Note: Descriptions are shown in the official language in which they were submitted.
~ 4~ ~ ~
This invention relates to new bornane derivatives
and to processes for their preparation, and in parti~ular
to lO-bornanamine and 7,7-dimethylnorbornan-1-amines and
to derivatives thereof.
7,7-Dimethylnorbornan-l-amine (i.e. l-amino-7,7-dimethyl-
~2,2,1~-bicycloheptane) is a known compound and has the
structure:
Nl 2
5~J3
10-Bornanamine (i.e. l-aminomethyl-7,7-dimethyl-
l [2,2,1~-bicycloheptane) is also a known compound and has
the structure:
5 ~ 3 II
No pharmaceutical activity has previously been
ascribed to these two compounds.
-2-
~ ~ .
~r
~(~6~92~3
.
Antiviral activity of varying degrees has hitherto
been shown~in compo~nds having a wide variety of structures.
Activity against rhino viruses in particular is not
uncommon but activity against the more important influenza
5 viruses is rare. In tests we ha~e carried out we have
surprisingly found good activity in the 10-bornanamine and
7,7-dimethylnorbornan-1-amine series against influenza
viruses, particularly the H2N2 and H3N2 types, for example
Iksha, Hong Kong 1/68 and England 42/72 strains.
We have for example found particularly interesting
antiviral activity of this nature in 10-bornanamine and
7,7-dimethylnorbornan-1-amine and derivativès thereof
having a basic nitrogen atom.
Compounds in these series are also of interest as
regards central nervous system activity9 e.g. analgesic
activity.
Thus in one aspect the in~ention provides ~
pharmaceutical composition comprislng a pharmaceutical
carrier or excipient and a 7,7-dimethyl-[2,2,1]-
bicycloheptane h~ving at the l-position a group R,
where R is an amino or aminomethyl group, or a
derivative thereof possessing a basic nitrogen atom and/
or a physiologically acceptable salt thereof, said
derLvative being a compo~md wherein R i9 sub~tituted
:
~\~", ' .
at the amlno nitrogen atom and/or at the 10-carbon atom by one or more
aliphatîc, cycloaliphatic, araliphatic or aryl groups or, in the case of the
amino group, by a heterocycl}c group in which the nitrogen atom of the amino
group forms part of the heterocyclic ring, or, in the case of an N-substituted
aminomethyl group, by an oxo group at the 10-carbon atom.
The compounds just described in which R is substituted are themselves
new compounds and constitute a further aspect of the inventionO
Thus this invention relates to a process for the preparation of
7,7-dime~hyl-[2,2,1]-bicycloheptanes of the formula
R CH2N~12
6 ~ 2 III
5 ~ 3
and the physiologically acceptable salts thereof, wherein R is a group
-NRlR2 or -CH2NRlR2 in which the methylene group is unsubstituted or sub-
stituted by a Cl 6 alkyl group; Rl and R2, which may be the same or different,
are hydrogen atons or Cl ~ alkyl, Cl 6 aminoalkanoyl, C2 6 alkenyl or phenalkyl
groups in which the alkyl group has 1-6 carbon atoms, or together with the
nitrogen atom represent a sa~urated 5- or 6- membered heterocyclic group
which can additionally contain N, 0 or S in the ring and are unsubstituted or
subs~ltuted by a Cl 6 alkyl group or used to a benzene ring, or together
represent a benzylidene group; or wherein R is a 3,5-di-(bornan-10-yl)-1,3,5-
triazino group; but excluding compounds in which R is -NH2 or -CH2NH2;
~ a) wherein the group R possesses a methylene group in an a-position
in relation to the 1- or 10- nitrogen atom, which comprises reducing the
corresponding amide;
` (b) wherein R is a methylamino group, which comprises reducing an ester
of the corresponding carboxyamino compound;
~ c~ wherein R is a dimethylamino group, which comprises reductively
methylating the corresponding primary amine;
.
` \~ -4-
49~3
(d) wherein the 1- or 10- nitrogen atom of R is substituted by a
benzylidene group, condensing the corresponding primary amine with benz-
aldehyde;
~e) wherein the product is 1,3,5-tris-(bornan-10-yl)-1,3,5-hexahydro-
triazine, which comprises reacting 10-bornanamine with formaldehyde;
(f) wherein R is an aminome~hyl group in ~hich one of the hydrogen atoms
on the methyl carbon atom is subs~ituted, which comprises reducing the cor-
responding ketoxime;
(g) wherein the 1- or 10- nitrogen atom of R is mono- or di- substituted
by an alkyl, alkenyl or phenylalkyl group, which comprises reacting a cor-
responding primary or secondary amine with a compound of the formula R5X
where R5 is an alkyl, alkenyl or ph~nylalkyl group and X is a readily eliminat-
able group;
(h) wherein R is an aminomethyl group in which the methyl group is
substituted, which comprises reducing the corresponding substitutad nitro-
methyl compound~
(i) wherein the 1- or 10- nitrogen atom of R is substituted by an
aminoalkanoyl group, which comprises reacting a corresponding haloalkanoyl
compound with ammonia;
2a ~j) wherein the 1- or 10- nitrogen atom of R forms par~ of a hetero-
cyclic ring, which comprises reacting the corresponding unsubstituted amine
with a compound XR7X where X is a readily eliminatable group and R7 is a
divalent alkylene eroup (which may bc interrupted by O or S) or a cyclic
group bearing two monovalent alkylene groups; or
(k) wherein the 1- or 10- nitrogen atom of R is substituted by a
phenylalkyl group, which comprises reducing the corresponding compound in which
the said nitrogen atom is linked to said group by a double bond.
It also relates to the products of this process.
The amino group may for example be mono- or disubstituted, such
3Q sub~tituents generally having up to a total of 12 carbon atoms on the nitrogen
atom~
~ 4a-
., r~
~ ~4~28
Such aliphatic groups may be branched or straight chain, saturated
or unsaturated, and substituted or unsubstituted. They preferably contain
1-6 carbon atoms and may for example be alkyl groups (e.g. methyl, ethyl,
n-propyl and n-butyl), alkenyl groups (e.gO allyl), or alkynyl groups
~e.g. propargyl)O The aliphatic group may be joined to the ni~trogen atom of
the amino group by a double bond, as in the case of an alkylidene
~ 4b-
9L9Z~ ,
group, such as pro W lidene.
Thèse aliphatic groups and particularly the alkyl
groups may for example be substituted by amino, mono-
or di-alkylamino, imino (e.g. as in amidino), hydroxy,
etherified or esterified hydroxy (e.g. alkoxy or a
alkanoyloxy)~ thiol, or esterified or etherified thiol
(e.g. alkylthio) groups.
