHz, CDC13) 6 3.98 (3H, s), 5.61 (2H, s), 6.90 (1H, d, J= 9.8 Hz), 7.51-7.60
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(3H, m), 7.94 (1H, s), 8.12 (1H, d, J= 9.8 Hz), 8.39 (2H, dd, J= 9.6, 1.5
Hz); MS (ES+) m/e 308 [MH]+.
c) 7-Cvclohexyl-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-3-phenvl-
1 2, 4-triazolo [4, 3-b]p,yridazine
To the product from Example 88 Step b) (0.91 g, 3.0 mmol) was
added water (12 ml) and sulphuric acid (0.24 ml, 1.5 mol eq, sp.gr. = 1.84).
The mixture was heated to 70 C and cyclohexane carboxylic acid (0.85 g,
2.3 mol eq) and silver nitrate (0.05 g, 0.1 mol eq) added. The reaction
mixture was degassed with nitrogen and a solution of ammonium
persulphate (1.0 g, 1.5 mol eq) in water (5 ml) added via syringe over 5
minutes. After an additional hour of heating at 70 C, the react:ion was
poured onto ice, basified to pH 8-9 with aqueous ammonium hydroxide and
extracted into dichloromethane (2 x 100 ml). The combined organic
extracts were dried (Na2SO4), filtered and evaporated to give the required
product (0.21 g, m.p. = 192 C). 1H NMR (250 MHz, CDC13) 8 1.22-1.54 (6H,
m), 1.72-2.04 (4H, m), 2.79 (1H, m), 3.98 (3H, s), 5.64 (2H, s), 7.48-7.60
(3H, m), 7.88 (1H, d, J= 0.9 Hz), 7.95 (1H, s), 8.34-8.38 (2H, m); MS (ES+)
mle 398 [MH]+. Anal. Found C, 65.01; H, 5.82; N, 25.10%. C21H23N70
requires C, 64.78; H, 5.95; N, 25.18%.
EXAMPLE 89
7-CvclohexXl-6-(1-methyl-lH-1,2,4-triazol-3-ylmethoxy)-3-phenyl-1,2,4-
triazolof4,3-b1pyridazine
This compound was prepared using the procedures described in
Example 88 Steps a), b) and c) with (1-methyl-lH-1,2,4-triazol-3-
yl)methanol (prepared using the conditions described in EP-A-421210)
used instead of (2-methyl-2H-1,2,4-triazol-3-yl)methanol in Step b). Data
for the title compound: IH NMR (360 MHz, CDCIa) S 1.20-1.52 (5H, m),
1.72-1.92 (3H, m), 1.20-2.03 (2H, m), 2.83-2.93 (1H, m), 3.94 (3H, s), 5.57
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(2H, s), 7.48-7.56 (3H, m), 7.83 (1H, s), 8.06 (1H, s), 8.48-8.54 (2H, m); MS
(ES+) m/e 398 [MH]+. Anal. Found C, 64.40; H, 5.95; N, 23.89%. C21H23N70
0.15C6H14 0.1H20 requires C, 64.79; H, 6.33; N, 24.15%.
EXAMPLE 90
7-Cyclopentyl-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-3-phenyl-1 2 4-
triazoloj4, 3-b]pyridazine
This compound was prepared using the procedures described in
Example 88 Steps a), b) and c) with cyclopentane carboxylic acid used
instead of cyclohexane carboxylic acid in Step c). Data for the title
compound: 1H NMR (360 MHz, CDC13) 8 1.56-1.88 (6H, m), 2.04-2.16 (2H,
m), 3.15-3.25 (1H, m), 3.97 (3H, s), 5.63 (2H, s), 7.51-7.57 (3H, m), 7.91
(1H, d, J= 0.8 Hz), 7.95 (1H, s), 8.37 (2H, dd, J= 6.6, 1.3 Hz); MS (ES+)
m/e 376 [MH]+. Anal. Found C, 63.65; H, 5.51; N, 25.26%. C2oH21N70.
0.2C2H60 requires C, 63.70; H, 5.82; N, 25.49%.
EXAMPLE 91
8-Methyl-6-(1-methyl-lH-1,2.4-triazol-3-ylmethoxy)-3,7-diphenyl-1,2,4-
triazolof4, 3-bipvridazine
This compound was prepared using the procedures described in
Example 8 Steps a), b), c) and d) with (1-methyl-lH-1,2,4-triazol-3-
yl)methanol (prepared using the conditions described in EP-A-421210)
used in Step d) instead of 2-pyridylcarbinol. Data for the title compound:
1H NMR (360 MHz, CDC13) 5 2.56 (3H, s), 3.87 (3H, s), 5.49 (2H, s), 7.36-
7.57 (8H, m), 7.97 (1H, s), 8.50-8.56 (2H, m); MS (ES+) m/e 398 [MH]+.
Anal. Found C, 66.45; H, 4.36; N, 23.95. C22Hi9N70 requires C, 66.49; H,
4.82; N, 24.67%.
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EXAMPLE 92
7-Cvclobutvl-6-(1-methvl-lH-1.2,4-triazol-3-vlmethoxy)-3-phenvl-1.2 4-
triazolo f 4, 3-bjpvridazine
This compound was prepared using the procedures described in
Example 88 Steps a), b) and c) using (1-methyl-lH-1,2,4-triazol-3-
yl)methanol (prepared using the conditions described in EP-A-421210)
instead of (2-methyl-2H-1,2,4-triazol-3-yl)methanol in Step b) and using
cyclobutane carboxylic acid instead of cyclohexane carboxylic acid in Step
c). Data for title compound: 1H NMR (360 MHz, CDC13) 8 1.88-2.05 (2H,
m), 2.06-2.39 (2H, m), 2.40-2.50 (2H, m), 3.67-3.71 (1H, m), 3.95 (3H, s),
5.53 (2H, s), 7.49-7.85 (3H, m), 8.06 (1H, s), 8.49 (1H, s), 8.51 (2H, d, J=
1.3 Hz); MS (ES+) m/e 362 [MH]+. Anal. Found C, 62.98; H, 5.07; N, 26.90.
C19H19N70 requires C, 63.14; H, 5.30; N, 27.13%.
EXAMPLE 93
7-tert-Butyl-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-3-phenyl-1,2 4-
triazolo f 4, 3-b]pyridazine
This compound was prepared using the procedures described in
Example 88 Steps a), b) and c) using trimethylacetic acid instead of
cyclohexane carboxylic acid in Step c). Data for the title compound:
1H NMR (360 MHz, CDC13) 8 1.41 (9H, s), 3.97 (3H, s), 5.65 (2H, s), 7.50-
7.57 (3H, m), 7.96 (1H, s), 8.01 (1H, s), 8.36-8.38 (2H, m); MS (ES+) m/e
364 [MH]+. Anal. Found C, 62.38; H, 5.83; N, 26.45. C19H21N70 0.15H20
requires C, 62.33; H, 5.86; N, 26.78%.
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EXAMPLE 94
7-Cyclobutyl-6-(2-methyl-2H-1,2 4-triazol-3-ylmethoxy)-3-phenvl-1 2 4-
triazolol4, 3-b]pyridazine
This compound was prepared using the procedures described in
Example 88 Steps a), b) and c) using cyclobutane carboxylic acid instead of
cyclohexane carboxylic acid in Step c). Data for the title compound: mp =
228 C. 1H NMR (360 MHz, CDC13) 8 1.86-1.98 (1H, m), 2.00-2.22 (3H, m),
2.26-2.45 (2H, m), 3.54-3.68 (1H, m), 3.97 (3H, s), 5.59 (2H, s), 7.47-7.60
(3H, m), 7.86 (1H, d, J= 1.6 Hz), 7.94 (1H, s), 8.35-8.42 (2H, m); MS (ES+)
m/e 397 [MH]+. Anal. Found C, 63.38; H, 5.22; N, 27.19. CisH19N70
requires C, 63.14; H, 5.30; N, 27.13%.
EXAMPLE 95
7-Ethvl-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-3-phenyl-1 2 4-
triazolo f4, 3-blpyridazine
This compound was prepared using the procedures described in
Example 88 Steps a), b) and c) -using propionic acid instead of cyclohexane
carboxylic acid in Step c). Data for the title compound: 1H NMR (360
MHz, CDC13) S 1.31 (3H, t, J= 7.4 Hz), 2.71 (2H, q, J= 7.4 Hz), 3.99 (3H,
s), 5.63 (2H, s), 7.47-7.60 (3H, m), 7.87 (1H, s), 7.94 (1H, s), 8.34-8.42
(2H,
m); MS (ES+) m/e 336 [MH]+. Anal. Found C, 60.85; H, 5.39; N, 28.22.
C17H17N70 0.1H20 requires C, 60.50; H, 4.98; N, 27.77%.
EXAMPLE 96
7-tert-Butyl-6-(1-methyl-lH-1,2,4-triazol-3-ylmethoxv)-3-phenyl-1 2 4-
triazolo [4, 3-b]pvridazine
This compound was prepared using the procedures described in
Example 88 Steps a), b) and c) using (1-methyl-lH-1,2,4-triazol-3-
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yl)methanol (prepared using the conditions described in EP-A-421210)
instead of (2-methyl-2H-1,2,4-triazol-3-yl)methanol in Step b), and using
trimethylacetic acid instead of cyclohexane carboxylic acid in Step c).
Data for the title compound: 'H NMR (360 MHz, CDC13) 5 1.45 (9H, s),
3.95 (3H, s), 5.59 (2H, s), 7.43-7.60 (3H, m), 7.95 (1H, s), 8.06 (1H, s),
8.49-
8.55 (2H, m); MS (ES+) m/e 364 [MH]+. Anal. Found C, 62.03; H, 5.58; N,
25.67. C19H21N70 0.12C6H14 0.33H20 requires C, 62.36; H, 6.19; N,
25.84%.
EXAMPLE 97
7-Ethyl-6-(1-methyl-lH-1,2,4-triazol-3-ylmethoxy)-3 .phenyl-1,2,4-
triazolo[4,3-b]pyridazine
This compound was prepared using the procedures described in
Example 88 Steps a), b) and c) using (1-methyl-lH-1,2,4-triazol-3-
yl)methanol (prepared using the conditions described in EP-A-421210)
instead of (2-methyl-2H-1,2,4-triazol-3-yl)methanol in Step b) and using
propionic acid instead of cyclohexane carboxylic acid in Step c). Data for
the title compound: 1H NMR (360 MHz, CDC13) 8 1.31 (3H, t, J= 7.4 Hz),
2.68-2.84 (2H, q, J= 7.4 Hz), 3.94 (3H, s), 5.56 (2H, s), 7.43-7.64 (3H, m),
7.82 (1H, s), 8.06 (1H, s), 8.46-8.60 (2H, m); MS (ES+) m/e 336 [MH]+. Anal.
Found C, 60.91; H, 4.73; N, 29.07. C17Hi7N70 requires C, 60.88; H, 5.11;
N, 29.24%.
EXAMPLE 98
7-Methyl-6-(2-methyl-2H-1, 2,4-triazol-3-ylmethoxy)-3-phenyl-1, 2,4-
triazolo [4, 3-b] nyridazine
This compound was prepared using the procedures described in
Example 5 Steps c) and d) using (2-methyl-2H-1,2,4-triazol-3-yl)methanol
(prepared using the conditions described in EP-A-421210) instead of 2-
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pyridyl carbinol in Step d). Data for title compound: 'H NMR (360 MHz,
CDC13) S 2.34 (3H, d, J= 1.2 Hz), 3.99 (3H, s), 5.62 (2H, s), 7.47-7.60 (3H,
m), 7.85 (1H, d, J= 1.3 Hz), 7.94 (1H, s), 8.34-8.41 (2H, m); MS (ES+) m/e
322 [MH]+. Anal. Found C, 60.26; H, 4.45; N, 30.18. C16Hi5N70 0.05 C6Hi4
requires C, 60.12; H, 4.86; N, 30.11%.
EXAMPLE 99
7-(1-Methylcyclobutyl)-6-(2-methyl-2H-1,2,4-triazol-3-vlmethoxy)-3-
phenyl-1,2,4-triazolo[4,3-blpvridazine
This compound was prepared using the procedures described in
Example 88 Steps a), b) and c) using 1-methylcyclobutane carboxylic acid
(Journal of Organometallic Chemistry, 1988,. 352, 263-272) instead of
cyclohexane carboxylic acid in Step c). Data for the title compound:
'H NMR (360 MHz, CDC13) 8 1.51 (3H, s), 1.80-1.92 (1H, m), 2.02-2.26 (3H,
m), 2.34-2.45 (2H, m), 3.95 (3H, s), 5.60 (2H, s), 7.47-7.60 (3H, m), 7.47
(1H, s), 7.94 (1H, s), 8.38 (2H, dd, J= 6.6, 1.7 Hz); MS (ES+) m/e 376
[MH]+. Anal. Found C, 63.82; H, 5.53; N, 25.82. C2oH2rN70 requires C,
63.98; H, 5.64; N, 26.12%.
EXAMPLE 100
7-Methyl-6-(1-methyl-lH-1,2,4-triazol-3-ylmethoxv)-3-phenyl-1,2 4-
triazolo f4,3-blpyridazine
This compound was prepared using the procedures described in
Example 5, Steps c) and d) using (1-methyl-lH-1,2,4-triazol-3-yl)methanol
(prepared using the conditions described in EP-A-421210) instead of
hydroxymethyl pyridine in Step d). Data for the title compound: 1H NMR
(360 MHz, CDC13) S 2.37 (3H, s), 3.95 (3H, s), 5.55 (2H, s), 7.45-7.59 (3H,
m), 7.83 (1H, d, J= 1.2 Hz), 8.07 (1H, s), 8.43-8.54 (2H, m); MS (ES+) m/e
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322 [MH]+. Anal. Found C, 59.51; H, 4.45; N, 29.88. C16Hi5N70 requires C,
59.80; H, 4.71; N, 30.51%.
EXAMPLE 101
7-Cyclobutvl-3-phenyl-6-(2H-1,2.4-triazol-3-ylmethoxy)-1,2,4-triazolo[4 3-
b]pyridazine
This compound was prepared in a similar way to that described in
Example 102 Steps a), b) and c) using cyclobutane carboxylic acid instead
of cyclopentane carboxylic acid in Step a), using benzoic hydrazide instead
of 2-thiophene carboxylic acid hydrazide in Step b) and using 3-
hydroxymethyl-2- [2-(trimethylsilanyl)ethoxy] methyl-2H-1, 2, 4-triazole
(prepared in Example 72 Step a) instead of 2-hydroxymethylpyridine in
Step c). This was followed by the procedure described in Example 72 Step
c) to give the title compound. Data for the title compound: 1H NMR (360
MHz, d6-DMSO) S 1.74-1.90 (1H, m), 1.90-2.29 (5H, m), 3.50-3.71 (1H, m),
5.54 (2H, s), 7.48-7.69 (3H, m), 8.14 (1H, d, J= 1.0 Hz), 8.30-8.49 (2H, m),
8.52 (1H, br s); MS (ES+) m/e 348 [MH]+. Anal. Found C, 61.93; H, 4.65; N,
27.58. C18H17N703 0.17H20 requires C, 61.69; H, 4.99; N, 27.98%.
EXAMPLE 102
7-Cyclopentyl-6-(QYridin-2-ylmethoxy)-3-(thiophen-2-yl)-1, 2, 4-triazolo [4.3-
b1pyridazine
a) 3 6-Dichloro-4-cyclopentylnyridazine
3,6-Dichloropyridazine (10 g) was suspended in water (200 ml),
conc. H2SO4 (19.7 g) and cyclopentane carboxylic acid (32.7 g) was added
and the reaction degassed under N2 at 70 C. Silver nitrate (2.28 g) was
added followed by dropwise addition of ammonium persulfate (45.9 g) in
water (120 ml). After an additional one hour heating at 70 C, the reaction
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was poured onto ice, basified to pH 8-9 with aqueous ammonium
hydroxide and extracted into ethyl acetate (3 x 500 ml), dried (MgSO4) and
evaporated to dryness. Purified with hexane-ethyl acetate mixtures to
obtain pure product (13.4 g). 1H NMR (360MHz, CDC13) 8 1.57 (2H, m),
1.82 (4H, m), 2.20 (1H, m), 3.30 (1H, m), 7.38 (1H, s); MS (ES+) m/e 217
[MH]+.
b) 6-Chloro-7-cyclopentyl-3-(thiophen-2-yl)-1 2 4-triazolo[4 3-
b1pvridazine
3,6-Dichloro-4-cyclopentylpyridazine (1.6 g) was heated with 2-
thiophene carboxylic acid hydrazide (1.16 g) and triethylamine
hydrochloride (1.16 g) in xylene (10 ml) at 140 C for 18 hours. The cooled
reaction was partioned between ethyl acetate and sodium carbonate
solution, the organic phase separated, dried (MgSO4), evaporated to
dryness and purified on silica gel eluting with hexane-ethyl acetate
mixtures to give both 7- and 8-cyclopentyl isomers. 'H NMR (360 MHz,
CDC13) S 1.89 (6H, m), 2.30 (2H, m), 6.93 (1H, s), 7.23 (1H, dd, J= 5.2, 3.9
Hz), 7.54 (1H, dd, J= 4.9, 0.9 Hz), 8.25 (1H, dd, J= 3.8, 1.0 Hz); MS (ES+)
m/e 305 [MH]+ (less polar isomer). 1H NMR (360 MHz, CDC13) 8 1.70 (6H,
m), 2.23 (2H, m), 3.36 (1H, m), 7.24 (1H, m), 7.55 (1H, dd, J= 7.0, 1.6Hz),
7.99 (1H, s), 8.24 (1H, dd, J= 5.3, 1.6 Hz); MS (ES+) m/e 305 [MH]+ (more
polar isomer).
c) 7-Cyclopentyl-6=(pyridin-2-vlmethoxy)-3-(thiophen-2-yl)-1 2 4-
triazolo[4,3-bjpyridazine
2-Hydroxymethylpyridine (56 mg) was dissolved in
dimethylformamide (2 ml) under N2. Sodium hydride (60% w/w in oil, 21
mg) was added followed after 5-10 minutes by 6-chloro-7-cyclopentyl-3-
(thiophen-2-yl)-1,2,4-triazolo[4,3-b]pyridazine (100 mg). Reaction was
stirred at room temperature for 18 hours, partitioned between ethyl
acetate and water, organic phase separated, dried (MgSO4) and evaporated
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to dryness. Recrystallized in ethyl acetate in ether or methanol to give
pure product. 1H NMR (250 MHz, CDC13) S 1.73 (6H, m), 2.16 (2H, m) 3.38
(1H, m), 5.68 (2H, s), 7.21 (1H, m), 7.28 (1H, m), 7.51 (2H, m), 7.77 (1H,
m), 7.88 (1H, d, J= 1.1Hz), 8.15 (1H, m), 8.65 (1H, m); MS (ES+) m/e 377
[MH]+.
