CA1064928A - 10-bornanamine, and 7,7-dimethylnorbornan-1-amines derivatives - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
This invention relates to a process for the preparation of 7,7-dimethyl-[2,2,1]-bicycloheptanes having at the 1-positions a group R, and the physiologically acceptable salts thereof, wherein R
is an amino or aminomethyl group possessing a basic nitrogen atom and is substituted at the amino nitrogen atom (via a single or double bond) and/or at the 10- carbon atom by one or more C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl groups, which may be unsubstituted or substituted by an amino, mono or dialkylamino,imino, hydroxy, thiol, an esterified or etherified hydroxy or thiol group or (when a basic nitrogen atom is also present on the group) an oxo group in an .alpha.-position in relation to the R nitrogen atom; a C3-8 cyclo-alkyl group; a monocyclic aralkyl, aralkenyl or aralkynyl group; a phenyl group or substituted phenyl group;
a 5 or 6 membered heterocyclic aryl group; or wherein the nitrogen atom of R forms part of 4 to 8 membered heterocyclic ring which may be unsubstituted or substituted by a C1-6 alkyl, hydroxy or C3-10 cycloalkyl group or which may be fused to a benzene ring;
(a) wherein the group R possesses a methylene group in an .alpha.-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 ??ter of the corresponding carboxyamino compound;

(c) wherein R is a methylamino group, which comprises reductively methylating the corresponding primary amine;
(d) wherein the 1- or 10- nitrogen atom of R is linked by a double bond to an aliphatic or araliphatic substituent, which comprises condensing the corresponding primary amine with an aldehyde or ketone;
(e) wherein the product is 1,3,5-tris-(bornan-10-yl)-1,3,5-hexahydrotriazine, which comprises reacting 10-bornanamine with formaldehyde;
(f) wherein R is an aminomethyl group in which one of the hydrogen atoms on the methyl carbon atom is substituted, which comprises reducing the corresponding ketoxime;
(g) wherein the 1- or 10- nitrogen atom of R bears a phenyl or substituted phenyl substituent, which comprises reacting the corresponding amine with a benzyne;
(h) wherein the 1- or 10- nitrogen atom of R is mono-or di- substituted by an aliphatic, cycloaliphatic or araliphatic group, which comprises reacting a corresponding primary or secondary amine with a compound of the formula R5X where R5 is an aliphatic, cyclaliphatic or araliphatic group and X is a readily eliminatable group;
(i) wherein the 1- or 10- nitrogen atom of R forms part of a hydroxy-substituted heterocyclic ring which contains at least 3 carbon atoms, which comprise cyclisation of a compound as defined above in which the nitrogen of R

is substituted by a hydroxyalkyl group carrying an eliminatable group, there being at least three carbon atoms between the nitrogen atom of the amino group and the readily eliminatable gro?p;
(j) wherein R is an aminomethyl group in which the methyl group is substituted, which comprises reducing the corresponding substituted nitromethyl compound;
(k) wherein the 1- or 10- nitrogen atom of R is substituted by an aminoacyl group (the amino group of which unsub-stituted, or substituted by one or two alkyl groups, which comprises reacting a corresponding haloacyl compound with ammonia or a mono-or dialkylamine;
(1) wherein the 1- or 10- nitrogen atom of R forms part of a heterocyclic 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 group (which may be interrupted by O or S) or a cyclic group bearing two monovalent alkylene groups; or (m) wherein the 1- or 10- nitrogen atom or R is substituted by an aliphatic or araliphatic group, which comprises reducing the corresponding compound in which the said nitrogen atom is linked to said group by a double bond.
The products have been found to possess antiviral activity.

Description

~ 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 ~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, 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, ~ ~ 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 ~ 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 ~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 ~ 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 .

. ~ , ~ 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 ' 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.

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 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.

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,~
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~1 ~ I ~ O ~ _l P~

~i ~ ~ l 1~ . _ ._ ~
r~
~ ~ l~
æ ~ ) ~ _ _ _ . ", , ~, ', . ~ a~
~ æ
_ _~

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~

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%.

