Note: Descriptions are shown in the official language in which they were submitted.
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NEW BISPIDINE COMPOUNDS USEFUL IN THE TREATMENT OF
CARDIAC A~RRHYTHMIAS
Field of the Invention
This invention relates to novel pharmaceutically useful compounds, in
particular compounds which are useful in the treatment of cardiac
arrhythmias .
Background and Prior Art
Cardiac arrhythmias may be defined as abnormalities in the rate, regularity,
or site of origin of the cardiac impulse or as disturbances in conduction
which causes an abnormal sequence of activation. Arrhythmias may be
is classified clinically by means of the presumed site of origin (i.e. as
supraventricular, including atrial and atrioventricular, arrhythmias and
ventricular arrhythmias) and/or by means of rate (i.e. bradyarrhythmias
(slow) and tachyarrhythmias (fast)).
2o In the treatment of cardiac arrhythmias, the negative outcome in clinical
trials (see, for example, the outcome of the Cardiac Arrhythmia Suppression
Trial (CAST) reported in New England Journal of Medicine, 321, 406
(1989)) with "traditional" antiarrhythmic drugs, which act primarily by
slowing the conduction velocity (class I antiarrhythmic drugs), has prompted
2s drug development towards compounds which selectively delay cardiac
repolarization, thus prolonging the QT interval. Class III antiarrhythmic
drugs may be defined as drugs which prolong the trans-membrane action
potential duration (which can be caused by a block of outward K+ currents
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or from an increase of inward ion currents) and refractoriness, without
affecting cardiac conduction.
One of the key disadvantages of hitherto known drugs which act by delaying
s repolarization (class III or otherwise) is that they all are known to
exhibit a
unique form of proarrhythmia known as torsades de pointes (turning of
points), which may, on occasion be fatal. From the point of view of safety,
the minimisation of this phenomenon (which has also been shown to be
exhibited as a result of administration of non-cardiac drugs such as
to phenothiazines, tricyclic antidepressants, antihistamines and antibiotics)
is a
key problem to be solved in the provision of effective antiarrhythmic drugs.
Antiarrhythmic drugs based on bispidines (3,7-diazabicyclo[3.3.1]nonanes),
are known from inter alia international patent application WO 91/07405,
i s European patent applications 306 871, 308 843 and 655 228 and US patents
3,962,449, 4,556,662, 4,550,112, 4,459,301 and 5,468,858, as well as
journal articles including inter alia J. Med. Chem. 39, 2559, (1996),
Pharmacol. Res., 24, 149 (1991), Circulation, 90, 2032 (1994) and Anal.
Sci. 9, 429, (1993). Known bispidine-based antiarrhythmic compounds
Zo include bisaramil (3-methyl-7-ethyl-9a,4'-(Cl-benzoyloxy)-3,7-
diazabicyclo[3.3.1]nonane), tedisamil (3',7'-bis(cyclopropylmethyl)spiro-
(cyclopentane-1,9')-3,7-diazabicyclo[3.3.1]nonane), SAZ-VII-22 (3-(4-
chlorobenzoyl)-7-iso-propyl-3,7-diazabicyclo[3.3.1]nonane), SAZ-VII-23
(3-benzoyl-7-iso-propyl-3,7-diazabicyclo[3.3.1]nonane), GLG-V-13 (3-[4-
Zs (1H-imidazol-1-yl)benzoyl]-7-iso-propyl-3,7-diazabicyclo[3.3.1]nonane),
KMC-IV-84 (7-[4'-(1H imidazolo-1-yl)benzenesulfonyl]-3-iso-propyl-3,7-
diazabicyclo[3.3.1]nonane dihydroperchlorate and ambasilide (3-(4-
aminobenzoyl)-7-benzyl-3,7-diazabicyclo[3.3.1]nonane).
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We have surprisingly found that a novel group of bispidine-based
compounds exhibit electrophysiological activity, preferably class III
electrophysiological activity, and are therefore expected to be useful in the
treatment of cardiac arrhythmias.
s
Disclosure of the Invention
According to the invention there is provided compounds of formula I,
RS O
R~\B IAA/
~N--Ra
R /s
Rs
wherein
Rl and R'- independently represent H, C,~ alkyl, ORZb or N(RZ')RZd, or
1 s together form -0-(CH,),-O-, -(CHZ)3-, -(CH,)4 or -(CHZ)s-;
RZb, R'-' and R'-d independently represent H or C,_6 alkyl;
R3 represents H, C1_6 alkyl or, together with R4, represents C3_~ alkylene
(which alkylene group is optionally interrupted by an O atom and/or is
zo optionally substituted by one or more CI_3 alkyl groups);
R4 represents H, C1_1~ alkyl, CI_6 alkoxy (which latter two groups are both
optionally substituted and/or terminated by one or more substituents
selected from -OH, halo, cyano, vitro, C,~ alkyl and/or C1_4 alkoxy),
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-(CHZ)q-aryl, -(CH2)q-oxyaryl, -(CH,)q-Hetl (which latter three groups are
optionally substituted (at the -(CH,)y- part and/or the aryl/Hetl part) by
one or more substituents selected from -OH, halo, cyano, nitro, -C(O)Rlo,
-C(O)OR1', -N(H)S(O)~Rla, C~_6 alkyl and/or C1_~ alkoxy),
s -(CH,)qN(H)C(O)R8, -(CHZ)qS(O)~Rg, -(CH~)qC(O)R8, -(CH,)qC(O)ORB,
-(CH2)qC(O)N(R9)R$ or, together with R3, represents C3_6 alkylene (which
alkylene group is optionally interrupted by an O atom and/or is optionally
substituted by one or more C1_3 alkyl groups);
q represents 0, 1, 2, 3, 4, 5 or 6;
to Rg represents H, C1_6 alkyl, aryl (which latter group is optionally
substituted and/or terminated by one or more substituents selected from
-OH, halo, cyano, vitro, -C(O)R1°, -C(O)OR11, -N(H)S(O)~Rlla, C1-6
alkyl
and/or C1_~ alkoxy) or, together with R~, represents C3_, alkylene;
R9 represents H, C j~ alkyl or, together with R8, represents C3_7 alkylene;
is Hetl represents a five to twelve-membered heterocyclic ring containing
one or more heteroatoms selected from oxygen, nitrogen and/or sulfur,
and which also optionally includes one or more =O substituents;
Ray R.~2, Ra3, Ray, R4s or R''~ independently represent H or C1_3 alkyl;
RS represents H, halo, C1_3 alkyl, -OR12, -N(R13)R12 or, together with R6,
represents =O;
R~ represents H, C1_4 alkyl or, together with R', represents =O;
R12 represents H, C1_6 alkyl, -S(O)S-C,~ alkyl, -C(O)R14, -C(O)OR14,
2s -C(O)N(Rl')Rl'a or aryl (which latter group is optionally substituted
and/or
terminated by one or more substituents selected from -OH, halo, cyano,
vitro, -C(O)Rl°, -C(O)ORII, -N(H)S(O)~Rla, C1_6 alkyl and/or C1_6
alkoxy);
R13 represents H or C1~ alkyl;
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R14 represents H or C1_6 alkyl;
R15 and Rlsa independently represent H or C1_:~ alkyl, or together represent
C3_~ alkylene, optionally interrupted by an O atom;
s A represents a single bond, C1_6 alkylene, -N(R16)(CHZ)~- or -O(CH2)r- (m
which two latter groups, the -(CH~)~- group is attached to the bispidine
nitrogen atom);
B represents a single bond, C1~ alkylene, -(CHZ)"N(Rl')-, -(CH2)nS(O)p-,
-(CH2)n0- (in which three latter groups, the -(CH~)n group is attached to
Io the carbon atom bearing R5 and R~), -C(O)N(Rl')- (in which latter group,
the -C(O)- group is attached to the carbon atom bearing R' and R6),
-N(R1')C(O)O(CH~)~-, -N(R1')(CHZ)~ (in which two latter groups, the
N(R1') group is attached to the carbon atom bearing RS and R~) or
-(CHZ)mC(H)(OH)(CHZ)n (in which latter group, the -(CH2)m- group is
is attached to the carbon atom bearing RS and R6);
m represents l, 2 or 3;
n and r independently represent 0, l, 2, 3 or 4;
p represents 0, 1 or 2;
R16 and Rl' independently represent H or C1~ alkyl;
R' represents C1_6 alkyl, aryl or Het'-, all of which groups are optionally
substituted and/or terminated (as appropriate) by one or more substituents
selected from -OH, cyano, halo, amino, vitro, Het3, -C(O)R'o,
-C(O)ORII, C1_6 alkyl, C1_6 alkoxy, -N(H)S(O)~R18, -S(O)ZRI~, -OS(O)~R'-
°,
2s -N(H)C(O)N(H)R'-', -C(O)N(H)R'-'- and/or aryl (which latter group is
optionally substituted by one or more cyano groups);
Het2 and Het3 independently represent a five to twelve-membered
heterocyclic group containing one or more heteroatoms selected from
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oxygen, nitrogen and/or sulfur, and which also optionally includes one or
more =O substituents;
R18, R1~ and R'-° independently represent C1_6 alkyl;
R'-1 and R'-2 independently represent H or C1_~ alkyl (optionally terminated
s by cyano); and
R1° and R' 1 independently represent, at each individual
occurrence, H or
C1_6 alkyl;
Rua represents, at each individual occurrence, C,_~ alkyl;
or a pharmaceutically acceptable derivative thereof;
provided that:
(a) when A and B are both single bonds and R' is optionally substituted
I s aryl, then R' and R6 do not both represent H;
(b) when A represents a single bond, then RS and R6 do not together
represent = O; and
(c) when RS represents -OR1'- or -N(R13)R1'-, then:-
(i) A does not represent -N(RI~)(CHZ)~- or -O(CH~)~-; and/or
(ii) n does not represent 0 when B represents -(CH,)nN(Ri')-,
-(CH2)nS(O)p- or -(CH,)~O-,
which compounds are referred to hereinafter as "the compounds of the
invention" .
Aryl groups that may be mentioned include C6_lo aryl groups, such as
phenyl, naphthyl and the like. Oxyaryl groups that may be mentioned
include C6_,o oxyaryl groups, such as oxyphenyl (phenoxy), oxynaphthyl
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(naphthoxy) and the like. When substituted, aryl and aryloxy groups are
preferably substituted by one to three substituents.
Hetl, Hetz and Het3 groups that may be mentioned include those
s containing 1 to 4 heteroatoms (selected from the group oxygen, nitrogen
and/or sulfur) and in which the total number of atoms in the ring system
are between five and twelve. Het (Hetl, Het'- and Het3) groups may be
wholly/partly aromatic in character and may be bicyclic. Heterocyclic
groups that may be mentioned include morpholinyl, thiazolyl, oxazolyl,
to isoxazolyl, cinnolinyl, quinazolinyl, phthalazinyl, purinyl,
benzimidazolyl,
pyrimindinyl, piperazinyl, pyrazinyl, piperidinyl, pyridinyl, triazolyl,
imidazolyl, quinolinyl, isoquinolinyl, dioxanyl, benzodioxanyl,
benzodioxolyl, benzodioxepanyl, benzomorpholinyl, indolyl, pyrazolyl,
pyrrolyl, benzothiophenyl, thiophenyl, chromanyl, thiochromanyl,
is benzofuranyl, pyranyl, tetrahydropyranyl, tetrahydrofuranyl, furanyl and
the like. Values of Hetl that may be mentioned include tetrahydropyranyl,
isoxazolyl, benzodioxolyl, benzodioxepanyl and thiophenyl. Values of
Het' that may be mentioned include quinolinyl, isoquinolinyl,
benzomorpholinyl, benzodioxanyl, piperazinyl, indolyl and pyrazolyl.
2o Values of Het3 that may be mentioned include imidazolyl. Substituents on
Het (Hetl, Het2 and Het3) groups may, where appropriate, be located on
any atom in the ring system including a heteroatom. The point of
attachment of Het (Het', Het'- and Het3) groups may be via any atom in the
ring system including (where appropriate) a heteroatom. Het (Hetl, Het'
2s and Het3) groups may also be in the N- or S-oxidised form.
Pharmaceutically acceptable derivatives include salts and solvates. Salts
which may be mentioned include acid addition salts. Pharmaceutically
acceptable derivatives also include, at the bispidine nitrogens, Cl_:~ alkyl
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quaternary ammonium salts and N-oxides, provided that when a N-oxide
is present:
(a) no Het (Hetl, Het2, Het3) group contains an unoxidised S-atom; and/or
(b) p does not represent 0 when B represents -(CH2)nS(O)p-.
s
The compounds of the invention may exhibit tautomerism. All tautomeric
forms and mixtures thereof are included within the scope of the invention.
The compounds of the invention may also contain one or more asymmetric
t o carbon atoms and may therefore exhibit optical and/or diastereoisomerism.
Diastereoisomers may be separated using conventional techniques, e.g.
chromatography or fractional crystallisation. The various stereoisomers may
be isolated by separation of a racemic or other mixture of the compounds
using conventional, e.g. fractional crystallisation or HPLC, techniques.
i s Alternatively the desired optical isomers may be made by reaction of the
appropriate optically active starting materials under conditions which will
not cause racemisation or epimerisation, or by derivatisation, for example
with a homochiral acid followed by separation of the diastereomeric esters
by conventional means (e.g. HPLC, chromatography over silica). All
2o stereoisomers are included within the scope of the invention.
Alkyl groups that R1, R'-, RZb, R2', RZa, R3, R4, Rs, R~, R', Rg, R~, Rlo,
Ru Rm Ria Ri3 Ria Ris Risa Ri6 Rm Ris Rm Rzo Rm R2~ Rai
> > > , , > > , > > >
R4'-, R43, Rte', R45 and R46 may represent, that R1'- may include, and with
2s which R3, R4, R', R8 and Rl' may be substituted; and alkoxy groups that
R4 may represent, and with which R'~, R', Rg and R12 may be substituted;
may be linear or, when there is a sufficient number (i.e. three) of carbon
atoms, be branched and/or cyclic. Further, when there is a sufficient
number (i.e. four) of carbon atoms, such alkyl and alkoxy groups may
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also be part cyclic/acyclic. Such alkyl and alkoxy groups may also be
saturated or, when there is a sufficient number (i.e. two) of carbon atoms,
be unsaturated and/or interrupted by oxygen.
s Alkylene groups that R3 and R4, R$ and R9, R15 and Rlsa, A, and B, may
represent; and -(CHZ)m-, -(CHZ)~-, -(CH2)q- and -(CHZ)r- chains that A, B
and R4 (as appropriate) may include, may be linear or, when there is a
sufficient number (i.e. two) of carbon atoms, be branched. Such alkylene
groups and -(CHI)- containing chains may also be saturated or, when there
to is a sufficient number (i.e. two) of carbon atoms, be unsaturated and/or
interrupted by oxygen.
Halo groups that RS may represent, and with which R'', R', Rg and Rl'- may
be substituted, include fluoro, chloro, bromo and iodo.
For the avoidance of doubt, each Rl°, Rl, and Rla, group identified
herein
is independent of other R'°, Rll, and Rla, groups, respectively. For
example, when R'~ and R' both represent aryl substituted by -C(O)R1°,
the
two individual -C(O)R1° substituents are independent of one another,
and are
2o not necessarily identical (though this possibility is not excluded).
Abbreviations are listed at the end of this specification.
According to a further aspect of the invention there is provided
2s compounds of formula I as hereinbefore defined, but with the further
provisos that:
(a) when A represents -N(R16)(CH2)~- or -O(CH~)~ , then r does not
represent 0 or 1; and
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(b) when RS represents -OH or -N(R13)R12, then B does not represent
-N(R17)C(O)O(CH~)~ or -N(R")(CHZ)~ .
Preferred compounds of the invention include those in which:
s Rl represents H;
R'- represents H;
R3 represents
H;
C1_~ alkyl; or,
to together with R4 represents C4_5 alkylene, optionally interrupted by an
O atom and/or optionally substituted by one or more methyl groups;
R4 represents
H;
linear or branched and/or saturated or unsaturated and/or cyclic,
is acyclic and/or part cyclic/acyclic C,_$ alkyl (which alkyl group is
optionally
substituted by one or more cyano or halo groups and/or interrupted by an O
atom);
C1~ alkoxy;
-(CH~)qS(O)~Rg, -(CH~)qC(O)ORB, -(CH2)qN(H)C(O)R8,
-(CH2)qC(O)R8, (in which latter four groups, q represents 0, 1 or 2 and R8
represents linear or branched and/or acyclic, cyclic and/or part
cyclic/acyclic C1~ alkyl, or phenyl (which phenyl group is optionally
substituted by one or more cyano and/or C1_3 alkyl groups));
-(CH2)qC(O)N(R9)R$ (in which latter group, q represents 0, 1 or 2
Zs and R8 and R9 independently represent H, linear or branched and/or acyclic,
cyclic and/or part cyclic/acyclic C,.~ alkyl, or together represent C.~
alkylene);
-(CHZ)q phenyl, -(CH~)q-oxyphenyl or -(CHz)q Heti (in which latter
three groups, q represents 0, 1, 2 or 3, the -(CHZ)q- part is optionally
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substituted by a cyano group, and the phenyl, or Het', part is optionally
substituted with one or more substituents selected from cyano, vitro, linear
or branched C,~ alkyl, linear or branched C1~ alkoxy and N(H)S(O)~R1'a);
or,
s together with R3, represents Cøs alkylene, optionally interrupted by
an O atom and/or optionally substituted by one or more methyl groups;
Rs represents
H;
fluoro;
1 o ORl'- (in which Rl'- represents H, phenyl (optionally substituted by
one or more methoxy groups) or C(O)N(H)Rlsa (in which Rlsa represents
linear or branched C,~ alkyl));
-N(R13)(Rl'-) (in which R1'- represents H, C1_~ alkyl, -S(O)2-C1_~ alkyl,
-C(O)R14 (in which R1'~ represents C1_2 alkyl), -C(O)OR'4 (in which Rla
is represents linear or branched C1_s alkyl) or -C(O)N(Rls)(Rlsa) (1n which
R's
and Rlsa independently represent H or linear or branched Ci_3 alkyl or
together represent C~5 alkylene, which alkylene group is optionally
interrupted by an O atom) and R13 represents H or C1_~ alkyl); or,
together with R~, represents =O (especially in the case where R'
2o represents alkyl or Het'-);
R6 represents H or C1_2 alkyl or together with Rs represents =O (especially
in the case where R' represents alkyl or Hetz);
A represents a single bond, linear or branched C,~, alkylene (which group is
also optionally interrupted by O), -N(H)(CH~)~ or -O(CH2)~ (in which
2s latter two groups r is 1 or 2);
B represents a single bond, C1~ alkylene, -(CH~)~O-, -(CHZ)nS(O)~-,
-(CH~)~N(H)- or -N(H)(CHZ)~ (in which latter four cases n is 0, l, 2 or 3);
R' represents
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linear or branched and/or acyclic, cyclic and/or part cyclic/acyclic
CI_6 alkyl (optionally substituted and/or terminated by OH);
Het2 (optionally substituted by one or more substituents selected from
cyano, C1_3 alkyl, phenyl (which latter group is optionally substituted with
s one or more cyano groups), =O, C(O)R1° (in which R1° is linear
or
branched C1_3 alkyl) or S(O)~R1~ (in which Rl9 is C1_~ alkyl)); or
phenyl (optionally substituted by one or more substituents selected
from cyano, vitro, linear or branched C1_3 alkyl, linear or branched C1_3
alkoxy, fluoro, chloro, C(O)N(H)R'-'- (in which R'-2 represents linear or
to branched and/or acyclic, cyclic and/or part cyclic/acyclic C1~, alkyl,
which
alkyl group is optionally terminated by cyano), N(H)S(O),R18 (in which R18
represents C1_Z alkyl) or Het3);
Ray Ra2, R43, Rte, R4s and R''6 all represent H.
Is More preferred compounds of the invention include those in which:
R3 represents H;
Rs represents H, OH or -N(H)C(O)N(Rls)(Rlsa);
R~ represents H;
A represents -CHI- or -(CH~)~-;
2o B represents a single bond, -CH,N(H)- or -CHZO- (where, for the avoidance
of doubt, the -CH2- part is attached to the carbon atom bearing Rs and R6);
R' represents phenyl (substituted by a cyano group (preferably in the 4-
position relative to B) and by one or more optional C(O)N(H)R'-'-
substituent) .
Preferred compounds of the invention include the compounds of the
Examples disclosed hereinafter.