EXAMPLE 103
7-CYclopentyl-3-(2 4-difluorophenyl)-6-(1-methyl-lH-1,2,4-triazol-3-
ylmethoxy)-1 2 4-triazolof4,3-b]pyridazine
Prepared in an analogous procedure as outlined in Example 102b
using 2,4-difluorobenzoic acid hydrazide and Example 102c using (1-
methyl-lH-1,2,4-triazol-3-yl)methanol to give the title compound. 'H NMR
(360 MHz, CDC13) S 1.75 (6H, m), 2.14 (2H, m) 3.24 (1H, m), 3.93 (3H, s),
5.42 (2H, s), 7.14 (2H, m), 7.86 (1H, s), 7.90 (1H, m), 8.04 (1H, s); MS (ES+)
m/e 412 [MH]+.
EXAMPLE 104
7-Cyclopentyl-6-(1-methvl-lH-1 2 4-triazol-3-ylmethoxv)-3-(thiophen-2-yl)-
1 2 4-triazolof4 3-binvridazine
Prepared in an analogous procedure as outlined in Example 102b
using 2-thiophene carboxylic acid hydrazide and Example 102c using (1-
methyl-lH-1,2,4-triazol-3-yl)methanol to give the title compound. 'H NMR
(250 MHz, CDC13) 8 1.32 (6H, m), 2.14 (2H, m), 3.28 (1H, m), 3.95 (3H, s),
5.61 (2H, s), 7.24 (1H, m), 7.50 (1H, dd, J= 1.2, 5.1 Hz), 7.84 (1H, d, J=
1.1 Hz), 8.07 (1H, s), 8.25 (1H, dd, J= 3.7, 1.1 Hz); MS (ES+) m/e 382
[MH]+.
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EXAMPLE 105
7-Cyclo1Dentyl-6-(2-methyl-2H-1.2 4-triazol-3-vlmethoxy)-3-(thiophen-2-vl)-
1, 2,4-triazolo [4, 3-blpyridazine
Prepared in an analogous procedure as outlined in Example 102b
using 2-thiophene carboxylic acid hydrazide and Example 102c using (2-
methyl-2H-1,2,4-triazol-3-yl)methanol to give the title compound. 1H NMR
(250 MHz, CDC13) S 1.73 (6H, m), 2.08 (2H, m), 3.18 (1H, m), 4.03 (3H, s),
5.69 (2H, s), 7.24 (1H, m), 7.52 (1H, dd, J= 5.0, 1.2 Hz), 7.88 (1H, d, J=
1.1 Hz), 8.01 (1H, s), 8.18 (1H, dd, J= 3.7, 1.1 Hz); MS (ES+) m/e 382
CMH]
EXAMPLE 106
7-Cyclopentyl-6-(2-methyl-2H-1.2,4-triazol-3-ylmethoxy)-3-(pyridin-4-yl)-
1, 2,4-triazolo [4, 3-blpyridazine
Prepared in an analogous procedure as outlined in Example 102b
using isonicotinic hydrazide and Example 102c using (2-methyl-2H-1,2,4-
triazol-3-yl)methanol to give the title compound. 1H NMR (250 MHz,
CDC13) 5 1.75 (6H, m), 2.12 (2H, m), 3.22 (1H, m), 4.02 (3H, s), 5.68 (2H, s),
7.96 (1H, m), 8.43 (2H, d, J= 6.2Hz), 8.83 (2H, d, J= 6.0Hz); MS (ES+) m/e
377 [MH]
EXAMPLE 107
7-Cyclot)entyl-3-(2-fluorophenyl)-6-(1-methvl-lH-1 2 4-triazol-3-
ylmethoxy)-1,2,4-triazolo[4, 3-b]pyridazine
Prepared in an analogous procedure as outlined in Example 102b
using o-fluorobenzyl hydrazide and Example 102c using (1-methyl-lH-
1,2,4-triazol-3-yl)methanol to give the title compound. 1H NMR (250MHz,
CDC13) 8 1.69 (6H, m), 2.12 (2H, m), 3.23 (1H, m), 3.93 (3H, s), 5.41 (2H, s),
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7.29 (2H, m), 7.51 (1H, m), 7.85 (1H, d, J= 0.7Hz), 7.97 (1H, m), 8.04 (1H,
s); MS (ES+) m/e 394 [MH]+.
EXAMPLE 108
7-Cyclopentyl-3-(2-fluorophenyl)-6-(2-methyl-2H-1, 2, 4-triazol-3-
ylmethoxy)-1, 2,4-triazolo f 4, 3-b]pyridazine
Prepared in an analogous procedure as outlined in Example 102b
using o-fluorobenzyl hydrazide and Example 102c using (2-methyl-2H-
1,2,4-triazol-3-yl)methanol to give the title compound. 1H NMR (250 MHz,
CDC13) 8 1.72 (6H, m), 2.08 (2H, m), 3.19 (1H, m), 3.84 (3H, s), 5.49 (2H, s),
7.32 (2H, m), 7.58 (1H, m), 7.87 (2H, m), 7.90 (1H, m); MS (ES+) m/e 394
[n'IH]+.
EXAMPLE 109
7-Cyclopentyl-3-(2-fluorophenyl)-6-(pyridin-2-ylmethoxy)-1, 2, 4-
triazolo j4, 3-b]pyridazine
Prepared in an analogous procedure as outlined in Example 102b
using o-fluorobenzyl hydrazide and Example 102c using 2-hydroxymethyl
pyridine to give the title compound. 1H NMR (250 MHz, CDC13) S 1.74 (6H,
m), 2.16 (2H, m), 3.32 (1H, m), 5.48 (2H, s), 7.25 (3H, m), 7.42 (1H, m),
7.51 (1H, m), 7.51 (1H, m), 7.71 (1H, d, J= 1.1Hz), 7.88 (1H, d, J= 0.7Hz),
8.60 (1H, m); MS (ES+) m/e 390 [MH]+.
EXAMPLE 110
7-Cyclopentyl-3-(2,4-difluoronhenyl)-6-(2-methyl-2H-1, 2, 4-triazol-3-
ylmethoxy)-1,2,4-triazolo[4, 3-bigyridazine
Prepared in an analogous procedure as outlined in Example 102b
using 2,4-difluorobenzoic acid hydrazide and Example 102c using (2-
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methyl-2H-1,2,4-triazol-3-yl)methanol to give the title compound. 'H NMR
(250 MHz, CDC13) 8 1.73 (6H, m), 2.09 (2H, m), 3.18 (1H, m), 3.85 (3H, s),
5.49 (2H, s), 7.07 (2H, m), 7.90 (3H, m); MS (ES+) m/e 412 [MH]+.
EXAMPLE 111
7-Cyclopentvl-3-uhenyl-6-(pyridin-2-ylmethoxy)-1 2 4-triazoloj4 3-
b]pyridazine
Prepared in an analogous procedure as outlined in Example 102b
using benzoic hydrazide and Example 102c using 2-hydroxymethyl
pyridine to give the title compound. 'H NMR (250 MHz, CDC13) S 1.76 (6H,
m), 2.18 (2H, m), 3.34 (1H, m), 5.62 (2H, s), 7.30 (1H, m), 7.50 (4H, m),
7.77 (1H, m), 7.88 (1H, d, J= 0.7Hz), 8.36 (2H, m), 8.65 (1H, m); MS (ES+)
m/e 372 [MH]+.
EXAMPLE 112
7-Cyclopentvl-8-methyl-6-(2-methvl-2H-1, 2, 4-triazol-3-vlmethoxy)-3-
phenyl-1, 2, 4-triazolo f 4, 3-b]pyridazine
Prepared in an analogous procedure as outlined in Example 102a
using 3,6-dichloro-4-methylpyridazine, Example 102b using benzoic
hydrazide and Example 102c using (2-methyl-2H-1,2,4-triazol-3-
yl)methanol to give the title compound. 1H NMR (250 MHz, CDC13) 6 1.63
(4H, m), 1.83 (4H, m), 2.74 (3H, s), 3.46 (1H, m), 3.94 (3H, s), 5.57 (2H, s),
7.51 (3H, m), 7.95 (1H, s), 8.36 (2H, m); MS (ES+) m/e 390 [MH]+.
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EXAMPLE 113
7-Cyclogentyl-3-phenvl-6-(2H-1, 2, 4-triazol-3-ylmethoxy)-1, 2, 4-triazolo[4,
3-
b]pyridazine
This compound was prepared using the procedures described in
Example 102 Steps a), b) and c) using benzoic hydrazide instead of 2-
thiophene carboxylic acid hydrazide in Step b) and using 3-hydroxymethyl-
2-[2-(trimethylsilanyl)ethoxy]methyl-2H-1,2,4-triazole (prepared in
Example 72 Step a) instead of 2-hydroxymethylpyridine in Step c). This
was followed by the procedure described in Example 72 Step c) to give the
title compound. Data for the title compound: 1H NMR (250 MHz, CDC13) 5
1.74 (6H, m), 2.11 (2H, m), 3.12 (1H, br s), 3.22 (1H, m), 5.58 (2H, m), 7.50
(3H, m), 7.85 (1H, d, J= 0.7Hz), 8.27 (1H, m), 8.37 (2H, m); MS (ES+) m/e
362 [MH]+.
EXAMPLE 114
3-(4-Methylphenvl)-7-phenyl-6-(nyridin-2-ylmethoxy)-1,2,4-triazolo[4, 3-
b1pyridazine -
This compound was prepared using the procedures described in
Example 2 Steps a), b), c) and d) except that in Step c) p-toluic hydrazide
was used instead of benzoylhydrazide. Data for the title compound: 1H
NMR (250 MHz, CDC13) S 2.45 (3H, s), 5.68 (2H, s), 7.29-7.39 (1H, m),
7.51-7.55 (3H, m), 7.66-7.77 (3H, m), 8.07 (1H, s), 8.18-8.31 (2H, m), 8.64
(1H, br d, J= 5.6 Hz). MS (ES+) m/e 394 [MH]+.
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EXAMPLE 115
3-(4-Methvlp henvl)-6-(3-methylpyridin-2-ylmethoxv)-7-p henyl-1, 2, 4-
triazolo (4, 3-bjpyridazine
This compound was prepared using the procedures described in
Example 2 Steps a), b), c) and d) except that in Step c) p-toluic hydrazide
was used instead of benzoylhydrazide; and in Step d) 3-methyl-2-
pyridinemethanol was used instead of 2-pyridylcarbinol. Data for the title
compound: 1H NMR (250 MHz, CDC13) S 2.31 (3H, s), 2.45 (3H, s), 5.68
(2H, s), 7.24 (1H, dd, J= 7.7, 4.9 Hz), 7.32-7.46 (5H, m), 7.54-7.64 (3H, m),
8.03 (1H, s), 8.30 (2H, d, J= 8.3 Hz), 8.46 (1H, br d, J= 5.5 Hz). MS (ES+)
m/e 408 [MH]+.
EXAMPLE 116
6-(1-Ethyl-lH-imidazol-2-ylmethoxy)-3-(4-methylphenyl)-7-phenyl-1,2,4-
triazolo[4, 3-blpvridazine
This compound was prepared using the procedures described in
Example 2 Steps a), b), c) and d) except that in Step c) p-toluic hydrazide
was used instead of benzoylhydrazide; and in Step d) 1-ethyl-2-
(hydroxymethyl)imidazole was used instead of 2-pyridylcarbinol. Data for
the title compound: 1H NMR (250 MHz, CD C13) S 1.14 (3H, t, J= 7.3 Hz),
2.46 (3H, s), 3.88 (2H, q, J= 7.3 Hz), 5.62 (2H, s), 6.98 (1H, d, J= 1.3 Hz),
7.10 (1H, d, J= 1.2 Hz), 7.34-7.54 (7H, m), 8.02 (1H, s), 8.40 (2H, d, J= 8.3
Hz). MS (ES+) m/e 411 [MH]+.
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EXAMPLE 117
3-Phenyl-6-(pyridin-2-ylmethoxy)-7-(thiomorpholin-4-yl)-1, 2, 4-triazolo [4, 3-
bjpyridazine
This compound was prepared using the procedures described in
Example 15 Steps a), b), c), d) and e) except that thiomorpholine was used
instead of piperidine in Step c). Data for the title compound: 'H NMR (360
MHz, CDCls) 5 2.81-2.84 (4H, m), 3.56-3.58 (4H, m), 5.62 (2H, s), 7.29-7.32
(2H, m), 7.49-7.53 (4H, m), 7.79 (1H, td, J= 7.7, 1.7 Hz), 8.31 (2H, dd, J=
8.3, 2.4 Hz), 8.64-8.66 (2H, m). MS (ES+) m/e 405 [MH]+. Anal. Found C,
62.30; H, 4.90; N, 20.60. C2iH2oN6OS requires C, 62.36; H, 4.98; N,
20.78%.
EXAMPLE 118
6-[2-(4-Methylthiazol-5-yl)ethoxy]-3, 7-diphenyl-1, 2, 4-triazolo (4, 3-
blpyridazine
This compound was prepared using the procedure described in
Example 61 except that 5-(2-hydroxyethyl)-4-methylthiazole was used
instead of 4-hydroxymethylbenzyl alcohol. Data for the title compound:
MS (ES+) m/e 414 [MH]+. HPLC 90% (run on a HP1090 using Hichrom
S5ODS2, 23cm column, flow rate of 1 ml/min and 70% acetonitrile/pH 3.5
phosphate buffer as the mobile phase).
EXAMPLE 119
(f)-7-(2-Methylpyrrolidin-1-yl)- 3-phenyl-6-(pyridin-2-ylmethoxv)-1, 2, 4-
triazolof 4, 3-b]pyridazine
This compound was prepared using the procedures described in
Example 15 Steps a), b), c), d) and e) except that 2-methylpyrrolidine
(racemic) was used instead of piperidine in Step c). Data for the title
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compound: 1H NMR (360 MHz, CDCla) S 1.17 (3H, d, J= 6.1 Hz), 1.64-1.69
(1H, m), 1.87-2.24 (3H, m), 3.42-3.48 (1H, m), 3.67-3.74 (1H, m), 4.23-4.28
(1H, m), 5.60 (2H, s), 6.81 (1H, s), 7.29 (1H, dd, J= 7.5, 4.8 Hz), 7.42-7.49
(4H, m), 7.74 (1H, td, J= 7.7, 1.8 Hz), 8.27-8.30 (2H, m), 8.66 (1H, br d, J
= 5.5 Hz). MS (ES+) m/e 387 [MH]+. Anal. Found C, 68.24; H, 5.76; N,
21.67. C22H22Ne0 requires C, 68.38; H, 5.74; N, 21.74%.
EXAMPLE 120
6-(1-Methyl-lH-1,2,4-triazol-3-_ylmethoxy)-3-phenyl-7-(pyridin-4-vl)-1 2,4-
triazolo j4, 3 -b]pyridazine
This compound was prepared using the procedures described in
Example 16 Steps a), b), c), d) and e) except that (1-methyl-lH-1,2,4-
triazol-3-yl)methanol (EP-A-421210) was used instead of 2-pyridyl carbinol
in Step c). Data for the title compound: 'H NMR (360 MHz, ds-DMSO) b
3.87 (3H, s), 5.56 (2H, s), 7.55-7.65 (3H, m), 7.75-7.77 (2H, m), 8.46-8.50
(3H, m), 8.61 (1H, s), 8.71 (2H, br d, J= 7 Hz). MS (ES}) m/e 385 [MH]+.
Anal. Found C, 61.66; H, 4.09; N, 28.14. C20H26N80. 0.05 (C4H802). 0.3
(H20) requires C, 61.55; H, 4.35; N, 28.43%.
EXAMPLE 121
7-Cyclopentvl-6-(1-methyl-lH-1,2,4-triazol-3-ylmethoxy)-3-phenvl-1,2 4-
triazolo[4, 3-b]pyridazine
This compound was prepared as described in Example 88 Steps a),
b) and c), except that (1-methyl-lH-1,2,4-triazol-3-yl)methanol
(EP-A-421210) was used instead of (2-methyl-2H-1,2,4-triazol-3-
yl)methanol in Step b) and cyclopentane carboxylic acid was used instead
of cyclohexane carboxylic acid in Step c). Data for the title compound: 1H
NMR (360 MHz, CDC13) 8 1.62-1.86 (6H, m), 2.10-2.18 (2H, m), 3.22-3.32
(1H, m), 3.95 (3H, s), 5.57 (2H, s), 7.46-7.57 (3H, m), 7.88 (1H, s), 8.02
(1H,
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s), 8.50 (2H, br d, J= 8 Hz). MS (ES+) m/e 376 [MH]+. Anal. Found C,
63.73; H, 5.56; N, 25.16. C2oH21N70. 0.1 (C4HioO). 0.1 (H20) requires C,
63.70; H, 5.82; N, 25.59%.
EXAMPLE 122
7-I sop roi)yl-6-(1-methyl-lH-1, 2, 4-triazol-3-ylmethoxy)- 3-phe nyl-1, 2, 4-
triazolo (4, 3-blpyridazine
This compound was prepared as described in Example 88 Steps a),
b) and c), except that (1-methyl-1H-1,2,4-triazol-3-yl)methanol
(EP-A-421210) was used instead of (2-methyl-2H-1,2,4-triazol-3-
yl)methanol in Step b) and 2-methylpropionic acid was used instead of
cyclohexane carboxylic acid in Step c). Data for the title compound: 1H
NMR (360 MHz, CDC13) S 1.31 (6H, d, J= 6.9 Hz), 3.25 (1H, hept, J= 6.7
Hz), 3.94 (3H, s), 5.57 (2H, s), 7.46-7.56 (3H, m), 7.86 (1H, s), 8.06 (1H,
s),
8.50 (2H, br d, J= 8 Hz). MS (ES+) m/e 350 [MH] +. Anal. Found C, 61.86;
H, 5.43; N, 27.71. C18H19N70 requires C, 61.88; H, 5.48; N, 28.06%.
EXAMPLE 123
3-Cvclopropyl-6-(1-methyl-lH-1,2,4-triazol-3-ylmethoxy)-7-phenyl-1,2,4-
triazolo f 4, 3-b]pyridazine
This compound was prepared using procedures described in
Example 2 a), b), c), d) with cyclopropyl hydrazide being used instead of
benzoyl hydrazine in Step c) and (1-methyl-lH-1,2,4-triazol-3-yl)methanol
being used instead of 2-pyridylcarbinol in Step d). IH NMR (360 MHz,
CDC13) 5 1.14-1.18 (2H, m), 1.36-1.40 (2H, m), 2.42-2.46 (1H, m), 3.92 (3H,
s), 5.55 (2H, s), 7.41-7.45 (3H, m), 7.61-7.64 (2H, m), 7.89 (1H, s), 8.03
(1H,
s); MS (ES+) m/e 348 [MH+]. Anal. Found C, 60.79; H, 4.79; N, 27.33.
C18H17N70 + 0.5% H20 requires C, 60.66; H, 5.09; N, 25.71%.