When a basic substituent such as an ~mino group
is present on the N-aliphatic substituent, an oxo group
may be at the ~-position in relation to the nitrogen
a~om of the R group, thus forming a basic substituted
. ~ , , .
acylamino group, e.g. an aminoacetamido group. When
R is substituted aminomethyl group, the oxo group may
be present at either a-position in relation to the
nitrogen atom.
; Cycloallphatic substituents may for example
be cycloalkyl groups havlng 3-8 or more (e.g. up to
10) carbon atoms such as cycIohex~l and 7,7-
; dimethylnorbornan-l-yl.
Araliphatic substituents may for example be monocyclic
aralkyl, aralkenyl or aralkynyl groups such as benzyl,
styryl and phenylethynyl groups. The araliphatic
,
,
1~ 6 ~
group may be joined to the nitrogen atom of the amino group by
a double bond as for example in a benzylidene group The
aliphatic portions of such araliphatic groups preferably
contain 1-6 carbon atoms -
Aryl substituents may for exæmple be monocyi~lic
aryl groups such as phe~yl, or heterocyclic aryl groups
containing for example 5 or 6 ring members and having one or
more hetero atoms, e~g. N,0 or S
Substituted amino groups in which the amino nitrogen
atom forms part of a heterocyclic ring may for example be
saturated or unsaturated, contain 1~-8, pre~erably 5 or 6,
ring members and they may contain another (e.g. a
second) hetero atom such as N, 0 or S. Examples of
such groups are piperidino, morpholino, thiomorpholi~o,pyrrolidin~
azetidino and piperazino groups. The heterocyclic ring may
itself be substituted, for example by hydroxy or
alkyl groups, such as a methyl group, as in a
~-methylpiperazino group, or a hydroxy group, AS in
a 3-hydroxyazetidino group, The heterocyclic ring
may also be fused to a second ring, e.g. a benzene
~ ring, as in an isoindolino group.
; The heterocyclic ring may also be substituted by
:
a cycloalkyl group such as described above, as for
--6--
~064~3Z~3
example in 1,3,5-tris-(bornan-10-yl)-hexahydro-1,3,5-
triazine.~
Thus, the amino group which is present in the R
group of the compounds used in the invention may be of
the formula NR R2 wherein R and R2, which may be the
same or different are hydrogen atoms or aliphatic,
cycloaliphatic, araliphatic or aryl groups as described
above, or wherein R and R2 taken together with the
intervening nitrogen atom represent a heterocyclic
ring as described above, or wherein Rl and R2 taken
together represent a divalent aliphatic or araliphatic
4 group
~ When R is an aminomethyl group, either or both
of the hydrogen atoms on the 10-carbon atom may be
~replaced by a substituent which may, or e~ample, be
~ , .
an aliphatic, cycloallphatic, araliphati.c or aryl
(particularl~ phenyl) substituent such as generally
referred to above. There may in particular be one or
two Cl 6 alkyl substituents such as methyl or ethyl
groups. When the 10-carbon atom is substituted, the
: amino group will usually but not necessariiy be
~nsubstituted.
Acid addition salts and especially physiologically
acceptable.acid addition salts are also included in the
invention, examples of such salts being hydrochlorides,
-- 7 --
hydrobromides, ph~os~p~ ~9e~ ~sulphates, p-toluene
sulphonates, methane sulphonates, citrates, tartrates,
acetates, ascorbates, lactates, maleates and succinates.
Compounds which are generally preferred for use
in accordance with the invention are those in which R is
an amino, mono- or di~alkylamino, aminomethyl, mono- or
dialkylaminomethyl, mono~ or di-alkenylaminomethyl, or
l-aminoethyl group, or a group (particularly an
aminomethyl group in which the nitrogen atom forms part
of a saturated 5 or 6 membered heterocyclic ring which
may contain a second hetero atom, or one or more
substituents, or is fused to a second (e.g. benzene
ring. More pre~erably, the alkyl groups have l-4 carbon
, l .. ,; , .
4 atoms, and especially are methyl or ethyl groups.
Specific compounds which are particularly preferred
on account of their activity are those in which R is an
aminomet~yl group or the monomethyl, monoethyl, dimethyl,
diethyl, monoallyl or mono-n-butylamino amino substituted
derivatives thereof, or a 4-methylpipera~inomethyl,
piperidinomethyl, isoindolinomethyl or morpholinomethyl
group; a l-aminoethyl group; or an amino, methylamino,
ethylamino or dimeth~lamino group.
In tissue culture tests which we have carried out,
compounds in which R is aminomethyl, mono- or
di-methylaminomethyl, mono- or di-ethylaminomethyl,
mono-n-butylaminomethyl, N-methylpiperazinomethyl,
piperidinomethyl, morpholinomethyl, isoindolinomethyl,
- - 8 -
~ ~ 6 49'~ ~
l-aminoethyl, amino, or monomethylamino have shown
high activity against the Iksha strain of the influenza
.' H2N2 virus.
Thè compounds in which R is aminomethyl, mono-
and di-ethylaminomethyl, mono-n-butylaminomethyl,
N-methylpiperazinomethyl,allylaminomethyl~ l~aminoethyl,
amino, mono- or di-methylamino or ethylamino have shown
high ~ctivity against the England ~2/72 strain o~ the
influenza H3N2 virus.
rests we have carried out in mice have shown that
certain of the compounds give protection agaLnst the
influenza England l~2/72 H3N2 virus when administered
orally. These compounds are particularly preferred,
and are those in which R is an aminomethyl group or
the methyl, ethyl Qr dimethyl amino-substituted
derivatives thereof, or a l-aminoethyl, dimethylamino,
or morpholinomethyl group. The diethylaminometh~l,
l~-methylpiperazinomethyl and isoindolinomethyl compounds
have been ound to give protection when administered
intraperitoneally to mice.
The physiologically active compounds of the
invention may be formulated for administration in
conjunction, if desired, with one or more pharmaceutical
(including veterinar~) carriers or excipients or other
medicinal agents suitable, for example, for oral,
topical, rectal, or parenteral administration.
They may be used together with other medicinal
agents for example antiinflammatory agents such as
steroids, e.g. betamethasone 21-phosphate or antibiotics
such as tetracycline. The compositions are convenlently
in dosage unit form and each dosage unit should gener~lly
contain above 0.025g, e.g. 0.05 to 4g and preferably 0.1
to l.Og, of the active compound, for admini~stration 1-3
times daily generally or, for intranasal or inhalation
administratîon, e.g. 6-8 times daily. The total daily
dose should generally be above 0.05g, e.g. from 0.10 to
7g. The carrier or excipient will in general be a solid
; carrier or excipient, a sterile liquid or a liquid
containing one or more stabilising, flavouringJ
; suspending, sweetening, emulsifying or preserving agents.
