Note: Descriptions are shown in the official language in which they were submitted.
WO 91/11909 2 0~7 ~ ~ 3 9 PCr/lJS91/00963
,, , "~.
-- 1 --
TITLE OF T~E lNVENTIO~
TRIAZOLE ANGIOTENSIN II ANTAGONISTS INCORPORATING A
SUBSTITUTED ~ENZYL ELEMENT
~ACKGROUND OF T~E INVENTION
The present application is a continuation in
part of Serial No 479,779 filet on Febuary 13, 1990.
The Renin-angiotensin system ~RAS) plays a
central role in the regulation of normal blood
pressure and seems to be critically involved in
hypertension dcvelopment and maintenance as well as
congestive heart ~ailure. Angiotensin II (A II), is
a~ octapcptide hormone produced mainly in the blood
during the cleavage of angiotensin I by angiotensin
converting enzyme (ACE) localized on the endothelium
of blood ve66els of lun~, ~idney, and many other
organs. It i 8 the end product of the renin-
angiotensin system (RAS) and is a powerful arterial
vasoconstrictor that eserts it6 action by interacting
with specific receptors pre8ent on cell membranes.
.
~ , : - . , ' :.
':
wos~/llsl~s 2 0:7 ~ & 3 ~ PCT/US91/0096~ ~
One of the pos6ible modes of controlling the RAS is
angiotensin II receptor antagonism. Several peptide
analog6 of A II are known to inhibit the effect of
this hormone by competitively bloc~ing the receptors,
but their e~perimental and clinical applications have
been limited by partial agonist activity and la.c~ of
oral absorption ~M. Antonaccio. Clin. Ex~.
~y~erten~. A4, 27-46 (1982); D. ~. P. Streeten and
G. ~. Anderson, Jr. - ~n~ook of ~y~eL~nEion,
C~inical ~harma~olo~y of Antihy~ ensive D~e~, ed.
A. E. Doyle, Vol. 5, pp. 246-271, Elsevier Science
Publisher, Amsterdam, The Netherlands, 1984].
Recently, several 6ubstituted imidazoles
have been described as A II antagoni6ts.
Illustrative of such compounds are those disclosed in
U.S. Patents 4,207,324; 4,340,598; 4,576,958; and
4,582,847; and 4,B80,~04 in European Patent
Applications 028,834; 245,637; 253,310; 291,969; and
324,377 and in articles by A.T. Chiu, ~ 1. tEur. J
~h~mh E~. The~2~ 7, 13-21 (1988)] and by P.C.
Wong, ~ ~1- tJ Pha~ml E~_ The~a~, 2~1.
1-~(1988)]. All of the ~.S. Patents, European Patent
Applications 028,834 and 253,310 and the two articles
disclose substituted imidazole compounts which are
generally bonded through a lower alkyl bridge to a
substituted phenyl. European Patent Application
245,637 discloseR derivatives of 4,5,6,7-tetrahydro-
2~-imidazo~4,5-~]-pyridine-6-carbo~ylic acid and
analo~s thereof as antihypertensive agents.
The compounds disclosed within this
application have not been identified in any US
Patents, European Applications or articles. The
compounds of the present invention are substituted
, WO 91/1 1909 2 0.7 5 ~ ~ 9 - p~/US91/00963
triazoles which are bonded through a methylene bridge
to a novel substituted phenyl element. DuPont also
has filed a European Application (EP0 0,323,841)
covering substituted pyrroles, pyrazoles and
triazoles. The present invention covers novel
antagonists which incorporate a novel substituted
benzyl element linked to the triazole moiety. The
above cited applications are hereby incorporated by
reference, serving as an information source as to the
preparation of 6ubstituted triazoles. A pending
Merck application, Serial No. 382,138, discloses
other novel triazoles and the 6ynthetic routes to
these triazoles are described in the Schemes I-l
through I-14 and the incorporation of the 6ustituted
benzyl element is de6cribed in Schemes I-15 through
I-30.
The compounds of this invention have central
nervous ~ystem (CNS) activity. They are useful in
the treatment of cognitive dy6functions including
Alzheimer~ E disea6e, amne6ia and senile dementia.
These compounds al60 have an~iolytic and
antidepressant propertie6 and are therefore, useful
in the relief of 6ymptoms of anxiety and tension and
in the treatment of patients with depressed or
dysphoric mental 6tate6.
In addition, these compounds e~hibit
antidopaminergic properties and are thus u6eful to
treat disorder6 that involve dopamine dysfunction
such as 6chizophrenia. The compounds of this
invention are especially u8eful in the treatment of
these conditions in patients who are al60
hypertensive or have a congestive heart failure
condition.
.....
wos~ gog 2 0 7 ~ ~`3 ~ PCT/US91~00963 ~
DET~ILE~ DE~~I~TION OF TH~ I~VENTIQ~
This invention relate6 to compounds of
Formula I:
N, ~ ~ T)b-R
R'-~ ~
R9 ~ Rl
X~z
Rll y--R12
FORMULA I
Wherein Rl is:
~a) (Cl-C6)-alkyl, (C2-C6)-alkenyl or
(C2-C6)-alkynyl each of which i6
unsubstituted or substituted with one or
more 6ub6tituent~ selected from the group
consi6ting of:
i) ~ryl, wherein aryl i6 defined as
phenyl os naphthyl, un6ub6tituted or
6ubstituted with l or 2 6ub6tituents
selected from the group con~isting of:
l) Cl, Br, I, F,
2) (Cl-C4)-alkyl,
3) (Cl-C4)-alko~y,
4) N02
5) CF3
6) S02NR2aR2a,
7) (Cl-C4)-alkylthio,
, wo9l/1]909 ~7~`3~
PCT/US91/00963
8) hydro~y,
9) amino,
10) (C3-C7~-cycloalkyl,
ll) (C3-ClO)-alkenyl; and
S ii) (C3-C7)-cycloalkyl,
iii) Cl, Br, I, F, or
i v ) COOR2,
v) -CF2CF3. or
vi) -C~2CF3; and
(b) perfluoro-(Cl-C4)-alkyl, or
(c) (C3-C6)-cycloalkyl, unsubstituted or
substituted with one or more substituents
from the group consi6ting of:
(Cl-C4)-alkoxy, (Cl-C4)-alkyl- thio,
perfluoro-(Cl-C4)-alkyl, hydroxy, or F, Cl,
~r, I: and
B ~s:
(a) a single bond,
(b) -S(O)n(C~2)~-, or
(c) -0-;and
n i6 0 to 2; and
6 i6 0 to 5; and
R2 is:
(a) ~, or
(b) (Cl-C6)-alkyl; and
~ ' .
- : .
wo 9""gog 2 0 7 ~ 6 3 9 PCT/US91/00963 ~
-- 6 --
R2a i 6
(a) R2,
(b) C82-aryl, or
(c) aryl; and
(d) when R2 and R2a are alkyl ~ubstituent~ on
the same nitrogen they can be joined to form
a ring; and
wherein there is more than one R2a group in the
definition of a structure of Formula I they may
be the same or different; and
R9 and R10 are independently:
(a) 8,
(b) (Cl-C6)-alkyl, unsubstituted or substituted
with (C3-C7)-cycloalkyl,
( c ) ( C2-C6 ) -alkenyl,
(d) (C2-C6)-alkynyl,
(e) Cl, Br, F, I,
(f) (Cl-C6)-alko~yl,
(g) when R9 and R10 are on adjacent carbons,
they can be joined to form an phenyl ring,
(h) perfluoro-(Cl-C6)-alkyl,
(i) (C3-C7)-cycloalkyl, unsubstituted or
substituted with (Cl-C6)-alkyl,
(;) aryl; and
X is:
(a) _o_,
(b) ~5(0)n~~
(c ) -nRl3_
(d) -C820-,
.
:
~-.WO~1/11909 ~ Q ~
G~ Pcr/US9l/00963
, ~
(e) -C~2S(O)n~,
(f) -C~2NR13-,
(g) -OC~2-.
(h) -NR13C~2-.
(i) -s(o)
( j ) -C~l2- ,
(k) -(C~2)2-'
(1) single bond, or
(m) -C~=, wherein Y and R12 are absent forming a
lo -C=C bridge to the carbon bearing Z and
Rll; and
Y is:
(a) single bond,
(b) _o_,
(C) ~S(O)n~,
(d) _NR13_ or
(e) -C~2-; and
Except that X and Y are not defined in such a way
that the carbon atom to which Z is attached also
6imultaneously i8 bonded to two heteroatoms (0, N, S,
SO . SO2 ) .
Rll and R12 are independently:
(a) E.
(b~ ~Cl-C6)-alkyl unsub6tituted or 6ubstituted
with:
(i) aryl, or
(ii) (C3-C7)-cycloal~yl,
(c) aryl, unsubstituted or substituted with 1 to
5 substitute~ts selected from the group
consisting of:
'
, '
.,
WO91/11909 ~2 ~ 7 ~
~ ~ ~ J PCT/US91/00963
i) Cl, Br, I, F,
ii) (Cl-C4)-alkyl,
iii) t(cl-cs)-alkenyl]c~2
iv) [ (Cl-C5 )-alkYnYl~C~2- .
v) (Cl-C4)-alko~y, or
vi) (Cl-C4)-al~ylthio, and
(d) aryl-(Cl-C2)-alkyl, wherein the aryl group
i~ unsub6tituted or ~ubstituted with l to 5
6ubstitutents selected from the group
consisting of:
i) Cl, Br, I, F,
i i ) ( Cl-C4 )-al~yl .
iii) [(Cl-C5)-alkenyl]C~2-,
iv) [ (Cl-C5 )-alkYnYl~C~2- .
v) (Cl-C4)-alko~y, or
vi) (Cl-C4)-al~ylthio. and
(e) (C3-C7)-cycloal~yl; and
Rl3 is:
(a) ~,
(b) (Cl-C6)-al~yl,
(c) aryl,
(d) aryl-(Cl-C6)-alkyl-(C=0)-,
(e) (Cl-C6)-alkyl-(CeO)-,
(f) t(C2-Cs)-alkenyl~C~2-,
( g ) r (C2-Cs)-alkynyl]C~2-, or
(h) aryl-C~2-, and
Z is:
(a) -C02~,
(b) -C02-(Cl-C6)-alkyl,
- (c) -tetrazol-5-yl,
(d) -C0-NB(tetrazol-5-yl)
,., - ~ ,
: -
,. :. , . ... . ,~.
. wos1~]1sos 207 639
~ PCT/VS91/00963
~ .~
(e) -CON~-S02-aryl,
(f) -CON~-S02-(Cl-CB)-alkyl, wherein the alkyl
group is unsub6tituted or substituted with a
substituent chosen from the group consi~ting
of: -0~, -SH, -O(Cl-C4)-alkyl,
- -S (Cl-C4)-al~Yl~ -CF3, Cl, Br, F, I, -N02,
-C02H~ -co2-(cl-c4)-alkyl~ -N~2,
-N~t(Cl-C4)-alkyl], -N[(Cl-C4)-alkyl]2; and
(g) -COM~-S02-perfluoro-(Cl-C4)-alkyl,
(h) -CONH-S02-heteroaryl, or
(i) -CON~S02NR2aR2a; and
( j ) -S02NHCO-aryl,
(k) -S02MCC0-(Cl-C8)-alkyl. wherein the alkyl
group is unsubstituted or ~ubstituted with a
lS sub6tituent chosen from the group consisting
of: -OH, -S~, -O(Cl-C4)-alkyl,
-S-(Cl-C4)-alkyl, -CF3, Cl, Br, F, I, -N02,
-CO2~, -co2-(cl-c4)-alkyl, -N~2,
-N~t(Cl-c4)-alkyl]~ -N~(Cl-C4)-alkyl]2; and
(l) -S02N~CO-(Cl-C4)-perfluoroalkyl,
(m) -S02N~CO-heteroaryl. or
(n) -S02N~CONR2aR2a; and
T is ~S(O)n~~ --. -N~CH2-, -N~C(=0) ,
-C(.O)N(R20)-~ or -N(R20)-; and
b is 0 or l; and
R15 i S
(a) ~,
(b) (Cl-C6)-alkyl,
(c) phenyl, or
(d) benzyl; and
wo 9~ gog 2iO`7 ~ 3 ~
. PCT/US91/00963 ~
-- 10 --
R16 i6
(a) (Cl-ClO)-alkyl;
(b) substituted (Cl-C10)-alkyl in which one or
more substituent(s) is selected from
(1) ~, Br, Cl, F,
(2) hydro~y,
(3) (Cl-ClO)-alkoxy,
(4) (Cl-C5)-alko~ycarbonyl,
(5) (Cl-C5)-acyloxy,
(6) (C3-C8)-cycloalkyl,
(7) aryl,
(8) substituted aryl in which the
substituents are V and W,
(9) (cl-clo)-alkyl-s(o)n
lS (lO) (C3-Cg)-cycloal~yl-s(o)
(11) phenyl-S(O)n~
(12) substituted phenyl-S(O)n in which
the substituents are V and W,
(13) oxo,
(14) carboxy,
(15) NR2R2a,
(16) (Cl-C5)-alkylaminocarbonyl,
(17) di(Cl-C5)-alkylaminocarbonyl, or
(18) cyano,
(c) perfluoro-(Cl-C4)-alkyl,
(d) (C2-C10)-alkenyl,
(e) (C2-ClO)-alkynyl,
(f) (C3-Cg)-cycloalkyl,
(g) sub~tituted (C3-C8)-cycloalkyl in which the
~ubstituent i~ selected from:
(l) (Cl-C5)-alkyl, or
(2) (Cl-C5)-alkoxy,
.
.
. ~ .
, . WO 91/11909 ~ U,7,~
, PCI`/US91/00963
(3) (Cl-C5)-alko~ycarbonyl,
(4) (Cl-C5)-acyloxy,
t5) (Cl-Cs)-acyl,
(6) hydro~y,
(7) Br, Cl, F, I,
(8) (C3-C8)-cycloalkyl,
(9) aryl,
(10) substituted aryl in which the
~ubstituents are V and W,
(11) (Cl-Clo)-alkYl~S(O)n~
(12) (C3-C8)-cycloalkyl-S(O)n.
(13) phenyl-S(O)n,
(14) substituted phenyl-S(O)n in which the
substituents are V and W,
(15) oxo,
(16) carboxy,
(17) NR2R2a
(18) (Cl-C5)-alkylaminocarbonyl,
(19) di(Cl-Cs)-alkylaminocarbonyl, or
(20) cyano,
(h) C02R2a,
(i) aryl,
(j) substituted aryl in which the substituents
are V and W,
(k) aryl-(C~2)r-~Ml)z~(C~2)t-
(1) substituted aryl-(CB2)r-(Ml)z-(CB2)t- in
which the aryl group is substituted with V
and W,
WOg~ 9O9 207~39
Pcr/US9 1 /00963 ~
W
(~ V~(CHz)r--(~)z--(CH2)t--~
(n) ~CH2)~)s--(CH~)t--,
V ~,,W
( ) ~4 CH2) r ~ ( CH2) t--,
(P) W~CH2)r ~M~)z~CH2)t--, or
(q) w~N
5 ~ (CH2)r--~(CH2)t ~ ~nd
Ml is ' S, -~R15)-, or -C(0)-; and
z i s 0 or 1; and
2S r and t are 0 to 2; and
V and W are each independently selected from:
(a) ~,
' (b) (Cl-C5)-al~oxy,
(c) (C1-Cs)-alkyl,
(d ) hydroxy,
(e) ((Cl-Cs)-alkYl)S(O)n~
- - , .
, . ~
- ; . -. ~ . :
.. ,, - ' . : : -
f WO 91/11909 2 ~-7 S ~ 3 ~ pCTJUS91~00963
(f) -CN,
(g) -N02 ~
(h) -NR2R2-a,
(i) [(Cl-C5)-alkyl)~C0-NR2R2a,
(j) -C02R2a,
(k) t(Cl-Cs)-al~yl)]Co-,
(l) CF3,
(m) I, Br, Cl, F,
(n) hydroxy-(Cl-C4)-alkyl-,
(O) carbo~cy-(Cl-C4)-alkyl-,
(p) -tetrazol-5-yl,
(q ) -NEI-S02CF3,
(r) aryl,
( S ) -O-CONR2R2a
lS (t) NR2a_c02R2a
(u ) -NR2a-coNR2aR2a
(~) _NR2a-CON(C~2C~2)2Ql~
(w) -0CON(C~2C~2)2Ql~ or
(x) -CONR2R2a; and
Ql is:
0, S(O)n, or NR2a; and
Rl8 i6
(a) phenyl, unsub6tituted or sub6tituted with:
V and W,
(b) . (Cl-C4)-al~yl, or
(c) perfluoro-(Cl-C4)-alkyl; and
R20 is
(a) ~,
(b) (Cl-C6)-alkyl,
..
WO91~]1909 2 0 7 5 ~ ~ ~ PCT/US91/OOg63~
- 14 -
(c) allyl,
(d) (C3-C6>-cycloalkyl,
(e) (Cl-C4)-acyl,
(f) benzyl, or
(g) phenyl; and
R24 groups are independently:
(a) ~,
(b) (Cl-C6)-al~Yl. (C2-C6)-alkenyl or
lo (C2-C6)-alkynyl each of which is
unsubstituted or substituted with a
substituent selected from the group
consisting of: (C3-C7)-cycloalkyl, Cl, Br,
, ~, 0~, -NR2, -M~[(Cl-C4)-alkyl].
-N[(Cl-C4)-alkyl]2, -N~So2R25, -Co2R25,
(Cl-C4)-alkosyl, (Cl-C4)-alkylthio,
(Cl-C4)-acyl~ or C(=O)N~2,
(c) aryl, unsubstituted or substituted with V or
W,
(d) aryl-(Cl-C4)-alkyl, unsubstituted or
6ub~tituted with V or W,
R25 is:
(a) ~.
(b) (Cl-C6)-alkyl,
(c) aryl, or
(d) aryl-(Cl-Cs)-alkyl; and
the pharmaceutically acceptable salts thereof.
,
- ' ~.
, wos~ sog 2 0 7 ~ ~ 3 ~ ` PCT/US91/00963
,~,
The al~yl substituten~6 recited above denote
straight and branched chain hydrocarbons of the
length specified 6uch as methyl, ethyl, isopropyl,
isobutyl, neopentyl, isopentyl, etc.
The alkenyl and alkynyl substituents denote alkyl
groups as describet above which are modified BO that
each contains a carbon to carbon double bond or
triple bond, respectively, such as vinyl, allyl and
2-butenyl.
Cycloalkyl denotes rings compo6ed of 3 to 8
methlene groups, each which may be substituted or
unsubstitued with other hydrocarbon 6ubstituents, and
include for example cyclopropyl, cyclopentyl,
cyclohexyl and 4-methylcyclohexyl.
The alkoxy 6ubstituent repre6ents an alkyl group
as described above attached through an oxygen bridge.
The aryl 6ubstituent recited above represents
phenyl or naphthyl.
