Note: Descriptions are shown in the official language in which they were submitted.
1 164457
BENZODIAZEPI~E COMPOUNDS A~D THEIR
USE AS PHARMACXUTICALS
This invention relates to novel cornpounds, a process for preparing
them,and their use as pharmaceuticals.
~ arious trfcyclic compounds with pharmaceutical properties have
already been investigated and these have been mainly of the tvpe that
comprfse two benzene nuclei. We have now dfscovered a new grou~ of
compounds having the following basic structure
The compounds of the invention are of the followfn~
formula (I)
or an acid addition salt thereof;
in which Rl, R2, R3 and R4 independently represent hydrogen, Cl_~ alkyl,
C2_4 alkenyl, C3_7 cycloalkyl, C3_7 cycloQlkyl
~ .
-2- ~ 1644.57
Cl_4 aL<vl, halogen, Cl_4 halo~lkyl, Cl_4 aL~anovl, nitro, amino, C2 4
acylamino, cy~no, hydroxyl, Cl_4 alkoxy, Cl_4 alkylthio, C~ haloalkoxy or
group of the formula -S02N(R8)2, ~02R8 or -S03R8 where R8 is Cl_4 alkvl,
Cl_4 halo~lkyl or optionally substituted phenyl; in which R5 is ~ group of the
formula
where R9 is hydrogen, C]_4 alkvl, C3_7 cvclo~lkYl, C3~7 cyCloalkYl C1_4
alkyl, Cl_4 haloalkyl, C2_4 alkenyl, Cl_~ alkanoyl, benzyl, cyano or option~lly
substituted phenyl, where R10 is hydrogen, Cl_~ alkyl or optionally substituted
phenyl and where n is O or l; in which R6 is hydrogen, Cl 10 alkyl, C3 7
cycloalkyl, C3 7 cycloallcyl Cl_4 alkyl, Cl_4 haloalkyl, benzyl, Cl 6 alkanoyl,
Cl_~ carbaL'coxy or benzoyl and in which R7 is one of the values of R6 or
halogen, nitro, cyano, amino or Cl 4 acylamino. The
aforesaid compounds of formula (I) are also disclosed and are claimed
in Canadian Application No. 362,328, filed October 14, 1980,
of which the present application is a divisional.
Compounds of formula (I) h~ve been found to possess useful
biological properties and the invention includes a compound of formula (n for
use as a pharmaceutical and especially for use in the treatment of disorders
o~ the central nervous system.
A particulQr group of compounds of formula (I~ is one in which Rl,
R2 and R3 independently represent hydrogen, Cl ,~
1 16d~4r~i7
--3--
alkyl, C2 4 alkenyl, h~logen, Cl_4 hsloalkvl, nitro, ~1 4 alkoxy, Cl a
haloalkoxy, Cl_~ alkylthio, Cl ,~ haloalkylsulphonvl or phenvlsulDhonyl iR~ is
hydrogen; R is hydrogen, Cl_6 alkyl, C3 7 cycloalkyl, C3 7 cycloal!~vl Cl 4
alkyl or benzyl; R7 is hydrogen or Cl_4 alkyl; i~9 is hydro~en, Cl 4 alkyl, ~3 7
cycloalkyl, C3 7 cycloalkyl Cl_4 alkyl or benzy~; and R10 is hvdrogen or Cl_4
aL~yl.
A preferred group of compounds is one of the following formula (II
~ 9
Rl N ~ NR
R ~ N ~R76 ( II )
or an acid addition salt thereof; in which Rl, R2 and R3 independentlv
represent hydrogen, Cl 4 alkyl, C2 4 alkenyl, halogen, Cl 4 haloalkyl, nitro,
Cl~ alkoxy, C1_4 alkylthio or phenylsulphonyl;R~ is hydrogen, Cl 10 alkyl,
C3_7 cycloalkyl, C3_7 cycloalkyl Cl_4 alkyl or benzyl; R7 is hydrogen or Cl 10
alkyl;and R is hydrogen, Cl 4 alkyl, C3_7 cycloalkyl, C3_7 cycloalkyl Cl_4
alkyl or benzyl.
A preferred group of compounds of formula (Il) is one in which Rl,
R2 and R3 independently represent hydrogen, halogen or Cl 4 haloalkvl; R6 is
Cl_6 alkyl, C3 7 cycloaL~yl or C3 7 cycloalkvl Cl .4 alkyl; R is hvdrogeniand
R9 is hydrogen, Cl_4 alkyl, C3_7 cyclo~kyl Cl_4 alkyl or benzvl,
.. , . , . . . ,. . ~
i 16~7
--4--
the compowlds in which R9 is hydrogen beinF! useful as intermec~iates in the
preparation of preferred compounds.
Within the scope of compounds defined in formula (II) there can be
listed compounds of especi~l interest, namely, those hQving one or more OI
the following fe~tures
(a) R2 is a halogen substituent, such as fluorine, chlorine or bromine~
and Rl and R3 are hydrogen.
(b) R2 snd R3 both represent halogen, especially fluorine or chlorine,
and Rl is hydrogen.
,o . ~c) R3 is hQlogen, especislly nuorine, and Rl and R2 are hydro~en.
(d) R is Cl_4 aL~yl, especially methvl or ethyl .
(e) R is hydrogen.
(f) R9 is methyl.
Specific examples of preferred compounds include
7-8romo-2,10 dihydr~2~nethyl-4~4-methyl-1-,oiperazinyl)pyrazolo
~3,4-b~ ~,5] benzodiazepine
7-Chloro-2-ethyl-2,10~ihydro-4~4-methyl-l~iperazinvl)pyrazolor3,4~1 n,51 hen
zodiazepine
7{~hloro-2,1G~ihydro-2-methyl-4~4-methyl-1-piperazinyl~pyrazolot3,4~1 n,51 be
nzodiazepine
7~8-Dichloro-2~10~ihydro-2-methyl-4~4-methyl-1-piperazinyl~pyrazolo~3~4-b
5] ~enzodiazepine
7-Fluoro-2-ethyl-2,10~ihydro-4-(4-methyl-1-piperazinyllpvrazolo[3,4-bl n,51 ben
zodiazepine
7-Fluoro-2,10-dihydro-2-methyl-4{4-methyl-1-piperazinvl~wrazolo~3,4~1 n,51 be
nzodiazepine
8-Fluoro-2,10-dihydro-2-methyl-4~4-methyl-l~iperazinyl~pvrazolo~3,4~1 ~1,51 be
nzodiazepine
.... . .. .. . . _ , . . . .