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Preparation
According to the invention there is also provided a process for the
preparation of compounds of formula I which comprises:
(a) for compounds of formula I in which R3 is H, reaction of a compound of
formula II,
R5
~H
R~~B ~\A
Rs
wherein R1, R'-, R5, R6, R7, R41, R'~'-, R43, R'~, R45, Rte, A and B are as
hereinbefore defined with a compound of formula III,
R4-N=C=O III
is wherein R4 is as hereinbefore defined, for example at between 0°C
and
reflux temperature in the presence of an appropriate organic solvent (e.g.
dichloromethane), or via solid phase synthesis under conditions known to
those skilled in the art;
(b) reaction of a compound of formula II, as hereinbefore defined, with a
carbonic acid derivative of formula IV,
(R3)(R4)NC(O)-L' IV
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wherein L1 represents a leaving group such as halo, imidazole or R'-30-
(wherein Rz3 represents, for example, C1_lo alkyl, aryl or C1_3 alkylaryl,
which groups are optionally substituted by one or more halo or vitro groups)
and R3 and R'~ are as hereinbefore defined, for example at between room
s and reflux temperature in the presence of a suitable base (e.g.
triethylamine
or potassium carbonate) and an appropriate organic solvent (e.g.
dichloromethane, THF, acetonitrile, toluene, or mixtures thereof);
(c) reaction of a compound of formula V,
io
v
Rs
\ /O
R7\B ~A/
Rs
wherein R1, R'-, R5, R6, R', R~1, R'''-, R43, Rte', R''S, Rte, A, B and L1 are
as
hereinbefore defined with a compound of formula VA,
is (R3)(R4)NH VA
wherein R3 and R4 are as hereinbefore defined, for example at between
room and reflux temperature in the presence of a suitable base (e.g.
triethylamine or potassium carbonate) and an appropriate organic solvent
(e.g. dichloromethane, THF, acetonitrile, toluene, or mixtures thereofj, or
2o via solid phase synthesis under conditions known to those skilled in the
art;
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1~
(d) for compounds of formula I in which A represents CHZ and RS
represents -OH or -N(H)Rl'-, wherein R12 is as hereinbefore defined,
reaction of a compound of formula VI,
VI
O
H
~N-~Ra
R3
wherein R', R'-, R3, R'', R41, R4'-, Ra3, Ray, R4s and R~ are as hereinbefore
defined, with a compound of formula VII,
Rs
R~ /~\~,~ VII
X
wherein X represents O or N(R1'-) and R6, R7, R12 and B are as hereinbefore
defined, for example at elevated temperature (e.g. 60°C to reflux) in
the
presence of a suitable solvent (e.g. a lower alkyl alcohol (e.g. IPA),
1 s acetonitrile, or a mixture of a lower alkyl alcohol and water);
(e) reaction of a compound of formula VI, as hereinbefore defined, with a
compound of formula VIII,
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R\ A-LZ
B
R6 VIII
wherein LZ represents a leaving group (e.g. mesylate, tosylate or halo) and
R5, R~, R', A and B are as hereinbefore defined, for example at elevated
s temperature (e.g. between 35°C and reflux temperature) in the
presence of a
suitable base (e.g. triethylamine or KZC03) and an appropriate organic
solvent (e.g. acetonitrile or DMSO);
(f) for compounds of formula I in which RS represents H or OH and R~
io represents H, reduction of a compound of formula IX,
~x
0 o
R'\
B A
/N~Ra
R/3
is wherein R1, R', R3, R4, R', R''1, R4z, R43, Ray, R45, Rte, A and B are as
hereinbefore defined, in the presence of a suitable reducing agent and under
appropriate reaction conditions; for example, for formation of compounds
of formula I in which RS represents OH, reduction may be performed under
mild reaction conditions in the presence of e.g. sodium borohydride and an
2o appropriate organic solvent (e.g. THF); and for formation of compounds of
formula I in which R5 represents H, reduction may be performed by
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17
activating the relevant C = O group using an appropriate agent (such as
tosylhydrazine) in the presence of a suitable reducing agent (e.g. sodium
borohydride or sodium cyanoborohydride) and an appropriate organic
solvent (e.g. a lower (e.g. C1~) alkyl alcohol);
s
(g) for compounds of formula I in which R1 and RZ both represent H,
reduction of a corresponding compound of formula X,
x
RS O
R'~B
~N-~Ra
Rs
R3
wherein R3, R4, R', R~, R7, R~1, R4', R43, R'~, R45, Rte, A and B are as
hereinbefore defined, and in which the bridgehead C = O group may be
activated using an appropriate agent, such as tosylhydrazine, in the presence
is of a suitable reducing agent (e.g. sodium borohydride, sodium
cyanoborohydride) and an appropriate organic solvent (e.g. a lower alkyl
alcohol), or under standard Wolff Kischner conditions known to those
skilled in the art; when the C = O group is activated, the activation step may
be carried out at between room and reflux temperature in the presence of an
2o appropriate organic solvent (e.g. a lower alkyl alcohol such as methanol,
ethanol or IPA), whereafter the reducing agent may be added to the reaction
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18
mixture and the reduction carried out at between 60 ° C and reflux,
advantageously in the presence of a suitable organic acid (e.g. acetic acid);
(h) for compounds of formula I in which R' and R'- together represent
s -O(CHZ)20-, reaction of a corresponding compound of formula X as
hereinbefore defined with ethane-1;2-diol under appropriate reaction
conditions, for example by refluxing in the presence of pTSA and an
appropriate organic solvent (e.g. toluene);
to (i) for compounds of formula I in which B represents -(CHz)n0-, reaction of
a compound of formula XI,
x~
R5 O
HO-(CHz)n ~~
~~'1 ~ Ra
R /s
R3
wherein R1, R2, R3, R4, Rs, R6, R41, R42, R43~ Raa~ R4s~ R'~s, A and n are as
is hereinbefore defined, with a compound of formula XIA,
R'OH XIA
in which R' is as hereinbefore defined, for example under Mitsunobu-type
conditions e.g. at between ambient (e.g. 25°C) and reflux temperature
in
the presence of a tertiary phosphine (e.g. tributylphosphine or
2o triphenylphosphine), an azodicarboxylate derivative (e.g.
diethylazodicarboxylate or 1,1'-(azodicarbonyl)dipiperidine) and an
appropriate organic solvent (e.g. dichloromethane or toluene);
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19
(j) for compounds of formula I which are bispidine-nitrogen N-oxide
derivatives, oxidation of the corresponding bispidine nitrogen of a
corresponding compound of formula I, in the presence of a suitable
oxidising agent (e.g. mCPBA), for example at 0°C in the presence of a
s suitable organic solvent (e.g. DCM);
(k) for compounds of formula I which are C,~ alkyl quaternary ammonium
salt derivatives, in which the alkyl group is attached to a bispidine
nitrogen, reaction, at the bispidine nitrogen, of a corresponding compound
to of formula I with a compound of formula XII,
RbL3 XII
wherein Rb represents C1~ alkyl and L3 is a leaving group such as halo,
alkane sulfonate or aryl sulfonate, for example at room temperature in the
presence of an appropriate organic solvent (e.g. DMF), followed by
is purification (using e.g. HPLC) in the presence of a suitable counter-ion
provider (e.g. NH40Ac);
(1) for compounds of formula I in which RS and R6 represent H, A
represents C1_6 alkylene and B represents -N(R1')(CH~)~-, reaction of a
2o compound of formula XIII,
x~~~
0
R, ~ N
%N- CH2
f-i ~N-~ Ra
R3
CA 02375841 2001-11-29
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wherein Aa represents C1_~ alkylene and R1, R'-, R3, R4, R41, R~'-, R''3, Rte,
R45, R~ and R17 are as hereinbefore defined with a compound of formula
XIV,
R'-(CHZ)~ L'- XIV
s wherein R', n and L'- are as hereinbefore defined, for example at
40°C in
the presence of a suitable organic solvent (e.g. acetonitrile);
(m) for compounds of formula I in which RS represents -NH,, reduction of a
corresponding compound of formula XV,
XV
N3 O
R~\B IAA/
~N~Ra
R /s
R3
wherein R1, R2, R3, R'~, R6, R7, R41, R4'-, R43, R'~, R45, R'~, A and B are as
hereinbefore defined, for example by hydrogenation at a suitable pressure in
the presence of a suitable catalyst (e.g. palladium on carbon) and an
is appropriate solvent (e.g. a water-ethanol mixture);
(n) for compounds of formula I in which RS represents
-N(R13)C(O)NH(Rl'), reaction of a corresponding compound of formula I in
which RS represents -N(R13)H with a compound of formula XVI,
2o R15N=C=O XVI
wherein R15 is as hereinbefore defined, for example at ambient temperature
(e.g. 25°C) in the presence of a suitable solvent (e.g. benzene);
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21
(o) for compounds of formula I in which RS represents -N(R'3)C(O)R''~,
reaction of a corresponding compound of formula I in which R5 represents
-N(R13)H with a compound of formula XVII,
R"C(O)Rx XVII
s wherein Rx represents a suitable leaving group, such as C,~ alkoxy, halo
(e.g. C1, Br) or p-nitrophenyl, and Rl'' is as hereinbefore defined, for
example at between ambient and reflux temperature in the presence of a
suitable solvent (e.g. dichloromethane or acetonitrile) and optionally in the
presence of a suitable base (e. g. triethylamine or potassium carbonate);
to
(p) for compounds of formula I in which R5 represents -N(H)Rlz, wherein
Rlz is as previously defined provided that it does not represent H, reaction
of a corresponding compound of formula I, in which RS represents -NH,
with a compound of formula XVIII,
is RlzaL1 XVIII
wherein Rlza represents Rlz as hereinbefore defined except that it does not
represent H and L1 is as hereinbefore defined, for example under conditions
that are well known to those skilled in the art;
20 (q) for compounds of formula I in which RS represents -ORIZ in which Rlz
represents C1_6 alkyl or optionally substituted aryl, reaction of a
corresponding compound of formula I in which RS represents -OH with a
compound of formula XIX,
RIZaOH XIX
2s wherein Rlza represents C1_6 alkyl or optionally substituted aryl, for
example
at between ambient (e.g. 25°C) and reflux temperature, under Mitsunobu-
type conditions (i.e. in the presence of e.g. triphenylphosphine, an
azodicarboxylate derivative (e.g. 1,1'-(azodicarbonyl)dipiperidine) and a
suitable organic solvent (e.g. dichloromethane));
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22
(r) for compounds of formula I in which RS represents -OR12, in which R''-
represents C1~ alkyl or optionally substituted aryl, reaction of a compound
of formula XX,
xx
O
R~\B IAA/
~fV--Ra
R /s
R3
wherein L'-, R1, R'-, R3, R4, R6, R', R41, Raz, Ra3, Raa~ Ras~ R~~ A and B are
as hereinbefore defined with a compound of formula XIX as hereinbefore
t o defined, for example at between ambient (e. g . 25 ° C) and reflux
temperature, under Williamson-type conditions (i.e. in the presence of an
appropriate base (e.g. KOH or NaH) and a suitable organic solvent (e.g.
dimethylsulfoxide or DMF));
i s (s) for compounds of formula I in which RS represents ORl'- and R'Z
represents C(O)R'4 and R14 is as hereinbefore defined, reaction of a
corresponding compound of formula I as hereinbefore defined in which RS
represents OH with a compound of formula XXI,
R14CO,H XXI
2o wherein Rl~ is as hereinbefore defined, for example at ambient temperature
(e.g. 25°C) in the presence of a suitable coupling agent (e.g. 1-(3-
dimethylaminopropyl)-3-ethylcarbodiimide), an appropriate catalyst (e.g. 4-
dimethylaminopyridine) and a reaction-inert organic solvent (e.g. THF);
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23
(t) for compounds of formula I in which RS represents halo, substitution of a
corresponding compound of formula I in which RS represents -OH, using an
appropriate halogenating agent (e.g., for compounds in which RS represents
fluoro, reaction with diethylaminosulfurtrifluoride);
s
(u) for compounds of formula I in which R3 and/or R4 as appropriate
represent alkyl groups (e.g. C,~ or C1_1, alkyl, as appropriate), alkylation
of
a corresponding compound of formula I, in which R3 and/or R'~ (as
appropriate) represent H under conditions well known to those skilled in the
1 o art;
(v) conversion of one R° group to another (e.g. conversion of
-(CH2)qC(O)OR$ to -(CH,)qC(O)N(R9)R8, wherein R8, R9 and q are as
hereinbefore defined) using techniques well known to those skilled in the
15 art; or
(w) for compounds of formula I in which one of Rl and R'- represents H,
and the other represents -OH, reduction of a corresponding compound of
formula X, as hereinbefore defined, in the presence of a mild reducing
zo agent, e.g. sodium borohydride, and an appropriate organic solvent (e.g. a
lower alcohol such as methanol or ethanol);
(x) for compounds of formula I in which one of R'- and R3 represents
-NH, and the other represents H, reduction of a compound of formula
2s XXIA,
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2=i
XXIA
RS O
R~\B IAA/
'N~Ra
R /s
R3
wherein R3, R4, R', R~, R', R'~', R'~'-, R43, Rte, R45, R'~, A and B are as
s hereinbefore defined, in the presence of a suitable reducing agent (e.g.
LiAlH4), for example under conditions that are well known to those skilled
in the art;
(y) for compounds of formula I in which one or both of R1 and RZ
io represent -N(R'-')R'-d in which one or both of Rz' and RZd represents C1_6
alkyl, alkylation of a corresponding compound of formula I in which R1
and/or R'- represent -N(R2')R'-d (as appropriate) in which RZ' and/or R'-d
(as appropriate) represent H, using a compound of formula XXIB,
RZeLI XXIB
is wherein R2e represents C1_~ alkyl and L1 is as hereinbefore defined, for
example under conditions that are well known to those skilled in the art;
or
(z) conversion of one substituent on R' to another using techniques well
2o known to those skilled in the art.
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Compounds of formula II may be prepared by reaction of a compound of
formula XXII,
xx~ ~
~H
H
5
wherein R', R'-, R'~', R4'-, R~3, Rte', R''' and R~ are as hereinbefore
defined,
with a compound of formula VIII as hereinbefore defined, for example as
described hereinbefore for synthesis of compounds of formula I (process
step (e)), or, in the case of compounds of formula II wherein A represents
io CHZ and RS represents OH or N(H)Rl'-, with a compound of formula VII as
hereinbefore defined, for example as described hereinbefore for synthesis of
compounds of formula I (process step (d)).
Compounds of formula II in which R1 and R'- both represent H may be
i s prepared by reduction of a compound of formula XXIII,
xx~~~
Rs
~~H
R~\B IAA/
Rs
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26
wherein R5, R~, R', R'~1, R4'-, R43, R''-', R45, R'~, A and B are as
hereinbefore
defined, and in which the C = O group may be activated using an
appropriate agent, such as tosylhydrazine, for example as described
hereinbefore for synthesis of compounds of formula I (process step (g)).
s
Compounds of formula IV may be prepared by reaction of a compound of
formula VA, as hereinbefore defined, with a compound of formula XXIV,
Ll-C(O)-L1 XXIV
wherein L1 is as hereinbefore defined, and in which the two L' groups may
io be the same or different, for example at between 0°C and reflux
temperature in the presence of a suitable base (e.g. triethylamine or
potassium carbonate) and an appropriate organic solvent (e.g. toluene or
dichloromethane) .
is Compounds of formula V may be prepared by reaction of a compound of
formula II, as hereinbefore defined, with a compound of formula XXIV, as
hereinbefore defined, for example as described hereinbefore for the
synthesis of compounds of formula IV .
2o Compounds of formula VI may be prepared by reaction of a compound of
formula XXII, as hereinbefore defined, with a compound of formula III, as
hereinbefore defined, for example as described hereinbefore for synthesis of
compounds of formula I (process step (a)), or with a compound of formula
IV, as hereinbefore defined, for example as described hereinbefore for
2s synthesis of compounds of formula I (process step (b)).
Compounds of formula VI may alternatively be prepared by reaction of a
compound of formula XXII, as hereinbefore defined, with a compound of
formula XXIV, as hereinbefore defined, for example as described
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27
hereinbefore for synthesis of compounds of formula IV, followed by
reaction of the resultant intermediate with a compound of formula VA, as
hereinbefore defined, for example as described hereinbefore for the
synthesis of compounds of formula I (process step (c)).
s
Compounds of formula VI in which Rl and R'- represent H may alternatively
be prepared by reduction of a corresponding compound of formula XXV,
XXV
O
H
/N- R4
R/3
wherein R3, R~, R4', R42, R'~3, R'~, R''S and R~ are as hereinbefore defined,
and in which the C=O group may be activated using an appropriate agent,
such as tosylhydrazine, for example as described hereinbefore for
compounds of formula I (process step (g)).
is
Compounds of formula VI in which one or more of R41, R~'-, R4' and/or R'~
represent C1_3 alkyl may be prepared by reaction of a compound of formula
VI in which R~1, R4z, Ras and/or R~ (as appropriate) represent H, with an
appropriate alkylating agent (e.g. dimethyl sulfate), for example in the
2o presence of a suitable strong base (e.g. s-BuLi), N,N,N',N'-
tetramethylethylenediamine and a reaction-inert solvent (e.g. THF).
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28
Compounds of formula VII may be prepared in accordance with
techniques which are known to those skilled in the art. For example,
compounds of formula VII in which:
s (1) B represents -CH~O- and X represents O may be prepared by reaction
of a compound of formula XIA as hereinbefore defined, with a compound
of formula XXVI,
Rs
XXV I
O
to
wherein Rb and LZ are as hereinbefore defined, for example at elevated
temperature (e.g. between 60°C and reflux temperature) in the presence
of
a suitable base (e.g. KZC03 or NaOH) and an appropriate organic solvent
(e.g. acetonitrile or toluene/water), or as otherwise described in the prior
i s art;
(2) R6 represents H and X represents O may be prepared by reduction of a
compound of formula XXVII,
O
RIB XXVII
wherein R' and B are as hereinbefore defined, for example at between
-15°C and room temperature in the presence of a suitable reducing agent
(e.g. NaBH4) and an appropriate organic solvent (e.g. THF), followed by
2s an internal displacement reaction in the resultant intermediate, for
example
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29
at room temperature in the presence of a suitable base (e.g. K~C03) and an
appropriate organic solvent (e.g. acetonitrile);
(3) B represents C,~ alkylene, -(CH,)~N(R1')-, -(CHz)nS(O)2- or -(CHZ)n0-
s (in which latter three groups n represents 1, 2, 3 or 4) or
-(CHZ)mC(H)(OH)(CHZ)~ and X represents O may be prepared by
oxidation of a compound of formula XXVIII,
R~
\B
XXVIII
Rs
in which Ba represents a single bond, CI_3 alkylene, -(CH,)~_1N(Rl')-,
io -(CHZ)~_1S(O)~- or -(CH~)~_10- (in which latter three groups n represents
l,
2, 3 or 4) or -(CH,)m_1C(H)(OH)(CHZ)n (in which latter group n is as
hereinbefore defined), and in all cases R17 and m are as hereinbefore
defined, in the presence of a suitable oxidising agent (e.g. mCPBA), for
example by refluxing in the presence of a suitable organic solvent (e.g.
is DCM); or
(4) B represents -(CHZ)~O- and X represents N(R1'-) and R1'- represents
-S(O)2-C1.~-alkyl or -C(O)OR14 may be prepared by cyclisation of a
compound of formula XXVIIIA,
R6 L2
XXVIIIA
RlO [~j(I--I)(~~2a
~ (CH2)r,
wherein Rlza represents -S(O)S-C1~-alkyl or -C(O)OR'4 and n, R6, R7, R'4
and Lz are as hereinbefore defined, for example at between 0°C and
reflux
2s temperature in the presence of a suitable base (e.g. sodium hydroxide), an
appropriate solvent (e.g. dichloromethane, water, or a mixture thereof)
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and, if necessary a phase transfer catalyst (such as tetrabutylammonium
hydrogensulfate) .
Compounds of formula VIII may be prepared by standard techniques. For
s example compounds of formula VIII in which:
(1) B represents -(CH~)n0- may be prepared by coupling a compound of
formula XIA, as hereinbefore defined, to a compound of formula XXIX,
L4-(CHZ)n C(R5)(R6)-A-L'- XXIX
io wherein L4 represents a suitable leaving group (e.g. halo) and n, R5, R~, A
and L2 are as hereinbefore defined; or
(2) B represents -C(O)N(Rl')- may be prepared by coupling a compound
of formula XXX,
is R'N(H)Rl' XXX
wherein R' and R1' are as hereinbefore defined, to a compound of formula
XXXI,
L4-C(O)-C(RS)(R~)-A-L2 XXXI
wherein L'~, R5, R6, A and L'- are as hereinbefore defined;
in both cases, under conditions which are well known to those skilled in
the art.
Compounds of formula VIII in which A represents CZ-alkylene and RS
2s represents ORl', in which Rl= represents C1~ alkyl or optionally
substituted
aryl may alternatively be prepared by reaction of a compound of formula
XIX as hereinbefore defined with a compound of formula XXXIA,
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31
R6 O
B \ ORv XXXIA
R~
wherein Ry represents C1~ alkyl or aryl (which two groups are optionally
substituted with one or more substituents selected from C1~ alkyl or halo)
and R~, R' and B are as hereinbefore defined, for example at between
s ambient temperature (e.g. 25 °C) and reflux temperature in the
presence of
a suitable base (e.g. KZC03) and an appropriate organic solvent (e.g.
acetonitrile), followed by conversion of the ester functionality to an LZ
group (in which LZ is as hereinbefore defined), under conditions that are
well known to those skilled in the art.
to
Compounds of formulae VII and VIII in which B represents -(CHZ)"S(O)- or
-(CH~)~S(O)Z- may be prepared by oxidation of corresponding compounds of
formulae VII and VIII wherein B represents -(CHZ)nS-, wherein n is as
hereinbefore defined, in the presence of an appropriate amount of a suitable
is oxidising agent (e.g. mCPBA) and an appropriate organic solvent.
Compounds of formulae IX and XI may be prepared in a similar fashion
to compounds of formula I (see, for example, process steps (a), (b), (c) or
(d)) .
Alternatively, compounds of formula IX in which A represents C
alkylene may be prepared by reaction of a compound of formula VI, as
hereinbefore defined with a compound of formula XXXII,
R'-B-C(O)-CH=CHI XXXII
2s wherein B and R' are as hereinbefore defined, for example a room
temperature in the presence of a suitable organic solvent (e.g. ethanol).
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32
Compounds of formula XIII may be prepared by removing an optionally
substituted benzyloxycarbonyl unit from (i.e. deprotecting) a
corresponding compound of formula I in which R' represents optionally
s substituted phenyl, RS and R6 both represent H, B represents
-N(Rl')C(O)O(CH~)-, A represents Aa and Aa is as hereinbefore defined
under conditions which are well known to those skilled in the art.
Compounds of formula XV may be prepared by reaction of a
io corresponding compound of formula I, as hereinbefore defined, in which
RS represents -OH, with a compound of formula XXXIII
R''S(O)~Cl XXXIII
wherein Ry is as hereinbefore defined, for example at between -10 and
25°C in the presence of a suitable solvent (e.g. dichloromethane),
is followed by reaction with a suitable source of the azide ion (e.g. sodium
azide) for example at between ambient and reflux temperature in the
presence of an appropriate solvent (e.g. DMF) and a suitable base (e.g.
NaHC03).
2o Compounds of formula XV may alternatively be prepared by reaction of a
corresponding compound of formula VI, as hereinbefore defined with a
compound of formula XXXIIIA,
R'-B-C(R~)(N3)-A-LZ XXXIIIA
wherein L2, R6, R', A and B are as hereinbefore defined, for example
2s under analogous conditions to those described hereinbefore for preparation
of compounds of formula I (process step (e)).
