Note: Descriptions are shown in the official language in which they were submitted.
1 This is a divisional application of Canadian
paten-t application serial number 346,685 filed on
February 29, 1980.
This inven-tion relates to novel heterocyclic
S derivatives having action on histamine receptors, to
processes Eor the preparation thereoE, to pharmaceutical
compositions containing them and to their use in thera-
peutics.
Certain novel he-terocyclic derivatives have now
been found which have potent activity as H2 ~ antagonists.
These compounds, which are more particularly described be-
low, for example show inhibi-tion of the secretion of gas-
tric acid when this is stimulated via histamine
- recep-tors (~sh and Schild, Brit, J. Pharmacol. Chemother,
1966, 27, 427). Their ability to do so can be demonstrated
in the perfused rat stomach using the method described in
German Offenlegungsschrift No. 2,734,070, modified by the
use of sodium pentobarbitone (50 mg/kg) as anasthetic in-
stead of urethane, and in conscious dogs equipped with
~eidenhain pouches using the method described by Black et al,
Nature 1972 236, 3~5. Furthermore the compounds antagonise
the effect of histamine on the contraction frequency of
isolated guinea pig right atrium but do not modify histamine
induced contractions of isolated gastrointestinal smooth
muscle which are mediated via El - receptors. ~ertain com-
pounds according to the invention have the advantage of an
extended duration of action.
Compounds with histamine H2 ~ blocking activity
may be used in the treatment of conditions where there is
an advantage in lowering gastric acidity, particularly in
gastric and peptic ulceration, as a prophylactic measure in
surgical procedures, and in the treatment of allergic and
, ~.
- ~ -
1 inflammatory conditions where histamine ls a known mediator.
Thus -they may be used :Eor example, either alone or in
comb:i.nation with o-ther ac-tive ingredlen-ts .in the treatmen-t
o:E aller~.ic and inflammatory conditions of the skin.
S ~rhe present invention provides compounds o:E the
general :Eormula (I) R3\
~_ N
~ N ~ R
1 2N Alk-Q-(C~2)nx CH2)mNH 4
and physiologically acceptable salts, hydrates and bio-
precursors thereof, in which
Rl and R2 which may be the same or diEferent, each
represent hydrogen, Cl 10 alkyl, cycloalkyl, alkenyl,
alkynyl, aralkyl, trifluoroalkyl, or alkyl substituted by
hydroxy, alkoxy, amino, alkylamino, dialkylamlno or
cycloalkyl or Rl and R2 may together with the ni-txogen atom
to which they are attached form a 5 to 10 membered ring
which may be saturated or may contain at least one double
bond, may be unsubstituted or may be substituted by one or
more Cl 3 alkyl groups, e.g. methyl or a hydroxy group and/
or may contain another heteroatom, e.gO oxygen or sulphur;
Alk represents a straight or branched alkylene
chain of 1 to 6 carbon atoms, preferably 1 to 4 carbon
atoms,
Q represents a furan or thiophen ring in which
incorporation into the rest of the molecule is through
bonds at the 2- and 5- positions, the furan ring optional-
ly bearing a further substituent R6 adjacent to the group
RlR2N-Alk-, or Q represents`a ben~ene ring in which incor~oration
into the rest of the molecule is through bonds at the 1-
and 3- or 1- and ~- positions;
R6 represents halogen or Cl 4 alkyl which may be
substituted by hydroxy or Cl 4 alkoxy;
1 X represents -CH2-, -O-, -S- or -N-
where R5 repxesents hydrogen or methyl;
n represents zero, 1 or 2;
m xepresents 2,3 or ~;
R3 represell-ts hydrogen, alkyl, alkenylr a.ralkyl,
hydroxyalk~l with at least -two carbon atoms, alkoxy-alkyl
or aryl; and
R~ represents hydrogen, alkyl, alkenyl, aryl,
aralkyl, hydroxyalkyl, acyloxyalkyl,alkoxyalkyl, or arylox-
yalkyl, aralky]oxyalkyl, aminoalkyl, alkylaminoalkyl,
dialkylaminoalkyl, hydroxy, alkoxy, alkylthio or halogen,
or the group NR7R8 where
R7 represents hydrogen, alkyl, alkenyl or aralkyl,
and R8 represents the group CORg where Rg represen-ts
hydrogen, alkyl, aryl, aralkyl, alkoxy, heteroaryl or
monocyclic heteroarylalkyl or R8 represents the group
SO2Rlo where Rlo represents alkyl or aryl, or R8 represents
the group ICI-NHRll where Y is oxygen or sulphur and
Y
Rll represents hydrogen, alkyl, cycloalkyl, aryl
or aralkyl. -N-
When X represents an oxygen atom I and
n is zero, then Q preferably represents benzene.
In particular, the present invention is directed
to a compound of the general formula (I)
3\
/N-N~ ~
1 2N Alk Q-(cH2)nx(cH2)mN~ N ~ (I)
1 and physiologically acceptable sal-ts, hydrates and bio-
precursors thereoE, in which
Rl and R2 which may be the same or difEerentr
each represent hydrocJen, CL 10 alkyl, cycloalkyl, alkenyl,
ara1.kyl, trl:Eluoroalkyl, or alkyl~ substituted by hydroxy,
alkoxy, amino, alkylamino or dialkylamino, or Rl and R2
may together wi-th the nitrogen atom to which they are
attached form a 5 to 10 membered ring which may be saturat-
ed or may con-tain at least one double bond, may be un-
substituted or may be substituted by one or more Cl 3
alkyl groups or a hydroxy group and/or may contain another
heteroatom which is oxygen or sulphur;
Al.k represents a straight or branched alkylene
chain of 1 to 6 carbon atoms
Q represents a furan or thiophene ring in which
incorporation into the rest of the molecule is through
bonds at the 2- and 5- positions, the furan ring option-
ally bearing a :Eurther substituent R6 adjacent to the
group RlR2N-Alk-, or Q represents a benzene ring in
which incorporation into the rest of the molecule is
through bonds at the 1- and 3- or 1- and 4- posi-tions;
R6 represents halogen or Cl 4 alkyl which may
be substituted by hydroxy or Cl 4 alkoxy;
X represents -CH2-, -0-, -S- or -N- where
R5
R5 represents hydrogen or methyl; n represents zero, 1 or 2,
m represents 2,3 or 4;
R3 represents hydrogen, alkyl, alkenyl, aralkyl, hydroxy-
alkyl with at least two carbon atoms, alkoxy-alkyl or
aryl; and
R4 represents hydrogen, alkyl, alkenyl, aryl,
aralkyl, hydroxyalkyl, acyloxyalkyl, alkoxyalkyl, aryloxy-
alkyl, aralkyloxyalkyl, aminoalkyl, alkylaminoalkyl, di-
alkylaminoalkyl, hydroxy, alkoxy, alkylthio or halogen.
- ~La -
1 To this end, in one of its aspects, the inven-tion
provides a process for the preparation of compounds of the
general :~ormula (I) R3
N_ N
/ ~ (I)
~ N '~\
RLR2N-Alk-Q-(CH2)nX(CH2)mNH R~
and physioloyically acceptable salts, hydrates and bio-
precursors thereof, in which
Rl and R2 which may be the same or different, each
represent hydrogen, Cl 10 alkyl, cycloalkyl, alkenyl,
aralkyl, trifluoroalkyl, or alkyl, suhstituted by hydroxy,
alkoxy, amino, alkylamino or dialkylamino, or Rl and R2
may together with the nitrogen atom to which they are
attached form a 5 to 10 membered ring which may be saturated
or may contain a-t least one double bond, may be unsub-
stituted or may be substituted by one or more Cl 3 alkyl
groups or a hydroxy group andfor may contain another
heteroatom which is oxygen or sulphur;
Alk represents a straight or branched alkylene
chain oE 1 to 6 carbon atoms
Q represents a furan or thiophene ring in which
incorporation into the rest of -the molecule is through bonds
at the 2- and 5- positions, the furan ring optionally
bearing a further substituent R6 adjacent to the group
RlR2N-Alk-, or Q represents a benzene ring in which incorp-
oration into the rest of the molecule is through bonds at
the 1- and 3- or 1- and 4- positions;
R6 represents halogen or Cl ~ alkyl which may be
substituted by hydroxy or Cl 4 alkoxy;
X represents -CH2-, -O-, -S- or -N- where
. R5
- 4b -
1 R5 represen-ts hydrogen or me-thyl; n represents zero, 1
or 2, m represents 2,3 or 4;
R3 represen-ts hydrogen, alkyl, alkenyl, aralkyl, hydroxy-
alkyl with at leas-t two carbon atoms, alkoxyalkyl or aryl;
and
R~ represen-ts hydrogen, alkyl, alkenyl, aryl,
aralkyl, hydroxyalkyl, acyloxyal]cyl, alkoxyalkyl, ary]oxy-
alkyl, aralky].oxyalkyl, aminoalkyl, alkylaminoalkyl,
dialkylaminoalkyl, hydroxy, alkoxy, alkylthio or halogen,
which comprises selecting a process from the group of
processes consisting of:
(a) for the production of compounds in which R~ represents
a halogen atom or a hydrogen atom, converting the group
-N-N Y in a diazonium salt (III)
R
IN~ N~
RlR2 N-Alk-Q~(CH2)nx(~H2)m ~ N ~ N--N Y ~III)
in which Rl, R2 and R3 are as defined in formula (I) or
are groups convertible thereto, Alk, Q, n, X and m as
defined in formula (I) and Y is the anion corresponding
to the acid used in the diazotisation reaction, into a
halogen atom or a hydrogen atom;
(b) for the production of compounds in which R4 is other
than a halogen atom or an alkoxy, alkythio or acyloxy-
alkyl group, cylising a compound of formula (V)
R
RlR2N-Alk-Q-(CH2)nX (CH2)mNH-I_NNHY' (V)
in which Rl, R2, Alk, Q, X, R3n and m are as defined in
formula (I) and V' is NCR~' and Y' is hydrogen where V is
oxygen or sulphur and R4 is a group as
- 4c -
1 defined for R~ or a group conver-tlble thereto under the
conditions of the cyclisation reac-tion or represents halo-
gen or alkoxy; or V' is NH and Y' is CR~ where Y
is sulphur, oxygen or Nll, except that when R~ is halogen
or ~lkoxy Y cannot be NM, or V' is sulphur or oxygen and
Y' is C~, with optional protection and subsequen-t de-
N~l
protection of any reactive groups in -the starting material
if clesired;
(c) reducing a compound of formula (XV)
Da_Q- (C~I2)nX(CH2)m~ DC (~V)
in which Q, n, X, m and R3 are as defined in formula (I),
at least one of Da, Db and Dc represents a reducible
group and the other(s) take the appropriate meaning
corresponding to formula (I),
D represents RlR2NAlk- or a group convertible
thereto under reducing conditions where Rl, R2 and Alk
are as defined in formula (I);
Db represents -CH2NH-, -CONH- or -CH=N-
D represents R~ as defined in formula (I) or a
group conver~ible thereto under reducing conditions, with
optional protection and subsequent deprotection of any
reactive groups in the starting material if desired;
(d) reacting a co~pound of formula (XX)
R1R2NAlkQE . (XX)
in which E represents (CH2)nX(CH2)mP or CH2P where P
and pl are leaving groups, with a triazole of the formula
(XVII)
- 4d -
1 R3
U ~ ~ ~ R~ (XVII)
N
where U represents amino, I-IS (CF12)mNEI or EIO (Cll2)mNH,
and R~ ls as deEined l.n formula (I) or is a group
convertible thereto wi.th optional protection and sub~
sequent depro-tection of any reac-tive groups in -the
s-tarting material if desired;
(e) in-troducing the group RlR2N-Alk into the group Q
presen-t in a suitable intermediate or converting another
group already present into a group RlR2N-Alk- with option-
al protection and subsequen-t deprotection of any reactive
groups in the starting material if desired;
(f) for the production of compounds in which R4 is a
secondary or tertiary hydroxyalkyl group, treating the
corresponding compound where R4 is the group (CH2)q lCHO,
(CH2)q_lCO2R12 or (CEI2)rCOR12 in which q is an integer from
1 to 6 inclusive, r is 0 to 4 and R12 is an alkyl group,
with an organometallic derivative;
(g) reacting a compound of formula (XXII)
- 3~ ~ N
/ ~ (XXII)
L Alk Q (CH2)nX (CH2)m NH ~ N ~ Lb
where eithe~ L is RlR2N and Lb is the group (CH2) L or
La is a group Ld and Lb is R4, where Lc and L are
leaving groups and q is an integer from 1 to 6 inclusive,
with a compound capable of replacing La by RlR2N or L
so as to convert Lb into the group R4 with optional
~rotection and subsequent deprotection of any reactive
groups in the starting material if desired;
- 4e -
l. (h) converting a compound of formula (I) in which R4
has a particular meaning into ano-ther compound of
Eoxmula (I) in which R4 has a di:E:Eerent meaning by standard
methods o:E interconversion;
(i) :Eor the produc-tion of compounds in which R~ is an
acyloxyalkyl group, treating the corresponding hyclroxy-
alkyl compound with an appropriate acid at elevated
temperature; or
(j) for the production of compounds in which R4 is a
hydroxyalkyl group removing a hydroxyl protecting group
from the hydroxyl group; and
(h) for the production of a sal-t of the compound of the
general formula (I), relating a process from the group
of processes consisting of the processes defined in
parts (a) to (j) hereinbefore, and converting the free
base into a salt.
The term "alkyl" as a group or a part of a
group means that the group is straight or branched and,
unless otherwise stated, has preferably l to 6 carbon
atoms, and in particular l to 4 carbon atoms, e.g. methyl
or ethyl, and the terms "alkenyl" and "alkynyl" means
that the group has preferably 3 to 6 carbon atoms.
The term "cycloalkyl" means that the group has 3 to 8
carbon atoms.
The term "aryl" as a group or part of a group preferably
means phenyl or subs-tituted phenyl, for example phenyl
substituted with one or more Cl 3 alkyl or alkoxy groups
h logeeng-;tfolrnUs~i~e~he acyl portion of an acyloxyalkyl
group means an aroyl, aralkanoyl or Cl 6 alkanoyl group.
Examples oE acyloxy,lkyl groups include acetoxymethyl,
formyloxyme-thyl, benzoyloxymethyl and phenylacetoxymethyl.
The term "heteroaryl" generally means a 5 or 6 membered
monocyclic ring or 9 or 10 membered bicyclic ring
either of which may contain 1 or more heteroatoms selected
from oxygen, nitrogen and sulphur, e.g. furyl,pyridyl,
thiazolyl, quinolinyl~ indolyl or thienyl.
According to one aspect the invention provides
compounds according to formula (I) and physiologically
acceptable salts, hydrates and bioprecursors thereof,
in which
Rl and R2 are as defined in formula (I) except
alkynyl or al]cyl substituted by cycloalkyl;
R4 represents the group NR7R8 where R7 and R8
are as defined in formula (I) except that Rg is other than
heteroaryl and Rll is other than cycloalkyl; or more
preferab]y R4 represents hydrogen, alkyl, alkenyl, aryl,
aralkyl, hydroxyalkyl, alkoxyalkyl, aryloxyalkyl,
aminoalkyl, alkyl-aminoalkyl, dialkylaminoalkyl, hydroxy,
alkoxy or halogen; provided that when X represents an
oxygen atom or -NR5- and when n is zero then Q represents
benzene.
The invention includes the compounds of
formula (I) in the form of physiologically acceptable
salts with inorganic and organic acids. Particularly
useful salts include hydrochlorides, hydrobromides, sulphates,
methanesulphona~,acetates, maleates, succinates, citrateS~tartratest
fumarates and be~oates. The compounds of formu]a ~I)
and their salts may also form h~dra-tes, which hydrates are
also to be considered as part of the invention. The
compounds of Eormula (I) can exhibit tautomerism and the
formula .is intended to cover aLl tautomers. Where
optical isomers may e~ist the formula is intended to
cover all diastereoisomers and op-tical enantiomers.
The compounds accordiny to the invention,
preferably .in the form of a salt, may be formulated for
administration in any convenient way and the invention
includes within its scope pharmaceutical compositions
containing at least one compound according to the
invention adapted for use in human or veterinary
medicine. Such compositions may be formulated in a
conventional manner using one or more pharmaceutically
acceptable carriers or excipients. Such composi-tions
may also contain if required other active ingredients
e.g. H1-antagonists.
Thus the compounds according to the invention
may be formulated for oral, buccal, topical, parenteral
or rectal administration. Oral administration is
2- preferred.
For oral administration, the pharmaceutical
composition may take the form of for e~ample, tablets,
capsules, powders, solutions, syrups or suspensions
prepared by conventional means with acceptable excipients.
25. For buccal administration the composition may take the
form of tablets or lozenges formulated in conventional
mannerO
The compounds of the invention may be formulated
for parenteral administration by bolus injection or
continuous infusion~ Formulations for injection may
be presented in unit dosage form in ampoules, or in multi-
dose containers, with an added preservative. The compositions
-7~ &~
1 may take such forms as suspensions, solu-tions or emulsions
in oily or aqueous vehicles, and may contain Eormulatory
agen-ts such as suspending, s-tabilising andJor disperslng
agents. ~l-ternatively, the active ingredient may be in
powder form for reconstitu-tion with a sui-table vehicle e.g.
sterile pyrogen-free water beEore use.
r~'he compounds of -the invention may also be Eormu-
lated in rectal compositions such as
suppos:itories or retention enemas, e.g. con-taining
L0 conventional supposi-tory bases such as cocoa butter or
other glyceride.
For topical application, the compounds of the
invention may be formulated as ointments, creams, gels,
lotions, powders or sprays in a conventional manner.
For internal administration a convenient daily dosage
regime of the compounds according to the invention would
be 1 to 4 doses to the total of some 5mg. to lg per day,
preferably 5 to 250mg per day, dependant upon the condition
of the patient.
In the compounds according to the invention,
preferably the total of m + n is 3 or 4.
Preferably Q is benzene incorporated into the rest
of the molecule through bonds at the 1- and 3- positions.
In the case where Q is benzene, preferably n is zero, X is
oxygen and m is 3 or 4. If ~ is furan, substituted furan
or thiophen, preferably n is 1, X is sulphur and m is 2.