5 7
--5--
In the above general formulae, the term "Cl 1O ~lkvl" me~ns a
straig~t or branched chain alkyl group containing 1 to 10 carbon atoms and is
especi~lly, for example, methyl, ethyl, isopropyl, propyl, butvl, sec.butvl,
isobutyl, tert, but~l, pentyl and hexyl. A preferred alkyl group is "Cl 4
slkyl". The term "Cl_4 haloalkyl" means any su~h Rlkyl group substituted bv
one or more, preferably three halogen atoms, snd is espec;slly
trifluoromethyl. The terms "Cl_~ alkoxy" and "Cl_~ alkylthio" mean anv Ci_4
alkyl group attached through an oxygen or sulphur atom to a ring atom and
"Cl_~ halo lkoxy" means a Cl_4 alkoxy group substituted bv one or more,
preferabl~ three h~logen atoms,andis especially trifluorometho~. The term
"Cl ~1 carbalkoxy" means fl Cl ~ alkoxy group attached via a carbonvl group to
a ring atom. "Cl_4 Alkanoyl" includes the formyl ~roup and ~roups of the
formula RllCO where Rll is Cl_4 alkyl. The term "C~ 4 alkenyl" refers to
groups such as vinyl, Rllyl and butenyl. The term "amino" indicates a ~roup of
formula -NH2 snd also substituted amino groups such as mono-Cl_4
aL"ylamino and di~l_4 alkyl~mino groups. The term "C2_4 acylamino" means
an amino group substituted by a C2_4 acyl group, espec ally acrtyl. "C3 7
Cycloalkyl" me~ns a saturated ring having 3 to 7 carbon atoms in the rirg
such as cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl or cycloheptvl, which
can, in the group "C3 7 cyclo lkyl Cl_4 alkyl", be attached to the ring via an
alkyl chain having 1 to 4 carbon atoms. The term "optionally substituted
phenyl" me~ns a phenyl group which is unsubstituted or substituted by one or
more groups, for example, halogen, Cl~ haloalkyl, Cl 4 ~lkyl,Cl_4 alkoxv or
nitro. Specific examples of such substituents include chlorine,
trifluoromethyl, methyl ~nd methoxy.
4 ~ ~ 7
~6~
As indicated above, the compounds of the invention are useful both
in their free base and acid addition sal~ forms. The acid addition salts are
preferably the pharmaceutically acceptable, non-toxic addition salts with
suitable acids, such as those with inor~anic acids, for e~ample hvdrochloric,
hydrobromic, nitric, sulphuri~ or phosphoric acids, or with organic ~cids, such
as organic carboxylic acids, for example, glvcollic, maleic, hvdrox~naleic,
fumaric, malic, tartaric, citric or lactic acid, or organic sulphonic acids for
exarnple methanesulp~onic, ethanesulphonic,2-hydroxvethane sul~honic,
toluene~ulphonic or naphthalene-2~ulphonic acid. Apart from
pharmaceutical~y acceptable acid addition salts, other salts are also included
within the scope of acid addition salts such as, for example, those with picric
or oxalic acid, ~nce they may serve as intermediates in the purification of
the compounds or in the preparation of other, for example, pharmaceuticallv
acceptable, acid addition selts, or are useful for identification,
characterization or purification of the bases.
According to a further aspect of the invention there is provided a
process for producing a compound of formula ~n or an acid addition salt
thereof, which comprises
(a) reacting an amine of formula R5H with a compound of formula (ml
R ~ (111)
~7~ i ~ 5~
where Q represents a radical capable of being split off with the hvdro~en
atom of the amine R5H, optionally followed ~hen R6 or R9 is hydro~en by
reaction with a compound of the formula R6X or R9X respectiYely, X bein~ a
leaving group, and optionally followed when n is 0 ~y oxi~ation, or
(b) ring-closing a compound of formula (Iv!
R~--2~ 6 , _ (IV)
optionally followed when R6 or R9 :Ls hydrogen by reactio~ with a compound of
the formula R6X or R9X respectively, X being a leavillg group, and optionally
foll~ when n is 0 by c~idation; and where desired, forming an acid
ad~ition salt of the compound of formula (1) so produced.
This process is also disclosed, and is claimed, in
Canadian Patent Application No. 362,328, filed October 14,
1980, of which this application is a divisional.
The above processes are of a general type previous]y describe~ in
the literature (see standard treatises for references to acylation, ~lhylation,
oxidation and ring closure) and suitable Q and X radicals and appropriate
reaction conditions can be readily chosen.
It may be mentioned, for example, that in reaction (a) the radical Q
can be hydroxyl, thiol, an aLkoxy or alkylthio group containin~ 1 to 4 carhon
atoms, for example a methoxy or methylthio grou~, a haloFen atom~
especially a chlorine atom, 3n amino group or a mon~ or dialkyl~ubstituted
~mino group, ea~h alkyl substituent cor.taining 1 to 4 carbon stoms.
Preferably, Q ic hydroxyl, thiol,
--8--
Cl_4 alkoxy, Cl_4alkylthio, halogen or amino ~nd it is especially preferred
that Q is hvdroxyl, thiol or amino (NH2~. When Q is hvdroxyl or thiol, the
intermediates of formula (m~ exist predominantlv in their amide asld
thioamide forms:
O S
NH - C or NH - i
and when Q is amino the intermediates of formula ~m~ mav ~lso exist in the
imino form:
NH
NH - ~
When Q is hydroxyl, and the compound of formula ~m) is an amide,
reaction (a) can be accomplished in the presence of titanium tetrachloride
which hss the ability to react with the amine of formula R5H to form Q metal
amine complex. Other metal chlorides such as those of zirconium, hafnium
or vanadium may also be employed. The reaction is preferably carried out in
the presence o~ an acid binding agent such as a tertiar!r amine, for example,
triethylamine. Alternatively, the reaction can be carried out usin~ excess of
tl~ amine o~ formula R5H to act as an acid-binding agent. A suitPble
organic solvent such as toluene or ~hloro~enzene can be used ~s reaction
medium, although it has been fo~md that the
5 7
g
use of ~nisole is particularly desirable, ~t le~st as a co~olvent, in view OI its
ability to form a soluble complex ~ith TiC14.
If desired, elevated temperatures, for example up to 200C, can be
used to expedite the rea~ tion ~nd a preferred temperature ran~e for carryinF
out the reaction is from lD0C to 150C.
The amidines of formula (~II) (Q is NH2), can be in a salt form for
example as the hydrochloride, and they can be similarly reacted with amines
of formula R5H, optionally diluted with a solvent such as anisole,
dimethylformamide or dimethylsulphoxide, and optionally using a catalvst
such as TiC14 at a temperature range of 100 to 150. Alternatively the
amidine can be converted into the correspondin~ amide of formula tlII) (G~ is
OH) by ~kaline hydrolysis.