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J~
Compounds of formula XX may be prepared by replacement of the OH
group of a compound of formula I in which RS represents OH with an LZ
group under conditions that are well known to those skilled in the art.
s Compounds of formula XXIA may be prepared by reaction of a
corresponding compound of formula X with hydroxylamine, for example
at elevated temperature (e.g. at reflux) in the presence of a suitable
organic solvent (e.g. methanol).
to Compounds of formula XXII are known in the literature or are readily
available using known techniques. For example, compounds of formula
XXII in which R1 and R'- together represent -O-(CHz)Z-O-, -(CH2)3-,
-(CH2),~ or -(CHZ)5-, and R41, R4'-, R~3, Rte', R45 and R'~ all represent H,
may be prepared by reduction of a compound of formula XXXIV,
XXX ~ V
H~ wH
wherein Rla and RZa together represent -O-(CHZ)2-O-, -(CH2)3-, -(CH2)4- or
-(CH2)5-, in the presence of a suitable reducing agent (e.g. LiAlH4) under
2o conditions which are well known to those skilled in the art.
Compounds of formula XXXIIIA may be prepared in analogous fashion to
compounds of formula XV (i.e. from the corresponding alcohol).
Qta p2a
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34
Compounds of formulae X, XXIII and XXV (in which, in all cases, R~' and
R~ both represent H), may be prepared, advantageously, by reaction of (as
appropriate) either (i) a compound of formula XXXV,
R4° R44
R4~ .. R4z
O/ \ORZ
s wherein RZ represents C1_lo alkyl or C1_3 alkylaryl (e.g. alkylphenyl, such
as
benzyl) and R41, R42, Ra3 and R~ are as hereinbefore defined, or (ii) 4-
piperidone (or a protected derivative thereof), with (as appropriate) either
(1) a compound of formula XXXVI,
R'-B-C(RS)(R6)-A-NHS XXXVI
io wherein R5, R6, R', A and B are as hereinbefore defined, or (2) NH3 (or a
protected (e.g. benzyl) derivative thereof), in all cases in the presence of a
formaldehyde (i.e. an appropriate source of formaldehyde, such as
paraformaldehyde or formalin solution) and, in the case of compounds of
formulae X and XXV, conversion of the C(O)ORZ group in the resultant
is intermediate to a C(O)N(R3)(R4) group using techniques such as those
described herein (e.g. process step (c) above).
The formation of compounds of formulae X, XXIII and XXV may be
carried out in this way for example at between room temperature and reflux
zo (depending upon the concentration of the reactants) in the presence of an
appropriate solvent (e.g. ethanol or methanol) and, preferably, in the
presence of an organic acid (e.g. a C1~ carboxylic acid, especially acetic
acid).
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It will be also appreciated by those skilled in the art that compounds of
formula XXII in which Rl and R'- both represent H may also be prepared
via this method (i.e. by reaction of a compound of 4-piperidone (or a
s protected derivative thereof) with NH3 (or a protected derivative thereof)
in
the presence of a formaldehyde), provided that the intermediate so formed is
subsequently reduced under appropriate reaction conditions.
The skilled person will also appreciate that this process may also be used
io to prepare compounds of formula I in which R41 and R42. are H, and R4s
and/or R'~6 are other than H, for example by:
(i) reacting a compound of formula XXXV in which R41 and/or R4'-
is/are other than H with, for example, benzylamine or a derivative
thereof;
is (ii) removal of the -C(O)ORZ unit;
(iii) reaction at the free bispidine nitrogen of the resultant compound
with a compound of formula VIII as hereinbefore defined;
(iv) removal of the benzyl protecting group; and
(v) reaction at the free bispidine nitrogen of the resultant compound
2o with, for example, a compound of formula III or IV as hereinbefore
defined,
under conditions well known to those skilled in the art including those
described hereinbefore. This reaction will be accompanied by, at some
point, conversion of the bridgehead carbonyl functionality to the desired
2s R1/R'- groups.
Compounds of formula XXXIV may be prepared in accordance with
techniques which are well known to those skilled in the art. For example,
compounds of formula XXXIV in which R'a and R'-a together represent
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36
-(CHZ)3-, -(CHZ)4- or -(CH2)s- may be prepared by reaction of a compound
of formula XXXVII,
N
XXXV I I
H
wherein Rla~ and R'-a~ together represent -(CHZ)3-, -(CH2)4- or -(CHZ)s-,
s with a mixture of phosphoric acid and sulfuric acid, for example at
120°C.
Compounds of formula XXXVI are well known in the literature or are
readily available using known techniques. For example, compounds of
formula XXXVI wherein Rs represents OH, R6 represents H and A
to represents CHI may be prepared by reaction of a compound of formula
VII in which R~ represents H and X represents O with ammonium
hydroxide under conditions which are well known to those skilled in the
art.
is Compounds of formulae III, VA, XIA, XII, XIV, XVI, XVII, XVIII,
XIX, XXI, XXIB, XXIV, XXVI, XXVII, XXVIII, XXVIIIA, XXIX,
XXX, XXXI, XXXIA, XXXII, XXXIII, XXXV and XXXVII and
derivatives thereof, are either commercially available, are known in the
literature, or may be obtained either by analogy with the processes
2o described herein, or by conventional synthetic procedures, in accordance
with standard techniques, from readily available starting materials using
appropriate reagents and reaction conditions.
Substituents on the aryl (e.g. phenyl), and (if appropriate) heterocyclic,
2s group(s) in compounds defined herein may be converted to other claimed
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37
substituents using techniques well known to those skilled in the art. For
example, nitrobenzene may be reduced to an aminobenzene, hydroxy may
be converted to alkoxy, alkoxy may be hydrolysed to hydroxy, etc.
s The compounds of the invention may be isolated from their reaction
mixtures using conventional techniques.
It will be appreciated by those skilled in the art that, in the process
described above, the functional groups of intermediate compounds may be,
io or may need to be, protected by protecting groups.
Functional groups which it is desirable to protect include hydroxy, amino
and carboxylic acid. Suitable protecting groups for hydroxy include
trialkylsilyl and diarylalkylsilyl groups (e.g. ten-butyldimethylsilyl, tert-
is butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl and
alkylcarbonyloxy groups (e.g. methyl- and ethylcarbonyloxy groups).
Suitable protecting groups for amino include benzyl, tent-butyloxycarbonyl,
9-fluorenylmethoxycarbonyl or benzyloxycarbonyl. Suitable protecting
groups for carboxylic acid include C,~ alkyl or benzyl esters.
The protection and deprotection of functional groups may take place before
or after any of the reaction steps described hereinbefore.
Protecting groups may be removed in accordance with techniques which are
2s well known to those skilled in the art and as described hereinafter.
The use of protecting groups is fully described in "Protective Groups in
Organic Chemistry", edited by J W F McOmie, Plenum Press (1973), and
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"Protective Groups in Organic Synthesis", 2nd edition, T W Greene & P G
M Wutz, Wiley-Interscience (1991).
Persons skilled in the art will appreciate that, in order to obtain compounds
s of the invention in an alternative, and, on some occasions, more convenient,
manner, the individual process steps mentioned herein may be performed in
a different order, and/or the individual reactions may be performed at a
different stage in the overall route (i.e. substituents may be added to and/or
chemical transformations performed upon, different intermediates to those
to associated hereinbefore with a particular reaction). This will depend inter
alia on factors such as the nature of other functional groups present in a
particular substrate, the availability of key intermediates and the protecting
group strategy (if any) to be adopted. Clearly, the type of chemistry
involved will influence the choice of reagent that is used in the said
is synthetic steps, the need, and type, of protecting groups that are
employed,
and the sequence for accomplishing the synthesis.
It will also be appreciated by those skilled in the art that, although certain
protected derivatives of compounds of formula I, which may be made prior
2o to a final deprotection stage, may not possess pharmacological activity as
such, they may be administered parenterally or orally and thereafter
metabolised in the body to form compounds of the invention which are
pharmacologically active. Such derivatives may therefore be described as
"prodrugs" . Moreover, we have found that certain compounds of formula I
2s may act as prodrugs of other compounds of formula I.
All prodrugs of compounds of formula I are included within the scope of the
invention.
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~9
Some of the intermediates referred to hereinbefore are novel. According to
a further aspect of the invention there is thus provided: (a) a compound of
formula II, as hereinbefore defined or a protected derivative thereof,
s provided that R7 does not represent optionally substituted phenyl; (b) a
compound of formula V, as hereinbefore defined or a protected derivative
thereof, provided that R' does not represent optionally substituted phenyl;
(c) a compound of formula X as hereinbefore defined or a protected
derivative thereof; (d) a compound of formula XI as hereinbefore defined or
io a protected derivative thereof; (e) a . compound of formula XIII, as
hereinbefore defined or a protected derivative thereof; (f) a compound of
formula XV, as hereinbefore defined or a protected derivative thereof; (g) a
compound of formula XX, as hereinbefore defined or a protected derivative
thereof; (h) a compound of formula XXIII, as hereinbefore defined or a
is protected derivative thereof, provided that R' does not represent
optionally
substituted phenyl; and (i) a compound of formula XXV, as hereinbefore
defined or a protected derivative thereof.
Medical and pharmaceutical use
The compounds of the invention are useful because they possess
pharmacological activity. They are therefore indicated as pharmaceuticals.
Thus, according to a further aspect of the invention there is provided the
2s compounds of the invention for use as pharmaceuticals.
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In particular, the compounds of the invention exhibit myocardial
electrophysiological activity, for example as demonstrated in the test
described below.
s The compounds of the invention are thus expected to be useful in both the
prophylaxis and the treatment of arrhythmias, and in particular atrial and
ventricular arrhythmias.
The compounds of the invention are thus indicated in the treatment or
to prophylaxis of cardiac diseases, or in indications related to cardiac
diseases,
in which arrhythmias are believed to play a major role, including ischaemic
heart disease, sudden heart attack, myocardial infarction, heart failure,
cardiac surgery and thromboembolic events.
is In the treatment of arrhythmias, compounds of the invention have been
found to selectively delay cardiac repolarization, thus prolonging the QT
interval, and, in particular, to exhibit class III activity. Although
compounds of the invention have been found to exhibit class III activity in
particular, in the treatment of arrhythmias, their models) of activity is/are
2o not necessarily restricted to this class.
According to a further aspect of the invention, there is provided a method of
treatment of an arrhythmia which method comprises administration of a
therapeutically effective amount of a compound of the invention to a person
2s suffering from, or susceptible to, such a condition.
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Pharmaceutical preparations
41
The compounds of the invention will normally be administered orally,
subcutaneously, intravenously, intraarterially, transdermally, intranasally,
s by inhalation, or by any other parenteral route, in the form of
pharmaceutical preparations comprising the active ingredient either as a free
base, a pharmaceutically acceptable ion exchanger or a non-toxic organic or
inorganic acid addition salt, in a pharmaceutically acceptable dosage form.
Depending upon the disorder and patient to be treated, as well as the route
to of administration, the compositions may be administered at varying doses.
The compounds of the invention may also be combined with any other drugs
useful in the treatment of arrhythmias and/or other cardiovascular disorders.
1 s According to a further aspect of the invention there is thus provided a
pharmaceutical formulation including a compound of the invention in
admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.
Suitable daily doses of the compounds of the invention in therapeutic
Zo treatment of humans are about 0.05 to 5.0 mg/kg body weight at parenteral
administration.
The compounds of the invention have the advantage that they are effective
against cardiac arrhythmias.
2~
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Compounds of the invention may also have the advantage that they may be
more efficacious than, be less toxic than, have a broader range of activity
(including exhibiting any combination of class I, class II, class III and/or
class IV activity (especially class I, class II and/or class IV activity in
s addition to class III activity)) than, be more potent than, be longer acting
than, produce fewer side effects (including a lower incidence of
proarrhythmias such as torsades de pointer) than, be more easily absorbed
than, or that they may have other useful pharmacological properties over,
compounds known in the prior art.
to
Biological Tests
Test A
Primary Electrophysiological Effects In Anaesthetised Guinea Pigs
Is Guinea pigs weighing between 660 an 1100 g were used. The animals were
housed for at least one week before the experiment and had free access to
food and tap water during that period.
Anaesthesia was induced by an intraperitoneal injection of pentobarbital (40
2o to 50 mg/kg) and catheters were introduced into one carotid artery (for
blood pressure recording and blood sampling) and into one jugular vein (for
drug infusions). Needle electrodes were placed on the limbs for recording
of ECGs (lead II). A thermistor was placed in the rectum and the animal
was placed on a heating pad, set to a rectal temperature of between 37.5 and
2s 38.5°C.
A tracheotomy was performed and the animal was artificially ventilated with
room air by use of a small animal ventilator, set to keep blood gases within
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43
the normal range for the species. In order to reduce autonomic influences
both vagi were cut in the neck, and 0.5 mg/kg of propranolol was given
intravenously, 15 minutes before the start of the experiment.
s The left ventricular epicardium was exposed by a left-sided thoracotomy,
and a custom-designed suction electrode for recording of the monophasic
action potential (MAP) was applied to the left ventricular free wall. The
electrode was kept in position as long as an acceptable signal could be
recorded, otherwise it was moved to a new position. A bipolar electrode
io for pacing was clipped to the left atrium. Pacing (2 ms duration, twice the
diastolic threshold) was performed with a custom-made constant current
stimulator. The heart was paced at a frequency just above the normal sinus
rate during 1 minute every fifth minute throughout the study.
is The blood pressure, the MAP signal and the lead II ECG were recorded on
a Mingograph ink jet recorder (Siemens-Elema, Sweden). All signals were
collected (sampling frequency 1000 Hz) on a PC during the last 10 seconds
of each pacing sequence and the last 10 seconds of the following minute of
sinus rhythm. The signals were processed using a custom-made program
zo developed for acquisition and analysis of physiological signals measured in
experimental animals (see Axenborg and Hirsch, Comput. Methods
Programs Biomed. 41, 55 (1993)).
The test procedure consisted of taking two basal control recordings, 5
2s minutes apart, during both pacing and sinus rhythm. After the second
control recording, the first dose of the test substance was infused in a
volume of 0.2 mL into the jugular vein catheter for 30 seconds. Three
minutes later, pacing was started and a new recording was made. Five
minutes after the previous dose, the next dose of test substance was
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administered. Six to ten consecutive doses were given during each
experiment.
Data analysis
s
Of the numerous variables measured in this analysis, three were selected as
the most important for comparison and selection of active compounds. The
three variables selected were the MAP duration at 75 percent repolarization
during pacing, the atrio-ventricular (AV) conduction time (defined as the
i o interval between the atrial pace pulse and the start of the ventricular
MAP)
during pacing, and the heart rate (defined as the RR interval during sinus
rhythm) . Systolic and diastolic blood pressure were measured in order to
judge the haemodynamic status of the anaesthetised animal. Further, the
ECG was checked for arrhythmias and/or morphological changes.
is
The mean of the two control recordings was set to zero and the effects
recorded after consecutive doses of test substance were expressed as
percentage changes from this value. By plotting these percentage values
against the cumulative dose administered before each recording, it was
Zo possible to construct dose-response curves. In this way, each experiment
generated three dose-response curves, one for MAP duration, one for AV-
conduction time and one for the sinus frequency (RR interval). A mean
curve of all experiments performed with a test substance was calculated, and
potency values were derived from the mean curve. All dose-response
2s curves in these experiments were constructed by linear connection of the
data points obtained. The cumulative dose prolonging the MAP duration by
% from the baseline was used as an index to assess the class III
electrophysiological potency of the agent under investigation (Dlo).
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Test B
Metabolic Stability of Test Compounds
An in vitro screen was set up to determine the metabolic stability of the
s compounds of the invention.
The hepatic S-9 fraction from dog, man, rabbit and rat with NADPH as co
factor was used. The assay conditions were as follows: S-9 (3 mg/mL),
NADPH (0.83 mM), Tris-HCl buffer (50 mM) at pH 7.4 and 10 u.M of test
io compound.
The reaction was started by addition of test compound and terminated after
0, 1, 5, 15 and 30 minutes by raising the pH in the sample to above 10
(NaOH; 1 mM). After solvent extraction, the concentration of test
i s compound was measured against an internal standard by LC
(fluorescence/UV detection).
The percentage of test compound remaining after 30 minutes (and thus tl,z)
were calculated and used as a measure for metabolic stability.
The invention is illustrated by way of the following examples.
Examples
2s General Experimental Procedures
Mass spectra were recorded on a Finnigan MAT TSQ 700 triple quadrupole
mass spectrometer equipped with an electrospray interface (FAB-MS) and
VG Platform II mass spectrometer equipped with an electrospray interface
(LC-MS), a Hewlett Packard model 6890 gas chromatograph connected to a
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Hewlett-Packard model 5973A mass spectrometer via a Hewlett Packard
HP-5-MS GC column, or a Shimadzu QP-5000 GC/mass spectrometer (CI,
methane). 1H NMR and 13C NMR measurements were performed on a
BRUKER ACP 300 and Varian UNITY plus 400 and 500 spectrometers,
s operating at 1H frequencies of 300, 400 and 500 MHz respectively, and at
13C frequencies of 75.5, 100.6 and 125.7 MHz respectively. Alternatively,
13C NMR measurements were performed on a BRUKER ACE 200
spectrometer at a frequency of 50.3 MHz.
to Rotamers may or may not be denoted in spectra depending upon ease of
interpretation of spectra. Unless otherwise stated, chemical shifts are given
in ppm with the solvent as internal standard.
Synthesis of intermediates
Example A
4-(2-Oxiranylmethoxy)benzonitrile
Epichlorohydrin (800 mL) and K,C03 (414 g) were added to a stirred
solution of p-cyanophenol (238 g) in 2.0 L MeCN and the reaction
2o mixture was refluxed under an inert atmosphere for 2 h. The hot solution
was filtered and the filtrate concentrated, giving a clear oil which was
crystallized from di-iso-propyl ether giving the product in 75 % yield.
13C NMR (CDC13): 8 44.4, 49.7, 69.0, 104.5, 115.3, 118.9, 134.0, 161.6
Example B
2(S~-Oxiranylmethyl 3-nitrobenzenesulfonate
m-Nitrobenzensulfonylchloride (12.6 g; 57 mmol) was added to a cold
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(-20°C) solution of (R)-(+)-glycidol (5.5 g; 74 mmol) and TEA (10.3 mL;
74 mmol). The reaction mixture was stirred at -20°C for 96 h. The
solution was filtered and the filtrate washed with tartaric acid (10% w/w),
brine, H20 and concentrated giving the title compound in a 97 % yield.
s
1H NMR (CDC13): 8 2.62 (dd,lH), 2.84 (dd,lH), 3.22 (m,lH), 4.07
(dd,1H), 4.49 (dd,1H), 7.80 (t,1H), 8.25 (m,1H), 8.52 (m,1H), 8.78
(m,1H)
1 o Example C
4-[(2S~-Oxiranylmethoxy]benzonitrile
The title compound was prepared in a 90 % yield according to the
procedure described in Example A above starting from (R)-(-)-
epichlorohydrin.
Example D
4-[(2R)-Oxiranylmethoxy]benzonitrile
The title compound was prepared according to the procedure described in
Example A above starting from (S~-(-)-epichlorohydrin.
[a]D2° _ -14.1 ° (c = 1.0; acetone)
1H NMR (CDC13): 8 2.79 (1H, m); 2.98 (1H, m); 3.39 (1H, m); 3.98
(1H, m); 4.37 (1H, m); 6.99 (2H, d); 7.60 (2H, d)
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Example E
48
3-Benzyl-3,7-diazabicyclo[3.3.1]nonane
(a) 3,7-Dibenzyl-3,7-diazabicyclo[3.3.1]nonane
s The sub-title compound was prepared according to the method described
in J. Org. Chem. 41, 1593, (1976) except that 3,7-dibenzyl-3,7-
diazabicyclo[3.3.1]nonan-9-one (also prepared according to the method
described in J. Org. Chem. 41, 1593 (1976)) was used instead of N
benzyl-N methylbispidone.
to
(b) 3-Benzyl-3,7-diazazbicyclo[3.3.1]nonane
3,7-Dibenzyl-3,7-diazabicyclo[3.3.1]nonane (1.97 g; 6.4 mmol; from step
(a) above) was dissolved in EtOH (95 % ) and hydrogenated over 5 % Pd/C
at 1 atm. until tlc indicated that the reaction was complete. The catalyst
is was removed by filtration through a pad of Celite~ and the residue was
concentrated under reduced pressure to give the title compound in a
quantitative yield.
13C NMR (CDC13): 8 30.1, 33.4, 36.0, 52.5, 59.6, 64.3, 126.9, 128.3,
20 128.7, 138.8
Example F
tert-Butyl 3,7-diazabicyclo[3.3.1]nonane-3-carboxylate
2s (a) tert-Butyl 7-benzyl-9-oxy-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate
Paraformaldehyde (4.00 g; 127 mmol) was added to a solution of
benzylamine (13.7 g; 126 mmol) in ethanol (190 mL). The solution was
heated to 60°C and a solution of acetic acid (15.2 g; 252 mmol) in
ethanol
(160 mL) was added over 2 hours. After additional stirring for 1 hour, the
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solution was cooled to room temperature. This solution was added (over 2
hours) to a mixture of 1-tert-butoxycarbonyl-4-piperidone (25.5 g; 127
mmol) and paraformaldehyde (4.80 g; 152 mmol) in ethanol (270 mL)
which had been heated to 60°C. After reflux overnight, the solution was
s cooled to room temperature. The ethanol was removed by evaporation.
Extractive work-up was performed in toluene: water and the material was
filtered through silica in a toluene:ethyl acetate system. Evaporation of the
eluant gave a solid material (37.4 g). The purity was 90 area% (HPLC)
and the yield was 60 % . By performing a crystallisation in iso-propanol, a
t o compound with a purity of 98 area % (HPLC) and a yield of 70 % was
obtained.