The heteroaryl substituent recited above
represent6 any 5- or 6-membered aromatic ring
containing from one to three heteroatoms selected
from the group con6isting of nitrogen, oxygen, and
sulfur, for example, pyridyl, thienyl, furyl,
imidazolyl, and thiazolyl.
~S
wo9l~llso9 2 0 7 ~ ~ 3 9 PCT/US91/00963 ~,;
- 16 -
The preferred compounds of this invention are:
3-Butyl-4-[[4~ carboxy-1-phenylmethoxy)phenyl]-
methyl]-5-(4-nitrobenzylthio)-4~-1,2,4-triazole.
3-Butyl-4-r[4-(1-carboxy-1-phenylmethoxy)phenyl]
methyl]-5-(4-nitrobenzylsulfinyl)-4~-1,2,4-triazole.
3-Butyl-4-[t4-[l-carbo~y-1-(2-chlorophenyl)methoxy]-
lo phenyl~methyl]-5-(4-nitrobenzylthio)-4~-1,2,4-
triazole
3-Butyl-4-[[4-[1-carboxy-1-(2-methylphenyl)methoxy]-
phenyl]methyl]-5-(4-nitrobenzylthio)-4~-1,2,4-
triazole~
3-Butyl-4-[[4-(1-carboxy-1-phenylmethoxy)phenyl]-
methyl]-5-(4-methoxybenzylthio)-4~-1,2~4-triazole.
3-Butyl-4-r[4-(1-carboxy-1-phenylmethoxy)phenyl]-
methyl]-5-(4-methoxybenzylsulfinyl)-4~-1,2,4-triazole.
3-Butyl-4-[[4-[l-carboxy-1-(2-chlorophenyl)methoxy]-
phenyl]methyl]-5-(4-methoxybenzylthio)-4~-1,2,4-
triazole.
3-Butyl-4-[[4-[1-carboxy-1-(2-methylphenyl)methoxy]-
phenyl]methyl]-5-(4-methoxybenzylthio)-4~-1,2,4-
triazole.
3-Butyl-5-(2-carbo~ybenzylthio)-4-[[4-(1-carboxy-1-
phenylmethoxy)phenyl~methyl-4~-1,2,4-triazole.
. - . ~ . . .
~ w091/1l~09 2 0 7 ~ & 3 9 PCT/~S9"00963
3-Butyl-5-(2-carboxybenzylthio)-4-[[4-[1-carboxy-1-(2-
chlorophenyl)methoxy3phenyl~methyl]-4~-1,2,4-triazole.
3-Butyl-5-(2-carboxybenzylthio)-4-[[4-[l-carbosy-1-(2-
methylphenyl)methosy~phenyl]methyl]-4~-1,2,4-triazole.
3-Butyl-4-[t4-[1-carboxy-1-phenylmethoxy]phenyl~-
methyl~-5-(4-chlorobenzylthio)-4~-1,2,4-triazole.
10 3-Buty'-4-t[4-[1-carboxy-1-(2-methylphenyl)methoxy~-
phenyl]methyl~-5-(4-chlorobenzylthio)-4~-1,2,4-
triazole.
3-Butyl-4-[[4-[1-carbosy-1-phenylmethoxy]phenyl]-
15 methyl~-5-(4-methylbenzylthio)-4~-1,2,4-triazole.
3-9utyl-4-[[4-[l-carboxy-1-(2-chlorophenyl)methoxy]-
phenyl~methyl~-5-(4-methylbenzylthio)-4~-1,2,4-
triazole.
3-Butyl-5-(4-nitrobenzylthio)-4-[[4-[1-phenyl-1-
(5-tetrazolyl)methoxy~phenyl~methyl~-4~-1,2,4-
triazole.
25 3-Butyl-4-t[4-tl-phenyl-1-(5-tetrazolyl)methoxy~-
phenyl]methyl]-5-(4-nitrobenzylsulfinyl)-4~-1,2,4-
triazole.
3-Butyl-4-[[4-[1-(2-chlorophenyl)-1-(5-tetrazolyl)-
methoxy]phenyl~methyl]-5-(4-nitrobenzylthio)-4E-
1,2,4-triazole.
~ .: .
WO91/11909 2 0 7 5 ~ j.3 ~ -` P~T/US91/00963 ~
- 18 -
3-Butyl-5-(4-methoxybenzylthio)-4-[[4-[1-phenyl-1-(5-
tetrazolyl)methoxy]phenyl]methyl3-4~-1,2,4-triazole.
3-Butyl-5-(4-metho~ybenzylthio)-4-[t4-rl-(2-chloro-
phenyl)-1-(5-tetrazolyl)methoxy]phenyl]methyl]-4~-
1,2,4-triazole;
3-Butyl-5-(4-methoxybenzylthio)-4-t[4-[1-(2-methyl-
phenyl)-1-(5-tetrazolyl)methoxy]phenyl~methyl]-4~-
1.2,4-triazole
3-Butyl-5-(2-carbo~ybenzylthio)-4-[[4-[1-phenyl-1-(5-
tetrazolyl)methoxy]phenyl]methyl]-4~-1,2,4-triazole.
3-Butyl-5-(2-carboxybenzylthio)-4-r[4-rl-(2-chloro-
phenyl)-l-(5-tetrazolyl)methoxy]phenyl]methyl-4~-
1,2,4-triazole.
3-Butyl-5-(4-chlorobenzylthio)-4-[[4-[1-phenyl-1-(5-
tetrazolyl)methoxy]phenyl~methyl]-4 -1,2,4-triazole.
3-~utyl-5-(4-chlorobenzylthio)-4-t~4-~1-(2-chloro-
phenyl)-1-(5-tetrazolyl)methoxy]phenyl]methyl]-4~-
1,2,4-triazole.
3-Butyl-4-[[4-~1 carboxy-1-(2,6-dichlorophenyl)-
metho~y~phenyl~methyl]-5-(4-methoxybenzylthio)-4~-1,2
4-triazole.
3-Butyl-4-tt4-rl-carboxy-1-(2-methoxyphenyl)methoxy~-
phenyl~methyl]-5-(4-chlorobenzylthio)-4~-1,2,4-
triazole.
.
:. , - ~ . . . -- - -
.
.
:
,
' ': ` -`. ~ : '
, . wo g~ go9 2 ~7~ ~ 3 ~ P~/Ussl/oo963
- 19 - 18059IA
3-Butyl-4-tt4-t(l-carboxy-1-phenylmethyl)amino]-
phenyl~methyl]-5-(4-methosybenzylthio)-4a-1,2,4-
triazole.
3-Butyl-4-tt4-ttl-carboxy-1-(2-chlorophenyl)methyl]-
amino]phenyl]methyl]-5-(4-nitrobenzylthio)-4~-1,2,4-
triazole.
3-Butyl-4-tt4-(1-carboxy-1-phenylmethoxy)phenyl]-
methyl]-5-(4-chlorobenzylsulf iDyl )-4~-1,2,4-triazole.
3-Butyl-4-tt4-tl-carboxy-1-(2-chlorophenyl)methosy]-
phenyl]methyl]-5-(4-chlorobenzylthio)-4~-1,2,4-
triazole.
3-Butyl-4-tt4-tl-carbo~y-1-(2-chlorophenyl)methoxy~-
phenyl]methyl]-5-(4-chlorobenzylsulfinyl)-4~-1,2,4-
triazole.
3-Butyl-4-tt4-(1-carbo~y-1-phenylmethosy)-3-
propylphenyl]methyl]-5-phenyl-4~-1,2,4-triazole.
3-Butyl-4-t[4-(1-carbo~y-1-phenylmetho~y)-3-
propylphenyl]methyl]-5-(4-chlorobenzylthio)-4~-
1.2.4-triazole,
3-~utyl-4-t[4-(1-carbosy-1-phenylmethosy)_3_
propylphenyl]metbyl]-5-(4-metho2ybenzylthio)-4~-
1,2,4-triazole.
3-Butyl-4-tt4-tl-carbosy-1-(2-chlorophenyl)metho2y]-
3-propylphenyl]methyl]-5-(4-chlorobenzylthio)-4~-
1,2,4-triazole.
-
,
.,
Wo9]/11909 2 ~7 S 6 3 ~ PCT/US91~00963 ~
- 20 - 18059IA
3-Butyl-4-[[4-[1-carboxy-1-(2-chlorophenyl)methoxy]-
3-propylphenyl~methyl]-5-(4-methoxybenzylthio)-4~-
1,2,4-triazole.
3-Butyl-4-tt4-tl-carboxy-1-~2-methylphenyl)methoxy~-
3-chlorophenyl]methyl]-5-(4-chlorobenzylthio)-4~-
1,2,4-triazole.
3-Butyl-4-tt4-(1-carboxy-1-phenylmethoxy)-3,5-
~o dipropylphenyl]methyl]-5-(4-chlorobenzylthio)-4~-
1,2,4-triazole.
3-Butyl-4-t[4-(1-carboxy-1-phenylmethoxy)-3,5-
dipropylphenyl]methyl]-5-(4-methoxybenzylthio)-4~-
1.2,4-triazole.
3-Butyl-4-[[4-tl-carboxy-1-(2,5-dibromo-3,4-
dimethoxyphenyl)methoxy~phenyl]methyl]-5-(4-chloro-
benzylthio)-4~-1,2,4-triazole.
3-Butyl-4-t~4-~1-carbo~y-1-(2.5-dibromo-3,4-
dimethoxyphenyl)methoxy]phenyl]methyl]-5-(4-metho~y-
benzylthio)-4~-1,2,4-triazole.
3-Butyl-5-(2-carboxybenzylthio)-4-tt4-(1-carboxy-1-
phenylmetho~y)-3-propylphenyl]methyl]-4~-1,2,4-
triazole.
3-Butyl-5-(2-carboxybenzylthio)-4-[[4-(1-carbo~y-1-
(2-chlorophenyl)methoxy]-3-propylphenyl]methyl]-4~-
1,2,4-triazole.
-; ' .................... . :
. . . .
': . .................... . , ' :
.
WO91/11909 2 ~ 7,3 5 3;9 `: P~T/US91/00963
3-Butyl-5-(2-carboxybenzylthio)-4-~t4-(1-carboxy-1-
(2-methylphenyl)methoxy]-3-chlorophenyl]methyl]-4~-
1,2,4-triazole.
3-Butyl-5-(2-carbosybenzylthio)-4-[[4-(1-carboxy-1-
phenylmethoxy)-3,5-dipropylphenyl]methyl]-4~-1,2,4-
triazole.
3-Butyl-5-(2-carboxybenzylthio)-4-[[4-tl-carboxy-1-
(2,5-dibromo-3,4-dimethoxyphenyl)methoxy]phenyl]-
methyl]-4~-1,2,4-triazole.
4-[~N-Allyl-N-[(l-carboxy-l-phenyl)methyl]amino]-
phenyl]methyl]-3-butyl-5-(4-chlorobenzylthio)-4~-
1.2.4-triazole
4-[ r tN-Allyl-N-[(l-carboxy-l-phenyl)methyl]amino]-
phenyl]methyl]-3-butyl-5-(4-methoxybenzylthio)-4~-
1,2,4-triazole
4-t~tN-Allyl-N-[(l-carboxy-l-phenyl)methyl]amino]-
phenyl]methyl~-3-butyl-5-(2-carboxybenzylthio)-4~-
1,2,4-triazole
2-~utyl-4-~t[N-t(l-carboxy-l-phenyl)methyl]-N-
ethylamino~phenyl]methyl]-5-(4-chlorobcnzylthio)-
4~-1,2,4-triazole
W091/11909 2 Q 7 ~ 6 3 9 PCT/US9l/00963 ~
- 22 -
Preparation of 3,4,5-trisubstituted-1,2,4-
triazole~ (Formula I)
The compound~ of Formula I can be prepared
by a variety of methods typified by those described
below. General synthetic method~ for 3,4,5-tri6ub-
6tituted 1,2,4-triazoles are discussed in book~ or
review articles ~uch as:
lo (1) C. Temple and J.A. Montgomery, ~'Triazole~:
1,2,4" (Vol. 37 of "The Chemistry of
~eterocyclic Compounds", A. Weis6berger and
E.C. Taylor, eds.), Wiley-Interscience, New
Yor~, 1981.
lS (2) J.B. Polya, in "Comprehensive ~eterocyclic
Chemistry. The Structure, Reactions,
Synthe~is and Uses of ~eterocyclic
Compound 8", A.R. Katritz~y and C.W. Rees,
ed~., Vol. 5, Pergamon Press, Oxford, 1984,
pp. 733-790.
(3) J.~. ~oyer, in "~eterocyclic Compounts",
R.C. Elderfield, ed., Vol. 7, John Wiley
Sons, New Yor~, 1961, pp. 384-461.
In general, the compounds of ~ormula I are
constructed in such a way that Nl and N2 of the
triazole ring are derived from hydrazine or a
hydrazine derivative, while N4 of the triazole and
the 4-(arylmethyl) substituent are derived directly
or indirectly from a ~uitably substituted benzylamine.
wo 9~ gog 2 0 7 ~ ~`3 9~ CT/US91/00963
- 23 -
Although the reaction scheme6 described
below are reasonably general, it will be understood
by those 6killed in the art of organic synthesis that
one or more functional groups pre6ent in a given
compound of Formula I may render the molecule
incompatible with a particular synthetic sequerlce.
In 6uch a case an alternative route, an altered order
of 6teps, or a strategy of protection and
deprotection may be employed. In all cases the
particular reaction conditions, including reagents,
solvent, temperature, and time, should be chosen so
that they are con6istent with the nature of the
functionality present in the molecule.
The Reaction Schemes below have been
lS generalized for 6implicity. It is to be understood
that the "ArC~2" 6ubstituent present at N4 of the
triazole derivatives or in their precursors is any
substituted arylmethyl moiety consistent with the
definition of the N4 substituent in Formula I or
which may be transformed to such a grouping either
before or after the as6embly of the triazole ring
system. Such transformations may involve protection
and/or deprotection as shown in Formula I, or other
modifications. It i8 also to be understood that in
most of the Reaction Scheme6, the "ArCE2 " (Ar ~
aryl) 6ubstituent i6 con6istent with the definition
of Formula I.
wo sl/119n9 2 n ~ n
v ~ ~ U ~ ~ PCT~US9l/00963 ~,
- 24 -
Abbreviations used in the scheme~ and examples
below are listed in Table 1.
~.`
- Re~ents
NBS N-bromosuccinimide
AIBN Azobis(isobutyronitrile)
DDQ Dichlorodicyanoquinone
10 Ac2o acetic anhydride
TEA triethylamine
DMAP 4-dimethylaminopyridine
PPh3 triphenylphosphine
TFA trifluoroacetic acid
15 TMS-Cl trimethylsilyl chloride
Im imidazole
AcSK potassium thioacetate
p-TsO~ p-toluenesulfonic acid
~olvents:
DMF dimethylformamide
~OAc (AcOB') acetic acid
EtOAc (EtAc) ethyl acetate
25 ~ex hexane
~F tetrahytrofuran
DMSO timethylsulfoxide
MeO~ methanol
iPrOE i 8 opropanol
.`
WO 91/1 1909 2 0 7 ~ ~`3 ~ `: Pcr/us91/00963
- 25 -
O~h~r~:
rt room temperature
T~DMS . t-butyldimethylæilyl
OTf . OSo2cF3
- Ph phenyl
FAB-MS Fast atom bombardment mass
~pectroscopy
NOE Nuclear Overhauser Effect
10 SiO2 silica gel
trityl triphenylmethyl
The compounds of the present invention may
be resolved using the techniques ~nown in the art.
The diastereomeric ~alts and esters of the
enantiomers are separated and the desired compound is
the more active stereoisomer. The invention is
intended to include individual stereoisomer6 a~ well
as racemic mixture~. The compounds of thi~
invention, their pharmaceutically acceptable salts
and their prodrug forms are included within the scope
of this invention.
It is further to be understood that in the
generalized scheme8 below, unless specified more
narrowly in the text, the groups Rl and R16 represent
functionalized or unfunctionalized al~yl, aryl,
heteroaryl, aralkyl, and the like. The moiety R16Q
represent~ an al~ylating agent in which R16 is
typically a functionalized or unfunctionalized alkyl
or aralkyl group, while Q is a leaving group ~uch as
chloro, bromo, iodo, methanesulfonate, or
p-toluenesulfonate.
wo 9", Igog 2 0 7 5 ~ ~ 9 PCI/l)S91/00963 ~
-- 26 --
~;~ I-l -
s
1 )CS~- Et~N, ~rCH~N}~ ~CH~?~NJiNH,
/~5 J
R~CN11NH, ll ll
ArC~NC~I ArC}~NHCN~NHCi?'
2 ) Et ococl 4 5
~H
~A~
o
R~ ~0, b~
2 0
~Jl.
Scheme I-l outlines some of the most widely
applicable routes to compounds of Formula I in which
either the 3- or 5-substituent is substituted thio.
Thus an appropriate benzylamine 1 may be converted to
dithiocarbamate ester 2 in a one-pot two-step sequence
involving treatment with carbon disulfide in the
presence of a base such as triethylamine followed by
al~ylation with methyl iodide. Treatment of ~ with
hydrazine ~preferably in excess) affords the
4-substituted thiosemicarbazide ~. This is also
.
W091/l1909 2 ~ 3 ~ ` PCT~US91/00963
readily obtained upon reaction of hydrazine with the
i60thiocyanate 4, which in turn i6 prepared from
amine 1 [for e~ample, y~ an intermediate carbetho~y
dithiocarbamate (J.E. ~odg~ins and M.G. Ettlinger, J.
Or~. Chem., ~1. 404 (1956)) or by one of the other
methods ~nown in the literature]. The acylthiosemi-
carbazide ~ may be prepared either by reaction of 3
with the appropriate acid chl-ride or anhydride or by
addition of an acid hydrazide (readily obtained from
lo the corresponding ester) to the isothiocyanate 4. As
described in G.F. Duffin, J.D. Kendall, and ~.R.J.
Waddington, J. Chem. Soc., 3799 (1959), S.M.
El-Khawass and N.S. ~abib, J. ~eterocyclic Chem., 26,
177 (1989), and numerous other papers, acylthiosemi-
carbazides related to 5 can by cyclized in thepresence of hydroxide or al~oxide to the mercapto-
triazoles (best represented as triazolinethiones)
corresponding to 6. Compounds of type 6 can also be
prepared by direct reaction of the thiosemicarbazide
derivative ~ with an appropriate acid derivative.
For e~ample, reaction of ~ with a trimethyl
orthoester at elevated temperature in a suitable
60lvent (such as 2-metho~yethanol st reflu~) yields
~. Similar 6yntheses of mercaptotriazoles have been
reported by G.A. Reynolds and J.A. Van Allan, 1~ ~L~
Chem., 2~. 1478 (1959~. Other acid derivatives such
as esters [in thé presence of al~oxite: M. Pesson, G.