Thioam~des of formula (m~ ~ is SH~, iminothioethers, iminoethers
or iminohalides, o~ other derivstives containing active Q radic~ls as specified
&bove, tend to be more renctive towards the amire RSH and can usually be
teacted without the necessity for the presence of TiC14, but otherwise
employing the same conditions of temperature and solvent.
In reaction (b) compounds of formuls (IV~ are rin~closed by
employing, for example, the same conditions in terms of catalyst and solvent
as those described above for reaction (Q) and preferal~ly at a temperature of
150C to 200C. The compound~ of formula ~N) Pre conveniently prepared in
situ without isolation.
When the compound prepared by reaction (a~ or (b~ is one in which
R6 or R9 is hydrogen, it may be further reacted to provide other ~ompounds
of the invention. For example when R6 is
.. _ . _ . _ _ . __ ., _ . . . . . . .
5 7
--10--
hydrogen, the compo~d can be reacted with R6X bv ~onvention~ lation
or acylation tvpe methods, X being a leaving group. The compound is
dissolved in a suitable inert polar solvent such as ethanol and the rea~ent of
formula R6X added, the reaction mixture then bein~ heated under reflux in
the presence of ~ base. The group X can be a suitable reactive atom such a
chlorine, bromine or iodine, or a reactive group such as tosyl or mesyl.
Similarly, when R LS hydrogen, the ~ompo~d can be reacted with a reaFent
of formula R X in an inert solvent and in the presence of a base.
When the compound prepared by reaction (a) or ~ ~ is one in which n
a is O it may be oxidised to provide other compounds of the invention, that is,
the corresponding compound in which n is 1. Suitable oxidising agents include
for e~ample m-chloroperbenzoic acid and the rea~tion is preferably carried
out in an inert solvent such as for example dichloromethane at a temperature
of from -10C to +10C.
The compounds of formula (I) produced by the ahove processes m~y
be isolated E~ se or may be converted to their corresponding acid addition
salts using conventional methods.
The present invention, in a urther aspect, as
disclosed and claimed herei.n, provides compounds of
formula
Q
R1 N - C
R2'~"`H~N~NR6
where R , R and R3 independenely repre~ent hydrogen, halogen or
Cl 4haloalkyl, R6 is Cl ~alkyl, C3_7cycloalkyl or C3_7CYC1al~YlC1-6alkYl
-lOa-
~nd Q i6 -OH or -NH2- These compounds, which are useful as
intermediates for the preparations of compounds of formula (I~:
R5
wherein R , R2, R3 and R6 are as defined above; and in which
R is a group of the formula
R10
/7~ R9
N/
/ ~n
-lOb-
where R9 is hydrogen, Cl 4 alkyl, C3 7 cycloalkyl, C3_7
cycloalkyl Cl 4 alkyl, Cl 4 haloalkyl, C2_4 alkenyl, Cl 4
alkanoyl, benzyl, cyano or optionally substituted phenyl,
where R10 is hydrogen, Cl 4 alkyl or optionally substituted
phenyl, and where n is O or 1, are prepared by ring closing
a compound of formula
R3 H
where Z is CN, COOH or COOR12, Rl being a Cl 4 alkyl group.
Theami~sofformula(m)(~isOH)canbepreparedbyaprocess
which invoIves the ring-closure of ~ amino~sterof form~a (V)
R2~,~ (V)
5 7
where R12 is a Cl_4 alkyl group, emploving for example sodium
methylsulphinyl methanide in a s~table solvent such a dimethyl sulphoxide.
Alternatively amides of formula (m) (~ is OH) can be pre~ared bv
ring~losure of an ~mino-acid of formula (YI)
R~ R6 IVI)
employing for example dicyclohexvlc~bodiimide (DCC) in a suitable solvent
such as tetrahydrofuran. These amin~acids can be obtained from the esters
of formula (V) by basic hydrolysis using for example sodium hvdroxide in
ethanol.
The esters of formula (V) c~n be prepared by condensation of a
pyrazole compound of formula
R1 202~ R7
~6
~2 N~
r~ 7
-12-
with an ortho-halonitrobenzene of formula
R2 ~'~2
~3 Z
14
where Z is halogen, preferably fluorine, chlorine or bromine, in the presence
of R base~,for example~sodium hydrideJin ~ solvent such as tetrahydrofuran or
dimethylformamide, n~utyl lithium in tetrahydrofuran, potassium carbonate
in dimethylsulphoxide or with a tetralkylammonium salt in a two~hsse
system, to form a nitro ester of formula
~NO ~7
which can be reduced to the amino ester of formula fV) catalyticallv,
employing for instance hydrogen and palladium,or ctlemica11v, emp~oyinF for
example, stannous chloride and hydrogen ehloride in aqueous ethanol, or
ammonium poly~ulphide.
Similarly, the amidines of formula ~m~ S NH2~ c9n be ~repared
by conder6ation of a pyrazole of formul~
5 ~
NC ~F=~ R7
~ ~I ,NR
H2N
with an orth~haloni$robenzene as outlined above, followed hy simultaneous
reduction and ring-closure to the amidine of formula tm) employing for
e~ample stannous chloride and h~vdrogen chloride in aquesus ethanol or,
alternatively, by reduction with hydrogen and palladium or ammonium
polysulphide followed by acid~at~lysed rin~ closure.
Pyrszole starting materials used in the processes described above
are either known compounds, see for example J. Am. Chem. Soc. tl956) 78
784; Helv. Chim. Acta (1958) 411052; Helv. Chim. Acta (1959~ 42 349 and
763; German Patent 1,106,330 and British Patent 884,851; or can be Drepared
by conventional techniques from known compounds. The
ortho-halonitrobenzene intermediates are either commercially availa~le
can be simply prepared from commercially available su~stances.
Thioamides of formula (m) (Q is SH) c~n be prepared bv treatinF a
solution of the corresponding amide in an ~nhydrous basic solvent such as for
example pyridine with phosphorus pent~sulphide. Similarly, the amides can
be converted to iminothioethers7 iminoethers or iminohalides, or other
derivatives containing active Q radicRls, by tre~tment with conventional
9 ~ 5 ~
- 1 4-
reagents such as for example in ~he case of an iminoch]oride, phosphorus
pentachloride.
Compounds of formula (m~ are novel and, in p~rticular, those in
which Q ~ hydroxyl, thiol or amino are included as an aspect of the invention.
In reaction (b)~ the compounds of formula (IV) are novel and thev
are included as a further aspect of this invention. They can be prepare~ in
situ without isolation by reacting a compound of formula (V~ with an amine of
formula R5H such as by heating to a temperature between 30~ ~d 120C,
~or example 100C, in R suitable solvent such as for example anisole and
employing TiC14 as catalyst~ or by convention~l methods from compounds of
formula (V) or ~VI).