MS (EI; 70 eV): m/z 91 ( 100 % ), m/z 57 (42 % ), m/z 273 (32 % ), m/z 330
(5 %)
is 13C NMR (CDCl3): ~ 28.72, 47.71, 49.91, 50.60, 58.83, 59.16, 61.96,
80.18, 127.37, 128.45, 128.89. 137.57, 154.89, 213.66 (using TMS as
reference)
(b) tert-Butyl 7-benzyl-9-oxy-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate
20 (alternative preparation)
Benzylamine (6.51 g; 60.2 mmol), acetic acid (72.3 g, 1200 mmol),
paraformaldehyde (3.71 g; 120 mmol) and 1-tert-butoxycarbonyl-4-
piperidone (12.0 g; 60.2 mmol), were added to ethanol (300 mL). The
solution was heated to 65°C and stirred at this temperature for 2
hours.
2s The same work-up procedure as that described in step (a) above was
performed, yielding 15.78 g of material with a purity of 92 area
(HPLC) and a yield of 70 % . Recrystallisation from iso-propanol yielded a
compound with a purity of 94 area % (HPLC) in a yield of 54 % .
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SO
(c) tert-Butyl 7-benzyl-3,7-diazabicyclo[3.3.1]-nonane-3-carboxylate
A mixture of 4-toluenesulfonehydrazide (12.4 mmol; 2.30 g) and tert-
butyl 7-benzyl-9-oxy-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (10.1
mmol; 4.00 g; 83.3 % ; from step (a) above) were dissolved in iso-propanol
s (30 mL) and heated at reflux for 2 hours. Acetic acid (2.5 mmol; 0.15 g)
and sodium cyanoborohydride ( 12.1 mmol, 0.76 g) were added and the
mixture was again heated at reflux for 2 hours. The slurry was cooled to
ambient temperature and filtered. The filtrate was concentrated and an
extractive work-up was performed in toluene:water. The toluene solution
io was concentrated to give 0.95 g of sub-title compound, with a purity of 90
area % (GC) in a yield of 60 % .
MS (EI; 70 eV): m/z 259 (100% ), m/z 91 (95 % ), m/z 169 (45 % ), m/z 57
(35 %), m/z 316 (25 % )
is 13C NMR (CDC13): 8 28.67, 28.95, 31.11, 47.55, 48.38, 58.70, 58.96,
63.46, 78.71, 126.57, 128.00, 128.53, 138.94, 155.20 (using TMS as a
reference)
(d) tert-Butyl 3,7-diazabicyclo[3.3.1]nonane-3-carboxylate
Zo tert-Butyl 7-benzyl-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (from
step (c) above) was debenzylated according to the method described in
Example E(b) above to give the title compound in quantitative yield.
13C NMR (CDC13): 8 28.05, 28.29, 31.33, 48.35, 49.11, 51.53, 79.34,
2s 155.16
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Example G
4-[3-(3,7-Diazabicyclo[3.3.1]non-3-yl)-2-hydroxypropoxy]benzonitrile
HCl-saturated EtOAc (600 mL) was added to a solution of tert-butyl 7-[3-
(4-cyanophenoxy)-2-hydroxypropyl]-3,7-diazabicyclo[3.3.1]nonane-3-
carboxylate (62 g; see Example 2 of international patent application No.
PCT/SE98/02276) in EtOAc (600 mL) and the mixture was stirred at rt.
for 4 h. The solvent was removed under reduced pressure, the residue was
dissolved in MeCN (1.3 L) and K,C03 (100 g) was added. The suspension
was stirred for 12 h and filtered. Concentration of the filtrate gave the
title
to compound in a 90% yield.
13C NMR (CDC13): 8 28.9, 29.2, 32.3, 50.9, 57.7, 60.8, 62.1, 66.0,
71.2, 104.0, 115.3, 119.1, 133.9, 162.1
(The title compound was also readily converted to the hydrochloride salt
using standard techniques.)
Preparation of Compounds of Formula I
2o Example 1
7-[(2S)-3-(4-Cyanophenoxy)-2-hydroxypropyl]-N ethyl-3,7-diazabicyclo-
[3.3.1]nonane-3-carboxamide
Ethyl isocyanate (1.42 g, 16.6 mmol) was added to a solution of 4-{[(2S~-
3-(3,7-diazabicyclo[3.3.1]non-3-yl)-2-hydroxypropyl]oxy}benzonitrile)
(5.0 g, 20 mmol, see Example G above) in 30 mL of dichloromethane.
The mixture was stirred for 4 hours at room temperature and was then
concentrated in vacuo and purified by column chromatography on silica,
eluting with dichloromethane: methanol (95:5), to yield 3.2 g (51 % ) of the
title compound.
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s2
13C NMR (CDC13): 8 15.52, 29.19, 29.50, 31.89, 35.77, 48.00, 49.17,
57.21, 60.49, 61.83, 65.41, 70.71, 103.88, 115.34, 119.15, 133.78,
133.84, 158.87, 162.19
s Example 2
7-[3-(4-Cyanophenoxy)-2-hydroxypropyl]-N (cyclopropylmethyl)-3,7-
diazabicyclo[3 .3 .1]nonane-3-carboxamide
(a) Cyclopropylmethyl isocyanate
to Cyclopropylmethylamine (1.4 g, 19.7 mmol) was added to a suspension of
1,1'-carbonyldiimidazole (3.2 g, 19.7 mmol) in THF (10 mL). The
resulting solution was stirred overnight at room temperature before being
subjected to distillation, yielding 0.4 g (21 % ) of the sub-title compound.
is (b) 7-[3-(4-Cyanophenoxy)-2-hydroxypropyl]-N (cyclopropylmethyl)-3,7-
diazabicyclo[3.3.1]nonane-3-carboxamide
Cyclopropylmethyl isocyanate (0.4 g, 4 mmol, from step (a) above) was
added to a solution of 4-[3-(3,7-diazabicyclo[3.3.1]non-3-yl)-2-hydroxy-
propoxy]benzonitrile (1.2 g, 4 mmol, see Example G above) in DCM.
2o The solution was stirred overnight, then concentrated in vacuo. The
resulting residue was purified by column chromatography on silica gel,
eluting with dichloromethane:methanol (93:7), to yield 0.85 g (50%) of
the title compound.
2s 13C NMR (CDC13): ~ 3.29, 11.21, 29.31, 29.61, 32.10, 46.11, 48.14,
49.39, 57.24, 60.58, 62.04, 65.46, 70.76, 104.03, 115.37, 119.18,
133.88, 158.97, 162.22
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S3
Example 3
4-({(2S~-2-Hydroxy-3-[7-(4-morpholinylcarbonyl)-3,7-diazabicyclo-
[3.3.1]non-3-yl]propyl}oxy)benzonitrile
A solution of 4-{[(2,5~-3-(3,7-diazabicyclo[3.3.1]non-3-yl)-2-hydroxy-
S propyl]oxy}benzonitrile) (2.0 g, 6.6 mmol, prepared analogously to the
method described in Example G above) in DCM (10 mL) was treated with
aqueous NaOH (0.8 mL of 10 M), followed by 4-morpholinecarbonyl
chloride (1.2 g, 8 mmol). The resulting mixture was stirred for 30 min. at
room temperature, before water was added. The organic layer was
io separated, washed with 2 M NaOH followed by brine, before being
separated, dried (MgSO.~) and concentrated in vacuo. The residue was
recrystallised twice, firstly from iso-propanol and then from ethanol, to
yield 0.73 g (26.5 % ) of the title compound.
tS 13C NMR (CDC13): b 23.36, 29.59, 30.05, 32.34, 47.45, 49.51, 52.18,
56.86, 60.78, 62.82, 65.35, 66.66, 70.82, 104.03, 115.33, 119.17,
133.88, 162.23, 164.99
Example 4
20 7-{3-(4-Cyanophenoxy)-2-[(methanesulfonyl)amino]-propyl}-N ethyl-3,7-
diazabicyclo[3.3.1]nonane-3-carboxamide
(a) 4-(3-Amino-2-hydroxypropoxy)benzonitrile
4-(2-Oxiranylmethoxy)benzonitrile (100 g, 0.57 mol, see Example A
2S above) was added to a mixture of concentrated aqueous ammonium
hydroxide (500 mL) and iso-propanol (300 mL). The resulting slurry was
stirred at room temperature for 3 days. The reaction mixture was filtered
to remove the insoluble by-product, and the filtrate was concentrated in
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54
vacuo to give a crude product, which was crystallised from acetonitrile to
yield 50 g (46 % ) of the sub-title compound.
(b) 2-(4-Cyanophenoxy)-1-{[(methanesulfonyl)amino]methyl}ethyl
s methanesulfonate
Methanesulfonyl chloride (17.5 g, 153 mmol) was slowly added to a
cooled (-10°C) solution of 4-(3-amino-2-hydroxypropoxy)benzonitrile
( 13 . 3 g, 69 mmol, from step (a) above) and 4-(dimethylamino)pyridine
(0.2 g, 1.64 mmol) in pyridine (100 mL). The yellow solution was stirred
Io at rt for 1.5 hours, concentrated in vacuo and then redissolved in DCM.
This solution was washed twice with 2 M HC1 and once with NaHC03
solution before the organic phase was separated, dried (MgSO,~) and
concentrated in vacuo to yield 23.5 g (100 % ) of the sub-title compound.
is (c) 4-{[1-(Methanesulfonyl)aziridin-2-yl]methoxy}benzonitrile
A stirred solution of 2-(4-cyanophenoxy)-1-{[(methanesulfonyl)amino]-
methyl}ethyl methanesulfonate (23.5 g, 67 mmol, from step (b) above) in
acetonitrile (200 mL), was treated with potassium carbonate (30 g,
210 mmol), forming a thick precipitate. After 1 hour, a further portion of
Zo K,C03 (30 g, 210 mmol) was added. Stirring was continued for 2 h at rt
before the reaction mixture was filtered and the filtrate concentrated in
vacuo. The resulting oil (13 g) was crystallised from toluene to give 8 g
(47 % ) of the sub-title compound.
2s mp 79-81 °C
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(d) N {2-(7-Benzyl-3,7-diazabicyclo[3.3.1]non-3-yl)-1-[(4-cyanophenoxy)-
methyl]ethyl~methanesulfonamide
A mixture of 3-benzyl-3,7-diazabicyclo[3.3.1]nonane (2 g, 10 mmol, see
Example E above) and 4-{[1-(methanesulfonyl)aziridin-2
s yl]methoxy}benzonitrile (2.5 g, 10 mmol, from step (c) above) in iso
propanol was refluxed overnight. The mixture was then concentrated in
vacuo, giving a residue which was then dissolved in water (pH 3) and
extracted with ether. The aqueous layer was made basic with 2 M NaOH
and extracted with DCM. The dichloromethane layer was separated, dried
io and concentrated in vaccco to give a residue which was purified by column
chromatography, eluting with a gradient of DCM:methanol:methanolic
ammonia (98:2:0 to 97:0:3) to give 2.5 g (53 % ) of the sub-title
compound.
is (e) N [2-(4-Cyanophenoxy)-1-(3,7-diazabicyclo[3.3.1]non-3-ylmethyl)-
ethyl]methanesulfonamide
A solution of N {2-(7-benzyl-3,7-diazabicyclo[3.3.1]non-3-yl)-1-[(4-
cyanophenoxy)methyl]ethyl}methanesulfonamide (2.3 g 4.9 mmol, from
step (d) above) in aqueous ethanol (95 % ; 55 mL) was hydrogenated over
20 5 % Pd/C at ambient pressure. The catalyst was removed by filtration
through a pad of Celite~ and the residue was concentrated in vacuo to give
1.6 g of a crude product. This was recrystallised from methanol to yield
0.3 g (16 % ) of the sub-title compound.
zs (f) 7-~3-(4-Cyanophenoxy)-2-[(methanesulfonyl)amino]propyl~-N ethyl-
3,7-diazabicyclo[3.3.1]nonane-3-carboxamide
A suspension of N [2-(4-cyanophenoxy)-1-(3,7-diazabicyclo[3.3.1]non-3-
ylmethyl)ethyl]methanesulfonamide (0.29 g, 0.77 mmol, from step (e)
above) in DCM (10 mL) was treated with ethyl isocyanate (66 pL,
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s6
RZ and R3 independently represent H, C,~ alkyl (optionally substituted
and/or terminated with one or more vitro or cyano groups), OR',
N(R'a)R'b, OC(O)Rg or together form -O-(CHZ)2-O-, -(CHZ)3-, -(CH2)4- or
s -(CH2)s-~
R' and Rg independently represent H, C 1_6 alkyl or -(CHZ)b-aryl (which
latter two groups are optionally substituted and/or terminated by one or
more substituents selected from -OH, halo, cyano, vitro, C1_4 alkyl and/or
C1_4 alkoxy);
io R'a and R'b independently represent H or C1_6 alkyl;
b represents 0, 1, 2, 3 or 4;
R4 represents H or C,_6 alkyl;
is D represents H, C,.~ alkyl, -OR9, or -(CH2)~N(R1°)(Rn);
R9 represents H, C1_6 alkyl, -C(O)Rlz, -(CH2)d-aryl or -(CH2)d-Het2 (which
latter three groups are optionally substituted by one or more substituents
selected from -OH, halo, cyano, vitro, C,_4 alkyl, C1~ alkoxy, C(O)R'3,
C(O)OR14 and/or -N(H)S(O)eRls);
2o Rl° represents H, C1_6 alkyl, -(CH2)~-aryl, -C(NH)NH2,
-S(O)zRisa~ -~C(O)~gN(Rib)(Rm)~ -C(O)Ris or -C(O)OR19;
a represents 0, 1 or 2;
g represent 1 or 2;
Rll represents H, C1_6 alkyl, -C(O)RZ° or -(CHZ)h-aryl (which
latter group
2s is optionally substituted and/or terminated (as appropriate) by one or more
substituents selected from -OH, cyano, halo, amino, vitro, C,_6 alkyl
and/or C1_6 alkoxy);
R~z, R~3, R'4, Rl~, Rl', Rlg, R~9 and RZ° independently represent
H, C,_6
alkyl, Het3 or -(CHZ)~-aryl (which latter three groups are optionally
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0.84 mmol) to give a clear solution. The mixture was stirred for 1 h at rt,
concentrated in vacuo and then purified by column chromatography,
eluting with 5 % MeOH in DCM, to give the title compound in 73 % yield.
s 13C NMR (CDC13): ~ 15.41, 28.88, 29.18, 30.77, 35.87, 41.78, 47.93,
48.65, 49.98, 58.24, 58.51, 60.15, 68.82, 104.51, 115.28, 118.95,
134.05, 158.58, 161.55
Example 5
l0 7-[(2,5~-3-(4-Cyanophenoxy)-2-hydroxypropyl]-N iso-propyl-3,7-
diazabicyclo[3.3.1]nonane-3-carboxamide
(a) 7-Benzyl-N iso-propyl-3,7-diazabicyclo[3.3.1]nonane-3-carboxamide
iso-Propyl isocyanate (1.7 g, 20 mmol) was slowly added to a solution of
is 3-benzyl-3,7-diazabicyclo[3.3.1]nonane (3.1 g, 14.3 mmol, see Example
E above) in DCM ( 10 mL) . The mixture was stirred at rt overnight and
then concentrated in vacuo to yield 4.2 g (97 % ) of the sub-title compound.
(b) N iso-Propyl-3,7-diazabicyclo[3.3.1]nonane-3-carboxamide
2o A solution of 7-benzyl-N iso-propyl-3,7-diazabicyclo[3.3.1]nonane-3-
carboxamide (4.2 g, 14 mmol, from step (a) above) in methanol/water
(17 mL of a 15:2 mixture) was hydrogenated over 5 % Pd/C at ambient
pressure. The catalyst was removed by filtration through a pad of Celite~,
and the filtrate concentrated in vacuo to yield 2.6 g (87 % ) of the sub-title
2s compound.
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(c) 7-[(2S~-3-(4-Cyanophenoxy)-2-hydroxypropyl]-N-iso-propyl-3,7-diaza-
bicyclo[3.3.1]nonane-3-carboxamide
A mixture of 4-[(2S)-oxiranylmethoxy]benzonitrile (0.55 g, 3.14 mmol,
see Example C above) and N iso-propyl-3,7-diazabicyclo[3.3.1]nonane-3-
s carboxamide (0.85 g, 4 mmol, from step (b) above) in iso-propanol/water
(6.5 mL of a 12:1 mixture) was stirred overnight at 60 ° C . The
mixture
was then concentrated in vacuo and the residue re-dissolved in DCM. The
organic solution was washed with water then brine, dried (MgS04) and
concentrated in vacuo to give the title compound in 91 % yield.
io
13C NMR (CDC13): 8 23.49, 29.29, 31.78, 42.26, 47.71, 49.09, 56.92,
60.27, 61.65, 65.19, 70.61, 103.54, 115.21, 119.09, 133.65, 158.11,
162.08
1 s Example 6
7-((2R)-3-(4-Cyano-2-~ [(2-cyanoethyl)amino] carbonyl~-
phenoxy)-2-hydroxypropyl]-N ethyl-3,7-diazabicyclo[3.3.1]nonane-3-
nnrhnvomir~a
20 (a) 7-Benzyl-N ethyl-3,7-diazabicyclo[3.3.1]nonane-3-carboxamide
A cooled (0°C) solution of 3-benzyl-3,7-diazabicyclo[3.3.1]nonane
(32.45 g, 0.15 mol, see Example E above) in DCM (300 mL) was treated
with ethyl isocyanate (11.4 g, 0.16 mol), added dropwise. The solution
was stirred for 2 h at rt before being concentrated in vacuo. The resulting
2s residue was purified by chromatography on silica gel, eluting with a
gradient of DCM:MeOH (100:0 to 90:10) to yield 36.4 g (84%) of the
sub-title compound.
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(b) N Ethyl-3,7-diazabicyclo[3.3.1]nonane-3-carboxamide
A solution of 7-benzyl-N ethyl-3,7-diazabicyclo[3.3.1]nonane-3-
carboxamide (4.4 g, 15.3 mmol, from step (a) above) in aqueous ethanol
(25 mL of 95 % ) was hydrogenated over 5 % Pd/C at ambient pressure.
s The catalyst was removed by filtration through a pad of Celite~, and the
residue was concentrated in vacuo to yield 2.88 g (95 % ) of the sub-title
compound.
(c) Methyl 5-bromo-2-hydroxybenzoate
io Br2 (52 g) was slowly added to a stirred solution of methyl salicylate (50
g; 330 mmol) in 300 mL acetic acid. The reaction mixture was stirred at
rt. for 10 h, poured onto ice-water and the precipitate recrystallized from
MeOH, giving the sub-title compound in a 83 % yield.
is (d) Methyl 5-cyano-2-hydroxybenzoate
Methyl 5-bromo-2-hydroxybenzoate (190.8 g; from step (c) above) and
CuCN (73.9 g) were refluxed in DMF (500 mL) for 7 h. The temperature
was allowed to decrease to 80°C and HCl (500 mL) and FeCl3 (165.0 g)
were added. The reaction mixture was stirred for 30 min., concentrated
2o and partitioned between HBO and DCM. The organic layer was dried,
concentrated the residue recrystallized from methylethyl ketone giving the
sub-title compound in a 61 % yield.
(e) 5-Cyano-N (2-cyanoethyl)-2-hydroxybenzamide
zs A mixture of methyl 5-cyano-2-hydroxybenzoate (20 g, 0.113 mol, from
step (d) above), 3-aminopropanenitrile (15.4 g, 0.22 mol) and sodium
cyanide (1 g, 20 mmol) in methanol (200 mL) was refluxed overnight.
Tlc showed incomplete reaction, so DMSO (50 mL) was added, and reflux
was continued for a further 5 h. The solution was concentrated in vacc~o,
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water added, followed by conc. HC1, until a precipitate formed. The
product was filtered off, washed with water and dried to yield 19.4 g
(80 % ) of the sub-title compound.
s (f) 5-Cyano-N (2-cyanoethyl)-2-[(2R)-oxiranylmethoxy]benzamide
A mixture of 5-cyano-N (2-cyanoethyl)-2-hydroxybenzamide (2.1 g,
9.8 mmol, from step (e) above) and 10 equivalents of (S)-epichlorohydrin
in iso-propanol: water (55 mL of 10:1 ) was refluxed overnight. The
mixture was concentrated in vacuo and the residue purified by column
io chromatography, eluting with ethyl acetate to yield 0.63. g (24%) of the
sub-title compound.
(g) 7-[(2R)-3-(4-Cyano-2-~[(2-cyanoethyl)amino]carbonyl~phenoxy)-2-
hydroxypropyl]-N ethyl-3,7-diazabicyclo[3.3.1]nonane-3-carboxamide
is A mixture of 5-cyano-N (2-cyanoethyl)-2-[(2R)-oxiranylmethoxy]-
benzamide (0.63 g, 2.3 mmol, from step (f) above) and N ethyl-3,7-
diazabicyclo[3.3.1]nonane-3-carboxamide (0.59 g, 3 mmol, from step (b)
above) in iso-propanol:water (33 mL of 10:1) was stirred under reflux
overnight. The reaction mixture was concentrated in vacuo and the
Zo residue purified by column chromatography, eluting with DCM:MeOH
(9:1), to yield 0.78 g (73 % ) of the title compound.
13C NMR (CDC13): S 15.40, 15.55, 17.94, 28.04, 29.21, 29.55, 31.31,
32.03, 35.69, 35.89, 36.21, 47.93, 48.65, 49.36, 57.00, 60.47, 61.05,
2s 65.32, 72.21, 105.39, 114.37, 118.22, 118.45, 123.28, 136.36, 136.45,
158.53, 159.20, 160.08, 163.75
ES-MS (M+1)+ 469.0 (m/z)
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Example 7
7-((2S~-3-{4-Cyano-2-[(cyclopropylamino)carbonyl]-
phenoxy}-2-hydroxypropyl)-N ethyl-3,7-diazabicyclo[3.3.1]nonane-3-
rarhnxamirja
(a) Ni-Cyclopropyl-5-cyano-2-hydroxybenzamide
Cyclopropylamine (14.3 g) and Na (100 mg) were added to a solution of
methyl 5-cyano-2-hydroxybenzoate (10.0 g; from step (d) above) in
DMSO (40 mL). The reaction mixture was heated at 80°C in a sealed
steel
to vessel overnight, diluted with HBO, acidified and extracted with EtOAc,
giving the sub-title compound (11.0 g), after concentration of the organic
layer.