When the composition is in the form of an aerosol,
; . .
it should be such that each spray provides approximately
1/20 to lj~Oth of the dosage unit amounts given above.
The total daily dose will usually be about 1/8th of
that referred to above.
The dosages referred to above are those for an
adult h~an (bodyweight approximately 70kg) and may o~
course be varied for children or animals according to
body weight.
Solid preparatlons for oral consumptlon are usually
presented in unit dose form and include for instance,
tabletsj capsules, lozenges, chewing gum and medicated
sweets. Conventional carriers for such preparations may
be sugars, starches, sugar alcohols, gelatin, chicle gum,
cocoa butter, etc.,together with other compounding
agents required such
- 10 -
~ 9 Z ~
as binders, lubricants, stabilisers, coatings, flavourings
and colourings. The compositions may also take the form of
liquid oral preparations for ingestion such as solutions,
suspensions, syrups, elixirs, emulsions, granules for
re-constitution before use, which may contain suspending,
emulsifying, stabilising and preserving agents and may also
contain acceptable sweétening, flavouring or colouring agents.
The compounds may be prepared for local application to the
mucous membranes of the nose and throat and may take the form
of liquid sprays, aerosols or powder insufflations,
nasal drops or ointments, throat paints, gargles or
similar preparations. Topical formulations for the
treatment of eyes may be prepared in oily or aqueous
media in the Eorm of conventional ophthalmic
preparations and collyria, for ex~mple creams,
ointments, eye drops and lotions. Suppositorles
may contain a conventional base e.g. oil of theobroma,
polyglycols, together with
surace active agents if required. The injectable
preparations may take the form of aqueous or oily
solutions, emulsions, suspensions or solids for reconstitution
~06~9'~
before use. Suitable vehicles include, for example, sterile,
pyrogen-free water, parenterally acceptable oils, oily esters
or other non-aqueous media such as propylene glycol, if
desired containing suspending, dispersing, stabilising,
preserving, solubilising, emulsifying or buffering agents.
Par~icularly suita~le forms of administration are tablets,
solutions for injection, nasal sprays or drops9 sprays
for the respiratory tract, e.g. aerosols for inhalation.
Compounds in accordance with the invention which
possess a methylene group i.n an a-position in
relation to the nitrogen atom of the R group may be
prepared by reduction of a corresponding amide.
This reaction may for example be carried out with a hydride
reagent capable of reducing amides to amines, such as lithium
aluminium hydride or diborane, in an ine~t organic
solvent, for example a hydrocarbon solvent such as
benzene or toluene or an ether solvent such as die~hyl
ether or tetrahydrofuran. The reaction with lithium
aluminium hvdride is suitably carried out at the reflux
temperature of the reaction mixture, although lower
temperatures may if desi~ed be used. The reaction
-12-
~6 ~ Z ~
with diborane may for example be effected at
temperatures of -10 to ~30C, conveniently at room
temperature. The amine produced is conveniently
isolated in the form of a salt, e.g. the hydrochloride.
Thus for example amino compounds having an
araliphatic substituent or an aliphatic substituent
may for example be prepared by reducing the corresponding
substituted amide compound (i.e. a compound where R is
an acylamino or acylaminomethyl group).
10. The amides required as starting materials for the
i latter reaction are readily obta-Lnable by acylation of
I ~
the parent amino compound, e.g. with an acid halide
corresponding to the desired substituent. This reaction
is desirably effected in the presence of an acid binding
agent and suitable basic conditions may be provided by
; using an excess of the starting amino compound, but
preferably ~n the presence o added ba8e.
Compounds in accordance with the invention
wherein R is a substituted aminometh~l group (e.g.
compounds having a l-substituent of the fonm~la
~164921~
-CH2NR R ) ma~ conveniently be prepared by reduction of
the corrèsponding 7~7 dimethyl-norbornane-l-carbonamide.
The l-carbonamides used as starting materials in
the preparation of the aminomethyl compounds are new
and constitute a further aspect of the invention. The
invention thus includes N-substituted 7,7~dimethyl-
norbornane-l-carbonamides. The N-substituents may of
course be the same as those described above with
reference to the amino substituted 10-bornanamines.
As indicated above, it will be appreciated that
in addition to their utîlity as interm~ediates in the
preparation of the lO-bornanamines of the invention
certain of these amides also possess antiviral activity
similar to that of the amines. These are amides in
which the N-substituent itself bears a basic
substituent, for example an aliphatic substituant, such
as an alk~l group, substltuted by an amlno group.
~n example of such a compound is the compound in which
R is a 4-methylpiperazinocarbonyl group.
The l-carbonamides may be prepared, for example,
by reaction of 7,7-dimethyl-norbornane-1-carboxylic acid
.
_ 14 -
or preferably a reactive derivative thereof such
as a halide (e.g. 7,7-dimethyl-norbornane-1-
carbonyl chloride) with a primary or
secondary amine corresponding to the
'~ 5 mono- or disubstituted amino group of the desired
amide,
This reaction is desirably carried out at a low
temperature (e,g. -80C to 10C) in the presence of an acid
binding agent (e,g, a base). These basic conditions c~n
also be provided by the use of an excess of the amine~
The reaction is conveniently carried out in a non-polar
; organic solvent such as an ether solvent, e.g. diethyl ether~
The 7~7-dimethyl-norbornane-1-carbonyl chloride
preferably used in the latter reaction i$ a known com~ound
and is readLly prepared from 7,7-dlmethyl-norbornane-1-
carboxylic acid,
Compounds according to the invention containing a mono-
methylamino substituent may be prepared for example by
reduction of an ester o~ the corresponding carboxyamino
compound, The ester is suitabl~an alkoxy carbonylamino
compound
-15-
~ 8
The reduction is desirably effected with a
hydride reducing agent, preferably lithium aluminium
hydride, in for example an ether solvent such as
diethyl ether. The reaction is preferably carried
,out at the reflux temperature of the medium. The
amine produced is conveniently isolated as a salt by
the addition of acid, e.g. hydrochloric acid.
Methylamino compounds may also be prepared by
, methylation (e.g. reductive methylation with
formaldehyde in the presence of formic acid or sodium
borohydride) of the parent amine.
I Compounds in accordance with the invention
, wherein the nitrogen a~om of the amine group is
,~ joined by a double bond to an aliphatic or araliphatic
substituent may be prepared by condensing the
unsubstituted amino compo~md ~which may be in the
form of a salt) with an aldehyde or ketone (e.g.
acetone or benzaldehyde) in asuitable medium preferably with
azeotropic removal of water, e,g, using toluene or benzene
or a chlorinated hydrocarbon as solve~t. The use of
formaldehyde in this reaction results in the preparation of the
.