It will be understood that electrophilic substitution on the aromatic
nucleus can be carried out on compounds of formulae (I), (m1 or (IV) in
~onventional manner to produce other deriv&tives. For instance, an amide of
formula (m) can be acetylated using acetyl chloride and stannic chlori~e or
halogenated employing for example N-chlorosuccinimide, to give the
corresponding acetyl or chloro derivatives. Products of forrnula (I) in which
Rl, R~, R3 or R4 is amino can be acylated or alkylated in conventional
manner to form the corresponding acylamino or all~ylamino derivatives.
As an illustration of the preparation of represent~ive compo~ds of
the invention the fo~lowing reaction scheme is given, in which various routes
for preparing a 4~4 a~ piperazinyl)
-2,10-dihydrowrazolo[3,4~ [1,5]benæodiazepine are shown:
.. . _ ~ . . . ... .
- 1 5
R 02~B 1~ B~ L~6
R3 ~F H~Pd
H N 25~Q3 R2 ~NH2
B~N ~ N/ DY30 R3~N~ N/
R \ 2 Rl CO~ / ~NR
J ~ \ }~R9 R[~ NY'2 ~ ~:_
}~2C3 \TiC14- R ~ ~ ~/ TiCl -a~isole
~tOX-~20 ~ R ~ rc~lux
R / ~ E 7
-- N~NG~ X ~ 7
DM R~ ~N~B6
. SnC12-HCl Rl
E tOH R2 ~NO 2
Rl ~3 ~F N 7
~ ~\ 6 H2N ~R
R3~ ~ ;~ Nf
5 7
The compounds of the invention have useful central nervous system activitv
RS demonstrated by well~cnown test procedures. In behaYiour~ studies in
mice, for instance, the compounds of the invention described in the followin~
Examples were observed to produoe h~7pothermia and acti~ty decrease at a
dose range of 12.5 to 200 mg/kg p.o. Preferred comPounds have also been
tested following chronic administration when Q behavioural supersensitivity is
produced to locally injected dopamine in a manner similar to thRt described in
Psychopharmacologia (1975) 45151-155. The activity profile observed in this
test along with the lack o~ re~ponse in tests such QS the production of
catalepsy indicate that these compoun~s possess useful central nervous
system activity and do not produce certain undesirable side effects. For
some time it has been recognised that conventional central nervous sVstem
drugs can have undesirable characteristics and the potentiRl a~sence of these
side effects in compounds according to the invention represents a siFni-ficant
advance. In addition, compounds of the invention possess unexpected
anxiolytic activity as demonstrated by their profile in the test described in
Neuropharmacology (1979)18 689~95. The compomlds of formula (I`) and acid
addition salts thereof are thus, potent centrally acting compounds with
neuroleptic, sedative~ relaxant, anxidytic or anti-emetic properties. l'hese
~o properties, coupled with their low toxicity render them useful in the
treatment of mild anxiety states and certain kinds of psychotic conditions
such a schizophrenia and acute mania~
_ _ _ .. . _ . _ _, _ . . ~, .. . . . . . . .
4 ~ 7
-17-
~ he compo~ds of this invention Ell'e effective over Q wide dosa~ze
range, the actual dose administered being depen~ent on such factors as th
particular compour,d being used, the condition bein~ treated and ths tvPe and
size of mammal being treated. However, the dosage required will norm 11v
fall within the range of 0.5 to 50 mg/kg per dav, for example in the treatment
of adult humans, do6ages of from 5 to ~00 mg per clay may be used.
The compounds of the invention will normally be administered
orally or by injection and, for this purpose, the compounds will usuall~ he
utilised in the form of a pharmaceutical cornposition. Such compositions ~re
prepared in a manner well known in the pharmaceutic 1 art ~nd compr;~e at
least one active compound. Accordingly the invention includes a
pharmaceutical composition comprising as active ingredient Q compound of
formula I or an acid addition salt thereof, associated with 8 pharmaceuticsl]v
acceptable carrier. In making the compositions of the invention, the active
ingredient will usually be mixed with a cQrrier, or diluted by a carrier, or
enclosed within a carrier which may be in the form of a capsule, sachet,
paper or other container. When the carrier serves as a diluent, it màv be a
solid, semi~olid or liquid material which acts as a vehicle, excipient or
medium for the active ingredient. Some examples of suitable carriers are
lactose, dextrose, sucrose, sorbitol, mannitol, starches, gurn acacia, c~lcium
phosphate, alginates, tragacanth, gelatin, syrup, methyl cellulose, methyl-
and propyl-hydroxvbenzoate, talc, magnesium stearate or mineral oil. The
compositions of the invention may, if desirPd, be formulated so &s to provide
quick, sustained or delayed release of the ~ctive in~redient after
administration to the patient.
_ . .. . , ..... . . _ . .... _ . . . .
-
5 7
~18--
Depending on the route of administration, the foregoin~
compositlons may be formulated as tablets, capsules or suspensions for oral
use and injection solutions for parenteral use or as suppositories. Preferablv
the compositions are formulated in a do6a~e ~mit form, each dosa2e
containing from l to 200 mg, more usuall 5 to 100 m~, of the active
ingredi ent.
The following Examples illustrate the invention:
-19-
EXAMPLE 1
Ethyl 3~4-fluoro-2-nitroanilino~-1-methylpyrazole ~arboxylate
A solution of ethyl 3-amino-1-methvlpvrazole-4~arhoxv1ate
tHelv. Chim. Acta (1959) 42 349~(17g~ in dry tetrahv~lrofuran (250ml~ w~s
stirred under nitrogen at -10C. n-Butyl lithium (75ml of 1.84 molar solution
in hexane~ was added at -lO to -15C. The mixture was stirred at -15C for 10
minutes and a solution of 2,5~ifluoronitrobenzene (16g! in dry
tetrahydrofuran (50ml) was added at -15 to -10C. The solution was warmed
to r oom temperature and stirred for 1 hour. The ink-~lue solution ~as poured
into 500 ml of a 1:1 mixture of hydrochloric acid (2M~ and ic~brine, ex~racted
with chloroforrn (3 x 250ml), washed with water (2 x 250mll, ~ried with
magnesium sulphate and evaporated to drvness. The brick-red residue WQS
crystallised from ethanol (800ml) to give the title compound havin~ a m.p. of
162C.
The following compounds were similarly prepared usin~ the
above process. In each case the recrystallisation solvent is ~iven in
parenthesis.
Ethyl l-methyl-3~4,5~ifluoro-2-nitroanilino) pyr~zole-4~arboxy1ate, m.p.