(b) 5-Cyano-N cyclopropyl-2-[(2,5~-oxiranylmethoxy]benzamide
is A mixture of N'-cyclopropyl-5-cyano-2-hydroxybenzamide (1.56 g,
7.7 mmol, from step (a) above), (2S~-oxiranylmethyl 3-nitrobenzene-
sulfonate (2 g, 7.7 mmol, see Example B above) and K~C03 (1.16 g, 8.4
mmol) in 2-butanone ( 15 mL) was stirred at 60 ° C for 18 h. The
mixture
was concentrated in vacico and the residue crystallised from di-i,ro-propyl
2o ether:MeCN (9:1) to yield 0.97 g (97%) of the sub-title compound.
(c) 7-((2S~-3-{4-Cyano-2- (cyclopropylamino)carbonyl]phenoxy}-2-
hydroxypropyl)-N ethyl-3,7-diazabicyclo[3.3.1]nonane-3-carboxamide
A mixture of 5-cyano-N cyclopropyl-2-[(2,5~-oxiranylmethoxy]benzamide
2s (0.97 g, 3.8 mmol, from step (b) above) and N ethyl-3,7-diazabicyclo-
[3.3.1]nonane-3-carboxamide (0.89 g, 4.5 mmol, see Example 6(b) above)
in iso-propanol:water (22 mL of 10:1) was refluxed overnight. The
solvent was removed in vacuo and the resulting residue purified by
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column chromatography on silica gel, eluting with DCM:MeOH (9:1), to
yield 1.37 g (79 % ) of the title compound.
13C NMR (CDC13): 8 6.62, 6.78, 15.81, 23.55, 29.61, 29.90, 32.48,
s 36.20, 48.32, 49.84, 53.68, 57.48, 60.92, 62.06, 65.61, 71.72, 105.42,
113.69, 118.64, 123.78, 136.26, 136.77, 159.70, 159.97, 164.75
Example 8
N Ethyl-7-(4-nitrophenethyl)-3,7-diazabicyclo[3.3.1]nonane-3-
i o carboxamide
A mixture of 1-(2-bromoethyl)-4-nitrobenzene (1.6 g, 7.0 mmol),
N ethyl-3,7-diazabicyclo[3.3.1]nonane-3-carboxamide (1.0 g, 5.1 mmol,
see Example 6(b) above) and K~C03 (1.38 g, 10 mmol) was stirred at rt
overnight. The mixture was then filtered and concentrated in vacuo and
is the resulting residue purified by column chromatography, eluting with a
gradient of DCM:MeOH (100:0 to 90:10), to yield 1.5 g (85 % ) of the title
compound.
13C NMR (CDCl3): 8 15.71, 28.83, 30.11, 33.03, 35.67, 47.97, 59.22,
20 59.49, 123.34, 129.65, 146.26, 149.15, 157.95
Example 9
N (Cyanomethyl)-7-[(2S~-3-(4-cyanophenoxy)-2-hydroxypropyl]-3,7-diaza-
bicyclo[3.3.1]nonane-3-carboxamide
2s
(a) Cyanomethyl isocyanate
The title compound was prepared according to the procedure described in
Example 2(a) above, using 2-aminoacetonitrile in place of
cyclopropylmethylamine.
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(b) N (Cyanomethyl)-7-[(2S~-3-(4-cyanophenoxy)-2-hydroxypropyl]-3,7-
diazabicyclo[3.3.1]nonane-3-carboxamide
The title compound was prepared in 26 % yield (counting steps (a) and (b)
s together) according to procedure described in Example 2(b) above, using
cyanomethyl isocyanate (from step (a) above) in place of
cyclopropylmethyl isocyanate.
13C NMR (CDC13): 8 28.99. 29.27, 29.47, 31.77, 48.32, 49.33, 56.88,
io 60.33, 61.61, 65.32, 70.63, 103.96, 115.31, 117.63, 119.21, 133.93,
157.74, 162.08
Example 10
N Ethyl-7-~4-[(methanesulfonyl)amino]phenethyl~-3,7-diazabicyclo-
Is [3.3.1]nonane-3-carboxamide
(a) 4-[(Methanesulfonyl)amino]phenethyl methanesulfonate
Methanesulfonyl chloride (45 g, 0.39 mol) was added, dropwise over 30
minutes, to a cooled (-5 °C) solution of 4-aminophenethyl alcohol (25.2
g,
20 0.18 mol) in pyridine (200 mL). The mixture was stirred at 0°C for 1
h
and then at rt overnight. The resulting red suspension was poured in to a
mixture of ice (300 mL) and conc. HCl (60 mL). The pink precipitate
that formed was filtered off, redissolved in DCM, dried and treated with
activated carbon. The resulting solution was concentrated in vacuo to give
2s a residue, which, on recrystallisation from ethyl acetate, gave 34.5 g
(64 % ) of the sub-title compound.
mp 133-134°C
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(b) N Ethyl-7-{4-[(methanesulfonyl)amino]phenethyl}-3,7-diazabicyclo-
[3 .3 .1 ]nonane-3-carboxamide
A mixture of N ethyl-3,7-diazabicyclo[3.3.1]nonane-3-carboxamide (1 g,
mmol, see Example 6(b) above), 4-[(methanesulfonyl)amino]phenethyl
s methanesulfonate (1.5 g, 5 mmol, from step (a) above) and NaHC03 (3 g,
35.7 mmol) in MeCN (50 mL) was refluxed for 3 h under nitrogen. The
reaction mixture was filtered and concentrated in vacuo to give 2.2 g of
crude product, which was filtered through a silica plug, with MeOH/2 N
HC1. The pH of the fractions was raised to pH 6 and extracted with
io DCM, yielding 0.2 g of the title compound.
13C NMR (CDC13): ~ 15.75, 28.87, 30.23, 32.58, 35.64, 35.76, 39.14,
48.18, 59.17, 60.26, 121.41, 129.85, 134.72
t 5 Example 11
7-[3-(4-Cyanophenoxy)-2-fluoropropyl]-N ethyl-3,7-diazabicyclo-
[3.3.1]nonane-3-carboxamide
(a) 7-[3-(4-Cyanophenoxy)-2-hydroxypropyl]-N ethyl-3,7-diazabicyclo-
20 [3.3.l~nonane-3-carboxamide
The title compound was prepared according to the procedure described in
Example 1 above, using 4-[3-(3,7-diazabicyclo[3.3.1]non-3-yl)-2-
hydroxypropoxy]benzonitrile (see Example G above) in place of 4-{[(2S~-
3-(3,7-diazabicyclo[3.3.1]non-3-yl)-2-hydroxypropyl]oxy}benzonitrile.
(b) 7-[3-(4-Cyanophenoxy)-2-fluoropropyl~-N ethyl-3,7-diazabicyclo-
[3.3.1]nonane-3-carboxamide
A solution of 7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-N ethyl-3,7-diaza-
bicyclo[3.3.1]nonane-3-carboxamide (1.0 g, 2.7 mmol, from step (a)
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above) in DCM (2.5 mL) was cooled to -78°C. A solution of
(diethylamino)sulfurtrifluoride in DCM (2.5 mL) was added slowly under
stirring. Stirring was continued for 35 minutes, during which time the
reaction was allowed to warm to room temperature. Dichloromethane was
s added and the reaction mixture was then washed with NaHC03, dried and
concentrated in vacuo. The resulting residue was purified by column
chromatography, eluting with DCM:MeOH (98:2), to yield 0.68 g (67 % )
of the title compound.
io 13C NMR (CDC13): 8 15.63, 29.00, 30.33, 35.70, 47.78, 47.93, 58.36,
58.67, 59.82, 60.39, 68.60, 68.89, 89.56, 91.86, 104.15, 115.56,
119.25, 133.97, 157.61, 161.92
Example 12
is 7-[3-(4-Cyanophenoxy)-2-hydroxypropyl]-N [2-oxo-2-(propylamino)-
ethyl]-3,7-diazabicyclo[3.3.1]nonane-3-carboxamide
(a) Ethyl 2-[(~7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-3,7-diazabicyclo-
[3.3.1]non-3-yl}carbonyl)amino]acetate
2o A cooled (0°C) solution of 4-[3-(3,7-diazabicyclo[3.3.1]non-3-yl)-2-
hydroxypropoxy]benzonitrile (23.1 g, 77 mmol, see Example G above) in
DCM (700 mL) was treated with ethyl 2-isocyanatoacetate (9.92 g, 77
mmol), and then stirred at rt for 7 h. The reaction mixture was
concentrated in vacuo to yield 33.6 g ( 100 % ) of the sub-title compound.
(b) 7-[3-(4-Cvanophenoxy)-2-hydroxypropyl]-N [2-oxo-2-(propylamino)-
ethyl]-3,7-diazabicyclo[3.3.1]nonane-3-carboxamide
A mixture of ethyl 2-[({7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-3,7-
diazabicyclo[3.3.1]non-3-yl}carbonyl)amino]acetate (0.76 g 1.8 mmol,
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from step (a) above), propylamine (5 mL, 3.6 g, 69.1 mmol) and NaCN
(0.01 g, 0.2 mmol) in methanol (10 mL) was warmed to 75°C in a sealed
tube overnight. The solvent was then removed in vacuo and the residue
diluted with Na~C03 solution. The aqueous mixture was extracted with
s DCM, and the resulting organic layer separated, dried and concentrated in
vacuo. The resulting residue was purified by column chromatography,
eluting with a gradient of dichloromethane:methanol (100:0 to 90:10), to
give the title compound in 70 % yield.
io 13C NMR (CDC13): b 11.36, 22.65, 29.12, 29.42, 31.78, 41.15, 44.75,
48.15, 49.10, 56.99, 60.40, 61.35, 65.33, 70.74, 103.99, 115.27,
119.12, 133.91, 158.71, 162.10, 170.62
Example 13
is 7-{3-(4-Cyanophenoxy)-2- (4-morpholinylcarbonyl)amino]propyl~-N
ethyl-3,7-diazabicyclo 3.3.1]nonane-3-carboxamide
(a) tert-Butyl 3-(4-cyanophenoxy)-2-hydroxypropylcarbamate
A cooled (0°C) solution of 4-(3-amino-2-
hydroxypropoxy)benzonitrile
Zo (44.6 g, 0.23 mol, see Example 4(a) above) in THF:H20 (1.5 L of 1:1)
was treated with di-tert-butyl dicarbonate (53 g, 0.24 mol). The mixture
was stirred at rt overnight, after which NaCI was added and the resulting
organic layer separated. The water layer was extracted with ether and the
combined organics were dried and concentrated in vacuo. The resulting
2s oil (70 g) was filtered through a plug of silica, and then crystallised
from
diethyl ether:di-iso-propyl ether to yield 50 g of the sub-title compound.
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(b) 2-[(tert-Butoxycarbonyl)amino]-1-[(4-cyanophenoxy)methyl]ethyl
methanesulfonate
Methanesulfonyl chloride (22.3 g 0.195 mol) was added over the course of
1.5 hours to a cooled (0 ° C) solution of tert-butyl 3-(4-cyanophenoxy)-
2
s hydroxypropylcarbamate (51.2 g, 0.177 mol, from step (a) above) and 4
(dimethylamino)pyridine (1.3 g, 10.6 mmol) in pyridine (250 mL), kept
under an inert atmosphere. The reaction mixture was stirred for 2 h at rt
before water and DCM were added. The organic layer was separated,
washed with water, dried (MgSO,,) and concentrated in vacuo to yield
l0 68.1 g ( 100 % ) of the sub-title compound.
(c) tert-Butyl 2-[(4-cyanophenoxy)methyl]-1-aziridinecarboxylate
A cooled (0°C) solution of 2-[(tert-butoxycarbonyl)amino]-1-[(4-
cyano
phenoxy)methyl]ethyl methanesulfonate (30.6 g, 82.6 mmol, from step (b)
is above) and tetrabutylammonium hydrogensulfate (3 g, 8.8 mmol) in DCM
( 100 mL) was treated with 50 wt. % aqueous NaOH (60 mL) under an
inert atmosphere. The resulting mixture was stirred, and the temperature
was slowly allowed to rise to rt over for 4 h, and then extracted with
ether. The organic layer was washed with water and concentrated in
zo vacuo to give a residue that was purified by column chromatography
(dichloromethane eluant). Crystallisation from diethyl ether:di-iso-propyl
ether gave the sub-title compound in quantitative yield.
(d) tert-Butyl 2-(4-cyanophenoxy)-1-(~7-[(ethylamino)carbonyl]-3,7-diaza-
as bicyclo[3.3.1]non-3-yl~methyl)ethylcarbamate
A mixture of N ethyl-3,7-diazabicyclo[3.3.1]nonane-3-carboxamide
(2.88 g, 14.6 mmol, see Example 6(b) above) and tert-butyl 2-[(4-
cyanophenoxy)methyl]-1-aziridinecarboxylate (4.0 g, 14.6 mmol, from
step (c) above) in iso-propanol (20 mL) was refluxed overnight. The
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reaction mixture was concentrated in vacuo to give 7.4 g of a yellow oil,
which was purified by column chromatography, eluting with a gradient of
DCM:MeOH (100:0 to 90:10), to yield 3.33 g of the sub-title compound.
s (e) 7-[2-Amino-3-(4-cyanophenoxy)propyl]-N ethyl-3,7-diazabicyclo-
[3.3.1]nonane-3-carboxamide
A solution of tert-butyl 2-(4-cyanophenoxy)-1-({7-[(ethylamino)carbonyl]-
3,7-diazabicyclo[3.3.1]non-3-yl}methyl)ethylcarbamate (2.4 g, 5.1 mmol,
from step (d) above) in HCl-saturated ethyl acetate was stirred for 1 h at
io rt. The reaction mixture was then concentrated in vacuo and resulting
residue re-dissolved in water. The aqueous solution was treated with
aqueous NaHC03 and extracted with DCM, which organic layer was then
dried and concentrated in vacuo to give 2 g of the sub-title compound.
is (f) 7-{3-(4-Cyanophenoxy)-2-[(4-morpholinylcarbonyl)amino]propyl}-N
ethyl-3,7-diazabicyclo[3.3.1]nonane-3-carboxamide
A cooled (5°C) solution of 7-[2-amino-3-(4-cyanophenoxy)propyl]-N
ethyl-3,7-diazabicyclo[3.3.1]nonane-3-carboxamide (0.33 g, 0.7 mmol,
from step (e) above) and triethylamine (0.4 mL, 3.0 mmol) in DCM
20 (5 mL) was treated with 4-morpholinecarbonyl chloride (0.11 g,
0.7 mmol), and then stirred at 5°C for 3 h. After further stirring at
room
temperature overnight, tlc analysis indicated incomplete reaction, and so a
further portion of 4-morpholinecarbonyl chloride (40 mg, 0.27 mmol) was
added. Stirring was continued at rt overnight again before NaHC03
2s solution was added. The organic layer was separated, dried and
concentrated in vacuo to give 400 mg of crude product, which was
purified by column chromatography on silica gel, eluting with
dichloromethane:methanolic ammonia (95:5) to give 250 mg of the title
compound.
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13C NMR (CDCl3): 8 161.94, 158.26, 157.81, 133.94, 119.15, 115.37,
103.90, 67.26, 66.66, 60.66, 60.51, 57.99, 48.93, 48.37, 47.39, 44.06,
35.93, 30.71, 29.34, 29.02, 15.51
s
Example 14
N (4-Cyanophenethyl)-7-(4-oxoheptyl)-3,7-diazabicyclo[3.3.1]nonane-3-
rarhnxamiriP
to (a) 3-Benzyl-7- 3-(2-propyl-1,3-dioxolan-2-yl)propyl]-3,7-diazabicyclo-
[3.3.1]nonane
A mixture of 3-benzyl-3,7-diazabicyclo[3.3.1]nonane (10.5 g, 48.5 mmol,
see Example E above), 2-(3-bromopropyl)-2-propyl-1,3-dioxolane (11.5 g,
48.5 mmol, Bajrowicsz et al., Tetrahedron, 41 (1985) 1833) and K~C03
is (13.8 g, 0.1 mol) in MeCN (50 mL) was refluxed overnight. The reaction
mixture was filtered and concentrated in vacuo to yield 18.8 g ( 100 % ) of
the sub-title compound.
(b) 3-[3-(2-Propyl-1,3-dioxolan-2-yl)propyl~-3,7-diazabicyclo[3.3.1]-
2o nonane
A solution of 3-benzyl-7-[3-(2-propyl-1,3-dioxolan-2-yl)propyl]-3,7-
diazabicyclo[3.3.1]nonane (18.8 g, 4.85 mmol, from step (a) above) in
ethanol (100 mL) was hydrogenated over 5 % Pd/C at ambient pressure.
The catalyst was removed by filtration through a pad of Celite~, and the
2s filtrate concentrated in vacuo to yield 13.7 g (100 % ) of the sub-title
compound.
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(c) N (4-Cyanophenethyl)-7-(4-oxoheptyl)-3,7-diazabicyclo 3.3.1]nonane-
3-carboxamide
A solution of 4-(2-aminoethyl)benzonitrile (1.0 g, 6.9 mmol, Wiley et al.,
Bioorg. Med. Chem. Lett., 6 (1996) 2387) in dry THF (10 mL) was
s treated with 1,1'-carbonyldiimidazole (1.17 g, 7.2 mmol), and the mixture
was stirred for 30 min. A solution of 3-[3-(2-propyl-1,3-dioxolan-2-
yl)propyl]-3,7-diazabicyclo[3.3.1]nonane (1.3 g, 4.6 mmol, from step (b)
above) in THF (5 mL) was added to the reaction mixture, and stirring was
continued overnight at rt. The solution was then concentrated in vacuo and
to the resulting residue diluted with MeOH and 2 M HCI, which solution was
stirred for 2 h at rt. The mixture was made alkaline and extracted with
DCM. The organic layer was separated, dried and concentrated in vacuo
to give a residue which was purified by flash chromatography, eluting
with DCM:MeOH (92:8), to yield 0.57 g (30%) of the title compound.
is
13C NMR (CDC13): 8 13.73, 17.21, 20.85, 28.79, 30.38, 36.91, 39.84,
41.83, 44.73, 47.94, 57.65, 59.05, 110.06, 118.93, 129.67, 132.20,
145.52, 157.47, 211.67
Zo Example 15
N' -(4-Cyanobenzoyl)-7-(4-oxoheptyl)-3 ,7-diazabicyclo[3 .3 .1 ] nonane-3-
carbohydrazide
A mixture of 4-cyanobenzohydrazide (0.82 g, 5.0 mmol) and 1,1'
carbonyldiimidazole (0.82 g, 5 mmol) in THF (15 mL) was stirred for 10
2s min at rt before 3-[3-(2-propyl-1,3-dioxolan-2-yl)propyl]-3,7-diazabicyclo
[3.3.1]nonane (1.44 g, 5.0 mmol, see Example 14(b) above) was added.
The reaction mixture was stirred overnight at rt, before being concentrated
in vacuo. The resulting residue was dissolved in DCM, and washed with
water. The organic layer was separated and concentrated in vacuo to give
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a residue which was dissolved in methanol/2M HCI. Evaporation of the
MeOH in vacuo and extraction of the remaining aqueous solution with
DCM, gave, after purification by flash chromatography on silica gel
(dichloromethane:methanolic ammonia eluant), 0.5 g (25 % ) of the title
s compound.
13C NMR (CDC13): 8 213.21, 164.24, 157.01, 136.31, 132.19, 128.24,
118.11, 115.11, 58.65, 57.89, 48.38, 44.31, 40.55, 31.52, 29.12, 21.60,
17.08, 13.69
io
Example 16
4-~2-Amino-3-[7-(1-piperidinylcarbonyl)-3,7-diazabicyclo[3.3.1]non-3-
yl]propoxy}benzonitrile
is (a) 7-Benzyl-3,7-diazabicyclo[3.3.1]non-3-yl(1-piperidinyl)methanone
The sub-title compound was prepared by way of a reaction between 3-
benzyl-3,7-diazabicyclo[3.3.1]nonane (see Example E above) and 1-
piperidinecarbonyl chloride (Boon, J. Chem. Soc. , (1947) 307, 313).
20 (b) 3,7-Diazabicyclo[3.3.1]non-3-yl(1-piperidinyl)methanone
The sub-title compound was obtained in quantitative yield according to the
procedure described in Example 14(b) above, using 7-benzyl-3,7-
diazabicyclo[3.3.1]non-3-yl(1-piperidinyl)methanone (from step (a) above)
in place of 3-benzyl-7-[3-(2-propyl-1,3-dioxolan-2-yl)propyl]-3,7-
2s diazabicyclo[3.3.1]nonane.
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(c) tert-Butyl 2-(4-cyanophenoxy)-1-{[7-(1-piperidinylcarbonyl)-3,7-diaza-
bicyclo 3.3.1]non-3-yl]methyl}ethylcarbamate
A mixture of tert-butyl 2-[(4-cyanophenoxy)methyl]-1-aziridinecarboxylate
(1.92 g, 7 mmol, see Example 13(c) above) and 3,7-diaza
s bicyclo[3.3.1]non-3-yl(1-piperidinyl)methanone (1.85 g, 7 mmol, from
step (a) above) in iso-propanol (15 mL) was refluxed for 30 h. The
solution was concentrated in vacuo to yield 3.7 g of crude product, which
was purified by chromatography using 2.5 % MeOH in DCM to give 2.0 g
(56 % ) of sub-title compound.
to
(d) 4-{2-Amino-3-[7-(1-piperidinylcarbonyl)-3,7-diazabicyclo[3.3.1]non-3-
yl]propoxy}benzonitrile
A cooled (0 ° C) solution of tent-butyl 2-(4-cyanophenoxy)-1-{ [7-
( 1-
piperidinylcarbonyl)-3,7-diazabicyclo[3.3.1]non-3-yl]methyl}ethyl-
is carbamate (1.9 g, 3.7 mmol, from step (c) above) in ethyl acetate was
treated with HC1-saturated ethyl acetate. The mixture was stirred for 4 h
before being concentrated in vacuo. The resulting residue was dissolved
in water, made basic with NaHC03 and extracted with DCM. The
organic layer was separated, dried and concentrated in vacuo to yield 1.5
2o g (100 % ) of the title compound.