-16-
. ~ ,
~ O ~ ~9
previously mentioned triazine.
Compounds wherein R is an aminomethyl group
wherein one of the hydrogen atoms on the methyl
carbon atom is replaced by a substituent and the amino
group is unsubstituted may be prepared by reduction of the
corresponding 10-hydroxyimino ~ketoxime) borna~e This
reduction may for example be effected by hydrogenation
over a nickel catalyst, or by reduction with zinc and
acetic acid, lithium aluminium hydride, or sodium in the presence
of a lower alkanol, e g~ ~thanol.
The 10-hydroxyimino compound required as the starting
material in the above reaction may be prepared by condensing
the correspondin~ ketone (i.e. a compound o fonmula II above
having at the l-position the group -CO~ where ~ is the
desired 10-substituent3 with hydroxylamine. This reaction
is conveniently carried out in an aqueous medium and prefer-
~bly ~t ~he rePlux temper~ture of the medium. The
hydroxylamine is normally used in the form of a salt e.g.
sulphate or hydrochloride, in the presence of a base.
The ketones required for the latter reaction may for
- example be prepared from 7,7-dimethyl-norbornane-1-carboxylic
~17-
~0~;49;~
acid by reaction with a metal ~e.g. lithium) derivative of the
formula MR~where M is the metal and ~ is the desired hydro-
carbon substituent in the 10-position.
The amino compounds having an aryl substituent
may for example be prepared by treating the parent
amino compound (e.g. in the form of a salt, e.g. a
lithium salt) with a benzyne. The benzyne required
for this reaction may suitably be prepared by reaction
of an aryl halide (e.g. chloride or bromide) with an
excess of the lithium salt of the parent amino
compound.
Compounds wherein the amino group is substituted
by an aliphatlc, cycloaliphatic or araliphatic group
; may also be prepared by reaction of the parent amine
with a compound of the formula R5X where R5 is the
desired substituent and X is a readily eliminatable
group, such as a halogen (e.g. chlorine) atom or a
toluenelsulphonyll ~roup. This reaction may be
carried out in a polar solvent (such as dlmethyl-
formamide) or acetone, in the presence of a base
; (e.g. sodium hydride), preferably using an excess of
'
-18-
the amine The reaction is ~artic-u]arly applicable to che
preparation of di.subs~ituted ~mines, but it may also be
used to prepare mo~o-substituted compo~mds ~lternatively,
the use in this reaction of an epoxide affords a method of
preparing hydroxyalkylamino compounds.
Compounds ~herein the c~m;no nitrogen atom is a mem'~er
of a heterocyclic ring may be prep~red by cyclisation of such
hydroxyal'~-'~mino compounds carrying a group capable of
elimination, Such a product may be obtained for example
by reacting the amine with epichlorhydrin, The cyclisation
may for example be e~fected by hea~ing the starting materials
in solution,
Compounds wl~erein R is an aminomethy] grOilp and the
10-car~on ~tom i3 sub~tituted may be prepared by reduction
of the corresponding nitro methyl compound, The reduction
may be e~fected for example with a hydride reducing agent
(such as lithium aluminium hydride or diborane)~ The reaction
is generally suitable for the preparation o compounds
whereln R is -CR R NH21 where R has the above meanlng and
R6 is hydrogen or an allphatic, cyc~oaliphatic or ara].i.phatic
group; it is preferred that R5 is lower alkyl e,g~ methyl
and R6 is hydrogen or lower ~lcyl, e.g, methyl. More
prefera~ly R and R,6 are both methyl.
- 19 -
Z~
The nitro derivatives required for the latter reaction
may be prepared by reacting a compound of the formula R X
with a corresponding nitro compound in which the carbon
atom of the R group is unsubstituted or monosubstituted
(i.e a compound where R is -CHR N02 where R has the
above meaning~, The conditions for this reaction are
generally similar to those described above with regard to the
reaction of R5X with an amine, and are desirably anhydrous.
A strong base such as an al~ali metal hydride is advantageously
; 10 present in order to form the reacting species~which is a
nitronic acid anion~
The monosubstituted or unsubstituted nitro
compounds may themselves be prepared by oxidation of
a cbrresponding amine or ketoxime (i.e. a compound
in which R is -CHR6NH2 or -CR6=NOH). The oxidation
may be effected for example with a peracid (e.g.
m-chloroperbenzoic or per-trifluoracetic) in a
hydrocarbon or chlorinated hydrocarbon solventl
preferRbly ~t room temperature. The pr~paration o
suitable ketoximes is described above.
Compounds in which the nitrogen atom of R is
substituted by an aminoacyl or mono- or di-alkyl~minoacyl
group may be prepared by reaction of the corresponding
haloacyl (e,g, bromoacyl) compound with ammonia or a mono-
or dialkylamine, A suitable solvent for this reaction is an
alcohol, e,g, methanol, An excess of ammonia is preferable,
Compounds in which the nitrogen atom of R is su~stituted
- 20 -
by a haloacyl group in which the halogen atom ls separated
from the carbonyl group by at least 2 carbon atoms may be
subjected to cyclisation to yield a corresponding lactam;
the cyclic amide grouping can then be reduced to give a
basic compound according ~o the invention. The
cyclisation may be effected under basic conditions, e.g.
using sodium hydride in a polar aprotic solvent such as
dimethylsulphoxideO The reduction of the cyclic amide
group may, for example, be effected using a hydride
reducing agent ~uch as lithium aluminium hydride or diborane.
Compounds wherein the amino nitrogen atom is a member
of a heterocyclic ring may also be prepared by reaction of
the parent amine with a compo~m~pOssessing two readily
eliminatable groups such as referred to above. The latter
compound may for example be of the formula XR7X where X is
as defined above and R is a divalent alkylene group (which)
may be interrupted by an oxygen or sulphur atom) or a cyclic
group bearing two monovalent alkylene groups (e.g. an
o-xylenyl group). The reaction may be per~onmed for example
as described above khe the reaction o~ R5~ with an amine.
Compounds possessing an amino group substituted by an
aliphatic or araliphatic group may also be prepared by
- reduction of the corresponding compound in which khe amino
; nitrogen atom is linked to the substituent by a double bond.
a5 The reduction may for example be effected with a metal
hydride for example as described above.
~ ~ ~ 4
The following Examples illustrate the invention.
Temperatures are in oc.
~.
.