Preferably Rl represents hydrogen or Cl ~ alkyl and
R2 represents C3_5 alkenyl, C5_7 cycloalkyl, benzyl, Cl
alkyl or Cl 4 alkyl substituted by Cl 3 alkoxy, hydroxy,
di-Cl 3 alkylamino or trifluoromethyl or Rl and R2 together
with the nitrogen atom to which they are attached form a
ring with 5 to 8 members and optionally containing one
double bond and/or substituted by hydroxy or one or two
Cl 3 alkyl group(s). More preferably Rl and R2 are Cl 3
alkyl, e.g. methyl or Rl and R2 together with the nitrogen
atom to which they are attached form a he-terocyclic ring
--8--
1 which is pyrrolidine, piperidine optionally subs-tituted in
the 4- position by Cl 3 alkyl e.g. me-thyl or hydroxy,
tetrahydropyridine, morpholine, 2,6-dialkylmorpholine,
hexamethyleneimine or hep-tamethylenimine. ~ost preferably
the he-terocyclic ring is piperidine.
Preferably R3 represen-ts hydrogen, alkyl or C2 4
hydroxyal]cyl. More preEerab]y R3 represents methyl.
PreEerably R~ represents hydrogen, al]cyl, hydroxy-
al]cyl, alkoxyalkyl, acylo~yal]cyl, aralkyl or hydroxy or
the yroup N~ICORg where Rg represen-ts hydrogen, alkyl, aryl,
he-teroaryl, or alkoxy, or the group NHCONHRll where R
represents alkyl, aryl or cycloalkyl. More preferably R~
is hydroxyalkyl, e.g. hydroxymethyl, benzyl, hydroxy,
alkoxyalkyl, e.g. methoxymethyl or -the group/NHCORg where
R9 is hydrogen, aryl e.g. phenyl, alkyl e.g. methyl, or
alkoxy e.g. ethoxy; or the group NHCONHRll where Rll is
aryl, e.g. phenyl. Most preferably R4 is hydroxymethyl,
-formylamino or acetylamino.
Pre-ferably Alk is CH2.
A particularly preferred group of compounds of
formula (I) are those of formula (II)
RlR2NCH2 _ ~ O-(CH2)m-NH ~ ~ R4
(II)
where Rl and R2 are methyl groups or together with the
nitrogen atom to w'nich they are attached form a pyrrolidino,
piperidino or hexamethyleneimino group; m is 3 or 4, R3
is hydrogen or methyl; and R4 is a hydroxyalkyl, alkoxy-
alkyl, benzyl, formamido, alkanoylamino, alkoxycarbonyl-
amino, hydroxy, aroylamino or phenylcarbamoylamino group
Particularly preferred compounds are
(1) 1-methyl-5-[[4-[3~(1-piperidinylmethyl) phenoxy]
butyl]amino]-lH-1,2,4- triazole -3-methanol
2) 1-methyl-5-[[3-[3-(1-piperidinylmethyl)
phenoxy]propyl]amino]-lH-1,2,4-triazole-3-
me-thanol.
3) N-[l-methyl-5-[[3-[3-(1-piperidinylmethyl)
phenoxy]propyl]amino]-lH- 1,2,4 triazol-3-
-yl] formamide
4) 3-methoxy--methyl-1-methyl-5-[[4-[3-(1-piper-
idinyl me-thyl) phenoxy]butyl]amino]-lE~-1,2,4-
triazole
S) 3-phenylmethyl-N-[3-[3-(dimethylaminomethyl)
phenoxy]propyl]-l~I-1,2,4-triazole-5-amine
6) 5-[4-[3-(1-piperidinylmethyl)phenoxy]butyl]
amino-lH-1,2,4-triazole-3-methanol
7) 3-phenylmethyl-N-[3-[3-ll-piperidinylmethyl)
phenoxy]propyl]-lH-1,2,4-triazole-5-amine
8) Ethyl l-methyl-5-[[3-[3-[(dimeth~tlamino)methyl]
phenoxy]propyl]amino]-lH-1,2,4-triazole-3-
carbamate
9) N-[5-[[3-[3-[(dimethylamino)methyl]phenoxy]
propyl]amino3-1-methyl-lH-1,2,4-triazole~3~yl]
benzamide
10) N-[5-[[3-[3-(1-piperidinylmethyl)phenoxy]propyl]
amino] l-methyl-lH-1,2,4-triazole-3-yl]-N -
phenylurea
25 11) 5-[[3-[3-(1-piperidinylmethyl)phenoxy]propyl]
amino~-lH-1,2,4-triazole-3-one
and their physiologically acceptable salts.
Of the above mentioned compounds, compounds Nos(l)
(2), (3) and (4) and their salts are particularly preferred.
It will be appreciated that in the methods for
the preparation of compounds of formula (I) given below,
for certain reaction steps it may be necessary to protect
various reactive substituents in the starting materials
~or a particular reaction and subsequently to remove
the protecting group. ~uch protection and subsequent
--10--
depro-tecticn may ~e particularly pertinent where Rl
and/or ~2 in intermediates used to prepare compounds
o:E formula (l) are hydrogen atoms and/or when ~3 in
in-termediates is an alkyl group bearing a hydroxy
subst:ituent and/or when R~ in certaln intermediates is
an a:lky:l group bearing a hydroxyl or a primary or
secondary amino substituent. Standard protection and
deprotection procedures can be employed, for example
formation of phthalimide (in the case of primary
amines), benzyl, benzyloxycarbonyl or trichloroethoxy-
carbonyl derivatives. Subsequent cleavage of the
protecting group is achieved by conventional procedures.
Thus a phthalimide group may be cleaved by treatment
with a hydrazine e.g. h~drazine hydrate or a prima.-y
amine, for example methylamine; benzyl or benzyloxy-
carbonyl derivatives may be cleaved by hydrogenolysis in
the presence of a catalyst,e.g. palladium, and trichlor-
oethoxycarbonyl derivatives may be cleaved by treatment
with zinc dust.
In describing theproces~swhich may be used for
preparing the compounds of formula (l) or intermediates
useful in the preparatio.n thereof, any of Rl to Rll,
Alk,Q,X,Y,nandmin the various formulae are as defined
in formula (l) unless otherwise stated.
Compounds according to formula (I) in which R4
represents a halogen atom or a hydrogen atom may be
prepared from the corresponding diazonium salt (III)
RlR2 N-Alk-Q-(c~2)nx(cH2)m ~ ~ N-N Y
(III~
39
1 in which Rl, R2 anc1 R3 are as defined in formula (I) or
are groups conver-tib~e there-to and Y is the anion
corresponding to the acid in the diazotisatiorl reaction.
Thus treatment of the diazonium salt (III) with a
concentrated mineral acid such as sulphuric acid or
hypophosphorous acid in a solven-t such as ethanol gives
the compound of Eormula (I) in which R~ represents hydro-
gen. Simllar]y the reaction of the diazonium salt (III)
with hydrochloric acid in the presence of chloride ions
e.g. aqueous cuprous chloride, at eleva-ted temperature
glves the compound of formula (I) in which R4 represents
a chlorine atom.
Compounds of formula (I) in which R4 iS the group
NR7R8 may be prepared by treating an amino triazole (IV)
R3
\ N-N
1 2 NAlk Q-(cH2)nx(cH2)mNH ~ ~ NH R (IV)
in which Rl, R2, R3 and R7 are as deEined in formula (I)
or are groups readily conver-tible -thereto with a reagent
capable of replacing the hydrogen atom in the group
NHR7 by the group R8 where R8 is as defined in formula (I).
Thus for example the aminotriazole (IV) may be
reacted with an activated derivative of either a carboxylic
acid
RgCOOH or a sulphonic acid
RloSO3H or the aminotriazole (IV) may be
reacted with an isocyanate or isothiocyanate RilNCY in
which
Rll has any of the meanings defined for Rll in
formula (I) except hydrogen or represents an alkali
metal atom such as potassium or sodium or an
alkoxycarbonyl group, e.g. ethoxycarbonyl, to give
a compound of formula (I) in which R8
(:
-12-
is respective~ the group CORg, SO2Rlo or C-NII Rll.
Suit~bLe act1vated deriva-tives include acid
halides e.g. acid chlorides, alkylchloroformates,
acid arlhydr:ides inclu~ing mi~ed anhydrides (e~g. acetic
formic anh~clride),esters such as alkyl esters, ortho
esters and (l~a]kyl-2-pyridinyl~ esters, or derivatives
~ormed frorn a coupling agent such as carbonyldiimidazole
or a carbodiimide such as dicyclohexylcarbodiimide.
The reaction with an acid halide is preferably
carried out in the presence of a ~se e.g. an inorganic
base such as sodium hydroxide or an organic base such
as triethylamine or pyridine. The reaction with an
alkylchloroformate is pre~erably carried out in the
15 presence of a base, e.g. potassium carbonate or
triethylamine, in a solvent such as dimethylformamide.
The reaction with an acid anhydride may be carried out
in the absence or presence of solvent such as pyridine.
Formylation may be effected by heating the amino-
triazole (IV) in dime-thylformamide in the presence
of a base, e.g. sodium hydride.
In the reaction with an isocyanate or isothio-
cyanate compounds of formula (I) in which Rll is other
than hyârogen are conveniently prepared by carrying
out the reaction in a solvent such as acetonitrile at
an elevated temperature,e.g. reflux. Compounds of formula
(I) in which Rll is hydrogen may be prepared by heating
the aminotriazole (IV) with an appropriate organic
isocyanate or isothiocyanate such as ethylcarbonisothio-
cyanatidate, at an elevated temperature followed byhydrolysis of the resulting ester, for example with a
base such as aqueous ethanolic sodium hydroxide.
.
Compounds of formula (I) in which R4 is other
than a halogen atom or an alkoxy, alkylthio or acyloxy-
alkyl group may be prepared by cyclisation of a compound of
formula (V)
1 2 N Alk Q (C~12)nX(CH2)mNH~C-N N~-IY' (V)
V'
in which V' is N~R'4 and Y' is hydrogen where V is oxygen
V
or sulphur and R4' is a group as defined for R4 or a
group convertible thereto under the conditions of the
cyclisation reaction or represents halogen or alkoxy;
or V' is NH and Y' is C R'4
y
where Y is sulphur, oxygen or NH except that when R4'
is halogen or alkoxy Y cannot be NH; or V' is sulphur
or oxygen and Y' is CIR4.
NH
The above process is partieularly suitable
for the produc-tion of compounds of formula (I) in which
R4 is other than NR7 R8. It should be noted that when
V' is sulphur in compound (V) this eompound is tautomerie
with the thiol (V1`).
13
RlR2N-Alk-Q-(CH2)nX(CH2)m N=IC-N NH ~ (Vl)
S~
and the corresponding S-alkyl,e.gOS-methyl, derivatives
may also be used in the cyelisation.
Thus for example compounds according to formula
(I) in whieh R4 is other than a halogen atom or an alkoxy,
alkythio, or acyloxyalkyl group may be prepared by thermal
3S eyclisation of a eompound of formula (Vll)
.
-14-
IR3
1 2 N ~lk Q(~H2)nx(cH2)mNHc N N=z ~Vll)
N-CR
V
whcre V repre~ents sulphur or more preferably
oxygerl and Z represents two hyclrogen atoms~
in the absence ~r presence o:. a solvent, e.g. acetone
or water.
It may be convenient to prepare compounds of
formula (Vll) in which Z represents two hydrogen atoms
in situ by treating a compound of formula (Vll) where
Z represents a divalent protecting group which can
readily be removed to yield two hydrogen atoms, for
example a benzylidene group, with an acid,e.g.hydrochloric
acid, preferably with heating and under such conditions
cyclisation to give compounds of formula (I) will
normally occur.
In a method for preparing the intermediate
(Vll) a compound of formula (Vlll)
RlR2NAlk Q (CEl2)nX (CH2)m NHIClL
NIClR4 (Vlll)
V
where V is oxygen or sulphur and L is a leaving group
such as alkylthio may be reacted with hydrazine R3NE~N=Z
where Z is as defined above, followed by removal
of the protecting group where necessary. Compounds of
formula (Vlll) may be prepared by treating a diamine of
formula (lX)
lR2NAlk Q (CH2)nX(CH2)m NH2 (lX)
with a compound of formula (X)
NCR4 (~)
V
,
--15--
where L and V are as defined, above.
As a Eur-ther possibility the diamine of
formula (lX) m~y be reactecl with a compound of
Eormula (Xl)
l3
LCNN=Z
~vR4 (Xl)
where L, V and Z are as defined above~ in the absence
or presence of a solvent such as acetone or acetonitrile
at a temperature oE ~rom room temperature to 70~C.
Subsequent removal of the protecting group where approp-
riate then gives the intermediate (Vll).
Compounds of formula (Xl) may be prepared by
acylating a compound of formula (Xll)
IR3
LCNN=Z (Xll)
NEI
with for examplean acid chloride R4COCl. The compound
of formula (Xll) may be prepared by treating a compound
LCL with the appropriate hydrazine
NH
R3NHN=Z.
When preparing compounds of formula (I) in
which R4 is a hydroxyalkyl group it is preferabie that in
the intermediates (Vll), (Vlll~ and (Xl) the hydroxy
groupis~protected form,e.g. as an acyloxy derivative
such as an alkanoyloxy or aroyloxy derivative. The
protecting group will normally be removed during the
cyclisation process.
In a further embodiment of the cyclisation
of compounds of formula (V) compounds of formula (I)-
B~9
-16-
in which R~ is other than a halogen atom, or an alkoxy,
alkylthio or acyloxyalkyl may also be prepared by
cyclisation of a compound of formula (Xlll)
l3
1 2NAlk Q(CH2)nX(CH2)mNHICINNHCR~ (Xlll)
where V i5 NH and Y is sulphur, oxygen or NH, or V
is sulphur or oxygen and Y is NH. The reaction is
preferably carried out by heating the compound (Xlll)
in a suitable solvent such as acetonitrile or dimethyl-
formamide.
-17-
In general intermediates of formula (Xlll) may be
prepared by methods analogous to those described in
British Patent Specification No.2023133. A.
In a particularly convenient embodiment of -the
above process an intermediate of formula (X]ll) in
whicl~ V is N~l and Y is oxygen may be prepared in situ
by the reaction oE an aminoguanidine (XlV)
l3
RlR2 N-~lk-Q-~CH2)nX (CH2)mNHICl-N-NH2
NH
(XlV)
with an acid ~ COO~ or with an activated derivative
thereof as defined above.
The acid and the amino guanidine (XlV) may be
heated together, under which conditions cyclisation of the
intermediate (Xlll) takes place directly to give a
compound of formula (I). In the case of an activated
derivative an aprotic solvent,e.g. tetrahydrofuran may
be used at temperaturesfrom ambient to re~lux. When
using an acyl chloride as the activated derivative the
reaction may also be carried out in the presence of a base
e.g. potassium hydroxide.
Compounds_of formula (I) may be prepared by
reducing a compound of formula (XV).
Da-Q-(C~2)nX(CH2)m-1 ~ N (XV
in which at least one of Da, D and Dc represents a
reducible group and the other(s) take the appropriate
meaning corresponding to formula (I).
~ f
Thus D may represent RlR2NAlk or a group
convertible ther~?to under reducing conditions;
D represents -CEI2NI1-, CONII- or -CH=N-;
and
S D represents R~ or a group conver-t.ible thereto
under reduc:ing condit:ions.
Examples oE the type of group that may be
reduced are an amide, imide, imine, ester, aldehyde,ketone
or nltrile group. Examples of the type of group D
which may be conver-ted into the group RlR2N.~lk under
reducing conditions are: an amide grouping P~lR2~CO(CH2)p
where p is 0,1,2,3,4 or 5 or Rl CONR2 ~lk - where Rl CO
represents a group which is reducible into Rl; an
aralkylidenaminoalkyl grouping; a nitrile group NC(CH2)p
where p is 0,1,2,3,4 or 5;ora~aldehyde group, When D
is analdehyde group the conversion into RlR2NAlk
under reducing conditions is carried out in the presence
of an appropriate amine RlR2NH, the reaction proceeding
by reductive alkylation,
Examples of the group Dc which may be converted
into R4 under reducing conditions are: an amide grouping
-(CH2)q lCO NRaRC where Ra represents hydrogen, alkyl,
or aralkyl~ Rc represents hydrogen or alkyl and q is an
integer from 1 to 6 inclusive with the possibility
that the alkylene chain (CH2)q_l may be straight or
branched, or an amide grouping ~(CH2)qNRaCORb where
Ra is as defined above, Rb is alkyl and CORb is a group
which is reducible into Rb and qisasdefined above with
the possibility that the alkylene chain (CH2)q may be
straight or branched; a nitrile group -(CH2)~ lCN;
an aldehyde group ~(CH2)q lCHOjan ester group ~(C~2)q 1
CO2R12 where q is as defined above and R12 is an alkyl
group,oraketone group -(CH2)rCOR12 where r`is 0 to 4 and
R12 is an alkyl group and the total number of carbon atoms
in (CH2)r and R12 is not more than 5.
~ 9 ~
1 Da and/or D may also represent an aminoalkyl
group, in which case the compound of formula (XV) is
reacted with an appropriate aldehyde or ketone under
reclucing conditions to give the group RlR2NAlk- and/or R~,
-the reaction proceeding by reductive alkylation.
~ variety of reducing agents may be used in the
above process.
Thus amides, imides, imines, esters, aldehydes,
ketones and nitriles may conveniently be reduced using for
example lithium aluminium hydride or aluminium hydride in
a solvent such as tetrahydro~uran, dioxan or diethyl ether.
Imines, aldehydes and ketones may be reduced using an
alkali or alkaline earth metal borohydride e.g. sodium
borohydride or by treatment with hydrogen and a suitable
metal catalyst such as platinum, palladium or Raney nickel,
in a suitable solvent such as an alkanol e.g. methanol
or ethanol. Imines may also be reduced using ~ormic acid.
In the particular process involving reductlve
alkylation of an amine with an aldehyde or ketone the
reaction is conveniently carried out without isolation
o~ the intermediate which is subsequently reduced using
~or example sodium borohydride, or hydrogen in the
presence o~ a suitable catalyst.