Polmanss, and S. Dupin, Compt. B~n~-. 248, 1677
(1959)] and selenoesters [V.I. Cohen, J. eterocyclic
Chem., 15, 237, (197B)] have al60 been reported to
react with 4-substituted thiosemicarbazides to give
mercaptotriazoles analogous to 6. In certain
wo91/]1909 2 0 7 ~ 6 3 9: - PCT/~S91/00963 ~
- 28 -
instance6 the carboxylic acid~ itself may be used.
Thu6, 4-substituted thiosemicarbazides have been
reacted with trifluoroacetic acid at elevated
temperature to give mercaptotriazoles analogous to
(R=CF3) [T. Cebalo, U.S. Patent 3,625,951 (1971) and
E.I. Aoyagi, ~.S. Patent 4,477,459 (1984)~.
The S-al~ylated mercaptotriazoles of
structure 7 are obtained by treatment of the
triazolinethione 6 with an appropriate alkylating
agent R16Q in which R16 is functionalized or
unfunctionalized alkyl, aralkyl, heterocyclyl, or the
like, and Q is a leaving group such as chloro, bromo,
iodo, methanesulfonate, or ~-toluenesulfonate. This
alkylation i6 conducted in any of a variety of
solvents (including methanol, ethanol, 2-methoxy-
ethanol, tetrahydrofuran, N,N-dimethylformamide,
dichloromethane and water, depending on the
properties of the particular substituents) in the
presence of a base (such as a trialkylamine,
alko~ide, or hydro~ide). Triazolinethiones
(mercaptotriazole6) are ~nown to give the S-alkylated
derivatives predominantly if not exclusively under
basic condition6 (see, for examples, C. Temple and
J.A. Montgomery, "Triazoles: 1,2,4",
Wiley-Interscience, New York, 1981, pp. 251-258).The
alkylation reaction is generally run at a temperature
of from O-C to 125-C., depending on the reactivity of
the alkylating agent.
The triazolinethiones ~ may be prepared by
alternative routes. In the method of F. Malbec, R.
Milcent, and G. Barbier t~ LQcycl Ch~mL, 21.
1689 (1984)~ (Scheme I-2), the imidate hydrochloride
WO 91/11909 2 0 7 ~ ~ ~ 9 PCT/US91/00963
,~
- 29 -
8 is reacted with thiosemicarbazide at ambient
temperature to give the ester thiosemicarbazone 9.
The conversion of 9 to the triazolinethione 6 can be
effected by heating with amiIe 1 in DMF at reflux.
Similarly, an N4-substituted ester thiosemicarbazone
2~. which i8 obtained by reaction of 8 with ~, can be
cyclized to 6 by heating in the presence of a base,
e.g., 1,8-diazabicyclo{5.4.0}undec-7-ene (DBU), in a
solvent ~uch as tetrahydrofuran.
SCHE~ I-2
NH HCl S NNHCNH~ H
R'COEt H2NHCNH2 RlCOE ArCH2NH2 ~--N
LA~
S 6
~0 3 1I N~cH2~r
. R' COEt - DBU
9o THF, a
_v_
For triazolinethiones of type ~ where
Rl-aryl, the method of T. Radha Vakula, V. Ranga Rao,
and V.R. Srinivasan ~ ia~ J. Chem~, 7, 577
(1969)](Scheme I-3) i6 applicable. Thus the
thiosemicarbazide derivative ~ is condensed with an
aromatic aldehyde lQ to give the thiosemicarbazone
11- Upon treatment Of 11 with bromine in acetic
acid, the triazolinethione 1~ is formed.
-
WO 91/11909 2 0 7 3 ~; 3 ~ PCI/lJ~i91/00963
-- 30 --
SC~: I-3
s
ArCH~ CH~ C~:N~C~
~ 10 1
R~-aryl
N--N
Br7 R~
~OH
0 12
Following the method of L. Strzemecka
[Polish J. Chem., 57 561 (1983)] (Scheme I-4~,
reaction of an ~midrazone 1~ with the i~othiocyanate
4 in ethanol at reflux gives triazolinethione 6.
SC~EME I-4
20 R1CNH ~HCl I ArCH2NCS ~~~~~~ Rl ~ N ~ S
13 4 Ar
_ 6
Certain S-sub~tituted mercaptotriazoles of
formula 7 which may not be accessible by the reactions
o~ Scheme I-l (e~pecially R16~ aryl) can be prepared
by an alternative route (Scheme I-5) involving
di~placement of a lea~ing group on the triazole by an
appropriate thiol. Treatment of the triazolinethione
6 with chlorine under anhydrous conditions in a
~ w091/ll90~ 2 0 7 ~ ~ 3-9 PCT/US9l/OOg63
- 31 -
~olvent such as chloroform or dichloromethane gives
as 8 major product the chlorotriazole 14 tD.S.
Deshpande, T.G. Surendra Nath, and V.R. Sriniva~an,
Indian J. ~hEm., 13, B52 (1975)]. In addition, the
synthe~is of chlorotriazoles by POC13/PCls treatment
of the corresponding triazolinone has been reported
tS- Naqui and V.R. Srinivasan, J. Sci. Industr. Res.,
Zl~, 195 (1962)]. Reaction of 1~ with a thiophenol
or other thiol in the presence of a base such as
N,N~diisopropylethylamine at elevated temperature
(for example, in DMF at reflux) gives 7. Similar
reactions have been reported by ~. Becker and K.
Wehner, British Patent 1,157,256 (1969).
Alternatively, the methylthiotriazole 1~ may be
prepared (by al~ylation of 6 with methyl iodide) and
SCEEME I-5
,~,~ Cl2 . ,~, ~Cl -- Rl~ ~SR t
~j 14 7
l~tI R~N~S~ R--~ ~S~
AcOH ~ Cl b~
Al'
16
', ` ~ " ' '': '
. - .
' ' ' :
,
wo g~ gO9 2 0 7 ~ & 3 9 PCT/US91/00963 ~
then oxidized to the methylsulfone 1~ using hydrogen
peroxide. Displacement of the methanesulfonyl group
Of 1~ e the chloro group Of 1~. by R16S~ in the
presence of a base afford6 7, e6pecially for Rl~ =
aryl. The preparation of a methane6ulfonyltriazole
analogous to 1~ and its nucleophilic tisplacement
have been reported by E.B. A~erblom and D.E.S.
Campbell, J. Med. Chem.. 1~, 312 (1973).
o ~l~k
N~ N o N--N o
R1--~5R1 ~ R1 _(~Rl ~ t R1 ~R'
15~Ar P~202/DAC ~Ar ~Ar
or
7 R' CO~H 17 18
The S-6ubstituted mercaptotriazoles 7 can
be converted to the corre6ponding 6ulfosides 17
and/or 6ulfones 1~ by o~idation with various reagents
6uch as hydrogen pero~ide in acetic acid or a
cuitable peracid. Reactions of this type have been
described by E.B. Akerblom and D.E.S. Campbell (see
reference above). Whether 11 or 1~ is tbe primary or
exclusive product depends on the stoichiometry of the
reagent6, reaction time, and temperature.
~WO91/11909 2 ~ 7 S;6 3 ~` PCT/US91/00963
~Z
.5 11 ~1 O 11 IOIR~ llrC}~
R1 COEt R' ~CNHNH
- R CO~ E:tOX ~ R1--~--R1
Ar
~9
__
The method of R. ~raft, ~. Paul, and G.
~ilgetag ~Chem, ~er.. lQl. 2028 (1968)] (Scheme I-7~
is u~eful for preparing triazoles of 6tructure 2Q in
which R16 i6 aryl or heterocyclic. Treatment of the
imidate hydrochloride 8 with an appropriate hydrazide
(typically at -10- to 5'C.) gives the adduct l9,
which can be reacted with the amine 1 and cyclized to
the triazole 20 upon heating in ethanol. ~y use of
the adaption of M. Pescon and M. Antoine tBUll. Soc.
Chi~. Fr., 1590 (1970)~, triazoles of type 2~ in
which R16 is a substituted carboxamide group are
obtained by employing a substituted osamic acid
hydrazide in Scheme I-7.
~SC~EME I-8
ArC*NCS NH~ ~tC*~ ArC~ S~ R' ~NICII~
bO~D
~- 22
3C
~" 1l
~rC*NHCNl~MCR' DMF R~--~R" ~ ( R~ Ar
i~_ ~ \ R"
.
wo 9,/1,gog 2 0 7 3 ~ 3 9 ~CT/US91/00963 ~
- 34 -
Aminotriazoles of formula 2~, where B is a
single bond, can be prepared as shown in Scheme I-8.
An analogous route ha6 been reported by E. A~erblom,
Acta Chem. Scand., 19, 1135 ~1965). Reaction of the
i60thiocyanate 4 with an appropriate amine gives the
thiourea ~l. which i8 al~ylated with methyl iodide to
give the isothiourea ~ydriodide 22. The
acylaminoguanidine 2~, obtained by reaction of 2
with a hydrazide in the presence of ba6e, can be
thermally cyclized to 2~, which i6 separated from the
isomeric byproduct 2~. Modest yields of
aminotriazoles analogous to 24 have al60 been
obtained by direct thermal reaction of intermediates
analo~ous to 2~ with a hydrazide ~L. Carey, B.J.
Price, J.W. Clitherow, J. Bradshaw, M. Martin-Smith,
D.~. Bays, and P. Blatcher, U.S. Patent 4,481,199
(1984)].
SCEEME I-9
H~OCN~CH~r CO,H ~" ( .2
2~ 27
IN,H,
K~ ' ~R"
~rC~
23
In another route i6 shown in Scheme I-9
following a sequence reported by L. Carey, ~ a1.,
U.S. Patent 4,481,199 (1984), amine 1 is heated with
the S-methyl thio6emicarbazide derivative 26 to give
, Wo91/11909 2 0 7 ~ ~ 3 9 PCT/VS9l/00963
., .;~
....
- 35 -
the aminoguanidine 21. ~eating 21 with an
appropriate carboxylic acid provides the
aminotriazole 2~, which i~ separated from the isomer
2~ if present. Similar chemistry has been reported
by C.F. ~roger, G. Scho~necht, and ~. Beyer, Ch~m.
~L~, 97, 396 (1964), R.G.W. Spic~ett and S.H.B.
Wright, British Patent 1,070,243 (1967), and G.J.
Durant, G.M. Smith, R.G.W. Spic~ett, and S.~.B.
Wright, J. Med. Che~., 2, 22 (1966). Thi~ last paper
lo also describes the 6ynthesi6 of aminoguanidines
analogous to 27 by hydrazine treatment of
isothioureas corresponding to ~ ee Scheme I-8).
SCEEME I-10
~NN~ RI ~N C}~ N~
~Ar ~
2~ 29 30
R'C-oryl
A useful route to certain N-(arylmethyl)
aminotriazoles 30 is 6hown in Scheme I-10. The
aminotriazole 2~ (equivalent to ~, R'.~), which can
be prepared by Scheme I-B or Scheme I-9 iB condensed
with an aromatic aldehyde to give the Schiff base
22. Reduction of 22 with a suitable reducing agent
such as sodium borohydride gives 30. Related
syntheses of benzylaminotriazoles have been reported
by Reiter tJ. Reiter, T. Somorai, P. Dvortsa~, and
Gy. Bujtss, 1~ e~ocycl. Cheml, 22, 385 (1985) and
J. Reiter, L. Pongo, and P. Dvort~ak, J. ~eterocvcl.
C~em , 24, 127 (1987)].
WOsl/11909 2 0 7 ~ ~ 3 ~ PCT/US91/00963 ~
, .
" .
- 36 -
SCEE~ I-ll
5 Rl ~ ~ Rl ~ R'~ LlA~ Rl ~ ~,R'
2~ 31 32
Following the methods of R.G. ~arrison,
W.B. Jamison, W.J. Ross, and J.C. Saunders, Australian
Patent Specification 518,316, aminotriazoles of
structure 2~ can be heated with an acid anhydride to
give the acylaminotriazoles ~1- These can be reduced
with lithium aluminum hydride to give the
~-substituted aminotriazoles of formula ~.
~C~E~F~1-12
R'~ ~Cl I~NII~ N 11
~ O
Ar A~ Ar
1 4 24 S ti
Aminotriazoles of structure 24 can also be
obtained by heating a chlorotriazole 1~ or a
methane6ulfonyltriazole 1~ with an amine. Amine
tisplacement~ on chlorotsiazole6 have been reported
by E.GØ Becker and Y. Eisenschmitt, Z. Ch~m_, 8,
105 ~1968) and ~. Becker and R. Wehner, Bsitish
Patent 1,157,256 (1969).
.~ WO91/l1909 2 0 7 t~ ~ 3 9 ` PCT/US91/00963
SC~EME. I-13
~ 11 ar 0~ o~
33 a-
L ~
~ ~N ~N
1 0 L,~
3~ ~ 3
Aminomercaptotriazoles of 6tructure 37 can
lS be prepared as outlined in Scheme I-13, which
utilize6 the chemistry of L.E. Godfrey and F. Kurzer,
J. Chem. ~Q~. 5137 (1961), J. Reiter, T. Somorai, P.
Dvort6ak, and Gy. Bujta6, J. ~eterocvcl. Chem., 2~.
385 (1985), and J. Reiter, L. Pongo, and P. Dvortsak,
1~ ~cterocvclic Chem., 24, 127 (1987). Reaction of
the isothlocyanate g with aminoguanidine gives 33,
whlch can be cyclized in the presence of base to the
aminotriazolinethione 34. Al~ylation of 34 in the
presence of base yields the 5-sub6tituted derivative
1~- Further tran6formations to the Schirf base 1
and then to 37 are as in Scheme I-10.
,
:.: - . . ~ ':
. .
- .. . . . : :: . . .
- ,
.. . . ,- .- . . . - . . . - . ::
. . .. .. . . . . . . . .
wos~9o9 ~ 0 7 ~ 6 3 9 PCT/U591/00963 ~
SCEEME I-14
RI ~Cl -- R~ OR~ ~ -- R~
~Ar ~Ar ~Ar
14 3~ 16
Alkoxy and arylo~ytriazoles of formula 38
can be prepared by heating a chlorotriazole l_ or a
methanesulfonyl triazole 16 with the appropriate
alkoxide or phenoxide anion. Such a tran~formation
has been de~cribed by E.B. Akerblom and D.E.S.
Campbell, J. Med. Chem., 1~. 312 (1973).
.- ' ~ ' . , '' :
, . ,
.
,
-
wO91/11909 2 f~ r~ s3~; PCI'/US91/00963
.;~ ~'
- 39 --
SC~ 1-15
~ NH2 rNHCSCH3
~ 1~ C52. Et3N
HO 39 2) CH3I 40
rNHCNHNH2 rNHCNHN= CR'
~Rl C= N~ HCl ~ DEIU
HOEt ( 42 ) HO4 3
N~N>C5 ~ > 5
>--N ~)--N
R ~Rl~r, lPr2NEt R
` 20 ~3 ~
HO 44 HO 45
~C2~? R y~N~N
R 46 1) OH- ~S-R
.~
~COJ 2) H~
47 C02H
~` . ' -: ' '~''' : . .'
.
,'' : .
.. , '' ' ' ' ,
' ' . ' ~. ' ' ':
':' ' '
.''' . ~ ,
w091/ll9o9 2 ~ 7 5 ~ 3 ~ PCT/US91/00963 ~
- 40 -
In Scheme 1-15, p-hydro~ybenzylamine ~ i6
treated first at room temperature with carbon
disulfide in the presence of triethylamine and then
at -lO to +20-C with iodomethane to give the
dithiocarbamate derivative 40. Upon heating w~th
e~ces~ hydrazine in ethanol, this is tran~formed to
the thio~emicarbazide 41. Reaction of ~1 with an
imidate ~ in N,N-dimethylformamide (DMF) at room
temperature gives the 6ubstituted ester
thiosemicarbazone ~, which cyclize6 to the
triazolinethione 44 upon heating with a ba6e such as
l,8-diazabicyclo{5.4.0}undec-7-ene (DBU) in a
suitable solvent such a6 anhydrous tetrahydrofuran
(T~). Next, treatment of 44 with an al~ylating
lS agent (e.g., an al~yl or aralkyl bromide) in the
presence of a tertiary amine base, preferably
N,N-disopropylethylamine, in a solvent such as
2-methoxyethanol generally affords the S-al~ylated
deri~ative 45 a~ the primary or exclu6ive product.
This reaction is typically carried out at 20-lOO-C,
dcpending on the reactivity of the al~ylating a~ent.
Treatment of 45 with the appropriate
~-bromophenylacetic acid e6ter 46 in the presence of
a base such a6 anhydrous sodium carbonate or Eodium
hydride in DMF or dimethyl sulfoside (DMS0) give6 an
0-al~ylated product which i6 nest saponified to the
acid 47. The last step i8 accomplished by treatment
of the intermcdiate ester with excess sodium or
potas6ium hydroxide in aqueou~ methanol followed by
acidification. A similar sequence may be carried out
starting with a ring-6ubstituted 4-hydro~ybenzylamine
(analog of 39)-
.
. ~ wog~ s~s 2 ~ 7 ~ ~ 3 9 PCT/US91/00963
i~,
- 41 -
The triazolinethione 44 may be prepared by
alternative methods (Scheme I-16). In one of these,
the thiosemicarbazide 41 i6 reacted with a trimethyl
orthoester, preferably in 2-metho~yethanol at
reflu~. In another method, 41 i8 treated with an
acid chloride or anhydride to give the acyl
derivative 48. ~eating 4B with a base such as ~odium
etho~ide or hydroxide in an alcoholic or aqueous
solvent results in ring clo~ure to 44 (and also
removes any phenolic 0-acyl group that may be present
as a by-product of the synthesis of 48).
It should be noted that a compound of ~tructure
47 may also be oxidized to the corresponding
sulfoxide or sulfone by treatment with hydrogen
lS pero~ide in acetic acid or with a Euitable peracid as
described for Scheme 1-6. The oxidation may be
carried out either before or after the ester
hydrolysis of Scheme I-lS.
As 6hown in Scheme I-17, the intermediate ester
4~. prepared a6 in Scheme I-15, may be converted to a
primary amide by treatment with methanolic ammonia.
~ehydration of the amide with phosphorus oxychloride
in the presence of triethylamine at O-C gives the
cyano derivative 50. Reaction of ~Q with
trimethyltin azide in toluene at reflux, followed by
removal of the trimethyltin moiety by treatment with
acid and/or 5ilica gel, yields the corresponding
tetrazole ~1
--
wos~ 9ns 207 ~39 ` ~
a PCr/US91/00963 ~
_`~
_ 42 --
SC~ 16
S
~HCN~H2 R
HO~ R1 C( OCH3 ) 3 --~N~
R1 COCl or ~\
(Rlc(=0))20 \~
44 OH
S O ,
~HCN~HCR1
NaOH or NaOEt
48 A
- _ . . . - . -
- . . ~
wos~ sos 2 0 ~ 5 ~ 3 9 PCT/US9l/00963
- 43 - 18059IA
SC~E~ I-17
N-N
--<NlS- R~ ~
~ ~R^ 1 ) N~CHIOH
~ 2~ /Et~N~0C (~
49 CN
N--N
R~ ~N~S- R'
1 ) (CH~)~SnN~tolwne/~
2) H' or ~ lllc~ g~
~ -
N~N~N
51
A~ shown in Scheme I-18, 4-(aminomethyl)-
benzoic acid (~2) can be reduced with lithium
aluminum hydride or diborane to the corresponding
benzyl slcohol ~, which is converted to a triazole
54 by methodE previously described. When 54 is
subjected to Swern osidation condition~, the aldehyde
~ results, and this can be used to reductively
al~ylate phenylalanine methyl ester in the pre~cnce
of sodium cyanoborohydride. The resulting product 56
may be acylated to yield 57, which is then saponified
to the free acid ~. Intermediate 56 may also be
saponified. sffording ~2
~,,., . , :
,,
s WO 9~/11909
PCr/US91/00963 ,~
2075~9 '~
-- 44 --
SC~EMI; I-18
`.