(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~.

~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%).

~ ~ 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%.

~ 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 . .

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 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) 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.

~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 ~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.

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 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.

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 .

~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 , 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, ~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.

. , `
. .

Claims (13)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for the preparation of 7,7-dimethyl-[2,2,1]-bicyclo-heptanes of the formula III

and the physiologically acceptable salts thereof, wherein R is a group -NR1R2 or -CH2NR1R2 in which the methylene group is unsubstituted or substituted by a C1-6 alkyl group; R1 and R2, which may be the same or different, are hydrogen atoms or C1-6 alkyl, C1-6 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 saturated 5- or 6- membered heterocyclic group which can additionally contain N, O or S in the ring and are unsubstituted or substituted by a C1-6 alkyl group or fused 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 .alpha.-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;
(d) wherein the 1- or 10- nitrogen atom of R is substituted by a benzylidene group, condensing the corresponding primary amine with benzaldehyde;

(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 aminomethyl group in which one of the hydrogen atoms on the methyl carbon atom is substituted, which comprises reducing the corresponding 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 corresponding primary or secondary amine with a compound of the formula R5X
where R5 is an alkyl, alkenyl or phenylalkyl group and X is a readily eliminatable group;
(h) wherein R is an aminomethyl group in which the methyl group is substituted, which comprises reducing the corresponding substituted 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;
(j) wherein the 1- or 10- nitrogen atom of R forms part of a heterocyclic 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 group (which may be 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 phenyl-alkyl group, which comprises reducing the corresponding compound in which the said nitrogen atom is linked to said group by a double bond.

2. A process as claimed in claim 1 wherein R in the compound produced is a substituted amino group.

3. A process as claimed in claim 1 wherein R in the compound produced is a substituted aminomethyl group.

4. A process as claimed in claim 1 wherein R in the compound produced is a group in which the nitrogen atom forms part of a saturated 5 or 6 membered heterocyclic ring which may contain a second hetero atom selected from nitrogen, oxygen or sulphur.

5. A process as claimed in parts (a), (g) or (j) of claim 1 wherein, in the compound produced, R is a mono- or dialkyl- or alkenyl- aminomethyl or wherein the nitrogen atom of R forms part of a saturated 5 or 6 membered heterocyclic ring which may contain O, S or N as a second hetero atom.

6. A process as claimed in parts (a), (f) or (g) of claim 1 wherein R, in the compound produced, is a monomethyl-, monoethyl-, dimethyl-, diethyl, monoallyl- or mono-n-butylaminomethyl group or a 4-methylpiperazinomethyl, morpholinomethyl, piperidino- methyl, or 1-aminoethyl group.

7. A process as claimed in part (j) of claim 1 wherein R in the compound produced is an isoindolinomethyl group.

8. A process as claimed in parts (a), (b) or (c) of claim 1 wherein R
in the compound produced is a methyl-, ethyl- or dimethylamino group.

9. A compound of the formula III as defined in claim 1 or a physiologi-cally acceptable salt thereof, whenever prepared by the process of claim 1 or by an obvious chemical equivalent thereof.

10. A process according to claim 1 in which 10-allylaminobornane and its hydrobromide and hydrochloride are prepared by reacting 10-bornamine with allyl bromide in the presence of a base, and when the hydrobromide or hydro-chloride is required reacting the 10-allylaminobornane so obtained with hydrogen bromide or hydrogen chloride.

11. 10-Allylaminobornane and its hydrobromide and hydrochloride whenever prepared by the process of claim 10 or by an obvious chemical equivalent thereof.

12. A process according to claim 1 in which 7,7-dimethyl-1-morpholino-norbornane and its hydrochloride are prepared by reacting 1-amino-7,7-dimethylnorbornane with 2,2'-dichlorodiethyl ether and when the hydrochloride is required reacting the base so obtained with hydrogen chloride.

13. 7,7-Dimethyl-1-morpholinonorbornane and its hydrochloride whenever prepared by the process of claim 12 or by an obvious chemical equivalent thereof.