Thus in one embodiment of the reduction process
compounds of ~ormula (I) in which R4 is other than -the
group NR7R8 or acyloxyalkyl may be prepared by reduction
of an amide of ~ormula (XV) in which
Da representS RlR2NCO(CI12)P
R~CONR2Alk,
Db represents -CH2NH- and D represents R4;
or
b) Da represents RlR2NAlk, D represents
-CONH- and D represents R~; or
c) Da represents RlR2NAlk, D represents
-CH2NH- and Dc represents (CH2)q lCONRaRC
or (CH2)qNHCORb ; where p,q,Ra,R and Rb are
fi~ ~
~o
as defined above, with a suitable reducing agent
such as lithium aluminium hydride or an aluminium
hydride in a solvent such as tetrahydrofuran, dioxan ox
~iethylether.
S A particularly useful amide of formula (XV)
is that in which D represents RlR2NAlk, D represents
~-CONEI~ and D represents R4.
In a further embodiment of the reduction
process a compound of formula (xv) in which Da or Dc
is a cyanoalkyl group NC(CH2)p or (CH2)q lCN respectively
may be reduced to a compound of formula (I) in which
RlR2NAlk is a primary aminoalkyl group or R4 is a primary
aminoalkyl group (CH2)q 1CH2NH2. Reduction may be effected
using for example lithium aluminium hydride in a solvent
such as diethyl ether or tetrahydrofuran.
In a further embodiment of the reduction process
compounds of formula (I) may be prepared by reduction of
an imine of formula (XV) in which
a) Da represents an aralkylidenaminoalkyl
group, D represents -CH2NH- and D represents R4; or
b) D represents RlR2NAlk, D represents
-CH=N- and Dc represents R4; with a suitable reducing
agent such as a metal hydride, e.g. an alkali or alkaline
~rthmetal borohydride, such as sodium borohydride, in a
solvent such as an alkanol, e.g. methanol or ethanol, or
aluminium hydride or lithium aluminium hydride in a solvent
such as tetrahydrofuran or dioxan. The imine (X~7) may
also be reduced with hydrogen and a suitable metal
catalyst such as platinum, in a solvent such as an alkanol
e.g. methanol or ethanol.
A particularly useful imine of formula (XV) is
that in which Da is RlR2NAlk, D is -CEI=N- and Dc is R4.
In the above process a borohydride reducing agent
is prefera~ly used when preparing compounds in which R4
is the group NR7R8.
~L~h3~
The process involving reductive alkylation of an
amine with an aldehyde or ketone to give the compounds
of Eormula ~I),without isolation of any intermediate,
is also part oE this embodiment. Thusl fox example
compounds oE formula (I) ln which Alk represents CH2
may be prepared from the compound (XV) in which Da represents
CHO, D represents -CH2NH- and Dc represents R4, by
reaction with ammonia or an amine RlR2NH in a solvent,e.g.
tetrahydrofuran or an alkanol such as ethanol or methanol,
followed by reduction e.g. with a hydride reducing agent
such as an alkali or alkaline earth metal borohydride, e.g.
sodium borohydride, or aluminium hydride or lithium
aluminium hydride or with hydrogen and a metal catalyst
e.g. palladium or platinum.
In another embodiment of the reduction process,
a compound of formula (I) in which R4 represents a
hydroxyalkyl group may be prepared from a compound
of formula (XV) in which Dc is a group that may be
reduced to a hydroxyalkyl group,e.g. an ester, aldehyde,
or ketone, Da is RlR2N~lk and D is -CH2N~ . Thus a
compound of formula (XV) in which Dc has the meaning
(CH2)q 1 CO2R12 may be reduced using for example li-thium
aluminium hydride to give a compound of formula (I) in
which R4 is the group ~(CH2)q 1 CH2OII. Compounds of formula
25 (XV) in which D has the meaning (CH2)q 1 CHO or (CH2)rCOR12
may be reduced using for instance sodium borohydride or lithium
aluminium hydride to give a compound of formula (I) in
which R4 is the group (CH2)q_lCH2OH or (CH2)r CHOH R12
where q,r and R12 are as defined above.
In certain instances it is convenient to reduce
for example more than one of the groups Da, Db and Dc
simultaneously. Thus for example compounds of formula
(X~) in which D represents (CH2)q_lCO2R12 or (CH2)q_l
CONRaRC and D is the group -CONH- and D is RlR2NAlk may
be reduced using for example lithium aluminium hydride to
give compounds of formula (I~ in which R4 is the group
(CH2)~OH or (CH~)qNRaRC respectively, where q, Ra
and R are d~fined above.
c Amides and imines of formula (XV) where Db
is -CON~I- or -CH-N-, Da is RlR2NAlk and Dc is R~ or
a group convertible thereto may be prepared by the
reaction of an activated deriva-tive of a carboxylic
acid or aldehyde (XVl)
RlR2N-~l]c-Q-(cH2)nx(cH2)m-l G (XVl~
where G is CO2H or CHOrespectively
wi-th the appropriate amino triazole (XVll)
R3 ~ _
U ~ ~ 4 (XV~I)
where U is NH2 and R4 is as defined in formula (I)
or is a group convertible thereto,using methods
analogous to those described in British Patent
Specification No. 2023133 A.
Aldehydes and carboxylic acids of formula (XVI)
may be prepared from an appropriate starting material (XVIII)
RlR2N Alk Q (CH2)nXH (XVIII)
in which X is other than CH2.
23 -
Thus for example a compound RlR2NAlk Q OH
may be -treated with a haloalkyl nitrile Elal (CH2)m lCN
in a solvent such as dimethylformamide and in -the
presence of a base e.g. sodium hyclricle, to give the
corresponding compound RlR2NAlk Q O (CH2)m lCN.
Subsecfuent reduction usiny for example hydrogen in the
presence oE E~aney Nickel aEfords the corresponding
aldehyde which may conveniently be isolated as its
semicarbazone. The desired aldehyde (XVI) may then be
generated by treatmen-t with hydrochloric acid and aqueous
formaldehyde.
Alternatively txeatment of the compound RlR2-
NAlk Q OII with an alkyl haloester Hal (CH2)m 1CO2Alk
affords the ester RlR2NAlk Q O(CH2)m_l 2
then be hydrolysed (e.g. by using potassium hydroxide in
aqueous ethanol) to give the corresponding carboxylic
acid (XVI).
The triazole (XVII) may be prepared by
standard methods such as those described by F.Kurzer and
L.E.A. Godfrey, Angew.Chem.International Edition 2,
459-476 (1963) and K.T.Potts, Chem.Reviews 61,87 (1961).
The compounds of formula (XV) in which Da
represents RlR2NCO(CH2)p or CHO, D represents -CEI2NH
and D represents R4 may be prepared from an amine of
formula (XIX)-
W~Q-(CH2)nX-(cH2)m N~2 (XIX)
in which W represents the group RlR2NCO(CH2)p or a
protected aldehyde group e.g. a cyclic ketal such as an
ethylene ketal, by methods analagous to those already
described for preparing the corresponding compounds of formula
(I).
The compounds of formula (XV) in which Da has
the meaning RalCONR~lk- and/or Dc has the meaning
24
(C~i2)qNRaCORb may be prepared by treati.ng the
correspondirlg compouncls in which D is IINR2~1k- and/
or Dc is (CH2)~N~I~a with an activated clerivative oE the
appropria-te acid RlCO21l or Rb CO2~1.
Compounds oE formula (XV) in which Da is
aralk~liclenaminoalkyl may be prepared from the
correspondin~ amine by standard procedures.
Compounds oE formula (I) can be produced
by reacting a compound of formula (XX)
RlR2NAlk Q E (XX)
in which E represents (Cll2)nX(CH2)mP or CH2P where P
and P' are leaving groups, with a triazole oE the
formula (XVII)
whe,re U represents amino, HS(C~12)mNH or HO(CH2)m
NH, and R4 is as defined in formula (I) or is a group
convertible thereto.
Thus for example compounds of formula (I) may be
prepared by reacting a compound of formula (XX) in
which E represents (CH2)nX(~H2~mP and P represents a leaving
group such as halogen, e.g. chlorine or bromine,
sulphonyloxy,e.g. mesyloxy or tosyloxy with the
triazole (XVII) in which U represents an amino
group, the reaction being carried out in a suitable
solvent such as dimethylformamide or aceto~trile.
Compounds of formula (I) may also be prepared
by introducing the group RlR2NAlk- into the group Q
present in a suitable intermediate or converting another
group already present into a groupRlR2NAlk. Thus
compounds of formula (I) in which Alk represents a methylene
group and Q represents a furan or substituted furan
ring as defined in formula (I) may be prepared from a
compound of formula (XXI) \,
-25-
Q-(CH2)n-x-(CH2)mNH ~ (XXI)
in which Q represerlts a furan or substituted furan
riny as clefined in formula (I), by means of a Mannich
reaction with forrnaldehyde and an amine RlR2NH or
a salt ther~of. The reaction may be carried out by
reacting the amine salt with aqueous formaldehyde and
the compound (XXI) or by refluxing the amine salt
with paraformaldehyde and compound (XXI) in a suitable
solvent such as ethanol.
Compounds of formula (I) in whichRl and R2 are
both methyl, ~lk is methylene and Q represents a thio-
phen ring, a furan ring or a substituted furan ring as
defined in formula (I) may be prepared from compound
(XXI) in which Q may additionally represent a ~ Q
thiophen ring, by reaction with a compound (CH3)2N=CH2Cl
in a solvent such as acetonitrile at an elevated
temperature, e.g. reflux. The compounds of formula (XXI)
may be prepared by methods analogous to those already
described for the compounds of formula (I).
Compounds of formula (I) in which R4 is a
secondary or tertiary hydroxyalkyl group may be prepared
by treating the corresponding compound where R4 is the
2 q~ 2)q_lC02R12 or (CH2)rCORi2 in which
q,r and R12 as defined previously with an organometallic
derivative such as a Grignard reagent,e.g. a Cl 5alkyl
magnesium halide or an organolithium,e.g. alkyl lithium
reagent in a suitable solvent such as diethyl ether or tetrahydco
Intermediates in preparing the compounds of furan
formula (I) wherein R4 is a group convertible into
R4 as defined in formula (I) include aldehydes, ketones,
es~ers, amides and nitriles~ Such intermediate~ may be
prepared by methods analogous to -those already described
for preparing compounds of formula (I).
-26-
1 Compoun~s o~ formula (I) may be prepared by
reactin~ a compound of formula (XXII)
~3
/N~I\
LaAlkQ(cH2)nx(cH2)m ~ \ ~ Lb (XXII)
where either L is RlR2N and Lb ls the group (CFI2) Lc
or I,'l is a group Ld ancl I,b is R~ where Lc and Ld are
leavi~g groups~ with a compound capable of replacing
La by RlR2N or Lc so as -to convert Lb into the group R4.
Examples of the leaving group L include halogen, e.g.
chlorine or bromine, or qua-ternary ammonium, e.g. trimethyl-
ammonium and examples of the leaving group Lc include
halogen, e.g. chlorine or bromine.
The leaving group Ld may be displaced by -treatment
with an amine RlR2NH to give a compound oE formula (I).
The leaving group Lc may be displaced by treating the
compound of formula tXXII) with either ammonia or a
primary or secondary amine to give a compound of formula
(I) in which R~ is an aminoalkyl, alkylaminoalkyl or
dialkylaminoalkyl group or wi-th the anion of an appropriate
alcohol or phenol, e.g. with alkoxide, to give a compound
of formula (I) in which R~ is an ether group, e.g.
alkoxyalkyl.
The displacement of halide ions with ammonia or
an amine may be carried out in the absence or presence
of a solvent such as acetonitrile. Displacement
with the anion of an appropriate alcohol or phenol may
be effected by treatment with a suitable alkali metal
derivative, e.g. sodium methoxide, in a suitable solvent
e.g. dimethylformamide, or the alcohol corresponding to
the anion. Displacement of a quaternary ammonium group
may be effected by heating with an excess of the
appropriate amine.
Compounds oE formula (I) in which R4 has a
particular meaniny may be converted into other compounds
of the invention by standard methods of interconversion.
Thus a compound in which R4 is an alkoxyalkyl group
may be prepared by treating a corresponding compound
of formula (I) in which R~ is a hydroxyalkyl group with
for example an alkyl halide in a suitable solvent such
as dimethylformamide in the presence oE a base e.g.
sodium hydride.
According to a further possibility alkylation
(e.g. methylation) of a compound in which R4 is aprimary orsec-
ondary aminoalkyl group may be effected by treatment
with formaldehyde and formic acid (the Eschweiler-
Clarke procedure).
Compounds of formula (I) in which R4 is an
acyloxyal]cyl group may be prepared by treating
the corresponding hydroxyalkyl compound with an
appropriate acid, e.g. acetic or benzoic acid at elevated
temperatures e.g. 80-120C in the absence or presence
of a solvent such as toluene.
Compounds of formula (I) in which R4 is an alkenyl
group may be prepared from the corresponding hydroxyalkyl
compound by heating with an acid,e.g. toluene sulphonic acid,
in a suitable solvent,e.g. acetonitrile.
Compounds of formula (I) in which R4 represents
a hydroxyalkyl group may be prepared by removal of a suitable
hydroxyl protecting group. Examples of such protected
hydroxyl groups include ethers, such as trialkylsilyl
e.g. trimethyl silyl, aralkyl such as benzyl, benzhydryl
or trityl, tetrahydro pyranyl or alkoxymethyl, e.g.
methoxymethyl ethers, or esters of carboxylic acids such as
alkanoic acids e.g. formic acid or acetic acid, or
aromatic acids such as benzoic acid, or aralk~noic acids
e.g. phenylacetic acid or haloalkanoic acids such as
trifluoroacetic acid or trichloropropionic acid.
28
The pro-tecting groups may be removed by
conventional procedures c.E. Protective Groups in
Organic Chemistry 1973 eclited by J.F.I~ lcOmie.For
example benzy1 and benzhydryl ether groups may be
S removed by catalytlc hyclrogenolysls wlth for example
hydrogen ancl a pallad:ium catalyst;the -trityl,
tetrahydropyranyl,alkoxymethyl and trialkylsllyl
ether groups may be removed by acid hydrolysls.
The esters may be cleaved by acid or alkallne
hydrolysis.
The dlazonium salts (III), the
aminotrlazoles (IV~, -the amlnoguanldines (XIV) and
the compounds of formula (XX) in which E represents
(CH2)nX(CE12)mP may be prepared as described
in British Patent Specification 1~o.2023133A.
~ here the product of any of the above
processes is a free base and a salt is required, the
salt may be formed in a conventional manner. Thus
for example, a generally convenient method of
forming the salts is to mix approprlate quantities of
the free base and the acid in an approprlate solven-t(s)
e.g. an alcohol such as ethanol or an ester such as
ethyl acetate.
The invention is illustrated but not limited
by the following Examples and preparatiOnS.
29 -
In the Eollowing examples tempera-tures ~re in C
"T.l.c " refers to thin layer chromatography carried out
on silica usin~, unless otherwise stated, one of the
following solvent systems:
System A methanol 0.88 ammonia (79.1)
System B ethyl acetate: water: isopropanol-
0.88 ammonia ( 25:8:15:2)
System C ethyl acetate : ethanol :
0.88 ammonia (20:3:2)
Preparative chroma-tography was carried out on silica
using methanol as eluant unless otherwise stated.
Preparation 1
a) 4-[3~ piperidinylmethyl)phenoxy]butanal
4-[3~ piperidinylmethyl)phenoxylbutannitrile
A mix-ture o~ sodlum hydride (1.5g) and 3-(1-
piperidinylmethyl)phenol (11.2g) in dimethylformamide
(60 ml) was stirred at room temperature for 5h. 4-
Bromobutannitrile (9~Og) was added, and stirring was
continued for a further 2~h. The mixture was poured
onto ice and extracted with ethyl acetate which was
washed with water and brine, and distilled to give
the title compound as a colourless oil (14.78g) b.p.
200,0.08 mm; tlc system A Rf 0.8
4-[3-~-piperidinylmethyl)~henoxy~butanal semi-
carbazone
-
A solution o~ 4-L3-(1-piperidinylmethyl)phenoxy]
butannitrile (51.6g) sodium acetate (73.8g) and semi-
carbazide hydrochloride (77.6g) in 50~ aqueous ethanol
(lL) was hydrogenated over Raney Nickel (50g). The cata-
lyst was removed by filtration. The filtrate was partially
evaporated, made basic with potassium carbonate and
extracted with ethyl acetate. The organic extract was
evaporated to leave an oil which was puri~ied by column
-3~
ch~omatography to give the title compound asa pale
yellow oil (48.6CJ); tlc Sys-tem B, R~ 0.8.
N.M.R. (CDC13) 0.28, brs, (l~I); 2.6,s, (lI-I);
2.9,t, (lH); 3-3.4,m,(3H); 4.4, brs, (2H); 6.02,t,
(2H);6.57,s, (2il); 7.4-7.8,m, (4H); 7.95, m
(2H); 8.2-8.9,m, (8H).
4-[3-(1-piperidinylmethyl)~henoxy]butanal
4-~3-(1-piperidinylmethyl)phenoxy]butanal semi-
carbazone (9.43g) and 37~ formaldehyde (80 ml) in 2N
hydrochloric acid (80 ml) were stirred at room temperature
for 2.5h and then diluted with water. The solution was
basified with sodium carbonate and extracted with ether.
The organic extract was washed with brine, and distilled
to give the title compound as a colourless oil (5.59g)
.
b.p. 200, 0~06mm; tlc methanol Rf 0.7.
.
b) Similarly prepared from 3-[~dimethylamino)methyl]
phenol (12.08g) was 4-~3-[(dimethylamino)methyl]
phenoxy]butanal (1.05g) as a colourless oil b.p. 150,
0.06 mm; tlc System A, Rf 0.59.