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EXAIVIPLE 124
3-(2-Fluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-7 phenyl-
1, 2, 4-triazolo (4.3-b],oyridazine
This compound was prepared using procedures described in
Example 2 a), b), c), d) with 2-fluorobenzyl hydrazide being used instead of
benzoyl hydrazine in Step c) and (2-methyl-2H-1,2,4-triazol-3-yl)methanol
being used instead of 2-pyridylcarbinol in Step d). 1H NMR (360MHz,
CDC13) S 3.89 (3H, s), 5.47 (2H, s), 7.32 (6H, m), 7.65-7.68 (2H, m), 7.96
(3H, m); MS (ES+) m/e 402 [MH+]. Anal. Found C, 61.85; H, 3.35; N, 23.77.
C21Hi6N70F + 1% Na requires C, 61.78; H, 3.95; N, 24.01%.
EXAMPLE 125
3-(2-Fluorophenyl)-6-(1-methyl-lH-1,2,4-triazol-3-vlmethoxy)-7-phenyl-
1, 2 , 4-triazolo [4, 3-b]pyridazine
This compound was prepared using procedures described in
Example 2 a), b), c), d) with 2-fluorobenzyl hydrazide being used instead of
benzoyl hydrazine in Step c) and (1-methyl-lH-1,2,4-triazol-3-yl)methanol
being used instead of 2-pyridylcarbinol in Step d). 1H NMR (360MHz,
CDC13) S 3.66 (3H, s), 5.53 (2H, s), 7.27 (8H, m), 7.85-7.88 (2H, m), 8.06
(1H, s); MS (ES+) m/e 402 [MH+]. Anal. Found C, 62.49; H, 3.73; N, 23.81.
C21H16N70F + 0.5% Na requires C, 62.48; H, 3.96; N, 24.29%.
EXAMPLE 126
6-(1-Methyl-lH-1,2,4-triazol-3-ylmethoxy)-7-phenyl-3-(thiophen-2-yl)-
1, 2. 4-triazolo f 4, 3-b]pyridazine
This compound was prepared using the procedures described in
Example 2 a), b), c) and d) with 2-thiophene carboxylic hydrazide being
used instead of benzoyl hydrazine in Step c) and (1-methyl-lH-1,2,4-
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triazol-3-yl)methanol (prepared as described in EP-A-421210) being used
instead of 2-pyridylcarbinol in Step d). 1H NMR (360 MHz, CDC13) S 3.91
(3H, s), 5.66 (2H, s), 7.25 (1H, m), 7.43-7.69 (6H, m), 8.03 (2H, m), 8.31
(1H, m); MS (ES+) m/e 390 [MH]+. Anal. Found C, 59.01; H, 3.64; N, 25.10.
C19H15N7OS requires C, 58.60; H, 3.88; N, 25.17%.
EXAMPLE 127
6-(1-Methyl-lH-1,2,4-triazol-3-ylmethoxy)-7-phenyl-3-(pyridin-3-yl)-1 2 4-
triazolo[4,3-b]pyridazine
This compound was prepared using procedures described in
Example 2 a), b), c), d) with 2-pyridyl hydrazide being used instead of
benzoyl hydrazine in Step c) and (1-methyl-lH-1,2,4-triazol-3-yl)methanol
being used instead of 2-pyridylcarbinol in Step d). 'H NMR (360MHz, d6-
DMSO) S 3.86 (3H, s), 5.55 (2H, s), 7.49-7.51 (3H, m), 7.64 (1H, m), 7.73
(2H, m), 8.44-8.48 (2H, d, J= 14.4Hz), 8.66 (1H, m), 8.82-8.84 (1H, d, J
7.2Hz), 9.56 (1H, s); MS (ES+) m/e 385 [MH+]. Anal. Found C, 62.03; H,
3.97; N, 28.54. C2oH16N80 + 0.2% H20 requires C, 61.91; H, 4.26; N,
28.88%.
EXAMPLE 128
6- (2-Methyl- 2H- 1, 2, 4-triazol-3-vlmethoxy)-7-phenyl-3-(thiop hen-2-yl)-
1, 2, 4-triazolo[4, 3-blpyridazine
This compound was prepared using the procedures described in
Example 2 a), b), c) and d) with 2-thiophene carboxylic hydrazide being
used instead of benzoyl hydrazine in Step c) and (2-methyl-2H-1,2,4-
triazol-3-yl)methanol (prepared as described in EP-A-421210) being used
instead of 2-pyridylcarbinol in Step d). iH NMR (360 MHz, CDCIs) 8 3.79
(3H, s), 5.74 (2H, s), 7.26 (1H, m), 7.47-7.57 (6H, m), 7.90 (1H, s), 8.05
(1H,
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s), 8.24 (1H, m); MS (ES+) m/e 390 [MH]+. Anal. Found C, 58.20; H, 4.09;
N, 25.02. C1sHisN70S requires C, 58.60; H, 3.88; N, 25.17%.
EXAMPLE 129
6-(2-Methyl-2H-1.2,4-triazol-3-ylmethoxy)-7-phenyl-3-(nvridin-3-vl) 1 2 4
triazolo [4, 3-bjpyridazine
This compound was prepared using the procedures described in
Example 2 a), b), c) and d) with 3-pyridyl carboxylic hydrazide being used
instead of benzoyl hydrazine in Step c) and (2-methyl-2H-1,2,4-triazol-3-
yl)methanol (prepared as described in EP-A-421210) being used instead of
2-pyridylcarbinol in Step d). 1H NMR (360 MHz, CDC13) S 3.79 (3H, s),
5.69 (2H, s), 7.47-7.57 (6H, m), 7.90 (1H, s), 8.10 (1H, s), 8.77 (2H, m),
9.76
(1H, s); MS (ES+) m/e 385 [MH]+. Anal. Found C, 62.48; H, 4.02; N, 25.56.
C2oH16N80 requires C, 62.49; H, 4.20; N, 29.15%.
EXAMPLE 130
3-(Furan-3-yl)-6-(1-methyl-lH-1,2 4-triazol-3-ylmethoxy)-7-phenv1-1 2 4-
triazolo(4,3-blpyridazine
This compound was prepared using procedures described in
Example 2 a), b), c), d) with 2-furan hydrazide being used instead of
benzoyl hydrazine in Step c) and (1-methyl-lH-1,2,4-triazol-3-yl)methanol
being used instead of 2-pyridyl carbinol in Step d). 1H NMR (360MHz, dr,
DMSO) S 3.85 (3H, s), 5.57 (2H, s), 6.84 (1H, m), 7.47 (3H, m), 7.68 (3H,
m), 8.01 (1H, s), 8.39 (1H, s), 8.47 (1H, s). MS (ES+) m/e 374 [MH+]. Anal.
Found C, 60.46; H, 4.12; N, 24.14. C19H15N702 + 0.1% H20, 0.1% Na
requires C, 60.46; H, 4.06; N, 25.97%.
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EXAMPLE 131
6-(1-Methyl-lH-1,2, 4-triazol-3-ylmethoxy)-7-phenyl-3-(thiophen-2-yl)-
1, 2, 4-triazolo j4, 3-b]pyridazine
This compound was prepared using procedures described in
Example 2 a), b), c), d) with 2-thiophene hydrazide being used instead of
benzoyl hydrazine in Step c) and (1-methyl-lH-1,2,4-triazol-3-yl)methanol
being used instead of 2-pyridylcarbinol in Step d). 1H NMR (360MHz, d6-
DMSO) S 3.86 (3H, s), 5.60 (2H, s), 7.34 (4H, m), 7.74-7.76 (2H, d, J=
7.2Hz), 7.84-7.86 (1H, d, J= 7.2Hz), 8.29 (1H, m), 8.39 (1H, s), 8.48 (1H, s).
MS (ES+) m/e 390 [MH+]. Anal. Found C, 58.33; H, 3.50; N, 24.63.
C1sH15N70S + 0.1% H20 requires C, 58.33; H, 3.92; N, 25.06%.
EXAMPLE 132
6-(5-Methvl-1,2,4-oxadiazol-3-ylmethoxy)-3,7-diphenvl-1 2,4-triazolo[4 3-
b1pyridazine
This compound was prepared using the procedures described in
Example 2 a), b), c) and d) with 3-hydroxymethN,l-5-methyl-1,2,4-
oxadiazole (J. Med. Chem., 1991, 34, 1086-94) being used instead of 2-
pyridylcarbinol in Step d). iH NMR (360 MHz, CDC13) S 2.62 (3H, s), 5.70
(2H, s), 7.50-7.80 (7H, m), 8.45 (2H, m), 8.48 (1H, s); MS (ES+) m/e 385
[MH+]. Anal. Found C, 65.24; H, 3.94; N, 21.21. C21H1sN602. 0.25 H20
requires C, 64.85; H, 4.28; N, 21.61%.
EXAMPLE 133
7-Phenyl-3-(thiophen-2-yl)-6-(2H-1,2,4-triazol-3-ylmethoxv)-1 2 4-
triazolo [4, 3-blpyridazine
This compound was prepared using the procedures described in
Examples 2 a), b), c), d) and 72 c) with 2-thiophene carboxylic hydrazide
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being used instead of benzoyl hydrazine in Step 2c) and the product of 72a)
being used instead of 2-pyridylcarbinol in Step 2d). 'H NMR (360 MHz,
CDC13) S 5.14 (2H, s), 6.72 (1H, m), 6.91 (3H, m), 7.05-7.26 (3H, m), 7.55
(1H, s), 7.76 (2H, m), 13.41 (1H, br s); MS (ES+) m/e 376 [MH]+. Anal.
Found C, 57.19; H, 2.98; N, 25.61. Ci8H13N7OS requires C, 57.58; H, 3.49;
N, 26.12%.
EXAMPLE 134
3-(Furan-2-yl)-6-(1-methyl-lH-1,2 4-triazol-3-ylmethoxy)-7-phenyl-1 2 4-
triazolo [4, 3-b]pyridazine
This compound was prepared using the procedures described in
Example 2 a), b), c) and d) with 2-furyl carboxylic hydrazide being used
instead of benzoyl hydrazine in Step c) and (1-methyl-lH-1,2,4-triazol-3-
yl)methanol (prepared as described in EP-A-421210) being used instead of
2-pyridylcarbinol in Step d). 1H NMR (360 MHz, CDC13) 5 3.91 (3H, s),
5.63 (2H, s), 6.66 (1H, m), 7.26-7.69 (7H, m), 8.02 (2H, m); MS (ES+) m/e
374 [MH]+. Anal. Found C, 60.77; H, 3.93; N, 25.82. C19H15N702 requires
C, 61.12; H, 4.05; N, 26.26%.
EXAMPLE 135
6-(1-Methyl-lH-1,2, 4-triazol-3-ylmethoxy)-3-phenvl-7-(thiophen-3-yl)-
1, 2, 4-triazolo [4, 3-bjp yridazine
This compound was prepared using the procedures described in
Example 16 Steps a), b) and c) except 3-thiophene boronic acid was used
instead of 4-pyridyl boronic acid, di-lithium salt in Step a), 1.1 equivalents
of triethylamine hydrochloride was used in Step b) instead of 1.1
equivalents of p-toluenesulphonic acid and triethylamine, and (1-methyl-
1H-1,2,4-triazol-3-yl)methanol (Example 65) was used in Step c) instead of
2-pyridylcarbinol. Data for the title compound: m.p. 233-235 C (MeOH).
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iH NMR (360 MHz, DMSO) S 3.89 (3H, s), 5.61 (2H, s), 7.56-7.65 (3H, m),
7.71 (1H, dd, J= 5, 2 Hz), 7.80 (1H, d, J= 5 Hz), 8.29 (1H, d, J= 2 Hz),
8.47 (2H, d, J= 7 Hz), 8.50 (1H, s), 8.65 (1H, s). MS (ES+) 390 [MH]+. Anal.
Found C, 57.92; H, 3.81; N, 24.79. C19H15N7OS . 0.25 H20 requires C,
57.93; H, 3.97; N, 24.89%.
EXAMPLE 136
6-(2-Methyl-2H-1,2,4-triazol-3-ylmethoxy)-7-(thiophen-3-yl)-1 2 4-
triazolo [4, 3-b]pyridazine
This compound was prepared using the procedures described in
Example 16 Steps a), b) and c) except 3-thiophene boronic acid was used
instead of 4-pyridyl boronic acid, di-lithium salt in Step a), 1.1 equivalents
of triethylamine hydrochloride was used in Step b) instead of 1.1
equivalents of p-toluenesulphonic acid and triethylamine, and (2-methyl-
2H-1,2,4-triazol-3-yl)methanol (Example 66) was used in Step c) instead of
2-pyridylcarbinol. Data for the title compound: m.p. 220-222 C (MeOH).
1H NMR (360 MHz, DMSO) S 3.91 (3H, s), 5.79 (2H, s), 7.58-7.65 (3H, m),
7.71-7.74 (2H, m), 8.00 (1H, s), 8.20 (1H, br s), 8.39 (2H, d, J= 7 Hz), 8.68
(1H, s). MS (ES+) 390 [MH]+. Anal. Found C, 58.46; H, 3.86. C19Hi;N70S
requires C, 58.60; H, 3.88%.
EXAMPLE 137
3-Phenyl-7-(thiophen-3-yl)-6-(2H-1,2,4-triazol-3-vlmethoxv)-1 2 4-
triazolo f 4, 3-blpvridazine
This compound was prepared using the procedures described in
Example 16 Steps a) and b) and Example 72 Steps b) and c) except 3-
thiophene boronic acid was used instead of 4-pyridyl boronic acid, di-
lithium salt in Example 16 Step a) and 1.1 equivalents of triethylamine
hydrochloride was used in Example 16 Step b) instead of 1.1 equivalents of
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p-toluenesulphonic acid and triethylamine. Data for the title compound:
m.p. 264-266 C (MeOH). 1H NMR (500 MHz, DMSO, 330K) 8 5.68 (2H, s),
7.54-7.62 (3H, m), 7.66 (1H, dd J= 5, 2 Hz), 7.77 (1H, d, J= 5 Hz), 8.26
(1H, d, J= 2 Hz), 8.41 (2H, d, J= 7 Hz), 8.50 (1H, br s), 8.58 (1H, s). MS
(ES+) 376 [MH]+. Anal. Found C, 56.23; H, 3.28. C18Hi3N70S . 0.14 CH2C12
requires C, 56.26; H, 3.46%.
EXAMPLE 138
6-(2-Methyl-2H-1,2,4-triazol-3-vlmethoxy)-3-phenyl-7-(thiophen-2-vl)-
1, 2, 4-triazolo [4, 3-b]pyridazine
This compound was prepared using the procedures described in
Example 16 Steps a), b) and c) except 2-thiophene boronic acid was used
instead of 4-pyridyl boronic acid, di-lithium salt in Step a), 1.1 equivalents
of triethylamine hydrochloride was used in Step b) instead of 1.1
equivalents of p-toluenesulphonic acid and triethylamine, and (2-methyl-
2H-1,2,4-triazol-3-yl)methanol (Example 66) was used in Step c) instead of
2-pyridylcarbinol. Data for the title compound: m.p. 250-254 C (DMF-
H20). 1H NMR (360 MHz, d6-DMSO) 8 3.96 (3H, s), 5.82 (2H, s), 7.24 (1H,
dd, J= 5 and 4 Hz), 7.52-7.65 (3H, m), 7.80 (1H, d, J= 5 Hz), 8.00 (1H, d, J
= 4 Hz), 8.02 (1H, s), 8.42 (2H, d, J= 7 Hz), 8.80 (1H, s). MS (ES+) 390
[MH]+. Anal. Found C, 58.56; H, 3.93; N, 25.35. CisH15N7OS requires C,
58.60; H, 3.88; N, 25.18%.
EXAMPLE 139
6-(1-Methyl-lH-1,2,4-triazol-3-ylmethoxy)-3-phenyl-7-(thiophen-2-yl)-
1,2 4-triazolo(4,3-blpyridazine
This compound was prepared using the procedures described in
Example 16 Steps a), b) and c) except 2-thiophene boronic acid was used
instead of 4-pyridyl boronic acid, di-lithium salt in Step a), 1.1 equivalents
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of triethylamine hydrochloride was used in Step b) instead of 1.1
equivalents of p-toluenesulphonic acid and triethylamine, and (1-methyl-
1H-1,2,4-triazol-3-yl)methanol (Example 65) was used in Step c) instead of
2-pyridylcarbinol. Data for the title compound: m.p. 237-239 C (DMF-
H20). 1H NMR (360 MHz, CDC13) 5 3.96 (3H, s), 5.69 (2H, s), 7.14 (1H, dd,
J= 6, 5 Hz), 7.47 (IH, d, J= 6 Hz), 7.50-7.60 (3H, m), 7.81 (1H, d, J= 5
Hz), 8.08 (1H, s), 8.27 (1H, s), 8.56 (2H, d, J= 7 Hz). MS (ES+) 390 [MH]+.
Anal. Found C, 57.11; H, 3.96; N, 24.70. C19H15N7OS. 0.5 H20 requires C,
57.27; H, 4.05; N, 24.61%.
EXAMPLE 140
7-(Furan-2-yl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-3 ;phenyl-1,2, 4-
triazolo[4, 3-b]pyridazine
a) 3,6-Dichloro-4-(furan-2-yl)-pyridazine
A mixture of 4-bromo-1,2-dihydropyridazine-3,6-dione (see Example
15 part a) (3.5 g, 18.3 mmol), 2-tributylstannylfuran (6.3 ml, 20 mmol) and
dichloropalladium bis(triphenylphosphine) (1.42 g, 11 mol %) in dry THF
(60 ml) was degassed and purged with nitrogen, then stirred at 70 C for 1
hour. Upon cooling, the mixture was concentrated. The residues were
triturated and washed with hexane, then diethyl ether, to give the crude
coupled product as a beige powder (5.23 g) which was used without
purification.
The above solid was mixed with phosphorus oxychloride (80 ml) and
refluxed for 4 hours. Excess phosphorus oxychloride was removed by
evaporation and azeotroping with toluene. The residue was diluted with
ice (100 ml) and dichloromethane (200 ml) and neutralised with saturated
aqueous sodium hydrogen carbonate (200 ml). The mixture was filtered
and the two phases were separated. The organic layer was dried (Na2SO4),
filtered and concentrated. Filtration on a short silica column, eluting with
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ethyl acetate, gave the title compound as brown crystals (1.67 g, 44% over
the two steps). 1H NMR (250 MHz, CDC13) S 6.67 (1H, dd, J= 4, 2 Hz),
7.63 (1H, d, J= 4 Hz), 7.71 (1H, d, J= 2 Hz), 7.92 (1H, s). MS (ES+) 215
and 217 [MH]+.
b) 7-(Furan-2-yl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-3-phenyl-
1, 2, 4-triazolo f 4, 3-b]pyridazine
This compound was prepared from 3,6-dichloro-4-(furan-2-yl)-
pyridazine using the procedures described in Example 16 Steps b) and c)
except 1.1 equivalents of triethylamine hydrochloride was used in Step b)
instead of 1.1 equivalents of p-toluenesulphonic acid and triethylamine,
and (2-methyl-2H-1,2,4-triazol-3-yl)methanol (Example 66) was used in
Step c) instead of 2-pyridylcarbinol.