The eight amides whose properties are summarised in
Table I below were prepared by the following general
method. Variations on the method are noted in the
footnote to the Table.
A solution of freshly prepared 7,7-dimethyl-
norbornane-l-carbonyl-chloride
(10 m~oles) in dry ether (usually about 10 ml.) was cooled
in an ice-bath and stirred whilst the appropriate amine
(2 equivalents) was added dropwise over 5-10 minutes. When
the addition was complete the mixture waQ allowed to come
to room temperature. After 1-2 hours the reaction mixture
WRg part:LtLoned between chloroform and dilute hydrochloric
acid and the organic extract washed with dilute sodium
carbonate and water and then dried over magnesil~ sulphate.
; 20 Evaporation of the organic solvent afforded the crude amide
whlch was purified by sublimation at abou~ 0.1 mm and/or
crystallisation.
-22- -
,
.
`~ g~8
-- u~
. ~ I~
z - ~
o,
I~
~ o o o ~i ~ o
: :c ~ ,~
l~ -- ~
., ~ o~ u~ ~D C`l C~l
' o
~ - -
a~ ~ ~ ~ -n O ~
C~ ~ r~
- ~ ~
oo ~ ~ O U~ ~D
. o ~ ~ u~ o ~
, ~ I~
~ ~~ . _ _ _ .. _ _ _._, .. _,. .... _
a) ~ ~ 0 Z æ Z; Z æ ~ Z æ
~_1 ~1 rl ~1 a~
~d
E-l l1:4 ~i _I c~ ~ ~ ~ u~ `;1 u
~1 ~ IL C~ V'~ I V~
~i ~ ._
,:
,~
~o ~ c~
C7
~1 ~ I ~ O ~ _l
P~
~i ~ ~ l
1~ . _ ._ ~
r~
~ ~ l~
æ ~ )
~ _ _ _ . ", ,
~,
', . ~ a~
~ æ
_ _~
-23-
Footnotesto Table 1
1. The acid chloride (25 mmoles), in ether (25 ml.), was
stirred at -700 whilst a large excess (10 ml.) of
liquid methylamine was added.
2. After crystallisation rom ether.
3. The crude amide was purified by chromatography over
silica 4efore sublimation and crystallisation from
petroleum ether.
4. Reaction mixture was allowed to stand at room temperature
for 1 week.
5. After crystallisation from petroleum ether.
6. The crude amide was purified by chromatography over
silica before ~ublimation,
7. , The reaction mixture was partitioned between chloroform
and dilute hydrochloric acid ~nd the aqueous layer
basi.fied with sodium carbonate and extracted with
chloroform. Evaporation of the organ~c solvent
afforded a solld which was purified by sublimation.
.
)
2'
~;49~ `
Exa~ 9-16
Eightl~-bornanamines were prepared by the following
general method and their propert;es summarised in lable 2
Variations on the method are given l:n the footnote to the
Table.
A solution of the appropriate amide in the chosen
solvent (see Table 2) was carefully added to a suspension
of an excess of lithium al~inium hydride in the same solvent
and the resulting mixture refluxed until the reaction, as
judged ~y thin-layer chromatography, was comple~e. The
exces~ lithium aluminium hydride was destroyed by the
careful addition of water, more benzene tor ether or
chloroform) was added and the insoluble inorganic material
removed by filtration. The organic layer was washed with
water, driFil (MgS04) and evaporated in VACUO. The r.e~ic1ual
crude amine was clissolved in ether, approx. 8N-ethanolic
hydrogen chlorid~ was added and the preclE~i l;a~.t~d arnine
h~drochloride collected by ~iltra~ion and dried.
-~5-
~ - ~
: a~ ~ ~
_.
æ ~
. ~ C5~ 0 10 LO N ~ O
O, ~
1:'~ -- ' u~ Ln -
. ~: ~
. ~ 1- ~D ~ er ~ ~
rl ~ rl r-l r~ rl r~ , _
1:~ ~
O '
_ h ,~ ~1
. . .. ~ ,~
. . . t~ , ~ o o
. ~ ~ ' _ _
. - . ~,: ~ D
. O ' O ~ ~ ~1 0 0
_ h . ,~
: ~ - ~ oo r -I
:, a~ ~ r
. p:; ~D ~ ~9 ~ ~ ~ In
~: ~ ~ o
., O d' ~ OD CO a~
. ~4,
a) 0 ~ ,
o . ,' ~ ,~i,Z ,Zj æ Z~ ; ~ ~ z~ .
rl ~ O ~ N t~ ~ o
O ~ q m m m
~C . ~ ~ ~ U C~
a) : ,~
: ~o~ ~ _
~, ~ ~ ,~ u)oo ~ ~ a~
~ rl ~ O : ~
h .~-, . Lo
O U~ P~ _ _
~1 f`~
o .
,~
O ~ ~ ~
' o ~ o o a) o o
. ~ h S~
u ~ . ~ ~ ~ ~ a
~ r-l ~ N ~ ~y N ~ ?~1 N
O ~ h a~ m
K _ ~
. ~ ~ . ~
. m $ Z; ~: Z ~ æ,i
~Zi ~ ~ ~ r~ r~ r~
-- 26 --
9 ~ 8
Footnotes to Table 2
1, After destruction of the excess hydride and removal of
the inorganic material the benzene solution was
extracted with dilute hydrochloric acid. Basifi-
cation of the acid solution and extraction with
chloroform gave the crude amine as an oil which was
converted into its hydrochloride.
2. Change of crystalline form about 170.
3. After destruction of the excess hydride and removal
of the inorganic material the reaction mixture was
partitioned between chloro~orm and dilute hydro-
chloric acid. Basification of the acid solution
and extraction with chloroform gave the crude amine
which was converted into its hydrochloride.
~, Change in crystalline form at about 2200.
5. After crystallisation from chloroorm.
- 6. The crude amine was purified by preparative thin-layer
chromatography over silica, converted to its dihydro-
chloride and crystallised from ethanol.
r~
~49~8
Example 17
l-(l'-Aminoethyl)-7,7-dimethyl-norbornane hydrochloride
(i ~7,7-Dimethylnor~ornyl-l-me~yl ketone oxime
A solution of 7,7-dimethylnorbornane-1-carboxylic
acid (2.54g.) in ether (60 ml) was treated dropwise,
under nitrogen with a ZM-solution of methyl lithium in
ether (24 ml). When the addition was complete the mixture
was refluxed for 2.5 hours. The cooled solution was washed
with 2N-hydrochloric acid, sodium carbonate solution and
water and then dried over sodium sulphate. Evaporation of
the ether afforded 7,7dimethylnorborn~1-1-meth~l ketone as
a pale yellow oil (2.49g.) ~maX(in CHBr3) 1682 cm . This
oil (2.~2g.) in ethanol (60 ml) was treated with hydroxyl-
amlne hydrochloride (1.29g.) and N-sodium hydroxide solution
(63ml) and the mixture, after being kept overnight at room
temperature, was refluxed for 0.5 hours. The cooled reaction
mixture was extracted wlth chloroform, the extracts washed
with water and dried (Na2S0l~) and the solvent removed
in vacuo to ~ford the crude crystallina product (2.65g.)
which was recrystallized from aqueous ethanol to give title
compound m.p. 109 - 111 (kofler).