Preparation 2
4-C3~ piperidinylmethyl)phenoxy~butanoic acid
Ethy~ 4-[3-(1-p~peridinYlmethy~lphenoxy]butanoa_e
A mixture of 3-~1-piperidinylmethy])phenol (11.2g)
sodium hydride (1.5g) and ethyl 4-bromobutyrate (11.7g)
in dimethylformamide (60 ml) was stirred at 25 during
20h. The mixture was poured onto ice (300g) and extracted
with ethyl acetate (3 x 100 ml). The combined ext ~lCts
were distilled to give the title compound as a colourless
oil (16.9g) b.p. 250, 0.1 mm; tlc System B, ~f 0.9
31-
4-~3-(1-pi~_idinylme-thyl)phenox~]butanoic acid
A solution of e-thyl-4-l3-(1-piperidinylmethyl)
phenoxy~butanoate (~.lg) an~ potassium hydroxide (6.0g)
in et}lanol (50 ml) and water (50 ml) w~s heated under
reflux durlng 0.5h. The cool solution was neutralised
to p~l 7 with 5N hydrochloric acid, and evaporated to
dryness under reduced pressure. The residue was
dissolved in ethanol (100 ml), filtered and the Eiltrate
was evaporated to leave a residue whichwas crystallised from
a mixture of methanol and ether to give the title com~ound
as a white crystalline solid (4.91g~ m.p. 73.5; tlc
Sys-tem B, RE 0 3
Preparation 3
Methyl 5-amino-1-meth~l-lH-1,2,4-triazole-3-
carboxylate
A stirred suspension of 5-amino-1-methyl-lH-l,
2,4-triazole-3-carboxylic acid (9.lOg) in methanol (100 ml?
was saturated with dry hydrogen chloride, and heated under
reflux for 4.5h. The cooled solution was partially
evaporated, diluted,wth water (100 ml) and the pH was
adjusted to pH 7 with potassium carbonate. The solution
was filtered, and the filtrate partially evaporated
to give the title compound as a white solid (4.60g) m.p.
190-1; tlc System B, Rf 0.6
Preparation 4
3-[3-(1-piperidinylmethyl~phenoxy]propanoic acid
_C3-~1-piperidinylmethyl~phenoxy]propannitrile
A solution of 3-(1-piperidinylmethyl)phenol
(26g), acrylonitrile (100 ml) and benzyltrimethylammonium
hydroxide (40~ methanolic solution, 5 ml) was heated at
reflux for 4Oh. The mixture was evaporated in vacuo,
diluted with ether (300 ml) and filtered. The fil-trate
was washecl with 2N so~ium hydroxide, water and distilled
to give the title ~ ound as a colourless oil (17.5g~
b~p. 170, 0.07 mm; tlc sys-tem B, Rf 0.8
3-[3~ piperidinylme-thyl)phenox~ propionic acid
A solution of 3-C3-(1-piperidinylmethyl)phenoxy
propannitrile (1.5y) in 2N sulphuric acid (115 ml)
was heatecl under reflux for 72h. The p~l of the coolecl
solution was adjusted to pH 7 and the suspension was
treated with ethanol, filtered and evaporated to
dryness. The resulting residue was extracted with hot
ethanol. Ether was added to the cooled extract to give the
title compound as a white solid (12g) m.p.l78.5-179.5; tlc
System B, Rf 0.4
Pre~ation 5
a) Meth 1 N-r2-~acetvloxv)acetvl1-1-me-thyl-2-
Y . . ~ ~ ~ ~ ~ _
~henvlmethYlene)hydrazinecarboximidothioate
MethYl l-methyl-2-(phenYlme-thylene)hydrazine-
carboximidothioate hydroiodide
A mixture of dimethyl dithiocarbamate hydroiodide
(lOg) and l-methyl-2-(phenylmethylene) hydrazine (5.4g)
was heated at 60 under water pump pressure for lh. The
residue was triturated with hot ethyl acetate (20ml) to give
the ~ (13.3g) as a yellow solid, m.p.l83.4
tlc System A Rf 0.75
Methyl N-C2-(acetyloxy)acetyl~-l-methyl-2-
(phenylmethylene)hydrazinecarboximidothioate
Methyl l-methyl-2-(phenylmethylene)hydrazine-
carboximidothioatel hydroiodide (1.34g) was dissolved in
saturated potassium carbonate solution and extracted with
ether. The combined organic extracts were dried and
evaporated to give an off-white solid which was dissolved
in acetone (25 ml) and treated with potassium carbonate
(l~lg) followed by (acetyloxy)acetyl chloride (0.85g).
The suspension was stirred at room temperature for 2h
and evaporatecl ir, vacuo. The residue was suspended in
__
water (50 ml) and fi:Ltered to c~ive the title com~ound
(1.01g) which was recrystallised from ethanol, m.p.
115-117
Found: C, 54.7; H; 5.6; N,13.4;
C14H17N3 3 q C, 54.7; H; 5.6; N,13.7%
The following compounds were similarly prepared
from the corresponding methyl-l-alkyl-2-(phenylmethylene)
hydrazinecarboximidothioate hydroiodide (A) and the
correspondlng acid chloride.
5 b) A (3.4g) and phenyl acetyl chloride (1.6g)
gave methyl-l-methyl-N-phenylacetyl-2-
(phenylmethylene)hydrazinecarboximidothioate
(1.3g) m.p. 147-8
tlc. silica; ethyl acetate Rf 0.75
preparation 6
Followiny the method of Prepara-tion 5, methyl
l-methyl-2-(pheny`me hylene) hydrazinecarboximidothioate
(20g)and ethyl malonyl chloride ~12g) gave ethyl 3-[[[1-
methyl-2-(phenylmethylene)hy~razino](methylthio)
methylene]amino~-3-oxopropanoate (5.6g)m.p. 74-5
N.m.r. (CDC13~ 2.2,s,(lH); 2.2-2.4,m,(2H); 2.5-2.7,m,
13H); 5.82,q,(2H); 6.49,s,(2H); 6.52,s,(3H3 7.6,s,~3H)
8.73,t,(3EI).
~ .
l~he following compound was prepared using the
method of Example 16:
3-[3-(1-piperidinylmethyl)phenoxy~propananamine (3.61g)
and ethyl 3-[[[1-methyl-2-(phenymethylene)hydrazino~
&~
-3~
(methylthio) methylellelamino]-3-oxopropanoate(4.7g)
gave ethyl 3-[[[1-methyl-2-(phenylmethylene)hydrazino]
[[3-[3-(1-piper:iclinylmethyl)phenoxy]propyl]amino]me-thylene]
amino]-3-oxopropanoate (7.3g)
Nmr. (CDC13) 2.1,br, (11l); 2.23,s, (lH); 2.3-2.5,m,(2H);
2.55-2.7,m,(311); 2,83,t,tlH), 3-3.3,m,(3H); 5.8,q,(2H)
5.9,t, (2H); 6.4,m,(2H); 6.53,2,(3H); 6.55,s,(2H); 6.68,s,
(2H); 7.5-8,m, (6H)i 8.5,m,(6H); 8.7,t,(3H); t.l.c. System
A Rf 0.65
10 The above ethyl ester (1.84gl was acidi~ied to give e-thyl
l-methyl-5~[[3-[3-(1-piperidinylmethyl)phenoxy]propyl]amino]
-lH-1,2,4-triazole-3-acetate (0.5g) N.m.r- (CDC13) 2.77,t r
(lH); 3-3.3,m, (31-1); 5.4,t,(lH); 5.8,q,(2H); 5.9,t,(2H)
6.3-6.6,3xs-~q, (9H); 7.6,m, (4H); 8.5,m,(6H), 8.2,t,(3H);
15 T.l.c. System A Rf 0.63
-34a-
Prepara-tion 8
5-C[3-(3-Form~ nox~propyl~amirlol-l-metilyl-lH-1,2,4-
tr ~o~ 3-me~h~lnol
e~Ll ~y~acetyl1-N'-~3-~3~ 3-dioxolan-2-
y~ henoxxl~r-opyl~-l-methx---2-(ph-enylmethylene)-hydrazine
-
arboximidalllide
A mixture of 3-[3-(1,3-dio~olan-2-yl)phenoxy]propanatnine
(2.9g~ and methyl-N-~2-(acetyloxy)acetyl]-1-methyl-2-
(phenylmethylene) hydra~inecarboximidothioate (4g) was
heated at 60 under water pump vacuum for 3h to give a glass
which was triturated with ether to give the title compound
as a white solid (5.39g) m.p. 78-80 t.l.c. silica
methanol Rf 0.8
5-c[3-(3-Formylphenoxy)propyl~amino~-l-n-l-et-yl~ L~ ~-
triazole-3-methanol
.
A suspension of N'-[2-[(acetyloxy)acetyl]-N'-[3-[3-(1,3-
dioxolan-2-yl)phenoxy]propyl]-1-methyl-2-(phenylmethylene)-
hydrazinecarboximidamide (Sg) in 2N hydrochloric acid
(lOOml) and ethanol (25ml ) was stirred at room temperature
for 16 h. The solution was neutralised to pH 7 with potassium
carbonate, treated with potassium hydroxide (1.7g) diluted with
ethanol (50 ml) and stirred for a further 15 min. The pH
of the solution was adjusted to pH 7 with 2N hydrochloric acid,
and the solvent was partially evaporated to leave an aquecus
solution which was extracted with ethyl acetate. The
combined organic extracts were dried and evaporated to give
the title compound as a foam 12.63~) t.l.c. silica ethyi
acetate:methanol: 2:1 Rf 0.5,nmr (CDC13) O.OO,s, (lH);
2.5 - 2.9,m, (4H); 5.4,t, (lH); 6.4,q,(2H); 6.50,s,(3H);
7.85,m, (2H).
-35
1 E a ple 1
a) 3-me-thyl-N-[3-[3-(N,N~dimethylaminomethyl)
___ __
phenoxy]propyl]-EI-1,2,_-triazole-5-amine
A mixture of 3-~3-am;nopropoxy)-N,N-dime-thyl-
benzencmethanamine (A) (2.0g) and methylisothio
semicarbazide hydroioclicle (2.24g) was heated at 40 Eor
6h. The residual gum was dissolved in ethanol and treated
with a solution oE tartaric acid in ethyl aceta-te. The
solid that precipitated was filtered oEf and heated under
reflux in glacial acetic acid (lS ml) for 4 h. The mixture
was cooled, basified with potassium carbonate and extracted
with ether. The organic extract was purified by column
chromatography to give -the title compound after recrystal-
lisation from a mixture of ethyl acetate and light
petroleum (b.p. 60-80) as a buEf solid (0.8g) m.p.
133-133.5 . tlc System A,Rf 0.58.
The following were similarly prepared from the
appropriate acid, the appropriate diamine and
methylisothiosemicarbazide hydroiodide (B).
b) Diamine A (1.46g), B (2.75g) and phenyl acetic acid
(3.0g) carrying out the reaction with the acid in refluxing
ethanol (50 ml) for 72 hr, gave 3-phenylmethyl-N-[3-~3-
[(dimethylamino)methyl]phenoxy]propyl~-lH-1,2,4-triazole-
- 5-amine (0.06g) m.p. 140-141. tlc System A,Rf 0.49
c) Diamine A (1.46g), B (1.73g) and benzoic acid (5.g)
carrying out the reaction with the acid by heating at 140
for 12 hr gave 3-phenyl-N-[3-[3-~(dimethylamino)methyl]
phenoxy]propyl]-1~-1,2,4-triazole-5-amine (0.62g) m.p.
126.5-127.5 tlc System A,Rf 0.48.
d) 3-[3-(1-piperidinylmethyl)phenoxy]propanamine (4.96g),
B(4.94g) and phenyl acetic acid (8.16g) carrying out the
reaction with the acid in refluxing toluene (20ml) for 6 hr
gave 3-phenylmethyl-N-~3-[3-(1-piperidinylmethyl) phenoxy]
propyl]-lH-1,2,4-triazole-5-amine (1.3g) m.p. 143-4
tlc System A,Rf 0.5.
36
Example 2
a) I-(N, _ imethylaminomethyl)
pheno~ylprop~ ,2,4-triazole -5-amine
___ _.
A sollltion of sodium nitrite (1.74y) in water
(15 ml) was adc1ed clropwise to a solution of l-methyl-
N -C3-[3-(N,N-dimethylaminomethyl)phenoxy]propyl] lEI
-1,2,4-triazole-3,5-diamine (Sg) in concentrated
sulphuric acid (3.6~g) and ethanol (200 ml). The
reaction mixt~re was heated at 65 for 4h, cooled,
treated with saturated brine (100 ml) and extracted
with ethyl acetate. Evaporation of the organic
extract gave a re~ oil which was extracted with ether.
Distillation of the ether extracts gave the title
compound as a pale yellow oil (1.8g) b.p. 190
(0.04 mm). tlc System A,Rf 0.6.
The following compounds were similarly prepared:
b) l-methyl-N5-[3-[3-(1-piperidinylmethyl)phenoxy]
propyl]-lH~1,2,4-triazole-3,5-diamine (1.72g) gave
l-methyl-N-[3-[3-(1-piperidinylmethyl)phenoxy~propyl~
-lE~-1,2,4-triazole-5-amine (1.25g) as a yellow oil;b.p.
220, 0.08 mm; tlc System B, Rf 0.5.
c) l-methyl-N5-[3-[3-[(hexamethyleneiminyl)methyl]
phenoxy]propyl-lH-1,2,4-triazole-3,5-diamine (1.79g)
gave l-me-thyl-N-[3-[3-[(hexamethyleneiminyl)methyl]
phenoxy]propyl]-lH-1,2,4--triazole-5-amine (500 mg)
b.p. 240 0.15 mm; tlc System B, Rf 0.75.
Exam~le_3
a) 3-chloro-1-methyl-N-~[3-(N,N-dimethylaminomethyl
~noxylpro~l]-lH-l,2,4-triazole-5-amine
. _
A solution of sodium nitrite -(0.46g) in wa-ter
(1.5 ml) ~as added dropwise to a solution of 1-
methyl-N5-[3-[3-(N,N-dimethylaminomethyl)phenoxy]propyl~
-1~l-1,2,4-triazole-3,5-diamine (2.0g ) in concentrated
-31-
hydrochloric acid a-t 5. This solution of the
diazoniurn salt w~s ac1decl to a solution o~ cuprous
chloride at 75 [prepared by adding a solution
of sodium metabisulphi-te (0.41g) and sodium hydroxide
(0.27g) in w~ter (3 ml) to a hot solu-tion of copper
sulphate (1.89g) and sodium chloride (1.61g) in water
(6 Ml) ].
Concentrated hydrochloric acid (S4 ml) was added
to the reaction mixture which was allo~ed to stand at
25 for 12h, cooled, basified with sodium bicarbonate
and extracted with ethyl acetate. Distillation of the
organic extract gave the title compound as a pale yellow
oil (1.23 g) b.p. 225 (0.04 mm). tlc System A,Rf 0.64.
b) Similarly prepared from l-methyl-N5-[3-[3~1-pip
eridinylmethyl)phenoxy~ propyl]-l~I-1/2,4-triazole-3,5-
diamine (11.3g) was 3-chloro-1-methyl-N-L3~[3-(1-
piperidinylmethyl)phenoxy]propyl]-lH-1,2,4-triazole-5-
amine (3.05y) b.p. 250, 0.06 mm, tlc System B,Rf 0.8
Example 4
a) N-[~-~3-[(dimethylamino)methyl]phenoxy]butyl7-
- 3-phenylmethyl-lH-1,2,4-triazole-5-amine
A solution of 4-~3-[(dimethylamino)methyl]phenoxy]
butanal (0.5g) and 3-phenyl methyl-1~-1,2,4-triazole
-5-amine ~0.39g~ in dry toluene (60 ml) was heated
under reflux during 3h. The solvent was evaporated
and replaced with methanol (50 ml). Sodium borohydride
(0O4g) was added and the mixture was stirred at 20
during 2h. The methanol was evaporated and the residue
partitioned between water and ethyl acetate. The organic
extract was evaporated and the residue was purified
by column chromatography to give the title compound, which
~39-
crystallised from a mixture oE ethyl aceta-te and
cyclohexane as pale yellow crystals (0.09g) m.p.
131--3; tlc system A,Rf 0.6.
The Eollowing compounds were similarly prepared
frorn the appropriate aldehyde and aminotriazole:
b) 4-[3-(l~piperidinylmethyl)phenoxy]butanal (0.4g),
3-methyl~ 1,2,4-triazole -5-amine (0.15g) and sodium
borohydride (0.4g) gave 3-methyl-N-[4-~3-(1-piper-
idinylmethyl)phenoxy~butyl]-lH-1,2,4-triazole-5-amine
t50 mg) m.p. 138-9; tlc System A, Rf 0.64
c ) 4 - L 3-(1-piperidinylmethyl)phenoxy]butanal (0.5g)
3-phenylmethyl-lH-1,2,4-triazole-5-amine (0.33g) and
sodium borohydride (0.4g) gave 3-phenylmethyl~N-~4-[3-
(1-pipericlinylmethyl)phenoxy]butyl~-lH-1,2,4-triazole-
5-amine (0.16g) m.p. 145-6 tlc. System A, Rf 0.6.
Example 5
-
a) 3-(2-phenylethy~-N-[4-~3-(1-piperidinylmethyl)
henoxvlbutYll-lH-~2,4-triazole-5-amine
~ ~
~3-(~Phenvleth~l)-lH-1,2,4-triazol-5-Y11-4r3-
~ ~ , ~
( i eridinvlmethYl) phenoxYlbutanamide
P- P ~ _ ~
A solution of 4-[3-(1-piperidinylmethyl)phenoxy]
butanoic acid (l.Og)~ thionyl chloride (1 29g) and
dimethylformamide (6 drops) in methylene
chloride (50 ml) was stirred at 25 during 5h. The
solvent was evaporated and the residue was dissolved in
methy]ene chloride (50 ml). 3-phenylethyl-lH-1,2,4-triazole
-5-amine (0.68g) was added and the mixture was stirred
at 25 during l~h. The solvent was removed and the residue
was diluted with water (50 ml). The pH of the aqueous
solution was adjusted to pH8with sodium bicarbonate and
extracted with ethyl acetate. The combined organic
extracts were evaporated and the residue was heated at
-39-
155 during 2il. The resulting solic~ was triturated
under ho-t methanol to give the title compound (0.5g)
as a white powder m.p. 192-3 tlc 'iystem A,R~ 0.62
3-(2-phe~ t~ )-N-~4-[3-(1-piperidinylmethyl)
~henoxxI~ _ ~ Il-1,2,4-triazole-5-amine
~ suspension of N-[3-(2-phenylethyl)-lEI-1,2,4-
triazol-5 yl]-4-L3-(1 piperidirlylmethyl)phenoxy]
butanamide (0.4g) and lithium aluminium hydride ~0.33g)
in dioxan (50 ml) was heated under reflux in a nitrogen
atmosphere during 12h. The cool mixture was quenched
with water (50 ml) and extracted with ethyl acetate.