141C (isopropanol)
Ethyl l-ethyl-3~4-fluoro-2-nitroanilino) pyrazole-4~arbo2~1ate, m.D. 136C
(ethanol).
Ethyl l-methyl-3~2-nitro-4-trifluoromethylQnilino) pyrazole-4~arboxvlate,
m.p. 158C (isopropanol).
Ethyl 3~5-fluoro-2-nitroanilino~1-methylpyrazole-4~arboxylate, m.o. 165C
(ethanol).
.. . . . . . . ... .
-20-
Ethyl 3~4-fluoro-~-nitroanilino)-l~l~ropyl~pvrazo.e-4~arboxvlate, m.p.
109C (ethanol~.
Ethyl 3~4-fluoro-2-nitroanilino)-1~1-methylethyl)pvrazol~4~arboxvlate,
m.p. 106.5~C (ethanol).
Ethyl 3~-fluoro-2-nitroanilino)-1l1-hexyl~pyrazole-4~arboxylate, m.p. 73 1
(ethanol~.
Ethyl 3~2-nitrosn~ino)-1-methylpyrRzole-4-carboxylate, m.p. 146 C
(isopropanol~ .
EXAMPLE 2~
3~4-Chloro-2-nitroanilino)-1-m eth~lDvr~zole-4~arbonitrile
.
3-Amino-1-methylpyrazole-4-carbonitrile (Helv. Chim. Acta (1959) 42 763)
(3.66g) was stirred in ~ry tetrshydrofuran (40ml~. Sodium h~7dride (509f, oil
dispersion, 2.28g) was added snd the mixture was stirred for 10 minutes.
2,5-Dichloronitrobenzene t5.76g~ was added and the solution stirred under
nitrogen for ~0 hours. Water was added dropwise to destrov any excess
sodium hydride, then the solution was poured`on to a mixture of ice and dilute
hydrochloric acid. After standing for 1 hour the brick-red precipitate was
f~tered, washed with water and dried. Crystallisntion from ethanol-ethvl
scetate afforded the product m.p. 205C.
The following compounds were simil~rly prepsred. In each case
the recrystallisation solvent is given in parenthesis.
3~4-Iodo-2-nitroanilino~ methylpyrszol~4-carbonitrile, m.o. 212C
(ethanol-ethyl acetate)
5 ~
-21 -
3~5~hloro-2-nitrcanilino!-1-methvlpyrazol~4~arhonitrile, m.p. 187C
(ethanol-ethyl acetate~
3~4,5-Dichloro-2-nitroanilino)-1-methylpyrazole-4~arbonitrile, m.D. 225C.
(ethanol~thyl acetate)
3~4-33rom~2-nitroanilino)-1-methylpyrazole-4~arbonitrile, m~D. 208C
(ethanol-ethyl acetate)
3~4-Trinuoromethyl-2-nitroanilino)-1-methylpvrazol~4-carbonitrile, m.P.
183C-i84C (ethanol~
3{4~hloro-2-nitroanilino)-l~thylpyrazol~4~arbonitrile, m.p. 1~2C
(ethanol-ethyl~cetate)
3~4-Chloro-2-nitroanilino~ 3-methyl-1-propyl)pyrazol~4~arbonitrile, m.p.
151C (ethanol)
3-(4~hloro-2-nitroanilino)-l~yclopentylpyrazole-~arbonitrile, m.p. 145 C
(ethanol)
3-(4-Fluoro-2-nitroanilino)-1-methylpyrazole-4~arbonitrile, m.p. 174C
(ethanol)
3~3~hloro-2-nitroanilino)-1-methylpyrazol~4~arbonitrile, m.p. 190C
(ethanol)
l-Methyl-3~2,4~initro~nilino)pyrazole-4~arbonitrile, m.p. 224C
(ethanol-ethyl acetate)
EXAMPLE 3
Ethyl 1,5~imethyl-3-(4-lluoro-2-nitroan lino~Dvrazole~art~o~vlate
Ethyl 3-amino-1,5-dimethylpyr~zol~4~arboxy1ate ~5.5g),
2~5-difluoronitrobenzene (6.6g) and anhydrous potassium ~arbonate (g.
were stirred in dimethylsulphox~de (60 ml) under dry
~ 3 ~;4~5~
-22-
nitrogen at ,0C for 20 hours. The mixture was poured on to 300 ml of
ic~cold dilute hydrochloric acid, extracted with chloroform (3x~, washed with
water ~2x), dried with magnesium sulphate and the solvent evaporated under
reduced pressure. The yellow~rown residue was crystallised from ethanol to
give the title compound havin~ a m.p. o~ 174C.
EXA~qPLE 4
l-Methvl-3~2~itroanilino)Dvrazole~arbonitrile
3-Amino-l-methylpyrazole-4~Qrbonitrile (Helv. Chim. Acta ~1959) a2, 763)
t7.5g) and 2-fluoronitrobenzene (8.4g) were stirred in toluene tl20ml~ with
I'Adogen 464 ~3.0g) and potassium carhonate (16.5~ at 60C. 50% Sodium
hydroxide solution (0.1 ml~ was added and the mixture was heated un~ler refl~lx
for a hours. The mixture was poured on to dilute hydrochloric acid,
extrscted, the aqueous layer washed with toluene and the combined extracts
washed twice with water. After evaporation the residue was crystallised
from ethanol (750 ml) to give the title compound, m.p. 172C.
_XAMPLE 5
Ethvl 3~2-amino~-trifluoromethvlanilino)-1-methvl~vrazole~_arboxvlate
Ethyl l-methyl-3~2-nitr~4-trifluoromethylanilino~pyrazole-4-carboxvlate
(9.2g) was hydrogenated at 60 poS~i~ in a mixture o~ ethyl acetate (200 ml) and
ethanol (50 ml) over 10% palladium on charcoal ~l.Og~. The catalyst was
removed by filtration, the solvent
* Trademark for trimethyl C ,Cl quaternary amm~nium chloride,
it has a nu~ber of uses inclua~g use as a chemical intermediate.
, . . . _ .. _ . . . . . .
5 7
--23~
evaporated and the residue crystallised from carbon tetrachloride to ~ive the
title compound m.p. 162C.
The following compounds were s;milarlq preDared and used in
Examples 10 and 13 without purification.
Ethyl 3~2-amino-4-fluoroanilino)-1-methylpyrazole-4-carhoxylate.
Ethyl 3 (2-amino~-fluoroanilino~1,5~im ethylpyrazole~-carboxvlate.
Ethyl 3~2-amino-4-fluoroanilino)-1-ethylpyrazole-4-carboxylate.
Ethyl 3~2-amino-5-fluoroanilino~l-methylpyrazole~-carl~oxvlate.