Data for the title compound: m.p. 263-265 C (DMF). IH NMR (360
MHz, d6-DMSO) S 3.95 (3H, s), 5.84 (2H, s), 6.74 (1H, dd, J= 4, 2 Hz), 7.21
(1H, d, J= 4 Hz), 7.55-7.65 (3H, m), 8.00 (1H, d, J= 2 Hz), 8.03 (1H, s),
8.41 (2H, d, J= 7 Hz), 8.47 (1H, s). MS (ES+) 374 [MH]+. Anal. Found C,
60.93; H, 4.00; N, 26.09. C19H15N702 requires C, 61.12; H, 4.05; N, 26.26%.
EXAMPLE 141
7-(Furan-2-yl)-6-(1-methyl-lH-1,2,4-triazol-3-ylmethoxy)-3-phenyl-1 2 4-
triazolo [4, 3-b]pyridazine
This compound was prepared from 3,6-dichloro-4-(furan-2-yl)-
pyridazine (Example 140 part a) using the procedures described in
Example 16 Steps b) and c) except 1.1 equivalents of triethylamine
hydrochloride was used in Step b) instead of 1.1 equivalents of
p-toluenesulphonic acid and triethylamine, and (1-methyl-lH-1,2,4-triazol-
3-yl)methanol (Example 65) was used in Step c) instead of 2-
pyridylcarbinol. Data for the title compound: m.p. 257-259 C (DMF). 1H
NMR (360 MHz, d6-DMSO) 3.91 (3H, s), 5.63 (2H, s), 6.74 (1H, dd, J= 4
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and 2 Hz), 7.33 (1H, d, J= 4 Hz), 7.54-7.65 (3H, m), 7.99 (1H, d, J= 2 Hz),
8.44 (1H, s), 8.46 (2H, d, J = 7 Hz), 8.57 (1H, s). MS (ES+) 374 [MH]+. Anal.
Found C, 60.68; H, 4.11; N, 25.82. C19H15N702 . 0.15 H20 requires C,
60.68; H, 4.10; N, 26.07%.
EXAMPLE 142
6 - (3-Methyl-1,2,4-oxadiazol-5-ylmethoxy)-3,7-diphenyl-1,2,4-triazoloj4 3-
b]pyridazine
a) 5-Chloromethyl-3-methyl- 1,2,4-oxadiazole
To a solution of acetamide oxime (1g, 0.0135 mol) in
dichloromethane (30m1) was added triethylamine (2.06m1, 0.015 mol) and
cooled to 0 C. Chloroacetyl chloride (1.18ml, 0.015 mol) was added
dropwise over 5 minutes. The reaction was stirred at 0 C for 10 minutes,
then at room temperature for 1 hour. The reaction was diluted with
dichloromethane (40m1) and washed with water (2 x 30m1), brine (1 x
30m1). The organic layer was dried (MgSO4), filtered and evaporated to
yield the crude product.
b) 6-(3-Methvl-1,2,4-oxadiazol-5-ylmethoxy)-3,7-diphenyl-1,2,4-
triazoloj4,3-blpyridazine
This compound was prepared using the procedures described in
Example 35 a) and b) using the product from Example 2 c) and the crude
product from this Example part a). 1H NMR (360 MHz, CDC13) 8 2.35 (3H,
s), 5.85 (2H, s), 7.51-7.80 (7H, m), 8.24 (2H, m) 8.48 (1H, s); MS (ES+) m/e
385 [MH+]. Anal. Found C, 65.19; H, 3.99; N, 21.07. C21HisN602. 0.05
CH2C12.. 0.1 EtOAc requires C, 64.82; H, 4.29; N, 21.15%.
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EXAMPLE 143
3-(4-Fluorophenyl)-6-(1-methyl-lH-1,2,4-triazol-3-ylmethoxv)-7-phenyl-
1, 2, 4-triazolo [4, 3-blpyridazine
This compound was prepared using procedures described in
Example 2 a), b), c), d) with 4-fluorobenzyl hydrazide being used instead of
benzoyl hydrazine in Step c) and (1-methyl-1H- 1,2,4-triazol-3-yl)methanol
being used instead of 2-pyridylcarbinol in Step d). m.p. = 233-235 C. 1H
NMR (360MHz, d6-DMSO) S 3.85 (3H, s), 5.52 (2H, s), 7.42 (5H, m), 7.73
(2H, m), 8.40 (1H, s), 8.49 (3H, m); MS (ES+) m/e 402 [MH+].
EXAMPLE 144
3,7-Diphenyl-6-(2H- 1,2,3-triazol-4-ylmethoxy)-1,2,4-triazolo[4,3-
blpyridazine
a) 5-Formyl-l-f2-(trimethylsilanyl)ethoxy]methyl-lH-1,2,3-triazole
To a stirred solution of 1-[2-(trimethylsilanyl)ethoxy]methyl-lH-
1,2,3-triazole (Holzer, W.; Ruso, K., J. Heterocycl. Chem., 1992, 29, 1203-7)
(2.0344 g, 10.2 mmol) in anhydrous THF (30 ml), cooled to <-75 C under
nitrogen, was added dropwise, over 11 min, a 1.6 M solution of
butyllithium in hexanes (6.70 ml, 10.7 mmol). The mixture was stirred at
this temperature for 30 min, then allowed to warm to -20 C over 13 min.
The mixture was then recooled to <-75 C, and anhydrous DMF (0.87 ml,
11.3 mmol) was added dropwise over 8 min. The mixture was stirred at <
-75 C for 1.75 h, then at 0 C for 75 min. Saturated aqueous NHaCI (50
ml) was then added and the mixture was extracted with diethyl ether (75
ml) then ethyl acetate (2 x 75 ml). The organic extracts were dried
(Na2SO4) and evaporated in vacuo. The residue was purified by flash
chromatography (silica gel, 40% EtOAc/hexane) to give 1.7256 g (74%) of
the title compound as a colourless oil: 1H NMR (360 MHz, CDCl3) 5 -0.03
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(9H, s), 0.91 (2H, m), 3.63 (2H, m), 6.01 (2H, s), 8.28 (1H, s), 10. 08 (1H,
s);
MS (ES+) m/e 170 [M-SiMe2+H]+.
b) 5-Hydroxymethyl-1-[2-(trimethylsilanyl)ethoxy]methyl-lH-1 2 3-
triazole
To a stirred solution of the product from Step a (1.7204 g, 7.57
mmol) in anhydrous methanol (8 ml), cooled to 0 C under nitrogen, was
added sodium borohydride (0.2875 g, 7.60 mmol) and the mixture was
stirred at this temperature for 20 min, then allowed to warm to room
temperature over 30 min. The reaction was quenched by adding water,
and the mixture was partitioned between saturated aqueous NaCl (40 ml)
and dichloromethane (30 ml). The aqueous laver was further extracted
with dichloromethane (3 x 30 ml), and the combined organic extracts were
dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash
chromatography (silica gel, 3% MeOH/CH2C12) to afford 1.4642 g (84%) of
the title compound: 1H NMR (360 MHz, CDC13) 8-0.02 (9H, s), 0.90 (2H,
m), 3.59 (2H, m), 4.82 (2H, s), 5.78 (2H, s), 7.67 (1H, s); MS (ES+) m/e 230
[M+H]+, 119.
c) 3,7-Diphenyl-6-[1-(2-(trimethylsilanyl)ethoxYjmethyl-lH-1,2,3-
triazol- 5-yllmethoxy-1, 2, 4-triazolo [4, 3-b]pyridazine
This compound was prepared in 84% yield using a similar procedure
to that described in Example 2, Step d, but using 5-hydroxvmethyl-l-[2-
(trimethylsilanyl)ethoxy]methyl-lH-1,2,3-triazole (from Step b) instead of
2-pyridylcarbinol. Data for the title compound: 1H NMR (360 MHz, CDC13)
8 -0.07 (9H, s), 0.80 (2H, m), 3.49 (2H, m), 5.62 (2H, s), 5.67 (2H, s), 7.47-
7.62 (8H, m), 7.77 (1H, s), 8.39 (1H, s), 8.40 (2H, dd); MS (ES+) m/e 500
[N1H]+.
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d) 3,7-Diphenyl-6-(2H-1,2,3-triazol-4-ylmethoxy)-1 2.4-triazolo[4 3-
b1p ri~ dazine
A mixture of the product from Step c (0.7025 g, 1.41 mmol) in
ethanol (12 ml) and 2 M aqueous HC1 (25 ml) was stirred at 60 C for 5.5 h.
The mixture was then neutralised by adding dropwise saturated aqueous
Na2CO3. The resulting precipitate was collected by filtration, washed with
water, then hexane, and dried under vacuum at 60 C. This was purified
by recrystallisation (MeOH-CH2C12), then flash chromatography (silica gel,
3-5% MeOH/CH2C12) to afford 0.2044 g (39%) of the title compound as a
white solid: mp 208-220 C; 1H NMR (360 MHz, ds-DMSO) S 5.66 (2H, s),
7.48-7.49 (3H, m), 7.58-7.72 (5H, m), 7.94 (1H, br s), 8.40 (1H, s), 8.47 (2H,
d, J= 7.2 Hz), 15.10 (1H, br s); MS (ES+) m/e 370 [MH]+; Anal. Found C,
65.07; H, 4.05; N, 26.01. C2oH15N70Ø1H20 requires C, 64.72; H, 4.13; N,
26.41%.
EXAMPLE 145
3, 7-Diphenyl-6-(pyrazin-2-ylmethoxy)-1, 2.4-triazolo (4, 3-b]pyridazine
a) 2-Hydroxymethvlpvrazine
To methyl 2-pyrazinecarboxylate (1.80 g) in THF (60 ml) was added
diisobutylaluminium hydride (1 M solution in THF; 39 ml) at -78 C with
stirring. The solution was allowed to warm to room temperature, and
stirred for 24 h. The reaction was quenched with solid tartaric acid, then
aqueous sodium potassium tartrate, and stirred for 30 min at room
temperature. Saturated aqueous sodium hydrogen carbonate was added
until the pH of the solution was >7. The solution was washed with ethyl
acetate (3 x 200 ml), and the organic layers combined, washed with
saturated sodium chloride solution (1 x 200 ml), dried (magnesium sulfate)
and concentrated in vacuo. The residue was purified by flash
chromatography (silica gel, eluent = 5% methanol in dichloromethane) to
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yield 2-hydroxymethylpyrazine as a dark brown oil (0.16 g). 'H NMR (250
MHz, CDCIs) 5 3.42 (1H, br s), 4.85 (2H, s), 8.55 (2H, m), 8.68 (1H, s); MS
(ES+) m/e 111 [MH+].
b) 3,7-Diphenyl-6-(pyrazin-2-ylmethoxy)-1,2,4-triazolo(4,3-blpyridazine
This compound was prepared using the procedures described in
Example 2 a), b), c) and d) with 2-hydroxymethylpyrazine being used
instead of 2-pyridylcarbinol in Step d). 1H NMR (360 MHz, CDC13) S 5.69
(2H, s), 7.54 (5H, m), 7.65 (2H, m), 8.09 (1H, s), 8.39 (2H, d, J= 6.6 Hz),
8.56 (1H, s), 8.60 (1H, s), 8.67 (1H, s); MS (ES+) m/e 381 [MH+].
EXAMPLE 146
3-(4-Methylphenyl)-6-(1-methyl-1H-1,2,4-triazol-3-ylmethoxy)-7-phenyl-
1, 2, 4-triazolo (4, 3-b]pyridazine
This compound was prepared using procedures described in
Example 2 a), b), c), d) with 4-methylbenzoyl hydrazine being used instead
of benzoyl hydrazine in Step c) and (1-methyl-lH-1,2,4-triazol-3-
yl)methanol being used instead of 2-pyridylcarbinol in Step d). m.p. _
218.6-219.7 C. 1H NMR (360MHz, DMSO) 8 2.51 (3H, s), 3.87 (3H, s), 5.54
(2H, s), 7.44 (5H, m), 7.76 (2H, s), 8.38 (4H, m); MS (ES+) m/e 398 [MH+].
EXAMPLE 147
6-(4-Methylthiazol-2-ylmethoxy)-3,7-diphenyl-1,2,4-triazoloj4,3-
blpyridazine
This compound was prepared using the procedures described in.
Example 2 a), b), c) and d) with 2-hydroxymethyl-4-methylthiazole being
used instead of 2-pyridylcarbinol in Step d). Data for the title compound:
m.p. = 177 C. 'H NMR (360 MHz, CDC13) 5 2.47 (3H, s), 5.79 (2H, s), 6.90
(1H, s), 7.50-7.67 (8H, m), 8.08 (1H, s), 8.50 (2H, d, J = 7.9 Hz); MS (ES+)
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-
m/e 400 [MH]+. Anal. Found C, 66.25; H, 3.90; N, 17.47. C22H17N50S
requires C, 66.14; H, 4.29; N, 17.53%.
EXAMPLE 148
6-(5-Methylthiazol-2-ylmethoxy)-3,7-diphenvl-1,2,4-triazolo(4 3-
b]pyridazine
This compound was prepared using the procedures described in
Example 2 a), b), c) and d) with 2-hydroxymethyl-5-methylthiazole being
used instead of 2-pyridylcarbinol in Step d). Data for the title compound:
m.p. = 182 C. IH NMR (360 MHz, CDC13) S 2.46 (3H, s), 5.75 (2H, s), 7.45-
7.65 (9H, m), 8.07 (1H, s), 8.49 (2H, d, J= 7.9 Hz); MS (ES+) m/e 400
(MH]+. Anal. Found C, 66.17; H, 4.02; N, 17.67. C22H17N50S requires C,
66.14; H, 4.29; N, 17.53%.
EXAMPLE 149
3, 7-Dinhenyl-6-(pyrimidin-4-ylmethoxy)-1, 2,4-triazolo j4, 3-b,pyridazine
This compound was prepared using the procedures described in
Example 79 a) and b), with 4-chloromethylpyrimidine (prepared by the
procedure of Jeronim et al., Chem. Ber., 1987, 120, 649-651) being used
instead of bromoacetonitrile in Step b). Data for the title compound: 'H
NMR (360 MHz, CDC13) 8 5.61 (2H, s), 7.33 (1H, d, J= 5.1 Hz), 7.55 (6H,
m), 7.67 (2H, m), 8.10 (1H, s), 8.38 (2H, m), 8.74 (1H, d, J= 5.1 Hz); MS
(ES+) m/e 381 [MH+]. Anal. Found C, 70.01; H, 3.96; N, 21.97. C22Hi6N60
requires C, 69.46; H, 4.24; N, 22.09 %.
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EXAMPLE 150
3,7-Diphenyl-6-(pyridazin-3-vlmethoxy)-1 2 4-triazolo[4 3-b]pyridazine
This compound was prepared using the procedures described in
Example 79 a) and b), with 3-chloromethylpyridazine (prepared by the
procedure of Jeronim et al., Chem. Ber., 1987, 120, 649-651) being used
instead of bromoacetonitrile in Step b). 'H NMR (360 MHz, CDC13) S 5.89
(2H, s), 7.53 (6H, m), 7.64 (2H, m), 8.09 (1H, s), 8.40 (2H, m), 9.18 (1H, m);
MS (ES+) m/e 381 [MH+].
EXAMPLE 151
6-(1-Methyl-lH-1,2,4-triazol-3-vlmethoxy)-7-(morpholin-4-vl)-3-(thiophen-
2-yl)-1, 2, 4-triazolo [4, 3-b]pyridazine
a) 4-(3,6-Dichloropyridazin-4-yl)morpholine
This was prepared using the procedure described in Example 15
part c) except that morpholine was used instead of piperidine. Data for the
title compound: 1H NMR (250 MHz, CDCls) S 3.30-3.34 (4H, m), 3.87-3.95
(4H, m), 6.89 (1H, s); MS (ES+) m/e 234, 236, 238 [MH+].
b) 6_Chloro-5-(mornholin-4-yl)pyridazin-3-ylhydrazine
A mixture of 4-(3,6-dichloropyridazin-4-yl)morpholine (5 g, 21.3
mmol) and hydrazine hydrate (7.0 ml, 141 mmol) in 1,4-dioxan (100 ml)
was stirred and heated at reflux for 20 hours. Upon cooling the 1,4-dioxan
was removed in vacuo. The residue was then partitioned between
dichloromethane and saturated aqueous sodium hydrogen carbonate. The
aqueous layer was further extracted with dichloromethane (x2). The
combined organic extracts were dried (Na2SO4), filtered and evaporated.
The residue was purified by chromatography on silica gel, eluting with
dichloromethane/methanol/aqueous ammonia (91:8:1) to give 6-chloro-5-
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(morpholin-4-yl)-pyridazin-3-ylhydrazine (3.6 g, 74%): 1H NMR (250 MHz,
ds-DMSO) 5 3.37-3.17 (4H, m), 3.72-3.77 (4H, m), 4.31 (2H, br s), 6.58 (1H,
s), 7.97 (1H, br s); MS (ES+) m/e 230, 232 [MH+].
c) 6-Chloro-7-(morpholin-4-yl)-2H-1,2,4-triazolof4,3-b]pyridazin-3-one
Triphosgene (750 mg, 2.5 mmol) was added to a stirred solution of 6-
chloro-5-(morpholin-4-yl)pyridazin-3-ylhydrazine (1.42 g, 6.2 mmol) in 1,2-
dichloroethane (60 ml) at room temperature under nitrogen. The mixture
was then stirred and heated at reflux for 22 hours. Upon cooling the
precipitate was collected by filtration. The solid was washed with diethyl
ether and then dried in vacuo to give 6-chloro-7-(morpholin-4-yl)-2H-1,2,4-
triazolo[4,3-b]pyridazin-3-one (1.1 g, 67%) which was used without further
purification. Data for the title compound: IH NMR (250 MHz, d6-DMSO) 8
3.02-3.05 (4H, m), 3.72-3.76 (4H, m), 7.19 (1H, s), 12.57 (1H, br s); MS
(ES+) m/e 256, 258 [MH+].
d) 3-Bromo-6-(1-methyl-lH-1,2,4-triazol-3-vlmethoxy)-7-(morpholin-4-
yl) -1, 2, 4-triazolo f4, 3-blpyrid azine
A mixture of 6-chloro-7-(morpholin-4-yl)-2H-1,2,4-triazolo[4,3-
b]pyridazin-3-one (1.1 g, 4.3 mmol) and phosphoryl bromide (25 g) was
stirred and heated at 80 C for 24 hours. Upon cooling the mixture was
treated with ice. The aqueous was then basified with aqueous ammonia.
The aqueous was then extracted with dichloromethane (x3). The combined
extracts were dried (Na2SO4), filtered and evaporated. The residue was
purified by chromatography on silica gel, eluting with 5%
methanol/dichloromethane to give 3-bromo-6-chloro-7-(morpholin-4-yl)-
1,2,4-triazolo[4,3-b}pyridazine (600 mg). 1H NMR and mass spectrum
revealed the product to be a mixture of the desired compound and the 6-
bromo compound. This mixture was used without further purification.