A similar sample, m.p. 109.5 - 110.5 (kofler) had C,
73.05; H, 10.7; N, 7.4; CllH19N0 requires C, 72.9; H, 10.55;
N,7.75%.
- 28 -
10649Z8
(ii) l-Ql'-Aminoethyl)-7,7-dimethyl norbornane hydrochloride
A solution of 7,7-dimethylnorbornyl-1-methyl ketone
oxime (253 mg) in ethanol (20ml~ containing Raney nickel
catalyst was shaken with hydrogen for 22 hours. The catalyst
was removed by filtration and the solu~ion evaporated
in vacuo to give~ an oil which was pa~titioned between chloro-
form and water. The chloroform layer was extracted with 2N-
hydrochloric acid (50ml) and after basification with sodium
carbonate solution was extracted with chlorofoTm. The
organic extract was washed with water, dried QMgS04) and
evaporated to give a yellow oil. This oil was dissolved
in ether~ ethanolic hydrogen chloride was added and precipit-
ate collected by filtration to give title compound, which
sublimes at about 263 (Kofler~.
- 29 -
~L~6~9;~8
Example 18
l-Methylamino-7 7-dimethy~norbornane hydro-
chloride
A solution of l-(methoxycarbonylamino)-7,7-dimethyl-
norbornane ( 197 mg . ) in ether ~ 5 ml ) was
added to a suspension of lithium aluminium hydride (80 mg.)
in ether (5 ml.) and the resulting mixture refluxed for
three hours. Excess lithium aluminium hydride was
decomposed by the addition of water and the precipitated
inorganic material removed by filtration. The ethereal
solution was washed with water, dried (MgS04) and the
solvent evaporated. Treatment of the residual oil, in
ether, with 8N-ethanolic hydrogen chloride afforded
l-methylamino-7,7-dimethyl- norbornane hydro-
chloride, sublimation point 260 (Kofler) (Found:
C, 63,1; H, 10.4; Cl, 18.7; N, 7,4. CloH20ClN requires
C, 63.3; U, 10.65; Cl, lB.7; N, 7.4%).
-30-
~ ~ 6 ~9
Example 19
l-Ethylamino-7,7-dimethylnorbornane hydrochloride
J
A solution of l-amino-7,7-dimethylnorbornane (1.022g)
in pyridine (10 ml) was cooled in an ice-bath and stirred
S whilst acetyl chloride (1 ml) was added dropwise. The
ice-bath was removed and the mixture was kept at room
temperature until the reaction was complete. Dilution
with water, acidification with dilute hydrochloric acid
` and extraction with ether afforded the crude product which
was purified by filtration through a small column o neutral
alumina and crystallization from ether-petroleum ether to
give l-acetamido~7,7-dimethylnorbornane m.p. 133-134
(Kofler) after pre~ious softening.
The above N-acetyl compound (776 mg) in dry ether
(25 ml) was added to a mixture of lithium aluminium hydride
(lg ) in ether (75 ml) and the mixture refluxed for two
hours. Excess reagent was destroyed by tha addition of
water (5 ml) and the precipitated material removed by
filtration. Extraction o the ~iltrate wlth ether aforded
the crude ethyl ~mino compound which was dissolved in ether
and treated with ethanolic hydrogen chloride. The insoluble
amine hydrochloride was collected by filtration and
crystallized from ethanol-ether to yield title compound;
sublimes above 150
Found: C, 65.0; H? 11.0; N, 6.95; Cl, 17.4
CllH22ClN requires: C, 64.85; Hj 10.9; N, 6.85j
Cl, 17.4%.
- 31 -
~ 2
Example 20
10-Ally_amino bornane hydrobromide and 10-diallylamino
bornane hydrochloride
A mixture of 10-bornanamine (lg.) sodium hydride
(0.16g.) and dimethyl formamide was stirred for 15~min.
~ It was then cooled in an ice bath and allyl bromide
; (0.55m1) was added. The mixture was stirred for 2 hours
I at room temperature and then partitioned between ether
and water. The organic layer was dried (MgS04) and
evaporated. The residue (1.04g) was subjected to
preparative layer chromatography using a mixture of 5~iO
methanol in chloroform for development of the plates.
. l ~ , , ~
The more polar fraction (0.6g) was dissolved in dry
ether and treated with hydrogen bromide to give a 10-
allylamino bornane hydrobromide (0.65g).
The less polar fraction (0.34g) was dissolved
in dry ether and treated with hydrogen chloride to give
10-diallylamino_bornane hydrochloride (0.25g), mp.163-
164, (Found: C, 70.3; H, 10.7; Cl, 13.2; N, S.2. G16H28
ClNo /4 H20 requires C, 70.0; H, 10.65; Cl, 12~9; N~ 5~1%)~
1. ' ~
(i) 10-Bromoacetamido bornane
- 32 -
. .
z~ ~
lO Bornanamine (0.5g) in dry ether (30ml) containing
pyridine (C.45ml) was treated at -80 with a solution of
bromoacetyl bromide (0.3ml~ in ether (5ml) over one minute
with stirring. The mixtura was allowed to warm to room
temperature and after a fuxther 30 min. it was partitioned
between ether and water. The organic layer was washed
with 2N-hydrochloric acid solution and then water. Itwas
dried (MgSO4) and evaporated. The residue (0.73g.) was
purified by preparative layer chromatography and by crys-
tallisation from petroleum ether ~bp. 60.80) to give the
'title compound (0.48g) mp. 89, (Found: C,52.4; ~1,7.3;
Br,2~.9; N,5.0; C12H20BrNO re~uires C,52.55; H,7.35;
J Br, 29.1; N,5.1%).