Ethyl 3~2-amino-4,5~ifluoroanilino)-1-methylpyrazole-4~arbo~1ate.
Ethyl 3~2-amino~-fluoroanilino~l-(l~ropyl~pyrazole~-carboxvlate.
Ethyl 3~2-amino-4-fluoroanilino?-1~1-methylethyl~pyrazole-4-carbox~late.
Ethyl 3~(2-amino~-fluoroanilino~l~l-hexyl~pyrazole 4-carboxylate.
Ethyl 3~2-aminoanilino)-1-methylpyrazole 4-carboxylate.
EXAMPLE 6.
3-(2-Amino~-nitroanilino)-l- ethvlDvrazole~arbonitrile
l-Methyl-3~2,4~initroanilino)pyrazole-4~arbonitrile (2.88g~ was stirred in a
mixture of 0.88 ammonia solution (60ml~, water (9Oml~ and ethanol t~Oml~
under ren ~c whilst a slow stream of hydrogen sulphide gas was bubbled
through for 2 hours. The mixture was cooled, filtered and the residue
crystallised from ethyl acetate- n-hexane to give the title compound m.p.
:~04C
.. . . _, _ _ _ . . . . . .. . .
1 1~4~7
-2~-
- EXAMPLE 7.
4-Methvl-1~3-~2-ami~o~-trifluoromethvlAnilino~ methvlDvrazole
4~arbonvl~DiDerazine
-
Ethyl 3~2-amino-4-trifluoromethylanilino~-1-methylpyrazole-4~arboxylate
(4.75g) was stirred in a mixture of ~-methylpiperazine (25ml~ and aniso]e
~65ml3. A solution of titanium tetrachloride (4.2ml) in anisole (20ml) was
added ~nd the mixture was stirred under nitrogen at 65C for 30 minutes.
mixture of isopro~anol (25ml) and 0.88 ammonia solution (25ml) was added
and the stirred mixture cooled to 25~C. The precipitate was removed by
filtration, washing with ethyl acetate. The combined filtrates were washed
with water (3X), dried over magnesium sulphate, the solvent evaporated and
the residue crystallised from acetonitrile to give the title compound m.p.
170C.
Other examples of this type were prepared in situ and cyclised as in ExamDle
13.
EXAMPLE 8
4-Amino-7~hloro-2.10-dihvdro-2-methvl~vrazolo r3~4-bl n 51 henzodiazeDine
To 1-methyl-3~4-chloro-2-nitroanilino~pyrazole-4~arbonitrile (16g~ stirred in
ethanol (500 ml) was added a solution of anhydrous stannous chloride t33.1g~ in
concentrated hydrochloric acid (176ml). The mîxture w~s heated under reflux
for 2 hours, cooled, f~tered and crystallised from methylated spirits (1 litre~
to give
_ . _ . _ .. .. . . . . _ ... . . . . .
-25-
the title compo~d as its hydrochloride salt m.p.~ 260C. 2.0~ of the
hydrochloride salt was phrtitioned between dilute ammonia solution ancl
chloroform. The organic phase was washed with water, dried with
magnesi~lm sulphate, evaporated and the residue cryst~llised ~rsm
chlorofor~n-n-hexane to give the title compo~md as the free base m.p. 240C.
The following compounds were similarly prepared and used as the
hydrochlorides without purification in Example iS.
4-Amin~2,10~ihydr~7-iodo-2~nethylpyrazolo[3,4~ ~1,51benzodia2epine
4-Amino-8~hloro-2,10-dihydro-2-methylpyrazolo
[3,4~] ~1,5]benzodiazepine
4-Amino-7,8~ichloro-2,1Wihydro-2-methylpyrazolo[3,4~1 ~1,51 benzodiazepine
4-Amino-7-brom~2,10-dihydro-2-methylpyrazolo[3,4-bl [1,51benzodiazepine
4-Amino-2~lo~ihydro-7-trifluoromethyl-2-methylpyrazlolor3~4~l ~1,51 henzodiaze
pine
4-Amino-7~hloro-2-ethyl-2,10~ihydropyrazolo[3,4-bl n,51 t~enzodiazeDine
4-Amino-7-chloro-2,10-dihydro-2-S2-m ethyl-l-propyl~pyrazolo
[3,4~] [195] benzodiazepine
4-Amino-7~hloro-2-cyclopentyl-2,10-dihydropyrazolor3,4-bl i],51 benzodiazepine
4-Amin~7-fluoro-2,10-dihydr~2~nethylpyrazolor3,4-bl n,51 benzodiazepine
4-Amino-6~hlo~o-2,10~ihydr~2-methylpyrazolo~3;4~1 ~l,Sl benzodiazepine
,, _ .. . _ _ .. . .. . .. .. .. . . .
5 7
-26-
EXAMPLE 9
4-Amino-2,10~ vdro-2-methvl-7-nitro~vrazolo~3,4~1 [1,51 benzodiaze~ine
hvdrochloride
3~2-Amino-4~itroanilino)-1-methylpyrazole-4~ar~onitrile (250 mg~ was
heated unde~ reflux in a mixture of isopropanol (10 ml~ and concentrated
hydrochloric acid (1 ml) for 20 hours. The solution was evaporated under
reduced pressure and the residue crystallised from methylated spirits to ~ive
the title compo~d m.p.>260.
EXAMPLE 10
7-Fluoro-2-methyl-2,~,5,10-tetrahvdro~vrazolo
[3.4~1 n,5] benzodiazeDin~-one
A solution of sodium methyl sulphinyl methanide was generated bv stirring
sodium hydride (50% oil disper~non, 1.5~ in dry dimethylsulphoxi~e ~15 ml) at
65C until gas evolution ceased. A solution of ethyl
3~2-smino~-nuoroanilino)-1- ~
methylpyrazol~4-carboxylate (2.7g~ dissolved in dry dimethyl sulphoxide (5
ml) was added dropwise and the mixture stirred at 65C for 2~ minutes. The
mixture was poured on to excess ice-water, filtered and dried to give the title
compound which was crystallised from chloroform-hexane m.p. 264C.
EXAMPLl~ D
7-chlor~2~4~5~lo-tetrah~dro-2-methv~ vrazolo~3~4~ln.51benzodiaze~in~one
4-Amin~7~hloro-2,10~ihydro-2-m ethylpyrazold394~~ 1 benzodiazepine
.. _ _ ~ , _ . . , . . . . , . . _ . . .