Sodium hydride (60% dispersion in oil, 80 mg, 2.0 mmol) was added in one
portion to a stirred solution of the product from above (600 mg) and (1-
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methyl-lH-1,2,4-triazol-3-yl)methanol (240 mg, 2.1 mmol, prepared as
described in Example 65) in dry DMF at 0 C under nitrogen. The ice bath
was removed and the mixture was stirred at room temperature for 2
hours. The reaction was quenched with water and then partitioned
between ethyl acetate and water. The aqueous layer was further extracted
with dichloromethane (x3). The combined organic extracts were dried
(Na2SO4), filtered and evaporated. The residue was purified by
chromatography on silica gel, eluting with 5 to 8%
methanol/dichloromethane to give the title compound (358 mg, 48% for 2
steps). 1H NMR (360 MHz, d6-DMSO) 5 3.20-3.22 (4H, m), 3.69-3.71 (4H,
m), 3.68 (3H, s), 5.47 (2H, s), 7.41 (1H, s), 8.49 (1H, s); MS (ES+) m/e 395,
397 [MH+].
e) 6-(1-Methyl-lH-1,2,4-triazol-3-ylmethoxy)-7-(morpholin-4- 1~)-3-
thiophen-2-yl)-1, 2,4-triazolo [4, 3-b]pyridazine
A mixture of 3-bromo-6-(1-methyl-lH-1,2,4-triazol-3-ylmethoxy)-7-
(morpholin-4-yl)-1,2,4-triazolo[4,3-b]pyridazine (100 mg, 0.25 mmol) and 2-
(tributylstannyl)thiophene (240 ml, 0.75 mmol) in dry DMF (3 ml) was
deoxygenated by bubbling through nitrogen gas for 15 minutes.
Dichlorobis(triphenylphosphine)palladium (II) (20 mg) was then added.
The whole apparatus was further deoxygenated by three 'evacuate/fill N2'
cycles. The mixture was then stirred and heated at 100 C for 16 hours
under nitrogen. The reaction mixture was partitioned between
dichloromethane and water. The aqueous layer was further extracted
with dichloromethane (x2). The combined extracts were dried (Na2SO4),
filtered and evaporated. Residual DMF was removed under high vacuum.
The residue was purified by chromatography on silica gel, eluting with 5%
methanol/dichloromethane to give the title compound (60 mg, 60%).
Data for the title compound: 1H NMR (360 MHz, CDC13) S 3.26-3.29 (4H,
m), 3.85-3.89 (4H, m), 3.94 (3H, s), 5.64 (2H, s), 7.19-7.23 (2H, m), 7.47-
7.59 (1H, m), 8.05 (1H, s), 8.18-8.20 (1H, m); MS (ES+) m/e 399 [MH+].
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Anal. Found C, 50.84; H, 4.39; N, 27.35. C17Hi8N802S. 0.3(H20) requires C,
50.56; H, 4.64; N, 27.75%.
EXAMPLE 152
3, 7-Diphenyl-6-(thiazol-4-ylmethoxy)-1, 2, 4-triazolo j4, 3-binyridazine
This compound was prepared using the procedures described in
Example 2 a), b), c) and d) with 4-hydroxymethylthiazole being used
instead of 2-pyridylcarbinol in Step d). Data for the title compound: m.p. _
236 C. 'H NMR (360 MHz, CDC13) S 5.73 (2H, s), 7.29 (1H, s), 7.49-7.66
(8H, m), 8.06 (1H, s), 8.49 (2H, d, J= 7.9 Hz), 8.85 (IH, s); MS (ES+) m/e
386 [MH]+. Anal. Found C, 65.11; H, 3.72; N, 17.97. C21H15N5OS requires
C, 65.44; H, 3.92; N, 18.17%.
EXAMPLE 153
6-(5-Methylisoxazol-3-ylmethoxy)-3,7-diphenyl-1,2,4-triazolo[4, 3-
b1pyridazine
This compound was prepared using the procedures described in
Example 2 a), b), c) and d) with 5-methylisoxazol-3-ylmethanol being used
instead of 2-pyridylcarbinol in Step d). Data for the title compound: m.p. =
180 C. 'H NIVIR (360 MHz, CDCIs) 5 2.42 (3H, s), 5.57 (2H; s), 6.00 (1H, s),
7.49-7.61 (8H, m), 8.06 (1H, s), 8.47 (2H, d, J= 7.9 Hz); MS (ES+) m/e 384
[MH]+. Anal. Found C, 68.45; H, 4.09; N, 17.79. C22H17N50SØ1 H20
requires C, 68.92; H, 4.47; N, 18.27%.
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EXAMPLE 154
3-(3-Fluorophenyl)-6-(1-methyl-1 H-1, 2, 4-triazol-3-ylmethoxv)-7-
(morpholin-4-yl)-1, 2, 4-triazolo [4, 3-b]pyridazine
A mixture of 3-bromo-6-(1-methyl-lH-1,2,4-triazol-3-ylmethoxy)-7-
(morpholin-4-yl)-1,2,4-triazolo[4,3-b]pyridazine (100 mg, 0.25 mmol, from
Example 151 part d), 3-fluorobenzene boronic acid (50 mg, 0.35 mmol) and
anhydrous sodium carbonate (70 mg, 0.66 mmol) in 1,2-dimethoxyethane/
water (2:1, 5 ml) was deoxygenated by bubbling through nitrogen gas for
15 minutes. Tetrakis(triphenylphosphine)palladium (0) (30 mg) was then
added. The whole apparatus was further deoxygenated by three
'evacuate/fill Nz' cycles. The mixture was then stirred and heated at 110
C for 16 hours under nitrogen. Upon cooling the reaction mixture was
partitioned between dichloromethane and water. The aqueous layer was
further extracted with dichloromethane (x2). The combined extracts were
dried (Na2SO4), filtered and evaporated. The residue was purified by
chromatography on silica gel, eluting with 5% methanol/dichloromethane
to give the title compound (65 mg, 63%). Data for the title compound: 1H
NMR (360 MHz, CDC13) S 3.27-3.29 (4H, m), 3.87-3.90 (4H, m), 3.94 (3H,
s), 5.60 (2H, s), 7.14-7.19 (1H, m), 7.20 (1H, s), 7.46-7.52 (1H, m), 8.05
(1H,
s), 8.21-8.28 (1H, m); MS (ES+) m/e 411 [MH+]. Anal. Found C, 53.16; H,
4.85; N, 25.59. C19Hi9N802F. 1.2(H20) requires C, 52.82; H, 4.99; N,
25.94%.
EXAMPLE 155
3. 7-Dip henyl-6-(pyrimidin-2-vlmethoxv)-1, 2. 4-triazolol4, 3-bipyridazine
a) Dimethyl2-(mrimidin-2-vl)malonate
To dimethyl malonate (41.6 g) in 1,4-dioxane (900 ml) was added
sodium hydride (60% dispersion in mineral oil; 18.9 g) portionwise. To the
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resultant gel was added 2-bromopyrimidine (50.0 g) in 1;4-dioxane (200
ml) dropwise. The mixture was stirred at room temperature for 1 h, then
at reflux overnight. To the cooled solution was added water (400 ml), and
N hydrochloric acid until the pH was - 1. The solution was washed with
5 ethyl acetate (2 x 400 ml), the organic layers combined, washed with
saturated sodium hydrogen carbonate solution (1 x 400 ml) and saturated
sodium chloride solution (1 x 400 ml), dried (magnesium sulfate) and
concentrated in vacuo. The residue was purified by flash chromatography
(silica gel, eluent = 0 to 20% ethyl acetate in dichloromethane) to yield
dimethyl2-(pyrimidin-2-yl)malonate as a yellow/orange oil (24.1 g). 1H
NMR (250 MHz, CDC13) S 3.83 (6H, s), 5.16 (1H, s), 7.28 (1H, t, J= 5.0
Hz), 8.87 (2H, d, J= 5.0 Hz); MS (ES+) m/e 211 [MH+].
b) 2-Methylpyrimidine
Dimethyl 2-(pyrimidin-2-yl)malonate (14.0 g), sodium chloride (17.1
g) and water (5.24 ml) were heated together in DMSO (50 ml) at 160 C
overnight. The solution was allowed to cool, and the inorganic material
filtered off. The filtrate was distilled at atmospheric pressure, and the
fraction boiling between 95 and 112 C was collected. The distillate was
redistilled at atmospheric pressure, with the fraction boiling between 97
and 99 C being collected - this was a mixture of 2-methylpyrimidine and
dimethylsulfide, present in a 2:1 ratio respectively (1.41 g). This material
was used in the next step without further purification. 'H NlvTR (250 MHz,
CDC13) 8 2.70 (3H, s), 7.13 (1H, t, J= 4.9 Hz), 8.66 (2H, d, J= 4.9 Hz); MS
(ES+) m/e 95 [MH+].
c) 2-Chloromethylpyrimidine
Trichloroisocyanuric acid (0.62 g) was added portionwise to the
product from Example 155 Step b) (0.60 g) in refluxing chloroform (30 ml),
and the slurry was stirred at reflux for 3 h. A further quantity of
trichloroisocyanuric acid (0.62 g) was added, and the mixture stirred as
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before for 6 h. The slurry was allowed to cool to room temperature,
filtered to remove insoluble material, and the filtrate washed with 1 M
sodium hydroxide solution (1 x 25 ml) and saturated sodium chloride
solution (1 x 25 ml). The filtrate was dried (magnesium sulfate) and
concentrated in vacuo to give 2-chloromethylpyrimidine as a pale
orange/brown oil (0.11 g). Data for the title compound: 1H NMR (250
MHz, CDC13) 8 4.77 (2H, s), 7.27 (1H, t, J = 4.9 Hz), 8.79 (2H, d, J = 4.9
Hz); MS (ES+) m/e 129 [MH+].
d) 3 7-Diphenyl-6-(pvrimidin-2-ylmethoxy)-1,2,4-triazolo[4,3-b]_
pyridazine
This compound was prepared using the procedures described in
Example 79 a) and b), with 2-chloromethylpyrimidine being used instead
of bromoacetonitrile in Step b). Data for the title compound: 'H NMR (360
MHz, CDCIa) 8 5.74 (2H, s), 7.23 (1H, t, J = 4.9 Hz), 7.48 (6H, m), 7.81 (2H,
m), 8.06 (1H, s), 8.22 (2H, m), 8.76 (2H, d, J= 4.9 Hz); MS (ES+) m/e 381
[MH+]. Anal. Found C, 69.45; H, 3.81; N, 22.11. C22H16N60 requires C,
69.46; H, 4.24; N, 22.09%.
EXAMPLE 156
6-(2-Methyl-2H-1,2,3-triazol-4-ylmethoxy)-3, 7-diphenyl-1,2,4-triazolo[4, 3-
b]t)yridazine
To a stirred mixture of sodium hydride (60% dispersion in oil, 22.6
mg, 0.565 mmol) and iodomethane (29.6 ml, 0.475 mmol) in anhydrous
DMF (2 ml), cooled under nitrogen to -5 C, was added dropwise, over 10
min, a solution of 3,7-diphenyl-6-(2H-1,2,3-triazol-4-ylmethoxy)-1,2,4-
triazolo[4,3-b]pyridazine (from Example 144, Step d) (0.1675 g, 0.453
mmol) in anhydrous DMF (7 ml). The mixture was then allowed to warm
to room temperature over 2.5 h, then partitioned between water (40 ml)
and ethyl acetate (40 ml). The aqueous layer was extracted further with
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ethyl acetate (4 x 30 ml), adding saturated aqueous NaCl to facilitate
separation of the layers. The combined organic extracts were dried
(Na2SO4) and evaporated in vacuo. The residue was purified by flash
chromatography (silica gel, 50-100% EtOAc/CH2C12) to give 69.8 mg (40%)
of the title compound as a white solid together with 75.8 mg (44%) of a
mixture of the 2-methyl-2H-1,2,3-triazol-4-yl analogue and the 1-methyl-
1H-1,2,3-triazol-5-yl analogue in a 63:37 ratio. Data for the title
compound: mp 203-205 C (CH2C12-EtOAc); 'H NMR (360 MHz, CDCIa) 8
4.19 (3H, s), 5.61 (2H, s), 7.47-7.61 (9H, m), 8.05 (1H, s), 8.40 (1H, s),
8.52
(2H, m); MS (ES+) m/e 384 [MH]+; Anal. Found C, 65.27; H, 4.17; N, 25.14.
C21H17N70. 0.1H20 requires C, 65.48; H, 4.50; N, 25.45%.
EXAMPLE 157
7-(1-Methylcvclobutyl)-6-(1-methvl-lH-1,2,4-triazol-3-ylmethoxy)-3-
phenyl-1, 2,4-triazoloj4,3-blpyridazine
This compound was prepared using the procedures described in
Example 88 Steps a), b) and c) using (1-methyl-lH-1,2,4-triazol-3-
yl)methanol (prepared using the conditions described in EP-A-421210)
instead of (2-methyl-2H-1,2,4-triazol-3-yl)methanol in Step b) and using 1-
methylcyclobutane carboxylic acid (Journal of Organometallic Chemistry,
1988, 352, 263-272) instead of cyclohexane carboxylic acid in Step c). Data
for the title compound: 1H NMR (360 MHz, CDC13) S 1.56 (3H, s), 1.80-1.91
(1H, m), 2.08-2.24 (3H, m), 2.38-2.52 (2H, m), 3.93 (3H, s), 5.54 (2H, s),
7.46-7.60 (3H, m), 7.69 (1H, s), 8.04 (1H, s), 8.48-8.55 (2H, m); MS (ES+)
m/e 376 [MH]+. Anal. Found C, 64.01; H, 5.51; N, 26.00. C2oH21N70
requires C, 63.98; H, 5.64; N, 26.12%.
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EXAMPLE 158
7-I sopropyl-6-(2-methyl-2H-1, 2, 4-triazol- 3-ylmethoxv)- 3-phenyl-1.2, 4-
triazoloL4, 3-blpyridazine
This compound was prepared using the procedures described in
Example 88 Steps a), b) and c) using 2- methylprop ionic acid instead of
cyclohexane carboxylic acid in Step c). Data for the title compound:
1H NMR (360 MHz, CDC13) 8 1.32 (6H, d, J= 6.8 Hz), 3.10-3.25 (1H, m),
3.98 (3H, s), 5.63 (2H, s), 7.47-7.61 (3H, m), 7.91 (1H, d, J= 0.7 Hz), 7.94
(1H, s), 8.32-8.43 (2H, m); MS (ES+) m/e 350 [MH]+. Anal. Found C, 62.20;
H, 5.28; N, 27.78. C18H N70 requires C, 61.88; H, 5.48; N, 28.06%.
EXAMPLE 159
7-tert-Butyl-3-(2-fluorophenyl)-6-(1-methyl-lH-1, 2,4-triazol-3-ylmethoxy)-
1 2,4-triazolo[4, 3-b]pyridazine
This compound was prepared using the procedures described in
Example 102 Steps a), b) and c) using trimethylacetic acid instead of
cyclopentane carboxylic acid in Step a), using 2-fluorobenzoic hydrazide
instead of 2-thiophene carboxylic acid hydrazide in Step b) and using (1-
methyl-lH-1,2,4-triazol-3-yl)methanol (prepared using the conditions
described in EP-A-421210) instead of 2-hydroxymethylpyridine in Step c).
Data for the title compound: 1H NMR (360 MHz, CDC13) S 1.43 (9H, s),
3.93 (3H, s), 5.44 (2H, s), 7.23-7.37 (2H, m), 7.48-7.58 (1H, m), 7.94 (1H,
s),
7.95-8.00 (1H, m), 8.04 (1H, s); MS (ES+) m/e 382 [MH]+. Anal. Found C,
60.20; H, 4.98; N, 25.53. C19H2oN7OF requires C, 59.83; H, 5.29; N,
25.71%.
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EXAMPLE 160
7-Cyclopentyl-3-(4-methoxyphenyl)-6-(2-methyl-2H-1.2, 4-triazol-3-
Ylmethoxy)-1, 2, 4-triazolo f4, 3-b)pyridazine
Prepared in an analogous procedure as outlined in Example 102b
using 4-methoxybenzoic acid hydrazide and Example 102c using (2-
methyl-2H-1,2,4-triazol-3-yl)methanol to give the title compound. 'H NMR
(250 MHz, CDC13) S 1.30 (3H, s), 1.75 (4H, m), 1.88 (4H, m), 3.96 (3H, s),
5.62 (2H, s), 7.53 (3H, m), 7.96 (2H, s), 8.38 (2H, m); MS (ES+) m/e 390
[MH]+.
EXAMPLE 161
7-(1-Methylcyclopentyl)-6-(1-methyl-lH-1, 2, 4-triazol-3-ylmethoxy)-3-
i)henyl-1,2,4-triazolo[4,3-b]pyridazine
Prepared in an analogous procedure as outlined in Example 102a
using 1-methylcyclopentanoic acid, Example 102b using benzoic acid
hydrazide and Example 102c using (1-methyl-lH-1,2,4-triazol-3-
yl)methanol to give the title compound. 1H NMR (250 MHz, CDC13) S 1.73
(6H, m), 2.08 (2H, m) 3.18 (1H, m), 3.90 (3H, s), 3.99 (3H, s), 5.62 (2H, s),
7.06 (3H, m), 7.88 (1H, d, J= 1.1Hz), 7.95 (1H, s), 8.36 (2H, m); MS (ES+)
m/e 406 [MH]+.
EXAMPLE 162
7-(1-Methylcyclopentyl)-6- (2-methyl-2H-1, 2, 4-triazol-3-ylmethoxy)-3-
phenYl-1,2 4-triazolo[4,3-blpyridazine
Prepared in an analogous procedure as outlined in Example 102a
using 1-methylcyclopentanoic acid, Example 102b using benzoic acid
hydrazide and Example 102c using (2-methyl-2H-1,2,4-triazol-3-
yl)methanol to give the title compound. 1H NMR (250 MHz, CDC13) 6 1.35
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(3H, s), 1.64 (4H, m), 1.72 (4H, m), 3.94 (3H, s), 5.57 (2H, s), 7.52 (3H, m),
7.91 (1H, s), 8.06 (1H, s), 8.49 (2H, m); MS (ES+) m/e 390 [MH]+.
EXAMPLE 163
7- Cyclopentyl-3-(furan-2-yl)-6-(2-methyl-2H-1, 2, 4-triazol-3-ylmethoxy)-
1 2, 4-triazolo [4, 3-b]pyridazine
Prepared in an analogous procedure as outlined in Example 102b
using 2-furoic acid hydrazide and Example 102c using (2-methyl-2H-1,2,4-
triazol-3-yl)methanol to give the title compound. 1H NMR (250 MHz,
CDC13) 8 1.72 (6H, m), 2.08 (2H, m), 3.19 (1H, m), 4.04 (3H, s), 5.67 (2H, s),
6.64 (1H, m), 7.42 (1H, d, J= 3.5Hz), 7.68 (1H, d, J= 1.6Hz), 7.86 (1H, d, J
= 1Hz), 7.95 (1H, s); MS (ES+) m/e 365 [MH]+.