¢l or ~H~ ~ by n-thod d rcr~bod
CO,H 7~F H~)
~2 ~3
Ntl
Cl~ (O-)C-~ ,01 Rt L~ "
~ D~O~H~C1~
5, OH O
N--N
R~ , R~ N--H
D- Or L-P~O~ ,H RCC1 Lt,N ~J~R
NtlDH,CN~Et OH (J~7CH~ O~CH~
~ ~ ~7 ¢~)
1 ) I N~ OH ~ OH
2)J~l 2)J~l
R~ R~ 7 R~ ~ T) ~- R"
~,H ~ " O
~ .
~:o H ~O~H
5B
Or L- con~lgur-~on
'
WO 91 /1 ] 909 2 Q :7 3 ~- 3 9.: Pcr/usgl/oo963
s~2
~ N
b~ ~thod~ d-~rl~d ~k'r)b- R
ln pr~ol~ ~rn~nr~ ~ nClp ~1
R' - 8~ ( T) b- Rl ~eD~ R - E~ ~( T) b- R'
~ ~"t' ~1
62 R
2 0 ~~, ~t ,N R - 8 ~ ~ HCI R - 8 ~( ~ b- R
~ R
R ~ ~ R ~~
~3 ) ~ON R l~ b-R
~) N~ l l
,
~ 0 7:5 ~ 3 3~ PCrtUS91/00963~
- 46 -
In Scheme I-l9, 4-nitrobenzylamine (60) i~
tran6formed to the triazole ~1 by previou~ly
described methods. Stannous chloride reduction of
the nitro group provide~ the amine ~2. which can be
al~ylated with the ~-bromophenylacetic ester 46 to
give 63. Acylation of 63 to give 64 and then
saponification to 65 proceed under normal
conditions. Intermediate-63 may also be directly
~aponified to give 66.
~C~EME I-20
N-~N
N-,N R - E~ ( T) ~- R'~
N~ R 1 ) 1~N,tll1,, 106t~ ,N
~ ~CN HN~
o 7
Rl~ T) R~
~) NCl ~N
R~N~ R~N~ H
¢~
- - ' ' - .
, ! . WO 91/11909 2 d 7 ~ ~ 3 9 - cr/us9l/Qo963
The aldehyde ~ may also be reacted with
benzylamine and trimethyl~ilyl cyanide to give the
adduct 67 (Scheme I-20). Treatment of ~1 with an
acid chloride in the pre~ence of triethylamine yields
the acyl derivative ~. Finally, tranb~formation of
the cyano group to tetrazole by heating with
trimethyltin azide afford~ the target 69.
~C~EME I-21
E!r
~
N3 ~NH,
o~3 O~0
N-~J
nolbod~ ~cr~o d R -~N~L(T) b- R
ln pr-vlo~ ch-~
~L~ eY,e
R~(T)b-Rt ~ N
~ R~- r71~N,~( ~) b- R
~CN ~~ KI~2 ' ~
13
'
'
Wo91/11909 2 0 ~ 5 & 3 9 PCT/US9l/00963 ~.j
- 48 -
In Scheme I-21, 4-methylbenzophenone (70) i6
~-brominated with N-bromosuccinimide in the presence
of a radical initiator such as benzoyl pero~ide or
azobis(i60butyronitrile). The resulting bromo
derivative 71 is converted to the azide 72, which is
then reduced with triphenylphosphine to the amine
73. By previously described method~, 73 is
transformed to the triazole 74. Treatment of 74 with
a trimethylsilyl cyanide-potassium cyanide mi~ture in
the presence of a crown ether yields the protected
cyanohydrin ~. Upon heating 75 with excess
trimethyltin azide, followed by acid treatment, the
~-hydroxy tetrazole 76 is obtained.
, .. . . .
., ~ .
~", WO91/11909 207~ 3~9 PCI/U591/00963
-- 49 --
SCIIEM~ I-22
~CO2H (CH3)2C=C~2 ~CO2t-E~u ~3r
~ ll250~ h~r X~
R 77 R 78
lo Br
[~Co2 t - Bu
R 79 CH3
~ 1) K~L 1S-cro~
~ 2) 79 ~ 2 cCl~/~
BO [~R-
CH2Br
O~CO2~3u- t
[~ 82
`~
W091/11909 ~
2 0 ~ PCT/US91/00963
- 50 -
Scheme~ I-22 and I-23 illustrate a typical
~ynthe~i~ in which the 4-(a-carbo~ybenzylo~y)benzyl
side chain (6ee alRo Schemes I-lS and I-16) i~ fully
con~tructed before formation of the triazole ring.
Fir~t, the appropriate phenylacetic acid 77 i~
converted to it6 t-butyl ester 78 by reaction with
isobutylene in the presence of concentrated sulfuric
acid, in a pres6ure vessel. Reaction of 78 with
bromine under controlled condition~ yielts the
a-brominated product 79. p-Cre601 (80) is converted
to it~ anion (for e~ample, with potassium hydride or
pota66ium t-butoxide in the presence of 18-crown-6 or
with anhydrous pota66ium carbonate in DME) and
treated with 79 to give ~1. Bromination with
N-bromo6uccinimide in the pre6ence of
azobis(i60butyronitrile) (AIBN) or benzoyl pero~ide
provides 82, which i~ readily converted to the azide
derivative ~ (for e~ample, with lithium azide in
DMS0). U~ing the methodology of 0. T6uge, S.
~snemasa, and R. Matsuda [1.~ . Chem., 49, 2688
~1984)], the azide ~ may be converted directly to
the isothiocyanate 84 by reaction with
triphenylpho6phine and carbon disulfide. Reaction of
84, which may be used without purification, with
hydrazine at room temperature in a 601vent such as
TgF or ethanol affords the thiosemicarbAzite ~. The
ring clo6ure of ~ with trimethyl orthoformate to
give ~ and the subsequent al~ylation of ~ to give
87 proceed as de8cribed for Schemes I-16 and I-15,
respectively. Finally, the t-butyl protecting group
in 87 is removed with trifluoroacetic acid at room
temperature, and the free acit ~ is thu~ obtained.
:
,. wos~ so9 2 0 7 ~ G 3 9 : PCT/US91/00963
In a variation of Scheme I-22 analogous to a
sequence in Scheme I-21, intermediate ~ i8 reduced
directly to a primary amine and then converted to a
triazole by one of the previously described methods.
SC~EME I-23
~N3 ~N=C=S
~ [~
82 LlN~,O~C02BU-t Ph,P~CS, O~C02BU-t H2NNI12
D~SO l l
~ R ~ R~
83 84
N_~S
~N ~ 2 ~N~
~ S ~ r, ~PrNEC2
O~CO2Bu- t OyCO2~3u- t
~ R B5 ~ R'
~ 5~ ~
O ~ O2Bu-t ~ O2H
~R~ 8 7 (~}R- 8 8
WO91/l1909 2 0 7 5 6 3 9 PCT/US91/00963 ~
Compound6 of formula I where Z i6
-CONHS02R18 may be prepared from the corresponding
carbo~ylic acid derivative6 (I) as outlined in Scheme
I-24. The carbo~ylic acid (I) can be converted into
the corresponding acid chloride by treatment with
reflu~ing thionyl chloride or preferably with
oxalylchloride and a catalytic amount of
dimethylformamide at low temperature tA. W.
Burgstahler, L. 0. Weigel, and C. G. Shaefer
Svnthesis, 767,(1976)]. The acid chloride then can
be treated with the alkali metal salt of R18S02N~2 to
form the de6ired acyl6ulfonamide ~. Alternatively,
these acylsulfonamides may be also prepared from the
carboxylic acids using N,N-diphenylcarbamoyl
anhydride intermediates tF. J. Brown et al - ~y~o~ean
Patent A~Dlication. ~P 100543; ~. L. Shepard and W.
Halczenko- J. Het. Chem., 1~, 321 (1979)].
Preferably the carbo~ylic acids can be converted into
acyl-imidazole intermediates, which then can be
treated with an appropriate aryl or alkylsulfonamide
and diazabicycloundecene (DBU) to give the de~ired
acylsulfonamide ~2 [J. T. Drummond and G. Johnson -
~ g-g ~ c.- 22, 1653 (1988)].
,- Wo91/11909 ` PCT/US91/00963
; 2~75~3~
SCHEME I-24
~ ~ ~b-R~ ~r~n~ ~d--ol~ ~b_R
R'- N ~) ''-o,~r4~ D~U Rl ~
C~ -rn- - ~th~d~ Cl~
R~-~ R1 o R~, Rl o
X CO~ H X CO- NH- S 0, R' r
Rl~ Rl~ R
~9
*Alternative Methods:
a) (i) SOC12, reflux (ii) R18S02N~-M+ (where M is
Na or Li)
b) (i) (COCl)2, DMF, -20-C; (ii) Rl8S02N~-M+
c) (i) N-(N,N-Diphenylcarbamoyl)pyridinium
chloride, aq. NaO~; (ii) R18S02N~-M~
Intermediate ring-substituted methyl ~-bromo-
phenylacetate6 46, as used in Scheme 1-15, may be
prepared as ~hown in Scheme I-25. A phenylacetic
acid derivative 77, bearing one or more ring
sub~tituent~, may be reacted under
~ell-Volhard-Zelins~y conditions with bromine and
thionyl chloride, ~ollowed by treatment with methanol
to give 46. AIternatively, a substituted
benzaldehyde 89 is reacted with trimethylsilyl
cyanide in the presence of potassium cyanide and 18-
crown-6 to give the cyanohydrin 90. Treatment of 2Q
i.. ...
WO 91/1 1909 ~ PCI`/US91/00963
-- 54 --
with anhydrou~ ~Cl in methanol provides the a-hydroxy
ester 91. Finally, reaction of 91 with carbon
tetrabromide and triphenylphosphine gives the a-bromo
ester 46.
g .SC~EMl; I-25
j~ H 1 )SOCI ~r ~ IC~r Ph P
R 77 2)~0H R ~6 ¦CH C1
OIMS 0
SlCN, ItCN
1 ~ - ~ r c~ wn- O ~- g O M~ OH .
An approach to compounds of Formula I having
a 3-substituent on the benzyl portion is illustrated
in Scheme I-26. A 2-substituted phenol such as 2-
ethylphcnol (92) can be selectively carboxylated upon
heating ~t reflux with carbon tetrachloride, 50%
aqueous sodium hydro~ide, and copper powder according
to EP 193,853, to give the substituted 4-hydro~y-
benzoic acid 93. Esterification of the acid followed
by silylation of the phenol and lithium aluminum
hydride reduction of the e6ter yields the benzyl
alcohol 94. Thi6 may be converted to the benzyl
bromide with carbon tetrabromide and
triphenylphosphine and then to the azide 95 with
lithium azide in DMS0. Triphenylphosphine reductio~
of the azide and then desilylation with tetrabutyl-
ammonium fluoride gives the substituted 4-hydroxy-
benzylamine derivative 96, which may be converted by
the methods of Scheme I-15 to a triazole of type 97.
. . . ~ .. . .. . . . . . .. . .
, ,, ~ ,; W0 91/11909 ~ 0 7 5 ~ 3 9 PC~/US91/00963
" -~
J
SCI~ 26
Ec ~ ~ Et ~ ~_,C02H l )~O~ H2SO,
HO~ ~JCCl~, 50% N~OH ;~J 2)t-Elu~2SlCl,
92Cu, ~ 93 DM~P, CH,Cl2
3)LiAlH,, THF
Et ~OH 1 )CE3r~, PH3P, CH2C12 Et ~3~N3
T~D~;-O 2)LlN3, D~SO I~D~S-O
1 ) Ph3 P, THF Et
2)H2 ~ by m~thods of
3)~u~N'F- 96 9ch~ -15
N--N
R~ R
2 0 ~,~;H
Et 97
The Claisen rearrangement of allyl phenyl
ethers is another useful route to intermediates for
incorporation of certain alkyl or al~enyl
6ubstituents (R9 or R10) at the 3-position of the
benzyl moiety in compounds of Formula I. As an
example (Scheme I-27), methyl 4-hydrosybenzoate (9R)
i6 alkylated under 6tandard conditions with allyl
wo 91/11909 2 ~ 7 5 ~ 3 3 PCT/USgl /00963 ~
- 56 -
bromide. The product 29 undergoes Claisen
rearrangement to lQ0 by heating at 185-C in Q-
dichlorobenzene. Silylation of the phenol, followed
by hydrogenation of the allyl group in the presence
of a catalyst such as rhodium on carbon, gives the n-
propyl deri~ative lOl. Lithium aluminum hydride
reduction of the ester then affords lQ2 By the
methods described for Scheme I-26, this is converted
to the sub6tituted 4-hydroxybenzylamine derivative
lQ~- By employing the methods of Scheme I-15, lO~
may be transformed to a triazole of structure 104.
SC~EM~ I-27
lS
BSC
9B X~Co~, ocotonc, ~ [~l
~ 1
~f 1 )t -~7u~SlCl, ~O
HD DMi~P, CH2Cl~ J~J LlAlH~
100 2)H~, Rh~C, 101
Et OH
by rn2t hods of ~
0 Scho~ 1-2~ HD by rnt hods of
~D~; 102 Sch~rn~ I- 7 5
103
R~ ~~ [~R-
~O23~
104
::
' ' ~
. W O 91/11909 PC~r/US91/00963
- 57 -
Succes~ive Claisen rearrangements may be
used to introduce two m-al~yl or al~enyl substituents
(R9 and R10) into the benzyl moiety of a compound of
Formula I. Thu~, the allyl phenol 100 from Scheme
I-27 is converted to an allyl ether and then
~ubjected to a second Claisen rearrangement to give
the diallyl phenol lQ~ (Scheme I-28). By the methods
described for earlier 6chemes, 105 may be transformed
to the 4-hydro~ybenzylamine derivative 106 and then
to a triazole of structure 107.
SC~EME 1-28
1 ) ~ ~r, K~co~ by nothod
HD ro-tono.
100 ~Cl ~) I-27 rnd I-2
2) W~ C lO5
}D ~J by n~t hod~ oF ~ R~
~ 9c~n~ I-lS R
'` ,. ' . ~. . . ' '
-
~ u ~
wogl/]lsog PCT/US91/00963
Another e~ample of incorporation of a
m-alkyl substituent (R9 or R10) on the benzyl ~roup
of a compound of Formula I i6 shown in Scheme I-29.
This route is useful for the preparation of triazoles
wherein the group R16 is aryl or heterocyclyl and is
directly attached to the triazole ring (see al60
Scheme I-7). Intermediate lQ~ (from Scheme I-27) may
be desilylated with tetrabutylammonium fluoride and
then alkylated with methyl a-bromophenylacetate (46)
in the presence of a base such as potassium carbonate
to give lQ~. Analogous to previously described
schemes, the benzylic alcohol of 108 may be replaced
by bromide and then azide. Triphenylphosphine
reduction of the azido group affords the benzylamine
derivative lQ2. Reaction of 109 with the ester
acylhydrazone 12 (from Scheme I-7) in ethanol at
elevated temperature give~ the triazole llQ
Finally, the methyl ester i6 saponified to yield 111.
.
, - ' ' ' - ' . ~ .
~ .- . - .:
- .
.
: . . .
~ u (~ & ~9
~, WO 91/11909 PCl/US91/00963
,, , ~
-- 59 --
SCE~EME I-2 9
~ ~OH
~D~i o~~ F~
-- 2)46, KzCO3~ 108
Acet one ~ CO2~*
1 )C~r~, Ph3P, CH2Cl2 ~NH2 o
2)LiN3, D~SO ~ NNHCRl6
3)Ph3P, IHF~ ¦~} R' COEt
4)H20 0~/~
T EtO~l 50-70C
1 og CO2~
N--N N--N
R~ N ~--R~ Rl ~ ~_
~ C 1 )NaOH, MaOH
1 10 111
The synthe6i6 of compounds of Formula I
wherein X~NR (R.alkyl, alkenyl, and the like) i6
illustrated in Scheme I-30. The ~-aminobenzyl
triazole ~ (from Scheme I-19) can be protected as
the ~L~-buto~ycarbonyl (~oc) derivative llZ The
carbamoylated N~ may be deprotonated using a 6trong
base such as 60dium hydride and then alkylated with
. :
. . .
.
WO 91/1 1909 2 ~ 7 ~ PCI/US91/0~963
-- 60 --
an appropriate al~yl (or allyl, etc.) halide.
Subseguent removal of the Boc group with
trifluoroacetic acid yields the monoal~ylated aniline
1~ The aniline N~ may be deprotonated again with
sodium hydride and al~ylated with the a-brOmO ester
46 to give 11~ Alternatively, 114 may be prepared
from the intermediate ~ (from Scheme I-19) by
deprotonation with a strong base such as lithium
bis(trimethylsilyl)amide followed by treatment with
the al~ylating agent RBr. ~pon saponification of the
methyl ester of 114, the target compound 11~ is
obtained.
S~EME 1-30
N--N N--N
N (Doc)~O Et,N R El N l)NtlH DMF
[~8 CH,Cl~
~2 ~r llZ
R' -13~ b- R ~ ~ R' - E~ R' R
~ H, DMF , <13
2 5 ~I R CO~
113 R ~l4
N--~N " / ¦~ ) NI~O~_ MeOH
R'-D--~N~ )b-R 1 )L~N(9~ 2)H~.
3R ~F / R' - EI~N~ ) b- R
-- ~ CO~ 3R
115 R CO~H
-- ' , .
: ' ` ,
' ' ' . :
~. W09~ 909 2 0 7 5 ~:3 9 PCT/US9]/00963
The compounds of this invention form salts
with variou6 inorganic and organic acids and bases
which are also within the scope of the iDvention.
Such salt6 include ammonium salts, al~ai metal salts
li~e sodium and potassium salts, al~aline earth metal
6alts like the calcium and magnesium salts, salts
with organic bases; e.g., dicyclohexylamine 6alts,
N-methyl-D-glucamine ~alts, salt6 with amino acids
like arginine, lysine, and the like. Also, salts
with organic and inorganic acids may be prepared;
g - ~Cl~ ~Br~ ~2S04~ ~3P04, methanesulfonic~
toluenesulfonic, maleic, fumaric, camphorsulfonic.