5 7
-27~
hydrochloride (11.3 g? and pota~sium carbonate (16.8 ~ were heated under
reflux in a mixture of ethanol f200 ml~ and water (20 ml) for 48 hours. Water
(30û ml) was added and the solution eooled. Tlle precipitate was crystallised
from acetic acid to give the title compo~d m.p.~260C
EXAMPLE 1 2
7 Ch oro-2,4.5~10-tetrahvdro-2-methvlpvrazolo~324~1 n,~ benZodiazeDine~-th
one
~hloro-2,4,5,10-tetrahydro-2-methylpyrazoloi~,4,bl n,51 henzodiazepine-4-one
(7.2 g) was added to a stirred solution of phosphoru5 pentasulphide f6.5 g~ in
~0 anhydrous pyridine (145 ml). The mixture was heated under reflu~ for 1.5
hours, poured on to ice, and the precipitate crystallised from chloroform - -
_methanol to yield the title compound m.p.~260C
l~XAMPLE 13
2-Ethvl-7-fluoro-2,10~ihvdro~4-methvl-l~iDerazinvl)pvrazolor3,4-bl rl,Sl benz
odiazee~
-
Ethyl 3~2-amin~4-fluoroanilino~l-ethylpyrazole-4~arboxylate (2.~4g~ was
dissolved in a mixtur~ of N-methyl piperazine /12.5ml.~ and anisole (~Oml~.
Titanium tetrachlor;de t3ml~ in anisole (12ml) was added, dropwise, and the
stirred solution was heated at reflux under an atmosphere of dry nitrogen for
24 hours. 'rhe mixture was cooled to 60C and ~ mixture of isopropsnol
(lOmV and 0.~8 ammonia solution (lOmV cautiously adcled. This mixture WRS
allowed to cool to room temperature over 1 hour, then filtered through a pad
-~9~ 5 ~ .
o~'Celite,"whilst washing with ethyl ~cetate. The filtrate was washed ~ith
water (3x), drie~ over m~nesium sulphate and the solvent removed. The
re~idue was f~tered through a short column of Florisil, elutin~ with ethvl
~cetate. After removal of solvent the title product was crvstal]ised from
acetonitrile m.p. 181G.
The followinF compo~ds were similarlv prepared:
_
7-Fluoro-2,10~ihydr~2,3~imethvl 4~4 ;nethyl-l-piperazinyl!pyrazolo
[3,4-b~ [195~ benzodiazepine, m.p. 234C (acetonitrile)
7{~hloro-2,10~ihvdro-2-methyl-4~4-methv!-l~iperazinyl~pyrazolo
[3,4~ [l,S] benzodiazepine, m.p. 107-109C (acetonitrile)
8-Fluoro-2,10~ihydro-2-m ethvl-4~4-~nethyl-l~iperazinvl~pvrazolo
13,4~ [l,Sl benzodiazepine, m.p. 192C (acetonitrile)
7,8-Difluoro-2,10-dihydro-~ methyl-4~4-methyl-l-piperazinyl~p~yrazolor3~4
5] benzodiazepine, m.p. 214C (acetonitrile).
7-Fluoro-2,10-dihydro-4-(4-methyl-1-piperazinyl~-2~1~ropvl)pvrazolor~,4~1 ~],51
b~nz~diazepine, m.p. 146C (a~etonitr~e~.
7-Fluoro-2,10-dihydro-2-(1-methylethyl!~4-methyl-1-piperazinyl)pvrazolo~,4-
b~ 11,5] benzodiazepine, m.p. 74-76C(cyclohexane-n-hexanel
7-Fluor~2~1-he2~yl)-2,1û~ihydro 4~4 rnethyl-l~iperazinyl)pyrazolo~3,4~1 ~l,Slb
enzodiazepine, m.p. 99C (cyciohexane~exane).
2,10-Dihydro-2 rnethyl~4 rnethyl-l~iperazinyl)pyrazolor3,4~1 ll,Slbenzodiaze
pine, m.p. 212C (scetonitrile)
EXAMPLE 1 4
?-Fluoro-2~10~ v~dro 2-methvl~-(4-methvl~ ' D~---l-
13 4~] n.5~ benzodiazeDine and citrate salt.
7-Fluor~2,4,5,10-tetrahydro-2~nethylpyrazolo [~4-bl [1,51
* Trademark for diatomaceous earth.
** Trademark for a highly selective adsorbent of magnesium silicate
in the fonm of hard white granules,
I :L64457
--29--
benzodiazepin-4~ne (0.9Sg) was stirred in a mixture of N-methvlpiperazine
(lOml~ and anisole (15ml!~ A solution of ti~anium tetrachloride (0.~5 ml~ in
anisole (lOml) was added and the mixture stirred under nitro~en at 130C for 2
hours, poured on to ice dilute ammonia solution and extra~ted into methylene
chloride. The extract was washed with water ~3x~, dried and evaporated.
The residue was chromatographed on'Plorisil"elutin~ with ethyl acetate and
crystallised from acetonitr~e, m.p. 192C~
The citrate salt wa~; prepared by adding a solution of citric aeid in eth~nol to
a solution of the title compound in a 1:1 mixture of ethano~ and ethyl acetate
m.p. 138C (softens)
EXAMPLE 15
2,10-Dihydro-7-iodo-?-methvl~4-methvl-l-Diperazinvl~p~7razolor~.4~1 1l~5l t-en
zodisze~ine
To a mixture of N-methylpiperazine ~10 ml~, dimethylsulphoxide ~25 ml~ and
toluene (25 ml~ through which nitrogen had been bubbled for ~0 minutes was
added 4-amino-2,10-dihydro-7-iodo-2-methylpyrszolo
~3,4-b] [1,5~ benzodiazepine hydrochloride (3.84 g). The stirred mixture ~vas
hested under nitrogen at 120C for 20 hours. The mixture was cooled to 60C
and water (25 ml) added. The residue was filtered, drie~ and crystPllised
from chloroform-n-hexane m.p. 113C.
The following compounds were similarly prepared:
8{~hloro-2,10-dihydro-2-methyl-4 (4~methyl-1-piperazinyl)pyrazolor~,4~~ s1 be
nzodiazepine, m.p. 221C (chlsroform~-hexane).
7,8-Dichloro-2,10~ihydr~2~nethyl-4~4-methyl-l~iperazinvl~pvrazo]o
.. . . _ , .. . ... .. .. .. . . . .