The combined organic extracts were evaporated and the
residue was crystallised from ethyl acetate to give the
title compound as a white solid (0.23g) m.p. 146-7
tlc System A, Rf 0.71.
The following compounds were similarly prepared
from 4-[3~ piperidinylmethyl)phenoxy]butanoic acid
(A) and the corresponding tria201es:
b) A (l.Og) and 3-methylthio-lH-1,2,4-triazole-5-
amine (0.47g) gave 3-methylthio-N-[4-[3-~1-piper-
idinylmethyl)phenoxy]butyl]-lH-1,2,4-triazole
-5-amine (O.lg)~ m.p. 122-3
tlc System A R~ 0.73
c) A (l.Og) and 3-(2-methylpropyl)-lH-1,2,4-triazole-
5-amine (0.68g) gave 3-(2-methylpropyl)~N-[4-
~3-(1-piperidinylmethyl)phenoxy]butyl]-lH-1,2,4-
triazole-5-amine (0.08g), m.p. 141-142~.
N.m.r. (CDC13) 2.78,t,(1H); 3.0-3.3,m,(3H); 5.02,
br, (lH); 6.0, m,(2H);6.60, s+m, (4H); 7.2-8.8,
m,(l8EI); 9.05,d,(6H)~
_40-
_a
5-~4-[~ dinylmethyl)~henoxyI~utyl~amino~
l.l~-1,2,4-triazole~3-methanol
~ [3-(1-p.iperidin~lmethyl)~henoxy~bu-tyl]
ami.no-llH,~,4-triazole-3-carbox~late
Methyl 5-amino-1ll-1,2,4--triazole-3-carboxylate
(0.568g) and 4-[~-(1-piperidinylmethyl)phenoxy~butanal
in ethanol (40 ml) were heated at reflux for 2h. The
cooled reaction mix-ture was treated with sodium boro
hydride ~0.4g) and stirred at room termperature for 15h.
The solvent was evaporated and the residue was dissolved
in 2N hydrochloric acid which was washed with ethyl
acetate, basified with sodium carbonate and extracted
with ethyl acetate. The'combined organic extracts were
evaporated to yield the title compound as a white solid
which was recrystallised from a. mixture of ethyl acetate
and ethanol (1:1) .(0.5g) m.p. 170-1 dec.; tlc System
B, Rf 0.8.
~ 4-[3~ iperidinylmethyl)phenoxyl_ut~l~amino-
lH-1,2,4-triazole-3-methanol
A mixture of ethyl 5-[4-[3-(1-piperidinylmethyl)
phenoxy]butyl~amino-lH-1,2,4-triazole-3-carboxylate
(0.3g) and lithium,aluminium hydride (O.lg) in tetra-
hydrofuran (50 ml) was stirred at room temperature for
0.5h, then quenched with water. The solid was-filtered
off and washed with methanol. The filtrate and washings
were evaporated to leave a residue which was extracted
with hot ethyl acetate. Evaporation of the extract
gave an oil that solidified. It was crystallised from
ethyl acetate to give the title compound as an off-white
solid (0.094g) m.p. 127-8 dec. tlc System B, Rf 0.7
Example 7
l-meth~ 5-C~4-~3~(1-piperidirlv _~'. y ]
butyl]amino~ 1,2,4-triazole-3 methanol
Methyl l-methyl-5-~[l-oxo-4-c3~ E~r 1DYI-
methyl)phenox ~ yl~aminoJ-lEI-1,2,4-triazole
-3 ~
A solution of A-[3-(1-piperidiny:Lmethyl)phenoxy3
butanoic acid (2.77q), thionyl chloride (2.5 ml) and
dimethylformamide (6 drops) in methylene chloride (80 ml)
was stirred at room temperature for 2h. The mixture was
evaporated in vacuu. The resulting solid was dissolved
in dimethylformami~e (50 ml) and treated with methyl
5-amino-1-methyl-lH-1,2,4-triazole-3-carboxylate (1.56g)
After 18h at room temperature, the mixture was evap-
orated in vacuo and the residue was dissolved in water.
The combined organic extracts were washed with water and
evaporated in vacuo. The resulting solid was recrystall-
ised from a mixture of ethyl acetate and cyclohexane
to yield the title compound as a white powder (2.0g)
m.p. 108-10 tlc System B, Rf 0.7
l-Methyl-5-[[4-[3-(1-piperidirlylmethyl?phenoxy~
butyl] amino~-lH-1,2,4-triazole-3-methanol
A suspension of methyl l-methyl-5-~[1-oxo-4-[
3-(1-piperidinylmethyl)phenoxy3butyl]amino~-lH-1,2,4-
triazole-3-carboxylate (1.25g) and lithium aluminium
hydride (l.Og) in tetrahydrofuran (30 ml) was stirred
under nitrogen at room temperature for Sh, cooled to
0 and quenched with water. The mixture was diluted
with ethyl acetate, filtered and the filtrate was
evaporated in vacuo. The residue was chromatographed
to give an oil, which crystallised on trituration with
ether to yield the title compound as a white solid
~0.33g) m.p. 84-5, tlc System B,Rf 0.6
Exam~l~ 8
1 ethyl ~ piperidinylmethyl)phenox~7
-1,2,4-triazole-3-methallol
~ stirred suspension oE 3-C3-(1-pipericlinylmethyl)
phcnoxy]propano:ic acicl (].34g~ :in methylene chloride
(50 ml) and dimethylformamide (5 drops) was treated with
thionyl chloricle (2.0 ml). The solution was maintained
for 2h at room temperature and then evaporated ln
vacuo. The oily product was dissolved in dimethyl-
10 ~ formamide (50 ml) and treated with methyl-5-amino-1-
methyl~lH-1,2,4-triazole-3-carboxylate (1.09g). The
reaction mixture was stirred at room temperature for
16h, evaporated in vacuo, the residue was dissolved
in 8% sodium bicarbonate solu-tion and washed with
ethyl acetate. The organic extracts were washed with
water and evaporated in vacuo to give methyll-methyl-5-[[1-oxo
' ~4-[3-(1-piperidinylmethyl)phenoxy]propyl]amino-lH-l,
2,4-triazole-3-carboxylate as an oil (0.832g) which was
dissolved in tetrahydrofuran (30 ml) and treated with
lithium aluminium hydride (0.6g) at 0, The mix-ture
was stirred at room temperature for 6h, then quenched
with water, diluted with ethyl acetate and filtered.
The filtrate was evaporated in vacuo to yield an oil
(0.586g), which was purified by colun~nchromatography
to give an oil, which crystallised on trituration
with ether to yield the title compound (0.136 mg) as
a white solid m.p. 118-9 tlc System B, Rf 0.7
Exam~e 9
a) N-[5-[~3-[3-~(dimethylamino)methy~l~henoxy~
pro~yl] amino~-l-methyl lH=1~,4-triazol-3-yl]-N'-
methylthiourea
A solution of l-methyl-N5-[3-~3-~,(dimethylamino)
-~3- ~
1 methyl]phenoxy]propyl]-lH-1,2,4-triazole-3,5-diamine (A)
(l.Og) and methyl isothiocyanate (0.24g) in dry
ace-toni-trile was heated under reflux for 48 houxs. rl'he
solvent was removed and the residual oil purified by
colum chromatography The residue was dissolved ln ethyl
aceta-te. A solution oE tartaric acid in ethyl aceta-te was
added to give -the title compound as the tartrate salt as
a white powder (0.22g). tlc System A Rf 0.51. NMR
(free base) CDC13, 0.4 brs. (lH); 2.78 t (lH); 3.0-3.3 m
(3H); 4.77 t (lH); 5.90 t (2H); 6.46 s-~q (5H); 6.60 s
(2M); 6.~0 d (3H); 7.76 s (6H); 7.90 m (2H).
The following compounds were similarly prepared
from the appropriate aminotriazole and isocyanate.
b) Aminotriazole (l.Og) and methylisocyanate (0.2g)
gave N-[5-[[3-[3-[(dimethylamino)methyl]phenoxy]propyl]
amino]-l-methyl-lH-1,2 r 4-triazol-3-yl]-N'-methylurea
tartrate (1.2g). tlc System A, Rf 0.55. NMR (free base)
(CD C13) 1.48,s, (lH); 2.10,q,(lH); 2.77,t, (lH);
3.0-3.3,m, (3H); 5.0,t, (lH); 5.9,t, (2H); 6.43,q,(2H);
6.48,s, (3H); 6.62,s,(2H); 7.15,d,(3H); 7.77,s,(6H);
7.9,m, t2H)
c) l-methyl-N5-~3-[3-(1-piperidinylmethyl)phenoxy]
propyl]-lH-1,2,4-triazole-3,5-diamine (B) (1.5g) and
phenylisocyanate (0.52g) gave N-[5-[[3-[3-(1-piperidinyl-
methyl) phenoxy]propyl]amino]-1-methyl-lH-1,2,4-triazol-3-
yl]-M'-phenylurea (1.07g) m.p. 137-9 (from ethyl acetate)
tlc System A, Rf 0.57.
d) Aminotriazole (B) (1.5g) and cyclohexylisocyanate
(0.64g) gave N-[5-[[3-[3-(1-piperidinylmethyl)phenoxy]
propyl]amino]-1-methyl-lH-1,2,4-triazol-3-yl]-N'cyclo-
hexylurea (0.43g) m.p. 129-130 (from cyclohexane). tlc
System B, Rf 0.6.
1 e) l-methyl~ 2-[[[5-[ldime-thylamino)methyl]-~-
methyl-2-f~lranyl]methyl]thio]ethyl]-lH-1,2,4-triazole-3,
5-diamine ~lg) and phenylisocyana-te (0.35 ml) gave N-[5-
[[2-[[[5-[(dimethylamino)me-thyl]-4-me-thyl-2-Euranyl~
methyl]thio]ethyl]amino]-1-methyl-lH-1,2,~-triazol-3-yl]-
N'-phenyLIlrea (0.65g) m.p. 166-7 (from acetonitrlle
methanol) tlc System ~ (79.1) Rf 0.5
f) l-methyl-N5-[2-[[15-(dimethylamlno)methy]]-2-Euranyl]
methyl]thio]ethyl]-lH-1,2,4-triazole-3,5-diamine (3 1g) and
methyl isocyanate (O.g7g) gave N-methyl-N'-[l-methyl-5-
[[2-[[[5-[(dimethylamino)methyl]-2-furanyl]me-thyl]thio]
ethyl]amino~-lH-1,2,4-triazole-3-yl]urea as a gum (2.5g)
tlc. System C Rf 0.41. NMR (CDC13) 1.70,s,(lH); 2.15,
br q (lH); 3.92,s,(2H); 5.06,t,(lH); 6.52,s,(3H); 6.63,
s~q, (4H), 7.20,d-~t,(5H);7.80,s, (6H).
Example 10
Ethyl l-methyl-5-[[3-[3-(N,N-dimethylami'nome'thyl)
phenoxy]propyl]amino]-lH-1,2,4-triazole-3-carbamate,
-tartrate
A solution of ethyl chloroformate (0.6 ml) and 1-
methyl-N5-[3-[3-(N,N-dimethylaminomethyl)phenoxy]propyl]
~lH-1,2,4-triazole-3, 5-diamine (2.0g) in dry
dimethylformamide (30 ml) was stirred at 25 for 12 h.
The reaction mixture was diluted with water and extracted
with ethyl acetate. The organic extracts were evaporated
to lea~e a yellow oil which was triturated with'a mixture
of ether, ethyl acetate and light petroleum ~b.p. 60-80 ).
Insoluble material was filtered off and the residual oil
dissolved in ethyl acetate. A saturated solution of
tartaric acid in ethyl acetate was added until no more
-45-
precipitate ~as formed, to give the title com~ound
as a white solid ~Or88g) m.p. 110-115 tlc Sys-tem
A, Rf 0~61.
b) Similarly prepared from l~me-thyl-N5-~3-r3-
(1-piperidinylmethyl)phenoxy]propyl]~lH-1,2,4-triazole-3,5-
diamine (5g) and ethyl chloroformate (1.56g) was e-thyl
[l-mel:hyl-5-C~3--~3-(1-piperidinylmethyl)phenoxy]propyl
amino~-lH-1,2,4-tr:iazol-3-yl]carbamate tartrate (0.85g)
m.p. 82 N.m.r. (D20) 2.51,m, (lH); 2.7-3.1,m, (3H);
5.42,s,(2H); 5.5-6,m, (6H); 6.3-6.7 m-~s, (7H); 6.8-7.3,
m, (2H); 7.6-8.6,m, (8H); 8.71,t, (3H).
_xam~e 11
a) ~ [3-~(dimethylamino)methyl]phenoxy]
~r ~ n~ -1-methyl-lH-1,2,4-triaæol-3-
yl] acetamide, tartra_
Acetlc anhydride (0.35g) was added dropwise to a
solution of l-methyl-N5-[3-[3-[(dimethylamino)methyl]
phenoxy]propyl]-lH-1,2,4-triazole-3,5-diamine (A) (lg)
in dry pyridine and the reaction was stirred at 25~ for
12h. Solveni was removed and the residue was dissolved
in ethyl acetate, washed with aqueous saturated sodium
caxbonate solution, dried and evaporated. The residual
oil was puri~ied by chromatography and treated with a
solution of tartaric acid in ethyl acetate to give the
title com~und (1.2g)m.p. 103-5 tlc System A,Rf 0.5
The following compound~ were similarly prepared from
the appropriate diamine:
b) 1-methyl-N5-C3-[3-~-piperidinylmethyl)phenoxy]
propyl]-lH-1,2,4-triazole-3,5-diamine (B) (2.5g) and
acetic anhydride (0.75g) gave N-[5-~3-[3-~(1-
piperidinylmethyl)phenoxy]propyl]amino~-l-methyl-lH-l,
2,4-triazole-3-yl]acetamide, tartrate (2.7g) m.p. 90
~6
(softens) tlc System A, Rf 0.6.
c) Diamine (~) (l.Og) and me-thanesulphonic
anhydride (0.59g) gave 5-[[3-C3-(1-p:iperidinylme-thyl)
phenoxy]propyl]amino~-l-methyl-lH-1,2,~-triazole-3-
sulphamic acid, methyl es-ter, methane sulphonate (1.2g)
m.p. 130-1~. tlc Systern A, RE 0 54
d) Diamine (A) (lg) and benzoic anhydride (0.8g) gave
N-[$~[[3-[3-[(dimethylamino)methyl]phenoxy]propyl]amino]
-l-methyl-lH-1,2,4-triazol-3-yl]benzamide, tartrate
~0.48g) m.p. 126-130. tlc System A,Rf 0.47.
e) l-methyl-N -[2-[[[5-[(dimethylamino)methyl]
2-furanyl]methyl]thio]ethyl~-lH-1,2,4-triazole-3,5-dia-
mine (1.9g) and benzoic anhydride (1.2g) gave N-[l-
methyl-5--[[2-[[~ 5-[(dimethylamino)methyl]-2-furanyl]
methyl]thio]ethyl]amino]-lH-1,2,4-trlazol-3yl]
benzamide (0.95g). tlc System C, R~ 0.45.
Found: C, 57.7; H, 6.4; N, 19.8
C20~I26N6 2 q C, 58.0; H, 6.3; N, 20.3~
f) 1-methyl-N5-[2-[[[5-[(dimethylamino)methyl]-4-
methyl-2-furanyl]methyl]thio]ethyl]-lH-1,2,4-triazole-
3,5-diamine (0.96g) and benzoic anhydride (l.OgJ gave
N-[l-methyl-5-[[2-[[[-5-[(dimethylamino)methyl]-4-methyl-
2-furanyl]methyl]thio~ethyl]amino]-lH-1,2,4-triazol-3-
yl~benæamide (0.6g). tlc System C, R~ 0.42 N.m.r. (CDC13)
O.90,s, (lH); 2.10,m,(2H); 2.5,m,(3H); 4.06,s,(lH);
5.10,t,(lH); 6.43,s,(2H); 6.52,s,(3H); 6.68,s+q,(4H);
7.32,t,(2H); 7.82,s,(6H); 8.10,s, ~3H)
g) l-methyl-N5-C2-~[5-~(dimethylamino)methyl]-2-
thienyl]methyl]thio]ethyl]-lH-1,2,4-triazole-3,5-
diamine (0.98g) and benzoic anhydride (l.Og) gave
~7_
N-[l-methyl-5-[[2 ~[[5-[(dime-thylamino)methyl]-2-
thienyl]methyl]thio]ethyl] amino]-l~l-l,2,4-triazol-
3-yl]benzam:ide (0.5g). tlc Sys-te~ C, Rf 0.46
N.m.r. (C~Cl3) l.021br.s,(lH); 2.07,m,(2~1); 2.5,m,(3H);
3.30,m, (2H); 5.43,t, (lH); 6.18,s,(2M); 6.5,2s-~q,
(711); 7~28,t,(2EI); 7.77,s,(6H).