13C NMR (CDCl3): 8 24.73, 25.72, 29.62, 29.95, 32.11, 47.44, 48.14,
49.53, 50.98, 57.87, 60.57, 62.59, 72.03, 103.90, 115.30, 119.22,
133.91, 162.23, 164.35
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Example 17
N Ethyl-7-{2-hydroxy-3-[4-(1H imidazol-1-yl)phenoxy]propyl}-3,7-
diazabicyclo[3.3.1]nonane-3-carboxamide
s (a) 1-[4-(2-Oxiranylmethoxy)phenyl]-1H-imidazole
A mixture of 4-(1H-imidazol-1-yl)phenol (10 g, 60 mmol), K,C03
(8.63 g, 60 mmol ) and 2-oxiranylmethyl 3-nitrobenzenesulfonate (15.5 g,
60 mmol, see Example B above) in DMF ( 140 mL) was stirred at 40 ° C
overnight. The mixture was then concentrated in vacuo and the resulting
io residue diluted with DCM, washed with water, dried and then
concentrated in vacuo. The crude product was then purified by flash
chromatography, eluting with a gradient of dichloromethane:methanol
( 100:0 to 70: 30) to yield 3 .4 g, (72. 6 % ) of the title compound.
is (b) N Ethyl-7-{2-hydroxy-3-[4-(1H-imidazol-1-yl)phenoxy]propyl}-3,7-
diazabicyclo[3.3.1]nonane-3-carboxamide
A mixture of 1-[4-(2-oxiranylmethoxy)phenyl]-1H-imidazole (3.16 g,
14.6 mmol, from step (a) above) and N ethyl-3,7-diazabicyclo-
[3.3.1]nonane-3-carboxamide (2.88 g 14.6 mmol, see Example 6(b)
Zo above) in iso-propanol:H,O (18 mL of 9:1) was refluxed for 3 hours,
concentrated in vacuo and purified by acid/base extraction to yield 4.4 g
(72.6 % ) of the title compound.
'3C NMR (CDC13): 8 15.52, 29.13, 29.44, 31.84, 35.70, 47.92, 49.07,
2s 57.21, 60.44, 61.94, 65.45, 70.76, 115.49, 118.58, 122.90, 129.86,
130.56, 135.66, 158.16, 158.78
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Example 18
N [3-(4-Cyanophenoxy)propyl]-7-(2-hydroxyethyl)-3,7-diazabicyclo-
[3.3.1]nonane-3-carboxamide
s (a) 4-(3-Bromopropoxy)benzonitrile
1,3-Dibromopropane (1.02 L; 10 mol) was added to a stirred suspension
of p-cyanophenol (238 g; 2 mol), K,C03 (276.4 g; 2 mol) in MeCN (2.7
L). The reaction mixture was refluxed for 4 h, filtered and concentrated.
The residue was recrystallized from iso-propyl ether to give the sub-title
io compound in a 69% yield.
(b) 4-[3-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)propoxy]benzonitrile
A mixture of 4-(3-bromopropoxy)benzonitrile (20 g, 84 mmol, see step (a)
above) and potassium phthalimide ( 15 .5 g, 84 mmol) in DMF ( 120 mL)
is was stirred at 95°C for 4 h. The solution was then concentrated in
vacuo
and the resulting residue dissolved in DCM and washed with water. The
organic layer was separated, dried (Na2S0~) and concentrated in vacuo to
yield 25.5 g (99%) of the sub-title compound.
20 (c) 4-(3-Aminopropoxy)benzonitrile
A mixture of 4-[3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propoxy]-
benzonitri1e (25.5 g, 83 mmol, from step (b) above) and hydrazine hydrate
(4.15 g, 83 mmol) in methanol (100 mL) was refluxed for 1 h before
water (120 mL) was added. The methanol was evaporated under reduced
2s pressure and concentrated hydrochloric acid (120 mL) was added. The
resulting mixture was heated on a steam bath for 1.5 h and then cooled in
the refrigerator overnight. The resulting precipitate was filtered off and
the filtrate was concentrated in vacuo. Water was added to the resulting
residue and the solution made basic. The aqueous solution was extracted
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with DCM, which organic layer was then separated, dried and
concentrated in vacuo to yield 6 g (41 % ) of the sub-title compound.
(d) 7-Benzyl-3,7-diazabicyclo[3.3.1]nonane-3-ethanol
The compound was prepared in 72% yield by reacting 3-benzyl-3,7
diazabicyclo[3.3.1]nonane (see Example E above) with 2-bromoethanol.
(e) 3,7-Diazabicyclo[3.3.1]nonane-3-ethanol
The sub-title compound was prepared according to the procedure
io described in Example 14(b) above, using 7-benzyl-3,7-
diazabicyclo[3.3.1]nonane-3-ethanol (from step (d) above) in place of 3-
benzyl-7-[3-(2-propyl-1,3-dioxolan-2-yl)propyl]-3,7-diazabicyc1o[3.3.1]-
nonane.
(f) N [3-(4-Cyanophenoxy)propyl]-7-(2-hydroxyethyl)-3,7-diazabicyclo-
[3.3.1]nonane-3-carboxamide
The title compound was prepared in 11 % yield according to the procedure
described in Example 14(c) above, using 3,7-diazabicyclo[3.3.1]nonane-3-
ethanol (from step (e) above) and 4-(3-aminopropoxy)benzonitrile (from
2o step (c) above) in place of 3-[3-(2-propyl-1,3-dioxolan-2-yl)propyl]-3,7-
diazabicyclo[3.3.1]nonane and 4-(2-aminoethyl)benzonitrile, respectively.
'3C NMR (CDC13): 8 162.04, 158.99, 133.66, 118.99, 115.03, 103.35,
66.55, 60.24, 57.87, 57.18, 50.02, 48.63, 37.93, 31.81, 29.26, 28.96
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Example 19
N {[7-(3-(4-Cyanophenoxy)-2-hydroxypropyl]-3,7-diazabicyclo[3.3.1]non-
3-yl]carbonyl}-4-methylbenzenesulfonamide
A solution of 4-[3-(3,7-diazabicyclo[3.3.1]non-3-yl)-2-hydroxypropoxy]-
s benzonitrile (200 mg, 0.66 mmol, see Example G above) in chloroform
(20 mL) was treated with a solution of p-toluenesulfonyl isocyanate (110
~L of 96 % purity, 0.136 g, 0.69 mmol in chloroform (4 mL), added
dropwise. A white precipitate immediately formed and the mixture was
then concentrated in vacuo. The crude product so obtained was subjected
io to chromatography on silica gel, eluting with hexane:ethyl
acetate:methanolic ammonia (75:75:50) to give the title compound in 53
yield.
13C NMR (CDC13): b 15.77, 29.18, 32.37, 36.13, 48.72, 52.27, 56.32,
is 109.83, 113.13, 118.27, 118.93, 120.10, 127.80, 131.39, 132.46,
132.73, 134.62, 138.75, 159.14, 167.09
Example 20
N Allyl-7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-3,7-diazabicyclo[3.3.1]-
2o nonane-3-carboxamide
A mixture of allylamine (125 ~L, 1.66 mmol) and l,l'-carbonyl-
diimidazole (269 mg, 1.66 mmol) in THF (10 mL) was stirred at rt for 40
min. The mixture was then treated with a solution of
4-[3-(3,7-diazabicyclo[3.3.1]non-3-yl)-2-hydroxypropoxy]benzonitrile (see
is Example G above) in THF (5 mL), and stirring continued overnight. The
mixture was concentrated in vacuo and the resulting residue purified by
chromatography on silica gel, eluting with hexane:methanolic ammonia
(1:l) to give the title compound in 57% yield.
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13C NMR (MeOD): 8 29.37, 30.79, 41.95, 42.91, 58.91, 59.55, 61.12,
66.52, 70.75, 103.31, 113.81, 115.39, 118.72, 133.73, 135.57, 136.06,
158.93,162.67
s Example 21
7-[3-(4-Cyanophenoxy)-2-hydroxypropyl]-N [2-(2-thienyl)ethyl]-3,7-
diazabicyclo[3 . 3.1]nonane-3-carboxamide
The title compound was prepared in 83 % yield according to the procedure
described in Example 19 above, using 2-(2-isocyanatoethyl)thiophene in
io place of p-toluenesulfonyl isocyanate.
13C NMR (CDC13): 8 29.19, 29.50, 30.59, 32.11, 42.26, 47.94, 49.37,
56.23, 60.47, 61.95, 65.32, 70.74, 103.88, 115.36, 119.52, 123.69,
125.25, 127.04, 133.90, 142.19, 158.74, 162.22
is
Example 22
7-[3-(4-Cyanophenoxy)-2-hydroxypropyl]-N [3-(ethylamino)-3-
oxopropyl]-3 ,7-diazabicyclo[3 .3 .1 ] nonane-3-carboxamide
20 (a) Ethyl 3- ({7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-3,7-diazabicyclo-
[3.3 .1]non-3-yl~carbonyl)amino]propanoate
The sub-title compound was prepared in 90 % yield according to the
procedure described in Example 12(a) above, using ethyl 3-
isocyanatopropanoate in place of ethyl 2-isocyanatoacetate.
2s
(b) 7-~3-(4-Cyanophenoxy)-2-hydroxypropyl]-N [3-(ethylamino)-3-oxo-
propyl]-3,7-diazabicyclo[3.3.1]nonane-3-carboxamide
The title compound was prepared in 22 % yield according to the procedure
described in Example 12(b) above, using ethyl 3-[({7-[3-(4-
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cyanophenoxy)-2-hydroxypropyl]-3,7-diazabicyclo[3.3.1]non-3-yl}-
carbonyl)amino]propanoate (from step (a) above) and ethylamine in place
of ethyl 2-[({7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-3,7-diazabicyclo-
[3.3.1]non-3-yl}carbonyl)amino]acetate and propylamine, respectively.
13C NMR (CDCl3): 8 172.46, 162.17, 158.89, 133.96, 119.14, 115.37,
104.16, 65.27, 61.73, 60.58, 56.97, 49.23, 47.89, 37.51, 36.60, 34.26,
32.00, 29.54, 29.16, 14.87
i o Example 23
N (1-Cyanoethyl)-7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-3,7-diaza-
bicyclo[3.3.1]nonane-3-carboxamide
(a) 2-Aminopropanenitrile
is Lactonitrile (28 g, 375 mmol) was added to liquid ammonia at -78°C
in a
reaction tube. The tube was sealed and the mixture was stirred overnight
at rt. The ammonia was removed by evaporation and the crude material
was used directly in the next step without any further purification.
20 (b) N (1-Cyanoethyl)-7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-3,7-diaza-
bicyclo[3.3.1]nonane-3-carboxamide
A mixture of 2-aminopropanenitrile (250 mg, 3.58 mmol, from step (a)
above) and N ethyl di-iso-propylamine (0.67 mL, 0.50 g, 3.84 mmol) in
DCM (9 mL) was added (by syringe pump), over the course of 1 hour, to
2s a solution of triphosgene (352 mg, 1.19 mmol) in DCM (7 mL). The
resulting mixture was stirred for 1 h at rt before a mixture of 4-[3-(3,7-
diazabicyclo[3.3.1]non-3-yl)-2-hydroxypropoxy]benzonitrile (1.08 g, 3.58
mmol, see Example G above) and N ethyl di-iso-propylamine (0.67 mL,
0.50 g, 3.84 mmol) in DCM (14 mL) was added. Stirring was continued
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for a further 20 min, before the solution was concentrated ira vacuo and
the resulting residue purified by flash chromatography, eluting with
dichloromethane:methanol (95:5), to give the title compound in 65 %
yield.
13C NMR (CDC13): S 20.02, 20.16, 29.11, 29.32, 29.46, 31.91, 37.83,
37.89, 48.23, 48.47, 49.36, 49.61, 56.95, 60.26, 60.51, 61.58, 62.077,
65.43, 70.69, 104.06, 115.40, 119.27, 120.77, 133.96, 157.08, 162.21
io Example 24
7-[3-(4-Cyanophenoxy)-2-hydroxypropyl]-N (2,2,2-trifluoroethyl)-3,7-
diazabicyclo[3.3.1]nonane-3-carboxamide
The title compound was prepared in 46 % yield according to the procedure
described in Example 23(b) above, using 2,2,2-trifluoroethylamine in
is place of 2-aminopropanenitrile.
13C NMR (CDC13): 8 29.11, 29.42, 31.79, 42.17, 42.51, 48.36, 49.58,
57.09; 60.45, 61.77, 65.39, 70.76, 104.08, 115.39, 119.23, 123.28,
126.05, 133.93, 157.76, 162.21
Example 25
7-[3-(4-Cyanophenoxy)-2-hydroxypropyl]-N [2-oxo-2-(1-piperidinyl)-
ethyl]-3,7-diazabicyclo[3.3.1]nonane-3-carboxamide
The title compound was prepared in 49 % yield according to the procedure
2s described in Example 12(b) above, using piperidine in place of
propylamine.
13C NMR (CDC13): 8 24.33, 25.41, 26.06, 28.74, 29.29, 29.44, 32.13,
42.67, 43.10, 45.30, 47.99, 48.09, 49.14, 49.28, 57.18, 60.42, 61.90,
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65.55, 70.77, 94.22, 103.89, 115.24, 115.43, 119.24, 133.74, 134.02,
158.49, 162.20, 167.42
Example 26
s N (1,3-Benzodioxol-5-yl)-7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-3,7-
diazabicyclo[3.3.1]nonane-3-carboxamide
The title compound was prepared in 33 % yield according to the procedure
described in Example 23(b) above, using 1,3-benzodioxol-5-amine in
place of 2-aminopropanenitrile.
io
13C NMR (CDC13): 8 162.22, 156.51, 147.47, 143.20, 133.98, 133.83,
119.41, 115.40, 113.68, 107.68, 103.83, 103.59, 100.96, 70.70, 65.98,
61.34, 60.34, 57.87, 49.17, 48.13, 31.52, 29.41, 29.11
i s Example 27
7-[3-(4-Cyanoanilino)propyl]-N [2-oxo-2-(propylamino)ethyl]-3,7-
diazabicyclo[3.3.1]nonane-3-carboxamide
(a) 4-[(3-Hydroxypropyl)amino]benzonitrile
2o A mixture of 4-fluorobenzonitrile (12.0 g, 99.1 mmol) and 3-amino-1-
propanol (59.6 g, 793 mmol) was stirred at 80°C under an inert
atmosphere for 3 hours before water (150 mL) was added. The mixture
was allowed to cool to rt, and was then extracted with diethyl ether. The
organic layer was separated, dried (Na~S04), filtered and concentrated in
2s vacuo to yield 17 g (97 % ) of the title compound as a oil that
crystallised
upon standing.
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(b) 3-(4-Cyanoanilino)propyl 4-methylbenzenesulfonate
A cooled (0°C) solution of 4-[(3-hydroxypropyl)amino]benzonitrile
(17 g,
96.5 mmol, from step (a) above) in dry MeCN (195 mL) was treated with
triethylamine (9.8 g, 96.5 mmol) and then p-toluenesulfonyl chloride
s (20.2 g, 106 mmol). The mixture was stirred at 0°C for 90 minutes
before being concentrated in vacuo. Water (200 mL) was added to the
residue, and the aqueous solution was extracted with DCM. The organic
phase was dried (Na,S04), filtered and concentrated in vacuo. The
resulting residue was purified by crystallisation from iso-propanol to yield
i o 24.6 g (77 % ) of the sub-title compound.
(c) Ethyl 2-~[(7-benzyl-3,7-diazabicyclo[3.3.1]non-3-yl)carbonyl]amino}-
a rata tP
The sub-title compound was prepared in 99 % yield according to the
is procedure described in Example 5(a) above, using
4-[3-(3,7-diazabicyclo[3.3.1]non-3-yl)-2-hydroxypropoxy]benzonitrile (see
Example G above) and ethyl 2-isocyanatoacetate in place of 3-benzyl-3,7-
diazabicyclo[3.3.1]nonane and iso-propyl isocyanate, respectively.
20 (d) 7-Benzyl-N [2-oxo-2-(propylamino)ethyl]-3,7-diazabicyclo[3.3.1]-
nonane-3-carboxamide
The sub-title compound was prepared in 88 % yield according to the
procedure described in Example 12(b) above, using ethyl 2-{ [(7-benzyl-
3,7-diazabicyclo[3.3.1]non-3-yl)carbonyl]amino}acetate (from step (c)
zs above) in place of ethyl 2-[({7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-3,7-
diazabicyclo[3.3.1]non-3-yl}carbonyl)amino]acetate.
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(e) N [2-Oxo-2-(propylamino)ethyl]-3,7-diazabicyclo[3.3.1]nonane-3-
rarhnsramirla
The title compound was prepared according to the procedure described in
Example 5(b) above, using 7-benzyl-N [2-oxo-2-(propylamino)ethyl]-3,7-
s diazabicyclo[3.3.1]nonane-3-carboxamide (from step (d) above) in place
of 7-benzyl-N iso-propyl-3,7-diazabicyclo[3.3.1]nonane-3-carboxamide.
(f) 7-[3-(4-Cyanoanilino)propyl]-N 2-oxo-2-(propylamino)ethyl]-3,7-
diazabicyclo[3.3.1]nonane-3-carboxamide
io A mixture of N [2-oxo-2-(propylamino)ethyl]-3,7-diazabicyclo[3.3.1]-
nonane-3-carboxamide (3.35 g, 12.5 mmol, from step (e) above),
K2C03 (6.9 g, 50 mmol) and sodium iodide (0.19 g, 1.25 mmol) in
acetonitrile (600 mL) was treated with 3-(4-cyanoanilino)propyl 4-methyl-
benzenesulfonate (4.2 g, 12.7 mmol, from step (b) above) and stirred
is under reflux for 5 h, followed by a further 21 h at rt. The mixture was
filtered, concentrated in vacuo and the crude product so obtained was
diluted with water. The aqueous solution was extracted with DCM, which
organic layer was separated, dried and concentrated in vacuo. The crude
product so obtained was purified by chromatography on silica gel, eluting
zo with DCM:MeOH (95:5) to yield 3.08 g (58%) of the title compound.
13C NMR (CDC13): 8 11.49, 22.85, 25.11, 29.09, 31.03, 40.78, 41.40,
44.80, 48.41, 56.22, 59.32, 97.43, 111.99, 120.97, 133.74, 151.98,
157.92, 170.37
2s
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83
dichloromethane:methanol (9:1) to yield 0.8 g (30 % ) of the title
compound.
13C NMR (CDC13): 8 162.18, 133.92, 119.24, 115.34, 103.92, 69.07,
s 67.86, 59.52, 58.42, 48.18, 35.68, 30.25, 28.81, 15.69
Example 29
7-[4-(4-Cyanophenyl)-4-(3,4-dimethoxyphenoxy)butyl]-N ethyl-3,7-diaza-
bicyclo[3.3.1]nonane-3-carboxamide
io
(a) 4-[1-(3,4-Dimethoxyphenoxy)-3-butenyl]benzonitrile
A cooled (0°C) mixture of 4-(1-hydroxy-3-butenyl)benzonitrile
(14.6 g,
84.3 mmol) and 3,4-dimethoxyphenol (19.5 g, 125.4 mmol) in toluene
(500 mL) was treated with tributylphosphine (32.14 mL of 97 % purity,
is 25.6 g, 126.4 mmol), followed by 1,1'-(azodicarbonyl)dipiperidine (31.8
g, 126.4 mmol). After addition was complete, the reaction mixture
thickened and the temperature rose to 15°C. Additional toluene was
added (500 mL), and the mixture stirred at rt overnight. The precipitate
of tributylphosphine oxide was then removed by filtration and the filtrate
2o concentrated in vacuo to give 65.8 g of crude product. This was purified
by chromatography on silica gel, eluting with toluene:methanol (98:2) to
yield 17.9 g of the sub-title compound.
(b) 4-[1-(3,4-Dimethoxyphenoxy)-4-hydroxybutyl]benzonitrile
2s Borane-methyl sulfide complex (2 M in ether, 11 mL, 22 mmol) was
added dropwise to a cooled (-5°C) solution of 4-[1-(3,4-dimethoxy-
phenoxy)-3-butenyl]benzonitrile (17.6 g, 56.8 mmol, from step (a) above)
in dry THF (15 mL) over a period of 15 minutes (during which time the
reaction temperature rose to 0°C). The resulting mixture was stirred at
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dichloromethane:methanol (9:1) to yield 0.8 g (30 % ) of the title
compound.
13C NMR (CDC13): 8 162.18, 133.92, 119.24, 115.34, 103.92, 69.07,
s 67.86, 59.52, 58.42, 48.18, 35.68, 30.25, 28.81, 15.69
Example 29
7-[4-(4-Cyanophenyl)-4-(3,4-dimethoxyphenoxy)butyl]-N ethyl-3,7-diaza-
bicyclo[3.3.1]nonane-3-carboxamide
io
(a) 4-[1-(3,4-Dimethoxyphenoxy)-3-butenyl]benzonitrile
A cooled (0°C) mixture of 4-(1-hydroxy-3-butenyl)benzonitrile
(14.6 g,
84.3 mmol) and 3,4-dimethoxyphenol (19.5 g, 125.4 mmol) in toluene
(500 mL) was treated with tributylphosphine (32.14 mL of 97 % purity,
25.6 g, 126.4 mmol), followed by l,1'-(azodicarbonyl)dipiperidine (31.8
g, 126.4 mmol). After addition was complete, the reaction mixture
thickened and the temperature rose to 15 ° C . Additional toluene was
added (500 mL), and the mixture stirred at rt overnight. The precipitate
of tributylphosphine oxide was then removed by filtration and the filtrate
Zo concentrated in vacuo to give 65.8 g of crude product. This was purified
by chromatography on silica gel, eluting with toluene:methanol (98:2) to
yield 17.9 g of the sub-title compound.