The non-toxic, physiologically, acceptable salts are
preferred, although other salts are also useful;
e.g., in isolating or purifying the product.
The salts can be formed by conventional
means such as by reacting the free acid or free base
forms of the product with one or more equivalents of
the appropriate base or acid in a solvent or medium
in which the salt is insoluble, or in a 601vent such
as water which is then removed in vacuo or by
freeze-drying or by exchanging the cations of an
existing salt for another cation on a suitable ion
exchtnge resin.
Angiotensin II (AII) i8 a powerful arterial
vasoconstrictor, and it e~erts its action by
interacting with specific receptors present on cell
membranes. The compounds de5cribed in the present
invention act as competitive antagonists of AII at
3a the receptors. In order to identify AII antagonists
and determine their efficacy in vitro, the following
two ligand-receptor binding assays were established.
'
'. ~ ~ ' .
wo9~ 9n9 2 0 7 ~ 3-9 ` PCT/US9l/009~3 ~
Receptor binding a66ay using rabbit aortae membrane
pre~atlon __ _
Three frozen rabbit aortae (obtained from
Pel-Freeze Biological6) were suspended in 5 mM
Tri6-0.25M Sucrose, p~ 7.4 buffer (50 mL) homogenized,
and then centifuged. The mixture was filtered through
a cheesecloth and the supernatant wa6 centrifuged for
30 minutes at 20,000 rpm at 4-C. The pellet thus
obtained was resuspended in 30 mL of 50 mM Tri6-5 mM
MgC12 buffer containing 0.2% Bovine Serum Albumin and
0.2 mg/mL Bacitracin ana the suspension was used for
100 assay tubes. Samples tested for screening were
done in duplicate. To the membrane preparation (0.25
mL) there was added 125I-SarlIle8-
angiotensin II [obtained from New England Nuclear~(10 mL; 20,000 cpm) with or without the test 6ample
and the mi~ture was incubated at 37C for 90
minutes. The mi~ture was then diluted with ice-cold
50 mM Tri6-0.9% NaCl, p~ 7.4 (4 mL) and filtered
through a ~las6 fiber filter (GF/B Whatman 2.4~
diameter). The filter was soaked in scintillation
cocktail (10 mL) and counted for radioactivity u6ing
Pac~ard 2660 Tricarb liquid scintillation counter.
The inhibitory concentration (ICsO) of potential AII
antagonist which gives 50% displacement of the total
specifically bound 125I-Sar1Ile8-angiotensin
II was pre~ented as a measure of the efficacy of such
compounds a~ AII antagonists.
, wo g~ gog 2 0 7 ~ 6 3 9 PCT/US9l/00963
~.. ~ .; .
-63-
Receptor assay usin~ Bovine adrenal cortex
~reparation
Bovine adrenal corte~ was selected as the
source of AII receptor. Weighed tis~ue (0.1 g is
needed for 100 assay tubes) was suspended in Tris ~Cl
(50 mM), p~ 7.7 buffer and homogenized. The
homogenate was centrifuged at 20,000 rpm for 15
minutes. Supernatant was discarded and pellets
resuspended in buffer [Na2~P04 (10 mM)-NaCl (120
mM)-disodium EDTA (5 mM! containing phenylmethane
sulfonyl fluoride (PMSE)(0.1 mM)]. (For ~creening of
compounds, generally duplicates of tubes are used).
To the membrane preparation (0.5 mL) there was added
3~-angiotensin II (50 mM) (10 mL) with or without the
test sample and the mixture was incubated at 37-C for
1 hour. The mi~ture was then diluted with Tris
buffer (4 mL) and filtered through a glass fiber
filter (GF/B Whatman 2.4~l diameter). The filter was
soaked in scintillation coc~tail (10 mL) and counted
for radioactivity using Pac~ard 2660 Tricarb liquid
scintillation counter. The inhibitory concentration
(IC50) of potential AII antagonist which gives 50%
displacement of the total specifically bound
3~-angiotensin II was presented as a measure of the
efficacy of such compounds as AII antagonists.
The potential antihypertensive effects of
the compount6 described in the present invention may
be evaluated using the methotology described below:
Male Charles River Sprague-Dawley rats (300-375 gm)
were anesthetized with methohe~ital (~revital; 50
mgl~g i.p.) and the trachea wa~ cannulated with PE
2 0 7 ~ & 3 3 PCT/US91/00963 ~
-64-
205 tubing. A ~tainless steel pithing rod (1.5 mm
thick, 150 mm long) was inserted into the orbit of
the right eye and down the spinal column. The rats
were immediately placed on a ~arvard Rodent
Ventilator (rate - 60 6trokes per minute, volume -
1.1 cc per 100 grams body weight). The right carotid
artery was ligated, both left and right vagal nerves
were cut, and the left carotid artery was cannulated
with PE 50 tubing for drug administration, and body
temperature was maintained at 37-C by a thermostati-
cally controlled heating pad which received ,nput
from a rectal temperature probe. Atropine (1 mg/kg
i.v.) was then administered, and 15 minutes later
propranolol (1 mg/~g i.v.). Thirty minutes later
angiotensin II or other agonists were administered
intravenously at 30 minute intervals and the increase
in the diastolic blood pres6ure was recorded before
and after drug or vehicle administration.
Using the methodology described above,
representative compounds of the invention were
evaluated and found to e~hibit an activity of at
least IC50 < 50 mM thereby demon6trating and
confirming the utility of the compounds of the
lnvention as effective AII antagonist~.
Thus, the compounds o~ the invention are
u~eful in treatin~ hypertension. They are also of
value in the management of acute and chronic
congestive heart failure, in the treatment of
secondary hyperaldosteronism, primary and ~econdary
pulmonary hyperaldosteronism, primary and secondary
pulmonary hypertension, renal failure and renal
~ W091/11~09 2 ~ 7 ~ ~ 3 ~ PCT/US91/00963
vascular hypertension, and in the management of
vascular disorders such as migraine or Raynaud~s
disease. The application of the compound~ of this
invention for these and similar disorders will be
apparent to those skilled in the art.
The compounds of this invention are also
useful to treat elevated intraocular pressure and can
be administered to patients in need of such treatment
with typical pharmaceutical formulations such.as
tablets, capsules, injectables, as well as topical
ocular formulations in the form of solutions,
ointments, inserts, gels and the like.
Pharmaceutical formulations prepared to
treat intraocular pressure would typically contain
about 0.1% to 15% by weight, and preferably 0.5% to
2.~% by weight of a compound of this invention.
In the management of hypertension and the
clinical conditions noted above, the compounds of
this invention may be utilized in compositions such
as tablets, capsules or elixirs for oral administra-
tion, suppositories for rectal administration,
sterile solutions or suspensions for parenteral or
intramuscular admini6tration, and the li~e. The
compounds o this invention can be administered to
patients (animals and human) in need of such
treatment in dosages that will provide optimal
pharmaceutical efficacy. Although the dose will vary
from patient to patient depending upon the nature and
severity of di8ease, the patient's weight, special
diets then being followed by a patient, concurrent
medication, and other factors which thosc s~illed in
2 ~ 7 ~ 6 3 9 PCT/US9ltO0963 ~
the art will reco~nize, the dosage range will
generally be about 1 to 1000 mg per patient per day
which can be administered in 6ingle or multiple
doses. Perferably, the dosage range will be about
2.5 to 250 mg per patient per day; more preferably
about 2.5 to 75 mg per patient per day.
The compounds of this invention can also be
admini~tered in combination with other antihyperten-
sives and/or diuretics and/or angiotensin converting
enzyme inhibitors and/or calcium channel blocker6.
For example, the compounds of this invention can be
given in combination with such compounds as amiloride,
atenolol, bendroflumethiazide, chlorothalidone,
chlorothiazide, clonidine, cryptenamine acetates and
cryptenamine tannates, deserpidine, diazoxide,
guanethidine sulfate, hydralazine hydrochloride,
hydrochlorothiazide, metolazone, metoprolol tartate,
methyclothiazide, methyldopa, methyltopate hydro-
chloride, mino~idil, pargyline hydrochloride,
polythiazide, prazosin, propranolol, rauwolfia
serpentina, rescinnamine, reserpine, sodium
nitroprusside, spironolactone, timolol maleate,
trichlormethlazide, trimethophan camsylate,
benzthlazlde, quinethazone, tlcryna~an, triamterene,
acetazolamide, aminophylline, cyclothiazide,
ethacrynic acid, furosemide, meretho~ylline p~ocaine,
sotium ethacrynate, captopril, telapril hytrochloride,
enalapril, enalaprilat, fosinopril sotium, lisinopril,
pentopril, quinaprll hydrochloride, ramapril,
teprotide, zofenoprll calcium, diflusinal, diltiazem,
felodipine, nicardipine, nifedipine, nilutipine,
nimodipine, nisoldipine, nitrendipine, and the like,
as well as admistures and combinations thereof.
~ WO 91/1 1909 2 0 7 ~) 6 3 9 Pcr/US9l/00963
-67~
Typically, the individual daily dosages for
these combinations can range from about one-fifth of
the minimally recommended clinical dosages to the
maximum recommended levels for the entities when they
are given ~ingly.
To illustrate these combination~, one of the
angiotensin II antagonists of this invention
effective clinically in the 2.5-250 milligrams per
. day range can be effectively combined at levels at
- lO the 0.5-250 milligrams per day range with the
following compounds at the indicated per day dose
range: hydrochlorothiazide (15-200 mg), chlorothiazide
(125-2000 mg), ethacrynic acid (15-200 mg), amiloride
(5-20 mg), furosemide (5-80 mg), propranolol (20-480
mg), timolol maleate ~5-60 mg), methyldopa (65-2000
mg), felodipine (5-60 mg), nifedipine (5-60 mg), and
nitrendipine (5-60 mg). In addition, triple drug
combinations of hydrochlorothiazide (15-200 mg) plus
miloride (5-20 mg) plus angiotensin II antagonist of
this invention (3-200 mg) or hydrochlorothiazide
(15-200 mg) plus timolol maleate (5-60) plus an
angiotensin II antagonist of this invention (0.5-250
mg) or hydrochlorothiazide (15-200 mg) and nifedipine
(5-60 mg) plu8 an angioten6in II antagoni6t of this
invention (0.5-250 mg) are effective combinations to
control blood pressure in hypertensive patients.
Naturally, these dose ranges can be adjusted on a
unit basi6 as necessary to permit divided daily
dosage and, as noted above, the dose will vary
depending on the nature and severity of the disease,
weight of patient, special diets and other factors.
.
; WO91/11909 2 0 7 5 ~ 3 ~ PC~/US91/00963 ~
-68-
Typically, these combinations can be
formulated into pharmaceutical compositions as
discussed below.
About 1 to 100 mg of compound or mi~ture of
compounds of Formula I or a physiologically
acceptable salt is compounded with a physiologically
acceptable vehicle, carrier, excipient, binder,
preservative, stabilizer, flavor, etc., in a unit
dosage form as called for by accepted pharmaceutical
practice. The amount of active substance in these
compositions or preparations is 6uch that a suitable
dosage in the range indicated is obtained.
Illustrative of the adjuvants which can be
incorporated in tablet6, capsules and the like are
the following: a binder such as gum tragacanth,
acacia, corn starch or gelatin; an excipient such as
microcrystalline cellulo6e; a disintegrating agent
such as corn starch, pregelatinized starch, alginic
acid and the li~e; a lubricant such as magnesium
stearate; a 6weetening agent such as 6ucrose, lactose
or 6accharin; a flavoring agent such as peppermint,
oil of wintergreen or cherry. When the dosage
unitform i6 a cap6ule, it may contain, in addition to
material6 of the above type, a liquid carrier 6uch as
fatty oil. Various other materials may be present as
coatings or to otherwi~e modify the physical form of
the dosage unit. For instance, tablets may be coated
with shellac, sugar or both. A syrup or eli~ir may
contain the active compound, sucrose as a sweetening
agent, methyl and propyl parabens as preservatives, a
dye and a flavoring such as cherry or orange flavor.
~; WO91/11909 ~7~-~-39 PCI/US91/00963
-69-
Sterile compositions for injection can be
formulated according to conventional pharmaceutical
practice by dissolving or su6pending the active
substance in a vehicle such as water for injection, a
naturally occurring vegetable oil like sesame oil,
coconut oil, peanut oil, cottonseed oil, etc., or a
synthetic fatty vehicle like ethyl oleate or the
like. Buffers, preservatives, antio~idants and the
like can be incorporated as required.
lo The compounds of this invention are also
useful tG treat elevated intraocular pressure and can
be administered to patients in need of such treatment
with typical pharmaceutical formulations such as
tablets, capsules, injectables, as well as topical
ocular formulations in the form of solutions,
ointments, inserts, gels and the like. Pharmaceutical
formulations prepared to treat intraocular pressure
would typically contain about 0.1% to 15% by weight,
and preferably 0.5% to 2.0% by weight of a compound
of this invention.
Thus, the compounds of the invention are
u~eful in treating hypertension. They are also of
value in the management of acute and chronic
conge6tive heart failure, in the treatment of
secondary hyperaldosteronism, primary and secondary
pulmonary hypertension, renal failure such as
diabetic nephropathy, glomerulonephritis, 6cleroderma,
and the like, renal vascular hypertension, left
ventricular dysfunction, diabetic retinopathy, and in
the management of va6cular disorders such as migraine
or Raynaud's disease. The application of the
compounds of this invention for these and similar
disorders will be apparent to those skilled in the
art.
2 0 7 ~ 6 3 9 PCT~US91/00963 ~
-70-
The useful central nervous system (CNS)
activities of the compounds of this invention are
demonstrated and e~emplified by the ensuing assays.
COGNITIVE FUNCTION ASS~Y
The efficacy of these compounds to enhance
cognitive function can be demonstrated in a rat
passive avoidance assay in which cholinomimetics such
as physostigmine and nOOtrGpiC agents are known to be
active. I~ this assay, rats are trained to inhibit
their natural tendency to enter dark areas. The test
apparatus used consists of two chambers, one of which
is brightly illuminated and the other is dark. Rats
are placed in the illuminated chamber and the elapsed
time it takes for them to enter the darkened chamber
is recorded. On entering the dark chamber, they
- receive a brief electric shoCk to the feet. The test
animals are pretreated with 0.2 mg/kg of the
muscarinic antagonist scopolamine which disrupts
learning or are treated with scopolamine and the
compound which is to be tested for possible reversal
of the scopolamine effect. Twenty-four hourE later,
the rats are returned to the lllumlnatet chamber.
Upon return to the illuminated chamber, normal young
rats who have been subjeCted to this training and who
have been treated only with control vehicle take
longer to re-enter the dark chamber than test animals
who have been e~poset to the apparatus but who have
not received a 8hock. Rat8 treatet with scopolamine
before training do not show thls hesitation when
tested 24 hours later. Efficacious test compounds can
overcome the disruptlve effect on learning which
,~. W091/11909 ~ ~ 7 ~ ~ 3 9 PCT/US~1/00963
scopolamine produces. Typically, compounds of this
invention should be efficacious in thi~ passive
avoidance as6ay in the dose range of from about O.l
mg/kg to about lOO mg/kg.
ANXIOLYTIC ASSAY
The anxiolytic activity of the invention
compounds can be demonstrated in a conditioned
emotional response (CER) assay. Diazepam is a
clinically useful anxiolytic which is active in this
assay. In the CER protocol, male Spra~ue-Dawley rats
(250-350 g)
are trained to press a lever on a variable interval
(VI) 60 second schedule for food reinforcement in a
standard operant chamber over weekly (five days per
week) training sessions. All animals then receive
daily 20 minute conditioning sessions, each session
partitioned into alternating 5 minute light (L) and 2
minute dark (D) periods in a fixed LlDlL2D2L3
sequence. During both period6 (L or D), pressing a
lever delivers food pellets on a VI 60 second
schedule: in the dark (D), lever pre6ses also elicit
mild footshock (O.B mA, 0.5 sec) on an independent
2~ shock presentatiOn schedule of VI 20 seconds. Lever
pressing is suppre6sed during the dark periods
reflecting the formation of a conditioned emotional
re6po~se ( OE R).
Drug testing in this paradigm is carried out
under e~tinction conditions. During estinction,
animals learn that responding for food in the dark is
no longer puni6hed by shock. Therefore, respon6e
rates gradually increase in the dark periods and
~ ~ .
.:
.
WO91/11909 2 ~ 7 5 ~ 3 ~ PCT/US91/00963 ~
-72-
animals treated with an anxiolytic drug show a more
rapid increase in response rate than vehicle treated
animals. Compounds of this invention should be
efficacious in this test procedure in the range of
from about 0.l mg/kg to about l00 mg/kg.
~E2RESSION ASSAY
The antidepressant activity of the compounds
of this inv~ntion can be demonstrated in a tail
suspension test using mice. A clinically useful
antidepressant which serves as a positive control in
this assay is desipramine. The method is based on
the observations that a mouse suspended by the tail
shows alternate periods of agitation and immobility
and that antidepressants modify the balance between
these two forms of behavior in favor of agitation.
Periods of immobility in a 5 minute test period are
recorded using a keypad linked to a microcomputer
which allows the experimenter to assign to each
animal an identity cote and to measure latency,
duration and frequency of immobile periods.
Compounds of this invention should be efficacious in
this test procedure in the range of from about 0.l
mg/kg to about lO0 mg/kg.
.S~IZnE3~E~I~ ASSAY
The antltopaminergic acti~ity of the
compounds of this invention can be demonstrated in an
apomorphine-induced stereotypy model. A clinically
useful antipsychotic drug that is used as a positive
~VO 91/1 1909 2 0 7 .~ PCT/US91/00963
-73-
control in this assay is haloperidol. The a3say
method is based upon the ob~ervation that 6timulation
of the dopaminergic system in rats produces stereo-
typed motor behavior. There i8 a strong correlation
between the effectivenes~ of cla~ical neuroleptic
drugs to block apomorphine-induced stereotypy and to
prevent schizophrenic symptom~. Stereotyped behavior
induced by apomorphine, with and without pretreatment
with test compounds, is recorded using a ~eypad
o linked to a microcomputer. Compounds of the inven-
tion should be efficacious in this assay in the range
of from about 0.1 m~/kg to about 100 mg/kg.
In the treatment of the clinical conditions
noted above, the compounds of thi~ invention may be
utilized in compositions such as tablets, capsules or
elixirs for oral administration, ~uppositories for
rectal administration, sterile solutions or ~uspen-
sions for parenteral or intramuscular administration,
and the like. The compounds of this invention can be
administered to patients (animals and human) in need
of such treatment in dosages that will provide
optimal pharmaceutical efficacy. Although the dose
will vary from patient to patient depending upon the
nature and severity of disease, the patient'~
weight, special diets then being followed by a
patient, concurrent medication, and other factors
which tho~e skilled in the art will recognize, the
dosage range will generally be about 5 to 6000 mg.
per patient per day which can be atministered in
single or multiple doses. Preferably, the dosage
range will be about 10 to 4000 mg. per patient per
day; more preferably about 20 to 2000 mg. per patient
per day.
wo ~", Igog 2 ~ PCT~US91/00963 ~
-74-
In order to obtain maximal enhancement of
cognitive function, the compounds of thi~ invention
may be combined with other cognition-enhancing
agents. These include acetylcholinesterase inhibitors
~uch as heptylphy60stigmine and tetrahydroacridine
(T~A; tacrine), muscarinic agonists such as
oxotremorine, inhibitors of angiotensin-converting
enzyme such as octylramipril, captopril, ceranapril,
enalapril, lisinopril, fosinopril and zofenopril,
centrally-acting calcium channel blockers such as
nimodipine, and nootropic agents such as piracetam.