5 7
-30-
[3,4~] ~1,5] benzodiazepine, m.P. 158C (acetonitrile~
7-8romo-2,10~ihydro-2-methyl-4~4-rnethvl-1-,Diperazinvl~pvrazolo~3,4~1 ~l,hl~e
nzodiazepine, m.p. 162C (acetonitrile)
2,10-Dihydro-7-trifluoromethyl-2-methyl-4-(4-methyl-1-piperazinyl)pyrQzolo~3,~
-b] n,5~ benzodiazepine, m.p. 129-130 C (ethyl acetat~hexane~
7~hloro-2-ethyl-2,10~ihydro~4-methyl~l-piperazinvl~pyrazolo~3,4~1 [l~5ll~en
zodiazepine, m.p. 165C (acetonitrile)
7~hloro-2,10-dihydro-4 (4-methyl-l~iperazinyl~2~2-methyl-1-propyl~pyrazolo~
3,4~] [1,5] ben~odiazepine, m.p. 161C (aeetonitrile)
7~oro~2-cy~lopenty~ o~ihydro-4~4-methv~ perazinyl~p~razolor3~4~l r
1,5] benzodiazepine, m.p. 151C (acetonitrile~
7-Fluoro-2,10-dihydro-2-m ethyl-4~1~ip e~azinyl~pyrazolo[3,4-bl rL 51 benzodiazep
ine, m.p. 183-185C (acetonitrile)
6-chloro-2~lo-dihydro-2-methyl~-(4-methyl-l~iperazinyl)~3~4-b1 ~l~5
benzodiazepine, rn.p~ 214C (chloroform-n-hexane~
-
EXAMPLE 16
7~hloro-2,10~ihvdro-2-methyl~4-methvl-l~iDerazinvllpvrazolor3,4,~1 n.51 b
enzodiazepine
7-Chloro-2,4,5,10-tetrahydro-2-methyl-4~4-methyl-l~iperazinyl)pvra~olor8,4
] n,5~ benzodiazepin-4-thione(0.265g! was heated under reflux in
N-methylpiperazine (~ ml) for 20 hollrs. The cooled mi~ture was dissolved in
lM hydrochloric acid, washed with ethyl acetate (2X~, basified with 0.88
ammoniQ and extracted into dichlorometllane. The extract was washed with
water, dried with magnesiusn sulphate snd evaporated to le~ve a residue
whlch was crystallised from chloroform-n-hexane m.p. 173-176C
.... . . .. _ ., . _ _ .. . . _ . . . . . . . .
5 7
-31 -
EXAMPLE 17
4~4-CvcloDroDvlmethvl~ iDerazinvl~-7-fluoro-~-methvl-2,10-dihvdroDvrszolo
[3.4~1 ~1. 51 benzodiaz eDine
A solution of 7-fluoro~2,10~ihydro-2-methyl~4-
(l-piperazinyl)pyr~zolo[3,4-bl [1,5jbenzodiazepine tl.Og),
bromomethylcyclopropane (0.5g~ and triethylamine (0.0375~) in ~cetonitrile
(30 ml) was stirred at ambient temperature for 20 hours. The solution w~
poured into water and the product extracted with chloroform (3X). The
organic extract was washed with saturated brine and water, dried over
magnesium s~phate, the solvent removed and the residue crvst llised from
ethyl acetate to give the title compound m.p. 188-189C
4~4-8enzyl-l~iperazinyl)-7-fluoro-2,10-dihydro-2 methyl~vrazolor~ n,.~ e
nzodiazepine was similarly prepared, m.p. 241-245C (ethyl acetat~diethyl
ether)
EXAMPLE 18
4~7-Fluoro-~,lO~ihydro2-methyl~vrazolo[3,4~1 n,51
benzodiazeDin~-yl~-l-methvl Diperazin~l-oxide monohvdrate
7-Fluoro-2,10-dihydro-2-m ethyl~4-m ethyl~
piper~zinyl~yrazolo~3,4-b] n,51 benzodi~zepine ~2.0g~ was stirred in
dichlorometh~e (50 ml) at 0-5C whilst m~hloroperbenzoic acid (l.~g~ was
added in portions. The solution was stirred for 30 minutes then filtered
through a column of basic alumina~,eluting with 9:1 chloroform: methanol to
give,afte3 remov~l of the solYent and crystallisation from acetonitrile~iethyl
ether,the title compound m.p. 228
.
-32
The following formulations were prepared emplovin~
7-fluoro-2,10~ihydro-2-methyl-4~4-methyl-1-piper~zin~l~wrazolo
~3,4~] ~1~5] benzodiazepine as the active ingredient. Formulations containiny
other active ingredients of the invention can be prepared in a similar manner
EXAMPLE 19
Tablets each containg iO mg of active ingredient were made up as follows
Active ingredient 10 rng
Starch 45 mg
M icr;:~crystal1ine
cellulo~e 35 mg
Polyvinylpyrrolidone 4 mg
(as 1096 solution in
water)
Sodium carboxymethyl
starch 4.5 mg
Magnesium stearate 0.5 mg
Tslc 1 mR'
Total 100 mg
The active ingredient, starch and cellulose were passed through a No. 44 mesh B.S.
sieve and mixed thoroughly. The solution of polvvinylpyrrolidone was mixed with t11e
resultant powders which were then passed through a No. 12 mesh B.S. sieve. The
granules so produced were dried at 50~0C and passed through a No. 16 mesh B.S.
sieveO The sodium c~rboxyme~hyl starch, magnesium stearate and talc, previously
passed through a No. 60 mesh B.5. sieve, were then added to the granules
- 3 ~-
which, after mixing, were comp~essed on a tablet machine to yield tablets eacl
weighting 100 mg.
EXAMPLE 20
CQPSU1eS eaeh containing 20 mg of medichment were made as ~ollows
Active ingredient 20 mg
Starch 89 mg
Microcrystalline
cellulose 89 mg
Magnesium stearate 2 mg
Total 200 m~
The active ingredient, cellulose, starch and magnesium stearate were
passed tho~lgh a No. 44 mesh B.S~ sieve and filled into hard gelatin capsules in 700
mg quantities.
EXAMPLE 21
Suppositories each containing 25 mg of active ingredient were macle as follows
Medicament 25 mg
Saturated fatty acid
glycerides to 2,000 mg
The active ingredient was passed throu~h ~ No. R0 mesh B.S. sieve and
suspended in the satura~ed fatty acid glycerides previously melted usinF the
minimum heat necessary. The mixture was then poured into a suppositorv mould of
nominal 2 g capacity and allowed to cool.
. . ~
5 7
--34--
A T~ P LE 2 2
Suspensions each containing 5 mg of medicament per 5 ml dose were
made as follows
Medicament 5 mg
Sodium carboxymethyl
celllllose 50 mg
Syr-up 1.25 ml
Benzoic acid solution 0.10 ml
Flavour q-5-
Colour q.s.
Purified wate~ to S ml
The medicament was passed through a No. 44 mesh B.S. sieve and
mixed with the sodium carboxymethylcellulose and svrup to ~orm a smooth paste.
The benzoic acid solution, flavour and colour were diluted with some of the water
and added, with stirring. Sufficient water was then added to produce the required
volume.
.., _ .. ~ . . . .. . . .
.