EXAMPLE 164
7- Cvclopentyl-3-(furan-2-yl)- 6- (1-methyl-lH-1, 2, 4-triazol-3-ylmethoxy) -
1 2 4-triazolo[4,3-blpyridazine
Prepared in an analogous procedure as outlined in Example 102b
using furoic acid hydrazide and Example 102c using (1-methyl-lH-1,2,4-
triazol-3-yl)methanol to give the title compound. 1H NMR (250 MHz,
CDC13) S 1.74 (6H, m), 2.13 (2H, m), 3.26 (1H, m), 3.95 (3H, s), 5.59 (2H, s),
6.64 (1H, m), 7.55 (1H, d, J = 3.5 Hz), 7.66 (1H, d, J = 1.4 Hz), 7.83 (1H, d,
J= 1.1 Hz), 8.06 (1H, s); MS (ES+) m/e 365 [MH]+.
EXAMPLE 165
3-(3 7-Diphenyl-1,2,4-triazolo[4,3-blpyridazin-6-yloxvmethyl)-1,2,4-triazol-
1-ylacetonitrile
The product from Example 72 Step c) (0.10 g) was suspended in
DMF (5 ml). Sodium hydride (15 mg of a 60% dispersion in mineral oil)
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was added, and the mixture stirred at room temperature for 15 min.
Chloroacetonitrile (41 l) was added, and the mixture stirred as before for
2 days. Water (25 ml) was added, and the resultant precipitate filtered off
and purified by flash chromatography (silica gel, 0 to 3% methanol in
dichloromethane). The product was recrystallised from ethyl
acetate/ethanol to yield colourless crystals (17 mg). iH NMR (360 MHz,
ds-DMSO) S 5.60 (2H, s), 5.61 (2H, s), 7.58 (6H, m), 7.76 (2H, m), 8.41 (1H,
s), 8.44 (2H, m), 8.68 (1H, s); MS (ES+) m/e 409 [MH+]. Anal. Found C,
64.62; H, 3.74; N, 26.82. C22H1sN80. 0.1 C4H802 requires C, 64.62; H, 4.06;
N, 26.87%.
EXAMPLE 166
7-(1-Methvlcyclopropyl)-6-(2-methyl-2H-1, 2, 4-triazol-3-ylmethoxy)-3-
phenvl-1.2,4-triazoloj4,3-blpyridazine
Prepared in an analogous procedure as outlined in Example 102a
using 1-methylcyclopropanoic acid, Example 102b using benzoic acid
hydrazide and Example 102c using (2-methyl-2H-1,2,4-triazol-3-
yl)methanol to give the title compound. 1H NMR (360 MHz, CDC13) 8 0.79-
0.88 (4H, m), 1.37 (3H, s), 4.02 (3H, s), 5.67 (2H, s), 7.51-7.58 (3H, m),
7.94
(2H, d, J= 4.8Hz), 8.38 (2H, d, J= 6.6Hz); MS (ES{) m/e 362 [MH+].
EXAMPLE 167
7-(1-Methylcvclopropyl)-6-(1-methyl-lH-1,2,4-triazol-3-ylmethoxy)-3-
p he nyl-1, 2, 4-tri a zolo [4 , 3-b] p yrid azine
Prepared in an analogous procedure as outlined in Example 102a
using 1-methylcyclopropanoic acid, Example 102b using benzoic acid
hydrazide and Example 102c using (1-methyl-lH-1,2,4-triazol-3-
yl)methanol to give the title compound. 'H NMR (360 MHz, CDC13) 8 0.78-
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0.90 (4H, m), 1.42 (3H, s), 3.94 (3H, s), 5.60 (2H, s), 7.46-7.58 (3H, m),
7.87
(1H, s), 8.05 (1H, s), 8.49 (2H, d, J= 6.6Hz); MS (ES+) m/e 362 [MH+].
EXAMPLE 168
3-(3-Fluorophenyl)-6-(1-methyl-lH-1, 2, 4-triazol-3-ylmethoxy)- 7-phenyl-
1, 2, 4-triazolo[4, 3-blpyridazine
This compound was prepared using procedures described in
Example 2 a), b), c), d) with 3-fluorobenzyl hydrazide being used instead of
benzoyl hydrazine in Step c) and (1-methyl-1H-1,2,4-triazol-3-yl)methanol
being used instead of 2-pyridylcarbinol in Step d). Data for the title
compound: m.p. = 250-251 C. 1H NMR (360 MHz, d6-DMSO) S 3.55 (3H, s),
5.25 (2H, s), 7.36 (3H, m), 7.42 (3H, m), 7.95 (1H, d, J= 7.2 Hz), 7.98 (1H,
d, J= 7.2 Hz), 8.12 (1H, s), 8.17 (1H, s); (ES+) m/e 402 [MH+]. Anal. Found
C, 61.66; H, 3.87; N, 23.29. C21H1sN70F + 0.5% H20 + 0.1% EtOAc
requires C, 61.64; H, 4.16; N, 23.51%.
EXAMPLE 169
7-(1-Methylcvclopentyl)-6-(3-methylpyridin-2-ylmethoxy)-3-phenvl-1,2 4-
triazolo f 4, 3-b]pyridazine
2-Hydroxymethyl-3-methylpyridine (43 mg) was dissolved in
dimethylformamide (2 ml) under N2. Sodium hydride (60% w/w in oil, 14
mg) was added followed after 5-10 minutes by 6-chloro-7-(1-methyl-
cyclopentyl)-3-phenyl-1,2,4-triazolo[4,3-b]pyridazine (100 mg). Reaction
was stirred at room temperature for 18 hours, partitioned between ethyl
acetate and water, organic phase separated, dried (MgSO4) and evaporated
to dryness. Recrystallized from ethyl acetate to give pure product. iH NMR
(360 MHz, CDC13) 5 1.30 (3H, s), 1.77 (6H, m), 1.93 (2H, m), 2.44 (3H, s),
5.62 (2H, s), 7.25 (1H, m), 7.50 (3H, m), 7.58 (1H, d, J= 7.8 Hz), 7.92 (1H,
s), 8.42 (2H, d, J= 6.4 Hz), 8.50 (1H, m), ms (ES+) m/e 400 [MH]+.
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EXAMPLE 170
6-(1-Methyl-lH-1,2,3-triazol-4-ylmethoxv)-3,7-diphenYl-1,2,4-triazolof4 3-
bipyridazine
The mixture of the title compound and the 2-methyl-2H-1,2,3-
triazol-4-yl analogue (from Example 156) was separated by preparative
HPLC using a KR100-SC18 (250 x 4.6 mm) column, eluting with 35%
MeCN/0.1% aqueous TFA at 1 ml/min. The fractions containing the
slower eluting isomer were combined and evaporated in vacuo. The
residue was partitioned between saturated aqueous NaHCO3 (30 ml) and
dichloromethane (15 ml). The aqueous layer was further extracted with
dichloromethane (2 x 15 ml), and the combined organic extracts were dried
(Na2SO4) and evaporated in vacuo. The residue was recrystallised from
CH2C12-EtOAc-hexane to give the title compound as a white solid with a
purity of >95% by HPLC; 'H NMR (360 MHz,CDC13) 8 4.05 (3H, s), 5.67
(2H, s), 7.46-7.62 (9H, m), 8.04 (1H, s), 8.51 (2H, m); MS (ES+) m/e 384
[MH]+
EXAMPLE 171
3-(5-Methylthiophen-2-yl)-6-(1-methyl-lH-1,2,4-triazol-3-ylmethoxy)-7-
p he nyl-1, 2, 4- tri a zolo [4, 3-b]p yrid azine
This compound was prepared using the procedures described in
Example 2 a), b), c), d) with 5-methylthiophene hydrazide being used
instead of benzoyl hydrazine in Step c) and (1-methyl-lH-1,2,4-triazol-3-
yl)methanol being used instead of 2-pyridylcarbinol in Step d). m.p. = 209-
210 C. 1H NMR (360 MHz, dG-DMSO) S 2.37 (3H, s), 3.66 (3H, s), 5.37 (2H,
s), 6.83-6.84 (1H, d, J= 3.6 Hz), 7.28 (3H, m), 7.52 (2H, m), 7.88-7.89 (1H,
d, J= 3.6 Hz), 8.17 (1H, s), 8.28 (1H, s); MS (ES+) m/e 404 [MH+].
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EXAMPLE 172
2-[3-(3,7-Diphenyl-1,2,4-triazolo[4,3-blpvridazin-6-yloxymethvl)-1 2 4-
triazol-l-vll-N,N-dimethylacetamide
This compound was prepared using the procedure described in
Example 165, with 2-chloro-N,1V dimethylacetamide being used instead of
chloroacetonitrile. 1H NMR (360 MHz, CDC13) S 2.99 (3H, s), 3.07 (3H, s),
4.99 (2H, s), 5.62 (2H, s), 7.50 (6H, m), 8.04 (1H, s), 8.24 (1H, s), 8.54
(2H,
m); MS (ES+) m/e 455 [MH+]. Anal. Found C, 62.83; H, 4.46; N, 24.31.
C24H22N802. 0.25 H20 requires C, 62.80; H, 4.94; N, 24.41%.
EXAMPLE 173
3,7-Diphenyl-6-[l-(pyridin-2-ylmethyl)-1H-1,2,4-triazol-3-vlmethoxvl-1 2 4-
triazolo[4,3-blpyridazine
This compound was prepared using the procedure described in
Example 165, with 2-picolyl chloride being used instead of
chloroacetonitrile. 1H NMR (360 MHz, CDC13) S 5.42 (2H, s), 5.63 (2H, s),
7.08 (1H, d, J= 7.8 Hz), 7.21 (1H, m), 7.51 (7H, m), 7.68 (2H, m), 8.03 (1H,
s), 8.24 (1H, s), 8.51 (3H, m); MS (ES+) m/e 461 [MH+]. Anal. Found C,
67.23; H, 4.22; N, 23.75. C26H2oN80. 0.1 C4H802 requires C, 67.57; H, 4.47;
N, 23.88%.
EXAMPLE 174
6-(1-Benzvl-lH-1,2.4-triazol-3-vlmethoxy)-3,7-diphenyl-1,2 4-triazolol4 3-
b1pyridazine
This compound was prepared using the procedure described in
Example 165, with benzyl bromide being used instead of
chloroacetonitrile. 1H NMR (360 MHz, CDC13) 8 5.30 (2H, s), 5.62 (2H, s),
7.22 (211, m), 7.33 (3H, m), 7.50 (6H, m), 7.68 (2H, m), 8.03 (1H, s), 8.04
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(1H, s), 8.53 (2H, m); MS (ES+) m/e 460 [MH+]. Anal. Found C, 70.40; H,
4.20; N, 21.40. C27H21N70 requires C, 70.57; H, 4.61; N, 21.34%.
EXAMPLE 175
2-(5-(3,7-Diphenyl-1,2,4-triazolo[4,3-b)pyridazin-6-ylommethyl -1 2 4-
triazol-1-yl] acetamide
This compound was prepared using the procedure described in
Example 165, with iodoacetamide being used instead of chloroacetonitrile.
'H NMR (400 MHz, CDC13 + dc-DMSO) S 4.82 (2H, s), 5.74 (2H, s), 6.55
(1H, br s), 7.18 (1H, br s), 7.54 (8H, m), 7.90 (1H, s), 8.06 (1H, s), 8.39
(2H,
m); MS (ES}) m/e 427 [MH+].
EXAMPLE 176
N-f2-f3-(3,7-Diphenyl-1,2,4-triazolo[4,3-b]pyridazin-6-yloxymethyl)-1,2 4-
triazol-1-yllethyll-N,N-dimethylamine
The product from Example 72 Step c) (0:10 g) was suspended in
THF (5 ml). Triphenylphosphine (71 mg), N,N-dimethylethanolamine (30
l) and diethylazodicarboxylate (43 l) were added, and the mixture was
stirred at room temperature for 24 h. More triphenylphosphine (71 mg)
and diethylazodicarboxylate (43 l) were added, and the mixture was
stirred as before for 24 h. Water (50 ml) was added, and the resultant
solution was acidified (pH - 1) with 5 N hydrochloric acid. The solution
was washed with dichloromethane (3 x 25 ml), basified with 4 N sodium
hydroxide (pH - 14), and extracted again with dichloromethane (3 x 25
ml). The organic layers from the second extraction were combined, dried
(magnesium sulfate) and concentrated in vacuo. The residue was purified
by flash chromatography (silica gel, 0 to 9% methanol in dichloromethane)
and recrystallised from ethyl acetate/hexane to yield colourless crystals
(33 mg). 1H NMR (360 MHz, CDC13) 8 2.22 (6H, s), 2.70 (2H, t, J= 6.2 Hz),
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4.21 (2H, t, J= 6.2 Hz), 5.61 (2H, s), 7.52 (6H, m), 8.04 (1H, s), 8.16 (1H,
s), 8.55 (2H, m); MS (ES+) m/e 441 [MH+]. Anal. Found C, 64.97; H, 5.22;
N, 25.06. C24H24N80 requires C, 65.44; H, 5.49; N, 25.44%.
EXAMPLE 177
3, 7-Diphenyl-6-(pyrimidin-5-ylmethoxy)-1-2, 4-triazolo [4, 3-b]pyridazine
a) 5-Bromomethylpyrimidine
5-Methylpyrimidine (3.0 g), N-bromosuccinimide (7.1 g) and benzoyl
peroxide (63 mg) were heated together at reflux in carbon tetrachloride
(480 ml) under irradiation from a 60 W light bulb for 2 h. The slurry was
allowed to cool to room temperature, and filtered. The filtrate was washed
with 10% sodium bicarbonate solution (2 x 250 ml), dried (magnesium
sulfate) and concentrated in vacuo to yield an orange solid - this was a
mixture of 5-bromomethylpyrimidine and 5-dibromomethylpyrimidine,
present in a 3:2 ratio respectively (4.2 g). This material was used in the
next step without further purification. 1H NMR (250 MHz, ds-DMSO) S
4.98 (2H, s), 9.30 (2H, s), 9.43 (1H, s); MS (ES+) m/e 172, 174 (1:1 ratio)
[MH+J.
b) 3,7-Diphen 1-(pyrimidin-5-ylmethoxy)-1,2,4-triazolo[4,3-
bjpvridazine
This compound was prepared using the procedures described in
Example 79 a) and b), with 5-bromomethylpyrimidine being used instead
of bromoacetonitrile in Step b). 'H NMR (360 MHz, CDCla) S 5.56 (2H, s),
7.56 (8H, m), 8.07 (1H, s), 8.38 (2H, m), 8.82 (2H, s), 9.22 (1H, s); MS (ES+)
m/e 381 [MH+].
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EXAMPLE 178
6- f 1-(2-(Morpholin-4-yl)-ethyl)-1H-1,2, 4-triazol-3-ylmethoxyl-3. 7-diphenyl-
1.2, 4-triazolo [4, 3-bjpyridazine
This compound was prepared using the procedure described in
Example 176, with 4-(2-hydroxyethyl)moi.-pholine being used instead of
N,N-dimethylethanolamine. 1H NMR (400 MHz, CDC13) S 2.41 (4H, t, J
4.6 Hz), 2.75 (2H, t, J= 6.2 Hz), 3.63 (4H, t, J= 4.6 Hz), 4.23 (2H, t, J=
6.2 Hz), 5.61 (2H, s), 7.51 (6H, m), 7.69 (2H, m), 8.05 (1H, s), 8.17 (1H, s),
8.55 (2H, m); MS (ES+) m/e 483 [MH+].
EXAMPLE 179
6-(2-Methvl-2H-1, 2, 4-triazol-3-ylmethoxy)-3-phenyl-7-(pyrrolidin-1-yl)-
1,2, 4-triazolo[4, 3-b]pyridazine
a) 6-Chloro-3-phenyl-7-(pyrrolidin-l-yl)-1,2,4-triazolof4,3-bjpyridazine
This compound was prepared using the procedures described in
Example 15 Steps a, b, c, d with pyrrolidine being used in Step c.
b) 6-(2-Methyl-2H-1.2,4-triazol-3-vlmethoxy)-3-phenyl-7-(pyrrolidin-l-
vl)-1, 2, 4-triazolol4, 3-b]pyridazine
To a solution of 6-chloro-3-phenyl-7-(pyrrolidin-l-yl)-1,2,4-
triazolo[4,3-b]pyridazine (100 mg, 0.33 mmol) and 3-hydroxymethyl-2-
methyl-1,2,4-triazole in dry DMF (5 ml) was added sodium hydride (60%
dispersion in oil, 20 mg, 0.36 mmol). The mixture was stirred at room
temperature for 2 hours. The reaction mixture was diluted with water (50
ml) and extracted with dichloromethane (3 x 25 ml). The combined
extracts were washed with brine, dried over magnesium sulphate, filtered
and evaporated. The solid was triturated with methanol, and collected by
filtration to afford the title pyridazine (68 mg, 55%). 1H NMR (360 MHz,
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CDC13) S 1.93-1.97 (4H, m), 3.41-3.45 (4H, m), 4.00 (3H, s), 5.58 (2H, s),
6.66 (1H, s), 7.43-7.53 (3H, m), 7.94 (1H, s), 8.28 (2H, d, J= 8.3 Hz). MS
(ES+) 377 [MHJ+.
EXAMPLE 180
7-(5-Chlorothiophen-2-yl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-3-
phenyl-1, 2,4-triazolo f 4, 3-blpyridazine
This compound was prepared using the procedures described in
Example 16 Steps a), b) and c) except 5-chloro-2-thiophene boronic acid
was used instead of 4-pyridyl boronic acid, di-lithium salt in Step a), 1.1
equivalents of triethylamine hydrochloride was used in Step b) instead of
1.1 equivalents of p-toluenesulphonic acid and triethylamine, and 3-
hydroxymethyl-2-methyl-1,2,4-triazole (Example 65) was used in Step c)
instead of 2-pyridylcarbinol. Data for the title compound: m.p. 244-247 C
(EtOAc). 'H NMR (360 MHz, d6-DMSO) S 3.95 (3H, s), 5.82 (2H, s), 7.30
(1H, d, J= 4 Hz), 7.55-7.65 (3H, m), 7.93 (1H, d, J= 4 Hz), 8.03 (1H, s),
8.41 (2H, d, J= 7 Hz), 8.88 (1H, s). MS (ES+) 424 [MH]+. Anal. Found C,
53.01; H, 3.37. C19H14N7C1OS.-0.35H20 requires C, 53.05; H, 3.44%.