(ii) 10-Aminoacetamldo-bornane hydrochloride
10-Bromoacetamido bornane (0.36g.) was added to a
15% solution of ammonia in methanol (lOml) and allowed
to stand at room temperature ~ox 20 hr. The mixture was
then evaporated and the residue partitioned between
2N~h~vdrochloric acid solution and ether~ ~he aqueous
layer was basified with sodium hydroxide and extr'acted
into ether. The organic extract was washed with water,
dried (MgSO4) and evaporated. The residue (0.18g) was
- 33 -
4~
dissolved in dry ether and treated with hydrogen
chloride to give the ~ (0.19g.) mpO233-235
(Found: C,57.5; H,9.2; C1,13.6; N,11.2. C12H~3CIN20. /4
H20 requires C,57.35; H,9.4t Cl,14.1~ N,11.15%).
Exam~le_22
(il l-Bromoacetamido-7,7-dlmethvl-n~lb~D~a
7,7-dimethyl-norbornane (lg.) in dry ether
(50m1~ containing pyridine (lml) was treated at -80
with a solution of bromoacetyl bromide (0.7ml) in
ether (lOml.). The mixture was then allowed to warm to
room temperature and stirred for 1 hr. It was then
partitioned between ether and 2N-hydrochloric acid
solution. The organic layer was washed with water!
dried (MgS04) and evaporated. The residue (1,48g) was
crystallised from petroleum ether (bp. 60-80) to
give the ~ltle com~our~ tl.35g) mp. 97-98 (Found:
C,51~0; H~7.1; Br,30.5; N,5.2, CllHlgarN~ requires
C,50,8; H,7.0; Br,30.7; N,5.4%).
(ii~ l-Aminoace~amido-7,7-dimethyl-norbornane hydro-
0 chloride.l-Bromoacetylamino-7~7-dimethyl-norbornane (1.12g)
was added o a 15% solution of ammonia in methanol (50ml)
-34
2~
and al~owed to stand at room temperature for 20 hr.
The mixture was then evaporated and the residue
partitioned between ether and water. The organic layer
was dried (MgS04) and evaporated. The resldue (0.43g)
was dissolved in dry ether and treated with hydrogen
chloride to give the ti~le compound (0.44g) mp.l79-182,
(Found: C,55.8; H,9.1; C1,15.1; N,ll.9. CllH21ClN20.
1/4H20 requires C,55.7; H,9.1; C1,14.9; N,11.8%~.
Example 23.
N-Ethyl-10-bornanamine hydrochloride.
A solution of boron trifluoride etherate (5.75ml)
in dry tetrahydrofuran (5ml) was adqed dropwlse over a
period of 5 min. to a stirred mixture of sodium
.
borohydride (1.14g.) in dry tetrahydrofuran (18ml.) at
lS -10. The mixture was allowed to stir at room temperature
for l.hr. and then a solution of N-ethyl-7,7-dimethyl-
norbornane-l-carbonamide (0.5g) in dry tetrahydrofuran
(5ml) was added. Ater a urther 20 hr. the mixture was
added to iced water ~SOml). Concentrated hydrochloric
~0 acid (lOml) was added and the mixture was heated under
reflux for 30 min. It was then cooled and partitioned
batween ether and dilute sodium hydroxide solution.
- 35 -
~o~
The organic layer was washed with water, dried (MgS04)
and evaporated. The residue was dissolved in dry ether
- and treated with h~drogen chloride to give ~he title
ompound (0.5g). Sublimes abo~e 285.
ethyl)-7?7-dimethylnorbornane ~drochloride.
A boiling solution of 7,7-dimethylnorborn-1-yl
methyl ketone oxime (2.9g) in absolute ethanol (lOOml)
was treated with sodium (8g). When all o the sodium
had reacted the mixture was cooled and partitioned
between ether and water. The organic layer was dried
~ (MgS04) and evaporated. The residue (1~89g) was
; dissolved in dry ether and treated with hydrogen chloride
to give the title compound (2.16g.). Sublimes above 260.
Example 25.
A solution o~ lO~bornanamine (1.274g) in
dimethylformamide (lOml) containing triethylamine
(2.31ml) was cooled in ice and stirred whilst a solution
of ~ dibromo-o-xylene (2,195g) in dimethylformamide
(5ml) was addedO The mixture was kept at room
temperature for 24 hours and then diluted with water
- 36
~OG49~8
and extracted several times with chloroform. The
combined organic extracts were washed well with water,
dried (MgSO4) and evaporated in vacu to afford an
orange oil (3.16g). This oil, in ethanol ~15ml), was
treated with a slight excess of ethanolic hydrogen
chloride, ether was added and the precipitated hydro-
chloride collected by filtration and recrystalli~ed
from ethanol-ether to afford title compound (1.4g) m.p.
above 300 after a change of crystalline form about
260. (Found: C,74.4; H,9.1; C1,12.2; N,4.65.
Cl~H26ClN requires C,74.1; H,9.0; C1,12.15i N.4.8
Example 26.
10-A~lylaminobornane h~drobromide.
A solution of 10-bornanamine (obtained by
basification, with sodium hydroxide, of 1.517g. 10-
~ bornanamine hydrochloride) in acetone (20ml) contalnlng
; allyl bromide (0.68ml) was kept at room temperature or
3.5 days during which time a small amount o~ solid
crystallized. ~he solution was evaporated to about one
third of its original volume, cooled to 0 and the
crystalline material collected by filtration to give
~itle compound m.p~ above 295 with slow decomp.
- 37 -
1(~64~2~
~ (Found: C,56.6; H,8.6; N,5.1. C13H24BrN requires C,56.95;
~ .
H,8.8; N,501%).
10-Bornanamine (824mg) in benzene (lOml) was
treated with formaldehyde (37%; 0.4~ml) and the mixture
was stirred at room temperature for 1 hour. A crushed
pellet of sodium hydroxide was added to the hetero-
geneous mixture which was then separated from the
aqueous layer. Evaporation of the solvent ~
aforded a crystalline solid which was recrystallized
from ether-methanol to give title compound_ (490mg)
m.p. 175-180 (sealed cap.) (Found: C,79.7; H,11.4;
N,8.25. C33H57N3 requires C,79.9; H,11.6; N,8.4S%).
10-Benzylam ~
10-Bornanamine (824mg) in toluene (~Oml) was
treated with ben~aldehyde (0.55ml) and the solution
re1uxed under nitrogen under a Dean and Stark water
trap for four days. Evaporation o~ the solvent in
vacuo afforded impure 10-benzylidene 10-bornanamine
which was dissolved in dimethoxyethane (lOml)
_ 38
z~
contal~ing lithium aluminium hydride (112mg.), The
resulting mixture was refluxed for 2.25 hc~urs~ cooled,
and the excess hydride decomposed by the a.ddition of
water, The precipitated inorganic material was removed
by ~iltration and the solvent was evaporated _n vacuo.