Exarnple 12
N~ methyl-5-[~3 13-1l piperidinylmethyl)
phenoxy~propyl~amino~-lH-l~2~4-tr_azol-3-y
~ormamlcle
A mixture of sodium hydride (0.72g) and l-methyl-
N5-[3-[3-(l-piperidinylmethyl) phenoxy3propyl]-lH-l,
2,4-triazole-3,5-diamine (3.44g) in dimethylformamide
(50 ml) was heated under reflux for 8h. The reaction
mixture was cooled, poured onto water (300 ml) and
extracted with ether. Evaporation of the organic
extract gave a yellow oil, which was extracted with
boiling cyclohexane (500 ml). As the cyclohexane
extract cooled a brown oil precipi-tated out. This oil
was discarded and the supernatant solution was cooled
to room ternperature to give the title compound which
was recrystallised from a mixture of ethyl aceta-te
and light petroleum (b.p.60-80) as a pale yellow solid
(0.35g) m.p. 68-75 (decomposition). tlc,
System C Rf 0.6
Example 13
N-[l-methyl-5-~2-~[C5-[(dimethylamino)methyl~ -
-2-uranylLmethylLthio]ethyl]amino~_lH_l~,4-
triazol-3- ~ rormamide
A stirred suspension of l-methyl-N -[2-[[[5-
tdimethylamino)methyl -2-furanyl]methyl]thio3ethyl]-lH-
l,2,4-triazole~3,5-diamine, dihydrochloride (3.83g' and
potassium carbonate (3.04g) in acetone (60 ml) was heated
at reflux for 30 min, and then cooled to 5C. Aceticformic
_~8~
anhydride (1.32g) was added and the suspension was
allowed to warm up to room -tempera-ture~ The inorganic
material was ~iltered off and the solution evaporated
to give an oil which was chromatoyraphed. I'he
resulting oil was dissolved in ethyl ace-tate, washed
with saturatecl aqueous sodium bicarbonate and
evaporatecl to aEforcl the ~ _d (0.47g) as a
colourless oil~ tlc System B, R~ 0.61.Nmr. (CDC13)
0.28 brd, (lH); 0.93 d, (lH); 3.81,s,(2H);
5.25, brt (lH); 6.28,s, (2H); 6.47,s,(3H); 6.52 s~m
(2H~; 7.16,t, (2H) 7.74,s, (6H).
Fxam~le 14
N-El-methyl-5-~C3- L3-(1-piperidinylmethyl)~henoxy]
~op~l~amino~-lH-1,2,4-triazol-3-~1]-2-furancarb-
oxamide
a) A solution oE l-methyl-N~-[3-[3-(1-piperidinyl-
methyl)phenoxy]propyl]-lH-1,2,4-triazole-3,5-diamine
(A) (l.Og) and 2-furancarboxylic acid, chloride
(0.42g) in pyridine (25 ml) was kept at ambient temperature
for lh. The pyridine was evaporated in vacuo and the
residue was azeotropically distilled with toluene to
give an oil which was partitioned between ethyl acetate
and 2M hydrochloric acid. The pH of the aqueous extract
was adjusted to pH 9 and it was extracted with ethyl
acetate. The organic extracts were evaporated to a gum
which was chromatographed on silica using ethyl acetate:
methanol (9:1) to give the title compound (0.30g) as a
- glassy solid. tlc System B, Rf 0.57. Nmr (CDC13~
1.5,brs, (lH); 2.53,m, (lH); 2.75,t-~m, (2H); 3.0-3.3-~,
(3H); 3.5,dd (lH); 5.31,t, (lH); 5.92,t, (2H);
6.42,q,(2H); 6.50,s,(3H); 6.59,s,(3H); 7.6,brs;(4H);
7.9,m,(2H); 8.5,m,(6H).
.
,
~9
b) Similarly prepared from diamine (A) (lg) and
3-pyridinecarbo~ylic acid, chloride, hydrochloride
(0.57g) was N-[l-methyl~5-[C3-[3-(l-piperidinylmethyl)
phenoxy]propyl]aminol-lH-1,2,4-triazol-3-yl¦-3-
pyridinecarboxamide (0~98g). tlc System B, Rf 0.64.
Nmr (CDC13) 0.85,d, (lH); 1.07,brs,(1H); 1.22,dd
(1~1); 1.78,m, (lH); 2.62,q,(lH); 2.77,t, (lH); 3.0-3.3,
m,(3H); 5.35,t, (lH); 5.92,t,(2H); 6.48,s,(3H)i 6.50,m
(2H) 6.55,s, (2H); 7.5-7.7,m, (4H); 7.90,m, (2H); 8.3-8.
m, (6H).
lhe following compounds were similarly prepared
from the appropriate aminotriazOle and acid chloride
c) The triazole ~A) (2.00g) and 4-methoxybenzoic
acid, chloride (l.lOg) gave 4-methoxy-N-[l-methyl-5-
[[3-~3-(1-piperidinylmethyl)phenoxy]propyl]amino]-lH-l,
2,4-triazol-3-yl]benzamide (2.00g),m.p. 93.5-97~.
tlc. System B Rf 0.78
Found : C, 65.0; H, 7.0;N.17.9;
2634 6 3 requires : C, 65.2; H, 7.1;N,17.5
d) The triazole (A) (2.00g) and 4-methylbenzene-
sulphonic acid, chloride~1.22gjwas 4-methyl-N~l-methyl-5-
[[3-[3-(1-piperidinylmethyl)phenoxy]propyl]amino]-lH-l,
2,4-triazol-3-yl]benzenesulphonamide (1.58g) m.p. 100.5-
102
Found: C, 57.1, H,6.7;N,15.7
C25H34N6o3S.32-H2o requires C,57.1; H,7.1;N,16.0%
-50-
Exam~le 15
5-- U3-~3~ idinylmethyl)phenoxy]propyl L
aminol-lM-1,2,4-triazole-3-one
.- _
A solution of 3-[3-(1-piperidinylme-thyl)phenoxy]
propanarnine (1.76g) in tetrahydrofuran (70 ml) was
treatecl with dimethyl N-methoxycarbonylcarbonimidodi-
thioate (1.27g) at room temperature, and the mixture
was stirred for 6h. Hydra~ine hydrate (2g) was added,
and the mixture was heated under re~lux for 18h.
The solution was evaporated, and the residue was chrom-
atographed to give the title compound (250mg) as a
colourless oil. tlc. System B, Rf 0.5. Nmr (D2O)
2~5,t, (lH); 2.8-3.0,m,(3H); 5.72,s,(1H); 5 8,t,
(3H); 6.5,m, (2H); 6.65,t, (2H); 7.05,br.t, (2H);
7.7-8.6,m, (8H).
Example 16
l-methyl~3-phenylmethyl-N-[3-[3-(1-piperidinyl-
_thyl ? phenoxy~propyl~-lH-1,2 ! 4 -triazole-5-amine,
tartrate
N-[[l-methyl-2-~phenylmethylene)hydrazinol r C3-
[3-(l~piperidinylmeth~l~phenoxylpropyl]amino]meth-
ylene~benzeneacetamide
A mi~ture of 3-~3-(1-piperidinylmethyl)phenoxy~
propanamine (0:38g) and methyl l-methyl-N-phenylacetyl-
2-(phenylmethylene) hydrazinecarboximidothioate (0.5g)
was hea-ted at 50 under water pump vacuum during 4h.
The residue was dissolved in c~clohexane (20 ml) and light
petroleum (b.p. 60-~0) was added. The precipitate was
removed by filtration and the ~iltrate was evaporated to
give the title compound (0.65g) as a colourless oil.
tlc. System A R~ 0.7.
N.m.r. (CDC13) 2.2-3.0,m, (12H); 3.0-3.3,m~(3H); 6.01,t,
(2H); 6.30,s, (2H); 6.55rbr.q., (2H); 6.62,s, (3H); G.66,s
(2H); 7.65,m, (4H); 8.00,m, (2H); 8.3-8.6,m,(6H).
1 ethyl-3-~enylmethyl~N-[ _ ~lpiperidinylmeth~)
phenoxy~pro ~
A solution of N-[[l-methyl-2-(phenylmethylene)
hydrazino ]~3-[3-(1-piperidinylmethyl)phenoxy]propyl]
amino]methylene~benzeneacetamide (0.65g) in acetone
(50 ml) was acidified to pII 1 with 2N hydrochloric
acid ancl heated under reflux during 4h. The solution was
washed with ethyl acetate, basified with potassium
carbonate and extracted with ethyl acetate. The combined
organic extracts were dried and evaporated to give a
residue which was purified by column chromatography.
The resulting oil (0.4g) was dissolved in ethyl acetate
(10 ml), and a solution of tartaric acid (125 mg) in
ethyl acetate (50 ml) was added to give the title
com~ound (0.42g) as a white powder.
tlc System A, Rf 0.65 N.m.r. (CDC13) (free base)
2.6-3.0,m,(6H); 3.0-3.4, m,(3H); 5.65,t, (lH);
5.95,t,~2H); 6.12,s,~2H); 6.47,q,~2H); 6.57,brs, ~5H);
7O67,m~ (4H); 7.93,m,(2H); 8.3-8.6,m, (6H).
Exam~e _
5-~[2-[~5-[(dimethylamino)methyl]-2-furanyl~
meth~ thio~ethyl~amino]-l-meth~-lH-1,2,4-
triazole-3-methanol
2-(~c-etyloxy)-N-[~[2-[[c5-L(dimethylamino)
methyl]-2-furanyl]methyllthio~ethyl~amino
~l-methyl(2-phenylmethylene)hydrazino]
methylene]acetamide
A mixture of methyl ~-[2-(acetyloxy)acetyl]-1-
methyl-2~(phenylmethylene) hydrazinecarboximidothioate
(0.92g) and 5- [[(2-aminoethyl)thio]methyl]-N,
N-dimethyl-2-furanmethanamine ~0.64g) in aceto~trile
~5 ml) was stirred at room temperature for 3h. The
solution was evaporated in vacuo. The oily residue was
suspended in ether (20 ml), filtered and the solid
which crystallised was collected to give the title
compound (0.8g), m.p. 78-80
52-
tlc. System A Rf 0.65
~ me-thy ~ furanyl]
meth ~ e ~ 4-
triaæole-3-methanol
A solution of 2-(acetylo~y)-N-[[[2-[[[5~~(di -
methylamino)mel:hyl]-2-furanyl]methyl]thio~ethyl]amino]
[l-methyl-2-(phenylmethylene)hydrazino]methylene]
acetamide (0.74y) in 2~ hydrochloric acid was heated
at 98-100~ for lh. Water (5 ml) was added to the
cooled solution which was washed with ethyl acétate.
The aqueous fraction was made alkaline with sodium
carbonate and the solution was evaporated to dryness
in vacuo. The residue was suspended in ethyl acetate
(20 ml), excess anhydrous sodium carbonate and
decolourising charcoal were added. The suspension was
boiled for 10 mins, cooled, filtered and the filtrate
was evaporated in vacuo. The residual oil was chroma-
tographed on silica using methanol:0.88 ammonia, (79:1)
to give the title compound (0.35g) as a pale brown oil.
tlc. System A Rf 0.6
N.m.r.~CDC13) 3.92,s,(2H); 5.18,t,5.32,b~, 5.49,s,
(4H); 6.33,s,(2H); 6.51,s,6.61,s~q,(7H); 7.23,t,(2H~;
7.78,s,(6H).
Example 18
l~~ethyl~5-[[4~ 1-piperidinylmethylLphenoxy~
butyll~ino]-lH-1,2_4~triazole-3-methanol acetate
A solution of l-methyl-5-[[4-[3~-piperidinylmethyl)
phenoxy]butyl]amino]-lH-1,2,4-triazole-3-methanol
(100 mg) in glacial acetic acid (S ml) was heated under
reflux for 8h. The mixture was evaporated and -the
residue was tri-turated with ether to give the title
compound as a white solid (97 mg) m.p. 119 20.
tlc. System ~,R~ 0.8
- -53-
E mple 19
3-Methoxymethyl-l-methy]-5-[[4-[3 _l-piper~
~ ~ o~lH-l,2,4-
_ iazol
A solution of l~methyl~3-[[4-[3-~1-piperid-
inylmethyl)phenoxy]bu-tyl~amino~-lH-1~2,4-triazOle-3-
me-thanol ~149mg~ and thionyl chloricle (3 ml) was
stirred at room temperature Eor 0.5h and evaporated.
The residue was dissolved in methanol (5 ml) and added
to a solution of sodium hydride (200 mg) in methanol
(5 ml). The mixture was stirred at room temperature
for 18h, evaporated, and the residue was partitioned
between ethyl acetate and water. The organic extracts
were dried and evaporated to give an oil which was
chromatographed on silica using ethyl acetate:
isopropanol:water: 0.88 ammonia (25:15:8:2), to yield
the title compound (108 mg).
tlc. System B, Rf 0.6. N.M.R. (CDC13) 2.8,t,(lH);
3.0-3.3,m,(4H); 5.67,s,(2H): 5.72,t,(1H); 6.00,br t,
(2H); 6.3-6 6,m,(lOH); 7.6,m,(4H); 8.0-8.7,m,(lOH~
Example 20
1,3-dimethyl-N-[4-[3-(~ iperidinylmethyl)
phenoxy~but~-lH-1,2,4-triazole-5-amine
A stirred suspension of 4-[3-(1-piperidinyl-
methyl)phenoxy]butanoic acid (4.0g) in methylene
chloride (100 ml) and dimethylformamide (24 drops) was
treated with thionyl chloride (5.16g). The solution
was stirred at room temperature for 18h and evapora-ted
in vacuo, to give a pale yellow solid which was
dissolved in methylene chloride (100 ml) and treated
with 5-amino-1,3-dimethyl~1,2,4-triazole (1.61g).
_54-
The reaction mixture was stirred at room temperature
for 2~h and evaporated in vacuo. The residue
was dissolvecl in aqueous sodi~lm bicarbonate solution
and extracted with ethyl aceta-te. The organic
extracts were ~Iried and evaporated to give a brown
oil which was dissolved in tetrahydrofuran (500ml),
treated with lithiurn aluminium hydride (3.04g), s-tirred
at room temperat~efor 18h and refluxed for 3h. The
cooled reac-tion mixture was quenched l~ith water (300 ml)
and extracted with ethyl acetate. The combined extracts
were washed with brine, dried and evaporated in vacuo
to give an oil which ~as distilled to give the
title compound (1~7g) as a pale yellow oil, b.p. 230/
__ _
0.06mm
N.m.r. 2.80,t, (lH); 3.0-3.3,m, (3H); 5.82,t,(lH)
6.02,m, (2EI); 6.58,s,s-~m, (7H); 7.65,7.77m,s,(7H)
8.0-8.7,m, (lOEI).
The following compounds were prepared using the method
of Example 2:
l-methyl- N5-t2-[[[5-[(dimethylamino)methyl]-2-furanyl3
methyl]thio]ethyl]-lH-1,2,4-triazole-3,5-diamine(l.Og)
gave 1-methyl-N-[2-[[[5-[(dimethylamino)methyl]-2-
furanyl]methyl]thio]ethyl]-lH,1,2,4-triazole-S-amine(0.32g)
T.l.c. System C P~f 0.54.N.m.r. (CDC13); 2.50,s,(lH);
3 90,s,(2H); 6.30,s,(2H); 6.5,2s+q, (7H); 7.18,t,(2H)
7.79,s,(6H).
b) 1-methyl-N5-[2-[[~5-[(dimethylamino)methyl]-2-
thienyl]methyl]thio]ethyl]-lH-1,2,4-triazole-3, S-diamine
(l.Og) gave l-methyl-N-[2-[[[S-[(dimethylamino)methyl]
-2-thienyl]methyl]thio]ethyl]-lH-1,2,4-triazole-5-amine
(0.31g)
T.l.c. System C Rf 0.52.N.m.r. (CDC13): 2.57,s,(lH);
-5~-
3.3,m,(2H); 5.58,br,s,(lH)i 6~16,s,(2I-I); 6.48,2s+q,t7H)i
7.20,m, (2H); 7.76,s,(6H).
E n~le 2
~ 3-C3-(1-pi~erldinylmethyl)phe}loxy~propyl~
ami ~ H-1,2,4-triazole-3-ethanol tartra-te salt
A suspension of ethyl l-methyl-5-[[3 [3-(1-
piperidinylmethyl)phenoxy]propyl]amino]-lH-1,2,4-triazole-
3-acetate (0.3g)and lithium aluminium hydride (lOOmg)
in tetrahydrofuran (50 ml) was stirred at 25 under
nitrogen during 24h. The mixture was quenched with water
and extracted with ethyl acetate. The combined organic
extracts were evaporated and the residue was chroma-tographed
to give a pale yellow oil which dissolved in boiling
cyclohexane. The hot solution was allowed to cool to room
temperature, and the oil that precipitated was treated with
a saturated ~lution of (d)-tartaric acid in ethyl acetate
to give the title compoun~ as a white powder (80 mg).
N.m.r. (free base) (CDC13); 2.8,t,(lH); 3-3.3,m,( 3H);
5.3,t,(lH); 5.9,t, (2II); 6.13,t,(2H); 6.0,br,s,(lH)
6.4,q,(2H); 6.52,s,(3H)-6.57,s,(2H); 7.2,t,(2H);
7.65,m,(4H); 7.88,m,(2H); 8.5,m,(6H)
T.l.c. System A Rf 0.55
Example 23
a) 5-[2-r~L~[(dimethylamino)methyl]-2-thienyl]methyll
thiol~_hyl~-l-methyl-3-phenylmethyl-lH-1,2,4-triazole-5-
amine
2-(~henyl)-N[~[2-~U5-[(dimethylamino)methy~-2-
thienyl~methyl~thio~ethyl]amino]cl-methyl-2-
(phenylmethylene)hydrazino]methylene]acetamide
.
A mixture of 5-[[[2-(amino)ethyl]thio]methyl] N,
-5~-
N-dimethyl-2--thiopI-Iene methanamine(c) (l.Og) ancl
methyl l-methyl N phenylacetyl-2-(phenylmethylene)
hydrazinecarboximidothioate (A) (1.42g) was heated
at 60 under wa-ter-pump vacuum during 3h. to gi~e the
title co~ uncl (1.9g) as a colourless oil.
T.]..C. System A RE 0.61
N-m-r- (CDC13) 2 19br,m, (lEI); 2.2-2.4m (3H);
2.5-2.85,m,~8H); 3.3,dd (2EI); 6.18,s,(2EI); 6.33,s,(2H)
6.48,s,(2H); 6.68-6.70rm,(5H); 7.4,t,(2H); 7.78,s,(6H);
5-[2-~C[~I(dimethylamino)methyl]-2-thienyl~methyll
thio~ethyl~ methvl-3-~henvlmethvl-lH-1,2,4-triazole
-5-amine
2N hydrochloric acid (5ml) was added to a
solution of 2-(phenyl)-N-[[[2-[[[5-~(dimethylamino)
methyl]-2-thienyl]methyl]thio]ethyl]amino][l-methyl-
2-(phenylmethylene)hydrazino]me-thylene]acetamide
(1.9g) in toluene (20ml) and the mixture was heated
on a steam bath for 30 min. The aqueous layer was
washed with toluene, treated with po-tassium carbonate,
ar,d evaporated in vacuo.The residue was dissolved
in ethyl acetate, filtered and the filtrate was
evaporated to yield an oil which was chromatographed
to give the title compound (0.47g) as a pale orange
25 oil.