EXAMPLE 181
7-(5-Chlorothiophen-2-yl)-6-(1-methyl-lH-1, 2, 4-triazol-3-ylmethoxy)-3-
phenyl-1, 2, 4-triazolo (4, 3-b]pyridazine
This compound was prepared using the procedures described in
Example 16 Steps a), b) and c) except 5-chloro-2-thiophene boronic acid
was used instead of 4-pyridyl boronic acid, di-lithium salt in Step a), 1.1
equivalents of triethylamine hydrochloride was used in Step b) instead of
1.1 equivalents of p-toluenesulphonic acid and triethylamine, and 3-
hydroxymethyl-l-methyl-1,2,4-triazole (Example 65) was used in Step c)
instead of 2-pyridylcarbinol. Data for the title compound: m.p. 248-250 C
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(EtOAc). 1H NMR (360 MHz, de-DMSO) S 3.89 (3H, s), 5.64 (2H, s), 7.29
(1H, d, J= 4 Hz), 7.56-7.62 (3H, m), 7.93 (1H, d, J= 4 Hz), 8.45 (2H, d, J=
7 Hz), 8.54 (1H, s), 8.83 (1H, s). MS (ES+) 424 [MH]+. Anal. Found C,
53.56; H, 3.36. Ci9Hi4N7C1OS. 0.1H20 requires C, 53.61; H, 3.36%.
EXAMPLE 182
6-(1H-Benzimidazol-2-ylmethoxv)-3-(2, 4-difluorophenyl)-7-(1-
methylcyclopentyl)-1,2,4-triazolof 4,3-b]pvridazine
2-(Hydroxymethyl)benzimidazole (39 mg) was dissolved in
dimethylformamide (2 ml) under N2. Sodium hydride (60% w/w in oil, 11
mg) was added followed after 5-10 minutes by 6-chloro-7-(1-methyl-
cyclopentyl)-3-phenyl-1,2,4-triazolo[3,4-b]pyridazine (80 mg). Reaction
was stirred at room temperature for 18 hours, partitioned between ethyl
acetate and water, organic phase separated, dried (MgSO4) and evaporated
to dryness. Chromatography on silica eluting with ethyl acetate gave pure
product. 'H NMR (500 MHz, CDC13) S 1.33 (3H, s), 1.67 (4H, m), 1.80 (2H,
m), 1.93 (2H, m), 5.69 (2H, s), 7.04 (1H, m), 7.13 (1H, m), 7.31 (2H, m),
7.40 (1H, m), 7.79 (1H, m), 7.88 (1H, m), 7.96 (1H, s); ms (ES+) m/e 461
[MH]+.
EXAMPLE 183
3-(Furan-3-Yl)-6-(2-pyridyl)meth_yloxy-7,8,9,10-tetrahydro-1,2,4-
triazoloL3,4-alphthalazine
a) 2,3,5,6,7,8-Hexahydrophthalazine-l,4-dione
3,4,5,6-Tetrahydrophthalic anhydride (25 g, 0.164 mol) was
dissolved in 40% aqueous acetic acid (500 ml) with sodium acetate
trihydrate (26.8 g, 0.197 mol) and hydrazine hydrate (9.58 ml, 0.197 mol).
The reaction mixture was heated under reflux overnight and then allowed
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to cool. The resulting solid was collected by filtration, washed with water
and diethyl ether and dried iia vacuo to give the title-product (23 g, 84%),
'H NMR (250 MHz, ds-DMSO) S 1.64 (4H, br s, 2 of CH2), 2.34 (4H, br s, 2
of CH2), 11.30 (2H, br s, 2 of NH); MS (ES-*) m/e 167 [MH]+.
b) 1,4-Dichloro-5,6,7,8-tetrahydrophthalazine
The preceding dione (23 g, 0.14 mol) was dissolved in phosphorus
oxychloride (200 ml) and heated at reflux overnight. The solvent was
evaporated in vacuo and azeotroped with toluene. The residue was
dissolved in dichloromethane (200 ml), stirred rapidly and saturated
sodium bicarbonate solution (200 ml) added slowly. Solid sodium
bicarbonate was added cautiously until effervescence ceased and the
mixture then partitioned between dichloromethane and water. The
organic layer was separated, dried (MgSO4) and evaporated in vacuo. The
residue was triturated with diethyl ether and dried in vacuo to give the
title-product (25.8 g, 92%), 'H NMR (250MHz, CDC13) S 1.84-1.90 (4H, m,
2 of CH2), 2.72-2.78 (4H, m, 2 of CH2).
c) 1-Chloro-4-hydrazino-5,6,7,8-tetrahydrophthalazine
A mixture of the preceding product (18.3 g, 0.090 mol) and
hydrazine monohydrate (13.6 ml, 0.28 mol) in ethanol (280 ml) was heated
at reflux overnight. The mixture was cooled to room temperature and the
resulting precipitate filtered off. The filtrate was evaporated in vacuo to
give the title-product (14.86 g, 83%), 'H NMR (250MHz, CDC13/d6-DMSO)
S 1.79-1.92 (4H, m, 2 of CH2), 2.59-2.65 (2H, m, CHz), 2.73-2.78 (2H, m,
CH2).
d) 6-Chloro-3-(furan-3-yl)-7.8,9,10-tetrahydro-1,2,4-triazolo(3 4-
a]phthalazine
1,1'-Carbonyldiimidazole (0.98 g, 6.1 mmol) was added to a stirred
mixture of 3-furoic acid (0.68 g, 6.1 mmol) in THF (30 ml). The mixture
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was stirred for 0.75h before adding the preceding hydrazine (1.0 g, 5.1
mmol). After 4h at room temperature, the solvent was evaporated
in vacuo, water added and the mixture stirred for 0.5h. The resultant
solid was collected by filtration, washed with water and hexane and dried
in vacuo to give the ketohydrazine. A mixture of the ketohydrazine (0.80
g) and triethylamine hydrochloride (0.10 g, 0.73 mmol) in xylene (10 ml)
was heated at reflux overnight. The solution was cooled to room
temperature and the solvent removed in vacuo. The residue was
chromatographed on silica gel, eluting with 5%
methanol/dichloromethane, to give the title-phthalazine (0.21 g), 'H NMR
(250MHz, CDC13) S 1.90-2.02 (4H, m, 2 of CH2), 2.74-2.80 (2H, m, CH2),
3.16-3.24 (2H, m, CH2), 7.28 (1H, m, Ar-H), 7.58 (1H, t, J=1.7Hz, Ar-H),
8.53 (1H, m, Ar-H).
e) 3-(Furan-3-yl)-6-(2-pyridyl)methtiloxy-7,8,9,10-tetrahvdro-1,2.4-
triazolo f 3, 4-a]p hthalazine
Sodium hydride (55 mg of a 60% dispersion in oil, 1.4 mmol) was
added to a solution of 2-pyridylcarbinol (160 mg, 1.46 mmol) in DMF
(10 ml) and the mixture was stirred at room temperature for 0.5h. After
this time, the preceding product (100 mg, 0.365 mmol) was added and the
reaction mixture stirred at room temperature for 3h before being poured
into water. The mixture was extracted with ethyl acetate (x3) and the
combined extracts washed with water (xl) and brine (xl), dried (Na2SO4)
and evaporated in vacuo. The resultant solid was washed with ethyl
acetate to give the title-cornpound, 'H NMR (250MHz, CDC13) S 1.92-2.02
(4H, m, 2 of CH2), 2.72-2.78 (2H, m, CH2), 3.12-3.16 (2H, m, CH2), 5.60
(2H, s, CH2), 7.24 (1H, m, Ar-H), 7.31 (1H, m, Ar-H), 7.51-7.57 (2H, m, Ar-
H), 7.79 (1H, m, Ar-H), 8.44 (1H, m, Ar-H), 8.64 (1H, m, Ar-H); MS (ES+)
m/e 348 (MH)+; Anal. Found C, 62.84; H, 4.98; N, 18.99. C19H17N.502.
0.9H20 requires C, 62.77; H, 5.21; N, 19.26%.
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EXAMPLE 184
7-CYclobutvl-3-phenyl-6-(prop-2-ynyloxy)-1, 2, 4-triazolo [4, 3-b]pyridazine
To a stirred solution of propargyl alcohol (47 mg, 0.84 mmol) in
DMF (2 ml) was added 60% sodium hydride suspension in oil (31 mg, 0.77
mmol). Left to stir for 5 minutes prior to the addition of 6-chloro-
7-cyclobutyl-3-phenyl-1,2,4-triazolo[4,3-b]pyridazine (200 mg, 0.70 mmol).
Left to stir for 90 minutes. Quenched (H20), extracted (ethyl acetate),
washed (H20, brine), dried (MgSO4) and evaporated in vacuo. The residue
was purified via silica gel chromatography using 50/50 ethyl
acetate/hexane to elute. The title compound was obtained as a white solid.
'H NMR (250 MHz, CDC13) S 2.19-2.26 (1H, m), 2.37-2.55 (3H, m), 2.69-
2.80 (2H, m), 2.90 (1H, m), 3.97 (1H, m), 5.35 (2H, d, J = 2.4 Hz), 7.77-7.89
(3H, m), 8.13 (1H, s), 8.80 (1H, s), 8.86 (1H, s). Mass spec. ES+ (M+1) _
305.
EXAMPLE 185
(7-Cyclobutyl-3-phenyl-1, 2, 4-triazolo [4, 3-b]pyridazin-6-yloxy)acetonitrile
a) 7-Cyclobutyl-3 phenyl-1,2,4-triazolo[4,3-b]pyridazin-6-one
6-Chloro-7-cyclobutyl-3-phenyl-1, 2, 4-triazolo [4, 3-b]pyridazine (2.0 g,
7.0 mmol), 2N NaOH (50 ml) and 1,4-dioxane (10 mi) were heated at
reflux for 16 hours. Cooled and water (150 ml) added. Precipitate filtered,
suspended in H20, acidified (2N HC1), filtered and dried to give a white
solid. iH NMR (250 MHz, CDC13) 5 1.89-2.02 (1H, m), 2.08-2.25 (3H, m),
2.36-2.48 (1H, m), 3.56-3.70 (1H, m), 7.48-7.60 (3H, m), 7.88 (1H, s), 8.38
(1H, m). Mass spec ES+ (M+1) = 267.
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b) (7-Cyclobutyl-3-phenyl-1,2,4-triazoloj4 3-b]pyridazin-6-yloxy)-
acetonitrile
The foregoing product (300 mg, 1.13 mmol), bromoacetonitrile (200
mg, 1.69 mmol) and 60% sodium hydride suspension in oil (54 mg,
1.35 mmol) were stirred together in DMF for 90 minutes. Quenched
(H20), extracted (ethyl acetate), washed (H20, brine), dried (MgSO4) and
evaporated in vacuo. Purified via silica gel chromatography using 50/50
ethyl acetate/hexane to elute. The title compound was obtained as a white
solid. 1H NMR (250 MHz, CDC13) S 1.95 (1H, m), 2.15-2.19 (3H, m), 2.41-
2.47 (2H, m), 3.61-3.65 (1H, m), 5.09 (2H, s), 7.49-7.59 (3H, m), 7.89
(1H, s), 8.39 (2H, m). Mass spec ES+ (M+1) = 306.
EXAMPLE 186
N-f4-(7-Cyclobutyl-3-phenvl-1,2,4-triazolof4,3-b]pyridazin-6-yloxv)but-2-
ynyl] -1V, N-dimethylamine
a) 6-(4-Chlorobut-2-ynvloxy)-7-cyclobutyl-3;phenyl-1 2 4-
triazolo j4, 3-b]pyridazine
Potassium carbonate (311 mg, 2.2 mmol) and 1,4 dichloro-2-butyne
(275 mg, 2.2 mol) in DMF (3 ml) were heated to 50 C prior to the dropwise
addition of the product from Example 185, Step a (200 mg, 0.75 mmol) in
DMF (2 ml). The reaction mixture was left to stir for 2 hours. Cooled and
partitioned (ethyl acetate/water). The organic layer was washed (H20,
brine), dried (MgSO4) and evaporated in vacuo. Purified via silica gel
chromatography using 50/50 ethyl acetate/hexane to elute. 'H NMR (250
MHz, CDC13) 5 1.93 (1H, m), 2.11-2.16 (3H, m), 2.42 (2H, m), 4.2 (2H, m),
5.10 (2H, m), 7.50-7.59 (3H, m), 7.84 (1H, s), 8.47 (2H, m).
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b) N[4-(7-Cyclobutyl-3-phenyl-1,2,4-triazolo[4,3-b]pyridazin-6-yloxy)-
b ut-2-ynyll -N, N-dimethylamine
The foregoing product (40 mg, 0.114 mmol) and dimethylamine
(1 ml) in 1,4-dioxane (4 ml) were heated in a sealed tube at 50 C for 60
minutes. Evaporated in vacuo. Purified via silica gel chromatography
using 50/50 ethyl acetate/hexane to elute. The title compound was
obtained as a white solid. 1H NMR (360 MHz, CDC13) S 1.93 (1H, m), 2.14
(3H, m), 2.25 (6H, s), 2.43 (2H, m), 3.30 (2H, s), 3.66 (1H, m), 5.09 (2H, s),
7.48-7.55 (3H, m), 7.82 (1H, s), 8.49 (2H, m).
EXAMPLE 187
2-[3-(3 7-Diphenyl-1,2,4-triazolof4,3-blpyridazin-6-yloxymethyl)-1,2,4-
triazol-l-yll ethylamine
This compound was prepared using the procedure described in
Example 176, with ethanolamine being used instead of N,N-
dimethylethanolamine. 1H NMR (500 MHz, CDC13 + DMSO) S 3.12 (2H, t,
J = 5.7 Hz), 4.23 (2H, t, J = 5.8 Hz), 5.62 (2H, s), 7.54 (6H, m), 7.72 (2H,
d,
J= 7.9 Hz), 8.07 (1H, s), 8.29 (s, 1H), 8.53 (2H, d, J= 7.4 Hz); MS (ES+)
m/e 413 [MH+].
EXAMPLE 188
3 7-Diphenyl-6-f 1-(2-(pyrrolidin-l-yl)ethvl)-1H-1,2,4-triazol-3-vlmethoxyl-
1 2 4-triazolo[4,3-b]pyridazine
This compound was prepared using the procedure described in
Example 176, with 1-(2-hydroxyethyl)pyrrolidine being used instead of
N,N-dimethylethanolamine. 1H NMR (400 MHz, CDC13) 8 1.73 (6H, m),
2,47 (4H, s), 2.91 (2H, t, J= 6.4 Hz), 4.27 (2H, t, J= 6.4 Hz), 5.62 (2H, s),
7.50 (6H, m), 7.69 (2H, m), 8.04 (1H, s), 8.17 (1H, s), 8.55 (2H, m); MS
(ES+) m/e 467 [MH+].
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EXA.MPLE 189
6-[1-(1-Methylpiperidin-4-vl)-1H-1,2,4-triazol-3-ylmethoxy]-3, 7-diphenyl-
1, 2, 4-triazolo j4, 3-blpyridazine
This compound was prepared using the procedure described in
Example 176, with 4-hydroxy-l-methylpiperidine being used instead of
N,N-dimethylethanolamine. 1H NMR (400 MHz, CDC13) 5 2.07 (6H, m),
2.33 (3H, s), 2.96 (2H, m), 4.13 (1H, m), 5.61 (2H, s), 7.50 (6H, m), 7.70
(2H, m), 8.04 (1H, s), 8.09 (1H, s), 8.53 (2H, m); MS (ES+) m/e 467 [MH+].
EXAMPLE 190
3, 7-Diphenyl-6- f 1-(2-(piperazin-1-yl)ethyl)-1H-1, 2, 4-triazol-3-ylmethoxyl-
1, 2, 4-triazolo (4, 3-b]pyridazine
This compound was prepared using the procedure described in
Example 176, with 1-(2-hydroxyethyl)piperazine being used instead of
N,N-dimethylethanolamine. 1H NMR (400 MHz, CDC13) b 2.52 (4H, s),
2.77 (2H, t, J= 6.0 Hz), 2.92 (4H, s), 4.22 (2H, t, J= 5.9 Hz), 5.61 (2H, s),
7.52 (6H, m), 7.69 (2H, m), 8.05 (1H, s), 8.15 (1H, s), 8.54 (2H, m); MS
(ES) m/e 482 [MH+].
EXAMPLE 191
7-(1-Meth l~vclopentyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxv)-3-(2 4-
difluorophenyl)-1,2,4-triazolo[4, 3-blpyridazine
Prepared in an analogous procedure as outlined in Example 102a
using 1-methylcyclopentanoic acid, Example 102b using 2,4-
difluorobenzoic acid hydrazide and Example 102c using 3-hydroxymethyl-
2-methyl-2H-1,2,4-triazole to give the title compound. 'H NMR (250 MHz,
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CDC13) S 1.30 (3H, s), 1.68-1.94 (8H, m), 3.88 (3H, s), 5.50 (2H, s), 6.99-
7.14 (2H, m), 7.82-7.95 (3H, m), ms (ES+) m/e 426 [MH]+.
EXAMPLE 192
7-(Cyclobut-l-envl)-6-(2-methyl-2H-1,2, 4-triazol-3-ylmethoxy)-3-phenyl-
1 2 4-triazoloL,3-b]pyridazine
Prepared in an analogous procedure to that outlined in Example
102 using 1-fluorocyclobutanecarboxylic acid (E. D. Bergmann and S.
Szinai, J. Chem. Soc., 1956, 1521) instead of cyclopentanecarboxylic acid
in Step (a), benzoic acid hydrazide instead of 2-thiophene carboxylic acid
hydrazide in Step (b), and (2-methyl-2H-1,2,4-triazol-3-yl)methanol
instead of 2-hydroxymethylpyridine in Step (c) to give the title compound
in 48% yield. 1H NMR (360 MHz, CDC13) S 2.63 (2H, br s), 2.89-2.87 (2H,
m), 3.97 (3H, s), 5.66 (2H, s), 6.54 (1H, s), 7.58-7.51 (3H, s), 7.78 (1H, s),
7.95 (1H, s), 8.40-8.38 (2H, m). MS (ES+) m/e 360 [MH]+.
EXAMPLE 193
7-(Furan-3-yl)-6-(1-methyl-lH-1,2,4-triazol-3-ylmethoxy)-3-phenyl-1,2.4-
triazolo[4 3-bjpyridazine
This compound was prepared using procedures described in
Example 139 with 3-furan boronic acid (J. Heterocycl. Chein., 1975, 12,
195-196) being used instead of 2-thiophene boronic acid, m.p. 241 C. 'H
NMR (360MHz, CDC13) 8 3.90 (3H, s), 5.62 (2H, s), 7.37 (1H, d, J = 1.8 Hz),
7.53-7.64 (3H, m), 7.85 (1H, t, J = 1.8 Hz), 8.46 (3H, m), 8.48 (1H, s), 8.67
(1H, s); MS (ES+) m/e 374 [MH+]. Anal. Found C, 60.96; H, 4.06; N, 25.94.
C19H15N702 requires C, 61.12; H, 4.05; N, 26.26%.