In order to achieve optimal anxiolytic
activity, the compounds of this invention may be
combined with other an~iolytic agents such as
alprazolam, lorazepam, diazepam, and buspirone.
In order to achieve optimal antidepressant
activity, combinations of the compounds of this
invention with other antidepressants are of use.
These include tricyclic antidepressants such as
nortriptyline, amitryptyline and trazodone, and
monoamine o~idase inhibitors ~uch as tranylcypromine.
In order to obtain ma~imal antipsychotic
activity, the compounds of this invention may be
combined with other antipsychotic agents such as
promethazine, fluphenazine and haloperidol.
The following e~amples illustrate the
preparation of the compounds of Formula I and their
incorporation into pharmaceutical compositions and as
such are not to be considered as limitin~ the
invention set forth in the claims appended hereto.
....
, WO91/]1909 2~7~`3-9- Pcr/uSgl/00963
EXAI~LE 1
3-Butyl-4-[t4-tl-carbo~y-1-phenylmetho~y]phenyl]-
methyll-5-(4-nitrobenzvlthio)-4H-1.2.4-triazole
Ste~ A: Methvl ~-~4-~vdroxvbenzyl)dithiocarbamate
To a ~olution of 8.4 g (33 mmol) of
4-hydro~ybenzylamine hydriodide [M. Tiffeneau, ~
Soc. Chim. Fr., 2. 819 (1911)] and 10.1 ml (7.3 g, 73
mmol) of triethylamine in 32 ml of MeO~ stirred under
0 N2 at ambient temperature was added gradually a
solution of 2.2 ml (2.8 g, 38 mmol) of carbon
disulfide in 12 ml of MeO~. After 1 hour, the
resulting solution was cooled to -10 C and treated
gradually with a solution of 2 ml (4.7 g, 33 mmol) of
iodomethane in 6 ml of MeO~. The solution wa~ then
stirred at room temperature for 2 hours. Next, the
solution was concentrated to small volume and
partitioned between ether and 0.2 ~ ~Cl. The
ethereal phase was washed further with 0.2 ~ ~Cl
followed by saturated NaCl. The ether solution was
dried (MgSO4), filtered, and concentrated to an oil,
which gratually solidified, affording 5.98 g. (85~),
mp 90-91 C; homogeneous by TLC in 2:1 hexane-EtOAc.
Mass Spectrum ~FA9): 214 (M+l).
Analvsis (CgBllNOS2)
calculated: C, 50.67; ~, 5.20; N, 6.57 and
found: C, 50.76; ~, 5.24; N, 6.41.
1~ NMR (CDC13, 300 M~z, ppm): ~ 2.64 (s,3~), 4.81
(d,2~), 6.80 (d,2~), 6.99 (br s, 1~), 7.20 (d,
2~).
wo 9~ gog 2 0 7 ~ ~ 3 9 ` PCT/US91/0096 ~
-76-
St~ B: 4-(4-~ydroxvbenzvl)-3-thiosemicarbazide
A mixture of 5.98 g (28 mmol) of methyl
N-(4-hydro~ybenzyl)dithiocarbamate (product of
Example 1, Step A), 27 ml (560 mmol) of hydrazine
hydrate, and 72 ml of absolute EtO~ was stirred at
reflux for 1 hour. The solution was purged with N2
and then concentrated. The residual oil was treated
with 100 ml of C~2C12, 100 ml of ethyl acetate, and
100 ml of H2O. The solid which separated was washed
first with H2O and then with ether. This material
was recrystallized twice from absolute EtO~ to ~ive
2.74 g (50~ of solid, mp 179-179.5 C; homo~eneous by
TLC in 19:1 C~2C12-MeO~.
Mass Spectrum (F~8): 198 (M+l).
15AnalySiS: {Cg~llN3OS 0 1 C2~6 (EtOH)}
calculated: C, 48.78; ~, 5.79; N, 20.82
found: C, 48.73; H, 5.52; N, 20.65.
(DMSO-d6, 300 M~z, ppm): ~ 4.47 (s,2~),
4.56 (d,2H), 6.68 (d,2H), 7.13 (d,2~), 8.09 (br
20s,l~), 8.67 (s,l~), 9.25 (s,l~).
2S
!~ WO 91/1 190~ 2 0 7 ~ G 3 ~ PCr/US91/00963
.~, "
~S~ C: Ethyl Valerate 4-(4-~ydroxybenzyl)-3-
thiosemicarbazone
A mixture of 2.67 g (13.6 mmol) of
4-(4-hydroxybenzyl)-3-thiosemicarbazide (Example 1,
Step B), 3.2 g (19 mmol) of ethyl valerimidate
hydrochloride [A.J. ~ill and I Rabinowitz, J. Am.
Chem. Soc., 48, 734 (1926)], and 30 ml of dry
N,N-dimethylformamide (DMF) wa6 6tirred overni~ht at
room temperature under N2. It was then concentrated
to small volume (oil pump, 50 C) and partitioned
between ethyl acetate and ~2 The or~anic phase was
washed with ~2 followed by saturated NaCl. The
organic solution was dried (MgSO4), filtered, and
concentrated to give a foam, which was
chromatographed on a silica gel column (initial
elution with C~2C12, followed by 0.5% MeO~ in
C~2C12). Evaporation of the pooled product fractions
yielded 928 mg (22%) of a 6tic~y white foam;
homogeneous by TLC in 19:1 C~2C12:MeO~; NMR indicated
a mi~ture of ~yn and anti isomer6.
Mass S~ectrum (FAB): 310 (M~l).
~nalvsi 6 (Cl 5~23N3O2S)
calculated: C, 58.22; ~, 7.49; N, 13.58 and
found: C, 58.11; ~, 7.41; N, 13.34.
1~ NMR (CDC13, 300 M~z, ppm): ~ 0.89 (q,3~),
1.2-1.4 (m,5~), 1.50 (m,2~), 2.27 (m,2~
3.94,4.07 (minor and major g, total 2 8), 4.80
(d,2~), 6.80 (d,2~), 7.22 (d,2~), 7.40 (br t,l~).
7.93, 8.91 (minor and major 6, total 1~).
.
' , ~, - , .
WO91/11909 2 0 7 a 6 3 9 PCT/~S91/0096 ~
-7~-
Ste~ D: 5-Butyl-2,4-dihydro-4-(4-hydroxybenzyl)-3~-
1.2.4-triazole-3-thione
A solution of 788 mg (2.55 mmol) of ethyl
valerate 4-(4-hydro2ybenzyl)-3-thiosemicarbazone
(Step C) and 761 ~1 (775 mg, 5.10 mmol) of
1,8-diazabicyclo{5.4.0}undec-7-ene (DB~) in 8 ml of
dry tetrahydrofuran (TaF) wa6 stirred at reflux under
N2 for 24 hour~. During thi6 time hea~y
precipitation occurred. The cooled mi2ture wa~
filtered, and the solid wa~ wa~hed with T~F followed
by ether. The solid (DBU 6alt of the product) was
partitioned between EtOAc and 0.2 ~ ~Cl. The EtOAc
phase wa~ washed with additional 0.2 ~ ~Cl and then
with saturated NaCl. The EtOAc ~olution wa~ tried
over MgS04, filtered, and concentrated to give 229 mg
(34%) of a white solid, mp 156-157 C; homogeneou6 by
TLC in 19:1 C~2C12:MeO~.
~UL5LQs~ (FAB): 264 (K+l)
Analvsis (C13~17N3OS):
calculated: C, 59.29; ~, 6.51; N, 15.96 and
found: C, 59.20; ~, 6.54; N, 15.59
B (DMS0-d6, 300 M~z, ppm): ~ O.78 (t,3~),
1.23 (m,2~), 1.41 (m,2~), 2.49 (t,2~), 5.11
(s,2~, 6.72 (d,Z~), 7.12 (d,2~), 9.45 (s,lE).
Step E: 3-Butyl-4-(4-hydro2ybenzyl)-5-(4-nitro-
benzylthio~-4~-1.2.4-triazole
A solution of 215 mg (0.82 mmol) of
5-butyl-2,4-dihydro-4-(4-hydroxybenzyl)-3~-1,2,4-
triazole-3-thione (Step D) in 3 ml of 2-metho~y-
ethanol was treated with 143 ml (106 mg, 0.82 mmol)
of N,N-diisopropylethylamine and then with 177 mg
~' ' . ~ .
.
,
, wos~ 909 2 0 ~ 3 ~ ; PCT/US9]/00963
(0.82 mmol) of 4-nitrobenzyl bromide. The solution
was stirred at room temperature in a stoppered
flask. ~eavy precipitation began within 30 minutes.
After 2.5 hour6, the misture was partitioned between
100 ml of EtOAc plus 10 ml of MeO~ and 100 ml of 0.2
~Cl. The EtOAc layer was washed further with 0.2~
~Cl and then with saturated NaCl. The organic phase
was dried (MgS04), filtered, and concentrated. After
drying in y~5~Q (oil pump) at 50 C., there was
obtained 327 mg (100%) of a solid, mp 132-133 C;
homogeneous by TLC in 97:3 C~C13-iPrO~.
Mass Spectrum (FAB): 399 (M+l)
MR (DMSO-d6, 300 M~z, ppm): ~ 0.80 (t,3~),
1.25 (m,2~) 1.48 (m,2~), 2.62 (t,2~), 4.45
(s,2~), 4.93 (s,2~), 6.67 (d,2~), 6.83 (d,2H),
7.57 (d,2~), 8.15 (d,2~), 9.53 (br s, 1 ~).
Ste~ F: 3-Butyl-4-[t4-[1-(carbomethoxy)-l-phenyl-
methoxy~phenyl~methyl]-5-(4-nitrobenzylthio)-
4~-1.2.4-triazole
A mixture of 322 mg (0.81 mmol) of 3-butyl-
4-(4-hydro~ybenzyl)-5-(4-nltrobenzylthio)-4~-1,2,4-
triazole (Example 1, Step E), 278 mg (1.21 mmol) of
methyl ~-bromophenylacetate, 16B mg (1.22 mmol) of
anhydrous K2CO3, and 3 ml of dry DM~ was stirred
under N2 at 60 C for 24 hours. The mi~ture was
concentrated in ~acuo (oil pump, 50-C), and the
resitue was partitioned between ~tOAc and ~2 The
organic solution was dried (MgS04), filtered, and
concentrated. The residual oil was chromatographed
on a column of silica gel (elution with a gradient of
0.5-10% MeO~ in C~2C12). TLC (97:3 C~C13-iPrO~ and
.
.
~. . . .
.
'' .: ' ' ' '~ . ' ' ~ '
W09~ 909 2 a7 3 & 39 PCT/VS91/00963
-80-
98:2 C~2Cl2-MeO~) and NMR were u6ed to identify the
appropriate product fractions, which were combined
and concentrated to give the product as a gum.
~ss S~ectrum (FAB): 441 (M+l).
l~ B ~CDC13, 300 M~z, ppm): ~ O.84 (t,3~), 1.31
(m,2~), 1.61 (m,2~), 2.55 (t,2~), 3.71 (8,3~),
4.40 (~,2H~ 4.80 (B,2~), 5.57 (~,lH), 6.82
(6,4~), 7.25-7.55 (m,7~), 8.10 (d,2~).
Ste~ G: 3-Butyl-4-[[4-tl-carbo~y-1-phenylmethoxy]-
phenyl]methyl~-5-(4-nitrobenzylthio)-
4~-1.2.4-triazole
A 601ution of 16 mg (0.03 mmol) of 3-butyl-
4-~[4-[1-(carbomethoxy)-1-phenylmethoxy~phenyl]-
methyl]-5-(4-nitrobenzylthio)-4~-1,2,4-triazole
(Example 1, Step F) in 240 ~l of C~3O~ was treated
with 120 ~l (0.3 mmol) of 2.5N NaO~. After 15
minutes of stirring at room temperature, TLC
indicated complete conversion of 6tarting material to
a lower Rf product. The solution was acidified to p~
1.5 by addition of 0.2N ~Cl. The precipitated ~olid
was collected on a filter, washed with ~2 then with
ether, and dried in vacuo over P205 to give 9.5 mg
(60%) of the product a6 a solid, mp 105-106 C
(preliminary softening); homogeneous by TLC in
90:10:1 C~2Cl2:c83o~:c~3cO2~-
Mass S~ectrum (F~8): 533 (M~l).
Analvsis [C2g~2gN4OsS-0.25~2O-0.25C4~1oO (ether)]:
calculated: C, 62.68; R, 5.62; N, 10.09 and
found: C, 63~05; ~, 5.23; N, 9.68.
:
,-. W091/l19~9 2 ~ 7 ~ ~ 3 ~ PCT/US9l/00963
1~ NMR (CDC13, 300 M~z, ppm): ~ O~75 (t,3~), 1.20
(m,2H), 1,49 (m,2~), 2,57 (t,2H), 4.37 (8, 2H),
4.81 (ABq,2~), 5.61 (6,1~), 6.86 (ABq,4~),
7.2-7.65 (m,7~), 8.07 (d,2~.
3-Butyl-4-[[4-[1-carboxy-1-phenylmethoxy]phenyl]-
methvl1-5-~4-nitrohenzylsulfinyl~-4~-1.2.4-triazole
Step A: 3-Butyl-4-[[4-[1-(carbomethoxy)-1-phenyl-
methoxy]phenyl]methyl]-5-(4-nitrobenzyl-
sulfinvl)-4~-1.2~4-triazole
A solution of 3-butyl-4-[[4-[1-(carbo-
methoxy)-1-phenylmetho~y~phenyl]methyl]-5-(4-nitro-
benzylthio)-4~-1,2,4-triazole (from E2ample 1, Step
F) in dry CH2C12 i~ treated with m-chloroperoxy-
benzoic acid (1 equivalent), and the resulting
mixture is stirred at room temperature for about 30
minutes or until TLC indicates complete reaction. At
this point the mi~ture i8 partitioned between ethyl
acetate and saturated Na~C03 solution. The organic
phase is washed repeatedly with saturated Na~C03,
then dried over MgS04, filtered, and concentrated.
The residue may be purified by chromatography on
silica ~el to give the title compound.
S~e~ B: 3-Butyl-4-~[4-[1-carboxy-1-phenylmethoxy]-
phenyl]methyl]-5-(4-nitrobenzylsulfinyl)-4~-
1.2.4-triazole
By the procedure of Example 1, Step G,
3-butyl-4-~[4-[1-(carbomethoxy)-1-phenylmethoxy]-
~ ' ' -
wos~ gO9 2 ~ 7 ~ 6 ~ 9 PCT/US9l/00963~.i
phenyl]methyl]-5-(4-nitrobenzyl6ulfinyl)-4~-1,2,4-tri-
azole (from Example 2, Step A) is converted to the
title compound.
E~AMPLE 3
3-Butyl-5-(4-nitrobenzylthio)-4-[[4-tl-phenyl-1-
(tetrazol-5-yl)methoxy]phenyl~methyl]-4H-1,2,4-
triazole
Step A: 3-Butyl-4-[[4-[l-carbamoyl-1-phenylmethoxy]-
phenyl]methyl~-5-~4-nitrobenzylthio)-4~-
1.2.4-triazole
A solution of 3-butyl-4-r[4-[l-(carbo-
methoxy)-l-phenylmethoxy]phenyl]methyl]-5-(4-nitro-
benzylthio)-4~-1,2,4-triazole (from Example l, Step
F) in methanol is saturated with gaseous ammonia at
0- and then stirred at that temperature in a
stoppered vessel for about 6 hours or until TLC
indicates complete reaction. The mi~ture is then
concentrated to dryncss to yield the title compound.
.St~ 3-Butyl-4-[[4-[1-cyano-1-phenylmethoxy]-
phenyl]methyl]-5-(4-nitrobenzylthio)-4~-
1.2.4-triazole
A 6u6pension of 3-butyl-4-[[4-[1-carbamoyl-
l-phenylmethoxy]phenyl~methyl~-5-(4-nitrobenzylthio)-
4~-1,2,4-triazole (from Example 3, Step A) in
phosphorus oxychloride (25-30 equivalent6) i6 stirred
~o at O-C under N2 as triethylamine (2.2 eguivalents) is
atded dropwise over about 1 hour. After the addition
is complete, the mixture is gradually warmed to room
~ WO9l/1]909 2 0 7 ~ ~`3 9 PCT/US91/00963
-83-
temperature and then heated to reflux for about 45
minutes or until TLC indicates complete reaction.
The cooled mixture iB concentrated ~n vacuo, and the
residue i~ partitioned between ice-water and an
organic ~olvent, 6uch a6 ether, ethyl acetate, or
toluene. The organic phase i6 washed with dilute
NaO~ and then with ~2 The organic solution i~
dried over MgS04, filtered, and concentrated to give
the title compound, which i6 u6ed directly or may be
lo purified by chromatography on silica gel.
Step C: 3-Butyl-5-(4-nitrobenzylthio)-4-t~4~
phenyl-l-(tetrazol-5-yl)methoxy]phenyl~-
methyll-4~-1.2.4-triazole
A mixture of 3-butyl-4-tt4-tl-cyano-1-
phenyl-methoxy]phenyl]methyl]-5-(4-nitrobenzylthio)-
4~-1,2,4-triazole (from Example 3, Step B),
trimethyltin azide (3.5 equivalent6), and toluene is
stirred at reflux for about 2 days. The mixture is
then cooled and concentrated ~n vacuo. The residue
is partitioned between 0.5 ~ ~Cl and ethyl acetate.
The ethyl acetate pha~e i6 dried (MgS04), filtered,
and concentrated. The residue is taken up in
methanol and ~tirred with 6ilica gel (4-5 g per mmol
or cyano starting material) for about 1 hour. The
mixture is then evaporated Ln vacuo to give a dry
powder, which i~ layered on top of a column of 6ilica
gel packed in C82C12. Elution of the column with a
gradient of methanol in C82C12 affords the title
compound.
wos~ gog ~ ~ J ~ ~ ~ PCT/US91/0096
-84-
EXAMPL~ 4
3-Butyl-5-(4-nitrobenzyl~ulfinyl~-4-t~4-tl-phenyl-1-
(tetrazol-5-yl)methoxy]phenyl]methyl]-4~-1,2,4-
triazole
To a stirred solution of 3-Butyl-4-tt4~
phenyl-l-(tetrazol-5-yl,methoxy]phenyl~methyl]-5-(4-
nitrobenzylthio)-4H-1,2,4-triazole (from Example 3,
Step C) in glacial acetic acid is added gradually an
equal volume of 30% hydrogen peroxide (aqueous). The
resulting solution is stirred at room temperature in
a stoppered flask for about 15-20 hours, until TLC
and/or NMR (from wor~-up of an aliquot) indicates
complete reaction. The reaction mi~ture i6 then
lS partitioned between ethyl acetate and dilute ~Cl.