T.l.c. System A. Rf 0.55.
Found C, 60.0; H,6.8; N,17.1;
C20 27 5 2 q C, 59.8; H,6.8; N,17.4
8S~ (
The followinc3 compouncls were similarly prepared from
-the ap~ropriate methyl l-m~-th~l M-acyl-2-(phenylmethylene~
hydrazinecar~oximidothioa-te ~nd the correspondiIl~ diamine
b) A (0.5g) an~ 5[[(2~aminoethyl)thio]methyl~-N,N-
dimethyl--2-fu~anmethanamine (0.33g) gave 5-[2-[[[5-
[(d.imethylamlno)me~hyl~-2-Eurar~yl]methyl]thio]e-thyl]-1-
methyl-3-phenylmethyl-liI-1,2,4-triazole-~5-amine (0.21g)~
T.l.c. System ~ Rf 0~61
N.m.r. (CDC13): 2.6-2.8,m,(5H); 3~95,s,(2H); 5.60,t,(lH);
6.12,s,(2H); 6.32,s,(2H); 6.55-6.63,m,(7H); 7.25,t,(2H);
7.79,s,(6H).
c) ~ (1.21g) and 5-[C(2-aminoethyl)thio]methyl]-3
-N,N-trimethyl-2-furanmethanamine (0.85g) gave 5-[2-
[[t5-[(dimethYlamino)methyl]-4-methyl-2-furany]]methyl]
thio]ethyl~-l-methyl-3-phenylmethyl-lH-1,2,4-triazole-5-
amine (0.42g) as a pale yellow oil.
T.l.c. System A Rf 0.58
N.m.r. (CDC13): 2.6-2.9,m, (5H); 4.06,s,(lH): 6.16,s,(2H);
5.53,t,(1~I); 6.40,s,(2H), 6.58-6.61,m,~7~1); 7.27,t,(2H);
7.8,s,(6H); 8.1,s,(3H);
d) N-[2~(acetyloxy)acetyl]-1-methyl-2-phenylmethylene)
hydrazinecarboximidothioate (B) (0.75g) and 3-[3-[(1-
hexamethyleneiminyl) methyl~phenoxy~propanamine (0.64g)
gave 1-methyl-5-[3-[3-[(1-hexamethyleneiminyl)methyl]
phenoxy]propyl]amino-lH-1,2,4-triazole-3-methanol (0.32g),
m.p. 80-82
N-m-r- (CDC13); 2.8,t,(1H); 3.0-3.3m, (3H); 5.42-5.45,m,
(3H); 5.88-7.0,m,(llH); 7.4,m,(4H); 7.9,m,(2H); 8.4,m,(8H).
e) B (1.37g) and diamine C ~l.Og) gave 5-[[2-[[[5-
[(dimethylamino)methyl]-2-thienyl]methyl]thio]ethyl]amino]
-l-methyl-lH-1,2,4-triazole-3-methanol (0.2g)
T.l.c. System B. Rf 0.48
N.m.r. (CDC13); 3.25,m,(2H); 5.1,m,(2H); 5.5,s,(2H);
6.16,s,(2H); 6.35-6.5,m, (7H); 7.22,t,(2H) 7.77,s,(6H).
-58-
f) B (0.75g) and 3- L3- ( l-pyrrolidinylmethyl)phenoxy]
propanamiIle (0.57g) gave 1-me-thyl-5-[ 3 - [ 3-(1-pyrrolidinyl-
methyl)phenoxy]propyl]amino]~EI-1,2,4-tria,.ole-3-methanol
(0.4~) m~p. 105-7C.
Fo~nd: C, 62.9; H, 7.9; N, 20.7
C18~l27Ns2 ~equ:lres : C, 62.6; ~I, 7.9; M, 20.3~
g) B (0.75~) and 5-[[(2-aminoethyl)thio]methyl~-3-
N, N-trimeth~1-2-furclnmethanamine (0.5g) gave 5-[[2-
[[[5~ L (dimethylamino)methyl]-4-methyl-2-furanyl]methyl~
10 thio]ethyl]amino]-1-me-thyl--lH-1,2,4-triazole-3-methanol
(0.32g~ T.l.c. System B Rf 0.53. N.m.r. (CDC13~ 4.02,s,
(lH~; 5.32-5.48,m,(3H~; 6.37,s, (2H); 6.50~6.7,m,(7H~;
7.25,t, (2H~; 7.82,s,(6H~; 8.08,s,(3H).
~
~,l-trimethyl-5-[~4-~3-(1-pi~eridinylmethyl~phenoxy]
_tyl]amino]-lH-1,2,4-triazole-3-methanol
N-[3-(1-h~droxy-1-methylethyl)-1-methyl-lH-1,2,4-
triazole-5-yl]-4-[3-(1-piperidin~lmethyl)phenoxy~
butanamide
A solution of methyl l-methyl-5-[[1-oxo-4-[3-
(l-piperidinylmethyl~phenoxy]butyl~amino~-lH-1,2,4-triaæole
-3-carboxylate (508 mg~ in tetrahydrofuran (10 ml) at
-78 was treated with a solution of methyl magnesium iodine
[(1.6 ml~ o~ a solution prepared from magnesium turnings
(400 mg) and methyl iodine (0.7 ml) in ether (10 ml~].
The mixture was maintained at -78 for 0.5h. allowed to
reach room temperature and quenched with water. The mixture
was partitioned between ethyl acetate and 2N sodium hydroxide,
the aqueous layer was extracted with ethyl acetate, and
the combined organic extracts were dried and evaporated
in VaGUO. The residue was chromatographed to give the
title compound (358 mg) as an oil.
T.l.c. System B. R~ 0.8
N.m.r. (CDC13): 2.82,t,(lH); 3.0-3.3,m,(4H~; 6.0,t,(2H);
6.20,s,(lH~; 6.32,s,(3II~; 6.60ls, (2H~; 7.3,m,(2H);
7.5-8.0,m,(6H); 8.45,S,(6H~; 8.5,m/(6H~.
-59-
a,~ trimeth~1-5-r[4-r3-(1-pi~eridinylmethyl)phenox~]
amino~lM-1,2,4-triazole-3-methanol
A stirrecl solution oE ~ [3-(1-hyclroxy-1-me-thylethyl)
-l-~ethyl-lH-1,2,~triazol-5-yl~-4-[3--(1-plperidinylmethyl)
pheno~y]blltanam:ide (30~mq)in tetrahydroEuran (20 ml) under
nitrogell was -treated, with lithium aluminium hydride
(0.5g) in an ice-bath. The mixture was stirred at room
temperature Eor 24h, quenched with wa-ter and extracted
with ethyl acetate. The comblned organic extracts were
dried and evaporated to give an oil (300 mg) which
was chromatographed on silica using ethyl acetate:
isopropanol:wa-ter: 0.~8 ammonia (25:15:8:2) to give the
title compounct (224 mg) as an oil. T.l.c. System B
Rf 0.7. N.m.r. (CDC13): 2.80,t,(lH); 3.0-3.3,m,(3H);
~5.65,t,(lH); 6.02,s, (2H); 6.52,m,(7H); 7.60,m,(4H);
8.0-~.7,m,(10M); 8.46,s,(6H).
Example 25
1 _ hyl-5-~C~-[3-(1-piperidinylmethyl)phenox~lbut~
aminol-lH-l 2 4-triazole-3- methanamine
' '
A solution of methyl l-methyl-5-[[1-oxo-4-[3-
(l-piperidinylmethyl)phenoxy]butyl]amino]-lH-1,2,4-triazole
-3-carboxylate (1.94g) in 0.8~ ammonia was stirred at
room temperature for 18h. The mixture was evaporated
to yield a yellow foam, which was triturated with ether
to give a yellow solid (1.56g) which was used without
further purification. A portion of this solid (1.20g)
was suspended in tetrahydrofuran (50 ml) and treated
at room temperature with lithium aluminium hydride (l.Og).
The mixture was heated under reflux for 24h, cooled and
quenched with water. The resulting mixture was extracted
with ethyl acetate, and the combined organic extracts
were evaporated to yield an oil (0.9Og) which was
chromatographed to give the title compound as an oil (210mg)
-60-
T.l.c. Systern B Rf 0.5. N~m.r. (D20); 2.5,t,(1II);
2~8--3.0,m,(3EI); 5.43,s,(4H); 5.72,s,(21I); 5.8,t,(2H);
5.~6,s,(2H); 6.47,s,(3EI); 6.6,m,(~EI); 7.05,bt,(2H);
8.0-8.6,m~(10H3.
E _ ~le 26
a) N,N,l-Tr~ 5- r r 4 - ~ 3-(1-piperidinylmethyl)
phenoxy~butyl]amino~-lH-:l,2,4--triazole-3-
-
methanamine
A solution of l-methyl-5-[[4-[3-5L-piperidinylmethyl)
phenoxy]butyl~amino]-lE~-1,2,4-triazole-3-methanol (200mg)
in thionyl chloride (4 ml) was stirred at room temperature
fox 0.5h. The mixture was evaporated to give a white
foam which was used without further purification, and
dissolved in a 33~ solution of dimethylamine in ethanol
(25 ml). The resulting solution was maintained at room
temperature for 16h, and evaporated to give an oil which
was chromatographed on silica using ethyl acetate:isopro-
panol:water:O.88 ammonia (25:~5:8:2) to give the title
compound (132mg) as an oil. T.l.c. System B. Rf 0.6
N.m.r. (CDC13): 2.8,t,(lH); 3.0-3.3,m,(3H); 5.66,t,51H);
6.02,t,(2H); 6.4-6.7,m, (9H); 7.6,m,(4H)i 7.7,s.(6H);
8.0-8.7,m, (lOH).
b) Similarly prepared from the same triazole methanol
(l5omg)l thionyl chloride ~3 ml) and 0.88 aqueous
ammonia (50 ml) was 1-methyl-5-[C4-[3-(1-piperidinyl-
methyl) phenoxy]butyl]amino]-lH-1,2,4-triazole-3-methana-
mine (109mg). T.l.c. System B and n.m.r. (D20) were
the same as for the product of Example 25.
-61-
Exam~le 27
~ . .
l-meth~1-5- ~ 3-(1-piperidinylmethyl)phenoxy~butyl~
amino~ l-1,2,4-triazole-3-methanol
A stirrecl solution of 1-methyl-5-[[~-[3-(1-
p:iperidinylmethyl)phenoxy~butyl]amino]-lH-1,2,~-triazole
-3-methanoll acetate (5mg) in ethanol (1 ml) w~s
treated with 2N sodium hydroxide solution (0.5 ml). The
mixture was maintained at room temperature for 2h,
- evaporated in vacuo, and the residue was partitioned
between ethyl acetate and water. The aquous layer
was extracted with ethyl acetate and the combined organic
extracts were dried and evaporated in vacuo to yield
the title compound ~4 mg) as a white solid,m.p. 82-83.
T.l.c. System B, Rf identical to product of Example 7.
Example 28
l-methyl-5-[[3-r3-[(1-piperidinyl)methy~]phenoxylpropyl~
aminol,-lH-1,2,~-triazole-3-methanol
3-[3-(1-piperidinylmethyl)phenoxy]propanamine (1.2~g)
and N-~2-acetyloxy) acetyl]-1-methyl-2-(phenylmethylene)
hydrazinecarboximidothioate (1.535g) were heated together
at 50 for 3h. The residual oil was used without
purification, and dissolved in acetone (30 ml). 2N
hyarochloric acid (5 ml) was added, the solution was
stirred at room temperature for 1.5h and left overnight
without stirring. A further quantity of 2N hydrochloric
acid (5 ml) was added and -the solution was heated a~
reflux for 2h. Water (50 ml) was added, the aqueous
solution was washed with ethyl acetate, and basified
with excess solid sodium carbonate. The basic solution was
extracted with ethyl acetate, and the organic extracts we~e
evaporated to give the title compound as a white solid
(l.lg) m.p. 119.
T.l.c. System B, ~f 0.7
-62-
Exam~le 29
Eollowing the method of Example 9,
l-methyl N5-[2-r~[5~ imethylamino) methyl]-2-thienyl]
methyl] thio] ethyl]-lH 1,2,4-triazo]e-3,5-diamin~ (0.67g)
and methyl isocyanate (0.17 ml) gave N-[5-[[2-
[[[5-[(climethylamino)methyl]-2-thienyl]me-thyl]thio]ethyl]
amino]-l-methyl-lH-,2,4-triazol--3-yl]-N'-methyl urea (0.4g).
N-m-r- (CDC13). 3-23,q, (2H); 6.02,s,(2H); 6.4-6.5,s-~s+t,
(7H); 7.1-7.2,s-~s,(5H); 7.75,s,(6H). T.l.c. System B
R~ 0.55.
Example 30
The following compounds were prepared using
the method of Example 11
a ) l-methyl-N5- [2- ~ [ [~5~ L (dimethylamino)methyl]-2-
thienyl]methyl]thio]ethyl]-lH-1,2,4-triazole-3,5-diamine
(0.5g) and methane sulphonic anhydride (0.3g) gave N-[l-
methyl-5-[[2-[[~5-[(dimethylamino)methyl]-2-thienyl]methyl]
thio]ethyl]amino]-lH-1,2,4-triazol-3-yl]methane sulphonamide
tO-05g)- N-m-r- (CDC13): 3.22,q,(2H); 4.28,t,(lH); 6.10,s,
(2H); 6.4-6.5,m,(7H); 6.80,s,(ca 3H); 1.28,t,(2H); 7-73,s~
(6H). T.l.c. System B Rf 0.25.
b) l-methyl-N -[2-[~[5-[(dimethylamino)methyl~-2-
furanyl]methyl]thio]ethyl]-lH-1,2,4-triazole-3,5-diamine
(1.55g) and acetic anhydride (0.5g) gave N-~l-methyl-5-
[ [2- [ [ [5-[(dimethylamino)methyl]~2-furanyl]methyl]thio]
ethyl~amino]-lH,1,2,4-triazol-3-yl]acetamide, oxalate (1 ! 3g)
m.p. 132-4~
N.m.r. (D2O): 3.30,d,(lH); 3.60,d,(lH); 5.67,s,(2H);
6.13,s,(2H); 6.45, s+t, (5H); 7.15,s~t, (8H) 7.80,s,(3H)
c) l-methyl-N5-[2-[[[5-[(dimethylamino)methyl]-4-
methyl-2-furanyl]methyl]thio]ethyl]-lH-1,2,4-triazole-3,
5-diamine (lg) and acetic anydride (0.32 ml ) ga~e N-[l-
63
methyl-5-[[2-[[~5-[(dimethylamino)me-thyl]-4-methyl-2-
furanyl]methyl~-thio]ethyl]amino]-lH-1,2,4-triazol-3-yl]
acet~mide (0.5g).
T.l.c. System B Rf 0.4
N.m.r. (CDC13): 1.2,br.s.(lH); ~.05,s,(lH); 5.2,t,(1H);
6.4,s,(2H); 6.5-6.7,m,(7H); 7.25,t,(2H); 7.75,s,(9H);
8.10,s,(3TI).
d) l-methyl-N5-[3-[~ piperidinylmethyl)phenoxy]
propyl]-lEI-1,2,4-triazole-3,5-diamine(0.5g) and acetic
anhydride (157mg) gave 1-methyl-N-[5-[C3-~4-(l-
piperidinylmethyl)phenoxy]propyl]amino]-lH-1,2,4-triazol-
3-ylJacetamide (0.58g).
N.m.r. (CDC13): 2.75,d,(2H); 3.18,d,(2H); 5.95,t,(2EI);
6.4-6.7,m,(2H); 6.55,s,(3H); 6.60,s,(2H) 7.5-8.1,m,(6.El);
7.87,s,(3H);8.3-8.7m,(6H)
T.l.c. System A,R~ 0.52
Example 31
The following compounds were prepared using the
method of Example 14:
a) l-methyl-N5~[3~3-(1-piperidinylmethyl)phenoxy]
propyl]-lH-1,2,4-triazole-3,5-diamine (A) (2.00g) and
phenylacetylchloride(0.99g) ga~e N-[l-methyl-5-~[3-~3-
(l-piperidinylmethyl)phenoxy]propyl]amino]-lH-1,2,4-
triazol-3-yl~benzeneacetamide (0.92g)
N.m.r. (CDC13): l.9,br,s, (lH); 2.70,2.80,s-~t,(6H);
3.0-3.3,m, (3H); 5.30,t,(lH); 5.98,t,(2H); 6.28,br.s,(2H)
6.55,s+s~q, (7H); 7.65,m,(4H); 8.0,m, (2H); 8.5,m,(6H).
T.l.c. System ~ r Rf 0.71
b) The trlazole (A) (2.00g) and benzoyl chloride
(0.9Og) gave N-[l-methyl-5-[[3-[3-(1-piperidinylmethyl)
phenoxy]propyl]amino]-lH-1,2,4-triazole-3-yl~benzamide
(1.05g)
6~-
N.m.r. (CDC13): O.9,br,s,(lH); 2.00-2.25,m,(2Hl,
2O4-2~7,2.8,m~t, (4~1); 3.00-3.35,m,(3H); 5.22,t,(lH)
5.98,t,(2H); 6.50,6~55,6.60,s-~s-~q,(71-1); 7.60,m,(4H)
8.0,m,(2~1); 8.5,m,(6H);
Found: C, 66.77; 1l, 7.30; N,18.72;
C25~32 6 2 q C, 66.94; H, 7.19; N,18.74~6
F,xample 32
N-methyl-N'-[l~nethy ~ [3-[3-(1-piperidinylmethyl)
~
A mixture of l-methyl-N5-[3-[3-(1-piperidinylmethyl)
phenoxy]propyl]~lH-1,2,4-triazole-3~5-diamine (2.00g) and
methylisocyanate (1~2g) in dry acetonitrile (60 ml)
was heated at reflux for 2h. and allowed to cool. The
precipitated solid was collected and recrystallised from
methanol to give the title compound (1.9g)
T.l.c. System B: Rf 0.71
N.m.r. (CDC13): 1.22,s,(lH); 2.07,q,(lH); 2.78,t,(lH);
3.00-3.30,m, (3H); 4.90,t,(lH); 5.90,t,(2H); 6.42,6.48,
20 6.58,q~s+s, (7H); 7.10,d,(3H); 7.60,7.90,m+m,(6H);
8~50,m,(6H).