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EXAMPLE 194
N,N-Diethyl-N-[6-(1-methvl-lH-1,2,4-triazol-3-ylmethoxv)-3-phenyl-1 2 4-
triazolo [4, 3-b]pyridazin-7-yll amine
a) N-(6-Chloro-3-phenyl-1.2,4-triazolo[4,3-blpyridazin-7-yl)-N N-
diethylamine
This compound was prepared using the procedures described in
Example 15, Steps a, b, c and d with diethylamine being used in Step c.
b) N,N-Diethyl-N-[6-(1-methyl-lH-1,2,4-triazol-3-ylmethoxy)-3=phenvl-
1, 2, 4-triazolo [4, 3-bjpyridazin-7-yl] amine
To a solution of N-(6-chloro-3-phenyl-1,2,4-triazolo[4,3-b]pyridazin-
7-yl)-N,N-diethylamine (180 mg, 0.33 mmol) and (1-methyl-lH-1,2,4-
triazol-3-yl)methanol (68 mg) in dry DMF (5 ml) was added sodium
hydride (60% dispersion in oil, 34 mg, 0.36 mmol). The mixture was
stirred at room temperature for 3 hours. The reaction mixture was diluted
with water (50 ml) and extracted with dichloromethane (3 x 25 ml). The
combined extracts were washed with brine, dried over magnesium
sulphate, filtered and evaporated. The solid was recrystallised from ethyl
acetate, and collected by filtration to afford the title pyridazine (81 mg,
36%). 1H NMR (500 MHz, DMSO-d6) S 1.08 (6H, t, J = 8.5 Hz), 3.31 (4H, q,
J= 8.5 Hz), 3.87 (3H, s), 5.50 (2H, s), 7.22 (1H, s), 7.47-7.59 (3H, m), 8.37
(2H, d, J= 8.5 Hz), 8.51 (1H, s). MS (ES+) 379 [MH]+.
EXAMPLE 195
7-(1-Methylcyclopentyl)-6-(1-methyl-lH-1,2,4-triazol-3-vlmethoxy)-3-(2.4-
difluorophenyl)-1, 2, 4-triazolo [4, 3-b]pyridazine
Prepared in an analogous procedure as outlined in Example 102a
using 1-methylcyclopentanoic acid, Example 102b using 2,4-
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difluorobenzoic acid hydrazide and Example 102c using 3-hydroxymethyl-
1-methyl-1HT 1,2,4-triazole to give the title compound. 1H NMR (250 MHz,
CDC13) 8 1.33 (3H, s), 1.58-2.00 (8H, m), 3.93 (3H, s), 5.43 (2H, s), 6.96-
7.14 (2H, m), 7.92-8.05 (3H, m), ms (ES+) m/e 426 [MH]+.
EXAMPLE 196
7-(1,1-Dimethylpropyl)-6-(1-methyl-lH-1, 2,4-triazol-3-ylmethoxy)-3-
phenyl-1, 2, 4-triazolo j4, 3-b]pyridazine
The compound was prepared using the procedures described in
Example 89, Steps a), b) and c) with 2,2-dimethylbutyric acid being used
instead of cyclohexanecarboxylic acid in Step c). Data for the title
compound: 1H NMR (360 MHz, CDC13) 5 0.70 (3H, t, J= 7.5 Hz), 1.41 (6H,
s), 1.89 (2H, q, J= 7.5 Hz), 3.94 (3H, s), 5.58 (2H, s), 7.46-7.56 (3H, m),
7.90 (1H, s), 8.06 (1H, s), 8.51 (2H, d, J= 8.0 Hz); MS (ES+) m/e 378 [MH]+.
Anal. Found C, 63.48; H, 6.19; N, 25.55. C2oH23N701 requires C, 63.34; H,
6.17; N, 25.85%.
EXAMPLE 197
6-(2-Methyl-2H-1, 2,4-triazol-3-ylmethoxy)-3-(4-fluorophenyl)-7-(thiophen-
3-yl)-1, 2, 4-triazolo f 4, 3-b]pyridazine
This compound was prepared using the procedures described in
Example 16, Steps a), b) and c) except that 3-thiophene boronic acid was
used instead of 4-pyridyl boronic acid, di-lithium salt in Step a), 1.1
equivalents of 4-fluorobenzhydrazide and triethylamine hydrochloride
were used in Step b) instead of 1.1 equivalents of benzhydrazide,
p-toluenesulphonic acid and triethylamine, and (2-methyl-2H-1,2,4-triazol-
3-yl)methanol (Example 66) was used in Step c) instead of 2-
pyridylcarbinol. Data for the title compound: m.p. 268-269 C (MeOH). 'H
NMR (360 MHz, DMSO) 8 3.92 (3H, s), 5.79 (2H, s), 7.46 (2H, t, J= 9 Hz),
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7.70-7.74 (2H, m), 8.01 (1H, s), 8.19-8.21 (1H, m), 8.45-8.49 (2H, m), 8.68
(1H, s). MS (ES+) 408 [MH]+. Anal. Found C, 55.90; H, 3.44; N, 24.02.
Ci9Hi4N7FOS requires C, 56.01; H, 3.46; N, 24.07%.
EXAMPLE 198
6-(1-Methyl-lH-1,2, 4-triazol-3-ylmethoxv)-3-(4-fluorophenyl)- 7-(thiophen-
3-yl)-1, 2, 4-triazolo f 4, 3-b]pyridazine
This compound was prepared using the procedures described in
Example 16, Steps a), b) and c) except that 3-thiophene boronic acid was
used instead of 4-pyridyl boronic acid, di-lithium salt in Step a), 1.1
equivalents of 4-fluorobenzhydrazide and triethylamine hydrochloride
were used in Step b) instead of 1.1 equivalents of benzhydrazide,
p-toluenesulphonic acid and triethylamine, and (1-methyl-lH-1,2,4-triazol-
3-yl)methanol (Example 65) was used in Step c) instead of 2-
pyridylcarbinol. Data for the title compound: m.p. 254-255 C (MeOH). 'H
NMR (360 MHz, DMSO) S 3.89 (3H, s), 5.61 (2H, s), 7.46 (2H, t, J= 9 Hz),
7.71 (1H, dd, J= 5, 3 Hz), 7.80 (1H, dd, J= 5, 1 Hz), 8.28-8.29 (1H, m),
8.51-8.56 (3H, m), 8.67 (1H, s). MS (ES+) 408 [MH]+. Anal. Found C, 55.88;
H, 3.40; N, 23.98. Ci9H14N7FOS requires C, 56.01; H, 3.46; N, 24.07%.
EXAMPLE 199
6-(2-Methyl-2H-1, 2, 4-triazol-3-vlmethoxy)-3- (2-fluorophenyl)- 7-(thiophen-
3-yl)-1,2,4-triazolof4,3-b]pyridazineØ6(H drate)
This compound was prepared using the procedures described in
Example 16, Steps a), b) and c) except that 3-thiophene boronic acid was
used instead of 4-pyridyl boronic acid, di-lithium salt in Step a), 1.1
equivalents of 2-fluorobenzhydrazide and triethylamine hydrochloride
were used in Step b) instead of 1.1 equivalents of benzhydrazide,
p-toluenesulphonic acid and triethylamine, and (2-methyl-2H-1,2,4-triazol-
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3-yl)methanol (Example 66) was used in Step c) instead of 2-
pyridylcarbinol. Data for the title compound: m.p. 175-176 C (MeOH). 'H
NMR (360 MHz, DMSO) S 3.81 (3H, s), 5.66 (2H, s), 7.48-7.59 (2H, m),
7.70-7.80 (3H, m), 7.96-8.02 (2H, m), 8.24 (1H, dd, J= 4, 3 Hz), 8.75 (1H,
s). MS (ES+) 408 (MH]+. Anal. Found C, 54.58; H, 3.94. C19H14N7FOS. 0.6
H20 requires C, 54.56; H, 3.66%.
EXAMPLE 200
3-(2-Fluorophenyl)-7-(1-methvlcyclobutyl)-6-(2-methvl-2H-1,2,4-triazol-3-
ylmethoxy)-1, 2, 4-triazolo j4, 3-blpyridazine
The compound was prepared using the procedures described in
Example 102, Steps a), b) and c) with 1-methylcvclobutane carboxylic acid
(US patent 4,220,795) being used instead of cvclopentane carboxylic acid
in Step a), and 2-fluorobenzhydrazide being used instead of 2-thiophene
carboxylic acid hydrazide in Step b), and (2-methvl-2H-1,2,4-triazol-3-
yl)methanol (prepared using the conditions described in EP-A-421210)
being used instead of 2-hydroxymethylpyridine in Step c). Data for the
title compound: 'H NMR (360 MHz, CDC13) S 1.51 (3H, s), 1.80-1.90 (1H,
m), 2.04-2.24 (3H, m), 2.35-2.46 (2H, m), 3.82 (3H, s), 5.47 (2H, s), 7.27
(1H, br t, J= 7.5 Hz), 7.34 (1H, br t, J= 7.5 Hz), 7.53-7.60 (1H, m), 7.73
(1H, s), 7.85 (1H, br t, J= 7.5 Hz), 7.88 (1H, s); 21S (ES+) m/e 394 [MH]+.
Anal. Found C, 61.16; H, 5.14; N, 24.90. C2oH2(N7OF requires C, 61.06; H,
5.12; N, 24.92%.
EXAMPLE 201
3-(2-Fluorophenyl)-7-(1-methylc_yclobutyl)-6-(1- methyl-lH-1,2,4-triazol-3-
ylmethoxy)-1, 2,4-triazolo (4, 3-b]pyridazine
The compound was prepared using the procedures described in
Example 102, Steps a), b) and c) with 1-methylcvclobutane carboxylic acid
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(US patent 4,220,795) being used instead of cyclopentane carboxylic acid
in Step a), and 2-fluorobenzhydrazide being used instead of 2-thiophene
carboxylic acid hydrazide in Step b), and (1-methyl-lH-1,2,4-triazol-3-
yl)methanol (prepared using the conditions described in EP-A-421210)
being used instead of 2-hydroxymethylpyridine in Step c). Data for the
title compound: 1H NMR (360 MHz, CDC13) 8 1.54 (3H, s), 1.78-1.88 (1H,
m), 2.04-2.22 (3H, m), 2.37-2.45 (2H, m), 3.92 (3H, s), 5.40 (2H, s), 7.23-
7.34 (2H, m), 7.49-7.55 (1H, m), 7.69 (IH, s), 7.95 (1H, br t, J= 7 Hz), 8.02
(1H, s); MS (ES+) m/e 394 [MH]+. Anal. Found C, 61.10; H, 4.96; N, 24.79.
C2oH2oN7OF requires C, 61.06; H, 5.12; N, 24.92%.
EXAMPLE 202
6-(1-Methyl-lH-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-7-(thiophen-
3-yl)-1,2,4-triazolo[4,3-b]pyridazine
This compound was prepared using the procedures described in
Example 16, Steps a), b) and c) except that 3-thiophene boronic acid was
used instead of 4-pyridyl boronic acid, di-lithium salt in Step a), 1.1
equivalents of 2-fluorobenzhydrazide and triethylamine hydrochloride
were used in Step b) instead of 1.1 equivalents of benzhydrazide,
p-toluenesulphonic acid and triethylamine, and (1-methyl-lH-1,2,4-triazol-
3-yl)methanol (Example 65) was used in Step c) instead of 2-
pyridylcarbinol. Data for the title compound: m.p. 216-218 C (MeOH). 'H
NMR (360 MHz, DMSO) 8 3.93 (3H, s), 5.50 (2H, s), 7.48-7.59 (2H, m),
7.69-7.78 (2H, m), 7.85 (1H, dd, J= 7, 2 Hz), 8.08-8.14 (1H, m), 8.34 (1H,
dd, J= 4, 2 Hz), 8.58 (IH, s), 8.77 (1H, s). MS (ES+) 408 [MH]+. Anal.
Found C, 55.82; H, 3.57; N, 24.30. C19H14N7FOS requires C, 56.01; H, 3.46;
N, 24.07%.
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EXAMPLE 203
8-Methyl-7- (1-methylcyclobutyl)-6-(1-methyl-lH-1, 2, 4-triazol-3-
ylmethoxy)-3-nhenyl-1,2, 4-triazolo f4, 3-blpvridazine
The compound was prepared using the procedures described in
Example 102, Steps a), b) and c) with 1-methylcyclobutane carboxylic acid
(US patent 4,220,795) and 3,6-dichloro-4-methylpyridazine being used
instead of cyclopentane carboxylic acid and 3,6-dichioropyridazine
respectively in Step a), and benzoic acid hydrazide being used instead of 2-
thiophene carboxylic acid hydrazide in Step b), and (1-methyl-lH-1,2,4-
triazol-3-yl)methanol (prepared using the conditions described in
EP-A-421210) being used instead of 2-hydroxymethylpyridine in Step c).
Data for the title compound: 1H NMR (360 MHz, CDC13) S 1.57 (3H, s),
1.74-1.84 (1H, m), 2.02-2.14 (1H, m), 2.20-2.26 (2H, m), 2.50-2.58 (2H, m),
2.62 (3H, s), 3.93 (3H, s), 5.48 (2H, s), 7.44-7.54 (3H, m), 8.04 (1H, s),
8.49
(2H, d, J= 8 Hz); MS (ES+) m/e 390 [MH]+. Anal. Found C, 64.74; H, 5.92;
N, 24.88. C21H23N70 requires C, 64.76; H, 5.95; N, 25.18%.
EXAMPLE 204
8-Methyl-7-(1-methylcyclobutyl)-6-(2-methyl-2H-1,2,4-triazol-3-
vlmethoxy)-3-phenyl-1,2,4-triazolo f 4, 3-blpyridazine
The compound was prepared using the procedures described in
Example 102, Steps a), b) and c) with 1-methylcyclobutane carboxylic acid
(US patent 4,220,795) and 3,6-dichloro-4-methylpyridazine being used
instead of cyclopentane carboxylic acid and 3,6-dichloropyridazine
respectively in Step a), and benzoic acid hydrazide being used instead of 2-
thiophene carboxylic acid hydrazide in Step b), and (2-methyl-2H-1,2,4-
triazol-3-yl)methanol (prepared using the conditions described in
EP-A-421210) being used instead of 2-hydroxymethylpyridine in Step c).
Data for the title compound: 1H NMR (360 MHz, CDC13) 8 1.54 (3H, s),
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1.76-1.84 (1H, m), 2.04-2.16 (3H, m), 2.46-2.53 (2H, m), 2.64 (3H, s), 3.94
(3H, s), 5.53 (2H, s), 7.46-7.56 (3H, m), 7.93 (1H, s), 8.34 (2H, d, J= 8 Hz);
MS (ES+) m/e 390 [MH]+. Anal. Found C, 64.83; H, 5.82; N, 25.04.
C21H23N70 requires C, 64.76; H, 5.95; N, 25.18%.
EXAMPLE 205
6-(1-Methyl-lH-1,2,4-triazol-3-ylmethoxy)-3-phen 1-y 7-(pyrrolidin-l-yl)-
1, 2, 4-triazolo [4, 3-b]pyridazine
iH NMR (250MHz, CDC13) S 1.95-2.00 (4H, m), 3.53-3.58 (4H, m),
3.95 (3H, s), 5.55 (2H, s), 6.69 (1H, s), 7.41-7.55 (3H, m), 8.07 (1H, s),
8.43-
8.45 (2H, m), ms (ES+) (M+1) = 377.
EXAMPLE 206
7-Cyclobutvl-8-methyl-6-(2-methyl-2H-1,2 4-triazol-3-vlmethoxv)-3-phenyl-
1,2,4-triazolo f 4, 3-b]pyridazine
Prepared in an analogous procedure as outlined in Example 102a
using 1-methylcyclobutane carboxylic acid, Example 102b using benzoic
acid hydrazide and Example 102c using 3-hydroxymethyl-2-methyl-2H-
1,2,4-triazole to give the title compound. 'H NMR (360 MHz, CDC13) S
2.06-2.09 (2H, m), 2.26 (3H, s), 2.42-2.50 (2H, m), 3.04-3.17 (2H, m), 3.97
(3H, s), 4.06 (1H, t, J= 10 Hz), 5.57 (2H, s), 7.48-7.56 (3H, m), 7.92 (1H,
s),
8.36 (2H, d, J= 7.7 Hz), ms (ES+) m/e 376 [MH]+.
EXAMPLE 207
7-Cyclobutyl-8-methyl-6-(1-methyl-lH-1 2 4-triazol-3-ylmethoxv)-3-phenyl-
1, 2, 4-triazolo (4, 3-b]pyridazine
Prepared in an analogous procedure as outlined in Example 102a
using 1-methylcyclobutane carboxylic acid, Example 102b using benzoic
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acid hydrazide and Example 102c using 3-hydroxymethyl-l-methyl-lH-
1,2,4-triazole to give the title compound. 1H NMR (360 MHz, CDC13) S
2.06-2.18 (2H, m), 2.24 (3H, s), 2.40-2.50 (2H, m), 3.02-3.16 (2H, m), 3.84
(3H, s), 3.88-4.10 (1H, m), 5.50 (2H, s), 7.42-7.56 (3H, m), 8.04 (1H, s),
8.48-8.52 (2H, m), ms (ES+) m/e 376 [MH]+.
EXAMPLE 208
7-(1-Methylcyclopentyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-
fluorophenyl)-1,2,4-triazolo[4,3-bjpyridazine
Prepared in an analogous procedure as outlined in Example 102a
using 1-methylcyclopentanoic acid, Example 102b using 2-fluorobenzoic
acid hydrazide and Example 102c using 3-hydroxymethyl-2-methyl-2H-
1,2,4-triazole to give the title compound. 1H NMR (360 MHz, CDC13) 6 1.31
(3H, s), 1.72-1.90 (8H, m), 3.82 (3H, s), 5.50 (2H, s), 7.25-7.37 (2H, m),
7.53-7.59 (1H, m), 7.83-7.87 (1H, m), 7.90 (1H, s), 7.94 (1H, m), ms (ES+)
m/e 409 [MH]+.
EXAMPLE 209
7-(1-MethYlcvclopentyl)-6-(1-methyl-lH-1,2,4-triazol-3-ylmethoxy)-3-(2-
fluorophenyl)-1, 2, 4-triazolo [4, 3-bl pyridazine
Prepared in an analogous procedure as outlined in Example 102a
using 1-methylcyclopentanoic acid, Example 102b using 2-fluorobenzoic
acid hydrazide and Example 102c using 3-hydroxymethyl-l-methyl-lH-
1,2,4-triazole to give the title compound. IH NMR (360 MHz, CDC13) 8
1.33 (3H, s), 1.70-1.93 (8H, m), 3.92 (3H, s), 5.43 (2H, s), 7.23-7.34 (2H,
m),
7.49-7.55 (1H, m), 7.90 (1H, s), 7.94-7.98 (1H, m), 8.04 (1H, m), ms (ES+)
m/e 409 [MH]+.
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EXAMPLE 210
7-Cyclobutyl-6-f4-(2,6-dimethvlmornholin-4-vl)but-2-ynvloxy1-3-phen y1-
1, 2, 4-triazolol4, 3-blpyridazine
1H NMR (250MHz, CDC13) S 1.11 (3H, s), 1.13 (3H, s), 1.21 (1H, m),
1.92 (3H, m), 2.13-2.20 (3H, m), 2.39-2.45 (2H, m), 2.68 (2H, m), 3.33 (2H,
m), 3.59-3.69 (3H, m), 5.09 (2H, m), 7.46-7.58 (3H, m), 7.82 (1H, d, J= 1.6
Hz), 8.50 (2H, m), ms (ES+) (M+1) = 432.