The ethyl acetate phase is dried (MgS04), filtered,
and concentrated Ln Y~S~Q- The resitue is triturated
with ether to give the title compound as a ~olid,
which i~ collected on a filter and washed further
with ether.
~L~
3-Butyl-4-tt4-(l-carboxy-l-phenylmethoxy)phenyl]
m~h~ll-5-~4-chlorobenzylthio~-4~-1.2.4-triazQle
Step A: 3-Butyl-5-(4-chlorobenzylthio)-4-(4-hydroxy-
A solution of 500 mg (1.9 mmol) of 5-butyl-
2,4-dihydro-4-(4-hydroxybenzyl)-3~-1,2,4-triazole-3-
thione (from Example 1, Step D) in 4 ml of 2-methoxy-
ethanol was treated with 330 ~1 (245 mg; 1.9 mmol) of
:` .: : ^; !`" '`
. wo 9l/l lgog 2 ~ 7 ~ ~ 3 ~ PCT/US91/00963
-85-
N~N-diisopropylethylamine and 306 mg (1.9 mmol) of
4-chlorobenzyl chloride. The misture was stirred at
room temperature in a stoppered flas~ for 5 hour~ and
then concentrated ~n vacuo to small ~olume. The
residue was partitioned between 50 ml of EtOAc and 50
ml of 0.2 _ HC1. The organic layer was washed with
an additional 50 ml of 0.2 ~ FCl followed by 50 ml of
saturated NaCl. The EtOAc solution was dried over
MgS04, filtered, and concentrated. The residue was
chromatographed on a column of silica gel (elution
with a gradient of 1 to 3% isopropanol in C~2C12) to
give 411 mg (56%) of the product as a white solid, mp
149-lSO-C; homogeneous by TLC in 97:3 C~2C12-iPrO~.
Mass S~ectrum (FAB): 388 (M~l).
Analysis (C20~22ClN30S):
calculated: C, 61.92; ~, 5.72; N, 10.83 and
found: C, 62.21; F, 5.79; N, 10.96
1~ NMR (DMSO-d6, 300 M~z, ppm) ~ O.81 (t, 3F),
1.26 (m, 2H), 1.48 (m, 2~), 2.57 (t, 2~), 4.30
(s, 2~), 4.B9 (s, 2~), 6.68 (d, 2~), 6.78 (d,
2~), 7.33 (ABq, 4~), 9.50 (s, 1~).
Ste~ B: 3-Butyl-4-t[4-~1-(carbomethoxy)-1-phenyl-
methoxy]phenyl]methyl]-5-(4-chlorobenzyl-
thio)-4a-1.2.4-triazole
A ~olution of 200 mg (0.52 mmol) of 3-butyl-
5-(4-chlorobenzylthio)-4-(4-hydrosybenzyl)-4~-1,2,4-
triazole (from Step A) in 2 ml of dry DMF was treate~
with 21 mg (0.52 mmol) of sodium hydride (60% in
oil), and the mi~ture was stirret under N2 at room
temperature for a few minutes until ~2 evolution had
ceased and a clear solution had resulted. To this
.
wo9~ 909 207~3~
P~T/US9~/~0963~
i -.s.;
-86-
was added 119 mg (0.52 mmol) of methyl a-bromo-
phenylacetate, and stirring was continued under N2
at room temperature for 10 minutes and then at 65-C
for 6 hours. The cooled mixture was treated with 1
ml of MeO~ and then concentrated Ln vacuo. The
residue was partitioned between 25 ml of EtOAc and 30
ml of H20. The EtOAc phase was washed with 2 x 25
ml f ~2 and then with 25 ml of saturated NaCl! The
organic solution was dried over MgS04, filtered, and
lo concentrated. Column chromatography of the residue
on silica gel (gradient elution with 0.75-1.2% MeOH
in CH2C12) yielded 191 mg (69~/.) of the title compound
as a glass; homogeneous by TLC in 97:3 C~2C12-MeOH.
Mass Spectrum (FAB): 535 (M+).
Analvsis (C2g~30ClN303S)
calculated: C, 64.97; ~, 5.64; N, 7.84 and
found: C, 64.80; ~, 5.79; N, 7.69.
(CDC13, 300 M~z, ppm) ~ O.84 (t, 3~), 1.30
(m, 2~), 1.59 (m, 2~, 2.52 (t, 2~), 3.71 (s,
3~), 4.27 (s, 2~), 4.75 (s, 2~), 5.58 (s, lB),
6.80 (ABq, 4~), 7.15-7.55 (m, 9~).
: 3-Butyl-4-~t4-(1-carbosy-1-phenylmetho~y)-
phenyl~methyl]-5-(4-chlorobenzylthio)-4~-
1.2.4-triazole
To a solution of 165 m~ (0.31 mmol) of
3-butyl-4-[t4-tl-(carbomethoxy)-1-phenylmethosy~-
phenyl]methyl~-5-(4-chlorobenzylthio~-4~-1,2,4-
triazole (from Step B) in 2.5 ml of MeO~ was added
1.23 ml (3.1 mmol) of 2.5 ~ NaO~. The resulting
, solution was stirred at room temperature in a
stoppered flask for 1 ~our and then adjusted to p~ 2
by addition of
.
~;; wo sl/llsos 2 0 7 ~ 6 ~ 9 - ` PCT/US9l/00963
dilute ~Cl. The mixture was concentrated ~n vacuo to
give a white ~olid, which was washed thoroughly with
dilute ~Cl (p~ 2) and then dried. After further
washing with Et20 and vacuum-drying over P205, 133
mg (79Z~ of the title compound was obtained as a
white solid, mp 66-67-C; homogeneous by TLC in
90:10:1 C~2C12-MeOH-AcOH.
Mass S~ectrum (FAB): 522 (M+l).
Analysis (C2g~2gclN303s-o 2 ~2 0-25 C4~10
(Et20)):
calculated: C, 64.00; ~, 5.72; N, 7.72 and
found: C, 63.69; ~, 5.67; N, 7.77
~ (DMSO-d6, 300 M~z, ppm): ~ 0.80 (t, 3~),
1.24 (m, 2~), 1.48 (m, 2~), 2.59 (t, 2H), 4.30
(s, 2~), 4.96 (s, 2~), 5.81 (s, 1~), 6.90
(apparent s, 4~), 7.25-7.55 (m, 9~).
E~AMPLE 6
3-Butyl-4-t[4-(1-carbo~y-1-phenylmethoxy)phenyl]-
methyll-5-(4-chlorobenzylsulfinyl~-4a-1.2.4-triazole
To a 6tirred solution of 60 mg (0.11 mmol)
of 3-butyl-4-t[4-[1-carboxy-1-phenylmetho~y]phenyl~-
methyl]-5-(4-chlorobenzylthio)-4~-1,2,4-triazole
(from Esample 5) in O.75 ml of glacial acetic acid
was adted gradually 0.75 ml of 30Z hydrogen peroxide
in ~2 The solution became turbid during the
addition but largely clarified within a few minutes.
After adting an addltional 4 drops of acetic acid,
the mi~ture was stirred at room temperature in a
6toppered flask for 16 hours. It was then diluted
with 50 ml of EtOAc and shaken with 50 ml of dilute
WO91/11909 2 0 7 ~ ~ 3 9 PC~/US91/00963 ~
HCl (p~ Z.5). The aqueous phase was extracted with
an additional 3 portions of EtOAc. The combined
EtOAc fractions were washed once with dilute ~Cl (pE
2), then dried (MgS04), filterèd, and concentrated.
Trituration of the residue with Et20 gave a gum.
Upon decantation of the Et20 and drying ~n vac~Q, 31
mg (51%) of the title compound was obtained as a
stiff foam, mp 76-78-C dec.
Mass Spec~rum (~AB): 538 (M+l).
l8 ~n~lY~i~ (C2g~2gClN304S-0.5 H20-0.1 C4~100
(Et20)):
calculated: C, 61.52; ~, 5.45; N, 7.58 and
found: C, 61.56; ~, 5.40; N, 7.52.
~(DMSO-d6, 300 M~z, ppm): ~ O.80 (m, 3~),
15 1.24 (m, 2~), 1.47 (m, 2~), 2.62 (m, 2~), 4.72 (ABq,
2~), 5.23, (ABq, 2~), 5.81 (s, 1~), 6.90 (m, 4~),
7.25-7.55 (m, 9~).
~X~MPLE 7
3-Butyl-6-t~4-(1-carbo~y-1-phenylmethosy)phenyl]-
met~yll-5-(4-methQ~ybenz~l~hiQ~-4a-1.2.4-triazole
S~e~ A: 3-Butyl-4-~4-hydrosybenzyl)-5-(4-metho~y-
benzvlthio~-4a-l.2~4-triaz-L~
Reaction of 5-butyl-2,4-dihydro-4-(4-hydroxy-
benzyl)-3~-1,2,4-triazole-3-thione (from Esample 1,
Step D) with 4-methosybenzyl chloride according to
the procedure o~ E~ample 5, Step A, gave a 70% yield
of the title compound as a solid, mp 130-131-C;
homogeneous by TLC in 95:5 C~2C12-MeO~.
Mass Spectrum (FAB): 384 (M+l)
Analy~s~-l8 (C21~25N302S)
w~ 91/1,gog 2 0 7 S ~ 9 PCT/US9l/00963
-89-
calculated: C, 65.77; ~, 6.57; N, 10.96 and
found: C, 65.89; ~, 6.56; N, 10.77
~ R (DMS0-d6, 300 M~z, ppm): ~ 0.81 (t, 3~),
1.26 (m, 2H), 1.48 (m, 2~), 2.57 (t, 2~), 3.73 (6,
3~), 4.24 (6, 2~), 4.87 (s, 2H), 6.67, 6.79, 6.85,
7.20 (d, each 2H), 9.48 (~, 1~).
S~ B: 3-Butyl-4-[t4-rl-(carbomethoxy)-1-phenyl-
methoxy]phenyl]methyl]-5-(4-metho~ybenzyl-
lo thio)-4~-1.2.4-triazole
The product from Step A was converted to the
title compound by the procedure of Example 5, Step
B. The material was obtained in 67% yield as a gum;
homogeneous by TLC in 97:3 C~2C12-MeO~.
Mass S~ m (FAB): 532 (M+l)
Analvsis (C30~33N3o4s):
calculated: C, 67.77; ~, 6.26; N, 7.91 and
found: C, 67.68; H, 6.41; N, 7.75
~ (CDC13, 400 M~z, ppm): ~ O.83 (t, 3~),
1.30 (m, 2~), 1.59 (m, 2~), 2.62 (t, 2~), 3.70, 3.77
(s, each 3~), 4.34 (s, 2~), 4.78 (R, 2~), 5.57 (s,
1~), 6.78 (d, 2~), 6.81 (ABg, 4~), 7.18 (d, 2~),
7.3-7.55 (m, 5~).
~ L: 3-~utyl-4-[t4-(l-carbosy-l-phenylmethosy)-
phenyl~methyl]-5-(4-methosybenzylthio)-4~-
1.2.4-triazole
The product from Step B was converted to the
tltle compound according to the procedure of ~ample
5, Step C. The material was obtainet in 8S% yield as
a white solid, mp 78-79-C; homogeneous by TLC in
90:10:1 C~2C12-MeO~-AcO~.
WO 91/11909 2 0 7 5 & 3 9 PCr/US91/00963~
--90--
Ma~ ectrum (FAB): 518 (M+l)
Analysis (C2gH31N304S-0.5 H20):
calculated: C, 66.13; H, 6.12; N, 7.98 and
found: C, 65.96; H, 6.10; N, 7.97.
1~ (DMS0-d6, 300 M~z, ppm): ~ O.81 (t, 3H),
1.25 (m, 2H), 1.49 (m, 2H), 2.61 (t, 2~), 3.73 (s,
3H), 4.26 (s, 2H), 4.96 (s, 2H), 5.81 (s, 1~),
6.8-7.7 (m, 13~).
1o EXAMPLE 8
3-Butyl-4-t[4-(1-carboxy-1-phenylmethoxy)phenyl]-
methyll-5-(4-methoxybenzylsulfinyl~-4E-1.2.4-triazQle
By the procedure of Example 6, the title
compound was prepared from 3-butyl-4-t[4-(1-carboxy-
l-phenylmethoxy)phenyl]methyl]-5-(4-methoxybenzyl-
thio)-4~-1,2,4-triazole (E~ample 7). The material
was obtained in 65% yield as a stiff foam, mp 74-75C.
Mass S~ectrum (FAB): 534 (M+l)
Analvsis (C2g~3lN305s-~2o 0-1 c4Hloo ( 2
calculated: C, 63.16; H, 6.13; N, 7.52 and
found: C, 63.37; H. 6.05; N, 7.42.
la~ (DMS0-d6, 300 M~z, ppm): ~ O.80 (t, 3H),
1.23~(m, 2H), 1.48 (m, 2H), 2.60 (m, 2H), 3.75 (s,
Z5 3~), 4.b4 (ABq, 2H), 5.1B (ABq, 2H), 5.80 (8, lH),
6.8-7.6 (m, 13~).
. .
:, ' . , ~
. ' '~ '
.
fi ~ wo 9~ gog 2 0 ~ 5 G 3 9 ` `~ PCT/US9]/009~3
. .- .
-91-
F`XAMPLF 9
3-Butyl-4-[[4-[1-carbosy-1-(2-chlorophenyl)methoxy]-
phenyl]methyl]-5-~4-chlorobenzylthio)-4~-1,2,4-
triazole
Ste~ A: Preparation of methyl 2-bromo-2-(2-chloro-
phenvl)acetate
A mixture of 2-chlorophenylacetic acid (5.00
g, 29.3 mmol) and thionyl chloride (2.67 mL, 1.2$ eq)
were heated at reflux while bromine (1.51 mL, 1.0 eq)
was added from a dropping funnel over 15 minutes.
The reaction mixture was heated at reflux 19.5 hours,
and then cooled to room temperature. Methanol (30
mL, 25 eq) was then added slowly, as an exotherm and
violent bubbling resulted. The reaction mixture was
then concentrated ~n yacuo. The residue was
partitioned between water and ether and the aqueous
phase was then extracted twice with ether. The
combined ether portions were washed with 5% Na~S03,
dried (MgS04), filteret, ant concentrated in vacuo.
The residue was purified on a silica gel flash
chromato~raphy column (170 s 45 mm) eluted with 15%
ethyl acetate/hesane to yield 2.13 g (28%) of the
t~tle compount,
1~ NMR (300 M~z, CDC13, ppm): ~ 3.8 (s, 3~), 5.95
(s, 1~), 7.25-7.45 (m, 3~), 7.7-7.8 (m, 1~).
.
wosl/llsos 2 07 a ~ ~ ~ PCT/US91/00963 ~
- ~i
. -92-
Ste~ B: 3-Butyl-4-[[4-[1-carbomethoxy)-1-(2-chloro-
phenyl)metho~y]phenyl]methyl]-5-(4-chloro-
benzylthio)-4~-1.2.4-triazole
Reaction of 3-butyl-5-(4-chlorobenzylthio)-4-
(4-hydroxybenzyl)-4~-1,2,4-triazole (from Example 5,
Step A) with methyl
2-bromo-2-(2-chlorophenyl)acetate, from Step A,
according to the procedure of Example 5, Step B,
provided a 75% yield of the title compound as a
10 glass; homo~eneous by TLC in 97:3 CH2C12-MeOH.
Mass S~ectrum (FAB): 570 (M+l)
Analvsis (C2g~2gC12N303S):
calculated: C, 61.05; H, 5.12; N, 7.37 and
found: C, 60.87; H, 5.33; N, 7.45.
15 1~ (CDC13, 300 M~z, ppm): ~ O.84 (t, 3H),
1.29 (m, 2H), 1.58 (m, 2H), 2.51 (t, 2H), 3.74 (s,
3H), 4.27 (s, 2H), 4.75 (s, 2~), 6.09 (8, lH), 6.81
(ABq, 4~), 7.15-7.6 (m, 8H).
20 Ste~ C: 3-Butyl-4-~[4-~1-carbo~y-1-(2-chlorophenyl)-
metho~y]phenyl]methyl]-5-(4-chlorobenzyl-
thio)-4~-1.2.4-triazole
The product from Step B was converted to the
title compound according to the procedure o~ Example
5, Stcp C. The mat-rial was obtained in 85Z yield as
a white 601id, mp 100-102-C, homogeneous by TLC in
90:10:1 CH2C12-MeOH-AcOH.
`:
~w~91tl1909 2 ~ 7 ~ ~ ~ 9 ~ PCT/US9l/00963
-93-
Mass Spectru~ (FAB): 556 (M+l)
(high resolution FAB):
calculated: 555.1150 and
found: 555.1239
1a NMR (DMS0-d6, 300 M~z, ppm): ~ 0.79 (t, 3~)
1.23 (m, 2~), 1.47 (m, 2~), 2.62 (t, 2~, 4.32 (s,
2~), 5.00 (s, 2~), 6.04 (s, 1~), 6.91 (m, 4~),
7.25-7.55 (m, ~H).
1o EXAMPLE 10
3-Butyl-4-[~4-[1-carboxy-1-(2-chlorophenyl)methoxy]-
phenyl]methyl~-5-(4-chlorobenzylsulfinyl)-4~-1,2,4-
triazole
The title compound was prepared from 3-butyl-
4-[[4-[1-carboxy-1-(2-chlorophenyl)methoxy]phenyl]-
methyl]-5-(4-chlorobenzylthio)-4~-1,2,4-triazole
(Example 9) according to the methot of Example 6.
The material was obtained in 71% yield as a stiff
foam, mp 89-90-C dec. (preliminary softening).
Mass Spectrum (FAB): 572 (M+l)
~D~ly~ie (C28~27C12N304S-~20)
calculated: C, 56.95; R, 4.95; N, 7.12 and
~ound: C, 56.71; ~, 4.91; N, 7.00
la ~ (DMSO-d6, 300 MRz, ppm): ~ 0.78 (m, 3R),
1.21 (m, 2~), 1.45 (m, 2~), 2.60 (m, 2~), 4.72 (ABq,
2~), 5.23 (ABg, 2~), 6.04 (s, 1~), 6.90 (m, 4~),
7.2-7.6 (m, 8~).