The residual gum was triturated with 2N-hydrochloric
; acid to afford an insoluble hydrochloride which was
collected by filtration and then partltioned between
ether and 2N-sodium hydroxide. The dried ethereal
layer was evaporated in vacuo to give a yellow oil which
was dissolved in ether and treated with ethanolic hydrogen
chloride, The precipitated solid w~s cQllected and
recrystalli~ed from water to give title compound
m.p. 310 tFound: C,72.65; H,9.65; Cl,13.3; N,4.95.
Cl7H~6ClN requires C,72.95; H.9.35; C1,12.65; N,S.0~).
: E~ample 29.
Dimethylamino-7~7-dimethylnorbornane h~drochloride.
A mixture of l-amino 7,7-dimethylnorbornane (718mg),
~ormic acid (98%, 1,4ml) and fo~maldehyde (37~; 2.4ml)
~0 was heated on the steam.bath for 15.5 hours. The
cooled solution was poured into 2N sodium hydroxide
- 39 -
la~szs
J
solutidn and extracted with ether. The washed extract
was evaporated to give a mobile oil which was dissolved
in ether and treated with a slight excess of e'thanolic
hydrogen chloride. The precipitated hydrochloride was
collect'ed by filtration and recrystallized from ethanol-
ether to afford title compound (627mg) sublimes above
150, M.p. 208-209. (Found: C,64.75; H,10.85; C1,17.5;
N,6.7. CllH22ClN requires C,64.85; H,1O.9;
Cl,17.4; N,6.i%).
EXample 30
7,7-Dimethyl-l-morpholinonorbornane hydrochloride.
A stirred mixture o~ l-amino-7,7-di~ethylnorbornane
(.7 gm) potasslum carbonate (.77 gmj and 2,2'-dichlorodi-
ethyl ether (3 ml) was heated at 130 fox 2 hrs. The
reaction mixture was then cooled and partitioned between
ether and 2 N hydrochloric acid solution. The aqueous
layer was separate~ basiied and extracted into ether.
The organia layer was dried, and evaporated. The residue
(.8 gm) a~ter puriflcatlon by chromatography wa~ dis-
solved in~dry ether and treated with hydrogen chloride to
give the title compound (0.33 gm) m.p. 243 to 246.
- 40 -
49~
.~
:,
Example A
Tablet.
7,7-dimethylnorbornan-1-amine-hydrochloride 250 mg
Lactose 30 mg
Gum Acacia 15 mg
Magnesium stearate 5 mg
Sufficient water is added to the active ingredient
to form a granulating fluid and the pH adjusted to about
5.0 with the aid of citric acid. The gum acacia is dis-
solved in and this solution used to granulate the lactose.
The ingredients are then passed through a 20 mesh ( B.S. )
sieve, dried, lubricated with the maLgnesium stearate and
compressed~
Example B
~ n
Antiviral compound 1.0% w/v
Sodium chloride 0.80%
Water for injection to 100%
Dissolve ~he sodium chloride and antiviral compound ~n
Water ~or Injection. Make up to volume and mix. Filter
and then fill into ampoules which are then sealed and
~teriliæed by aukoclaving. Similarly preparations having
2,0% w/v antiviral compound can be prepared.
- 41 ~
4~
.~
EXample C.
E~e drops
Antiviral compound 2.0% w/v
Propylene glycol 5.0%
Sodium chloride 0.6%
Sodium edetate 0.01~
Thiomersal 0.01%
Methyl p-hydroxy benzoate 0.03%
I Propyl p-hydroxy benzoate 0.02%
1 10 Butyl p-hydroxy benzoate 0.01
Distilled Water to 100.0~
Dissolve the para hydroxy benzoLates in the propylene
glycol and add the solution to water; mix. Add and dis-
solve the thiomersal, sodium chloride and antiviral com-
pound. Make up to volume and mix. Sterilize the solu-
.; - .
tion by filtration and fill aseptically into polythene
eye drop bottles previously sterilized by y radiation.
Exampl~ D
Nasal Drop~
Antiviral compound 2.0% w/v
Chlorbutol 0.5%
Sodium chlorlde 0.7%
Distilled Water to 100%
Dissolve the chlorbutol in water,heating to 60C.Cool
42 -
.
~L0~45\215
and add the sodium chlorlde and antiviral compound, Make up
to volume, clarify by filtration and fill into suitable glass
bottles fitted with a dropper,
Nasal Aerosol
. .. . _
(for doses of 1000 ~g)
Antiviral compound 1,17% w/w
Ethanol 30%
Dichlorodifluoromethane 35%
Dichlorotetrafluoroethane to 100%
Dissolve the antiviral compound in the ethanol, Fill
the required quantity of this solution into aluminium aerosol
cans or plastic coated glass aerosol bottles, seal with a
metered valve delivering 85 mg per burst and pressurize by
forcing through the valve the required quantity of the required
mixture of dichlcrodifluoromethane and dichlorotetrafluoroethane,
E ample (li) (for do~es of 1 m~)
Antiviral compound 1,17% w/w
Sorbitan trioleate 0,59% w/w
: 20 Dichlorodifluoromethane 50,0%
Trichlorofluoromethane to 100%
Micronize the antiviral compound, Mix the sorbitan
- 43 -
,
trioleate with the trichlorofluoromethane (cooled to ~10C)
c~'S;o~nS~
and ~pcrse the antiviral compound into the mixture, Fill
the required quantity of this mixture into cans (as above) 7
fit the valve (as above) and pressurize with
dichlorodifluoromethane (as above).
Example F
Inhalation Aerosol
(doses of 1 mg)
Antiviral compound 1,17% w/w
Dichlorodifluoromethane 70%
Ethanol to 100%
Method:
EITHER
Dissolve the antiviral compound in the alcohol. Add the
solution to the dichlorodifluoromethane (cooled to -50C),
Mix and fill into aerosol bottles or cans and seal with valves
(as above for nasal aerosols),
0~
Dissolve the antiviral compound in the alcohol. Fill the
required quantity into bottles or cans (as above) and seal with
suitable metering valves (as above), Pressurize (as above)
with the required quantity of dichlorodlfluoromethane,
- 44 -
~64~
Examplè (ii) (for doses of 1 mg)
Antiviral compound 1.17% w/w
Sorbitan trioleate 0.59%
Dichlorodifluoromethane 70.0%
Trichlorofluoromethane to 100.0%
Method - as Example E tii).
Example G
; Suppository
Antiviral compound 200 mg
*Suppository base to 2.0 grams
(*This can be selected ~rom a wide variety of natural
and proprietary semi synthetic bas~?.; .
Micronize the antiviral compound and disperse in the
molten suppository base (at 50C). Cool to 35-37C and
: 15 fill into suitable suppository moulds.
. ,
`
. .