Example 33
Ethyl- rS-u2-r ~rs-r (dimeth~ylamino~methyl]-2-thien~l~
meth llthiolethYllamino~ methYl-lH-l~2~4-triazole~3
Y_J
yl]carbamate
A cooled mixture of ethylchloroformate (0.45g) in
pyridine was trea-ted with a solution of N5-[2-[rr5-
[(dimethylamino)methyl]-2-thienyl]methyl~thio]ethyl]-1-
30 methyl-lH-1,2,4-triazole-3,5-diamine (0.7g) in pyridine
(8 ml). Sodium carbonate (2g) and water (10 ml) were
added and the mixture evaporated in vacuo. The residue
was dissolved in water (15 ml) and extracted with hot
isopropanol (30 ml). The extract was evaporated and the
i8~ -
--65--
residue puxified by column chromatography ~silica:methanol:
0.88 arnmonia; 79:l) to give the ~ (0.48g)
T.l.c. System A Xf 0.6
N.m.r. (CDCl3) 1.8, brs (lH); 3.25,m,(2~I); 5.47,brt
(l~1); 5.~8,q, (211); 6.13,s,(2~1); 6.~7,2s ~q,
(711); 7.2~,t,(2H); 7.75,s,(6H); 8.73,t,(3H).
Example 34
The following compound was prepared using -the method of
Example l6:
3-[4-~l-piperidinylmethyl)phenoxylpropanamine (0.61g)
and methyl N-C2-(acetyloxy) acetyl~-l-methyl-2-
(phenylmethylene) hydrazinecarboximidothioate (0.75g)
gave 2-(acetyloxy)-N-[C[3-[4-(l-piperidinylmethyl)
phenoxy]propyl]amino] [l-methyl-(2-phenylmethylene)
hydrazino~methylene]acetamide (l,2g)
T.l.c. System A RE 0 59
N.m.r. (CDCl3) 2.2,s,(lH); 2.3-2.45,m, (2H); 2.5-2.75,m,
(3H); 2.85,d,(2H); 3.2,d,(2H); 5.4,s,(2H); 5.9,t,(2H),
6.45,q,(2H); 6.6,s,(3H); 6.64,s,(2H); 7.55-7.~,m,(6H)
7.85,s,(3H3; 8.3-8.6,m,(6H)
The above acetamide (1.2g) was acidified to give
l-methyl-N-[[3-C4-(l-piperidinylmethyl)phenoxy]
propyl]amino]-lH-l,2,4-triazole-3-methanol
T.l.c. System A. Rf 0.6. N.m.r. (CDCl3) 2.?8,d,(2H) 3.20,d,
(2H); 5.48,s, (2H); 5.94,t,(2H); 6.42,q,(2H);
6.52,s,(3H); 6.62,s,(2H~; 6.8,br,s,(lH); 7.68,m,(4H)
7.9,m,(2H); 8.3-8.7,m, (6H).
a,l-dimeth~l-N-[ L4-[3-(l-piperidinylmethyl)
phenoxy]butyl]amino~ lH-l,2,4-triazole-3=methanol
l-Methyl-N-C[4-[3-(l-piperidinylmethyl)phenoxy ]
~ amino] -lH-l,2,4-triazole-3-carbaldehyde
Dimethyl sulphoxide (304mg) was added to a solution
-66-
of oxalyl chloride (254mg) in dichloromethane (20ml)
a-t -60 under nitrogen. The solution was stirred at
-50 to -60 for 2 min and a solu-tion of l-methyl--N-
[~4-c3-(l-piperidinylmethyl)phenoxy]butyllamino]
-1~-1-1,2,4 triazole-3-methanol (0.5g) in dichloromethane
(lOml) was added. The mixture was stirred at -50 to
-60 for 15 min and then quenched with triethylamine
(657mg). The solution was allowed to warm to 25 and
was diluted with water. The aqueous phase was
extracted with dichloromethane and the combined
organic extracts were dried and evaporated to leave
the t le compound as a pale yellow oil (0.4g). N.m.r.
CDC13 0.2,s,(lH); 2.78,t,(lH), 3.0-3.3,m,(3H);
5.25,br,t, (lH); 6.06, br t, (2H); 6.40,s,(3H);
Ç.5,q, (2H); 6.60,s, (2~1); 7.68,br, (4H); 8.0-8.6,m,
(lOH)~ Tlc System A Rf 0.55
a,l-dimethyl-N-C~4-~3-(l-pi~èridinylmethyl)phenoxyl_
butyl~amino~-lEI-1,2,4-triazole-3-methanol
A solution of methyl lithium [(0.6m in ether),
lOml] was added to a solution of the above carbaldehyde
(0.4g) in -tetrahydrofuran (20ml) a-t 25 under nitrogen.
The mixture was stirred for 12 h, quenched with water and
extrac-ted with ethyl acetate. The combined organic
extracts were evaporated to give a yellow oil ~0.3g)
Tlc System C Rf 0.3.
Example 36
Following the method of Example 23,
N-[2-(acetyloxy)acetyl]-1-methyl-2-(phenylmethylene)
hydrazinecarboximidothioate (0.75g) and
3-[3-[1-(4-hydroxypiperidinyl)methyl]phenoxy~propanamine
(0.65g) gave 1-methyl-5-{[3-[3-[1-(4-hydroxypiperidinyl)
-67-
methyllphenoxy]propyl]amino]-lEI-1,2,4-triazole-3-
methanol (0.3g), -tlc Systern B Rf 0.~. NMR(CDC]3)
2.80,-t,(ll-I); 3~0-3O3,m,(3H); 4.63,t,(lH); 5.52,s,(2H);
5.8-6.1,m,(5H); 6.3-6.7,m,(7~1); 7.1-7.4,m,(2H)
7.7-8.7,m, (8H).
xam~ 37
l~me~yl-[5-[[3-[3 _l p~e _ inylmethyl)phenoxylpropyl~
amino]-lH-1,2,4-triazole--3-one
The ~ollowing compound was prepared using the method
of preparation 5:me-thyl 1-methyl-2-(phenylmethylene)
hydrazinecarboximido thioate hydroiodide (2.35g) and
methylchloro~ormate (0.58 ml) gave methyl-N-methoxycarbonyl-
l-methyl-2-(phenylmethylene)hydrazinecarboximido-thioate
(0.65g),m.p. 85-6.
The ~ollowing compound was prepared using the
method o~ Example 16:
3-[3-(1-piperidinylmethyl)phenoxy]propanamine (0.62g)
and methyl-N-methoxy carbonyl-l-methyl-2-(phenylmethylene)
hydrazinecarboximidothioate (0.59g) gave methyl[[l-methyl-
2-(phenylmethylene)hydrazino][[3-[3-(1-piperidinylmethyl)
phenoxy]propyl]amino]methylene]carbamate (0.9g).
~lc silica; methanol. R~ 0.35.
The above carbamate (0.6g) was acidi~ied to give
l-methyl-[5-~[3-[3-(1-piperidinylmethyl)phenoxy]propyl]
amino~-lH-1,2,4-triazole-3-one tartrate (0.03g);
Tlc System B. R~ 0.23
NMR (D20); 2.50,t,(lH); 2.8-3.0,m,(3H); 5.45,s,(2H);
5.8,s+m,(4H); 6.4-6.6,m,(4H); 6.73,s,(3H); 7.05,t,(2H);
7.7-8.6,m,(~H).
&~
-67a-
3xample 38
The following compound was prepared using the me-thod
of Example 23:
Methyl-N-[2-(acetyloxy)acetyl]-1-methyl-2-(phenylmethylene)
hydrazinecarboximiclothioate (0.75g) and 3-~3 aminopropoxy)
-N,N-climethylbenzenemethanamine tO.51g) gave
l-methyl-5-[~3-[3-[(dimethylamino)methyl]phenoxy]propyl]amino~
-lH-1,2,4-trazole-3-methanol (0.3g).
T.l.c. System B. Rf 0.52
N.m.r. (CDC13); 2.76,t,(lH); 3-3.3,m,(3H); 5.4-5.9,m,
(6H); 6.42-6.64,m, (8H); 7.8-7.9,m,(8H).
-67b-
Fxample ~9
.S-r~7)-r~-r(Phenylmethylamino~methrllphenox~ ro~yllamino~ 2,~L-
A solution o~ 5-[[3-(3-formyl phenoxy)propyl]amino]-1-methyl-lE-1,2,4-
triazole-3~e-thanol (532 mg) in e-thanol (15 ml) was treated with ben~ylamine
(5 ml) and stirred at roorn temperat~re for 1.5h. ~he solution was -treated
with sodiurn borohydride (500 mg) and stirred at room tempera-ture for 16h.
'~he mixture was evaporatbd, and the residue partitioned between 2~ hydrochloric
acid and ethyl acetate. ~he aqueous layer was washed with e-thyl acetate,
neu-tralised with potas~ium carbanate, and extracted with ethyl acetate. ~he
combined extracts were dried and evaporated in vacuo to yield an oil. ~his
oil was chroma-tographed on silioa gel, using a mixture of methanol-ethyl
acetate (1:1) to give -the title compound as an oil (315 mg).
T.l.c. silica: methanol, Rf 0.5
N.m.r (CDCl3): 2.72,s+t,(6E); 3.0-3.3,m,(3H); 5.24,br.t,(1E); 5.52,s,(2E);
5.98,t9(2E); 6.1-607,m,~8E); 6.60,s,(3H); 7.98,m,(2H).
me following compound was similarly prepared from the above aldehyde (A)
and l-heptylamine.
(1) A (558 mg) and l-heptylamine (5 ml) gave 5-[[3-[3-[(1-heptylamino)methyl~ ~,
pheno~y]propyl]amino]-lE-1,2,4-tria~ole-3-methanol, as an oil (153 mg).
T.l~c. Silica; methanol Rf 0.3
. . .
N.m.r. (CDCl3): 2.80,t,(1E); 3.1-3.3,m,(3E); 5.50,9+m,(3E); 5.97,t,(2H);
6.30,s,(2H); 6.50,q9(2H); 6~58,s,(3H); 6.90,b9,(2E); 7.41,-t,(2H);
7.96,m,(2E); 8.3-8.9,m,(10); 9.2,bt,(3H).
1.
_. .. ~ .
-67c-
Ex~nple ~0
N-rr)~rr4-r5-r(Dime-th~yla~nino~r~et~11-2-fura~yllbutyllarninol-l ~et~yl-lH-1,2
triazol-~-yl ~N ~phenyl urea
N -~4-rS-r ~Tnet~ylarnino~met;~ -2-fura~yllbu-tyll l~n~thyl-1~-1,? 4-triazole-
~, r)-diarninc-~,
~ mixture of N-cyano-l-methyl-2-~phenylmethylene)-hyclrazine carboxirnidothioic acid
methyl es-ter (2.32g~ and 4-[5-[(aimethylaTnino)methyl]-2-furanyl]butana~ine (1.96g)
was hea-ted at 60D under reduced water-pump pressure for lh. The residual oil
was used without further purifica-tion, and stirred with 2N hydrochloric acid (lO ml~ ~
for 005h. me pE of the acidic solution was adjusted -to pH ~ wi-th potassiurn
carbonate, and washed with toluene. ~n excess of potassium carbonate was added
to the aqueous phase which was then extracted with e-thyl acetate. me organic
extracts were dried and evaporated to give a solid which was recrystallised frome-thyl acetate to give the title com~ound as a white solid (2.1g), m.p. 105 C.
.
~sing -the method of Example 9:
-[4-[5-[(Dimethylamino)methyl]-2-~uranyl]bu-tyl]-l~ne-thyl-lE-1,2,4-tria~ole-3,5-
diaTnine (0.73g) and phenylisocyanate (0025 ml) gave N-[5-[[4-[5-[(aimethylamino~
methyl]-2-furanyl]butyl~amino]-l~nethyl-1~-1,2,4-tria~ol-3-yl]-~ -phenyl urea
(o.67g), m.p. 124-5.
T.l.c. system C~ Rf 0.42
' ' ' ' , " '` ' '' '~ " ' ,' , ' '' '
.
., ' ' ; ''' ' ' . ~.
. .
-67d-
Example 41
~he following compound~ were prepared ueing the method of Example 23.
a) 4-~5-[(dimethylami~o)methyl~-2-furanyl]bu-tananline (1.96g) and
me-thyl l~nethyl-N-phenyl-ace-tyl-2-(phenylme-thylene)hydrazinecarboximidothioate
(3.25g) gave 5-[4-[5-[(dimethylamino)methyl]-2-furanyl]butyl]-l~nethyl-3-
phenylm2thyl-lH-1,2,4-triazole-5-amine (2.0g).
rr l.c. cystem ~, ~ 0 52.
N.m.r. (CDC13): 2.6-2.9;m,(5~); 3.98,d,(1H); 4.13,d,(1~); 5.80,t~(1E);
6.13,s,(2H); 6.13,s,(Za); 6.60-6.65,m~(7H); 7.38,t,(2H); 7.80,a,(6H);
8.3.m.(4~)-
b) 4-[5~[(Dimethylamino)methyl]-2-furanyl~bu-tanamine (l.lg) and N-
~2-(acetyloxy)acetyl~-1-methyl-2-(phenylmethylene)hydrazinecarboximidothioate
(1.9g) gave 5-[[4-[-[(dimethylamino~methyl~-2-furanyl]butyl]amino]-1-methyl-
1~-1,2,4--triazole-3-methanol (0.5g).m.p.88-90 .
r~ 1 C. System C, Rf 0.34-
.
,
. ~ .
.
. _ _ _ _ . _ __ ~ __ , .. . . ..... _ __ _ _ ___ _ .... . ,. . .. _, . . . . . . .. . . . ...
.. . . . . . . ....
~7e-
Example 42
~ ethyl-5-~c3-[3~ ridin~]methyl)phenoxyJ~_op
amlno-l~l 1,2,4-triazole-3-methanol,sulpha-te (1:1)
l-Methyl-5-[[3-[3~ piperidinylme-thyl)phenoxy]propyl]
amino]-1~ 1,2,4-triazole-3-metilanol(300mg) was dissolved
in ethyl aceta-te ;20ml) with heating and the addition of a
few drops of ethanol to give a clear solution.
A 0.45 ml aliquot oE a hot solution of concentrated
sulphuric acid (1~1) in ethanol (9ml) was added dropwise.
The solid which separated on cooling and standing was
filtered off, washed with diethyl ester and dried in vacuo
to give the title compound as a white crystalline solid
(400mg)m.p. 170.
In a similar manner:
(b) A solution of the free base (300 mg) as in (a) above was
treated with a hot solution of tartaric acid (125mg) in
ethanol (lOml) to give the tartrate salt (2:1) as a white
crystalline solid (50 mg), m.p~ 144
(c) A solution of free base (300 mg) as in (a) above
was treated with ho-t solution of succinic acid (99mg) in
ethanol (lOml) to give the succinate salt (2:1) as a white
crystalline solid (150mg). m.p. 137.
- 68 -
1 Examples oE Pharmaceu-tical compositions according to the
invention are as follows:
(a) TABLETSmg/-tablet mg/tablet
Active incredient20.0 40-0
Microcrystalllne99.5 199.0
cellulose BPC
Magneslum stearate
B.P. 0.5 1-0
Compression weight 120.0 240.0
The drug is seived through a 250 ~m sieve, blended with the
excipients and compressed using 6.5 mm and 8.0 mm diameter
punches for the 20 and ~0 mg strengths respectively.
Tablets of other streng-ths may be prepared by increasing
the compression weight and using punches to suit.
The tablets may be film coated with suitable film
forming materials, e.g. methyl cellulose, ethyl cellulose
or hydroxypropylmethyl cellulose, using standard techniques.
Alternatively the tablets may be sugar coated.
` (b) CAPSULES mg/capsule
Active ingredient 20.0
**Sta-Rx 1500 Starch 79.5
Magnesium Stearate B.PØ5
Fill weight100.0
** A form of directly compressible starch supplied by
Colorcon Ltd. Orpington, Kent.
The active ingredien-t is sieved through a 250 ~Im
sieve and blended with other materials. The mix is filled
into No. 3. hard gelatin capsules using a suitable filling
machine. Other doses may be prepared by increasing the
fill weight and if necessary changing the
~ Trade Mark
- ~9 - ~
l capsule size to accommoda-te the increase.
(c) SUSTAINED RELF,ASE TABLETS mg/-tablet
Active ingredient ~0
*Cutina HR 25
I,actose B.P. 142.5
MacJnesium Steara-te B . P . 2.5
Compression weight 250.0
*Cutlna HR is a grade of microfine hydrogenated castor
oil supplied by Sipon Products Ltd., London.
The drug is sieved through a 250 ~m sieve and
blended with Cutina HR~ and lactose. The mixed powders
are moistened with Industrial Methylated Spirits 74
O.P., granules are made, dried, screened and blended with
the magnesium stearate. The lubricated granules are
compressed using ~.5 mm punches to produce tablets with a
hardness of not less than 10 Xp (Schleuniger tester).
(d) IN~ECTION FOR INTR~VENOUS ADMINISTRATION
% w/v
Active ingredient 0.25
Water for Injections BP to 100.00
Sodium chloride may be added to adjust -the
tonicity of the solution ana the pH may be adjusted to that
of maximum stability using either dilute acid or alkali.
The solution is prepared, clarified and filled
under nitrogen into appropriate sized ampoules sealed by
fusion of the glass. The injection is sterilised by
heating in an autoclave using one of the acceptable cycles.
Alternatively the solution may be sterilised by filtration
and filled into sterile ampoules under aseptic conditions.
~ Trade Mark
-~Q-
(e) SYRUP mg/5ml dose
Active ingredient 20.0 mg
Sucrose 2750.0 mg
Glycer:ine 500.0 mg
BufEer
Flavour ) as necessary
Colour
Preservative )
Distilled water to 5.0 ml
~ The active ingredient, buffer, flavour,
preservative and colour are dissolved in some of the
water. The remainder of the water is heated to
approximately 80C and the sucrose is dissolved in
this and cooled. The two solutions are mixed,
adjusted to volume and clarified by filtration.