(b) 4-[1-(3,4-Dimethoxyphenoxy)-4-hydroxybutyl]benzonitrile
2s Borane-methyl sulfide complex (2 M in ether, 11 mL, 22 mmol) was
added dropwise to a cooled (-5°C) solution of 4-[1-(3,4-dimethoxy-
phenoxy)-3-butenyl]benzonitrile (17.6 g, 56.8 mmol, from step (a) above)
in dry THF (15 mL) over a period of 15 minutes (during which time the
reaction temperature rose to 0°C). The resulting mixture was stirred at
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between 0 and 10 ° C for 1.5 h, before being allowed to warm to rt.
Stirring was continued for a further 3.5 h at this temperature before water
(22 mL) and sodium perborate tetrahydrate (11 g, 66 mmol) were added.
The biphasic mixture was stirred for 2 h at rt before the water layer was
s separated and extracted with ether. The combined organic layers were
washed with brine, dried and concentrated in vacuo. The resulting residue
was purified by chromatography on silica gel, eluting with iso-
propanol:ethyl acetate:heptane (5:25:70) to yield 14.5 g (77%) of the sub-
title compound.
to
(c) 4-(4-Cyanophenyl)-4-(3,4-dimethoxyphenoxy)butyl methanesulfonate
A solution of methanesulfonyl chloride (3.4 mL, 5.0 g, 44 mmol) in DCM
( 15 mL) was added slowly to a cooled (-5 ° C) mixture of 4-[ 1-(3,4-
dimethoxyphenoxy)-4-hydroxybutyl]benzonitrile (11 g, 34 mmol, from
is step (b) above) and triethylamine (7 mL, 5.2 g, 50.6 mmol) in DCM
(50 mL), during which addition the temperature did not rise above 2°C.
Stirring was continued at between 0 and 5°C for a further 2 h
before
water was added. The resulting organic layer was separated, and washed
with water, separated again and then dried to give the sub-title compound
2o in 100 % yield.
(d) tert-Butyl 7-[4-(4-cyanophenyl)-4-(3,4-dimethoxyphenoxy)butyl~-3,7-
diazabicyclo[3.3.1]nonane-3-carboxylate
A mixture of 4-(4-cyanophenyl)-4-(3,4-dimethoxyphenoxy)butyl methane-
2s sulfonate (522 mg, 1.29 mmol, from step (c) above), tert-butyl 3,7-
diazabicyclo[3.3.1]nonane-3-carboxylate (307 mg, 1.356 mmol, see
Example F above) and K~C03 (216 mg, 1.56 mmol) in
chloroform: acetonitrile ( 10 mL of 1:1 ) was stirred at 70 ° C for 23
h. The
reaction mixture was filtered and the filtrate concentrated in vacuo to give
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708 mg of crude product. This was purified by flash chromatography,
eluting with a gradient of toluene:methanol (97:3 to 10:1), to yield 607 mg
(88 % ) of the sub-title compound.
s (e) 4-[4-(3,7-Diazabicyclo[3.3.1]non-3-yl)-1-(3,4-dimethoxyphenoxy)-
butyl]benzonitrile
A cooled (0°C) solution of tert-butyl 7-[4-(4-cyanophenyl)-4-(3,4-
dimethoxyphenoxy)butyl]-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate
(1.92 g, 3.6 mmol, from step (d) above) in ethyl acetate (20 mL) was
to treated with HCl-saturated ethyl acetate (30 mL). The resulting mixture
was stirred for 2 h at between 0 and 5 °C before being concentrated ira
vacuo. The resulting residue was dissolved in acetonitrile (50 mL) and
treated with KZC03 (3.5 g, 25.2 mmol) and water (2.25 mL). This
mixture was stirred for 3h at rt and the solids removed by filtration,
i s before the solvent was removed in vacuo (with toluene added to effect
azeotropic removal of water) to give 1.5 g of the sub-title compound.
(f) 7-[4-(4-Cyanophenyl)-4-(3,4-dimethoxyphenoxy)butyl]-N ethyl-3,7-
diazabicyclo[3.3.1]nonane-3-carboxamide
2o A solution of 4-[4-(3,7-diazabicyclo[3.3.1]non-3-yl)-1-(3,4-dimethoxy-
phenoxy)butyl]benzonitrile (109 mg, 0.25 mmol, from step (e) above), in
CHC13 (1.43 mL) was treated with a solution of ethyl isocyanate (18.6 pL,
16.8 mg, 0.237 mmol) in MeCN (0.5 mL). The resulting mixture was
stirred for 30 h. at rt. The solution was then loaded onto an ion-exchange
2s solid phase extraction plug (Si02, 0.5 g from ISOLUTE). The plug was
washed with CHC13 (2.5 mL) and the product then eluted with MeCN
(3 x 2.5 mL). This gave the title compound (93 mg, 73 % ) in a purity
better than 90% (as determined by HPLC: UV at 254 nm and ELS
detection).
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MS (ES) m/z = 507 (M + 1)+, 505 (M - 1)-
Example 30
s 7-(3-{4-Cyano-2-[(cyclopropylamino)carbonyl]phenoxy~-2-hydroxy-
propyl)-N phenyl-3,7-diazabicyclo[3.3.1]nonane-3-carboxamide
(a) 5-Cyano-N cyclopropyl-2-[2-oxiranylmethoxy]benzamide
The sub-title compound was prepared according to the method described
io in Example 7(b) above using 2-oxiranylmethyl 3-nitrobenzenesulfonate
(prepared analogously to the method described in Example B above).
(b) 7-Benzyl-N phenyl-3,7-diazabicyclo[3.3.1]nonane-3-carboxamide
A cooled (0°C) solution of 3-benzyl-3,7-diazabicyclo[3.3.1]nonane
(10 g,
is 46 mmol, see Example E above) in DCM (100 mL) was treated with
phenyl isocyanate (4.9 mL, 45 mmol). The mixture was stirred at rt for
30 min. The product formed as white crystals, which were removed by
filtration to give 10 g (66 % ) of the sub-title compound.
zo (c) N Phenyl-3,7-diazabicyclo[3.3.1]nonane-3-carboxamide
A solution of 7-benzyl-N phenyl-3,7-diazabicyclo[3.3.1]nonane-3-
carboxamide ( 10 g, 29. 8 mmol, from step (b) above) in ethanol ( 100 mL)
was subjected to hydrogenation, over 10 % Pd/C and at ambient pressure,
overnight. The catalyst was removed through a pad of Celite~ and the
2s residue was concentrated in vacuo to give the sub-title compound in
quantitative yield.
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(d) 7-(3-~4-Cyano-2-[(cyclopropylamino)carbonyl~phenoxy}-2-hydroxy-
propyl)-N phenyl-3,7-diazabicyclo[3.3.1]nonane-3-carboxamide
A mixture of 5-cyano-N cyclopropyl-2-[2-oxiranylmethoxy]benzamide
(0.8 g, 3.1 mmol, from step (a) above) and N phenyl-3,7-diaza
s bicyclo[3.3.1]nonane-3-carboxamide (0.9 g, 3.6 mmol, from step (c)
above) in iso-propanol:H~O (10 mL of 9:1) was refluxed for 180 min.
before dichloromethane was added and the solvent removed in vacuo.
Purification of the resulting residue by flash chromatography, eluting with
DCM:MeOH (9:1), gave 1 g (64%) of the title compound.
io
13C NMR (CDC13): 8 6.33, 6.56, 23.23, 29.18, 29.51, 31.66, 48.27,
49.60, 53.44, 57.94, 60.51, 65.74, 71.28, 104.93, 113.46, 118.45,
119.54, 119.65, 122.88, 123.27, 128.84, 136.07, 156.44, 159.69, 164.53
i s Example 31
N. (4-Cyanophenyl)-7-[3-(ethanesulfonyl)propyl~-3,7-diazabicyclo-
f 3 . 3 .11 nonane-3-carboxamide
(a) 3-(Ethanesulfonyl)propyl 4-methylbenzenesulfonate
2o Triethylamine (13.36 g, 132 mmol) was added dropwise to a mixture of
3-(ethanesulfonyl)-1-propanol (13.4 g, 88 mmol, Martin-Smith et al., J.
Pharm. Pharmacol., 19, (1967) 649) and p-toluenesulfonyl chloride
(16.78 g, 88 mmol) in DCM (150 mL), resulting in a mildly exothermic
reaction. After addition was complete, the reaction mixture was washed
zs twice with aqueous ammonium chloride solution, the organic layer was
then separated, dried, and concentrated in vacuo. The resulting residue
was recrystallised from diethyl ether/DCM to give 17.9 g (65 % ) of the
sub-title compound.
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(b) tert-Butyl 7-[(4-cyanoanilino)carbonyl]-3,7-diazabicyclo[3.3.1]nonane-
3-carboxylate
A suspension of tert-butyl-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate
(2.0 g, 8 . 8 mmol, see Example F above) in chloroform ( 15 mL) was
s treated with 4-isocyanatobenzonitrile (1.53 g, 10.6 mmol). The mixture
was stirred at rt for 1.5 h, at which time some solid particles were
observed in the mixture. An additional 10 mL of chloroform was added
in order to dissolve the particles. Mass spectroscopic analysis of the
mixture indicated that the starting materials had been consumed, and so
to the solvent was removed in vacuo. The resulting residue was purified by
flash chromatography, eluting with a gradient of DCM:MeCN (5:1 to 2:1)
to yield 2.31 g (71 % ) of the sub-title compound.
(c) N (4-Cyanophenyl)-3,7-diazabicyclo[3.3.1]nonane-3-carboxamide
is A cooled (0°C) solution of tert-butyl 7-[(4-cyanoanilino)carbonyl]-
3,7
diazabicyclo[3.3.1]nonane-3-carboxylate (2.2 g 5.94 mmol, from step (b)
above) in ethyl acetate (40 mL) was treated with HCl-saturated ethyl
acetate (65 mL) over the course of 30 minutes. The resulting mixture was
stirred at rt for a further 4 h before being concentrated irc vacuo to give
Zo 1.8 g (99 % ) of the hydrochloride salt of the sub-title compound.
(d) N (4-Cyanophenyl)-7-[3-(ethanesulfonyl)propyl]-3,7-diazabicyclo-
[3 .3 .1 ~ nonane-3-carboxamide
A mixture of N (4-cyanophenyl)-3,7-diazabicyclo[3.3.1]nonane-3-
2s carboxamide (67.6 mg, 0.25 mmol, from step (c) above) and K~C03
(80 mg, 0.57 mmol) in DMF (0.5 mL) was treated with a solution of
3-(ethanesulfonyl)propyl 4-methylbenzenesulfonate (153 mg, 0.50 mmol,
from step (a) above), in MeCN (1.0 mL). The resulting suspension was
stirred for 5 days at 50°C before being cooled and filtered. The
filtrate
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was then added to a ion-exchange solid phase extraction plug (CBA, 2 g
from ISOLUTE). After 1 h the plug was washed with CHC13 (3 x 2.5 mL)
and the product eluted with CHCI3:MeOH:Et3N (8:1:1) to give the title
compound (63.6 mg, 63 % ) in a purity better than 90 % (as determined by
s HPLC: UV at 254 nm and ELS detection).
MS (ES): m/z = 405 (M + 1)+, m/z = 403 (M - 1)-
Example 32
l0 7-~3-[(2-Cyano-1H-indol-4-yl)oxy -2-hydroxypropyl~-N phenyl-3,7-
diazabicyclo[3.3. l~nonane-3-carboxamide
A mixture of 4-(2-oxiranylmethoxy)-1H-indole-2-carbonitrile (1.0 g,
4.7 mmol, Pitha et al., J. Med. Chem., 30 (1987) 612) and Nphenyl-3,7-
diazabicyclo[3.3.1]nonane-3-carboxamide (1.4 g, 5.5 mmol, see Example
i s 30(d) above) in iso-propanol: H,O ( 10 mL of 9:1 ) was stirred under
reflux
for 3 h before being concentrated in vacuo. The resulting residue was
purified by column chromatography on silica gel, eluting with a gradient
of DCM:MeOH (99:1 to 97:3), to yield 0.8 g (37%) of the title
compound.
13C NMR (CDC13): 8 29.03, 29.39, 31.27, 48.37, 49.31, 57.89, 60.42,
61.41, 66.07, 70.04, 100.72, 104.39, 105.13, 111.31, 114.95, 117.66,
120.18, 120.30, 123.00, 126.54, 128.84, 138.39, 139.16, 152.55, 156.29
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Example 33
7-[(7-Cyano-2,3-dihydro-1,4-benzodioxin-2-yl)methyl]-N ethyl-3,7-
diazabicyclo[3.3.1]nonane-3-carboxamide
s (a) 5-Bromo-2-(3-chloro-2-hydroxypropoxy)benzaldehyde
A mixture of 5-bromo-2-hydroxy benzaldehyde (20.1 g, 0.1 mol),
epichlorohydrin (25 mL, 0.32 mol) and 6 drops of piperidine was stirred
under reflux for 6 h before being concentrated in vacuo. The resulting
residue was dissolved in chloroform (25 mL) and treated with
io concentrated HCl (10 mL). The resulting mixture was stirred for 3 h at rt
before the organic layer was washed with water, separated, dried and
concentrated in vacuo to yield 28.2 g (96 % ) the sub-title compound. This
was used directly in the next step without any further purification.
is (b) 5-Bromo-2-(3-chloro-2-hydroxypropoxy)phenyl formate
A solution of 5-bromo-2-(3-chloro-2-hydroxypropoxy)benzaldehyde
(28.2 g, 96 mmol, from step (a) above) in DCM (200 rriL) was treated
with 3-chloroperoxybenzoic acid (25 g of 70-75 % purity, approximately
100 mmol). The resulting exothermic reaction caused the mixture to
2o reflux for 20 min. Stirring was continued for a further 3 days before the
mixture was filtered (to remove precipitated 3-chlorobenzoic acid). The
filtrate was washed with K~C03-solution and water, dried and concentrated
in vacuo to yield 26.1 g of sub-title compound. This was used directly in
the next step without any further purification.
2s
(c) (7-Bromo-2,3-dihydro-1,4-benzodioxin-2-yl)methanol
A solution of 5-bromo-2-(3-chloro-2-hydroxypropoxy)phenyl formate
(26.1 g, 84 mmol, from step (b) above) in ethanol (100 mL) was treated
with a solution of potassium hydroxide (6.1 g of 85 % purity,
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approximately 92 mmol) in water (10 mL). The resulting mixture was
refluxed for 1.5 h before. being filtered and concentrated in vacuo. The
resulting residue was dissolved in ethyl acetate and washed with brine.
The organic layer was separated, dried and concentrated in vacuo to give
s 28.8 g of crude product. This was purified by column chromatography on
silica gel, eluting with diethyl ether:hexane (70:30), to yield 10.0 g
(49.1 % ) of the sub-title compound.
(d) 3-(Hydroxymethyl)-2,3-dihydro-1,4-benzodioxin-6-carbonitrile
Io A mixture of (7-bromo-2,3-dihydro-1,4-benzodiaxin-2-yl)methanol
(10.0 g, 41.2 mmol, from step (c) above) and CuCN (4. 0 g, 45.3 mmol)
in DMF ( 10 mL, dried over molecular sieves) was stirred at 170 ° C for
4.5 h. The reaction mixture was poured into a warm aqueous solution of
sodium cyanide (8.10 g, 165 mmol of NaCN in 25 mL HBO). The
Is resulting mixture was extracted with toluene and DCM. The combined
organic layers were washed with water and then brine, dried and
concentrated in vacuo. The residue so obtained was crystallised from
toluene and DCM to yield 2.8 g (35 %) of the sub-title compound.
2o (e) (7-Cyano-2,3-dihydro-1,4-benzodioxin-2-yl)methyl methanesulfonate
A solution of methanesulfonyl chloride (1.81 g, 15.8 mmol) in
dichloromethane (5 mL) was added dropwise to a cooled (0 ° C) mixture
of
3-(hydroxymethyl)-2,3-dihydro-1,4-benzodioxin-6-carbonitrile (2.75 g,
14.4 mmol, from step (d) above) and pyridine (1.26 g, 16 mmol) in DCM
zs (25 mL). After addition was complete, the mixture was stirred at 0°C
for
1 h, and then at rt overnight. TLC analysis indicated incomplete reaction
after this time, and so further portions of methanesulfonyl chloride (0.4 g,
3.5 mmol) and pyridine (0.5 mL, 0.49 g, 6.2 mmol) were added. The
mixture was retluxed for 3.5 h before being washed twice with saturated
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NaZC03 solution, dried and concentrated in vacuo. The crude product
(4.5 g) so obtained was purified by flash chromatography, eluting with
DCM, to give 3.5 g of the sub-title compound, which crystallised on
standing .
(f) 7-[(7-Cyano-2,3-dihydro-1,4-benzodioxan-2-yl)methyl]-N ethyl-3,7-
diazabicyclo[3.3.1]nonane-3-carboxamide
A mixture of (7-cyano-2,3-dihydro-1,4-benzodioxin-2-yl)methyl methane-
sulfonate (150 mg, 0.9 mmol, from step (e) above), N ethyl-3,7-diaza-
to bicyclo[3.3.1]nonane-3-carboxamide (186 mg, 0.94 mmol, see Example
6(b) above), K,C03 (265 mg, 2.0 mmol) and NaI (14 mg, 0.09 mmol) in
CH3CN was refluxed for 20 h. The solvent was removed in vacuo and the
resulting residue treated with DCM and water. The organic layer was
separated, dried (Na,S04) and concentrated in vacuo. The resulting
is residue was purified by flash chromatography, eluting with DCM:MeOH
(95:5) to yield 113.2 mg (34 % ) of the title compound.
13C NMR (CDC13): 8 15.61, 29.19, 30.72, 35.72, 47.78, 58.34, 59.02,
60.64, 67.01, 71.38, 71.49, 71.60, 104.10, 120.76, 120.89, 125.39,
20 125.79, 143.50, 147.80, 157.46
Example 34
7-~ [(2S)-6-Cyano-4-(methanesulfonyl)-3,4-dihydro-2H-1,4-benzoxazin-2-
yl]methyl-N ethyl-3,7-diazabicyclo[3.3.1]nonane-3-carboxamide
Zs
(a) (2R)-2-(Hydroxymethyl)-3,4-dihydro-2H 1,4-benzoxazine-6-
carbonitrile
A mixture of 3-amino-4-hydroxybenzonitrile (25 g, 0.186 mol) and S-
epichlorohydrin (10.7 g, 0.22 mol) in aqueous ethanol (500 mL of 99 % )
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was stirred at 60°C for 24 h. The mixture was concentrated in vacuo
before ethanol (500 mL) was added, followed by K~C03 (27 g, 0.195
mol). The resulting mixture was refluxed for 1 h before being filtered.
The filtrate was concentrated in vacuo to give 61 g of a black oil. This
s was diluted with water (500 mL), and then extracted twice with DCM and
ethyl acetate. The combined organic extracts were dried and concentrated
in vacuo to yield 20 g (57 % ) of the sub-title compound as yellow crystals.
(b) (2R)-6-Cyano-4-(methanesulfonyl)-3,4-dihydro-2H-1,4-benzoxazin-2-
lo yl~methyl methanesulfonate
Methanesulfonyl chloride (45 g, 0.395 mol) was added dropwise to a
cooled (0°C) mixture of (2R)-2-(hydroxymethyl)-3,4-dihydro-2H-1,4-
benzoxazine-6-carbonitrile (30 g, 0.158 mol, from step (a) above) and
pyridine (200 mL, excess). The mixture was stirred at rt overnight before
is being concentrated in vacuo. The resulting residue was treated with water
and crystals of the product were isolated by filtration. These were
recrystallised from MeCN to give 29 g of pure material. The mother
liquor was concentrated in vacuo to give a residue which was crystallised
from chloroform to give a further crop (7.5 g) of product. The total yield
20 of the sub-title compound was 36.5 g (67 % ) .
(c) 7-~[(2,5~-6-Cyano-4-(methanesulfonyl)-3,4-dihydro-2H-1,4-benzoxazin-
2-yl~methyl~-N ethyl-3,7-diazabicyclo[3.3.l~nonane-3-carboxamide
A solution of (2R)-6-cyano-4-(methanesulfonyl)-3,4-dihydro-2H-1,4-
2s benzoxazin-2-yl]methyl methanesulfonate (1 g, 2.89 mmol, from step (b)
above) in MeCN (5 mL) was treated with triethylamine (8 mL, 5.8 g,
57.4 mmol), followed by N ethyl-3,7-diazabicyclo[3.3. lJnonane-3-
carboxamide (0.85 g, 4.33 mmol, see Example 6(b) above). The resulting
mixture was stirred at 70 ° C for 5h, and then at rt overnight. The
mixture
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was concentrated in vacuo and purified by acid/base extraction, followed
by flash chromatography, eluting with DCM:MeOH, to yield 100 mg
( 14 % ) of the title compound.
s 13C NMR (CDC13): 8 15.63, 28.87, 29.09, 30.48, 35.73, 39.50, 45.96,
47.65, 48.11, 59.03, 59.19, 60.59, 73.40, 104.15, 118.72, 119.90,
124.92, 126.51, 128.92, 150.04, 157.74
Example 35
io 7-[2-({2-[4,5-Bis(4-cyanophenyl)-1H-pyrazol-1-yl]acetyl}amino)ethyl]-N
ethyl-3,7-diazabicyclo[3.3.1]nonane-3-carboxamide
(a) 4-[(E)-1-(4-Cyanobenzoyl)-2-(dimethylamino)ethenyl]benzonitrile
N, N Dimethylformamide dimethylacetal ( 135.2 g, 0.29 mol) was added
is dropwise, under an inert atmosphere, to a heated (60°C) solution of
4-[2-(4-cyanophenyl)acetyl]benzonitrile (60.2 g, 0.24 mol, Ashley et al. ,
J. Chem. Soc. (1942) 103, 110) in 1,2-dimethoxyethane. The resulting
mixture was then filtered and concentrated in vacuo to give a residue that
was crystallised from MeOH. This gave 27.9 g (38 % ) of the sub-title
2o compound.