~ ,.., , :
WO91/11909 2 0 7 ~ ~ 3 ~ PCT/US9l/00963 ~
-94-
~LE 1 1
3-~utyl-4-[[4-[1-carboxy-1-(2-chlorophenyl)methoxy]-
phenyl]methyl]-5-(4-methoxybenzylthio)-4~-1,2,4-
triazole
S~p A: 3-Butyl-4-~t4-[1-(carbomethoxy)-1-(2-chloro-
phenyl)methoxy]phenyl]methyl]-5-(4-methoxy-
benzvlthio~-4~-1.2.4-triazole
lo Reaction of 3-butyl-4-(4-hydroxybenzyl)-5-
(4-methoxybenzylthio)-4~-1,2,4-triazole (from Example
7, Step A) with methyl 2-bromo-2-(2-chlorophenyl)-
acetate, as prepared in Example 9, Step A, according
to the procedure of Example 5, Step B, gave a 62%
yield of the title compound as a glass; homogeneous
by TLC in 97:3 C~2C12-MeO~.
Mass Sgectrum (FAB): 566 (M+l)
Analysis (C30~32ClN304S~0.2 ~2):
calculated: C, 63,24; ~, 5.73; N, 7.38
found: C, 63.08; ~, 5.81; N, 7.47
~ R (CDC13, 300 M~z, ppm): ~ O. 83 (t, 3~),
1.29 (m, 2~), 1.57 (m, 2~), 2.51 (t, 2~), 3.74, 3.77
(6, each 38), 4.25 (8, 2B), 4.72 (6, 2~), 6.08 (s,
1~), 6.77 (d, 2~), 6.81 (ABg, 4~), 7.15 (d, 2~),
2S 7.2-7.6 (m, 4~),
Step B: 3-Butyl-4-~4-tl-carbo~y-l-(2-chlorophenyl)
methoxy]phenyl]methyl]-5-(4-metho~ybenzyl-
thio)-4~-1.2.4-triazole
The product from Step A was converted to the
title compound by the method of Example 5, Step C.
ri; WO 91/11909 2 0 7 ~ 3 9 ` PCT/USg1/00963
... .
-95-
The material was obtained in 79% yield as ~ white
601id, mp 84-86-C; homogeneous by TLC in 90:10:1
C~12C12-MeO~-AcOI~ .
Mass S~ectLum (FAB): 552 (M+l)
AnaLysi~ (C29H30ClN304S-0.5 ~2)
calculated: C, 62.07; ~, 5.57; N, 7.49 and
found: C, 62.30; ~, 5.70; N, 7.43.
~ (DMS0-d6, 300 M~z, ppm): ~ O.79 (t, 3~),
1.24 (m, 2H), 1.47 (m, 2~), 2.60 (t, 2~), 3.73 (s,
lo 3~), 4.25 (s, 2~), 4.95 (s, 2H), 6.04 (s, 1~),
6.8-6.95 (m, 6H), 7.20 (d, 2~), 7.40 (m, 2~), 7.53
(m, 2~).
E~A~
3-Butyl-4-[[4-(l-carboxy-l-phenylmethoxy)-3-propyl-
~he~yllmethvll-5-phenvl-4~-1.2.4-triazole
Ste~ A: Preparation of methyl 4-(2-propen-1-yloxy)-
benzoate
A 2 L flask wa6 equipped with a mechanical
~tirrer, a reflux condenser and a stopper, then
charged with 50.05 g (0.329 mol) of methyl 4-hydroxy-
benzoate, 960 mL of acetone, 22.50 g (1.625 mol) of
anhydrou6 potassium carbonate, 80.5 mL (112.6 g,
0.932 mol) of allyl bromide and the misture was
6tirred snd reflused for 14 hours. The mixture was
cooled to room temperature, filtered and concentrated
to an oil. The residual oil was purified by
di6tillation (97-C @ 0.03 mm ~g) to afford 53.52 g
(86Z) of the title compound.
W09l/ll90g 2~7~3~3
Pcr/ussJ/oos~3~g
-96-
~ (300 MHz, CDC13, ppm): ~ 3.84 (s, 3~),
4.56 (d, J=7 Hz, 2H), 5.28 (dd, J=3,12 Hz, lH), 5.40
(dd, J=3,19Hz, lH), 5.96-6.10 (m, lH), 6.90 (d, J=10
Hz, 2H), 7.96 (d, J=10 Hz, 2H).
F~ : m/e 193 (M+l).
Ste~ B: Preparation of methyl 4-hydroxy-3-(2-prop-
en-l-vl)benzoate
A solution of 15.05 g (78.3 mmol) of the
product of Step A in 25 mL of 1,2-dichlorobenzene was
magnetically stirred and refluxed (183-C) under an
argon atmosphere for 18 hours. At this point, the
reaction mixture was cooled to room temperature and
applied to a 6 cm diameter by 18 cm silica gel flash
chromatography column and eluted with 25% ethyl
acetate-hexane to ~eparate the 1,2-dichlorobenzene,
then with 40% ethyl acetate-hexane to elute the
product. The product fractions were concentrated
~n vacuo and the residual oil was crystallized from
hexane to afford 13.70 g (9lZ) of the title compound.
~ B (300 M~z, CDC13, ppm): ~ 3.42 (d, J.8 ~z,
2H), 3.8~ (s, 3H), 5.14-5.20 (m, 2H), 5.48 (s, lH),
5.94-6.06 (m, lH), 6.82 (d, J~12 Hz, lH), 7.80-7.85
(m, 2H).
F~B-MS: m/e 193 (M+l).
Step C: Preparation of methyl 4-(tert-butyldimethyl-
8ilvlo~cv)-3-(2-grogen-l-vl~benzoate
-
To a solution of 5.168 g (26.9 mmol) of the
product of Step B in 50 mL of dichloromethane was
atded 4.40 mL (2.95 mmol) of triethylamine, 4.46 g
- : . : .
'-, ~
. - . - . - .
,- WO 91/11909 2 ~ 7 ~ ~ 3 9 PCI/~S91/00963
. .
-97-
(2.95 mmol) of tert-butyldimethylchlorosilane,0.100 g
of 4-dimethylaminopyridine, and the reaction mixture
was stirred at room temperature for 2 hours. The
mi~ture was then diluted with S0 mL dichloromethane,
washed with 100 mL 1 N hydrochloric acid, dried
(MgS04), filtered and evaporated. The re~idual oil
(7.993 g, 97X) was used in the next step without
further purification.
1~ NMR (300 M~z, CDC13, ppm>: ~ O.24 (s, 6H),
lo 1.02 (s, 9~), 3.36 (d, J=8 ~z, 2~), 3.84 (s, 3~),
4.98-5.08 (m, 2~), 5.88-6.03 (m, 1~), 6.78 (d, J=ll
~z, 1~), 7.76-8.40 (m, 2~).
FAB-MS: m/e 307 (M~l).
Step D: Preparation of 4-(tert-butyldimethyl-
silvloxy)-3-(2-~ropen-1-yl)benzvl alcohol
To a magnetically 6tirred solution of 8.523
g (28.0 mmol) of the product from Step C in 35 mL of
anhydrous T~F was added 15.0 mL of a 1.Q M solution
f lithium aluminum hydride in T~F, and the reaction
mixture was 6tirred under a nitrogen atmosphere for 2
hour~. At this point, the reaction was quenched by
cautious addition of 10 mL water, the re6ulting
precipitate was dissolved by addition of 1.0 N
hytrochloric acid and the product was estracted into
ethyl acetate. The organic layer was separated,
dried (MgS04), filtered and evaporatet ~n Ya~ to
affort 7.258 g (93%) of the title compound,
1~ NMR (300 M~z, CDC13, ppm): ~ O.20 (8, 6~),
1.00 (6, 9~), 3.34 (d, Jc8 ~z, 2~), 3.84 (8, 1~),
4.57 (s, 2~), 4.97-5.07 (m, 2E), 5.88-6.03 (m, 1~),
6.86 (d, J=10 Hz, 1~), 7.05-7.14 (m, 2~).
E~ m/e 279, 261 (M+l).
wo 9~ gog 2 0 7 5 ~ 3 ~ PCT/US91/00963 ~
Preparation of 4-hydro~y-3-(2-propen-1-yl)-
benzvl alcohol
To a ~olution of approximately 7.26 g ~2.6
mmol) of crude 4-tert-butyldlmethylsilyloxy-3-(2-
propen-l-yl)benzyl alcohol, from Step D, dissolved in
50 mL of anhydrous TEF was added 26 mL (2.6 mmol) of
tetra-n-butylammonium fluoride and the reaction
mixture was stirred at room temperature for 16 hours.
The mixture was then evaporated in vacuo and the
lo residual oil was purified on a silica gel flash
chromatography column eluted with 5% methanol/chloro-
form to afford 3.386 g (79%) of the title compound as
a colorless oil.
la~ (300 M~z, CDC13, ppm): ~ 2.12 (br s, lH),
3.35 (d, J=8 ~z, 2~), 4.54 (s, 3~), 5.05-5.15 (m,
2~), 5.90 (br s, 1~), 5.90-6.05 (m, 1~), 6.70 td.
J-10 ~z, 1~), 7.02-7.10 (m, 2~).
FAL-~S: m/e 165 (M+l).
Ste~ F: Preparation of 4-hydroxy-3-propylbenzyl
To a solution of 0.370 g (2.25 mmol) of the
product o~ Step E dis~olved in 25 mL of absolute
ethanol was added 53 mg oS a 5% rhodium on carbon
2S catalyst and the misture was sha~en under a 40 psig
pressure of hydrogen on a Parr apparatus. After 30
minutes, the reaction mi~ture was removed, filtered
ant evaporated ~n Y~Q. ~he residue was purified on
a ~ilica gel flash chromatography column eluted with
35% ethyl acetate/he~ane to afford the title compound.
~ E (300 M~z, CDC13, ppm): ~ O.95 (t, J~8 ~z,
3~), 1.55-1.68 (m, 2~), 2.22 (br s, 1~), 2.57 (t, J=8
Jz, 2~), 4.56 (s, 2~), 5.93 (br 8, 1), 6.66 (d, J-10
.' .: , . . - - . .
- ~
.
,
~ Wog"llgo9 2Q7 7 ~3~ ~ :; PCT/US91/00963
_99_
~z, 1~), 7.00 (dd, J=2, 10 Hz, 1~), 7.08 (d, J=2 ~z,
1~)
FAB-MS: m/e 167 (M+l).
Ste~ G: Preparation of methyl 2-(4-hydro~ymethyl-2-
~ro~vl~henoxv~-2-~henYlacetate
To a solution of 0.484 g (2.91 mmol) of the
product of Step F di6solved in 12 mL of acetone were
added 0.667 g (2.91 mmol) of methyl 2-bromo-2-phenyl-
acetate, 0.804 g (5.82 mmol) of anhydrous K2C03 and
the mixture was stirred and heated at reflu~ for 5
hours. The mixture was then cooled, filtered and
evaporated ~n vacuo. The residual oil wa6 purified
on a silica gel flash chromatography column eluted
wi~h 30% ethyl acetate/he~ane to afford 0.756 g (83%)
of the title compound.
~ (300 M~z, CDC13, ppm): ~ O.95 (t, J=8 ~z,
3~), 1.58 (br s, 1~), 1.60-1.75 (m, 2~), 2.70 (t, J=8
~z, 2~), 3.68 (s, 3~), 4.57 (m, 2~), 5.62 (s, 1~),
6.68 (d, J=10 ~z, 1~), 7.07 (dd, J=2, 10 ~z, 1~),
7.16 (d, J=2 ~z, 1~), 7.32-7.44 (m, 3~), 7.55-7.60
(m, 2~).
E~ m/e 315 (M~l).
Step ~: Methyl 2-(4-bromomethyl-2-propylpheno~y)-2-
~henylacetate
A solution of 402 mg (1.28 mmol) of methyl2-(4-hydro~ymethyl-2-propylphenoxy)-2-phenylacetate,
from Step G, in 4 ml of C~2C12 was treated with 510
mg (1.54 mmol) of carbon tetrabromide. The solution
was stirred ~igorously under N2 at room temperature
as 403 mg (1.54 mmole) of triphenylphosphine was
: '
...
`
11909 2 ~7:~ 6 ~ ~ PCT/US91/00963 ~
--100--
added portionwise. The mixture was diluted with an
additional 2 ml of C~2C12 and stirred at room
temperature for 2 hours. Ne~t, the mixture was
filtered through Celite, and the filtrate was
concentrated Ln vacuo. Flash chromatography of the
residue on silica gel (gradient elution with 2.5-10%
EtoAc in hexane) afforded 184 mg (38%) of the product
as a gum; satisfactory purity by TLC in 98:2
C~2C12-MeO~ .
lo Mass S~ectrum (FAB): 378 (M+l)
1~ NMR (CDC13, 400 M~z, ppm): ~ O.96 (t, 3H),
1.68 (m, 2~), 2.69 (m, 2~), 3.70 (s, 3~), 4.45 (s,
2H), 5.63 (s, 1~), 6.65 (d, 1~), 7.1-7.6 (m, 7~).
~ I: Methyl 2-(4-azidomethyl-2-propylpheno~y)-2-
~henvlacetate
To a solution of 45 mg (0.12 mmol) of theproduct from Step ~ in 0.37 ml of dry DMSO was added
7.3 mg (0.15 mmol) of lithium azide. The solution
was stirred at room temperature under N2 for 4.5
hours. After flash chromatography on silica gel
(elution with 10:1 he~ane-EtOAc), 33 mg (83%) of the
title compound wa~ obtained a8 a gum; satisfactory
purity by TLC in 4:1 he~ane-EtOAc.
2S Ma8s Spectrum (FAB): 340 (M~l)
1~ NMR (CDC13, 400 M~z, ppm): ~ 0.96 (t, 3~),
1.68 (m, 2~), 2.71 (t, 2~), 3.70 (6, 3~), 4.22 (s,
2N), 5.64 (8, 1~), 6.70 (d, 1~), 7.03 (dd, 1~), 7.10
(fine d, 1~), 7.35-7.45 (m, 3~), 7.57 (dd, 2~).
- .
s 2 0 7 ~ ~ 3 9 - - Pcr/US91/00963
-101-
J: Methyl 2-(4-aminomethyl-2-propylphenoxy)-2-
~h~nYlace~te
A solution of 185 mg (0.546 mmol) of the
product from step I in 1.36 ml of T~F was treated
portionwi~e with 179 mg (0.682 mmol) of triphenyl-
phosphine. The solution was stirred at 40-C for 2
hours. Then 19.6 ~1 of H20 was added, and the
solution wa6 stirred at room temperature under N2
overnight. The solution was concentrated La vacuo,
lo and the residue was re-concentrated from CH2C12.
Column chromatography on silica gel (elution with a
gradient of 1.5-10% MeO~ in C~2C12 afforded 160 mg
(94%) of the product as a colorless oil; satisfactory
purity by TLC in 95:5 C~2C12-MeO~.
Mass S~ectrum (FAB): 314 (M+l)
1~ NMR (CDC13, 400 M~z, ppm): ~ 0.94 (t, 3~),
1.67 (m, 2~), 2.03 (br m, 2~), 2.68 (t, 2~), 3.43 (s,
2~), 3.68 (s, 3~), 5.61 (s, 1~), 6.6-7.6 (m, 8~).
St~: Ethvl valerate benzoylhyd~azone
A solution of 2.2 g (15.9 mmol) of benzoic
hydrazide in 50 ml of dry EtO~ was stirred under N2
at -10-C as a solution of 2.5 g (15.1 mmol) of ethyl
valerimidate hydrochlorlde tpreparcd by method of
2S A.J. ~ill and I. Rabinowitz, J. Am. Chem. Soc. 48,
734 ~1926)] in 50 ml of dry EtO~ was added dropwise
over about 15 minutes. Stirring was continued at
-lO-C for 3 hour8, during which time a white
precipitate separated. The cold misture was f iltered
through Celite, and the f iltrate was co-evaporated
with C~C13 at 10-C. The residue was chromatographed
twice on silica gel columns (gradient elution with
wog~ gOg 207;a639
PCT/US9l/00963
-102-
0.3-5% MeOH in C~2C12) to give 951 mg (25%) of the
title compound as a cream-colored semi-601id,
suitable for use without further purification (TLC in
97:3 C~2C12-MeO~ NMR (CDC13, 400 M~z) was
comple~, suggesting that the product iB a mixture of
syn- and anti-isomers.
Mass S~ectrum (FAB): 249 (Mll)
Ste~ L: 3-Butyl-4-[t4-[l-(carbomethoxy)-l-phenyl-
1o metho~y]-3-propylphenyl]methyl]-5-phenyl-4~-
1.2.4-triazole
To a solution of 43.2 mg (0.175 mmol) of
ethyl valerate benzoylhydrazone (from Step K) in 0.2
ml of ethanol was added a solution of 82 mg (0.262
mmol) of methyl 2-(4-aminomethyl-2-propylphenoxy)-2-
phenylacetate (from Step J) in 0.2 ml of ethanol.
The resulting solution was stirred under N2 at 50-C
for 5.5 hours. After dilution with O.4 ml of
ethanol, the solution was then stirret at ~O-C under
a condenser for 13 hour6. Next, the solution was
co-evaporated with C~C13. The residue was
chromatographed twice on silica gel columns (gradient
elution, first with 0.5-3% and then with 0.3-2% MeO~
in C~C12) to give 32 mg (37Z) o~ the title compound
a8 a whlte gla~s; homogeneous by TLC in 9:1
C~2C12-MeO~ .
Mas8 Spectrum (FAB): 49B (M+l)
la NMR (CDC13, 400 M~z, ppm): ~ 0.86, 0.90 (t,
each 3~), 1.3S, 1.60, 1.72 (m, each 2~), 2.64 (m,
4~), 3.69 (8, 3~), 5.08 (6, 2~), 5.60 (s, 1~),
6.6-7.6 (m, 13~).
.. ~ . - :
-
~ wo 9l/, ]gog ~ 0 7 5;~;3 9 Pcr/US9l/00963
-103-
Ste~ M: 3-Butyl-4-[t4-(1-carboxy-1-phenylmethoxy)-3-
propylphenyl]methyl]-5-phenyl-4~-1,2,4-tri-
azole
To a solution of 32 mg (0.064 mmol) of the
5 product from Step L in 320 ~l of TBF was added 320 ~l
(0.32 mmol) of 1~ NaOH in MeOH. The solution was
stirred under N2 at room temperature overnight and
then concentrated. The residue was dissolved in 1 ml
of MeOH and acidified to p~ l.S by addition of l~ ~Cl
10 in MeO~. This was then concentrated, and the residue
was leached with CHC13. The CHC13 e~tract was dried
over anhydrous Na2S04, filtered through Celite, and
evaporated Ln vacuo. The residue was chromatographed
on a silica gel column (gradient elution with 2-15%
15 MeOH in CH2C12) to yield 25 mg (72%) of the title
compound as a white glass; satisfactory purity by TLC
in 9:1 CH2C12-MeOB.
Mass Spectrum (FAB): 484 (M+l)
AnalvSiS (C30~33N303-2/3 C~2C12)
calculated: C, 68.20; H, 6.50; N, 7.78 and
fount: C, 68.31; B, 6.30; N, 7.93
~ (CD30D, 400 MH2, ppm): ~ 0.8-O.9S (m, 6H),
1.62, 1.59, 1.73, 2.63, 2.97 (m, each 2~), 5.40 (s,
2B), 5.71 (~, lH), 6.8-7.7 (m, 13B).