(b) Ethyl 2-[4,5-bis(4-cyanophenyl)-1H-pyrazol-1-yl]acetate
A solution of 4-[(E~-1-(4-cyanobenzoyl)-2-(dimethylamino)ethenyl]
benzonitrile (6.2 g, 20 mmol from step (a) above) in aqueous ethanol (100
zs mL of 99 % ) was treated with ethyl 2-hydrazinoacetate hydrochloride (3 .5
g, 22.6 mmol). The mixture was stirred at rt overnight before being
concentrated in vacuo. The resulting residue was diluted with water,
which aqueous mixture was extracted with DCM. The organic layer was
then separated, dried and concentrated in vacuo to give a residue which
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was recrystallised from diethyl ether to yield 1.7 g (23.5 % ) of the sub-
title
compound.
(c) 2-[4,5-Bis(4-cyanophenyl)-1H-pyrazol-1-yl]-N (2-hydroxyethyl)-
s acetamide
A mixture of ethyl 2-[4,5-bis(4-cyanophenyl)-1H pyrazol-1-yl]acetate
(3.9 g, 10.9 mmol, from step (b) above), 2-amino-1-ethanol (1.3 g,
21.8 mmol) and triethylamine (0.8 g, 76 mmol) was stirred at 100°C
overnight. Water and DCM were added, the product crystallised and was
io isolated by filtration to yield 3.53 g of sub-title compound:
(d) 2-[4,5-Bis(4-cyanophenyl)-1H-pyrazol-1-yl]-N (2-bromoethyl)-
acetamide
A mixture of 2-[4,5-bis(4-cyanophenyl)-1H-pyrazol-1-yl]-N (2-hydroxy-
is ethyl)acetamide (0.7 g, 1.88 mmol, from step (c) above), N bromo-
succinimide (0.75 g, 5.64 mmol) and triphenylphosphine (2.22 g,
8.4 mmol) in DCM (100 mL) was stirred under reflux for 3 h. The
reaction mixture was allowed to cool before being washed with water. The
organic layer was separated, dried and concentrated in vacuo to give a
Zo residue that was purified by flash chromatography, eluting with diethyl
ether:methanol (95:5), to yield 0.7 g sub-title compound contaminated
with triphenylphosphine oxide. This product was used directly in the next
step without any further purification.
2s (e) 7-[2-(~2-[4,5-Bis(4-cyanophenyl)-1H-pyrazol-1-yl]acetyl~amino)ethyl]-
N ethyl-3,7-diazabicyclo[3.3.1]nonane-3-carboxamide
A mixture of 2-[4,5-bis(4-cyanophenyl)-1H-pyrazol-1-yl)-N (2-bromo-
ethyl)acetamide (0.7 g, 1.6 mmol, from step (d) above), N ethyl-3,7-
diazabicyclo[3.3.1]nonane-3-carboxamide (0.32 g, 1.6 mmol, see
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Example 6(b) above) and K2C03 (0.55 g, 4 mmol) in acetonitrile (15 mL)
was stirred under reflux overnight. Extraction with diethyl ether and
water gave an organic layer that was separated, dried and concentrated in
vacuo. The resulting residue was purified by chromatography on silica
s gel, eluting with diethyl ether : MeOH (95:5), to yield 0.27 g of the title
compound.
13C NMR (CDC13): ~ 15.77, 29.18, 32.37, 36.13, 48.72, 52.27, 56.32,
109.83, 113.13, 118.27, 118.93, 120.10, 127.80, 131.39, 132.46,
io 132.73, 134.62, 138.75, 159.14, 167.09
Example 36
The following compounds (all of which are title compounds of this
Example 36) were also prepared, using analogous methods to those
is described herein:
7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-N ethyl-3,7-diazabicyclo[3.3.1]-
nonane-3-carboxamide;
7-[(2R)-3-(4-cyanophenoxy)-2-hydroxypropyl]-N ethyl-3,7-diazabicyclo-
[3 .3 .1 ] nonane-3-carboxamide;
20 7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-N propyl-3,7-diazabicyclo-
[3 .3 .1 ] nonane-3-carboxamide;
7-[2-(4-cyanophenoxy)ethyl]-N ethyl-3,7-diazabicyclo[3.3.1]nonane-3-
carboxamide;
7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-N tetrahydro-2H-pyran-2-yl-3,7-
Zs diazabicyclo[3.3.1]nonane-3-carboxamide;
7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-3,7-diazabicyclo[3.3.1]nonane-
3-carboxamide;
7-(4-cyanophenethyl)-N ethyl-3,7-diazabicyclo[3.3.1]nonane-3-
carboxamide;
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7-[(2S)-3-(4-cyanophenoxy)-2-hydroxypropyl]-N,N dimethyl-3,7-
diazabicyclo[3.3.1]nonane-3-carboxamide;
tert-butyl 2-(4-cyanophenoxy)-1-({7-[(ethylamino)carbonyl]-3,7-diazabi-
cyclo[3.3.1]non-3-yl}methyl)ethylcarbamate;
s 7-(3-(4-cyanophenoxy)-2-{[(ethylamino)carbonyl]amino}propyl)-N ethyl-
3,7-diazabicyclo[3.3.1]nonane-3-carboxamide;
7-(3-(4-cyanophenoxy)-2-{[(ethylamino)carbonyl]amino}propyl)-N ethyl-
3,7-diazabicyclo[3.3.1]nonane-3-carboxamide;
7-(3-(4-cyanophenoxy)-2-{ [(dimethylamino)carbonyl]amino}propyl)-N
to ethyl-3,7-diazabicyclo[3.3.1]nonane-3-carboxamide;
methyl 2-(4-cyanophenoxy)-1-({7-[(ethylamino)carbonyl]-3,7-diazabi-
cyclo[3.3.1]non-3-yl}methyl)ethylcarbamate;
7-[2-(acetylamino)-3-(4-cyanophenoxy)propyl]-N ethyl-3,7-diazabicyclo-
[3.3 .1]nonane-3-carboxamide;
is 7-[3-(2,4-dicyanophenoxy)-2-hydroxypropyl]-N ethyl-3,7-diazabicyclo-
[3.3 .1]nonane-3-carboxamide;
tert-butyl (1,5~-2-(4-cyanophenoxy)-1-({7-[(ethylamino)carbonyl]-3,7-
diazabicyclo[3.3.1]non-3-yl}methyl)ethylcarbamate;
7-[(2,5~-2-[(aminocarbonyl)amino]-3-(4-cyanophenoxy)propyl]-N ethyl-3,7-
Zo diazabicyclo[3.3.1]nonane-3-carboxamide;
tert-butyl (1R)-2-(4-cyanophenoxy)-1-({7-[(ethylamino)carbonyl]-3,7-
diazabicyclo[3.3.1]non-3-yl}methyl)ethylcarbamate;
N acetyl-7-[(2R)-3-(4-cyanophenoxy)-2-hydroxypropyl]-3,7-diazabicyclo-
[3.3 .1]nonane-3-carboxamide;
N acetyl-7-[(2S~-3-(4-cyanophenoxy)-2-hydroxypropyl]-3,7-diazabicyclo-
[3.3 .1]nonane-3-carboxamide;
7-[(2R)-3-(4-cyanophenoxy)-2-hydroxypropyl]-N methyl-3,7-diazabi-
cyclo[3.3.1]nonane-3-carboxamide;
7-[(2,5~-3-(4-cyanophenoxy)-2-hydroxypropyl]-N methyl-3,7-diazabicyclo-
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[3 . 3 . l~nonane-3-carboxamide;
7-[(2S~-3-(4-cyano-2-{[(2-cyanoethyl)amino]carbonyl}phenoxy)-2-
hydroxypropyl]-N ethyl-3,7-diazabicyclo[3.3.1]nonane-3-carboxamide;
methyl (1R)-2-(4-cyanophenoxy)-1-({7-[(ethylamino)carbonyl]-3,7-diaza-
s bicyclo[3.3.1]non-3-yl}methyl)ethylcarbamate;
7-[(2R)-3-(4-cyanophenoxy)-2-hydroxypropyl]-N propyl-3,7-diazabicyclo-
[3.3.1]nonane-3-carboxamide;
7-[(2,5~-3-(4-cyanophenoxy)-2-hydroxypropyl]-N propyl-3,7-di-
azabicyclo[3.3.1]nonane-3-carboxamide;
io 7-((2S~-3-{4-cyano-2-[(methylamino)carbonyl]phenoxy}-2=hydroxypropyl)-
N ethyl-3,7-diazabicyclo[3.3.1]nonane-3-carboxamide;
7-[(2,5~-3-(4-cyanophenoxy)-2-hydroxypropyl]-N propionyl-3,7-diaza-
bicyclo[3.3.1]nonane-3-carboxamide;
7-[(2R)-3-(4-cyanophenoxy)-2-hydroxypropyl]-N propionyl-3,7-diazabi-
is cyclo[3.3.1]nonane-3-carboxamide;
7-[2-(4-cyanophenyl)-2-hydroxyethyl]-N ethyl-3,7-diazabicyclo[3.3.1]-
nonane-3-carboxamide;
7-[(2S~-3-(4-cyanophenoxy)-2-hydroxypropyl]-N (2-propynyl)-3,7-diazabi-
cyclo[3.3.1]nonane-3-carboxamide;
Zo 7-(4-cyanophenethyl)-N iso-propyl-3,7-diazabicyclo[3.3.1]nonane-3-
carboxamide;
N ethyl-7-[(2S)-2-hydroxy-3-(4-nitrophenoxy)propyl]-3,7-diazabicyc1o-
[3 .3 .1 ] nonane-3-carboxamide;
methyl (1,5~-2-(4-cyanophenoxy)-1-({7-[(ethylamino)carbonyl]-3,7-diazabi-
2s cyclo[3.3.1]non-3-yl}methyl)ethylcarbamate;
7-[(2S~-3-(4-cyanophenoxy)-2-hydroxypropyl]-N (cyclopropylmethyl)-3,7-
diazabicyclo[3.3.1]nonane-3-carboxamide;
N (4-nitrophenyl)-7-(4-oxoheptyl)-3,7-diazabicyclo[3.3.1]nonane-3-
carboxamide;
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7-[(2R)-3-(4-cyanophenoxy)-2-hydroxypropyl]-N (2-propynyl)-3,7-
diazabicyclo[3.3.1]nonane-3-carboxamide;
7-(3-{4-cyano-2-[(cyclopropylamino)carbonyl]phenoxy}-2-hydroxy-
propyl)-N propionyl-3,7-diazabicyclo[3.3.1]nonane-3-carboxamide;
s 7-[(2S~-3-(4-cyanophenoxy)-2-hydroxypropyl]-N phenyl-3,7-diaza-
bicyclo [3 .3.1 ] nonane-3-carboxamide;
7-[(2R)-3-(4-cyanophenoxy)-2-hydroxypropyl]-N (cyclopropylmethyl)-3,7-
diazabicyclo[3.3.1]nonane-3-carboxamide;
tert-butyl (1R)-2-(4-cyanophenoxy)-1-({7-[(propionylamino)carbonyl]-3,7-
lo diazabicyclo[3.3.1]non-3-yl}methyl)ethylcarbamate;
7-(3-{4-cyano-2-[(iso-propylamino)carbonyl]phenoxy}-2-hydroxypropyl)-
N ethyl-3,7-diazabicyclo[3.3.1]nonane-3-carboxamide;
tert-butyl 2-(4-cyanophenoxy)-1-({7-[(propionylamino)carbonyl]-3,7-di-
azabicyclo[3.3 .1]non-3-yl}methyl)ethylcarbamate;
is tent-butyl 2-(4-cyanophenoxy)-1-({7-[(iso-propylamino)carbonyl]-3,7-
diazabicyclo[3.3.1]non-3-yl}methyl)ethyl(methyl)carbamate;
7-[3-(4-cyanophenoxy)-2-(methylamino)propyl]-N iso-propyl-3,7-
diazabicyclo[3.3.1]nonane-3-carboxamide;
7-{3-(4-cyanophenoxy)-2-[methyl(methylsulfonyl)amino]propyl}-N iso-
2o propyl-3,7-diazabicyclo[3.3.1]nonane-3-carboxamide;
N (tert-butyl)-7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-3,7-diazabicyclo-
[3.3 .1]nonane-3-carboxamide;
7-[2-amino-3-(4-cyanophenoxy)propyl]-3,7-diazabicyclo[3.3.1]nonane-3-
carboxamide;
2s tert-butyl2-[7-(aminocarbonyl)-3,7-diazabicyclo[3.3.1]non-3-yl]-1-[(4-
cyanophenoxy)methyl]ethylcarbamate;
tert-butyl 2-(4-cyanophenoxy)-1-({7-[(tetrahydro-2H-pyran-2-ylamino)-
carbonyl]-3,7-diazabicyclo[3.3.1]non-3-yl}methyl)ethylcarbamate;
N (4-cyanophenyl)-7-(4-oxoheptyl)-3,7-diazabicyclo[3.3.1]nonane-3-
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carboxamide;
7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-N (2,2-dimethylpropanoyl)-3,7-
diazabicyclo[3.3.1]nonane-3-carboxamide;
N (tert-butoxy)-7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-3,7-
s diazabicyclo[3.3.1]nonane-3-carboxamide;
2-[7-(aminocarbonyl)-3 ,7-diazabicyclo[3 .3 .1 ]non-3-yl]-1-[(4-cyano-2-
methylphenoxy)methyl]ethyl tert-butylcarbamate;
7-[(2,5~-3-(4-cyanophenoxy)-2-hydroxypropyl]-N iso-propyl-N methyl-3,7-
diazabicyclo[3.3.1]nonane-3-carboxamide;
io N (4-cyanophenethyl)-7-iso-propyl-3,7-diazabicyclo[3.3.1]nonane-3-
carboxamide;
N (tert-butoxy)-7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-N methyl-3,7-
diazabicyclo[3.3.1]nonane-3-carboxamide;
N (4-cyanophenethyl)-7-(3,4-dimethoxyphenethyl)-3,7-diazabicyclo-
ls [3.3.1]nonane-3-carboxamide;
7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-N cyclopropyl-3,7-diazabicyclo-
[3.3.1]nonane-3-carboxamide;
7-[2-amino-3-(4-cyanophenoxy)propyl]-N (ten-butyl)-3,7-diazabicyclo-
[3 .3 .1 ] nonane-3-carboxamide;
2o N [3-(4-cyanophenoxy)propyl]-7-[5-(ethylamino)-5-oxopentyl]-3,7-diaza-
bicyclo[3.3.1]nonane-3-carboxamide;
7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-N (3,5-dimethyl-4-isoxazolyl)-
3,7-diazabicyclo[3.3.1]nonane-3-carboxamide;
7-[3-(4-cyanoanilino)propyl]-N iso-propyl-3,7-diazabicyclo[3.3.1]nonane-
2s 3-carboxamide;
7-[4-(4-cyanophenyl)-4-hydroxybutyl]-N ethyl-3,7-diazabicyclo[3.3.1]-
nonane-3-carboxamide;
ethyl {7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-3,7-diazabicyclo[3.3.1]-
non-3-yl}carbonylcarbamate;
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7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-N (2,6-dimethoxyphenyl)-3,7-
diazabicyclo[3.3.1]nonane-3-carboxamide;
7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-N (4-cyanophenyl)-3,7-diazabi-
cyclo[3.3.1]nonane-3-carboxamide;
s N benzyl-7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-3,7-diazabicyclo-
[3.3.1]nonane-3-carboxamide;
7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-N hexyl-3,7-diazabicyclo[3.3.1]-
nonane-3-carboxamide;
ethyl 3-[({7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-3,7-diazabicyclo-
lo [3.3.1]non-3-yl}carbonyl)amino]propanoate;
N (4-butoxyphenyl)-7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-3,7-diazabi-
cyclo[3.3.1]nonane-3-carboxamide;
7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-N (3-cyanophenyl)-3,7-diazabi-
cyclo[3.3.1]nonane-3-carboxamide;
is 7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-N (3,4-dimethoxyphenyl)-3,7-
diazabicyclo[3.3.1]nonane-3-carboxamide;
butyl 2-[({7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-3,7-diazabicyclo-
[3.3.1]non-3-yl}carbonyl)amino]acetate;
7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-N (4-methoxyphenyl)-3,7-diaza-
2o bicyclo[3.3.1]nonane-3-carboxamide;
7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-N (3,4-dimethoxyphenethyl)-
3,7-diazabicyclo[3.3.1]nonane-3-carboxamide;
7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-N (3,4-dimethoxybenzyl)-3,7-
diazabicyclo[3.3.1]nonane-3-carboxamide;
2s 7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-N (3,4,5-trimethoxyphenyl)-3,7-
diazabicyclo[3.3 .1]nonane-3-carboxamide;
7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-N (3,4-dihydro-2H-1,5-benzo-
dioxepin-7-yl)-3,7-diazabicyclo[3.3.1]nonane-3-carboxamide;
7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-N (2,6-dimethylphenyl)-3,7-
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diazabicyclo[3.3.1]nonane-3-carboxamide;
iso-propyl {7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-3,7-diazabicyclo-
[3.3.1]non-3-yl}carbonylcarbamate;
7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-N (2-fluoroethyl)-3,7-diazabi-
s cyclo[3.3.1]nonane-3-carboxamide;
7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-N {2-[(cyclopropylmethyl)-
amino]-2-oxoethyl}-3,7-diazabicyclo[3.3.1]nonane-3-carboxamide;
N (tert-butyl)-7-{2-hydroxy-3-[(2-methyl-1-oxo-1,2-dihydro-4-
isoquinolinyl)oxy]propyl}-3,7-diazabicyclo[3.3.1]nonane-3-carboxamide;
to N (1-cyano-1-methylethyl)-7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-3,7-
diazabicyclo [3 .3 .1 ] nonane-3-carboxamide;
7-[2-amino-3-(4-cyanophenoxy)propyl]-N (1,3-benzodioxol-5-ylmethyl)-
3,7-diazabicyclo[3.3.1]nonane-3-carboxamide;
7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-N iso-propyl-3,7-diazabicyclo-
ls [3.3.1]nonane-3-carboxamide;
4-(3-{7-[(2,6-dimethyl-4-morpholinyl)carbonyl]-3,7-diazabicyclo[3.3.1]-
non-3-yl}-2-hydroxypropoxy)benzonitrile;
N [cyano(4-fluorophenyl)methyl]-7-[3-(4-cyanophenoxy)-2-hydroxy-
propyl]-3,7-diazabicyclo[3.3.1]nonane-3-carboxamide;
2o N (cyanomethyl)-7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-N methyl-3,7-
diazabicyclo[3.3.1]nonane-3-carboxamide;
7-[4-(4-cyanophenoxy)-2-hydroxybutyl]-N ethyl-3,7-diazabicyclo[3.3.1]-
nonane-3-carboxamide;
7-[4-(4-cyanophenyl)butyl]-N [2-oxo-2-(propylamino)ethyl]-3,7-diazabi-
2s cyclo[3.3.1]nonane-3-carboxamide;
7-[4-(4-cyanophenyl)butyl]-N propyl-3,7-diazabicyclo[3.3.1]nonane-3-
carboxamide;
7-[2-amino-4-(4-cyanophenoxy)butyl]-N propyl-3,7-diazabicyclo[3.3.1]-
nonane-3-carboxamide;
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7-[4-(4-cyanophenyl)butyl]-N ethyl-3,7-diazabicyclo[3.3.1]nonane-3-
carboxamide;
7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-N [2-(2-methoxyethoxy)ethyl]-
3,7-diazabicyclo(3.3.1]nonane-3-carboxamide;
s N (4-cyanophenyl)-7-(3,3-dimethyl-2-oxobutyl)-3,7-diazabicyclo[3.3.1]-
nonane-3-carboxamide;
N (4-cyanophenyl)-7-(3,4-dimethoxyphenethyl)-3,7-diazabicyclo[3.3.1]-
nonane-3-carboxamide;
N (4-cyanophenyl)-7-(cyclopropylmethyl)-3,7-diazabicyclo[3.3.1]nonane-
io 3-carboxamide;
N (4-cyanophenyl)-7-[2-(2-methoxyethoxy)ethyl]-3,7-diazabicyclo[3.3.1]-
nonane-3-carboxamide;
N (4-cyanophenyl)-7-[2-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-oxoethyl]-
3,7-diazabicyclo[3 .3 .1]nonane-3-carboxamide;
is 7-[3-(4-acetyl-1-piperazinyl)propyl]-N (4-cyanophenyl)-3,7-diazabicyclo-
[3.3.1]nonane-3-carboxamide; and
7-[(2,5~-3-(4-cyanophenoxy)-2-hydroxypropyl]-N [2-oxo-2-(propylamino)-
ethyl]-3,7-diazabicyclo[3.3.1]nonane-3-carboxamide.
2o Example 37
Title compounds of the above Examples were tested in Test A above and
were found to exhibit Dlo values of more than 6Ø
Abbreviations
AcOH = acetic acid
ADDP = 1,1'-(azodicarbonyl)dipiperidine
aq. - aqueous
atm. = atmospheres
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CBz = benzyloxycarbonyl
CDI = carbonyl diimidazole
Bu = butyl
DCM = dichloromethane
s DMF = dimethylformamide
DMSO = ~ dimethylsulfoxide
Et = ethyl
EtOAc = ethyl acetate
EtOH = ethanol
io ESI = electron spray interface
eq. - equivalents
FAB = fast atom bombardment
h = hours
IPA = iso-propanol
1 s i-PrOH = iso-propanol
LC = liquid chromatography
HPLC = high performance liquid chromatography
mCPBA = meta-chloroperbenzoic acid
Me = methyl
2o MeCN = acetonitrile
MeOH = methanol
mesyl = methanesulfonate
min. = minutes
Ms = mesylate
2s MS = mass spectroscopy
NADPH = nicotinamide adenine dinucleotide phosphate,
reduced
form
NMR = nuclear magnetic resonance
OSu = O-succinyl
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Pd/C = palladium on carbon
pTSA = para-toluenesulfonic acid
rt. = room temperature
satd. = saturated
s TEA = triethylamine
THF = tetrahydrofuran
tlc = thin layer chromatography
TMS = tetramethylsilane
to
Prefixes n-, s-, i-, iso-, t- and tert- have their usual meanings: normal,
iso,
secondary and tertiary.
